Substituted N,2-diarylquinoline-4-carboxamides and the use thereof as anti-inflammatory agents

Patent metadata

Field	Value
Publication number	US-10479765-B2
Application number	US-201816125645-A
Country	US
Kind code	B2
Filing date	Sep 7, 2018
Priority date	Sep 9, 2014
Publication date	Nov 19, 2019
Grant date	Nov 19, 2019

Abstract

The present application relates to novel substituted N,2-diarylquinoline-4-carboxamide derivatives, to processes for preparation thereof, to the use thereof alone or in combinations for treatment and/or prevention of diseases, and to the use thereof for production of medicaments for treatment and/or prevention of diseases, especially for treatment and/or prevention of fibrotic and/or inflammatory disorders.

First claim

The invention claimed is:

1. A method for treatment of idiopathic pulmonary fibrosis in a human or an animal, comprising administering to the human or animal in need thereof a compound of the formula (I)

in which
R A is hydrogen, halogen, pentafluorosulfanyl, cyano, nitro, (C 1 -C 4 )-alkyl, hydroxyl, (C 1 -C 4 )-alkoxy, amino or a group of the formula —NH—C(═O)—R 6 , —NH—C(═O)—NH—R 6 or —S(═O)—R 7 ,
where (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkoxy may be up to trisubstituted by fluorine,
and in which
R 6 is hydrogen or (C 1 -C 4 )-alkoxy which may be up to trisubstituted by fluorine,
R 7 is (C 1 -C 4 )-alkyl which may be substituted by hydroxyl, methoxy or ethoxy or up to trisubstituted by fluorine,
and
n is the number 0, 1 or 2,

D is C—R b or N,
E is C—R E or N,
G is C—R G or N,
where not more than two of the ring members D, E and G at the same time are N,
and in which
R D and R E are each independently hydrogen, fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy,
and
R G is hydrogen, fluorine, chlorine, bromine, methyl or trifluoromethyl,

Z is OH or a group of the formula —NH—R 8 , —NH—SO 2 R 9 or —NH—SO 2 —NR 10A R 10B , in which
R 8 is hydrogen or (C 1 -C 4 )-alkoxy which may be up to trisubstituted by fluorine,
R 9 is (C 1 -C 4 )-alkoxy which may be up to trisubstituted by fluorine, or phenyl,
and
R 10A and R 10B are each independently hydrogen or (C 1 -C 4 )-alkyl which may be up to trisubstituted by fluorine,

R 1 is halogen, trifluoromethoxy, (trifluoromethyl)sulfanyl, pentafluorosulfanyl, (C 1 -C 4 )-alkyl, trimethylsilyl, cyclopropyl or cyclobutyl,
where (C 1 -C 4 )-alkyl may be up to trisubstituted by fluorine
and
cyclopropyl and cyclobutyl may be up to disubstituted by fluorine,

R 2 , R 3 and R 4 are each independently hydrogen, fluorine, chlorine, methyl or trifluoromethyl,
R 5 is (C 1 -C 4 )-alkyl which may be up to trisubstituted by fluorine, or is fluorine, chlorine, methoxy or cyclopropyl,
and
Ar is phenyl which may be mono- or disubstituted identically or differently by fluorine and chlorine, or is pyridyl or thienyl,

and an N-oxide, salt, solvate, salt of the N-oxide and solvate of the N-oxide and salt thereof.

2. The method of claim 1 , wherein the compound of the formula (I) is in a medicament, wherein the medicament comprises the compound of the formula (I) in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

3. The method of claim 2 wherein the medicament further comprises at least one compound selected from the group consisting of
PDE 5 inhibitor,
sGC activator,
sGC stimulator,
prostacyclin analog,
IP receptor agonist,
endothelin antagonist,
compound that inhibit the signal transduction cascade, and
pirfenidone.

4. The method of claim 1 , wherein the compound is a compound of formula (I) in which
R A is hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy or a group of the formula —S(═O) n —R 7 in which
R 7 is methyl or trifluoromethyl,
and
n is the number 0 or 2,

D is C—R D or N, in which
R D is hydrogen or fluorine,

E is C-H,
G is C—R G or N, in which
R G is hydrogen, fluorine or chlorine,

Z is OH,
R 1 is chlorine, bromine, iodine, methyl, ethyl, isopropyl, trifluoromethyl, trifluoromethoxy, (trifluoromethyl)sulfanyl, pentafluorosulfanyl or trimethylsilyl,
R 2 and R 3 are each hydrogen,
R 4 is hydrogen, fluorine or chlorine,
R 5 is methyl, chlorine or cyclopropyl,
and
Ar is phenyl which may be monosubstituted by fluorine, or pyridyl, and a salt, solvate and solvate of the salt thereof.

5. The method of claim 1 , wherein the compound is a compound of formula (I) in which
R A is fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy, trifluoromethoxy or a group of the formula —S(═O) n —R 7 in which
R 7 is methyl or trifluoromethyl,
and
n is the number 0 or 2,

D is C-H,
E is C-H,
G is C—R G or N, in which
R G is hydrogen, fluorine or chlorine,

Z is OH,
R 1 is chlorine, bromine, methyl, trifluoromethyl or trimethylsilyl,
R 2 and R 3 are each hydrogen,
R 4 is hydrogen or chlorine,
R 5 is methyl,
and
Ar is phenyl which may be monosubstituted by fluorine, or 4-pyridyl,
and a salt, solvate and solvate of the salt thereof.

6. The method of claim 1 , wherein the compound is 6-{[6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-fluoronicotinic acid

7. The method of claim 1 , wherein the compound is 4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3 fluorobenzoic acid

8. The method of claim 1 , wherein the compound is 3-Fluoro-4-{[6-iodo-3-methyl-2-phenylquinolin-4-yl)carbonyl]-amino}-benzoic acid

9. The method of claim 1 , wherein the compound is 4-{[(6-Bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic acid

10. The method of claim 1 , wherein the compound is 4-{[(6-Bromo-3-cyclopropyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic acid

Assignees

• Bayer Pharma AG

Inventors

• Beck Hartmut
• Thaler Tobias
• Kast Raimund
• Meibom Daniel
• Meininghaus Mark
• Terjung Carsten
• Delbeck Martina
• Lustig Klemens
• Muenster Uwe
• Olenik Britta

Classifications

• A61P43/00

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P27/02

  Ophthalmic agents · CPC title