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

Patent metadata

Field	Value
Publication number	US-10189788-B2
Application number	US-201515509600-A
Country	US
Kind code	B2
Filing date	Sep 7, 2015
Priority date	Sep 9, 2014
Publication date	Jan 29, 2019
Grant date	Jan 29, 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 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) n —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 D 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 the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof.

2. A compound of the formula (I) as claimed in claim 1 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 the salts, solvates and solvates of the salts thereof.

3. A compound of the formula (I) as claimed in claim 1 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 the salts, solvates and solvates of the salts thereof.

4. A process for preparing a compound as defined in claim 1 , wherein a compound of the formula (II)

in which R 1 , R 2 , R 3 , R 4 , R 5 and Ar have the definitions given above, with activation of the carboxylic acid function is coupled with an amine compound of the formula (III)

in which R A , D, E and G have the definitions given above,
and
T is (C 1 -C 4 )-alkyl or benzyl
to give a compound of the formula (IV)

in which R A , D, E, G, R 1 , R 2 , R 3 , R 4 , R 5 , Ar and T have the definitions given above,
and then the ester radical T is eliminated to give the inventive carboxylic acid of the formula (I-A)

in which R A , D, E, G, R 1 , R 2 , R 3 , R 4 , R 5 and Ar have the definitions given above,
and if necessary the carboxylic acid (I-A) is converted to the corresponding acid chloride of the formula (V)

in which R A , D, E, G, R 1 , R 2 , R 3 , R 4 , R 5 and Ar have the definitions given above,
and the latter is subsequently reacted with a compound of the formula (VI)
H 2 N—R 8   (VI)

in which R 8 has the definition given in claim 1
to give the inventive carboxamide of the formula (I-B)

in which R A , D, E, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 and Ar have the definitions given above,
and the compounds of the formulae (I-A) and (I-B) thus obtained are optionally converted with the appropriate (i) solvents and/or (ii) bases or acids to the solvates, salts and/or solvates of the salts thereof.

5. A medicament comprising a compound as defined in claim 1 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

6. A medicament comprising a compound as defined in claim 1 in combination with one or more further active ingredients selected from the group consisting of phosphodiesterase type 5 (PDE 5) inhibitors, soluble guanylyl cyclase (sGC) activators, sGC stimulators, prostacyclin analogs, prostacyclin (IP) receptor agonists, endothelin antagonists, compounds that inhibit signal transduction cascades, and pirfenidone.

7. The compound according to claim 1 , which is 6-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-5-fluoronicotinic acid

8. The compound according to claim 1 , which is 4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic acid

9. The compound according to claim 1 , which is 3-Fluoro-4-{[(6-iodo-3-methyl-2-phenylquinolin-4-yl)carbonyl]-amino}-benzoic acid

10. The compound according to claim 1 , which is 4-{[(6-Bromo-3-chloro-2-phenylquinolin-4-yl)carbonyl]amino}-3-fluorobenzoic acid

11. The compound according to claim 1 , which 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

• A61P9/12

  Antihypertensives · CPC title

• 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

• 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