Muscarinic agonists

Patent metadata

Field	Value
Publication number	US-11254656-B2
Application number	US-202016942167-A
Country	US
Kind code	B2
Filing date	Jul 29, 2020
Priority date	Aug 3, 2015
Publication date	Feb 22, 2022
Grant date	Feb 22, 2022

Abstract

This invention relates to compounds that are agonists of the muscarinic M1 receptor and/or M4 receptor and which are useful in the treatment of muscarinic M1/M4 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds include those according to formula 1or a salt thereof, wherein q, r, s, Q, R1, R2′, R2″, R3 and R4 are as defined herein.

First claim

The invention claimed is:

1. A method for the treatment of Alzheimer's Disease, dementia with Lewy bodies or schizophrenia in a subject, comprising administering to the subject an effective amount of a compound of the formula (1):

or a salt thereof, wherein
q is 1;
r is 1 or 2;
s is 0 or 1 where the total of r and s is 1 or 2;
Q is an azetidine linked to the adjacent six-membered ring by the nitrogen atom of the azetidine ring;
R 1 is selected from hydrogen; methyl; ethyl; fluorine oxo; and COOMe;
R 2′ and R 2″ are independently selected from hydrogen; fluorine; and a C 1-6 non-aromatic hydrocarbon group;
R 3 is hydrogen;
R 4 is hydrogen or a C 1-6 non-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms and
the dotted line indicates a single bond.

2. The method according to claim 1 , wherein R 4 is selected from hydrogen and methyl.

3. The method according to claim 1 , wherein the compound is selected from the group consisting of:
Ethyl 2-[4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[(2R)-2-(methoxycarbonyl)azetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-[4-(2-oxoazetidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[(2S)-2-methyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[(2S)-2-ethyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[(2R)-2-methyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[(2R)-2-ethyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
or a salt thereof.

4. The method according to claim 1 , wherein the compound is a pharmaceutically acceptable salt of a compound as defined in claim 1 .

5. The method according to claim 1 , wherein the compound is administered to the subject as in the form of a pharmaceutical composition comprising the compound as defined in claim 1 and a pharmaceutically acceptable excipient.

6. The method according to claim 1 wherein the moiety:

is selected from:

7. The method according to claim 1 wherein the moiety:

is selected from:

8. The method according to claim 1 , wherein the disorder is Alzheimer's Disease.

9. The method according to claim 1 , wherein the disorder is dementia with Lewy bodies.

10. The method according to claim 1 , wherein the disorder is schizophrenia.

Assignees

• Heptares Therapeutics Ltd

Inventors

• Brown Giles Albert
• Cansfield Julie Elaine
• Pickworth Mark
• Tehan Benjamin Gerald
• Teobald Barry John

Classifications

• 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

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P25/18

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