Biodefenses using triazole-containing macrolides
View Patent ↗Use of macrolide and ketolide antibiotics for the treatment of acute exposure and diseases caused by biodefense pathogens is described.
1. A method for acute-exposure treatment of a patient exposed to one or more organisms selected from the group consisting of Bacillus anthracis and Burkholderia mallei , and combinations thereof; the method comprising the step of administering to the patient an effective amount of one or more compounds of the formula
or pharmaceutically acceptable salt thereof, wherein:
R 10 is hydrogen or acyl;
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 C 0 -C 10 alkylene, C 2 -C 10 alkenylene, or C 2 -C 10 alkynylene; 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;
or a pharmaceutical composition thereof further comprising one or more pharmaceutically acceptable carriers, diluents, or excipients, or a combination thereof.
2. A method for treating a patient with a disease caused at least in part by one or more organisms selected from the group consisting of Bacillus anthracis and Burkholderia mallei , and combinations thereof; the method comprising the step of administering to the patient an effective amount of one or more compounds of the formula
or pharmaceutically acceptable salt thereof, wherein:
R 10 is hydrogen or acyl;
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 C 0 -C 10 alkylene, C 2 -C 10 alkenylene, or C 2 -C 10 alkynylene; 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;
or a pharmaceutical composition thereof further comprising one or more pharmaceutically acceptable carriers, diluents, or excipients, or a combination thereof.
3. The method of claim 1 wherein R 10 is hydrogen.
4. The method of claim 1 wherein A is CH 2.
5. The method of claim 1 wherein B is (CH 2 ) n , where n is an integer from 1-5.
6. The method of claim 1 wherein C is aryl or heteroaryl, each of which is optionally substituted.
7. The method of claim 1 wherein C is 3-aminophenyl or 3-pyridinyl.
8. The method of claim 1 wherein V is C(O).
9. The method of claim 1 wherein W is H or F.
10. The method of claim 1 wherein W is F.
11. The method of claim 1 wherein V is C(O); and W is F.
12. The method of claim 1 wherein A is CH 2 , B is (CH 2 ) n , and n is an integer from 2-4.
13. The method of claim 12 wherein C is 3-aminophenyl.
14. The method of claim 13 wherein V is C(O).
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 compound is of the formula
or a pharmaceutically acceptable salt thereof.
19. The method of claim 1 wherein the compound is of the formula
where HX is a pharmaceutically acceptable salt forming acid.
20. The method of claim 19 wherein HX is selected from the group consisting of hydrochloric acid, tartaric acid, and combinations thereof.
21. The method of claim 1 wherein the compound is of the formula
22. The method of claim 2 wherein the compound is of the formula
or a pharmaceutically acceptable salt thereof.
23. The method of claim 2 wherein the compound is of the formula
where HX is a pharmaceutically acceptable salt forming acid.
24. The method of claim 23 wherein HX is selected from the group consisting of hydrochloric acid, tartaric acid, and combinations thereof.
25. The method of claim 2 wherein the compound is of the formula
26. The method of claim 18 wherein the organism is Bacillus anthracis.
27. The method of claim 22 wherein the organism is Bacillus anthracis.