[go: up one dir, main page]

WO2006015261A2 - Nucleoside phosphonate conjugates as anti hiv agents - Google Patents

Nucleoside phosphonate conjugates as anti hiv agents Download PDF

Info

Publication number
WO2006015261A2
WO2006015261A2 PCT/US2005/027088 US2005027088W WO2006015261A2 WO 2006015261 A2 WO2006015261 A2 WO 2006015261A2 US 2005027088 W US2005027088 W US 2005027088W WO 2006015261 A2 WO2006015261 A2 WO 2006015261A2
Authority
WO
WIPO (PCT)
Prior art keywords
conjugate
formula
groups
independently
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2005/027088
Other languages
French (fr)
Other versions
WO2006015261A3 (en
Inventor
Constantine G. Boojamra
Kuei-Ying Lin
Richard L. Mackman
David Y. Markevitch
Oleg V. Petrakovsky
Adrian S. Ray
Lijun Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gilead Sciences Inc
Original Assignee
Gilead Sciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to KR1020077004803A priority Critical patent/KR101233823B1/en
Priority to HK07111940.1A priority patent/HK1103648B/en
Priority to DE602005021506T priority patent/DE602005021506D1/en
Priority to MX2007001059A priority patent/MX2007001059A/en
Priority to AU2005267800A priority patent/AU2005267800B2/en
Priority to AT05777315T priority patent/ATE469163T1/en
Priority to HR20070079A priority patent/HRP20070079A2/en
Priority to NZ553406A priority patent/NZ553406A/en
Priority to US11/658,628 priority patent/US8329926B2/en
Priority to JP2007523866A priority patent/JP4954877B2/en
Priority to EP05777315A priority patent/EP1778249B1/en
Priority to PL382843A priority patent/PL230036B1/en
Priority to EA200700362A priority patent/EA019559B1/en
Priority to UAA200701991A priority patent/UA91688C2/en
Priority to CN2005800325568A priority patent/CN101031306B/en
Priority to AP2007003899A priority patent/AP2629A/en
Priority to CA2574121A priority patent/CA2574121C/en
Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Priority to BRPI0512683-5A priority patent/BRPI0512683A/en
Publication of WO2006015261A2 publication Critical patent/WO2006015261A2/en
Publication of WO2006015261A3 publication Critical patent/WO2006015261A3/en
Priority to IL180758A priority patent/IL180758A/en
Priority to IS8595A priority patent/IS8595A/en
Anticipated expiration legal-status Critical
Priority to ZA2007/01466A priority patent/ZA200701466B/en
Priority to NO20071078A priority patent/NO339020B1/en
Priority to US13/626,687 priority patent/US8697861B2/en
Priority to US14/178,237 priority patent/US9457035B2/en
Priority to US15/254,684 priority patent/US20170088576A1/en
Priority to NO20161521A priority patent/NO342132B1/en
Priority to US15/643,168 priority patent/US20180086784A1/en
Priority to NO20180243A priority patent/NO20180243A1/en
Priority to US16/196,075 priority patent/US20190345190A1/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/44—Amides thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the invention relates generally to compounds with HIV inhibitory activity. BACKGROUND OF THE INVENTION
  • agents currently administered to a patient parenterally are not targeted, resulting in systemic delivery of the agent to cells and tissues of the body where it is unnecessary, and often undesirable. This may result in adverse drug side effects, and often limits the dose of a drug (e.g., glucocorticoids and other anti-inflammatory drugs) that can be administered.
  • a drug e.g., glucocorticoids and other anti-inflammatory drugs
  • oral administration can result in either (a) uptake of the drug through the cellular and tissue barriers, e.g., blood/brain, epithelial, cell membrane, resulting in undesirable systemic distribution, or (b) temporary residence of the drug within the gastrointestinal tract.
  • a major goal has been to develop methods for specifically targeting agents to cells and tissues. Benefits of such treatment includes avoiding the general physiological effects of inappropriate delivery of such agents to other cells and tissues, such as uninfected cells.
  • HIV is recognized as a chronic viral disease of the liver which is characterized by liver disease.
  • drugs targeting the liver are in wide use and have shown effectiveness, toxicity and other side effects have limited their usefulness.
  • Assay methods capable of determining the presence, absence or amounts of HIV are of practical utility in the search for inhibitors as well as for diagnosing the presence of HIV.
  • Inhibitors of HIV are useful to limit the establishment and progression of infection by HIV as well as in diagnostic assays for HIV.
  • HIV therapeutic agents i.e. drugs
  • new HIV inhibitors should have fewer side effects, less complicated dosing schedules, and be orally active.
  • a less onerous dosage regimen such as one pill, once per day.
  • Intracellular targeting may be achieved by methods and compositions that allow accumulation or retention of biologically active agents inside cells.
  • the present invention provides compositions and methods for inhibition of HIV or therapeutic activity against HIV.
  • the present invention relates generally to the accumulation or retention of therapeutic compounds inside cells.
  • the invention is also related to attaining high concentrations of phosphonate molecules in liver cells.
  • Such effective targeting may be applicable to a variety of therapeutic formulations and procedures.
  • Compositions of the invention include anti- viral compounds having optionally at least one phosphonate group. Accordingly, in one embodiment, the invention provides a compound of the invention which is linked to one or more phosphonate groups.
  • the invention provides a conjugate, enantiomers thereof, or a pharmaceutically acceptable salt or solvate thereof, that is a compound of the formula A:
  • a 0 is absent, H, a bond, A 1 , A 2 or W 3 with the proviso that the conjugate includes at least one A 1 ;
  • a 1 is:
  • a 2 is:
  • a 3 is:
  • Y 1 is independently O, S, N(R X ), N(O)(R X ), N(OR X ), N(O)(OR X ), or N(N(R X )( R X ));
  • Y 2 is independently absent, a bond, O, C(R X )(R X ), N(R X ), N(O)(R X ), N(OR X ), N(0)(0R x ), N(N(R X )( R x )), -S(O) M2 -, or -S(O) M 2-S(O) M2 -; and when Y 2 joins two phosphorous atoms Y 2 can also be C(R 2 )(R 2 );
  • R x is independently absent, a bond, H, R 1 , R 2 , W 3 , a protecting group, or the formula:
  • R y is independently H, W 3 , R 2 or a protecting group
  • R 1 is independently H or alkyl of 1 to 18 carbon atoms
  • R 2 is independently H, R 1 , R 3 or R wherein each R is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring or fused rings of 3 to 12 carbon, nitrogen, and optionally oxygen, atoms, and the ring system may be substituted with 0 to 3 R 3 groups;
  • R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
  • R 3a is F, Cl, Br, I, -CN, N 3 , -NO 2 , -OR 1 or -OR 6a ;
  • R 3c is -R x , -N(R X )(R X ), -SR X , -S(O)R X , -S(O) 2 R X , -S(O)(OR X ), - S(O) 2 (OR X ), -OC(Y ] )R X , -OC(Y 1 )OR X , -OC ⁇ CNCR”) ⁇ )), -SC(Y 1 )R X , - SCCY ⁇ OR", -SCCY ⁇ CNCR ⁇ CR * )), -NCR ⁇ CCY ⁇ R*, -NCR ⁇ CQT ⁇ OR*, or -
  • R 3d is -C(Y ! )R X , -CCY ⁇ OR" or -C ⁇ R") ⁇ ));
  • R 4 is H, an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
  • R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
  • W 3 is W 4 or W 5 ;
  • W 4 is R 5 , -C(Y ⁇ R 5 , -C(Y ⁇ W 5 , -SO M2 R 5 , or -SO M2 W 5 ;
  • W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
  • W 6 is W 3 independently substituted with 0, 1 , 2, or 3 A 3 groups
  • K and K' are independently absent, a bond, or optionally substituted R y ;
  • M2 is 0, 1 or 2;
  • M12a is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12
  • M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • MIa, MIc, and MId are independently 0 or 1;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • the invention provides a compound of the formula:
  • DRUG is a compound of the formula A; nn is 1, 2, or 3;
  • K and K' are as defined above;
  • a 0 is A 1 , A 2 or W 3 with the proviso that the conjugate includes at least one A 1 ;
  • A" is:
  • a 3 is:
  • Y 1 is independently O, S, N(R X ), N(O)(R X ), N(OR X ), N(O)(OR X ), or N(N(R X )( R X ));
  • Y 2 is independently a bond, O, C(R X )(R X ), N(R X ), N(O)(R X ), N(OR X ), N(0)(0R x ), N(N(R X )( R x )), -S(O) M2 - ; or -S(O)M 2 -S(O)M 2 -; and when Y 2 joins two phosphorous atoms Y 2 can also be C(R 2 )(R 2 );
  • R x is independently H, R 1 , R 2 , W 3 , a protecting group, or the formula:
  • R y is independently H, W 3 , R 2 or a protecting group
  • R 1 is independently H or alkyl of 1 to 18 carbon atoms
  • R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups
  • R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
  • R 3a is F, Cl, Br, I, -CN, N 3, -NO 2, -OR 1 or -OR 6a ; R 31 Ms Y 1 ;
  • R 3c is -R x , -N(R X )(R X ), -SR X , -S(O)R X , -S(O) 2 R X , -S(O)(OR X ), - S(O) 2 (OR X ), -OC(Y 1 )R X , -0C(Y 1 )0R x , -OQY ⁇ XR 3 ')), -SC(Y 1 ⁇ 5 - SC(Y 1 )OR X , -SC(Y 1 )(N(R X )(R X )), -N(R X )C(Y 1 )R X , -N(R ⁇ C(Y 1 PR*, or - N(R X )C(Y 1 )(N(R X )(R X )) ;
  • R 3d is -C(Y ⁇ R*, -C(Y 1 )OR X or -C(Y 1 )(N(R X )(R X ));
  • R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
  • R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups; W 3 is W 4 or W 5 ;
  • W 4 is R 5 , -C(Y ! )R 5 , -C(Y ⁇ W 5 , -SO M2 R 5 , or -SO M2 W 5 ;
  • W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
  • W 6 is W 3 independently substituted with 0, 1, 2, or 3 A 3 groups; M2 is 0, 1 or 2;
  • M12a is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12
  • Ml 2b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12
  • MIa, MIc, and MId are independently 0 or 1;
  • K and K' are as defined above; and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • the invention provides a compound of the formulae A:
  • a 0 is A 1 ;
  • a 1 is:
  • a 3 is:
  • Y 1 is independently O, S, N(R X ), N(O)(R X ), N(OR X ), N(O)(OR X ), or N(N(R X )( R X ));
  • Y 2 is independently absent, bond, O, C(R X )(R X ), N(R X ), N(O)(R X ), N(OR X ), N(0)(0R x ), N(N(R X )( R x )), -S(0) M2 -, or -S(O) M 2-S(O) M2 -; and when
  • Y joins two phosphorous atoms Y can also be C(R )(R );
  • R x is independently H, R 2 , W 3 , a protecting group, or the formula:
  • R y is independently H, W 3 , R 2 or a protecting group;
  • R 1 is independently H or alkyl of 1 to 18 carbon atoms;
  • R 2 is independently H, R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups;
  • R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3 ° or R 3d ;
  • R 3a is F, Cl, Br, I, -CN, N 3, -NO 2, -ORi or -OR 6a ;
  • R 3b is Y 1 ;
  • R 3c is -R x , -N(R X )(R X ), -SR X , -S(O)R X , -S(O) 2 R X , -S(O)(OR X ), - S(O) 2 (OR X ), -OC(Y 1 )R X , -0C(Y 1 )0R x , -OC(Y 1 XN(R ⁇ )), -SC(Y 1 )R X , - SC(Y 1 )OR X , -SCCY ⁇ CNCR ⁇ CR )), -N(R X )C(Y 1 )R X , -N(R X )C(Y 1 )OR X , or - NCR ⁇ CCY ⁇ CN ⁇ XR ⁇ ) ;
  • R 3d is -C(Y 1 )R X , -C(Y 1 )OR X or -C(Y ⁇ (N(R 35 XR"));
  • R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
  • R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
  • R 5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R 3 groups;
  • W 3 is W 4 or W 5 ;
  • W 4 is R 5 , -C(Y ⁇ R 5 , -C(Y ⁇ W 5 , -SO 2 R 5 , or -SO 2 W 5 ;
  • W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
  • W 6 is W 3 independently substituted with 0, 1, 2, or 3 A 3 groups
  • K and K' are as defined above; M2 is 0, 1 or 2;
  • M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • MIa, MIc, and MId are independently 0 or 1;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • Bioavailability is the degree to which the pharmaceutically active agent becomes available to the target tissue after the agent's introduction into the body. Enhancement of the bioavailability of a pharmaceutically active agent can provide a more efficient and effective treatment for patients because, for a given dose, more of the pharmaceutically active agent will be available at the targeted tissue sites.
  • phosphonate and “phosphonate group” include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double-bonded to a heteroatom , 3) single-bonded to a heteroatom, and 4) single-bonded to another heteroatom, wherein each heteroatom can be the same or different.
  • phosphonate and “phosphonate group” also include functional groups or moieties that comprise a phosphorous in the same oxidation state as the phosphorous described above, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having the characteriatics described above.
  • the terms “phosphonate” and “phosphonate group” include phosphonic acid, phosphonic monoester, phosphonic diester, phosphonamidate, and phosphonthioate functional groups.
  • the terms “phosphonate” and “phosphonate group” include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, T) double- bonded to an oxygen, 3) single-bonded to an oxygen, and 4) single-bonded to another oxygen, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having such characteriatics.
  • the terms "phosphonate” and “phosphonate group” include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double-bonded to an oxygen, 3) single-bonded to an oxygen or nitrogen, and 4) single-bonded to another oxygen or nitrogen, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having such characteriatics.
  • prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s).
  • a prodrug is thus a covalently modified analog or latent form of a therapeutically- active compound.
  • Prodrug moiety refers to a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in A Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191).
  • Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases.
  • Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy.
  • a prodrug moiety may include an active metabolite or drug itself.
  • the acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sd. 72: 324; also US Patent Nos.
  • acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability.
  • a close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention.
  • the phosphonate group may be a phosphonate prodrug moiety.
  • the prodrug moiety may be sensitive to hydrolysis, such as, but not limited to a pivaloyloxymethyl carbonate (POC) or POM group.
  • the prodrug moiety may be sensitive to enzymatic potentiated cleavage, such as a lactate ester or a phosphonamidate-ester group.
  • Aryl esters of phosphorus groups, especially phenyl esters, are reported to enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem. 37: 498).
  • Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109- 4115). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ort/z ⁇ -or/> ⁇ r ⁇ -position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g., esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C-O bond to generate the phosphoric acid and the quinone methide intermediate.
  • enzymes e.g., esterases, oxidases, etc.
  • prodrugs examples include Mitchell et al. (1992) J. Chem. Soc. Perkin Trans. /72345; Glazier WO 91/19721. Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier WO 91/19721). Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterif ⁇ ed with an acyl group or combined with another thiol group to form a disulfide.
  • Protecting group refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole.
  • Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry. Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion.
  • Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools.
  • Chemically protected intermediates may themselves be biologically active or inactive.
  • Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs.
  • Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug.
  • Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g., alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
  • any reference to any of the compounds of the invention also includes a reference to a physiologically acceptable salt thereof.
  • physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX 4 + (wherein X is C 1 -C 4 alkyl).
  • Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • Physiologically acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX 4 + (wherein X is independently selected from H or a C 1 -C 4 alkyl group).
  • salts of active ingredients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base.
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
  • Alkyl is Ci -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1- propyl Oa-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1- butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l -propyl (i-Bu, i-butyl, - CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2- propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH3), 2-pentyl (n
  • Alkynyl is C2-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples include, but are not limited to, acetylenic (-C ⁇ CH) and propargyl (-CH 2 CsCH),
  • Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • Typical alkylene radicals include, but are not limited to, methylene (-CH 2 -) 1,2-ethyl (-CH 2 CH 2 -), 1,3- ⁇ ro ⁇ yl (-CH 2 CH 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • Alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2- 18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2- 18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
  • Aryl means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • “Arylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, , naphthylmethyl, 2-naphthylethan-l- yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like.
  • the arylalkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
  • Substituted alkyl mean alkyl, aryl, and arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent.
  • Heterocycle as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.
  • “heterocycle” includes a "carbocycle” as defined herein, wherein one or more ⁇ e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom ⁇ e.g. O, N, or S).
  • heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinol
  • carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5- pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3- pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1- pyrazolyl, and 1-piperidinyl.
  • Carbocycle refers to a saturated, unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
  • Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
  • Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as abicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as abicyclo [5,6] or [6,6] system.
  • Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1- cyclopent-1-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1- cyclohex-1-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
  • Linker refers to a chemical moiety comprising a covalent bond or a chain or group of atoms that covalently attaches aphosphonate group to a drug.
  • Linkers include portions of substituents A 1 and A 3 , which include moieties such as: repeating units of alkyloxy (e.g., polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
  • the term “chiral” refers to molecules which have the property of non- superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • treatment or “treating,” to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
  • d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • racemic mixture and racemate refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • protecting groups include prodrug moieties and chemical protecting groups.
  • Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group "PG" will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. The PG groups do not need to be, and generally are not, the same if the compound is substituted with multiple PG. hi general, PG will be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency.
  • protecting groups for -OH groups include "ether- or ester- 5 027088
  • Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein. However, some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below.
  • Ester-forming groups include: (1) phosphonate ester-forming groups, such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and pliosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3) sulphur ester-forming groups, such as sulphonate, sulfate, and sulfmate.
  • the optional phosphonate moieties of the compounds of the invention may or may not be prodrug moieties, i.e. they may or may be susceptible to hydrolytic or enzymatic cleavage or modification. Certain phosphonate moieties are stable under most or nearly all metabolic conditions. For example, a dialkylphosphonate, where the alkyl groups are two or more carbons, may have appreciable stability in vivo due to a slow rate of hydrolysis.
  • phosphonate prodrug moieties a large number of structurally-diverse prodrugs have been described for phosphonic acids (Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997) and are included within the scope of the present invention.
  • An exemplary phosphonate ester-forming group is the phenyl carbocycle in substructure A 3 having the formula:
  • R 1 may be H or C 1 -C 12 alkyl; ml is 1, 2, 3, 4, 5, 6, 7 or 8, and the phenyl carbocycle is substituted with 0 to 3 R 2 groups.
  • Y 1 is O, a lactate ester is formed, and where Y 1 is N(R 2 ), N(OR 2 ) or N(N(R 2 ) 2 , a phosphonamidate ester results.
  • a protecting group typically is bound to any acidic group such as, by way of example and not limitation, a -CO2H or
  • R x for example includes the enumerated ester groups of WO 95/07920.
  • protecting groups include: C3-C12 heterocycle (described above) or aryl. These aromatic groups optionally are polycyclic or monocyclic.
  • Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4- pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and 5-pyrimidinyl,
  • Such groups include 2-, 3- and 4-alkoxyphenyl (C1-C12 alkyl), 2-, 3- and 4- methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5- diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4- hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6- hydroxyphenyl, 2-, 3- and 4-O-acetylphenyl, 2-, 3- and 4-dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4-halophenyl (including 2-, 3- and 4-fluorophenyl and 2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-,
  • esters of 2-carboxyphenyl and C1-C4 alkylene-C 3 -C6 aryl (including benzyl, - CH2-pyrrolyl, -CH2-thienyl, -CH2-imidazolyl, -CH2-oxazolyl, -CH2-isoxazolyl, -CH2-thiazolyl, -CH 2 -isotliiazolyl, -CH 2 -pyrazolyl, -CH2-pyridinyl and -CH 2 - pyrimidinyl) substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen, C1-C12 alkoxy (including methoxy and ethoxy), cyano, nitro, OH, C1-C12 haloalkyl (1 to 6 halogen atoms; including - CH2CCI3), C1-C12 alkyl (including methyl and ethy
  • hydroxyl groups of the compounds of this invention optionally are substituted with one of groups III, IV or V disclosed in WO 94/21604, or with isopropyl.
  • Table A lists examples of protecting group ester moieties that for example can be bonded via oxygen to -C(O)O- and -P(0)(0-) 2 groups.
  • amidates also are shown, which are bound directly to -C(O)- or -P(0)2- Esters of structures 1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting the compound herein having a free hydroxyl with the corresponding halide (chloride or acyl chloride and the like) and N ⁇ -dicyclohexyl-N-morpholine carboxamidine (or another base such as DBU, triethylamine, CsCO 3 , N,N-dimethylaniline and the like) in DMF (or other solvent such as acetonitrile or N-methylpyrrolidone).
  • the esters of structures 5-7, 11, 12, 21, and 23-26 are synthesized by reaction of the alcohol or alkoxide salt (or the corresponding amines in the case of compounds such as 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate (or another activated phosphonate).
  • # - chiral center is (R), (S) or racemate.
  • esters that are suitable for use herein are described in EP 632048.
  • Protecting groups also includes "double ester" forming profunctionalities
  • alkyl- or aryl-acyloxyalkyl groups of the structure -CH(R 1 or W 5 )O((CO)R 37 ) or -CH(R 1 or W 5 X(CO)OR 38 ) (linked to oxygen of the acidic group) wherein R 37 and R 38 are alkyl, aryl, or alkylaryl groups (see U.S. Patent No. 4968788).
  • R 37 and R 38 are bulky groups such as branched alkyl, ortho- substituted aryl, meta-substituted aryl, or combinations thereof, including normal, secondary, iso- and tertiary alkyls of 1-6 carbon atoms.
  • An example is the pivaloyloxymethyl group.
  • Such useful protecting groups are alkylacyloxymethyl esters and their derivatives, including -
  • the protected acidic group is an ester of the acidic group and is the residue of a hydroxyl-containing functionality.
  • an amino compound is used to protect the acid functionality.
  • the residues of suitable hydroxy! or amino-containing functionalities are set forth above or are found in WO 95/07920.
  • residues of amino acids, amino acid esters, polypeptides, or aryl alcohols are described on pages 11-18 and related text of WO 95/07920 as groups Ll or L2.
  • WO 95/07920 expressly teaches the amidates of phosphonic acids, but it will be understood that such amidates are formed with any of the acid groups set forth herein and the amino acid residues set forth in WO 95/07920.
  • Typical esters for protecting acidic functionalities are also described in WO 95/07920, again understanding that the same esters can be formed with the acidic groups herein as with the phosphonate of the '920 publication.
  • Typical ester groups are defined at least on WO 95/07920 pages 89-93 (under R ⁇ 1 or
  • esters of unsubstituted aryl such as phenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy- and/or alkylestercarboxy-substituted aryl or alkylaryl, especially phenyl, ortho-ethoxyphenyl, or C1-C4 alkylestercarboxyphenyl (salicylate C1-C12 alkylesters).
  • the protected acidic groups are useful as prodrugs for oral administration. However, it is not essential that the acidic group be protected in order for the compounds of this invention to be effectively administered by the oral route.
  • the compounds of the invention having protected groups in particular amino acid amidates or substituted and unsubstituted aryl esters are administered systemically or orally they are capable of hydro lytic cleavage m vivo to yield the free acid.
  • One or more of the acidic hydroxyls are protected. If more than one acidic hydroxyl is protected then the same or a different protecting group is employed, e.g., the esters may be different or the same, or a mixed amidate and ester may be used.
  • Typical hydroxy protecting groups described in Greene include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters including sulfonic acid esters, and carbonates.
  • substituted methyl and alkyl ethers include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters including sulfonic acid esters, and carbonates.
  • Methyl Ethers (Methoxymethyl, Methylthiomethyl, t- Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p- Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t- Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl, 2- Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2- cliloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3-
  • Ethyl Ethers 1 -Ethoxyethyl, 1 -(2-Chloroethoxy)ethyl, 1 -Methyl- 1 -methoxyethyl, 1 -Methyl- 1 -benzyloxyethyl, 1 -Methyl- 1 -benzyloxy-2- fluoroethyl, 2,2,2-Trichloroethyl, 2-Trimethylsilylethyl, 2- (Phenylselenyl)ethyl,
  • Triphenylmethyl Triphenylmethyl, ⁇ -Naphthyldiphenylmethyl, /?- methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Tri( ⁇ - methoxyphenyl)methyl, 4-(4'-Bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-Tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"- Tris(levulinoyloxyphenyl)methyl, 4,4',4"-Tris(benzoyloxyphenyl)methyl, 3-
  • Methoxycrotonate Benzoate, />-Phenylbenzoate, 2,4,6-Trimethylbenzoate (Mesitoate));
  • Typical 1,2-diol protecting groups are described in Greene at pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1- ⁇ Butylethylidene, 1-Phenylethylidene, (4-Methoxyphenyl) ethylidene, 2,2,2- Trichloroethylidene, Acetonide (Isopropylidene), Cyclopentylidene,
  • 1,2-diol protecting groups include those shown in Table B, still more typically, epoxides, acetonides, cyclic ketals and aryl acetals.
  • R ⁇ is Cl -C6 alkyl
  • Another set of protecting groups include any of the typical amino protecting groups described by Greene at pages 315-385. They include:
  • N-Metal Derivatives iV-borane derivatives, N-diphenylborinic acid derivatives, 7V-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, N- copper or N-zinc chelate
  • N-P Derivatives (N-diphenylphospliinyl, N-dimetliylthiophosphinyl, N- diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, N- diphenyl phosphoryl); • N-Si Derivatives, N-S Derivatives, and N-Sulfenyl Derivatives: (N- benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N- pentachlorobenzenesulfenyl, N-2-nitro-4-methoxybenzenesulfenyl, N- triphenylmethylsulfenyl, N-3-nitropyridinesulfenyl); and N-sulfonyl Derivatives (N-p-toluenesulfonyl)
  • Another protecting group, also useful as a prodrug for amino or -NH(R 5 ), is:
  • An amino acid or polypeptide protecting group of a compound of the invention has the structure R 15 NHCH(R 16 )C(O)-, where R 15 is H, an amino acid or polypeptide residue, or R 5 , and R 16 is defined below.
  • R 16 is lower alkyl or lower alkyl (Ci-Ce) substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl, C 6 -C 7 aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate.
  • R 10 is generally the side group of a naturally-occurring amino acid such as H, - CH 3 , -CH(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , -CHCH 3 -CH 2 -CH 3 , -CH 2 -C 6 H 5 , -CH 2 CH 2 - S-CH 3 , -CH 2 OH, -CH(OH)-CH 3 , -CH 2 -SH, -CH 2 -C 6 H 4 OH, -CH 2 -CO-NH 2 , - CH 2 -CH 2 -CO-NH 2 , -CH 2 -COOH, -CH 2 -CH 2 -COOH, -(CH 2 ) 4 -NH 2 and - (CH 2 ) 3 -NH-C(NH 2 )-NH 2 .
  • a naturally-occurring amino acid such as H, - CH 3 , -CH(CH 3 ) 2 , -CH
  • Rio also includes l-guanidinoprop-3-yl, benzyl, A- hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.
  • Another set of protecting groups include the residue of an amino- containing compound, in particular an amino acid, a polypeptide, a protecting group, -NHSO2R NHC(O)R, -N(R)2, NH2 or -NH(R)(H) 5 whereby for example a carboxylic acid is reacted, i.e. coupled, with the amine to form an amide, as in C(O)NR 2 .
  • a phosphonic acid may be reacted with the amine to form a phosphonamidate, as in -P(O)(OR)(NR 2 ).
  • amino acids have the structure R 17 C(O)CH(R 16 )NH-, where
  • R 17 is -OH, -OR, an amino acid or a polypeptide residue.
  • Amino acids are low molecular weight compounds, on the order of less than about 1000 MW and which contain at least one amino or imino group and at least one carboxyl group. Generally the amino acids will be found in nature, i.e., can be detected in biological material such as bacteria or other microbes, plants, animals or man. Suitable amino acids typically are alpha amino acids, i.e. compounds characterized by one amino or imino nitrogen atom separated from the carbon atom of one carboxyl group by a single substituted or unsubstituted alpha carbon atom.
  • hydrophobic residues such as mono-or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the partition coefficient of the parental drug. Typically, the residue does not contain a sulfhydryl or guanidino substituent.
  • Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof. Polypeptides most typically will be substantially composed of such naturally- occurring amino acid residues.
  • amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline.
  • unnatural amino acids for example, valanine, phenylglycine and homoarginine are also included.
  • Commonly encountered amino acids that are not gene- encoded may also be used in the present invention. All of the amino acids used in the present invention may be either the D- or L- optical isomer.
  • any site in the parental molecule is amidated with an amino acid as described herein, although it is within the scope of this invention to introduce amino acids at more than one permitted site.
  • a carboxyl group of R 3 is amidated with an amino acid.
  • the ⁇ -amino or ⁇ -carboxyl group of the amino acid or the terminal amino or carboxyl group of a polypeptide are bonded to the parental functionalities, i.e., carboxyl or amino groups in the amino acid side chains generally are not used to form the amide bonds with the parental compound (although these groups may need to be protected during synthesis of the conjugates as described further below).
  • carboxyl-containing side chains of amino acids or polypeptides it will be understood that the carboxyl group optionally will be blocked, e.g., by R 1 , esterified with R 5 or amidated. Similarly, the amino side chains R 16 optionally will be blocked with R 1 or substituted with R 5 .
  • esters or amide bonds with side chain amino or carboxyl groups like the esters or amides with the parental molecule, optionally are hydrolyzable in vivo or in vitro under acidic (pH ⁇ 3) or basic (pH >10) conditions. Alternatively, they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments.
  • the esters or amino acid or polypeptide amidates also are useful as intermediates for the preparation of the parental molecule containing free amino or carboxyl groups.
  • the free acid or base of the parental compound for example, is readily formed from the esters or amino acid or polypeptide conjugates of this invention by conventional hydrolysis procedures.
  • any of the D, L, meso, threo or erythro (as appropriate) racemates, scalemates or mixtures thereof may be used.
  • D isomers are useful.
  • L isomers are more versatile since they can be susceptible to both non-enzymatic and enzymatic hydrolysis, and are more efficiently transported by amino acid or dipeptidyl transport systems in the gastrointestinal tract.
  • suitable amino acids whose residues are represented by R x or R y include the following: Glycine;
  • Aminopolycarboxylic acids e.g., aspartic acid, ⁇ -hydroxyaspartic acid, glutamic acid, ⁇ -hydroxyglutamic acid, ⁇ -methylaspartic acid, ⁇ -methylglutamic acid, ⁇ , ⁇ -dimethylaspartic acid, ⁇ -hydroxyglutamic acid, ⁇ , ⁇ -dihydroxyglutamic acid, ⁇ -phenylglutamic acid, ⁇ -methyleneglutamic acid, 3-aminoadipic acid, 2- aminopimelic acid, 2-aminosuberic acid and 2-aminosebacic acid; Amino acid amides such as glutamine and asparagine;
  • Polyamino- or polybasic-nionocarboxylic acids such as arginine, lysine, ⁇ -aminoalanine, ⁇ -aminobutyrine, ornithine, citruline, homoarginine, homocitruUine, hydroxylysine, allohydroxylsine and diaminobutyric acid;
  • Diaminodicarboxylic acids such as ⁇ , ⁇ '-diaminosuccinic acid, ⁇ , ⁇ '- diaminoglutaric acid, ⁇ , ⁇ '-diaminoadipic acid, ⁇ , ⁇ '-diaminopimelic acid, ⁇ , ⁇ 1 - diamino- ⁇ -hydroxypimelic acid, ⁇ , ⁇ '-diaminosuberic acid, ⁇ , ⁇ '-diaminoazelaic acid, and ⁇ , ⁇ '-diaminosebacic acid;
  • Imino acids such as proline, hydroxyproline, allohydroxyproline, ⁇ - methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2- carboxylic acid;
  • a mono- or di-alkyl (typically Ci-Cs branched or normal) amino acid such as alanine, valine, leucine, allylglycine, butyrine, norvaline, norleucine, heptyline, ⁇ -methylserine, ⁇ -amino- ⁇ -methyl- ⁇ -hydroxyvaleric acid, ⁇ -amino- ⁇ - methyl- ⁇ -hydroxyvaleric acid, ⁇ -amino- ⁇ -methyl- ⁇ -hydroxycaproic acid, isovaline, ⁇ -methylglutamic acid, ⁇ -aminoisobutyric acid, ⁇ -aminodiethylacetic acid, ⁇ -aminodiisopropylacetic acid, a-aminodi-n-propylacetic acid, ⁇ - aminodiisobutylacetic acid, ⁇ -aminodi-n-butylacetic acid, ⁇ - aminoethylisopropylacetic acid, ⁇ -a
  • Aliphatic ⁇ -amino- ⁇ -hydroxy acids such as serine, ⁇ -hydroxyleucine, ⁇ - hydroxynorleucine, ⁇ -hydroxynorvaline, and ⁇ -amino- ⁇ -hydroxystearic acid; ⁇ -Amino, ⁇ -, ⁇ -, ⁇ - or ⁇ -hydroxy acids such as homoserine, ⁇ - hydroxynorvaline, ⁇ -hydroxynorvaline and ⁇ -hydroxynorleucine residues; canavine and canaline; ⁇ -hydroxyornithine; 2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminic acid; ⁇ -Amino- ⁇ -thiols such as penicillamine, ⁇ -thiolnorvaline or ⁇ - thiolbutyrine; Other sulfur containing amino acid residues including cysteine; homocystine, ⁇ -phenylmethionine, methionine, S
  • Phenylalanine, tryptophan and ring-substituted ⁇ -amino acids such as the phenyl- or cyclohexylamino acids ⁇ -aminophenylacetic acid, ⁇ - aminocyclohexylacetic acid and ⁇ -amino- ⁇ -cyclohexylpropionic acid; phenylalanine analogues and derivatives comprising aryl, lower alkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-, 3,4-dichloro, o ⁇ , m- or ⁇ -methyl-, 2,4,6- trimethyl-, 2-ethoxy-5-nitro-, 2-hydroxy-5 -nitro- and p-nitro-phenylalanine); furyl-, thienyl-,
  • Polypeptides are polymers of amino acids in which a carboxyl group of one amino acid monomer is bonded to an amino or imino group of the next amino acid monomer by an amide bond.
  • Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000 MW) and proteins. Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, and suitably are substantially sequence-homologous with human, animal, plant or microbial proteins. They include enzymes (e.g., hydrogen peroxidase) as well as immunogens such as KLH, or antibodies or proteins of any type against which one wishes to raise an immune response. The nature and identity of the polypeptide may vary widely.
  • polypeptide amidates are useful as immunogens in raising antibodies against either the polypeptide (if it is not immunogenic in the animal to which it is administered) or against the epitopes on the remainder of the compound of this invention.
  • Antibodies capable of binding to the parental non-peptidyl compound are used to separate the parental compound from mixtures, for example in diagnosis or manufacturing of the parental compound.
  • the conjugates of parental compound and polypeptide generally are more immunogenic than the polypeptides in closely homologous animals, and therefore make the polypeptide more immunogenic for facilitating raising antibodies against it. Accordingly, the polypeptide or protein may not need to be immunogenic in an animal typically used to raise antibodies, e.g., rabbit, mouse, horse, or rat, but the final product conjugate should be immunogenic in at least one of such animals.
  • the polypeptide optionally contains a peptidolytic enzyme cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatom. Such cleavage sites are flanked by enzymatic recognition structures, e.g., a particular sequence of residues recognized by a peptidolytic enzyme.
  • Peptidolytic enzymes for cleaving the polypeptide conjugates of this invention are well known, and in particular include carboxypeptidases.
  • Carboxypeptidases digest polypeptides by removing C-terminal residues, and are specific in many instances for particular C-terminal sequences.
  • Such enzymes and their substrate requirements in general are well known.
  • a dipeptide (having a given pair of residues and a free carboxyl terminus) is covalently bonded through its ⁇ -amino group to the phosphorus or carbon atoms of the compounds herein.
  • Wl is phosphonate it is expected that this peptide will be cleaved by the appropriate peptidolytic enzyme, leaving the carboxyl of the proximal amino acid residue to autocatalytically cleave the phosplionoamidate bond.
  • Suitable dipeptidyl groups are AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, C
  • Tripeptide residues are also useful as protecting groups.
  • the sequence -X -pro-X 5 - (where X is any amino acid residue and X 5 is an amino acid residue, a carboxyl ester of proline, or hydrogen) will be cleaved by luminal carboxypeptidase to yield X 4 with a free carboxyl, which in turn is expected to autocatalytically cleave the phosphonoamidate bond.
  • the carboxy group of X 5 optionally is esterified with benzyl.
  • Dipeptide or tripeptide species can be selected on the basis of known transport properties and/or susceptibility to peptidases that can affect transport to intestinal mucosal or other cell types.
  • Dipeptides and tripeptides lacking an ⁇ - amino group are transport substrates for the peptide transporter found in brush border membrane of intestinal mucosal cells (Bai, J.P.F., (1992) Pharm Res. 9:969-978).
  • Transport competent peptides can thus be used to enhance bioavailability of the amidate compounds.
  • Di- or tripeptides having one or more amino acids in the D configuration are also compatible with peptide transport and can be utilized in the amidate compounds of this invention.
  • Amino acids in the D configuration can be used to reduce the susceptibility of a di- or tripeptide to hydrolysis by proteases common to the brush border such as aminopeptidase N.
  • di- or tripeptides alternatively are selected on the basis of their relative resistance to hydrolysis by proteases found in the lumen of the intestine.
  • tripeptides or polypeptides lacking asp and/or glu are poor substrates for aminopeptidase A
  • di- or tripeptides lacking amino acid residues on the N-terminal side of hydrophobic amino acids are poor substrates for endopeptidase
  • peptides lacking a pro residue at the penultimate position at a free carboxyl terminus are poor substrates'for carboxypeptidase P.
  • Similar considerations can also be applied to the selection of peptides that are either relatively resistant or relatively susceptible to hydrolysis by cytosolic, renal, hepatic, serum or other peptidases.
  • Such poorly cleaved polypeptide amidates are immunogens or are useful for bonding to proteins in order to prepare immunogens.
  • a 1 is of the formula:
  • a 1 is of the formula:
  • a 1 is of the formula:
  • a 1 is of the formula:
  • W 5a is a carbocycle or a heterocycle where W 5a is independently substituted with 0 or 1 R 2 groups.
  • a specific value for M12a is 1.
  • a 1 is of the formula:
  • a 1 is of the formula:
  • a 1 is of the formula:
  • W 5a is a carbocycle independently substituted with 0 or 1 R 2 groups;
  • a 1 is of the formula:
  • a 1 is of the formula:
  • a 1 is of the formula:
  • W 5a is a carbocycle or heterocycle where W 5a is independently substituted with 0 or 1 R groups.
  • a 1 is of the formula:
  • Y r2 / b D is O or N(R Z ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 2 is of the formula:
  • M 12b is 1.
  • M 12b is 0, Y 2 is a bond and W 5 is a carbocycle or heterocycle where W 5 is optionally and independently substituted with 1, 2, or 3 R groups.
  • a 2 is of the formula:
  • W 5a is a carbocycle or heterocycle where W 5a is optionally and independently substituted with 1 , 2, or 3 R groups.
  • M 12a is 1.
  • a 2 is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl and substituted pyridyl.
  • a 2 is of the formula:
  • a 2 is of the formula:
  • Ml 2b is 1. hi a specific embodiment of the invention A is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • M12d wherein Y 2b is O or N(R X ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 3 is of the formula:
  • M12d wherein Y 2b is O or N(R X ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • M12d is 1.
  • a 3 is of the formula:
  • a 3 is of the formula:
  • W 5 is a carbocycle.
  • a 3 is of the formula:
  • W 5 is phenyl
  • a 3 is of the formula:
  • Y la is O or S; and Y 2a is O, N(R X ) or S.
  • a 3 is of the formula: wherein Y 2 Ms O or N(R X ).
  • a 3 is of the formula:
  • Y 2b is O or N(R X ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • R 1 is H.
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • Y 2b is O or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 3 is of the formula:
  • Y 2b is O or N(R 2 ).
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • Y la is O or S
  • Y 2b is O or N(R 2 );
  • Y 2c is O, N(R y ) or S.
  • a 3 is of the formula:
  • a 3 is of the formula:
  • Y 2b is O or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 3 is of the formula:
  • Y 2b is O or N(R 2 ).
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 0 is of the formula: wherein each R is independently (C 1 -C 6 )EIlCyI.
  • R x is independently H, R 1 , W 3 , a protecting group, or the formula:
  • R y is independently H, W 3 , R 2 or a protecting group
  • R 1 is independently H or alkyl of 1 to 18 carbon atoms
  • R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R groups or taken together at a carbon atom, two R groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups; wherein R 3 is as defined herein.
  • Y la is O or S; and Y 2c is O, N(R y ) or S.
  • R x is of the formula: wherein Y la is O or S; and Y 2d is O or N(R y ).
  • R y is hydrogen or alkyl of 1 to 10 carbons.
  • R x is of the formula:
  • Y 1 is O or S
  • Y 2 is O, N(R y ) or S.
  • ml a, mlb, mlc, mid and mle are independently 0 or 1; ml2c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • R y is H, W 3 , R 2 or a protecting group; wherein W 3 , R 2 , Y 1 and Y 2 are as defined herein; provided that: if mla, ml2c, and mid are 0, then mlb, mlc and mle are 0; if mla and ml2c are 0 and mid is not 0, then mlb and mlc are 0; if mla and mid are 0 and ml2c is not 0, then mlb and at least one of mlc and mle are 0; if mla is 0 and ml2c and mid are not 0, then mlb is 0; if ml 2c and mid are 0 and mla is not 0, then at least two of mlb, mlc and mle are 0; if ml2c is 0 and mla and mid are not 0, then at least one of mlb and mlc
  • W 5 carbocycles and W 5 heterocycles may be independently substituted with 0 to 3 R 2 groups.
  • W 5 may be a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle.
  • W 5 may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms.
  • the W 5 rings are saturated when containing 3 ring atoms, saturated or mono-unsaturated when containing 4 ring atoms, saturated, or mono- or di-unsaturated when containing 5 ring atoms, and saturated, mono- or di-unsaturated, or aromatic when containing 6 ring atoms.
  • a W 5 heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S).
  • W 5 heterocyclic monocycles may have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S).
  • W 5 heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system.
  • the W 5 heterocycle may be bonded to Y 2 through a carbon, nitrogen, sulfur or other atom by a stable covalent bond.
  • W 5 heterocycles include for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isotliiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl.
  • W 5 also includes, but is not limited to, examples such as:
  • W carbocycles and heterocycles may be independently substituted with 0 to 3 R 2 groups, as defined above.
  • substituted W 5 carbocycles include:
  • substituted phenyl carbocycles include:
  • conjugates that comprise an HIV inhibiting compound that is optionally linked to one or more phosphonate groups either directly (e.g. through a covalent bond) or through a linking group (i.e. a linker).
  • the nature of the linker is not critical provided it does not interfere with the ability of the phosphonate containing compound to function as a therapeutic agent.
  • the phosphonate or the linker can be linked to the compound (e.g. a compound of formula A) at any synthetically feasible position on the compound by removing a hydrogen or any portion of the compound to provide an open valence for attachment of the phosphonate or the linker.
  • the linking group or linker (which can be designated "L”) can include all or a portions of the group A 0 , A 1 , A 2 , or
  • the linking group or linker has a molecular weight of from about 20 daltons to about 400 daltons. In another embodiment of the invention the linking group or linker has a length of about 5 angstroms to about 300 angstroms.
  • the linking group or linker is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 2 to 25 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-), and wherein the chain is optionally substituted on carbon with one or more (e.g.
  • the linking group or linker is of the formula W-A wherein A is (d-C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 -C 24 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 6 -C !
  • the linking group or linker is a divalent radical formed from a peptide.
  • the linking group or linker is a divalent radical formed from an amino acid.
  • the linking group or linker is a divalent radical formed from poly-L-glutamic acid, poly-L-aspartic acid, poly-L- histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine- L-tyrosine.
  • the linking group or linker is methylene, ethylene, or propylene.
  • linking group or linker is attached to the phosphonate group through a carbon atom of the linker.
  • the optionally incorporated phosphonate group of the compounds of the invention may cleave in vivo in stages after they have reached the desired site of action, i.e. inside a cell.
  • One mechanism of action inside a cell may entail a first cleavage, e.g. by esterase, to provide a negatively-charged "locked-in" intermediate. Cleavage of a terminal ester grouping in a compound of the invention thus affords an unstable intermediate which releases a negatively charged "locked in” intermediate.
  • intracellular enzymatic cleavage or modification of the phosphonate or prodrug compound may result in an intracellular accumulation of the cleaved or modified compound by a "trapping" mechanism.
  • the cleaved or modified compound may then be "locked-in" the cell by a significant change in charge, polarity, or other physical property change which decreases the rate at which the cleaved or modified compound can exit the cell, relative to the rate at which it entered as the phosphonate prodrug.
  • Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphatases.
  • the compounds of the invention include those with HIV-inliibitory activity.
  • the compounds of the inventions optionally bear one or more (e.g. 1, 2, 3, or 4) phosphonate groups, which may be a prodrug moiety.
  • HlV-inhibitory compound includes those compounds that inhibit HIV.
  • compounds of the invention have a molecular weight of from about 400 amu to about 10,000 amu; in a specific embodiment of the invention, compounds have a molecular weight of less than about 5000 amu; in another specific embodiment of the invention, compounds have a molecular weight of less than about 2500 amu; in another specific embodiment of the invention, compounds have a molecular weight of less than about 1000 amu; in another specific embodiment of the invention, compounds have a molecular weight of less than about 800 amu; in another specific embodiment of the invention, compounds have a molecular weight of less than about 600 amu; and in another specific embodiment of the invention, compounds have a molecular weight of less than about 600 amu and a molecular weight of greater than about 400 amu.
  • the compounds of the invention also typically have a logD(polarity) less than about 5.
  • the invention provides compounds having a logD less than about 4; in another one embodiment the invention provides compounds having a logD less than about 3; in another one embodiment the invention provides compounds having a logD greater than about -5; in another one embodiment the invention provides compounds having a logD greater than about -3; and in another one embodiment the invention provides compounds having a logD greater than about 0 and less than about 3.
  • R x contains a R y substituent.
  • R y can be R 2 , which in turn can be R 3 . IfR 3 is selected to be R 3c , then a second instance of R x can be selected.
  • Such properties include, by of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.
  • W 3 , R y and R 3 are all recursive substituents in certain embodiments. Typically, each of these may independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times in a given embodiment. More typically, each of these may independently occur 12 or fewer times in a given embodiment. More typically yet, W 3 will occur 0 to 8 times, R y will occur 0 to 6 times and R 3 will occur 0 to 10 times in a given embodiment.
  • the compound is in an isolated and purified form.
  • isolated and purified means that the compound is substantially free from biological materials (e.g. blood, tissue, cells, etc.).
  • the term means that the compound or conjugate of the invention is at least about 50 wt.% free from biological materials; in another specific embodiment, the term means that the compound or conjugate of the invention is at least about 75 wt.% free from biological materials; in another specific embodiment, the term means that the compound or conjugate of the invention is at least about 90 wt.% free from biological materials; in another specific embodiment, the term means that the compound or conjugate of the invention is at least about 98 wt.% free from biological materials; and in another embodiment, the term means that the compound or conjugate of the invention is at least about 99 wt.% free from biological materials. In another specific embodiment, the invention provides a compound or conjugate of the invention that has been synthetically prepared (e.g., ex vivo).
  • the invention is provides compounds capable of accumulating in human PBMC (peripheral blood mononuclear cells).
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • PBMC are critical components of the mechanism against infection.
  • PBMC may be isolated from heparmized whole blood of normal healthy donors or buffy coats, by standard density gradient centrifugation and harvested from the interface, washed ⁇ e.g. phosphate-buffered saline) and stored in freezing medium.
  • PBMC may be cultured in multi-well plates. At various times of culture, supernatant may be either removed for assessment, or cells may be harvested and analyzed (Smith R. etal (2003) Blood 102(7):2532-2540).
  • the compounds of this embodiment may
  • compounds of the invention demonstrate improved intracellular half-life of the compounds or intracellular metabolites of the compounds in human PBMC when compared to analogs of the compounds not having the phosphonate or phosphonate prodrug.
  • the half-life is improved by at least about 50%, more typically at least in the range 50-100%, still more typically at least about 100%, more typically yet greater than about 100%.
  • the intracellular half-life of a metabolite of the compound in human PBMCs is improved when compared to an analog of the compound not having the phosphonate or phosphonate prodrug.
  • the metabolite may be generated intracellularly, e.g. generated within human PBMC.
  • the metabolite may be a product of the cleavage of a phosphonate prodrug within human PBMCs.
  • the optionally phosphonate-containing phosphonate prodrug may be cleaved to form a metabolite having at least one negative charge at physiological pH.
  • the phosphonate prodrug may be enzymatically cleaved within human PBMC to form a phosphonate having at least one active hydrogen atom of the form P-OH.
  • the compounds of the invention may have chiral centers, e.g., chiral carbon or phosphorus atoms.
  • the compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers.
  • the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms.
  • the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures.
  • racemic mixtures are separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances.
  • optically active adjuncts e.g., acids or bases
  • the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
  • the compounds of the invention can also exist as tautomeric isomers in certain cases. All though only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.
  • ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
  • compositions of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na + , Li + , K + > Ca + ⁇ and Mg + ⁇ .
  • Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid.
  • Monovalent salts are preferred if a water soluble salt is desired.
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention.
  • metal salts which are prepared in this way are salts containing Li + , Na + , and K + .
  • a less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • salts may be formed from acid addition of certain organic and inorganic acids, e.g., HCl, HBr, H2SO4 5 H3PO4 or organic sulfonic acids, to basic centers, typically amines, or to acidic groups.
  • the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • the salts of the parental compounds with one or more amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • a basic or acidic group e.g., lysine, arginine or glutamic acid
  • a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • Another aspect of the invention relates to methods of inhibiting the activity of HIV comprising the step of treating a sample suspected of containing HIV with a composition of the invention.
  • compositions of the invention may act as inhibitors of HIV, as intermediates for such inhibitors or have other utilities as described below.
  • the inhibitors will generally bind to locations on the surface or in a cavity of the liver.
  • Compositions binding in the liver may bind with varying degrees of reversibility. Those compounds binding substantially irreversibly are ideal candidates for use in this method of the invention.
  • the substantially irreversibly binding compositions are useful as probes for the detection of HIV. Accordingly, the invention relates to methods of detecting NS3 in a sample suspected of containing HIV comprising the steps of: treating a sample suspected of containing HIV with a composition comprising a compound of the invention bound to a label; and observing the effect of the sample on the activity of the label.
  • Suitable labels are well known in the diagnostics field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens.
  • the compounds herein are labeled in conventional fashion using functional groups such as hydroxyl or amino.
  • samples suspected of containing HIV include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like.
  • biological material samples blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like
  • laboratory samples food, water, or air samples
  • bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like.
  • sample will be suspected of containing HIV.
  • Samples can be contained in any medium including water and organic solvent/water mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures.
  • the treating step of the invention comprises adding the composition of the invention to the sample or it comprises adding a precursor of the composition to the sample.
  • the addition step comprises any method of administration as described above.
  • the activity of HTV after application of the composition can be observed by any method including direct and indirect methods of detecting HIV activity. Quantitative, qualitative, and semiquantitative methods of determining HW activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
  • the compounds of this invention are useful in the treatment or prophylaxis of conditions associated with HIV activation in animals or in man.
  • compositions of the invention are screened for inhibitory activity against HIV by any of the conventional techniques for evaluating enzyme activity.
  • typically compositions are first screened for inhibition of HIV in vitro and compositions showing inhibitory activity are then screened for activity in vivo.
  • Compositions having in vitro Ki (inhibitory constants) of less then about 5 X 10"6 M, typically less than about I X lO- 7 M and preferably less than about 5 X 10" ⁇ M are preferred for in vivo use.
  • Ki inhibitory constants
  • the compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice.
  • Tablets will contain excipients, glidants, fillers, binders and the like.
  • Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic.
  • AU formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • the pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
  • the formulations both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • a tablet is made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
  • the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
  • compositions according to the present invention comprise one or more compounds of the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • binding agents such as cellulose, microcrystalline cellulose, starch,
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g.
  • polyoxyethylene stearate polyoxyethylene stearate
  • a condensation product of ethylene oxide with a long chain aliphatic alcohol e.g., heptadecaethyleneoxycetanol
  • a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride e.g., polyoxyethylene sorbitan monooleate
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
  • a dispersing or wetting agent e.g., sodium tartrate
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • sweetening agents such as glycerol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic
  • a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weightweight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • Formulations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • Suitable formulations include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of conditions associated with HIV activity.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • Compounds of the invention can also be formulated to provide controlled release of the active ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, the invention also provided compositions comprising one or more compounds of the invention formulated for sustained or controlled release.
  • Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day. Typically, from about 0.01 to about 10 mg/kg body weight per day. More typically, from about .01 to about 5 mg/kg body weight per day. More typically, from about .05 to about 0.5 mg/kg body weight per day.
  • the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.
  • One or more compounds of the invention are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.
  • Combination Therapy Active ingredients of the invention are also used in combination with other active ingredients. Such combinations are selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco-properties of the combination. It is also possible to combine any compound of the invention with one or more other active ingredients in a unitary dosage form for simultaneous or sequential administration to a patient.
  • the combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations .
  • the combination therapy may provide "synergy” and "synergistic effect", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect may be attained when the active ingredients are: (1) co- formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
  • Metabolites of the Compounds of the Invention are the in vivo metabolic products of the compounds described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such products typically are identified by preparing a radiolab led (e.g., C ⁇ or H ⁇ ) compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples.
  • a detectable dose e.g., greater than about 0.5 mg/kg
  • an animal such as rat, mouse, guinea pig, monkey, or to man
  • sufficient time for metabolism to occur typically about 30 seconds to 30 hours
  • isolating its conversion products from the urine, blood or other biological samples typically isolating its conversion products from the urine, blood or other biological samples.
  • the invention also relates to methods of making the compositions of the invention.
  • the compositions are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B.
  • compositions of the invention are provided below. These methods are intended to illustrate the nature of such preparations and are not intended to limit the scope of applicable methods.
  • reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed.
  • the cited reference material, together with material cited therein, contains detailed descriptions of such conditions.
  • temperatures will be -100°C to 200°C
  • solvents will be aprotic or protic
  • reaction times will be 10 seconds to 10 days.
  • Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
  • Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20 0 C), although for metal hydride reductions frequently the temperature is reduced to 0 °C to -100 °C, solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
  • Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0 0 C to -100 °C) are also common.
  • Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
  • Standard synthetic techniques such as azeotropic removal of reaction by ⁇ products and use of anhydrous reaction conditions (e.g., inert gas environments) are common in the art and will be applied when applicable.
  • reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed.
  • the cited reference material, together with material cited therein, contains detailed descriptions of such conditions.
  • temperatures will be -100°C to 200 0 C
  • solvents will be aprotic or protic
  • reaction times will be 10 seconds to 10 days.
  • Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
  • Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20 0 C), although for metal hydride reductions frequently the temperature is reduced to 0 °C to -100 0 C, solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
  • Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0 °C to -100 0 C) are also common.
  • Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
  • Standard synthetic techniques such as azeotropic removal of reaction by ⁇ products and use of anhydrous reaction conditions ⁇ e.g., inert gas environments) are common in the art and will be applied when applicable.
  • treated when used in connection with a chemical synthetic operation, mean contacting, mixing, reacting, allowing to react, bringing into contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities.
  • This means that "treating compound one with compound two” is synonymous with “allowing compound one to react with compound two", “contacting compound one with compound two”, “reacting compound one with compound two”, and other expressions common in the art of organic synthesis for reasonably indicating that compound one was “treated”, “reacted”, “allowed to react", etc., with compound two.
  • treating indicates the reasonable and usual manner in which organic " chemicals are allowed to react.
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • reagents selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
  • reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
  • the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
  • a single stereoisomer e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eli el, McGraw Hill; Lochmuller, C. H., (1975) J.
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, ⁇ -methyl- ⁇ -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • a diastereomeric pair Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched xanthene.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloro formate in the presence of base, or Mosher ester, ⁇ -methoxy-oc- (trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers.
  • chiral esters such as a menthyl ester, e.g., (-) menthyl chloro formate in the presence of base, or Mosher ester, ⁇ -methoxy-oc- (trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers.
  • Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111).
  • a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) J. ofChromatogr. 513 :375-378).
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
  • synthesis of phosphonate esters is achieved by coupling a nucleophile amine or alcohol with the corresponding activated phosphonate electrophilic precursor.
  • chlorophosphonate addition on to 5'- hydroxy of nucleoside is a well known method for preparation of nucleoside phosphate monoesters.
  • the activated precursor can be prepared by several well known methods.
  • Chlorophosphonates useful for synthesis of the prodrugs are prepared from the substituted- 1,3 -propanediol (Wissner, et al, (1992) J. Med Chem. 35:1650). Chlorophosphonates are made by oxidation of the corresponding chlorophospholanes (Anderson, et al, (1984) J. Org. Chem.
  • chlorophosphonate agent is made by treating substituted-l,3-diols with phosphorusoxychloride (Patois, et al, (1990) J. Chem. Soc. Perkin Trans. 1, 1577). Chlorophosphonate species may also be generated in situ from corresponding cyclic phosphites (Silverburg, et al., (1996) Tetrahedron lett., 31:111-11 A), which in turn can be either made from chlorophospholane or phosphoramidate intermediate.
  • Phosphoroflouridate intermediate prepared either from pyrophosphate or phosphoric acid may also act as precursor in preparation of cyclic prodrugs (Watanabe et al., (1988) Tetrahedron lett., 29:5763-66).
  • Phosphonate prodrugs of the present invention may also be prepared from the free acid by Mitsunobu reactions (Mitsunobu, (1981) Synthesis, 1; Campbell, (1992) J. Org. Chem. 57:6331), and other acid coupling reagents including, but not limited to, carbodiimides (Alexander, et al, (1994) Collect. Czech. Chem. Commun. 59:1853; Casara et al, (1992) Bioorg.
  • aryl phosphonate esters are prepared from aryl phosphates under anionic rearrangement conditions (Melvin (1981) Tetrahedron Lett. 22:3375; Casteel et al (1991) Synthesis, 691).
  • N-Alkoxy aryl salts with alkali met al derivatives of cyclic alkyl phosphonate provide general synthesis for heteroaryl-2 -phosphonate linkers (Redmore (1970) J. Org. Chem. 35:4114).
  • Cyclic- 1, 3 -propanyl prodrugs of phosphonates are also synthesized from phosphonic diacids and substituted propane- 1, 3 -diols using a coupling reagent such as 1,3- dicyclohexylcarbodiimide (DCC) in presence of a base (e.g., pyridine).
  • a coupling reagent such as 1,3- dicyclohexylcarbodiimide (DCC) in presence of a base (e.g., pyridine).
  • DCC 1,3- dicyclohexylcarbodiimide
  • EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • the conversion of a phosphonate diester S32.1 into the corresponding phosphonate monoester S32.2 is accomplished by a number of methods.
  • the ester S32.1 in which R 1 is an aralkyl group such as benzyl is converted into the monoester compound S32.2 by reaction with a tertiary organic base such as diazabicyclooctane (DABCO) or quinuclidine, as described in J. Org. Chem. (1995) 60:2946.
  • DABCO diazabicyclooctane
  • the reaction is performed in an inert hydrocarbon solvent such as toluene or xylene, at about 110 °C.
  • the conversion of the diester S32.1 in which R 1 is an aryl group such as phenyl, or an alkenyl group such as allyl, into the monoester S32.2 is effected by treatment of the ester S32.1 with a base such as aqueous sodium hydroxide in acetonitrile or lithium hydroxide in aqueous tetrahydrofuran.
  • Phosphonate diesters in which both of the groups R 1 are alkenyl, such as allyl, is converted into the monoester S32.2 in which R 1 is alkenyl, by treatment with chlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in aqueous ethanol at reflux, optionally in the presence of diazabicyclooctane, for example by using the procedure described in J. Org. Chem. (1973) 38:3224, for the cleavage of allyl carboxylates.
  • the conversion of a phosphonate diester S32.1 or a phosphonate monoester S32.2 into the corresponding phosphonic acid S32.3 can be effected by reaction of the diester or the monoester with trimethylsilyl bromide, as described in J. Chem. Soc, Chem. Comm., (1979) 739.
  • the reaction is conducted in an inert solvent such as, for example, dichloromethane, optionally in the presence of a silylating agent such as bis(trimethylsilyl)trifluoroacetamide, at ambient temperature.
  • the conversion of a phosphonate monoester S32.2 into a phosphonate diester S32.1 (Scheme 32, Reaction 4) in which the newly introduced R 1 group is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl is effected by a number of reactions in which the substrate S32.2 is reacted with a hydroxy compound R 1 OH, in the presence of a coupling agent.
  • the second phosphonate ester group is different than the first introduced phosphonate ester group, i.e.
  • R 1 is followed by the introduction of R 2 where each of R 1 and R 2 is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl (Scheme 32, Reaction 4a) whereby S32.2 is converted to S32.1a.
  • Suitable coupling agents are those employed for the preparation of carboxylate esters, and include a carbodiimide such as dicyclohexylcarbodiimide, in which case the reaction is preferably conducted in a basic organic solvent such as pyridine, or (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma), in which case the reaction is performed in a polar solvent such as dimethylformamide, in the presence of a tertiary organic base such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in which case the reaction is conducted in a basic solvent such as pyridine, in the presence of a triaryl phosphine such as triphenylphosphine.
  • a carbodiimide such as dicyclohexylcarbodiimide
  • PYBOP benzotriazol-1- yloxy)tripyrrolidinophospho
  • the conversion of the phosphonate monoester S32.2 to the diester S32.1 is effected by the use of the Mitsunobu reaction, as described above.
  • the substrate is reacted with the hydroxy compound R 1 OH, in the presence of diethyl azodicarboxylate and a triarylphosphine such as triphenyl phosphine.
  • the phosphonate monoester S32.2 is transformed into the phosphonate diester S32.1, in which the introduced R group is alkenyl or aralkyl, by reaction of the monoester with the halide R 1 Br, in which R 1 is as alkenyl or aralkyl.
  • the alkylation reaction is conducted in a polar organic solvent such as dimethylformamide or acetonitrile, in the presence of a base such as cesium carbonate.
  • a polar organic solvent such as dimethylformamide or acetonitrile
  • a base such as cesium carbonate.
  • the phosphonate monoester is transformed into the phosphonate diester in a two step procedure.
  • the phosphonate monoester S32.2 is transformed into the chloro analog RP(O)(OR 1 )C1 by reaction with thionyl chloride or oxalyl chloride and the like, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p.
  • a phosphonic acid R-HnIc-P(O)(OH) 2 S32.3 is transformed into a phosphonate diester R-IMc-P(O)(OR 1 ) 2 S32.1 (Scheme 32, Reaction 6) by a coupling reaction with the hydroxy compound R 1 OH, in the presence of a coupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine.
  • the reaction is conducted in a basic solvent such as pyridine.
  • phosphonic acids S32.3 are transformed into phosphonic esters S32.1 in which R 1 is aryl, by means of a coupling reaction employing, for example, dicyclohexylcarbodiimide in pyridine at ca 70 0 C.
  • phosphonic acids S32.3 are transformed into phosphonic esters S32.1 in which R 1 is alkenyl, by means of an alkylation reaction. The phosphonic acid is reacted with the alkenyl bromide R 1 Br in a polar organic solvent such as acetonitrile solution at reflux temperature, the presence of a base such as cesium carbonate, to afford the phosphonic ester S32.1.
  • Phosphonate esters may contain a carbamate linkage.
  • the preparation of carbamates is described in Comprehensive Organic Functional Group Transformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff, and in Organic Functional Group Preparations, by S. R. Sandler and W. Karo, Academic Press, 1986, p. 26OfT.
  • the carbamoyl group may be formed by reaction of a hydroxy group according to the methods known in the art, including the teachings of Ellis, US 2002/0103378 Al and Hajima, US 6018049.
  • Scheme 33 illustrates various methods by which the carbamate linkage is synthesized.
  • an alcohol S33.1 in the general reaction generating carbamates, an alcohol S33.1, is converted into the activated derivative S33.2 in which Lv is a leaving group such as halo, imidazolyl, benztriazolyl and the like, as described herein.
  • the activated derivative S33.2 is then reacted with an amine S33.3, to afford the carbamate product S33.4.
  • Examples 1 - 7 in Scheme 33 depict methods by which the general reaction is effected.
  • Examples 8 - 10 illustrate alternative methods for the preparation of carbamates.
  • Example 1 illustrates the preparation of carbamates employing a chloroformyl derivative of the alcohol S33.5.
  • the alcohol S33.5 is reacted with phosgene, in an inert solvent such as toluene, at about 0 °C, as described in Org. Svn. Coll. Vol. 3, 167, 1965, or with an equivalent reagent such as trichloromethoxy chloroformate, as described in Org. Svn. Coll. Vol. 6, 715, 1988, to afford the chloroformate S33.6.
  • the latter compound is then reacted with the amine component S33.3, in the presence of an organic or inorganic base, to afford the carbamate S33.7.
  • the chloroformyl compound S33.6 is reacted with the amine S33.3 in a water- miscible solvent such as tetrahydrofuran, in the presence of aqueous sodium hydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yield the carbamate S33.7.
  • the reaction is performed in dichloromethane in the presence of an organic base such as diisopropylethylamine or dimethylaminopyridine.
  • Example 2 depicts the reaction of the chloroformate compound S33.6 with imidazole to produce the imidazolide S33.8.
  • the imidazolide product is then reacted with the amine S33.3 to yield the carbamate S33.7.
  • the preparation of the imidazolide is performed in an aprotic solvent such as dichloromethane at 0°, and the preparation of the carbamate is conducted in a similar solvent at ambient temperature, optionally in the presence of a base such as dimethylaminopyridine, as described in J. Med. Chem., 1989, 32, 357.
  • Example 3 depicts the reaction of the chloroformate S33.6 with an activated hydroxyl compound R"OH, to yield the mixed carbonate ester S33.10.
  • the reaction is conducted in an inert organic solvent such as ether or dichloromethane, in the presence of a base such as dicyclohexylamine or triethylamine.
  • the hydroxyl component R"OH is selected from the group of compounds S33.19 - S33.24 shown in Scheme 33, and similar compounds.
  • the mixed carbonate S33.10 is obtained by the reaction of the chloroformate with the hydroxyl compound in an ethereal solvent in the presence of dicyclohexylamine, as described in Can. J. Chem., 1982, 60, 976.
  • Example 4 illustrates the preparation of carbamates in which an alkyloxycarbonylimidazole S33.8 is employed.
  • an alcohol S33.5 is reacted with an equimolar amount of carbonyl diimidazole S33.ll to prepare the intermediate S33.8.
  • the reaction is conducted in an aprotic organic solvent such as dichloromethane or tetrahydrofuran.
  • the acyloxyimidazole S33.8 is then reacted with an equimolar amount of the amine RTSTH 2 to afford the carbamate S33.7.
  • the reaction is performed in an aprotic organic solvent such as dichloromethane, as described in Tet. Lett., 42, 2001, 5227, to afford the carbamate S33.7.
  • Example 5 illustrates the preparation of carbamates by means of an intermediate alkoxycarbonylbenztriazole S33.13.
  • an alcohol ROH is reacted at ambient temperature with an equimolar amount of benztriazole carbonyl chloride S33.12, to afford the alkoxycarbonyl product S33.13.
  • the reaction is performed in an organic solvent such as benzene or toluene, in the presence of a tertiary organic amine such as triethylamine, as described in Synthesis., 1977, 704.
  • the product is then reacted with the amine R 1 NH 2 to afford the carbamate S33.7.
  • the reaction is conducted in toluene or ethanol, at from ambient temperature to about 80 ° C as described in Synthesis., 1977, 704.
  • Example 6 illustrates the preparation of carbamates in which a carbonate (RO) 2 CO, S33.14, is reacted with an alcohol S33.5 to afford the intermediate alkyloxycarbonyl intermediate S33.15. The latter reagent is then reacted with the amine R 1 NH 2 to afford the carbamate S33.7.
  • the procedure in which the reagent S33.15 is derived from hydroxybenztriazole S33.19 is described in Synthesis, 1993, 908; the procedure in which the reagent S33.15 is derived from N-hydroxysuccinimide S33.20 is described in Tet.
  • Example 7 illustrates the preparation of carbamates from alkoxycarbonyl azides S33.16.
  • an alkyl chloroformate S33.6 is reacted with an azide, for example sodium azide, to afford the alkoxycarbonyl azide S33.16.
  • the latter compound is then reacted with an equimolar amount of the amine R 1 NH 2 to afford the carbamate S33.7.
  • the reaction is conducted at ambient temperature in a polar aprotic solvent such as dimethylsulfoxide, for example as described in Synthesis., 1982, 404.
  • Example 8 illustrates the preparation of carbamates by means of the reaction between an alcohol ROH and the chloroformyl derivative of an amine S33.17. m this procedure, which is described in Synthetic Organic
  • Example 9 illustrates the preparation of carbamates by means of the reaction between an alcohol ROH and an isocyanate S33.18.
  • the reactants are combined at ambient temperature in an aprotic solvent such as ether or dichloromethane and the like, to afford the carbamate S33.7.
  • Example 10 illustrates the preparation of carbamates by means of the reaction between an alcohol ROH and an amine R 1 NH 2 . In this procedure, which is described in Chem. Lett.
  • Phosphonic acids are converted into activated imidazolyl derivatives by reaction with carbonyl diimidazole, as described in J. Chem. Soc, Chem. Comm.
  • Activated sulfonyloxy derivatives are obtained by the reaction of phosphonic acids with trichloromethylsulfonyl chloride or with triisopropylbenzenesulfonyl chloride, as described in Tet. Lett. (1996) 7857, orBioorg. Med. Chem. Lett. (1998) 8:663.
  • the activated sulfonyloxy derivatives are then reacted with amines or hydroxy compounds to afford amidates or esters.
  • the phosphonic acid and the amine or hydroxy reactant are combined in the presence of a diimide coupling agent.
  • the preparation of phosphonic amidates and esters by means of coupling reactions in the presence of dicyclohexyl carbodiimide is described, for example, inJ. Chem. Soc, Chem.
  • Phosphonic acids are converted into amidates and esters by means of the Mitsunobu reaction, in which the phosphonic acid and the amine or hydroxy reactant are combined in the presence of a triaryl phosphine and a dialkyl azodicarboxylate.
  • the procedure is described in Org. Lett, 2001, 3, 643, or J. Med. Chem., 1997, 40, 3842.
  • Phosphonic esters are also obtained by the reaction between phosphonic acids and halo compounds, in the presence of a suitable base.
  • the method is described, for example, in Anal. Chem., 1987, 59, 1056, or J. Chem. Soc. Perkin Trans., 1, 1993, 19, 2303, or J. Med. Chem., 1995, 38, 1372, or Tet. Lett, 2002, 43, 1161.
  • Schemes 34-37 illustrate the conversion of phosphonate esters and phosphonic acids into carboalkoxy-substituted phosphonbisamidates (Scheme 34), phosphonamidates (Scheme 35), phosphonate monoesters (Scheme 36) and phosphonate diesters, (Scheme 37).
  • Scheme 38 illustrates synthesis of gem- dialkyl amino phosphonate reagents.
  • Scheme 34 illustrates various methods for the conversion of phosphonate diesters S34.1 into phosphonbisamidates S34.5.
  • the diester S34.1 prepared as described previously, is hydrolyzed, either to the monoester S34.2 or to the phosphonic acid S34.6. The methods employed for these transformations are described above.
  • the monoester S34.2 is converted into the monoamidate S34.3 by reaction with an aminoester S34.9, in which the group R 2 is H or alkyl; the group R 4b is a divalent alkylene moiety such as, for example, CHCH 3 , CHCH 2 CH 3 , CH(CH(CH 3 ) 2 ), CH(CH 2 Ph), and the like, or a side chain group present in natural or modified aminoacids; and the group R 5b is C 1 -C 12 alkyl, such as methyl, ethyl, propyl, isopropyl, or isobutyl; C 6 -C 20 aryl, such as phenyl or substituted phenyl; or C 6 -C 20 arylalkyl, such as benzyl or benzyhydryl.
  • the group R 2 is H or alkyl
  • the group R 4b is a divalent alkylene moiety such as, for example, CHCH 3 , CHCH 2 CH 3
  • the reactants are combined in the presence of a coupling agent such as a carbodiimide, for example dicyclohexyl carbodiimide, as described in J. Am. Chem. Soc, (1957) 79:3575, optionally in the presence of an activating agent such as hydroxybenztriazole, to yield the amidate product S34.3.
  • a coupling agent such as a carbodiimide, for example dicyclohexyl carbodiimide, as described in J. Am. Chem. Soc, (1957) 79:3575
  • an activating agent such as hydroxybenztriazole
  • the reactants S34.2 and S34.9 are transformed into the monoamidate S34.3 by means of a Mitsunobu reaction.
  • the preparation of amidates by means of the Mitsunobu reaction is described in J. Med. Chem. (1995) 38:2742.
  • Equimolar amounts of the reactants are combined in an inert solvent such as tetrahydrofuran in the presence of a triaryl phosphine and a dialkyl azodicarboxylate.
  • the thus- obtained monoamidate ester S34.3 is then transformed into amidate phosphonic acid S34.4.
  • the conditions used for the hydrolysis reaction depend on the nature of the R 1 group, as described previously.
  • the phosphonic acid amidate S34.4 is then reacted with an aminoester S34.9, as described above, to yield the bisamidate product S34.5, in which the amino substituents are the same or different.
  • the phosphonic acid S34.6 may be treated with two different amino ester reagents simulataneously, i.e. S34.9 where R 2 , R 4b or R 5b are different.
  • the resulting mixture of bisamidate products S34.5 may then be separable, e.g. by chromatography.
  • the phosphonic acid S34.6 is converted into the bisamidate S34.5 by use of the coupling reactions described above.
  • the reaction is performed in one step, in which case the nitrogen-related substituents present in the product S34.5 are the same, or in two steps, in which case the nitrogen- related substituents can be different.
  • the phosphonic acid S34.6 is converted into the mono or bis-activated derivative S34.7, in which Lv is a leaving group such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc.
  • Lv is a leaving group such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc.
  • Phosphorus Compounds G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 17.
  • the phosphonic acid is activated by reaction with triisopropylbenzenesulfonyl chloride, as described in Nucleosides and Nucleotides, 2000, 10, 1885.
  • the activated product is then reacted with the aminoester S34.9, in the presence of a base, to give the bisamidate S34.5.
  • the reaction is performed in one step, in which case the nitrogen substituents present in the product S34.5 are the same, or in two steps, via the intermediate S34.ll, in which case the nitrogen substituents can be different.
  • Example 5 the phosphonic acid S34.6 is reacted, as described inJ. Chem. Soc. Chem. Comm., 1991, 312, with carbonyl diimidazole to give the imidazolide S34.S32.
  • the product is then reacted in acetonitrile solution at ambient temperature, with one molar equivalent of ethyl alaninate S34.33 to yield the monodisplacement product S34.S34.
  • the latter compound is then reacted with carbonyl diimidazole to produce the activated intermediate S34.35, and the product is then reacted, under the same conditions, with ethyl N-methylalaninate S34.33a to give the bisamidate product S34.36.
  • the intermediate monoamidate S34.3 is also prepared from the monoester S34.2 by first converting the monoester into the activated derivative S34.8 in which Lv is a leaving group such as halo, imidazolyl etc, using the procedures described above.
  • the product S34.8 is then reacted with an aminoester S34.9 in the presence of a base such as pyridine, to give an intermediate monoamidate product S34.3.
  • the latter compound is then converted, by removal of the R 1 group and coupling of the product with the aminoester S34.9, as described above, into the bisamidate S34.5.
  • the latter compound is hydrogenated in ethylacetate over a 5% palladium on carbon catalyst to produce the monoacid product S34.29.
  • the product is subjected to a Mitsunobu coupling procedure, with equimolar amounts of butyl alaninate S34.30, triphenyl phosphine, diethylazodicarboxylate and triethylamine in tetrahydrofuran, to give the bisamidate product S34.31.
  • the activated phosphonic acid derivative S34.7 is also converted into the bisamidate S34.5 via the diamino compound S34.10.
  • the conversion of activated phosphonic acid derivatives such as phosphoryl chlorides into the corresponding amino analogs S34.10, by reaction with ammonia, is described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976.
  • S34.5 may be treated with two different amino ester reagents simulataneously, i.e. S34.12 where R 4b or R 5b are different.
  • the resulting mixture of bisamidate products S34.5 may then be separable, e.g. by chromatography.
  • Scheme 35 illustrates methods for the preparation of phosphonate monoamidates.
  • a phosphonate monoester S34.1 is converted, as described in Scheme 34, into the activated derivative S34.8. This compound is then reacted, as described above, with an aminoester S34.9, in the presence of a base, to afford the monoamidate product S35.1.
  • the phosphonic acid is then transformed into the ester amidate product S35.3, by reaction with the hydroxy compound R 3 OH, in which the group R 3 is aryl, heterocycle, alkyl, cycloalkyl, haloalkyl etc, using the same coupling procedures (carbodiimide, Aldrithiol-2, PYBOP, Mitsunobu reaction etc) described in Scheme 34 for the coupling of amines and phosphonic acids.
  • Scheme 34 Example 1
  • Example 3 the monoamidate S35.13 is coupled, in tetrahydrofuran solution at ambient temperature, with equimolar amounts of dicyclohexyl carbodiimide and 4-hydroxy-N- methylpiperidine S35.16, to produce the amidate ester product S35.17.
  • the activated phosphonate ester S34.8 is reacted with ammonia to yield the amidate S35.4.
  • the product is then reacted, as described in Scheme 34, with a haloester S35.5, in the presence of a base, to produce the amidate product S35.6.
  • the nature of the R 1 group is changed, using the procedures described above, to give the product S35.3.
  • the method is illustrated in Scheme 35, Example 4.
  • the monophenyl phosphoryl chloride S35.18 is reacted, as described in Scheme 34, with ammonia, to yield the amino product S35.19.
  • This material is then reacted in N- methylpyrrolidinone solution at 170° with butyl 2-bromo-3-phenylpropionate S35.20 and potassium carbonate, to afford the amidate product S35.21.
  • the monoamidate products S35.3 are also prepared from the doubly activated phosphonate derivatives S34.7.
  • the intermediate S34.7 is reacted with a limited amount of the aminoester S34.9 to give the mono-displacement product S34.ll.
  • the latter compound is then reacted with the hydroxy compound R 3 OH in a polar organic solvent such as dimethylformamide, in the presence of a base such as diisopropylethylamine, to yield the monoamidate ester S35.3.
  • Scheme 36 illustrates methods for the preparation of carboalkoxy- substituted phosphonate diesters in which one of the ester groups incorporates a carboalkoxy substituent.
  • a phosphonate monoester S34.1 prepared as described above, is coupled, using one of the methods described above, with a hydroxyester S36.1, in which the groups R and R 5b are as described in Scheme 34.
  • equimolar amounts of the reactants are coupled in the presence of a carbodiimide such as dicyclohexyl carbodiimide, as described in Aust. J. Chem., 1963, 609, optionally in the presence of dimethylaminopyridine, as described in Tet., 1999, 55, 12997.
  • the reaction is conducted in an inert solvent at ambient temperature.
  • the conversion of a phosphonate monoester S34.1 into a mixed diester S36.2 is also accomplished by means of a Mitsunobu coupling reaction with the hydroxyester S36.1, as described in Org. Lett., 2001, 643.
  • the reactants 34.1 and S36.1 are combined in a polar solvent such as tetrahydrofuran, in the presence of a triarylphosphine and a dialkyl azodicarboxylate, to give the mixed diester S36.2.
  • the R 1 substituent is varied by cleavage, using the methods described previously, to afford the monoacid product S36.3.
  • the mixed diesters S36.2 are also obtained from the monoesters S34.1 via the intermediacy of the activated monoesters S36.5.
  • the resultant activated monoester is then reacted with the hydroxyester S36.1, as described above, to yield the mixed diester S36.2.
  • the mixed phosphonate diesters are also obtained by an alternative route for incorporation of the R 3 O group into intermediates S36.3 in which the hydroxyester moiety is already incorporated, hi this procedure, the monoacid intermediate S36.3 is converted into the activated derivative S36.6 in which Lv is a leaving group such as chloro, imidazole, and the like, as previously described.
  • the activated intermediate is then reacted with the hydroxy compound R 3 OH, in the presence of a base, to yield the mixed diester product S36.4.
  • the phosphonate esters S36.4 are also obtained by means of alkylation reactions performed on the monoesters S34.1.
  • the reaction between the monoacid S34.1 and the haloester S36.7 is performed in a polar solvent in the presence of a base such as diisopropylethylamine, as described in Anal. Chem., 1987, 59, 1056, or triethylamine, as described in J. Med. Chem., 1995, 38, 1372, or in a non-polar solvent such as benzene, in the presence of 18-crown-6, as described in Syn. Comm., 1995, 25, 3565.
  • the method is illustrated in Scheme 36, Example 5.
  • the monoacid S36.26 is reacted with ethyl 2-bromo-3-phenylpropionate S36.27 and diisopropylethylamine in dimethylformamide at 80 0 C to afford the mixed diester product S36.28.
  • Scheme 37 illustrates methods for the preparation of phosphonate diesters in which both the ester substituents incorporate carboalkoxy groups.
  • the compounds are prepared directly or indirectly from the phosphonic acids S34.6. hi one alternative, the phosphonic acid is coupled with the hydroxyester S37.2, using the conditions described previously in Schemes 34- 36, such as coupling reactions using dicyclohexyl carbodiimide or similar reagents, or under the conditions of the Mitsunobu reaction, to afford the diester product S37.3 in which the ester substituents are identical.
  • the diesters S37.3 are obtained by alkylation of the phosphonic acid S34.6 with a haloester S37.1.
  • the alkylation reaction is performed as described in Scheme 36 for the preparation of the esters S36.4.
  • the diesters S37.3 are also obtained by displacement reactions of activated derivatives S34.7 of the phosphonic acid with the hydroxyesters S37.2.
  • the displacement reaction is performed in a polar solvent in the presence of a suitable base, as described in Scheme 36.
  • the displacement reaction is performed in the presence of an excess of the hydroxyester, to afford the diester product S37.3 in which the ester substituents are identical, or sequentially with limited amounts of different hydroxyesters, to prepare diesters S37.3 in which the ester substituents are different.
  • Example 4 depicts the displacement reaction between equimolar amounts of the phosphoryl dichloride S35.22 and ethyl 2-methyl-3- hydroxypropionate S37.ll, to yield the monoester product S37.12.
  • the reaction is conducted in acetonitrile at 70° in the presence of diisopropylethylamine.
  • the product S37.12 is then reacted, under the same conditions, with one molar equivalent of ethyl lactate S37.13, to give the diester product S37.14.
  • 2,2-Dimethyl-2-aminoethylphosphonic acid intermediates can be prepared by the route in Scheme 5.
  • Condensation of 2-methyl-2- propanesulfmamide with acetone give sulfinyl imine S38.ll (J. Org. Chem. 1999, 64, 12).
  • Addition of dimethyl methylphosphonate lithium to S38.ll afford S38.12.
  • Acidic methanolysis of S38.12 provide amine S38.13. Protection of amine with Cbz group and removal of methyl groups yield phosphonic acid S38.14, which can be converted to desired S38.15 (Scheme 38a) using methods reported earlier on.
  • An alternative synthesis of compound S38.14 is also shown in Scheme 38b.
  • the mixture was cooled to -60 °C and then a cold solution of iodine monobromide 2 g, 9.6 mmol) in CH 2 Cl 2 (10 ml) was added.
  • the reaction mixture was warmed to -10 0 C and then kept at -10 °C for 1 h.
  • the reaction mixture was diluted with CH 2 Cl 2 , washed with saturated aqueous NaHCO 3 , and then with aqueous sodium thiosulfate.
  • the organic phase was separated, dried over MgSO 4 , and concentrated under reduced pressure to dryness.
  • reaction mixture was purified by silica gel chromatography (eluting with 25 % ethyl acetate in CH 2 Cl 2 , then switching to 3 % methanol in CH 2 Cl 2 ) to afford product 6 (0.9 g, 33 %).
  • R 1 is distinct from R 1 .

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Virology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention is related to phosphorus substituted anti-viral inhibitory compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

Description

ANTIVIRAL COMPOUNDS
This application claims priority to U.S. Application No. 60/591,811, filed July 27, 2004, the disclosures of which are incorporated by reference in their entirety. In particular, the figures described on pages 161 to 184 are incorporated as Figures herein.
FIELD OF THE INVENTION
The invention relates generally to compounds with HIV inhibitory activity. BACKGROUND OF THE INVENTION
Improving the delivery of drugs and other agents to target cells and tissues has been the focus of considerable research for many years. Though many attempts have been made to develop effective methods for importing biologically active molecules into cells, both in vivo and in vitro, none has proved to be entirely satisfactory. Optimizing the association of the inhibitory drug with its intracellular target, while minimizing intercellular redistribution of the drug, e.g., to neighboring cells, is often difficult or inefficient.
Most agents currently administered to a patient parenterally are not targeted, resulting in systemic delivery of the agent to cells and tissues of the body where it is unnecessary, and often undesirable. This may result in adverse drug side effects, and often limits the dose of a drug (e.g., glucocorticoids and other anti-inflammatory drugs) that can be administered. By comparison, although oral administration of drugs is generally recognized as a convenient and economical method of administration, oral administration can result in either (a) uptake of the drug through the cellular and tissue barriers, e.g., blood/brain, epithelial, cell membrane, resulting in undesirable systemic distribution, or (b) temporary residence of the drug within the gastrointestinal tract. Accordingly, a major goal has been to develop methods for specifically targeting agents to cells and tissues. Benefits of such treatment includes avoiding the general physiological effects of inappropriate delivery of such agents to other cells and tissues, such as uninfected cells.
HIV is recognized as a chronic viral disease of the liver which is characterized by liver disease. Although drugs targeting the liver are in wide use and have shown effectiveness, toxicity and other side effects have limited their usefulness.
Assay methods capable of determining the presence, absence or amounts of HIV are of practical utility in the search for inhibitors as well as for diagnosing the presence of HIV. Inhibitors of HIV are useful to limit the establishment and progression of infection by HIV as well as in diagnostic assays for HIV.
There is a need for HIV therapeutic agents, i.e. drugs, having improved inhibitory and pharmacokinetic properties, including enhanced activity against development of viral resistance, improved oral bioavailability, greater potency and extended effective half-life in vivo. New HIV inhibitors should have fewer side effects, less complicated dosing schedules, and be orally active. In particular, there is a need for a less onerous dosage regimen, such as one pill, once per day.
SUMMARY OF THE INVENTION
Intracellular targeting may be achieved by methods and compositions that allow accumulation or retention of biologically active agents inside cells. The present invention provides compositions and methods for inhibition of HIV or therapeutic activity against HIV. The present invention relates generally to the accumulation or retention of therapeutic compounds inside cells. The invention is also related to attaining high concentrations of phosphonate molecules in liver cells. Such effective targeting may be applicable to a variety of therapeutic formulations and procedures. Compositions of the invention include anti- viral compounds having optionally at least one phosphonate group. Accordingly, in one embodiment, the invention provides a compound of the invention which is linked to one or more phosphonate groups.
In another embodiment, the invention provides a conjugate, enantiomers thereof, or a pharmaceutically acceptable salt or solvate thereof, that is a compound of the formula A:
that is substituted with one or more groups A o ,
Figure imgf000004_0001
wherein,
A0 is absent, H, a bond, A1, A2 or W3 with the proviso that the conjugate includes at least one A1;
A1 is:
Figure imgf000004_0002
A2 is:
Figure imgf000004_0003
A3 is:
Figure imgf000005_0001
Y1 is independently O, S, N(RX), N(O)(RX), N(ORX), N(O)(ORX), or N(N(RX)( RX));
Y2 is independently absent, a bond, O, C(RX)(RX), N(RX), N(O)(RX), N(ORX), N(0)(0Rx), N(N(RX)( Rx)), -S(O)M2-, or -S(O)M2-S(O)M2-; and when Y2 joins two phosphorous atoms Y2 can also be C(R2)(R2);
Rx is independently absent, a bond, H, R1, R2, W3, a protecting group, or the formula:
Figure imgf000005_0002
wherein:
Ry is independently H, W3, R2 or a protecting group;
R1 is independently H or alkyl of 1 to 18 carbon atoms;
R2 is independently H, R1, R3 or R wherein each R is independently substituted with 0 to 3 R3 groups or taken together at a carbon atom, two R2 groups form a ring or fused rings of 3 to 12 carbon, nitrogen, and optionally oxygen, atoms, and the ring system may be substituted with 0 to 3 R3 groups;
R3 is R3a, R3b, R3c or R3d, provided that when R3 is bound to a heteroatom, then R3 is R3c or R3d;
R3a is F, Cl, Br, I, -CN, N3, -NO2, -OR1 or -OR6a;
R31Ms Y1;
R3c is -Rx, -N(RX)(RX), -SRX, -S(O)RX, -S(O)2RX, -S(O)(ORX), - S(O)2(ORX), -OC(Y])RX, -OC(Y1)ORX, -OC^CNCR")^)), -SC(Y1)RX, - SCCY^OR", -SCCY^CNCR^CR*)), -NCR^CCY^R*, -NCR^CQT^OR*, or -
N(RX)C(Y1)(N(RX)(RX)) ;
R3d is -C(Y!)RX, -CCY^OR" or -C^^R")^));
R4 is H, an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R5 is R4 wherein each R4 is substituted with 0 to 3 R3 groups;
W3 is W4 or W5;
W4 is R5, -C(Y^R5, -C(Y^W5, -SOM2R5, or -SOM2W5;
W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
W6 is W3 independently substituted with 0, 1 , 2, or 3 A3 groups;
K and K' are independently absent, a bond, or optionally substituted Ry;
M2 is 0, 1 or 2;
M12a is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
MIa, MIc, and MId are independently 0 or 1; and
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. In another embodiment, the invention provides a compound of the formula:
Figure imgf000006_0001
enantiomers thereof or a pharmaceutically acceptable salt thereof wherein,
DRUG is a compound of the formula A; nn is 1, 2, or 3;
K and K' are as defined above;
A0 is A1, A2 or W3 with the proviso that the conjugate includes at least one A1;
A1 Is:
Figure imgf000007_0001
A" is:
Figure imgf000007_0002
A3 is:
Figure imgf000007_0003
Y1 is independently O, S, N(RX), N(O)(RX), N(ORX), N(O)(ORX), or N(N(RX)( RX));
Y2 is independently a bond, O, C(RX)(RX), N(RX), N(O)(RX), N(ORX), N(0)(0Rx), N(N(RX)( Rx)), -S(O)M2-; or -S(O)M2-S(O)M2-; and when Y2 joins two phosphorous atoms Y2 can also be C(R2)(R2);
Rx is independently H, R1, R2, W3, a protecting group, or the formula:
Figure imgf000007_0004
wherein:
Ry is independently H, W3, R2 or a protecting group;
R1 is independently H or alkyl of 1 to 18 carbon atoms; R2 is independently H, R1, R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups or taken together at a carbon atom, two R2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R3 groups; R3 is R3a, R3b, R3c or R3d, provided that when R3 is bound to a heteroatom, then R3 is R3c or R3d;
R3a is F, Cl, Br, I, -CN, N3, -NO2, -OR1 or -OR6a; R31Ms Y1;
R3c is -Rx, -N(RX)(RX), -SRX, -S(O)RX, -S(O)2RX, -S(O)(ORX), - S(O)2(ORX), -OC(Y1)RX, -0C(Y1)0Rx, -OQY^^XR3')), -SC(Y1^5 - SC(Y1)ORX, -SC(Y1)(N(RX)(RX)), -N(RX)C(Y1)RX, -N(R^C(Y1PR*, or - N(RX)C(Y1)(N(RX)(RX)) ;
R3d is -C(Y^R*, -C(Y1)ORX or -C(Y1)(N(RX)(RX)); R4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R5 is R4 wherein each R4 is substituted with 0 to 3 R3 groups; W3 is W4 or W5;
W4 is R5, -C(Y!)R5, -C(Y^W5, -SOM2R5, or -SOM2W5; W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
W6 is W3 independently substituted with 0, 1, 2, or 3 A3 groups; M2 is 0, 1 or 2;
M12a is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; Ml 2b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; MIa, MIc, and MId are independently 0 or 1;
K and K' are as defined above; and M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. In another embodiment, the invention provides a compound of the formulae A:
Figure imgf000009_0001
wherein:
A0 is A1; A1 is:
Figure imgf000009_0002
A3 is:
Figure imgf000010_0001
Y1 is independently O, S, N(RX), N(O)(RX), N(ORX), N(O)(ORX), or N(N(RX)( RX));
Y2 is independently absent, bond, O, C(RX)(RX), N(RX), N(O)(RX), N(ORX), N(0)(0Rx), N(N(RX)( Rx)), -S(0)M2-, or -S(O)M2-S(O)M2-; and when
Y joins two phosphorous atoms Y can also be C(R )(R );
Rx is independently H, R2, W3, a protecting group, or the formula:
Figure imgf000010_0002
Ry is independently H, W3, R2 or a protecting group; R1 is independently H or alkyl of 1 to 18 carbon atoms;
R2 is independently H, R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
R3 is R3a, R3b, R3c or R3d, provided that when R3 is bound to a heteroatom, then R3 is R3° or R3d; R3a is F, Cl, Br, I, -CN, N3, -NO2, -ORi or -OR6a;
R3b is Y1;
R3c is -Rx, -N(RX)(RX), -SRX, -S(O)RX, -S(O)2RX, -S(O)(ORX), - S(O)2(ORX), -OC(Y1)RX, -0C(Y1)0Rx, -OC(Y1XN(R^)), -SC(Y1)RX, - SC(Y1)ORX, -SCCY^CNCR^CR )), -N(RX)C(Y1)RX, -N(RX)C(Y1)ORX, or - NCR^CCY^CN^XR^) ;
R3d is -C(Y1)RX, -C(Y1)ORX or -C(Y^(N(R35XR")); R4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R5 is R4 wherein each R4 is substituted with 0 to 3 R3 groups; R5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups;
W3 is W4 or W5; W4 is R5, -C(Y^R5, -C(Y^W5, -SO2R5, or -SO2W5;
W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
W6 is W3 independently substituted with 0, 1, 2, or 3 A3 groups;
K and K' are as defined above; M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
MIa, MIc, and MId are independently 0 or 1; and
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the embodiments.
DEFINITIONS
Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:
When tradenames are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product.
"Bioavailability" is the degree to which the pharmaceutically active agent becomes available to the target tissue after the agent's introduction into the body. Enhancement of the bioavailability of a pharmaceutically active agent can provide a more efficient and effective treatment for patients because, for a given dose, more of the pharmaceutically active agent will be available at the targeted tissue sites.
The terms "phosphonate" and "phosphonate group" include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double-bonded to a heteroatom , 3) single-bonded to a heteroatom, and 4) single-bonded to another heteroatom, wherein each heteroatom can be the same or different. The terms "phosphonate" and "phosphonate group" also include functional groups or moieties that comprise a phosphorous in the same oxidation state as the phosphorous described above, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having the characteriatics described above. For example, the terms "phosphonate" and "phosphonate group" include phosphonic acid, phosphonic monoester, phosphonic diester, phosphonamidate, and phosphonthioate functional groups. In one specific embodiment of the invention, the terms "phosphonate" and "phosphonate group" include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, T) double- bonded to an oxygen, 3) single-bonded to an oxygen, and 4) single-bonded to another oxygen, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having such characteriatics. In another specific embodiment of the invention, the terms "phosphonate" and "phosphonate group" include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double-bonded to an oxygen, 3) single-bonded to an oxygen or nitrogen, and 4) single-bonded to another oxygen or nitrogen, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having such characteriatics.
The term "prodrug" as used herein refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s). A prodrug is thus a covalently modified analog or latent form of a therapeutically- active compound.
"Prodrug moiety" refers to a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, "Design and Application of Prodrugs" in A Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases. Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy. A prodrug moiety may include an active metabolite or drug itself. Exemplary prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters -CH2OC(^O)R9 and acyloxymethyl carbonates -CH2OC(=O)OR9 where R9 is C1-C6 alkyl, C1-C6 substituted alkyl, C6-C20 aryl or C6-C2O substituted aryl. The acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sd. 72: 324; also US Patent Nos. 4816570, 4968788, 5663159 and 5792756. Subsequently, the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability. A close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention. An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM) -CH2OC(=O)C(CH3)3. An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC) -CH2OC(=O)OC(CH3)3.
The phosphonate group may be a phosphonate prodrug moiety. The prodrug moiety may be sensitive to hydrolysis, such as, but not limited to a pivaloyloxymethyl carbonate (POC) or POM group. Alternatively, the prodrug moiety may be sensitive to enzymatic potentiated cleavage, such as a lactate ester or a phosphonamidate-ester group. Aryl esters of phosphorus groups, especially phenyl esters, are reported to enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109- 4115). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ort/zø-or/>αrø-position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g., esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C-O bond to generate the phosphoric acid and the quinone methide intermediate. Examples of this class of prodrugs are described by Mitchell et al. (1992) J. Chem. Soc. Perkin Trans. /72345; Glazier WO 91/19721. Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier WO 91/19721). Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterifϊed with an acyl group or combined with another thiol group to form a disulfide. Deesterification or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria et al. (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds (Erion et al., US Patent No. 6312662).
"Protecting group" refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection/deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry. Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.
Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g., alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
Any reference to any of the compounds of the invention also includes a reference to a physiologically acceptable salt thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX4 + (wherein X is C1-C4 alkyl). Physiologically acceptable salts of an hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids. Physiologically acceptable salts of a compound of an hydroxy group include the anion of said compound in combination with a suitable cation such as Na+ and NX4 + (wherein X is independently selected from H or a C1-C4 alkyl group). For therapeutic use, salts of active ingredients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable acid or base. However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
"Alkyl" is Ci -C 18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1- propyl Oa-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1- butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l -propyl (i-Bu, i-butyl, - CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2- propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2- butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl- 1 -butyl (-CH2CH2CH(CH3)2), 2-methyl-l -butyl (-CH2CH(CH3)CH2CH3), 1- hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3- hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (- C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4- methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (- C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3- dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-
CH(CH3)C(CH3)3. "Alkenyl" is C2-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp2 double bond. Examples include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2 CH2CH2CH2CH=CH2). "Alkynyl" is C2-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. Examples include, but are not limited to, acetylenic (-C≡CH) and propargyl (-CH2CsCH),
"Alkylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to, methylene (-CH2-) 1,2-ethyl (-CH2CH2-), 1,3-ρroρyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.
"Alkenylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2- 18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (-CH=CH-).
"Alkynylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2- 18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne. Typical alkynylene radicals include, but are not limited to, acetylene (-C≡C-), propargyl (-CH2C=C-), and 4-pentynyl (-CH2CH2CH2C=CH-). "Aryl" means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like. "Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, , naphthylmethyl, 2-naphthylethan-l- yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like. The arylalkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
"Substituted alkyl", "substituted aryl", and "substituted arylalkyl" mean alkyl, aryl, and arylalkyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent. Typical substituents include, but are not limited to, -X, -R, -O", -OR, -SR, -S", -NR2, -NR3, =NR, -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N2, -N3, NC(=O)R, -C(=O)R, -C(=0)NRR -St=O)2O", -S(=O)2OH, -S(=O)2R, - OS(=O)2OR, -SC=O)2NR, -S(=O)R, -OPC=O)O2RR, -P(=O)O2RR -P(=0)(0")2, -PC=O)(OH)2, -C(=0)R, -C(=0)X, -C(S)R, -C(O)OR, -C(O)O", -C(S)OR, -C(O)SR, -C(S)SR, -C(O)NRR, -C(S)NRR, -C(NR)NRR, where each X is independently a halogen: F, Cl, Br, or I; and each R is independently -H, alkyl, aryl, heterocycle, protecting group or prodrug moiety. Alkylene, alkenylene, and alkynylene groups may also be similarly substituted.
"Heterocycle" as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment of the invention "heterocycle" includes a "carbocycle" as defined herein, wherein one or more {e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom {e.g. O, N, or S).
Examples of "heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5- thiadiazinyl, 2H,6H-l,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H- indolyl, lH-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β- carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl:
Figure imgf000019_0001
By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5- pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3- pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl. By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1- pyrazolyl, and 1-piperidinyl.
"Carbocycle" refers to a saturated, unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as abicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as abicyclo [5,6] or [6,6] system. Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1- cyclopent-1-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1- cyclohex-1-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
"Linker" or "link" refers to a chemical moiety comprising a covalent bond or a chain or group of atoms that covalently attaches aphosphonate group to a drug. Linkers include portions of substituents A1 and A3, which include moieties such as: repeating units of alkyloxy (e.g., polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, Jeffamine™); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide. The term "chiral" refers to molecules which have the property of non- superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.
The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
"Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
"Enantiomers" refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
The term "treatment" or "treating," to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw- Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
Protecting Groups
In the context of the present invention, protecting groups include prodrug moieties and chemical protecting groups.
Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group "PG" will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. The PG groups do not need to be, and generally are not, the same if the compound is substituted with multiple PG. hi general, PG will be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency. The order of deprotection to yield free, deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan. Various functional groups of the compounds of the invention may be protected. For example, protecting groups for -OH groups (whether hydroxyl, carboxylic acid, phosphonic acid, of other functions) include "ether- or ester- 5 027088
forming groups". Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein. However, some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below.
A very large number of hydroxyl protecting groups and amide-forming groups and corresponding chemical cleavage reactions are described in Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) ("Greene"). See also Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), which is incorporated by reference in its entirety herein, hi particular Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184. For protecting groups for carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other protecting groups for acids see Greene as set forth below. Such groups include by way of example and not limitation, esters, amides, hydrazides, and the like.
Ether- and Ester-forming protecting groups
Ester-forming groups include: (1) phosphonate ester-forming groups, such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and pliosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3) sulphur ester-forming groups, such as sulphonate, sulfate, and sulfmate. The optional phosphonate moieties of the compounds of the invention may or may not be prodrug moieties, i.e. they may or may be susceptible to hydrolytic or enzymatic cleavage or modification. Certain phosphonate moieties are stable under most or nearly all metabolic conditions. For example, a dialkylphosphonate, where the alkyl groups are two or more carbons, may have appreciable stability in vivo due to a slow rate of hydrolysis.
Within the context of phosphonate prodrug moieties, a large number of structurally-diverse prodrugs have been described for phosphonic acids (Freeman and Ross in Progress in Medicinal Chemistry 34: 112-147 (1997) and are included within the scope of the present invention. An exemplary phosphonate ester-forming group is the phenyl carbocycle in substructure A3 having the formula:
Figure imgf000023_0001
wherein R1 may be H or C1-C12 alkyl; ml is 1, 2, 3, 4, 5, 6, 7 or 8, and the phenyl carbocycle is substituted with 0 to 3 R2 groups. Where Y1 is O, a lactate ester is formed, and where Y1 is N(R2), N(OR2) or N(N(R2)2, a phosphonamidate ester results.
In its ester-forming role, a protecting group typically is bound to any acidic group such as, by way of example and not limitation, a -CO2H or
-C(S)OH group, thereby resulting in -Cθ2Rx where Rx is defined herein. Also, Rx for example includes the enumerated ester groups of WO 95/07920. Examples of protecting groups include: C3-C12 heterocycle (described above) or aryl. These aromatic groups optionally are polycyclic or monocyclic. Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5-isothiazolyl, 3- and 4- pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and 5-pyrimidinyl,
C3-C12 heterocycle or aryl substituted with halo, R1, R^O-Ci-C^ alkylene, C1-C12 alkoxy, CN, NO2, OH, carboxy, carboxyester, thiol, thioester, C1-C12 haloalkyl (1-6 halogen atoms), C2-C12 alkenyl or C2-C12 alkynyl. Such groups include 2-, 3- and 4-alkoxyphenyl (C1-C12 alkyl), 2-, 3- and 4- methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5- diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4- hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6- hydroxyphenyl, 2-, 3- and 4-O-acetylphenyl, 2-, 3- and 4-dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4-halophenyl (including 2-, 3- and 4-fluorophenyl and 2-, 3- and 4-chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-biscarboxyethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dihalophenyl (including 2,4-difluorophenyl and 3,5-difluorophenyl), 2-, 3- and 4-haloalkylphenyl (1 to 5 halogen atoms, Ci-Ci2 alkyl including 4- trifluoromethylphenyl), 2-, 3- and 4-cyanophenyl, 2-, 3- and 4-nitrophenyl, 2-, 3- and 4-haloalkylbenzyl (1 to 5 halogen atoms, C1-C12 alkyl including 4- trifluoromethylbenzyl and 2-, 3- and 4-trichloromethylphenyl and 2-, 3- and 4- trichloromethylphenyl), 4-N-methylpiperidinyl, 3-N-methylpiperidinyl, 1- ethylpiperazinyl, benzyl, alkylsalicylphenyl (C1-C4 alkyl, including 2-, 3- and 4- ethylsalicylphenyl), 2-,3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl (-CioHβ- OH) and aryloxy ethyl [Q-C9 aryl (including phenoxy ethyl)], 2,2'- dihydroxybiphenyl, 2-, 3- and 4-N,N-dialkylaminophenol, -C6H4CH2-N(CH3)2, trimethoxybenzyl, triethoxybenzyl, 2-alkyl pyridinyl (Ci .4 alkyl);
Figure imgf000024_0001
esters of 2-carboxyphenyl; and C1-C4 alkylene-C3-C6 aryl (including benzyl, - CH2-pyrrolyl, -CH2-thienyl, -CH2-imidazolyl, -CH2-oxazolyl, -CH2-isoxazolyl, -CH2-thiazolyl, -CH2-isotliiazolyl, -CH2-pyrazolyl, -CH2-pyridinyl and -CH2- pyrimidinyl) substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen, C1-C12 alkoxy (including methoxy and ethoxy), cyano, nitro, OH, C1-C12 haloalkyl (1 to 6 halogen atoms; including - CH2CCI3), C1-C12 alkyl (including methyl and ethyl), C2-C12 alkenyl or C2-C12 alkynyl; alkoxy ethyl [Ci-C6 alkyl including -CH2-CH2-O-CH3 (methoxy ethyl)]; alkyl substituted by any of the groups set forth above for aryl, in particular OH or by 1 to 3 halo atoms (including -CH3j -CH(CH3)2, -C(CH3)3, - CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3, -CH2CH2F, - CH2CH2Cl, -CH2CF3, and -CH2CCl3);
Figure imgf000025_0001
propylmorpholino, 2,3-dihydro-6-hydroxyindene, sesamol, catechol monoester, - CH2-C(O)-N(Ri)2, -CH2-S(O)(R1), -CH2-S(O)2(R1), -CH2-CH(OC(O)CH2R1)- CH2(OC(O)CH2R1), cholesteryl, enolpyruvate (H00C-C(=CH2», glycerol; a 5 or 6 carbon monosaccharide, disaccharide or oligosaccharide (3 to 9 monosaccharide residues); triglycerides such as α-D-β-diglycerides (wherein the fatty acids composing glyceride lipids generally are naturally occurring saturated or unsaturated C6-26, C6-i8 or Cg.io fatty acids such as linoleic, lauric, myristic, palmitic, stearic, oleic, palmitoleic, linolenic and the like fatty acids) linked to acyl of the parental compounds herein through a glyceryl oxygen of the triglyceride; phospholipids linked to the carboxyl group through the phosphate of the phospholipid; phthalidyl (shown in Fig. 1 of Clayton et al, Antimicrob. Agents Chemo.
(1974) 5(6):670-671); cyclic carbonates such as (5-Rd-2-oxo-l,3-dioxolen-4-yl) methyl esters (Sakamoto et al., Chem. Pharm. Bull. (1984) 32(6)2241-2248) where Rd is Ri, R4 or aryl; and
-CH2C(O)N O N — / ;
The hydroxyl groups of the compounds of this invention optionally are substituted with one of groups III, IV or V disclosed in WO 94/21604, or with isopropyl.
Table A lists examples of protecting group ester moieties that for example can be bonded via oxygen to -C(O)O- and -P(0)(0-)2 groups. Several amidates also are shown, which are bound directly to -C(O)- or -P(0)2- Esters of structures 1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting the compound herein having a free hydroxyl with the corresponding halide (chloride or acyl chloride and the like) and N ^-dicyclohexyl-N-morpholine carboxamidine (or another base such as DBU, triethylamine, CsCO3, N,N-dimethylaniline and the like) in DMF (or other solvent such as acetonitrile or N-methylpyrrolidone). When the compound to be protected is a phosphonate, the esters of structures 5-7, 11, 12, 21, and 23-26 are synthesized by reaction of the alcohol or alkoxide salt (or the corresponding amines in the case of compounds such as 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate (or another activated phosphonate).
Figure imgf000026_0001
1. -CH2-C(O)-N(Ri)2 * 10. -CH2-O-C(O)-C(CH3)3
2. -CH2-S(O)(Ri) 11. -CH2-CCl3
3. -CH2-S(O)2(Ri) 12. -C6H5
4. -CH2-O-C(O)-CH2-C6H5 13. -NH-CH2-C(O)O-CH2CH3
5. 3-cholesteryl 14. -N(CH3)-CH2-C(O)O-CH2CH3
6. 3-pyridyl 15. -NHRi
7. N-ethylmorpholino 16. -CH2-O-C(O)-Ci0Hi5
8. -CH2-O-C(O)-C6H5 17. -CH2-O-C(O)-CH(CH3)2
9. -CH2-O-C(O)-CH2CH3 18. -CH2-C#H(OC(O)CH2Ri)-CH2- -(0C(O)CH2Ri)*
Figure imgf000026_0002
Figure imgf000026_0003
Figure imgf000027_0001
# - chiral center is (R), (S) or racemate.
Other esters that are suitable for use herein are described in EP 632048. Protecting groups also includes "double ester" forming profunctionalities
such as -CH2θC(O)OCH3,
Figure imgf000027_0002
-CH2SCOCH3, -CH2θCON(CH3)2, or alkyl- or aryl-acyloxyalkyl groups of the structure -CH(R1 or W5)O((CO)R37) or -CH(R1 or W5X(CO)OR38) (linked to oxygen of the acidic group) wherein R37 and R38 are alkyl, aryl, or alkylaryl groups (see U.S. Patent No. 4968788). Frequently R37 and R38 are bulky groups such as branched alkyl, ortho- substituted aryl, meta-substituted aryl, or combinations thereof, including normal, secondary, iso- and tertiary alkyls of 1-6 carbon atoms. An example is the pivaloyloxymethyl group. These are of particular use with prodrugs for oral administration. Examples of such useful protecting groups are alkylacyloxymethyl esters and their derivatives, including -
CH(CH2CH2θCH3)OC(O)C(CH3)3,
Figure imgf000027_0003
CH2OC(O)CI0HI5, -CH2OC(O)C(CH3)3, -CH(CH2OCH3)OC(O)C(CH3)3, - CH(CH(CH3)2)OC(O)C(CH3)3, -CH2OC(O)CH2CH(CH3)2, - CH2OC(O)C6Hn, -CH2OC(O)C6H5, -CH2OC(O)CI0HI5, - CH2OC(O)CH2CH3, -CH2OC(O)CH(CH3)2 , -CH2OC(O)C(CH3)3 and - CH2OC(O)CH2C6H5. hi some embodiments the protected acidic group is an ester of the acidic group and is the residue of a hydroxyl-containing functionality. In other embodiments, an amino compound is used to protect the acid functionality. The residues of suitable hydroxy! or amino-containing functionalities are set forth above or are found in WO 95/07920. Of particular interest are the residues of amino acids, amino acid esters, polypeptides, or aryl alcohols. Typical amino acid, polypeptide and carboxyl-esterified amino acid residues are described on pages 11-18 and related text of WO 95/07920 as groups Ll or L2. WO 95/07920 expressly teaches the amidates of phosphonic acids, but it will be understood that such amidates are formed with any of the acid groups set forth herein and the amino acid residues set forth in WO 95/07920.
Typical esters for protecting acidic functionalities are also described in WO 95/07920, again understanding that the same esters can be formed with the acidic groups herein as with the phosphonate of the '920 publication. Typical ester groups are defined at least on WO 95/07920 pages 89-93 (under R^ 1 or
R35)S the table on page 105, and pages 21-23 (as R). Of particular interest are esters of unsubstituted aryl such as phenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy- and/or alkylestercarboxy-substituted aryl or alkylaryl, especially phenyl, ortho-ethoxyphenyl, or C1-C4 alkylestercarboxyphenyl (salicylate C1-C12 alkylesters).
The protected acidic groups, particularly when using the esters or amides of WO 95/07920, are useful as prodrugs for oral administration. However, it is not essential that the acidic group be protected in order for the compounds of this invention to be effectively administered by the oral route. When the compounds of the invention having protected groups, in particular amino acid amidates or substituted and unsubstituted aryl esters are administered systemically or orally they are capable of hydro lytic cleavage m vivo to yield the free acid.
One or more of the acidic hydroxyls are protected. If more than one acidic hydroxyl is protected then the same or a different protecting group is employed, e.g., the esters may be different or the same, or a mixed amidate and ester may be used.
Typical hydroxy protecting groups described in Greene (pages 14-118) include substituted methyl and alkyl ethers, substituted benzyl ethers, silyl ethers, esters including sulfonic acid esters, and carbonates. For example:
• Ethers (methyl, /"-butyl, allyl);
• Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, t- Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p- Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t- Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl, 2- Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2- cliloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3-
Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, A- Methoxytetrahydropyranyl, 4-Methoxytetrahydrotliiopyranyl, A- Methoxytetrahydropthiopyranyl .S^-Dioxido, l-[(2-Chloro-4- methyl)phenyl] -4-methoxypiperidin-4-yl, 1 ,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-Octahydro-
7,8,8-trimethyl-4,7-methanobenzofuran-2-yl));
• Substituted Ethyl Ethers ( 1 -Ethoxyethyl, 1 -(2-Chloroethoxy)ethyl, 1 -Methyl- 1 -methoxyethyl, 1 -Methyl- 1 -benzyloxyethyl, 1 -Methyl- 1 -benzyloxy-2- fluoroethyl, 2,2,2-Trichloroethyl, 2-Trimethylsilylethyl, 2- (Phenylselenyl)ethyl,
• /?-Chlorophenyl,/?-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl);
• Substituted Benzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o- Nitrobenzyl, />-Nitrobenzyl, />-Halobenzyl, 2,6-Dichlorobenzyl, p- Cyanobenzyl,j9~Phenylbenzyl, 2- and 4-Picolyl, 3-Methyl-2-picolyl iV- Oxido, Diphenylmethyl^jp'-Dinitrobenzhydryl, 5-Dibenzosuberyl,
Triphenylmethyl, α-Naphthyldiphenylmethyl, /?- methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Tri(ρ- methoxyphenyl)methyl, 4-(4'-Bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-Tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"- Tris(levulinoyloxyphenyl)methyl, 4,4',4"-Tris(benzoyloxyphenyl)methyl, 3-
•(hnidazόl- 1 -ylmethyl)bis(4',4"-dimethoxyphenyl)methyl, 1 , 1 -Bis(4- methoxyphenyl)-r-pyrenylmethyl, 9-Anthryl, 9-(9-Phenyl)xanthenyl, 9-(9- Phenyl-10-oxo)anthryl, l,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S- Dioxido); • Silyl Ethers (Trimethylsilyl, Triethylsilyl, Triisopropylsilyl,
Dimethylisopropylsilyl, Diethylisopropylsilyl, Dimethylthexylsilyl, t- Butyldimethylsilyl, t-Butyldiphenylsilyl, Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl, ^-Butylmethoxyphenylsilyl); • Esters (Formate, Benzoylformate, Acetate, Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate, Methoxyacetate,
Triphenylmethoxyacetate, Phenoxyacetate, jp-Chlorophenoxyacetate, p-poly- Phenylacetate, 3-Phenylpropionate, 4-Oxopentanoate (Levulinate), 4,4- (Ethylenedithio)pentanoate, Pivaloate, Adamantoate, Crotonate, 4-
Methoxycrotonate, Benzoate, />-Phenylbenzoate, 2,4,6-Trimethylbenzoate (Mesitoate));
• Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl, 2,2,2-Trichloroethyl, 2- (Trimethylsilyl)ethyl, 2-(Phenylsulfonyl)ethyl, 2- (Triphenylphosphonio)ethyl, Isobutyl, Vinyl, Allyl,/>-Nitrophenyl, Benzyl, j3-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl, /?-Nitrobenzyl, S- Benzyl Thiocarbonate, 4-Ethoxy-l-naphthyl, Methyl Dithiocarbonate);
• Groups With Assisted Cleavage (2-Iodobenzoate, 4-Azidobutyrate, 4-Nitro- 4-methylpentanoate, o-(Dibromomethyl)benzoate, 2- Formylbenzenesulfonate, 2-(Methylthiomethoxy)ethyl Carbonate, 4-
(Methylthiomethoxy)butyrate, 2-(Methylthiomethoxymethyl)benzoate); Miscellaneous Esters (2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro- 4-(l,l,3,3 tetramethylbutyl)phenoxyacetate, 2,4-Bis(l,l- dimethylpropyl)phenoxyacetate, Chlorodiphenylacetate, Isobutyrate, Monosuccinate, (E)-2-Methyl-2-butenoate (Tigloate), o-
(Methoxycarbonyl)benzoate,p-poly-Benzoate, α-Naphthoate, Nitrate, Alkyl N,iV;N'iV'-Tetramethylphosphorodiamidate, iV-Phenylcarbamate, Borate, Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); and
• Sulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate, Tosylate).
Typical 1,2-diol protecting groups (thus, generally where two OH groups are taken together with the protecting functionality) are described in Greene at pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1- ΛButylethylidene, 1-Phenylethylidene, (4-Methoxyphenyl) ethylidene, 2,2,2- Trichloroethylidene, Acetonide (Isopropylidene), Cyclopentylidene,
Cyclohexylidene, Cycloheptylidene, Benzylidene, j3-Methoxybenzylidene, 2,4- Dimethoxybenzylidene, 3,4-Dimethoxybenzylidene, 2-Νitrobenzylidene); Cyclic Ortho Esters (Methoxymethylene, Ethoxymethylene, Dimethoxymethylene, 1- Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene, α- Methoxybenzylidene, l-(N,Λf-Dimethylamino)ethylidene Derivative, α -(NN- Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene); Silyl Derivatives (Di-t-butylsilylene Group, 1,3 -(1,1,3,3- Tetraisopropyldisiloxanylidene), and Tetra-r-butoxydisiloxane-l,3-diylidene), Cyclic Carbonates, Cyclic Boronates, Ethyl Boronate and Phenyl Boronate.
More typically, 1,2-diol protecting groups include those shown in Table B, still more typically, epoxides, acetonides, cyclic ketals and aryl acetals.
Table B
Figure imgf000032_0001
wherein R^ is Cl -C6 alkyl.
Amino protecting groups
Another set of protecting groups include any of the typical amino protecting groups described by Greene at pages 315-385. They include:
• Carbamates: (methyl and ethyl, 9-fluorenylmethyl, 9(2- sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t-butyl-[9- (10,10-dioxo- 10,10,10,10-tetrahydrothioxanthyl)]methyl, 4- methoxyphenacyl);
• Substituted Ethyl: (2,2,2-trichoroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1 -(I -adamantyl)- 1 -methylethyl, 1 , 1 -dimethyl-2-haloethyl, 1 , 1 -dimethyl-2,2- dibromoethyl, 1 , 1 -dimethyl-2,2,2-trichloroethyl, 1 -methyl- 1 -(4- * ■ biphenylyl)etliyl, 1 -(3 ,5 -di-t-butylphenyl)- 1 -methylethyl, 2-(T- and 4'- pyridyl)ethyl, 2-(ΛζiV-dicyclohexylcarboxamido)ethyl, t-butyl, 1 -adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N- hydroxypiperidinyl, alkyldithio, benzyl, />-methoxybenzyl, /?-nitrobenzyl, p- bromobenzyl, />-chlorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl);
• Groups With Assisted Cleavage: (2-methylthioethyl, 2-methylsulfonylethyl, 2-(ρ-toluenesulfonyl)ethyl, [2-(l ,3-dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2-phosphonioethyl, 2- triphenylphosphonioisopropyl, 1 ,l-dimethyl-2-cyanoethyl, m-c\\oxo-p- acyloxybenzyl, j!?-(dihydroxyboryl)benzyl, 5-benzisoxazolylmethyl, 2- (trifluoiOmethyl)-6-chromonylmethyl);
• Groups Capable of Photolytic Cleavage: (m-nitrophenyl, 3,5- dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl(ø- nitrophenyl)methyl); Urea-Type Derivatives (phenothiazinyl-(lθ)-carbonyl,
N-j^-toluenesulfonylaminocarboiiyl, N'-phenylaminothiocarbonyl) ;
• Miscellaneous Carbamates: (Y-amyl, iS-benzyl thiocarbamate, /?-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, ø-(NN- dimethylcarboxamido)benzyl, l,l-dimethyl-3-(N,N- dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2- ruranylmethyl, 2-Iodoethyl, Isobornyl, Isobutyl, Isonicotinyl, p-(p'- Methoxyphenylazo)benzyl, 1-metliylcyclobutyl, 1-methylcyclohexyl, 1- methyl-1 -cyclopropylmethyl, l-methyl-l-(3,5-dimethoxyphenyl)ethyl, 1- methyl- l-(p-phenylazophenyl)ethyl, 1 -methyl- 1-phenylethyl, 1 -methyl- 1 -(4- pyridyl)ethyl, phenyl, />-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, A- (trimethylammonium)benzyl, 2,4,6-trimethylbenzyl);
• Amides: (N-formyl, JV-acetyl, N-choroacetyl, iV-trichoroacetyl, N- trifluoroacetyl, JV-phenylacetyl, iV-3-phenylpropionyl, N-picolinoyl, N-3- pyridylcarboxamide, N-benzoylphenylalanyl, iV-benzoyl, N-p- phenylbenzoyl);
• Amides With Assisted Cleavage: (N-o-nitrophenylacetyl, N-o- nitrophenoxyacetyl, iV-acetoacetyl, (N'- dithiobenzyloxycarbonylamino)acetyl, N-3 -(p-hydroxyphenyl)propionyl, N- 3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o-nitrophenoxy)propionyl, N-2- methyl-2-(o-phenylazophenoxy)propionyl, N-4-clilorobutyryl, N-3 -methyl-3 - nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine, N-o-nitrobenzoyl, N- o-(benzoyloxymethyl)benzoyl, 4,5-diphenyl-3-oxazolin-2-one);
• Cyclic Imide Derivatives: (N-phthalimide, N-dithiasuccinoyl, N-2,3- diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N-1, 1,4,4- tetramethyldisilylazacyclopentane adduct, 5-substituted l,3-dimethyl-l,3,5- triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3-5-triazacyclohexan-2- one, 1 -substituted 3,5-dinitro-4-pyridonyl); • N-Alkyl and N-Aryl Amines: (iV-methyl, N-allyl, N-[I- (trimethylsilyl)ethoxy]methyl, N-3 -acetoxypropyl, N-( 1 -isopropyl-4-nitro-2- oxo-3-pyπOlin-3-yl), Quaternary Ammonium Salts, N-benzyl, N-di(4- methoxyphenyl)methyl, iV-5-dibenzosuberyl, N-triphenylmethyl, N-(4- niethoxyphenyl)diphenylmethyl, N-9-phenylfluorenyl, N-2,7-dichloro-9- fluorenylmethylene, N-ferrocenylmethyl, N-2-picolylamine N-oxide);
• Imine Derivatives: (N-l,l-dimethylthiomethylene, N-benzylidene, N-p- methoxybenylidene, N-diplienylmethylene, iV-[(2-pyridyl)mesityl]methylene, iV,(7V,iV-dimetliylaminomethylene, iV,iV-isopropylidene, N-p- nitrobenzylidene, iV-salicylidene, iV-5-chlorosalicylidene, JV-(5-chloro-2- hydroxyphenyl)phenylmethylene, N-cyclohexylidene) ;
• Enamine Derivatives: (/^-(S^-dimethyl-S-oxo-l-cyclohexenyl));
• N-Metal Derivatives (iV-borane derivatives, N-diphenylborinic acid derivatives, 7V-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, N- copper or N-zinc chelate) ;
• Ν-Ν Derivatives: (N-nitro, N-nitroso, iV-oxide);
• N-P Derivatives: (N-diphenylphospliinyl, N-dimetliylthiophosphinyl, N- diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, N- diphenyl phosphoryl); • N-Si Derivatives, N-S Derivatives, and N-Sulfenyl Derivatives: (N- benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4-dinitrobenzenesulfenyl, N- pentachlorobenzenesulfenyl, N-2-nitro-4-methoxybenzenesulfenyl, N- triphenylmethylsulfenyl, N-3-nitropyridinesulfenyl); and N-sulfonyl Derivatives (N-p-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl-4- methoxybenzenesulfonyl, N-2,4,6-trimethoxybenzenesulfonyl, N-2,6- dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N- 2,3,5,6,-tetramethyl-4-methoxybenzenesulfonyl, N-4- methoxybenzenesulfonyl, N-2,4,6-trimethylbenzenesulfonyl, N-2,6- dimethoxy-4-methylbenzenesulfonyl, N-2,2,5,7,8-pentamethylclτroman-6- sulfonyl, N-methanesulfonyl, N-β-trimethylsilyethanesulfonyl, N-9- anthracenesulfonyl, N-4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl, N-phenacylsulfonyl) .
More typically, protected amino groups include carbamates and amides, still more typically, -NHC(O)R1 or -N=CR1N(R1^. Another protecting group, also useful as a prodrug for amino or -NH(R5), is:
Figure imgf000035_0001
See for example Alexander, J. et al. (1996) J. Med Chem. 39:480-486.
Amino acid and polypeptide protecting group and conjugates
An amino acid or polypeptide protecting group of a compound of the invention has the structure R15NHCH(R16)C(O)-, where R15 is H, an amino acid or polypeptide residue, or R5, and R16 is defined below.
R16 is lower alkyl or lower alkyl (Ci-Ce) substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl, C6-C7 aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate. R10 also is taken together with the amino acid α N to form a proline residue (R10 = -CH2)3-). However, R10 is generally the side group of a naturally-occurring amino acid such as H, - CH3, -CH(CH3)2, -CH2-CH(CH3)2, -CHCH3-CH2-CH3, -CH2-C6H5, -CH2CH2- S-CH3, -CH2OH, -CH(OH)-CH3, -CH2-SH, -CH2-C6H4OH, -CH2-CO-NH2, - CH2-CH2-CO-NH2, -CH2-COOH, -CH2-CH2-COOH, -(CH2)4-NH2 and - (CH2)3-NH-C(NH2)-NH2. Rio also includes l-guanidinoprop-3-yl, benzyl, A- hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl. Another set of protecting groups include the residue of an amino- containing compound, in particular an amino acid, a polypeptide, a protecting group, -NHSO2R NHC(O)R, -N(R)2, NH2 or -NH(R)(H)5 whereby for example a carboxylic acid is reacted, i.e. coupled, with the amine to form an amide, as in C(O)NR2. A phosphonic acid may be reacted with the amine to form a phosphonamidate, as in -P(O)(OR)(NR2). In general, amino acids have the structure R17C(O)CH(R16)NH-, where
R17 is -OH, -OR, an amino acid or a polypeptide residue. Amino acids are low molecular weight compounds, on the order of less than about 1000 MW and which contain at least one amino or imino group and at least one carboxyl group. Generally the amino acids will be found in nature, i.e., can be detected in biological material such as bacteria or other microbes, plants, animals or man. Suitable amino acids typically are alpha amino acids, i.e. compounds characterized by one amino or imino nitrogen atom separated from the carbon atom of one carboxyl group by a single substituted or unsubstituted alpha carbon atom. Of particular interest are hydrophobic residues such as mono-or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the partition coefficient of the parental drug. Typically, the residue does not contain a sulfhydryl or guanidino substituent. Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof. Polypeptides most typically will be substantially composed of such naturally- occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline. Additionally, unnatural amino acids, for example, valanine, phenylglycine and homoarginine are also included. Commonly encountered amino acids that are not gene- encoded may also be used in the present invention. All of the amino acids used in the present invention may be either the D- or L- optical isomer. In addition, other peptidomimetics are also useful in the present invention. For a general review, see Spatola, A. F., in Chemistry and Biochemistry of Amino Acids, Peptides and Proteins, B. Weinstein, eds., Marcel Dekker, New York, p. 267 (1983). When protecting groups are single amino acid residues or polypeptides they optionally are substituted at R3 of substituents A1, A2 or A3 in a compound of the invention. These conjugates are produced by forming an amide bond between a carboxyl group of the amino acid (or C-terminal amino acid of a polypeptide for example). Similarly, conjugates are formed between R3 and an amino group of an amino acid or polypeptide. Generally, only one of any site in the parental molecule is amidated with an amino acid as described herein, although it is within the scope of this invention to introduce amino acids at more than one permitted site. Usually, a carboxyl group of R3 is amidated with an amino acid. In general, the α-amino or α-carboxyl group of the amino acid or the terminal amino or carboxyl group of a polypeptide are bonded to the parental functionalities, i.e., carboxyl or amino groups in the amino acid side chains generally are not used to form the amide bonds with the parental compound (although these groups may need to be protected during synthesis of the conjugates as described further below).
With respect to the carboxyl-containing side chains of amino acids or polypeptides it will be understood that the carboxyl group optionally will be blocked, e.g., by R1, esterified with R5 or amidated. Similarly, the amino side chains R16 optionally will be blocked with R1 or substituted with R5.
Such ester or amide bonds with side chain amino or carboxyl groups, like the esters or amides with the parental molecule, optionally are hydrolyzable in vivo or in vitro under acidic (pH <3) or basic (pH >10) conditions. Alternatively, they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments. The esters or amino acid or polypeptide amidates also are useful as intermediates for the preparation of the parental molecule containing free amino or carboxyl groups. The free acid or base of the parental compound, for example, is readily formed from the esters or amino acid or polypeptide conjugates of this invention by conventional hydrolysis procedures.
When an amino acid residue contains one or more chiral centers, any of the D, L, meso, threo or erythro (as appropriate) racemates, scalemates or mixtures thereof may be used. In general, if the intermediates are to be hydrolyzed non-enzymatically (as would be the case where the amides are used as chemical intermediates for the free acids or free amines), D isomers are useful. On the other hand, L isomers are more versatile since they can be susceptible to both non-enzymatic and enzymatic hydrolysis, and are more efficiently transported by amino acid or dipeptidyl transport systems in the gastrointestinal tract. Examples of suitable amino acids whose residues are represented by Rx or Ry include the following: Glycine;
Aminopolycarboxylic acids, e.g., aspartic acid, β-hydroxyaspartic acid, glutamic acid, β -hydroxyglutamic acid, β-methylaspartic acid, β-methylglutamic acid, β, β-dimethylaspartic acid, γ-hydroxyglutamic acid, β, γ-dihydroxyglutamic acid, β -phenylglutamic acid, γ-methyleneglutamic acid, 3-aminoadipic acid, 2- aminopimelic acid, 2-aminosuberic acid and 2-aminosebacic acid; Amino acid amides such as glutamine and asparagine;
Polyamino- or polybasic-nionocarboxylic acids such as arginine, lysine, β -aminoalanine, γ -aminobutyrine, ornithine, citruline, homoarginine, homocitruUine, hydroxylysine, allohydroxylsine and diaminobutyric acid;
Other basic amino acid residues such as histidine; Diaminodicarboxylic acids such as α, α'-diaminosuccinic acid, α, α'- diaminoglutaric acid, α, α'-diaminoadipic acid, α, α'-diaminopimelic acid, α, α1- diamino- β-hydroxypimelic acid, α, α'-diaminosuberic acid, α, α'-diaminoazelaic acid, and α, α'-diaminosebacic acid;
Imino acids such as proline, hydroxyproline, allohydroxyproline, γ- methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2- carboxylic acid;
A mono- or di-alkyl (typically Ci-Cs branched or normal) amino acid such as alanine, valine, leucine, allylglycine, butyrine, norvaline, norleucine, heptyline, α-methylserine, α-amino-α-methyl-γ-hydroxyvaleric acid, α-amino- α- methyl-δ-hydroxyvaleric acid, α-amino- α-methyl-ε-hydroxycaproic acid, isovaline, α-methylglutamic acid, α-aminoisobutyric acid, α-aminodiethylacetic acid, α-aminodiisopropylacetic acid, a-aminodi-n-propylacetic acid, α- aminodiisobutylacetic acid, α-aminodi-n-butylacetic acid, α- aminoethylisopropylacetic acid, α-amino-n-propylacetic acid, α- aminodiisoamyacetic acid, α-methylaspartic acid, α-methylglutamic acid, 1- aminocyclopropane-1-carboxylic acid, isoleucine, alloisoleucine, tert-leucine, β- methyltryptophan and α-amino- β-ethyl-β-phenylpropionic acid; β-phenylserinyl;
Aliphatic α-amino- β-hydroxy acids such as serine, β-hydroxyleucine, β- hydroxynorleucine, β -hydroxynorvaline, and α-amino-β-hydroxystearic acid; α-Amino, α-, γ-, δ- or ε-hydroxy acids such as homoserine, δ - hydroxynorvaline, γ-hydroxynorvaline and ε-hydroxynorleucine residues; canavine and canaline; γ -hydroxyornithine; 2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminic acid; α-Amino-β-thiols such as penicillamine, β-thiolnorvaline or β- thiolbutyrine; Other sulfur containing amino acid residues including cysteine; homocystine, β-phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2- thiolhistidine, cystathionine, and thiol ethers of cysteine or homocysteine;
Phenylalanine, tryptophan and ring-substituted α-amino acids such as the phenyl- or cyclohexylamino acids α-aminophenylacetic acid, α- aminocyclohexylacetic acid and α-amino-β-cyclohexylpropionic acid; phenylalanine analogues and derivatives comprising aryl, lower alkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-, 3,4-dichloro, o~, m- or ^-methyl-, 2,4,6- trimethyl-, 2-ethoxy-5-nitro-, 2-hydroxy-5 -nitro- and p-nitro-phenylalanine); furyl-, thienyl-, pyridyl-, pyrimidinyl-, purinyl- or naphthyl-alanines; and tryptophan analogues and derivatives including kynurenine, 3- hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophan; α-Amino substituted amino acids including sarcosine (N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine, N-methylphenylalanine, N- benzylphenylalanine, N-methylvaline and N-benzylvaline; and α-Hydroxy and substituted α -hydroxy amino acids including serine, threonine, allothreonine, phosphoserine and phosphothreonine.
Polypeptides are polymers of amino acids in which a carboxyl group of one amino acid monomer is bonded to an amino or imino group of the next amino acid monomer by an amide bond. Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000 MW) and proteins. Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, and suitably are substantially sequence-homologous with human, animal, plant or microbial proteins. They include enzymes (e.g., hydrogen peroxidase) as well as immunogens such as KLH, or antibodies or proteins of any type against which one wishes to raise an immune response. The nature and identity of the polypeptide may vary widely.
The polypeptide amidates are useful as immunogens in raising antibodies against either the polypeptide (if it is not immunogenic in the animal to which it is administered) or against the epitopes on the remainder of the compound of this invention.
Antibodies capable of binding to the parental non-peptidyl compound are used to separate the parental compound from mixtures, for example in diagnosis or manufacturing of the parental compound. The conjugates of parental compound and polypeptide generally are more immunogenic than the polypeptides in closely homologous animals, and therefore make the polypeptide more immunogenic for facilitating raising antibodies against it. Accordingly, the polypeptide or protein may not need to be immunogenic in an animal typically used to raise antibodies, e.g., rabbit, mouse, horse, or rat, but the final product conjugate should be immunogenic in at least one of such animals. The polypeptide optionally contains a peptidolytic enzyme cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatom. Such cleavage sites are flanked by enzymatic recognition structures, e.g., a particular sequence of residues recognized by a peptidolytic enzyme.
Peptidolytic enzymes for cleaving the polypeptide conjugates of this invention are well known, and in particular include carboxypeptidases. Carboxypeptidases digest polypeptides by removing C-terminal residues, and are specific in many instances for particular C-terminal sequences. Such enzymes and their substrate requirements in general are well known. For example, a dipeptide (having a given pair of residues and a free carboxyl terminus) is covalently bonded through its α-amino group to the phosphorus or carbon atoms of the compounds herein. In embodiments where Wl is phosphonate it is expected that this peptide will be cleaved by the appropriate peptidolytic enzyme, leaving the carboxyl of the proximal amino acid residue to autocatalytically cleave the phosplionoamidate bond.
Suitable dipeptidyl groups (designated by their single letter code) are AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, CI, CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG, EH, EI, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE, QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM, KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK, MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE, SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, TT, TW, TY, TV, WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW, YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS, VT, VW, VY and VV.
Tripeptide residues are also useful as protecting groups. When a phosphonate is to be protected, the sequence -X -pro-X5- (where X is any amino acid residue and X5 is an amino acid residue, a carboxyl ester of proline, or hydrogen) will be cleaved by luminal carboxypeptidase to yield X4 with a free carboxyl, which in turn is expected to autocatalytically cleave the phosphonoamidate bond. The carboxy group of X5 optionally is esterified with benzyl.
Dipeptide or tripeptide species can be selected on the basis of known transport properties and/or susceptibility to peptidases that can affect transport to intestinal mucosal or other cell types. Dipeptides and tripeptides lacking an α- amino group are transport substrates for the peptide transporter found in brush border membrane of intestinal mucosal cells (Bai, J.P.F., (1992) Pharm Res. 9:969-978). Transport competent peptides can thus be used to enhance bioavailability of the amidate compounds. Di- or tripeptides having one or more amino acids in the D configuration are also compatible with peptide transport and can be utilized in the amidate compounds of this invention. Amino acids in the D configuration can be used to reduce the susceptibility of a di- or tripeptide to hydrolysis by proteases common to the brush border such as aminopeptidase N. hi addition, di- or tripeptides alternatively are selected on the basis of their relative resistance to hydrolysis by proteases found in the lumen of the intestine. For example, tripeptides or polypeptides lacking asp and/or glu are poor substrates for aminopeptidase A, di- or tripeptides lacking amino acid residues on the N-terminal side of hydrophobic amino acids (leu, tyr, phe, val, tip) are poor substrates for endopeptidase, and peptides lacking a pro residue at the penultimate position at a free carboxyl terminus are poor substrates'for carboxypeptidase P. Similar considerations can also be applied to the selection of peptides that are either relatively resistant or relatively susceptible to hydrolysis by cytosolic, renal, hepatic, serum or other peptidases. Such poorly cleaved polypeptide amidates are immunogens or are useful for bonding to proteins in order to prepare immunogens.
Specific Embodiments of the Invention
Specific values described for radicals, substituents, and ranges, as well as specific embodiments of the invention described herein, are for illustration only; they do not exclude other defined values or other values within defined ranges.
In one specific embodiment of the invention A1 is of the formula:
Figure imgf000042_0001
M12b
In another specific embodiment of the invention A1 is of the formula:
Figure imgf000043_0001
M12b
In another specific embodiment of the invention A1 is of the formula:
Figure imgf000043_0002
M12b
In another specific embodiment of the invention A1 is of the formula:
Figure imgf000043_0003
In another specific embodiment of the invention A is of the formula:
Figure imgf000043_0004
and W5a is a carbocycle or a heterocycle where W5a is independently substituted with 0 or 1 R2 groups. A specific value for M12a is 1. In another specific embodiment of the invention A1 is of the formula:
Figure imgf000044_0001
M12b
In another specific embodiment of the invention A1 is of the formula:
Figure imgf000044_0002
M12a
In another specific embodiment of the invention A1 is of the formula:
Figure imgf000044_0003
wherein W5a is a carbocycle independently substituted with 0 or 1 R2 groups; In another specific embodiment of the invention A1 is of the formula:
Figure imgf000044_0004
wherein Y r2/bD . is O or N(RZ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. In another specific embodiment of the invention A1 is of the formula:
Figure imgf000045_0001
M12a wherein W5a is a carbocycle independently substituted with 0 or 1 R2 groups; In another specific embodiment of the invention A1 is of the formula:
Figure imgf000045_0002
wherein W5a is a carbocycle or heterocycle where W5a is independently substituted with 0 or 1 R groups. hi another specific embodiment of the invention A1 is of the formula:
Figure imgf000045_0003
wherein Y r2/bD is O or N(RZ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In a specific embodiment of the invention A2 is of the formula:
Figure imgf000046_0001
M12b
In another specific embodiment of the invention A is of the formula:
Figure imgf000046_0002
M12b
hi another specific embodiment of the invention M 12b is 1.
In another specific embodiment of the invention M 12b is 0, Y2 is a bond and W5 is a carbocycle or heterocycle where W5 is optionally and independently substituted with 1, 2, or 3 R groups.
In another specific embodiment of the invention A2 is of the formula:
Figure imgf000046_0003
M12a wherein W5a is a carbocycle or heterocycle where W5a is optionally and independently substituted with 1 , 2, or 3 R groups. hi another specific embodiment of the invention M 12a is 1. In another specific embodiment of the invention A2 is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl and substituted pyridyl.
In another specific embodiment of the invention A2 is of the formula:
Figure imgf000047_0001
M12b
In another specific embodiment of the invention A2 is of the formula:
Figure imgf000047_0002
In another specific embodiment of the invention Ml 2b is 1. hi a specific embodiment of the invention A is of the formula:
Figure imgf000047_0003
M12b In another specific embodiment of the invention A3 is of the formula:
Figure imgf000048_0001
Ml 2a
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000048_0002
M12a wherein Yla is O or S; and Y2a is O, N(RX) or S.
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000048_0003
M12a wherein Y2b is O or N(Rx).
In another specific embodiment of the invention A is of the formula:
Figure imgf000049_0001
M12d wherein Y2b is O or N(RX); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000049_0002
M12d wherein Y2b is O or N(RX); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In another specific embodiment of the invention M12d is 1.
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000049_0003
M12b
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000050_0001
M12b
In another specific embodiment of the invention W5 is a carbocycle. In another specific embodiment of the invention A3 is of the formula:
Figure imgf000050_0002
M12b
hi another specific embodiment of the invention W5 is phenyl.
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000050_0003
wherein Yla is O or S; and Y2a is O, N(RX) or S.
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000051_0001
wherein Y2Ms O or N(RX).
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000051_0002
wherein Y2b is O or N(RX); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. In another specific embodiment of the invention R1 is H. In another specific embodiment of the invention A3 is of the formula:
Figure imgf000051_0003
wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R2 groups.
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000052_0001
In another specific embodiment of the invention A 3 i •s of the formula:
Figure imgf000052_0002
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000052_0003
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000053_0001
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000053_0002
M12a wherein Yla is O or S; and Y2a is O, N(R2) or S. hi another specific embodiment of the invention A3 is of the formula:
Figure imgf000053_0003
Ml 2a
wherein Yla is O or S; Y2b is O or N(R2); and Y2c is O, N(Ry) or S. In another specific embodiment of the invention A3 is of the formula:
Figure imgf000054_0001
M12d wheren Yla is O or S; Y2b is O or N(R2); Y2d is O or N(Ry); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000054_0002
M12d
wherein Y2b is O or N(R2); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000054_0003
wherein Y2b is O or N(R2).
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000054_0004
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000055_0001
M12a
hi another specific embodiment of the invention A3 is of the formula:
Figure imgf000055_0002
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000055_0003
wherein Yla is O or S; Y2b is O or N(R2); and Y2c is O, N(Ry) or S.
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000056_0001
wherein Yla is O or S; Y2b is O or N(R2); Y2d is O or N(Ry); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000056_0002
wherein Y2b is O or N(R2); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000056_0003
wherein Y2b is O or N(R2).
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000056_0004
wherein: Y r22bb is O or N(RX); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8. In another specific embodiment of the invention A3 is of the formula:
Figure imgf000057_0001
wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R2 groups.
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000057_0002
wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R2 groups.
In another specific embodiment of the invention A3 is of the formula:
Figure imgf000057_0003
hi a specific embodiment of the invention A0 is of the formula:
Figure imgf000058_0001
wherein each R is independently (C1-C6)EIlCyI.
In a specific embodiment of the invention Rx is independently H, R1, W3, a protecting group, or the formula:
Figure imgf000058_0002
wherein:
Ry is independently H, W3, R2 or a protecting group;
R1 is independently H or alkyl of 1 to 18 carbon atoms;
R2 is independently H, R1, R3 or R4 wherein each R4 is independently substituted with 0 to 3 R groups or taken together at a carbon atom, two R groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R3 groups; wherein R3 is as defined herein.
In a specific embodiment of the invention Rx is of the formula:
Figure imgf000058_0003
wherein Yla is O or S; and Y2c is O, N(Ry) or S.
In a specific embodiment of the invention Rx is of the formula:
Figure imgf000059_0001
wherein Yla is O or S; and Y2d is O or N(Ry).
In a specific embodiment of the invention Rx is of the formula:
Figure imgf000059_0002
In a specific embodiment of the invention Ry is hydrogen or alkyl of 1 to 10 carbons. hi a specific embodiment of the invention Rx is of the formula:
Figure imgf000059_0003
In a specific embodiment of the invention Rx is of the formula:
Figure imgf000059_0004
In a specific embodiment of the invention Rx is of the formula:
Figure imgf000060_0001
In a specific embodiment of the invention Y1 is O or S
In a specific embodiment of the invention Y2 is O, N(Ry) or S.
In one specific embodiment of the invention Rx is a group of the formula:
Figure imgf000060_0002
wherein: ml a, mlb, mlc, mid and mle are independently 0 or 1; ml2c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
Ry is H, W3, R2 or a protecting group; wherein W3, R2, Y1 and Y2 are as defined herein; provided that: if mla, ml2c, and mid are 0, then mlb, mlc and mle are 0; if mla and ml2c are 0 and mid is not 0, then mlb and mlc are 0; if mla and mid are 0 and ml2c is not 0, then mlb and at least one of mlc and mle are 0; if mla is 0 and ml2c and mid are not 0, then mlb is 0; if ml 2c and mid are 0 and mla is not 0, then at least two of mlb, mlc and mle are 0; if ml2c is 0 and mla and mid are not 0, then at least one of mlb and mlc are 0; and if mid is 0 and ml a and ml 2c are not 0, then at least one of mlc and mle are 0.
In compounds of the invention W5 carbocycles and W5 heterocycles may be independently substituted with 0 to 3 R2 groups. W5 may be a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle. W5 may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms. The W5 rings are saturated when containing 3 ring atoms, saturated or mono-unsaturated when containing 4 ring atoms, saturated, or mono- or di-unsaturated when containing 5 ring atoms, and saturated, mono- or di-unsaturated, or aromatic when containing 6 ring atoms.
A W5 heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). W5 heterocyclic monocycles may have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S). W5 heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system. The W5 heterocycle may be bonded to Y2 through a carbon, nitrogen, sulfur or other atom by a stable covalent bond.
W5 heterocycles include for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isotliiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl. W5 also includes, but is not limited to, examples such as:
Figure imgf000062_0001
W carbocycles and heterocycles may be independently substituted with 0 to 3 R2 groups, as defined above. For example, substituted W5 carbocycles include:
Figure imgf000062_0002
Figure imgf000062_0003
l → - P l → SH ι →( \θ2
Examples of substituted phenyl carbocycles include:
Figure imgf000063_0001
Linking Groups and Linkers
The invention provides conjugates that comprise an HIV inhibiting compound that is optionally linked to one or more phosphonate groups either directly (e.g. through a covalent bond) or through a linking group (i.e. a linker).
The nature of the linker is not critical provided it does not interfere with the ability of the phosphonate containing compound to function as a therapeutic agent. The phosphonate or the linker can be linked to the compound (e.g. a compound of formula A) at any synthetically feasible position on the compound by removing a hydrogen or any portion of the compound to provide an open valence for attachment of the phosphonate or the linker. In one embodiment of the invention the linking group or linker (which can be designated "L") can include all or a portions of the group A0, A1, A2, or
W3 described herein.
In another embodiment of the invention the linking group or linker has a molecular weight of from about 20 daltons to about 400 daltons. In another embodiment of the invention the linking group or linker has a length of about 5 angstroms to about 300 angstroms.
In another embodiment of the invention the linking group or linker separates the DRUG and a P(=Y1) residue by about 5 angstroms to about 200 angstroms, inclusive, in length. In another embodiment of the invention the linking group or linker is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 2 to 25 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (-O-), and wherein the chain is optionally substituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituents selected from (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C1-C6)alkanoyl, (C1-Cg)alkanoyloxy, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo (=0), carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
In another embodiment of the invention the linking group or linker is of the formula W-A wherein A is (d-C24)alkyl, (C2-C24)alkenyl, (C2-C24)alkynyl, (C3-C8)cycloalkyl, (C6-C!o)aryl or a combination thereof, wherein W is - N(R)C(=O)-, -C(=0)N(R)-, -OC(=O)-, -C(=0)0-, -0-, -S-, -S(O)-, -S(O)2-, - N(R)-, -C(=0)-, or a direct bond; wherein each R is independently H or (Ci- C6)alkyl. In another embodiment of the invention the linking group or linker is a divalent radical formed from a peptide. hi another embodiment of the invention the linking group or linker is a divalent radical formed from an amino acid.
In another embodiment of the invention the linking group or linker is a divalent radical formed from poly-L-glutamic acid, poly-L-aspartic acid, poly-L- histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine- L-tyrosine. hi another embodiment of the invention the linking group or linker is of the formula W-(CH2)n wherein, n is between about 1 and about 10; and W is - N(R)C(=0)-, -C(=O)N(R)-, -OCC=O)-, -C(=O)O-, -0-, -S-, -S(O)-, -S(O)2-, - C(=0)-, -N(R)-, or a direct bond; wherein each R is independently H or (C1- C6)alkyl. hi another embodiment of the invention the linking group or linker is methylene, ethylene, or propylene.
In another embodiment of the invention the linking group or linker is attached to the phosphonate group through a carbon atom of the linker. Intracellular Targeting
The optionally incorporated phosphonate group of the compounds of the invention may cleave in vivo in stages after they have reached the desired site of action, i.e. inside a cell. One mechanism of action inside a cell may entail a first cleavage, e.g. by esterase, to provide a negatively-charged "locked-in" intermediate. Cleavage of a terminal ester grouping in a compound of the invention thus affords an unstable intermediate which releases a negatively charged "locked in" intermediate. After passage inside a cell, intracellular enzymatic cleavage or modification of the phosphonate or prodrug compound may result in an intracellular accumulation of the cleaved or modified compound by a "trapping" mechanism. The cleaved or modified compound may then be "locked-in" the cell by a significant change in charge, polarity, or other physical property change which decreases the rate at which the cleaved or modified compound can exit the cell, relative to the rate at which it entered as the phosphonate prodrug. Other mechanisms by which a therapeutic effect are achieved may be operative as well. Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphatases.
From the foregoing, it will be apparent that many different drugs can be derivatized in accord with the present invention. Numerous such drugs are specifically mentioned herein. However, it should be understood that the discussion of drug families and their specific members for derivatization according to this invention is not intended to be exhaustive, but merely illustrative.
HlV-Inhibitory Compounds
The compounds of the invention include those with HIV-inliibitory activity. The compounds of the inventions optionally bear one or more (e.g. 1, 2, 3, or 4) phosphonate groups, which may be a prodrug moiety.
The term "HlV-inhibitory compound" includes those compounds that inhibit HIV.
Typically, compounds of the invention have a molecular weight of from about 400 amu to about 10,000 amu; in a specific embodiment of the invention, compounds have a molecular weight of less than about 5000 amu; in another specific embodiment of the invention, compounds have a molecular weight of less than about 2500 amu; in another specific embodiment of the invention, compounds have a molecular weight of less than about 1000 amu; in another specific embodiment of the invention, compounds have a molecular weight of less than about 800 amu; in another specific embodiment of the invention, compounds have a molecular weight of less than about 600 amu; and in another specific embodiment of the invention, compounds have a molecular weight of less than about 600 amu and a molecular weight of greater than about 400 amu. The compounds of the invention also typically have a logD(polarity) less than about 5. In one embodiment the invention provides compounds having a logD less than about 4; in another one embodiment the invention provides compounds having a logD less than about 3; in another one embodiment the invention provides compounds having a logD greater than about -5; in another one embodiment the invention provides compounds having a logD greater than about -3; and in another one embodiment the invention provides compounds having a logD greater than about 0 and less than about 3.
Selected substituents within the compounds of the invention are present to a recursive degree. In this context, "recursive substituent" means that a substituent may recite another instance of itself. Because of the recursive nature of such substituents, theoretically, a large number may be present in any given embodiment. For example, Rx contains a Ry substituent. Ry can be R2, which in turn can be R3. IfR3 is selected to be R3c, then a second instance of Rx can be selected. One of ordinary skill in the art of medicinal chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis. By way of example and not limitation, W3, Ry and R3 are all recursive substituents in certain embodiments. Typically, each of these may independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times in a given embodiment. More typically, each of these may independently occur 12 or fewer times in a given embodiment. More typically yet, W3 will occur 0 to 8 times, Ry will occur 0 to 6 times and R3 will occur 0 to 10 times in a given embodiment. Even more typically, W3 will occur 0 to 6 times, Ry will occur 0 to 4 times and R3 will occur 0 to 8 times in a given embodiment. Recursive substituents are an intended aspect of the invention. One of ordinary skill in the art of medicinal chemistry understands the versatility of such substituents. To the degree that recursive substituents are present in an embodiment of the invention, the total number will be determined as set forth above. Whenever a compound described herein is substituted with more than one of the same designated group, e.g., "R1" or "R6a"5 then it will be understood that the groups may be the same or different, i.e., each group is independently selected. Wavy lines indicate the site of covalent bond attachments to the adjoining groups, moieties, or atoms. In one embodiment of the invention, the compound is in an isolated and purified form. Generally, the term "isolated and purified" means that the compound is substantially free from biological materials (e.g. blood, tissue, cells, etc.). In one specific embodiment of the invention, the term means that the compound or conjugate of the invention is at least about 50 wt.% free from biological materials; in another specific embodiment, the term means that the compound or conjugate of the invention is at least about 75 wt.% free from biological materials; in another specific embodiment, the term means that the compound or conjugate of the invention is at least about 90 wt.% free from biological materials; in another specific embodiment, the term means that the compound or conjugate of the invention is at least about 98 wt.% free from biological materials; and in another embodiment, the term means that the compound or conjugate of the invention is at least about 99 wt.% free from biological materials. In another specific embodiment, the invention provides a compound or conjugate of the invention that has been synthetically prepared (e.g., ex vivo).
Cellular Accumulation
In one embodiment, the invention is provides compounds capable of accumulating in human PBMC (peripheral blood mononuclear cells). PBMC refer to blood cells having round lymphocytes and monocytes. Physiologically, PBMC are critical components of the mechanism against infection. PBMC may be isolated from heparmized whole blood of normal healthy donors or buffy coats, by standard density gradient centrifugation and harvested from the interface, washed {e.g. phosphate-buffered saline) and stored in freezing medium. PBMC may be cultured in multi-well plates. At various times of culture, supernatant may be either removed for assessment, or cells may be harvested and analyzed (Smith R. etal (2003) Blood 102(7):2532-2540). The compounds of this embodiment may further comprise a phosphonate or phosphonate prodrug. More typically, the phosphonate or phosphonate prodrug can have the structure A3 as described herein.
Typically, compounds of the invention demonstrate improved intracellular half-life of the compounds or intracellular metabolites of the compounds in human PBMC when compared to analogs of the compounds not having the phosphonate or phosphonate prodrug. Typically, the half-life is improved by at least about 50%, more typically at least in the range 50-100%, still more typically at least about 100%, more typically yet greater than about 100%.
In one embodiment of the invention the intracellular half-life of a metabolite of the compound in human PBMCs is improved when compared to an analog of the compound not having the phosphonate or phosphonate prodrug. In such embodiments, the metabolite may be generated intracellularly, e.g. generated within human PBMC. The metabolite may be a product of the cleavage of a phosphonate prodrug within human PBMCs. The optionally phosphonate-containing phosphonate prodrug may be cleaved to form a metabolite having at least one negative charge at physiological pH. The phosphonate prodrug may be enzymatically cleaved within human PBMC to form a phosphonate having at least one active hydrogen atom of the form P-OH. Stereoisomers
The compounds of the invention may have chiral centers, e.g., chiral carbon or phosphorus atoms. The compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention. The racemic mixtures are separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances. In most instances, the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
The compounds of the invention can also exist as tautomeric isomers in certain cases. All though only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention. For example, ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
Salts and Hydrates The compositions of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na+, Li+, K+> Ca+^ and Mg+^. Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. Monovalent salts are preferred if a water soluble salt is desired.
Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound. In addition, salts may be formed from acid addition of certain organic and inorganic acids, e.g., HCl, HBr, H2SO45 H3PO4 or organic sulfonic acids, to basic centers, typically amines, or to acidic groups. Finally, it is to be understood that the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids. Any of the amino acids described above are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
Methods of Inhibition of HIV
Another aspect of the invention relates to methods of inhibiting the activity of HIV comprising the step of treating a sample suspected of containing HIV with a composition of the invention.
Compositions of the invention may act as inhibitors of HIV, as intermediates for such inhibitors or have other utilities as described below. The inhibitors will generally bind to locations on the surface or in a cavity of the liver. Compositions binding in the liver may bind with varying degrees of reversibility. Those compounds binding substantially irreversibly are ideal candidates for use in this method of the invention. Once labeled, the substantially irreversibly binding compositions are useful as probes for the detection of HIV. Accordingly, the invention relates to methods of detecting NS3 in a sample suspected of containing HIV comprising the steps of: treating a sample suspected of containing HIV with a composition comprising a compound of the invention bound to a label; and observing the effect of the sample on the activity of the label. Suitable labels are well known in the diagnostics field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens. The compounds herein are labeled in conventional fashion using functional groups such as hydroxyl or amino.
Within the context of the invention samples suspected of containing HIV include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like. Typically the sample will be suspected of containing HIV. Samples can be contained in any medium including water and organic solvent/water mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures.
The treating step of the invention comprises adding the composition of the invention to the sample or it comprises adding a precursor of the composition to the sample. The addition step comprises any method of administration as described above.
If desired, the activity of HTV after application of the composition can be observed by any method including direct and indirect methods of detecting HIV activity. Quantitative, qualitative, and semiquantitative methods of determining HW activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
Many organisms contain HIV. The compounds of this invention are useful in the treatment or prophylaxis of conditions associated with HIV activation in animals or in man.
However, in screening compounds capable of inhibiting HIV it should be kept in mind that the results of enzyme assays may not correlate with cell culture assays. Thus, a cell based assay should be the primary screening tool.
Screens for HIV Inhibitors
Compositions of the invention are screened for inhibitory activity against HIV by any of the conventional techniques for evaluating enzyme activity. Within the context of the invention, typically compositions are first screened for inhibition of HIV in vitro and compositions showing inhibitory activity are then screened for activity in vivo. Compositions having in vitro Ki (inhibitory constants) of less then about 5 X 10"6 M, typically less than about I X lO-7 M and preferably less than about 5 X 10"^ M are preferred for in vivo use. Useful in vitro screens have been described in detail.
Pharmaceutical Formulations
The compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. AU formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.
A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom. For administration to the eye or other external tissues e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.
If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
Pharmaceutical formulations according to the present invention comprise one or more compounds of the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g. , polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.
The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weightweight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
Formulations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of conditions associated with HIV activity.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate. Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
Compounds of the invention can also be formulated to provide controlled release of the active ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, the invention also provided compositions comprising one or more compounds of the invention formulated for sustained or controlled release.
Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day. Typically, from about 0.01 to about 10 mg/kg body weight per day. More typically, from about .01 to about 5 mg/kg body weight per day. More typically, from about .05 to about 0.5 mg/kg body weight per day. For example, the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.
Routes of Administration
One or more compounds of the invention (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.
Combination Therapy Active ingredients of the invention are also used in combination with other active ingredients. Such combinations are selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco-properties of the combination. It is also possible to combine any compound of the invention with one or more other active ingredients in a unitary dosage form for simultaneous or sequential administration to a patient. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations .
The combination therapy may provide "synergy" and "synergistic effect", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co- formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
Metabolites of the Compounds of the Invention Also falling within the scope of this invention are the in vivo metabolic products of the compounds described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolab led (e.g., C^ or H^) compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g. , by MS or NMR analysis, hi general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no HIV - inhibitory activity of their own.
Recipes and methods for determining stability of compounds in surrogate gastrointestinal secretions are known. Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are deprotected in surrogate intestinal or gastric juice upon incubation for 1 hour at 37 °C. Simply because the compounds are stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. The phosphonate prodrugs of the invention typically will be stable in the digestive system but are substantially hydrolyzed to the parental drug in the digestive lumen, liver or other metabolic organ, or within cells in general.
Exemplary Methods of Making the Compounds of the Invention.
The invention also relates to methods of making the compositions of the invention. The compositions are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., Advanced Organic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985), Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief (P ergamon Press, New York, 1993 printing).
A number of exemplary methods for the preparation of the compositions of the invention are provided below. These methods are intended to illustrate the nature of such preparations and are not intended to limit the scope of applicable methods.
Generally, the reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed. The cited reference material, together with material cited therein, contains detailed descriptions of such conditions. Typically the temperatures will be -100°C to 200°C, solvents will be aprotic or protic, and reaction times will be 10 seconds to 10 days. Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20 0C), although for metal hydride reductions frequently the temperature is reduced to 0 °C to -100 °C, solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0 0C to -100 °C) are also common. Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
Standard synthetic techniques such as azeotropic removal of reaction by¬ products and use of anhydrous reaction conditions (e.g., inert gas environments) are common in the art and will be applied when applicable.
Schemes and Examples
General aspects of these exemplary methods are described below and in the Examples. Each of the products of the following processes is optionally separated, isolated, and/or purified prior to its use in subsequent processes.
Generally, the reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed. The cited reference material, together with material cited therein, contains detailed descriptions of such conditions. Typically the temperatures will be -100°C to 2000C, solvents will be aprotic or protic, and reaction times will be 10 seconds to 10 days. Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20 0C), although for metal hydride reductions frequently the temperature is reduced to 0 °C to -100 0C, solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0 °C to -100 0C) are also common. Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
Standard synthetic techniques such as azeotropic removal of reaction by¬ products and use of anhydrous reaction conditions {e.g., inert gas environments) are common in the art and will be applied when applicable.
The terms "treated", "treating", "treatment", and the like, when used in connection with a chemical synthetic operation, mean contacting, mixing, reacting, allowing to react, bringing into contact, and other terms common in the art for indicating that one or more chemical entities is treated in such a manner as to convert it to one or more other chemical entities. This means that "treating compound one with compound two" is synonymous with "allowing compound one to react with compound two", "contacting compound one with compound two", "reacting compound one with compound two", and other expressions common in the art of organic synthesis for reasonably indicating that compound one was "treated", "reacted", "allowed to react", etc., with compound two. For example, treating indicates the reasonable and usual manner in which organic " chemicals are allowed to react. Normal concentrations (0.0 IM to 1OM, typically 0.1M to IM), temperatures (-100 °C to 250 0C, typically -78 °C to 150 °C, more typically -78 0C to 100 °C, still more typically 0 °C to 100 °C), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated. The knowledge of similar reactions known in the art of organic synthesis are used in selecting the conditions and apparatus for "treating" in a given process. In particular, one of ordinary skill in the art of organic synthesis selects conditions and apparatus reasonably expected to successfully carry out the chemical reactions of the described processes based on the knowledge in the art.
Modifications of each of the exemplary schemes and in the examples (hereafter "exemplary schemes") leads to various analogs of the specific exemplary materials produce. The above-cited citations describing suitable methods of organic synthesis are applicable to such modifications.
In each of the exemplary schemes it may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
Selection of appropriate methods of separation depends on the nature of the materials involved. For example, boiling point, and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One skilled in the art will apply techniques most likely to achieve the desired separation. A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eli el, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
Under method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched xanthene. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloro formate in the presence of base, or Mosher ester, α-methoxy-oc- (trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) J. ofChromatogr. 513 :375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
Examples General Section A number of exemplary methods for the preparation of compounds of the invention are provided herein, for example, in the Examples hereinbelow. These methods are intended to illustrate the nature of such preparations are not intended to limit the scope of applicable methods. Certain compounds of the invention can be used as intermediates for the preparation of other compounds of the invention. For example, the interconversion of various phosphonate compounds of the invention is illustrated below.
INTERCONVERSIONS OF THE PHOSPHONATES R-LINK-P(O)(OR V R- LINK-P(O)(OR1VOm AND R-LINK-P(O)(OH)2. The following schemes 32-38 describe the preparation of phosphonate esters of the general structure R-link-P(O)(OR1)2, in which the groups R1 may be the same or different. The R1 groups attached to a phosphonate ester, or to precursors thereto, may be changed using established chemical transformations. The interconversion reactions of phosphonates are illustrated in Scheme S32. The group R in Scheme 32 represents the substructure, i.e. the drug "scaffold, to which the substituent link-P(O)(OR!)2 is attached, either in the compounds of the invention, or in precursors thereto. At the point in the synthetic route of conducting a phosphonate interconversion, certain functional groups in R may be protected. The methods employed for a given phosphonate transformation depend on the nature of the substituent R1, and of the substrate to which the phosphonate group is attached. The preparation and hydrolysis of phosphonate esters is described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 9ff.
In general, synthesis of phosphonate esters is achieved by coupling a nucleophile amine or alcohol with the corresponding activated phosphonate electrophilic precursor. For example, chlorophosphonate addition on to 5'- hydroxy of nucleoside is a well known method for preparation of nucleoside phosphate monoesters. The activated precursor can be prepared by several well known methods. Chlorophosphonates useful for synthesis of the prodrugs are prepared from the substituted- 1,3 -propanediol (Wissner, et al, (1992) J. Med Chem. 35:1650). Chlorophosphonates are made by oxidation of the corresponding chlorophospholanes (Anderson, et al, (1984) J. Org. Chem.
49:1304) which are obtained by reaction of the substituted diol with phosphorus trichloride. Alternatively, the chlorophosphonate agent is made by treating substituted-l,3-diols with phosphorusoxychloride (Patois, et al, (1990) J. Chem. Soc. Perkin Trans. 1, 1577). Chlorophosphonate species may also be generated in situ from corresponding cyclic phosphites (Silverburg, et al., (1996) Tetrahedron lett., 31:111-11 A), which in turn can be either made from chlorophospholane or phosphoramidate intermediate. Phosphoroflouridate intermediate prepared either from pyrophosphate or phosphoric acid may also act as precursor in preparation of cyclic prodrugs (Watanabe et al., (1988) Tetrahedron lett., 29:5763-66). Phosphonate prodrugs of the present invention may also be prepared from the free acid by Mitsunobu reactions (Mitsunobu, (1981) Synthesis, 1; Campbell, (1992) J. Org. Chem. 57:6331), and other acid coupling reagents including, but not limited to, carbodiimides (Alexander, et al, (1994) Collect. Czech. Chem. Commun. 59:1853; Casara et al, (1992) Bioorg. Med. Chem. Lett. 2:145; Ohashi et al, (1988) Tetrahedron Lett., 29:1189), and benzotriazolyloxytris-(dimethylamino)pliosphonium salts (Campagne et al (1993) Tetrahedron Lett. 34:6743). Aryl halides undergo Ni+2 catalyzed reaction with phosphite derivatives to give aryl phosphonate containing compounds (Balthazar, et al (1980) J. Org. Chem. 45:5425). Phosphonates may also be prepared from the chlorophosphonate in the presence of a palladium catalyst using aromatic triflates (Petrakis et al (1987) J. Am. Chem. Soc. 109:2831; Lu et al (1987) Synthesis 726). In another method, aryl phosphonate esters are prepared from aryl phosphates under anionic rearrangement conditions (Melvin (1981) Tetrahedron Lett. 22:3375; Casteel et al (1991) Synthesis, 691). N-Alkoxy aryl salts with alkali met al derivatives of cyclic alkyl phosphonate provide general synthesis for heteroaryl-2 -phosphonate linkers (Redmore (1970) J. Org. Chem. 35:4114). These above mentioned methods can also be extended to compounds where the W5 group is a heterocycle. Cyclic- 1, 3 -propanyl prodrugs of phosphonates are also synthesized from phosphonic diacids and substituted propane- 1, 3 -diols using a coupling reagent such as 1,3- dicyclohexylcarbodiimide (DCC) in presence of a base (e.g., pyridine). Other carbodiimide based coupling agents like 1,3-disopropylcarbodiimide or water soluble reagent, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) can also be utilized for the synthesis of cyclic phosphonate prodrugs. The conversion of a phosphonate diester S32.1 into the corresponding phosphonate monoester S32.2 (Scheme 32, Reaction 1) is accomplished by a number of methods. For example, the ester S32.1 in which R1 is an aralkyl group such as benzyl, is converted into the monoester compound S32.2 by reaction with a tertiary organic base such as diazabicyclooctane (DABCO) or quinuclidine, as described in J. Org. Chem. (1995) 60:2946. The reaction is performed in an inert hydrocarbon solvent such as toluene or xylene, at about 110 °C. The conversion of the diester S32.1 in which R1 is an aryl group such as phenyl, or an alkenyl group such as allyl, into the monoester S32.2 is effected by treatment of the ester S32.1 with a base such as aqueous sodium hydroxide in acetonitrile or lithium hydroxide in aqueous tetrahydrofuran. Phosphonate diesters S32.1 in which one of the groups R1Js aralkyl, such as benzyl, and the other is alkyi, is converted into the monoesters S32.2 in which R1 is alkyl by hydrogenation, for example using a palladium on carbon catalyst. Phosphonate diesters in which both of the groups R1 are alkenyl, such as allyl, is converted into the monoester S32.2 in which R1 is alkenyl, by treatment with chlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in aqueous ethanol at reflux, optionally in the presence of diazabicyclooctane, for example by using the procedure described in J. Org. Chem. (1973) 38:3224, for the cleavage of allyl carboxylates. The conversion of a phosphonate diester S32.1 or a phosphonate monoester S32.2 into the corresponding phosphonic acid S32.3 (Scheme 32, Reactions 2 and 3) can be effected by reaction of the diester or the monoester with trimethylsilyl bromide, as described in J. Chem. Soc, Chem. Comm., (1979) 739. The reaction is conducted in an inert solvent such as, for example, dichloromethane, optionally in the presence of a silylating agent such as bis(trimethylsilyl)trifluoroacetamide, at ambient temperature. A phosphonate monoester S32.2 in which R1 is aralkyl such as benzyl, is converted into the corresponding phosphonic acid S32.3 by hydrogenation over a palladium catalyst, or by treatment with hydrogen chloride in an ethereal solvent such as dioxane. A phosphonate monoester S32.2 in which R1 is alkenyl such as, for example, allyl, is converted into the phosphonic acid S32.3 by reaction with Wilkinson's catalyst in an aqueous organic solvent, for example in 15% aqueous acetonitrile, or in aqueous ethanol, for example using the procedure described in HeIv. Chim. Acta. (1985) 68:618. Palladium catalyzed hydrogenolysis of phosphonate esters S32.1 in which R1 is benzyl is described in J. Org. Chem. (1959) 24:434. Platinum-catalyzed hydrogenolysis of phosphonate esters S32.1 in which R1 is phenyl is described in J. Am. Chem. Soc. (1956) 78:2336.
The conversion of a phosphonate monoester S32.2 into a phosphonate diester S32.1 (Scheme 32, Reaction 4) in which the newly introduced R1 group is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl is effected by a number of reactions in which the substrate S32.2 is reacted with a hydroxy compound R1OH, in the presence of a coupling agent. Typically, the second phosphonate ester group is different than the first introduced phosphonate ester group, i.e. R1 is followed by the introduction of R2 where each of R1 and R2 is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl (Scheme 32, Reaction 4a) whereby S32.2 is converted to S32.1a. Suitable coupling agents are those employed for the preparation of carboxylate esters, and include a carbodiimide such as dicyclohexylcarbodiimide, in which case the reaction is preferably conducted in a basic organic solvent such as pyridine, or (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP, Sigma), in which case the reaction is performed in a polar solvent such as dimethylformamide, in the presence of a tertiary organic base such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in which case the reaction is conducted in a basic solvent such as pyridine, in the presence of a triaryl phosphine such as triphenylphosphine. Alternatively, the conversion of the phosphonate monoester S32.2 to the diester S32.1 is effected by the use of the Mitsunobu reaction, as described above. The substrate is reacted with the hydroxy compound R1OH, in the presence of diethyl azodicarboxylate and a triarylphosphine such as triphenyl phosphine. Alternatively, the phosphonate monoester S32.2 is transformed into the phosphonate diester S32.1, in which the introduced R group is alkenyl or aralkyl, by reaction of the monoester with the halide R1Br, in which R1 is as alkenyl or aralkyl. The alkylation reaction is conducted in a polar organic solvent such as dimethylformamide or acetonitrile, in the presence of a base such as cesium carbonate. Alternatively, the phosphonate monoester is transformed into the phosphonate diester in a two step procedure. In the first step, the phosphonate monoester S32.2 is transformed into the chloro analog RP(O)(OR1)C1 by reaction with thionyl chloride or oxalyl chloride and the like, as described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 17, and the thus-obtained product RP(O)(OR1)C1 is then reacted with the hydroxy compound R1OH, in the presence of a base such as triethylamine, to afford the phosphonate diester S32.1. A phosphonic acid R-ImIc-P(O)(OH)2 is transformed into a phosphonate monoester RP(O)(OR1)(0H) (Scheme 32, Reaction 5) by means of the methods described above of for the preparation of the phosphonate diester R-link- P(O)(OR1)2 S32.1, except that only one molar proportion of the component R1OH or R1Br is employed. Dialkyl phosphonates may be prepared according to the methods of: Quast et al (1974) Synthesis 490; Stowell et al (1990) Tetrahedron Lett. 3261; US 5663159.
A phosphonic acid R-HnIc-P(O)(OH)2 S32.3 is transformed into a phosphonate diester R-IMc-P(O)(OR1 )2 S32.1 (Scheme 32, Reaction 6) by a coupling reaction with the hydroxy compound R1 OH, in the presence of a coupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine. The reaction is conducted in a basic solvent such as pyridine. Alternatively, phosphonic acids S32.3 are transformed into phosphonic esters S32.1 in which R1 is aryl, by means of a coupling reaction employing, for example, dicyclohexylcarbodiimide in pyridine at ca 70 0C. Alternatively, phosphonic acids S32.3 are transformed into phosphonic esters S32.1 in which R1 is alkenyl, by means of an alkylation reaction. The phosphonic acid is reacted with the alkenyl bromide R1Br in a polar organic solvent such as acetonitrile solution at reflux temperature, the presence of a base such as cesium carbonate, to afford the phosphonic ester S32.1.
Scheme 32
R-link R-link — P-OR1
OH S32.2
Figure imgf000092_0001
O 2 O
R-link — P-OR1 R-link — P^-OH
OR1 OH
S32.1 S32.3
O 3
R-link- -PN-OR1 R-link — PN-OH
OH S32.3 0H S32.2
R-link S32.1
Figure imgf000092_0002
O O
4a
R-link — R-OR1 R-link - -R-OR1
OH OR^ S32.1a
S32.2
O
R-link- -P-OH R-link- -{i-OR1 OH OH S32.2
S32.3
O O
R-link — P-OH R-link — R-OR OH OR
S32.3 S32.1
Preparation of phosphonate carbamates.
Phosphonate esters may contain a carbamate linkage. The preparation of carbamates is described in Comprehensive Organic Functional Group Transformations, A. R. Katritzky, ed., Pergamon, 1995, Vol. 6, p. 416ff, and in Organic Functional Group Preparations, by S. R. Sandler and W. Karo, Academic Press, 1986, p. 26OfT. The carbamoyl group may be formed by reaction of a hydroxy group according to the methods known in the art, including the teachings of Ellis, US 2002/0103378 Al and Hajima, US 6018049.
Scheme 33 illustrates various methods by which the carbamate linkage is synthesized. As shown in Scheme 33, in the general reaction generating carbamates,, an alcohol S33.1, is converted into the activated derivative S33.2 in which Lv is a leaving group such as halo, imidazolyl, benztriazolyl and the like, as described herein. The activated derivative S33.2 is then reacted with an amine S33.3, to afford the carbamate product S33.4. Examples 1 - 7 in Scheme 33 depict methods by which the general reaction is effected. Examples 8 - 10 illustrate alternative methods for the preparation of carbamates. Scheme 33, Example 1 illustrates the preparation of carbamates employing a chloroformyl derivative of the alcohol S33.5. hi this procedure, the alcohol S33.5 is reacted with phosgene, in an inert solvent such as toluene, at about 0 °C, as described in Org. Svn. Coll. Vol. 3, 167, 1965, or with an equivalent reagent such as trichloromethoxy chloroformate, as described in Org. Svn. Coll. Vol. 6, 715, 1988, to afford the chloroformate S33.6. The latter compound is then reacted with the amine component S33.3, in the presence of an organic or inorganic base, to afford the carbamate S33.7. For example, the chloroformyl compound S33.6 is reacted with the amine S33.3 in a water- miscible solvent such as tetrahydrofuran, in the presence of aqueous sodium hydroxide, as described in Org. Syn. Coll. Vol. 3, 167, 1965, to yield the carbamate S33.7. Alternatively, the reaction is performed in dichloromethane in the presence of an organic base such as diisopropylethylamine or dimethylaminopyridine.
Scheme 33, Example 2 depicts the reaction of the chloroformate compound S33.6 with imidazole to produce the imidazolide S33.8. The imidazolide product is then reacted with the amine S33.3 to yield the carbamate S33.7. The preparation of the imidazolide is performed in an aprotic solvent such as dichloromethane at 0°, and the preparation of the carbamate is conducted in a similar solvent at ambient temperature, optionally in the presence of a base such as dimethylaminopyridine, as described in J. Med. Chem., 1989, 32, 357.
Scheme 33 Example 3, depicts the reaction of the chloroformate S33.6 with an activated hydroxyl compound R"OH, to yield the mixed carbonate ester S33.10. The reaction is conducted in an inert organic solvent such as ether or dichloromethane, in the presence of a base such as dicyclohexylamine or triethylamine. The hydroxyl component R"OH is selected from the group of compounds S33.19 - S33.24 shown in Scheme 33, and similar compounds. For example, if the component ROH is hydroxybenztriazole S33.19, N- hydroxysuccinimide S33.20, or pentachlorophenol, S33.21, the mixed carbonate S33.10 is obtained by the reaction of the chloroformate with the hydroxyl compound in an ethereal solvent in the presence of dicyclohexylamine, as described in Can. J. Chem., 1982, 60, 976. A similar reaction in which the component ROH is pentafluorophenol S33.22 or 2-hydroxypyridine S33.23 is performed in an ethereal solvent in the presence of triethylamine, as described in Syn., 1986, 303, and Chem. Ber. 118, 468, 1985.
Scheme 33 Example 4 illustrates the preparation of carbamates in which an alkyloxycarbonylimidazole S33.8 is employed. In this procedure, an alcohol S33.5 is reacted with an equimolar amount of carbonyl diimidazole S33.ll to prepare the intermediate S33.8. The reaction is conducted in an aprotic organic solvent such as dichloromethane or tetrahydrofuran. The acyloxyimidazole S33.8 is then reacted with an equimolar amount of the amine RTSTH2 to afford the carbamate S33.7. The reaction is performed in an aprotic organic solvent such as dichloromethane, as described in Tet. Lett., 42, 2001, 5227, to afford the carbamate S33.7.
Scheme 33, Example 5 illustrates the preparation of carbamates by means of an intermediate alkoxycarbonylbenztriazole S33.13. hi this procedure, an alcohol ROH is reacted at ambient temperature with an equimolar amount of benztriazole carbonyl chloride S33.12, to afford the alkoxycarbonyl product S33.13. The reaction is performed in an organic solvent such as benzene or toluene, in the presence of a tertiary organic amine such as triethylamine, as described in Synthesis., 1977, 704. The product is then reacted with the amine R1NH2 to afford the carbamate S33.7. The reaction is conducted in toluene or ethanol, at from ambient temperature to about 80 ° C as described in Synthesis., 1977, 704.
Scheme 33, Example 6 illustrates the preparation of carbamates in which a carbonate (RO)2CO, S33.14, is reacted with an alcohol S33.5 to afford the intermediate alkyloxycarbonyl intermediate S33.15. The latter reagent is then reacted with the amine R1NH2 to afford the carbamate S33.7. The procedure in which the reagent S33.15 is derived from hydroxybenztriazole S33.19 is described in Synthesis, 1993, 908; the procedure in which the reagent S33.15 is derived from N-hydroxysuccinimide S33.20 is described in Tet. Lett., 1992, 2781; the procedure in which the reagent S33.15 is derived from 2- hydroxypyridine S33.23 is described in TeL Lett, 1991, 4251; the procedure in which the reagent S33.15 is derived from 4-nitrophenol S33.24 is described in Synthesis. 1993, 103. The reaction between equimolar amounts of the alcohol ROH and the carbonate S33.14 is conducted in an inert organic solvent at ambient temperature.
Scheme 33, Example 7 illustrates the preparation of carbamates from alkoxycarbonyl azides S33.16. In this procedure, an alkyl chloroformate S33.6 is reacted with an azide, for example sodium azide, to afford the alkoxycarbonyl azide S33.16. The latter compound is then reacted with an equimolar amount of the amine R1NH2 to afford the carbamate S33.7. The reaction is conducted at ambient temperature in a polar aprotic solvent such as dimethylsulfoxide, for example as described in Synthesis., 1982, 404.
Scheme 33, Example 8 illustrates the preparation of carbamates by means of the reaction between an alcohol ROH and the chloroformyl derivative of an amine S33.17. m this procedure, which is described in Synthetic Organic
Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 647, the reactants are combined at ambient temperature in an aprotic solvent such as acetonitrile, in the presence of a base such as triethylamine, to afford the carbamate S33.7.
Scheme 33, Example 9 illustrates the preparation of carbamates by means of the reaction between an alcohol ROH and an isocyanate S33.18. In this procedure, which is described in Synthetic Organic Chemistry, R. B. Wagner, H. D. Zook, Wiley, 1953, p. 645, the reactants are combined at ambient temperature in an aprotic solvent such as ether or dichloromethane and the like, to afford the carbamate S33.7. Scheme 33, Example 10 illustrates the preparation of carbamates by means of the reaction between an alcohol ROH and an amine R1NH2. In this procedure, which is described in Chem. Lett. 1972, 373, the reactants are combined at ambient temperature in an aprotic organic solvent such as tetrahydrofuran, in the presence of a tertiary base such as triethylamine, and selenium. Carbon monoxide is passed through the solution and the reaction proceeds to afford the carbamate S33.7. Scheme 33. Preparation of carbamates. General reaction
R1MH «
ROH - ROCOLv 2 > ROCONHR
S33.1 S33.2 S33.3 S33.4
Examples
R1NH2 S33.3
(1) ROH- ROCOCI >- ROCONHR'
S33.5 S33.6 S33.7
(2)
Figure imgf000096_0001
R1NH2 S33.3 ROCONHR'
*~ S33.7
R"0H R1NH2
(3) ROH- ROCOCI ROCOOR^ -→~ ROCONHR1 S33.5 S33.6 S33.9 S33.10 S33.3 S33.7
0
JJ
N
(4) ROH S33.11 R'NH2 f3 -3 ROCONHR' S33.5 0 S33.8 S33.7
(5) R1
Figure imgf000096_0002
(RO2)C=O
(6) ROH ROCOR" R'NH2 > ROCONHR' S33.5 S33.14 S33.15 S33.3 S33.7
(7) ROH - — >- ROCOCI ROCON3
S33.5 S33.6 S33.16
R1NH2 33.3 ROCONHR1 >- 33.7
(8) ROH R1NHCOC^ RQCONHR'
S33.5 S33.17 S33.7
R1NCO (9) ROH ► ROCONHR'
S33.5 S33-18 S33.7
R1NH2 (10) ROH →- ROCONHR1
S33.5 S33.3 S33.7
Figure imgf000097_0001
PREPARATION OF CARBOALKOXY-SUBSTITUTED PHOSPHONATE BISAMIDATES, MONOAMIDATES, DIESTERS AND MONOESTERS. A number of methods are available for the conversion of phosplionic acids into amidates and esters. In one group of methods, the phosphonic acid is either converted into an isolated activated intermediate such as a phosphoryl chloride, or the phosphonic acid is activated in situ for reaction with an amine or a hydroxy compound.
The conversion of phosphonic acids into phosphoryl chlorides is accomplished by reaction with thionyl chloride, for example as described in J. Gen. Chem. USSR, 1983, 53, 480, Zh. Obschei Khim., 1958, 28, 1063, or J. Org.
Chem., 1994, 59, 6144, or by reaction with oxalyl chloride, as described in J.
Am. Chem. Soc, 1994, 116, 3251, or J. Org. Chem., 1994, 59, 6144, or by reaction with phosphorus pentachloride, as described in J. Org. Chem., 2001, 66,
329, or inJ. Med. Chem., 1995, 38, 1372. The resultant phosphoryl chlorides are then reacted with amines or hydroxy compounds in the presence of a base to afford the amidate or ester products.
Phosphonic acids are converted into activated imidazolyl derivatives by reaction with carbonyl diimidazole, as described in J. Chem. Soc, Chem. Comm.
(1991) 312, or Nucleosides &Nucleotides (2000) 19:1885. Activated sulfonyloxy derivatives are obtained by the reaction of phosphonic acids with trichloromethylsulfonyl chloride or with triisopropylbenzenesulfonyl chloride, as described in Tet. Lett. (1996) 7857, orBioorg. Med. Chem. Lett. (1998) 8:663.
The activated sulfonyloxy derivatives are then reacted with amines or hydroxy compounds to afford amidates or esters. Alternatively, the phosphonic acid and the amine or hydroxy reactant are combined in the presence of a diimide coupling agent. The preparation of phosphonic amidates and esters by means of coupling reactions in the presence of dicyclohexyl carbodiimide is described, for example, inJ. Chem. Soc, Chem.
Comm. (1991) 312 or Coll. Czech. Chem. Comm. (1987) 52:2792. The use of ethyl dimethylaminopropyl carbodiimide for activation and coupling of phosphonic acids is described in Tet. Lett., (2001) 42:8841, or Nucleosides &
Nucleotides (2000) 19:1885.
A number of additional coupling reagents have been described for the preparation of amidates and esters from phosphonic acids. The agents include Aldrithiol-2, and PYBOP and BOP, as described in J. Org. Chem., 1995, 60,
5214, and J. Med. Chem. (1997) 40:3842, mesitylene-2-sulfonyl-3-nitro-l,2,4- triazole (MSNT), as described in J. Med. Chem. (1996) 39:4958, diphenylphosphoryl azide, as described in J. Org. Chem. (1984) 49:1158, 1- (2,4,6-triisopropylbenzenesulfonyl-3-nitro-l,2,4-triazole (TPSNT) as described in Bioorg. Med. Chem. Lett. (1998) 8:1013, bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), as described in Tet. Lett., (1996) 37:3997, 2-chloro-5,5-dimethyl-2-oxo-l,3,2- dioxaphosphinane, as described in Nucleosides Nucleotides 1995, 14, 871, and diphenyl chlorophosphate, as described in J. Med. Chem., 1988, 31, 1305.
Phosphonic acids are converted into amidates and esters by means of the Mitsunobu reaction, in which the phosphonic acid and the amine or hydroxy reactant are combined in the presence of a triaryl phosphine and a dialkyl azodicarboxylate. The procedure is described in Org. Lett, 2001, 3, 643, or J. Med. Chem., 1997, 40, 3842.
Phosphonic esters are also obtained by the reaction between phosphonic acids and halo compounds, in the presence of a suitable base. The method is described, for example, in Anal. Chem., 1987, 59, 1056, or J. Chem. Soc. Perkin Trans., 1, 1993, 19, 2303, or J. Med. Chem., 1995, 38, 1372, or Tet. Lett, 2002, 43, 1161.
Schemes 34-37 illustrate the conversion of phosphonate esters and phosphonic acids into carboalkoxy-substituted phosphonbisamidates (Scheme 34), phosphonamidates (Scheme 35), phosphonate monoesters (Scheme 36) and phosphonate diesters, (Scheme 37). Scheme 38 illustrates synthesis of gem- dialkyl amino phosphonate reagents.
Scheme 34 illustrates various methods for the conversion of phosphonate diesters S34.1 into phosphonbisamidates S34.5. The diester S34.1, prepared as described previously, is hydrolyzed, either to the monoester S34.2 or to the phosphonic acid S34.6. The methods employed for these transformations are described above. The monoester S34.2 is converted into the monoamidate S34.3 by reaction with an aminoester S34.9, in which the group R2 is H or alkyl; the group R4b is a divalent alkylene moiety such as, for example, CHCH3, CHCH2CH3, CH(CH(CH3)2), CH(CH2Ph), and the like, or a side chain group present in natural or modified aminoacids; and the group R5b is C1-C12 alkyl, such as methyl, ethyl, propyl, isopropyl, or isobutyl; C6-C20 aryl, such as phenyl or substituted phenyl; or C6-C20 arylalkyl, such as benzyl or benzyhydryl. The reactants are combined in the presence of a coupling agent such as a carbodiimide, for example dicyclohexyl carbodiimide, as described in J. Am. Chem. Soc, (1957) 79:3575, optionally in the presence of an activating agent such as hydroxybenztriazole, to yield the amidate product S34.3. The amidate- forming reaction is also effected in the presence of coupling agents such as BOP, as described in J. Org. Chem. (1995) 60:5214, AldrithioL PYBOP and similar coupling agents used for the preparation of amides and esters. Alternatively, the reactants S34.2 and S34.9 are transformed into the monoamidate S34.3 by means of a Mitsunobu reaction. The preparation of amidates by means of the Mitsunobu reaction is described in J. Med. Chem. (1995) 38:2742. Equimolar amounts of the reactants are combined in an inert solvent such as tetrahydrofuran in the presence of a triaryl phosphine and a dialkyl azodicarboxylate. The thus- obtained monoamidate ester S34.3 is then transformed into amidate phosphonic acid S34.4. The conditions used for the hydrolysis reaction depend on the nature of the R1 group, as described previously. The phosphonic acid amidate S34.4 is then reacted with an aminoester S34.9, as described above, to yield the bisamidate product S34.5, in which the amino substituents are the same or different. Alternatively, the phosphonic acid S34.6 may be treated with two different amino ester reagents simulataneously, i.e. S34.9 where R2, R4b or R5b are different. The resulting mixture of bisamidate products S34.5 may then be separable, e.g. by chromatography. Scheme 34
O O O
R-link — P-OR R-link -P-OR1- R-link — P-OH - 34.7
OR1 OH OH
R-link
Figure imgf000100_0001
R-link
Figure imgf000101_0001
Figure imgf000101_0002
S34.5
An example of this procedure is shown in Scheme 34, Example 1. In this procedure, a dibenzyl phosphonate S34.14 is reacted with diazabicyclooctane (DABCO) in toluene at reflux, as described in J. Org. Chem., 1995, 60, 2946, to afford the monobenzyl phosphonate S34.15. The product is then reacted with equimolar amounts of ethyl alaninate S34.16 and dicyclohexyl carbodiimide in pyridine, to yield the amidate product S34.17. The benzyl group is then removed, for example by hydrogenolysis over a palladium catalyst, to give the monoacid product S34.18 which may be unstable according to J. Med. Chem. (1997) 40(23):3842. This compound S34.18 is then reacted in a Mitsunobu reaction with ethyl leucinate S34.19, triphenyl phosphine and diethylazodicarboxylate, as described in J. Med. Chem., 1995, 38, 2742, to produce the bisamidate product S34.20. Using the above procedures, but employing in place of ethyl leucinate
S34.19 or ethyl alaninate S34.16, different aminoesters S34.9, the corresponding products S34.5 are obtained.
Alternatively, the phosphonic acid S34.6 is converted into the bisamidate S34.5 by use of the coupling reactions described above. The reaction is performed in one step, in which case the nitrogen-related substituents present in the product S34.5 are the same, or in two steps, in which case the nitrogen- related substituents can be different.
An example of the method is shown in Scheme 34, Example 2. m this procedure, a phosphonic acid S34.6 is reacted in pyridine solution with excess ethyl phenylalaninate S34.21 and dicyclohexylcarbodiimide, for example as described inJ. Chem. Soc, Chem. Comm., 1991, 1063, to give the bisamidate product S34.22.
Using the above procedures, but employing, in place of ethyl phenylalaninate, different aminoesters S34.9, the corresponding products S34.5 are obtained.
As a further alternative, the phosphonic acid S34.6 is converted into the mono or bis-activated derivative S34.7, in which Lv is a leaving group such as chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc. The conversion of phosphonic acids into chlorides S34.7 (Lv = Cl) is effected by reaction with thionyl chloride or oxalyl chloride and the like, as described in Organic
Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976, p. 17. The conversion of phosphonic acids into monoimidazolides S34.7 (Lv = imidazolyl) is described inJ. Med. Chem., 2002, 45, 1284 and inJ. Chem. Soc. Chem. Comm., 1991; 312. Alternatively, the phosphonic acid is activated by reaction with triisopropylbenzenesulfonyl chloride, as described in Nucleosides and Nucleotides, 2000, 10, 1885. The activated product is then reacted with the aminoester S34.9, in the presence of a base, to give the bisamidate S34.5. The reaction is performed in one step, in which case the nitrogen substituents present in the product S34.5 are the same, or in two steps, via the intermediate S34.ll, in which case the nitrogen substituents can be different.
Examples of these methods are shown in Scheme 34, Examples 3 and 5. In the procedure illustrated in Scheme 34, Example 3, a phosphonic acid S34.6 is reacted with ten molar equivalents of thionyl chloride, as described in Zh. Obschei KMm., 1958, 28, 1063, to give the dichloro compound S34.23. The product is then reacted at reflux temperature in a polar aprotic solvent such as acetonitrile, and in the presence of a base such as triethylamine, with butyl serinate S34.24 to afford the bisamidate product S34.25.
Using the above procedures, but employing, in place of butyl serinate S34.24, different aminoesters S34.9, the corresponding products S34.5 are obtained.
In the procedure illustrated in Scheme 34, Example 5, the phosphonic acid S34.6 is reacted, as described inJ. Chem. Soc. Chem. Comm., 1991, 312, with carbonyl diimidazole to give the imidazolide S34.S32. The product is then reacted in acetonitrile solution at ambient temperature, with one molar equivalent of ethyl alaninate S34.33 to yield the monodisplacement product S34.S34. The latter compound is then reacted with carbonyl diimidazole to produce the activated intermediate S34.35, and the product is then reacted, under the same conditions, with ethyl N-methylalaninate S34.33a to give the bisamidate product S34.36.
Using the above procedures, but employing, in place of ethyl alaninate S34.33 or ethyl N-methylalaninate S34.33a, different aminoesters S34.9, the corresponding products S34.5 are obtained. The intermediate monoamidate S34.3 is also prepared from the monoester S34.2 by first converting the monoester into the activated derivative S34.8 in which Lv is a leaving group such as halo, imidazolyl etc, using the procedures described above. The product S34.8 is then reacted with an aminoester S34.9 in the presence of a base such as pyridine, to give an intermediate monoamidate product S34.3. The latter compound is then converted, by removal of the R1 group and coupling of the product with the aminoester S34.9, as described above, into the bisamidate S34.5.
An example of this procedure, in which the phosphonic acid is activated by conversion to the chloro derivative S34.26, is shown in Scheme 34, Example 4. hi this procedure, the phosphonic monobenzyl ester S34.15 is reacted, in dichloroniethane, with thionyl chloride, as described in Tet. Letters., 1994, 35, 4097, to afford the phosphoryl chloride S34.26. The product is then reacted in acetonitrile solution at ambient temperature with one molar equivalent of ethyl 3-amino-2-methylpropionate S34.27 to yield the monoamidate product S34.28. The latter compound is hydrogenated in ethylacetate over a 5% palladium on carbon catalyst to produce the monoacid product S34.29. The product is subjected to a Mitsunobu coupling procedure, with equimolar amounts of butyl alaninate S34.30, triphenyl phosphine, diethylazodicarboxylate and triethylamine in tetrahydrofuran, to give the bisamidate product S34.31. Using the above procedures, but employing, in place of ethyl 3-amino-2- methylpropionate S34.27 or butyl alaninate S34.30, different aminoesters S34.9, the corresponding products S34.5 are obtained. The activated phosphonic acid derivative S34.7 is also converted into the bisamidate S34.5 via the diamino compound S34.10. The conversion of activated phosphonic acid derivatives such as phosphoryl chlorides into the corresponding amino analogs S34.10, by reaction with ammonia, is described in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley, 1976. The bisamino compound S34.10 is then reacted at elevated temperature with a haloester S34.12 (Hal = halogen, i.e. F, Cl, Br, I), in a polar organic solvent such as dimethylformamide, in the presence of a base such as 4, 4- dimethylaminopyridine (DMAP) or potassium carbonate, to yield the bisamidate S34.5. Alternatively, S34.6 may be treated with two different amino ester reagents simulataneously, i.e. S34.12 where R4b or R5b are different. The resulting mixture of bisamidate products S34.5 may then be separable, e.g. by chromatography.
An example of this procedure is shown in Scheme 34, Example 6. In this method, a dichlorophosphonate S34.23 is reacted with ammonia to afford the diamide S34.37. The reaction is performed in aqueous, aqueous alcoholic or alcoholic solution, at reflux temperature. The resulting diamino compound is then reacted with two molar equivalents of ethyl 2-bromo-3-methylbutyrate S34.38, in a polar organic solvent such as N-methylpyrrolidinone at ca. 150 "C, in the presence of a base such as potassium carbonate, and optionally in the presence of a catalytic amount of potassium iodide, to afford the bisamidate product S34.39.
Using the above procedures, but employing, in place of ethyl 2-bromo-3- methylbutyrate S34.38, different haloesters S34.12 the corresponding products S34.5 are obtained.
The procedures shown in Scheme 34 are also applicable to the preparation of bisamidates in which the aminoester moiety incorporates different functional groups. Scheme 34, Example 7 illustrates the preparation of bisamidates derived from tyrosine, hi this procedure, the monoimidazolide S34.32 is reacted with propyl tyrosinate S34.40, as described in Example 5, to yield the monoamidate S34.41. The product is reacted with carbonyl diimidazole to give the imidazolide S34.42, and this material is reacted with a further molar equivalent of propyl tyrosinate to produce the bisamidate product S34.43. Using the above procedures, but employing, in place of propyl tyrosinate S34.40, different aminoesters S34.9, the corresponding products S34.5 are obtained. The aminoesters employed in the two stages of the above procedure can be the same or different, so that bisamidates with the same or different amino substituents are prepared.
Scheme 35 illustrates methods for the preparation of phosphonate monoamidates.
In one procedure, a phosphonate monoester S34.1 is converted, as described in Scheme 34, into the activated derivative S34.8. This compound is then reacted, as described above, with an aminoester S34.9, in the presence of a base, to afford the monoamidate product S35.1.
The procedure is illustrated in Scheme 35, Example 1. In this method, a monophenyl phosphonate S35.7 is reacted with, for example, thionyl chloride, as described in J. Gen. Chem. USSR., 1983, 32, 367, to give the chloro product S35.8. The product is then reacted, as described in Scheme 34, with ethyl alaninateS3, to yield the amidate S35.10.
Using the above procedures, but employing, in place of ethyl alaninate S35.9, different aminoesters S34.9, the corresponding products S35.1 are obtained. Alternatively, the phosphonate monoester S34.1 is coupled, as described in Scheme 34, with an aminoester S34.9 to produce the amidateS335.1. If necessary, the R1 substituent is then altered, by initial cleavage to afford the phosphonic acid S35.2. The procedures for this transformation depend on the nature of the R1 group, and are described above. The phosphonic acid is then transformed into the ester amidate product S35.3, by reaction with the hydroxy compound R3OH, in which the group R3 is aryl, heterocycle, alkyl, cycloalkyl, haloalkyl etc, using the same coupling procedures (carbodiimide, Aldrithiol-2, PYBOP, Mitsunobu reaction etc) described in Scheme 34 for the coupling of amines and phosphonic acids. Scheme 34 Example 1
R-link
Figure imgf000106_0001
S34.14 S34.15 S34.17
Figure imgf000106_0002
Scheme 34 Example 2
Bn
0 H2NCH(Bn)CO2Et 0 )— COOEt
R-link — PN-OH S34.21 R-link — PN-NH OH NH Bn- (
COOEt
S34.6 S34.22
Figure imgf000107_0001
S34.25
Scheme 34 Example 4
Figure imgf000107_0002
S34.28
Figure imgf000107_0003
Scheme 34 Example 5
R-l
Figure imgf000107_0004
S34.36
Figure imgf000107_0005
Scheme 34 Example 7
Figure imgf000108_0001
Figure imgf000108_0002
Examples of this method are shown in Scheme 35, Examples 2 and 3. In the sequence shown in Example 2, a monobenzyl phosphonate S35.ll is transformed by reaction with ethyl alaninate, using one of the methods described above, into the monoamidate S35.12. The benzyl group is then removed by catalytic hydrogenation in ethylacetate solution over a 5% palladium on carbon catalyst, to afford the phosphonic acid amidate S35.13. The product is then reacted in dichloromethane solution at ambient temperature with equimolar amounts of l-(dimethylaminopropyl)-3-ethylcarbodiimide and trifluoroethanol S35.14, for example as described in Tet. Lett., 2001, 42, 8841, to yield the amidate ester S35.15.
In the sequence shown in Scheme 35, Example 3, the monoamidate S35.13 is coupled, in tetrahydrofuran solution at ambient temperature, with equimolar amounts of dicyclohexyl carbodiimide and 4-hydroxy-N- methylpiperidine S35.16, to produce the amidate ester product S35.17.
Using the above procedures, but employing, in place of the ethyl alaninate product S35.12 different monoacids S35.2, and in place of trifluoroethanol S35.14 or 4-hydroxy-N-methylpiperidine S35.16, different hydroxy compounds R3OH, the corresponding products S35.3 are obtained.
Alternatively, the activated phosphonate ester S34.8 is reacted with ammonia to yield the amidate S35.4. The product is then reacted, as described in Scheme 34, with a haloester S35.5, in the presence of a base, to produce the amidate product S35.6. If appropriate, the nature of the R1 group is changed, using the procedures described above, to give the product S35.3. The method is illustrated in Scheme 35, Example 4. In this sequence, the monophenyl phosphoryl chloride S35.18 is reacted, as described in Scheme 34, with ammonia, to yield the amino product S35.19. This material is then reacted in N- methylpyrrolidinone solution at 170° with butyl 2-bromo-3-phenylpropionate S35.20 and potassium carbonate, to afford the amidate product S35.21.
Using these procedures, but employing, in place of butyl 2-bromo-3- phenylpropionate S35.20, different haloesters S35.5, the corresponding products S35.6 are obtained.
The monoamidate products S35.3 are also prepared from the doubly activated phosphonate derivatives S34.7. In this procedure, examples of which are described in Synlett, 1998, 1, 73, the intermediate S34.7 is reacted with a limited amount of the aminoester S34.9 to give the mono-displacement product S34.ll. The latter compound is then reacted with the hydroxy compound R3OH in a polar organic solvent such as dimethylformamide, in the presence of a base such as diisopropylethylamine, to yield the monoamidate ester S35.3.
The method is illustrated in Scheme 35, Example 5. hi this method, the phosphoryl dichloride S35.22 is reacted in dichloromethane solution with one molar equivalent of ethyl N-methyl tyrosinate S35.23 and dimethylaminopyridine, to generate the monoamidate S35.24. The product is then reacted with phenol S35.25 in dimethylformamide containing potassium carbonate, to yield the ester amidate product S35.26.
Using these procedures, but employing, in place of ethyl N-methyl tyrosinate S35.23 or phenol S35.25, the aminoesters 34.9 and/or the hydroxy compounds R OH, the corresponding products S35.3 are obtained. Scheme 35
S35.3
Figure imgf000110_0001
S35.3
Scheme 35 Example 1
R-link
Figure imgf000110_0002
Scheme 35 Example 2
O O O R-link — P-OBn -= ^R-link — R \-OBn ■ R-link — Px-OH
N0H NH NH Me— ( Me— (
CO2Et CO2Et
S35.11 S35.12 S35.13
Figure imgf000110_0003
Scheme 35 Example 3
Figure imgf000111_0001
S35.13 S35.17
Scheme 35 Example 4
O O BrCH(Bn)CO2Bu 0
R-link — R-OPh R-link — R-OPh R-link — R-OPh Cl NH2 S35.20 NH
Bn
S35.18 S35.19
CO2Bu S35.21
Scheme 35 Example 5
Figure imgf000111_0002
Scheme 36 illustrates methods for the preparation of carboalkoxy- substituted phosphonate diesters in which one of the ester groups incorporates a carboalkoxy substituent. In one procedure, a phosphonate monoester S34.1, prepared as described above, is coupled, using one of the methods described above, with a hydroxyester S36.1, in which the groups R and R5b are as described in Scheme 34. For example, equimolar amounts of the reactants are coupled in the presence of a carbodiimide such as dicyclohexyl carbodiimide, as described in Aust. J. Chem., 1963, 609, optionally in the presence of dimethylaminopyridine, as described in Tet., 1999, 55, 12997. The reaction is conducted in an inert solvent at ambient temperature.
The procedure is illustrated in Scheme 36, Example 1. In this method, a monophenyl phosphonate S36.9 is coupled, in dichloromethane solution in the presence of dicyclohexyl carbodiimide, with ethyl 3-hydroxy-2- methylpropionate S36.10 to yield the phosphonate mixed diester S36.ll.
Using this procedure, but employing, in place of ethyl 3-hydroxy-2- methylpropionate S36.10, different hydroxyesters S33.1, the corresponding products S33.2 are obtained.
The conversion of a phosphonate monoester S34.1 into a mixed diester S36.2 is also accomplished by means of a Mitsunobu coupling reaction with the hydroxyester S36.1, as described in Org. Lett., 2001, 643. hi this method, the reactants 34.1 and S36.1 are combined in a polar solvent such as tetrahydrofuran, in the presence of a triarylphosphine and a dialkyl azodicarboxylate, to give the mixed diester S36.2. The R1 substituent is varied by cleavage, using the methods described previously, to afford the monoacid product S36.3. The product is then coupled, for example using methods described above, with the hydroxy compound R3OH, to give the diester product S36.4. The procedure is illustrated in Scheme 36, Example 2. hi this method, a monoallyl phosphonate S36.12 is coupled in tetrahydrofuran solution, in the presence of triphenylphosphine and diethylazodicarboxylate, with ethyl lactate S36.13 to give the mixed diester S36.14. The product is reacted with tris(triphenylphosphine) rhodium chloride (Wilkinson catalyst) in acetonitrile, as described previously, to remove the allyl group and produce the monoacid product S36.15. The latter compound is then coupled, in pyridine solution at ambient temperature, in the presence of dicyclohexyl carbodiimide, with one molar equivalent of 3-hydroxypyridine S36.16 to yield the mixed diester S36.17.
Il l Using the above procedures, but employing, in place of the ethyl lactate S36.13 or 3-hydroxypyridine, a different hydroxyester S36.1 and/or a different hydroxy compound R3OH, the corresponding products S36.4 are obtained.
The mixed diesters S36.2 are also obtained from the monoesters S34.1 via the intermediacy of the activated monoesters S36.5. In this procedure, the monoester S34.1 is converted into the activated compound S36.5 by reaction with, for example, phosphorus pentachloride, as described in J. Org. Chem., 2001, 66, 329, or with thionyl chloride or oxalyl chloride (Lv = Cl), or with triisopropylbenzenesulfonyl chloride in pyridine, as described in Nucleosides and Nucleotides, 2000, 19, 1885, or with carbonyl diimidazole, as described in J. Med. Chem., 2002, 45, 1284. The resultant activated monoester is then reacted with the hydroxyester S36.1, as described above, to yield the mixed diester S36.2.
The procedure is illustrated in Scheme 36, Example 3. In this sequence, a monophenyl phosphonate S36.9 is reacted, in acetonitrile solution at 70 0C, with ten equivalents of thionyl chloride, so as to produce the phosphoryl chloride S36.19. The product is then reacted with ethyl 4-carbamoyl-2-hydroxybutyrate S36.20 in dichloromethane containing triethylamine, to give the mixed diester S36.21. Using the above procedures, but employing, in place of ethyl A- carbamoyl-2-hydroxybutyrate S36.20, different hydroxyesters S36.1, the corresponding products S36.2 are obtained.
The mixed phosphonate diesters are also obtained by an alternative route for incorporation of the R3O group into intermediates S36.3 in which the hydroxyester moiety is already incorporated, hi this procedure, the monoacid intermediate S36.3 is converted into the activated derivative S36.6 in which Lv is a leaving group such as chloro, imidazole, and the like, as previously described. The activated intermediate is then reacted with the hydroxy compound R3OH, in the presence of a base, to yield the mixed diester product S36.4.
The method is illustrated in Scheme 36, Example 4. In this sequence, the phosphonate monoacid S36.22 is reacted with trichloromethanesulfonyl chloride in tetrahydrofuran containing collidiiie, as described in J. Med. Chem., 1995, 38, 4648, to produce the trichloroniethanesulfonyloxy product S36.23. This compound is reacted with 3-(morpholinomethyl)phenol S36.24 in dichloromethane containing triethylamine, to yield the mixed diester product S36.25. Using the above procedures, but employing, in place of with 3-
(morpholinomethyl)phenol S36.24, different alcohols R3OH, the corresponding products S36.4 are obtained.
The phosphonate esters S36.4 are also obtained by means of alkylation reactions performed on the monoesters S34.1. The reaction between the monoacid S34.1 and the haloester S36.7 is performed in a polar solvent in the presence of a base such as diisopropylethylamine, as described in Anal. Chem., 1987, 59, 1056, or triethylamine, as described in J. Med. Chem., 1995, 38, 1372, or in a non-polar solvent such as benzene, in the presence of 18-crown-6, as described in Syn. Comm., 1995, 25, 3565. The method is illustrated in Scheme 36, Example 5. hi this procedure, the monoacid S36.26 is reacted with ethyl 2-bromo-3-phenylpropionate S36.27 and diisopropylethylamine in dimethylformamide at 80 0C to afford the mixed diester product S36.28.
Using the above procedure, but employing, in place of ethyl 2-bromo-3- phenylpropionate S36.27, different haloesters S36.7, the corresponding products S36.4 are obtained.
Scheme 36
HOR1 (1 equiv.) O
R-link — PN-OH HO-R4b-COOR5b OH
Figure imgf000115_0001
b
Figure imgf000115_0002
Figure imgf000116_0001
Scheme 36 Example 2
Figure imgf000116_0002
S36.14 S36.15
Figure imgf000116_0003
Scheme 36 Example 3
Figure imgf000116_0004
S36.9 S36.19
EtO2CCH
Figure imgf000116_0005
Scheme 36 Example 4
Figure imgf000117_0001
S36.22 S36.23
Figure imgf000117_0002
S36.25
Scheme 36 Example 5
O BrCH(Bn)CO2Et O
Il R-link — PN-OH R-link — Px-OCH(Bn)CO2Et
OCH2CF3 S36.27 OCH2CF3
S36.26 S36.28
Scheme 37 illustrates methods for the preparation of phosphonate diesters in which both the ester substituents incorporate carboalkoxy groups.
The compounds are prepared directly or indirectly from the phosphonic acids S34.6. hi one alternative, the phosphonic acid is coupled with the hydroxyester S37.2, using the conditions described previously in Schemes 34- 36, such as coupling reactions using dicyclohexyl carbodiimide or similar reagents, or under the conditions of the Mitsunobu reaction, to afford the diester product S37.3 in which the ester substituents are identical.
This method is illustrated in Scheme 37, Example 1. hi this procedure, the phosphonic acid S34.6 is reacted with three molar equivalents of butyl lactate S37.5 in the presence of Aldrithiol-2 and triphenyl phosphine in pyridine at ca. 70 0C, to afford the diester S37.6.
Using the above procedure, but employing, in place of butyl lactate S37.5, different hydroxyesters S37.2, the corresponding products S37.3 are obtained.
Alternatively, the diesters S37.3 are obtained by alkylation of the phosphonic acid S34.6 with a haloester S37.1. The alkylation reaction is performed as described in Scheme 36 for the preparation of the esters S36.4.
This method is illustrated in Scheme 37, Example 2. In this procedure, the phosphonic acid S34.6 is reacted with excess ethyl 3-bromo-2- methylpropionate S37.7 and diisopropylethylamine in dimethylformamide at ca. 80 0C, as described in Anal. Chem., 1987, 59, 1056, to produce the diester S37.8. Using the above procedure, but employing, in place of ethyl 3-bromo-2- methylpropionate S37.7, different haloesters S37.1, the corresponding products S37.3 are obtained.
The diesters S37.3 are also obtained by displacement reactions of activated derivatives S34.7 of the phosphonic acid with the hydroxyesters S37.2. The displacement reaction is performed in a polar solvent in the presence of a suitable base, as described in Scheme 36. The displacement reaction is performed in the presence of an excess of the hydroxyester, to afford the diester product S37.3 in which the ester substituents are identical, or sequentially with limited amounts of different hydroxyesters, to prepare diesters S37.3 in which the ester substituents are different.
The methods are illustrated in Scheme 37, Examples 3 and 4. As shown in Example 3, the phosphoryl dichloride S35.22 is reacted with three molar equivalents of ethyl 3-hydroxy-2-(hydroxymethyl)propionate S37.9 in tetrahydrofuran containing potassium carbonate, to obtain the diester product S37.10.
Using the above procedure, but employing, in place of ethyl 3-hydroxy- 2-(hydroxymethyl)propionate S37.9, different hydroxyesters S37.2, the corresponding products S37.3 are obtained.
Scheme 37, Example 4 depicts the displacement reaction between equimolar amounts of the phosphoryl dichloride S35.22 and ethyl 2-methyl-3- hydroxypropionate S37.ll, to yield the monoester product S37.12. The reaction is conducted in acetonitrile at 70° in the presence of diisopropylethylamine. The product S37.12 is then reacted, under the same conditions, with one molar equivalent of ethyl lactate S37.13, to give the diester product S37.14.
Using the above procedures, but employing, in place of ethyl 2-methyl-3- hydroxypropionate S37.ll and ethyl lactate S37.13, sequential reactions with different hydroxyesters S37.2, the corresponding products S37.3 are obtained. Scheme 37
Figure imgf000119_0001
S34.7 S37.4
Scheme 37 Example 1
R-link
Figure imgf000119_0002
Scheme 37 Example 2
R-link
Figure imgf000119_0003
Scheme 37 Example 3
O (HOCH2)2CHCO2Et Q
R-hnk PN-CI **- R |ink — L0CH CH(CH2QH)CO2Et u S37.9 \
S35 22 OCH2CH(CH2OH)CO2Et
S37.10 Scheme 37 Example 4
RPx--OCH2CH(CH3)CO2Et
Figure imgf000120_0001
S35.22 S37.12
Figure imgf000120_0002
2,2-Dimethyl-2-aminoethylphosphonic acid intermediates can be prepared by the route in Scheme 5. Condensation of 2-methyl-2- propanesulfmamide with acetone give sulfinyl imine S38.ll (J. Org. Chem. 1999, 64, 12). Addition of dimethyl methylphosphonate lithium to S38.ll afford S38.12. Acidic methanolysis of S38.12 provide amine S38.13. Protection of amine with Cbz group and removal of methyl groups yield phosphonic acid S38.14, which can be converted to desired S38.15 (Scheme 38a) using methods reported earlier on. An alternative synthesis of compound S38.14 is also shown in Scheme 38b. Commercially available 2-amino-2-methyl-l-propanol is converted to aziridines S38.16 according to literature methods (J. Org. Chem. 1992, 57, 5813; Syn. Lett. 1997, 8, 893). Aziridine opening with phosphite give S38.17 (Tetrahedron Lett. 1980, 21, 1623). Reprotection) of S38.17 affords S38.14. Scheme 38a
Figure imgf000121_0001
S38.14
The invention will now be illustrated by the following non-limiting Examples and Exemplary Embodiments:
Figure imgf000121_0002
2-deoxy-2-fluoro-3,5-di-0-benzoyI-α-D-arabinofuranosylbromide (2) Tann et al, JOC 1985, 50, p3644 Howell et al. JOC 1988, 53,p85
To a solution of 1 (120 g, 258 mmol), commercially available from Davos or
CMS chemicals, in CH2Cl2 (1 L) was added 33% HBr / Acetic acid (80 mL). The mixture was stirred at room temperature for 16 h, cooled with ice-water, and slowly neutralized over 1 -2 h with NaHCO3 (150 g / 1.5 L solution). The CH2Cl2 phase was separated and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with NaHCO3 until no acid was present. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to give product 2 as a yellow oil (~115 g).
Figure imgf000121_0003
2-deoxy-2-fluoro-3, 5-di-O-benzoyl-β-D-arabinofuranosyl-9H-6- chloropurine (3) Ma et al, J. Med. Chetn. 1997, 40, 2750
Marquez et al, J. Med. Client. 1990, 33, 978 midebrand et al, J. Org. Chem. 1992, 57, 1808 Kazimierczuk et al JACS 1984, 106, 6379 To a suspension of NaH (14 g, 60%) in ACETONITRILE (900 mL), 6- chloropurine (52.6 g) was added in 3 portions. The mixture was stirred at room temperature for 1.5 h. A solution of 2 (258 mmol) in ACETONITRILE (300 mL) was added drop wise. The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with Acetic acid (3.5 mL), filtered and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and water. The organic phase was dried over MgSO4, filtered and concentrated. The residue was treated with CH2Cl2 and then EtOH (~1 :2 overall) to precipitate out the desired product 3 as a yellowish solid (83 g, 65% from 1).
Figure imgf000122_0001
2-deoxy-2-fluoro -β-D-arabinofuranosyl-6-methoxyadenine (4)
To a suspension of 3 (83 g, 167 mmol) in Methanol (1 L) at 0 0C, NaOMe (25% wt, 76 mL) was added. The mixture was stirred at room temperature for 2 h, and then quenched with Acetic acid (- 11 mL, pH=7). The mixture was concentrated under reduced pressure and the resultant residue partitioned between hexane and water (approximately 500 mL hexane and 300 mL water). The aqueous layer was separated and the organic layer mixed with water once again (approximately 300 mL). The water fractions were combined and concentrated under reduced pressure to -100 mL. The product, 4, precipitated out and was collected by filtration (42 g, 88%).
Figure imgf000122_0002
2-deoxy-2-fluoro-5-carboxy-β-D-arabinofuranosyI-6-methoxyadenine (5) Moss et al. J. Client. Soc. 1963,pll49 A mixture of Pt/C (10%, 15 g (20-30% mol equiv.) as a water slurry) and NaHCO3 (1.5 g, 17.94 mmol) in H2O (500 rnL) was stirred at 65 0C under H2 for 0.5 h. The reaction mixture was then allowed to cool, placed under a vacuum and flushed with N2 several times to completely remove all H2. Compound 4 (5.1 g, 17.94 mmol) was then added at room temperature. The reaction mixture was stirred at 65 0C under O2 (balloon) until the reaction was complete by LC- MS (typically 24-72h). The mixture was cooled to room temperature and filtered. The Pt/C was washed with H2O extensively. The combined filtrates were concentrated to ~ 30 mL, and acidified (pH 4) by the addition of HCl (4N) at 0 °C. A black solid precipitated out which was collected by filtration. The crude product was dissolved in a minimum amount of Methanol and filtered through a pad of silica gel (eluting with Methanol). The filtrate was concentrated and crystallized from water to give compound 5 (2.5 g) as an off- white solid.
Figure imgf000123_0001
(2'R, 3'S, 4'R, 5'R)-6-Methoxy-9-[tetrahydro 4-iodo-3-fluoro -5- (diethoxyphosphinyl)methoxy-2-furanyl]purine (6) Zemlicka et al, J. Amer. Chem. Soc. 1972, 94, p3213
To a solution of 5 (22 g, 73.77 mmol) in DMF (400 mL), DMF dineopentyl acetal (150 mL, 538 mmol) and methanesulfonic acid (9.5 mL, 146.6 mmol) were added. The reaction mixture was stirred at 80-93 0C (internal temperature) for 30 min, then cooledto room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was separated and washed with NaHCO3 followed by brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue and diethyl (hydroxymethyl)phosphonate (33 mL, 225 mmol) were dissolved in CH2Cl2 (250 mL) and cooled down to -40 0C. A solution of iodine monobromide (30.5 g, 1.1 mol) in CH2Cl2 (100 mL) was added dropwise. The mixture was stirred at -20 to -5 0C for 6 h. The reaction was then quenched with NaHCO3 and Na2S2O3. The organic phase was separated and the water phase was extracted with CH2Cl2. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give product 6 (6 g, 15.3%).
Alternative Procedure for the Preparation of 6
A solution of 5 (2.0 g, 6.7 mmol) in THF (45 mL) was treated with triphenyl phosphine (2.3 g, 8.7 mmol) under N2. Diisopropyl azodicarboxylate (1.8 g, 8.7 mmol) was added slowly. The resultant mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure to dryness. The residue was dissolved in CH2Cl2 (20 ml), and then treated with diethyl(hydroxymethyl)phosphonate (4.5 g, 27 mmol). The mixture was cooled to -60 °C and then a cold solution of iodine monobromide 2 g, 9.6 mmol) in CH2Cl2 (10 ml) was added. The reaction mixture was warmed to -10 0C and then kept at -10 °C for 1 h. The reaction mixture was diluted with CH2Cl2, washed with saturated aqueous NaHCO3, and then with aqueous sodium thiosulfate. The organic phase was separated, dried over MgSO4, and concentrated under reduced pressure to dryness. The reaction mixture was purified by silica gel chromatography (eluting with 25 % ethyl acetate in CH2Cl2, then switching to 3 % methanol in CH2Cl2) to afford product 6 (0.9 g, 33 %).
Figure imgf000124_0001
(2'R, 5'R)-6-Methoxy-9-[3-fluoro-2,5-dihydro-5- (diethoxyphosphinyl)methoxy-2-furanyl]purine (7)
To a solution of compound 6 (6 g, 11.3 mmol) in acetic acid (2.5 mL) and methanol (50 mL), NaClO (10-13%) (50 mL) was added dropwise. The reaction mixture was then stirred for 0.5 h and concentrated under reduced pressure. The residue was treated with ethyl acetate and then filtered to remove solids. The filtrate was concentrated and the residue was purified by silica gel chromatography to give product 7 (4 g, 88%).
Figure imgf000125_0001
(2'R, 5'R)-9-(3-fluoro-2,5-dihydro-5-phosphonomethoxy-2-furanyl)adenine di sodium salt (8) A solution of compound 7 (2.3 g, 5.7 mmol) in methanol (6 mL) was mixed with ammonium hydroxide (28-30%) (60 mL). The resultant mixture was stirred at 120 °C for 4 h, cooled, and then concentrated under reduced pressure. The residue was dried under vacuum for 12 h. The residue was dissolved in DMF (40 mL) and bromotrimethylsilane (3.5 mL) was added. The mixture was stirred at room temperature for 16 h, and then concentrated under reduced pressure.
The residue was dissolved in aqueous NaHCO3 (2.3 g in 100 mL of water). The solution was evaporated and the residue was purified on C-18 (40 μm) column, eluting with water. The aqueous fractions were freeze dried to give di-sodium salt 8 (1.22 g, 57%).
Figure imgf000125_0002
Example of Monoamidate Preparation (9)
Di sodium salt 8 (25 mg, 0.066 mmol), (S)-Ala-O-cyclobutyl ester hydrochloride (24 mg, 2 eq., 0.133 mmol) and phenol (31 nig, 0.333 mmol) were mixed in anhydrous pyridine (1 mL). Triethylamine (111 μL, 0.799 mmol) was added and the resultant mixture was stirred at 60 0C under nitrogen. In a separate flask, 2'-Aldrithiol (122 mg, 0.466 rnmol) and triphenylphosphine (103 mg, 0.466 mmol) were dissolved in anhydrous pyridine (0.5mL) and the resulting yellow solution was stirred for 15-20 min. The solution was then added to the solution of 8 in one portion. The combined mixture was stirred at 60 0C under nitrogen for 16 h to give a clear yellow to light brown solution. The mixture was then concentrated under reduced pressure. The resultant oil was dissolved in CH2Cl2 and purified by silica gel chromatography (eluting with a linear gradient of 0 to 5% MeOH in CH2Cl2) to give an oil. The resulting oil was dissolved in acetonitrile and water and purified by preparative HPLC (linear gradient, 5-95% acetonitrile in water). Pure fractions were combined and freeze-dried to give mono amidate 9 as a white powder.
Figure imgf000126_0001
Example of bis amidate preparation (10) Di sodium salt 8 (12 mg, 0.032 mmol) and (S)-Ala-O-n-Pr ester hydrochloride (32 mg, 6 eq., 0.192 mmol) were mixed in anhydrous pyridine (1 mL). Triethylamine (53 μL, 0.384 mmol) was added and the resultant mixture was stirred at 60 0C under nitrogen. In a separate flask, 2'-Aldrithiol (59 mg, 0.224 mmol) and triphenylphosphine (49 mg, 0.224 mmol) were dissolved in anhydrous pyridine (0.5 mL) and the resulting yellow solution was stirred for 15-20 min. The solution was then added to the solution of 8 in one portion. The combined mixture was stirred at 60 0C under nitrogen for 16 h to give a clear yellow to light brown solution. The mixture was then concentrated under reduced pressure. The resultant oil was dissolved in CH2Cl2 and purified by silica gel chromatography (eluting with a linear gradient of 0 to 5% MeOH in CH2Cl2) to give an oil. The resulting oil was dissolved in acetonitrile and water and purified by preparative HPLC (linear gradient, 5-95% acetonitrile in water). Pure fractions were combined and freeze-dried to give bis amidate as a white powder.
EXEMPLARY EMBODIMENTS
Figure imgf000127_0001
Figure imgf000127_0002
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Example 11
1H NMR (CDC13) δ 8.39 (s, IH) δ 8.12 (s, IH) δ 6.82 (m, IH) δ 5.96-5.81 (m,
4H) δ 4.03-3.79 (m, 10H) δ 3.49 (s, IH) δ 3.2 (m, 2H) δ 1.96-1.69 (m, 10H) δ 1.26 (m, 4H) δ 0.91 (m, 12H) 3 IP NMR (CDC13) 20.37 (s, IP) MS (M+l) 614
Example 12
1H NMR (CDCB) δ 8.39 (s, IH) δ 8.13 (s, IH) δ 7.27-7.11 (m, 5H) δ 6.82 (s,
IH) δ 5.97-5.77 (m, 4H) δ 4.14-3.79 (m, 6H) δ 3.64 (t, 1 H) δ 2.00-1.88 (bm, 4H) δ 1.31 (dd, 3H) δ 0.91 (m, 6H). 31P NMR (CDC13) δ 20.12 (s, 0.5P) δ 19.76 (s, 0.5P) MS (M+l) 535
Example 13
1H NMR (CDCl3): δ 8.39 (s, IH), 8.13 (s, IH), 6.81 (m IH), 5.95 (m, IH),
5.81(s, IH), 4.98 (m, 2H), 3.90 (m, 2H), 3.37 (m, IH), 3.19 (m, IH), 1.71 (m, 4H), 1.25 (m, 12H), 0.90 (m, 6H) Mass Spectrum Qn/e): (M+H)+ 586.3
Example 14
1H NMR (CDCl3): δ 8.38 (s, IH), 8.12 (s, IH), 6.80 (m IH), 5.93 (m, IH), 5.79
(s, IH), 4.02 (m, 6H), 3.42 (m, IH), 3.21 (m, IH), 1.65 (m, 4H), 1.35 (m, 8H),
0.92 (m, 12H)
Mass Spectrum (m/e): (M+H)+ 614.3 Example 15
1H NMR (CDCl3): δ 8.38 (s, IH), 8.12 (s, IH), 6.80 (m IH), 5.93 (m, 2H), 5.80
(s, IH), 3.91 (m, 6H), 3.42 (m, IH), 3.30 (m, IH), 1.91 (m, 2H), 1.40 (m, 6H), 0.90 (m, 12H) Mass Spectrum (m/e): (M+H)+ 586.3
Example 16
1H NMR (CDCl3): δ 8.37 (s, IH), 8.17 (s, IH), 6.80 (m IH), 6.18 (s, IH), 5.93
(m, IH), 5.79 (s, IH), 4.02 (m, 6H), 3.46 (m, IH), 3.37 (m, IH), 1.61 (m, 4H), 1.32 (m, 10H), 0.92 (m, 6H)
Mass Spectrum (m/e): (M+H)+ 614.3
Example 17
1H NMR (CD3OD): δ 8.29 (s, IH), 8.25 (s, IH), 6.84 (m IH), 6.00 (s, IH), 5.96 (m, IH), 4.04 (m, 8H), 1.66 (m, 4H), 1.38 (m, 6H), 0.98 (m, 6H) Mass Spectrum (m/e): (M+H)+ 558.3
Example 18
1H NMR (CD3OD): δ 8.29 (s, IH), 8.25 (s, IH), 6.84 (m IH), 5.99 (s, IH), 5.96 (m, IH), 4.04 (m, 8H), 1.67 (m, 4H), 1.23 (m, 6H), 0.95 (m, 6H) Mass Spectrum (m/e): (M+H)+ 558.3
Example 19
1H NMR (CD3OD): δ 8.29 (s, IH), 8.25 (s, IH), 6.84 (m IH), 5.99 (s, IH), 5.96 (m, IH), 4.03 (m, 8H), 1.66 (m, 8H), 0.93 (m, 12H) Mass Spectrum (m/e): (M+H)+ 586.3
Example 20
1H NMR (CD3OD): δ 8.25 (s, IH), 8.17 (s, IH), 7.21 (m, 10H), 6.80 (m IH), 5.91 (s, IH), 5.72 (m, IH), 4.04 (m, 6H), 3.50 (m, 2H), 2.90 (m, 4H), 1.47 (m, 8H), 0.92 (m, 6H) Mass Spectrum (m/e): (M+H)+ 738.4
Example 21 1H NMR (CD3OD): δ 8.24 (s, 2H), 7.33 (m, 10H), 6.81 (m IH), 5.88 (s, IH),
5.84 (m, IH), 5.12 (m, 4H), 3.94 (m, 4H), 1.35 (m, 6H) Mass Spectrum (m/e): (M+H)+ 654.3 Example 22
1H NMR (CDCB) δ 8.38 (d, IH) δ 8.12 (d, IH) δ 7.31-7.10 (m, 5H) δ 6.81 (m,
IH) δ 5.98-5.75 (m, 4H) δ 4.23-3.92 (M, 7H) δ 3.65 (m, IH) δ 1.63 (m, 3H) δ 1.26 (m, 4H) δ 1.05-0.78 (m, 3H) 31P NMR 821.01 (s, 0.6P) δ 20.12 (s, 0.4P) MS (M+l) 521
Example 23
1H NMR (CDC13) δ 8.40 (d, IH) δ 8.13 (d, IH) δ 7.30-7.10 (m, 5H) δ 6.82 (m,
IH) δ 5.99-5.77 (m, 3H) δ 4.22-3.92 (m, 6H) δ 3.61 (m, IH) δ 1.65 (m, 4H) δ 1.26-0.71 (m, 6H) 3 IP NMR (CDC13) δ 20.99 (s, 0.6P) δ 20.08 (s, 0.4P) MS (M+l) 535
Example 24
1H NMR (CDC13) δ 8.39 (d, IH) δ 8.08 (d, IH) δ 7.28-6.74 (m, 10H) δ 5.90 (m, 4H) δ 4.37 (m, IH) δ 4.05 (m, 5H) δ 3.56 (m, 2H) δ 2.99 (m, 2H) δ 1.55 (m, 2H) δ 1.22 (m, 3H) δ 0.88 (m, 3H) 3 IP NMR (CDC13) δ 20.95 (s, 0.5P) δ 20.01 (s, 0.5P) MS (M+l) 611
Example 25 1H NMR (CDCB) δ 8.38 (d, IH) δ 8.11 (s, IH) δ 7.31-7.11 (m, 5H) δ 6.82 (s,
IH) δ 5.96-5.76 (m, 4H) δ 4.22-3.63 (m, 6H) δ 2.17 (bm, 2H) δ 1.65 (m, 2H) 1.30 (m, 4H) δ 0.88 (m, 3H). 31P NMR (CDC13) δ 20.75 (s, 0.5P) δ 19.82 (s, 0.5P) MS (M+l) 521
Example 26
1H NMR (CDCB) δ 8.40 (d, IH) δ 8.09 (d, IH) δ 7.27-6.74 (m, 10H) δ 5.93-
5.30 (m, 4H) δ 4.39 (m, IH) δ 4.14-3.77 (m, 4H) δ 3.58 (m, 2H) δ 2.95 (m, 2H) δ 1.90 (m, 3H) δ 1.26 (m, IH) δ 0.85 (m, 6H). 3 IP NMR (CDCB) δ 20.97 (s, 0.5P) δ 20.04 (s, 0.5P) MS (M+l) 611
Example 27
1H NMR (CD3OD): 8.31 (s, IH), 8.25 (s, IH), 6.84 (m IH), 6.02 (s, IH), 5.98
(m, IH), 4.98 (m, 2H), 4.01 (m, 2H), 3.66 (m, 4H), 1.23 (m, 12H) Mass Spectrum (m/e): (M+H)+ 530.2 Example 28
1H NMR (CD3OD): 8.31 (s, IH), 8.25 (s, IH), 6.84 (m IH), 6.01 (s, IH), 5.98
(m, IH), 4.03 (m, 2H), 3.86 (m, 4H), 3.68 (m, 4H), 1.92 (m, 2H), 0.93 (m, 12H) Mass Spectrum (m/e): (M+H)+ 558.3
Example 29
1H NMR (CD3OD): 8.29 (s, IH), 8.25 (s, IH), 6.84 (m IH), 5.99 (s, IH), 5.97
(m, IH), 4.01 (m, 8H), 1.66 (m, 8H), 1.32 (m, 8H), 0.96 (m, 12H) Mass Spectrum (m/e): (M+H)+ 642.4
Example 30
1H NMR (CD3OD): 8.25 (s, IH), 8.16 (s, IH), 7.24 (m, 10H), 6.80 (m IH),
5.90 (s, IH), 5.71 (m, IH), 5.25 (m, 4H), 4.57 (m, 2H), 4.51 (m, 2H), 4.05 (m, 2H), 3.46 (m, 2H), 2.92 (m, 6H) Mass Spectrum (m/e): (M+H)+ 706.4
Example 31
1H NMR (CD3OD): 8.32 (s, IH), 8.25 (s, IH), 6.84 (m IH), 6.00 (s, IH), 5.97
(m, IH), 3.93 (m, 4H), 3.71 (s, 3H), 3.60 (s, 3H), 1.51 (m, 26H) Mass Spectrum (m/e): (M+H)+ 666.5
Example 32
1H NMR (CDC13) δ 8.39 (s, IH) δ 8.17 (d, IH) δ 7.32-6.82 (m, 5H) δ 6.82 (s,
IH) δ 5.98-5.81 (m, 3H) δ 4.27-3.64 (m, 6H) δ 1.94 (m, IH) δ 0.90 (m, 6H). 3 IP NMR (CDC13) δ 21.50 (s, 0.5P) δ 21.37 (s, 0.5P) MS (M+l) 521
Example 33
1H NMR (CDC13) δ 8.39 (s, IH) δ 8.13 (s, IH) δ 7.27 - 7.14 (m, 5H) δ 6.85 (s,
IH) δ 5.97-5.77 (m, 4H) δ 4.186-4.05 (m, 7H) δ 1.60 (m, 3H) δ 1.29 (m, 7H) δ 0.90 (m, 3H) 3 IP NMR (CDC13) 20.69 (s, 0.6P) δ 19.77 (s, 0.4P) MS (M+l) 549
Example 34
1H NMR (CDC13) δ 8.39 (d, IH) δ 8.07 (d, IH) δ7.27 - 6.74 (m, 10H) δ 5.91
(m, 2H) δ 5.69 (m 2H) δ 5.27 (m, 2H) δ 4.55 (m, 2H) δ 4.30 (m, IH) δ 3.69 (m, IH) δ 2.95 (m, IH) δ 5.05 (m, 2H) 31P NMR (CDC13) δ 20.94 (s, 0.5P) δ 19.94 (s, 0.5P) MS (M+l) 595 Example 35
1H NMR (CDC13) δ 8.39 (d, 1 H) δ 8.11 (d, 1 H) δ 7.28 - 7.10 (m, 5 H) δ 6.82
(s, 1 H) δ 5.98 - 5.76 (m, 3 H) δ 4.18 - 3.56 (m, 4 H) δ 3.59 (m, 1 H) δ 1.74 - 0.70 (m, 12 H). 3 IP NMR (CDC13) δ 21.00 (s, 0.6 P) δ 20.09 (s, 0.4 P). MS (M + 1) 549
Example 36
1H NMR (CDC13) δ 8.39 (d, 1 H) δ 8.12 (d. 1 H) δ 7.29 (m, 2 H) δ 7.15 (m, 3 H) δ 6.82 (s, 1 H) δ 5.94 (dd, 1 H) δ 5.80 (s , 3 H) δ 5.02 (m, 1 H) δ 4.23 - 3.58 (m, 6 H) δ 2.18 (s, 3 H) δ 1.23 (m, 6 H). 31P NMR (CDC13) δ 21.54 (s, 0.5 P) δ 21.43 (s, 0.5 P). MS (M + 1) 507
Example 37
1H NMR (CD3OD): 8.30 (s, IH), 8.25 (s, IH), 6.84 (m IH), 6.00 (s, IH), 5.95 (m, IH), 4.06 (m, 8H), 1.31 (m, 12H) Mass Spectrum (m/e): (M+H)+ 530.3
Example 38
1H NMR (CD3OD): 8.25 (s, IH), 8.16 (s, IH), 7.24 (m, 10H), 6.84 (m IH), 5.91 (s, IH), 5.75 (m, IH), 4.08 (m, 6H), 3.60 (m, 2H), 2.90 (m, 4H), 1.21 (m, 6H) Mass Spectrum (m/e): (M+H)+ 682.4
Example 39 1H NMR (CD3OD): 8.25 (s, IH), 8.16 (s, IH), 7.22 (m, 10H), 6.81 (m IH),
5.90 (s, IH), 5.72 (m, IH), 4.02 (m, 6H), 3.63 (m, 2H), 2.90 (m, 4H), 1.58(m,
4H), 0.87(m, 6H)
Mass Spectrum (m/e): (M+H)+ 710.4
Example 40
1H NMR (CD3OD): 8.25 (m, 2H), 7.22 (m, 8H), 6.95 (m, IH), 6.82 (m IH),
5.90 (m, 2H), 5.72 (m, IH), 3.95 (m, 4H), 3.63 (m, IH), 3.07 (m, IH), 2.81 (m, IH), 1.55 (m, 2H), 0.86 (m, 3H) " Mass Spectrum (m/e): (M+H)+ 597.4 Example 41
1H NMR (CD3OD): 8.25 (m, 2H), 7.20 (m, 9H), 6.96 (m, IH), 6.81 (m IH),
5.97 (m, 2H), 5.73 (m, IH), 4.05 (m, 2H), 3.60 (m, IH), 3.02 (m, IH), 2.81 (m, IH), 1.13 (m, 6H) Mass Spectrum (m/e): (M+H)+ 597.5
Example 42
1H NMR (CD3OD): 8.25 (m, 2H), 7.33 (m, 10H), 6.83 (m, IH), 5.92 (m, 2H),
5.15 (m, 2H), 4.25 (m, 4H), 3.20 (m, IH), 1.90 (m, 4H) Mass Spectrum (m/e): (M+H)+ 595.6
Example 43
1H NMR (CD3OD): 8.25 (m, 2H), 7.15 (m, 5H), 6.83 (m, IH), 5.98 (m, 2H), 4.10 (m, 5H), 2.50 (m, 4H), 2.01 (m, 3H), 1.22 (m, 3H) Mass Spectrum (m/e): (M+H)+ 567.3
Example 44
1H NMR (CD3OD): 8.25 (m, 2H), 7.15 (m, 5H), 6.83 (m, IH), 5.98 (m, 2H), 4.10 (m, 5H), 2.57 (m, IH), 1.80 (m, 6H), 1.25 (m, 3H) Mass Spectrum (m/e): (M+H)+ 547.7
Example 45
1H NMR (CD3OD): 8.25 (m, 2H), 7.17 (m, 5H), 6.85 (m, IH), 5.99 (m, 2H), 4.66 (m, IH), 4.12 (m, 3H), 1.56 (m, 4H), 1.28 (m, 3H), 0.88 (m, 6H) Mass Spectrum (m/e): (M+H)+ 549.3
Example 46
1H NMR (CD3OD): 8.25 (m, 2H), 7.12 (m, 10H), 6.83 (m, IH), 5.99 (m, 2H), 5.72 (m, IH), 4.10 (m, 4H), 3.65 (m, IH), 3.02 (m, IH), 2.79 (m, IH), 2.50 (m, IH), 1.89 (m, 6H) Mass Spectrum (m/e): (M+H)+ 623.4
Example 47 1H NMR (CD3OD): 8.25 (m, 2H), 7.15 (m, 10H), 6.82 (m, IH), 5.99 (m, 2H),
5.73 (m, IH), 3.99 (m, 4H), 3.65 (m, IH), 3.05 (m, IH), 2.85 (m, IH), 1.02 (m, IH), 0.51 (m, 2H), 0.20 (m, 2H)
Mass Spectrum (m/e): (M+H)+ 609.3 Example 48
1H NMR (CD3OD): 8.25 (m, 2H), 7.20 (m, 9H), 6.96 (m, IH), 6.81 (m IH),
5.97 (m, 2H), 5.73 (m, IH), 4.71 (m, IH)), 4.05 (m, 2H), 3.60 (m, IH), 3.02 (m, IH), 2.81 (m, IH), 1.49 (m, 2H) 1.07 (m, 3H), 0.82 (m, 3H) Mass Spectrum (m/e): (M+H)+ 611.2
Example 49
1H NMR (CD3OD): 8.20 (m, 2H), 7.25 (m, 6H), 6.82 (m IH), 5.95 (m, 2H), 5.68 (m, IH), 3.93 (m, 6H), 3.50 (m, IH), 3.20 (m, IH), 2.81 (m, IH), 1.90 (m, IH), 0.95 (m, 6H) Mass Spectrum (m/e): (M+H)+ 617.3
Example 50 1H NMR (CD3OD): 8.23 (m, 2H), 7.18 (m, 10H), 6.96 (m, IH), 6.81 (m IH),
5.94 (m, 2H), 5.72 (m, IH), 4.81 (m, IH)), 4.05 (m, 2H), 3.60 (m, IH), 3.02 (m, IH), 2.81 (m, IH), 2.25 (m, 2H) 1.81 (m, 4H) Mass Spectrum (m/e): (M+H)+ 609.3
Example 51
1H NMR (CD3OD): 8.25 (m, 2H), 7.20 (m, 9H), 6.96 (m, IH), 6.81 (m IH),
5.97 (m, 2H), 5.73 (m, IH), 4.71 (m, IH)), 4.05 (m, 2H), 3.60 (m, IH), 3.02 (m, IH), 2.81 (m, IH), 1.49 (m, 2H) 1.07 (m, 3H), 0.82 (m, 3H) Mass Spectrum (m/e): (M+H)+ 611.4
Example 52
1H NMR (CD3OD): δ 8.29 (m, IH), 8.25 (m, IH), 7.20 (m, 5H), 6.85 (m, IH),
5.97 (m, 2H), 4.85 (m, IH), 4.15 (m, 2H), 3.95 (m, IH), 2.28 (m, 2H), 1.99 (m, 2H), 1.77 (m, 2H) 1.26 (m, 3H) Mass Spectrum (m/e): (M+H)+ 533.3
Example 53
1H NMR (CD3OD): δ 8.29 (m, IH), 8.25 (m, IH), 7.20 (m, 5H), 6.85 (m, IH),
5.98 (m, 2H), 5.18 (m, IH), 4.03 (m, 7H), 2.15 (m, IH), 1.95 (m, IH), 1.26 (m, 3H)
Mass Spectrum (m/e): (M+H)+ 549.2 Example 54
1H NMR (CD3OD): δ 8.24 (m, 2H), 6.85 (m, IH), 6.01 (m, 2H), 4.43 (m, 2H),
4.09 (m, 5H), 1.38 (m, 3H) 1.23 (m, 3H) Mass Spectrum (m/e): (M+H)+ 513.2
Example 55
1H NMR for mixture of diastereomers at phosphorus (300 MHz, CD3OD ref. solv. resid. 3.30 ppm): δ (ppm) = 8.22-8.27 (m, 2H), 7.09-7.34 (m, 5H), 6.84 (br s, IH), 5.93-6.02 (m, 2H), 5.00-5.14 (m, IH), 4.01-4.26 (m, 2H) 3.89-3.94 (m, IH), 1.50-1.88 (m, 8H), 1.23, (br t, 3H, J = 6.8). 31P NMR for mixture of diastereomers at phosphorus(121 MHz, 1H decoupled): δ (ppm) = 23.56, 22.27 (-60:40 ratio).
Figure 1:
+ = > 1000 ++ = 100-1000
+++ = 1-100 ++++ = o.Ol-l
EC50 CC50 Resistance - fold EC50mtDNA Compound [uM] [uM] IC50 HIV-I MT-2 K65R 6TAM Ml 84V [uM]
Tenofovir + +++ +++ ++++ ++ d4AP +++ + +++ +++ +++ +++ d4TP + +++ +++ d4CP ++ d4UP ++
Figure 2: + = > 1000
++ = 100-1000 +++ = 1-100 ++++ = 0.01-1 EC50[UM] CC50 [uM] IC50[UM]
Compound Base HIV-1 MT-2 mtDNA
2'F-d4AP Adenine +++ + ++
2'F-d4GP Guanine +++ ++
2'F-d4IP lnosine ++
2'F-d4DAPP 2,6-Diaminopurine ++
Figure 3:
+ = >1000 ++=100-1000 +++=1-100 ++++ = 0.01-1
Figure imgf000139_0001
R1 (aa) EC5o [nM]
H Ethyl Methyl Phenyl
R2 (ester) (GIy) (α-ABA) (Ala) (Phe)
Ethyl ++ +++ +++ n-Propyl ++ +++ +++
lsopropyl + + ++ +++ n-Butyl +++ +++ +++ lsobutyl + ++ +++ +++
Chb-cyclopropyl +++ +++
CH2-cyclobutyl +++ +++ n-Pentyl +++
Benzyl +++
* Same prodrug moiety as GS-7340
All prodrugs show good selectivity with SI of +
Figure 4:
+ = >1000 ++=100-1000 +++ = 1-100 ++++ = 0.01-1
Figure imgf000141_0001
Mono(Phe-iBu)
Isomer A and B
Figure imgf000141_0002
Figure 5:
+ = > 1000 ++ = 100-1000 +++ = 1-100 ++++ = 0.01-1
Figure imgf000142_0001
R1 (aa) EC50 [nM]
H Ethyl Methyl Phenyl
R2 (ester) (GIy) (α-ABA) (Ala) (Phe)
Ethyl + ++ +++
n-Propyl + ++ +++
Isopropyl + +
n-Butyl +++ +++ +++
lsobutyl + ++ ++
n-Pentyl +++
Benzyl ++ Figure 6:
Figure imgf000143_0001
Figure 7:
Figure imgf000144_0001
Figure 8:
Alternative embodiments of Figures include
Figure imgf000144_0002
All literature and patent citations above are hereby expressly incorporated by reference at the locations of their citation. Specifically cited sections or pages of the above cited works are incoiporated by reference with specificity. The invention has been described in detail sufficient to allow one of ordinary skill in the art to make and use the subject matter of the following Embodiments. It is apparent that certain modifications of the methods and compositions of the following Embodiments can be made within the scope and spirit of the invention.
hi the embodiments hereinbelow, the subscript and superscripts of a given variable are distinct. For example, R1 is distinct from R1.

Claims

CLAIMS:
1. A conjugate comprising a compound that inhibits HIV linked to one or more phosphonate groups; or a pharmaceutically acceptable salt or solvate thereof.
2. The conjugate of claim 1 , enantiomers thereof, or a pharmaceutically acceptable salt or solvate thereof, that is a compound of
formula A
Figure imgf000146_0001
substituted with one or more groups A0, wherein:
A0 is A1, A2 or W3 with the proviso that the conjugate includes at least one A1;
A1 is:
Figure imgf000146_0002
A2 is:
Figure imgf000147_0001
A3is:
Figure imgf000147_0002
Y1 is independently O, S, N(RX), N(O)(RX), N(ORX), N(O)(ORX), or N(N(RX)( RX));
Y2 is independently absent, a bond, O, C(RX)(RX), N(RX), N(O)(RX), N(ORX), N(0)(0Rx), N(N(RX)( Rx)), -S(O)M2-, or -S(O)M2-S(O)M2-; and when Y2 joins two phosphorous atoms Y2 can also be C(R2)(R2);
Rx is independently H, R1, R2, W3, a protecting group, or the formula:
Figure imgf000147_0003
wherein:
Ry is independently H, W3, R2 or a protecting group; R1 is independently H or alkyl of 1 to 18 carbon atoms; R2 is independently H, R1, R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups or taken together at a carbon atom, two R2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3
R3 groups;
RJ is R j3a , τ Ri 3b , τ R> 3icc o _r π R3d , provided that when Rj is bound to a heteroatom, then R3 is R3c or R3d;
R , 3jaa is F, Cl, Br, I, -CN, N3, -NO2, -OR1 or -OR6a; R3b is Y1;
R3c is -Rx, -N(RX)(RX), -SRX, -S(O)RX, -S(O)2RX, -S(O)(ORX), - S(O)2(ORX), -OC(YI)RX, -OC(Y1)ORX, -OCCY^CNCR^CR")), -SC(Y1)^, - SC(Y')ORX, -SC(Y1XN(R")^)), -N(RX)C(Y1)RX, -N(RX)C(Y')ORX, or - N(R^C(Y1XNOEO(R*)) ;
R3d is -C(Y1)RX, -C(Y1)ORX or -C(Y!)(N(RX)(RX));
R4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R5 is R4 wherein each R4 is substituted with 0 to 3 R3 groups; W3 is W4 or W5;
W4 is R5, -C(Y^R5, -C(Y^W5, -SOM2R5, or -SCV2W5;
W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
W6 is W3 independently substituted with 0, 1 , 2, or 3 A3 groups; M2 is 0, 1 or 2;
M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
MIa, MIc, and MId are independently 0 or 1;
K and K' are independently absent, a bond, or optionally substituted Ry; and
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
3. The conjugate of claim 2, or a pharmaceutically acceptable salt or solvate thereof, which has the formula:
Figure imgf000148_0001
wherein:
DRUG is a compound of formulae A; and nn is 1, 2, or 3.
4. The conjugate of claim 2 which has any one of formulae A wherein: one A0 is A1;. X61 is methoxy, ethoxy, propoxy, difluoromethoxy, trifluoromethoxy, vinyl, ethyl, methyl, propyl, butyl, cyclopropyl, N-methylamino, or N- formylamino;
X62 is methyl, chloro, or trifluoromethyl;
X63 is H, methyl, ethyl, cyclopropyl, vinyl, or trifluoromethyl; and
X64 is H, methyl, ethyl, cyclopropyl, chloro, vinyl, allyl, 3-methyl-l- buten-lyl.
5. The conjugate of any one of claims 2-4, wherein each A1 is of the formula:
Figure imgf000149_0001
6. The conjugate of any one of claims 2-4, wherein each A is of the formula:
Figure imgf000149_0002
7. The conjugate of any one of claims 2-4, wherein each A is of the formula:
Figure imgf000150_0001
8. The conjugate of any one of claims 2-4, wherein each A1 is of the formula:
Figure imgf000150_0002
9. The conjugate of any one of claims 2-4, wherein each A1 is of the formula:
Figure imgf000150_0003
wherein: W5a is a carbocycle or a heterocycle where W5a is independently substituted with 0 or 1 R groups.
10. The conjugate of any one of claims 2-4, wherein M 12a is 1.
11. The conjugate of any one of claims 2-4, wherein each A1 is of the formula:
Figure imgf000151_0001
M12b
12. The conjugate of any one of claims 2-4, wherein each A1 is of the formula:
Figure imgf000151_0002
M12a
13. The conjugate of any one of claims 2-4, wherein each A1 is of the formula:
Figure imgf000151_0003
wherein: W r5a a is a carbocycle independently substituted with 0 or 1 R groups.
14. The conjugate of any one of claims 2-4, wherein each A1 is of the formula:
Figure imgf000152_0001
wherein:
Y"D is O or N(Rz); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
15. The conjugate of any one of claims 2-4, wherein each A1 is of the formula:
Figure imgf000152_0002
M12a wherein: W τ5a is a carbocycle independently substituted with 0 or 1 R groups.
16. The conjugate of any one of claims 2-4, wherein each A1 is of the formula:
Figure imgf000152_0003
wherein: W5a is a carbocycle or heterocycle where W5a is independently substituted with 0 or 1 R2 groups.
17. The conjugate of any one of claims 2-4, wherein each A1 is of the formula:
Figure imgf000153_0001
wherein:
Y^D is O or N(Rz); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
18. The conjugate of any one of claims 2-17 wherein each A2 is of the formula:
Figure imgf000153_0002
Ml 2b
19. The conjugate of any one of claims 2-17 wherein each A2 is of the formula:
Figure imgf000153_0003
Ml 2b
20. The conjugate of any one of claims 2-17 wherein each M 12b is 1.
21. The conjugate of claim 20 where M 12b is 0, Y2 is a bond and W5 is a carbocycle or he etterocycle where W5 is optionally and independently substituted with 1, 2, or 3 R2 groups.
22. The conjugate of any one of claims 2-17 wherein each A2 is of the formula:
Figure imgf000154_0001
M12a ; wherein: W5a is a carbocycle or heterocycle where W5a is optionally and independently substituted with 1, 2, or 3 R2 groups.
23. The conjugate of claim 22 wherein M 12a is 1.
24. The conjugate of any one of claims 2-17 wherein each A2 is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl and substituted pyridyl.
25. The conjugate of any one of claims 2-17 wherein each A2 is of the formula:
M12b
26. The conjugate of any one of claims 2-17 wherein each A2 is of the formula:
Figure imgf000155_0001
27. The conjugate of claim 26 wherein M12b is 1.
28. The conjugate of any one of claims 2-27 wherein each A is of the formula:
Figure imgf000155_0002
M12b
29. The conjugate of any one of claims 2-27 wherein each A is of the formula:
Figure imgf000156_0001
Ml 2a
30. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000156_0002
Ml 2a wherein:
Yla is O or S; and Y2a is O, N(RX) or S.
31. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000156_0003
Ml 2a wherein Y Λ/bD is O or N(Rx).
32. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000157_0001
M12d ; wherein:
Y2bisOorN(Rx);and M12d is 1,2,3,4,5, 6, 7 or 8.
33. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000157_0002
wherein:
Y r2ZhDisOorN(Rx);and M12d is 1,2, 3, 4, 5, 6, 7 or 8.
34. The conjugate of claim 33 wherein M 12d is 1.
35. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000158_0001
M12b
36. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000158_0002
M12b
37. The conjugate of claim 36 wherein W5 is a carbocycle.
38. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000159_0001
M12b
39. The conjugate of claim 38 wherein W5 is phenyl.
40. The conjugate of claim 39 wherein M 12b is 1.
41. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000159_0002
wherein:
Y Aiaa is O or S; and
Y /z2aa is O, N(RX) or S.
42. The conjugate of any one of claims 2-27 wherein each A is of the formula:
Figure imgf000160_0001
whereinY2bisOorN(Rx).
43. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000160_0002
wherein:
Y r22bDisOorN(Rx);and M12dis 1,2, 3,4, 5, 6, 7 or 8.
44. The conjugate of claim 43 wherein R1 is H.
45. The conjugate of claim 44 wherein M12d is 1.
46. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000160_0003
wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R2 groups.
47. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000161_0001
wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R2 groups.
48. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000161_0002
49. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000162_0001
50. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000162_0002
51. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000162_0003
M12a
wherein:
Y rliaa is O or S; and
Y 72/aa is O, N(RZ) or S.
52. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000163_0001
M12a
wherein:
Yla is O or S;
Y2b is O or N(R2); and
Y2c is O, N(Ry) or S.
53. The conjugate of any one of claims 2-27 wherein each A is of the formula:
Figure imgf000163_0002
M12d wherein:
Yla is O or S; Y2bisOorN(R2); Y2disOorN(Ry);and M12d is 1,2, 3, 4, 5, 6, 7 or 8.
54. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000164_0001
wherein:
Y2b is O or N(R2); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
55. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000164_0002
wherein Y2b is O or N(R2).
56. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000164_0003
57. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000165_0001
M12a
58. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000165_0002
wherein:
Yla is O or S; and Y2a is O, N(R2) or S.
59. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000165_0003
wherein:
Yla is O or S; Y >-2-bD is O or N(RO; and
Y2C is O, N(Ry) or S.
60. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000166_0001
wherein:
Yla is O or S; Y2bisOorN(R2); Y2disOorN(Ry);and M12d is 1,2, 3, 4, 5, 6, 7 or 8.
61. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000166_0002
wherein:
Y2bis O orN(R 2); and
M12d is 1 X,2 Z,, 3 J, 4, 5,6, 7 or 8.
62. The conjugate of any one of claims 2-27 wherein each A3 is of the formula:
Figure imgf000167_0001
wherein Y2b is O or N(R2).
63. The conjugate of claim 3 wherein A0 is of the formula:
Figure imgf000167_0002
wherein each R is independently alkyl.
64. The conjugate of claim 1, 2, 3, or 4 which has the formula:
Figure imgf000167_0003
or a pharmaceutically acceptable salt or solvate thereof, wherein:
DRUG is a compound that inhibits HIV;
Y1 is independently O, S, N(RX), N(O)(RX), N(ORX), N(0)(0Rx), or N(N(RX)( Rx));
Y2 is independently a bond, O, N(RX), N(O)(RX), N(ORX), N(0)(0Rx), N(N(RX)( Rx)), -S(O)M2-, or -S(O)M2-S(O)M2-;
Rx is independently H, R2, W3, a protecting group, or the formula:
Figure imgf000168_0001
Ry is independently H, W , R or a protecting group;
R i2 : is independently H, R or R wherein each R is independently substituted with 0 to 3 R3 groups;
Figure imgf000168_0002
or R ,3d , provided that when RJ is bound to a heteroatom, then R3 is R3c or R3d;
R3a is F, Cl, Br, I, -CN, N3, -NO2, -OR1 or -OR6a;
R31Ms Y1;
R3c is -Rx, -N(RX)(RX), -SRX, -S(O)RX, -S(O)2RX, -S(O)(ORX), -
Figure imgf000168_0003
-OC(Y1)RX, -0C(Y1)0Rx, -OCCY^CNCR^CR5')), -SC(Y1)RX, -SC(Y1)ORX, -SC(Y1)(N(RX)(RX)), -NCR^CCY^R*, -N(RX)C(Y1)ORX, or - Wβ?)C(Yx)(N(Rx)(Rxy) ;
R3d is -C(Y1)RX, -C(Y!)ORX or -C^CNCR51)^));
R4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R5 is R4 wherein each R is substituted with 0 to 3 R3 groups;
W3 is W4 or W5;
W4 is R5, -C(Y^R5, -C(Y^W5, -SO2R5, or -SO2W5;
W is carbocycle or heterocycle wherein W is independently substituted with 0 to 3 R2 groups;
M2 is 1, 2, or 3;
MIa, MIc, and MId are independently 0 or 1;
M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; nn is 1, 2, or 3; and
L is a direct bond or a linking group.
65. The conjugate of claim 64 wherein each Rx is of the formula:
Figure imgf000169_0001
Yla is O or S; and Y2c is O, N(Ry) or S.
66. The conjugate of claim 64 wherein each Rx is of the formula:
Figure imgf000169_0002
Yla is O or S; and Y2d is O or N(Ry).
67. The conjugate of claim 64 wherein each Rx is of the formula:
Figure imgf000169_0003
68. The conjugate of any one of claims 65-67 wherein each Ry is independently H or alkyl of 1 to 10 carbons.
69. The conjugate of claim 64 wherein each Rx is of the formula:
Figure imgf000170_0001
70. The conjugate of claim 64 wherein each Rx is of the formula:
Figure imgf000170_0002
71. The conjugate of claim 64 wherein each Rx is of the formula:
Figure imgf000170_0003
72. The conjugate of claim 64 wherein each Y1 is O or S.
73. The conjugate of claim 64 wherein each Y2 is O, N(Ry) or S.
74. The conjugate of any one of claims 64-73 wherein nn is 1.
75. The conjugate of any one of claims 64-73 wherein nn is 2.
76. The conjugate of any one of claims 64-73 wherein nn is 3.
77. The conjugate of claim 64 wherein the compound that inhibits IMPDH is a compound of formula A.
78. The conjugate of claim 77 wherein each L has a molecular weight of from about 20 daltons to about 400 daltons.
79. The conjugate of claim 77 wherein each L has a length of about 5 angstroms to about 300 angstroms.
80. The conjugate of claim 77 wherein each L separates the compound of any one of formula A and the phosphorous of the phosphonate group by about 5 angstroms to about 200 angstroms, inclusive.
81. The conjugate of claim 77 wherein each L is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 2 to 25 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by (-O-), and wherein the chain is optionally substituted on carbon with one or more substituents selected from (Ci-C6)alkoxy, (C3-C6)cycloalkyl, (C^C^alkanoyl,
Figure imgf000171_0001
(C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo (—0), carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.
82. The conjugate of claim 77 wherein each L is of the formula W-A wherein A is
Figure imgf000171_0002
(C2-C24)alkenylene, (C2-C24)alkynylene, (C3-
C8)cycloalkylene, (C6-C10)aryl or a combination thereof, wherein each W is -N(R)C(=O)-, -C(=O)N(R)-, -OC(=O)-, -C(=O)O-, -O-, -S-, -S(O)-, -S(O)2-, -N(R)-, -C(=O)-, -N(R)C=N(R)-N(R)-, -C(R)=N(R)-, -S(O) M2-N(R)-, -N(R)-S(O)M2-, or a direct bond; wherein each R is independently H or alkyl of 1 to 10 carbons.
83. The conjugate of claim 82 wherein each A is alkylene of 1 to 10 carbons.
84. The conjugate of claim 77 wherein each L is a divalent radical formed from a peptide.
85. The conjugate of claim 77 wherein each L is a divalent radical formed from an amino acid.
86. The conjugate of claim 77 wherein each L is a divalent radical formed from poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L- ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine-L-tyrosine.
87. The conjugate of claim 77 wherein each L is of the formula W-(CH2)n wherein, n is between about 1 and about 10; and W is -N(R)C(=O)-, - C(=O)N(R)-, -OC(=O)-. -CC=O)O-, -O-, -S-, -SCO)-, -S(O)2-, -C(=O)-, -N(R)-, -N(R)C=N(R)-N(R)-, -C(R)=N(R)-, -S(O) M2-N(R)-, -N(R)-S(O)M2-, or a direct bond; wherein each R is independently H or (Ci-C6)alkyl.
88. The conjugate of claim 77 wherein each L is methylene, ethylene, or propylene.
89. The conjugate of claim 77 wherein each L is linked to P at a carbon atom of L.
90. The conjugate as described in any one of claims 1-89, which is isolated and purified.
91. An HTV inhibitor conjugate as described herein.
92. A compound of the formula MBF .
93. A compound of claim 92 selected from Table 100.
94. A pharmaceutical composition comprising a pharmaceutical excipient and a conjugate as described in any one of claims 1-89 and 91-93.
95. A unit dosage form comprising a conjugate as described in any one of claims 1-89 and 91-93 and a pharmaceutical excipient.
96. A method for inhibiting 2 in vitro or in vivo comprising contacting a sample in need of such treatment with a conjugate as described in any one of claims 1-89 and 91-93.
97. The method of claim 96 wherein the contacting is in vivo.
98. The invention also provides a method of inhibiting HIV in a mammal, comprising administering a compound as described in any one of claims 1-89 and 91-93 to the mammal.
99. The method of claim 98 wherein the compound is formulated with a pharmaceutically acceptable excipient.
100. The method of claim 99 wherein the formulation further comprises a second active ingredient.
101. A compound as described in any one of claims 1-89 and 91-93 for use in medical therapy.
102. The use of a conjugate as described in any one of claims 1-89 and 91 -93 to prepare a medicament for inhibiting HTV in an animal.
103. A method of preparing a compound or conjugate described herein according to the Examples or Schemes.
PCT/US2005/027088 2004-07-27 2005-07-27 Nucleoside phosphonate conjugates as anti hiv agents Ceased WO2006015261A2 (en)

Priority Applications (29)

Application Number Priority Date Filing Date Title
CA2574121A CA2574121C (en) 2004-07-27 2005-07-27 Antiviral compounds
DE602005021506T DE602005021506D1 (en) 2004-07-27 2005-07-27 PHOSPHONATE PRODROGEN FROM AN ANALOG OF 2'-FLUORHIV MEDIUM
MX2007001059A MX2007001059A (en) 2004-07-27 2005-07-27 Nucleoside phosphonate conjugates as anti hiv agents.
AU2005267800A AU2005267800B2 (en) 2004-07-27 2005-07-27 Nucleoside phosphonate conjugates as anti HIV agents
AT05777315T ATE469163T1 (en) 2004-07-27 2005-07-27 PHOSPHONATE PRODROGEN FROM AN ANALOG OF 2'-FLUORO-2',3'-DIDEHYDRO-2',3'-DIDEOXYADENOSINE AS AN ANTI-HIV AGENT
HR20070079A HRP20070079A2 (en) 2004-07-27 2005-07-27 Nucleoside phosphonate conjugates as anti hiv agents
NZ553406A NZ553406A (en) 2004-07-27 2005-07-27 Nucleoside phosphonate conjugates as anti-HIV agents
US11/658,628 US8329926B2 (en) 2004-07-27 2005-07-27 Antiviral compounds
JP2007523866A JP4954877B2 (en) 2004-07-27 2005-07-27 Nucleoside phosphonate conjugates as anti-HIV agents
BRPI0512683-5A BRPI0512683A (en) 2004-07-27 2005-07-27 antiviral compounds
PL382843A PL230036B1 (en) 2004-07-27 2005-07-27 Anti-virus compounds
EA200700362A EA019559B1 (en) 2004-07-27 2005-07-27 Antiviral compounds, in particular that inhibitis hiv, pharmaceutical composition based thereon and method for inhibiting using same
UAA200701991A UA91688C2 (en) 2004-07-27 2005-07-27 Antiviral compounds
CN2005800325568A CN101031306B (en) 2004-07-27 2005-07-27 Nucleoside phosphonate conjugates as anti-HIV agents
AP2007003899A AP2629A (en) 2004-07-27 2005-07-27 Nucleoside phosphonate conjugates as anti HIV agents
KR1020077004803A KR101233823B1 (en) 2004-07-27 2005-07-27 Antiviral compounds
HK07111940.1A HK1103648B (en) 2004-07-27 2005-07-27 Phosphonate prodrugs of a 2'-fluoro-2',3'-didehydro-2',3'-dideoxyadenosine analogue as anti-hiv agents
EP05777315A EP1778249B1 (en) 2004-07-27 2005-07-27 Phosphonate prodrugs of a 2'-fluoro-2',3'-didehydro-2',3'-dideoxyadenosine analogue as anti-hiv agents
IL180758A IL180758A (en) 2004-07-27 2007-01-17 Phosphonates of a 2 -fluoro-2' ,3' -didehydro-2' ,3' -dideoxyadenosine analogue, pharmaceutical compositions comprising them and use thereof for the preparation of medicaments for inhibiting hiv
IS8595A IS8595A (en) 2004-07-27 2007-01-23 Antiviral compounds
ZA2007/01466A ZA200701466B (en) 2004-07-27 2007-02-20 Nucleoside phosphonate conjugates as anti hiv agents
NO20071078A NO339020B1 (en) 2004-07-27 2007-02-26 Phosphonate prodrug of a 2'-fluoro-2 ', 3'-didehydro-2', 3'-dideoxyadenosine analogue as an anti-HIV agent
US13/626,687 US8697861B2 (en) 2004-07-27 2012-09-25 Antiviral compounds
US14/178,237 US9457035B2 (en) 2004-07-27 2014-02-11 Antiviral compounds
US15/254,684 US20170088576A1 (en) 2004-07-27 2016-09-01 Antiviral compounds
NO20161521A NO342132B1 (en) 2004-07-27 2016-09-23 Antiviral compounds
US15/643,168 US20180086784A1 (en) 2004-07-27 2017-07-06 Phosphonate analogs of HIV inhibitor compounds
NO20180243A NO20180243A1 (en) 2004-07-27 2018-02-16 Antiviral compounds
US16/196,075 US20190345190A1 (en) 2004-07-27 2018-11-20 Phosphonate analogs of hiv inhibitor compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US59181104P 2004-07-27 2004-07-27
US60/591,811 2004-07-27

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US11/658,628 A-371-Of-International US8329926B2 (en) 2004-07-27 2005-07-27 Antiviral compounds
US13/626,687 Division US8697861B2 (en) 2004-07-27 2012-09-25 Antiviral compounds

Publications (2)

Publication Number Publication Date
WO2006015261A2 true WO2006015261A2 (en) 2006-02-09
WO2006015261A3 WO2006015261A3 (en) 2006-11-16

Family

ID=35502668

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US2005/026504 Ceased WO2006110157A2 (en) 2004-07-27 2005-07-26 Nucleoside phosphonate conjugates as anti hiv agents
PCT/US2005/027088 Ceased WO2006015261A2 (en) 2004-07-27 2005-07-27 Nucleoside phosphonate conjugates as anti hiv agents

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/US2005/026504 Ceased WO2006110157A2 (en) 2004-07-27 2005-07-26 Nucleoside phosphonate conjugates as anti hiv agents

Country Status (35)

Country Link
US (11) US8318701B2 (en)
EP (4) EP3539546A1 (en)
JP (3) JP2008508291A (en)
KR (2) KR101233824B1 (en)
CN (4) CN101027062A (en)
AP (2) AP2412A (en)
AR (1) AR051922A1 (en)
AT (2) ATE505196T1 (en)
AU (2) AU2005330489B2 (en)
BR (2) BRPI0512690A (en)
CA (2) CA2574514A1 (en)
CY (2) CY1111709T1 (en)
DE (2) DE602005027466D1 (en)
DK (2) DK1778251T3 (en)
EA (2) EA019419B1 (en)
ES (3) ES2720618T3 (en)
HR (4) HRP20110527T1 (en)
HU (1) HUE043207T2 (en)
IL (2) IL180758A (en)
IS (2) IS8595A (en)
LT (1) LT2258376T (en)
ME (2) ME03423B (en)
MX (2) MX2007001053A (en)
NO (5) NO339020B1 (en)
NZ (2) NZ553405A (en)
PL (4) PL216369B1 (en)
PT (2) PT1778251E (en)
RS (2) RS58600B1 (en)
SG (1) SG155164A1 (en)
SI (2) SI1778251T1 (en)
TR (1) TR201906416T4 (en)
TW (1) TWI362934B (en)
UA (2) UA88313C2 (en)
WO (2) WO2006110157A2 (en)
ZA (2) ZA200701466B (en)

Cited By (112)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006110157A2 (en) 2004-07-27 2006-10-19 Gilead Sciences, Inc. Nucleoside phosphonate conjugates as anti hiv agents
WO2007014352A3 (en) * 2005-07-27 2007-03-29 Gilead Sciences Inc Antiviral phosphonate conjugates for inhibition of hiv
WO2007112028A3 (en) * 2006-03-23 2008-03-06 Rfs Pharma Llc 2'-fluoronucleoside phosphonates as antiviral agents
WO2008100447A3 (en) * 2007-02-09 2008-12-24 Gilead Sciences Inc Nucleoside analogs for antiviral treatment
WO2010005986A1 (en) * 2008-07-08 2010-01-14 Gilead Sciences, Inc. Salts of hiv inhibitor compounds
EP2567961A1 (en) 2011-09-08 2013-03-13 Straitmark Holding AG Method for the manufacture of compounds containing an alpha-oxyphosphorus group by using an activator
US8871785B2 (en) 2003-04-25 2014-10-28 Gilead Sciences, Inc. Antiviral phosphonate analogs
US8987437B2 (en) 2011-05-19 2015-03-24 Gilead Sciences, Inc. Processes and intermediates for preparing anti-HIV Agents
WO2016036759A1 (en) 2014-09-04 2016-03-10 Gilead Sciences, Inc. Methods of treating or preventing hiv in patients using a combination of tenofovir alafenamide and dolutegravir
WO2016105564A1 (en) 2014-12-24 2016-06-30 Gilead Sciences, Inc. Quinazoline derivatives used to treat hiv
WO2016106237A1 (en) 2014-12-23 2016-06-30 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
WO2016105534A1 (en) 2014-12-24 2016-06-30 Gilead Sciences, Inc. Isoquinoline compounds for the treatment of hiv
WO2016105532A1 (en) 2014-12-24 2016-06-30 Gilead Sciences, Inc. Fused pyrimidine compounds for the treatment of hiv
WO2016141092A1 (en) 2015-03-04 2016-09-09 Gilead Sciences, Inc. Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds
WO2016161382A1 (en) 2015-04-02 2016-10-06 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
WO2017035230A1 (en) 2015-08-26 2017-03-02 Gilead Sciences, Inc. Deuterated toll-like receptor modulators
WO2017059120A1 (en) 2015-09-30 2017-04-06 Gilead Sciences, Inc. Compounds and combinations for the treatment of hiv
WO2017106346A2 (en) 2015-12-15 2017-06-22 Gilead Sciences, Inc. Human immunodeficiency virus neutralizing antibodies
EP3255045A1 (en) * 2007-02-16 2017-12-13 Debiopharm International SA Salts, prodrugs and polymorphs of fab i inhibitors
WO2018035359A1 (en) 2016-08-19 2018-02-22 Gilead Sciences, Inc. Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection
WO2018042332A1 (en) 2016-08-31 2018-03-08 Glaxosmithkline Intellectual Property (No.2) Limited Combinations and uses and treatments thereof
WO2018045150A1 (en) 2016-09-02 2018-03-08 Gilead Sciences, Inc. 4,6-diamino-pyrido[3,2-d]pyrimidine derivaties as toll like receptor modulators
WO2018042331A1 (en) 2016-08-31 2018-03-08 Glaxosmithkline Intellectual Property (No.2) Limited Combinations and uses and treatments thereof
WO2018045144A1 (en) 2016-09-02 2018-03-08 Gilead Sciences, Inc. Toll like receptor modulator compounds
WO2018051250A1 (en) 2016-09-14 2018-03-22 Viiv Healthcare Company Combination comprising tenofovir alafenamide, bictegravir and 3tc
WO2018064080A1 (en) 2016-09-28 2018-04-05 Gilead Sciences, Inc. Benzothiazol-6-yl acetic acid derivatives and their use for treating hiv infection
WO2018081292A1 (en) 2016-10-27 2018-05-03 Gilead Sciences, Inc. Crystalline forms of darunavir free base, hydrate, solvates and salts
EP3321270A1 (en) 2014-06-20 2018-05-16 Gilead Sciences, Inc. Sodium (2r, 5s, 13ar) -7, 9-dioxo-10- ( (2,4,6-trifluorobenzyl) carbamoyl) -2, 3, 4, 5, 7, 9, 13, 13a-octahydro-2, 5-methanopyrido [1',2' : 4.5] pyrazino [2, 1-b] oxazepin-8-olate
WO2018144390A1 (en) 2017-01-31 2018-08-09 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
WO2018145021A1 (en) 2017-02-06 2018-08-09 Gilead Sciences, Inc. Atazanavir (atv) analogues for treating hiv infections
WO2018237148A1 (en) 2017-06-21 2018-12-27 Gilead Sciences, Inc. MULTISPECIFIC ANTIBODIES TARGETING HIV GP120 AND CD3
WO2019027920A1 (en) 2017-08-01 2019-02-07 Gilead Sciences, Inc. Crystalline forms of ethyl ((s)-((((2r,5r)-5-(6-amino-9h-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-l-alaninate (gs-9131) for treating viral infections
WO2019035904A1 (en) 2017-08-17 2019-02-21 Gilead Sciences, Inc. Solid forms of an hiv capsid inhibitor
WO2019035973A1 (en) 2017-08-17 2019-02-21 Gilead Sciences, Inc Choline salt forms of an hiv capsid inhibitor
WO2019075291A1 (en) 2017-10-13 2019-04-18 Gilead Sciences, Inc. 1-benzyl-2-imino-4-phenyl-5-oxoimidazolidine derivatives as hiv protease inhibitors
WO2019084020A1 (en) 2017-10-24 2019-05-02 Gilead Sciences, Inc. Methods of treating patients co-infected with a virus and tuberculosis
WO2019113462A1 (en) 2017-12-07 2019-06-13 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
WO2019161017A1 (en) 2018-02-15 2019-08-22 Gilead Sciences, Inc. Pyridine derivatives and their use for treating hiv infection
WO2019193542A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides
WO2019193533A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'2'-cyclic dinucleotides
WO2019193543A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides
EP3564244A1 (en) 2014-06-20 2019-11-06 Gilead Sciences, Inc. Crystalline forms of (2r,5s,13ar)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido [1',2':4,5]pyrazino [2,1-b][1,3]oxazepine-10-carboxamide
WO2019211799A1 (en) 2018-05-03 2019-11-07 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide
WO2020010107A1 (en) 2018-07-03 2020-01-09 Gilead Sciences, Inc. Antibodies that target hiv gp120 and methods of use
WO2020018459A1 (en) 2018-07-16 2020-01-23 Gilead Sciences, Inc. Capsid inhibitors for the treatment of hiv
WO2020028272A1 (en) 2018-07-30 2020-02-06 Gilead Sciences, Inc. Anti-hiv compounds
WO2020072656A1 (en) 2018-10-03 2020-04-09 Gilead Sciences, Inc. Imidozopyrimidine derivatives
WO2020092528A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity
WO2020092621A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds as hpk1 inhibitors
US10696657B2 (en) 2018-02-16 2020-06-30 Gilead Sciences, Inc. Methods and intermediates for preparing therapeutic compounds
WO2020176510A1 (en) 2019-02-25 2020-09-03 Gilead Sciences, Inc. Protein kinase c agonists
WO2020176505A1 (en) 2019-02-25 2020-09-03 Gilead Sciences, Inc. Protein kinase c agonists
WO2020178770A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides and prodrugs thereof
WO2020178768A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
WO2020178769A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides and prodrugs thereof
WO2020197991A1 (en) 2019-03-22 2020-10-01 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use
WO2020214716A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. 2-imino-5-oxo-imidazolidine inhibitors of hiv protease
WO2020214652A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
WO2020214663A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
WO2020214647A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Solid forms of an hiv protease inhibitor
WO2020237025A1 (en) 2019-05-23 2020-11-26 Gilead Sciences, Inc. Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors
WO2020236753A1 (en) 2019-05-21 2020-11-26 Gilead Sciences, Inc. Methods of identifying hiv patients sensitive to therapy with gp120 v3 glycan-directed antibodies
WO2020246910A1 (en) 2019-06-03 2020-12-10 Александл Васильевич ИВАЩЕНКО ANNELATED 9-HYDROXY-1,8-DIOXO-1,3,4,8-TETRAHYDRO-2Н-PYRIDO[1,2-α]PYRAZINE-7-CARBOXAMIDES AS HIV INTEGRASE INHIBITORS
WO2020255038A1 (en) 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and pyridopyrimidine derivatives
WO2020263830A1 (en) 2019-06-25 2020-12-30 Gilead Sciences, Inc. Flt3l-fc fusion proteins and methods of use
WO2021011891A1 (en) 2019-07-18 2021-01-21 Gilead Sciences, Inc. Long-acting formulations of tenofovir alafenamide
WO2021011544A1 (en) 2019-07-16 2021-01-21 Gilead Sciences, Inc. Hiv vaccines and methods of making and using
WO2021034804A1 (en) 2019-08-19 2021-02-25 Gilead Sciences, Inc. Pharmaceutical formulations of tenofovir alafenamide
US10966999B2 (en) 2017-12-20 2021-04-06 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
US11034668B2 (en) 2011-07-06 2021-06-15 Gilead Sciences, Inc. Compounds for the treatment of HIV
WO2021130638A1 (en) 2019-12-24 2021-07-01 Carna Biosciences, Inc. Diacylglycerol kinase modulating compounds
WO2021173522A1 (en) 2020-02-24 2021-09-02 Gilead Sciences, Inc. Tetracyclic compounds for treating hiv infection
WO2021188959A1 (en) 2020-03-20 2021-09-23 Gilead Sciences, Inc. Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same
WO2021236944A1 (en) 2020-05-21 2021-11-25 Gilead Sciences, Inc. Pharmaceutical compositions comprising bictegravir
US11203610B2 (en) 2017-12-20 2021-12-21 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
WO2021262990A1 (en) 2020-06-25 2021-12-30 Gilead Sciences, Inc. Capsid inhibitors for the treatment of hiv
WO2022031894A1 (en) 2020-08-07 2022-02-10 Gilead Sciences, Inc. Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use
CN114262348A (en) * 2020-09-16 2022-04-01 上海本仁科技有限公司 Cyclic nucleoside phosphate ester compound and application thereof
WO2022072520A1 (en) 2020-09-30 2022-04-07 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
WO2022087149A2 (en) 2020-10-22 2022-04-28 Gilead Sciences, Inc. Interleukin-2-fc fusion proteins and methods of use
WO2022103758A1 (en) 2020-11-11 2022-05-19 Gilead Sciences, Inc. METHODS OF IDENTIFYING HIV PATIENTS SENSITIVE TO THERAPY WITH gp120 CD4 BINDING SITE-DIRECTED ANTIBODIES
WO2022159387A1 (en) 2021-01-19 2022-07-28 Gilead Sciences, Inc. Substituted pyridotriazine compounds and uses thereof
WO2022245671A1 (en) 2021-05-18 2022-11-24 Gilead Sciences, Inc. Methods of using flt3l-fc fusion proteins
WO2022271684A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271650A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271659A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271677A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
US11628181B2 (en) 2014-12-26 2023-04-18 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
WO2023102523A1 (en) 2021-12-03 2023-06-08 Gilead Sciences, Inc. Therapeutic compounds for hiv virus infection
WO2023102529A1 (en) 2021-12-03 2023-06-08 Gilead Sciences, Inc. Therapeutic compounds for hiv virus infection
WO2023102239A1 (en) 2021-12-03 2023-06-08 Gilead Sciences, Inc. Therapeutic compounds for hiv virus infection
WO2023196875A1 (en) 2022-04-06 2023-10-12 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
US11807625B2 (en) 2019-11-26 2023-11-07 Gilead Sciences, Inc. Capsid inhibitors for the prevention of HIV
WO2024006982A1 (en) 2022-07-01 2024-01-04 Gilead Sciences, Inc. Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection
WO2024015741A1 (en) 2022-07-12 2024-01-18 Gilead Sciences, Inc. Hiv immunogenic polypeptides and vaccines and uses thereof
WO2024044477A1 (en) 2022-08-26 2024-02-29 Gilead Sciences, Inc. Dosing and scheduling regimen for broadly neutralizing antibodies
WO2024076915A1 (en) 2022-10-04 2024-04-11 Gilead Sciences, Inc. 4'-thionucleoside analogues and their pharmaceutical use
WO2024220624A1 (en) 2023-04-19 2024-10-24 Gilead Sciences, Inc. Dosing regimen of capsid inhibitor
WO2024249592A1 (en) 2023-05-31 2024-12-05 Gilead Sciences, Inc. Quinazolinyl-indazole derivatives as therapeutic compounds for hiv
WO2024249517A1 (en) 2023-05-31 2024-12-05 Gilead Sciences, Inc. Anti-hiv compounds
WO2024249573A1 (en) 2023-05-31 2024-12-05 Gilead Sciences, Inc. Solid forms of compounds useful in the treatment of hiv
WO2025029247A1 (en) 2023-07-28 2025-02-06 Gilead Sciences, Inc. Weekly regimen of lenacapavir for the treatment and prevention of hiv
WO2025042394A1 (en) 2023-08-23 2025-02-27 Gilead Sciences, Inc. Dosing regimen of hiv capsid inhibitor
WO2025076542A1 (en) 2023-10-05 2025-04-10 Jones R Brad Atovaquone as an ros inducer for use in the elimination of hiv-infected t-cells
WO2025080863A1 (en) 2023-10-11 2025-04-17 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
WO2025080879A1 (en) 2023-10-11 2025-04-17 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
WO2025080850A1 (en) 2023-10-11 2025-04-17 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
WO2025137245A1 (en) 2023-12-22 2025-06-26 Gilead Sciences, Inc. Solid forms of hiv integrase inhibitors
WO2025184447A1 (en) 2024-03-01 2025-09-04 Gilead Sciences, Inc. Pharmaceutical compositions comprising hiv integrase inhibitors
WO2025184609A1 (en) 2024-03-01 2025-09-04 Gilead Sciences, Inc. Antiviral compounds
WO2025184452A1 (en) 2024-03-01 2025-09-04 Gilead Sciences, Inc. Solid forms of hiv integrase inhibitors
WO2025212814A1 (en) 2024-04-03 2025-10-09 Gilead Sciences, Inc. Anti-hiv compounds

Families Citing this family (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MY164523A (en) 2000-05-23 2017-12-29 Univ Degli Studi Cagliari Methods and compositions for treating hepatitis c virus
DK1576138T3 (en) 2002-11-15 2017-05-01 Idenix Pharmaceuticals Llc 2'-METHYL NUCLEOSIDES IN COMBINATION WITH INTERFERON AND FLAVIVIRIDAE MUTATION
US7964580B2 (en) 2007-03-30 2011-06-21 Pharmasset, Inc. Nucleoside phosphoramidate prodrugs
US8173621B2 (en) * 2008-06-11 2012-05-08 Gilead Pharmasset Llc Nucleoside cyclicphosphates
US8716263B2 (en) 2008-12-23 2014-05-06 Gilead Pharmasset Llc Synthesis of purine nucleosides
US8618076B2 (en) 2009-05-20 2013-12-31 Gilead Pharmasset Llc Nucleoside phosphoramidates
TWI598358B (en) 2009-05-20 2017-09-11 基利法瑪席特有限責任公司 Nucleoside phosphoramidates
US8563530B2 (en) 2010-03-31 2013-10-22 Gilead Pharmassel LLC Purine nucleoside phosphoramidate
PT3290428T (en) 2010-03-31 2021-12-27 Gilead Pharmasset Llc Tablet comprising crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate
WO2012075140A1 (en) 2010-11-30 2012-06-07 Pharmasset, Inc. Compounds
WO2012154321A1 (en) 2011-03-31 2012-11-15 Idenix Pharmaceuticals, Inc. Compounds and pharmaceutical compositions for the treatment of viral infections
EP2755983B1 (en) 2011-09-12 2017-03-15 Idenix Pharmaceuticals LLC. Substituted carbonyloxymethylphosphoramidate compounds and pharmaceutical compositions for the treatment of viral infections
UA116087C2 (en) 2011-09-16 2018-02-12 Гіліад Фармассет Елелсі Methods for treating hcv
TW201331221A (en) 2011-10-14 2013-08-01 Idenix Pharmaceuticals Inc Substituted 3',5'-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections
US8889159B2 (en) 2011-11-29 2014-11-18 Gilead Pharmasset Llc Compositions and methods for treating hepatitis C virus
EP2785184B1 (en) 2011-11-30 2020-06-10 Emory University Compositions comprising jak inhibitors and haart drugs for use in the prevention or treatment of hiv
EP2852605B1 (en) 2012-05-22 2018-01-31 Idenix Pharmaceuticals LLC 3',5'-cyclic phosphate prodrugs for hcv infection
EP2852604B1 (en) 2012-05-22 2017-04-12 Idenix Pharmaceuticals LLC 3',5'-cyclic phosphoramidate prodrugs for hcv infection
SG11201407674TA (en) 2012-05-22 2014-12-30 Idenix Pharmaceuticals Inc D-amino acid compounds for liver disease
PL2861611T3 (en) 2012-05-25 2017-08-31 Janssen Sciences Ireland Uc Uracyl spirooxetane nucleosides
US9192621B2 (en) 2012-09-27 2015-11-24 Idenix Pharmaceuticals Llc Esters and malonates of SATE prodrugs
PT2764002T (en) 2014-04-11 2018-05-16 Gilead Sciences Inc METHODS FOR THE PREPARATION OF ANTI-VIRUS NUCLEOTIDES ANALOGS
CN104936970A (en) 2012-10-08 2015-09-23 埃迪尼克斯医药公司 2'-chloronucleoside analogues for HCV infection
EP2909222B1 (en) 2012-10-22 2021-05-26 Idenix Pharmaceuticals LLC 2',4'-bridged nucleosides for hcv infection
WO2014099941A1 (en) 2012-12-19 2014-06-26 Idenix Pharmaceuticals, Inc. 4'-fluoro nucleosides for the treatment of hcv
SG10201705514WA (en) * 2012-12-28 2017-08-30 Tarveda Therapeutics Inc Targeted conjugates encapsulated in particles and formulations thereof
CN104144682A (en) 2013-01-31 2014-11-12 吉利德法莫赛特有限责任公司 Combination formulation of two antiviral compounds
US9339541B2 (en) 2013-03-04 2016-05-17 Merck Sharp & Dohme Corp. Thiophosphate nucleosides for the treatment of HCV
WO2014137926A1 (en) 2013-03-04 2014-09-12 Idenix Pharmaceuticals, Inc. 3'-deoxy nucleosides for the treatment of hcv
EP2970357B1 (en) 2013-03-13 2025-01-01 Idenix Pharmaceuticals LLC Amino acid phosphoramidate pronucleotides of 2'-cyano, azido and amino nucleosides for the treatment of hcv
EP2981542B1 (en) 2013-04-01 2021-09-15 Idenix Pharmaceuticals LLC 2',4'-fluoro nucleosides for the treatment of hcv
WO2014197578A1 (en) 2013-06-05 2014-12-11 Idenix Pharmaceuticals, Inc. 1',4'-thio nucleosides for the treatment of hcv
WO2015017713A1 (en) 2013-08-01 2015-02-05 Idenix Pharmaceuticals, Inc. D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease
KR102239196B1 (en) 2013-08-27 2021-04-12 길리애드 파마셋 엘엘씨 Combination formulation of two antiviral compounds
US10202411B2 (en) 2014-04-16 2019-02-12 Idenix Pharmaceuticals Llc 3′-substituted methyl or alkynyl nucleosides nucleotides for the treatment of HCV
EP3273028B1 (en) * 2014-05-28 2019-07-10 Volvo Truck Corporation A turbocompound unit
WO2016030863A1 (en) 2014-08-29 2016-03-03 Glaxosmithkline Intellectual Property Development Limited Compounds and methods for treating viral infections
EP3426642A4 (en) * 2016-03-09 2019-10-09 Janssen BioPharma, Inc. ACYCLIC ANTIVIRALS
WO2017197046A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
EP3454862B1 (en) 2016-05-10 2024-09-11 C4 Therapeutics, Inc. Spirocyclic degronimers for target protein degradation
WO2017197051A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. Amine-linked c3-glutarimide degronimers for target protein degradation
EP4491236A3 (en) 2016-05-10 2025-04-02 C4 Therapeutics, Inc. Heterocyclic degronimers for target protein degradation
US20180085387A1 (en) * 2016-09-27 2018-03-29 Gilead Sciences, Inc. Therapeutic compositions for treatment of human immunodeficiency virus
RU2647576C1 (en) * 2017-02-28 2018-03-16 Васильевич Иващенко Александр Cyclobutyl (s)-2-[[[r)-2-(6-aminopurin-9-yl)-1-methyl-etoxy]methyl-phenoxy-phosphoryl]amino]-propanoates, method of their production and application
EP3641762A4 (en) 2017-06-20 2021-03-10 C4 Therapeutics, Inc. N / O BONDED DEGRONS AND DEGRONIMERS FOR PROTEIN DEGRADATION
EP3946611A2 (en) 2019-03-31 2022-02-09 Yeda Research and Development Co. Ltd Anti-viral and anti-tumoral compounds
EP4228656A4 (en) 2020-08-18 2024-09-04 Yeda Research and Development Co. Ltd ANTIVIRAL AND ANTITUMORAL COMPOUNDS
US20240261317A1 (en) * 2021-05-17 2024-08-08 Rome Therapeutics, Inc. Methods of treating medical conditions and inhibiting line1 reverse transcriptaseusing a substituted 4-fluoro-2,5-dihydrofuranyl phosphonic acid or related compound
JP2024540012A (en) 2021-10-26 2024-10-31 サウザーン リサーチ インスチチュート Development of novel clofarabine analogues for cancer therapy
WO2024238794A2 (en) * 2023-05-16 2024-11-21 Lilac Therapeutics, Inc. Phenol prodrugs

Family Cites Families (184)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4276351A (en) 1980-06-30 1981-06-30 E. I. Du Pont De Nemours And Company Polyvinyl butyral plasticized with tetraethyleneglycol di-2-ethylhexanoate
US4816570A (en) * 1982-11-30 1989-03-28 The Board Of Regents Of The University Of Texas System Biologically reversible phosphate and phosphonate protective groups
US4649041A (en) 1983-07-20 1987-03-10 Warner-Lambert Company Magnesium trisilicate suitable for preparation of medicament adsorbates of antinauseants
DK159431C (en) 1984-05-10 1991-03-18 Byk Gulden Lomberg Chem Fab 6-PHENYL-3 (2H) -PYRIDAZINONES, METHOD OF PREPARING THEREOF, PHARMACEUTICALS CONTAINING THESE AND USING THE COMPOUNDS FOR THE PREPARATION OF MEDICINAL PRODUCTS
US4724232A (en) 1985-03-16 1988-02-09 Burroughs Wellcome Co. Treatment of human viral infections
CS263952B1 (en) 1985-04-25 1989-05-12 Holy Antonin Remedy with antiviral effect
JPH035439Y2 (en) 1985-06-04 1991-02-12
WO1987001284A1 (en) 1985-08-26 1987-03-12 United States Of America, Represented By The Unite Inhibition of in vitro infectivity and cytopathic effect of htlv-iii/lav by 2',3'-dideoxynosine, 2',3'-dideoxyguanosine, or 2',3'-dideoxyadenosine
US6492352B1 (en) 1985-10-31 2002-12-10 Astra Lakemedel Aktiebolag Method for the control and treatment of acquired immunodeficiency syndrome (AIDS)
US4968788A (en) * 1986-04-04 1990-11-06 Board Of Regents, The University Of Texas System Biologically reversible phosphate and phosphonate protective gruops
US5455339A (en) * 1986-05-01 1995-10-03 University Of Georgia Research Foundation, Inc. Method for the preparation of 2',3'-dideoxy and 2',3'-dideoxydide-hydro nucleosides
IE63869B1 (en) 1986-11-06 1995-06-14 Res Dev Foundation Aerosols containing liposomes and method for their preparation
US4978655A (en) 1986-12-17 1990-12-18 Yale University Use of 3'-deoxythymidin-2'-ene (3'deoxy-2',3'-didehydrothymidine) in treating patients infected with retroviruses
FR2611203B1 (en) 1987-02-20 1989-06-09 Sturtz Georges GEM-DIPHOSPHONIC ANALOGS OF AMETHOPTERIN (METHOTREXATE) AND DEAZA-N-10 AMETHOPTERINE DERIVATIVES. THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
US5028595A (en) 1987-09-18 1991-07-02 Hoffmann-La Roche Inc. Method for preventing AIDS in a subject or treating a subject infected with the AIDS virus
US5631370A (en) 1988-01-20 1997-05-20 Regents Of The University Of Minnesota Optically-active isomers of dideoxycarbocyclic nucleosides
US5466793A (en) * 1988-03-01 1995-11-14 Ajinomoto Co., Inc. Process for preparing 2', 3'- dideoxyinosine
US5047407A (en) 1989-02-08 1991-09-10 Iaf Biochem International, Inc. 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties
ZA894534B (en) * 1988-06-20 1990-03-28 Merrell Dow Pharma Novel neplanocin derivatives
GB8815265D0 (en) 1988-06-27 1988-08-03 Wellcome Found Therapeutic nucleosides
CA2001715C (en) 1988-11-14 1999-12-28 Muzammil M. Mansuri Carbocyclic nucleosides and nucleotides
US5744600A (en) * 1988-11-14 1998-04-28 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Phosphonomethoxy carbocyclic nucleosides and nucleotides
US5202128A (en) 1989-01-06 1993-04-13 F. H. Faulding & Co. Limited Sustained release pharmaceutical composition
US5366972A (en) 1989-04-20 1994-11-22 Boehringer Ingelheim Pharmaceuticals, Inc. 5,11-dihydro-6H-dipyrido(3,2-B:2',3'-E)(1,4)diazepines and their use in the prevention or treatment of HIV infection
CA2479846C (en) * 1989-05-15 2007-07-24 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Scienc Es Of The Czech Republic Phosphonomethoxymethylpurine/pyrimidine derivatives
US5552558A (en) 1989-05-23 1996-09-03 Abbott Laboratories Retroviral protease inhibiting compounds
JP2722673B2 (en) 1989-05-31 1998-03-04 住友化学工業株式会社 Process for producing optically active acylbiphenyl derivatives
GB8927913D0 (en) 1989-12-11 1990-02-14 Hoffmann La Roche Amino acid derivatives
GB8927915D0 (en) 1989-12-11 1990-02-14 Hoffmann La Roche Novel alcohols
US5563142A (en) 1989-12-28 1996-10-08 The Upjohn Company Diaromatic substituted compounds as anti-HIV-1 agents
US5204466A (en) 1990-02-01 1993-04-20 Emory University Method and compositions for the synthesis of bch-189 and related compounds
US6642245B1 (en) 1990-02-01 2003-11-04 Emory University Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane
DE4003574A1 (en) 1990-02-07 1991-08-08 Bayer Ag NEW DIPEPTIDES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS RENININHIBITORS IN MEDICINAL PRODUCTS
EP0533833B1 (en) 1990-06-13 1995-12-20 GLAZIER, Arnold Phosphorous produgs
EP0465297B1 (en) 1990-07-04 1996-01-31 Merrell Dow Pharmaceuticals Inc. 9-Purinyl phosphonic acid derivatives
US5177064A (en) 1990-07-13 1993-01-05 University Of Florida Targeted drug delivery via phosphonate derivatives
EP0468119A1 (en) 1990-07-24 1992-01-29 Merrell Dow Pharmaceuticals Inc. Novel carbocyclic analogs of certain nucleosides
US5223618A (en) 1990-08-13 1993-06-29 Isis Pharmaceuticals, Inc. 4'-desmethyl nucleoside analog compounds
EP0481214B1 (en) 1990-09-14 1998-06-24 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Prodrugs of phosphonates
US5672697A (en) * 1991-02-08 1997-09-30 Gilead Sciences, Inc. Nucleoside 5'-methylene phosphonates
DE4111730A1 (en) 1991-04-10 1992-10-15 Knoll Ag NEW CYTARABIN DERIVATIVES, THEIR PRODUCTION AND USE
JP2648897B2 (en) 1991-07-01 1997-09-03 塩野義製薬株式会社 Pyrimidine derivatives
EP0531597A1 (en) 1991-09-12 1993-03-17 Merrell Dow Pharmaceuticals Inc. Novel unsaturated acyclic phosphonate derivatives of purine and pyrimidine
US5610294A (en) 1991-10-11 1997-03-11 The Du Pont Merck Pharmaceutical Company Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors
US5413999A (en) 1991-11-08 1995-05-09 Merck & Co., Inc. HIV protease inhibitors useful for the treatment of AIDS
DE4138584A1 (en) 1991-11-23 1993-05-27 Hoechst Ag New carbocyclic phosphonate-nucleotide analogues - are effective antiviral agents against retroviral infections, e.g. HIV
GB9126144D0 (en) 1991-12-10 1992-02-12 British Bio Technology Compounds
FR2692265B1 (en) 1992-05-25 1996-11-08 Centre Nat Rech Scient BIOLOGICALLY ACTIVE COMPOUNDS OF THE PHOSPHOTRIESTER TYPE.
US5663169A (en) 1992-08-07 1997-09-02 Merck & Co., Inc. Benzoxazinones as inhibitors of HIV reverse transcriptase
IS2334B (en) 1992-09-08 2008-02-15 Vertex Pharmaceuticals Inc., (A Massachusetts Corporation) Aspartyl protease inhibitor of a new class of sulfonamides
US5484926A (en) 1993-10-07 1996-01-16 Agouron Pharmaceuticals, Inc. HIV protease inhibitors
DE4308096A1 (en) 1993-03-13 1994-09-15 Hoechst Ag Prodrug derivatives of enzyme inhibitors with hydroxyl groups, process for their preparation and their use
US5654286A (en) 1993-05-12 1997-08-05 Hostetler; Karl Y. Nucleotides for topical treatment of psoriasis, and methods for using same
EP0632048B1 (en) 1993-06-29 2001-03-21 Mitsubishi Chemical Corporation Phosphonate-nucleotide ester derivatives
AU7491694A (en) 1993-07-14 1995-02-13 Ciba-Geigy Ag Cyclic hydrazine compounds
AU691527B2 (en) 1993-09-17 1998-05-21 Gilead Sciences, Inc. Nucleotide analogs
US5656745A (en) 1993-09-17 1997-08-12 Gilead Sciences, Inc. Nucleotide analogs
US5446137B1 (en) 1993-12-09 1998-10-06 Behringwerke Ag Oligonucleotides containing 4'-substituted nucleotides
US5493030A (en) 1994-02-18 1996-02-20 Syntex (U.S.A.) Inc. 5-substituted derivatives of mycophenolic acid
US5854227A (en) 1994-03-04 1998-12-29 Hartmann; John F. Therapeutic derivatives of diphosphonates
WO1997011092A1 (en) 1994-04-07 1997-03-27 Nippon Shinyaku Co., Ltd. Cyclosporin phosphate derivatives and medicinal composition
KR100387157B1 (en) 1994-09-26 2003-09-29 시오노기세이야쿠가부시키가이샤 Imidazole derivative
CA2203570A1 (en) 1994-11-04 1996-05-17 Lawrence R. Mcgee Thiepane compounds inhibiting and detecting hiv protease
US5543523A (en) 1994-11-15 1996-08-06 Regents Of The University Of Minnesota Method and intermediates for the synthesis of korupensamines
ES2097703B1 (en) 1995-04-12 1997-12-01 Decox S L A NEW STIMULATING COMPOSITION OF BRAIN ACTIVITY BASED ON EBURNAMENINE NUCLEUS ALKALOIDS, AND ITS PREPARATION METHODS.
US5747498A (en) 1996-05-28 1998-05-05 Pfizer Inc. Alkynyl and azido-substituted 4-anilinoquinazolines
AU6299496A (en) 1995-06-29 1997-01-30 Novo Nordisk A/S Novel substituted azabicyclic compounds
US5750493A (en) 1995-08-30 1998-05-12 Raymond F. Schinazi Method to improve the biological and antiviral activity of protease inhibitors
US5646180A (en) 1995-12-05 1997-07-08 Vertex Pharmaceuticals Incorporated Treatment of the CNS effects of HIV
US5914332A (en) 1995-12-13 1999-06-22 Abbott Laboratories Retroviral protease inhibiting compounds
RU2106353C1 (en) 1996-03-19 1998-03-10 Корпорация "С энд Ти Сайенс энд Текнолоджи Инк." 5-h-phosphonate-3-azido-3-desoxyttemidine salts which are specific inhibitors vich-1 and vich-2
US5874577A (en) 1996-04-03 1999-02-23 Medichem Research, Inc. Method for the preparing 9-12-(Diethoxyphosphonomethoxy)ethyl!adenine and analogues thereof
US5849911A (en) 1996-04-22 1998-12-15 Novartis Finance Corporation Antivirally active heterocyclic azahexane derivatives
US5795909A (en) 1996-05-22 1998-08-18 Neuromedica, Inc. DHA-pharmaceutical agent conjugates of taxanes
JP4033494B2 (en) 1996-07-26 2008-01-16 ギリヤド サイエンシーズ， インコーポレイテッド Nucleotide analogs
CA2263286A1 (en) 1996-08-13 1998-02-19 Naoko Ueda Phosphonate nucleotide compound
WO1998011906A1 (en) 1996-09-17 1998-03-26 Amur Pharmaceuticals, Inc. Phospholipid drug derivatives
WO1998015563A1 (en) 1996-10-09 1998-04-16 Pharmasset, Ltd. Tetraphosphonate bicyclic trisanhydrides
US6018049A (en) * 1996-12-26 2000-01-25 Shionogi & Co., Ltd. Process for the preparation of carbamoylated imidazole derivatives
WO1999029702A2 (en) 1997-12-10 1999-06-17 The Government Of The United States Of America Reppresented By The Secretary, Department Of Health And Human Services METHOD FOR SYNTHESIZING 9-(2,3-DIDEOXY-2-FLUORO-β-D-THREO-PENTOFURANOSYL)ADENINE (β-FddA)
US6436989B1 (en) 1997-12-24 2002-08-20 Vertex Pharmaceuticals, Incorporated Prodrugs of aspartyl protease inhibitors
US6312662B1 (en) 1998-03-06 2001-11-06 Metabasis Therapeutics, Inc. Prodrugs phosphorus-containing compounds
US6174888B1 (en) 1998-05-28 2001-01-16 Novartis Ag 2-amino-7-(1-substituted-2-hydroxyethyl)-3,5-dihydropyrrolo[3,2-D]pyrimidin-4-ones
AU4125099A (en) 1998-06-01 1999-12-20 S & T Science And Technology Inc. Antiviral phosphorus derivatives of 4'-thio-5-ethyl-2'-deoxyuridine
GB9815567D0 (en) 1998-07-18 1998-09-16 Glaxo Group Ltd Antiviral compound
TNSN00027A1 (en) 1999-02-12 2005-11-10 Vertex Pharma ASPARTYLE PROTEASE INHIBITORS
US6761903B2 (en) 1999-06-30 2004-07-13 Lipocine, Inc. Clear oil-containing pharmaceutical compositions containing a therapeutic agent
AU775332B2 (en) 1999-03-05 2004-07-29 Metabasis Therapeutics, Inc. Novel phosphorus-containing prodrugs
DE19912636A1 (en) 1999-03-20 2000-09-21 Aventis Cropscience Gmbh Bicyclic heterocycles, processes for their preparation and their use as herbicides and pharmaceutical agents
US6258831B1 (en) 1999-03-31 2001-07-10 The Procter & Gamble Company Viral treatment
US6608027B1 (en) 1999-04-06 2003-08-19 Boehringer Ingelheim (Canada) Ltd Macrocyclic peptides active against the hepatitis C virus
DE19927689A1 (en) 1999-06-17 2000-12-21 Gruenenthal Gmbh Oral dosage formulation containing tramadol and diclofenac, useful for treating pain, contains the active ingredients in separate subunits
MXPA02000294A (en) 1999-06-25 2002-06-21 Vertex Pharma Prodrugs of carbamate inhibitors of impdh.
US6581606B2 (en) 1999-07-06 2003-06-24 The Rx Files Corporation Method, apparatus and system for use in treating patient with a drug having an antineoplastic effect to optimize therapy and prevent an adverse drug response
CA2381425A1 (en) 1999-08-24 2001-03-01 Cellgate, Inc. Enhancing drug delivery across and into epithelial tissues using oligo arginine moieties
GB9920872D0 (en) 1999-09-04 1999-11-10 Glaxo Group Ltd Benzophenones as inhibitors of reverse transcriptase
IL131887A0 (en) 1999-09-14 2001-03-19 Dpharm Ltd Phospholipid prodrugs of anti-proliferative drugs
WO2001039724A2 (en) 1999-12-03 2001-06-07 The Regents Of The University Of California, San Diego Phosphonate compounds
US6448429B1 (en) 1999-12-22 2002-09-10 Merck Frosst Canada & Co. Protein tyrosine phosphatase 1B (PTP-1B) inhibitors containing two ortho-substituted aromatic phosphonates
AU2001234174A1 (en) 2000-02-29 2001-09-12 Mitsubishi Pharma Corporation Phosphonate nucleotide compound
MY164523A (en) * 2000-05-23 2017-12-29 Univ Degli Studi Cagliari Methods and compositions for treating hepatitis c virus
BR0111678A (en) 2000-06-13 2003-06-03 Shionogi & Co Medicinal compositions containing propenone derivatives
FR2810322B1 (en) 2000-06-14 2006-11-10 Pasteur Institut COMBINATORY PRODUCTION OF NUCLEOTIDE AND NUCLEOTIDE ANALOGUES (XiTP)
UA72612C2 (en) 2000-07-06 2005-03-15 Pyrido[2.3-d]pyrimidine and pyrimido[4.5-d]pyrimidine nucleoside analogues, prodrugs and method for inhibiting growth of neoplastic cells
US6617310B2 (en) 2000-07-19 2003-09-09 Bristol-Myers Squibb Pharma Company Phosphate esters of bis-amino acid sulfonamides containing substituted benzyl amines
DK1301519T4 (en) * 2000-07-21 2021-12-20 Gilead Sciences Inc PRODUCTS OF PHOSPHONATE NUCLEOTIDE ANALOGS AND METHODS OF SELECTION AND PREPARATION
US6420586B1 (en) 2000-08-15 2002-07-16 University Of Kansas Amino acid-derived cyclic phosphonamides and methods of synthesizing the same
EP1315488B1 (en) 2000-09-08 2006-10-25 Zeria Pharmaceutical Co., Ltd. Pharmaceutical compositions containing aminothiazole derivatives for the treatment of colonic motor dysfunctions
RU2188203C2 (en) 2000-10-05 2002-08-27 Государственный научный центр вирусологии и биотехнологии "Вектор" 2',3'-didehydro-2',3'-dideoxythymidine-5'-[(ethoxy-carbonyl)(ethyl)phosphonate] as inhibitor of reproduction of human immunodeficiency virus
GB0028429D0 (en) 2000-11-22 2001-01-10 Astrazeneca Ab Therapy
AU2002232660A1 (en) 2000-12-15 2002-06-24 Pharmasset Ltd. Antiviral agents for treatment of flaviviridae infections
DE60138768D1 (en) 2000-12-28 2009-07-02 Kissei Pharmaceutical Glucopyranosylpyrrazole derivatives and their use in medicines
EP1539188B1 (en) 2001-01-22 2015-01-07 Merck Sharp & Dohme Corp. Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase
BR0206806A (en) * 2001-01-31 2004-02-03 Warner Lambert Co Method for carbamoylation of alcohols
BR0207157A (en) 2001-02-12 2004-02-17 Wyeth Corp O-desmethyl-venlafaxine succinate salt
US6962684B2 (en) 2001-05-31 2005-11-08 Sumitomo Chemical Company, Limited Activated alumina formed body and method for producing the same
GB0114286D0 (en) 2001-06-12 2001-08-01 Hoffmann La Roche Nucleoside Derivatives
KR20020097384A (en) 2001-06-20 2002-12-31 미쯔비시 도꾜 세이야꾸 가부시끼가이샤 A Medicament which is Effective for a Virus Having a Resistance Mutation against a Known Medicament
EP1905829B1 (en) 2001-06-20 2016-02-17 Nuevolution A/S Templated molecules and methods for using such molecules
CN1533279A (en) 2001-07-20 2004-09-29 �����ɷ� Organo-phosphorous compounds for activating gamma/delta T-cells
ES2330089T3 (en) * 2001-08-17 2009-12-04 Mitsui Chemicals Agro, Inc. DERIVED FROM 3-FENOXI-4-PIRIDAZINOL AND HERBICIDE COMPOSITION THAT CONTAINS.
JP2005508924A (en) 2001-08-30 2005-04-07 三菱ウェルファーマ株式会社 Antiviral agent
CA2468705A1 (en) 2001-11-29 2003-06-05 Pfizer Products Inc. Succinic acid salts of 5,8,14-triazatetracyclo'10.3.1.0<2,11>.0<4,9>-hexadeca-2(11),3,5,7,9-pentaene and pharmaceutical compositions thereof
KR20050044587A (en) 2001-12-07 2005-05-12 미쯔비시 웰 파마 가부시키가이샤 Use of phosphonate nucleotide analogue for treating hepatitis b virus infections
BR0214876A (en) 2001-12-12 2004-12-28 Pfizer Prod Inc E-2-Methoxy-n- (3- (4- (3-methyl-pyridin-3-yloxy) -phenylamino) quinazolin-6-yl) -allyl) -acetamide salt forms, their preparations and their use same against cancer
AU2002360682B2 (en) 2001-12-21 2008-06-26 Eisai Inc. Process for preparing water-soluble phosphonooxymethyl derivatives of alcohol and phenol
US20030198666A1 (en) 2002-01-07 2003-10-23 Richat Abbas Oral insulin therapy
EP2407473A3 (en) 2002-02-01 2012-03-21 ARIAD Pharmaceuticals, Inc Method for producing phosphorus-containing compounds
CA2474508A1 (en) 2002-02-08 2003-08-14 Conforma Therapeutics Corporation Ansamycins having improved pharmacological and biological properties
US7927613B2 (en) 2002-02-15 2011-04-19 University Of South Florida Pharmaceutical co-crystal compositions
WO2003080078A1 (en) 2002-03-18 2003-10-02 Mitsubishi Pharma Corporation Treatment of pre-core hepatitis b virus mutant infections
AU2003226188A1 (en) * 2002-04-10 2003-10-27 Ortho-Mcneil Pharmaceutical, Inc. Novel heteroaryl alkylamide derivatives useful as bradykinin receptor modulators
US20050239054A1 (en) 2002-04-26 2005-10-27 Arimilli Murty N Method and compositions for identifying anti-HIV therapeutic compounds
US6872827B2 (en) 2002-04-26 2005-03-29 Chembridge Research Laboratories, Inc. Somatostatin analogue compounds
HRP20041113B1 (en) 2002-04-26 2008-09-30 Gilead Sciences Cellular accumulation of phosphonate analogs of hiv protease inhibitor compounds and the compounds as such
CA2499819A1 (en) 2002-09-30 2004-04-08 A/S Gea Farmaceutisk Fabrik Novel raloxifene acid addition salts and/or solvates thereof, improved method for purification of said raloxifene acid addition salts and/or solvates thereof and pharmaceutical compositions comprising these
US20040157793A1 (en) * 2002-11-12 2004-08-12 Stuyver Lieven J. Modified nucleosides as antiviral agents
BRPI0407374A (en) 2003-02-19 2006-01-10 Univ Yale Antiviral nucleoside analogues and methods for treating viral infections, especially HIV infections
WO2004100960A2 (en) 2003-04-25 2004-11-25 Gilead Sciences, Inc. Anti-inflammatory phosphonate compounds
US7407965B2 (en) 2003-04-25 2008-08-05 Gilead Sciences, Inc. Phosphonate analogs for treating metabolic diseases
US7452901B2 (en) * 2003-04-25 2008-11-18 Gilead Sciences, Inc. Anti-cancer phosphonate analogs
EP1620110A2 (en) 2003-04-25 2006-02-01 Gilead Sciences, Inc. Immunomodulator phosphonate conjugates
WO2004096287A2 (en) 2003-04-25 2004-11-11 Gilead Sciences, Inc. Inosine monophosphate dehydrogenase inhibitory phosphonate compounds
CN101410120A (en) 2003-04-25 2009-04-15 吉里德科学公司 Anti-inflammatory phosphonate compounds
US7470724B2 (en) 2003-04-25 2008-12-30 Gilead Sciences, Inc. Phosphonate compounds having immuno-modulatory activity
MXPA05011287A (en) * 2003-04-25 2006-01-24 Gilead Sciences Inc Anti-cancer phosphonate analogs.
US7300924B2 (en) 2003-04-25 2007-11-27 Gilead Sciences, Inc. Anti-infective phosphonate analogs
EA200501676A1 (en) 2003-04-25 2006-04-28 Джилид Сайэнс, Инк. PHOSPHONATE-CONTAINING KINASE INHIBITORS (OPTIONS), METHOD FOR THEIR RECEIVING, PHARMACEUTICAL COMPOSITION, PHARMACEUTICAL FORM ON THEIR BASIS AND METHOD FOR INHIBING KINASE IN MOLOPYTIC TREATMENT THEM
WO2004096233A2 (en) 2003-04-25 2004-11-11 Gilead Sciences, Inc. Nucleoside phosphonate conjugates
WO2005002626A2 (en) 2003-04-25 2005-01-13 Gilead Sciences, Inc. Therapeutic phosphonate compounds
WO2004096237A2 (en) 2003-04-25 2004-11-11 Gilead Sciences, Inc. Phosphonate analogs for treating metabolic diseases
EA014685B1 (en) 2003-04-25 2010-12-30 Джилид Сайэнс, Инк. Phosphonate-containing antiviral compounds (variants) and pharmaceutical composition based thereon
US7432261B2 (en) 2003-04-25 2008-10-07 Gilead Sciences, Inc. Anti-inflammatory phosphonate compounds
EP1617848A2 (en) * 2003-04-25 2006-01-25 Gilead Sciences, Inc. Anti-cancer phosphonate conjugates
JP2007502329A (en) 2003-05-23 2007-02-08 トランスフォーム・ファーマシューティカルズ・インコーポレイテッド Sertraline composition
KR100933185B1 (en) * 2003-06-16 2009-12-22 아지노모토 가부시키가이샤 Inosine derivatives and preparation methods thereof
AU2004260789B2 (en) * 2003-07-30 2011-06-30 Gilead Sciences, Inc. Nucleobase phosphonate analogs for antiviral treatment
WO2005016901A1 (en) 2003-08-18 2005-02-24 H. Lundbeck A/S Trans-1(6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine
US7427624B2 (en) 2003-10-24 2008-09-23 Gilead Sciences, Inc. Purine nucleoside phosphorylase inhibitory phosphonate compounds
US7432273B2 (en) 2003-10-24 2008-10-07 Gilead Sciences, Inc. Phosphonate analogs of antimetabolites
JP2007508844A (en) 2003-10-24 2007-04-12 ギリアード サイエンシーズ， インコーポレイテッド Methods and compositions for the identification of therapeutic compounds
CA2548951A1 (en) 2003-12-22 2005-07-14 Gilead Sciences, Inc. Kinase inhibitor phosphonate conjugates
AU2004309418B2 (en) 2003-12-22 2012-01-19 Gilead Sciences, Inc. 4'-substituted carbovir-and abacavir-derivatives as well as related compounds with HIV and HCV antiviral activity
EP1550665A1 (en) * 2003-12-26 2005-07-06 Ajinomoto Co., Inc. A process for the production of purine nucleoside compounds
US7404949B2 (en) 2004-03-15 2008-07-29 Unilever Home & Personal Care Usa, Division Of Conopco, Inc. Methods and compositions useful to prevent in-grown hair arising from shaving
AU2005254155A1 (en) 2004-06-17 2005-12-29 Osteologix A/S Treatments comprising strontium for rheumatic and arthritic diseases and pain
DE602005027466D1 (en) * 2004-07-27 2011-05-26 Gilead Sciences Inc NUCLEOSIDE PHOSPHONATE CONJUGATES AS ANTI HIV MEDIUM
WO2006015262A2 (en) 2004-07-29 2006-02-09 Coherix, Inc. Method for processing multiwavelength interferometric imaging data
US20060069060A1 (en) 2004-09-27 2006-03-30 Sanjeev Redkar Salts of decitabine
US7154505B2 (en) 2004-11-11 2006-12-26 Stonecube Limited Method of and apparatus for generating a representation of an object
KR20060080817A (en) 2005-01-06 2006-07-11 씨제이 주식회사 Dicarboxylate of Sibutramine
MY148074A (en) 2005-05-10 2013-02-28 Novartis Ag Pharmaceutical compositions comprising imatinib and a release retardant
CN101238099A (en) 2005-08-04 2008-08-06 诺瓦提斯公司 Salts of vildagliptin
DE102005041860A1 (en) 2005-09-02 2007-03-08 Schering Ag Nano-particle embedded- and charged-complex, useful for the production of a pharmaceutical composition, comprises two complex partners, where the complex partner is an embedded anionic and a cationic active substance
TW200730530A (en) 2005-12-16 2007-08-16 Wyeth Corp Lyophilized compositions of a triazolopyrimidine compound
US20060223820A1 (en) 2006-03-21 2006-10-05 Chemagis Ltd. Crystalline aripiprazole salts and processes for preparation and purification thereof
US8895531B2 (en) * 2006-03-23 2014-11-25 Rfs Pharma Llc 2′-fluoronucleoside phosphonates as antiviral agents
AP2986A (en) * 2007-02-23 2014-09-30 Gilead Sciences Inc Modulators of pharmacokinetic properties of therapeutics
US20090163449A1 (en) 2007-12-20 2009-06-25 Eastman Chemical Company Sulfo-polymer powder and sulfo-polymer powder blends with carriers and/or additives
JP5620376B2 (en) 2008-07-08 2014-11-05 ギリアード サイエンシーズ， インコーポレイテッド Salts of HIV inhibitor compounds
JP4330086B1 (en) 2009-02-09 2009-09-09 株式会社テクネス Method for producing non-oxide ceramic products
EP2305680A3 (en) 2009-09-30 2011-05-18 Aurobindo Pharma Limited Novel salts of (1S,4R)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol
WO2014055618A1 (en) 2012-10-03 2014-04-10 Gilead Sciences, Inc. Solid state forms of hiv inhibitor: hemi-succinate of (2s)-2-tert-butoxy-2-(4-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-2-methylquinolin-3-yl)acetic acid)
WO2014055603A1 (en) 2012-10-03 2014-04-10 Gilead Sciences, Inc. Process for the preparation of an hiv integrase inhibitor

Cited By (206)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8871785B2 (en) 2003-04-25 2014-10-28 Gilead Sciences, Inc. Antiviral phosphonate analogs
US9139604B2 (en) 2003-04-25 2015-09-22 Gilead Sciences, Inc. Antiviral phosphonate analogs
US8329926B2 (en) 2004-07-27 2012-12-11 Gilead Sciences, Inc. Antiviral compounds
US9457035B2 (en) 2004-07-27 2016-10-04 Gilead Sciences, Inc. Antiviral compounds
NO339222B1 (en) * 2004-07-27 2016-11-21 Gilead Sciences Inc Nucleoside phosphonate conjugates as anti-HIV agents
US8318701B2 (en) 2004-07-27 2012-11-27 Gilead Sciences, Inc. Phosphonate analogs of HIV inhibitor compounds
WO2006110157A3 (en) * 2004-07-27 2007-01-18 Gilead Sciences Inc Nucleoside phosphonate conjugates as anti hiv agents
WO2006110157A2 (en) 2004-07-27 2006-10-19 Gilead Sciences, Inc. Nucleoside phosphonate conjugates as anti hiv agents
EA019419B1 (en) * 2004-07-27 2014-03-31 Джилид Сайэнс, Инк. Phosphonate analogs of hiv inhibitor compounds, pharmaceutical composition and kit containing them and method for treating disorders associated with hiv
US9579332B2 (en) 2004-07-27 2017-02-28 Gilead Sciences, Inc. Phosphonate analogs of HIV inhibitor compounds
WO2007014352A3 (en) * 2005-07-27 2007-03-29 Gilead Sciences Inc Antiviral phosphonate conjugates for inhibition of hiv
WO2007112028A3 (en) * 2006-03-23 2008-03-06 Rfs Pharma Llc 2'-fluoronucleoside phosphonates as antiviral agents
US8895531B2 (en) 2006-03-23 2014-11-25 Rfs Pharma Llc 2′-fluoronucleoside phosphonates as antiviral agents
WO2008100447A3 (en) * 2007-02-09 2008-12-24 Gilead Sciences Inc Nucleoside analogs for antiviral treatment
US8324179B2 (en) 2007-02-09 2012-12-04 Gilead Sciences, Inc. Nucleoside analogs for antiviral treatment
EP3255045A1 (en) * 2007-02-16 2017-12-13 Debiopharm International SA Salts, prodrugs and polymorphs of fab i inhibitors
EA018308B1 (en) * 2008-07-08 2013-07-30 Джилид Сайэнс, Инк. Salts of hiv inhibitor compounds
AU2009268681B2 (en) * 2008-07-08 2014-10-02 Gilead Sciences, Inc. Salts of HIV inhibitor compounds
US8951986B2 (en) 2008-07-08 2015-02-10 Gilead Sciences, Inc. Salts of HIV inhibitor compounds
US9783568B2 (en) 2008-07-08 2017-10-10 Gilead Sciences, Inc. Salts of HIV inhibitor compounds
AP3347A (en) * 2008-07-08 2015-07-31 Gilead Sciences Inc Salts of HIV inhibitor compounds
US8658617B2 (en) 2008-07-08 2014-02-25 Gilead Sciences, Inc. Salts of HIV inhibitor compounds
US9381206B2 (en) 2008-07-08 2016-07-05 Gilead Sciences, Inc. Salts of HIV inhibitor compounds
KR20110029165A (en) * 2008-07-08 2011-03-22 길리애드 사이언시즈, 인코포레이티드 Salts of HIV Inhibitor Compounds
WO2010005986A1 (en) * 2008-07-08 2010-01-14 Gilead Sciences, Inc. Salts of hiv inhibitor compounds
KR101642527B1 (en) 2008-07-08 2016-07-25 길리애드 사이언시즈, 인코포레이티드 Salts of hiv inhibitor compounds
US9783567B2 (en) 2011-05-19 2017-10-10 Gilead Sciences, Inc. Processes and intermediates for preparing anti-HIV agents
US9296779B2 (en) 2011-05-19 2016-03-29 Gilead Sciences, Inc. Processes and intermediates for preparing anti-HIV agents
EP3199537A1 (en) 2011-05-19 2017-08-02 Gilead Sciences, Inc. Processes and intermediates for preparing anti-hiv agents
EP3450438A1 (en) 2011-05-19 2019-03-06 Gilead Sciences, Inc. Processes and intermediates for preparing anti-hiv agents
US8987437B2 (en) 2011-05-19 2015-03-24 Gilead Sciences, Inc. Processes and intermediates for preparing anti-HIV Agents
US10196419B2 (en) 2011-05-19 2019-02-05 Gilead Sciences, Inc. Processes and intermediates for preparing anti-HIV agents
US11034668B2 (en) 2011-07-06 2021-06-15 Gilead Sciences, Inc. Compounds for the treatment of HIV
EP2567961A1 (en) 2011-09-08 2013-03-13 Straitmark Holding AG Method for the manufacture of compounds containing an alpha-oxyphosphorus group by using an activator
WO2013034730A2 (en) 2011-09-08 2013-03-14 Straitmark Holding Ag Method for the manufacture of compounds containing an alpha-oxyphosphorus group by using an activator
EP4309736A2 (en) 2014-06-20 2024-01-24 Gilead Sciences, Inc. Crystalline forms of (2r,5s,13ar)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido [1',2':4,5]pyrazino [2,1-b][1,3]oxazepine-10-carboxamide
EP3564244A1 (en) 2014-06-20 2019-11-06 Gilead Sciences, Inc. Crystalline forms of (2r,5s,13ar)-8-hydroxy-7,9-dioxo-n-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido [1',2':4,5]pyrazino [2,1-b][1,3]oxazepine-10-carboxamide
EP3321270A1 (en) 2014-06-20 2018-05-16 Gilead Sciences, Inc. Sodium (2r, 5s, 13ar) -7, 9-dioxo-10- ( (2,4,6-trifluorobenzyl) carbamoyl) -2, 3, 4, 5, 7, 9, 13, 13a-octahydro-2, 5-methanopyrido [1',2' : 4.5] pyrazino [2, 1-b] oxazepin-8-olate
WO2016036759A1 (en) 2014-09-04 2016-03-10 Gilead Sciences, Inc. Methods of treating or preventing hiv in patients using a combination of tenofovir alafenamide and dolutegravir
WO2016106237A1 (en) 2014-12-23 2016-06-30 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
EP3388431A1 (en) 2014-12-23 2018-10-17 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
US9701677B2 (en) 2014-12-24 2017-07-11 Gilead Sciences, Inc. Fused pyrimidine compounds
US9730936B2 (en) 2014-12-24 2017-08-15 Gilead Sciences, Inc. Quinazoline compounds
US11304948B2 (en) 2014-12-24 2022-04-19 Gilead Sciences, Inc. Quinazoline compounds
US9624195B2 (en) 2014-12-24 2017-04-18 Gilead Sciences, Inc. Isoquinoline compounds
WO2016105532A1 (en) 2014-12-24 2016-06-30 Gilead Sciences, Inc. Fused pyrimidine compounds for the treatment of hiv
EP3521282A1 (en) 2014-12-24 2019-08-07 Gilead Sciences, Inc. Quinazoline derivatives used to treat hiv
EP4302830A2 (en) 2014-12-24 2024-01-10 Gilead Sciences, Inc. Quinazoline derivatives used to treat hiv
EP3960735A1 (en) 2014-12-24 2022-03-02 Gilead Sciences, Inc. Quinazoline derivatives used to treat hiv
US10548898B2 (en) 2014-12-24 2020-02-04 Gilead Sciences Inc. Quinazoline compounds
US10206926B2 (en) 2014-12-24 2019-02-19 Gilead Sciences, Inc. Quinazoline compounds
WO2016105564A1 (en) 2014-12-24 2016-06-30 Gilead Sciences, Inc. Quinazoline derivatives used to treat hiv
WO2016105534A1 (en) 2014-12-24 2016-06-30 Gilead Sciences, Inc. Isoquinoline compounds for the treatment of hiv
US11628181B2 (en) 2014-12-26 2023-04-18 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
EP3321265A1 (en) 2015-03-04 2018-05-16 Gilead Sciences, Inc. 4,6-diamino-pyrido[3,2-d]pyrimidine compounds and their utilisation as modulators of toll-like receptors
WO2016141092A1 (en) 2015-03-04 2016-09-09 Gilead Sciences, Inc. Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds
EP3722297A1 (en) 2015-03-04 2020-10-14 Gilead Sciences, Inc. Toll-like receptor modulating 4,6-diamino-pyrido[3,2-d]pyrimidine compounds
EP3736274A1 (en) 2015-04-02 2020-11-11 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
WO2016161382A1 (en) 2015-04-02 2016-10-06 Gilead Sciences, Inc. Polycyclic-carbamoylpyridone compounds and their pharmaceutical use
WO2017035230A1 (en) 2015-08-26 2017-03-02 Gilead Sciences, Inc. Deuterated toll-like receptor modulators
WO2017059120A1 (en) 2015-09-30 2017-04-06 Gilead Sciences, Inc. Compounds and combinations for the treatment of hiv
WO2017106346A2 (en) 2015-12-15 2017-06-22 Gilead Sciences, Inc. Human immunodeficiency virus neutralizing antibodies
EP3992206A1 (en) 2015-12-15 2022-05-04 Gilead Sciences, Inc. Human immunodeficiency virus neutralizing antibodies
WO2018035359A1 (en) 2016-08-19 2018-02-22 Gilead Sciences, Inc. Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection
US10654827B2 (en) 2016-08-19 2020-05-19 Gilead Sciences, Inc. Therapeutic compounds
US11993583B2 (en) 2016-08-19 2024-05-28 Gilead Sciences, Inc. Therapeutic compounds
EP3597646A1 (en) 2016-08-19 2020-01-22 Gilead Sciences, Inc. Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection
EP4265299A2 (en) 2016-08-19 2023-10-25 Gilead Sciences, Inc. Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection
WO2018042331A1 (en) 2016-08-31 2018-03-08 Glaxosmithkline Intellectual Property (No.2) Limited Combinations and uses and treatments thereof
WO2018042332A1 (en) 2016-08-31 2018-03-08 Glaxosmithkline Intellectual Property (No.2) Limited Combinations and uses and treatments thereof
WO2018045150A1 (en) 2016-09-02 2018-03-08 Gilead Sciences, Inc. 4,6-diamino-pyrido[3,2-d]pyrimidine derivaties as toll like receptor modulators
WO2018045144A1 (en) 2016-09-02 2018-03-08 Gilead Sciences, Inc. Toll like receptor modulator compounds
WO2018051250A1 (en) 2016-09-14 2018-03-22 Viiv Healthcare Company Combination comprising tenofovir alafenamide, bictegravir and 3tc
WO2018064080A1 (en) 2016-09-28 2018-04-05 Gilead Sciences, Inc. Benzothiazol-6-yl acetic acid derivatives and their use for treating hiv infection
WO2018081292A1 (en) 2016-10-27 2018-05-03 Gilead Sciences, Inc. Crystalline forms of darunavir free base, hydrate, solvates and salts
WO2018144390A1 (en) 2017-01-31 2018-08-09 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
EP4424374A2 (en) 2017-01-31 2024-09-04 Gilead Sciences, Inc. Crystalline forms of tenofovir alafenamide
US11078208B1 (en) 2017-02-06 2021-08-03 Gilead Sciences, Inc. HIV inhibitor compounds
EP3909949A1 (en) 2017-02-06 2021-11-17 Gilead Sciences, Inc. Atazanavir (atv) analogues for treating hiv infections
WO2018145021A1 (en) 2017-02-06 2018-08-09 Gilead Sciences, Inc. Atazanavir (atv) analogues for treating hiv infections
US12084455B2 (en) 2017-02-06 2024-09-10 Gilead Sciences, Inc. HIV inhibitor compounds
US10752636B2 (en) 2017-02-06 2020-08-25 Gilead Sciences, Inc. HIV inhibitor compounds
WO2018237148A1 (en) 2017-06-21 2018-12-27 Gilead Sciences, Inc. MULTISPECIFIC ANTIBODIES TARGETING HIV GP120 AND CD3
EP3960740A1 (en) 2017-08-01 2022-03-02 Gilead Sciences, Inc. Crystalline forms of ethyl ((s)-((((2r,5r)-5-(6-amino-9h-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-l-alaninate (gs-9131) vanillate for treating viral infections
US10851125B2 (en) 2017-08-01 2020-12-01 Gilead Sciences, Inc. Crystalline forms of ethyl ((S)-((((2R,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl(-L-alaninate
WO2019027920A1 (en) 2017-08-01 2019-02-07 Gilead Sciences, Inc. Crystalline forms of ethyl ((s)-((((2r,5r)-5-(6-amino-9h-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-l-alaninate (gs-9131) for treating viral infections
US10849892B2 (en) 2017-08-17 2020-12-01 Gilead Sciences, Inc. Choline salt forms of an HIV capsid inhibitor
EP4092020A1 (en) 2017-08-17 2022-11-23 Gilead Sciences, Inc. Solid forms of an hiv capsid inhibitor
US11267799B2 (en) 2017-08-17 2022-03-08 Gilead Sciences, Inc. Solid forms of an HIV capsid inhibitor
US11266638B2 (en) 2017-08-17 2022-03-08 Gilead Sciences, Inc. Choline salt forms of an HIV capsid inhibitor
EP4458415A2 (en) 2017-08-17 2024-11-06 Gilead Sciences, Inc. Solid forms of an hiv capsid inhibitor
EP4046994A1 (en) 2017-08-17 2022-08-24 Gilead Sciences, Inc. Choline salt forms of an hiv capsid inhibitor
WO2019035904A1 (en) 2017-08-17 2019-02-21 Gilead Sciences, Inc. Solid forms of an hiv capsid inhibitor
WO2019035973A1 (en) 2017-08-17 2019-02-21 Gilead Sciences, Inc Choline salt forms of an hiv capsid inhibitor
EP4382105A2 (en) 2017-08-17 2024-06-12 Gilead Sciences, Inc. Choline salt forms of an hiv capsid inhibitor
US11833143B2 (en) 2017-08-17 2023-12-05 Gilead Sciences, Inc. Choline salt forms of an HIV capsid inhibitor
WO2019075291A1 (en) 2017-10-13 2019-04-18 Gilead Sciences, Inc. 1-benzyl-2-imino-4-phenyl-5-oxoimidazolidine derivatives as hiv protease inhibitors
WO2019084020A1 (en) 2017-10-24 2019-05-02 Gilead Sciences, Inc. Methods of treating patients co-infected with a virus and tuberculosis
EP4491232A2 (en) 2017-12-07 2025-01-15 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11331331B2 (en) 2017-12-07 2022-05-17 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
WO2019113462A1 (en) 2017-12-07 2019-06-13 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US12329770B2 (en) 2017-12-07 2025-06-17 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11903959B2 (en) 2017-12-07 2024-02-20 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11203610B2 (en) 2017-12-20 2021-12-21 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
US10966999B2 (en) 2017-12-20 2021-04-06 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
WO2019161017A1 (en) 2018-02-15 2019-08-22 Gilead Sciences, Inc. Pyridine derivatives and their use for treating hiv infection
US11753399B2 (en) 2018-02-15 2023-09-12 Gilead Sciences, Inc. Therapeutic compounds
US10836746B2 (en) 2018-02-15 2020-11-17 Gilead Sciences, Inc. Therapeutic compounds
US11267801B2 (en) 2018-02-15 2022-03-08 Gilead Sciences, Inc. Therapeutic compounds
US12122765B2 (en) 2018-02-16 2024-10-22 Gilead Sciences, Inc. Methods and intermediates for preparing therapeutic compounds
US11117886B2 (en) 2018-02-16 2021-09-14 Gilead Sciences, Inc. Methods and intermediates for preparing therapeutic compounds
US11760746B2 (en) 2018-02-16 2023-09-19 Gilead Sciences, Inc. Methods and intermediates for preparing therapeutic compounds
US10696657B2 (en) 2018-02-16 2020-06-30 Gilead Sciences, Inc. Methods and intermediates for preparing therapeutic compounds
US11149052B2 (en) 2018-04-06 2021-10-19 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2′3′-cyclic dinucleotides
WO2019193542A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides
US11292812B2 (en) 2018-04-06 2022-04-05 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′-cyclic dinucleotides
WO2019193543A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides
WO2019193533A1 (en) 2018-04-06 2019-10-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'2'-cyclic dinucleotides
WO2019211799A1 (en) 2018-05-03 2019-11-07 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide
EP4624491A2 (en) 2018-07-03 2025-10-01 Gilead Sciences, Inc. Antibodies that target hiv gp120 and methods of use
EP4257600A2 (en) 2018-07-03 2023-10-11 Gilead Sciences, Inc. Antibodies that target hiv gp120 and methods of use
WO2020010107A1 (en) 2018-07-03 2020-01-09 Gilead Sciences, Inc. Antibodies that target hiv gp120 and methods of use
WO2020018459A1 (en) 2018-07-16 2020-01-23 Gilead Sciences, Inc. Capsid inhibitors for the treatment of hiv
US11944611B2 (en) 2018-07-16 2024-04-02 Gilead Sciences, Inc. Capsid inhibitors for the treatment of HIV
US11052087B2 (en) 2018-07-30 2021-07-06 Gilead Sciences, Inc. Anti-HIV compounds
WO2020028272A1 (en) 2018-07-30 2020-02-06 Gilead Sciences, Inc. Anti-hiv compounds
WO2020072656A1 (en) 2018-10-03 2020-04-09 Gilead Sciences, Inc. Imidozopyrimidine derivatives
WO2020092621A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds as hpk1 inhibitors
EP4371987A1 (en) 2018-10-31 2024-05-22 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds as hpk1 inhibitors
WO2020092528A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity
WO2020176510A1 (en) 2019-02-25 2020-09-03 Gilead Sciences, Inc. Protein kinase c agonists
WO2020176505A1 (en) 2019-02-25 2020-09-03 Gilead Sciences, Inc. Protein kinase c agonists
WO2020178768A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
US11766447B2 (en) 2019-03-07 2023-09-26 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3′3′-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
WO2020178769A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides and prodrugs thereof
WO2020178770A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides and prodrugs thereof
US12227520B2 (en) 2019-03-22 2025-02-18 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use
EP4122537A1 (en) 2019-03-22 2023-01-25 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use
WO2020197991A1 (en) 2019-03-22 2020-10-01 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use
WO2020214647A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Solid forms of an hiv protease inhibitor
EP4458416A2 (en) 2019-04-17 2024-11-06 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
WO2020214663A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
WO2020214652A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. Solid forms of a toll-like receptor modulator
WO2020214716A1 (en) 2019-04-17 2020-10-22 Gilead Sciences, Inc. 2-imino-5-oxo-imidazolidine inhibitors of hiv protease
WO2020236753A1 (en) 2019-05-21 2020-11-26 Gilead Sciences, Inc. Methods of identifying hiv patients sensitive to therapy with gp120 v3 glycan-directed antibodies
EP4513188A2 (en) 2019-05-21 2025-02-26 Gilead Sciences, Inc. Methods of identifying hiv patients sensitive to therapy with gp120 v3 glycan-directed antibodies
WO2020237025A1 (en) 2019-05-23 2020-11-26 Gilead Sciences, Inc. Substituted exo-methylene-oxindoles which are hpk1/map4k1 inhibitors
WO2020246910A1 (en) 2019-06-03 2020-12-10 Александл Васильевич ИВАЩЕНКО ANNELATED 9-HYDROXY-1,8-DIOXO-1,3,4,8-TETRAHYDRO-2Н-PYRIDO[1,2-α]PYRAZINE-7-CARBOXAMIDES AS HIV INTEGRASE INHIBITORS
WO2020255038A1 (en) 2019-06-18 2020-12-24 Janssen Sciences Ireland Unlimited Company Combination of hepatitis b virus (hbv) vaccines and pyridopyrimidine derivatives
WO2020263830A1 (en) 2019-06-25 2020-12-30 Gilead Sciences, Inc. Flt3l-fc fusion proteins and methods of use
WO2021011544A1 (en) 2019-07-16 2021-01-21 Gilead Sciences, Inc. Hiv vaccines and methods of making and using
WO2021011891A1 (en) 2019-07-18 2021-01-21 Gilead Sciences, Inc. Long-acting formulations of tenofovir alafenamide
WO2021034804A1 (en) 2019-08-19 2021-02-25 Gilead Sciences, Inc. Pharmaceutical formulations of tenofovir alafenamide
US11807625B2 (en) 2019-11-26 2023-11-07 Gilead Sciences, Inc. Capsid inhibitors for the prevention of HIV
EP4445902A2 (en) 2019-12-24 2024-10-16 Carna Biosciences, Inc. Diacylglycerol kinase modulating compounds
WO2021130638A1 (en) 2019-12-24 2021-07-01 Carna Biosciences, Inc. Diacylglycerol kinase modulating compounds
US12122776B2 (en) 2020-02-24 2024-10-22 Gilead Sciences, Inc. Tetracyclic compounds and uses thereof
WO2021173522A1 (en) 2020-02-24 2021-09-02 Gilead Sciences, Inc. Tetracyclic compounds for treating hiv infection
WO2021188959A1 (en) 2020-03-20 2021-09-23 Gilead Sciences, Inc. Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same
WO2021236944A1 (en) 2020-05-21 2021-11-25 Gilead Sciences, Inc. Pharmaceutical compositions comprising bictegravir
WO2021262990A1 (en) 2020-06-25 2021-12-30 Gilead Sciences, Inc. Capsid inhibitors for the treatment of hiv
US11680064B2 (en) 2020-06-25 2023-06-20 Gilead Sciences, Inc. Capsid inhibitors for the treatment of HIV
US12077537B2 (en) 2020-06-25 2024-09-03 Gilead Sciences, Inc. Capsid inhibitors for the treatment of HIV
WO2022031894A1 (en) 2020-08-07 2022-02-10 Gilead Sciences, Inc. Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use
CN114262348A (en) * 2020-09-16 2022-04-01 上海本仁科技有限公司 Cyclic nucleoside phosphate ester compound and application thereof
WO2022072520A1 (en) 2020-09-30 2022-04-07 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
WO2022087149A2 (en) 2020-10-22 2022-04-28 Gilead Sciences, Inc. Interleukin-2-fc fusion proteins and methods of use
WO2022103758A1 (en) 2020-11-11 2022-05-19 Gilead Sciences, Inc. METHODS OF IDENTIFYING HIV PATIENTS SENSITIVE TO THERAPY WITH gp120 CD4 BINDING SITE-DIRECTED ANTIBODIES
WO2022159387A1 (en) 2021-01-19 2022-07-28 Gilead Sciences, Inc. Substituted pyridotriazine compounds and uses thereof
EP4321217A2 (en) 2021-01-19 2024-02-14 Gilead Sciences, Inc. Substituted pyridotriazine compounds and uses thereof
WO2022245671A1 (en) 2021-05-18 2022-11-24 Gilead Sciences, Inc. Methods of using flt3l-fc fusion proteins
WO2022271684A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271677A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271650A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271659A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
EP4445900A2 (en) 2021-12-03 2024-10-16 Gilead Sciences, Inc. Therapeutic compounds for hiv virus infection
WO2023102523A1 (en) 2021-12-03 2023-06-08 Gilead Sciences, Inc. Therapeutic compounds for hiv virus infection
US12084467B2 (en) 2021-12-03 2024-09-10 Gilead Sciences, Inc. Therapeutic compounds for HIV virus infection
EP4566608A2 (en) 2021-12-03 2025-06-11 Gilead Sciences, Inc. Therapeutic compounds for hiv virus infection
US11787825B2 (en) 2021-12-03 2023-10-17 Gilead Sciences, Inc. Therapeutic compounds for HIV virus infection
WO2023102529A1 (en) 2021-12-03 2023-06-08 Gilead Sciences, Inc. Therapeutic compounds for hiv virus infection
US12187753B2 (en) 2021-12-03 2025-01-07 Gilead Sciences, Inc. Therapeutics compounds for HIV virus infection
US12404262B2 (en) 2021-12-03 2025-09-02 Gilead Sciences, Inc. Therapeutic compounds for HIV virus infection
WO2023102239A1 (en) 2021-12-03 2023-06-08 Gilead Sciences, Inc. Therapeutic compounds for hiv virus infection
EP4438123A2 (en) 2022-04-06 2024-10-02 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
WO2023196875A1 (en) 2022-04-06 2023-10-12 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
EP4310087A1 (en) 2022-04-06 2024-01-24 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
WO2024006982A1 (en) 2022-07-01 2024-01-04 Gilead Sciences, Inc. Therapeutic compounds useful for the prophylactic or therapeutic treatment of an hiv virus infection
WO2024015741A1 (en) 2022-07-12 2024-01-18 Gilead Sciences, Inc. Hiv immunogenic polypeptides and vaccines and uses thereof
WO2024044477A1 (en) 2022-08-26 2024-02-29 Gilead Sciences, Inc. Dosing and scheduling regimen for broadly neutralizing antibodies
WO2024076915A1 (en) 2022-10-04 2024-04-11 Gilead Sciences, Inc. 4'-thionucleoside analogues and their pharmaceutical use
WO2024220624A1 (en) 2023-04-19 2024-10-24 Gilead Sciences, Inc. Dosing regimen of capsid inhibitor
WO2024249573A1 (en) 2023-05-31 2024-12-05 Gilead Sciences, Inc. Solid forms of compounds useful in the treatment of hiv
WO2024249592A1 (en) 2023-05-31 2024-12-05 Gilead Sciences, Inc. Quinazolinyl-indazole derivatives as therapeutic compounds for hiv
WO2024249517A1 (en) 2023-05-31 2024-12-05 Gilead Sciences, Inc. Anti-hiv compounds
WO2025029247A1 (en) 2023-07-28 2025-02-06 Gilead Sciences, Inc. Weekly regimen of lenacapavir for the treatment and prevention of hiv
WO2025042394A1 (en) 2023-08-23 2025-02-27 Gilead Sciences, Inc. Dosing regimen of hiv capsid inhibitor
WO2025076542A1 (en) 2023-10-05 2025-04-10 Jones R Brad Atovaquone as an ros inducer for use in the elimination of hiv-infected t-cells
WO2025080863A1 (en) 2023-10-11 2025-04-17 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
WO2025080879A1 (en) 2023-10-11 2025-04-17 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
WO2025080850A1 (en) 2023-10-11 2025-04-17 Gilead Sciences, Inc. Bridged tricyclic carbamoylpyridone compounds and uses thereof
WO2025137245A1 (en) 2023-12-22 2025-06-26 Gilead Sciences, Inc. Solid forms of hiv integrase inhibitors
WO2025184609A1 (en) 2024-03-01 2025-09-04 Gilead Sciences, Inc. Antiviral compounds
WO2025184452A1 (en) 2024-03-01 2025-09-04 Gilead Sciences, Inc. Solid forms of hiv integrase inhibitors
WO2025184447A1 (en) 2024-03-01 2025-09-04 Gilead Sciences, Inc. Pharmaceutical compositions comprising hiv integrase inhibitors
WO2025212814A1 (en) 2024-04-03 2025-10-09 Gilead Sciences, Inc. Anti-hiv compounds

Also Published As

Publication number Publication date
DK1778251T3 (en) 2011-07-18
KR20070043867A (en) 2007-04-25
NO342571B1 (en) 2018-06-18
ZA200701465B (en) 2008-09-25
UA91688C2 (en) 2010-08-25
AR051922A1 (en) 2007-02-21
ME03423B (en) 2020-01-20
EA019419B1 (en) 2014-03-31
HRP20110527T1 (en) 2011-08-31
KR20070053722A (en) 2007-05-25
NZ553405A (en) 2010-03-26
HRP20070078A2 (en) 2007-05-31
RS58600B1 (en) 2019-05-31
AP2007003912A0 (en) 2007-02-28
US20180086784A1 (en) 2018-03-29
HUE043207T2 (en) 2019-08-28
NO339020B1 (en) 2016-11-07
AU2005267800B2 (en) 2012-05-24
WO2006110157A9 (en) 2007-03-08
DE602005021506D1 (en) 2010-07-08
US20070049754A1 (en) 2007-03-01
AU2005267800A1 (en) 2006-02-09
US20130090299A1 (en) 2013-04-11
IS2840B (en) 2013-06-15
KR101233823B1 (en) 2013-02-18
EA019559B1 (en) 2014-04-30
CY1111709T1 (en) 2015-10-07
IL180758A0 (en) 2007-07-04
EP1778249B1 (en) 2010-05-26
JP2008508315A (en) 2008-03-21
CN101914124B (en) 2012-07-18
NZ553406A (en) 2010-08-27
TWI362934B (en) 2012-05-01
KR101233824B1 (en) 2013-02-18
IS8595A (en) 2007-01-23
ATE469163T1 (en) 2010-06-15
SI1778251T1 (en) 2011-07-29
HK1103648A1 (en) 2007-12-28
US20190345190A1 (en) 2019-11-14
IL180781A0 (en) 2007-06-03
DK2258376T3 (en) 2019-04-15
CN101914124A (en) 2010-12-15
DE602005027466D1 (en) 2011-05-26
CN101027062A (en) 2007-08-29
US8697861B2 (en) 2014-04-15
TW200618804A (en) 2006-06-16
BRPI0512690A (en) 2007-11-27
EP1778251B1 (en) 2011-04-13
IS8594A (en) 2007-01-23
US9457035B2 (en) 2016-10-04
US8329926B2 (en) 2012-12-11
US20090012037A1 (en) 2009-01-08
EA200700363A1 (en) 2009-12-30
WO2006110157A2 (en) 2006-10-19
PL382843A1 (en) 2008-01-21
AP2629A (en) 2013-03-28
AP2007003899A0 (en) 2007-02-28
JP4954877B2 (en) 2012-06-20
US20170210770A1 (en) 2017-07-27
IL180758A (en) 2011-12-29
UA88313C2 (en) 2009-10-12
IL180781A (en) 2011-12-29
EP1778251A2 (en) 2007-05-02
RS51799B (en) 2011-12-31
CA2574514A1 (en) 2006-10-19
ATE505196T1 (en) 2011-04-15
JP2008508291A (en) 2008-03-21
HK1103649A1 (en) 2007-12-28
NO20161612A1 (en) 2007-04-26
SG155164A1 (en) 2009-09-30
ZA200701466B (en) 2008-04-30
MX2007001059A (en) 2008-01-16
NO20161521L (en) 2007-04-26
NO20071078L (en) 2007-04-26
US8318701B2 (en) 2012-11-27
EP3539546A1 (en) 2019-09-18
US20190315785A1 (en) 2019-10-17
HRP20190712T1 (en) 2019-05-31
CN101935333A (en) 2011-01-05
NO20180243A1 (en) 2007-04-26
US7871991B2 (en) 2011-01-18
PL1778251T3 (en) 2011-09-30
ES2363160T3 (en) 2011-07-22
PL230036B1 (en) 2018-09-28
US20130090302A1 (en) 2013-04-11
CN101031306A (en) 2007-09-05
SI2258376T1 (en) 2019-04-30
CA2574121A1 (en) 2006-02-09
US9579332B2 (en) 2017-02-28
MX2007001053A (en) 2007-07-25
AP2412A (en) 2012-06-01
JP2011201911A (en) 2011-10-13
CA2574121C (en) 2014-07-15
PL382846A1 (en) 2008-01-21
PT2258376T (en) 2019-05-31
CY1121623T1 (en) 2020-07-31
TR201906416T4 (en) 2019-05-21
ME01945B (en) 2011-12-31
BRPI0512683A (en) 2008-04-01
HRP20070079A2 (en) 2007-05-31
WO2006110157A3 (en) 2007-01-18
EA200700362A1 (en) 2008-08-29
PL216369B1 (en) 2014-03-31
CN101031306B (en) 2010-09-22
US20140288294A1 (en) 2014-09-25
LT2258376T (en) 2019-05-10
NO20071077L (en) 2007-04-26
NO339222B1 (en) 2016-11-21
ES2720618T3 (en) 2019-07-23
US20090202470A1 (en) 2009-08-13
WO2006015261A3 (en) 2006-11-16
AU2005330489A1 (en) 2006-10-19
ES2346454T3 (en) 2010-10-15
EP2258376A1 (en) 2010-12-08
PL2258376T3 (en) 2019-09-30
EP1778249A2 (en) 2007-05-02
US20170088576A1 (en) 2017-03-30
EP2258376B1 (en) 2019-02-27
NO342132B1 (en) 2018-03-26
PT1778251E (en) 2011-06-29
AU2005330489B2 (en) 2011-08-25

Similar Documents

Publication Publication Date Title
US8697861B2 (en) Antiviral compounds
EP1907403B1 (en) Antiviral compounds
US7300924B2 (en) Anti-infective phosphonate analogs
US20070281907A1 (en) Kinase Inhibitor Phosphonate Conjugates
US20070078081A1 (en) Antiviral compounds
WO2005063258A1 (en) Kinase inhibitor phosphonate conjugates
US20070027116A1 (en) Therapeutic phosphonate derivatives
US20090156558A1 (en) Phosphonate analogs of antimetabolites
US20080076740A1 (en) Antiviral compounds
WO2005012324A2 (en) Nucleobase phosphonate analogs for antiviral treatment
US7427624B2 (en) Purine nucleoside phosphorylase inhibitory phosphonate compounds
US20050153990A1 (en) Phosphonate substituted kinase inhibitors
US20080171724A1 (en) Phosphonate Derivatives of Mycophenolic Acid
EP1809299A2 (en) Phosphonate substituted kinase inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KM KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NG NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU LV MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2574121

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 180758

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2005267800

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: MX/a/2007/001059

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2007523866

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 382843

Country of ref document: PL

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 1211/DELNP/2007

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 2005267800

Country of ref document: AU

Date of ref document: 20050727

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2005267800

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2007/01466

Country of ref document: ZA

Ref document number: 200701466

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 553406

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 2005777315

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 1020077004803

Country of ref document: KR

Ref document number: P20070079A

Country of ref document: HR

WWE Wipo information: entry into national phase

Ref document number: 200700362

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 200580032556.8

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2005777315

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 11658628

Country of ref document: US

ENP Entry into the national phase

Ref document number: PI0512683

Country of ref document: BR