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WO2011071981A2 - Activité anti-cytomégalovirus de dimères dérivés de l'artémisinine - Google Patents

Activité anti-cytomégalovirus de dimères dérivés de l'artémisinine Download PDF

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WO2011071981A2
WO2011071981A2 PCT/US2010/059390 US2010059390W WO2011071981A2 WO 2011071981 A2 WO2011071981 A2 WO 2011071981A2 US 2010059390 W US2010059390 W US 2010059390W WO 2011071981 A2 WO2011071981 A2 WO 2011071981A2
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unsubstituted
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alkyl
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WO2011071981A3 (fr
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Ravit Arav-Boger
Gary Posner
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Johns Hopkins University
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Johns Hopkins University
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    • 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
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • 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
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/18—Bridged systems
    • 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

Definitions

  • CMV cytomegalovirus
  • Infection with cytomegalovirus (CMV) is common in humans and is usually asymptomatic. Weller TH. The cytomegaloviruses: ubiquitous agents with protean clinical manifestations. U. N Engl JMed 1971 ;285:267-274; Weller TH. The cytomegaloviruses: ubiquitous agents with protean clinical manifestations. /. N Engl J Med. 1971 ;285:203-214.
  • CMV infection is associated with significant morbidity and mortality.
  • Griffiths PD Clark DA, Emery VC. Betaherpesviruses in transplant recipients. J Antimicrob Chemother.
  • CMV has been associated with a variety of syndromes including hypertension, severe pulmonary complications in patients in intensive care- units, and with a specific brain tumor, glioblastoma multiforme.
  • CMV CMV
  • Available anti-CMV drugs e.g., ganciclovir (GCV), cidofovir and foscarnet, effectively inhibit virus replication by targeting the viral DNA polymerase.
  • GCV ganciclovir
  • cidofovir cidofovir
  • foscarnet available anti-CMV drugs
  • GCV ganciclovir
  • cidofovir cidofovir
  • foscarnet effectively inhibit virus replication by targeting the viral DNA polymerase.
  • GMV bone marrow toxicity
  • Foscarnet and cidofovir nephrotoxicity
  • the presently disclosed subject matter provides a method for treating a cytomegalovirus (CMV) infection in a subject in need of treatment thereof, the method comprising administering to the subject a therapeutically-effective amount of a compound selected from the group consisting of:
  • m is an integer from 0 to 3;
  • n is an integer from 0 to 4.
  • p is an integer from 1 to 2;
  • Ri is selected from the group consisting of hydrogen, substituted or unsubstituted alky 1, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl;
  • a 0 is selected from the group consisting of a halogen-substituted phenyl; substituted or unsubstituted heteroaryl; and -Si(R2) 3 , wherein each R2 is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, peril uoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl; (c)
  • n is independently an integer from 0 to 2;
  • Ri is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl, wherein Ri is optionally substituted with 1 to 5 R2 groups;
  • each R2 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl. substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -(CH 2 ) j CN, -(CH 2 ) j OR 3 ,
  • R3, R4, R5, Re. and R7 are each independently selected from the group consiting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl. or
  • R 3 , R( personally and R7 are as described above, and and R5, together with the N atom to which they are attached, form substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl, wherein R3, R4, R5, R f t, and R7 are each optionally independently substituted with 1 to 5 Rs groups; and
  • Rs is independently selected from the group consisting of halogen, hydroxy 1, cyano, nitro, alkyl, perfluoroalkyl, oxo, NH2, NH(alkyl), N(alkyl)2, O-alkyl, S-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl;
  • X i is O or S
  • a I and A 2 can be the same or different and are each independently selected from the group consisting of hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or A
  • q is an integer from 0 to 5;
  • each occurrence of R.3d is independently selected from the group consisting of hydroxyl, alkoxyl, amino, mercapto, nitro, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl; or
  • the presently disclosed subject matter provides a method for inhibiting cytomegalovirus (CMV) replication in a cell, the method comprising contacting the cell with a compound of Formula (I-V).
  • CMV cytomegalovirus
  • FIG. 1 provides representative artemisinin-derived monomers (top) and artemisinin-derived dimers (bottom) suitable for use with the presently disclosed methods;
  • FIG. 2 shows relative luciferase activity in CMV-infected HFF treated with artemisinin and three artemisinin-derived monomers
  • FIG. 3 shows the effect of artemisinin-derived monomers and artemisinin- derived dimers on luciferase expression in CMV-infected HFF;
  • FIG. 4 provides CMV copies/mL at 10 days post infection in the presence of artemisinin-derived monomers and artemisinin-derived dimers;
  • FIG. 5 shows Western blots for IE 1 , GFP and ⁇ actin in artemisinin treated CMV infected cells
  • FIG. 6 shows a comparison of CMV inhibition with artemisinin-derived monomers and artemisinin-derived dimers before infection and 90 minutes after virus inoculation.
  • FIG. 7 shows Luciferase activity in CMV infected cells treated with eight representative presently disclosed artemisinin-derived dimers
  • FIG. 8 shows a selectivity index of eight representative presently disclosed artemisinin-derived dimers.
  • the antimalarial compound sodium artesunate (FIG. 1 2d), a semisynthetic derivative of artemisinin (FIG. 1 , 1), has good tolerability, and lacks significant adverse side effects.
  • Adjuik M Babiker A, Garner P, Olliaro P, Taylor W, et al. Artesunate combinations for treatment of malaria: meta-analysis. Lancet. 2004;363:9- 17.
  • artesunate is cytotoxic to several cancer cell lines. Efferth T, Dunstan H, Sauerbrey A, Miyachi H, Chitambar CR.
  • the antimalarial artesunate is also active against cancer. Int J Oncol. 2001 ; 18:767-773.
  • Dihydroartemisinin (FIG. 1 2a, DHA), artemether (2c) and artesunate (2d) were originally prepared in China in the 1970s. These derivatives and others, including artemisone, arteether and artelinic acid, are known as monomeric artemisinins. Artemisinin dimers were later synthesized for use as a single dose therapy for malaria to improve compliance. These orally active compounds display potent antimalarial and anticancer activities. Posner GH, Paik IH, Sur S, McRiner AJ, Borstnik , et al. Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers with high stability and efficacy. J Med Chem.
  • the presently disclosed subject matter demonstrates the in-vitro anti-CMV activity of four artemisinin monomers: artemisinin (1), artesunate (2d), artemether (2c), and artefanilide (3) and representative artemisinin-derived dimers. More particularly, the presently disclosed subject matter demonstrates that, based on the concentration required for complete inhibition of CMV replication, artemisinin- derived dimers have up to 500-fold higher activity against CMV replication than the artemisinin monomers.
  • artemisinin-derived dimers are potent inhibitors of CMV replication in-vitro with no significant cytotoxicity.
  • CMV inhibition by artemisinin-derived dimers was up to 500-fold higher as compared to the four artemisinin monomers tested: artemisinin, artesunate, artemether and artefanilide.
  • the presently disclosed results were comparable using several anti-viral assays and different viral strains, including a laboratory adapted strain (Towne) and a clinical isolate.
  • CMV is an important pathogen in solid organ transplantation, Sia IG, Patel R. New strategies for prevention and therapy of cytomegalovirus infection and disease in solid-organ transplant recipients.
  • Clin Microbiol Rev. 2000; 13:83-121 in patients with AIDS, Yust I, Fox Z, Burke M, Johnson A, Turner D, et al. Retinal and extraocular cytomegalovirus end-organ disease in HIV-infected patients in Europe: a EuroSIDA study, 1994-2001 . Eur J Clin Microbiol Infect Dis. 2004;23 :550-559, and when transmitted during pregnancy from mother to fetus. Demmler GJ. Infectious Diseases Society of America and Centers for Disease Control.
  • Artesunate (2d) a semisynthetic derivative of artemisinin (1), the active compound of the Chinese herb Artemisia annua, is highly active against malaria parasites. It is available orally, has good tolerability, and lacks significant side effects.
  • Adjuik M Babiker A, Garner P, Olliaro P, Taylor W, et al. Artesunate combinations for treatment of malaria: meta-analysis. Lancet. 2004;363:9-1 7. Artesunate was first reported to inhibit CMV replication in-vitro similar to GCV. Efferth T, Marschall M, Wang X, Huong SM, Hauber 1, et al.
  • Artemisinin-derived dimers were originally synthesized to provide a single dose regimen for malaria. Although the first generation of dimers was unstable, the second-generation proved to be thermally and hydrolytically stable. Posner GH, Ploypradith P, Parker MH, O'Dowd H, Woo SH, et al. Antimalarial, antiproliferative, and antitumor activities of artemisinin-derived, chemically robust, trioxane dimers. J Med Chem. 1999;42:4275-4280. These orally active compounds display potent antimalarial and anticancer activities, Posner GH, Paik IH, Sur S, McRiner AJ, Borstnik , et al.
  • New dimeric sulfones were reported to cure malaria infected mice with a single oral dose and to be selectively and powerfully cytotoxic to cancer cells.
  • artemisinin-derived dimers are more inhibitory to CMV replication than artemisinin monomers, without associated cytotoxicity.
  • Artemisinin-derived dimers although containing only two artemisinin units, are shown herein to be much more than twice potent as anti-CMV agents than the corresponding monomeric artemisinins.
  • the antiviral activity was observed with a laboratory adapted strain and a clinical isolate of CMV. Although experience in humans with artemisinins in CMV disease is not yet available, artesunate was successfully used to treat a child with ganciclovir-resistant CMV following bone marrow transplantation.
  • the presently disclosed subject matter provides a method for treating a herpes virus, e.g., a cytomegalovirus (CMV) or an HHV8, infection in a subject in need of treatment thereof and/or inhibiting CMV replication in a cell, the method comprising administering to the subject and/or contacting a cell with a therapeutical ly-effective amount of a compound selected from the group consisting of:
  • n m is an integer from 0 to 3;
  • n is an integer from 0 to 4.
  • p is an integer from 1 to 2;
  • Ri is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl;
  • a 0 is selected from the group consisting of a halogen-substituted phenyl; substituted or unsubstituted heteroaryl; and -Si(R2)3, wherein each R2 is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl; wherein such compounds and methods of preparation thereof are disclosed in International PCT Patent Publication No. WO/2010/135427 for Trioxane Monomers and Dimers, which is
  • A is -OH or S(0) n -Ri ;
  • n is independently an integer from 0 to 2;
  • Ri is selected from the group consisting of hydrogen, substituted or unsubstituted alky 1, substituted or unsubstituted heteroalkyl, perfluoroalkyl.
  • each R2 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -(CH 2 ) j CN, -(CH 2 )jOR3,
  • R 3 , 4, R5, Re. and R7 are each independently selected from the group consiting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted heterocycloalkyi, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyi. substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl. or
  • R3, .6, and R7 are as described above, and 4 and R5, together with the N atom to which they are attached, form substituted or unsubstituted heterocycloalkyi, or substituted or unsubstituted heteroaryl, wherein R3, R4, R5, R , and R7 are each optionally independently substituted with 1 to 5 Rs groups; and
  • RR is independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, alky I, perfluoroalkyl, oxo, NH;, NH(alkyl), N(alkyl)2, O-alkyl.
  • X. is O or S
  • a I and A2 can be the same or different and are each independently selected from the group consisting of hydrogen, substituted or unsubstituted cycloalkyi, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or Aj and A 2 together form a substituted or unsubstituted biphenyl moiety; and (e)
  • q is an integer from 0 to 5;
  • each occurrence of R3d is independently selected from the group consisting of hydroxyl, alkoxyl, amino, mercapto, nitro, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyi, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl; or
  • the compound is a compound of Formula (II) and A 0 is a halogen-substituted phenyl:
  • n is an integer from 0 to 3;
  • n is an integer from 0 to 4.
  • q is an integer from 0 to 4.
  • X is halogen
  • Ria is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyi, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl; and each occurrence of R is independently selected from the group consisting of hydroxyl, alkoxyl, amino, mercapto, nitro, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstit
  • the compound of Formula (II) is selected from the group consisting of:
  • the compound is a compound of Formula (I I) and A 0 is selected from the group consisting of 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-benzothiazolyl, purinyl, 2- benzimidazolyl, 5-indolyl, 1 -isoquinolyl
  • the compound of Formula (II) is selected from the group consisting of:
  • the compound of Formula (II) is selected from the
  • the compound is a compound of Formula (II) and A 0 is -Si(R 2 ) 3 :
  • the compound of Formula (II) is selected from the group consisting of:
  • the compound of Formula (III) has the following structure:
  • the compound of Formula (III) has the following structure:
  • n is independently an integer from 0 to 2;
  • Ri is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl. substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryi, and substituted or unsubstituted heteroarylalkyl, wherein R
  • each 2 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryi, substituted or unsubstituted heteroarylalkyl, -(CH 2 ) j CN, -(CH 2 ) j OR 3 ,
  • R 3 , R4 , Rj, R f disturb and R7 are each independently selected from the group 21 onsisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalk l, or
  • R.3, Rft. and 7 are as described above, and R4 and R5, together with the N atom to which they are attached, form substituted or unsubstituted heterocycloalkyl. or substituted or unsubstituted heteroaryl, wherein R3, R4, R5, Re, and R7 are each optionally independently substituted with I to 5 Rg groups; and
  • Rs is independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, alkyl, perfluoroalkyl, oxo, NH 2 , NH(alkyl), N(alkyl) 2 , O-alkyl, S-alkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.
  • each R2 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted (Ci-C6)alkyl, substituted or unsubstituted (C i -C6)heteroalkyl, perfluoroalkyl, substituted or unsubstituted (C3- C7)cycloalkyl, substituted or unsubstituted (C3-C7)heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl.
  • substituted or unsubstituted isoquinolinyl, substituted or unsubstituted phthalazinyl, substituted or unsubstituted quinazol inyl, substituted or unsubstituted quinoxalinyl, -(CH 2 ) j CN, -(CH 2 ) j OR 3 , -( ⁇ 2 ) ⁇ ⁇ ( ⁇ 2 ),( ⁇ 3 ,
  • R , R4, R5, Re, and R7 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted (Ci-C6)alkyl, substituted or unsubstituted (Ci-C6)heteroalkyl, peril uoroalkyl, substituted or unsubstituted (C 3 - C7)cycloalkyl, substituted or unsubstituted (C 3 - C7)heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or
  • substituted or unsubstituted benzthiazolyl substituted or unsubstituted quinoiinyi, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted phthalazinyl, substituted or unsubstituted quinazolinyl, and substituted or unsubstituted quinoxalinyl, or
  • Ri, R f t. and R7 are as described above, and R4 and R5, together with the N atom to which they are attached, form substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted imidazolidiny l, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted pyrroiyl, or substituted or unsubstituted imidazolyl; and
  • each Rg is independently selected from the group consisting of halogen, hydroxyl, cyano, nitro, perfluoroalkyl, oxo, NH 2 , NH((C
  • is substituted or unsubstituted (C i -C 2 o)alkyl
  • R 2 is selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted (Ci-C6)alkyl, substituted or unsubstituted (C
  • is substituted or unsubstituted (Ci-C o)alkyl; and each R 2 is independently selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, substituted or unsubstituted pyrroiyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl,
  • substituted or unsubstituted pyrazinyl substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted benzothienyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzoisooxazolyl, substituted or unsubstituted benzthiazolyl, substituted or unsubstituted quinol inyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted phthalazinyl, substituted or unsubstituted quinazolinyl, and substituted or unsubstituted quinoxalinyl.
  • Ri is substituted or unsubstituted (Ci-C2o)alkyl; and each R 2 is independently selected from the group consisting of -(CH 2 )jCN,
  • each R is independently selected from the group consisting of -(CH 2 )jOR , -(CH2)qO(CH 2 ) j OR 3 , -(CH 2 ) q O(CH 2 ) t O(CH 2 ) j OR 3 , and -(CH 2 ) (
  • R 3 is hydrogen.
  • R ⁇ is substituted or unsubstituted phenyl; and each R 2 is independently selected from the group consisting of hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted (C i-C6)alkyl, substituted or unsubstituted (C
  • each R 2 is independently selected from the group consisting of substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl.
  • Ri is substituted or unsubstituted phenyl; and each R2 is independently selected from the group consisting of -(CH2.) j CN, -(CH2/JOR3,
  • each R 2 is independently selected from the group consisting of -(CH 2 ) j OR 3 . -(CH 2 ) q O(CH2) j OR 3 , -(CH 2 ) q O(CH 2 ),0(CH 2 )jOR 3 , and -(CH 2 ) q O(CH2),0(CH2) l ,0(CH2) j OR 3 .
  • R 3 is hydrogen;
  • R4 and R5 are (Ci -C6)alk l; and
  • R 7 is (Ci-Ce ' jalk l or phenyl.
  • each R2 is independently selected from the group consisting of -(CH2) j OR 3 ;
  • R 3 is arylalkyl; and Rg is halogen.
  • the compound has the following chemical structure:
  • the compound is a compound of Formula (IV), wherein Ai and A2 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, l -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2- imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazoIyl, 5- oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2- pyrimidyl, 4- pyrimid
  • and A2 are each independently substituted or unsubstituted phenyl or A
  • each q is independently an integer from 0 to 5, provided that at least one occurrence of q is not 0;
  • the dashed line is a bond that can be present or absent; and each occurrence of R3 is independently selected from the group consisting of hydroxyl, alkoxyl, amino, mercapto, nitro, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroaryl alkyl.
  • R3 is halogen or alkyl.
  • and A2 together form a biphenyl moiety.
  • the compound of Formula (IV) is selected from the group consisting of:
  • the compound is a compound of Formula (V), and the compound of Formula (V) is selected from the group consisting of
  • the treating comprises a prophylactic treatment.
  • the presently disclosed subject matter provides a compound of Fo
  • a I and A2 can be the same or different and are each independently selected from the group consisting of hydrogen, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, or Ai and A2 together form a substituted or unsubstituted biphenyl moiety;
  • and A2 are each independently selected from the group consisting of substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4- imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3- furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-ind
  • Ai and A2 are each independently substituted or unsubstituted phenyl or A i and A2 together form a substituted or unsubstituted biphenyl moiety and the compound of Formula (IV) has the following chemical structure:
  • each q is independently an integer from 0 to 5, provided that at least one occurrence of q is not 0;
  • the dashed line is a bond that can be present or absent; and each occurrence of R3 is independently selected from the group consisting of hydroxy!, alkoxyl, amino, mercapto, nitro, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl.
  • R3 is halogen or alkyl. In other embodiments, A2 together form a biphenyl moiety.
  • the compound of Formula (IV) is selected from the group consisting of:
  • the presently disclosed subject matter also includes metabolites, e.g., mono- and or bis-hydrolysis products of compounds of Formula (IV).
  • metabolites e.g., mono- and or bis-hydrolysis products of compounds of Formula (IV).
  • or A2, or both, are hydrogen.
  • the compounds of Formula (IV) can be prepared as a salt, e.g., any pharmaceutically acceptable salt as provided hereinbelow, wherein either A
  • q is an integer from 0 to 5;
  • each occurrence of R3 is independently selected from the group consisting of hydroxyl, alkoxyl, amino, mercapto, nitro, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkenyl, alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroarylalkyl; or
  • the compound of Formula (V) is selected from the group consisting of:
  • the presently disclosed subject matter provides a pharmaceutical composition including one or more presently disclosed artemisinin- derived monomers or artemisinin-derived dimers alone or in combination with one or more additional therapeutic agents in admixture with a pharmaceutically acceptable excipient.
  • a pharmaceutically acceptable excipient include the pharmaceutically acceptable salts of the compounds described above.
  • the compounds of the disclosure can be formulated for a variety of modes of administration, including systemic and topical or localized administration. Techniques and formulations generally may be found in Remington: The Science and Practice of Pharmacy (20 th ed.) Lippincott, Williams & Wilkins (2000).
  • the compounds according to the disclosure are effective over a wide dosage range.
  • dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
  • a non-limiting dosage is 10 to 30 mg per day.
  • the exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • salts are generally well known to those of ordinary skill in the art, and may include, by way of example but not limitation, acetate, benzenesulfonate, besylate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, carnsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, steacetate
  • salts may be found in, for example, Remington: The Science and Practice of Pharmacy (20 lh ed.) Lippincott, Williams & Wilkins (2000).
  • Pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate, mesylate, napsylate, pamoate (embonate), phosphate, salicylate, succinate, sulfate, or tartrate.
  • agents may be formulated into liquid or solid dosage forms and administered systemically or locally.
  • the agents may be delivered, for example, in a timed- or sustained- low release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20 th ed.) Lippincott, Williams & Wilkins (2000).
  • Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra-articullar, intra -sternal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery.
  • the agents of the disclosure may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • compositions of the present disclosure in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection.
  • the compounds can be formulated readily using
  • Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject (e.g., patient) to be treated.
  • the agents of the disclosure also may be formulated by methods known to those of skill in the art, and may include, for example, but not limited to, examples of solubilizing, diluting, or dispersing substances such as, saline, preservatives, such as benzyl alcohol, absorption promoters, and fluorocarbons.
  • compositions suitable for use in the present disclosure include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
  • compositions for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium
  • CMC carboxymethyl-cellulose
  • PVP polyvinylpyrrolidone
  • polyvinylpyrrolidone agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dye- stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs).
  • PEGs liquid polyethylene glycols
  • stabilizers may be added.
  • R groups such as groups Ri , R2, and the like, or variables, such as "m” and “n"
  • substituents being referred to can be identical or different.
  • Ri and R 2 can be substituted alkyls, or Ri can be hydrogen and R 2 can be a substituted alkyl, and the like.
  • a when used in reference to a group of substituents herein, mean at least one.
  • a compound is substituted with “an” alkyl or aryl, the compound is optionally substituted with at least one alkyl and/or at least one aryl.
  • R substituent the group may be referred to as "R-substituted.”
  • R- substituted the moiety is substituted with at least one R substituent and each R substituent is optionally different.
  • R or group will generally have the structure that is recognized in the art as corresponding to a group having that name, unless specified otherwise herein.
  • certain representative “R” groups as set forth above are defined below.
  • hydrocarbon refers to any chemical group comprising hydrogen and carbon.
  • the hydrocarbon may be substituted or unsubstituted. As would be known to one skilled in this art, all valencies must be satisfied in making any substitutions.
  • the hydrocarbon may be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic.
  • Illustrative hydrocarbons are further defined herein below and include, for example, methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, ally 1, vinyl, n-butyl, tert-butyl, ethynyl, cyclohexyl, methoxy, diethylamino, and the like.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched chain, acyclic or cyclic hydrocarbon group, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent groups, having the number of carbon atoms designated (i.e., Ci-Cio means one to ten carbons).
  • alkyl refers to C1.20 inclusive, linear (i.e., “straight-chain”), branched, or cyclic, saturated or at least partially and in some cases fully unsaturated (i.e., alkenyl and alkynyl) hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom.
  • saturated hydrocarbon groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, iso-pentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl, n-octyl, n-decyl, n- undecyl, dodecyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, and homologs and isomers thereof.
  • Branched refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain.
  • Lower alkyl refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C ⁇ .s alkyl), e.g., 1 , 2, 3, 4, 5, 6, 7, or 8 carbon atoms.
  • Higher alkyl refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 1 1 , 12, 1 3, 14, 15, 16, 17, 1 8, 19, or 20 carbon atoms.
  • alkyl refers, in particular, to C
  • alkyl refers, in particular, to Ci.8 branched-chain alkyls.
  • Alkyl groups can optionally be substituted (a "substituted alkyl") with one or more alkyl group substituents, which can be the same or different.
  • alkyl group substituent includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl.
  • alkyl chain There can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as "alkylaminoalkyl”), or aryl.
  • substituted alkyl includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon group, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized.
  • the heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule.
  • Examples include, but are not limited to, -CH 2 -CH 2 -0-CH 3> -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 - N(CH 3 )-CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 25 -S(0)-CH 3 , -CH 2 -CH 2 -S(0) 2 -CH 3 , -
  • Up to two or three heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and -CH 2 -0-Si(CH 3 ) 3 .
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as - C(0)R ⁇ - C(0)NR ⁇ -NR'R", -OR', -SR, and/or -S0 2 R ⁇
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R or the like, it will be understood that, the terms heteroalkyl and -NR' R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
  • Cyclic and “cycloalkyl” refer to a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms, e.g., 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
  • the cycloalkyl group can be optionally partially unsaturated.
  • the cycloalkyl group also can be optionally substituted with an alkyl group substituent as defined herein, oxo, and/or alkylene.
  • cyclic alkyl chain There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl, thus providing a heterocyclic group.
  • Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl.
  • Multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl, and fused ring systems, such as dihydro- and
  • cycloalkylalkyl refers to a cycloalkyl group as defined hereinabove, which is attached to the parent molecular moiety through an alkyl group, also as defined above.
  • alkyl group also as defined above.
  • examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.
  • cycloheteroalkyl or “heterocycloalkyl” refer to a non-aromatic ring system, unsaturated or partially unsaturated ring system, such as a 3- to 10- member substituted or unsubstituted cycloalkyl ring system, including one or more heteroatoms, which can be the same or different, and are selected from the group consisting of nitrogen ( ), oxygen (O), sulfur (S), phosphorus (P), and silicon (Si), and optionally can include one or more double bonds.
  • the cycloheteroalkyl ring can be optionally fused to or otherwise attached to other cycloheteroalkyl rings and/or non-aromatic hydrocarbon rings.
  • Heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • heterocylic refers to a non-aromatic 5-, 6-, or 7- membered ring or a polycyclic group wherein at least one ring atom is a heteroatom selected from O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), including, but not limited to, a bi- or tri-cyclic group, comprising fused six-membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7- membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring.
  • Representative cycloheteroalkyl ring systems include, but are not limited to pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, quinuclidinyl, morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, and the like.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1 -(1 ,2,5,6- tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2- l, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
  • the terms are not limited to, 1 -(1 ,2,5,6- tetrahydropyridyl), 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2- l
  • cycloalkylene and “heterocycloalkylene” refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2- propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1 - and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • Alkyl groups which are limited to hydrocarbon groups are termed "homoalkyl.”
  • alkenyl refers to a monovalent group derived from a Ci-20 inclusive straight or branched hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • Alkenyl groups include, for example, ethenyl (i.e., vinyl), propenyl, butenyl, 1 - methyl-2-buten- l -yl, pentenyl, hexenyl, octenyl, and butadienyl.
  • cycloalkenyl refers to a cyclic hydrocarbon containing at least one carbon-carbon double bond.
  • Examples of cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1 ,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.
  • alkynyl refers to a monovalent group derived from a straight or branched C1.2 0 hydrocarbon of a designed number of carbon atoms containing at least one carbon-carbon triple bond.
  • alkynyl include ethynyl, 2-propynyl (propargyl), 1 -propynyl, pentynyl, hexynyl, heptynyl, and allenyl groups, and the like.
  • alkylene by itself or a part of another substituent refers to a straight or branched bivalent aliphatic hydrocarbon group derived from an alkyl group having from 1 to about 20 carbon atoms, e.g., 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms.
  • the alkylene group can be straight, branched or cyclic.
  • the alkylene group also can be optionally unsaturated and/or substituted with one or more "alkyl group substituents.” There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as "alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described.
  • alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (- CH2)3 ⁇ );
  • An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbons. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being some embodiments of the present disclosure.
  • a "lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • heteroalkylene by itself or as part of another substituent means a divalent group derived from heteroalkyl, as exemplified, but not limited by, -CH2- CH2-S- CH 2 -CH2- and -CH2-S-CH2-CH2-NH-CH2-.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like).
  • no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(0)OR'- represents both -C(0)OR'- and -R'OC(O)-.
  • aryl means, unless otherwise stated, an aromatic hydrocarbon substituent that can be a single ring or multiple rings (such as from 1 to 3 rings), which are fused together or linked covalently.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms (in each separate ring in the case of multiple rings) selected from N, O, and S, wherein the nitrogen and sulfur ⁇
  • aryl and heteroaryl groups include phenyl, 1 - naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2- imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5- oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-
  • arylene and heteroarylene refer to the divalent forms of aryl and heteroaryl, respectively.
  • aryl when used in combination with other terms (e.g., aryloxo ⁇ arylthioxo, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl and heteroarylalkyl are meant to include those groups in which an aryl or heteroaryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl, and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
  • haloaryl as used herein is meant to cover only aryls substituted with one or more halogens.
  • heteroalkyl where a heteroalkyl, heterocycloalkyl, or heteroaryl includes a specific number of members (e.g. "3 to 7 membered"), the term “member” refers to a carbon or heteroatom.
  • a ring structure for example, but not limited to a 3-carbon, a 4-carbon, a 5-carbon, a 6-carbon, a 7-carbon, and the like, aliphatic and/or aromatic cyclic compound, including a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure, comprising a substituent R group, wherein the R group can be present or absent, and when present, one or more R groups can each be substituted on one or more available carbon atoms of the ring structure.
  • R group can be present or absent, and when present, one or more R groups can each be substituted on one or more available carbon atoms of the ring structure.
  • the presence or absence of the R group and number of R groups is determined by the value of the variable "n," which is an integer generally having a value ranging from 0 to the number of carbon atoms on the ring available for substitution.
  • n is an integer generally having a value ranging from 0 to the number of carbon atoms on the ring available
  • a dashed line representing a bond in a cyclic ring structure indicates that the bond can be either present or absent in the ring. That is, a dashed line representing a bond in a cyclic ring structure indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.
  • heterocycloalkyl aryl
  • heteroaryl aryl
  • phosphonate and “sulfonate” as well as their divalent derivatives
  • divalent derivatives are meant to include both substituted and unsubstituted forms of the indicated group.
  • Optional substituents for each type of group are provided below.
  • R', R", R'" and R" each may independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1 -3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl ⁇ groups.
  • an "alkoxy" group is an alkyl attached to the remainder of the molecule through a divalent oxygen.
  • each of the R groups is independently selected as are each R', R", R'" and R"" groups when more than one of these groups is present.
  • R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring.
  • -NR'R is meant to include, but not be limited to, 1 - pyrrolidinyl and 4- morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and - CH 2 CF 3 ) and acyl (e.g., -C(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 OCH 3 , and the like).
  • haloalkyl e.g., -CF3 and - CH 2 CF 3
  • acyl e.g., -C(0)CH 3 , -C(0)CF 3 , -C(0)CH 2 OCH 3 , and the like.
  • Two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally form a ring of the formula -T-C(0)-(CRR') q -U-, wherein T and U are independently -NR-, -0-, -CRR'- or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2) r -B-, wherein A and B are independently -CRR'-, -0-, -NR-, -S-, -S(O)-, -S(0) 2 -, -S(0) 2 NR'- or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR')s-X'- (C"R"')d-, where s and d are independently integers of from 0 to 3, and X' is -0-, -NR'-, -S-, -S(O)-, -S(0) 2 -, or -S(0) 2 NR'-.
  • R, R', R" and R' may be independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • R is an alkyl, alkenyl, alkynyl, aryl, carbocylic, heterocyclic, or aromatic heterocyclic group as defined herein).
  • acyl specifically includes arylacyl groups, such as an acetylfuran and a phenacyl group. Specific examples of acyl groups include acetyl and benzoyl.
  • alkoxyl or “alkoxy” are used interchangeably herein and refer to a saturated (i.e., alkyl-O-) or unsaturated (i.e., alkenyl-O- and alkynyl-O-) group attached to the parent molecular moiety through an oxygen atom, wherein the terms “alkyl,” “alkenyl,” and “alkynyl” are as previously described and can include C 1 .2 0 inclusive, linear, branched, or cyclic, saturated or unsaturated oxo-hydrocarbon chains, including, for example, methoxyl, ethoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, t-butoxyl, and n-pentoxyl, neopentoxy, n-hexoxy, and the like.
  • alkoxyalkyl refers to an alkyl-O-alkyl ether, for example, a methoxyethyl or an ethoxymethyl group.
  • Aryloxyl refers to an aryl-O- group wherein the aryl group is as previously described, including a substituted aryl.
  • aryloxyl as used herein can refer to phenyloxyl or hexyloxyl, and alkyl, substituted alky 1, halo, or alkoxyl substituted phenyloxyl or hexyloxyl.
  • Alkyl refers to an aryl-alkyl-group wherein aryl and alkyl are as previously described, and included substituted aryl and substituted alkyl.
  • exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl.
  • Alkyloxyl refers to an aralkyl-O- group wherein the aralkyl group is as previously described.
  • An exemplary aralkyloxyl group is benzyloxyl.
  • Alkoxycarbonyl refers to an alkyl-O-CO- group.
  • alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, and t-butyloxycarbonyl.
  • Aryloxycarbonyl refers to an aryl-O-CO- group.
  • aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl.
  • Alkoxycarbonyl refers to an aralkyl-O-CO- group.
  • An exemplary aralkoxycarbonyl group is benzyloxycarbonyl.
  • Carbamoyl refers to an amide group of the formula -CONH2.
  • AlkylcarbamoyI refers to a R'RN-CO- group wherein one of R and R' is hydrogen and the other of R and R' is alkyl and/or substituted alkyl as previously described.
  • Dialkylcarbamoyl refers to a R' RN-CO- group wherein each of R and R' is independently alkyl and/or substituted alkyl as previously described.
  • carbonyldioxyl refers to a carbonate group of the formula -O— CO— OR.
  • acyloxyl refers to an acyl-O- group wherein acyl is as previously described.
  • amino refers to the -NH2 group and also refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic radicals.
  • amino refers to the -NH2 group and also refers to a nitrogen containing group as is known in the art derived from ammonia by the replacement of one or more hydrogen radicals by organic radicals.
  • acylamino and alkylamino refer to specific N-substituted organic radicals with acyl and alkyl substituent groups respectively.
  • An “aminoalkyl” as used herein refers to an amino group covalently bound to an alkylene linker. More particularly, the terms alkylamino, dialkylamino, and trialkylamino as used herein refer to one, two, or three, respectively, alkyl groups, as previously defined, attached to the parent molecular moiety through a nitrogen atom.
  • alkylamino refers to a group having the structure -NH ' wherein R' is an alkyl group, as previously defined; whereas the term dialkylamino refers to a group having the structure -NR' R", wherein R' and R" are each independently selected from the group consisting of alkyl groups.
  • dialkylamino refers to a group having the structure -NR' R", wherein R' and R" are each independently selected from the group consisting of alkyl groups.
  • trialkylamino refers to a group having the structure -NR'R"R"', wherein R', R", and R'" are each independently selected from the group consisting of alkyl groups.
  • R', R", and/or R'" taken together may optionally be -(CH 2 ) k - where k is an integer from 2 to 6.
  • Examples include, but are not limited to, methylamino, dimethylamino, ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, iso-propylamino, piperidino, trimethylamino, and propylamino.
  • the amino group is -NR'R", wherein R' and R" are typically selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • alkylthioether and thioalkoxyl refer to a saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl-S- and alkynyl-S-) group attached to the parent molecular moiety through a sulfur atom.
  • thioalkoxyl moieties include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, and the like.
  • Acylamino refers to an acyl-NH- group wherein acyl is as previously described.
  • “Aroylamino” refers to an aroyl-NH- group wherein aroyl is as previously described.
  • Carboxyl refers to the -COOH group. Such groups also are referred to herein as a “carboxylic acid” moiety.
  • halo refers to fluoro, chloro, bromo, and iodo groups. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(Ci-C4)alkyl is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4- ch!orobutyl, 3-bromopropyl, and the like.
  • hydroxyl refers to the -OH group.
  • hydroxyalkyl refers to an alkyl group substituted with an -OH group.
  • mercapto refers to the -SH group.
  • oxo as used herein means an oxygen atom that is double bonded to a carbon atom or to another element.
  • nitro refers to the -NO2 group.
  • thio refers to a compound described previously herein wherein a carbon or oxygen atom is replaced by a sulfur atom.
  • thiohydroxyl or thiol refers to a group of the formula
  • ureido refers to a urea group of the formula -NH— CO— H2.
  • a "substituent group,” as used herein, includes a functional group selected from one or more of the following moieties, which are defined herein:
  • a “lower substituent” or “lower substituent group,” as used herein means a group selected from all of the substituents described hereinabove for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C ⁇ -Cg alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C5- C7 cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 5 to 7 membered heterocycloalkyl.
  • a “size-limited substituent” or “size-limited substituent group,” as used herein means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted Gt-Cs cycloalkyl, and each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 4 to 8 membered heterocycloalkyl.
  • Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure do not include those which are known in art to be too unstable to synthesize and/or isolate.
  • the present disclosure is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefenic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
  • tautomer refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or l4 C-enriched carbon are within the scope of this disclosure.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon- 14 ( l4 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • the term "monomer” refers to a molecule that can undergo polymerization, thereby contributing constitutional units to the essential structure of a macromolecule or polymer.
  • a "polymer” is a molecule of high relative molecule mass, the structure of which essentially comprises the multiple repetition of unit derived from molecules of low relative molecular mass, i.e., a monomer.
  • an "oligomer” includes a few monomer units, for example, in contrast to a polymer that potentially can comprise an unlimited number of monomers. Dimers, trimers, and tetramers are non-limiting examples of oligomers.
  • the compounds of the present disclosure may exist as salts.
  • the present disclosure includes such salts.
  • Examples of applicable salt forms include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates (e.g. (+)- tartrates, (-)-tartrates or mixtures thereof including racemic mixtures, succinates, benzoates and salts with amino acids such as glutamic acid.
  • These salts may be prepared by methods known to those skilled in art.
  • base addition salts such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like.
  • Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.
  • salts are meant to include salts of active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituent moieties found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like ⁇ see, for example, Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1 - 19).
  • Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the present disclosure provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure.
  • prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • protecting group refers to chemical moieties that block some or all reactive moieties of a compound and prevent such moieties from participating in chemical reactions until the protective group is removed, for example, those moieties listed and described in T. W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd ed. John Wiley & Sons (1999). It may be advantageous, where different protecting groups are employed, that each (different) protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions allow differential removal of such protecting groups. For example, protective groups can be removed by acid, base, and hydrogenolysis.
  • Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • Carboxylic acid and hydroxy reactive moieties may be blocked with base labile groups such as, without limitation, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as tert-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable.
  • Carboxylic acid and hydroxy reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc.
  • Carboxylic acid reactive moieties may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while coexisting amino groups may be blocked with fluoride labile silyl carbamates.
  • Ally] blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and can be subsequently removed by metal or pi- acid catalysts.
  • an allyl-blocked carboxylic acid can be deprotected with a pal!adium(O)- catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups.
  • Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
  • Typical blocking/protecting groups include, but are not limited to the following moieties:
  • a subject treated by the presently disclosed methods in their many embodiments is desirably a human subject, although it is to be understood that the methods described herein are effective with respect to all vertebrate species, which are intended to be included in the term "subject.”
  • a "subject" can include a human subject for medical purposes, such as for the treatment of an existing condition or disease or the prophylactic treatment for preventing the onset of a condition or disease, or an animal subject for medical, veterinary purposes, or developmental purposes.
  • Suitable animal subjects include mammals including, but not limited to, primates, e.g., humans, monkeys, apes, and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; caprines, e.g., goats and the like; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, zebras, and the like; felines, including wild and domestic cats; canines, including dogs;
  • an animal may be a transgenic animal.
  • the subject is a human including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects.
  • a "subject” can include a patient afflicted with or suspected of being afflicted with a condition or disease.
  • the terms “subject” and “patient” are used interchangeably herein.
  • Effective amount In general, the “effective amount” of an active agent or drug delivery device refers to the amount necessary to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of an agent or device may vary depending on such factors as the desired biological endpoint, the agent to be delivered, the composition of the encapsulating matrix, the target tissue, and the like.
  • the term "about,” when referring to a value can be meant to encompass variations of, in some embodiments, ⁇ 100% in some embodiments ⁇ 50%, in some embodiments ⁇ 20%, in some embodiments ⁇ 10%, in some embodiments ⁇ 5%, in some embodiments ⁇ 1 %, in some embodiments ⁇ 0.5%, and in some embodiments ⁇ 0.1 % from the specified amount, as such variations are appropriate to perform the disclosed methods or employ the disclosed compositions. .
  • HFF Human Foreskin Fibroblasts
  • HEL human lung fibroblasts
  • the CMV strains used for infections were the highly-passaged Towne virus, and a clinical isolate obtained from the urine of a neonate with congenital CMV infection (SB) and passaged once in tissue culture. Experiments were performed with multiplicity of infection (MOI) of 0.1 , 0.5, 1 , and 3.
  • MOI multiplicity of infection
  • Marchini A Liu H, Zhu H. Human cytomegalovirus with IE-2 (UL l 22) deleted fails to express early lytic genes. J Virol. 2001 ;75: 1870-1878.
  • luciferase reporter system Based on pilot experiments using Towne-GFP, a more sensitive luciferase reporter system was selected to evaluate potential differences in CMV inhibition by various artemisinin derivatives.
  • a recombinant virus expressing luciferase reporter gene under the control of UL99 (pp28) late promoter was generated by insertion of the reporter gene between the US9 and US 10 ORFs in the Towne genome.
  • This extragenic reporter gene displays authentic late transcription characteristics after infection of HFF. Ahn JH, Hay ward GS. Disruption of PML-associated nuclear bodies by IE 1 correlates with efficient early stages of viral gene expression and DNA replication in human cytomegalovirus infection. Virology. 2000;274:39-55.
  • Pp28 - luciferase expression is strongly activated at 48-72 hours and is almost completely inhibited in the presence of DNA synthesis inhibitors (GCV).
  • HFF or HEL were grown to subconfluent monolayers and infected with the CMV viruses at MOI 0.1 to 3. Based on previously reported methods, cells were treated with artemisinin derivatives at various concentrations and infected with CMV 30 min thereafter. Efferth T, Marschall M, Wang X, Huong SM, Hauber I, et al. Antiviral activity of artesunate towards wild-type, recombinant, and ganciclovir-resistant human cytomegaloviruses. JMol Med. 2002;80:233-242. The concentration of each compound was calculated and adjusted by volume such that it was constant throughout the experiment.
  • luciferase assay Wizard® SV Lysis Buffer (Promega, Madison, WI) was added to each well, incubated for 10 minutes at 37°C, followed by 10 minutes of freezing at -80°C and incubation at 37°C for 10 minutes. Luciferase activity was determined in cell extracts using an automated luminescent assay (Promega, Madison, WI). The dynamic range of the luciferase assay is 6-7 logs, and data obtained with it highly correlates with real-time PC and with plaque reduction assay (manuscript in preparation). Cellular cytotoxicity was determined using CellTiter-Glo®
  • Luminescent Cell Viability Assay Promega, Madison, WI. The assay determines the number of viable cells in culture based on quantification of the ATP present.
  • plaque reduction assay human embryonic lung cells were seeded into six- well plates and incubated at 37°C one day prior to infection with the recombinant luciferase-expressing CMV. Serial dilutions of GCV, artesunate and artefanilide were used. The virus was diluted to a desired concentration which gave 50-60 plaques per well. Medium was aspirated from the wells, and 0.2 ml of virus suspension was added to each well in triplicates. Plates were incubated for 90 minutes with shaking every 10 min, thereafter drugs were added and a methylcellulose overlay applied to each well. After incubation for 10 days, cells were stained with crystal violet. The stain was aspirated, wells were washed with phosphate-buffered saline, and plaques were counted.
  • Monoclonal antibodies to CMV immediate early proteins IE- 1 and IE-2 (MAb810) and to cellular ⁇ -actin were purchased from Millipore (Billerica, MA). Confluent cells were infected with CMV in the presence of artemisinin compounds. At the indicated times cells were harvested in sample buffer (RIPA buffer, Tris 50 mM, Nacl 150 mM, SDS 0.1 %, Na Deoxycholate 0.5%, NP40 1 %, and protease inhibitor cocktail), boiled and loaded onto SDS-PAGE. Proteins were separated by electrophoresis . and transferred to nitrocellulose membrane.
  • sample buffer Tris 50 mM, Nacl 150 mM, SDS 0.1 %, Na Deoxycholate 0.5%, NP40 1 %, and protease inhibitor cocktail
  • GCGTGCTTTTTAGCCTCTGCA-3 ' reverse 5'- AAAAGTTTGTGCCCCAACGGTA-3 ' and US 17 probe FAM- 5' TGA TCGGGCGTTA TCGCGTTCT-3 '.
  • the limit of detection is 10 copies/reaction ( 100 copies/mL) and the dynamic range of the assay is 2.4-8.0 logioCopies/mL.
  • Ganciclovir was obtained from Roche, USA and stock was prepared in aqueous solution.
  • Artemisinin (1) was obtained from Sigma-Aldrich.
  • Artesunate (2d), artemether (2C), artefanilde (3), dimer primary alcohol (4) and dimer sulfone dimethyl carbamate (6) were synthesized at Johns Hopkins University (GHP).
  • HFF human foreskin fibroblasts
  • the four monomers, artemisinin, artesunate, artemether and artefanilide (FIG. 1 ), were tested first for CMV inhibition in comparison with GCV. These monomers exhibited a similar degree of anti-CMV activity. At 10 ⁇ , ganciclovir (GCV) was more potent in CMV inhibition than all four monomers (FIG. 2). Similar results were obtained by a plaque reduction assay performed in human embryonic lung cells (HEL) with the same luciferase virus; at 10 ⁇ , monomers achieved 40-50% reduction in plaque formation, while GCV reached 80% reduction in plaque formation.
  • HEL human embryonic lung cells
  • the selectivity index (SI) of all artemisinin derivatives and GCV was calculated based on the effective drug concentration that results in 50% virus inhibition, EC 50 , and the drug concentration that leads to 50% cellular cytotoxicity,
  • CC50 (Table 1 ). SI was determined as the ratio between CC50 and EC50. For EC50 and CC50 reported values represent the mean and SD of data derived from at least five independent experiments performed in triplicates.
  • the concentrations of monomers used for calculating EC50 were 1 , 5, 10, 25, 50, and 100 ⁇ .
  • the concentrations of dimers used for EC50 calculations were 1 nM, 10 nM, 100 nM, 250 nM, 1 ⁇ and 10 ⁇ .
  • the curve fitting toolbox, Matlab software (v7.5), Mathworks (Natick, MA) was used to determine EC50 values using a four-parameter logistic regression.
  • GCV was approximately 10 times more selective than the monomers.
  • the dimer sulfone carbamate (6) had the highest selectivity, approximately 10 times more than GCV (Table 1 ).
  • CMV immediate early (IE) protein was tested by western blot to determine whether artemisinins' inhibition of CMV replication occurs early in the virus life cycle.
  • IE 1 immediate early 1
  • GFP immediate early 1
  • MOI artemisinin
  • FIG. 5a Further evidence for the early effect of artemisinins on IE1 protein expression was obtained with the clinical isolate (SB, FIG. 5b).
  • Stinski MF Sequence of protein synthesis in cells infected by human cytomegalovirus: early and late virus-induced polypeptides. J Virol. 1978;26:686-701 .
  • the enhancer of the MIE regulatory region consists of multiple different binding sites for cellular transcription factors (TF) that are repeated several times in its distal and proximal components. Multiple pathways are utilized by CMV for regulation of TF necessary for maintenance of the viral life cycle. Dimers may affect several pathways at different times during CMV replication, resulting in abortive CMV replication. Transactivation of the MIE following infection is required for generation of the major IE transcripts, viral replication and production of infectious virus. The MIE responds to signal transduction events and to cellular differentiation, and regulates the expression of the downstream MIE genes IE 1 (UL 123) and 1 E2 (UL 122].
  • NF-kB plays a critical role in the efficient transactivation of MIE, but the CRES site in the proximal enhancer also was reported to have the greatest independent effect on viral replication in different cell types.
  • MAPKs phosphorylate and activate CREB which facilitates an interaction with the CREB binding protein (CBP).
  • CBP CREB binding protein
  • CSP interacts with other TF such as API, NF-kB, and Spl .
  • CMV induces an increase in Sp-I DNA binding activity and its replication is greatly diminished with deletion of one or two Sp-1 sites.
  • Sp- I interacts with other Tf.
  • Spl is phosphorylated by various kinases at different sites within the protein. These include cyclin dependent kinase (CD K), atypical protein kinase C-s, extracellular signal regulated kinase (ERK), case in kinase II, and DNA-dependent protein kinase.
  • CD K cyclin dependent kinase
  • ERK extracellular signal regulated kinase
  • Spl phosphorylation can both positively and negatively influence transcriptional activity, for example, native Sp-I activates
  • FGF-2 fibroblast growth factor
  • the presently disclosed dimers were tested against Herpes simplex virus 1 (HSV 1 ) and Herpes simplex virus 2 (HSV2) and exhibited no activity at concentrations of 100 nM, 1 ⁇ , and 10 ⁇ .
  • the presently disclosed dimers were tested against HHV8, the virus that causes Kaposi sarcoma herpes virus (KSHV), and at 100 nM exhibited a strong inhibition of latency (expression of latency-associated nuclear antigen (LANA)), but exhibited no apparent effect on lytic replication.
  • KSHV Kaposi sarcoma herpes virus
  • Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker Avance 400 MHz FT-NMR spectrometer (400 MHz for ⁇ , 100 MHz for l 3 C). The following abbreviations are used in the experimental section for the description of ⁇ NMR spectra: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad singlet (bs), doublet of doublets (dd), doublet of triplets (dt), and doublet of quartets (dq).
  • High resolution mass spectral data was collected at the NIH Chemical Genomics Center using and Agilent 6210 time-of-flight mass spectrometer, also coupled to an Agilent Technologies 1200 series HPLC system.
  • diaryl phosphorochloridates or diaryl phosphorochloridothioates 3 may be prepared by heating phenols 5 with phosphorus oxychloride or
  • 2,6-dimethylphenol 1 g, 8.18 mmol
  • aluminum trichloride 109 mg, 0.818 mmol, 0.1 eq
  • Phosphorus oxychloride 0.375 mL, 4.09 mmol, 0.5 eq
  • the reaction mixture was diluted with dicholoromethane, washed with water and brine, dried over MgSC , and filtered through celite. The filtrate was concentrated under reduced pressure providing an oily residue that was taken directly to the next step without further purification.
  • Tricyclohexyl phosphite 23 (2.3g, 7.0 mmol, 1 .0 eq) and 1 ,3- dimethylimidazolidin-2-one (24 mg, 0.21 mmol, 0.13 eq) and dichloromethane (30 mL) were added to a round bottom flask, and the stirring solution was cooled to 0 °C in an ice bath.
  • dimer oxime 28 is prepared in two steps from isobutylene dimer
  • dimer ketone 27 which can be prepared according to the procedure described in J. Med. Chem,. 2003, 46, 1060-1065. Synthesis of dimer oxime (28)
  • Dimer ketone 27 ( 1 10 mg, 0.1 86 mmol, 1 .0 eq), hydroxylamine hydrochloride (64.7 mg, 0.931 mmol, 5.0 eq) and pyridine (5 mL) were added to a round bottom flask. The reaction mixture was stirred at rt for 1 h, at which point the reaction was deemed complete by TLC. The reaction mixture was diluted with dichloromethane and washed with 10% aq. citric acid. The organic layer was dried over MgSO ⁇ , filtered, and the solvent was removed under reduced pressure. The residue was purified directly on silica.
  • dimer oxime 28 as a colorless, amorphous solid: yield (94 mg, 0.1 55 mmol, 84%); ⁇ NMR (400 MHz, CDC1 3 ) ⁇ 8.53 (bs, 1 H), 5.49 (s, 1 H), 5.43 (s, 1 H), 4.29 - 4.
  • dimer oxime 28 (20 mg, 0.04 mmol, 1 .0 eq)
  • phenyl isocyanate (8 mg, 0.066 mmol, 2.0 eq)
  • dichloromethane (2 mL).
  • the reaction mixture was allowed to stir for 2 h.
  • the reaction mixture was concentrated under reduced pressure, and the residue was purified directly on silica.
  • Stinski MF Sequence of protein synthesis in cells infected by human cytomegalovirus: early and late virus-induced polypeptides. J Virol. 1978;26:686- 701.
  • Sia IG Patel R. New strategies for prevention and therapy of cytomegalovirus infection and disease in solid-organ transplant recipients. Clin Microbiol Rev.
  • Maribavir prophylaxis for prevention of cytomegalovirus infection in allogeneic stem cell transplant recipients a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study. Blood. 2008; 1 1 1 :5403-5410.

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Abstract

L'invention concerne des monomères dérivés de l'artémisinine et des dimères d'artémisinine qui sont démontrés pour faire preuve d'activité anti-cytomégalovirus (CMV) in vitro. Les dimères d'artémisinine inhibent de manière efficace la réplication des CMV dans les fibroblastes de prépuce humain et dans les fibroblastes du poumon embryonnaire humain sans cytotoxicité aux concentrations requises pour l'inhibition complète des CMV. Les dimères d'artémisinine se sont avérés être de puissants inhibiteurs non cytotoxiques de la réplication des CMV, ce qui indique leur utilisation comme agents thérapeutiques pour le traitement d'une infection par un CMV chez les êtres humains.
PCT/US2010/059390 2009-12-08 2010-12-08 Activité anti-cytomégalovirus de dimères dérivés de l'artémisinine Ceased WO2011071981A2 (fr)

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Publication number Priority date Publication date Assignee Title
WO2014116642A1 (fr) * 2013-01-22 2014-07-31 The Johns Hopkins University Dimères de trioxane dérivés d'artémisinine liés à deux atomes de carbone

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EP2838903B1 (fr) 2012-04-18 2017-09-06 The Hong Kong University of Science and Technology Méthodes et compositions de traitement d'infections virales
US11358970B2 (en) 2017-11-21 2022-06-14 Ming Zhao Artemisinin-derived trimers and tetramers and their use thereof

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WO2004028476A2 (fr) * 2002-09-27 2004-04-08 Johns Hopkins University Dimeres de trioxane derives d'artemisinine actifs par voie orale, antipaludeens, anticancereux, presentant une selectivite, une stabilite et une efficacite elevees et procedes de production associes
CN1758905A (zh) * 2003-02-12 2006-04-12 乔治敦大学 青蒿素在治疗致癌病毒诱导的肿瘤和治疗病毒感染中的应用
FR2899586B1 (fr) * 2006-04-11 2008-06-20 Sanofi Aventis Sa Dimeres de derives d'artemisinine, leur preparation et leur application en therapeutique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014116642A1 (fr) * 2013-01-22 2014-07-31 The Johns Hopkins University Dimères de trioxane dérivés d'artémisinine liés à deux atomes de carbone
US9487538B2 (en) 2013-01-22 2016-11-08 The Johns Hopkins University Two-carbon linked artemisinin-derived trioxane dimers

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US20130109654A1 (en) 2013-05-02
WO2011071981A3 (fr) 2011-10-13

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