Imidazole derivative, process for producing the same, and use

• US 20070004736A1
• Filed: 11/20/2003
• Published: 01/04/2007
• Est. Priority Date: 11/22/2002
• Status: Abandoned Application

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Imaeda, Yasuhiro, Kuroita, Takanobu, Kawamura, Masaki, Kubo, Keiji
• Application Number:
  US10/535,268
• Publication Number:
  US 20070004736A1
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

There is provided an imidazole derivative useful as a thrombosis treating agent, which is represented by the formula (I):
wherein R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, W represents a bond or an optionally substituted divalent linear hydrocarbon group, X represents an optionally substituted divalent hydrocarbon group, Y represents —CO—, —S(O)—, —S(O)₂— or a bond, ring A represents an optionally substituted pyrrolidine ring, an optionally substituted piperidine ring or an optionally substituted perhydroazepine ring, Z¹ and Z³ independently represent a bond or an optionally substituted divalent linear hydrocarbon group, Z² represents —N(R¹)—, —O—, —S(O)—, —S(O)₂—, —CO—, —CH(R¹)— or a bond, ring B represents an optionally substituted imidazole ring, wherein a substituent which the optionally substituted imidazole ring represented by ring B may have may be taken together with R¹ to form an optionally substituted ring, and a represents 0, 1 or 2.

Claims

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

wherein R represents an optionally substituted cyclic hydrocarbon group or an optionally substituted heterocyclic group, W represents a bond or an optionally substituted divalent linear hydrocarbon group, X represents an optionally substituted divalent hydrocarbon group, Y represents —

CO—

, —

S(O)—

, —

S(O)₂—

or a bond, ring A represents an optionally substituted pyrrolidine ring, an optionally substituted piperidine ring or an optionally substituted perhydroazepine ring, Z¹ and Z³ independently represent a bond or an optionally substituted divalent linear hydrocarbon group, Z² represents —

N(R¹)—

, —

O—

, —

S(O)—

, —

S(O)₂—

, —

CO—

, —

CH(R¹)—

or a bond (R¹ represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted acyl group, an optionally esterified carboxyl group or an optionally substituted carbamoyl group), ring B represents an optionally substituted imidazole ring, wherein a substituent which the optionally substituted imidazole ring represented by ring B may have may be taken together with R¹ to form an optionally substituted ring, and a represents 0, 1 or 2, or a salt thereof.

2. A prodrug of the compound according to claim 1.

3. The compound according to claim 1, wherein R is an optionally substituted aryl group.

4. The compound according to claim 1, wherein R is naphthyl optionally substituted with a halogen atom or indolyl optionally substituted with a halogen atom.

5. The compound according to claim 1, wherein W is a bond.

6. The compound according to claim 1, wherein X is an optionally substituted divalent linear hydrocarbon group.

7. The compound according to claim 1, wherein Y is —

CO—

.

8. The compound according to claim 1, wherein ring A is an optionally substituted piperidine ring.

9. The compound according to claim 1, wherein the formula:

is the formula;

wherein R², R³, R^4, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted acyl group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group or an optionally substituted amino group, or R² and R³, R⁵ and R⁶, R⁶ and R⁷, R⁸ and R⁹, R⁹ and R¹⁰, or R¹¹ and R¹² may be taken together to form an optionally substituted ring.

10. The compound according to claim 1, wherein the formula:

is the formula;

wherein ring C represents an optionally substituted nitrogen-containing heterocyclic ring, and other symbols are as defined in claim 9.

11. The compound according to claim 1, wherein a substituent which the optionally substituted imidazole ring represented by ring B may have and R¹ together do not form a ring.

12. The compound according to claim 1, wherein Z² is —

N(R¹)—

or —

CH(R¹)—

(R¹ is as defined in claim

     1), and a substituent which the optionally substituted imidazole ring represented by ring B may have and R¹ are taken together to form an optionally substituted ring.

13. The compound according to claim 1, wherein the formula (I) is the formula (Ia):

wherein ring B′

represents an optionally further substituted imidazole ring, Z^2a represents N or CH, Z⁴ represents an optionally substituted divalent linear hydrocarbon group, and other symbols are as defined in claim 1.

14. The compound according to claim 13, wherein Z^2a is a nitrogen atom.

15. The compound according to claim 13, wherein Z³ and Z⁴ are independently a divalent linear hydrocarbon group optionally substituted with an oxo group.

16. The compound according to claim 1, wherein the formula (I) is the formula (Ib):

wherein R¹⁴ and R¹⁵ independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted acyl group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, or an optionally substituted amino group, or R¹⁴ and R¹⁵ may be taken together to form an optionally substituted ring, and other symbols are as defined in claim 1 or 13.

17. The compound according to claim 1, wherein the formula (I) is the formula (Ic):

wherein R¹⁶ and R¹⁷ independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted acyl group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group or an optionally substituted amino group, or R¹⁶ and R¹⁷ may be taken together to form an optionally substituted ring, and other symbols are as defined in claim 1 or 13.

18. The compound according to claim 1, wherein the formula (I) is the formula (Id):

wherein R¹⁸ and R¹⁹ independently represent a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group, an optionally substituted thiol group, an optionally substituted alkylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted acyl group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, or an optionally substituted amino group, and other symbols are as defined in claim 1 or 13.

19. The compound according to claim 1, wherein a is 2.

21. A pharmaceutical preparation which comprises the compound according to claim 1.

22. The pharmaceutical preparation according to claim 21, which is an anticoagulant.

23. The pharmaceutical preparation according to claim 21, which is an activated blood coagulation factor X inhibitor.

24. The pharmaceutical preparationn according to claim 21, which is an agent for preventing or treating myocardial infarction, cerebral infarction, deep venous thrombosis, pulmonary thromboembolism or arterioscleroticobliterans.

25. The pharmaceutical preparation according to claim 21, which is an agent for preventing or treating economy class syndrome, thromboembolism during or after an operation, or a secondary onset of deep venous thrombosis.

26. A process for preparing the compound according to claim 1, which comprises reacting a compound represented by the formula (II):

wherein L¹ represents a leaving group and other symbols are as defined in claim 1, or a salt thereof with a compound represented by the formula (III);

wherein M¹ represents a hydrogen atom, an alkaline metal, an alkaline earth metal or a leaving group, and other symbols are as defined in claim 1, or a salt thereof;

or

reacting a compound represented by the formula (IV);

wherein M² represents a hydrogen atom, an alkaline metal, an alkaline earth metal or a leaving group, and other symbols are as defined in claim 1, or a salt thereof with a compound represented by the formula (V);

wherein L² represents a leaving group or a formyl group, and other symbols are as defined in claim 1, or a salt thereof;

or

reacting a compound represented by the formula (Ie);

wherein L³ represents a leaving group and other symbols are as defined in claim 1 or 13, or a salt thereof with a base;

or

reacting a compound represented by the formula (If);

wherein symbols are as defined in claim 1 or 13, or a salt thereof with a compound represented by the formula (VI);

L⁴-Z⁴-L^4, 

 

(VI)

wherein L⁴ and L^4′

represent a leaving group and other symbols are as defined in claim 13, or a salt thereof;

or

oxidizing a compound represented by the formula (Ig);

wherein symbols are as defined in claim 1, or a salt thereof, and optionally subjecting a compound obtained in the above reaction to hydrolysis, esterification, amidation, alkylation, acylation, reduction, oxidation or/and deprotection reaction.

27. A method for inhibiting blood coagulation in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a prodrug thereof to said mammal.

28. A method for inhibiting activated blood coagulation factor X in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a prodrug thereof to said mammal.

29. A method for preventing or treating myocardial infarction, cerebral infarction, deep venous thrombosis, pulmonary thromboembolism or arteriosclerotic obliterans in a mammal, which comprises administering an effective amount of the compound according to claim 1 or a prodrug thereof to said mammal.

33. A pharmaceutical preparation which comprises the compound according to claim 2.

34. The pharmaceutical preparation according to claim 33, which is an anticoagulant.

35. The pharmaceutical preparation according to claim 33, which is an activated blood coagulation factor X inhibitor.

36. The pharmaceutical preparationn according to claim 33, which is an agent for preventing or treating myocardial infarction, cerebral infarction, deep venous thrombosis, pulmonary thromboembolism or arterioscleroticobliterans.

37. The pharmaceutical preparation according to claim 33, which is an agent for preventing or treating economy class syndrome, thromboembolism during or after an operation, or a secondary onset of deep venous thrombosis.

20. A compound selected from the group consisting of 7-(1-{3-[(6-chloro-2-naphthyl)sulfonyl]propanoyl}-4-piperidinyl)-3-methyl-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-o one, 7-(7-{3-[(6-choloro-2-naphthyl)sulfonyl]propanoyl}-4-piperidinyl)-1-methyl-6,7-dihydroimidazo[1,5-a]pyrazin-8(5H)-one, 2-(1-{3-[(6-choloro-2-naphthyl)sulfonyl]propanoyl}-4-piperidinyl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one, 2-(1-{3-[(6-choloro-2-naphthyl)sulfonyl]propanoyl}-4-piperidinyl)-5,7-dimethyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one, 2-(1-{3-[(7-choloro-2H-chromen-3-yl)sulfonyl]propanoyl}-4-piperidinyl)-5-methyl-1,2-dihydro-3H-imidazo 1,5-c]imidazol-3-one, 2-[1-(3-{[(E)-2-(4-cholorophenyl)vinyl]sulfonyl}propanoyl)-4-piperidinyl]-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one, 2-(1 {-3-[(5-chloro-1H-indol-2-yl)sulfonyl]propanoyl}-4-piperidinyl)-5-methyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one, 2-(1-{3-[(6-chloro-2-naphthyl)sulfonyl]propanoyl}-4-piperidinyl)-5-(hydroxymethyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one, 2-(1-{(2S)-3-[(6-chloro-2-naphthyl)sulfonyl]-2-hydroxypropanoyl}-4-piperidinyl)-5-(hydroxymethyl)-1, 2-dihydro-3H-imidazo[1,5-c]imidazol-3-one, [2-(1-{(2S)-3-[(6-chloro-2-naphthyl)sulfonyl]-2-hydroxypropanoyl}-4-piperidinyl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-c]imidazol-5-yl]methyl 1-acetylpiperidine-4-carboxylate, [2-(1-{(2S)-3-[(6-chloro-2-naphthyl)sulfonyl]-2-hydroxypropanoyl}-4-piperidinyl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-c]imidazol-5-yl]methyl 3-(2-oxo-1-pyrrolidinyl)propionate, [2-(1-{(2S)-3-[(6-chloro-2-naphthyl)sulfonyl]-2-hydroxypropanoyl}-4-piperidinyl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-c]imidazol-5-yl]methyl(2-oxo-1-pyrrolidinyl)acetate, [2-(1-{(2S)-3-[(6-chloro-2-naphthyl)sulfonyl]-2-hydroxypropanoyl}-4-piperidinyl)-3-oxo-2,3-dihydro-1H-imidazo[1,5-c]imidazol-5-yl]methyl 4-(acetylamino)butanoate, and 2-(1-{(2S)-3-[(6-chloro-2-naphthyl)sulfonyl]-2-hydroxypropanoyl}-4-piperidinyl)-5,7-dimethyl-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one or a salt thereof.

30-32. -32. (canceled)