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US 2008/0167329 A1Published application
Quinazolinone T-Type Calcium Channel Antagonists
AssigneeMerck Sharp & Dohme Corp.
InventorsJames C. Barrow, Rowena V. Cube, Phung Le Ngo, Kenneth E. Rittle, Zhiqiang Yang, Steven D. Young
Life of this patent
Estimating the term…
Abstract
The present invention is directed to quinazolinone compounds which are antagonists of T-type calcium channels, and which are useful in the treatment or prevention of disorders and diseases in which T-type calcium channels are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which T-type calcium channels are involved.
Claims22
1-29. (canceled)
A compound of the formula I:
- wherein:
- X1, X2 and X3 are independently selected from the group consisting of:
- (1) hydrogen,
- (2) fluoro,
- (3) chloro, and
- (4) bromo;
- R1 is phenyl, C1-6alkyl, or C3-6cycloalkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of:
- (1) halogen,
- (2) C1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,
- (3) —OC1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,
- (4) —CN,
- (5) —NR5R6, wherein R5 and R6 are independently selected from hydrogen, C1-6alkyl and C1-6alkyl-phenyl, and
- (6) —S(O)nC1-6alkyl, wherein n is 0, 1 or 2;
- R2 is C1-6alkyl, C3-6cycloalkyl, phenyl, C2-6alkenyl, or C2-6alkynyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of:
- (1) fluoro,
- (2) chloro,
- (3) —OC1-6alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl,
- (4) —S(O)nC1-6alkyl,
- (5) —OH,
- (6) ═O,
- (7) —CHO,
- (8) —CO2—C1-6alkyl,
- (9) C3-6cycloalkyl,
- (10) dioxanyl, and
- (11) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, C1-6alkyl or —O—C1-6alkyl;
- R3 is C1-6alkyl which is substituted with one or more fluoro, and which is optionally substituted with an additional substituent selected from the group consisting of:
- (1) C1-6alkyl,
- (2) C3-6cycloalkyl,
- (3) phenyl, and
- (4) pyridyl;
- or a pharmaceutically acceptable salt thereof.
28 more elements
A compound which is selected from the group consisting of:
- 4-Ethyl-6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 4-Ethyl-6-fluoro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(H)-one;
- 6-Chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 4-Allyl-6-chloro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-(4-fluorophenyl)-4-propyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 4-Allyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 4-(2,2-Difluoroethyl)-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 4-Ethyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(4-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-cyclopropyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-cyclopropyl-4-(4-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-quinazolin-2(1H)-one;
- 6-Chloro-4-(fluorophenyl)-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-quinazolin-2(1H)-one;
- 6-Chloro-4-allyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-quinazolin-2(1H)-one;
- 6-Chloro-4-propyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-quinazolin-2(1H)-one;
- 4-Butyl-6-chloro-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2(H)-one;
- 6-Chloro-4-cyclopropyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-quinazolin-2(1H)-one;
- 6-Chloro-4-(cyclopropylethynyl)-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydroquinazolin-2((1H)-one;
- 6-Chloro-4-ethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(4-methoxyphenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(3-methoxyphenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(4-methylphenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(3-methylphenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(3-chlorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(3-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(4-chlorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(4-dimethylaminophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(2-methoxyphenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-ethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(3,4-difluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-ethyl-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-butyl-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(H)-one;
- 6-Fluoro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-methoxymethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethoxymethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 4-Ethyl-4-(4-fluoro-phenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-allyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-(2,2-dimethylpropyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-(2-phenyl-2-methylpropyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-ethyl-4-phenyl-3-(2-fluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-butyl-4-phenyl-3-(2-fluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-ethyl-4-phenyl-3-(2,2,3,3,3-pentafluoropropyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-butyl-4-phenyl-3-(2,2,3,3,3-pentafluoropropyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-ethyl-4-phenyl-3-(2,2-difluoropropyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-butyl-4-phenyl-3-(2,2-difluoropropyl)-3,4-dihydroquinazolin-2(H)-one;
- 6-Fluoro-4-pentyl-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 5-fluoro-4-ethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-5-fluoro-4-ethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-(1-propynyl)-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 3-(2,2-Difluoroethyl)-4-[2-(1,3-dioxan-2-yl)ethyl]-6-fluoro-4-phenyl-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-(2-propenyl)-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-butyl-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-ethyl-4-(4-thiomethylphenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-cyclopropyl-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 3-(2,2-difluoroethyl)-6-fluoro-4-phenyl-4-(phenylethynyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4,4-diphenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 3-(2,2-difluoroethyl)-4-(2-ethylbutyl)-6-fluoro-4-phenyl-3,4-dihydroquinazolin-2(1H)-one;
- 3-(2,2-Difluoroethyl)-6-fluoro-4-phenyl-4-(2-phenylethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 3-(2,2-Difluoroethyl)-6-fluoro-4-phenyl-4-(2-(4-chlorophenyl)ethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 3-(2,2-Difluoroethyl)-6-fluoro-4-phenyl-4-(2-(3-chlorophenyl)ethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 3-(2,2-Difluoroethyl)-6-fluoro-4-phenyl-4-(2-(4-fluorophenyl)ethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 3-(2,2-Difluoroethyl)-6-fluoro-4-phenyl-4-(2-(4-methoxyphenyl)ethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 3-(2,2-Difluoroethyl)-6-fluoro-4-phenyl-4-(2-(3-methoxyphenyl)ethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 5-Fluoro-4-cyclopropyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-methyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-propyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-cyclopropyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-cyclopropyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-cyclopropyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-cyclopropyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 5,6-Difluoro-4-ethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(H)-one;
- 5,8-Difluoro-4-ethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 5,8-Difluoro-4-methyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 5,8-Difluoro-4-ethyl-4-phenyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Fluoro-4-cyclopropylmethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 5-fluoro-4-ethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-(3-propenyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-cyclopropylmethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-cyclopropylmethyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 5,6-difluoro-4-propyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-ethyl-4-(3-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-(3-formylmethyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-(3-hydroxyethyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-(methoxycarbonyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-cyclopropyl-4-(3,4-difluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 4-[2-(Benzylamino)ethyl]-6-chloro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-(3-propenyl)-4-(3,4-difluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-propyl-4-(3,4-difluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-(2,2-difluoroethyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-(2-fluoroethyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 5,6-Difluoro-4-cyclopropylmethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-(2-ethoxyethyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-(2-methoxyethyl)-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-propyl-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 5,6-Difluoro-4-(2-fluoroethyl)-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-(2hydroxyethyl)-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-(2,2-difluoroethyl)-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-(2-fluoroethyl)-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-(3-propenyl)-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-cyclopropyl-4-isobutyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 6-Chloro-4-cyclopropyl-4-ethyl-3-(2-fluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 4-Butyl-6-chloro-4-cyclopropyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- 4-Butyl-6-chloro-4-cyclopropyl-3-(2,2-difluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- and
- 4-Butyl-6-chloro-4-cyclopropyl-3-(2-fluoroethyl)-3,4-dihydroquinazolin-2(1H)-one;
- or a pharmaceutically acceptable salt thereof.
108 more elements
Dependencies are inferred from the claim text.