Substituted 4-aminocyclohexane derivatives

Patent metadata

Field	Value
Publication number	US-9403767-B2
Application number	US-201313803295-A
Country	US
Kind code	B2
Filing date	Mar 14, 2013
Priority date	Mar 27, 2008
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

The invention relates to compounds that have an affinity to the μ-opioid receptor and the ORL 1-receptor, methods for their production, medications containing these compounds and the use of these compounds for the treatment of pain and other conditions.

First claim

The invention claimed is:

1. A compound of the formula:

wherein
Q stands for —C 1-8 -alkyl, —C 1-8 -alkyl-C 5-6 -cycloalkyl, -phenyl, —C 1-8 -alkyl-phenyl, -indolyl, —C(═O)-indolyl or —C(═NH)-indolyl, wherein said -phenyl, —C 1-8 -alkyl-phenyl, -indolyl, —C(═O)-indolyl and —C(═NH)-indolyl are each unsubstituted or substituted by one or more substituents independently selected from the group consisting of —CH 3 , —CH 2 —O—CH 3 , —F, —Cl, —Br, —I, —CN, —NO 2 , —CF 3 , —OH and —OCH 3 ;
R 1 and R 2 , independently of one another, stand for —H or —C 1-8 -alkyl; on condition that R 1 and R 2 do not both simultaneously stand for —H;
R 3 stands for phenyl, which is unsubstituted or substituted by one or more substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —CN, —NO 2 , —CF 3 , —OH and —OCH 3 ; or stands for thienyl;
n stands for 0, 1, 2, 3 or 4;
X stands for —O— or —NR A —;
R A stands for —C 1-8 -alkyl, which is unsubstituted or substituted by phenyl, indolyl, pyridyl, pyrazolyl, C 5-6 -cycloalkyl, —OH, —C(═O)OH, —C(═O)OR 0 , —C(═O)NH 2 , —C(═O)NHR 0 or —C(═O)N(R 0 ) 2 ; or represents phenyl; or represents C 5-6 -cycloalkyl; or represents indolyl; or represents triazinyl; or represents pyridyl; wherein said phenyl, C 5-6 -cycloalkyl, indolyl, pyridyl, and pyrazolyl are unsubstituted or substituted by one or more substituents independently selected from the group consisting of —CH 3 , —F, —Cl, —Br, —I, —CN, —NO 2 , —CF 3 , —OH, —CH 2 OH and —OCH 3 ; wherein said triazinyl is unsubstituted or substituted by one or more substituents independently selected from the group consisting of —NH 2 , —NHR 0 , —N(R 0 ) 2 , piperidinyl, —NH—C 6 H 5 , —NH(CH 2 C 6 H 5 ) and —O—C 6 H 4 —OCH 3 ; and wherein R 0 represents —C 1-8 -alkyl;
R B stands for —H or —C 1-8 -alkyl, which is unsubstituted or substituted by phenyl, wherein said phenyl is unsubstituted or substituted by more or more substituents independently selected from the group consisting of —F, —Cl, —Br, —I, —CN, —NO 2 , —CF 3 , —OH and —OCH 3 ; on condition that when X stands for —O— and at the same time n stands for 0, R B does not stand for —H;
said compound being in the form of a single stereoisomer or mixture thereof, the free compound and/or a physiologically compatible salt thereof.

2. Compound according to claim 1 , wherein n=0 and X stands for —NR A —.

3. Compound according to claim 1 , which has the formula (2.2):

wherein
R C stands for —H, —F, —Cl, —Br, —I, —CN, —NO 2 , —CF 3 , —OH or —OCH 3 .

4. A pharmaceutical composition comprising at least one compound according to claim 1 , said compound being in the form of a single stereoisomer or mixture thereof, the free compound and/or a physiologically compatible salt thereof, and optionally suitable additives and/or adjuvants and/or further active substances.

5. A method of treating pain in a patient in need of such treatment, said method comprising administering to said patient an effective amount therefor of a compound according to claim 1 , said compound being in the form of a single stereoisomer or mixture thereof, the free compound and/or a physiologically compatible salt thereof.

6. The compound according to claim 1 , which has the formula:

wherein
R 1 and R 2 independently represent —C 1-8 -alkyl;
n stands for 0, 1, 2, 3 or 4;
R A stands for —C 1-8 -alkyl, which is unsubstituted or substituted by —C(═O)OH, —C(═O)OR 0 , —C(═O)NH 2 , —C(═O)NHR 0 or —C(═O)N(R 0 ) 2 ; and wherein R 0 represents —C 1-8 -alkyl; and
R B stands for —C 1-8 -alkyl.

7. A compound selected from the group consisting of:
1-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine;
1-(imino(1-methyl-1H-indol-2-yl)methyl)-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine;
1,4-bis(dimethylamino)-4-phenylcyclohexyl)(1-methyl-1H-indol-2-yl)methanone;
N1,N1,N4-trimethyl-1,4-diphenylcyclohexane-1,4-diamine;
N1,N1,N4,N4-tetramethyl-1,4-diphenylcyclohexane-1,4-diamine;
1-benzyl-N1,N1,N4,N4-tetramethyl-4-phenylcyclohexane-1,4-diamine;
4-methoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine;
4-(benzyloxy)-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1phenylcyclohexanamine;
4-ethoxy-4-(3-(methoxymethyl)-1H-indol-2-yl)-N,N-dimethyl-1-phenylcyclohexanamine;
(4-(dimethylamino)-4-phenyl-1-(4-phenylbutyl)cyclohexyl)methanol;
4-benzyl-4-((dimethylamino)methyl)-N,N-dimethyl-1-phenylcyclohexanamine;
4-(((1H-indol-2-yl)methylamino)methyl)-N,N,4-trimethyl-1-phenylcyclohexanamine;
N1,N1,N4,N4-tetramethyl-1-(3-methyl-1H-indol-2-yl)-4-phenylcyclohexane-1,4-diamine;
[4-benzyl-4-(dimethylaminomethyl)-1-phenyl-cyclohexyl]-dimethylamine;
(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methyl-dimethylamine (non-polar diastereomer);
(4-benzyl-4-((dimethylamino)methyl)-N-methyl-1-phenylcyclohexanamine (polar diastereomer);
(1-benzyl-4-dimethylamino-4-phenyl-cyclohexyl)-methyl-dimethylamine (polar diastereomer);
[4-(dimethylamino)-4-(3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethylamine (polar diastereomer);
[4-dimethylamino-4-(3-methyl-1H-indol-2-yl)-1-phenyl-cyclohexyl]-dimethylamine (non-polar diastereomer);
[4-(dimethylaminomethyl)-1,4-diphenyl-cyclohexyl]-dimethylamine (polar diastereomer);
dimethyl-(4-methylamino-4-phenyl-1-thiophen-2-yl-cyclohexyl)-amine (non-polar diastereomer);
dimethyl-(4-methylamino-4-phenyl-1-thiophen-2-yl-cyclohexyl)-amine (polar diastereomer);
[4-(dimethylamino)-4-phenyl-1-thiophen-2-yl-cyclohexyl]-dimethylamine (polar diastereomer);
(4-dimethylamino-4-phenyl-1-thiophen-2-yl-cyclohexyl)-dimethylamine (non-polar diastereomer);
(1-butyl-4-methylamino-4-phenyl-cyclohexyl)-dimethylamine (non-polar diastereomer);
(1-butyl-4-methylamino-4-phenyl-cyclohexyl)-dimethylamine (polar diastereomer);
[4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (non-polar diastereomer);
[4-(butyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (polar diastereomer);
[4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (non-polar diastereomer);
[4-(benzyl-methyl-amino)-1,4-diphenyl-cyclohexyl]-dimethylamine (polar diastereomer);
(4-butyl-4-dimethylamino-1-phenyl-cyclohexyl)-dimethylamine (non-polar diastereomer);
(4-butyl-4-dimethylamino-1-phenyl-cyclohexyl)-dimethylamine (polar diastereomer);
[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-methylamine (non-polar diastereomer);
[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-methylamine (polar diastereomer);
[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-dimethylamine (non-polar diastereomer);
[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-dimethylamine (polar diastereomer);
2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methylamino]-acetic acid (polar diastereomer);
2-[(4-dimethylamino-1,4-diphenyl-cyclohexyl)-methylamino]-acetic acid (non-polar diastereomer);
[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethylamine (non-polar diastereomer);
[1-(4-methoxyphenyl)-4-methylamino-4-phenyl-cyclohexyl]-dimethylamine (polar diastereomer);
dimethyl-[4-methylamino-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-amine (non-polar diastereomer);
dimethyl-[4-methylamino-4-phenyl-1-[4-(trifluoromethyl)-phenyl]-cyclohexyl]-amine (polar diastereomer);
[4-(dimethylamino)-4-phe

Assignees

• Gruenenthal Gmbh
• Gruenenthal Gmbh

Inventors

• Nolte Bert
• Schröder Wolfgang
• Linz Klaus
• Englberger Werner
• Schick Hans
• Graubaum Heinz
• Braun Birgit
• Ozegowski Sigrid
• Bálint József
• Sonnenschein Helmut

Classifications

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

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

• A61P9/02

  Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives · CPC title

• A61P9/12

  Antihypertensives · CPC title