Arylethynyl derivatives
The present invention relates to ethynyl compounds of formula I wherein R1, R2, R2′, R3, R3′, R4, R4′, U, V, W, Y, m, and n are as defined herein and to a pharmaceutically acceptable acid addition salts, to a racemic mixtures, or to its corresponding enantiomers and/or optical isomers and/or stereoisomers thereof. Compounds of formula I are allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5).
1. A compound having formula I-C1
wherein
U ═C(R 5 )—;
V is —CH═;
W is ═CH—;
R 5 is hydrogen, methyl or halogen;
R 6 is hydrogen or lower alkyl;
R 1 is phenyl or heteroaryl, each of which is optionally substituted by one or two substituents, selected from halogen, lower alkyl and lower alkoxy;
R 2 and R 2′ are each independently hydrogen, lower alkyl, hydroxy, lower alkoxy, C 3 -C 6 -cycloalkyl, or CH 2 -lower alkoxy, or together with the carbon atom to which they are attached form a C 3 -C 6 -cycloalkyl group or a ring containing —CH 2 OCH 2 —; and
R 3 and R 3′ are each independently hydrogen, lower alkyl, or CH 2 -lower alkoxy or together with the carbon atom to which they are attached form a C 3 -C 6 -cycloalkyl group;
or R 3 and R 2 together with the carbon atom to which they are attached form a C 3-6 -cycloalkyl group or a ring containing —(CH 2 ) 2 OCH 2 —;
or R 6 and R 2 together with the carbon atom and the nitrogen atom to which they are attached form a C 3-6 -cycloalkyl group;
or a pharmaceutically acceptable acid addition salt, a racemic mixture, an enantiomer, an optical isomer or stereoisomer thereof.
2. The compound of claim 1 , selected from the group consisting of
4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one;
3,4,4-trimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one;
3-ethyl-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one;
3-isopropyl-4,4-dimethyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one;
1-methyl-3-(5-phenylethynyl-pyridin-2-yl)-1,3-diaza-spiro[4.4]nonan-2-one;
(RS)-4-cyclopentyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one;
1-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;
3,4,4-trimethyl-1-(5-pyridin-3-ylethynyl-pyridin-2-yl)-imidazolidin-2-one;
1-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;
3,4,4-trimethyl-1-[5-(1-methyl-1H-pyrazol-4-ylethynyl)-pyridin-2-yl]-imidazolidin-2-one;
1-[5-(5-chloro-pyridin-3-ylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one; and
3,4,4-trimethyl-1-(5-pyridazin-4-ylethynyl-pyridin-2-yl)-imidazolidin-2-one.
3. The compound of claim 1 , selected from the group consisting of
1-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;
1-[5-(3-chloro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;
3,4,4-trimethyl-1-(5-pyrimidin-5-ylethynyl-pyridin-2-yl)-imidazolidin-2-one;
3,4,4-trimethyl-1-(5-m-tolylethynyl-pyridin-2-yl)-imidazolidin-2-one;
1-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;
(RS)-2-(5-phenylethynyl-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one;
(RS)-2-(5-pyridin-3-ylethynyl-pyridin-2-yl)-hexahydro-imidazo[1,5-a]pyridin-3-one;
(RS)-2-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-hexahydro-imidazo[1,5-a]pyridin-3-one;
(RS)-4-cyclopropyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one;
(3aSR,7aRS)-(3aRS,7RS)-1-methyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one; and
(3aSR,7aRS)-(3aRS,7RS)-1-methyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one.
4. The compound of claim 1 , selected from the group consisting of
(3aSR,7aRS)-(3aRS,7RS)-1-[5-(5-fluoro-pyridin-3-ylethynyl)-pyridin-2-yl]-3-methyl-octahydro-benzoimidazol-2-one;
4-methyl-6-(5-phenylethynyl-pyridin-2-yl)-4,6-diaza-spiro[2.4]heptan-5-one;
(3aSR,7aRS)-(3aRS,7RS)-1-ethyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one;
(3aSR,7aRS)-(3aRS,7RS)-1-ethyl-3-(5-pyridin-3-ylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one;
(3aSR,7aRS)-(3aRS,7RS)-1-isopropyl-3-(5-phenylethynyl-pyridin-2-yl)-octahydro-benzoimidazol-2-one;
(3aRS, 6aSR)-1-methyl-3-(5-(phenylethynyl)pyridin-2-yl) hexahydrocyclopenta[d]imidazol-2(1H)-one;
(RS)-4-tert-butyl-3-methyl-1-(5-phenylethynyl-pyridin-2-yl)-imidazolidin-2-one;
1-[5-(3-fluoro-phenylethynyl)-3-methyl-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one;
(3aSR,6aRS)-1-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-3-methyl-hexahydro-cyclopenta-imidazol-2-one;
1-[3-fluoro-5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one; and
1-[3-fluoro-5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-3,4,4-trimethyl-imidazolidin-2-one.
5. The compound of claim 1 , selected from the group consisting of
6-[5-(4-fluoro-phenylethynyl)-pyridin-2-yl]-4-methyl-4,6-diaza-spiro[2.4]heptan-5-one; and
6-[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-4-methyl-4,6-diaza-spiro[2.4]heptan-5-one.
6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I-C1
wherein
U is ═C(R 5 )—;
V is —CH═;
W is ═CH—;
R 5 is hydrogen, methyl or halogen;
R 6 is hydrogen or lower alkyl
R 1 is phenyl or heteroaryl, each of which is optionally substituted by one or two substituents, selected from halogen, lower alkyl and lower alkoxy;
R 2 and R 2′ are each independently hydrogen, lower alkyl, hydroxy, lower alkoxy, C 3 -C 6 -cycloalkyl, or CH 2 -lower alkoxy, or together with the carbon atom to which they are attached form a C 3 -C 6 -cycloalkyl group or a ring containing —CH 2 OCH 2 —;
R 3 and R 3′ are each independently hydrogen, lower alkyl, or CH 2 -lower alkoxy or together with the carbon atom to which they are attached form a C 3 -C 6 -cycloalkyl group;
or R 3 and R 2 together with the carbon atom to which they are attached form a C 3-6 -cycloalkyl group or a ring containing —(CH 2 ) 2 OCH 2 —; and
or R 6 and R 2 together with the carbon atom and the nitrogen atom to which they are attached form a C 3-6 -cycloalkyl group;
or a pharmaceutically acceptable acid addition salt, a racemic mixture, an enantiomer, an optical isomer or stereoisomer thereof and a pharmaceutically acceptable carrier.