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

Patent metadata

Field	Value
Publication number	US-12404247-B2
Application number	US-202418603405-A
Country	US
Kind code	B2
Filing date	Mar 13, 2024
Priority date	Jul 27, 2018
Publication date	Sep 2, 2025
Grant date	Sep 2, 2025

Abstract

A method for treating or preventing a disease involving autotaxin including administering a carboxylic acid compound of formula (1)or a pharmacologically acceptable salt thereof to a patient in need thereof.

First claim

The invention claimed is:

1. A method for treating a disease involving autotaxin, comprising:
administering an effective amount of a carboxylic acid compound of formula (1)

or a pharmacologically acceptable salt thereof to a patient in need thereof,
wherein R 1 in the formula (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 in the formula (1) is —N═ or —CH═,
ring A in the formula (1) 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 in the formula (1) 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,
wherein the disease involving autotaxin is cancer or tumor, a fibrotic disease, an inflammatory disease, an ophthalmic disease, a urological disease, type II diabetes-related obesity or an acute coronary syndrome,
the cancer or tumor is malignant melanoma, brain tumor, neuroblastoma, glioblastoma multiforme, EBV positive Hodgkin lymphoma, glioblastoma, non-small cell lung cancer, lung tumor, breast tumor, ovary tumor, pancreas tumor, prostate intraepithelial tumor, prostate tumor, thyroid gland tumor, follicular lymphoma, liver tumor or renal cell carcinoma,
the fibrotic disease is lung fibrosis, scleroderma, hepatic fibrosis, renal fibrosis, diabetic nephropathy or atherosclerosis,
the inflammatory disease is asthma, COPD, rheumatoid arthritis, arthritis deformans, NASH, NAFLD, inflammatory bowel disease, Crohn's disease, ulcerative colitis, neuropathic pain or pruritus,
the acute coronary syndrome is angina pectoris or myocardial infarction,
the ophthalmic disease is glaucoma, and
the urological disease is prostatomegaly.

2. The method of claim 1 , wherein the administering the carboxylic acid compound of formula (1) or a pharmacologically acceptable salt thereof includes administering a pharmaceutical composition comprising the carboxylic acid compound of formula (1) or a pharmacologically acceptable salt thereof, and a pharmaceutically acceptable carrier to the patient in need thereof.

3. The method of claim 1 , wherein R 1 in the formula (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.

4. The method of claim 1 , wherein the ring A in the formula (1) 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.

5. The method of claim 1 , wherein the ring A in the formula (1) 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.

6. The method of claim 1 , wherein the ring A in the formula (1) 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.

7. The method of claim 1 , wherein L in the formula (1) 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.

8. The method of claim 1 , wherein X in the formula (1) is —N═.

9. The method of claim 1 , wherein the carboxylic acid compound of 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} pyr

Assignees

• Mitsubishi Tanabe Pharma Corp

Inventors

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

Classifications

• C07D413/04

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

• C07D401/04 Primary

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

• C07D237/08

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

• C07D213/89

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

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title