Substituted 4-aminocyclohexane derivatives

Patent metadata

Field	Value
Publication number	US-9580386-B2
Application number	US-201414459540-A
Country	US
Kind code	B2
Filing date	Aug 14, 2014
Priority date	Mar 27, 2008
Publication date	Feb 28, 2017
Grant date	Feb 28, 2017

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 (1):

wherein
Y 1 , Y 1 ′, Y 2 , Y 2 ′, Y 3 , Y 3 ′, Y 4 and Y 4 ′ are each —H;
Q stands for -aryl or -heteroaryl;
R 1 and R 2 , independently of one another, stand for —H or —CH 3 ; on condition that R 1 and R 2 do not both simultaneously stand for —H;
R 3 stands for —C 3-12 -cycloaliphatic, -aryl, —C 1-8 -aliphatic-C 3-12 -cycloaliphatic, or —C 1-8 -aliphatic-aryl;
n stands for 0;
X stands for —NR A —;
R A stands for —H or —C 1-8 -aliphatic;
R B stands for —C(═O)—C 1-8 aliphatic-aryl or —C(═O)—C 1-8 aliphatic-heteroaryl;
wherein
“aliphatic” respectively is a branched or unbranched, saturated or a mono- or polyunsaturated, unsubstituted or mono- or polysubstituted, aliphatic hydrocarbon residue;
“cycloaliphatic” respectively is a saturated or a mono- or polyunsaturated, unsubstituted or mono- or polysubstituted, alicyclic, mono- or multicyclic hydrocarbon residue;
wherein with respect to “aliphatic” and “cycloaliphatic”, “mono- or polysubstituted” means the mono- or polysubstitution of one or more hydrogen atoms by substituents selected independently of one another from the group consisting of —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, ═O, —R 0 , —C(═O)R 0 , —C(═O)H, —C(═O)OH, —C(═O)OR 0 , —C(═O)NH 2 , —C(═O)NHR 0 , —C(═O)N(R 0 ) 2 , —OH, —OR 0 , —OC(═O)H, —OC(═O)R 0 , —OC(═O)OR 0 , —OC(═O)NHR 0 , —OC(═O)N(R 0 ) 2 , —SH, —SR 0 , —SO 3 H, —S(═O) 1-2 —R 0 , —S(═O) 1-2 NH 2 , —NH 2 , —NHR 0 , —N(R 0 ) 2 , —N + (R 0 ) 3 , —N + (R 0 ) 2 O − , —NHC(═O)R 0 , —NHC(═O)OR 0 , —NHC(═O)NH 2 , —NHC(═O)—NHR 0 , —NH—C(═O)N(R 0 ) 2 , —Si(R 0 ) 3 and —PO(OR 0 ) 2 ;
“aryl”, respectively independently, stands for a carbocyclic ring system with at least one aromatic ring, but without heteroatoms in this ring, wherein, optionally, the aryl residues can be condensed with further saturated, (partially) unsaturated or aromatic ring systems, and each aryl residue can be present in unsubstituted or mono- or polysubstituted form, wherein the aryl substituents can be the same or different and in any desired and possible position of the aryl;
“heteroaryl” stands for a 5-, 6- or 7-membered cyclic aromatic residue, which contains 1, 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms, the same or different, are nitrogen, oxygen or sulphur, and the heterocycle can be unsubstituted or mono- or polysubstituted; wherein in the case of the substitution on the heterocycle the substituents can be the same or different and can be in any desired and possible position of the heteroaryl; and wherein the heterocycle can also be part of a bi- or polycyclic system;
wherein with respect to “aryl” and “heteroaryl”, “mono- or polysubstituted” means the mono- or polysubstitution of one or more hydrogen atoms of the ring system by substituents selected from the group consisting of —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, ═O, —R 0 , —C(═O)R 0 , —C(═O)H, —C(═O)OH, —C(═O)OR 0 , —C(═O)NH 2 , —C(═O)NHR 0 , —C(═O)—N(R 0 ) 2 , —OH, —O(CH 2 ) 1-2 O—, —OR 0 , —OC(═O)H, —OC(═O)R 0 , —OC(═O)OR 0 , —OC(═O)NHR 0 , —OC(═O)N(R 0 )R 2 , —SH, —SR 0 , —SO 3 H, —S(═O) 1-2 —R 0 , —S(═O) 1-2 NH 2 , —NHR 0 , —N(R 0 ) 2 , —N + (R 0 ) 3 , —N + (R 0 ) 2 O − , —NHC(═O)R 0 , —NHC(═O)OR 0 , —NH—C(═O)NH 2 , —NHC(═O)NHR 0 , —NHC(═O)N(R 0 ) 2 , —Si(R 0 ) 3 or —PO(OR 0 ) 2 ; wherein any N-ring atoms present can be respectively oxidised; and
wherein R 0 respectively independently stands for —C 1-8 -aliphatic, —C 3-12 -cycloaliphatic, -aryl, -heteroaryl, —C 1-8 -aliphatic-C 3-12 -cycloaliphatic, —C 1-8 -aliphatic-aryl, —C 1-8 -aliphatic -heteroaryl, -C 3-8 -cycloaliphatic-C 1-8 -aliphatic, —C 3-8 -cycloaliphatic-aryl or —C 3-8 -cycloaliphatic-heteroaryl;
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 , 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 .

3. Compound according to claim 1 , wherein
R 1 stands for —CH 3 ; and
R 2 stands for —H or —CH 3 .

4. Compound according to claim 3 , wherein
Q stands for -phenyl, or -indolyl;
R 1 stands for —CH 3 ;
R 2 stands for —H or —CH 3 ;
R A stands for —H or —C 1-8 -alkyl; and
R B stands for —C(═O)—C 1-8 -alkyl-aryl or —C(═O)—C 1-8 -alkyl-heteroaryl;
wherein aliphatic, aryl and heteroaryl are respectively unsubstituted or mono- or polysubstituted.

5. 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.

6. 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.

7. A method of treating a condition 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 and/or solvate thereof, wherein said condition is selected from the group consisting of anxiety conditions, stress and stress-related syndromes, depressive illnesses, epilepsy, Alzheimer's disease, senile dementia, general cognitive dysfunctions, learning and memory disabilities (as nootropic), withdrawal symptoms, alcohol and/or drug and/or medication misuse and/or dependence, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinitus, pruritus, migraine, hearing impairment, deficient intestinal motility, eating disorders, anorexia, bulimia, mobility disorders, diarrhoea, cachexia, urinary incontinence, or as muscle relaxant, anticonvulsive or anaesthetic, or wherein said administering is for coadministration in the treatment with an opioid analgesic or with an anaesthetic, for diuresis or anti-natriuresis, anxiolysis, for modulating movement activity, for modulating neurotransmitter release and for treating neuro-degenerative diseases associated therewith, for treating withdrawal symptoms and/or for reducing the addiction potential of opioids.

8. Compound according to claim 1 , which is selected from the group consisting of:
N-(4-(dimethylamino)-1-(3-methyl-1H-indol-2-yl)-4-phenylcyclohexyl)-N-methyl-cinnamamide;
(E)-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide (non-polar diastereomer);
(E)-N-(4-dimethylamino-1,4-diphenyl-cyclohexyl)-N-methyl-3-phenyl-acrylamide (polar diastereomer);
N-[4-(dimethylamino)-1,4-diphenyl-cyclohexyl]-N-methyl-2,2-diphenyl-acetamide (polar diastereomer);
(E)-N-[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide (non-polar diastereomer);
(E)-N-[4-(cyclopentyl-methyl)-4-dimethylamino-1-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide (polar diastereomer); and
(E)-N-[4-dimethylamino-1-(3-methyl-1H-indol-2-yl)-4-phenyl-cyclohexyl]-N-methyl-3-phenyl-acrylamide (polar diastereomer);
and physiologically compatible salts thereof.

Assignees

• Gruenenthal Gmbh
• Grünenthal

Inventors

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

Classifications

• A61P43/00

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

• A61P9/12

  Antihypertensives · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P9/02

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