Substituted dihydro benzocycloalkyloxymethyl oxazolopyrimidinones, preparation and use thereof
View Patent ↗The present invention relates to a series of substituted dihydro benzocycloalkyl-oxymethyl oxazolopyrimidinones of formula (I): Wherein n, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined herein. This invention also relates to methods of making these compounds including novel intermediates. The compounds of this invention are modulators of metabotropic glutamate receptors (mGluR), particularly, mGluR2 receptor. Therefore, the compounds of this invention are useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of central nervous system disorders (CNS), including but not limited to acute and chronic neurodegenerative conditions, psychoses, cognition deficit disorders, convulsions, anxiety, depression, migraine, pain, sleep disorders and emesis.
1. A compound of the formula (I):
wherein:
n is 1, 2 or 3;
R 1 is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl and propyl;
R 2 is selected from the group consisting of hydrogen, methyl, fluoromethyl, ethyl, 2-fluoroethyl, propyl, 1,1-difluoropropyl, methoxymethyl and 2-fluoroethoxymethyl;
R 3 and R 4 are the same or different and independently of each other selected from the group consisting of (C 1 -C 4 )alkyl, phenyl and benzyl; and
R 5 and R 6 are the same or different and independently of each other selected from the group consisting of hydrogen, halogen, (C 1 -C 4 )alkyl and (C 1 -C 4 )alkoxy.
2. The compound according to claim 1 , which has the formula II:
wherein:
R 1 is selected from the group consisting of hydrogen, methyl and ethyl;
R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl and 1,1-difluoropropyl;
R 3 and R 4 are the same or different and independently of each other selected from the group consisting of methyl, ethyl and propyl; and
R 5 and R 6 are the same or different and independently of each other selected from the group consisting of hydrogen, fluorine, bromine, methyl and ethyl.
3. The compound according to claim 2 , wherein:
R 1 is hydrogen or ethyl;
R 2 is hydrogen or methyl;
R 3 and R 4 are each methyl; and
R 5 is hydrogen or methyl;
R 6 is hydrogen or methyl.
4. The compound according to claim 2 , which is selected from the group consisting of:
(S)-2-(1,1-dimethyl-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;
(S)-2-(6-bromo-1,1-dimethyl-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;
(S)-2-(6-chloro-1,1-dimethyl-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;
(S)-2-(6-fluoro-1,1-dimethyl-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;
(S)-2-(1,1,6-trimethyl-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;
(S)-2-(1,1-dimethyl-indan-5-yloxymethyl)-6-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;
(S)-5-(1,1-difluoro-propyl)-2-(1,1-dimethyl-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; and
(S)-2-(1,1-dimethyl-indan-5-yloxymethyl)-5-methyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one.
5. The compound according to claim 2 , which is selected from the group consisting of:
(S)-2-(6-fluoro-1 ,1 -dimethyl-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;
(S)-2-(6-bromo-1 ,1 -dimethyl-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;
(S)-2-(1,1,6-trimethyl-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; and
(S)-2-(6-chloro-1 ,1 -dimethyl-indan-5-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one.
6. The compound according to claim 1 , which has the formula III:
wherein:
R 1 is selected from the group consisting of hydrogen, methyl and ethyl;
R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl and 1,1 -difluoropropyl;
R 3 and R 4 are the same or different and independently of each other selected from the group consisting of methyl, ethyl and propyl; and
R 5 and R 6 are the same or different and independently of each other selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl and ethyl.
7. The compound according to claim 6 , wherein:
R 1 is hydrogen or ethyl;
R 2 is hydrogen, methyl or 1,1-difluoropropyl;
R 3 and R 4 are each methyl; and
R 5 is hydrogen, fluorine, or methyl;
R 6 is hydrogen or methyl.
8. A compound selected from the group consisting of:
(S)-2-(5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one;
(S)-2-(5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-6-ethyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one
(S)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one; and
(S)-5-(1,1-difluoro-propyl)-2-(5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one.
9. A compound of the formula IV:
wherein:
R 1 is selected from the group consisting of hydrogen, methyl and ethyl;
R 2 is selected from the group consisting of hydrogen, methyl, ethyl, propyl and 1,1-difluoropropyl;
R 3 and R 4 are the same or different and independently of each other selected from the group consisting of methyl, ethyl and propyl; and
R 5 and R 6 are the same or different and independently of each other selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl and ethyl.
10. The compound according to claim 9 , wherein:
R 1 is hydrogen;
R 2 is hydrogen;
R 3 and R 4 are each methyl; and
R 5 is hydrogen, fluorine or methyl;
R 6 is hydrogen or methyl.
11. The compound according to claim 9 , which is:
(S)-2-(5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxymethyl)-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one.
12. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 11 in combination with one or more pharmaceutically acceptable carriers, diluents or excipients.