WO2002083668A1 - Derives d'isoxaxole utilises comme inhibiteurs de proteines kinases src et d'autres proteines kinases - Google Patents

Derives d'isoxaxole utilises comme inhibiteurs de proteines kinases src et d'autres proteines kinases Download PDF

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WO2002083668A1
WO2002083668A1 PCT/US2002/011609 US0211609W WO02083668A1 WO 2002083668 A1 WO2002083668 A1 WO 2002083668A1 US 0211609 W US0211609 W US 0211609W WO 02083668 A1 WO02083668 A1 WO 02083668A1
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Edmund Harrington
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Vertex Pharmaceuticals Incorporated
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Priority to MXPA03009257A priority patent/MXPA03009257A/es
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Definitions

  • the present invention relates to inhibitors of c-Jun N-terminal kinases (JNK) and kinases belonging to the Src family of protein kinases, especially Src and Lck protein kinases.
  • JNK c-Jun N-terminal kinases
  • Src kinases are implicated in cancer, immune disorders and bone diseases.
  • the invention also provides pharmaceutical compositions comprising the inhibitors of the invention and methods of utilizing those compositions in the treatment and prevention of various disorders.
  • Mammalian cells respond to extracellular stimuli by activating signaling cascades that are mediated by members of the mitogen-activated protein (MAP) kinase family, which include the extracellular signal regulated kinases (ERKs) , the p38 MAP kinases and the c-Jun N-terminal kinases (JNKs) .
  • MAP kinases are activated by a variety of signals including growth factors, cytokines, UV radiation, and stress-inducing agents .
  • MAPKs are serine/threonine kinases whose activation occurs by dual phosphorylation of threonine and tyrosine at the Thr-X-Tyr segment in the activation loop. MAPKs phosphorylate various substrates including transcription factors, which in turn regulate the expression of specific sets of genes and thus mediate a specific response to the stimulus.
  • kinase family of particular interest is the Src family of kinases. These kinases are implicated in cancer, immune system dysfunction and bone remodeling diseases.
  • Src family of kinases are implicated in cancer, immune system dysfunction and bone remodeling diseases.
  • Thomas and Brugge Annu. Rev. Cell Dev. Biol . (1997) 13, 513; Lawrence and Niu, Pharmacol . Ther. (1998) 77, 81; Tatosyan and Mizenina, Biochemistry (Moscow) (2000) 65, 49; Boschelli et al., Drugs of the Future 2000, 25(7), 717, (2000).
  • Src Src
  • Fyn Yes, Fgr, Lyn, Hck
  • Lck and Blk. These are nonreceptor protein kinases that range in molecular mass from 52 to 62 kD. All are characterized by a common structural organization that is comprised of six distinct functional domains : Src homology domain 4 (SH4) , a unique domain, SH3 domain, SH2 domain, a catalytic domain (SHI) , and a C-terminal regulatory region. Tatosyan et al . Biochemistry (Moscow) 65, 49-58 (2000) .
  • Src kinases are considered as potential therapeutic targets for various human diseases. Mice that are deficient in Src develop osteopetrosis, or bone build-up, because of depressed bone resorption by osteoclasts. This suggests that osteoporosis resulting from abnormally high bone resorption can be treated by inhibiting Src. Soriano et al., Cell , 69, 551 (1992) and Soriano et al . , Cell , 64, 693 (1991) . Suppression of arthritic bone destruction has been achieved by the overexpression of CSK in rheumatoid synoviocytes and osteoclasts. Takayanagi et al . , J. Clin . Invest .
  • Lck inhibitors may be useful for treating autoimmune disease such as rheumatoid arthritis.
  • Molina et al . Nature, 357, 161 (1992) .
  • Hck, Fgr and Lyn have been identified as important mediators of integrin signaling in myeloid leukocytes. Lowell et al . , J " . Leukoc . Biol . , 65, 313 (1999) . Inhibition of these kinase mediators may therefore be useful for treating inflammation.
  • Boschelli et al. Drugs of the Future 2000, 25(7), 717, (2000).
  • JNKs In the c-Jun ⁇ H 2 -terminal protein kinases, also known as JNKs, three distinct genes, JNK1, JNK2 , JNK3 have been identified and at least ten different splicing isofor s of JNKs exist in mammalian cells [Gupta et al . , EMBO J. , 15, 2760-70 (1996)].
  • JNKs proinflammatory cytokines, such as tumor necrosis factor- ⁇ (TNF ⁇ ) and interleukin-l ⁇ (IL-l ⁇ ) , as well as by environmental stress, including anisomycin, UV irradiation, hypoxia, and osmotic shock [Minden et al .
  • JNKs include transcription factors c-Jun, ATF-2, Elkl, p53 and a cell death domain protein (DENN) [Zhang et al . , Proc. Natl . Acad. Sci . USA, 95, 2586-91 (1998)].
  • ENN cell death domain protein
  • Each JNK isoform binds to these substrates with different affinities, suggesting a regulation of signaling pathways by substrate specificity of different JNKs in vivo (Gupta et al . , supra) .
  • JNKs have been implicated in the mediation of cellular response to cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and heart disease.
  • the therapeutic conditions related to activation of the JNK pathway include chronic myelogenous leukemia (CML) , rheumatoid arthritis, asthma, osteoarthritis, ischemia, cancer and neurodegenerative diseases.
  • CML chronic myelogenous leukemia
  • rheumatoid arthritis asthma, osteoarthritis, ischemia, cancer and neurodegenerative diseases.
  • J ⁇ K mediates hypertrophic responses to various forms of cardiac stress [ Circ . Res . 83, 167-78 (1998); Circulation 97, 1731-7 (1998); J. Biol . Chem . 272, 28050-6 (1997); Circ . Res . 79, 162-73 (1996); Circ . Res . 78, 947-53 (1996; ; J. Clin . Invest . 97, 508-14 (1996)].
  • J ⁇ K cascade also plays a role in T-cell activation, including activation of the IL-2 promoter.
  • inhibitors of J ⁇ K have potential therapeutic value in altering pathologic immune responses [J. Immunol . 162, 3176-87 (1999) ; Eur. J. Immunol . 28, 3867-77 (1998); J " . Exp . Med . 186, 941-53 (1997); Eur. J. Immunol . 26, 989-94 (1996)].
  • J ⁇ K activation in various cancers has also been established, suggesting the potential use of J ⁇ K inhibitors in cancer.
  • constitutively activated J ⁇ K is associated with HTLV-1 mediated tumorigenesis [Oncogene 13, 135-42 (1996)].
  • the proliferative effects of bFGF and OSM on Kaposi's sarcoma (KS) cells are mediated by their activation of the J ⁇ K signaling pathway [J " . Clin . Invest . 99, 1798-804 (1997)].
  • Other proliferative effects of other cytokines implicated in KS proliferation such as vascular endothelial growth factor (VEGF) , IL-6 and T ⁇ F ⁇ , are also mediated by J ⁇ K.
  • VEGF vascular endothelial growth factor
  • JNK1 and JNK2 are widely expressed in a variety of tissues.
  • JNK3 is selectively expressed in the brain and to a lesser extent in the heart and testis [Gupta et al . , supra ; Mohit et al . , Neuron 14, 67- 78 (1995); Martin et al . , Brain Res . Mol . Brain Res . 35, 47-57 (1996)].
  • JNK3 has been linked to neuronal apoptosis induced by kainic acid, indicating a role of JNK in the pathogenesis of glutamate neurotoxicity.
  • JNK3 expression is localized to a subpopulation of pyramidal neurons in the CAl, CA4 and subiculum regions of the hippocampus and layers 3 and 5 of the neocortex [Mohit et al . , supra] .
  • the CAl neurons of patients with acute hypoxia showed strong nuclear JNK3-immunoreactivity compared to minimal, diffuse cytoplasmic staining of the hippocampal neurons from brain tissues of normal patients [Zhang et al., supra] .
  • JNK3 appears to be involved involved in hypoxic and ischemic damage of CAl neurons in the hippocampus.
  • JNK3 co-localizes immunochemically with neurons vulnerable in Alzheimer's disease [Mohit et al . , supra] .
  • Disruption of the JNK3 gene caused resistance of mice to the excitotoxic glutamate receptor agonist kainic acid, including the effects on seizure activity, AP-1 transcriptional activity and apoptosis of hippocampal neurons, indicating that the JNK3 signaling pathway is a critical component in the pathogenesis of glutamate neurotoxicity (Yang et al . , Nature, 389, 865- 870 (1997)] .
  • JNK signaling especially that of JNK3, has been implicated in the areas of apoptosis-driven neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, ALS (Amyotrophic Lateral Sclerosis) , epilepsy and seizures, Huntington's Disease, traumatic brain injuries, as well as ischemic and hemorrhaging stroke.
  • apoptosis-driven neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, ALS (Amyotrophic Lateral Sclerosis) , epilepsy and seizures, Huntington's Disease, traumatic brain injuries, as well as ischemic and hemorrhaging stroke.
  • the present invention provides a compound of formula I :
  • G is -XR or -XAr; each X is independently selected from a C ⁇ _ 6 alkylidene chain wherein one or two non-adjacent methylene units of X are optionally and indpendently replaced by -0-, -NR-, -S-, -C(O)-, -C(0)NR-, -NRC(O)-, -NRC(0)NR-, -SO-, -S0 2 -, -NRSO2-, -SO 2 NR-, or -NRSO2NR-;
  • A is N or CR; each R is independently selected from hydrogen or an optionally substituted C ⁇ - 8 aliphatic group, or two R groups bound to the same nitrogen are taken together with the nitrogen to form a 3-7 membered heterocyclic ring having 0-2 heteroatoms in addition to the nitrogen, and independently selected from nitrogen, oxygen, or sulfur; provided that when G is -N(R) 2 , the two R groups are not taken together to form
  • T is selected from -C(O)-, -C0 2 -, -C(0)C(0)-,
  • an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
  • aliphatic or "aliphatic group” as used herein means a straight-chain or branched C ⁇ -C 8 hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic C 3 -C 8 hydrocarbon or bicyclic C 8 -C ⁇ 2 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” or "cycloalkyl”), that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members.
  • suitable aliphatic groups include, but are not limited to, linear or branched or alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl) alkyl, (cycloalkenyl) alkyl or (cycloalkyl) alkenyl .
  • alkyl alkoxy
  • hydroxyalkyl hydroxyalkyl
  • alkoxyalkyl alkoxyalkyl
  • alkoxycarbonyl used alone or as part of a larger moiety include both straight and branched chains containing one to twelve carbon atoms .
  • alkenyl and “alkynyl” used alone or as part of a larger moiety shall include both straight and branched chains containing two to twelve carbon atoms .
  • heteroatom 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-2H-pyrrolyl) , NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl) .
  • 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” .
  • aryl also refers to heteroaryl ring systems as defined hereinbelow.
  • heterocycle means non-aromatic, monocyclic, bicyclic or tricyclic ring systems having five to fourteen 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 having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and 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 are selected from halogen, -R°, -0R°, -SR°, 1, 2-methylene-dioxy, 1,2- ethylenedioxy, phenyl (Ph) optionally substituted with R°, -O(Ph) optionally substituted with R°, -CH 2 (Ph) optionally substituted with R°, -CH 2 CH 2 (Ph) , optionally substituted with R°, -N0 2 , -CN, -N(R°) 2 , -NR°C(0)R°, -NR°C (O) N (R°) _ , -
  • Optional substituents on the aliphatic group of R° are selected from NH 2 , NH(d- 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), O(halo Ci- 4 aliphatic), or halo C ⁇ _ aliphatic.
  • Optional substituents on the aliphatic group of R * are selected from NH 2 , NH(C ⁇ _ 4 aliphatic) , (C ! - 4 aliphatic) 2 , halogen, C ⁇ - 4 aliphatic, OH, 0(C ⁇ - 4 aliphatic), N0 2 , CN, C0 2 H, C0 2 (C ⁇ _ 4 aliphatic), O (halo C ⁇ _ 4 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 1 _ 4 aliphatic), N(C 1 _ 4 aliphatic) 2 / halogen, ⁇ -_ aliphatic, OH, O (C ⁇ _ 4 aliphatic), N0 2 , CN, C0 2 H, C0 2 (Ci- 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. It will be apparent to one skilled in the art that certain compounds of this invention may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the invention.
  • 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 invention.
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, 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 14 C-enriched carbon are within the scope of this invention.
  • Preferred G groups of formula I are -X-R and -X-Ar, wherein X is a C ⁇ _ alkylidene chain and wherein one or two non-adjacent methylene units of X are independently replaced by -S-, -SO-, -S0 2 -, -O- , or -NH- . More preferred X groups of formula I are selected from -S-, -0-, -NH-, -SO 2 -, -NHCH 2 CH 2 NHCH 2 CH 2 -, -NHCH 2 CH 2 CH 2 -, -HCH2CH20CH 2 CH 2 -, or -NHCH 2 CH 2 -.
  • Preferred R groups within the -X-R moiety of formula I are selected from an optionally substituted C ⁇ _ 6 aliphatic group and more preferably an optionally substituted Ca . _ 4 alkyl.
  • Preferred substituents on the R group of -X-R of formula I are selected from halo, CN, oxo, N(R°) 2 , OH, OR°, C0 2 R°, C(0)R°, C(0)N(R°) 2 , NR°C0 2 R°, SR°, NR°S0 2 R°, S0 2 R°, NR°C(0)R°, OC(0)R°, or NR°C (O)N (R°) 2 , wherein each R° group is independently selected from hydrogen or C ⁇ - 4 aliphatic.
  • R groups of -X-R of formula I are selected from methyl, ethyl, isopropyl, isobutyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, CH 2 CN, CH 2 OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 CF 3 , CH 2 cyclopropyl, CH 2 C(0)CH 3 , CH 2 CH 2 N (Me) 2 , CH 2 CH 2 NHC (O) CH 3 , CH 2 CH 2 NHC0 2 CH 3 , CH 2 CH 2 OC (O) CH 3 , CH 2 CH (NH 2 ) C0 2 Et , CH 2 C ⁇ CCH 3 , or CH 2 CH(Me) 2 .
  • Preferred Ar groups within the -X-Ar moiety of formula I are selected from an optionally substituted 5-6 membered saturated or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9-10 membered bicyclic aryl or heteroaryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Ar groups within -X-Ar of formula I are optionally substituted rings selected from phenyl, pyridyl, imidazolyl, thienyl, thiazolyl, [1, 3] dioxanyl, piperidinyl, morpholinyl, pyrrolyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, pyranyl, imidazolyl, benzimidazolyl, pyrrolyl, piperazinyl, thiomorpholinyl, naphthyl, oxazolyl, triazinyl, tetrazolyl, dithiolanyl, dioxalanyl, benzofuranyl , benzothienyl, or indolyl .
  • Preferred R 1 groups of formula I are T( n )-Ar wherein n is zero.
  • Preferred Ar groups within the R 1 moiety are selected from an optionally substituted 6- membered saturated or aryl ring having 0-2 nitrogens, or an optionally substituted 9-10 membered partially unsaturated or fully unsaturated bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. More preferred Ar groups within the R 1 moiety are optionally substituted rings selected from phenyl, cyclohexyl, pyridyl, naphthyl, quinolinyl, isoquinolinyl, or indanyl .
  • Preferred substituents on Ar of R 1 of formula I are selected from R°, halogen, N0 2 , CN, OR°, SR°, N(R°) 2 , C0 2 R°, C(0)R°, CON(R°) 2 , phenyl, S0 2 R°, or NR°C(0)R°, wherein each R° is independently selected from hydrogen or an optionally substituted C ⁇ - 4 aliphatic.
  • More preferred substituents on Ar of R 1 of formula I are selected from methyl, ethyl, oxo, CF 3 , OMe, C(0)Me, C(O) phenyl, CH ⁇ CH, C0 2 H, C(0)NH 2 , SMe, C0 2 Me, fluoro, S0 2 Me, N0 2 , CN, chloro, N(Me) 2/ NHC(0)Me, NH 2 , cyanophenyl, C0 2 Et, CH 2 OH, CH 2 0Me, 3-CH 2 C0 2 H-phenyl, or 3-CH 2 CH 2 C0 2 H-phenyl .
  • R 2 groups of formula I are selected from R, CH 2 N(R) 2 , or CH 2 Ar, wherein R is hydrogen or optionally substituted C ⁇ _ 4 aliphatic, and Ar is an optionally substituted 6 membered saturated or unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. More preferred R 2 groups of formula I are methyl, ethyl, CH 2 (morpholin-4-yl) , CH 2 N(Me) 2 , CH 2 N(Et) 2 , CH 2 N(Me)CH 2 C0 2 CH 3 , or CH 2 (piperazin-1-yl) .
  • a preferred embodiment of this invention relates to a compound of formula I where G is S-R, as shown by the general formula IA below:
  • R, R 1 , and R 2 groups of formula IA are those described for formula I above.
  • the present invention relates to a compound of formula IIA:
  • Preferred Ar, R, and R 2 groups of formula IIA are those described for formula I above.
  • Table 1 below shows representative examples of
  • Another embodiment of this invention relates to a compound of formula IB or IB' :
  • X is independently selected from a C ⁇ _ 4 alkylidene chain and wherein one or two non-adjacent methylene units of X are optionally and independently replaced by -S-, -0-, or -NH-, and wherein A, R, Ar, R 1 , and R 2 are as defined above.
  • R, Ar, R 1 and R 2 groups within formulae IB and IB' are as described above for formula I.
  • G is -NH-R (formula IC)
  • G is -NH-Ar (formula ID)
  • G is -O-R (formula IE)
  • G is -O-Ar (formula IF)
  • G is -S0 2 -R (formula IG)
  • G is -S0 2 -Ar (formula IH)
  • G is -S (O) -R (formula IJ)
  • G is -S(0)-Ar (formula IK). Specific examples of these embodiments are shown below in Table 5.
  • Scheme I above shows a general route to prepare compounds of formulae IA, IC, ID, or IG, wherein R 2 is methyl.
  • step (a) following the condensation of diacetone 1 with carbon disulfide, the resulting dimercaptomethylene dianion may be quenched with an iodoalkane (such as CH 3 I) to give the 3-(bis- alkylsulfanyl-methylene) -pentane-2, -dione (2).
  • an iodoalkane such as CH 3 I
  • Treatment of 2 with hydroxylamine provides the isoxazole 3, which may then be condensed with dimethylformamide-dimethylacetal (DMF-DMA) according to step (c) to give the enamine 4.
  • Compound 4 may be cyclized with various guanidine derivatives to provide compounds of formula IA.
  • Oxidation of a IA compound with oxone provides the corresponding sulfonyl compound of formula IG.
  • the sulfonyl group of IG may be displaced by various amines to provide IC or ID.
  • the sulfonyl group or corresponding sulfoxide group may be displaced by -SAr, -SR, -OAr, or -OR to provide other compounds of this invention.
  • the activity of a compound utilized in this invention as an inhibitor of JNK3 , Lck, or Src may be assayed in vitro, in vivo or in a cell line according to methods known in the art.
  • In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of activated JNK3 , Lck, or Src. Alternate in vitro assays quantitate the ability of the inhibitor to bind to JNK3 , Lck, or Src. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/JNK3 , inhibitor/Lck, or inhibitor/Src complex and determining the amount of radiolabel bound.
  • inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with JNK3 , Lck, or Src bound to known radioligands .
  • Detailed conditions for assaying a compound utilized in this invention as an inhibitor of JNK3 , Lck, or Src kinase are set forth in the Examples below.
  • the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the amount of compound in the compositions of this invention is such that is effective to detectably inhibit a protein kinase, particularly JNK3 , Lck, or Src in a biological sample or in a patient.
  • the composition of this invention is formulated for administration to a patient in need of such composition.
  • the composition of this invention is formulated for oral administration to a patient .
  • patient means an animal, preferably a mammal, and most preferably a human.
  • pharmaceutically acceptable carrier, adjuvant, or vehicle refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
  • 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-polyoxypropylene-block polymers, polyethylene glycol and wool fat .
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate
  • detectably inhibit means a measurable change in JNK3 , Lck, or Src activity between a sample comprising said composition and a JNK3 , Lck, or Src kinase and an equivalent sample comprising JNK3, Lck, or Src kinase in the absence of said composition.
  • a “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • 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, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
  • 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
  • N + (C ⁇ _ 4 alkyl) 4 salts e.g., sodium and potassium
  • alkaline earth metal e.g., magnesium
  • 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 e.g., sodium and potassium
  • ammonium e.g., sodium and potassium
  • parenteral 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.
  • the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration.
  • 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.
  • the pharmaceutically acceptable compositions of this invention are formulated for oral administration.
  • the 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 tng/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.
  • compositions of this invention will also depend upon the particular compound in the composition.
  • additional therapeutic agents which are normally administered to treat or prevent that condition in a monotherapy, may also be present in the compositions of this invention.
  • chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of this invention to treat proliferative diseases and cancer.
  • known chemotherapeutic agents include, but are not limited to, GleevecTM, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives .
  • 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 JNK3, Lck, or Src kinase 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.
  • JNK3 , Lck, or Src kinase 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 JNK3-, Lck- or Src-mediated disease or condition in a patient comprising the step of administering to said patient a composition according to the present invention.
  • JNK-mediated disease as used herein means any disease or other deleterious condition in which JNK is known to play a role.
  • Such conditions include, without limitation, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, cancer, infectious diseases, neurodegenerative diseases, allergies, reperfusion/ischemia in stroke, heart attacks, angiogenic disorders, organ hypoxia,' vascular hyperplasia, cardiac hypertrophy, thrombin- induced platelet aggregation, and conditions associated with prostaglandin endoperoxidase synthase-2.
  • Inflammatory diseases that may be treated or prevented by the compounds of this invention include, but are not limited to, acute pancreatitis, chronic pancreatitis, asthma, allergies, and adult respiratory distress syndrome.
  • Autoimmune diseases which may be treated or prevented by the compounds of this invention include, but are not limited to, glomerulonephritis, 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.
  • Destructive bone disorders that may be treated or prevented by the compounds of this invention include, but are not limited to, osteoporosis, osteoarthritis and multiple myeloma-related bone disorder.
  • 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 haemangiomas .
  • Infectious diseases that may be treated or prevented by the compounds of this invention include, but are not limited to, sepsis, septic shock, and Shigellosis .
  • Viral diseases that may be treated or prevented by the compounds of this invention include, but are not limited to, acute hepatitis infection (including hepatitis A, hepatitis B and hepatitis C) , HIV infection and CMV retinitis.
  • Neurodegenerative diseases that may be treated or prevented by the compounds of this invention include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) , epilepsy, seizures, Huntington's disease, traumatic brain injury, ischemic and hemorrhaging stroke, cerebral ischemias or neurodegenerative disease, including apoptosis-driven neurodegenerative disease, caused by traumatic injury, acute hypoxia, ischemia or glutamate neurotoxicity.
  • ALS amyotrophic lateral sclerosis
  • JNK-mediated diseases also include ischemia/reperfusion in stroke, heart attacks, myocardial ischemia, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, hepatic ischemia, liver disease, congestive heart failure, pathologic immune responses such as that caused by T cell activation and thrombin-induced platelet aggregation.
  • compounds of the instant invention may be capable of inhibiting the expression of inducible pro-inflammatory proteins. Therefore, other "JNK- mediated conditions" that may be treated by the compounds of this invention include edema, analgesia, fever and pain, such as neuromuscular pain, headache, cancer pain, dental pain and arthritis pain.
  • the compounds of this invention are also useful as inhibitors of Src-family kinases, especially Src and Lck.
  • Src-mediated or Lck-mediated disease as used herein means any disease or other deleterious condition in which Src or Lck is known to play a role. Accordingly, these compounds are useful for treating diseases or conditions that are known to be affected by the activity of one or more Src-family kinases.
  • Such diseases or conditions include hypercalcemia, restenosis, osteoporosis, osteoarthritis, symptomatic treatment of bone metastasis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, lupus, graft vs. host disease, T-cell mediated hypersensitivity disease, Hashimoto's thyroiditis, Guillain-Barre syndrome, chronic obtructive pulmonary disorder, contact dermatitis, cancer, Paget's disease, asthma, ischemic or reperfusion injury, allergic disease, atopic dermatitis, and allergic rhinitis.
  • Diseases that are affected by Src activity include hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis, and Paget's disease.
  • Diseases that are affected by Lck activity include autoimmune diseases, allergies, rheumatoid arthritis, and leukemia.
  • a preferred embodiment relates to the method used to treat or prevent a JNK-mediated disease selected from inflammatory diseases, autoimmune diseases, destructive bone disorders, neurodegenerative diseases, allergies, reperfusion/ischemia in stroke, heart attacks, angiogenic disorders, organ hypoxia, vascular hyperplasia, cardiac hypertrophy, or thrombin-induced platelet aggregation.
  • Another preferred embodiment relates to the method used to treat or prevent a Src- or Lck-mediated disease selected from hypercalcemia, osteoperosis, osteoarthritis, or sympomatic treatment of bone metastasis.
  • 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.
  • 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. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor.
  • 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.
  • Example 2 3-Dimethylamino-l- (5-methyl-3-methylsulfanyl- isoxazol-4-yl) -propenone (Compound 4): To a solution of above prepared compound 3_ (0.375 g, 2.19 mmol) in toluene was added 1.5 ml of dimethylformamide-dimethylacetal . The reaction mixture was heated at 100 °C overnight resulting in complete conversion to product by thin layer chromatography (TLC) . The reaction was partitioned between ethyl acetate and water.
  • TLC thin layer chromatography
  • Example 3 (3, 5-Dimeth.oxy-phenyl) - [4- (5-m.eth.yl-3- methylsulfanyl-isoxazol-4-yl) -pyrimidin-2-yl] -amine (Compound IIA-18) and 4- [2- (3, 5-dimethoxy-phenylamino) - pyrimidin-4-yl] -5-methyl-isoxazol-3-ol (Compound 5): To a solution of the above-prepared compound 4 (200mg, 0.884 mmol) and 3 , 5-dimethoxyphenyl guanidine (207mg, 1.061 mmol) in methanol was added sodium ethoxide (excess) .
  • the reaction was heated at 70 °C overnight in a sealed tube. TLC indicated complete disappearance of starting material 4 and the formation of two distinct products.
  • the reaction was partitioned between ethyl acetate and water and the aqueous layer was extracted with fresh ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo.
  • the crude products were purified by silica gel chromatography (2% MeOH:CH 2 Cl 2 ) to provide 49mg (0.137 mmol) of title compound IIA-18 and 10 mg (0.03 mmol) of title compound 5.
  • Example 5 (3, 5-Dimethoxy-phenyl) - [4- (5-methyl-3- piperidin-l-yl-isoxazol-4-yl) -pyrimidin-2-yl] -amine (Compound ID-4) : To a solution of the above-prepared compound 6_ (7 mg, 0.019 mmol) in ethanol (1.5 ml) was added piperidine (0.01 ml, excess). The reaction mixture was heated at 70 °C overnight resulting in conversion to product by LC/MS . The mixture was evaporated using a pierce block evaporator and purified by reverse phase preparative HPLC giving the title compound (1.7 mg, 0.004 mmol) .
  • Example 6 Src Inhibition Assays The compounds were evaluated as inhibitors of human src kinase using either a radioactivity-based assay or spectrophotometric assay.
  • all the reaction components with the exception of ATP were pre-mixed and aliquoted into assay plate wells.
  • Inhibitors dissolved in DMSO were added to the wells to give a final DMSO concentration of 2.5%.
  • the assay plate was incubated at 30 °C for 10 minutes before initiating the reaction with 33 P-ATP. After 20 minutes of reaction, the reactions were quenched with 150 ⁇ l of 10% trichloroacetic acid (TCA) containing 20 mM Na 3 P0 4 . The quenched samples were then transferred to a 96-well filter plate (Whatman, UNI-Filter GF/F Glass Fiber
  • Filter cat no. 7700-3310 installed on a filter plate vacuum manifold. Filter plates were washed four times with 10% TCA containing 20 mM Na 3 P0 and then 4 times with methanol . 200 ⁇ l of scintillation fluid was then added to each well. The plates were sealed and the amount of radioactivity associated with the filters was quantified on a TopCount scintillation counter. The radioactivity incorporated was plotted as a function of the inhibitor concentration. The data was fitted to a competitive inhibition kinetics model to get the Ki for the compound.
  • the ADP produced from ATP by the human recommbinant src kinase-catalyzed phosphorylation of poly Glu-Tyr substrate was quanitified using a coupled enzyme assay (Fox et al (1998) Protein Sci 1 , 2249) .
  • a coupled enzyme assay Fox et al (1998) Protein Sci 1 , 2249) .
  • this assay one molecule of NADH is oxidized to NAD for every molecule of ADP produced in the kinase reaction. The disappearance of NADH can be conveniently followed at 340 nm.
  • Example 7 Lck Inhibition Assays The compounds were evaluated as inhibitors of human src kinase using either a radioactivity-based assay or spectrophotometric assay.
  • all the reaction components with the exception of ATP were pre-mixed and aliquoted into assay plate wells.
  • Inhibitors dissolved in DMSO were added to the wells to give a final DMSO concentration of 2.5%.
  • the assay plate was incubated at 30 °C for 10 minutes before initiating the reaction with 150 ⁇ M ATP.
  • the absorbance change at 340 nm with time, the rate of the reaction was monitored on a molecular devices plate reader.
  • the data of rate as a function of the inhibitor concentration was fitted to competitive inhibition kinetics model to get the Ki for the compound.
  • Many of the present compounds tested in the Lck inhibition assays provided an IC 50 value below one micromolar.
  • a BLAST search of the EST database using the published JNK3 ⁇ l cDNA as a query identified an EST clone (#632588) that contained the entire coding sequence for human JNK30C1.
  • Polymerase chain reactions (PCR) using pfu polymerase (Strategene) are used to introduce restriction sites into the cDNA for cloning into the pET-15B expression vector at the Ncol and BamHI sites.
  • the protein is expressed in E. coli . Due to the poor solubility of the expressed full-length protein (Met 1- Gln 422) , an N-terminally truncated protein starting at Ser residue at position 40 (Ser 40) is produced.
  • This truncation corresponds to Ser 2 of JNK1 and JNK2 proteins, and is preceded by a methionine (initiation) and a glycine residue.
  • the glycine residue is added in order to introduce an Ncol site for cloning into the expression vector.
  • systematic C-terminal truncations are performed by PCR to identify a construct that give rise to diffraction-quality crystals.
  • One such construct encodes amino acid residues Ser40-Glu402 of JNK30C1 and is preceded by Met and Gly residues.
  • the construct is prepared by PCR using deoxyoligonucleotides : 5' GCTCTAGAGCTCCATGGGCAGCA ⁇ AAGCAAAGTTGACAA 3' (forward primer with initiation codon underlined) (SEQ ID NO:l) and 5' TAGCGGATCCTCATTCTGAATTCATTACTTCCTTGTA 3' (reverse primer with stop codon underlined) (SEQ ID NO: 2) as primers and is confirmed by DNA sequencing.
  • SEQ ID NO: 2 forward primer with initiation codon underlined
  • SEQ ID NO: 2 reverse primer with stop codon underlined
  • E. coli strain BL21 (DE3) (Novagen) is transformed with the JNK3 expression construct and grown at 30°C in LB supplemented with 100 ⁇ g/ml carbenicillin in shaker flasks until the cells were in log phase (OD 6 oo ⁇ 0.8).
  • Isopropylthio- ⁇ -D-galactosidase (IPTG) is added to a final concentration of 0.8 mM and the cells are harvested 2 hours later by centrifugation.
  • E. coli cell paste containing JNK3 is resuspended in 10 volumes/g lysis buffer (50 mM HEPES, pH 7.2, containing 10% glycerol (v/v) , 100 mM NaCl, 2 mM DTT, 0.1 mM PMSF, 2 ⁇ g/ml Pepstatin, I ⁇ g/ml each of E-64 and Leupeptin) .
  • lysis buffer 50 mM HEPES, pH 7.2, containing 10% glycerol (v/v) , 100 mM NaCl, 2 mM DTT, 0.1 mM PMSF, 2 ⁇ g/ml Pepstatin, I ⁇ g/ml each of E-64 and Leupeptin
  • the 100,000 x g supernatant is diluted 1:5 with Buffer A (20 mM HEPES, pH 7.0, 10% glycerol (v/v) , 2 mM DTT) and purified by SP-Sepharose (Pharmacia) cation-exchange chromatography (column dimensions: 2.6 x 20 cm) at 4 °C.
  • the resin is washed with 5 column volumes of Buffer A, followed by 5 column volumes of Buffer A containing 50 mM NaCl .
  • Bound JNK3 is eluted with a 7.5 column volume linear gradient of 50-300 mM NaCl. JNK3 eluted between 150-200 mM NaCl.
  • HEPES buffer pH 7.5, containing 100 mM NaCl, 5 mM DTT, 20 mM MgCl 2 and 1 mM ATP.
  • GST-MKK7 (DD) is added at a molar ratio of 1:2.5 GST-MKK7 : JNK3. After incubation for 30 minutes at 25°C, the reaction mixture is concentrated 5-fold by ultrafiltration in a Centriprep-30 (Amicon,
  • JNK3 by a spectrophotometric coupled-enzyme assay.
  • a fixed concentration of activated JNK3 (10 nM) is incubated with various concentrations of a potential inhibitor dissolved in DMSO for 10 minutes at 30°C in a buffer containing 0.1 M HEPES buffer, pH 7.5, containing 10 mM MgCl 2 , 2.5 mM phosphoenolpyruvate, 200 ⁇ M NADH, 150 ⁇ g/mL pyruvate kinase, 50 ⁇ g/mL lactate dehydrogenase, and 200 ⁇ M EGF receptor peptide.
  • the EGF receptor peptide has the sequence
  • KR ⁇ LVEPLTPSGEAPNQALLR(SEQ ID NO : 3 ) is a phosphoryl acceptor in the JNK3-catalyzed kinase reaction.
  • the reaction is initiated by the addition of 10 ⁇ M ATP and the assay plate is inserted into the spectrophotometer' s assay plate compartment that is maintained at 30°C.
  • the decrease of absorbance at 340 nm is monitored as a function of time.
  • the rate data as a function of inhibitor concentration is fitted to competitive inhibition kinetic model to determine the Ki.

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Abstract

La présente invention concerne des composés représentés par la formule I. Dans cette formule A est N ou CR et R1, G et R2 sont tels que décrits dans les spécifications. Ces composés sont des inhibiteurs de protéine kinase, en particulier de protéine kinase Src de mammifère impliquée dans la prolifération cellulaire, dans la mort cellulaire et dans la réponse aux stimuli extracellulaires. Cette invention concerne aussi des techniques de production de ces inhibiteurs. Cette invention concerne enfin des compositions pharmaceutiques comprenant ces inhibiteurs et des techniques d'utilisation de ces compositions dans le traitement et la prévention de pathologies diverses.
PCT/US2002/011609 2001-04-10 2002-04-10 Derives d'isoxaxole utilises comme inhibiteurs de proteines kinases src et d'autres proteines kinases WO2002083668A1 (fr)

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EP02731356A EP1377572A1 (fr) 2001-04-10 2002-04-10 Derives d'isoxaxole utilises comme inhibiteurs de proteines kinases src et d'autres proteines kinases
JP2002581423A JP2005500261A (ja) 2001-04-10 2002-04-10 Ｓｒｃおよび他のプロテインキナーゼのインヒビターとしてのイソキサゾール誘導体
CA002443234A CA2443234A1 (fr) 2001-04-10 2002-04-10 Derives d'isoxaxole utilises comme inhibiteurs de proteines kinases src et d'autres proteines kinases
MXPA03009257A MXPA03009257A (es) 2001-04-10 2002-04-10 Derivados de isoxaxol como inhibidores de src y otras proteinas cinasas.

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US60/282,935 2001-04-10

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004017968A1 (fr) * 2002-08-19 2004-03-04 Merckle Gmbh Derives d'isoxazole substitues et leur utilisation en pharmacie
WO2004041814A1 (fr) * 2002-11-04 2004-05-21 Vertex Pharmaceuticals Incorporated Derives d'heteroaryle pyrimidine utilises comme inhibiteurs de jak (janus kinase)
WO2005028475A2 (fr) * 2003-09-04 2005-03-31 Vertex Pharmaceuticals Incorporated Compositions utiles pour inhiber des proteines kinases
EP1567160A2 (fr) * 2002-11-18 2005-08-31 The Scripps Research Institute Procede de traitement de l'infarctus du myocarde
WO2006044457A1 (fr) * 2004-10-13 2006-04-27 Wyeth Analogues d'anilino-pyrimidine a substitution n-benzenesulfonyle
WO2006070927A1 (fr) * 2004-12-28 2006-07-06 Aska Pharmaceutical Co., Ltd. Derive de pyrimidinylisoxazole
EP1417205B1 (fr) * 2001-07-03 2006-08-23 Vertex Pharmaceuticals Incorporated Isoxazolyl-pyrimidines utilisees en tant qu'inhibiteurs des proteines kinases src et lck
JP2008502729A (ja) * 2004-06-10 2008-01-31 アイアールエム・リミテッド・ライアビリティ・カンパニー タンパク質キナーゼ阻害剤としての化合物および組成物
JP2008526692A (ja) * 2004-12-31 2008-07-24 ▲飄▼▲揚▼ ▲孫▼ アミノピリミジン類の化合物及びその塩の調製方法と薬物の用途
JP2013504532A (ja) * 2009-09-10 2013-02-07 エフ．ホフマン−ラ ロシュ アーゲー Ｊａｋの阻害剤
WO2016016894A1 (fr) 2014-07-30 2016-02-04 Yeda Research And Development Co. Ltd. Milieux pour la culture de cellules souches pluripotentes
WO2020152686A1 (fr) 2019-01-23 2020-07-30 Yeda Research And Development Co. Ltd. Milieux de culture pour cellules souches pluripotentes
CN115677617A (zh) * 2022-11-04 2023-02-03 济南大学 一种靶向c-Src激酶SH3结构域的化合物及其应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001012621A1 (fr) * 1999-08-13 2001-02-22 Vertex Pharmaceuticals Incorporated INHIBITEURS DE c-JUN N-TERMINAL KINASES (JNK) ET D'AUTRES PROTEINES-KINASES

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001012621A1 (fr) * 1999-08-13 2001-02-22 Vertex Pharmaceuticals Incorporated INHIBITEURS DE c-JUN N-TERMINAL KINASES (JNK) ET D'AUTRES PROTEINES-KINASES

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1417205B1 (fr) * 2001-07-03 2006-08-23 Vertex Pharmaceuticals Incorporated Isoxazolyl-pyrimidines utilisees en tant qu'inhibiteurs des proteines kinases src et lck
WO2004017968A1 (fr) * 2002-08-19 2004-03-04 Merckle Gmbh Derives d'isoxazole substitues et leur utilisation en pharmacie
WO2004041814A1 (fr) * 2002-11-04 2004-05-21 Vertex Pharmaceuticals Incorporated Derives d'heteroaryle pyrimidine utilises comme inhibiteurs de jak (janus kinase)
US7259161B2 (en) 2002-11-04 2007-08-21 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of JAK and other protein kinases
EP1567160A4 (fr) * 2002-11-18 2009-06-10 Scripps Research Inst Procede de traitement de l'infarctus du myocarde
EP1567160A2 (fr) * 2002-11-18 2005-08-31 The Scripps Research Institute Procede de traitement de l'infarctus du myocarde
WO2005028475A3 (fr) * 2003-09-04 2005-06-09 Vertex Pharma Compositions utiles pour inhiber des proteines kinases
US7446199B2 (en) 2003-09-04 2008-11-04 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of protein kinases
WO2005028475A2 (fr) * 2003-09-04 2005-03-31 Vertex Pharmaceuticals Incorporated Compositions utiles pour inhiber des proteines kinases
JP2008502729A (ja) * 2004-06-10 2008-01-31 アイアールエム・リミテッド・ライアビリティ・カンパニー タンパク質キナーゼ阻害剤としての化合物および組成物
JP4688876B2 (ja) * 2004-06-10 2011-05-25 アイアールエム・リミテッド・ライアビリティ・カンパニー タンパク質キナーゼ阻害剤としての化合物および組成物
WO2006044457A1 (fr) * 2004-10-13 2006-04-27 Wyeth Analogues d'anilino-pyrimidine a substitution n-benzenesulfonyle
US7799915B2 (en) 2004-10-13 2010-09-21 Wyeth Llc Anilino-pyrimidine analogs
WO2006070927A1 (fr) * 2004-12-28 2006-07-06 Aska Pharmaceutical Co., Ltd. Derive de pyrimidinylisoxazole
US7939536B2 (en) 2004-12-28 2011-05-10 Aska Pharmaceutical Co., Ltd. Pyrimidinylisoxazole derivatives
KR101181692B1 (ko) 2004-12-28 2012-09-19 아스카 세이야쿠 가부시키가이샤 피리미디닐이속사졸 유도체
JP5100126B2 (ja) * 2004-12-28 2012-12-19 あすか製薬株式会社 ピリミジニルイソオキサゾール誘導体
JP2008526692A (ja) * 2004-12-31 2008-07-24 ▲飄▼▲揚▼ ▲孫▼ アミノピリミジン類の化合物及びその塩の調製方法と薬物の用途
JP4698681B2 (ja) * 2004-12-31 2011-06-08 ▲飄▼▲揚▼ ▲孫▼ アミノピリミジン類の化合物及びその塩の調製方法と薬物の用途
JP2013504532A (ja) * 2009-09-10 2013-02-07 エフ．ホフマン−ラ ロシュ アーゲー Ｊａｋの阻害剤
WO2016016894A1 (fr) 2014-07-30 2016-02-04 Yeda Research And Development Co. Ltd. Milieux pour la culture de cellules souches pluripotentes
WO2020152686A1 (fr) 2019-01-23 2020-07-30 Yeda Research And Development Co. Ltd. Milieux de culture pour cellules souches pluripotentes
CN115677617A (zh) * 2022-11-04 2023-02-03 济南大学 一种靶向c-Src激酶SH3结构域的化合物及其应用
CN115677617B (zh) * 2022-11-04 2023-12-26 济南大学 一种靶向c-Src激酶SH3结构域的化合物及其应用

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