3, 5-disubstituted pyridine and 3, 5-disubstituted pyridazine derivatives and pharmaceutical use of same

Patent metadata

Field	Value
Publication number	US-11958812-B2
Application number	US-201917258682-A
Country	US
Kind code	B2
Filing date	Jul 26, 2019
Priority date	Jul 27, 2018
Publication date	Apr 16, 2024
Grant date	Apr 16, 2024

Abstract

Provided is a compound superior in an ATX inhibitory action and useful for the prophylaxis or treatment of diseases involving ATX. A carboxylic acid compound represented by the following formula (1) or a pharmacologically acceptable salt thereof:wherein each symbol is as defined in the SPECIFICATION.

First claim

The invention claimed is:

1. A carboxylic acid compound of formula (1)

or a pharmacologically acceptable salt thereof,
wherein R 1 is

where X 1a is —C(R 1a ) 2 — where plural R 1a are the same or different and each R 1a is a hydrogen atom, a halogen atom, C 1 -C 2 perfluoroalkyl, C 1 -C 2 perfluoroalkoxy or C 1 -C 6 alkyl, or plural R 1a are bonded to form 1,1-C 3 -C 6 cycloalkylene or —NR 1b — where R 1b is a hydrogen atom or C 1 -C 2 perfluoroalkyl, X 1b and X 1c are the same or different and each of X 1b and X 1c is —O— or —CH 2 — provided X 1b and X 1c are not simultaneously —O—, R 1c is a hydrogen atom, a halogen atom, C 1 -C 2 perfluoroalkyl, C 1 -C 2 perfluoroalkoxy, C 1 -C 6 alkyl or C 1 -C 2 perfluoroalkylthio, R 1d is a hydrogen atom, a halogen atom or C 1 -C 6 alkyl, and R 1e is a hydrogen atom, C 1 -C 2 perfluoroalkyl or C 1 -C 2 perfluoroalkoxy,
X is —N═ or —CH═,
ring A is

where X 2a is —N═ or —CR 2a ═ where R 2a is a hydrogen atom, a halogen atom, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, R 2b is a hydrogen atom, a halogen atom, C 1 -C 6 alkyl or C 1 -C 6 alkoxy, R 2c is a hydrogen atom or C 1 -C 6 alkyl, X 2b is —O—, —NR 2d — where R 2d is a hydrogen atom or C 1 -C 2 perfluoroalkyl or —CHR 2e — where R 2e is a hydrogen atom or C 1 -C 6 alkyl, X 2c is —(CH 2 ) n′ — where n′ is 0 or 1 or —O—, and
L is —(CHR 3a ) n — where n is 0, 1, 2 or 3, plural R 3a are the same or different and each R 3a is a hydrogen atom or a C 1 -C 6 alkyl, —(CH 2 ) m —O—(CH 2 ) m′ — where m and m′ are the same or different and each of m and m′ is 0, 1 or 2, C 2 -C 3 alkenylene,

where R 3b and R 3c are the same or different and each of R 3b and R 3c is a hydrogen atom or C 1 -C 6 alkyl, R 3d is a hydrogen atom, C 1 -C 6 alkoxy, C 1 -C 6 alkyl or C 1 -C 2 perfluoroalkyl, R 3e is a hydrogen atom, C 1 -C 6 alkoxy, C 1 -C 6 alkyl or C 1 -C 2 perfluoroalkyl.

2. The carboxylic acid compound according to claim 1 , wherein R 1 is

where X 1aa is —C(R 1aa ) 2 — where plural R 1aa are the same or different and each R 1aa is a hydrogen atom, C 1 -C 2 perfluoroalkyl or C 1 -C 6 alkyl, or plural R 1aa are bonded to form 1,1-C 3 -C 6 cycloalkylene, or —NR 1ba — where R 1ba is a hydrogen atom or C 1 -C 2 perfluoroalkyl, R 1ca is C 1 -C 2 perfluoroalkyl, C 1 -C 2 perfluoroalkoxy or C 1 -C 2 perfluoroalkylthio, and R 1da is a halogen atom or C 1 -C 6 alkyl, or a pharmacologically acceptable salt thereof.

3. The carboxylic acid compound according to claim 1 wherein the ring A is

where R 2ab is a hydrogen atom, C 1 -C 6 alkoxy or C 1 -C 6 alkyl, R 2bb is a hydrogen atom, C 1 -C 6 alkoxy or C 1 -C 6 alkyl, and R 2cb is a hydrogen atom or C 1 -C 6 alkyl, or a pharmacologically acceptable salt thereof.

4. The carboxylic acid compound according to claim 1 , wherein the ring A is

where R 2ac is a hydrogen atom, C 1 -C 6 alkoxy or C 1 -C 6 alkyl, R 2bc is a hydrogen atom, C 1 -C 6 alkoxy or C 1 -C 6 alkyl, and R 2cc is a hydrogen atom or C 1 -C 6 alkyl, or a pharmacologically acceptable salt thereof.

5. The carboxylic acid compound according to claim 1 , wherein the ring A is

where R 2ad is a hydrogen atom, C 1 -C 6 alkoxy or C 1 -C 6 alkyl, R 2bd is a hydrogen atom, C 1 -C 6 alkoxy or C 1 -C 6 alkyl, and R 2cd is a hydrogen atom or C 1 -C 6 alkyl, or a pharmacologically acceptable salt thereof.

6. The carboxylic acid compound according to claim 1 , wherein L is —(CH 2 ) n — where n is 1 or 2 or

where R 3ab and R 3bb are the same or different and each of R 3ab and R 3bb is a hydrogen atom or C 1 -C 6 alkyl, or a pharmacologically acceptable salt thereof.

7. The carboxylic acid compound according to claim 1 , wherein X is —N═, or a pharmacologically acceptable salt thereof.

8. The carboxylic acid compound according to claim 1 , wherein the carboxylic acid compound of the formula (1) is
trans-2-[2-methoxy-5-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)phenyl]cyclopropanecarboxylic acid,
trans-2-[2-methoxy-5-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid,
(1S,2S)-2-[2-methoxy-5-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid,
(1R,2R)-2-[2-methoxy-5-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid,
(1S,2S)-2-(5-methoxy-5′-{[4-(trifluoromethoxy)benzyl]oxy}-2,3′-bipyridin-6-yl)cyclopropanecarboxylic acid,
(1S,2S)-2-[3-methoxy-6-(6-{[4-(trifluoromethoxy)benzyl]oxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid,
(1S,2S)-2-[3-methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid,
(1S,2S)-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4′-bipyridin-2′-yl)cyclopropanecarboxylic acid,
(1R,2R)-2-(5-{[4-(trifluoromethoxy)benzyl]oxy}-3,4′-bipyridin-2′-yl)cyclopropanecarboxylic acid,
(1S,2S)-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4′-bipyridin-2′-yl)cyclopropanecarboxylic acid,
(1R,2R)-2-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-3,4′-bipyridin-2′-yl)cyclopropanecarboxylic acid,
(1S,2S)-2-[4-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid,
(1R,2R)-2-[4-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]cyclopropanecarboxylic acid,
(1S,2S)-2-(5′-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-2,3′-bipyridin-6-yl)cyclopropanecarboxylic acid,
(1R,2R)-2-(5′-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}-2,3′-bipyridin-6-yl)cyclopropanecarboxylic acid,
(1S,2S)-2-[3-methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]-1-methylcyclopropanecarboxylic acid,
(1R,2R)-2-[3-methoxy-6-(6-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridazin-4-yl)pyridin-2-yl]-1-methylcyclopropanecarboxylic acid,
(1S,2S)-2-[2-ethoxy-5-(6-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]methoxy}pyridazin-4-yl)phenyl]cyclopropanecarboxylic acid,
3-[(2S)-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid,
3-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]methoxy}pyridin-3-yl)morpholin-2-yl]propanoic acid,
3-[(2S)-4-(5-{[3-fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid,
3-[(2S)-4-(5-{[2-fluoro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid,
3-[(2S)-4-(5-{[2-methyl-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid,
3-[(2S)-4-(5-{[3-chloro-4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid,
3-[(2S,6R)-6-methyl-4-(5-{[4-(trifluoromethoxy)benzyl]oxy}pyridin-3-yl)morpholin-2-yl]propanoic acid,
(1S,2S)-2-[(2S)-4-(5-{[trans-4-(trifluoromethyl)cyclohexyl]me

Assignees

• Mitsubishi Tanabe Pharma Corp

Inventors

• Takahashi Taichi
• Takamatsu Hisayuki
• Iijima Daisuke
• Takeda Shuzo

Classifications

• C07D237/14 Primary

  Oxygen atoms · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D213/89

  with hetero atoms directly attached to the ring nitrogen atom · CPC title

• C07D237/08

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title