Phosphonated Rifamycins and uses thereof for the prevention and treatment of bone and joint infections

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

B is a bisphosphonate is selected from the group consisting of:

wherein:

each R* is independently selected from the group consisting of H, lower alkyl, cycloalkyl, aryl and heteroaryl, with the proviso that at least two R* are H;

X is H, OH, NH 2 , or a halo group; and

X 1 are both H, or each is independently selected from the group consisting of H, OH, NH 2 , and a halo group;

L is a cleavable linker for coupling B to A;

m is 1, 2, 3 or 4; and

A is a Rifamycin having a structure represented by the following Formula A1:

wherein:

X is H— or R 1 CO—, wherein R 1 is a substituted or unsubstituted alkyl chain of 1-6 carbons;

each Y is independently selected from the group consisting of H— and RO—, wherein R is H—, R 1 —, or R 1 CO—, ith R 1 defined as above;

 is selected from the group consisting of formulae A2-A10:

wherein

R 2 is H—, a substituted or unsubstituted alkyl chain of 1-10 carbons, or a dialkyl amino group;

R 3 is H— or a substituted or unsubstituted alkyl chain of 1-7 carbons;

R 4 is a hydroxyl group, a sulfhydryl group or a substituted or unsubstituted alkyl chain of 1-3 carbons;

W 1 is oxygen or —NR 2 with R 2 defined as above;

W 2 is a substituted or unsubstituted methylene, comprising

 wherein R 5 and R 6 are independently H— or a substituted or unsubstituted alkyl chain of 1-5 carbons, and Z′ is an oxygen atom, a sulfur atom, a substituted methylene, a carbonyl, —NR 1 or —N(O)R 1 where R 1 is defined as above;

T is a halogen or R 2 , where R 2 is defined as above; and

Z is O, S or NR 3 , where R 3 is defined as above,

wherein at least one of said B-L- is coupled to a nitrogen atom on said Rifamycin A, and wherein each of said B-L- coupled to a nitrogen atom is independently selected from the group consisting of:

wherein:

B represents said bisphophonate;

n is an integer ≦10;

each p is independently 0 or an integer ≦10;

each R L is independently selected from the group consisting of H, ethyl and methyl;

q is 2 or 3;

X is O, —CONR L —, —CO—O—CH 2 —, or —CO—O—; and

R a is C x H y where x is an integer of 0 to 20 and y is an integer of 1 to 2x+1.

2. The compound of claim 1 , wherein R 2 is a dialkyl amino group selected from the group consisting of a substituted piperidine, a substituted morpholine or a substituted piperazine.

3. The compound of claim 1 , wherein said Rifamycin A has a structure represented by the following formula or an antimicrobial derivative thereof:

4. The compound of claim 1 , wherein said Rifamycin A has a structure represented by the following formula or an antimicrobial derivative thereof:

5. The compound of claim 1 , wherein said Rifamycin A has a structure represented by the following formula or an antimicrobial derivative thereof:

6. The compound of claim 1 , wherein said Rifamycin A has a structure represented by the following formula or an antimicrobial derivative thereof:

7. The compound of claim 1 , wherein said Rifamycin A has a structure represented by the following formula or an antimicrobial derivative thereof:

8. The compound of claim 1 , wherein said Rifamycin A is Rifampicin or an antimicrobial derivative thereof.

9. The compound of claim 1 , wherein said Rifamycin A is Rifapentin or an antimicrobial derivative thereof.

10. The compound of claim 1 , wherein said Rifamycin A is Rifabutin or an antimicrobial derivative thereof.

11. The compound of claim 1 , wherein said Rifamycin A is Rifalazil or an antimicrobial derivative thereof.

12. The compound of claim 1 , wherein said Rifamycin A is Rifaximin or an antimicrobial derivative thereof.

13. The compound of claim 1 , wherein said Rifamycin A is Rifandin or an antimicrobial derivative thereof.

14. A compound represented by a formula selected from the group consisting of:

15. A compound represented by Formula (II) or a pharmaceutically acceptable salt thereof:

wherein:

Q 1 is H— or R 1 CO—, wherein R 1 is a substituted or unsubstituted alkyl chain of 1-6 carbons;

each Q 2 is independently selected from the group consisting of H— and RO—, wherein R is H—, R 1 — or R 1 CO—, with R 1 defined as above;

each Q 3 is independently selected from the group consisting of H—;

 is selected from the group consisting of formulae A2-A10:

wherein

R 2 is H—, a substituted or unsubstituted alkyl chain of 1-10 carbons or a dialkyl amino group, wherein when R 2 is a substituted alkyl chain of 1-10 carbons the substituent is L 6 NR 7 —, wherein R 7 is a substituted or unsubstituted alkyl chain of 1-7 carbons;

R 3 is H—, a substituted or unsubstituted alkyl chain of 1-7 carbons or L 7 -;

R 4 is a hydroxyl group, a sulfhydryl group or a substituted or unsubstituted alkyl chain of 1-3 carbons;

W 1 is oxygen or —NR 2 , with R 2 defined as above;

W 2 is a substituted or unsubstituted methylene, comprising

 wherein R 5 and R 6 are independently H— or a substituted or unsubstituted alkyl chain of 1-5 carbons, and Z′ is an oxygen atom, a sulfur atom, a substituted methylene, a carbonyl, —NR 1 or —N(O)R 1 where R 1 is defined as above;

T is a halogen or R 2 , where R 2 is defined as above;

Z is O, S or NR 3 , where R 3 is defined as above;

each L 6 and L 7 is a cleavable linker independently selected from the group consisting of:

wherein:

n is an integer ≦10;

each p is independently 0 or an integer ≦10;

q is 2 or 3;

each R L is independently selected from the group consisting of H, ethyl and methyl;

R a is C x H y where x is an integer of 0 to 20 and y is an integer of 1 to 2x+1; and

X is O, —CONR L —, —CO—O—CH 2 —, or —CO—O—;

B is a phosphonated group selected from the group consisting of:

wherein:

each R* is independently selected from the group consisting of H, lower alkyl, cycloalkyl, aryl and heteroaryl, with the proviso that at least two R* are H;

X is H, OH, NH 2 , or a halo group;

each X 1 is independently selected from the group consisting of H, OH, NH 2 , and a halo group; with the proviso that at least one of L 6 and L 7 is present.

16. The compound of claim 15 , wherein R 2 is a dialkyl amino group selected from the group consisting of a substituted piperidine, a substituted morpholine or a substituted piperazine, and wherein the substituent L 6 NR 7 —, wherein R 7 is a substituted or unsubstituted alkyl chain of 1-7 carbons.

17. A compound represented by the formula:

or a pharmaceutically acceptable salt thereof.

18. A compound represented by the formula:

or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound as defined in any one of claims 1 , 14 - 17 and 18 , and a pharmaceutically acceptable carrier or excipient.

20. A method for treating a bacterial infection in a bone or a joint of a subject, comprising administering to a subject in need of such treating a pharmaceutically effective amount of a pharmaceutical composition according to claim 19 .

21. A method of prophylaxis for a bacterial infection in a subject, comprising administering to a subject in need of such prophylaxis a prophylactically effective amount of a pharmaceutical composition according to claim 19 .

22. The method of claim 21 , wherein said pharmaceutical composition is administered to said subject prior to, during, or after an invasive medical treatment.

23. The method of claim 20 wherein said subject is a human.

24. The method of claim 21 wherein said subject is a human.

25. The method of claim 20 , further comprising administering an antibiotic concurrent with administration of said pharmaceutical composition.

26. The method of claim 25 , wherein said antibiotic is selected from the group consisting of tetracycline, a tetracycline derived antibacterial agent, glycylcycline, a glycylcycline derived antibacterial agent, minocycline, a minocycline derived antibacterial agent, an oxazolidinone antibacterial agent, an aminoglycoside antibacterial agent, a quinolone antibacterial agent, vancomycin, a vancomycin derived antibacterial agent, a teicoplanin, a teicoplanin derived antibacterial agent, eremomycin, an eremomycin derived antibacterial agent, chloroeremomycin, a chloroeremomycin derived antibacterial agent, daptomycin, and a daptomycin derived antibacterial agent.

27. A method for accumulating a Rifamycin in a bone of a subject, comprising administering to a subject a pharmaceutical composition according to claim 19 .

28. A compound of claim 1 , wherein m is 1, 2 or 3.