Guanidine compounds, and use thereof as binding partners for 5-HT5 receptors

Patent metadata

Field	Value
Publication number	US-9475782-B2
Application number	US-201213683296-A
Country	US
Kind code	B2
Filing date	Nov 21, 2012
Priority date	Feb 19, 2004
Publication date	Oct 25, 2016
Grant date	Oct 25, 2016

Abstract

The present invention relates to guanidine compounds of the general formula I

corresponding enantiomeric, diastereomeric and/or tautomeric forms thereof as well as pharmaceutically acceptable salts thereof. The present compound further relates to the use of guanidine compounds as binding partners for 5-HT5 receptors for the treatment of diseases which are modulated by a 5-HT5 receptor activity, in particular for the treatment of neurodegenerative and neuropsychiatric disorders as well as the associated signs, symptoms and dysfunctions.

First claim

The invention claimed is:

1. A method of treating a disease selected from the group consisting of schizophrenia, autism, depression, states of anxiety, and combinations thereof, comprising administering to a patient having said disease an effective amount of a guanidine compound of formula IA

corresponding enantiomeric, diastereomeric and/or tautomeric forms thereof as well as pharmaceutically acceptable salts thereof
wherein the given moieties have the following definitions:
W:
a moiety of the general formula W1 or W2

A:
NO 2 , NH 2 , OH, CN, CF 3 , OCF 3 , CHF 2 , OCHF 2 , COOH, O—CH 2 —COOH, halogen, or SH, or
each optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-C 3 -C 7 -cycloalkyl or C 1 -C 4 -alkylene-hetero-cycloalkyl, aryl, hetaryl, heterocycloalkyl, C 1 -C 4 -alkylene-hetaryl or C 1 -C 4 -alkylene-aryl, or O—R A 1 , CO—R A 1 , S—R A 1 , SO—R A 1 , NR A 4 —CO—O—R A 1 , O—CH 2 —COO—R A 1 , NR A 2 R A 3 , CONH 2 , SO 2 NH 2 , NR A 4 —CO—R A 1 , SO 2 —R A 1 , NR A 4 —SO 2 —R A 1 , SO 2 —NR A 2 R A 3 or CO—NR A 2 R A 3 ;

R A 1 :
each optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-heterocyclo-alkyl, aryl, hetaryl, heterocycloalkyl, C 1 -C 4 -alkylene-aryl, C 2 -C 6 -alkenylene-aryl or C 1 -C 6 -alkylene-hetaryl;

R A 2 :
hydrogen, OH, or CN, or
each optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 4 -alkylene-C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-heterocycloalkyl, aryl, hetaryl, heterocycloalkyl, C 1 -C 4 -alkylene-aryl, C 1 -C 4 -alkylene-hetaryl, C 1 -C 6 -alkylene-O—C 1 -C 6 -alkyl, CO—C 1 -C 6 -alkyl, CO-aryl, CO-hetaryl, CO—C 1 -C 4 -alkylene-aryl, CO—C 1 -C 4 -alkylene-hetaryl, CO—O—C 1 -C 6 -alkyl, CO—O-aryl, CO—O—C 1 -C 4 -alkylene-aryl, CO—O-hetaryl, CO—O—C 1 -C 4 -alkylene-hetaryl, SO 2 —C 1 -C 6 -alkyl, SO 2 -aryl, SO 2 -hetaryl, SO 2 —C 1 -C 4 -alkylene-aryl or SO 2 —C 1 -C 4 -alkylene-hetaryl;

R A 3 :
each optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 4 -alkylene-C 3 -C 7 -cycloalkyl, C 1 -C 4 -alkylene-heterocycloalkyl, aryl, hetaryl, heterocycloalkyl, C 1 -C 4 -alkylene-aryl, C 1 -C 4 -alkylene-hetaryl, C 1 -C 6 -alkylene-O—C 1 -C 6 -alkyl CO—C 1 -C 6 -alkyl, CO-aryl, CO-hetaryl, CO—C 1 -C 4 -alkylene-aryl, CO—C 1 -C 4 -alkylene-hetaryl, CO—O—C 1 -C 6 -alkyl, CO—O-aryl, CO—O—C 1 -C 4 -alkylene-aryl, CO—O-hetaryl, CO—O—C 1 -C 4 -alkylene-hetaryl, SO 2 —C 1 -C 6 -alkyl, SO 2 -aryl, SO 2 -hetaryl, SO 2 —C 1 -C 4 -alkylene-aryl or SO 2 —C 1 -C 4 -alkylene-hetaryl;
or the moieties R A 2 and R A 3 form, together with the nitrogen, a 3 to 7-membered, optionally substituted, saturated or aromatic heterocycle, which can contain one, two or three further different or identical heteroatoms from the group O, N, S;
wherein optionally two moieties substituted on this heterocycle can together form an anellated, saturated, unsaturated or aromatic carbocycle or heterocycle, wherein the heterocycle can contain up to three different or identical heteroatoms, O, N, S and wherein the so-formed cycle can optionally be substituted or a further, optionally substituted cycle can be condensed onto this cycle;

R A 4 ;
hydrogen, or
each optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylene-O—C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 12 -alkynyl, CO—C 1 -C 6 -alkyl, CO—O—C 1 -C 6 -alkyl, SO 2 —C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, aryl, C 1 -C 4 -alkylene-aryl, CO—O-arylalkyl, CO—C 1 -C 4 -alkylene-aryl, CO-aryl, SO 2 -aryl, hetaryl, CO-hetaryl or SO 2 —C 1 -C 4 -alkylene-aryl;

B:
hydrogen or as moiety A is defined,
or each independently of one another two of the moieties A, B or R W 1 together form a 3 to 7-membered, optionally substituted, saturated or unsaturated carbocycle with an optionally substituted, saturated or unsaturated or aromatic heterocycle which can contain one, two or three further different or identical heteroatoms from the group O, N, S; wherein optionally two moieties substituted on this carbo- or heterocycle can form an anellated, saturated, unsaturated or aromatic carbocycle or heterocycle, wherein the heterocycle can contain up to three different or identical heteroatoms O, N, S and wherein the cycle formed can optionally be substituted or a further, optionally substituted cycle can be condensed onto this cycle;

R W 1 :
hydrogen, OH, halogen, NO 2 , NH 2 , CN, CF 3 , CHF 2 , O—CF 3 , or O—CHF 2 , or each optionally substituted C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, C 1 -C 6 -alkylene-O—C 1 -C 6 -alkyl, C 1 -C 6 -alkylene-S—C 1 -C 6 -alkyl, aryl, hetaryl, O—C 1 -C 6 -alkyl, O-aryl, O-benzyl, C 1 -C 6 -alkylamino, C 1 -C 6 -dialkylamino, pyrrolidinyl, piperidinyl, morpholinyl, CO—C 1 -C 6 -alkyl, SO 2 —C 1 -C 6 -alkyl, CO-aryl, SO 2 -aryl, CO—C 1 -C 4 -alkylene-aryl, SO 2 —C 1 -C 4 -alkylene-aryl, SO-aryl, CONH 2 , CONH—C 1 -C 6 -alkyl, SO 2 NH—C 1 -C 6 -alkyl, CON(C 1 -C 6 -alkyl) 2 , SO 2 N(C 1 -C 6 -alkyl) 2 , NH—SO 2 —C 1 -C 6 -alkyl or NH—CO—C 1 -C 6 -alkyl;

D:
as moiety A is defined;

Z:
a moiety of the general formula Z1

with the indices
a=0-4
b=0, 1
c=0-4
wherein the sum of a, b and c is at least 1 and no more than 5;

R Z 1 , R Z 2 , R Z 3 , R Z 4 independently of one another:
hydrogen, halogen, or OH, or
each optionally substituted C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkylene-C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl, aryl, C 1 -C 4 -alkylene-aryl, hetaryl or C 1 -C 4 -alkylene-hetaryl, or
each independently of one another two moieties R Z 1 and R Z 2 or R Z 3 and R Z 4 together form a 3 to 7-membered, optionally substituted, saturated or unsaturated carbo- or heterocycle, which can contain up to three heteroatoms from the group O, N or S;

V Z :
—CO—, —CO—NR z 5 —, —NR z 5 —CO—, —O—, —S—, —SO—, —SO 2 —, —SO 2 —NR z 5 —, —NR z 5 —SO 2 —, —CS, —NR z 5 —CS—, —CS—O—, —O—CS—, —CO—O—, —O—CO—, —O—, ethynylene, —C(═CR Z 6 R z 7 )—, —CR Z 6 ═CR Z 7 —,—NR z 5* , —O—CO—NR z 5 —, or —NR z 5 —;

R Z 5 , R Z 5 * independently of one another:
hydrogen, or
each optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylene-O—C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 12 -alkynyl, CO—C 1 -C 6 -alkyl, CO—O—C 1 -C 6 -alkyl, SO 2 —C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, Aryl, C 1 -C 4 -alkylene-aryl, CO—O—C 1 -C 4 -alkylene-aryl, CO—C 1 -C 4 -alkylene-aryl, CO-aryl, SO 2 -aryl, hetaryl, CO-hetaryl or SO 2 —C 1 -C 4 -alkylene-aryl;

R Z 6 , R Z 7 independently of one another:
hydrogen, or OH, or
each optionally substituted C 1 -C 6 -alkyl, C 1 -C 4 -alkoxy, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 1 -C 6 -alkylene-C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl, aryl, C 1 -C 4 -alkylene-aryl, hetaryl or C 1 -C 4 -alkylene-hetaryl;

R 1 , R 2 , R 3 independently of one another:
hydrogen, OH, or CN, or
each optionally substituted C 1 -C 6 -alkyl, O—C 1 -C 6 -alkyl, C 1 -C 6 -alkylene-O—C 1 -C 6 -alkyl, C 3 -C 7 -cycloalkyl, O—C 3 -C 7 -cycloalkyl, aryl, hetaryl, C 1 -C 4 -alkylene-aryl, C 1 -C 4 -alkylene-hetaryl, O-aryl, O—C 1 -C 4 -alkylene-aryl, O-hetaryl, O—C 1 -C 4 -alkylene-hetaryl, CO—C 1 -C 6 -alkyl, CO-aryl, CO

Assignees

• Abbvie Deutschland

Inventors

• Netz Astrid
• Amberg Wilhelm
• Lange Udo
• Ochse Michael
• Hutchins Charles W
• Garcia-Ladona Francisco-Xavier
• Wernet Wolfgang
• Kling Andreas

Classifications

• A61P39/02

  Antidotes · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P25/24

  Antidepressants · CPC title