Substituted N-bicyclo-2-aryl-quinolin-4-carboxamides and use thereof

Patent metadata

Field	Value
Publication number	US-10117864-B2
Application number	US-201615552997-A
Country	US
Kind code	B2
Filing date	Mar 15, 2016
Priority date	Mar 18, 2015
Publication date	Nov 6, 2018
Grant date	Nov 6, 2018

Abstract

The present application relates to novel substituted N-bicyclo-2-arylquinoline-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 inflammatory disorders.

First claim

The invention claimed is:

1. A compound of the formula (I)

in which
the ring Q represents a group of the formula

where
# 1 represents the point of attachment to the carbonyl group,
# 2 represents the point of attachment to the nitrogen atom,
Y represents a group of the formula —O—, —CF 2 —, —C(H)(OH)—, —CHF— or —C(═O)—

Z represents —OH or represents a group of the formula —NH—R 6 or —NH—SO 2 —R 7 in which
R 6 represents hydrogen, methyl or ethyl which is up to trisubstituted by fluorine, and
R 7 represents (C 1 -C 2 )-alkyl which is up to trisubstituted by fluorine,
R 1 represents halogen, (C 1 -C 4 )-alkyl which is up to pentasubstituted by fluorine, methoxy which is up to trisubstituted by fluorine, (trifluoromethyl)sulfanyl, pentafluorosulfanyl, trimethylsilyl, ethynyl, cyclopropyl or cyclobutyl,
where cyclopropyl and cyclobutyl may be up to tetrasubstituted by fluorine,

R 2 , R 3 and R 4 independently of one another represent hydrogen, halogen or methyl which is up to trisubstituted by fluorine,
R 5 represents halogen, (C 1 -C 4 )-alkyl which is up to pentasubstituted by fluorine, methoxy which is up to trisubstituted by fluorine, represents hydroxy, methylsulfanyl, cyano, ethenyl, cyclopropyl or cyclobutyl,
where cyclopropyl and cyclobutyl may be up to tetrasubstituted by fluorine, and

Ar represents phenyl which may be up to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, methyl, which is up to trisubstituted by fluorine, and methoxy, which is up to trisubstituted by fluorine, or represents thienyl which may be mono- or disubstituted by methyl or monosubstituted by chlorine or bromine, or represents thiazolyl or pyridyl,
and the N-oxides, salts, solvates, salts of the N-oxides and solvates of the N-oxides and salts thereof.

2. The compound of the formula (I) as claimed in claim 1 in which
the ring Q represents a group of the formula

where
# 1 represents the point of attachment to the carbonyl group,
# 2 represents the point of attachment to the nitrogen atom,
Y represents a group of the formula —C(H)(OH)— or —CHF—

Z represents —OH,
R 1 represents chlorine, bromine, iodine, methyl, isopropyl, tert-butyl, difluoromethyl, trifluoronnethyl, trifluoronnethoxy, (trifluoromethyl)sulfanyl, trimethylsilyl, ethynyl, cyclopropyl or cyclobutyl,
R 2 represents hydrogen,
R 3 and R 4 independently of one another represent hydrogen, chlorine or methyl,
R 5 represents fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, hydroxy, methylsulfanyl or cyclopropyl, and
Ar represents phenyl which may be mono- or disubstituted by fluorine, represents thienyl which may be mono- or disubstituted by methyl or monosubstituted by chlorine or bromine or represents a group of the formula

where
# 3 represents the point of attachment to the quinoline ring,
R 8 represents chlorine or methyl, and
R 9 represents chlorine or methoxy,
and the salts, solvates and solvates of the salts thereof.

3. The compound of the formula (I) as claimed in claim 1 , in which
the ring Q represents a group of the formula

Z represents a group of the formula —OH,
R 1 represents chlorine, bromine, iodine, methyl, tert-butyl, difluoromnethyl, trifluoromethyl, trimethylsilyl, ethynyl or cyclopropyl,
R 2 represents hydrogen,
R 3 and R 4 independently of one another represent hydrogen, chlorine or methyl,
where at least one of the radicals R 3 and R 4 represents hydrogen,

R 5 represents fluorine, chlorine, methyl, ethyl, methoxy, hydroxy, methylsulfanyl or cyclopropyl, and
Ar represents phenyl which may be monosubstituted by fluorine,
and the salts, solvates and solvates of the salts thereof.

4. The compound of the formula (I) as claimed in claim 1 in which
the ring Q represents a group of the formula

Z represents a group of the formula —OH,
R 1 represents ethynyl, bromine or iodine,
R 2 , R 3 and R 4 each represent hydrogen,
R 5 represents chlorine, methyl, methylsulfanyl or cyclopropyl, and
Ar represents phenyl,
and the salts, solvates and solvates of the salts thereof.

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

is coupled with an amine compound of the formula (III)

and
T represents an ester protective group,
to give a compound of the formula (IV)

and then the ester radical T is eliminated to give the carboxylic acid of the formula (I-A)

and the carboxylic acid (I-A) is optionally converted in a further step into the corresponding acid chloride of the formula (V)

and the latter is subsequently reacted with a compound of the formula (VI)
H 2 N—R 6   (VI)

to give the carboxamide of the formula (I-B)

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.

6. A method for treatment of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, inflammatory and fibrotic skin and eye disorders and fibrotic disorders of the internal organs in humans and animals by administration of an effective amount of a medicament comprising at least one compound as defined in claim 1 .

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

8. 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 PDE 5 inhibitors, sGC activators, sGC stimulators, prostacyclin analogs, IP receptor agonists, endothelin antagonists, compounds that inhibit the signal transduction cascade and pirfenidone.

9. A method for treatment of idiopathic pulmonary fibrosis, pulmonary hypertension, bronchiolitis obliterans syndrome, inflammatory and fibrotic skin and eye disorders and fibrotic disorders of the internal organs in humans and animals

Assignees

• Bayer Pharma AG

Inventors

• Beck Hartmut
• Thaler Tobias
• Kast Raimund
• Meininghaus Mark
• Terjung Carsten
• Muenster Uwe
• Olenik Britta

Classifications

• A61P43/00

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

• A61P17/00

  Drugs for dermatological disorders · CPC title