Hydrolytically-resistant boron-containing therapeutics and methods of use
Compositions and methods of use of boron derivatives, including benzoxaboroles, benzazaboroles and benzthiaboroles, as therapeutic agents for treatment of diseases caused by fungi, yeast, bacteria or viruses are disclosed, as well as methods for synthesis of said agents and compositions thereof.
1. A compound of Formula (I)
wherein
B is boron;
q1 is an integer selected from 1 to 3;
M is a member selected from halogen, —OCH 3 , and —CH 2 —O—CH 2 —O—CH 3 ;
R 1 and R 2 are members independently selected from H, OH, NH 2 , SH, CN, NO 2 , OSO 2 OH, OSO 2 NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R* is a member selected from:
with the proviso that when M is F, R* is not a member selected from:
wherein s is an integer selected from 1 and 2;
and with the proviso that when M is Cl, R* is not a member selected from:
wherein s is 1; and
R 3 and R 4 are methyl;
including salts thereof.
2. A compound of Formula (I)
wherein
B is boron;
q1 is an integer selected from 1 to 3;
M is a member selected from halogen, —OCH 3 , and —CH 2 —O—CH 2 —O—CH 3 ;
R 1 and R 2 are members independently selected from H, OH, NH 2 , SH, CN, NO 2 , OSO 2 OH, OSO 2 NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted hetcroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R* is a member selected from
with the proviso that when M is F, R* is not a member selected from:
wherein s is 2;
and with the proviso that when M is Cl, R* is not:
including salts thereof.
3. The compound of claim 1 , wherein M is Cl or F.
4. The compound of claim 2 , wherein M is F, and R* is a member selected from:
5. The compound of claim 4 , wherein R* is a member selected from:
6. A compound of Formula (I)
wherein
B is boron;
q1 is an integer selected from 1 to 3;
M is H,
R 1 and R 2 are members independently selected from H, OH, NH 2 , SH, CN, NO 2 , OSO 2 OH, OSO 2 NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R* is a member selected from:
7. A compound of Formula (I)
wherein
B is boron;
q1 is an integer selected from 1 to 3;
M is H,
R 1 and R 2 are members independently selected from H, OH, NH 2 , SH, CN, NO 2 , OSO 2 OH, OSO 2 NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R* is a member selected from:
8. A compound of Formula (I)
wherein
B is boron;
q1 is an integer selected from 1 to 3;
M is H,
R 1 and R 2 are members independently selected from H, OH, NH 2 , SH, CN, NO 2 , OSO 2 OH, OSO 2 NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R* is a member selected from:
9. A compound of Formula (I)
wherein
B is boron;
q1 is an integer selected from 1 to 3;
M is Cl;
R 1 and R 2 are members independently selected from H, OH, NH 2 , SH, CN, NO 2 , OSO 2 OH, OSO 2 NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; and
R* is a member selected from:
including salts thereof.
10. The compound of claim 9 , wherein R* is a member selected from:
11. A compound of a structure which is a member selected from:
12. A compound of Formula (II)
wherein
B is boron;
q1 is an integer selected from 1 to 3;
M 1 is a member selected from halogen, —CH 2 OH, and —OCH 3 ;
R 1 and R 2 are members independently selected from H, OH, NH 2 , SH, CN, NO 2 , OSO 2 OH, OSO 2 NH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R* is a member selected from substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and substituted or unsubstituted vinyl, wherein said aryl has the structure:
wherein
R 10 , R 11 , R 12 , R 13 and R 14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted oxazolidin-2-yl, (CH 2 ) t OH, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 , OHSH, S-alkyl, S-aryl, SO-alkyl, SO-aryl, SO 2 -alkyl, SO 2 -aryl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 ) u NR 22 R 23 , SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NH-alkyl and OCH 2 CH 2 N(alkyl) 2
wherein
t is a member selected from 1, 2 and 3;
u is a member selected from 0, 1 and 2;
R 22 and R 23 are members independently selected from H, substituted or unsubstituted alkyl, and substituted or unsubstituted alkanoyl; and
with the proviso that when M 1 is F, R* is not a member selected from:
including salts thereof.
13. The compound of claim 12 wherein R* is substituted or unsubstituted arylalkyl.
14. The compound of claim 13 wherein said arylalkyl has the structure:
wherein
R 10 , R 11 , R 12 , R 13 and R 14 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted oxazolidin-2-yl, (CH 2 ) t OH, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 , OH, SH, S-alkyl, S-aryl, SO-alkyl, SO-aryl, SO 2 -alkyl, SO 2 -aryl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 ) u NR 22 R 23 , SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NH-alkyl and OCH 2 CH 2 N(alkyl) 2 ;
wherein
t is an integer selected from 1, 2 and 3;
u is a member selected from 0, 1 and 2;
R 22 and R 23 are members independently selected from H, substituted or unsubstituted alkyl, and substituted or unsubstituted alkanoyl;
R 15 and R 16 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted oxazolidin-2-yl, (CH 2 ) t OH, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 , OH, SH, S-alkyl, S-aryl, SO-alkyl, SO-aryl, SO 2 -alkyl, SO 2 -aryl, SO 3 H, SCF 3 , CN, halogen, CF 3 , NO 2 , (CH 2 ) u NR 22 R 23 , SO 2 NH 2 , OCH 2 CH 2 NH 2 , OCH 2 CH 2 NH-alkyl and OCH 2 CH 2 N(alkyl) 2 ;
w is a member selected from 1 to 6.
15. The compound of claim 12 wherein R* is substituted or unsubstituted heteroaryl.
16. The compound of claim 15 wherein said heteroaryl has a structure which is a member selected from:
wherein
X is a member selected from CH═CH, N═CH, NR 19 , O and S;
wherein
R 19 is a member selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl and substituted or unsubstituted arylalkyl;
Y is a member selected from CH and N; and wherein at least one of X and Y is or includes a heteroatom;
R 17 and R 18 are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, (CH 2 ) v OH, (CH 2 ) w NR 24 R 25 , CO 2 H, CO 2 -alkyl, CONH 2 , S-alkyl, S-aryl, SO-alkyl, SO-aryl, SO 2 -alkyl, SO 2 -aryl, SO 3 H, SCF 3 , CN, halogen, CF 3 and NO 2 ;
wherein
R 24 and R 25 are members independently selected from hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted alkanoyl;
v is a member selected from 1, 2 and 3; and
w is a member selected from 0, 1, 2 and 3.
17. A composition comprising the compound of claim 12 and a pharmaceutically acceptable carrier.
18. The compound of claim 12 , wherein R* is a member selected from:
19. The compound of claim 12 , wherein R* is a member selected from
20. The compound of claim 12 , wherein M 1 is Cl or F, and R* is a member selected from:
21. The compound of claim 12 , wherein M 1 is F, R* is a member selected from:
22. The compound of claim 12 , wherein M 1 is F, R* is a member selected from:
23. A compound of a structure which is a member selected from: