Benzamides and related inhibitors of factor Xa

• US 6,376,515 B2
• Filed: 02/28/2001
• Issued: 04/23/2002
• Est. Priority Date: 02/29/2000
• Status: Expired due to Term

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: COR Therapeutics, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Wang, Lingyan, Zuckett, Jingmei, Goldman, Erick A., Song, Yonghong, Zhu, Bing-Yan, Zhang, Penglie, Scarborough, Robert M., Huang, Wenrong, Li, Wenhao
• Primary Examiner(s): Davis, Zinna Northington
• Application Number:
  US09/794,225
• Publication Number:
  US 20020002183A1
• Time in Patent Office: 419 Days
• Field of Search: 514/318, 514/341, 514/343, 514/352, 546/194, 546/275.1, 546/276.4, 546/309
• US Class Current: 514/318
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/616 by carboxylic acids, e.g. acetylsalicylic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: A61K 9/4866 Organic macromolecular compounds
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07C 237/42 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07C 255/60 at least one of the singly-bound nitrogen atoms being acylated
• CPC Class Codes: C07C 257/18 having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 259/18 having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 311/16 having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07C 311/46 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 317/40 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07C 317/44 having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 217/22 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 295/125 : with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings

Abstract

Novel benzamide compounds including their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives having activity against mammalian factor Xa are described. Compositions containing such compounds are also described. The compounds and compositions are useful in vitro or in vivo for preventing or treating coagulation disorders.

Claims

1. A compound of formula VI:

wherein;

Z′ and

Z″

are each independently a C₁-C₆ alkyl which is optionally substituted with a hydroxyl, carboxylic acid or carboxylic acid ester group;

R^1a is a member selected from the group of H, —

F, —

Cl and Br;

R^1d2 and R^1d4 are each H;

R^1d1 and R^1d3 are each independently a member selected from the group of H, —

Cl, —

F, —

Br, —

OH and —

OMe;

R^1e is a member selected from the group of —

F, —

Cl, —

Br, —

OH, —

Me and —

OMe,

and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.

2. A compound of claim 1 wherein Z′

is —

Me and Z″

is —

CH₂OH, —

CH₂CO₂H, or —

CH₂CO₂CH₃.

3. A compound of claim 1 having the following structure:

4. A compound of claim 1 having the following structure:

5. A compound of claim 1 having the following structure:

6. A compound of claim 1 having the following structure:

7. A compound of claim 1 having the following structure:

8. A compound of claim 1 having the following structure:

9. A compound of claim 1 having the following structure:

10. A compound of claim 1 having the following structure:

11. A compound of claim 1 having the following structure:

12. A compound of claim 1 having the following structure:

13. A compound of claim 1 having the following structure:

14. A compound of claim 1 having the following structure:

15. A compound of claim 1 having the following structure:

16. A compound of claim 1 having the following structure:

17. A compound of claim 1 having the following structure:

18. A compound of claim 1 having the following structure:

19. A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of one of claims 1-18.

20. A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising administering to said mammal a therapeutically effective amount of a compound of one of claims 1-18.

21. The method of claim 20, wherein the condition is selected from the group consisting of:

acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboangiitis obliterans, thrombotic disease associated with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation, and thrombotic complications associated with the fitting of prosthetic devices.

22. A method for inhibiting the coagulation of a biological sample comprising the step of administering a compound of one of claims 1-18.

23. A compound formula VII:

wherein;

A-Q is a member selected from the group of;

where Z′

is a C₁-C₆ alkyl which is optionally substituted with a hydroxyl, carboxylic acid or carboxylic acid ester group;

R^1a is a member selected from the group of H, —

F, —

Cl and Br;

R^1d2 and R^1d4 are each H;

R^1d1 and R^1d3 are each independently a member selected from the group of H, —

Cl, —

F, —

Br, —

OH and —

OMe;

R^1e is a member selected from the group of —

F, —

Cl, —

Br, —

OH, —

Me and —

OMe;

and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.

24. A compound of claim 23, wherein A-Q is:

and Z′

is —

Me, —

CH₂OH, —

CH₂CO₂H, or —

CH₂CO₂CH₃.

25. A compound of claim 24 having the following structure:

26. A compound of claim 24 having the following structure:

27. A compound of claim 24 having the following structure:

28. A compound of claim 24 having the following structure:

29. A compound of claim 24 having the following structure:

30. A compound of claim 24 having the following structure:

31. A compound of claim 24 having the following structure:

32. A compound of claim 24 having the following structure:

33. A compound of claim 24 having the following structure:

34. A compound of claim 24 having the following structure:

35. A compound of claim 24 having the following structure:

36. A compound of claim 24 having the following structure:

37. A compound of claim 24 having the following structure:

38. A compound of claim 24 having the following structure:

39. A compound of claim 24 having the following structure:

40. A compound of claim 24 having the following structure:

41. A compound of claim 23 having the following formula:

42. A compound of claim 23 having the following formula:

43. A compound of claim 23 having the following structure:

44. A compound of claim 23 having the following structure:

45. A compound of claim 23 having the following structure:

46. A compound of claim 23 having the following structure:

47. A compound of claim 23 having the following structure:

48. A compound of claim 23 having the following structure:

49. A compound of claim 23 having the following structure:

50. A compound of claim 23 having the following structure:

51. A compound of claim 23 having the following structure:

52. A compound of claim 23 having the following structure:

53. A compound of claim 23 having the following structure:

54. A compound of claim 23 having the following structure:

55. A compound of claim 23 having the following structure:

56. A compound of claim 23 having the following structure:

57. A compound of claim 23 having the following structure:

58. A compound of claim 23 having the following structure:

59. A compound of claim 23 having the following structure:

60. A compound of claim 23 having the following structure:

61. A compound of claim 23 having the following structure:

62. A compound of claim 23 having the following structure:

63. A compound of claim 23 having the following structure:

64. A compound of claim 23 having the following structure:

65. A compound of claim 23 having the following structure:

66. A compound of claim 23 having the following structure:

67. A compound of claim 23 having the following structure:

68. A compound of claim 23 having the following structure:

69. A pharmaceutical composition for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of one of claims 23-68.

70. A method for preventing or treating a condition in a mammal characterized by undesired thrombosis comprising administering to said mammal a therapeutically effective amount of a compound of one of claims 23-68.

71. The method of claim 70, wherein the condition is selected from the group consisting of:

acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, occlusive coronary thrombus occurring post-thrombolytic therapy or post-coronary angioplasty, a thrombotically mediated cerebrovascular syndrome, embolic stroke, thrombotic stroke, transient ischemic attacks, venous thrombosis, deep venous thrombosis, pulmonary embolus, coagulopathy, disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, thromboanglitis obliterans, thrombotic disease associated with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with instrumentation, and thrombotic complications associated with the fitting of prosthetic devices.

72. A method for inhibiting the coagulation of a biological sample comprising the step of administering a compound of one of claims 23-68.