Pharmaceutical compounds

Patent metadata

Field	Value
Publication number	US-10858352-B2
Application number	US-201916450279-A
Country	US
Kind code	B2
Filing date	Jun 24, 2019
Priority date	Jun 22, 2018
Publication date	Dec 8, 2020
Grant date	Dec 8, 2020

Abstract

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

where X 1 ; X 2 ; X 3 ; X 4 ; R 1 R 2 and R 4 are as defined herein.

First claim

The invention claimed is:

1. A compound of the formula (1):

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

forms a monocyclic or bicyclic ring system, or
X 1 and X 2 link together such that the moiety:

forms

X 3 and X 4 are saturated hydrocarbon groups which together contain a total of three to six carbon atoms and which link together such that the moiety:

forms a monocyclic or bicyclic ring system;
R 1 is selected from NR 5 R 6 ; CONR 5 R 6 ; COOR 7 ; 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; or R 1 is linked to R 2 to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof;
R 2 is selected from hydrogen; fluorine; cyano; hydroxy; amino; and a C 1-3 hydrocarbon group which is optionally substituted with one to six fluorine atoms and wherein one of the carbon atoms of the hydrocarbon group may optionally be replaced by a heteroatom selected from O, N and S and oxidized forms thereof, or R 2 is linked to R 1 to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof;
R 4 is H, halo, OH, CN, a C 1-6 alkyl group or a C 3-6 cycloalkyl group, wherein the alkyl and cycloalkyl groups are optionally substituted with one or more fluorine atoms, and wherein any one atom of the alkyl or cycloalkyl group may be optionally replaced by an O heteroatom;
R 5 is selected from hydrogen, COCH 3 , a non-aromatic C 1-10 hydrocarbon group optionally substituted with one or more fluorine atoms wherein any one atom of the C 1-10 hydrocarbon group may be optionally replaced by a heteroatom selected from O, N and S, or a group —(CH 2 ) n -aryl, wherein n is 0-3, or R 5 can be joined together with R 6 to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof;
R 6 is selected from hydrogen, a non-aromatic C 1-10 hydrocarbon group optionally substituted with one or more fluorine atoms wherein any one atom of the C 1-10 hydrocarbon group may be optionally replaced by a heteroatom selected from O, N and S, or a group —(CH 2 ) n -aryl, wherein n is 0-3, or R 6 can be joined together with R 5 to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof; and
R 7 is a non-aromatic C 1-6 hydrocarbon group optionally substituted with one or more fluorine atoms.

2. The compound according to claim 1 wherein R 1 is selected from NR 5 R 6 ; CONR 5 R 6 ; COOR 7 ; or an optionally substituted 5- or 6-membered ring containing 0, 1, or 2 nitrogen heteroatoms; or R 1 is linked to R 2 to form an optionally substituted monocyclic or bicyclic ring.

3. The compound according to claim 1 wherein R 1 is linked to R 2 to form an optionally substituted monocyclic or bicyclic ring containing 0, 1 or 2 heteroatoms selected from O or N, wherein the optional substituents are selected from C 1 -C 6 alkyl, C 1 -C 3 alkoxy, halogen, cyano, oxo, hydroxyl, amino or a group —(CH 2 ) n -aryl wherein n is 0-3.

4. The compound according to claim 1 wherein R 1 is selected from NR 5 R 6 ; CONR 5 R 6 ; or COOR 7 .

5. The compound according to claim 1 wherein R 1 is an optionally substituted 5- or 6-membered ring containing 0, 1 or 2 nitrogen heteroatoms, wherein the optional substituents are selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, CONR 5 R 6 , halogen, cyano, oxo, hydroxyl, amino or an optionally substituted heterocyclic ring containing 1 or 2 heteroatoms selected from O or N wherein the optional substituent is C 1 -C 3 alkyl.

6. The compound according to claim 1 wherein R 2 is H.

7. The compound according to claim 1 wherein R 1 is selected from NR 5 R 6 ; CONR 5 R 6 ; or COOR 7 ; R 5 is selected from COCH 3 , or a non-aromatic C 1-6 hydrocarbon group, or R 5 can be joined together with R 6 to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof; and R 6 is selected from hydrogen, a non-aromatic C 1-10 hydrocarbon group optionally substituted with one or more fluorine atoms wherein any one atom of the C 1-10 hydrocarbon group may be optionally replaced by a heteroatom selected from O, N and S, or a group —(CH 2 ) n -aryl, wherein n is 0-3, or R 6 can be joined together with R 5 to form an optionally substituted monocyclic or bicyclic ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof.

8. The compound according to claim 7 wherein R 6 is selected from hydrogen, or a non-aromatic C 1-6 hydrocarbon group, or R 6 can be joined together with R 5 to form an optionally substituted monocyclic ring wherein the optional substituents are selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen, cyano, oxo, hydroxyl or amino, wherein the C 1 -C 3 alkyl or C 1 -C 3 alkoxy groups can have an optional substituent selected from halogen, cyano, oxo, hydroxyl or amino.

9. The compound according to claim 1 wherein R 1 is selected from:

10. The compound according to claim 1 wherein R 1 is linked to R 2 to form a moiety selected from:

11. The compound according to claim 1 wherein R 4 is methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl.

12. The compound according to claim 1 wherein the ring system formed by the moiety:

is selected from:

13. The compound according to claim 1 wherein the ring system formed by the moiety:

is selected from:

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

or a salt thereof wherein:
X 1 , X 2 , R 1 , R 2 and R 4 are as defined in claim 1 .

15. The compound according to claim 1 of the formula (3):

Assignees

• Heptares Therapeutics Ltd

Inventors

• Brown Giles Albert
• Teobald Barry John
• Tehan Benjamin Gerald

Classifications

• A61P25/04

  Centrally acting analgesics, e.g. opioids · 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

• A61P25/18

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D487/10

  Spiro-condensed systems · CPC title