Muscarinic agonists
This invention relates to compounds that are agonists of the muscarinic M 4 receptor and/or M 4 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 1a or a salt thereof, wherein n, p, Q, R 1 , R 2 , R 3 , R 9 and R 4 are as defined herein.
1. A compound of the formula (1a):
or a salt thereof, wherein
n is 2;
p is 1;
Q is a five, six or seven membered monocyclic heterocyclic ring containing 1, 2, 3 or 4 heteroatom ring members selected from N, O and S;
R 1 is selected from hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR 5 ;
NR 5 R 6 ; COR 5 ; COOR 5 ; OCOR 5 ; NR 7 COR 5 ; CONR 5 R 6 ; NR 7 CONR 5 R 6 ; NR 7 COOR 5 ; OCONR 5 R 6 ; SR 5 ; SOR 5 and SO 2 R 5 ; 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 oxidized forms thereof; and an optionally substituted 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof;
R 2 is selected from hydrogen; fluorine; chlorine; bromine; cyano; hydroxy; methoxy; OR 5 ; NR 5 R 6 ; COR 5 ; COOR 5 ; OCOR 5 ; NR 7 COR 5 ; CONR 5 R 6 ; NR 7 CONR 5 R 6 ; NR 7 COOR 5 ; OCONR 5 R 6 ; SR 5 ; SOR 5 and SO 2 R 5 ; and a C 1-6 non-aromatic hydrocarbon group; or R 1 and R 2 can be joined together to form a 6 membered fused aromatic ring; R 9 is selected from hydrogen, CH 3 , CH 2 OH, CH(CH 3 )OH, C(CH 3 ) 2 OH and COOCH 3 ; 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 oxidized forms thereof;
R 5 , R 6 and R 7 are the same or different and each is independently selected from hydrogen, a non-aromatic C 1-4 hydrocarbon group optionally substituted with one or more fluorine atoms, and a group of formula CH 2 N(R a )COOR b ;
R a is selected from hydrogen and a non-aromatic C 1-4 hydrocarbon group;
R b is a non-aromatic C 1-4 hydrocarbon group which is optionally substituted with one or more groups selected from fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; and a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
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.
2. The compound according to claim 1 of the formula (1):
or a salt thereof, wherein
n is 2;
p is 1;
Q is a five, six or seven membered monocyclic heterocyclic ring containing 1, 2, 3 or 4 heteroatom ring members selected from N, O and S;
R 1 is selected from hydrogen; fluorine; chlorine; bromine; cyano; oxo; hydroxy; OR 5 ; NR 5 R 6 ; COR 5 ; COOR 5 ; OCOR 5 ; NR 7 COR 5 ; CONR 5 R 6 ; NR 7 CONR 5 R 6 ; NR 7 COOR 5 ; OCONR 5 R 6 ; SR 5 ; SOR 5 and SO 2 R 5 ; 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 oxidized forms thereof; and an optionally substituted 5- or 6-membered ring containing 0, 1, 2 or 3 heteroatoms selected from O, N and S and oxidized forms thereof;
R 2 is selected from hydrogen; fluorine; chlorine; bromine; cyano; hydroxy; methoxy; OR 5 ; NR 5 R 6 ; COR 5 ; COOR 5 ; OCOR 5 ; NR 7 COR 5 ; CONR 5 R 6 ; NR 7 CONR 5 R 6 ; NR 7 COOR 5 ; OCONR 5 R 6 ; SR 5 ; SOR 5 and SO 2 R 5 ; and a C 1-6 non-aromatic hydrocarbon group; or R 1 and R 2 can be joined together to form a 6 membered fused aromatic ring;
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 oxidized forms thereof;
R 5 , R 6 and R 7 are the same or different and each is independently selected from hydrogen, a non-aromatic C 1-4 hydrocarbon group optionally substituted with one or more fluorine atoms, and a group of formula CH 2 N(R a )COOR b ;
R a is selected from hydrogen and a non-aromatic C 1-4 hydrocarbon group;
R b is a non-aromatic C 1-4 hydrocarbon group which is optionally substituted with one or more groups selected from fluorine; chlorine; bromine; cyano; hydroxy; methoxy; amino; and a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group;
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.
3. The compound according to claim 1 wherein Q is an aromatic heterocyclic ring.
4. The compound according to claim 3 wherein Q is an aromatic heterocyclic ring containing one or two nitrogen atoms.
5. The compound according to claim 4 wherein Q is (i) an imidazole ring or (ii) a pyrazole ring.
6. The compound according to claim 1 wherein R 1 is selected from hydrogen; fluorine; cyano; hydroxy; OR 5 ; NR 5 R 6 ; COR 5 ; COOR 5 ; OCOR 5 ; NR 7 COR 5 ;
CONR 5 R 6 ; NR 7 CONR 5 R 6 ; NR 7 COOR 5 ; SO 2 R 5 ; and a C 1-4 non-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms.
7. The compound according to claim 6 wherein R 1 is selected from hydrogen; NH 2 , COR 5 ; COOR 5 and a C 1-4 saturated non-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms, and wherein R 5 is selected from C 1-4 alkyl.
8. The compound according to claim 6 wherein R 1 is selected from hydrogen; methyl; ethyl; COOMe; COOEt; COMe; COEt; CONH 2 ; CF 3 ; CONHMe; CON(Me) 2 ; COCF 3 ; CO-cyclopropyl; CO-cyclobutyl; CONHEt; COH; NH 2 and OMe.
9. The compound according to claim 1 wherein R 2 is hydrogen.
10. The compound according to claim 1 wherein R 3 is present and the optional second carbon-carbon bond is absent.
11. The compound according to claim 1 wherein R 3 is selected from hydrogen; fluorine; hydroxy, methoxy and cyano.
12. The compound according to claim 11 wherein R 3 is hydrogen.
13. The compound according to claim 1 wherein R 9 is hydrogen or CH 2 OH.
14. The compound according to claim 1 wherein R 4 is selected from hydrogen and methyl.
15. A compound, which is
Methyl 6-[4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate;
Ethyl 6-[4-(1-methyl-1H-imidazol-2-yl)piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate;
Ethyl 6-[4-(1H-pyrazol-1-yl)piperidin-1-yl]-2-azaspiro[3.3]heptane-2-carboxylate;
Ethyl 6-{4-[(2S)-1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylate;
Ethyl 6-{4-[2-(1,2-oxazol-3-yl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylate;
Ethyl 6-{4-[(2R)-2-(1,3-oxazol-5-yl)pyrrolidin-1-yl]piperidin-1yl}-2-azaspiro[3.3]heptane-2-carboxylate;
Ethyl 6-{4-[(2R)-2-(3-methyl-2-oxo-2,3-dihydro-1,3-oxazol-5-yl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylate;
Ethyl 6-{4-[(2S)-2-methyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylate;
Ethyl 6-{4-[(2R)-2-methyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylate;
Ethyl 6-{4-[(2S)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylate;
Ethyl 6-{4-[(2R)-2-ethyl-5-oxopyrrolidin- 1-yl]piperidin-1-yl}-2-azaspiro[3.3]heptane-2-carboxylate;
Ethyl 6-{4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro [3.3]heptane-2-carboxylate;
Methyl 6-[4-(1-methyl- 1H-imidazol-2-yl)piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate;
Ethyl 6-[4-(1-methyl- 1H-imidazol-2-yl)piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate;
Ethyl 6-[4-(1H-pyrazol- 1-yl)piperidin-1-yl]-2-azaspiro[3.4]octane-2-carboxylate;
Ethyl 6-{4-[(2S)- 1-(methylcarbamoyl)pyrrolidin-2-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate;
Ethyl 6-{4-[(2S)-2-methyl-5-oxopyrrolidin- 1-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate;
Ethyl 6-{4-[(2S)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate;
Ethyl 6-{4-[(2R)-2-methyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate;
Methyl 6-{4-[(2R)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3 .4]octane-2-carboxylate;
Ethyl 6-{4-[(2R)-2-ethyl-5-oxopyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate;
Ethyl 6-{4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate;
Methyl 6-{4-[(2R)-2-(1,3 -oxazol-5-yl)pyrrolidin-1 -yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate; or
Ethyl 6-{4-[(2R)-2-(1,3 -oxazol-5-yl)pyrrolidin-1-yl]piperidin-1-yl}-2-azaspiro[3.4]octane-2-carboxylate.
16. The compound according to claim 1 having muscarinic M 1 receptor and/or M 4 receptor agonist activity.
17. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable excipient.