Substituted azaspiro(4.5)decane derivatives

Patent metadata

Field	Value
Publication number	US-10214520-B2
Application number	US-201515326138-A
Country	US
Kind code	B2
Filing date	Jul 14, 2015
Priority date	Jul 15, 2014
Publication date	Feb 26, 2019
Grant date	Feb 26, 2019

Abstract

The invention relates to substituted spirocyclic cyclohexane derivatives which have an affinity for the μ opioid receptor and/or the ORL1 receptor, processes for the preparation thereof, medicaments containing these compounds and the use of these compounds for the preparation of medicaments.

First claim

The invention claimed is:

1. A compound of the general formula (1)

wherein
Y 1 , Y 1 ′, Y 2 ′, Y 2 ′, Y 3 , Y 3 ′, Y 4 and Y 4 ′ in each case independently of each other are chosen from the group consisting of —H, —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, —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 , —S(═O) 1-2 —NHR 0 , —S(═O) 1-2 —N(R 0 ) 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 and —NHC(═O)N(R 0 ) 2 ; or Y 1 and Y 1 ′, or Y 2 and Y 2 ′, or Y 3 and Y 3 ′, or Y 4 and Y 4 ′ together represent ═O;
X 1 , X 1 ′, X 2 , X 2 ′, X 3 and X 3 in each case independently of each other represent —H, —F, —Cl, —Br, —I, —NO 2 , —CF 3 , —OR 5 , —SR 5 , —SO 2 R 5 , —S(═O) 2 OR 5 , —CN, —COOR 5 , —CONR 5 , —NR 6 R 7 , or —R 0 ; or X 1 and X 1 ′, or X 2 and X 2 ′, or X 3 and X 3 ′ together represent ═O;
or X 1 and X 2 or X 2 and X 3 together represent —(CH 2 ) 2-6 —, wherein individual hydrogen atoms can also be replaced by —F, —Cl, —Br, —I, —NO 2 , —CF 3 , —OR 5 , —CN or —C 1-6 -aliphatic;
or X 1 and X 1 ′ or X 2 and X 2 ′ or X 3 and X 3 ′ in each case together represent a C 3-6 -cycloaliphatic, wherein individual hydrogen atoms can also be replaced by —F, —Cl, —Br, —I, —NO 2 , —CF 3 , —OR 5 , —CN or —C 1-6 -aliphatic;
R 0 in each case independently represents —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;
R 1 and R 2 independently of each other represent —H or —R 0 ; or R 1 and R 2 together represent —CH 2 CH 2 OCH 2 CH 2 —, —CH 2 CH 2 NR 8 CH 2 CH 2 — or —(OH 2 ) 3-6 —;
R 3 represents —R 0 ;
R 4 represents —R 11 , —O(═O)R 11 , —O(═O)OR 12 , —C(═O)N(R 12 ) 2 ; —O(═O)—O—O(C═O)—R 12 —S(═O)R 11 or —S(═O) 2 R 11 ;
R 5 in each case independently represents —H or —R 0 ;
R 6 and R 7 independently of each other represent —H or —R 0 ; or R 6 and R 7 together represent —CH 2 CH 2 OCH 2 CH 2 —, —CH 2 CH 2 NR 10 CH 2 CH 2 — or —(OH 2 ) 3-6 —;
R 8 represents —H, —R 0 or —O(═O)R 0 ;
R 9 represents —H, —R 0 or —OR 5 , or —NR 6 R 7 ;
R 10 represents —H or —C 1-6 -aliphatic;
R 11 represents
a) —C 1-6 -alkyl, —C 3-6 -cycloalkyl, or —C 1-3 -alkyl-C 3-6 -cycloalkyl, wherein in the C 3-6 -cycloalkyl group a ring carbon atom can be replaced by an oxygen atom and —C 1-6 -alkyl, —C 3-6 -cycloalkyl or —C 1-3 -alkyl-C 3-6 -cycloalkyl is mono- or polysubstituted by substituents independently of each other selected from the group consisting of —NO 2 , —CHO, ═O, —O(═O)R 0 , —O(═O)H, —C(═O)—OH, —O(═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 , —S(═O) 1-2 —NHR 0 , —S(═O) 1-2 —N(R 0 ) 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 ;
or
b) unsubstituted or mono- or polysubstituted —C 7-8 -alkyl, —C 7-12 -cycloalkyl or C 3-12 -cycloheteroalkyl having up to 3 hetero atoms in the ring selected from the group of O, N and S, with the proviso that heterocycles having only one oxygen atom as a hetero atom are excluded,
or
c) -aryl, -heteroaryl, —C 4-8 -cycloalkyl-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,
and R 12 represents H, —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;

wherein
“aliphatic” in each case is a branched or unbranched, saturated or a mono- or polyunsaturated, unsubstituted or mono- or polysubstituted, aliphatic hydrocarbon radical;
“cycloaliphatic” in each case is a saturated or mono- or polyunsaturated, unsubstituted or mono- or polysubstituted, alicyclic, mono- or multicyclic hydrocarbon radical;
wherein with respect to “aliphatic”, including —C 4-8 -alkyl, —C 7-12 -alkyl, and “cycloaliphatic” including —C 7-12 -cycloalkyl or C 3-12 -cycloheteroalkyl “mono- or polysubstituted” is understood as meaning substitution once or several times of one or more hydrogen atoms by —F, —Cl, —Br, —I, —CN, —NO 2 , —CHO, ═O, —R 0 , —O(═O)R 0 , —O(═O)H, —C(═O)—OH, —O(═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 , —PO(OR 0 ) 2 ;
“aryl” in each case independently represents a carbocyclic ring system having at least one aromatic ring, but without hetero atoms in this ring, wherein the aryl radicals can optionally be fused with further saturated, (partially) unsaturated or aromatic ring systems and each aryl radical can be unsubstituted or mono- or polysubstituted, wherein the substituents on aryl can be identical or different and can be in any desired and possible position of the aryl;
“heteroaryl” represents a 5-, 6- or 7-membered cyclic aromatic radical which contains 1, 2, 3, 4 or 5 hetero atoms, wherein the hetero atoms are identical or different and are nitrogen, oxygen or sulfur and the heterocycle can be unsubstituted or mono- or polysubstituted; wherein in the case of substitution on the heterocycle the substituents can be identical 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” is understood as meaning substitution once or several times of one or more hydrogen atoms of the ring system by substituents chosen 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 ) 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 , —NHC(═O)N(R 0 ) 2 , —Si(R 0 ) 3 , —PO(OR 0 ) 2 ; wherein N ring atoms optionally present can in each case be oxidised (N-oxide);
in the form of an individual stereoisomer or mixture thereof, the free compounds and/or its physiologically acceptable salts and/or solvates.

2. A compound as claimed in claim 1 , wherein Y 1 ′, Y 2 ′, Y 3 ′ and Y 4 ′ each represent —H.

3. A compound as claimed in claim 1 , wherein
R 0 in each case independently represents —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; whe

Assignees

• Gruenenthal Gmbh

Inventors

• Wegert Anita
• Kuehnert Sven
• Koenigs Rene Michael
• Nolte Bert
• Linz Klaus
• Harlfinger Stephanie
• Koegel Babette-Yvonne
• Ratcliffe Paul
• Theil Fritz
• Groeger Olga
• Braun Birgit

Classifications

• A61P43/00

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

• A61P9/12

  Antihypertensives · CPC title

• A61P9/02

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title