Antitumor agent and bromodomain inhibitor

Patent metadata

Field	Value
Publication number	US-10987349-B2
Application number	US-201916453393-A
Country	US
Kind code	B2
Filing date	Jun 26, 2019
Priority date	Dec 27, 2016
Publication date	Apr 27, 2021
Grant date	Apr 27, 2021

Abstract

It is an object of the present invention to provide an antitumor agent, which is further excellent as a treatment agent used in the prevention and/or therapy of tumor associated with a bromodomain, and also to provide a bromodomain inhibitor, which is useful as a treatment agent for diseases or states associated with a bromodomain.
An antitumor agent and a bromodomain inhibitor, comprising a compound represented by the following formula, have an excellent bromodomain inhibitory activity and are useful as treatment agents in the prevention and/or therapy of tumor associated with a bromodomain, and the like:

wherein R 1 represents a C 1-6 alkyl group, etc.; R 2 represents a hydrogen atom, etc.; R 3 represents a halogen atom, etc.; Z 1 , Z 2 and Z 3 each represent CH, etc.; X 1 represents CONH, etc.; Ring A represents a phenyl group, etc.; R 4 represents a halogen atom, etc.; and m represents an integer from 0 to 5.

First claim

The invention claimed is:

1. A method for treating tumor, comprising administering a therapeutically effective amount of a compound represented by the following formula [1] or a salt thereof, wherein the tumor is blood cancer, thymoma, myeloma, liver cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, osteosarcoma, colon cancer, breast cancer, skin cancer, epithelial cell cancer, bladder cancer, lymphoma or stomach cancer:

wherein R 1 represents an optionally substituted C 1-6 alkyl group;
R 2 represents a hydrogen atom;
R 3 represents an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, or an optionally substituted heterocyclic group;
Z 1 , Z 2 and Z 3 each represents CH;
X 1 represents
(1) a group represented by the formula C(═O)N(R 6 ) (wherein the carbon atom binds to Ring A, and R 6 represents a hydrogen atom, an amino-protecting group, or an optionally substituted C 1-6 alkyl group),
(2) a group represented by the formula N(R 7 )C(═O) (wherein the nitrogen atom binds to Ring A, and R 7 represents a hydrogen atom, an amino-protecting group, or an optionally substituted C 1-6 alkyl group; or R 7 represents, together with one substituent R 4 of Ring A, an optionally substituted C 2-4 alkylene group,
(3) an optionally substituted divalent cyclic hydrocarbon group that is formed by removing each one hydrogen atom on the two adjacent atoms, or
(4) an optionally substituted divalent heterocyclic group that is formed by removing each one hydrogen atom on the two adjacent atoms;
Ring A represents an aryl group;
an m number of R 4 , which are the same or different, each represents a halogen atom, an optionally substituted C 1-6 alkyl group,
an optionally substituted C 2-5 alkylene group formed together by the two adjacent R 4 ,
an optionally substituted C 2-4 alkylene group formed by one R 4 together with R 7 , and
m represents an integer from 0 to 2.

2. The method according to claim 1 , wherein
R 3 represents an optionally substituted C 3-8 cycloalkyl group or an optionally substituted heterocyclic group.

3. The method according to claim 1 , wherein
R 3 represents any one of the following heterocyclic groups:

wherein R 9 represents a hydrogen atom, an amino-protecting group, or an optionally substituted C 1-6 alkyl group, and * represents a binding site.

4. The method according to claim 1 , wherein
X 1 represents
(2) a group represented by the formula N(R 7 )C(═O) (wherein the nitrogen atom binds to Ring A, and R 7 represents a hydrogen atom, an amino-protecting group, or an optionally substituted C 1-6 alkyl group; or R 7 represents, together with one substituent R 4 of Ring A, an optionally substituted C 2-4 alkylene group, or
(4) an optionally substituted divalent heterocyclic group that is formed by removing each one hydrogen atom on the two adjacent atoms.

5. The method according to claim 1 , wherein
the compound is represented by the following formula [1-1]:

wherein R 1 represents a hydrogen atom;
R 3a represents an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, or an optionally substituted heterocyclic group;
Ring A 1 represents an aryl group;
R 7a represents an amino-protecting group or an optionally substituted C 1-6 alkyl group; or
R 7a represents, together with one substituent R 4a of Ring A 1 , an optionally substituted C 2-3 alkylene group,
an m 1 number of R 4a , which are the same or different, each represents a halogen atom,
an optionally substituted C 1-3 alkyl group,
an optionally substituted C 2-5 alkylene group formed together by the two adjacent R 4a ,
an optionally substituted C 2-3 alkylene group formed by one R 4a together with R 7a , and
m 1 represents an integer from 0 to 2.

6. The method according to claim 1 , wherein
X 1 represents an optionally substituted dihydrooxoimidazole-1,5-diyl group, an optionally substituted imidazole-1,2-diyl group, an optionally substituted imidazole-4,5-diyl group, an optionally substituted 1,2,4-triazole-1,5-diyl group, an optionally substituted 1H-pyrazole-4,5-dihyl group, an optionally substituted oxopyrrolidine-1,2-diyl group, an optionally substituted dioxotriazolidine-1,2-diyl group, an optionally substituted dioxopyrazolidine-1,2-diyl group, an optionally substituted oxopyrazoline-1,2-diyl group, an optionally substituted pyridine-2,3-diyl group, or an optionally substituted pyrazine-2,3-diyl group.

7. The method according to claim 1 , wherein
the compound is at least one selected from the group consisting of:
N-(4-cyclopropyl-1-ethyl-2-oxo-1,2-dihydroquinolin-6-yl)-N-methylbenzamide,1-ethyl-4-(1-ethylpiperidin-4-yl)-N-methyl-2-oxo-N-phenyl-1,2-dihydroquinoline-6-carboxamide,
6-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)-1-ethyl-4-(1-methylpiperidin-4-yl)quinolin-2(1H)-one,
1-ethyl-N-methyl-N-(4-methylphenyl)-4-(1-methylpiperidin-4-yl)-2-oxo-1,2-dihydroquinoline-6-carboxamide,
N-(2,3-dihydro-1H-inden-5-yl)-1-ethyl-N-methyl-4-(1-methylpiperidin-4-yl)-2-oxo-1,2-dihydroquinoline-6-carboxamide,
6-(5-(4-chlorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-ethyl-4-(morpholin-4-yl)quinolin-2(1H)-one,
6-(5-(4-chlorophenyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-1-ethyl-4-(morpholin-4-yl)quinolin-2(1H)-one,
1-ethyl-4-(morpholin-4-yl)-6-(2-oxo-5-phenyl-3-(propan-2-yl)-2,3-dihydro-1H-imidazol-1-yl)quinolin-2(1H)-one,
1-(4-cyclopropyl-1-ethyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-phenyl-1,2,4-triazolidine-3,5-dione,
4-chloro-N-(1-ethyl-4-(morpholin-4-yl)-2-oxo-1,2-dihydroquinolin-6-yl)-N-methylbenzamide,
4-(1-acetylpiperidin-4-yl)-1-ethyl-N-methyl-N-(4-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-carboxamide,
1-ethyl-N-(3-fluoro-4-methylphenyl)-N-methyl-4-(1-methylpiperidin-4-yl)-2-oxo-1,2-dihydroquinoline-6-carboxamide,
N-(3-chloro-4-methylphenyl)-1-ethyl-N-methyl-4-(1-methylpiperidin-4-yl)-2-oxo-1,2-dihydroquinoline-6-carboxamide, and
N-(3,4-dimethylphenyl)-1-ethyl-N-methyl-4-(1-methylpiperidin-4-yl)-2-oxo-1,2-dihydroquinoline-6-carboxamide.

8. The method according to claim 1 , wherein
the tumor is blood cancer, thymoma, myeloma, liver cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, osteosarcoma, colon cancer, breast cancer, skin cancer, or epithelial cell cancer.

9. A method of inhibiting bromodomains wherein diseases treatable by such inhibition include diseases selected from the group consisting of blood cancer, thymoma, myeloma, liver cancer, pancreatic cancer, ovarian cancer, prostate cancer, lung cancer, osteosarcoma, colon cancer, breast cancer, skin cancer, epithelial cell cancer, bladder cancer, lymphoma or stomach cancer, said method comprising administering a therapeutically effective amount of a compound represented by the formula [1] or a salt thereof:

wherein R 1 represents an optionally substituted C 1-6 alkyl group;
R 2 represents a hydrogen atom;
R 3 represents an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group or an optionally substitu

Assignees

• Fujifilm Corp
• Fujifilm Toyama Chemical Co Ltd
• Aist

Inventors

• Makita Keiko
• Saeki Kazunori
• Tanaka Tadashi
• Fujino Masataka
• Natsume Tohru
• Furuya Kentaro

Classifications

• A61K31/498

  Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine · CPC title

• A61K31/4704 Primary

  2-Quinolinones, e.g. carbostyril · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title