(AZA)INDOLIZINE DERIVATIVE AND PHARMACEUTICAL USE THEREOF

• US 20130217878A1
• Filed: 09/28/2011
• Published: 08/22/2013
• Est. Priority Date: 09/29/2010
• Status: Active Grant

• Current Assignee: Kissei Pharmaceutical Company Limited
• Original Assignee: Kissei Pharmaceutical Company Limited
• Inventors: Shimizu, Kazuo, Iizuka, Masato
• Granted Patent: US 9,643,969 B2
• Time in Patent Office: Days
• US Class Current: 544/235
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/04 for urolithiasis
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

(Aza)indolizine derivatives represented by Formula (I) having xanthine oxidase inhibitory activities and useful as agents for the prevention or treatment of a disease associated with abnormality of serum uric acid level, prodrugs thereof, salts thereof or the like. In Formula (I), 0 to 2 of X¹, X², X³ and X⁴ are a nitrogen atom and the others are CR¹; one of T¹ and T² represents cyano and the other represents a group represented by Formula (A), with the proviso that when T¹ is cyano, at least one of X¹ to X⁴ is a nitrogen atom; R¹ independently represents a hydrogen atom, a halogen atom, a hydroxy group, C_1-6 alkyl, C_1-6 alkoxy or the like; ring U represents a benzene ring or the like; m represents integral number from 0 to 2; R² independently represents a fluorine atom, a hydroxy group or the like.

Claims

1. An (aza)indolizine derivative represented by the formula (I):

2. The (aza)indolizine derivative as claimed in claim 1 wherein the (aza)indolizine derivative represented by the formula (I) is a compound, represented by the following formula (Ia) to (Ii):

3. The (aza)indolizine derivative as claimed in claim 2, wherein ring U represents a benzene ring, a pyridine ring or a thiazole ring, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

4. The (aza)indolizine derivative as claimed in claim 3, wherein the group represented by the formula:

5. The (aza)indolizine derivative as claimed in claim 3, wherein R^1a, R^1b and R^1c independently represent any one of the following (b1) to (b4):

(b1) a hydrogen atom;

(b2) a halogen atom;

(b3) a hydroxy group;

(b4) C_1-6 alkyl, C_1-6 alkoxy, mono(di) C_1-6 alkylamino or hydroxyC_1-6 alkyl each of which may be substituted by a fluorine atom, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

6. The (aza)indolizine derivative as claimed in claim 1, represented by the formula (II):

7. The (aza)indolizine derivative as claimed in claim 6, wherein R³ independently represents any one of the following (d1) to (d4):

(d1) a hydrogen atom;

(d2) a halogen atom;

(d3) a hydroxy group;

(d4) C_1-6 alkyl, C_1-6 alkoxy, mono(di)C_1-6 alkylamino or hydroxyC_1-6 alkyl each of which may be substituted by a fluorine atom, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

8. The (aza)indolizine derivative as claimed in claim 7, represented by the formula (IIa):

9. The (aza)indolizine derivative as claimed in claim 7, represented by the formula (IIb):

10. The (aza)indolizine derivative as claimed in claim 8, wherein R^2b is a hydroxy group;

R^3a is a hydrogen atom, a fluorine atom or a chlorine atom;

R^3b is a hydrogen atom, a fluorine atom, methyl, ethyl or methoxy; and

R^3c is a hydrogen atom, a fluorine atom, a chlorine atom, methyl or trifluoromethyl, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

11. The (aza)indolizine derivative as claimed in claim 9, wherein R^2b is a hydroxy group;

R^3b is a hydrogen atom, a fluorine atom, methyl, ethyl or methoxy; and

R^3c is a hydrogen atom, a fluorine atom, a chlorine atom, methyl or trifluoromethyl, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

12. The (aza)indolizine derivative as claimed in claim 5, represented by the formula (Ij):

13. The (aza)indolizine derivative as claimed in claim 12, wherein R^2b is a hydroxy group;

R^1a is a hydrogen atom, a fluorine atom, a chlorine atom or methyl; and

R^1b is a hydrogen atom, a fluorine atom, methyl, ethyl or methoxy, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

14. A xanthine oxidase inhibitor comprising a compound as claimed in claim 1, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

15. A pharmaceutical composition comprising a compound as claimed in claim 1, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

16. The pharmaceutical composition as claimed in claim 15, which is for the prevention or treatment of a disease selected from the group consisting of hyperuricemia, gouty tophus, gouty arthritis, renal disorder associated with hyperuricemia and urinary calculi.

17. The pharmaceutical composition as claimed in claim 16, which is for the prevention or treatment of hyperuricemia.

18. The pharmaceutical composition as claimed in claim 15, which is an agent for lowering serum uric acid level.

19. The pharmaceutical composition as claimed in claim 15, which is a uric acid production inhibitor.