Rifamycin C-11 oxime cyclo derivatives effective against drug-resistant microbes
View Patent ↗The current invention relates to a series of rifamycin derivatives having antimicrobial activities, including activities against drug-resistant microorganisms, specifically, the 3,4-cyclo-rifamycin derivatives having an oxime group at the C-11 position.
1. A compound of structural Formula I or Formula II:
or pharmaceutically acceptable salts thereof;
wherein:
L 11 is any combination of 0 to 5 groups which are independently the same or different and are selected from —CR 1 R 2 —, —NR 3 —, —O—, —C(═O)—, —S(═O) 0-2 —, —C═N—, alkylene, alkenylene, and alkynylene;
X 11 is —H, —OH, —NH 2 , —CO 2 H, halo, haloalkyl, —CN, alkyl, aryl, or Q 11 ;
X and Y, joined together with C-1 to C-4 of Formula I or Formula II, are, structures III or IV, when the compound is Formula I:
wherein X 3 is —O—, —S(O) 0-2 , or —NR 4 —, or
structures V or VI, when the compound is Formula II:
Z is —H or —COCH 2 R 11 , wherein R 11 is —H, —OH, halo, —CN, —CO 2 H, —CONR 12 R 13 , —NR 14 R 15 , —OR 16 , —S(═) 0-2 R 17 , or —Q 25 ,
wherein R 1 , R 5 , R 8 , and R 9 independently are the same or different and are —H, —OH, —SH, —NH 2 , alkyl, aryl, alkoxy, alkylthio, alkylamino, or dialkylamino,
wherein R 2 , R 3 , R 4 , R 6 , R 7 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 independently are the same or different and are H, alkyl, or aryl, and
wherein Q 11 and Q 25 independently are the same or different and are any of the structures:
2. The compound of claim 1 , wherein L 11 X 11 is —H.
3. The compound of claim 1 , wherein the compound is Formula I, and wherein X and Y, joined together with C-1 to C-4 of Formula I, are structure IIIa or IVa:
4. A method of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of the compound of claim 1 .
5. The method of claim 4 , wherein the bacterial infection is caused by a drug-resistant bacterium.
6. A compound having a formula:
7. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-5′-(2-methylpropyl)-1-oxo-rifamycin XIV:
8. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-[4-(2-methylpropyl)-1-piperazinyl]-1-oxo-rifamycin VIII:
9. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-(morpholin-4-yl)-1-oxo-rifamycin VIII:
10. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-(4-methyl-1-piperazinyl)-1-oxo-rifamycin VIII:
11. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-(4-ethyl-1-piperazinyl)-1-oxo-rifamycin VIII:
12. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-(4-isopropyl-1-piperazinyl)-1-oxo-rifamycin VIII:
13. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-(4-butyl-1-piperazinyl)-1-oxo-rifamycin VIII:
14. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-(4-cyclohexylmethyl-1-piperazinyl)-1-oxo-rifamycin VIII:
15. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-[4-(1-Methyl-piperidin4-ylmethyl)-1-piperazinyl]-1-oxo -rifamycin VIII:
16. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-[(1,4′)-bipiperidinyl-1′-yl]-1-oxo-rifamycin VIII:
17. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-(3,5-dimethyl-1-piperazinyl)-1-oxo-rifamycin VIII:
18. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-(3-amino-pyrrolidin-1-yl)-1-oxo-rifamycin VIII:
19. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-(pyrrolidin-1-yl)-1-oxo-rifamycin VIII:
20. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-{4-[2-(2-hydroxy-ethoxy)-ethyl]-piperazin-1-yl}-1-oxo -rifamycin VIII:
21. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-hydroxy-5′-[bis-(2-hydroxy-ethyl)-amino]-1-oxo-rifamycin VIII:
22. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-3′-methyl-5′-(4-methyl-1-piperazinyl)-1-oxo-rifamycin VIII:
23. A compound having a formula 11-Deoxy-11-hydroxyimino-1′,4-didehydro-1-deoxy-1,4-dihydro-5′-(4-isobutyl-1-piperazinyl)-1-oxo-rifamycin VIII:
24. A compound having a formula 11-Deoxy-11-(4-carboxymethoxyimino)-1′,4-didehydro-1-deoxy-1,4-dihydro-5′-(2-methylpropyl)-1-oxo-rifamycin XIV:
25. A compound having a formula 11-Deoxy-11-{2-oxo-2-[2-methyl-4-(3-carboxy -1-cyclopropl-2-methoxy-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)piperazin-1-yl]ethoxyimino}-1′,4-didehydro-1-deoxy-1,4-dihydro-5′-(2-methylpropyl)-1-oxo-rifamycin XIV:
26. A pharmaceutical composition, useful as medicament for treatment or prevention of bacterial infections, comprising a therapeutically effective amount of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.
27. A pharmaceutical composition, useful as a medicament for treatment or prevention of bacterial infections, comprising a therapeutically effective amount of a compound in accordance with claim 6 in combination with a pharmaceutically acceptable carrier.