Claims
- 1. A compound of the following formula (I):
- 2. The compound of claim 1, wherein:
A1 and A2 are each independently an L-amino acid selected from the group consisting of alanine, β-alanine, arginine, homoarginine, cyclohexylalanine, citrulline, cysteine (optionally substituted with C1-C4 alkyl, aryl, or arC1-C4 alkyl), 2,4-diaminobutyric acid (optionally substituted with acyl, C1-C4 alkyl, aroyl, amidino, or MeC(NH)—), 2,3-diaminopropionic acid (optionally substituted with acyl, C1-C4 alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine, indanylglycine lysine (optionally substituted with acyl, C1-C4 alkyl, aroyl, MeC(NH)—), valine, methionine, proline, serine (optionally substituted with C1-C4 alkyl, aryl, or arC1-C4 alkyl), homoserine (optionally substituted with C1-C4 alkyl, aryl, or arC1-C4 alkyl), tetrahydroisoquinoline-3-COOH, threonine (optionally substituted with C1-C4 alkyl, aryl, or arC1-C4 alkyl), ornithine (optionally substituted with acyl, C1-C4 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-β-alanine, and heteroaryl-β-alanine wherein the substituents on the aromatic amino acid are independently selected from one or more of halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, C1-C4 alkoxycarbonyl, amino, amidino, guanidino, fluorinated C1-C4 alkyl, fluorinated C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 alkylcarbonyl, cyano, aryl, heteroaryl, arC1-C4 alkyl, C2-C4 alkenyl, alkynyl, or nitro; R1 is selected from amino, C1-C6 alkylamino, C1-C6 dialkylamino, arylamino, arC1-C6 alkylamino, heteroalkylC1-C6 alkylamino, —N(C1-C6 alkyl)-C1-C6 alkyl-N(C1-C6 alkyl)2, heteroalkyl or substituted heteroalkyl wherein the substituent on the heteroalkyl is selected from oxo, amino, C1-C6 alkoxy C1-C6 alkyl, C1-C6 alkylamino or C1-C6 dialkylamino; R2 is selected from hydrogen, halogen or phenyl; R3 is selected from hydrogen or C1-C6 alkyl; R4 is selected from C1-C8 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkylC1-C6 alkyl, aryl, heteroarylC1-C6 alkyl, substituted heteroarylC1-C6 alkyl wherein the substituent is C1-C4 alkyl, heteroalkyl, heteroalkylC1-C6 alkyl, indanyl, acetamidinoC1-C6 alkyl, aminoC1-C6 alkyl, C1-C6 alkylaminoC1-C6 alkyl, C1-C6 dialkylaminoC1-C6 alkyl, arC1-C8 alkyl, substituted arC1-C8 alkyl wherein the substituent on the aralkyl group is one to five substituents independently selected from halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, hydroxyalkyl or aminosulfonyl; or R3 and R4, 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 C1-C6 alkyl; R5 is selected from unsubstituted or substituted aryl, arC1-C6 alkyl, C3-C6 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, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, fluorinated C1-C4 alkyl, fluorinated C1-C4 alkoxy or C1-C4 alkylsulfonyl; R6 is hydrogen; and X is oxygen; and p is 1; and pharmaceutically acceptable salts thereof.
- 3. The compound of claim 2, wherein:
A1 is an L-amino acid selected from the group consisting of alanine, arginine, cyclohexylalanine, glycine, proline, tetrahydroisoquinoline-3-COOH, and an unsubstituted or substituted aromatic amino acid selected from the group consisting of phenylalanine, naphthylalanine, homophenylalanine, and O-methyl tyrosine, wherein the substituents on the aromatic amino acid are independently one to five substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, C1-C4 alkoxycarbonyl, amino, amidino, guanidino, fluorinated C1-C4 alkyl, fluorinated C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 alkylcarbonyl, cyano, aryl, heteroaryl, arC1-C4 alkyl, C2-C4 alkenyl, alkynyl, or nitro; A2 is an L-amino acid selected from the group consisting of alanine, β-alanine, arginine, citrulline, cysteine (optionally substituted with C1-C4 alkyl, aryl, or arC1-C4 alkyl), 2,4-diaminobutyric acid (optionally substituted with acyl, C1-C4 alkyl, aroyl, amidino, or MeC(NH)—), 2,3-diaminopropionic acid (optionally substituted with acyl, C1-C4 alkyl, aroyl, amidino, or MeC(NH)—), glutamine, glycine, lysine (optionally substituted with acyl, C1-C4 alkyl, aroyl, MeC(NH)—), valine, methionine, serine (optionally substituted with C1-C4 alkyl, aryl, or arC1-C4 alkyl), homoserine (optionally substituted with C1-C4 alkyl, aryl, or arC1-C4 alkyl), threonine (optionally substituted with C1-C4 alkyl, aryl, or arC1-C4 alkyl), ornithine (optionally substituted with acyl, C1-C4 alkyl, aroyl, MeC(NH)—), and an unsubstituted or substituted aromatic amino acid selected from the group consisting of phenylalanine, heteroarylalanine, and histidine, wherein the substituents of the aromatic amino acid are independently one to five substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, hydroxy, C1-C4 alkoxycarbonyl, amino, amidino, guanidino, fluorinated C1-C4 alkyl, fluorinated C1-C4 alkoxy, C1-C4 alkylsulfonyl, C1-C4 alkylcarbonyl, cyano, aryl, heteroaryl, arC1-C4 alkyl, C2-C4 alkenyl, alkynyl, or nitro; R2 is selected from hydrogen, chlorine or phenyl; R3 is selected from hydrogen or C1-C4 alkyl; and m and n are both 1; and pharmaceutically acceptable salts thereof.
- 4. The compound of claim 3 of the formula:
- 5. The compound of claim 4, wherein:
R1 is 29and pharmaceutically acceptable salts thereof.
- 6. The compound of claim 5, wherein:
R5 is selected from 30and pharmaceutically acceptable salts thereof.
- 7. The compound of claim 6, wherein:
A1 is selected from 3,4-Difluorophenylaianine or 4-Chlorophenylalanine; A2 is selected from 2,4-Diaminobutyric acid or 4-Pyridylalanine; R3 is hydrogen; and R4 is selected from benzyl or 2-aminoethyl; and pharmaceutically acceptable salts thereof.
- 8. A compound of the formula (11):
- 9. A process for preparing a compound of the formula (III):
- 10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1.
- 11. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
- 12. A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.
- 13. A method of treating a condition selected from the group consisting of thrombosis, restenosis, hypertension, heart failure, arrhythmia, myocardial infarction, glomerulonephritis, reocclusion following thrombolytic therapy, reocclusion following angioplasty, inflammation, angina, stroke, atherosclerosis, ischemic conditions, a vaso-occlusive disorder, neurodegenerative disorders, Angiogenesis related disorders and cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim 1.
- 14. The method of claim 13, wherein the therapeutically effective amount of the compound is from about 0.1 mg/kg/day to about 300 mg/kg/day.
- 15. A method of treating a condition selected from the group consisting of thrombosis, restenosis, hypertension, heart failure, arrhythmia, myocardial infarction, glomerulonephritis, reocclusion following thrombolytic therapy, reocclusion following angioplasty, inflammation, angina, stroke, atherosclerosis, ischemic conditions, a vaso-occlusive disorder, neurodegenerative disorders, Angiogenesis related disorders and cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition of claim 10.
- 16. The method of claim 15, wherein the therapeutically effective amount of the compound is from about 0.1 mg/kg/day to about 300 mg/kg/day.
- 17. A method of inhibiting platelet aggregation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim 1.
- 18. The method of claim 17, wherein the therapeutically effective amount of the compound is from about 0.1 mg/kg/day to about 300 mg/kg/day.
- 19. A method of inhibiting platelet aggregation in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition of claim 10.
- 20. The method of claim 19, wherein the therapeutically effective amount of the compound is from about 0.1 mg/kg/day to about 300 mg/kg/day.
- 21. A method of treating a condition mediated by thrombin receptor (PAR-1) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim 1.
- 22. The method of claim 21, wherein the therapeutically effective amount of the compound is from about 0.1 mg/kg/day to about 300 mg/kg/day.
- 23. A method of treating a condition mediated by thrombin receptor (PAR-1) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the composition of claim 10.
- 24. The method of claim 23, wherein the therapeutically effective amount of the compound is from about 0.1 mg/kg/day to about 300 mg/kg/day.
FIELD OF THE INVENTION
[0001] This patent application claims priority from provisional patent application Serial No. 60/141,550, which was filed on Jun. 29, 1999. 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.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60141550 |
Jun 1999 |
US |
Divisions (1)
|
Number |
Date |
Country |
Parent |
09603231 |
Jun 2000 |
US |
Child |
10403542 |
Mar 2003 |
US |