Imide derivatives and use thereof as medicine

Patent metadata

Field	Value
Publication number	US-10407408-B2
Application number	US-201615743091-A
Country	US
Kind code	B2
Filing date	Jul 8, 2016
Priority date	Jul 9, 2015
Publication date	Sep 10, 2019
Grant date	Sep 10, 2019

Abstract

Provided is a novel low-molecular-weight compound that suppresses production of induction type MMPs, particularly MMP-9, rather than production of hemostatic type MMP-2. The present invention relates to a compound represented by the following formula (I):

wherein each symbol is as described in the DESCRIPTION. The compound has a selective MMP-9 production suppressive action, and is useful as a drug for the prophylaxis and/or treatment of autoimmune diseases such as rheumatoid arthritis and the like, inflammatory bowel diseases (ulcerative colitis, Crohn's disease) or osteoarthritis.

First claim

The invention claimed is:

1. An imide derivative represented by the following formula (I)

wherein
A is a 6-membered ring of the structure

each of which is optionally substituted by one or the same or different 2 or 3 substituents selected from a halogen atom; hydroxyl group;
nitro; cyano; C 1 -C 6 alkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 3 -C 6 cycloalkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; amino optionally mono- or di-substituted by C 1 -C 6 alkyl; and C 1 -C 6 alkoxy optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy, the right bond is linked to carbonyl and the left bond is linked to quaternary carbon bonded to R 2 ,
R 1a , R 1b and R 1c are the same or different and each is a hydrogen atom; a halogen atom; a hydroxyl group; cyano; oxo; carboxy; C 1 -C 6 alkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 1 -C 6 alkoxy optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 2 -C 7 alkoxycarbonyl; or aminocarbonyl optionally mono- or di-substituted by C 1 -C 6 alkyl; or two of R 1a , R 1b and R 1c are joined to show C 3 -C 6 cycloalkyl; or two of R 1a , R 1b and R 1c are joined to show a saturated nonaromatic heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 3-7 ring-constituting atoms,
R 2 is C 1 -C 6 alkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, a hydroxyl group, C 1 -C 6 alkoxy or amino; a saturated nonaromatic heterocyclic group containing 1-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 3-7 ring-constituting atoms; C 6 -C 10 aryl optionally substituted by substituent B shown below; or heteroaryl containing 1-6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, having 5-10 ring-constituting atoms, and optionally substituted by substituent B shown below,
R 3 is a hydrogen atom; C 1 -C 6 alkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group, C 1 -C 6 alkoxy or C 2 -C 7 acyloxy; C 3 -C 6 cycloalkyl; arylalkyl wherein the C 6 -C 10 aryl moiety is optionally substituted by a halogen atom, a hydroxyl group, C 1 -C 6 alkoxy, C 1 -C 6 alkyl or amino, and the alkyl moiety has a carbon number of 1-6; or heteroarylalkyl wherein the heteroaryl moiety containing 1-6 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom and having 5 to 10 ring-constituting atoms is optionally substituted by a halogen atom, a hydroxyl group, C 1 -C 6 alkoxy, C 1 -C 6 alkyl or amino and the alkyl moiety has a carbon number of 1-6,
W is —N(R x )— wherein R x is a hydrogen atom or C 1 -C 6 alkyl optionally substituted by a halogen atom, a hydroxyl group, C 1 -C 6 alkoxy or C 2 -C 7 acyloxy or methylene optionally substituted by a halogen atom, a hydroxyl group, C 1 -C 6 alkyl or C 1 -C 6 alkoxy,
m+n is 0, 1, 2 or 3,
X is a carbon atom (any one of R 1a , R 1b and R 1c may be bonded to the carbon atom but the carbon atom is not substituted by oxo) or a nitrogen atom (when V is a bond, the nitrogen atom may be oxidized to form N-oxide),
V is a bond; carbonyl; C 1 -C 6 alkylene optionally substituted by a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; an oxygen atom; or —N(R Y )— wherein R Y is a hydrogen atom, C 1 -C 6 alkyl or C 2 -C 7 acyl,
Y is a 5-membered ring group, a 6-membered ring group, a 5-membered ring group substituted by a 5-membered ring group, a 5-membered ring group substituted by a 6-membered ring group, a 6-membered ring group substituted by a 5-membered ring group, a 6-membered ring group substituted by a 6-membered ring group, a fused ring group of a 5-membered ring and a 5-membered ring, a fused ring group of a 5-membered ring and a 6-membered ring or a fused ring group of a 6-membered ring and a 6-membered ring (wherein the 5-membered ring and the 5-membered ring group contain 0-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the rest is constituted of a carbon atom, the 6-membered ring and the 6-membered ring group contain 0-4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the rest is constituted of a carbon atom), and these ring groups are optionally substituted by a halogen atom; a hydroxyl group; C 1 -C 6 alkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, a hydroxyl group, amino or C 1 -C 6 alkyl; or C 1 -C 6 alkoxy optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, and
substituent B is a halogen atom; a hydroxyl group; cyano; C 1 -C 6 alkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, a hydroxyl group or amino; C 1 -C 6 alkoxy optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; amino optionally mono- or di-substituted by C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl,
or a pharmacologically acceptable salt thereof.

2. The imide derivative according to claim 1 wherein Y is phenyl, pyridyl, pyrazinyl, pyridazinyl, naphthyl, quinolyl or a ring group shown below

and
these ring groups are optionally substituted by a halogen atom; a hydroxyl group; C 1 -C 6 alkyl optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group or C 1 -C 6 alkoxy; C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, a hydroxyl group, amino or C 1 -C 6 alkyl; or C 1 -C 6 alkoxy optionally substituted by amino optionally mono- or di-substituted by C 1 -C 6 alkyl, a halogen atom, a hydroxyl group, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, or a pharmacologically acceptable salt thereof.

3. The imide derivative according to claim 1 wherein Y is phenyl or pyridyl represented by the following formula

wherein
Z 5 is a carbon atom or a nitrogen atom,
R 4 and R 5 are the same or different and each is C 1 -C 6 alkyl optionally substituted by a halogen atom; or C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, and
R 6 is a hydrogen atom; C 1 -C 6 alkyl optionally substituted by a halogen atom; or C 3 -C 6 cycloalkyl optionally substituted by a halogen atom, or a ring group represented by the following formula

Assignees

• Mitsubishi Tanabe Pharma Corp

Inventors

• Ishibuchi Seigo
• Saruta Kunio
• Hamada Maiko
• Matoba Nobuatsu
• Matsudaira Tetsuji
• Seki Maki
• Tarao Akiko
• Honjo Takashi
• Ogata Shingo
• Kawata Atsushi
• Morokuma Kenji
• Fujie Naoto
• Aoyama Yukio

Classifications

• C07D513/04

  Ortho-condensed systems · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D233/78

  Radicals substituted by oxygen atoms · CPC title