Bicyclic aza compounds as muscarinic M1 receptor antagonists
This invention relates to compounds (Formula (1)) that are agonists of the muscarinic M1 receptor and which are useful in the treatment of muscarinic M1 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula where R 1 -R 5 , X 1 , X 2 and p are as defined herein.
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
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 bicyclic ring system selected from the group consisting of ring systems BA, BB, CA, and CB below:
R 1 is selected from 2-methylpropyl; 2,2-dimethylpropyl; tert-butyl; 2-methyl-but-2-yl; 2,3-dimethylbut-2-yl; cyclopropylmethyl; cyclobutylmethyl; cyclopentyl; cyclopentylmethyl; 1-methylcyclobutyl; 1-methylcyclopentyl; 1-methylcyclohexyl; 1-methylcyclopentylmethyl; cyclopropyl-prop-2-yl; 1-methylcyclobutylmethyl and 1-ethyl-cyclobutylmethyl groups;
R 2 is selected from hydrogen, methyl, ethyl and isopropyl;
R 3 is selected from hydrogen, fluorine and methoxy; and
R 4 is 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.
2. The compound according to claim 1 wherein R 1 is 1-methylcyclobutyl.
3. The compound according to claim 1 wherein R 2 is hydrogen.
4. The compound according to claim 1 wherein R 3 is hydrogen.
5. The compound according to claim 1 wherein R 4 is selected from methyl, fluoromethyl, ethyl, ethynyl and 1-propynyl.
6. The compound according to claim 1 wherein the moiety
represents ring system CA:
7. The compound according to claim 1 , wherein the compound is ethyl 3-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-8-azabicyclo[3.2.1]octane-8-carboxylate or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1 , wherein the compound is ethyl 3-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-9-azabicyclo[3.3.1]nonane-9-carboxylate or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1 , wherein the compound is ethyl 2-{4-fluoro-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1 , wherein the compound is ethyl 6-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1 , wherein the compound is prop-2-yn-1-yl 6-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1 , wherein the compound is ethyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate or a pharmaceutically acceptable salt thereof.
13. The compound according to claim 1 , wherein the compound is ethyl 2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate or a pharmaceutically acceptable salt thereof.
14. The compound according to claim 1 , wherein the compound is ethyl 2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate or a pharmaceutically acceptable salt thereof.
15. The compound according to claim 1 , wherein the compound is (2,2,2-trideutero)ethyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate or a pharmaceutically acceptable salt thereof.
16. The compound according to claim 1 , wherein the compound is (2,2,2-trideutero)ethyl 2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate or a pharmaceutically acceptable salt thereof.
17. The compound according to claim 1 , wherein the compound is (2,2,2-trideutero)ethyl 2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate or a pharmaceutically acceptable salt thereof.
18. The compound according to claim 1 , wherein the compound is (1,1,2,2,2-pentadeutero) ethyl 2-{4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate or a pharmaceutically acceptable salt thereof.
19. The compound according to claim 1 , wherein the compound is (1,1,2,2,2-pentadeutero)ethyl 2-(4-{[1-(1,1,1-trideuteromethyl)cyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate or a pharmaceutically acceptable salt thereof.
20. The compound according to claim 1 , wherein the compound is (1,1,2,2,2-pentadeutero)ethyl 2-(4-{[1-(1,1,1-trideuteromethyl)-2,2,3,3,4,4-hexadeuterocyclobutyl]carbamoyl}piperidin-1-yl)-6-azaspiro[3.4]octane-6-carboxylate or a pharmaceutically acceptable salt thereof.