Aryl-quinoline derivatives

Patent metadata

Field	Value
Publication number	US-9809599-B2
Application number	US-201514938005-A
Country	US
Kind code	B2
Filing date	Nov 11, 2015
Priority date	Nov 4, 2011
Publication date	Nov 7, 2017
Grant date	Nov 7, 2017

Abstract

The invention provides novel compounds having the general formula (I)

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n are as described herein, compositions including the compounds and methods of using the compounds. The present compounds are useful as fatty-acid binding protein (FABP) 4 and/or 5 inhibitors and may be used for the treatment or prophylaxis of lipodystrophy, type 2 diabetes, dyslipidemia, atherosclerosis, liver diseases involving inflammation, steatosis and/or fibrosis, such as non-alcoholic fatty liver disease, in particular non-alcoholic steatohepatitis, metabolic syndrome, obesity, chronic inflammatory and autoimmune inflammatory diseases.

First claim

The invention claimed is:

1. A compound according to formula (I),

wherein
R 1 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, halocycloalkyl, haloalkoxy, cycloalkoxy, halocycloalkoxy, hydroxyalkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted amino, aminocarbonyl or substituted aminocarbonyl, wherein substituted heterocycloalkyl is substituted with one to three substituents independently selected from the group consisting of oxo, halogen, alkyl, cycloalkyl and haloalkyl, and wherein substituted amino and substituted aminocarbonyl are substituted on the nitrogen atom with one to two substituents independently selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl, with the proviso that R 1 is not methyl or ethyl;
R 2 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, nitro, cyano, amino, aminoalkyl, substituted amino and substituted aminoalkyl, wherein substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;
R 3 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, nitro, cyano, amino, aminoalkyl, substituted amino and substituted aminoalkyl, wherein substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;
R 4 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, nitro, cyano, amino, aminoalkyl, substituted amino and substituted aminoalkyl, wherein substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;
R 5 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, nitro, cyano, amino, aminoalkyl, substituted amino and substituted aminoalkyl, wherein substituted amino and substituted aminoalkyl are substituted on the nitrogen atom with one to two substituents independently selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;
R 6 is selected from the group consisting of phenyl, substituted phenyl, pyridinyl and substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted with one to three substituent independently selected from the group consisting of alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, cycloalkoxy, cycloalkoxyalkyl, alkylcycloalkylalkyl, halocycloalkyl, halocycloalkylalkyl, halogen, cyano, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkoxy, hydroxyalkoxy, alkoxyalkoxy, alkoxyalkoxyalkyl, hydroxyhaloalkyl, amino and substituted amino, wherein substituted amino is substituted with one to two substituents independently selected from the group consisting of alkyl, cycloalkyl, haloalkyl, alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkylalkyl, hydroxyalkyl and alkoxyalkyl;
R 7 is selected from the group consisting of —COOH, 3H-[1,3,4]oxadiazol-2-on-5-yl, 3H-[1,3,4]oxadiazole-2-thion-5-yl, 4H-[1,2,4]oxadiazol-5-on-3-yl, 4H-[1,2,4]oxadiazole-5-thion-3-yl, 3H-[1,2,3,5]oxathiadiazole-2-oxide-4-yl, 4H-[1,2,4]thiadiazol-5-on-3-yl, isoxazol-3-ol-5-yl, 5-alkylisoxazol-3-ol-4-yl, 5-cycloalkylisoxazol-3-ol-4-yl, furazan-3-ol-4-yl, 5-alkylsulfonylamino-[1,3,4]oxadiazol-2-yl, 5-cycloalkylsulfonylamino-[1,3,4]oxadiazol-2-yl, 5-alkylsulfonylamino-2H-[1,2,4]triazol-3-yl, 5-cycloalkylsulfonylamino-2H-[1,2,4]triazol-3-yl, 5-alkylisothiazol-3-ol-4-yl, 5-cycloalkylisothiazol-3-ol-4-yl, [1,2,5]thiadiazol-3-ol-4-yl, 1,4-dihydro-tetrazol-5-on-1-yl, 2H-tetrazol-5-ylcarbamoyl, 2H-tetrazole-5-carbonyl, [1,2,4]oxadiazolidine-3,5-dion-2-y, 4H-[1,2,4]oxadiazol-5-on-3-yl, 2,4-dihydro-[1,2,4]triazol-3-on-5-sulfanyl, 4H-[1,2,4]triazole-3-sulfanyl, 4H-[1,2,4]triazole-3-sulfinyl, 4H-[1,2,4]triazole-3-sulfonyl, 4-alkyl-pyrazol-1-ol-5-yl, 4-cycloalkyl-pyrazol-1-ol-5-yl, 4-alkyl-[1,2,3]triazol-1-ol-5-yl, 4-cycloalkyl-[1,2,3]triazol-1-ol-5-yl, 5-alkyl-imidazol-1-ol-2-yl, 5-cycloalkyl-imidazol-1-ol-2-yl, 4-alkyl-imidazol-1-ol-5-yl, 4-cycloalkyl-imidazol-1-ol-5-yl, 4-alkyl-1,1-dioxo-1%-[1,2,5]thiadiazolidin-3-on-5-yl, 4,4-dialkyl-1,1-dioxo-1λ 6 -[1,2,5]thiadiazolidin-3-on-5-yl, 4-cycloalkyl-1,1-dioxo-1λ 6 -[1,2,5]thiadiazolidin-3-on-5-yl, 4,4-dicycloalkyl-1,1-dioxo-1λ 6 1,2,5]thiadiazolidin-3-on-5-yl, thiazolidine-2,4-dion-5-yl, oxazolidine-2,4-dion-5-yl, 3-[1-Hydroxy-meth-(E)-ylidene]-pyrrolidine-2,4-dion-1-yl, 3-[1-Hydroxy-meth-(Z)-ylidene]-pyrrolidine-2,4-dion-1-yl, 5-methyl-4-hydroxy-5H-furan-2-on-3-yl, 5,5-dialkyl-4-hydroxy-5H-furan-2-on-3-yl, 5-cycloalkyl-4-hydroxy-5H-furan-2-on-3-yl, 5,5-dicycloalkyl-4-hydroxy-5H-furan-2-on-3-yl, 3-hydroxy-cyclobut-3-ene-1,2-dion-4-yl and 3-hydroxy-cyclobut-3-ene-1,2-dion-4-amino; and
n is zero or 1;

with the proviso that at least one of R 2 , R 3 , R 4 and R 5 is different from hydrogen and that said compound is not 6-methoxy-4-phenyl-2-trifluoromethyl-quinoline-3-carboxylic acid or 4-(3,4-dimethoxy-phenyl)-2-hydroxymethyl-6,7-dimethoxy-quinoline-3-carboxylic acid; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, haloalkoxy, cycloalkoxy, hydroxyalkyl, heterocycloalkyl, substituted heterocycloalkyl, substituted amino and substituted aminocarbonyl, wherein substituted heterocycloalkyl is substituted with one to three substituents independently selected from the group consisting of oxo, halogen and alkyl, and wherein substituted amino and substituted aminocarbonyl are substituted on the nitrogen atom with one to two substituents independently selected from the group consisting of alkyl, hydroxyalkyl and alkoxyalkyl, with the proviso that R 1 is not methyl or ethyl.

3. The compound according to claim 1 , wherein R 1 is selected from the group consisting of heterocycloalkyl, substituted heterocycloalkyl and substituted amino, wherein substituted heterocycloalkyl is substituted with one alkyl, and wherein substituted amino is substituted on the nitrogen atom with two alkyl.

4. The compound according to claim 1 , wherein R 1 is piperidinyl or methylpyrrolidinyl.

5. The compound according to claim 1 , wherein R 1 is substituted amino, wherein substituted amino is substituted on the nitrogen atom with one to two alkyl.

6. The compound according to claim 1 , wherein R 2 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy and substituted amino, wherein substituted amino is substituted on the nitrogen atom with one to two alkyl.

7. The compound according to claim 1 , wherein R 2 is hydrogen or halogen.

8. The compound according to claim 1 , wherein R 3 i

Assignees

• Hoffmann La Roche

Inventors

• Ceccarelli Simona M
• Conte Aurelia
• Kuehne Holger
• Kuhn Bernd
• Neidhart Werner
• Obst Sander Ulrike
• Rudolph Markus

Classifications

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title