Substituted quinoxalines as positive allosteric modulators of mGluR4

Patent metadata

Field	Value
Publication number	US-9763938-B2
Application number	US-201615210320-A
Country	US
Kind code	B2
Filing date	Jul 14, 2016
Priority date	Feb 7, 2013
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

The present invention relates to the use of novel quinoxaline derivatives of formula (I)

as positive allosteric modulators for modulating metabotropic glutamate receptor subtype 4 (mGluR4) and/or altering glutamate level or glutamatergic signalling.

First claim

The invention claimed is:

1. A method for modulating metabotropic glutamate receptor subtype 4 and/or altering glutamate level or glutamatergic signaling in a subject, comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
X each denotes C;
R 1 , and R 2 independently from each other denote aryl, heteroaryl or heterocyclyl, which can optionally be substituted by one or more identical or different substituents T;
R 3a , R 3b , R 4a ,
R 4b , R 5a , R 5b ,
R 6a , and R 6b independently from each other denote substituent T, if the individual X is C; or if the individual X is N, then one of the R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b substituents is absent and the other one of the R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b substituents denotes substituent T or forms a double bond with one of the R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b substituents of an adjacent X;
T independently from each other denotes H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, OH, CN, NO 2 , NYY, CF 3 , OCF 3 , alkyl-OH, alkyl-NYY, alkyl-CN, O-alkyl, O-cycloalkyl, O-alkyl-cycloalkyl, O-aryl, O-alkyl-aryl, O-heteroaryl, O-alkyl-heteroaryl, O-heterocyclyl, O-alkyl-heterocyclyl, C(O)-alkyl, C(O)-cycloalkyl, C(O)-alkyl-cycloalkyl, C(O)-aryl, C(O)-alkyl-aryl, C(O)-heteroaryl, C(O)-alkyl-heteroaryl, C(O)-heterocyclyl, C(O)-alkyl-heterocyclyl, C(O)O-alkyl, C(O)O-cycloalkyl, C(O)O-alkyl-cycloalkyl, C(O)O-aryl, C(O)O-alkyl-aryl, C(O)O-heteroaryl, C(O)O-alkyl-heteroaryl, C(O)O-heterocyclyl, C(O)O-alkyl-heterocyclyl, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-alkyl-cycloalkyl, C(O)NH-aryl, C(O)NH-alkyl-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-heteroaryl, C(O)NH-heterocyclyl, C(O)NH-alkyl-heterocyclyl, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-alkyl-cycloalkyl, NHC(O)-aryl, NHC(O)-alkyl-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-heteroaryl, NHC(O)-heterocyclyl, NHC(O)-alkyl-heterocyclyl, O-alkyl-NYY, C(O)H, C(O)OY, C(O)NY-alkyl-NYY, or C(O)NYY, wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl moieties can optionally be substituted by one or more identical or different substituents Z;
Y independently from each other denotes H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl can optionally be substituted by one or more identical or different substituents Z; and
Z independently from each other denotes alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, OH, CN, NO 2 , NH 2 , NH-alkyl, N(alkyl) 2 , NH-alkyl-OH, NH-alkyl-O-alkyl, NH-alkyl-aryl, CF 3 , OCF 3 , alkyl-OH, alkyl-NH 2 , alkyl-NH-alkyl, alkyl-N(alkyl) 2 , alkyl-CN, alkyl-C(O)-heterocyclyl, O-alkyl, O-cycloalkyl, O-alkyl-cycloalkyl, O-aryl, O-alkyl-aryl, O-heteroaryl, O-alkyl-heteroaryl, O-heterocyclyl, O-alkyl-heterocyclyl, O-alkyl-NH 2 , C(O)H, C(O)OH, C(O)NH-alkyl-NH 2 , C(O)NH 2 , C(O)—C(O)—NH 2 , C(O)-alkyl-NH-alkyl, C(O)-alkyl-NH-alkyl-O-alkyl, C(O)-alkyl, C(O)-cycloalkyl, C(O)-alkyl-cycloalkyl, C(O)-aryl, C(O)-alkyl-aryl, C(O)-heteroaryl, C(O)-alkyl-heteroaryl, C(O)-heterocyclyl, C(O)-alkyl-heterocyclyl, C(O)-heterocyclyl-alkyl, C(O)O-alkyl, C(O)O-cycloalkyl, C(O)O-alkyl-cycloalkyl, C(O)O-aryl, C(O)O-alkyl-aryl, C(O)O-heteroaryl, C(O)O-alkyl-heteroaryl, C(O)O-heterocyclyl, C(O)O-alkyl-heterocyclyl, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-alkyl-cycloalkyl, C(O)NH-aryl, C(O)NH-alkyl-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-heteroaryl, C(O)NH-heterocyclyl, C(O)NH-alkyl-heterocyclyl, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-alkyl-cycloalkyl, NHC(O)-aryl, NHC(O)-alkyl-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-heteroaryl, NHC(O)-heterocyclyl, NHC(O)-alkyl-heterocyclyl C(O)NH-aryl-halogen, C(O)NH-aryl-O-alkyl, C(O)N(alkyl)-aryl, C(O)N(aryl) 2 , S-alkyl, S-cycloalkyl, S-alkyl-cycloalkyl, S-aryl, S-alkyl-aryl, S-heteroaryl, S-alkyl-heteroaryl, S-heterocyclyl, or S-alkyl-heterocyclyl.

2. The method according to claim 1 , wherein in the compound of formula (I)

denotes

3. The method according to claim 2 , wherein in the compound of formula (I)
T independently from each other denotes H, F, Cl, methyl, methoxy, hydroxy, ethoxy, isopropoxy, hydroxy-methyl, methyl-carbonyl, 4-methyl-piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl, 4-methyl-piperazin-1-yl-carbonyl, (2-hydroxy-1,1-dimethyl-ethyl)-carboxylic acid amide, pyrrolidin -1-yl-carbonyl, carboxylic acid cyclopentylamide, piperidin-1-yl-carbonyl, carboxylic acid cyclohexylamide, azetidin-1-yl-carbonyl, carboxylic acid cyclohexylmethylamide, carboxylic acid (3-methyl-butyl)-amide, carboxylic acid (5-methyl-isoxazol-3-yl)-amide, carboxylic acid pyridin-2-ylamide, carboxylic acid pyridin-3-ylamide, carboxylic acid pyridin-4-ylamide, carboxylic acid (4-hydroxy-cyclohexyl)-amide, carboxylic acid (2-cyano-ethyl) -amide, carboxylic acid (2-hydroxy-propyl)-amide, carboxylic acid cyclopropylmethyl-amide, carboxylic acid methylamide, carboxylic acid dimethylamide, carboxylic acid (2-hydroxy-ethyl)-amide, carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide, carboxylic acid thiazol-2-ylamide, carboxylic acid ethyl ester, carboxylic acid isopropyl ester, carboxylic acid [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide, carboxylic acid (2-dimethylamino-ethyl)-amide, carboxylic acid (6-chloro-benzothiazol-2-yl) -amide, methoxymethyl, 4-methyl-piperazin-1-yl-methyl, morpholin-4-ylmethyl, pyrrolidin-1-yl-methyl, 4-hydroxy-piperdin-1-yl, [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-aminomethyl, methylaminomethyl, 2-pyrrolidin-1-yl-ethoxy, 1-methyl-pyrrolidin-3-yloxy, 4-methyl-piperazin-1-yl)-propoxy, 2-dimethylamino-ethyloxy,3-dimethylamino-propyloxy, 4-methyl-piperazin-1-yl)-ethoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 1-methyl-tetrazol-5-yl, or 2-methyltetrazol-5-yl.

4. The method according to claim 1 , wherein in the compound of formula (I)
R 1 , and R 2 independently from each other denote phenyl, furanyl, pyridinyl, thiophenyl, pyrrolidinyl, naphthalenyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl, quinolinyl, indolyl, indazolyl or benzooxazolonyl, which can optionally be substituted by one or more identical or different substituents T.

5. A method according to claim 1 , wherein the subject suffers from a physiological and/or pathophysiological condition selected from the group consisting of anxiety, rigidity, an addiction, a phobia, a tic a central nervous system disorder, a tolerance disorder, a dependence disorder, an affective disorder, a mood disorder, a bipolar disorder, a psychotic disorder, a movement disorder, a cognitive disorder, a neurological disorder, a metabolic disorder associated with glutamate dysfunction, a disorder of the retina, a disorder of the gastrointestinal tract, a lower esophageal sphincter disorder, a disease of the retina, a disease of the gastrointestinal tract, a lower esophageal disease and a disease of gastrointestinal motility.

6. The method according to claim 5 , wherein the central nervous system disorder or movement disorder is selected from the group consisting of an inf

Assignees

• Merck Patent Gmbh

Inventors

• Richardson Thomas E

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P27/00

  Drugs for disorders of the senses · CPC title

• A61K31/498 Primary

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