Rifamycin analogs and uses thereof
View Patent ↗The present invention features rifamycin analogs that can be used as therapeutics for treating or preventing a variety of microbial infections. In one form, the analogs are acetylated at the 25-position, as is rifamycin. In another form, the analogs are deacetylated at the 25-position. In yet other forms, benzoxazinorifamycin, benzthiazinorifamycin, and benzdiazinorifamycin analogs are derivatized at various positions of the benzene ring, including 3′-hydroxy analogs, and/or various fused ring systems with the benzene ring at the 4′,5′ or 5′,6′ positions.
1. A compound having the formula:
or a pharmaceutically acceptable salt thereof, wherein
A is H, OH, O—(C 1 –C 6 alkyl), O—(C 1 –C 4 alkaryl), or O—(C 6 –C 12 aryl);
W is O, S, or NR 1 , wherein R 1 is H, C 1 –C 6 alkyl, or C 1 –C 4 alkaryl;
X is H or COR 2 , wherein R 2 is C 1 –C 6 alkyl, which can be substituted with 1–5 OH groups, O—(C 3 –C 7 alkyl), which can be substituted with 1–4 OH groups, C 6 –C 12 aryl, or C 1 –C 4 alkaryl, wherein each alkyl carbon is bound to no more than one oxygen atom;
Z is H, Hal, or OR 3 , wherein R 3 is C 1 –C 6 alkyl, C 6 –C 12 aryl, or C 1 –C 4 alkaryl;
R 4 is OR 5 , SR 5 , or NR 5 R 6 , wherein R 5 is defined below in relation to R 7 and R 6 is H, C 1 –C 6 alkyl, C 6 –C 12 aryl, C 1 –C 4 alkaryl, COR 9 , CO 2 R 9 , CONHR 9 , CSR 9 , COSR 9 , CSOR 9 , CSNHR 9 , SO 2 R 9 , or SO 2 NHR 9 , wherein R 9 is C 1 –C 6 alkyl, C 6 –C 12 aryl, or C 1 –C 4 alkaryl; and
Y is (CR 11 R 12 ) n NR 7 R 8 , wherein n is 0 or 1, R 7 and R 5 together represent a bond or form a substituted or unsubstituted C 1 –C 4 linkage, R 8 is H, C 1 –C 6 alkyl, C 6 –C 12 aryl, C 1 –C 4 alkaryl, COR 10 , CO 2 R 10 , CONHR 10 , CSR 10 , COSR 10 , CSOR 10 , CSNHR 10 , SO 2 R 10 , or SO 2 NHR 10 , wherein R 10 is C 1 –C 6 alkyl, C 6 –C 12 aryl, or C 1 –C 4 alkaryl, or R 8 does not exist and a double bond is formed between N and an R 5 –R 7 C 1 carbon linkage, each of R 11 and R 12 is, independently, H, C 1 –C 6 alkyl, or C 1 –C 4 alkaryl, or R 12 does not exist and a double bond is formed between N and the carbon bearing R 11 .
2. The compound of claim 1 , wherein
A is H, OH, O—(C 1 –C 6 alkyl), or O—(C 1 –C 4 alkaryl);
W is O, S, or NR 1 , wherein R 1 is H or C 1 –C 6 alkyl;
X is H or COR 2 , wherein R 2 is C 1 –C 6 alkyl, which can be substituted with from 1 to 5 OH groups, or O—(C 3 –C 7 alkyl), which can be substituted with from 1 to 4 OH groups, wherein each alkyl carbon is bound to no more than one oxygen atom;
Z is H, Hal, or OR 3 , wherein R 3 is C 1 –C 6 alkyl or C 1 –C 4 alkaryl;
R 4 is OR 5 , SR 5 , or NR 5 R 6 , wherein R 5 is defined below in relation to R 7 and R 6 is H, C 1 –C 6 alkyl, C 1 –C 4 alkaryl, COR 9 , CO 2 R 9 , CONHR 9 , CSR 9 , COSR 9 , CSOR 9 , CSNHR 9 , SO 2 R 9 , or SO 2 NHR 9 , wherein R 9 is C 1 –C 6 alkyl, C 6 –C 12 aryl, or C 1 –C 4 alkaryl; and
Y is (CR 11 R 12 ) n NR 7 R 8 , wherein n is 0 or 1, R 7 and R 5 together represent a bond or form a substituted or unsubstituted C 1 –C 4 linkage, R 8 is H, C 1 –C 6 alkyl, C 1 –C 4 alkaryl, COR 10 , CO 2 R 10 , CONHR 10 , CSR 10 , COSR 10 , CSOR 10 , CSNHR 10 , SO 2 R 10 , or SO 2 NHR 10 , wherein R 10 is C 1 –C 6 alkyl, C 6 –C 12 aryl, or C 1 –C 4 alkaryl, or R 8 does not exist and a double bond is formed between N and an R 5 –R 7 C 1 carbon linkage, each of R 11 and R 12 is, independently, H, C 1 –C 6 alkyl, or C 1 –C 4 alkaryl, or R 12 does not exist and a double bond is formed between N and the carbon bearing R 11 .
3. The compound of claim 1 , wherein said compound of formula I is selected from the group consisting of:
(a) the compound wherein A is OH, X is COCH 3 , W is O, Z is H, and Y and R 4 together are
(b) the compound wherein A is OH, X is H, W is O, Z is H, and Y and R 4 together are
(c) the compound wherein A is OH, X is COCH 3 , W is O, Z is H, and Y and R 4 together are
(d) the compound wherein A is OH, X is H, W is O, Z is H, and Y and R 4 together are
(e) the compound wherein A is OH, X is COCH 3 , W is O, Z is H, and Y and R 4 together are
(f) the compound wherein A is OH, X is COCH 3 , W is O, Z is H, and Y and R 4 together are
4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and the compound of claim 1 .
5. A method of treating a Gram-positive bacterial infection in an animal, said method comprising administering to said animal the compound of claim 1 in an amount sufficient to treat said infection.
6. The method of claim 5 , wherein said compound is administered orally, topically, intravenously, intramuscularly, or subcutaneously.
7. The method of claim 5 , wherein said animal is a human.
8. The method of claim 5 , wherein said infection is an infection of a Gram-positive coccus.
9. The method of claim 5 , wherein said infection is an infection of N. gonorrhoeae.
10. The method of claim 5 , wherein said infection is an infection of C. difficile.
11. The method of claim 5 , wherein said infection is an infection of C. pneumoniae.
12. The method of claim 5 , wherein said infection is an infection of H. pylori .