Anti-malarial compounds
The present invention provides tricyclic compounds, arylamide compounds, and other compounds, and compositions comprising the same, for treating malaria, and methods of treating malaria comprising administering such compounds to an animal.
1. A compound of Formula I:
wherein:
X is N(R 9 ), O, S, S(═O), or S(═O) 2 ;
R 9 is H or C 1 -C 8 alkyl;
R 1 and R 2 are H;
R 3 and R 4 are, independently,
wherein each W, Y, and Z are, independently, C or N;
each R 5 is, independently, H or C 1 -C 8 alkoxy; and
each R 6 is, independently, the free base or salt form of —(CH 2 ) n —NH 2 , or —(CH 2 ) n —NH—(CH 2 ) n —NH 2 , or —(CH 2 ) n —NH—C(═NH)NH 2 , where each n is, independently, 1 to 8;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein X is N(R 9 ), O, S, or S(═O) 2 .
3. The compound of claim 1 wherein R 3 and R 4 are,
independently
wherein each W, Y, and Z are C; or each Y and Z are C and each W is N.
4. The compound of claim 1 wherein:
X is NH, O, S, or S(═O) 2 ;
R 1 and R 2 are H;
R 3 and R 4 are, independently,
wherein each W, Y, and Z are, independently, C or N;
each R 5 is H; and
each R 6 is, independently, the free base or salt form of —(CH 2 ) n —NH 2 , where each n is, independently, 1 to 3.
5. The compounds of claim 1 chosen from:
or pharmaceutically acceptable salt thereof.
6. The compound of claim 1 which is:
or pharmaceutically acceptable salt thereof.
7. A compound of Formula I:
wherein:
X is NH or S;
R 1 and R 2 are H;
R 3 and R 4 are, independently,
wherein each W, Y, and Z are, independently, C or N;
each R 5 is, independently, H or C 1 -C 8 alkoxy; and
each R 6 is, independently, heterocycle, or the free base or salt form of —(CH 2 ) n —NH 2 , or —(CH 2 ) n —NH—(CH 2 ) n —NH 2 , or —(CH 2 ) n —NH—C(═NH)NH 2 , where each n is, independently, 1 to 8;
or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7 which is
or a pharmaceutically acceptable salt thereof.
9. A compound of Formula I:
wherein:
X is N(R 9 ), O, S, S(═O), or S(═O) 2 ;
R 9 is H or C 1 -C 8 alkyl;
R 1 and R 2 are H;
R 3 and R 4 are, independently,
wherein each W, Y, and Z are, independently, C or N;
each R 5 is, independently, H or C 1 -C 8 alkoxy; and
each R 6 is piperazinyl or the free base or salt form of —(CH 2 ) n —NH 2 where each n is, independently, 1 to 3.
10. A compound of Formula I:
wherein:
X is NH, O, or S;
R 1 and R 2 are H;
R 3 and R 4 are
where each Z and Y are C, and each W is N; or each W, Y, and Z are C; each R 5 is H, and each R 6 is piperazinyl or the free base or salt form of —(CH 2 ) n —NH 2 , where each n is, independently, 1 to 3.
11. A pharmaceutical composition comprising the compound
or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. A method of treating malaria in an animal or killing or inhibiting the growth of a Plasmodium species comprising administering to the animal a therapeutically effective amount of a compound of Formula I or contacting the species with an effective amount of a compound of Formula I:
wherein:
X is N(R 9 ), O, S, S(═O), or S(═O) 2 ;
R 9 is H, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halo, OH, or CF 3 ;
R 1 and R 2 are, independently, H, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halo, OH, haloC 1 -C 8 alkyl, or CN;
R 3 and R 4 are, independently,
wherein each W, Y, and Z are, independently, C or N;
each R 5 and each R 6 are, independently, H, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halo, OH, CF 3 , aromatic group, heterocycle, or the free base or salt form of —(CH 2 ) n —NH 2 , —(CH 2 ) n —NH—(CH 2 ) n —NH 2 , or —(CH 2 ) n —NH—C(═NH)NH 2 , where each n is, independently, 1 to 8;
or a pharmaceutically acceptable salt thereof.
13. The method of claim 12 wherein X is N(R 9 ), O, S, or S(═O) 2 .
14. The method of claim 12 wherein R 1 and R 2 are, independently, H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo, OH, haloC 1 -C 3 alkyl, or CN.
15. The method of claim 12 wherein each R 5 is, independently, H, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, halo, OH, CF 3 , or the free base or salt form of —(CH 2 ) n —NH 2 , —(CH 2 ) n —NH—(CH 2 ) n —NH 2 , or —(CH 2 ) n —NH—C(═NH)NH 2 , where each n is, independently, 1 to 8, and each R 6 is, independently, heterocycle or the free base or salt form of —(CH 2 ) n —NH 2 , —(CH 2 ) n —NH—(CH 2 ) n —NH 2 , or —(CH 2 ) n —NH—C(═NH)NH 2 , where each n is, independently, 1 to 8.
16. The method of claim 12 wherein:
X is NH, O, S, or S(═O) 2 ;
R 1 and R 2 are H;
R 3 and R 4 are, independently,
wherein each W, Y, and Z are, independently, C or N; and each R 5 and each R 6 are, independently, H, heterocycle, or the free base or salt form of —(CH 2 ) n —NH 2 , where each n is, independently, 1 to 3.
17. The method of claim 12 wherein the malaria is chloroquine-sensitive or chloroquine-resistant.
18. The method of claim 12 wherein the compound is chosen from:
or pharmaceutically acceptable salt thereof.
19. The method of claim 12 wherein the compound is:
or pharmaceutically acceptable salt thereof.
20. The method of claim 12 wherein:
X is N(R 9 ), O, S, S(═O), or S(═O) 2 ;
R 9 is H or C 1 -C 8 alkyl;
R 1 and R 2 are H;
R 3 and R 4 are, independently,
wherein each W, Y, and Z are, independently, C or N;
each R 5 is, independently, H or C 1 -C 8 alkoxy; and
each R 6 is, independently, the free base or salt form of —(CH 2 ) n —NH 2 , or —(CH 2 ) n —NH—(CH 2 ) n —NH 2 , or —(CH 2 ) n —NH—C(═NH)NH 2 , where each n is, independently, 1 to 8;
or a pharmaceutically acceptable salt thereof.