Amide derivative

Patent metadata

Field	Value
Publication number	US-10925848-B2
Application number	US-201816487401-A
Country	US
Kind code	B2
Filing date	Feb 20, 2018
Priority date	Feb 21, 2017
Publication date	Feb 23, 2021
Grant date	Feb 23, 2021

Abstract

An object of the present invention is to find a novel pharmaceutical that has an excellent tryptophanase inhibitory effect, and suppresses worsening of renal function to preserve the kidney by reducing production of indoxyl sulfate in the blood. Provided is a pharmaceutical composition containing, as an active ingredient, a compound represented by formula (I) or a pharmacologically acceptable salt thereof. In the formula (I), R1 and R2 are the same or different, and represent a C1-C6 alkyl group, a halogeno C1-C6 alkyl group or a C3-C6 cycloalkyl group; n represents 0, 1 or 2; each X represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogen atom or the like; and Y represents a hydrogen atom, a C1-C6 alkoxy group, a C3-C6 cycloalkoxy group or a halogeno C1-C6 alkoxy group.

First claim

The invention claimed is:

1. A pharmaceutical composition comprising, as an active ingredient, a compound represented by formula (I) or a pharmacologically acceptable salt thereof:

wherein R 1 and R 2 are the same or different, and represent a C1-C6 alkyl group, a halogeno C1-C6 alkyl group or a C3-C6 cycloalkyl group; n represents 0, 1 or 2; each X is the same or different, and represents a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogen atom, a cyano group, a halogeno C1-C6 alkyl group, a C1-C6 alkoxy group, a halogeno C1-C6 alkoxy group or a C3-C6 cycloalkoxy group; and Y represents a hydrogen atom, a C1-C6 alkoxy group, a C3-C6 cycloalkoxy group or a halogeno C1-C6 alkoxy group.

2. A compound represented by formula (Ia) or a pharmacologically acceptable salt thereof:

wherein
(A) R 1 and R 2 are the same or different, and represent a C 1 -C 6 alkyl group, a halogeno C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group; n represents 1; X represents a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a halogen atom, a cyano group, a halogeno C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogeno C 1 -C 6 alkoxy group or a C 3 -C 6 cycloalkoxy group; and Y represents a C 1 -C 6 alkoxy group, a C 3 -C 6 cycloalkoxy group or a halogeno C 1 -C 6 alkoxy group; or
(B) R 1 represents an ethyl group; R 2 represents a C 1 -C 6 alkyl group, a halogeno C 1 -C 6 alkyl group or a C 3 -C 6 cycloalkyl group; n represents 0, 1 or 2; X represents a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group, a halogen atom, a cyano group, a halogeno C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group or a halogeno C 1 -C 6 alkoxy group; and Y represents a hydrogen atom, provided that X does not represent a halogen atom or a C 1 -C 6 alkoxy group when R 2 represents an ethyl group; and neither X represents a C 1 -C 6 alkoxy group when n represents 2.

3. The compound according to claim 2 represented by formula (I-1) or a pharmacologically acceptable salt thereof:

wherein R 1 and R 2 are the same or different, and represent a C 1 -C 4 alkyl group or a C 3 -C 4 cycloalkyl group; n represents 1; X represents a C 1 -C 4 alkyl group, a C 3 -C 4 cycloalkyl group, a halogen atom, a cyano group or a halogeno C 1 -C 4 alkyl group; and Y represents a C 1 -C 4 alkoxy group or a halogeno C 1 -C 4 alkoxy group.

4. The compound according to claim 3 represented by formula (I-1a) or a pharmacologically acceptable salt thereof:

wherein R 1 and R 2 are the same or different, and represent a C 1 -C 3 alkyl group or a cyclopropyl group; X represents a C 1 -C 3 alkyl group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group or a fluoro-C 1 -C 3 alkyl group; and Y represents a C 1 -C 3 alkoxy group or a fluoro-C 1 -C 3 alkoxy group.

5. The compound according to claim 4 , or a pharmacologically acceptable salt thereof, wherein R 1 and R 2 are the same or different, and represent a methyl group, an ethyl group, a propyl group or a cyclopropyl group.

6. The compound according to claim 4 , or a pharmacologically acceptable salt thereof, wherein R 1 and R 2 are the same or different, and represent a methyl group or an ethyl group.

7. The compound according to claim 4 , or a pharmacologically acceptable salt thereof, wherein X represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

8. The compound according to claim 4 , or a pharmacologically acceptable salt thereof, wherein X represents a fluorine atom or a chlorine atom.

9. The compound according to claim 4 , or a pharmacologically acceptable salt thereof, wherein Y represents a methoxy group, an ethoxy group or a propoxy group.

10. The compound according to claim 2 represented by formula (I-2) or a pharmacologically acceptable salt thereof:

wherein R 1 represents an ethyl group; R 2 represents a C 1 -C 4 alkyl group or a C 3 -C 4 cycloalkyl group; n represents 0, 1 or 2; each X is the same or different, and represents a C 1 -C 4 alkyl group, a C 3 -C 4 cycloalkyl group, a halogen atom, a cyano group or a halogeno C 1 -C 4 alkyl group; and Y represents a hydrogen atom, provided that X does not represent a halogen atom or a C 1 -C 4 alkoxy group when R 2 represents an ethyl group, and neither X represents a C 1 -C 4 alkoxy group when n represents 2.

11. The compound according to claim 10 represented by formula (I-2a) or a pharmacologically acceptable salt thereof:

wherein R 2 represents a C 1 -C 3 alkyl group or a cyclopropyl group; X represents a C 1 -C 3 alkyl group, a fluorine atom, a chlorine atom or a bromine atom, provided that X does not represent a fluorine atom, a chlorine atom or a bromine atom when R 2 represents an ethyl group.

12. The compound according to claim 11 , or a pharmacologically acceptable salt thereof, wherein R 2 represents a methyl group, an ethyl group or a cyclopropyl group.

13. The compound according to claim 11 , or a pharmacologically acceptable salt thereof, wherein X represents a methyl group or a chlorine atom.

14. The compound according to claim 2 , selected from the group consisting of 2-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-2-ethylbutanoic acid, (−)-N-(4-amino-5-fluoro-2-propoxybenzoyl)-D-isovaline, (+)-N-(4-amino-5-chloro-2-methoxybenzoyl)-L-isovaline, (−)-N-(4-amino-5-chloro-2-methoxybenzoyl)-D-isovaline, (+)-N-(4-amino-5-chloro-2-ethoxybenzoyl)-L-isovaline, (−)-N-(4-amino-5-chloro-2-ethoxybenzoyl)-D-isovaline, (−)-N-(4-amino-5-chloro-2-propoxybenzoyl)-D-isovaline, (+)-N-(4-amino-5-bromo-2-methoxybenzoyl)-L-isovaline, (−)-N-(4-amino-5-bromo-2-methoxybenzoyl)-D-isovaline, (+)-N-(4-amino-5-bromo-2-ethoxybenzoyl)-L-isovaline, (−)-N-(4-amino-5-bromo-2-ethoxybenzoyl)-D-isovaline, (+)-N-(4-amino-5-iodo-2-methoxybenzoyl)-L-isovaline, (−)-N-(4-amino-5-iodo-2-methoxybenzoyl)-D-isovaline, (+)-N-(4-amino-2-ethoxy-5-fluorobenzoyl)-L-isovaline, (−)-N-(4-amino-2-ethoxy-5-fluorobenzoyl)-D-isovaline, (+)-N-(4-amino-2-ethoxy-5-iodobenzoyl)-L-isovaline, and (−)-N-(4-amino-2-ethoxy-5-iodobenzoyl)-D-isovaline;
or a pharmacologically acceptable salt thereof.

15. A pharmaceutical composition comprising, as an active ingredient, the compound according to claim 2 or a pharmacologically acceptable salt thereof.

16. A crystalline form of the compound according to claim 2 , selected from the group consisting of:
crystalline 2-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-2-ethylbutanoic acid having characteristic peaks at interplanar spacings d of 7.51, 7.33, 6.67, 6.15, 5.32, 5.24, 4.98, 4.79, 3.96 and 3.59 angstroms;
crystalline (−)-N-(4-amino-5-fluoro-2-propoxybenzoyl)-D-isovaline having characteristic peaks at interplanar spacings d of 10.02, 7.39, 5.47, 5.00, 4.79, 4.70, 4.54, 4.39, 4.28 and 2.95 angstroms;
crystalline (−)-N-(4-amino-5-chloro-2-methoxybenzoyl)-D-isovaline having characteristic peaks at interplanar spacings d of 6.61, 5.96, 5.16, 5.10, 4.85, 4.68, 4.50, 4.08, 3.43 and 2.69 ang

Assignees

• Daiichi Sankyo Co Ltd

Inventors

• Soneda Tsuyoshi
• Sakai Hiroki
• Matsumoto Koji
• Tanaka Naomi
• Fukunaga Taichi

Classifications

• C07C237/36 Primary

  having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups · CPC title

• A61K31/198 Primary

  Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00) · CPC title

• A61K31/277

  having a ring, e.g. verapamil · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61K47/38

  Cellulose; Derivatives thereof · CPC title