Muscarinic receptor agonists

Patent metadata

Field	Value
Publication number	US-10030035-B2
Application number	US-201515126935-A
Country	US
Kind code	B2
Filing date	Mar 19, 2015
Priority date	Mar 19, 2014
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

This invention relates to compounds that are agonists of the muscarinic M 1 receptor and which are useful in the treatment of muscarinic M 1 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula where m, p, q, W, Z, Y, X 1 , X 2 , R 1 , R 2 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:
“F” is fluorine;
m is 1;
p is 0, 1 or 2;
q is 0, 1 or 2;
W is C;
Z is CH 2 ;
Y is NH, O, S or CH 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 bridged bicyclic ring system;
R 1 can be H, halo, CN, OH, C 1-3 alkoxy, NH 2 , optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 cycloalkenyl, NR 5 R 6 , COOR 5 , CONR 5 R 6 , NR 7 CONR 5 R 6 , NR 7 COOR 5 , OCONR 5 R 6 , SR 5 , SOR 5 , SO 2 R 5 , SO 3 R 5 or CH 2 —W a , where W a is an optionally substituted 5 or 6 membered cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring;
R 2 is H;
R 3 is H, OH, or an optionally substituted C 1-6 non-aromatic hydrocarbon group;
R 4 can be H, optionally substituted C 1-5 alkyl, optionally substituted C 2-5 alkenyl, optionally substituted C 2-5 alkynyl, optionally substituted C 3-6 cycloalkyl, or optionally substituted C 3-6 cycloalkenyl; and
R 5 , R 6 and R 7 can be independently H or C 1-6 alkyl.

2. A compound according to claim 1 , wherein R 1 is selected from H, halo, CN, OH, C 1-3 alkoxy, NH 2 , optionally substituted C 1-5 alkyl and benzyl.

3. A compound according to claim 1 , wherein R 4 is selected from H, methyl, fluoromethyl, ethyl, ethynyl and 1-propynyl.

4. A compound according to claim 3 wherein p is 0 and q is 0.

5. A compound according to claim 1 wherein the moiety

is an azabicyclo-heptane, azabicyclo-octane or azabicyclo-nonane ring system.

6. A compound according to claim 5 where the moiety

is selected from ring systems BA to BH below which may be substituted with 0-2 optional fluorine atoms (q is 0-2):

7. A compound according to claim 1 which is selected from the group consisting of:
ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
prop-2-yn-1-yl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl (3-endo)-3-(2-hydroxy-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 5-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate, and
ethyl 6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate or a salt thereof.

8. A compound according to claim 1 which is selected from the group consisting of:
ethyl 5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate,
methyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
2-fluoroethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
prop-2-yn-1-yl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
but-2-yn-1-yl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
8-(8-butanoyl-8-azabicyclo[3.2.1]oct-3-yl)-2,8-diazaspiro[4.5]decan-3-one,
ethyl 3-(1-methyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(1-ethyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(3-oxo-1-propyl-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(1-benzyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 2-fluoro-3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(6-fluoro-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(2-ethyl-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(2-hydroxy-3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-(3-oxo-2-propyl-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-[3-oxo-2-(propan-2-yl)-2,8-diazaspiro[4.5]dec-8-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-[2-(2-methylpropyl)-3-oxo-2,8-diazaspiro[4.5]dec-8-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-[2-(cyclopropylmethyl)-3-oxo-2,8-diazaspiro[4.5]dec-8-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate,
ethyl 3-[2-(2-methoxyethyl)-3-oxo-2,8-diazaspiro[4.5]dec-8-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate,
(1,1- 2 H 2 )ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
(2,2,2- 2 H 3 )ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
( 2 H 5 )ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate,
S-methyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carbothioate,
S-ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carbothioate,
ethyl 5-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-2-azabicyclo[2.2.2]octane-2-carboxylate,
ethyl 8-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate,
ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate,
prop-2-yn-1-yl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate,
but-2-yn-1-yl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-9-azabicyclo[3.3.1]nonane-9-carboxylate,
methyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azabicyclo[3.2.1]octane-6-carboxylate,
ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-6-azabicyclo[3.2.1]octane-6-carboxylate,
ethyl 6-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.2.1]octane-3-carboxylate, and
ethyl 6-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-3-azabicyclo[3.1.1]heptane-3-carboxylate,
or a salt thereof.

9. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable excipient.

10. A method of treating dementia in a subject, comprising administering an effective amount of the compound according to claim 1 to the subject in need thereof.

11. A method of selectivity activating the M 1 receptor and/or the M 1 and M 4 receptor relative to the M 2 and M 3 receptor subtypes with an effective amount of a compound of claim 1 .

12. A compound according to claim 1 , wherein R 1 is selected from H, OH, C 1-6 alkyl optionally substituted with 1 to 6 fluorine atoms, CH 2 -aryl or CH 2 -heteroaryl.

13. A compound according to claim 7 which is ethyl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, or a salt thereof.

14. A compound according to claim 7 which is prop-2-yn-1-yl 3-(3-oxo-2,8-diazaspiro[4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, or a salt thereof.

15. A compound according to claim 7 which is ethyl (3-endo)-3-(2-hydroxy-3-oxo-2,8-diazaspiro [4.5]dec-8-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, or a salt thereof.

16. A compound according to claim 7 which is ethyl 5-(3-oxo-2,8-diazas

Assignees

• Heptares Therapeutics Ltd

Inventors

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

Classifications

• A61P43/00

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

• A61P29/00

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

• A61P25/36

  Opioid-abuse · 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