Heterocyclic compound

• US 10,919,891 B2
• Filed: 04/26/2018
• Issued: 02/16/2021
• Est. Priority Date: 04/27/2017
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Kitamura, Shuji, Ikeda, Zenichi, Morimoto, Sachie, Ikoma, Minoru, Watanabe, Koji, Hirose, Hideki, Yukawa, Takafumi, Sato, Kenjiro
• Primary Examiner(s): O'Dell, David K
• Application Number:
  US16/608,140
• Publication Number:
  US 20200131174A1
• Time in Patent Office: 1,027 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention provides a compound or a salt thereof having a calcium-sensing receptor antagonistic activity, and being expected to be useful as an agent for preventing or treating heart failure, pulmonary hypertension, or the like. The compounds represented by formula (I) or a salt thereof has a calcium-sensing receptor antagonistic activity, and is expected to be useful as an agent for preventing or treating heart failure, pulmonary hypertension, or the like, wherein each symbol is as described in the specification.

Claims

1. A compound represented by formula (I):

2. The compound or a salt thereof according to claim 1, wherein Ring A is a benzene ring.

3. The compound or a salt thereof according to claim 1, wherein R¹ is a hydrogen atom.

4. The compound or a salt thereof according to claim 1, wherein each of R² and R³ is a C_1-6 alkyl group.

5. The compound or a salt thereof according to claim 1, wherein R⁴ is a C_6-14 aryl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, or a C_1-6 alkyl group, each of which is optionally substituted with one or two substituents selected from the group consisting of

(a) a halogen atom,

(b) a C_1-6 alkyl group which is optionally substituted with one to three halogen atoms, and

(c) a C_1-6 alkoxy group which is optionally substituted with one to three halogen atoms.

6. The compound or a salt thereof according to claim 1, wherein R⁵ and R⁶ each independently represent a hydrogen atom or a fluorine atom.

7. The compound or a salt thereof according to claim 1, wherein

Ring A is a benzene ring;

R¹ is a hydrogen atom;

each of R² and R³ is C_1-6 alkyl;

R⁴ is a C_6-14 aryl group, a 5- or 6-membered monocyclic aromatic heterocyclic group, or a C_1-6 alkyl group, each of which is optionally substituted with one or two substituents selected from the group consisting of

(a) a halogen atom,

(b) a C_1-6 alkyl group which is optionally substituted with one to three halogen atoms, and

(c) a C_1-6 alkoxy group which is optionally substituted with one to three halogen atoms; and

R⁵ and R⁶ each independently represent a hydrogen atom or a fluorine atom.

8. The compound or a salt thereof according to claim 1, wherein

Ring A is a benzene ring;

R¹ is a hydrogen atom;

each of R² and R³ is C_1-6 alkyl;

R⁴ is a phenyl group which is substituted with one or two substituents selected from the group consisting of

(a) a halogen atom, and

(b) a C_1-6 alkyl group which is optionally substituted with one to three halogen atoms; and

each of R⁵ and R⁶ is a hydrogen atom.

9. The compound or a salt thereof according to claim 1, which is ((1S,5R)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone or a salt thereof.

10. The compound or a salt thereof according to claim 1, which is (1-(3,5-Dichlorophenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone or a salt thereof.

11. The compound or a salt thereof according to claim 1, which is (1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hex-3-yl)((5R)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)methanone or a salt thereof.

12. A medicament comprising the compound or a salt thereof according to claim 1.

13. The medicament according to claim 12, wherein the medicament is a calcium-sensing receptor antagonist.

14. The medicament according to claim 12, wherein the medicament is an agent for treating heart failure.

15. The medicament according to claim 12, wherein the medicament is an agent for treating pulmonary hypertension.

16. The compound or a salt thereof according to claim 1, for use in treating heart failure.

17. The compound or a salt thereof according to claim 1, for use in treating pulmonary hypertension.

18. A method of antagonizing a calcium-sensing receptor in a mammal, comprising administering an effective amount of the compound or a salt thereof according to claim 1 to the mammal.

19. A method of treating heart failure in a mammal, comprising administering an effective amount of the compound or a salt thereof according to claim 1 to the mammal.

20. A method of treating pulmonary hypertension in a mammal, comprising administering an effective amount of the compound or a salt thereof according to claim 1 to the mammal.