Azabenzimidazoles as respiratory syncytial virus antiviral agents
View Patent ↗A compound satisfying formula I, a prodrug, N-oxide, addition salt, quaternary amine, metal complex, or a stereochemically isomeric form thereof; compositions contain these compounds as active ingredient and processes for preparing these compounds and compositions.
1. A compound of formula I, a N-oxide, addition salt, quaternary amine, or a stereochemically isomeric form thereof;
wherein each X independently is C or N; at least one X═N;
each Y independently is C or N;
R 1 is present when X═C and each R 1 is independently selected from the group of H, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, N(R 5 ) 2 , CO(R 6 ), CH 2 NH 2 , CH 2 OH, CN, C(═NOH)NH 2 , C(═NOCH 3 )NH 2 , C(═NH)NH 2 , CF 3 , OCF 3 , B(OH) 2 , and B(O—C 1 -C 6 alkyl) 2 ;
R 1 is absent when X═N;
R 2 is —(CR 7 R 8 ) n —R 9 ;
R 3 is selected from the group consisting of H, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 10 alkenyl, SO 2 —R 7 , CH 2 CF 3 and a 4 to 6 membered saturated ring containing an oxygen atom;
R 4 is present where Y is C and each R 4 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 alkoxy, CO(R 7 ), COO(R 7 ), CF 3 and halogen,
R 4 is absent when X═N
R 5 is selected from the group consisting of H, C 1 -C 6 alkyl, COOCH 3 , and CONHSO 2 CH 3 ;
R 6 is selected from the group consisting of OH, O(C 1 -C 6 alkyl), NH 2 , NHSO 2 N(C 1 -C 6 alkyl) 2 , NHSO 2 NHCH 3 , NHSO 2 (C 1 -C 6 alkyl), NHSO 2 (C 3 -C 7 cycloalkyl), and N(C 1 -C 6 -alkyl) 2 ;
R 7 and R 8 are each independently selected from H, C 1 -C 10 alkyl, or C 3 -C 7 cycloalkyl, or R 7 and R 8 taken together form a 4 to 6 membered aliphatic ring that optionally contains a heteroatom selected from the group N, S, or O;
R 9 is selected from the group consisting of H, R 10 , C 1 -C 6 alkyl, OH, CN, F, CF 2 H, CF 3 , CONR 7 R 8 , COOR 7 , CON(R 7 )SO 2 R 8 , CON(R 7 )SO 2 N(R 7 R 8 ), NR 7 R 8 , NR 7 COOR 8 , OCOR 7 , O-Benzyl, NR 7 SO 2 R 8 , SO 2 NR 7 R 8 , SO 2 R 7 , OCONR 7 R 8 , OCONR 7 R 10 , N(R 7 )CON(R 7 R 8 ), N(R 7 )COOR 10 ; phtalimido, 2-methyl-benzothiophene(1,1)dioxide, and a 4 to 6 membered saturated ring containing an oxygen atom;
n is an integer from 2 to 6;
R 10 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl, pyridine and pyrazole, optionally substituted with one or more substituents selected from CF 3 , CH 3 , OCH 3 , OCF 3 or halogen.
2. A compound according to claim 1 wherein R 3 is selected from the group consisting of H, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 10 alkenyl, SO 2 —R 7 , and a 4 to 6 membered saturated ring containing an oxygen atom;
R 9 is selected from the group consisting of H, C 1 -C 6 alkyl, OH, CN, F, CF 2 H, CF 3 , CONR 7 R 8 , COOR 7 , CON(R 7 )SO 2 R 8 , CON(R 7 )SO 2 N(R 7 R 8 ), NR 7 R 8 , NR 7 COOR 8 , OCOR 7 , O-Benzyl, NR 7 SO 2 R 8 , SO 2 NR 7 R 8 , SO 2 R 7 , and a 4 to 6 membered saturated ring containing an oxygen atom.
3. A compound according to claim 1 wherein one X is N, said N being in either of the two positions ortho to the imidazole ring.
4. A compound according to claim 1 , wherein each R 1 is independently selected from the group consisting of H, and halogen.
5. A compound according to claim 1 , wherein R 1 in the para position to C—N—R 2 is selected from the group consisting of H, halogen, and CH 2 —NH 2 , and all other R 1 are H.
6. A compound according to claim 1 , wherein R 7 and R 8 are H and n is 2-4.
7. A compound according to claim 1 , wherein R 9 is selected from the group consisting of OH, F, CF 2 H, CF 3 , C 1 -C 6 alkyl, and SO 2 R 7 .
8. A compound according to claim 1 , wherein R 3 is selected from the group consisting of C 3 -C 7 cycloalkyl, and a 4 membered saturated ring containing an oxygen atom.
9. A compound according to claim 1 , wherein R 3 is cyclopropyl or CH 2 CF 3 .
10. A compound according to claim 1 , wherein one Y is N, and the other Y's are C, the one Y that is N being in para position to N—R 3 .
11. A compound according to claim 1 , wherein the R 4 on the one Y that is being in para position to N—R 3 is F.
12. A compound according to claim 1 , wherein all R 4 are H.
13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as claimed in claim 1 .
14. A process for preparing a pharmaceutical composition as claimed in claim 13 , said process comprising intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of the compound.