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  Novel indazole peptidomimetics as thrombin receptor antagonistsUSPTO Application #: 20060166896Title: Novel indazole peptidomimetics as thrombin receptor antagonists Abstract: The invention is directed to novel indazole peptidomimetic compounds which are useful as thrombin receptor antagonists for the treatment of diseases associated with thrombosis, restenosis, hypertension, heart failure, arrhythmia, inflammation, angina, stroke, atherosclerosis, ischemic conditions, Angiogenesis related disorders, cancer, and neurodegenerative disorders. Pharmaceutical compositions comprising the substituted indazole peptidomimetics of the present invention and methods of treating conditions mediated by the thrombin receptor are also disclosed. (end of abstract) Agent: Philip S. Johnson, Esq. Johnson & Johnson - New Brunswick, NJ, US Inventors: Han-Cheng Zhang, Bruce E. Maryanoff, Anjali Pandey, Robert M. Scarborough USPTO Applicaton #: 20060166896 - Class: 514019000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides, 2 Peptide Repeating Units In Known Peptide Chain The Patent Description & Claims data below is from USPTO Patent Application 20060166896. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This patent application is a divisional of patent application Ser. No. 10/403,218, filed on Mar. 31, 2003, currently pending, which is a division of patent application Ser. No. 09/603,338, filed on Jun. 26, 2000, now abandoned, which claims priority from provisional patent application Ser. No. 60/141,553, which was filed on Jun. 29, 1999. FIELD OF THE INVENTION [0002] This invention relates to certain novel thrombin receptor antagonists, their synthesis and their use for the treatment of diseases associated with thrombosis, restenosis, hypertension, heart failure, arrhythmia, inflammation, angina, stroke, atherosclerosis, ischemic conditions, angiogenesis related disorders, cancer, and neurodegenerative disorders. BACKGROUND OF THE INVENTION [0003] Thrombin is an important serine protease in hemostasis and thrombosis. One of the key actions of thrombin is cellular modulation via receptor activation. A functional human thrombin receptor (PAR-1), cloned by Coughlin in 1991 (T.-K. Vu, Cell 1991, 64, 1057), was found to be a member of the G-protein coupled receptor (GPCR) superfamily. The receptor activation putatively occurs by N-terminal recognition and proteolytic cleavage at the Arg-41/Ser-42 peptide bond to reveal a truncated N-terminus. This new receptor sequence, which has an SFLLRN (Ser-Phe-Leu-Leu-Arg-Asn) (SEQ. ID. NO. 1) N-terminus acting as a tethered ligand to recognize a site on the receptor, can trigger activation and signal transduction leading to platelet aggregation. Since 1991, three other protease-activated receptors with extensive homology to the thrombin receptor, "PAR-2" (S. Nystedt, Proc. Natl. Acad. Sci USA 1994, 91, 9208), "PAR-3" (H. Ishihara, Nature 1997, 386, 502), and "PAR-4" (W.-F. Xu, Proc. Natl. Acad. Sci USA 1998, 95, 6642), have been cloned. Thrombin receptor (PAR-1) specific antibody-induced blockade of the platelet thrombin receptor has shown efficacy against arterial thrombosis in vivo (J. J. Cook Circulation 1995, 91, 2961). Hence, antagonists of the thrombin receptor (PAR-1) are useful to block these protease-activated receptors and, as such, may be used to treat platelet mediated thrombotic disorders such as myocardial infarction, stroke, restenosis, angina, atherosclerosis, and ischemic conditions. [0004] The thrombin receptor (PAR-1) has also been identified on other cell types: endothelial, fibroblast, renal, osteosarcoma, smooth muscle, myocytes, tumor, and neuronal/glia. Thrombin activation of endothelial cells upregulates P-selectin to induce polymorphonuclear leukocyte adhesion--an inflammatory response of the vessel wall (Y. Sugama, J. Cell Biol. 1992, 119, 935). In fibroblasts, thrombin receptor (PAR-1) activation induces proliferation and transmission of mitogenic signals (D. T. Hung, J. Cell Biol. 1992, 116, 827). Thrombin has been implicated in osteoblast proliferation through its activation of osteoblast cells (D. N. Tatakis, Biochem. Biophys. Res. Commun. 1991, 174, 181). Thrombin has been implicated in the regulation and retraction of neurons (K. Jalink, J. Cell. Biol. 1992, 118, 411). Therefore, in this context, the antagonist compounds of this invention may also be useful against inflammation, osteoporosis, Angiogenesis related disorders, cancer, neurodegenerative disorders, hypertension, heart failure, arrhythmia, glomerulonephritis. [0005] The compounds of the present invention are a structurally novel class of indazole peptidomimetics represented by the general formula (I) below. SUMMARY OF THE INVENTION [0006] The present invention is directed to structurally novel compounds represented by the following general formula (I): wherein [0007] A.sub.1 and A.sub.2 are each independently a D- or L-amino acid selected from the group consisting of alanine, .quadrature.-alanine, arginine, homoarginine, cyclohexylalanine, citrulline, cysteine (optionally substituted with C.sub.1-C.sub.4 alkyl, aryl, or arC.sub.1-C.sub.4 alkyl), 2,4-diaminobutyric acid (optionally substituted with acyl, C.sub.1-C.sub.4 alkyl, aroyl, amidino, or MeC(NH)--), 2,3 diaminopropionic acid (optionally substituted with acyl, C.sub.1-C.sub.4 alkyl, aroyl, amidino, or MeC(NH)--), glutamine, glycine, indanylglycine, lysine (optionally substituted with acyl, C.sub.1-C.sub.4 alkyl, aroyl, MeC(NH)--), valine, methionine, proline, serine (optionally substituted with C.sub.1-C.sub.4 alkyl, aryl, or arC.sub.1-C.sub.4 alkyl), homoserine (optionally substituted with C.sub.1-C.sub.4 alkyl, aryl, or arC.sub.1-C.sub.4 alkyl), tetrahydroisoquinoline-3-COOH, threonine (optionally substituted with C.sub.1-C.sub.4 alkyl, aryl, or arC.sub.1-C.sub.4 alkyl), ornithine (optionally substituted with acyl, C.sub.1-C.sub.4 alkyl, aroyl, MeC(NH)--), and an unsubstituted or substituted aromatic amino acid selected from the group consisting of phenylalanine, heteroarylalanine, naphthylalanine, homophenylalanine, histidine, tryptophan, tyrosine, arylglycine, heteroarylglycine, aryl-.beta.-alanine, and heteroaryl-.beta.-alanine wherein the substituents on the aromatic amino acid are independently selected from one or more of halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, hydroxy, C.sub.1-C.sub.4 alkoxycarbonyl, amino, amidino, guanidino, fluorinated C.sub.1-C.sub.4 alkyl, fluorinated C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkylsulfonyl, C.sub.1-C.sub.4 alkylcarbonyl, cyano, aryl, heteroaryl, arC.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, alkynyl, or nitro; [0008] R.sub.1 is selected from amino, C.sub.1-C.sub.8 alkylamino, C.sub.1-C.sub.8 dialkylamino, arylamino, arC.sub.1-C.sub.8 alkylamino, C.sub.3-C.sub.8 cycloalkylamino, heteroalkylC.sub.1-C.sub.8 alkylamino, heteroalkylC.sub.1-C.sub.8 alkyl-N-methylamino, C.sub.1-C.sub.8 dialkylaminoC.sub.1-C.sub.8 alkylamino, --N(C.sub.1-C.sub.8alkyl)-C.sub.1-C.sub.8 alkyl-N(C.sub.1-C.sub.8alkyl).sub.2, N(C.sub.1-C.sub.8alkyl)(C.sub.1-C.sub.8alkenyl), --N(C.sub.1-C.sub.8alkyl)(C.sub.3-C.sub.8cycloalkyl), heteroalkyl or substituted heteroalkyl wherein the substituent on the heteroalkyl is selected from oxo, amino, C.sub.1-C.sub.8 alkoxyC.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkylamino or C.sub.1-C.sub.8 dialkylamino; [0009] Preferably, R.sub.1 is selected from amino, C.sub.1-C.sub.6 alkylamino, C.sub.1-C.sub.6 dialkylamino, arylamino, arC.sub.1-C.sub.6 alkylamino, heteroalkylC.sub.1-C.sub.6 alkylamino, --N(C.sub.1-C.sub.6alkyl)-C.sub.1-C.sub.6alkyl-N(C.sub.1-C.sub.6alkyl).su- b.2, heteroalkyl or substituted heteroalkyl wherein the substituent on the heteroalkyl is selected from oxo, amino, C.sub.1-C.sub.6 alkoxyC.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylamino or C.sub.1-C.sub.6 dialkylamino; [0010] R.sub.2 and R.sub.3 are each independently selected from hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkylC.sub.1-C.sub.8 alkyl, aryl, heteroalkyl, substituted heteroalkyl (wherein the substituent on the heteroalkyl is one or more substituents independently selected from C.sub.1-C.sub.8 alkoxycarbonyl, C.sub.1-C.sub.8 alkyl, or C.sub.1-C.sub.4 alkylcarbonyl), heteroalkylC.sub.1-C.sub.8 alkyl, indanyl, acetamidinoC.sub.1-C.sub.8 alkyl, aminoC.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkylaminoC.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 dialkylaminoC.sub.1-C.sub.8 alkyl, unsubstituted or substituted heteroarylC.sub.1-C.sub.8 alkyl or unsubstituted or substituted arC.sub.1-C.sub.8 alkyl, wherein the substituent on the aralkyl or heteroarylalkyl group is one or more substituents independently selected from halogen, nitro, amino, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy, hydroxy, cyano, C.sub.1-C.sub.4 alkylcarbonyl, C.sub.1-C.sub.8 alkoxycarbonyl, hydroxyC.sub.1-C.sub.8 alkyl or aminosulfonyl; or [0011] R.sub.2 and R.sub.3 together with the nitrogen to which they are attached, alternatively form an unsubstituted or substituted heteroalkyl group selected from piperidinyl, piperazinyl, morpholinyl or pyrrolidinyl, wherein the substituent is one or more substituents independently selected from C.sub.1-C.sub.8 alkyl C.sub.1-C.sub.8 alkoxycarbonyl or C.sub.1-C.sub.4 alkylcarbonyl; [0012] Preferably, R.sub.2 is selected from hydrogen or C.sub.1-C.sub.6 alkyl; and [0013] R.sub.3 is selected from C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.3-C.sub.6 cycloalkylC.sub.1-C.sub.6 alkyl, aryl, heteroarylC.sub.1-C.sub.6 alkyl, substituted heteroarylC.sub.1-C.sub.6 alkyl wherein the substituent is C.sub.1-C.sub.4 alkyl, heteroalkyl, heteroalkylC.sub.1-C.sub.6 alkyl, indanyl, acetamidinoC.sub.1-C.sub.6 alkyl, aminoC.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkylaminoC.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 dialkylaminoC.sub.1-C.sub.6 alkyl, arC.sub.1-C.sub.8 alkyl, substituted arC.sub.1-C.sub.8 alkyl wherein the substituent on the aralkyl group is one to five substituents independently selected from halogen, nitro, amino, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkoxycarbonyl, hydroxyalkyl or aminosulfonyl; or [0014] R.sub.2 and R.sub.3, together with the nitrogen to which they are attached, alternatively form an unsubstituted or substituted heteroalkyl group selected from piperidinyl, piperazinyl or pyrrolidinyl, wherein the substituent is independently one or two substituents selected from C.sub.1-C.sub.6 alkyl; [0015] R.sub.4 is selected from unsubstituted or substituted aryl, arC.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, or heteroaryl, where the substituents on the aryl, arC.sub.1-C.sub.8 alkyl, cycloalkyl or heteroaryl group are independently selected from one or more of halogen, nitro, amino, cyano, hydroxyalkyl, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 alkoxy, hydroxy, C.sub.1-C.sub.4 alkylcarbonyl, C.sub.1-C.sub.8 alkoxycarbonyl, fluorinated C.sub.1-C.sub.4 alkyl, fluorinated C.sub.1-C.sub.4 alkoxy or C.sub.1-C.sub.4 alkylsulfonyl; [0016] Preferably, R.sub.4 is selected from unsubstituted or substituted aryl, arC.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 cycloalkyl or heteroaryl, where the substituents on the aryl, aralkyl, cycloalkyl or heteroaryl group are independently selected from one to three substituents selected from halogen, cyano, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxycarbonyl, fluorinated C.sub.1-C.sub.4 alkyl, fluorinated C.sub.1-C.sub.4 alkoxy or C.sub.1-C.sub.4 alkylsulfonyl; [0017] R.sub.5 is selected from hydrogen or C.sub.1-C.sub.8 alkyl; preferably, R.sub.5 is hydrogen [0018] X is oxygen or sulfur; preferably, X is oxygen; [0019] m is an integer selected from 0, 1, 2 or 3; [0020] n is an integer selected from 1 or 2; Continue reading... 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