CYCLIC AMIDE DERIVATIVE, AND ITS PRODUCTION AND USE

• US 20100160629A1
• Filed: 03/02/2010
• Published: 06/24/2010
• Est. Priority Date: 05/21/2004
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: KUBO, Keiji, Imaeda, Yasuhiro
• Granted Patent: US 8,697,865 B2
• Time in Patent Office: Days
• US Class Current: 540/524
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 211/76 attached in position 2 or 6
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

Abstract

The present invention provides a cyclic amide derivative useful as a drug for treating thrombosis, which is represented by the formula (I):

wherein R¹ represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, W represents a bond or an optionally substituted divalent chain hydrocarbon group, a represents 0, 1, or 2, X¹ represents an optionally substituted lower alkylene or an optionally substituted lower alkenylene, Y¹ represents —C(O)—, —S(O)— or —S(O)₂—, A represents a piperazine ring which may be further substituted or a piperidine ring which may be further substituted, X² represents a bond or an optionally substituted lower alkylene, Y² represents —C(O)—, —S(O)—, —S(O)₂— or —C(═NR⁷)—, X³ represents an optionally substituted C_1-4 alkylene or an optionally substituted C_2-4 alkenylene, Z³ represents —N(R⁴)—, —O— or a bond, Z¹ represents —C(R²)(R^2′)—, —N(R²)—, etc., and Z² represents —C(R³)(R^3′)—, —N(R³)—, etc., or a salt thereof.

Claims

1. A compound represented by the formula (I):

wherein R¹ represents a cyclic hydrocarbon group which may be optionally substituted or a heterocyclic group which may be optionally substituted,

W represents a bond or a divalent chain hydrocarbon group which may be optionally substituted,

a represents 0, 1, or 2,

X¹ represents a lower alkylene which may be optionally substituted or a lower alkenylene which may be optionally substituted,

Y¹ represents —

C(O)—

, —

S(O)—

or —

S(O)₂—

,

A represents a piperazine ring which may be further substituted or a piperidine ring which may be further substituted,

X² represents a bond or a lower alkylene which may be optionally substituted,

Y² represents —

C(O)—

, —

S(O)—

, —

S(O)₂—

or —

C(═

NR⁷)—

(wherein R⁷ represents a hydrogen atom, a hydroxy group which may be optionally substituted, a lower alkoxycarbonyl group or an acyl group),

X³ represents a C_1-4 alkylene which may be optionally substituted or a C_2-4 alkenylene which may be optionally substituted,

in which two alkyl groups may be bound to each other to form an aryl ring together with carbon atoms which they attach to when X³ represents a C_2-4 alkenylene substituted with two alkyl groups,

Z³ represents —

N(R⁴)—

, —

O—

or a bond (wherein R⁴ represents a hydrogen atom, a hydrocarbon group which may be optionally substituted or an acyl group),

represents a single bond or a double bond, when

represents a single bond, Z¹ represents —

C(R²)(R^2′

)—

, —

N(R²)—

or —

O—

, and Z² represents —

C(R³)(R^3′

)—

, —

N(R³)—

, —

O—

or a bond (provided that, when Z¹ is —

O—

, Z² is other than —

O—

), and when

is a double bond, Z¹ represents —

C(R²)═

or a nitrogen atom, and Z² represents ═

C(R³)—

or a nitrogen atom,

each of R², R^2′

, R³ and R^3′

represents a hydrogen atom, a hydrocarbon group which may be optionally substituted or a heterocyclic group which may be optionally substituted, respectively, or each pair of R² and R³, and R^2′

and R^3′

may be bound to each other respectively to form a ring which may be optionally substituted, or a salt thereof.

2. The compound according to claim 1, wherein X³ represents a C_1-4 alkylene which may be optionally substituted or a C_2-4 alkenylene which may be optionally substituted.

4. The compound according to claim 2, wherein R¹ is an aryl which may be optionally substituted.

5. The compound according to claim 2, wherein R¹ is a naphthyl which may be substituted with a halogen atom.

6. The compound according to claim 2, wherein W is a bond.

7. The compound according to claim 2, wherein Y¹ is —

C(O)—

.

8. The compound according to claim 2, wherein —

X¹—

Y¹—

is represented by the formula;

9. The compound according to claim 2, wherein A is a group represented by the formula:

wherein a ring A′

represents a piperazine ring which may be further substituted and a ring A″

represents a piperidine ring which may be further substituted.

10. The compound according to claim 2, wherein X² is a bond.

11. The compound according to claim 2, wherein Y² is —

C(O)—

or —

C(═

NR⁷)—

.

12. The compound according to claim 2, wherein

is a single bond.

13. The compound according to claim 2, wherein Z³ is a bond.

14. The compound according to claim 2, wherein the group:

is represented by the formula;

wherein each symbol in the formula is as defined in claim 1.

15. The compound according to claim 2, wherein the group:

is represented by the formula;

wherein each symbol in the formula is as defined in claim 1.

16. The compound according to claim 2, wherein a is 2.

17. The compound according to claim 1, wherein W is a bond, a is 2, —

X¹—

Y¹—

is represented by the formula;

and X² is a bond.

18. The compound according to claim 17, wherein R¹ is an aryl which may be optionally substituted, and A is a group represented by the formula:

wherein a ring A′

represents a piperazine ring which may be further substituted and a ring A″

represents a piperidine ring which may be further substituted.

19. The compound according to claim 18, wherein R¹ is an aryl which may be substituted with 1 to 3 halogen atom(s), Y² is —

C(O)—

or —

C(═

NR⁷)—

,

is a single bond, and Z³ is a bond.

20. The compound according to claim 19, wherein the group:

is represented by the formula;

wherein each symbol in the formula is as defined in claim 1.

21. The compound according to claim 19, wherein the group:

is represented by the formula;

wherein each symbol in the formula is as defined in claim 1.

24. A pharmaceutical composition comprising the compound according to claim 1.

25. The pharmaceutical composition according to claim 24, which is an anticoagulant.

26. The pharmaceutical composition according to claim 24, which is an activated blood coagulation factor X inhibitor.

27. The pharmaceutical composition according to claim 24, which is a medicament for preventing or treating myocardial infarction, cerebral infarction, deep vein thrombosis, pulmonary thromboembolism or atherosclerotic obliterans.

3. (canceled)

22. (canceled)

23. (canceled)

28. (canceled)

29. (canceled)

30. (canceled)

31. (canceled)

32. (canceled)