Bicyclic aza compounds as muscarnic M1 receptor and/or M4 receptor antagonists

Patent metadata

Field	Value
Publication number	US-10385039-B2
Application number	US-201816217570-A
Country	US
Kind code	B2
Filing date	Dec 12, 2018
Priority date	Feb 6, 2014
Publication date	Aug 20, 2019
Grant date	Aug 20, 2019

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 1, or a salt thereof wherein Q, R 1 , R 2 , R 3 and R 4 are as defined herein.

First claim

The invention claimed is:

1. A method of synthesizing a compound of formula 1b:

or a salt thereof, wherein
Q is an optionally substituted five or six or seven membered heterocyclic ring containing 1, 2, 3 or 4 heteroatom ring members selected from N, O and S;
R 3 is selected from hydrogen; fluorine; cyano; hydroxy; amino; and a C 1-9 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;
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;
comprising reacting a compound of formula:

with a compound of formula:

in the presence of a reducing agent, under conditions suitable for reductive amination;
or comprising reacting a compound of formula:

with a compound of the formula Cl—C(═O)—OCH 2 —R 4 , in the presence of a base;
or comprising reacting a compound of formula:

wherein R is methyl, trifluoromethyl or 4-methylphenyl; with a compound of formula:

under conditions suitable for nucleophilic substitution.

2. The method according to claim 1 , wherein the method comprises reacting a compound of formula:

with a compound of formula:

in the presence of a reducing agent, under conditions suitable for reductive amination.

3. The method according to claim 2 , wherein the reducing agent is selected from the group consisting of sodium borohydride, sodium triacetoxyborohydride and sodium cyanoborohydride.

4. The method according to claim 1 , wherein Q is an aromatic heterocyclic ring.

5. The method according to claim 4 , wherein Q is an aromatic heterocyclic ring containing one or two nitrogen atoms.

6. The method according to claim 5 , wherein Q is (i) an imidazole ring or (ii) a pyrazole ring.

7. The method according to claim 1 , wherein Q is (i) a piperidin-2-one ring or (ii) a pyrrolidine ring.

8. The method according to claim 1 , wherein Q is a 5, 6 or 7 membered unsaturated heterocyclic ring.

9. The method according to claim 1 , wherein the moiety:

is selected from groups AAA to ACB, BAA to BCZ, CAA to CBZ, DAA to DBG and EAA to EAB:

10. The method according to claim 1 , wherein R 3 is selected from hydrogen; fluorine;
hydroxyl, methoxy and cyano.

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

12. The method according to claim 1 , wherein the compound of formula 1b is a compound selected from the group consisting of:
Ethyl 2-[4-(1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-[4-(4-chloro-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[4-(trifluoromethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-[4-(4-cyano-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-[4-(4,5-dichloro-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Methyl 2-[4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-[4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[1-(ethoxycarbonyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
Methyl 2-[4-(1,5-dimethyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-[4-(1,5-dimethyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Methyl 2-[4-(1,4-dimethyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-[4-(1,4-dimethyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
methyl 2-[4-(5-chloro-1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-[4-(5-chloro-1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
Methyl 2-[4-(4,5-dichloro-1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-

Assignees

• Heptares Therapeutics Ltd

Inventors

• Brown Giles Albert
• Cansfield Julie Elaine
• Congreve Miles Stuart
• O'Brien Michael Alistair
• Pickworth Mark
• Rackham Mark David
• Tehan Benjamin Gerald
• Teobald Barry John

Classifications

• A61P43/00

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

• A61P29/02

  without antiinflammatory effect · CPC title

• A61P29/00

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

• A61P25/30

  for treating abuse or dependence · 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