Anti-influenza compositions and methods
View Patent ↗Disclosed are novel compounds comprising an imino-ribose derivative covalently linked to a carbocycle or heterocycle. Pharmaceutical compositions comprising the compounds of the invention are also described. Methods of inhibition, treatment and/or suppression of viral infections with the compounds of the invention are also described. The compositions or methods may optionally comprise one or more additional anti-viral agents.
1. A compound of formula I:
wherein
R 1 is selected from
R 2 is a bond, O, or S;
R 3 is a bond, C(═O), C(═S), C(═NR 10 ), OC(═O), OC(═S), OC(═NR 10 ), N(R 11 )C(═O), N(R 11 )C(═S), or N(R 11 )C(═NR 10 );
R 4 is OH or N(R 15 ) 2 ;
R 5 is H or N(R 15 ) 2 ;
R 6 is R 11 , C(═O)—R 11 , or SO 2 —R 11 ;
R 7 is H or R 12 , wherein R 12 is optionally substituted with one or more groups selected from lower alkyl, OR 11 , O—C(═O)—R 11 , O—C(═O)O—R 11 , O—C(═O)N(R 11 ) 2 , O—C(═S)—R 11 , O—C(═S)O—R 11 , and O—C(═S)N(R 11 ) 2 ;
R 8 is OR 11 , O—C(═O)—R 11 , O—C(═O)O—R 11 , O—C(═O)N(R 11 ) 2 , O—C(═S)—R 11 , O—C(═S)O—R 11 , O—C(═S)N(R 11 ) 2 , N(R 11 ) 2 , N(R 11 )C(═O)—R 11 , N(R 11 )C(═O)O(R 11 ) 2 , N(R 11 )C(═O)N(R 11 ) 2 , N(R 11 )C(═S)—R 11 , N(R 11 )C(═S)O—R 11 , N(R 11 )C(═S)N(R 11 ) 2 , or N(R 11 )C(═NR 10 )N(R 11 ) 2 ;
R 9 is H, OH, O—C(═O)O—R 11 , O—C(═O)N(R 11 ) 2 , O—C(═S)—R 11 , O—C(═S)O—R 11 , O—C(═S)N(R 11 ) 2 ;
B is a bond, R 12 , R 12 —R 13 , R 12 —R 13 —R 14 , R 12 —O—R 13 , R 12 —S—R 13 , R 12 —N(R 11 ) 2 —R 13 , R 12 —C(═O)—R 13 , R 12 —C(═S)—R 13 , R 12 —C(═NR 10 )—R 13 , R 12 —OC(═O)—R 13 , R 12 —OC(═S)—R 13 , R 12 —OC(═NR 10 )—R 13 , R 12 —SC(═O)—R 13 , R 12 —SC(═S)—R 13 , R 12 —SC(═NR 10 )—R 13 , R 12 —N(R 11 )C(═O)—R 13 , R 12 —N(R 11 )C(═S)—R 13 , R 12 —N(R 11 )C(═NR 10 )—R 13 , R 12 —OC(═O)—OR 13 , R 12 —OC(═S)—OR 13 , R 12 —OC(═NR 10 )—OR 13 , R 12 —OC(═O)—N(R 11 )R 13 , R 12 —OC(═S)—N(R 11 )R 13 , R 12 —OC(═NR 10 )—N(R 11 )R 13 , R 12 —OC(═O)—SR 13 , R 12 —OC(═S)—SR 13 , R 12 —OC(═NR 10 )—SR 13 , R 12 —N(R 11 )C(═O)—OR 13 , R 12 —N(R 11 )C(═S)—OR 13 , R 12 —N(R 11 )C(═NR 10 )—OR 13 , R 12 —N(R 11 )C(═O)—N(R 11 )R 13 , R 12 —N(R 11 )C(═S)—N(R 11 )R 13 , R 12 —N(R 11 )C(═NR 10 )—N(R 11 )R 13 , R 12 —N(R 11 )C(═O)—SR 13 , R 12 —N(R 11 )C(═S)—SR 13 , R 12 —N(R 11 )C(═NR 10 )—SR 13 , R 12 —SC(═O)—OR 13 , R 12 —SC(═S)—OR 13 , R 12 —SC(═NR 10 )—OR 13 , R 12 —SC(═O)—SR 13 , R 12 —SC(═S)—SR 13 , R 12 —SC(═NR 10 )—SR 13 , R 12 —SC(═O)—N(R 11 )R 13 , R 12 —SC(═S)—N(R 11 )R 13 , or R 12 —SC(═NR 10 )—N(R 11 )R 13 ; wherein each R 12 , R 13 , and R 14 are optionally substituted with one or more R 15 ;
R 10 is independently H, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, heteroaryl, OR 11 , or N(R 11 ) 2 ;
R 11 is independently H, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl;
R 12 is independently lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl;
R 13 is independently lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl;
R 14 is independently lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl; and
R 15 is independently halogen, R 10 , OC(═O)R 11 , OC(═S)R 11 , OC(═NR 10 )R 11 , OC(═O)OR 11 , OC(═S)OR 11 , OC(═NR 10 )OR 11 , OC(═O)N(R 11 ) 2 , OC(═S)N(R 11 ) 2 , OC(═NR 10 )N(R 11 ) 2 , N(R 11 )C(═O)R 11 , N(R 11 )C(═S)R 11 , N(R 11 )C(═NR 10 )R 11 , N(R 11 )C(═O)OR 11 , N(R 11 )C(═S)OR 11 , N(R 11 )C(═NR 10 )OR 11 , N(R 11 )C(═O)N(R 11 ) 2 , N(R 11 )C(═S)N(R 11 ) 2 , or N(R 11 )C(═NR 10 )N(R 11 ) 2 ;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 1 is selected from the group consisting of
R 2 is a bond, O, or S;
R 3 is a bond, C(═O), C(═S), or N(R 11 )C(═O);
R 4 is OH or NH 2 ;
R 5 is H or NH 2 ;
R 6 is C(═O)—R 11 ;
R 7 is lower alkyl, optionally substituted with one or more groups selected from lower alkyl, OR 11 , O—C(═O)—R 11 , O—C(═O)O—R 11 , and O—C(═O)N(R 11 ) 2 ;
R 8 is OR 11 , O—C(═O)—R 11 , O—C(═O)O—R 11 , O—C(═O)N(R 11 ) 2 , N(R 11 ) 2 , N(H)C(═O)O(R 11 ) 2 , or N(H)C(═NH)NH 2 ;
R 9 is H, OH, O—C(═O)O—R 11 , or O—C(═O)N(R 11 ) 2 ;
B is a bond, R 12 , R 12 —R 13 , R 12 —O—R 13 ; R 12 —OC(═O)—R 13 , R 12 —N(R 11 )C(═O)—R 13 , R 12 —OC(═O)—OR 13 , R 12 —OC(═O)—N(R 11 )R 13 , R 12 —N(R 11 )C(═O)—OR 13 , or R 12 —N(R 11 )C(═O)—N(R 11 )R 13 ; wherein each R 12 , R 13 , and R 14 are optionally substituted with one or more R 15 ;
R 10 is independently H, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, heteroaryl, OR 11 , or N(R 11 ) 2 ;
R 11 is independently H, or lower alkyl optionally substituted with one or more lower alkyl;
R 12 is independently lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl;
R 13 is independently lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl;
R 14 is independently lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl; and
R 15 is independently R 10 , N(R 11 )C(═O)R 11 , or N(R 11 )C(═O)OR 11 ;
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein R 1 is
R 2 is a bond or O;
R 3 is a bond or C(═O);
R 4 is NH 2 ;
R 5 is hydrogen;
R 6 is C(═O)—CH 3 ;
R 7 is —CH(CH 2 CH 3 ) 2 ;
R 8 is N(H)C(═NH)NH 2 ;
R 9 is OH;
B is a bond, lower alkyl, lower alkyl-OC(═O)—R 13 ; wherein R 13 is optionally substituted with R 15 ;
R 11 is independently H, or lower alkyl;
R 13 is lower alkyl; and
R 15 is lower alkyl, N(R 11 ) 2 , or N(H)C(═O)R 11 ;
or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 , wherein R 1 is
R 2 is a bond or O;
R 3 is a bond or C(═O);
R 4 is NH 2 ;
R 5 is hydrogen;
R 6 is C(═O)—CH 3 ;
R 7 is —CH(CH 2 CH 3 ) 2 ;
R 8 is NH 2 ;
B is a bond, lower alkyl, lower alkyl-OC(═O)—R 13 ; wherein R 13 is optionally substituted with R 15 ;
R 11 is independently H, or lower alkyl;
R 13 is lower alkyl; and
R 15 is lower alkyl, N(R 11 ) 2 , or N(H)C(═O)R 11 ;
or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , wherein R 1 is
R 2 is a bond, or O;
R 3 is a bond or C(═O);
R 4 is NH 2 ;
R 5 is hydrogen;
R 6 is C(═O)—CH 3 ;
R 7 is 1,2,3-trihydroxypropyl;
R 8 is NH 2 C(═NH)NH 2 ;
B is a bond, lower alkyl, lower alkyl-OC(═O)—R 13 ; wherein R 13 is optionally substituted with R 15 ;
R 11 is independently H, or lower alkyl;
R 13 is lower alkyl; and
R 15 is lower alkyl, N(R 11 ) 2 , or N(H)C(═O)R 11 ;
or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 , wherein the compound is
wherein n is an integer from 1 to 6; or a pharmaceutically acceptable salt thereof.
7. The compound of claim 1 , wherein the compound is
wherein n is an integer from 1 to 6; or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
9. A method for inhibiting, treating or suppressing a viral infection, comprising administering to a subject in need thereof an effective amount of a compound of formula I:
wherein
R 1 is selected from
R 2 is a bond, O, or S;
R 3 is a bond, C(═O), C(═S), C(═NR 10 ), OC(═O), OC(═S), OC(═NR 10 ), N(R 11 )C(═O), N(R 11 )C(═S), or N(R 11 )C(═NR 10 );
R 4 is OH or N(R 15 ) 2 ;
R 5 is H or N(R 15 ) 2 ;
R 6 is R 11 , C(═O)—R 11 , or SO 2 —R 11 ;
R 7 is H or R 12 , wherein R 12 is optionally substituted with one or more groups selected from lower alkyl, OR 11 , O—C(═O)—R 11 , O—C(═O)O—R 11 , O—C(═O)N(R 11 ) 2 , O—C(═S)—R 11 , O—C(═S)O—R 11 , and O—C(═S)N(R 11 ) 2 ;
R 8 is OR 11 , O—C(═O)—R 11 , O—C(═O)O—R 11 , O—C(═O)N(R 11 ) 2 , O—C(═S)—R 11 , O—C(═S)O—R 11 , O—C(═S)N(R 11 ) 2 , N(R 11 ) 2 , N(R 11 )C(═O)—R 11 , N(R 11 )C(═O)O(R 11 ) 2 , N(R 11 )C(═O)N(R 11 ) 2 , N(R 11 )C(═S)—R 11 , N(R 11 )C(═S)O—R 11 , N(R 11 )C(═S)N(R 11 ) 2 , or N(R 11 )C(═NR 10 )N(R 11 ) 2 ;
R 9 is H, OH, O—C(═O)O—R 11 , O—C(═O)N(R 11 ) 2 , O—C(═S)—R 11 , O—C(═S)O—R 11 , O—C(═S)N(R 11 ) 2 ;
B is a bond, R 12 , R 12 —R 13 , R 12 —R 13 —R 14 , R 12 —O—R 13 , R 12 —S—R 13 , R 12 —N(R 11 ) 2 —R 13 , R 12 —C(═O)—R 13 , R 12 —C(═S)—R 13 , R 12 —C(═NR 10 )—R 13 , R 12 —OC(═O)—R 13 , R 12 —OC(═S)—R 13 , R 12 —OC(═NR 10 )—R 13 , R 12 —SC(═O)—R 13 , R 12 —SC(═S)—R 13 , R 12 —SC(═NR 10 )—R 13 , R 12 —N(R 11 )C(═O)—R 13 , R 12 —N(R 11 )C(═S)—R 13 , R 12 —N(R 11 )C(═NR 10 )—R 13 , R 12 —OC(═O)—OR 13 , R 12 —OC(═S)—OR 13 , R 12 —OC(═NR 10 )—OR 13 , R 12 —OC(═O)—N(R 11 )R 13 , R 12 —OC(═S)—N(R 11 )R 13 , R 12 —OC(═NR 10 )—N(R 11 )R 13 , R 12 —OC(═O)—SR 13 , R 12 —OC(═S)—SR 13 , R 12 —OC(═NR 10 )—SR 13 , R 12 —N(R 11 )C(═O)—OR 13 , R 12 —N(R 11 )C(═S)—OR 13 , R 12 —N(R 11 )C(═NR 10 )—OR 13 , R 12 —N(R 11 )C(═O)—N(R 11 )R 13 , R 12 —N(R 11 )C(═S)—N(R 11 )R 13 , R 12 —N(R 11 )C(═NR 10 )—N(R 11 )R 13 , R 12 —N(R 11 )C(═O)—SR 13 , R 12 —N(R 11 )C(═S)—SR 13 , R 12 —N(R 11 )C(═NR 10 )—SR 13 , R 12 —SC(═O)—OR 13 , R 12 —SC(═S)—OR 13 , R 12 —SC(═NR 10 )—OR 13 , R 12 —SC(═O)—SR 13 , R 12 —SC(═S)—SR 13 , R 12 —SC(═NR 10 )—SR 13 , R 12 —SC(═O)—N(R 11 )R 13 , R 12 —SC(═S)—N(R 11 )R 13 , or R 12 —SC(═NR 10 )—N(R 11 )R 13 ; wherein each R 12 , R 13 , and R 14 are optionally substituted with one or more R 15 ;
R 10 is independently H, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, heteroaryl, OR 11 , or N(R 11 ) 2 ;
R 11 is independently H, lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl;
R 12 is independently lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl;
R 13 is independently lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl;
R 14 is independently lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, aryl, or heteroaryl; and
R 15 is independently halogen, R 10 , OC(═O)R 11 , OC(═S)R 11 , OC(═NR 10 )R 11 , OC(═O)OR 11 , OC(═S)OR 11 , OC(═NR 10 )OR 11 , OC(═O)N(R 11 ) 2 , OC(═S)N(R 11 ) 2 , OC(═NR 10 )N(R 11 ) 2 , N(R 11 )C(═O)R 11 , N(R 11 )C(═S)R 11 , N(R 11 )C(═NR 10 )R 11 , N(R 11 )C(═O)OR 11 , N(R 11 )C(═S)OR 11 , N(R 11 )C(═NR 10 )OR 11 , N(R 11 )C(═O)N(R 11 ) 2 , N(R 11 )C(═S)N(R 11 ) 2 , or N(R 11 )C(═NR 10 )N(R 11 ) 2 ;
or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 , wherein a neuraminidase inhibitor is generated following administration of the compound of formula I, wherein the neuraminidase inhibitor is peramivir, or a pharmaceutically acceptable salt thereof.
11. The method of claim 9 , wherein a polymerase inhibitor is generated following administration of the compound of formula I, wherein the polymerase inhibitor is comprised of compound (A)
wherein
R 4 is NH 2 ; and
R 5 is hydrogen;
or a pharmaceutically acceptable salt thereof.
12. The method of claim 9 , wherein a neuraminidase inhibitor is generated following administration of the compound of formula I, wherein the neuraminidase inhibitor is peramivir, or a pharmaceutically acceptable salt thereof; and
a polymerase inhibitor is generated following administration of the compound of formula I, wherein the polymerase inhibitor is comprised of compound (A)
wherein
R 4 is NH 2 ; and
R 5 is hydrogen; or
a pharmaceutically acceptable salt thereof.
13. The method of claim 9 , wherein the compound of formula I is
wherein n is an integer from 1 to 6; or a pharmaceutically acceptable salt thereof.
14. The method of claim 9 , wherein the compound of formula I is
wherein n is an integer from 1 to 6; or a pharmaceutically acceptable salt thereof.
15. The method of claim 9 , wherein the compound of formula I is
or a pharmaceutically acceptable salt thereof.
16. The method of claim 9 , wherein the viral infection is influenza.
17. The method of claim 9 , further comprising administering to the subject an effective amount of an additional anti-viral agent.
18. The method of claim 17 , wherein the additional anti-viral agent is rimantadine or amantadine.
19. The method of claim 9 , wherein the compound of formula I is administered orally.
20. The method of claim 9 , wherein the compound of formula I is administered intravenously.
21. The method of claim 9 , wherein the compound of formula I is administered intramuscularly.
22. The method of claim 9 , wherein the subject is a mammal.
23. The method of claim 9 , wherein the subject is a human.
24. The method of claim 9 , wherein the subject is an avian.