Claims
- 1. A compound according to formula (I),
- 2. A compound according to claim 1, or a stereoisomer or a pharmaceutically-acceptable salt thereof, wherein the compound is of formula (Ia):
- 3. A compound according to claim 2, wherein:
X is selected from —OH, —O(phenyl), —O(benzyl), —NH(phenyl), and wherein each phenyl or benzyl group is optionally subsituted with one to two R25, W is hydrogen or —(CH2)q—H; Z is selected from the group: 55R1 and R2 are OR12; R9 is selected from hydrogen, halogen, alkyl, substituted alkyl, haloalkyl, haloalkoxy, cyano, nitro, —S(O)uR21, —NR22SO2R21, —C(═O)NR22R23, —OR22, —CO2R22, —C(═O)R22, —SR22, —NR22R23, —NR22CO2R23, —NR22C(═O)R23, —NR22C(═O)NR23R24, —SO2NR22R23, —NR22SO2NR23R24, five or six membered heterocyclo or heteroaryl, phenyl, and C3-7cycloalkyl; R12, R22, R23 and R24 are selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, or heterocyclo; R21 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, heteroaryl, cycloalkyl, and heterocyclo; R25 at each occurrence is selected from C1-4alkyl, C1-4alkoxy, C1-4hydroxyalkyl, C1-4aminoalkyl, halogen, hydroxy, haloalkyl, haloalkoxy, amino, C1-4alkylamino, and/or cyano; q is 1, 2 or 3; s is 0, 1, or 2; and u is 1 or 2; provided that when Z is phenyl, R9 and/or R11 are other than cyano or —C(═NR22)NR23R24.
- 4. A compound according to claim 1, or a stereoisomer or a pharmaceutically-acceptable salt thereof, wherein the compound is of formula (Ib),
- 5. A compound according to claim 1, or a stereoisomer or a pharmaceutically-acceptable salt thereof, wherein Z is selected from:
- 6. A compound according to claim 1, or a stereoisomer or a pharmaceutically-acceptable salt, hydrate or prodrug thereof, wherein Z is selected from:
- 7. A compound according to claim 1, or a stereoisomer or a pharmaceutically-acceptable salt, hydrate or prodrug thereof, wherein R1 and R2 are OR12.
- 8. A compound according to claim 7, or a stereoisomer or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein R12 is C1-6alkyl, phenyl, or benzyl optionally substituted with one to two of halogen, cyano, haloalkyl, haloalkoxy, nitro, hydroxy, C1-4alkyl, C1-4hydroxyalkyl, C1-4alkoxy, amino, NH(C1-4alkyl), and N(C1-4alkyl)2.
- 9. A compound according to claim 8, or a stereoisomer or a pharmaceutically-acceptable salt, hydrate or prodrug thereof, wherein W is hydrogen.
- 10. A compound according to claim 9, or a stereoisomer or a pharmaceutically-acceptable salt, hydrate or prodrug thereof, wherein X is NH(phenyl), NH(benzyl), SO2alkyl, or SO2(phenyl) optionally substituted with one to two of C1-4alkyl, C1-4alkoxy, C1-4hydroxyalkyl, C1-4aminoalkyl, halogen, hydroxy, haloalkyl, haloalkoxy, amino, C1-4alkylamino, and/or cyano.
- 11. A compound having the formula (Ib),
- 12. A compound according to claim 11, or a stereoisomer or a pharmaceutically-acceptable salt thereof, wherein Z is selected from
- 13. A compound according to claim 1, wherein:
X is NR5(benzyl) optionally substituted with one to two R25; W is hydrogen; Z is 75and R25 at each occurrence is selected from halogen, cyano, nitro, C1-10alkyl, C2-10alkenyl, substituted C1-10alkyl, substituted C2-10alkenyl, —C(═O)NR12R13, —OR12, —CO2R12, —C(═O)R12, —SR12, —S(O)tR15, —NR12R13, —NR12SO2R15, —NR14SO2NR12R13, —NR12CO2R13, —NR12C(═O)R13, —NR14C(═O)NR12R13, —SO2NR12R13, aryl, heteroaryl, cycloalkyl, and heterocyclo.
- 14. A compound according to claim 13, wherein:
Z is 76
- 15. A compound according to claim 13, wherein:
Z is 77
- 16. A compound according to claim 1, wherein:
X is OH; W is hydrogen; and Z is 78
- 17. A compound according to claim 16, wherein:
Z is 79
- 18. A compound according to claim 16, wherein:
Z is 80
- 19. A compound according to claim 1, wherein the compound is selected from the group:
2-(4-Aminomethyl-phenylamino)-N-benzyl-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamide; 7-{[Carboxy-(3-ethoxy-4-isopropoxy-phenyl)-methyl]-amino}-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester; [3-(tert-Butoxycarbonylamino-methyl)-phenylamino]-(3-ethoxy-4-isopropoxy-phenyl)-acetic acid; (1-Amino-isoquinolin-6-ylamino)-(3-ethoxy-4-isopropoxy-phenyl)-acetic acid; 2-(1-Amino-isoquinolin-6-ylamino)-N-benzyl-2-(3-ethoxy-4-isopropoxy-phenyl)-acetamide; or a stereoisomer or a pharmaceutically-acceptable salt thereof.
- 20. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1, or a stereoisomer or a pharmaceutically-acceptable salt thereof.
- 21. A method for treating a thromboembolic disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof.
- 22. A method according to claim 21, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart.
- 23. A method according to claim 21, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
- 24. The pharmaceutical composition of claim 20 further comprising at least one other therapeutic agent selected from one or more of potassium channel openers, calcium channel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmic agents, antiatherosclerotic agents, anticoagulants, antithrombotic agents, prothrombolytic agents, fibrinogen antagonists, diuretics, antihypertensive agents, ATPase inhibitors, mineralocorticoid receptor antagonists, phospodiesterase inhibitors, antidiabetic agents, anti-inflammatory agents, antioxidants, angiogenesis modulators, antiosteoporosis agents, hormone replacement therapies, hormone receptor modulators, oral contraceptives, antiobesity agents, antidepressants, antianxiety agents, antipsychotic agents, antiproliferative agents, antitumor agents, antiulcer and gastroesophageal reflux disease agents, growth hormone agents and/or growth hormone secretagogues, thyroid mimetics, anti-infective agents, antiviral agents, antibacterial agents, antifungal agents, cholesterol/lipid lowering agents and lipid profile therapies, and agents that mimic ischemic preconditioning and/or myocardial stunning.
- 25. The pharmaceutical composition of claim 20 wherein the at least one other therapeutic agent is an antihypertensive agent selected from ACE inhibitors, AT-1 receptor antagonists, ET receptor antagonists, dual ET/AII receptor antagonists, and vasopepsidase inhibitors, or an antithrombotic agent selected from an antiplatelet agent selected from GPIIb/IIIa blockers, P2Y1 and P2Y12 antagonists, thromboxane receptor antagonists, and aspirin.
- 26. A method of treating a Factor VIIa-associated disorder comprising administering an effective amount of at least one compound of claim 1, or a stereoisomer or a pharmaceutically-acceptable salt thereof, to a patient in need thereof.
- 27. The method of claim 26 wherein the Factor VIIa-associated disorder is selected from myocardial infarction, coronary artery disease, non-Q wave MI, congestive heart failure, cardiac arrhythmias, unstable angina, chronic stable angina, Prinzmetal's angina, high blood pressure, intermittent claudication, and peripheral occlusive arterial disease.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application claims the priority benefit of U.S. Provisional Application No. 60/446,578, filed Feb. 11, 2003, which is expressly incorporated fully herein by reference.
Provisional Applications (1)
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Number |
Date |
Country |
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60446578 |
Feb 2003 |
US |