Piperidine urea derivatives

Patent metadata

Field	Value
Publication number	US-2016184285-A1
Application number	US-201414909784-A
Country	US
Kind code	A1
Filing date	Jul 9, 2014
Priority date	Aug 7, 2013
Publication date	Jun 30, 2016
Grant date	—

Abstract

Compounds of the formula I

in which R 1 -R 3 have the meanings indicated in Claim 1,

are inhibitors of Tankyrase, and can be employed, inter alia, for the treatment of diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation.

First claim

1 . Compounds of the formula I

in which
R 1 denotes A or CH 2 COOA,
R 2 , R 3 each, independently of one another, denote Ar or Het 1 ,
R 1 and R 2 together with the N atom to which they are attached, denote a heterocylic ring selected from 2,3-dihydro-indolyl or 3,4-dihydro-quinolyl,
Het 1 denotes pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which may mono-, di- or trisubstituted by Hal, A, OH, CN and/or OA,
Ar denotes phenyl, which is unsubstituted, or mono-, di- or trisubstituted by Hal, NO 2 , CN, A, OR 4 , S(O) m R 4 , N(R 4 ) 2 , COA, COOR 4 , CON(R 4 ) 2 , SO 2 N(R 4 ) 2 , NR 4 COR 4 , NR 4 SO 2 A, NR 4 CON(R 4 ) 2 and/or Het 2 ,
R 4 denotes H or A′,
A denotes unbranched or branched alkyl with 1-8 C-Atoms, wherein one or two non-adjacent CH- and/or CH 2 -groups may be replaced by N- or O-atoms and wherein 1-7 H-atoms may be replaced by F or Cl,
A′ denotes unbranched or branched alkyl with 1, 2, 3 or 4 C-Atoms,
Het 2 denotes pyrazolyl, which may be substituted by A or (CH 2 ) n Het 3 ,
Het 3 denotes pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, each of which may substituted by A,
Hal denotes F, Cl, Br or I,
m denotes 0, 1 or 2,
n denotes 1, 2, 3 or 4,
with the proviso, that
4-(4-fluorobenzoyl)-N-methyl-N-phenyl-piperidine-1-carboxamide and 4-(4-fluorobenzoyl)-N-(4-fluorophenyl)-N-methyl-piperidine-1-carboxamide are excluded,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

2 . Compounds according to claim 1 , in which
Ar denotes phenyl, which is unsubstituted, or mono- or disubstituted by Hal, CN, A, OA, NHSO 2 A and/or Het 2 ,
and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

3 . Compounds according to claim 1 , in which
A denotes unbranched or branched alkyl with 1-8 C-Atoms, wherein one or two non-adjacent CH 2 -groups may be replaced by O-atoms,
and pharmaceutically acceptable solvates, salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

4 . Compounds according to claim 1 , in which
R 1 denotes A or CH 2 COOA, R 2 , R 3 denote Ar, R 1 and R 2 together with the N atom to which they are attached, denote a heterocylic ring selected from 2,3-dihydro-indolyl or 3,4-dihydro-quinolyl, Ar denotes phenyl, which is unsubstituted, or mono-, di- or trisubstituted by Hal, CN, A, OA, NHSO 2 A and/or Het 2 , R 4 denotes H or A′, A denotes unbranched or branched alkyl with 1-8 C-Atoms, wherein one or two non-adjacent CH 2 -groups may be replaced by O-atoms, A′ denotes unbranched or branched alkyl with 1, 2, 3 or 4 C-Atoms, Het 2 denotes pyrazolyl, which may be substituted by A or (CH 2 ) n Het 3 , Het 3 denotes pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, each of which may substituted by A, Hal denotes F, Cl, Br or I, m denotes 0, 1 or 2, n denotes 1, 2, 3 or 4,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

5 . Compounds according to claim 1 , in which
R 1 denotes A or CH 2 COOA, R 2 denotes Ar or Het 1 , R 3 denote Ar, R 1 and R 2 together with the N atom to which they are attached, denote a heterocylic ring selected from 2,3-dihydro-indolyl or 3,4-dihydro-quinolyl, Ar denotes phenyl, which is unsubstituted, or mono-, di- or trisubstituted by Hal, CN, A, OA, NHSO 2 A and/or Het 2 , R 4 denotes H or A′, A denotes unbranched or branched alkyl with 1-8 C-Atoms, wherein one or two non-adjacent CH 2 -groups may be replaced by O-atoms, A′ denotes unbranched or branched alkyl with 1, 2, 3 or 4 C-Atoms, Het 1 denotes pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which may mono- or disubstituted by CN and/or OA, Het 2 denotes pyrazolyl, which may be substituted by A or (CH 2 ) n Het 3 , Het 3 denotes pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, each of which may substituted by A, Hal denotes F, Cl, Br or I, m denotes 0, 1 or 2, n denotes 1, 2, 3 or 4,
and pharmaceutically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios.

6 . Compounds according to claim 1 , selected from the group

No.
Name

“A1”
4-benzoyl-piperidine-1-carboxylic acid methyl-m-tolyl-amide

“A2”
4-benzoyl-piperidine-1-carboxylic acid methyl-p-tolyl-amide

“A3”
4-benzoyl-piperidine-1-carboxylic acid (3-methoxy-phenyl)-

methyl-amide

“A4”
4-benzoyl-piperidine-1-carboxylic acid (4-methoxy-phenyl)-

methyl-amide

“A5”
4-(4-methyl-benzoyl)-piperidine-1-carboxylic acid (4-

methoxy-phenyl)-methyl-amide

“A6”
4-(4-methoxy-benzoyl)-piperidine-1-carboxylic acid (4-

methoxy-phenyl)-methyl-amide

“A7”
4-(3-fluoro-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-

phenyl)-methyl-amide

“A8”
4-(4-fluoro-benzoyl)-piperidine-1-carboxylic acid (4-methoxy-

phenyl)-methyl-amide

“A9”
4-(4-chloro-benzoyl)-piperidine-1-carboxylic acid (4-

methoxy-phenyl)-methyl-amide

“A10”
4-benzoyl-piperidine-1-carboxylic acid (3-cyano-phenyl)-

methyl-amide

“A11”
4-benzoyl-piperidine-1-carboxylic acid (4-cyano-phenyl)-

methyl-amide

“A12”
4-benzoyl-piperidine-1-carboxylic acid (3-fluoro-phenyl)-

methyl-amide

“A13”
4-benzoyl-piperidine-1-carboxylic acid (4-fluoro-phenyl)-

methyl-amide

“A14”
4-benzoyl-piperidine-1-carboxylic acid ethyl-(4-methoxy-

phenyl)-amide

“A15”
4-benzoyl-piperidine-1-carboxylic acid (2-hydroxy-ethyl)-(4-

methoxy-phenyl)-amide

“A16”
(4-benzoyl-piperidin-1-yl)-(2,3-dihydro-indol-1-yl)-methanone

“A17”
(2,3-dihydro-indol-1-yl)-[4-(4-methyl-benzoyl)-piperidin-1-yl]-

methanone

“A18”

Assignees

• Merck Patent Gmbh

Inventors

• Buchstaller Hans-Peter
• Dorsch Dieter

Classifications

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

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