Claims
- 1. A compound having the structure
- 2. The compound of claim 1 wherein:
each of X1, X2, X3, X4, and X5 are as defined in claim 1;L1 is —X9NH— wherein X9 is covalently bonded directly to Z1 and X9 is a direct bond or —(CH2)m— wherein m is 1 to 5; L3 is a glycine derivative; L4 is a direct bond; Z1 is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with a halogen; Z3 comprises a phenyl, furanyl or thienyl ring, the phenyl, furanyl or thienyl ring being optionally further substituted with fluorine or hydroxy; Z4 comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of Z4 being Z40, Z41, Z42, Z44 and Z45 when Z4 is a 5-membered ring and Z40, Z41, Z42, Z43, Z44 and Z45 when Z4 is a 6-membered ring, Z40, Z41, Z42, Z43, Z44 and Z45, being carbon, nitrogen, oxygen or sulfur, Z40 being the ring atom through which Z4 is attached to the heterocyclic ring, Z41 and Z45 each being in an alpha position relative to Z40, Z42 and Z44 each being in a beta position relative to Z40, Z43 being in the gamma position relative to Z40 when Z4 is a 6-membered ring, Z4 having a substituent R42 covalently attached to Z42, and a second substituent bonded to one of Z41, Z43, Z44, or Z45, the substituent being R41 when bonded to Z41, the substituent being R43 when bonded to Z43, the substituent being R44 when bonded to Z44, and the substituent being R45 when bonded to Z45; R42 is amino; and R41, R43, R44 and R45 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus, provided at least one of R41, R43, R44 or R45 is other than hydrogen.
- 3. The compound of claim 2 wherein:
X9 is a direct bond; L3 is —CH2CONHCH2— and Z3 is covalently bonded to the methylene bonded to the amine nitrogen of L3; Z1 is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl; Z3 comprises a phenyl ring, the phenyl ring being optionally further substituted with fluorine or hydroxy; Z4 comprises a phenyl or thienyl ring having two substituents, R42 and R44, and two ring atoms each of which is in the beta position relative to the ring atom of Z4 through which Z4 is covalently bonded to X, wherein one of R42 and R44 is covalently bonded to one of the beta positions and the other of R42 and R44 is covalently bonded to the other of the beta positions; R42 is amino; and R44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, and an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus.
- 4. The compound of claim 1 wherein L1 is —X9NH— wherein X9 is covalently bonded directly to Z1 and X9 is a direct bond or —(CH2)m— wherein m is 1 to 5.
- 5. The compound of claim 1 wherein L3 is selected from the group consisting of a glycine derivative, an alanine derivative, an amino derivative, and a sulfonyl derivative.
- 6. The compound of claim 5 wherein L3 is a glycine derivative.
- 7. The compound of claim 6 wherein L3 is —CH2CONHCH2— and Z3 is covalently bonded to the methylene bonded to the amine nitrogen of L3.
- 8. The compound of claim 1 wherein L4 is selected from the group consisting of a direct bond, methylene, ethylene and an optionally substituted heteroatom selected from the group consisting of nitrogen, oxygen, sulfur and phosphorus.
- 9. The compound of claim 8 wherein L4 is a direct bond.
- 10. The compound of claim 1 having the structure
- 11. The compound of claim 10 wherein:
X9 is selected from the group consisting of a direct bond, methylene, and ethylene; Z1 is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with a halogen; Z3 comprises a phenyl, furanyl or thienyl ring, the phenyl, furanyl or thienyl ring being optionally further substituted with fluorine or hydroxy; Z4 comprises a phenyl or thienyl ring having two substituents, R42 and R44, and two ring atoms each of which is in the beta position relative to the ring atom of Z4 through which Z4 is covalently bonded to X, wherein one of R42 and R44 is covalently bonded to one of said beta positions and the other of R42 and R44 is covalently bonded to the other of said beta positions; R42 is amino; and R44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, and an optionally substituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus.
- 12. The compound of claim 11 wherein:
X9 is a direct bond; Z1 is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl; Z3 is a phenyl ring, the phenyl ring being optionally further substituted with fluorine or hydroxy; Z4 is a substituted phenyl ring; and R44 is selected from the group consisting of hydroxy, isobutylsulfonyl, trifluoromethyl, carboxamidobenzyl, carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p-fluorobenzylamide, cyclobutylamide, -fluorobenzylamide, 1-methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1-carboxyl-2-methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl, and carbmethoxy.
- 13. The compound of claim 1 or 10 wherein:
X1, X2 and X5 are carbon; and X3 and X4 are nitrogen.
- 14. The compound of claim 1 or 10 wherein:
X1, X3, X4 and X5 are carbon; and X2 is nitrogen.
- 15. The compound of claim 1 or 10 wherein:
X1, X2, X3, X4 and X5 are carbon.
- 16. The compound of claim 1 or 10 wherein:
X1, X4 and X5 are carbon; and X2 and X3 are nitrogen.
- 17. The compound of claim 1 or 10 wherein X1, X2, X3, X4, and X5 are selected to provide a heterocyclic or carbocyclic ring selected from the group consisting of pyrazolinone, pyrrole, thiophene, pyrazole-N-oxide, 1-amino, pyrazole, 1,3,4-triazole, 2-amino-4-aryl-thiazole, 2-amino-5-aryl-thiazole, pyrrolidine, 2-amino-5-aryl-oxazole, 3-amino-pyrazole, 2-amio-4-aryl-oxazole, tetrahydrofuran, cyclopentadienone, and N-hydroxypyrrolidine.
- 18. The compound of 17 wherein the heterocyclic or carbocyclic ring is selected from the group consisting of cyclopentadienone, pyrazole-N-oxide, pyrazolinone and N-hydroxypyrrolidine.
- 19. The compound of claim 18 wherein the heterocyclic ring is pyrazolinone.
- 20. The compound of claim 2 or 10 wherein X9 is a direct bond.
- 21. The compound of claim 2 or 10 wherein X9 is methylene or ethylene.
- 22. The compound of claim 1 or 10 wherein Z1 is selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl, the alkyl, alkenyl, or alkynyl being optionally substituted at any substitutable position with a halogen.
- 23. The compound of claim 22 wherein Z1 is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl.
- 24. The compound of claim 23 wherein Z1 is selected from the group consisting of cyclopropyl, isopropyl, cyclobutyl, isobutyl, and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl.
- 25. The compound of claim 24 wherein Z1 is isopropyl or cyclobutyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl.
- 26. The compound of claim 1 or 10 wherein Z3 comprises a phenyl, furanyl or thienyl ring, the phenyl, furanyl or thienyl ring being optionally further substituted with fluorine or hydroxy.
- 27. The compound of claim 26 wherein Z3 is —R300C(═NH)NH2, wherein R300 is a 6-membered carbocyclic aromatic ring, the 6-membered ring being optionally substituted at any substitutable position with a halogen or hydroxy.
- 28. The compound of claim 27 wherein Z3 is
- 29. The compound of claim 1 or 10 wherein Z3 is —R300C(═NR301)NR302R303, wherein R300 is a 6-membered carbocyclic aromatic ring, R301, R302, R303 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur, provided at least one of R301, R302, R303 is other than hydrogen.
- 30. The compound of claim 29 wherein Z3 is a benzamidine derivative, which upon hydrolysis, oxidation, reduction or elimination forms a benzamidine.
- 31. The compound of claim 1 or 10 wherein Z4 comprises a 5- or 6-membered heterocyclic or carbocyclic ring, the ring atoms of Z4 being Z40, Z41, Z42, Z44 and Z45 when Z4 is a 5-membered ring and Z40, Z41, Z42, Z43, Z44 and Z4 when Z4 is a 6-membered ring, Z40, Z41, Z42, Z43, Z44 and Z45, being carbon, nitrogen, oxygen or sulfur, Z40 being the ring atom through which Z4 is attached to the heterocyclic ring, Z41 and Z45 each being in an alpha position relative to Z40, Z42 and Z44 each being in a beta position relative to Z40, Z43 being in the gamma position relative to Z40 when Z4 is a 6-membered ring, Z4 having a substituent R42 covalently attached to Z42, and a second substituent bonded to one of Z41, Z43, Z44, or Z45, the substituent being R41 when bonded to Z41, the substituent being R43 when bonded to Z43, the substituent being R44 when bonded to Z44, and the substituent being R45 when bonded to Z45;
R42 is amino; and R41, R43, R44 and R45 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclo, halogen, or a substituted or unsubstituted heteroatom selected from nitrogen, oxygen, sulfur and phosphorus, provided at least one of R41, R43, R44 or R45 is other than hydrogen.
- 32. The compound of claim 31 wherein Z4 is a substituted, 6-membered, carbocyclic aromatic ring.
- 33. The compound of claim 32 wherein Z4 has the structure
- 34. The compound of claim 33 wherein R44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamido, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkyl, haloalkoxy, haloalkylthio, carboalkoxy, carboxy, carboxamidoalkyl, and carboxamidoalkylaryl.
- 35. The compound of claim 33 wherein R44 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroaryl, heterocyclo, halogen, acetamido, guanidino, hydroxy, nitro, amino, amidosulfonyl, acylamido, hydrocarbyloxy, substituted hydrocarbyloxy, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylsulfonyl, and substituted hydrocarbylsulfonyl.
- 36. The compound of claim 33 wherein R44 is selected from the group consisting of hydroxy, isobutylsulfonyl, trifluoromethyl, carboxamidobenzyl, carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p-fluorobenzylamide, cyclobutylamide, m-fluorobenzylamide, 1-methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1-carboxyl-2-methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl, and carbmethoxy.
- 37. The compound of claim 33 wherein each of R41, R43 and R45 is hydrogen.
- 38. The compound of claim 31 wherein Z4 has the structure
- 39. The compound of claim 38 wherein R44 is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, acetamido, alkoxy, hydroxy, amino, alkylsulfonyl, haloalkyl, haloalkoxy, haloalkylthio, carboalkoxy, carboxy, carboxamidoalkyl, and carboxamidoalkylaryl.
- 40. The compound of claim 38 wherein R44 is selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, heteroaryl, heterocyclo, halogen, acetamido, guanidino, hydroxy, nitro, amino, amidosulfonyl, acylamido, hydrocarbyloxy, substituted hydrocarbyloxy, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbylsulfonyl, and substituted hydrocarbylsulfonyl.
- 41. The compound of claim 38 wherein R44 is selected from the group consisting of hydroxy, isobutylsulfonyl, trifluoromethyl, carboxamidobenzyl, carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p-fluorobenzylamide, cyclobutylamide, m-fluorobenzylamide, 1-methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1-carboxyl-2-methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl, and carbmethoxy.
- 42. The compound of claim 38 wherein each of R41, R42 and R45 is hydrogen.
- 43. The compound of claim 10 having the structure
- 44. The compound of claim 10 having the structure
- 45. The compound of claim 10 having the structure
- 46. The compound of claim 10 having the structure
- 47. The compound of each of claims 43 to 46 wherein:
Z1 is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, tert-butyl and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl; Z3 is —R300C(═NR301)NR302R303, wherein R300 is a phenyl ring, R301, R302, R303 are independently selected from the group consisting of hydrogen, halogen, optionally substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur; and Z4 is a phenyl ring having the structure 106wherein: R42 is amino; R44 is selected from the group consisting of hydroxy, isobutylsulfonyl, trifluoromethyl, carboxamidobenzyl, carboxamidobutyl-2-yl, isobutyramido, isobutoxy, carboethoxy, carboxyl, amino, 3-aminomethylthiophene, benzylamine, phenethylamine, isobutylamine, methoxyethylamide, 1-carboxylbenzylamide, p-fluorobenzylamide, cyclobutylamide, -fluorobenzylamide, 1-methylbenzylamide, sec-butylamide, benzylacylamine, isobutylamide, sec-pentylamine, cyclopentylacylamine, 1-carboxyl-2-methylbutylamide, isobutylacylamine, isobutylsulfoxyl, 2-cyclohexylamide, methoxy, sulfonamide, isobutylsulfonamide, aminoacyltrifluoromethyl, and carbmethoxy; and R41, R43 and R45 are independently selected from the group consisting of hydrogen, halogen, hydrocarbyl, substituted hydrocarbyl, and an optionally substituted heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur.
- 48. The compound of claim 47 wherein:
Z1 is selected from the group consisting of cyclopropyl, isopropyl, methyl, ethyl, cyclobutyl, isobutyl, and sec-butyl optionally substituted at any substitutable position with fluorine, hydroxy, carboxy, or alkoxycarbonyl; and Z3 is as defined in claim 28.
- 49. The compound of claim 10 having the structure
- 50. The compound of claim 10 having the structure
- 51. The compound of claim 50 having the structure
- 52. The compound of claim 50 having the structure
- 53. A composition for substantially inhibiting thrombotic conditions in blood comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
- 54. A method for substantially inhibiting thrombotic conditions in blood comprising adding to blood the composition of claim 53.
- 55. A method for substantially inhibiting formation of platelet aggregates in blood comprising adding to blood the composition of claim 53.
- 56. A method for substantially inhibiting thrombus formation in blood comprising adding to blood the composition of claim 53.
- 57. A method for treating or preventing venous thromboembolism and pulmonary embolism in a mammal comprising administering to the mammal the composition of claim 53.
- 58. A method for treating or preventing deep vein thrombosis in a mammal comprising administering to the mammal the composition of claim 53.
- 59. A method for treating or preventing cardiogenic thromboembolism in a mammal comprising administering to the mammal the composition of claim 53.
- 60. A method for treating or preventing thromboembolic stroke in a mammal comprising administering to the mammal the composition of claim 53.
- 61. A method for treating or preventing thrombosis associated with cancer and cancer chemotherapy in a mammal comprising administering to the mammal the composition of claim 53.
- 62. A method for treating or preventing unstable angina in a mammal comprising administering to the mammal the composition of claim 53.
- 63. A method for inhibiting thrombus formation in blood comprising adding to blood the composition of claim 53 along with a fibrinogen receptor antagonist.
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from Provisional Application Serial No. 60/326,721 filed Oct. 3, 2001, No. 60/338,623 filed Oct. 24, 2001, No. 60/332,857 filed Nov. 6, 2001, No. 60/344,957 filed on Nov. 7, 2001, No. 60/332,107 and from 60/332,104 both filed on Nov. 21, 2001, which are all hereby incorporated by reference in their entirety.
Provisional Applications (6)
|
Number |
Date |
Country |
|
60326721 |
Oct 2001 |
US |
|
60338623 |
Oct 2001 |
US |
|
60332857 |
Nov 2001 |
US |
|
60344957 |
Nov 2001 |
US |
|
60332107 |
Nov 2001 |
US |
|
60332104 |
Nov 2001 |
US |