Ethynyl derivatives
The present invention relates to positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) that may be used for the treatment of conditions such as Parkinson's disease, anxiety, emesis, obsessive compulsive disorder, autism, neuroprotection, cancer, depression and diabetes type 2.
1. A method for the treatment of Parkinson's disease, the method comprising administering to a mammal in need thereof an effective amount of a compound of formula I:
wherein:
R 1 is lower alkyl;
R 2 is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;
n is 0, 1 or 2;
V/U are independently from each other O or CH 2 , wherein V and U cannot be simultaneously O;
L is a five or six membered heteroaryl group, selected from:
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
2. The method of claim 1 , wherein the compound of formula I is a compound of formula IA:
wherein:
R 1 is lower alkyl;
R 2 is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;
L is a five or six membered heteroaryl group, selected from:
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
3. The method of claim 1 , wherein the compound of formula I is selected from the group consisting of:
(8S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[6,7-dihydro-5H-isoquinoline-8,6′-hexahydropyrimidine]-2′,4′-dione;
(6S)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1-methyl-spiro[hexahydropyrimidine-6,1′-tetralin]-2,4-dione;
(5S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[7,8-dihydro-6H-quinoline-5,6′-hexahydropyrimidine]-2′,4′-dione;
(5S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[7,8-dihydro-6H-isoquinoline-5,6′-hexahydropyrimidine]-2′,4′-dione;
(5S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[7,8-dihydro-6H-quinazoline-5,6′-hexahydropyrimidine]-2′,4′-dione;
(8S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-ethyl-spiro[6,7-dihydro-5H-isoquinoline-8,6′-hexahydropyrimidine]-2′,4′-dione;
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[1,5,6,7-tetrahydroindazole-4,6′-hexahydropyrimidine]-2′,4′-dione;
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′,2-dimethyl-spiro[6,7-dihydro-5H-indazole-4,6′-hexahydropyrimidine]-2′,4′-dione; and
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1,1′-dimethyl-spiro[6,7-dihydro-5H-indazole-4,6′-hexahydropyrimidine]-2′,4′-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
4. The method of claim 1 , wherein the compound of formula I is a compound of formula IB:
wherein:
R 1 is lower alkyl;
R 2 is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;
L is a five or six membered heteroaryl group, selected from:
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
5. The method of claim 1 , wherein the compound of formula I is:
(6S)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1-methyl-spiro[hexahydropyrimidine-6,1′-indane]-2,4-dione; or
(5S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[6,7-dihydrocyclopenta[b]pyridine-5,6′-hexahydropyrimidine]-2′,4′-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
6. The method of claim 1 , wherein the compound of formula I is a compound of formula IC:
wherein:
R 1 is lower alkyl;
R 2 is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;
L is a five or six membered heteroaryl group, selected from:
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
7. The method of claim 1 , wherein the compound of formula I is:
(4S)-3′-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1′-methyl-spiro[chromane-4,6′-hexahydropyrimidine]-2′,4′-dione; or
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[2,3-dihydropyrano[2,3-b]pyridine-4,6′-hexahydropyrimidine]-2′,4′-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
8. The method of claim 1 , wherein the compound of formula I is a compound of formula ID:
wherein:
R 1 is lower alkyl;
R 2 is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;
L is a five or six membered heteroaryl group, selected from:
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
9. The method of claim 1 , wherein the compound of formula I is:
(6S)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1-methyl-spiro[hexahydropyrimidine-6,4′-isochromane]-2,4-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
10. The method of claim 1 , wherein the compound of formula I is a compound of formula IE:
wherein:
R 1 is lower alkyl;
R 2 is phenyl or pyridinyl, wherein the N atom in the pyridinyl group may be in different positions;
L is a five or six membered heteroaryl group, selected from:
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
11. The method of claim 1 , wherein the compound of formula I is selected from the group consisting of:
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[5,6,7,8-tetrahydro-1H-cyclohepta[c]pyrazole-4,6′-hexahydropyrimidine]-2′,4′-dione;
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1,1′-dimethyl-spiro[5,6,7,8-tetrahydrocyclohepta[c]pyrazole-4,6′-hexahydropyrimidine]-2′,4′-dione; and
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′,2-dimethyl-spiro[5,6,7,8-tetrahydrocyclohepta[c]pyrazole-4,6′-hexahydropyrimidine]-2′,4′-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
12. A method for the treatment of Parkinson's disease, the method comprising administering to a mammal in need thereof an effective amount of a compound, wherein the compound is:
(6S)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1-methyl-spiro[hexahydropyrimidine-6,1′-tetralin]-2,4-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
13. A method for the treatment of Parkinson's disease, the method comprising administering to a mammal in need thereof an effective amount of a compound, wherein the compound is:
(6S)-3-[2,6-Difluoro-4-[2-(3-pyridyl)ethynyl]phenyl]-1-methyl-spiro[hexahydropyrimidine-6,1′-indane]-2,4-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
14. A method for the treatment of Parkinson's disease, the method comprising administering to a mammal in need thereof an effective amount of a compound, wherein the compound is:
((5S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[7,8-dihydro-6H-quinoline-5,6′-hexahydropyrimidine]-2′,4′-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
15. A method for the treatment of Parkinson's disease, the method comprising administering to a mammal in need thereof an effective amount of a compound, wherein the compound is:
(5S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[7,8-dihydro-6H-quinazoline-5,6′-hexahydropyrimidine]-2′,4′-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.
16. A method for the treatment of Parkinson's disease, the method comprising administering to a mammal in need thereof an effective amount of a compound, wherein the compound is:
(4S)-3′-[2,6-Difluoro-4-(2-phenylethynyl)phenyl]-1′-methyl-spiro[2,3-dihydropyrano[2,3-b]pyridine-4,6′-hexahydropyrimidine]-2′,4′-dione;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof.