Bicyclic heterocyclic spiro compounds
There are disclosed bicyclic heterocyclic spiro compounds; pharmaceutical compositions comprising these compounds; and methods for the treatment in a mammal of diseases and conditions which are susceptible to modulation of the M1 muscarinic receptor, including Alzheimer's disease, insulin resistance syndrome and type 2 diabetes. Other embodiments are also disclosed.
1. A spiro compound of formula I:
wherein A is selected from the group consisting of
wherein
in all structures the carbon indicated by “C” denotes the spiro carbon,
R is selected from the group consisting of H and optionally substituted C 1-6 alkyl,
n and p are each independently selected from 0, 1 and 2, provided that n+p=2;
Y is —O— or —S—;
R 1 , R 2 , R 3 , R 4 , and R 6 are each independently selected at each occurrence from H, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 1-6 hydroxyalkyl, optionally substituted C 2-6 alkenyl, and optionally substituted phenyl;
R 5 is selected from the group consisting of optionally substituted —C(O)—(C 1-3 )-indol-3-yl, —SO 2 -4-fluorophenyl, —C(O)CH(n-propyl) 2 , —C(O)-(4-hydroxy-3,5-di-tertbutylphenyl), —C(O)—CH(NH 2 )—CH 2 -indol-3-yl, and —C(O)—CH 2 CH 3 ;
provided that when A is other than
the compound is selected from the group consisting of:
(1-(2,8-dimethyl-1-oxa-4,8-diazaspiro[4.5]dec-4-yl-3-(1H-indol-3-yl)-propan-1-one),
(1-(2-dimethyl-1-oxa-4,8-diaza-spiro[4.5]dec-4-yl)-2-propyl-pentan-1-one),
(4-(4-fluoro-benzenesulfonyl)-2,8-dimethyl-1-oxa-4.8-diaza-spiro[4.5]-decane),
(1′,4-dimethyl-6-(3-indolpropionyl)-spiro-(3-oxa-6-aza-bicyclo[3.1.0]-hexane-2,4′-piperidine)), and
(1′,4-dimethyl-6-[3-(4-fluorobenzenesulfonyl)]-spiro-(3-oxa-6-aza-bicyclo[3.1.0]hexane-2,4′-piperidine)),
N-(2,8-dimethyl-1-oxa-8-aza-spiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)-propionamide,
N-(2,8-Dimethyl-1-thia-8-aza-spiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)-propionamide, and
(3E)-2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one-O-[3-(1H-indol-3-yl)propanyl]oxime;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 wherein R is methyl.
3. A compound according to claim 1 wherein p and n are each 1.
4. A compound according to claim 1 wherein A is
5. A compound according to claim 1 wherein R 1 is methyl.
6. A compound according to claim 5 wherein R 2 is H.
7. A compound according to claim 5 wherein R 3 and R 4 are each H.
8. A compound according to any claim 1 wherein Y is S.
9. A compound according to claim 1 wherein Y is O.
10. A compound according to claim 1 wherein R 5 is optionally substituted —C(O)—(C 1-3 )-indol-3-yl.
11. A compound according to claim 10 wherein R 5 is selected from the group consisting of —C(O)—CH 2 -indol-3-yl, —C(O)—CH 2 CH 2 -indol-3-yl, —C(O)—CH 2 CH 2 CH 2 -indol-3-yl, trans —C(O)—CH═CH-indol-3-yl and —C(O)—CH(NH 2 )—CH 2 -indol-3-yl.
12. A compound according to claim 1 wherein A is
and R 5 is —O—C(═O)—CH 2 CH 2 -indol-3-yl.
13. A compound according to claim 1 wherein R 5 is selected from the group consisting of —SO 2 -4-fluorophenyl, —C(O)CH(n-propyl) 2 , R 5 is —C(O)-(4-hydroxy-3,5-di-tertbutylphenyl) and —C(O)—CH 2 CH 3 .
14. A compound according to claim 1 which is selected from one of the following:
(1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one),
((R)-1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one),
((S)-1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl) propan-1-one),
1-(2,8-Dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1-methyl-indol-3-yl)propan-1-one,
(3-(4-fluorobenzenesulfonyl)-2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]-decane),
(1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-2-propylpentan-1-one),
((3,5-di-tert-butyl-4-hydroxy-phenyl)-(2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]dec-3-yl)-methanone),
(1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-4-(1H-indol-3-yl)butan-1-one),
(1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-2-(1H-indol-3-yl)ethan-1-one),
(1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-propan-1-one),
(1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)prop-2-ene-1-one),
1-(2,8-dimethyl-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)-propan-1-one,
((R)-1-(2,8-dimethyl-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)-propan-1-one),
((S)-1-(2,8-dimethyl-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)-propan-1-one),
(1-(2,8-dimethyl-1-oxa-3,8-diaza-spiro[4.5]dec-3-yl)-2-propyl-pentan-1-one),
(3-(4-fluorobenzenesulfonyl)-2,8-dimethyl-1-oxa-3,8-diazaspiro[4.5]-decane),
(1-(2,8-dimethyl-1-oxa-4,8-diazaspiro[4.5]dec-4-yl)-3-(1H-indol-3-yl)-propan-1-one),
(1-(2,8-dimethyl-1-oxa-4,8-diaza-spiro[4.5]dec-4-yl)-2-propyl-pentan-1-one),
(4-(4-fluoro-benzenesulfonyl)-2,8-dimethyl-1-oxa-4,8-diaza-spiro[4.5]-decane),
(1′,4-dimethyl-6-(3-indolpropionyl)-spiro-(3-oxa-6-aza-bicyclo[3.1.0]-hexane-2,4′-piperidine)), and
(1′,4-dimethyl-6-[3-(4-fluorobenzenesulfonyl)]-spiro-(3-oxa-6-aza-bicyclo[3.1.0]hexane-2,4′-piperidine)),
N-(2,8-dimethyl-1-oxa-8-aza-spiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)-propionamide,
N-(2,8-Dimethyl-1-thia-8-aza-spiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)-propionamide,
(3E)-2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one-O-[3-(1H-indol-3-yl)propanoyl]oxime, or a pharmaceutically acceptable salt thereof.
15. A compound according to claim 1 which is selected from the group consisting of (1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one), (+)-(1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one), (−)-(1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one), 1-(2,8-dimethyl-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)-propan-1-one, (+)-1-(2,8-dimethyl-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)-propan-1-one, and (−)-1-(2,8-dimethyl-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)-propan-1-one.
16. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, excipient or diluent therefor.
17. A method of treating a disease or condition which is
selected from the group consisting of (i) Alzheimer's Disease, (ii) insulin resistance syndrome and (iii) type 2 diabetes
comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 1 .
18. A compound according to claim 1 which is
(1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one) or a pharmaceutically acceptable salt thereof.
19. A compound according to claim 1 which is
((R)-1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one) or a pharmaceutically acceptable salt thereof.
20. A compound according to claim 1 which is
((S)-1-(2,8-dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl) propan-1-one) or a pharmaceutically acceptable salt thereof.