Spiro-imidazo compounds
View Patent ↗Novel heterocyclic compounds of the general formula (I) and salts, preferably pharmaceutically acceptable salts, thereof, in which R, R 1 , R 1 ′, Q, m and n have the meanings explained in detail in the description, a process for their preparation and the use of these compounds as medicaments, in particular as aldosterone synthase inhibitors.
1. A compound of the formula
in which
R is deuterium, halogen or hydrogen;
a) R 1 is in each case hydrogen, and R 1 ′ and R 1 ′ are together a radical of the formula
or
b) R 1 and R 1 are together a radical of the formula
and R 1 ′ is in each case hydrogen,
and for both a) and b):
A 1 and A 2 are two ortho ring atoms, and A is aryl or heterocyclyl, which radicals are unsubstituted or substituted by 1-4 C 1 -C 8 alkoxy, C 1 -C 8 alkoxycarbonyl, C 1 -C 8 alkyl, C 0 -C 8 alkylcarbonyl, C 1 -C 8 alkylsulphonyl, optionally substituted aryl, aryl-C 0 -C 4 alkoxycarbonyl, cyano, halogen, optionally substituted heterocyclyl, hydroxy, nitro, oxide, oxo, tri-C 1 -C 4 -alkylsilyl, trifluoromethoxy or trifluoromethyl;
L 1 is —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —CH═N—, —CH 2 —CH═N—, —CH═N—O—, —CH 2 —CH═N—O—, —CH 2 —O—, —CH 2 —CH 2 —O—, —CH═CH—O—, —CH 2 —S—, —CH 2 —CH 2 —S—, —CH═CH—S—, —CH 2 —NH—, —CH 2 —CH 2 —NH—, —CH═CH—NH—, —CH 2 —NH—O—, —CH 2 —CH 2 —NH—O—, —CH═CH—NH—O—, —CH 2 —O—NH—, —CH 2 —CH 2 —O—NH—, —CH═CH—O—NH—, —CH 2 —N═N—, —CH 2 —CH 2 —N═N—, —CH═CH—N═N—, —CH 2 —S(O)—, —CH 2 —CH 2 —S(O)—, —CH═CH—S(O)—, —CH 2 —SO 2 —, —CH 2 —CH 2 —SO 2 —, —CH═CH—SO 2 —, —O—, —S—, —NH—, —NH—O—, —O—NH—, —N═N—, —S(O)—or —SO 2 —, which radicals are unsubstituted or substituted by 1-3 R 3 ;
L 2 is —CH 2 —, —CH 2 —CH 2 —, —CH═CH— or, if L 1 is —CH 2 —, —CH 2 —CH 2 — or —CH═CH—, is also —N═CH—, —N═CH—CH 2 —, —O—N═CH—CH 2 or —O—N═CH—, which radicals are unsubstituted or substituted by 1-3 R 3 or, if L 1 is not —O—, —S—, —NH—, —NH—O—, —O—NH—, —N═N—, —S(O)— or —SO 2 —, is also a bond;
R 3 is C 1 -C 8 alkoxy, C 1 -C 8 alkoxycarbonyl, C 1 -C 8 alkyl, C 0 -C 8 alkylcarbonyl or C 1 -C 8 alkylsulphonyl;
Q is oxygen or sulphur;
m is a number 0, 1 or 2;
n is a number 0, 1 or 2;
p is a number 0, 1, 2, 3 or 4;
where
m and n are not simultaneously 0 and, if R 1 is hydrogen, n is 1 or 2;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , which corresponds to the formula
or a pharmaceutically acceptable salt thereof, where the meanings of the substituents R, R 1 , R 1 ′, Q, m and n are as indicated for compounds of the formula (I) according to claim 1 , and * designates an asymmetric carbon atom at the C atom for which the respective pairs of R 1 and R 1 ′ substituents are not both hydrogen.
3. A compound according to claim 1 , where R is deuterium or hydrogen.
4. A compound according to claim 1 , where A is optionally substituted 4-acetylphenyl, 4-cyanophenyl, 4-methanesulphonylphenyl, 4-methoxyphenyl, 4-nitrophenyl, 4-heterocyclylphenyl, where the heterocycle preferably comprises at least one nitrogen atom, or pyridyl.
5. A compound according to claim 1 , where the group -L 1 -L 2 - is C 1 -C 4 alkylene which is optionally substituted by 1-3 C 1 -C 8 alkoxy, C 1 -C 8 alkoxycarbonyl, C 1 -C 8 alkyl, C 0 -C 8 alkylcarbonyl or C 1 -C 8 alkylsulphonyl.
6. A compound according to claim 1 , where n is 1.
7. A compound according to claim 1 , where p is 0.
8. A pharmaceutical composition comprising a compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , and conventional excipients.
9. A pharmaceutical composition comprising a compound of the general formula (Ia) or a pharmaceutically acceptable salt thereof according to claim 2 , and conventional excipients.
10. A pharmaceutical composition in the form of a product or of a kit composed of individual components consisting a) of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 , and b) at least one pharmaceutical form whose active ingredient has a blood pressure-lowering, an inotropic, a metabolic or a lipid-lowering effect.
11. A pharmaceutical composition in the form of a product or of a kit composed of individual components consisting a) of a compound of the general formula (Ia) or a pharmaceutically acceptable salt thereof according to claim 2 , and b) at least one pharmaceutical form whose active ingredient has a blood pressure-lowering, an inotropic, a metabolic or a lipid-lowering effect.