Indoles as respiratory syncytial virus antiviral agents
View Patent ↗Indoles having inhibitory activity on RSV replication and having the formula I the prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms thereof; compositions containing these compounds as active ingredient and processes for preparing these compounds and compositions.
1. A method of treating a respiratory syncytial viral (RSV) infection comprising administering to a subject in need thereof an anti-virally effective amount of a compound of formula I, or a N-oxide, addition salt, quaternary amine, or a stereochemically isomeric form thereof;
wherein each X independently is C or N;
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 6 ) 2 , CO(R 7 ), 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 , and B(OH) 2 ; B(O—C 1 -C 6 alkyl) 2 ;
R 2 is selected from the group consisting of H, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, and CO(R 7 );
R 3 is —(CR 8 R 9 ) n —R 10 ;
R 4 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 8 , CH 2 CF 3 , SO 2 CH 3 , and a 4 to 6 membered saturated ring containing an oxygen atom;
R 5 is present where X is C, and wherein each R 5 is independently selected from the group consisting of H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, CO(R 7 ), CF 3 and halogen;
R 5 is absent where X is N;
R 6 is selected from the group consisting of H, C 1 -C 6 alkyl, COOCH 3 , and CONHSO 2 CH 3 ;
R 7 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 cyclo-alkyl), N(C 1 -C 6 -alkyl) 2 , NR 8 R 9 , and NR 9 R 10 ;
n is an integer from 2 to 6;
R 8 and R 9 are each independently chosen from H, C 1 -C 10 alkyl, C 3 -C 7 cycloalkyl or R 8 and R 9 taken together form a 4 to 6 membered aliphatic ring that optionally contains one or more heteroatoms selected from the group consisting of N, S, and O; and
R 10 is selected from the group consisting of H, C 1 -C 6 alkyl, OH, CN, F, CF 2 H, CF 3 , C(═NOH)NH 2 , CONR 8 R 9 , COOR 8 , CONR 8 SO 2 R 9 , CON(R 8 )SO 2 N(R 8 R 9 ), NR 8 R 9 , NR 8 COOR 9 , OCOR 8 , NR 8 SO 2 R 9 , SO 2 NR 8 R 9 , SO 2 R 8 and a 4 to 6 membered saturated ring containing an oxygen atom.
2. A method according to claim 1 ,
wherein
R 4 is selected from the group consisting of H, C 1 -C 10 alkyl, C 3 - 7 cycloalkyl, C 2 -C 10 alkenyl, SO 2 —R 8 , and a 4 to 6 membered saturated ring containing an oxygen atom.
3. A method according to claim 1 wherein each R 1 is independently selected from the group consisting of H, and halogen.
4. A method according to claim 1 , wherein R 1 in the para position to N—R 3 is selected from the group consisting of H, and halogen, and all other R 1 are H.
5. A method according to claim 4 wherein R 1 in the para position to N—R 3 is selected from the group consisting of bromo and chloro.
6. A method according to claim 1 , wherein R 2 is selected from the group consisting of H, halogen, and CO(R 7 ).
7. A method according to claim 1 , wherein R 2 is selected from the group consisting of H, I, and CONH 2 .
8. A method according to claim 1 , wherein R 3 comprises a —(CR 8 R 9 ) n chain wherein R 8 and R 9 are H and n is 2-4.
9. A method according to claim 1 , wherein R 10 is selected from the group consisting of F, CF 3 , OH, SO 2 R 8 , and CN, with R 8 being methyl.
10. A method according to claim 1 , wherein R 4 is C 3 -C 7 cycloalkyl or CH 2 CF 3 .
11. A method according to claim 1 , wherein R 4 is isopropyl.
12. A method according to claim 1 , wherein R 4 is oxetan-3-yl.
13. A method according to claim 1 , wherein the X in para position to N—R 4 is C and the R 5 on that X is F.
14. A method according to claim 1 , wherein one X is N and the other X's are C, the N being in para position to N—R 4 .
15. A method according to claim 1 , wherein at most one R 5 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 -alkoxy, and halogen, and the other R 5 are H.
16. A method according to claim 1 , wherein all R 5 are H.
17. A method of treating a respiratory syncytial viral (RSV) infection comprising administering to a subject in need thereof an anti-virally effective amount of a compound of the formula
or N—oxide, addition salt, or quaternary amine thereof.
18. A method of claim 17 wherein the compound is