Hydrolytically-resistant boron-containing therapeutics and methods of use
Compositions and methods of use of borole derivatives, including benzoxaboroles, benzazaboroles and benzthiaboroles, as therapeutic agents for treatment of diseases caused by bacteria or viruses are disclosed, as well as methods for synthesis of said agents and compositions thereof.
1. A compound having the structure of Formula 1
wherein B is boron, M is oxygen
wherein R* is substituted or unsubstituted aryl,
and wherein A is CH or CR 1
and wherein D is CR 2
and wherein E is CH or CR 3
and wherein G is CH or CR 4
and wherein J is (CH 2 ) n (n=1)
and wherein W is (CH 2 ) m (m=0)
wherein R 2 is a member selected from the group consisting of haloalkyl, alkyl, (CH 2 ) p OH (p=1 to 3), halogen, CHO, CH═NOH, CO 2 H, CO 2 -alkyl, S-alkyl, SO 2 -alkyl, S-aryl, (CH 2 ) q NR 18 R 19 (wherein R 18 and R 19 are independently selected from hydrogen, alkyl, and alkanoyl) (q=0 to 2), alkoxy, CF 3 , SCF 3 , NO 2 , SO 3 H, OH, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, fused substituted or unsubstituted aryl, fused substituted or unsubstituted heteroaryl,
R 1 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, haloalkyl, alkyl, (CH 2 ) p OH (p=1 to 3), halogen, CHO, CH═NOH, CO 2 H, CO 2 -alkyl, S-alkyl, SO 2 -alkyl, S-aryl, (CH 2 ) q NR 18 R 19 (wherein R 18 and R 19 are independently selected from hydrogen, alkyl, and alkanoyl) (q=0 to 2), alkoxy, CF 3 , SCF 3 , NO 2 , SO 3 H, OH, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, fused substituted or unsubstituted aryl, fused substituted or unsubstituted heteroaryl, or a salt thereof including pharmaceutically acceptable salts.
2. The compound of claim 1 wherein R* has the structure
wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH 2 ) s OH (where s=1 to 3), CO 2 H, CO 2 alkyl, CONH 2 , CONHalkyl, CON(alkyl) 2 , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO 2 alkyl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 ) t NR 22 R 23 (wherein R 22 and R 23 are independently selected from hydrogen, alkyl, and alkanoyl) (t=0 to 2), SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NHalkyl, OCH 2 CH 2 N(alkyl) 2 , oxazolidin-2-yl, or alkyl substituted oxazolidin-2-yl.
3. A composition comprising a compound of claim 1 in a pharmaceutically acceptable carrier.
4. A method for inhibiting bacterial growth comprising contacting a bacterium with a compound of claim 1 .
5. The method of claim 4 wherein R* has the structure
wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH 2 ) s OH (where s=1 to 3), CO 2 H, CO 2 alkyl, CONH 2 , CONHalkyl, CON(alkyl) 2 , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO 2 alkyl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 ) t NR 22 R 23 (wherein R 22 and R 22 are independently selected from hydrogen, alkyl, and alkanoyl) (t=0 to 2), SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NHalkyl, OCH 2 CH 2 N(alkyl) 2 , oxazolidin-2-yl, or alkyl substituted oxazolidin-2-yl.
6. The method of claim 4 wherein said compound has a structure which is a member selected from
7. The method of claim 4 wherein said contacting occurs in vivo.
8. A method for inhibiting viral multiplication comprising contacting a virus with a compound of claim 1 ; wherein the virus is selected from a group consisting of Yellow Fever and Hepatitis.
9. The method of claim 8 wherein R* has the structure
wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH 2 ) s OH (where s=1 to 3), CO 2 H, CO 2 alkyl, CONH 2 , CONHalkyl, CON(alkyl) 2 , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO 2 alkyl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 )NR 22 R 23 (wherein R 22 and R 23 are independently selected from hydrogen, alkyl, and alkanoyl) (t=0 to 2), SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NHalkyl, OCH 2 CH 2 N(alkyl) 2 , oxazolidin-2-yl, or alkyl substituted oxazolidin-2-yl.
10. The method of claim 8 wherein said compound has a structure which is a member selected from
11. The method of claim 8 wherein said contacting occurs in vivo.
12. A compound having the structure of Formula 1
wherein B is boron, M is oxygen,
wherein R* is substituted or unsubstituted aryl,
and wherein A is CR 1
and wherein D is CH or CR 2
and wherein E is CH or CR 3
and wherein G is CH or CR 4
and wherein J is (CH 2 ) n (n=1) and wherein W is (CH 2 ) m (m=0)
wherein R 1 is a member selected from the group consisting of haloalkyl, alkyl, (CH 2 ) p OH (p=1 to 3), halogen, CHO, CH═NOH, CO 2 H, CO 2 -alkyl, S-alkyl, SO 2 -alkyl, S-aryl, (CH 2 ) q NR 18 R 19 (wherein R 18 and R 19 are independently selected from hydrogen, alkyl, and alkanoyl)(q=0 to 2), alkoxy, CF 3 , SCF 3 , NO 2 , SO 3 H, OH, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, fused substituted or unsubstituted aryl, fused substituted or unsubstituted heteroaryl, R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, haloalkyl, alkyl, (CH 2 ) p OH (p=1 to 3), halogen, CHO, CH═NOH, CO 2 H, CO 2 -alkyl, S-alkyl, SO 2 -alkyl, S-aryl, (CH 2 ) q NR 18 R 19 (wherein R 18 and R 19 are independently selected from hydrogen, alkyl, and alkanoyl)(q=0 to 2), alkoxy, CF 3 , SCF 3 , NO 2 , SO 3 H, OH, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, fused substituted or unsubstituted aryl, fused substituted or unsubstituted heteroaryl,
or a salt thereof including pharmaceutically acceptable salts.
13. The compound of claim 12 wherein R* has the structure:
wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH 2 ) s OH (where s=1 to 3), CO 2 H, CO 2 alkyl, CONH 2 , CONHalkyl, CON(alkyl) 2 , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO 2 alkyl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 ) t NR 22 R 23 (wherein R 22 and R 23 are independently selected from hydrogen, alkyl, and alkanoyl) (t=0 to 2), SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NHalkyl, OCH 2 CH 2 N(alkyl) 2 , oxazolidin-2-yl, or alkyl substituted oxazolidin-2-yl.
14. A compound having the structure of Formula 1
wherein B is boron, M is oxygen,
wherein R* is substituted or unsubstituted aryl,
and wherein A is CH or CR 1
and wherein D is CH or CR 2
and wherein E is CR 3
and wherein G is CH or CR 4
and wherein J is (CH 2 ) n (n=1)
and wherein W is (CH 2 ) m (m=0)
wherein R 3 is a member selected from the group consisting of haloalkyl, alkyl, (CH 2 ) p OH (p=1 to 3), halogen, CHO, CH═NOH, CO 2 H, CO 2 -alkyl, S-alkyl, SO 2 -alkyl, S-aryl, (CH 2 ) q NR 18 R 19 (wherein R 18 and R 19 are independently selected from hydrogen, alkyl, and alkanoyl)(q=0 to 2), alkoxy, CF 3 , SCF 3 , NO 2 , SO 3 H, OH, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, fused substituted or unsubstituted aryl, fused substituted or unsubstituted heteroaryl
R 1 , R 2 and R 4 are each independently selected from the group consisting of hydrogen, haloalkyl, alkyl, (CH 2 ) p OH (p=1 to 3), halogen, CHO, CH═NOH, CO 2 H, CO 2 -alkyl, S-alkyl, SO 2 -alkyl, S-aryl, (CH 2 ) q NR 18 R 19 (wherein R 18 and R 19 are independently selected from hydrogen, alkyl, and alkanoyl)(q=0 to 2), alkoxy, CF 3 , SCF 3 , NO 2 , SO 3 H, OH, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, fused substituted or unsubstituted aryl, fused substituted or unsubstituted heteroaryl, or a salt thereof including pharmaceutically acceptable salts.
15. The compound of claim 14 wherein R* has the structure:
wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH 2 ) s OH (where s=1 to 3), CO 2 H, CO 2 alkyl, CONH 2 , CONHalkyl, CON(alkyl) 2 , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO 2 alkyl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 ) t NR 22 R 23 (wherein R 22 and R 23 are independently selected from hydrogen, alkyl, and alkanoyl) (t=0 to 2), SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NHalkyl, OCH 2 CH 2 N(alkyl) 2 , oxazolidin-2-yl, or alkyl substituted oxazolidin-2-yl.
16. A compound having the structure of Formula 1
wherein B is boron, M is oxygen,
wherein R* is substituted or unsubstituted aryl,
and wherein A is CH or CR 1
and wherein D is CH or CR 2
and wherein E is CH or CR 3
and wherein G is CR 4
and wherein J is (CH 2 ) n (n=1)
and wherein W is (CH 2 ) m (m=0)
wherein R 4 is a member selected from the group consisting of haloalkyl, alkyl, (CH 2 ) p OH (p=1 to 3), halogen, CHO, CH═NOH, CO 2 H, CO 2 -alkyl, S-alkyl, SO 2 -alkyl, S-aryl, (CH 2 ) q NR 18 R 19 (wherein R 18 and R 19 are independently selected from hydrogen, alkyl, and alkanoyl) (q=0 to 2), alkoxy, CF 3 , SCF 3 , NO 2 , SO 3 H, OH, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, fused substituted or unsubstituted aryl, fused substituted or unsubstituted heteroaryl
R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, haloalkyl, alkyl, (CH 2 ) p OH (p=1 to 3), halogen, CHO, CH═NOH, CO 2 H, CO 2 -alkyl, S-alkyl, SO 2 -alkyl, S-aryl, (CH 2 ) q NR 18 R 19 (wherein R 18 and R 19 are independently selected from hydrogen, alkyl, and alkanoyl) (q=0 to 2), alkoxy, CF 3 , SCF 3 , NO 2 , SO 3 H, OH, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, fused substituted or unsubstituted aryl, fused substituted or unsubstituted heteroaryl, or a salt thereof including pharmaceutically acceptable salts.
17. The compound of claim 16 wherein R* has the structure:
wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH 2 ) s OH (where s=1 to 3), CO 2 H, CO 2 alkyl, CONH 2 , CONHalkyl, CON(alkyl) 2 , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO 2 alkyl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 ) t NR 22 R 23 (wherein R 22 and R 23 are independently selected from hydrogen, alkyl, and alkanoyl) (t=0 to 2), SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NHalkyl, OCH 2 CH 2 N(alkyl) 2 , oxazolidin-2-yl, or alkyl substituted oxazolidin-2-yl.
18. The compound of claim 1 wherein R 2 is halogen or alkoxy; and R 1 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen and alkoxy.
19. The compound of claim 2 wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, (CH 2 ) s OH (where s=1), OH, alkoxy, aryloxy, CN, halogen, (CH 2 ) t NR 22 R 23 (wherein R 22 and R 23 are independently selected from hydrogen and alkyl) (t=1).
20. The compound of claim 12 wherein R 1 is halogen or alkoxy; and R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen and alkoxy.
21. The compound of claim 13 wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, (CH 2 ) s OH (where s=1), OH, alkoxy, aryloxy, CN, halogen, (CH 2 )NR 22 R 23 (wherein R 22 and R 23 are independently selected from hydrogen and alkyl) (t=1).
22. A composition comprising a compound of claim 12 in a pharmaceutically acceptable carrier.
23. The compound of claim 14 wherein R 3 is halogen or alkoxy; and R 1 , R 2 and R 4 are each independently selected from the group consisting of hydrogen, halogen and alkoxy.
24. The compound of claim 15 wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, (CH 2 ) s OH (where s=1), OH, alkoxy, aryloxy, CN, halogen, (CH 2 ) t NR 22 R 23 (wherein R 22 and R 23 are independently selected from hydrogen and alkyl) (t=1).
25. A composition comprising a compound of claim 14 in a pharmaceutically acceptable carrier.
26. The compound of claim 16 wherein R 4 is halogen or alkoxy; and R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, halogen and alkoxy.
27. The compound of claim 17 wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, (CH 2 ) s OH (where s=1), OH, alkoxy, aryloxy, CN, halogen, (CH 2 ) t NR 22 R 23 (wherein R 22 and R 23 are independently selected from hydrogen and alkyl) (t=1).
28. A composition comprising a compound of claim 16 in a pharmaceutically acceptable carrier.
29. A method for inhibiting bacterial growth comprising contacting a bacterium with a compound of claim 12 .
30. The method of claim 29 wherein R* has the structure
wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH 2 ) s OH (where s=1 to 3), CO 2 H, CO 2 alkyl, CONH 2 , CONHalkyl, CON(alkyl) 2 , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO 2 alkyl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 ) t NR 22 R 23 (wherein R 22 and R 22 are independently selected from hydrogen, alkyl, and alkanoyl) (t=0 to 2), SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NHalkyl, OCH 2 CH 2 N(alkyl) 2 , oxazolidin-2-yl, or alkyl substituted oxazolidin-2-yl.
31. The method of claim 29 wherein said contacting occurs in vivo.
32. A method for inhibiting viral multiplication comprising contacting a virus with a compound of claim 12 ; wherein the virus is selected from a group consisting of Yellow Fever and Hepatitis.
33. The method of claim 32 wherein R* has the structure
wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH 2 ) s OH (where s=1 to 3), CO 2 H, CO 2 alkyl, CONH 2 , CONHalkyl, CON(alkyl) 2 , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO 2 alkyl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 ) t NR 22 R 23 (wherein R 22 and R 23 are independently selected from hydrogen, alkyl, and alkanoyl) (t=0 to 2), SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NHalkyl, OCH 2 CH 2 N(alkyl) 2 , oxazolidin-2-yl, or alkyl substituted oxazolidin-2-yl.
34. The method of claim 32 wherein said contacting occurs in vivo.
35. A method for inhibiting bacterial growth comprising contacting a bacterium with a compound of claim 14 .
36. The method of claim 35 wherein R* has the structure
wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH 2 ) s OH (where s=1 to 3), CO 2 H, CO 2 alkyl, CONH 2 , CONHalkyl, CON(alkyl) 2 , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO 2 alkyl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 )NR 22 R 23 (wherein R 22 and R 22 are independently selected from hydrogen, alkyl, and alkanoyl) (t=0 to 2), SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NHalkyl, OCH 2 CH 2 N(alkyl) 2 , oxazolidin-2-yl, or alkyl substituted oxazolidin-2-yl.
37. The method of claim 35 wherein said compound has a structure which is a member selected from
38. The method of claim 35 wherein said contacting occurs in vivo.
39. A method for inhibiting viral multiplication comprising contacting a virus with a compound of claim 14 ; wherein the virus is selected from a group consisting of Yellow Fever end Hepatitis.
40. The method of claim 39 wherein R* has the structure
wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH 2 ) s OH (where s=1 to 3), CO 2 H, CO 2 alkyl, CONH 2 , CONHalkyl, CON(alkyl) 2 , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO 2 alkyl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 ) t NR 22 R 23 (wherein R 22 and R 23 are independently selected from hydrogen, alkyl, and alkanoyl) (t=0 to 2), SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NHalkyl, OCH 2 CH 2 N(alkyl) 2 , oxazolidin-2-yl, or alkyl substituted oxazolidin-2-yl.
41. The method of claim 39 wherein said compound has a structure which is a member selected from
42. The method of claim 39 wherein said contacting occurs in vivo.
43. A method for inhibiting bacterial growth comprising contacting a bacterium with a compound of claim 16 .
44. The method of claim 43 wherein R* has the structure
wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH 2 ) s OH (where s=1 to 3), CO 2 H, CO 2 alkyl, CONH 2 , CONHalkyl, CON(alkyl) 2 , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO 2 alkyl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 )NR 22 R 23 (wherein R 22 and R 22 are independently selected from hydrogen, alkyl, and alkanoyl) (t=0 to 2), SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NHalkyl, OCH 2 CH 2 N(alkyl) 2 , oxazolidin-2-yl, or alkyl substituted oxazolidin-2-yl.
45. The method of claim 43 wherein said contacting occurs in vivo.
46. A method for inhibiting viral multiplication comprising contacting a virus with a compound of claim 16 ; wherein the virus is selected from a group consisting of Yellow Fever and Hepatitis.
47. The method of claim 46 wherein R* has the structure
wherein R 10 , R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of hydrogen, alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, (CH 2 ) s OH (where s=1 to 3), CO 2 H, CO 2 alkyl, CONH 2 , CONHalkyl, CON(alkyl) 2 , OH, alkoxy, aryloxy, SH, S-alkyl, S-aryl, SO 2 alkyl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 )NR 22 R 23 (wherein R 22 and R 23 are independently selected from hydrogen, alkyl, and alkanoyl) (t=0 to 2), SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NHalkyl, OCH 2 CH 2 N(alkyl) 2 , oxazolidin-2-yl, or alkyl substituted oxazolidin-2-yl.
48. The method of claim 46 wherein said contacting occurs in vivo.