COMT inhibitors

Patent metadata

Field	Value
Publication number	US-9656971-B2
Application number	US-201514752177-A
Country	US
Kind code	B2
Filing date	Jun 26, 2015
Priority date	Dec 27, 2012
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

The present invention relates to compounds of formula

wherein the substituents are described in claim 1 and to the pharmaceutically acceptable salts thereof.

These compounds inhibit the enzyme catechol-O-methyltransferase (COMT). The compounds may be used for the treatment of Parkinson's disease, depression, cognitive impairment and motor symptoms, resistant depression, cognitive impairment, mood and negative symptoms of schizophrenia.

First claim

The invention claimed is:

1. A compound of formula

wherein
R 1 is hydrogen;
R 2 is heteroaryl, selected from the group consisting of pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, imidazolyl, isoxazolyl, isothiazolyl, thiophenyl, 1-thia-3,4-diazolyl, imidazo[1,2-a]pyridinyl, indazolyl, quinolinyl or isoquinolinyl, and which groups are optionally substituted by R 5 , or is C(O)-heteroaryl, selected from pyridinyl or thiophenyl, wherein the heteroaryl groups are optionally substituted by lower alkyl;
R 5 is halogen, lower alkyl, lower alkoxy, lower alkyl substituted by halogen, lower alkoxy substituted by halogen, hydroxy, (CH 2 ) 1,2 -lower alkoxy, CH 2 -di-lower alkyl amino, di-lower alkyl amino, morpholinyl, piperazinyl, pyrrolidin-1-yl, C(O)-piperidinyl, C(O)-4-methyl-piperazinyl, phenyl optionally substituted by halogen, pyridinyl, S(O) 2 N(CH 3 ) 2 , C(O)O-lower alkyl, NHC(O)-lower alkyl,
or is C(O)-heteroaryl, selected from pyridinyl or thiophenyl, wherein the heteroaryl groups are optionally substituted by lower alkyl,

R 3 is hydrogen;
and pharmaceutically acceptable salts thereof.

2. A compound selected from the group consisting of:
8-Hydroxy-6-(1-(2-methoxyethyl)-1H-pyrazol-5-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(4-(methoxymethyl)-2-methylthiazol-5-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)quinazolin-4(3H)-one;
6-(6-(Dimethylamino)pyridin-3-yl)-8-hydroxyquinazolin-4(3H)-one;
8-Hydroxy-6-(6-morpholinopyridin-2-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(6-(pyrrolidin-1-yl)pyridin-2-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(5-methylthiazol-2-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(1-methyl-1H-imidazol-2-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-nicotinoylquinazolin-4(3H)-one;
8-Hydroxy-6-(1-methyl-1H-imidazol-4-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(5-methyl-3-phenylisoxazol-4-yl)quinazolin-4(3H)-one;
4-(8-Hydroxy-4-oxo-3,4-dihydroquinazolin-6-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide;
6-(3,5-Dimethylisoxazol-4-yl)-8-hydroxyquinazolin-4(3H)-one;
8-Hydroxy-6-(1-methyl-1H-imidazol-5-yl)quinazolin-4(3H)-one;
Ethyl 2-(8-hydroxy-4-oxo-3,4-dihydroquinazolin-6-yl)-4-methyl-1H-imidazole-5-carboxylate;
Methyl 5-(8-hydroxy-4-oxo-3,4-dihydroquinazolin-6-yl)-4-methylthiophene-2-carboxylate;
8-Hydroxy-6-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(5-methyl-1,3,4-thiadiazol-2-yl)quinazolin-4(3H)-one;
Methyl 2-(8-hydroxy-4-oxo-3,4-dihydroquinazolin-6-yl)thiazole-4-carboxylate;
8-Hydroxy-6-(2-methylthiazol-4-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(imidazo[1,2-a]pyridin-3-yl)quinazolin-4(3H)-one;
6-(1,2-Dimethyl-1H-imidazol-5-yl)-8-hydroxyquinazolin-4(3H)-one;
Methyl 4-(8-hydroxy-4-oxo-3,4-dihydroquinazolin-6-yl)-1-methyl-1H-pyrazole-3-carboxylate;
8-Hydroxy-6-(5-(pyridin-2-yl)thiophen-2-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(thiazol-5-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(thiazol-4-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(isothiazol-4-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-isonicotinoylquinazolin-4(3H)-one;
8-Hydroxy-6-(5-methylthiophene-2-carbonyl)quinazolin-4(3H)-one;
6-(1,5-Dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-8-hydroxyquinazolin-4(3H)-one;
8-Hydroxy-6-(1-methyl-1H-indazol-5-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(3-methyl-5-(piperidine-1-carbonyl)thiophen-2-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-[3-methyl-5-(4-methyl-piperazine-1-carbonyl)-thiophen-2-yl]-3H-quinazolin-4-one;
N-(5-(8-Hydroxy-4-oxo-3,4-dihydroquinazolin-6-yl)-6-(methoxymethyl)pyridin-2-yl)pivalamide;
8-Hydroxy-6-(2-(methoxymethyl)pyridin-3-yl)quinazolin-4(3H)-one bis(2,2,2-trifluoroacetate);
8-Hydroxy-6-(2-methylpyridin-4-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(2-methylpyridin-3-yl)quinazolin-4(3H)-one;
6-(6-Bromo-pyridin-3-yl)-8-hydroxy-3H-quinazolin-4-one;
6-(2,5-Dimethyl-2H-pyrazol-3-yl)-8-hydroxy-3H-quinazolin-4-one;
6-[1-(4-Fluoro-phenyl)-1H-pyrazol-4-yl]-8-hydroxy-3H-quinazolin-4-one;
8-Hydroxy-6-(pyrimidin-5-yl)quinazolin-4(3H)-one 2,2,2-trifluoroacetate;
8-Hydroxy-6-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-3H-quinazolin-4-one;
6-(2-((Dimethylamino)methyl)phenyl)-8-hydroxyquinazolin-4(3H)-one;
8-Hydroxy-6-(1-methyl-1H-indazol-4-yl)quinazolin-4(3H)-one;
6-(2,4-Dimethoxypyrimidin-5-yl)-8-hydroxyquinazolin-4(3H)-one;
8-Hydroxy-6-(2-methoxypyridin-3-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(6-methoxypyridin-3-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(4-methylthiophen-3-yl)quinazolin-4(3H)-one;
6-(2,5-Dimethylthiophen-3-yl)-8-hydroxyquinazolin-4(3H)-one;
8-Hydroxy-6-(6-methylpyridin-3-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(quinolin-8-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(isoquinolin-4-yl)quinazolin-4(3H)-one;
6-(2,4-Dimethylthiazol-5-yl)-8-hydroxyquinazolin-4(3H)-one;
8-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(2-hydroxypyridin-3-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(1-methyl-1H-pyrazol-5-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(6-morpholinopyridin-3-yl)quinazolin-4(3H)-one;
6-(6-(Dimethylamino)pyridin-2-yl)-8-hydroxyquinazolin-4(3H)-one;
8-Hydroxy-6-(6-(piperazin-1-yl)pyridin-3-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(2-(piperazin-1-yl)pyridin-4-yl)quinazolin-4(3H)-one;
6-(1,4-Dimethyl-1H-imidazol-2-yl)-8-hydroxyquinazolin-4(3H)-one;
6-(2,6-Dimethyl-pyridin-3-yl)-8-hydroxy-3H-quinazolin-4-one;
8-Hydroxy-6-(4-methyl-2-phenylthiazol-5-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(5-methyl-1-phenyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(3-methyl-1H-pyrazol-4-yl)quinazolin-4(3H)-one;
6-(1,5-Dimethyl-1H-pyrazol-4-yl)-8-hydroxyquinazolin-4(3H)-one;
8-Hydroxy-6-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)quinazolin-4(3H)-one;
8-Hydroxy-6-(3-methylpyridin-4-yl)quinazolin-4(3H)-one; and
8-Hydroxy-6-(1-methyl-3-(4-methylpiperazine-1-carbonyl)-1H-pyrazol-5-yl)quinazolin-4(3H)-one.

3. A Pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutical acceptable carrier and/or adjuvant.

Assignees

• Hoffmann La Roche

Inventors

• Bissantz Caterina
• Bonnafous René
• Buettelmann Bernd
• Jakob-Roetne Roland
• Lerner Christian
• Rudolph Markus

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/24

  Antidepressants · CPC title