Muscarinic M1 receptor agonists

Patent metadata

Field	Value
Publication number	US-9907805-B2
Application number	US-201715436224-A
Country	US
Kind code	B2
Filing date	Feb 17, 2017
Priority date	Nov 18, 2011
Publication date	Mar 6, 2018
Grant date	Mar 6, 2018

Abstract

This invention relates to compounds that are agonists of the muscarinic M1 receptor and which are useful in the treatment of muscarinic M1 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula I, where n is 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; and R 1 -R 6 are as defined herein.

First claim

The invention claimed is:

1. A method of treating a cognitive disorder, comprising administering an effective amount of the compound having the formula:

or a salt thereof, wherein:
n is 1 or 2;
R 1 is a C 1-10 non-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms and wherein one or two, but not all, carbon atoms of the hydrocarbon group may optionally be replaced by a heteroatom selected from O, N and S and oxidised forms thereof;
R 2 is hydrogen or a C 1-10 non-aromatic hydrocarbon group;
or R 1 and R 2 together with the nitrogen atom to which they are attached form a non-aromatic heterocyclic group of four to nine ring members, wherein the heterocyclic ring may optionally contain a second heteroatom selected from O, N and S and oxidised forms thereof; and wherein the heterocyclic ring may optionally be substituted with one to six more substituents selected from C 1-2 alkyl; fluorine; and cyano;
R 3 is selected from hydrogen; halogen; cyano; hydroxy; C 1-3 alkoxy; and a C 1-5 non-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms and wherein one or two, but not all, carbon atoms of the hydrocarbon group may optionally be replaced by a heteroatom selected from O, N and S; and
R 4 is a C 1-6 non-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms and wherein one or two, but not all, carbon atoms of the hydrocarbon group may optionally be replaced by a heteroatom selected from O, N and S and oxidised forms thereof.

2. The method of claim 1 , wherein R 1 is selected from:
C 1-6 alkyl optionally substituted with 1 to 6 fluorine atoms;
methoxy-C 1-4 alkyl optionally substituted with 1 to 6 fluorine atoms;
C 1-6 alkoxy;
C 2-6 alkenyl;
C 2-6 alkynyl;
C 3-6 cycloalkyl optionally substituted with one or two methyl groups;
C 4-5 cycloalkyl-CH 2 — wherein the C 4-5 cycloalkyl moiety is optionally substituted with one C 1-2 alkyl group and wherein one carbon atom of the C 4-5 cycloalkyl moiety may optionally be replaced by an oxygen atom;
cyclopropyl-C 1-3 alkyl;
cyclopentenyl;
adamantyl; and
methyl-bicyclo[2.2.2]octanyl.

3. The method of claim 2 , wherein R 1 is selected from 2-methylpropyl, tert-butyl, 2-methylbutyl, 2,2-dimethylpropyl, 2-methylbut-2-yl, cyclobutylmethyl, cyclopropylmethyl, cyclopentylmethyl, isopropyl, 1-methylcyclohexyl, 1-methylcyclopentylmethyl, 2-cyclopropylpropyl, 1-methylcyclobutyl, cyclopentyl, 2,3-dimethylbutan-2-yl, 1-ethylcyclobutylmethyl, 1-methylcyclopentyl, 2-cyclopropylpropan-2-yl, cyclobutyl, 1-methylcyclobutylmethyl, 1-(trifluoromethyl)cyclobutyl, 1-ethylcyclobutyl, ( 2 H 3 )methyl( 2 H 6 )propyl and 2-methylpentan-2-yl.

4. The method of claim 3 , wherein R 2 is selected from hydrogen, methyl, ethyl and isopropyl.

5. The method of claim 4 , wherein R 3 is selected from hydrogen, fluorine, cyano, methoxy and methyl.

6. The method of claim 5 , wherein R 4 is selected from methyl, ethyl, ethynyl and 1-propynyl.

7. The method of claim 6 , wherein n is 1.

8. The method of claim 6 , wherein n is 2.

9. The method of claim 1 , wherein the compound is represented by the following formula:

or a salt thereof, wherein:
R 1 is selected from 2-methylpropyl, tert-butyl, 2-methylbutyl, 2,2-dimethylpropyl, 2-methylbut-2-yl, cyclobutylmethyl, cyclopropylmethyl, cyclopentylmethyl, isopropyl, 1-methylcyclohexyl, 1-methylcyclopentylmethyl, 2-cyclopropylpropyl, 1-methylcyclobutyl, cyclopentyl, 2,3-dimethylbutan-2-yl, 1-ethylcyclobutylmethyl, 1-methylcyclopentyl, 2-cyclopropylpropan-2-yl, cyclobutyl, 1-methylcyclobutylmethyl, 1-(trifluoromethyl)cyclobutyl, 1-ethylcyclobutyl, ( 2 H 3 )methyl( 2 H 6 )propyl and 2-methylpentan-2-yl;
R 2 is selected from hydrogen, methyl, ethyl and isopropyl;
or R 1 and R 2 together with the nitrogen atom to which they are attached form a non-aromatic heterocyclic group of four to nine ring members, wherein the heterocyclic ring may optionally contain a second heteroatom selected from O, N and S and oxidised forms thereof; and wherein the heterocyclic ring may optionally be substituted with one to six more substituents selected from C 1-2 alkyl; fluorine; and cyano;
R 3 is selected from hydrogen; fluorine; cyano; methoxy and methyl; and
R 4 is selected from methyl, ethyl, ethynyl and 1-propynyl.

10. The method of claim 1 , wherein the compound is represented by the following formula:

or a salt thereof, wherein:
R 1 is selected from 2-methylpropyl, tert-butyl, 2-methylbutyl, 2,2-dimethylpropyl, 2-methylbut-2-yl, cyclobutylmethyl, cyclopropylmethyl, cyclopentylmethyl, isopropyl, 1-methylcyclohexyl, 1-methylcyclopentylmethyl, 2-cyclopropylpropyl, 1-methylcyclobutyl, cyclopentyl, 2,3-dimethylbutan-2-yl, 1-ethylcyclobutylmethyl, 1-methylcyclopentyl, 2-cyclopropylpropan-2-yl, cyclobutyl, 1-methylcyclobutylmethyl, 1-(trifluoromethyl)cyclobutyl, 1-ethylcyclobutyl, ( 2 H 3 )methyl( 2 H 6 )propyl and 2-methylpentan-2-yl;
R 2 is selected from hydrogen, methyl, ethyl and isopropyl;
or R 1 and R 2 together with the nitrogen atom to which they are attached form a non-aromatic heterocyclic group of four to nine ring members, wherein the heterocyclic ring may optionally contain a second heteroatom selected from O, N and S and oxidised forms thereof; and wherein the heterocyclic ring may optionally be substituted with one to six more substituents selected from C 1-2 alkyl; fluorine; and cyano;
R 3 is selected from hydrogen; fluorine; cyano; methoxy and methyl; and
R 4 is selected from methyl, ethyl, ethynyl and 1-propynyl.

Assignees

• Heptares Therapeutics Ltd

Inventors

• Congreve Miles Stuart
• Brown Giles Albert
• Cansfield Julie Elaine
• Tehan Benjamin Gerald

Classifications

• A61P43/00

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

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P29/00

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

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title