Sulfhydryl rifamycins and uses thereof

1. A compound of formula I:

wherein

X 1 represents an oxygen atom or a sulfur atom;

R 1 represents a hydrogen or an acetyl group;

R 2 represents a hydrogen or hydroxyl group; and

R 3 represents a hydrogen atom or a group expressed by the formula:

 wherein each of R 4 and R 5 is, independently, an alkyl group having 1 to 7 carbon atoms, or R 4 and R 5 combine to form a 3–8 membered cyclic system,

or R 3 represents a group expressed by the formula:

 in which g represents an integer between 1 and 3;

or R 3 represents a group expressed by the formula:

 wherein each of R 6 and R 7 is, independently, a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, X 2 represents an oxygen atom, a sulfur atom, a carbonyl group,

or X 2 represents a group expressed by the formula:

 in which each of R 8 and R 9 is, independently, a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms, or R 8 and R 9 , in combination with each other, represent —(CH 2 ) k — in which k represents an integer between 1 and 4;

or X 2 represents a group expressed by the formula:

 in which m represents 0 or 1, R 10 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or —(CH 2 ) n X 3 in which n represents an integer between 1 and 4, and X 3 represents an alkoxy group having 1 to 3 carbon atoms, a vinyl group, an ethynyl group,

or X 2 represents a group expressed by the formula:

2. The compound of claim 1 , wherein said compound is described by formula II.

wherein

R 1 is hydrogen or an acetyl group;

R 2 is hydrogen or a hydroxyl group; and

R 10 is selected from the group consisting of methyl, ethyl, iso-propyl, n-propyl, iso-butyl, (S)-sec-butyl, and (R)-sec-butyl.

3. The compound of claim 1 , wherein said compound is described by the chemical structure:

4. The compound of claim 1 , wherein said compound is described by the chemical structure:

5. The compound of claim 1 , wherein said compound is described by the chemical structure:

6. A method of treating a Gram-positive bacterial infection, said method comprising contacting the Gram-positive bacteria or a site susceptible to Gram-positive bacterial growth with a compound of claim 1 .

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and one or more compounds of formula I:

wherein

X 1 represents an oxygen atom or a sulfur atom;

R 1 represents a hydrogen or an acetyl group;

R 2 represents a hydrogen or hydroxyl group; and

R 3 represents a hydrogen atom or a group expressed by the formula:

 wherein each of R 4 and R 5 is, independently, an alkyl group having 1 to 7 carbon atoms, or R 4 and R 5 combine to form a 3–8 membered cyclic system,

or R 3 represents a group expressed by the formula:

 in which g represents an integer between 1 and 3;

or R 3 represents a group expressed by the formula:

 wherein each of R 6 and R 7 is, independently, a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, X 2 represents an oxygen atom, a sulfur atom, a carbonyl group,

or X 2 represents a group expressed by the formula:

 in which each of R 8 and R 9 is, independently, a hydrogen atom, or an alkyl group having 1 to 3 carbon atoms, or R 8 and R 9 , in combination with each other, represent —(CH 2 ) k — in which k represents an integer between 1 and 4;

or X 2 represents a group expressed by the formula:

 in which m represents 0 or 1, R 10 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or —(CH 2 ) n X 3 in which n represents an integer between 1 and 4, and X 3 represents an alkoxy group having 1 to 3 carbon atoms, a vinyl group, an ethynyl group,

or X 2 represents a group expressed by the formula:

or formula II:

wherein

R 1 is hydrogen or an acetyl group;

R 2 is hydrogen or a hydroxyl group; and

R 10 is selected from the group consisting of methyl, ethyl, iso-propyl, n-propyl, iso-butyl, (S)-sec-butyl, and (R)-sec-butyl.

8. A method of, treating a Gram-positive bacterial infection in an animal, said method comprising administering to the animal a pharmaceutical composition of claim 7 .

9. The method of claim 8 , wherein said Gram-positive bacterium is selected from the group consisting of S. aureus , methicillin-resistant S. aureus , and vancomycin-resistant enterococci.

10. The method of claim 8 , said method further comprising co-administering an effective therapeutic amount of an, antibacterial agent.

11. The method of claim 8 , wherein said animal is a human.

12. A method of synthesizing a sulfhydryl rifamycin compound of formula VII,

wherein

X 1 represents an oxygen atom or a sulfur atom;

R 1 represents a hydrogen or an acetyl group;

R 2 represents a hydrogen or hydroxyl group; and

P 1 represents a sulfhydryl protecting group,

said method comprising reacting rifamycin S with a compound of formula VIII

wherein

Z 1 represents a hydroxyl or sulfhydryl group; and

P 1 represents a sulfhydryl protecting group.

13. The method of claim 12 , wherein P 1 is betacyanoethyl.

14. The method of claim 12 , wherein said compound of formula VIII is further described by formula IX

wherein P 1 is a sulfhydryl protecting group.

15. A method of synthesizing a compound of claim 1 , said method comprising the steps of:

(a) reacting rifamycin S with a compound of formula VIII,

 wherein

Z 1 represents a hydroxyl or sulfhydryl group, and

P 1 represents a sulfhydryl protecting group,

 to form a sulfhydryl rifamycin compound of formula VII,

 wherein

X 1 represents an oxygen atom or a sulfur atom,

R 1 represents a hydrogen or an acetyl group, and

R 2 represents a hydrogen or hydroxyl group, and

(b) reacting the sulfhydryl rifamycin compound of step (a) to synthesize a compound of claim 1 .