Quinazolinone T-Type Calcium Channel Antagonists

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.

1 - 29 . (canceled) 
     
     
         30 . A compound of the formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         X 1 , X 2  and X 3  are independently selected from the group consisting of:
 (1) hydrogen, 
 (2) fluoro, 
 (3) chloro, and 
 (4) bromo; 
 
         R 1  is phenyl, C 1-6 alkyl, or C 3-6 cycloalkyl, which is unsubstituted or substituted with a substituent selected from the group consisting of:
 (1) halogen, 
 (2) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, 
 (3) —OC 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, 
 (4) —CN, 
 (5) —NR 5 R 6 , wherein R 5  and R 6  are independently selected from hydrogen, C 1-6 alkyl and C 1-6 alkyl-phenyl, and 
 (6) —S(O) n C 1-6 alkyl, wherein n is 0, 1 or 2; 
 
         R 2  is C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, C 2-6 alkenyl, or C 2-6 alkynyl, which is unsubstituted or substituted with one or more substituents selected from the group consisting of:
 (1) fluoro, 
 (2) chloro, 
 (3) —OC 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, 
 (4) —S(O) n C 1-6 alkyl, 
 (5) —OH, 
 (6) ═O, 
 (7) —CHO, 
 (8) —CO 2 —C 1-6 alkyl, 
 (9) C 3-6 cycloalkyl, 
 (10) dioxanyl, and 
 (11) phenyl, which is unsubstituted or substituted with halogen, hydroxyl, C 1-6 alkyl or —O—C 1-6 alkyl; 
 
         R 3  is C 1-6 alkyl which is substituted with one or more fluoro, and which is optionally substituted with an additional substituent selected from the group consisting of:
 (1) C 1-6 alkyl, 
 (2) C 3-6 cycloalkyl, 
 (3) phenyl, and 
 (4) pyridyl; 
 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         31 . The compound of  claim 30  wherein X 1  is selected from the group consisting of:
 (1) fluoro,   (2) chloro, and   (3) bromo;   
       X 2  is selected from the group consisting of:
 (1) fluoro, 
 (2) chloro, and 
 
       X 3  is hydrogen. 
     
     
         32 . The compound of  claim 30  wherein R 1  is phenyl or cyclopropyl, which is unsubstituted or substituted with a substituent selected from the group consisting of:
 (1) fluoro,   (2) chloro,   (3) CH 3 ,   (4) CF 3 ,   (5) OCF 3 ,   (6) OCH 3 , and   (7) —N(CH 3 ) 2 .   
     
     
         33 . The compound of  claim 32  wherein R 1  is cyclopropyl. 
     
     
         34 . The compound of  claim 32  wherein R 1  is phenyl. 
     
     
         35 . The compound of  claim 32  wherein R 1  is para-fluorophenyl. 
     
     
         36 . The compound of  claim 30  wherein R 2  is selected from the group consisting of:
 (1) CH 2 CH 3 ,   (2) CH 2 CH 2 CH 3 ,   (3) cyclopropyl,   (4) CF 3 ,   (5) CH 2 CF 3 ,   (6) CH 2 CHF 2 ,   (7) CH 2 C(CH 3 ) 3 ,   (8) CH 2 CH═CH 2 ,   (9) C═CH 2 (CH 3 ),   (10) CH 2 C≡CCH 3 ,   (11) —CO 2 —CH 3 ,   (12) CH 2 OCH 2 CH 3 ,   (13) CH 2 CH 2 CH 2 CH 3 ,   (14) CH 2 CH 2 -dioxanyl, and   (15) CH 2 C(CH 3 ) 2 -phenyl.   
     
     
         37 . The compound of  claim 30  wherein R 3  is selected from the group consisting of:
 (1) CF 3 ,   (2) CF 2 H,   (3) CH 2 CF 3 ,   (4) CH 2 CHF 2 ,   (5) CH 2 CH 2 F,   (6) CH 2 CF 2 CH 3 ,   (6) CH 2 CF 2 CF 3 ,   (7) CH 2 CF 2 -phenyl, and   (8) CH 2 CF 2 -pyridyl.   
     
     
         38 . The compound of  claim 37  wherein R 3  is CH 2 CF 3  or CH 2 CHF 2 . 
     
     
         39 . 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(1H)-one;   4-Allyl-6-chloro-4-(4-fluorophenyl)-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-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-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-quinazolin2(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(1H)-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-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(1H)-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(1H)-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(1H)-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.   
     
     
         40 . The compound of  claim 39  which is selected from the group consisting of:
 4-Ethyl-6-fluoro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one; and   6-Chloro-4-cyclopropyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-quinazolin-2(1H)-one;   or a pharmaceutically acceptable salt thereof.   
     
     
         41 . The compound of  claim 40  which is 4-Ethyl-6-fluoro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one, or a pharmaceutically acceptable salt thereof. 
     
     
         42 . The compound of  claim 40  which is 6-Chloro-4-cyclopropyl-3-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)-3,4-dihydro-quinazolin-2(1H)-one, or a pharmaceutically acceptable salt thereof. 
     
     
         43 . A pharmaceutical composition which comprises an inert carrier and a compound of  claim 30 , or a pharmaceutically acceptable salt thereof. 
     
     
         44 . A pharmaceutical composition which comprises an inert carrier and a compound of  claim 39 , or a pharmaceutically acceptable salt thereof. 
     
     
         45 . A method for the treatment of a disorder or disease in which T-type calcium channels are involved which comprises administering to a mammalian patient in need of such treatment an effective amount of the compound of  claim 30  or a pharmaceutically acceptable salt thereof. 
     
     
         46 . The method of  claim 45  wherein said disorder or disease is selected from the group consisting of: epilepsy; pain; neuropathic pain; movement disorder; Parkinson's disease; essential tremor; cognitive disorder; decreased cognition; decreased memory retention; psychosis; schizophrenia; sleep disorder; insomnia; decreased quality of sleep; increased time to sleep onset; decreased REM sleep; decreased slow-wave sleep; increased fragmentation of sleep patterns; decreased sleep maintenance; increased wake after sleep onset; decreased total sleep time; hot flashes; fibromyalgia; mood disorder; anxiety disorder; and substance withdrawal.