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EP1583747A2 - Inhibiteurs de phosphatases - Google Patents

Inhibiteurs de phosphatases

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Publication number
EP1583747A2
EP1583747A2 EP03800372A EP03800372A EP1583747A2 EP 1583747 A2 EP1583747 A2 EP 1583747A2 EP 03800372 A EP03800372 A EP 03800372A EP 03800372 A EP03800372 A EP 03800372A EP 1583747 A2 EP1583747 A2 EP 1583747A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
substituents
straight
independently selected
aliphatic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03800372A
Other languages
German (de)
English (en)
Inventor
Jeffrey O. Saunders
Gregory F. Miknis
Alexandre J. Buckmelter
Kevin W. Hunt
James F. Blake
Guy P. A. Vigers
Xicheng Sun
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Vertex Pharmaceuticals Inc
Original Assignee
Vertex Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vertex Pharmaceuticals Inc filed Critical Vertex Pharmaceuticals Inc
Publication of EP1583747A2 publication Critical patent/EP1583747A2/fr
Withdrawn legal-status Critical Current

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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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Definitions

  • the present invention relates to compounds that inhibit phosphatases, compositions thereof, and methods of using those compounds and compositions for treating diseases .
  • phosphate group transfer Many biologically important functions are regulated by the transfer of a phosphate group. Often, the active or inactive form of a compound is determined by the presence or absence of a phosphate group bound to that compound. Accordingly, many biological enzymes are involved in regulating this phosphate group transfer. For example, kinase enzymes catalyze transfer of a phosphate group from a nucleoside triphosphate to a protein receptor. In contrast, phosphatase enzymes remove a phosphate group from a substrate by hydrolysis.
  • SHP-2 src homology 2-containing protein tyrosine phosphatase
  • SHPTP2 68 kDa phosphatase protein and is also known as SHPTP2 , Syp, PTPlD and PTP2C. Lu et al., Molecular Cell (2001) 8, 759. The enzyme is expressed in the cytoplasm of every tissue. SHP-2 is an important signaling enzyme, and the biological functions of SHP-2 have been extensively reviewed. Feng, Exp . Cell Res . (1999) 253, 45; Neel and Tonks, Curr. Opin . Cell Biol . (1997) 9, 193; Tonks, Adv. Pharmacol . (1996) 36, 91.
  • the enzyme is activated through interactions with a variety of ligands including growth factors, cytokine receptor tyrosine kinases, and adhesion molecules and is most notably recognized as a positive regulator of cell proliferation.
  • SHP-2 also plays an important function in immune signaling. Huyer and Alexander, Curr. Biol . (1999) 9, R129; Cohen et al . , Cell (1995) 80, 237.
  • the SHP-2 enzyme is required for activation of the Ras-MAP kinase cascade, although its precise role in the pathway is unclear. Van Vactor et al . , Curr. Opin . Genet . Dev. (1998) 8, 112.
  • SHP-2 has recently been identified as an intracellular target of Helicobacter pylori . Higashi et al . , Science (2002) 295, 683. Due to the critical role SHP-2 plays in various biological pathways, development of inhibitors against the enzyme would provide useful treatments for cancer and other autoimmune diseases.
  • the present invention relates to compounds of formula (I) :
  • ring A is an aryl or heteroaryl ring
  • R a is -COOH, a salt or an ester thereof, or a bioisostere thereof; n is 1-3;
  • Ri is H, hydroxyaliphatic, aminoaliphatic, aliphatic- COOH, aliphatic-CONH , or arylaliphatic;
  • R 2 is aliphatic, arylaliphatic, cycloaliphatic- aliphatic, heteroarylaliphatic, or heterocyclylaliphatic,-
  • R and R are independently selected from RU, R ⁇ 2 , R14 or
  • each R 11 is independently selected from 1,2- methylenedioxy, 1, 2-ethylenedioxy, R 6 or (CH2) m - ⁇ ; wherein m is 0, 1 or 2 ; and Y is selected from halogen, CN, NO2 , CF3, OCF3,
  • each R ⁇ -2 ⁇ s independently selected from (C ⁇ -Cg)- straight or branched alkyl, or (C2-C5) -straight or branched alkenyl or alkynyl; and each R ⁇ 2 optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is selected from R ⁇ , R1 nc : R15, an ⁇ ⁇ the second of said substituents, if present, is RU; each R!4 is independently selected from OR ⁇ -S, OC(0)R 6 , OC(0)R 15 , OC(0)OR 6 , OC(0)OR 15 , OC(0)N(R 6 ) , OP(0)(OR 6 ) 2 , SR 6 , SR 15 , S(0)R 6 , S
  • Z is selected from halogen, CN, O2 , CF3 , OCF3, OH, S(C ⁇ -Cg) -alkyl, SO (Ci-Cg) -alkyl, S0 (C ⁇ Cg) -alkyl, NH2 ,
  • R 8 is an amino protecting group; provided that :
  • R3 and R ⁇ are not simultaneously hydrogen; when R3 is H, then R ⁇ is not chloro; and when R 4 is H, then R 3 is not -SCH 3 or -NH-C(0)CH 3 .
  • the present invention also relates to compositions thereof, and methods of treating diseases using such compounds and compositions.
  • the present invention relates to compounds of formula (I) :
  • ring A is an optionally substituted aryl or heteroaryl ring
  • R a is -COOH; n is 0-4;
  • Ri is H, or an optionally substituted hydroxyaliphatic, aminoaliphatic, aliphatic-COOH, aliphatic-CONH 2 , or arylaliphatic;
  • R 2 is an optionally substituted aliphatic, arylaliphatic, cycloaliphatic-aliphatic, heteroarylaliphatic, or heterocyclylaliphatic;
  • R and R are independently selected from R ⁇ --, R ⁇ , R ⁇ - ⁇ or R15.
  • each RU is independently selected from 1,2- methylenedioxy, 1, 2-ethylenedioxy, R 6 or (CH2) m -Y; wherein m is 0, 1 or 2 ;
  • Y is selected from halogen, CN, NO2 , CF3 , OCF3 ,
  • each R!2 i s independently selected from (Ci-Cg)- straight or branched alkyl, or (C2 ⁇ Cg) -straight or branched alkenyl or alkynyl; and each R ⁇ 2 optionally comprises up to 2 substituents, wherein: the first of said substituents, if present, is selected from R 11 , R 14 and R 15 ' and the second of said substituents, if present, is
  • each R!4 ⁇ S independently selected from OR 1 ⁇ OC(0)R 6 , OC(0)R 15 , OC(0)OR 6 , OC(0)OR 15 , OC(0)N(R 6 ) 2 , OP(0)(OR 6 ) 2 , SR 6 , SR 15 , S(0)R 6 , S(0)R 15 , S0 2 R 6 , S0 2 R 15 , S0 2 N(R 6 ) , S0 NR 15 R 6 , SO3R 6 , C(0)R 15 , C(0)OR 15 , C(0)R 6 , C(0)OR 6 , NC(0)C(0)R 6 , NC(0)C(0)R 15 , NC (0) C (0) OR 6 , NC(0)C(0)N(R 6 ) 2 , C(0)N(R 6 )2, C (0)N (OR 6 ) R 6 , C (O)N (OR 6 ) R 15 , C(NOR 6 )R 6 , C(NOR 6 )R 15 , N(R 6 ) ,
  • ⁇ 0 is a cycloaliphatic, aryl, heterocyclyl, or heteroaromatic; and each R0 optionally comprises up to 2 substituents independently chosen from H, (C]_-Cg)- straight or branched alkyl, (C2 ⁇ C ) straight or branched alkenyl, 1, 2-methylenedioxy, 1, 2-ethylenedioxy, or (CH 2 ) p -Z; wherein p is 0, 1 or 2 ; and
  • Z is selected from halogen, CN, NO2, CF3 , OCF3 , OH, S(C ⁇ -Cg) -alkyl, SO (C ⁇ -Cg) -alkyl, SO2 (C ⁇ Cg) -alkyl, NH 2 , NH(C ⁇ -Cg) -alkyl, ( (Ci-Cg) -alkyl) 2 , N ( (Ci-Cg) -alkyl) R 8 , COOH, C(0)0(C ⁇ -C 6 ) -alkyl or 0 (Ci-C ) -alkyl; and
  • R 8 is an amino protecting group; provided that :
  • R3 and R 4 are not simultaneously hydrogen; when R 3 is H, then R 4 is not chloro; and when R 4 is H, then R 3 is not -SCH 3 or -NH-C(0)CH 3 .
  • aliphatic or "aliphatic group”, as used herein, means a straight-chain or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated (alkyl) or is unsaturated (alkenyl or alkynyl) . Unless otherwise specified, an aliphatic group has 1 to 12 carbon atoms. Preferably, an aliphatic group has 1-6 carbon atoms. Up to two -CH 2 - in said aliphatic may be replaced with 0, S, or -NR X - .
  • cycloaliphatic means a 3-8 membered monocyclic hydrocarbon ring or a 8-12 membered bicyclic hydrocarbon ring that is completely saturated (e.g., cycloalkyl) or that contains one or more units of unsaturation (e.g., cycloalkenyl), but which is not aromatic, and has a single point of attachment to the rest of the molecule.
  • heteroatom unless otherwise specified means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.
  • nitrogen includes a substitutable nitrogen of a heterocyclic ring.
  • the nitrogen in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3 , 4-dihydro-2Jf-pyrrolyl) , NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl) .
  • unsaturated means a double bond or a triple bond. Each such bond constitutes one unit of unsaturation.
  • aryl used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” , refers to monocyclic, bicyclic and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring” . Phenyl is an example of aryl.
  • heterocycle means non-aromatic, monocyclic, bicyclic or tricyclic ring systems having in total 5 to 14 ring members in which one or more ring members is a heteroatom, wherein each ring in the system contains 3 to 7 ring members .
  • heteroaryl used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy” , refers to monocyclic, bicyclic and tricyclic ring systems, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms. Unless otherwise specified, such ring systems have a total of 5 to 15 ring members, wherein each ring in the system contains 3 to 7 ring members.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic” .
  • An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents .
  • Suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group include halogen, -R°, -OR°, -SR°, 1, 2-methylene-dioxy, 1,2- ethy1enedioxy, phenyl (Ph) optionally substituted with R°,
  • R° is independently selected from hydrogen, optionally substituted C1-C6 aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -CH 2 (Ph), or wherein two occurrences of R°, on the same substituent or different substituents, taken together, form a 5-8- membered heterocyclyl or heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Optional substituents on the aliphatic group of R° are selected from NH 2 , NH(C ⁇ _ 4 aliphatic), N(C ⁇ _ 4 aliphatic) 2 , halogen, C 1 - 4 aliphatic, OH, 0(C ⁇ _ 4 aliphatic), N0 2 , CN, C0 2 H, C0 2 (Ci_ 4 aliphatic), 0(halo C ⁇ _ 4 aliphatic), or halo C 1 - 4 aliphatic.
  • Optional substituents on the aliphatic group of R * are selected from NH , NH(C ⁇ - 4 aliphatic), N(C ⁇ _ 4 aliphatic) , halogen, C ⁇ _ aliphatic, OH, 0(C ⁇ _4 aliphatic), N0 2 , CN, C0 2 H, C0 2 (C ⁇ _ 4 aliphatic), 0 (halo C ⁇ _ aliphatic), or halo(C ⁇ _ 4 aliphatic) .
  • Optional substituents on the aliphatic group or the phenyl ring of R + are selected from NH 2 , NH(C ⁇ _ 4 aliphatic), N(C ⁇ _4 aliphatic) 2 , halogen, C ⁇ _ 4 aliphatic, OH, 0(Ci_ 4 aliphatic), N0 2 , CN, C0 2 H, C0 2 (C ⁇ _ 4 aliphatic), 0(halo C ⁇ _ 4 aliphatic), or halo(C ⁇ _ 4 aliphatic).
  • alkylidene chain refers to a straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule.
  • a combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound.
  • a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
  • compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13 C- or 1 C-enriched carbon are within the scope of this invention.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays .
  • ring A is an optionally substituted 5 or 6 membered aryl or heteroaryl ring, wherein said heteroaryl ring contains up to 2 ring heteroatoms independently selected from 0, S, or NR + .
  • ring A is phenyl.
  • i R is hydrogen, -(CH ⁇ réelle) Cj-X, wherein q is 1-4, and X is OH,
  • R is hydrogen, hydroxymethyl, methyl, -CH 2 COOH, -CHC0NH adjective, aminobutyl, methyl, or isopentyl .
  • R is selected from butyl, isobutyl, methoxypropyl, cyclopentyl, cyclohexylmethyl, phenyl, trifluorophenyl, benzyl, fluorobenzyl, methylenedioxybenzyl, pyridylmethyl, furanylmethyl , tetrahydrofuranylmethyl, N- morpholinylmethyl, thienylmethyl, 2-oxo- pyrrolodinylpropyl, phenylethyl, chlorophenylethyl, methoxyphenylethyl, or dimethoxyphenylethyl .
  • R is selected from 2-furanylmethyl or methyl.
  • R and R are independently selected from hydrogen, halo, acetamido, allyloxy, thiophenyl, sulfoxyalkyl, or sulfoxyphenyl .
  • amino protecting group refers to a suitable chemical group that may be attached to a nitrogen atom.
  • protected refers to when the designated functional group is attached to a suitable chemical group (protecting group) .
  • suitable amino protecting groups and protecting groups are described in T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994) ; L. Paquette, ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and are exemplified in certain of the specific compounds used in this invention.
  • the present invention provides compounds of formula (II) :
  • X is -(CH2)n-, or -C(O)-; n is 1-3;
  • Y is 0, S, NH, or N(Cl-C6 aliphatic);
  • Z is H or C1-C6 aliphatic
  • Q is 0 or 1
  • R x , Y, and R z are independently selected from R ⁇ ,
  • each RH is independently selected from 1,2- methylenedioxy, 1, 2-ethylenedioxy, R 6 or (CH2) m -Y; wherein m is 0, 1 or 2 ; and Y is selected from halogen, CN, NO2 , CF3 , OCF3 ,
  • R 7 is a cycloaliphatic, aryl, heterocyclyl, or heteroaromatic; and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C ⁇ -Cg)- straight or branched alkyl, (C2 ⁇ Cg) straight or branched alkenyl, 1, 2-methylenedioxy, 1, 2-ethylenedioxy, or (CH 2 ) p -Z; wherein p is 0, 1 or 2 ; and
  • Z is selected from halogen, CN, N0 2 , CF3 , OCF3 , OH, S(C ⁇ -Cg) -alkyl, SO (C ⁇ -Cg) -alkyl, SO2 (Ci-C ) -alkyl, NH ,
  • R 8 is an amino protecting group; x y or R and R , taken together, form an optionally substituted heterocyclic ring having up to 3 substituents .
  • the scope of the present invention includes within its scope pharmaceutically acceptable prodrugs of the compounds of the present invention.
  • a "pharmaceutically acceptable prodrug” means any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present invention that, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention or an active metabolite or residue thereof .
  • Preferred prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
  • Step 2 Loading of Substituted Anthranilic acids to Resin
  • CAUTION The following procedure involves the use of phosgene and should only be carried out by an experienced technician in a well-vented chemical hood.
  • the chloroformate resin was subsequently washed 2x 100 ml dry THF, 2x 100 ml dry DCM using positive pressure to drain the vessel.
  • a 100 ml DCM solution containing the anthranilic acid (3eq) and DIEA (10 eq) was added quickly to the freshly prepared chloroformate resin and the flasks resealed and swirled on the orbital shaker for an additional 3 x hours.
  • the resins were drained, washed and washed extensively.
  • the resins were dried under high vacuum overnight .
  • the approximate loading was determined by weight gain. Typical loadings of 0.7-0.9 mmol/g were routinely obtainable using this method.
  • Step 3 Coupling of Amino Acids to anthranilic acid functionalized resin l-methyl-2-pyrrolidinone (NMP) solutions of HOBT (1M) , HBTU (0.5 M) , amino acid ester (1M) and Hunigs base (2M) were made freshly prior to carrying out the coupling reactions .
  • the resin was suspended in NMP and a solution of HOBT (5 eq) was added followed by the addition of HBTU (5.0 eq) .
  • the reaction was sealed and shaken for 15 minutes .
  • the vessel was unsealed and the reaction block placed on the Packard for addition of the remaining reagents.
  • compositions of this invention refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxy
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oxalate, palmo
  • Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N + (C ⁇ _ 4 alkyl) 4 salts.
  • alkali metal e.g., sodium and potassium
  • alkaline earth metal e.g., magnesium
  • ammonium and N + (C ⁇ _ 4 alkyl) 4 salts e.g., sodium and potassium
  • alkali metal e.g., sodium and potassium
  • alkaline earth metal e.g., magnesium
  • ammonium e.g., sodium and sodium and sodium and potassium
  • N + (C ⁇ _ 4 alkyl) 4 salts e.g., sodium and potassium
  • ammonium e.g., sodium and potassium
  • N + (C ⁇ _ 4 alkyl) 4 salts e.g., sodium and potassium
  • ammonium e.g., sodium and potassium
  • N + (C ⁇ _ 4 alkyl) 4 salts
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally, intraperitoneally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol .
  • a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1, 3-butanediol .
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides .
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
  • the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
  • compositions of this invention are formulated for oral administration.
  • amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration.
  • the compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.
  • additional therapeutic agents which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention.
  • additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition are known as "appropriate for the disease, or condition, being treated. "
  • chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this invention to treat cancer and proliferative diseases.
  • known chemotherapeutic agents include, but are not limited to, GleevecTM, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.
  • agents with which the compounds of this invention may be combined include, without limitation, anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, chol
  • the amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent.
  • the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent .
  • the invention relates to a method of inhibiting SHP-2 phosphatase activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.
  • biological sample includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
  • Inhibition of SHP-2 phosphatase activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ-transplantation, biological specimen storage, and biological assays.
  • the invention provides a method for treating or lessening the severity of a disease selected from autoimmune diseases, proliferative diseases, angiogenic disorders, and cancers .
  • the invention provides a method for treating or lessening the severity of a SHP-2-mediated disease or condition in a patient comprising the step of administering to said patient a composition according to the present invention.
  • SHP-2-mediated disease means any disease or other deleterious condition in which SHP-2 is known to play a role. Such conditions include, without limitation, autoimmune diseases, proliferative diseases, angiogenic disorders, and cancers .
  • Autoimmune diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, glo erulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, or graft vs. host disease.
  • Proliferative diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, acute myelogenous leukemia, chronic myelogenous leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma and HTLV-1-mediated tumorigenesis .
  • Angiogenic disorders that may be treated or prevented by the compounds of this invention include solid tumors, ocular neovasculization, infantile haemangio as .
  • Cancers that may be treated or prevented by the compounds of this invention include, without limitation, colon, breast, stomach, and ovarian cancers.
  • the methods of this invention that utilize compositions that do not contain an additional therapeutic agent comprise the additional step of separately administering to said patient an additional therapeutic agent.
  • additional therapeutic agents When these additional therapeutic agents are administered separately, they may be administered to the patient prior to, sequentially with or following administration of the compositions of this invention.
  • the compounds of this invention or pharmaceutical compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters.
  • vascular stents for example, have been used to overcome restenosis (re- narrowing of the vessel wall after injury) .
  • patients using stents or other implantable devices risk clot formation or platelet activation.
  • Suitable coatings and the general preparation of coated implantable devices are described in US Patents 6,099,562; 5,886,026; and 5,304,121.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof .
  • the coatings may be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled-release characteristics in the composition.
  • Implantable devices coated with a compound of this invention are another embodiment of the present invention.
  • the 4-amino-2-nitrobenzoic acid (3g) was suspended in 20 ml 4:1 THF/MeOH, cooled to 0°C .
  • TMS-diazomethane (5.6 g, 49 mmol, 3 eq, 2M in hex) was added dropwise and the solution stirred at room temperature for 2 hrs .
  • the reaction was quenched with IN acetic acid and the organics removed under vacuum.
  • the aqueous layer poured into ethyl acetate, neutralized with sodium bicarbonate, dried over sodium sulfate, filtered and concentrated to a yellow oil.
  • the ester was purified by flash column chromatography using 30% Acetone/hex. Isolated the nitroester as a bright yellow solid (92% yield) .
  • the ester (1.0 g, 5.1 mmol) was dissolved in 20 ml DCM at room temperature. DIEA (0.98g, 7.6mmol, 1.5 eq) was added followed by the addition of acetyl chloride (0.48g, 6.1 mmol, 1.2 eq) . Reaction was stirred at room temperature for 4 hrs. Reaction was poured into 1M HCl, dried over sodium sulfate, filtered and concentrated to a yellow oil/solid. The crude reaction was taken up in -20 ml MeOH, saturated NH4C1 was added followed by the addition of excess Zn powder. Reaction was stirred at room temperature for 45 minutes when TLC showed complete reduction.
  • the reaction was filtered to remove the Zn particulates, extracted with ethyl acetate.
  • the aqueous layer was extracted 2X with ethyl aceate and the organics combined. Dried over sodium sulfate, filtered, and concentrated to a yellow film.
  • Reductive amination was carried out by dissolving the anthranilate (2.3g, llmmol, leq) , 2-furylaldehyde (3.2g, 33 mmol, 3 eq) and 1 ml acetic acid in 50 ml DCE at room temperature. After 15 minutes sodium triacetoxyborohydride (9.4g, 44 mmol, 4 eq) was added and the solution stirred at room temperature for 4 hrs. The reaction was quenched by addition of excess IN NaOH. After stirring for 20 minutes, the suspension was extracted 3X with ethyl acetate. Washed the organics with brine, dried over sodium sulfate, filtered and concentrated to a brown oil . The product was isolated by flash column using 10-30% acetone/hex. The desired anilide was obtained a light yellow solid.
  • the ester was taken up in THF and IN LiOH (1.5 eq) was added and stirred at 60°C for 12 hrs. Reaction was cooled, concentrated to remove organics and diluted with water. The solution was washed with ether and the aqueous layer acidified with 1M HCl . A thick white precipitate formed and was collected by filtration to afford the desired compound.
  • the resin (400mg) was suspended in NMP and treated with HBTU (4eq) . HOBT (4eq) for fifteen minutes before adding aspartic acid dit-butyl ester hydrochloride (3eq.) and finally DIEA (4eq) . The reaction was agitated for 12 hours before filtering and washing extensively with NMP, DMF, MeOH. The resin was resuspended in 8ml of 10%
  • HM-PS Hydroxymethyl polystyrene
  • the PS resin was taken up in NMP and HOBT-H 2 0 (4 equiv in NMP) and HBTU (4 equiv in NMP) were added. After shaking for -5 min, L-aspartic acid D, D-di- -butyl ester hydrochloride (4 equiv in NMP) and DIEA (5 equiv) were added to the mixture. After shaking overnight, the solution was drained, and the resin washed successively with NMP (2X) , DCM (3x) , and MeOH (3x) and dried under high vacuum. The resin was heated to 60 °C overnight in 10% Et 3 N/MeOH solution in order to affect cyclative cleavage of the compound from resin.
  • Step A 6- (tert-Butyl-dimethyl-silanyloxy) -lH-indole-2- ⁇ arboxylic acid
  • 6-Hydroxy-lH-indole-2-carboxylic acid (5.40 g, 30.48 mmol) is dissolved in THF (100 ml) and imidazole (10.38, 152.4 mmol) is added. The mixture is stirred for 5 minutes, TBDMS-C1 (13.78 g, 91.44 mmol) is added. The reaction is stirred at room temperature for 1 hour. The mixture is filtered into water (200 ml) . The solid is washed with THF (50 ml) . The filtrate is concentrated to remove THF. The product is extracted with ethyl acetate (100 ml) three times.
  • Step B [6- (tert-Butyl-dimethyl-silanyloxy) -lH-indol-2-yl] - methanol
  • Step C 2-Azidomethyl-6- (tert-butyl-dimethyl-silanyloxy)-lH- indole
  • Step D [6- (tert-Butyl-dimethyl-silanyloxy) -lH-indol ⁇ 2-yl] - methylamine
  • Step E [6- (tert-Butyl-dimethyl-silanyloxy) -lH-indol-2 ylm ⁇ thyl] -carbamic acid benzyl ester
  • [6- (tert-Butyl-dimethyl-silanyloxy) -lH-indol-2-yl] -methylamine (0.70 g, 1.01 mmol) is dissolved in DCM (10 ml), cooled to 0°C .
  • DIEA (0.35 ml, 2.02 mmol
  • Cbz-Cl (0.17 g, 1.01 mmol
  • reaction mixture is concentrated and the residue is purified by column chromatography (10% ethyl acetate in hexanes) to provide [6- (tert-Butyl-dimethyl-silanyloxy) -1H- indol-2-ylmethyl] -carbamic acid benzyl ester.
  • Step F (6-Hydroxy-lH-indol-2-ylmethyl) -carbamic acid benzyl ester
  • Step G 2- (2-Aminomethyl-lH-indol-6-yloxy) -malonic acid diethyl ester
  • Step H 2- [2- (Benzenesulfonyla ino-methyl) -lH-indol-6-yloxy] - malonic acid diethyl ester
  • N-terminal 6 His-tagged, catalytic domain of SHP-2 (250-527) is expressed in E. coli and protein is purified by conventional methods.
  • SHP-2 ' s activity was assessed by measuring the fluorescent signal generated by the dephosphorylation of fluorescein diphosphate (FDP) .
  • the assay is carried out in 96-well polypropylene black plate.
  • the final assay volume is 100 ⁇ L and comprises of 25 mM NaOAc, pH 6, 0.02% Triton X-100, 10 mM DTT and 2 nM SHP-2.
  • Inhibitors are suspended in DMSO, and all reactions, including controls are performed at a final concentration of 3% DMSO. Reactions are initiated by the addition of 3 ⁇ M FDP and incubated at ambient temperature for 25 minutes. Plates were read using a Molecular Devices Gemini plate reader, Ex 485, Em 538, Cutoff 530.

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Abstract

La présente invention concerne, d'une part des composés qui inhibent les phosphatases, d'autre part leurs compositions, et enfin des procédés permettant d'utiliser ces composés et compositions pour traiter des maladies.
EP03800372A 2002-12-31 2003-12-31 Inhibiteurs de phosphatases Withdrawn EP1583747A2 (fr)

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US437576P 2002-12-31
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Cited By (3)

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US7557135B2 (en) 2005-05-27 2009-07-07 Wyeth Inhibitors of cytosolic phospholipase A2
US7605156B2 (en) 2001-12-03 2009-10-20 Wyeth Methods for the use of inhibitors of cytosolic phospholipase A2
US7713964B2 (en) 2001-12-03 2010-05-11 Wyeth Llc Methods for treating asthmatic conditions

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TW200911755A (en) 2007-04-19 2009-03-16 Astellas Pharma Inc Bicyclic heterocyclic compounds
FR2985258A1 (fr) * 2011-12-28 2013-07-05 Sanofi Sa Composes dimeres agonistes des recepteurs des fgfs (fgfrs), leur procede de preparation et leur application en therapeutique
EP3016652A4 (fr) 2013-07-03 2017-03-08 Indiana University Research and Technology Corporation Inhibiteurs de shp2 et méthodes de traitement de maladies auto-immunes et associées à la glomérulonéphrite à l'aide d'inhibiteurs de shp2
WO2019233810A1 (fr) * 2018-06-04 2019-12-12 Bayer Aktiengesellschaft Inhibiteurs de shp2
CN111265529B (zh) * 2020-02-22 2021-07-23 南京大学 蛋白酪氨酸磷酸酶shp2抑制剂在制备治疗银屑病药物中的应用
CN111333628B (zh) * 2020-04-20 2022-05-10 大连医科大学附属第一医院 吲哚类生物碱、制备方法及作为降血糖药物的应用

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
US7605156B2 (en) 2001-12-03 2009-10-20 Wyeth Methods for the use of inhibitors of cytosolic phospholipase A2
US7713964B2 (en) 2001-12-03 2010-05-11 Wyeth Llc Methods for treating asthmatic conditions
US7906548B2 (en) 2001-12-03 2011-03-15 Wyeth Llc Methods for the use of inhibitors of cytosolic phospholipase A2
US7557135B2 (en) 2005-05-27 2009-07-07 Wyeth Inhibitors of cytosolic phospholipase A2
US8283373B2 (en) 2005-05-27 2012-10-09 Pfizer Inc. Inhibitors of cytosolic phospholipase A2

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CA2511925C (fr) 2012-11-13
JP4619795B2 (ja) 2011-01-26
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