Bicyclic aza compounds as muscarinic M1 receptor agonists

Patent metadata

Field	Value
Publication number	US-9669013-B2
Application number	US-201614996829-A
Country	US
Kind code	B2
Filing date	Jan 15, 2016
Priority date	Sep 18, 2012
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

This invention relates to compounds (Formula (1)) 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 where R 1 -R 5 , X 1 , X 2 and p are as defined herein.

First claim

The invention claimed is:

1. A method for the treatment of a cognitive disorder or psychotic disorder, wherein the cognitive disorder or psychotic disorder is schizophrenia, Alzheimer's disease and dementia, comprising administering an effective amount of the compound of formula (1) to a subject in need thereof, wherein the compound of formula (1) is

or a salt thereof, wherein:
p is 0, 1 or 2;
X 1 and X 2 are saturated hydrocarbon groups which together contain a total of five to nine carbon atoms and which link together such that the moiety:

forms a bicyclic ring system;
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 ring 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 substitutents 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;
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; and
R 5 is fluorine.

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; and
methyl-bicyclo[2.2.2]octanyl.

3. The method of claim 1 wherein R 1 is selected from 2-methylpropyl; 2,2-dimethylpropyl; tert-butyl; 2-methyl-but-2-yl; 2,3-dimethylbut-2-yl; cyclopropylmethyl; cyclobutylmethyl; cyclopentyl; cyclopentylmethyl; 1-methylcyclobutyl; 1-methylcyclopentyl; 1-methylcyclohexyl; 1-methylcyclopentylmethyl; cyclopropyl-prop-2-yl; 1-methylcyclobutylmethyl and 1-ethyl-cyclobutylmethyl groups.

4. The method of claim 1 wherein R 2 is selected from hydrogen, methyl, ethyl and isopropyl.

5. The method of claim 1 wherein R 3 is selected from hydrogen, fluorine and methoxy.

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

7. The method of claim 1 wherein p is 0.

8. The method of claim 1 wherein the bicyclic ring system formed by the moiety:

is selected from:
(a) an azabicyclo-octane or azabicyclo-nonane ring system;
(b) a 2-aza-spiro[3.4]octane or a 6-aza-spiro[3.4]octane ring system; and
(c) a cyclopentanopyrrolidine ring system.

9. The method according to claim 8 wherein the bicyclic ring system formed by the moiety:

is selected from ring systems BA, BB, BC, CA, CB and DA below:

10. The method of claim 1 where the compound of formula (1) has the formula (3):

wherein s is 0 or 1 and t is 0 or 1.

11. The method of claim 10 wherein s=0 and t=1.

12. The method of claim wherein the compound of formula (1) is selected from
ethyl 3-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-9-azabicyclo[3.3.1]nonane-9-carboxylate,
ethyl 3-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azabicyclo[3.2.1]octane-6-carboxylate,
ethyl 5-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate,
ethyl 2-{4-fluoro-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,
ethyl 6-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate,
prop-2-yn-1-yl 6-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate,
ethyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,
ethyl (2r,4s)-2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,
ethyl (2s,4r)-2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,
ethyl 2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,
ethyl (2r,4s)-2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,
ethyl (2s,4r)-2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,
ethyl 2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,
ethyl (2r,4s)-2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,
ethyl (2s,4r)-2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,
ethyl 2-(4-{[1-(fluoromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,
ethyl (2r,4s)-2-(4-{[1-(fluoromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,
ethyl (2s,4r)-2-(4-{[1-(fluoromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,
(2,2,2-trideutero)ethyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,
(2,2,2-trideutero)ethyl (2r,4s)-2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,
(2,2,2-trideutero)ethyl (2s,4r)-2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate,
(2,2,2-trideutero)ethyl 2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,
(2,2,2-trideutero)ethyl (2r,4s)-2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,
(2,2,2-trideutero)ethyl (2s,4r)-2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate,
(2,2,2-trideutero)ethyl 2-(4-{[1-(1,1,1-trideuteromethyl)

Assignees

• Heptares Therapeutics Ltd

Inventors

• Brown Giles Albert
• Cansfield Julie Elaine
• Congreve Miles Stuart
• Pickworth Mark
• 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