Muscarinic agonists

Patent metadata

Field	Value
Publication number	US-9758506-B2
Application number	US-201615227325-A
Country	US
Kind code	B2
Filing date	Aug 3, 2016
Priority date	Aug 3, 2015
Publication date	Sep 12, 2017
Grant date	Sep 12, 2017

Abstract

This invention relates to compounds that are agonists of the muscarinic M 1 receptor and/or M 4 receptor and which are useful in the treatment of muscarinic M 1 /M 4 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds include those according to formula (1a)

or a salt thereof, wherein p, q, r, s, Q, R 3 and R 4 are as defined herein.

First claim

The invention claimed is:

1. A compound of the formula (1a):

or a salt thereof, wherein
p is 1 or 2;
q is 0, 1 or 2;
r is 1 or 2;
s is 0 or 1, where the total of r and s is 1 or 2;
Q is CR 1 R 2 NR 5 R 6 , NR 5 R 6 , OR 7 or SR 7 ;
R 1 is selected from hydrogen and 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 oxidized forms thereof;
R 2 is selected from hydrogen and 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 oxidized forms thereof;
R 3 is selected from hydrogen; fluorine; cyano; hydroxy; amino; and a C 1-6 non-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms and wherein one, two or three, but not all, carbon atoms of the hydrocarbon group may optionally be replaced by a heteroatom selected from O, N and S and oxidized forms thereof;
R 4 is a hydrogen or 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;
R 5 is selected from hydroxy; OR 7 ; COR 7 ; COOR 7 ; CH 2 COR 7 ; CH 2 COOR 7 ; 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 oxidized forms thereof; and a group W or CH 2 W where W is an optionally substituted 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof;
R 6 is selected from hydroxy; OR 7 ; COR 7 ; COOR 7 ; CH 2 COR 7 ; CH 2 COOR 7 ; 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 oxidized forms thereof; and a group W or CH 2 W where W is an optionally substituted 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof;
R 7 is selected from hydrogen; 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 oxidized forms thereof; and a group W or CH 2 W or C 1-4 hydrocarbon group-W where W is an optionally substituted 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof;
and the dotted line indicates an optional second carbon-carbon bond, provided that when a second carbon-carbon bond is present, then R 3 is absent.

2. The compound according to claim 1 of the formula (1):

or a salt thereof, wherein
q is 0, 1 or 2;
r is 1 or 2;
s is 0 or 1, where the total of r and s is 1 or 2;
Q is CR 1 R 2 NR 5 R 6 , NR 5 R 6 , OR 7 or SR 7 ;
R 1 is selected from hydrogen and 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 oxidized forms thereof;
R 2 is selected from hydrogen and 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 oxidized forms thereof;
R 3 is selected from hydrogen; fluorine; cyano; hydroxy; amino; and a C 1-6 non-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms and wherein one, two or three, but not all, carbon atoms of the hydrocarbon group may optionally be replaced by a heteroatom selected from O, N and S and oxidized forms thereof;
R 4 is a hydrogen or 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;
R 5 is selected from hydroxy; OR 7 ; COR 7 ; COOR 7 ; CH 2 COR 7 ; CH 2 COOR 7 ; 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 oxidized forms thereof; and a group W or CH 2 W where W is an optionally substituted 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof;
R 6 is selected from hydroxy; OR 7 ; COR 7 ; COOR 7 ; CH 2 COR 7 ; CH 2 COOR 7 ; 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 oxidized forms thereof; and a group W or CH 2 W where W is an optionally substituted 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof;
R 7 is selected from hydrogen; 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 oxidized forms thereof; and a group W or CH 2 W where W is an optionally substituted 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof;
and the dotted line indicates an optional second carbon-carbon bond, provided that when a second carbon-carbon bond is present, then R 3 is absent.

3. The compound according to claim 1 wherein Q is NR 5 R 6 .

4. The compound according to claim 1 wherein Q is CR 1 R 2 NR 5 R 6 .

5. The compound according to claim 1 wherein R 1 is selected from hydrogen, methyl and ethyl.

6. The compound according to claim 1 wherein R 2 is selected from hydrogen, methyl and ethyl.

7. The compound according to claim 1 wherein R 5 is selected from a C 1-4 alkyl group which is optionally substituted with one to four fluorine atoms; and a group W or CH 2 W where W is an optionally substituted 5- or 6-membered aromatic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S.

8. The compound according to claim 7 wherein R 5 is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, fluoroethyl, difluoroethyl, butyl and cyclobutyl.

9. The compound according to claim 7 wherein R 5 is a group W or CH 2 W where W is an optionally substituted phenyl, pyridyl or isoxazole ring.

10

Assignees

• Heptares Therapeutics Ltd

Inventors

• Brown Giles Albert
• 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

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/18

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

• A61P25/04

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