Methods for treating resistant diseases using triazole containing macrolides
View Patent ↗Triazole-containing macrolide and ketolide antibiotics, therapeutic compositions containing them and methods of use for treating diseases caused by one or more resistant organisms are described.
1. A method for inhibiting the growth of bacteria in a host animal, having the bacteria that is resistant to one or more penicillins, cephalosporins, quinolones, macrolides, vancomycin, or a combination thereof, the method comprising the step of administering to the host animal an effective amount of a compound of the formula
or pharmaceutically acceptable salt thereof, wherein:
R 10 is hydrogen or acyl;
X is H; and Y is OR 7 ; where R 7 is monosaccharide, disaccharide, alkyl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted, or acyl or C(O)NR 8 R 9 ; where R 8 and R 9 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, heteroalkyl, alkoxy, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted, and dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; or X and Y are taken together with the attached carbon to form carbonyl;
V is C(O), C(═NR 11 ), CH(NR 12 ,R 13 ), or N(R 14 )CH 2 ; where N(R 14 ) is attached to the C-10 carbon; where R 11 is hydroxy or alkoxy; R 12 and R 13 are each independently selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, heteroalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, each of which is optionally substituted, and dimethylaminoalkyl, acyl, sulfonyl, ureido, and carbamoyl; R 14 is hydrogen, hydroxy, alkyl, alkoxy, heteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted, or dimethylaminoalkyl, acyl, sulfonyl, ureido, or carbamoyl;
W is H, F, Cl, Br, I, or OH;
A is CH 2 , C(O), C(O)O, C(O)NH, S(O) 2 , S(O) 2 NH, or C(O)NHS(O) 2 ;
B is (CH 2 ) n where n is an integer from 0 to 10; or an unsaturated carbon chain of 2 to 10 carbons; and
C is hydrogen, hydroxy, alkyl, alkoxy, heteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted, or acyl, acyloxy, sulfonyl, ureido, or carbamoyl, where C is other than 2-pyridinyl;
or an antibacterial composition thereof further comprising one or more pharmaceutically acceptable carriers, excipients, or diluents therefor, or a combination thereof.
2. A method for killing one or more bacteria in a host animal, having at least one of the bacteria that is resistant to one or more penicillins, cephalosporins, quinolones, macrolides, vancomycin, or a combination thereof, the method comprising the step of administering to the host animal an effective amount of the compound recited in claim 1 , or an antibacterial composition thereof further comprising one or more pharmaceutically acceptable carriers, excipients, or diluents therefor, or a combination thereof.
3. The method of claim 1 wherein R 10 is hydrogen.
4. The method of claim 1 wherein C is aryl or heteroaryl, each of which is optionally substituted.
5. The method of claim 1 wherein C is 3-aminophenyl or 3-pyridinyl.
6. The method of claim 1 wherein V is C(O).
7. The method of claim 1 wherein W is H or F.
8. The method of claim 1 wherein W is F.
9. The method of claim 1 wherein X and Y are taken together with the attached carbon to form carbonyl.
10. The method of claim 1 wherein V is C(O); X and Y are taken together with the attached carbon to form carbonyl; and W is F.
11. The method of claim 1 wherein A is CH 2 , B is (CH 2 ) n , and n is an integer from 2-4.
12. The method of claim 11 wherein C is 3-aminophenyl.
13. The method of claim 12 wherein V is C(O).
14. The method of claim 13 wherein X and Y are taken together with the attached carbon to form carbonyl.
15. The method of claim 14 wherein W is F.
16. The method of claim 15 wherein n is 3.
17. The method of claim 16 wherein R 10 is hydrogen.
18. The method of claim 1 wherein the organism is a MRSA, VRSA, Macrolide-Lincosamide-Streptogramin B (MLS B ) resistant organism, MDR pneumococcus, S. pneumoniae serotype 19A, erythromycin resistant S. pyogenes , erythromycin resistant staphylococci, or S. pneumoniae with at least one erm(B), erm(A), mef(A), mef(E), mef(I), erm(B)+mef(A), L4, or 23S ribosomal protein mutation, or a combination thereof.
19. The method of claim 1 wherein the organism is a S. pneumoniae with at least one erm(B), erm(A), mef(A), mef(E), mef(I), erm(B)+mef(A), L4, or 23S ribosomal protein mutation, or a combination thereof.
20. The method of claim 1 wherein the organism is macrolide or ketolide resistant.
21. The method of claim 1 wherein the organism is a Neisseria gonorrhoeae, Mycoplasma, Ureaplasma, Legionella pneumophila, Moraxella catarrhalis, Enterococcus faecalis , or Chlamydia , or a combination thereof.
22. The method of claim 1 wherein the therapeutically effective amount is bactericidal to at least one of S. aureus, S. epidermidis, S. pneumoniae, S. pyogenes , and S. mitis.
23. The method of claim 1 wherein the MBC/MIC ratio is about 16 or less.
24. The method of claim 1 wherein C is substituted aryl.
25. The method of claim 1 wherein the compound recited in claim 1 is of the formula
26. The method of claim 1 wherein the compound recited in claim 1 is of the formula
where HX is a pharmaceutically acceptable salt forming acid.
27. The method of claim 26 wherein HX is selected from the group consisting of hydrochloric acid, tartaric acid, and combinations thereof.
28. The method of claim 17 wherein the host animal is a human.
29. The method of claim 17 wherein the bacteria is resistant to one or more penicillins, quinolones, tetracyclines, clindamycin, trimethoprim, sulfamethoxazole, or a combination thereof.
30. The method of claim 17 wherein the bacteria is resistant to one or more macrolides selected from the group consisting of clarithromycin, azithromycin, and telithromycin.