Benzodiazepine derivatives and pharmaceutical compositions containing them
Benzodiazepine derivative of formula (I), and pharmaceutically acceptable salts thereof, are found to be active against RSV. Formula (I) Wherein: —R 1 represents C 1-6 alkyl, aryl or heteroaryl; —R 2 represents hydrogen or C 1-6 alkyl; —each R 3 is the same or different and represents halogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, amino, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, nitro, cyano, —CO 2 R′, —CONR′R″, —NH—CO—R′, —S(O)R′, —S(O) 2 R′, —NH—S(O) 2 R′, —S(O)NR′R″ or —S(O) 2 NR′R″ wherein each R′ and R″ is the same or different and represents hydrogen or C 1-6 alkyl; —n is from 0 to 3; R 4 represents hydrogen or C 1-6 alkyl; —R 6 represents C 1-6 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C 1-6 alkyl)-, heteroaryl-(C 1-6 alkyl)-, carbocyclyl-(C 1-6 alkyl)-, heterocyclyl-(C 1-6 alkyl)-, aryl-C(O)—C(O)—, heteroaryl-C(O)—C(O)—, carbocyclyl-C(O)—C(O)—, heterocyclyl-C(O)—C(O)— or, —XR 6 ; —X represents —CO—, —S(O)— or —S(O) 2 —; and —R 6 represents C 1-6 alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkylthio, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C 1-6 alkyl)-, heteroaryl-(C 1-6 alkyl)-, carbocyclyl-(C 1-6 alkyl)-, heterocyclyl-(C 1-6 alkyl)-, aryl-(C 1-6 hydroxyalkyl)-, heteroaryl-(C 1-6 hydroxyalkyl)-, carbocyclyl-(C 1-6 hydroxyalkyl)-, heterocyclyl-(C 1-6 hydroxyalkyl)-, aryl-(C 1-6 alkyl)-O—, heteroaryl-(C 1-6 alkyl)-O—, carbocyclyl-(C 1-6 alkyl)-O—, heterocyclyl-(C 1-6 alkyl)-O— or —NR′R″ wherein each R′ and R″ is the same or different and represents hydrogen, C 1-6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, aryl-(C 1-6 alkyl)-, heteroaryl-(C 1-6 alkyl)-, carbocyclyl-(C 1-6 alkyl)- or heterocyclyl-(C 1-6 alkyl)-.
1. A compound of formula (Ic), or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is phenyl;
R 3 is methyl or chlorine;
n is 0 or 1;
R 4 is hydrogen or methyl;
R 5 ′ is —X′;
X′ is —CONR′R″ and
each R′ R″ is the same or different and represents hydrogen, C 1-4 alkyl, phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH 2 )—;
wherein:
the phenyl moiety in the group R 1 being unsubstituted or substituted by a single C 1-2 alkyl, C 1-2 alkoxy, C 1-2 alkylthio, C 1-2 haloalkyl or C 1-2 haloalkoxy substituent;
the phenyl, thienyl, cyclohexyl, cyclopentyl or phenyl-(CH 2 )— moieties in the R′ and R″ being unsubstituted or substituted by one or two substituents selected from fluorine, chlorine, bromine, and nitro.
2. A compound of formula (Ie) or pharmaceutically acceptable salts thereof
wherein R′* is an aryl group which is unsubstituted or substituted by 1 or 2 substituents selected from fluorine, chlorine, bromine, and nitro.
3. A compound according to claim 1 , selected from 1,1-Diethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-urea;
(S)-1-(2-Fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-urea;
1-(4-Nitro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-urea;
1-tert-Butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-urea;
1-Cyclohexyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-urea;
1-Ethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-urea;
1-Butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-urea;
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 2 , wherein R′* is a phenyl group which is unsubstituted or substituted by a single fluorine, chlorine, or bromine substituent.
5. A compound according to claim 2 , wherein the compound is (S)-1 -(2-Fluoro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-urea.
6. A compound according to claim 2 , wherein the compound is 1-(4-Nitro-phenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-urea.
7. A compound according to claim 2 , wherein the compound is 1-Butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-urea.
8. A compound according to claim 1 wherein the compound is 1,1-Diethyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-urea.
9. A compound according to claim 2 , wherein the compound is 1-tert-Butyl-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-urea.
10. A compound according to claim 1 , wherein R 1 is phenyl.