Methods for inhibiting the transmission of HIV using topically applied substituted 6-benzyl-4-oxopyrimidines
A method for inhibiting sexual transmission of HIV comprising topically applying to the skin or epithelial tissue of a human a composition comprising a non-nucleoside reverse transcriptase inhibitor (“NNRTI”) that is able to inhibit viral replication for periods exceeding 12, 24, or even 36 days, at concentrations below even 10 uM. In one embodiment the NNRTI is a dihydro-alkyloxy-benzyl-oxopyrimidine (DABO).
1 ) A method for inhibiting sexual transmission of HIV comprising topically applying to the skin or epithelial tissue of a human an effective amount of a dihydro-alkyloxy-benzyl-oxopyrimidine of formula (A):
wherein:
X is —O, —CH 2 , —CHK 1 (wherein K 1 is —H, —C 1-4 alkyl, —C 3-6 Cycloalkyl), —S, —NK 2 (wherein K 2 is —H, —C 1-4 alkyl, —C 3-6 cycloalkyl, or a bond when X—R is nitro), -aryl, or -arylalkyl;
R is —H, —C 1-4 alkyl (optionally containing one or more of heteroatoms selected from O, S, and N), —C 3-6 cycloalkyl (optionally containing one or more of heteroatoms selected from O, S, N), -aryl, -arylakl, heterocycle, oxo, thio, or a primary amine;
Y is —H, —C 1-4 alkyl, or —C 3-6 cycloalkyl;
Z is —H, —C 1-4 alkyl, or —C 3-6 cycloalkyl;
R 1 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , aryl), or —SW
(wherein W is —H, —CH 3 , -aryl);
R 2 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl); or —SW
(wherein W is —H, —CH 3 , -aryl);
R 3 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl); or —SW
(wherein W is —H, —CH 3 , -aryl);
R 4 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl); or —SW
(wherein W is —H, —CH 3 , -aryl); and
R 5 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl), or —SW (wherein W is —H, —CH 3 , -aryl).
2 ) The method of claim 1 wherein the composition is applied to the vaginal endothelium, the rectal endothelium, or the male genetalia.
3 ) The method of claim 1 wherein the composition is in the form of a cream, lotion, gel, or foam.
4 ) The method of claim 1 wherein the composition is in the form of an intra-vaginal pill, an intra-rectal pill, or a suppository.
5 ) The method of claim 1 wherein the composition is topically applied by release from an intravaginal device selected from a vaginal ring, a vaginal sponge, a diaphram, or a cervical cap.
6 ) The method of claim 1 wherein the composition is topically applied from the exterior surface of a condom or vaginal applicator.
7 ) The method of claim 1 wherein the composition further comprises a second anti-HIV agent, a viruside effective against viral infections other than HIV, and/or a spermicide.
8 ) The method of claim 1 wherein the composition further comprises a lubricant.
9 ) The method of claim 1 wherein, in formula (A), Y is —C 1-4 alkyl, and Z is —C 1-4 alkyl.
10 ) The method of claim 1 wherein, in formula (A), R 1 and R 5 are halogen.
11 ) The method of claim 1 wherein, in formula (A), Y is methyl, Z is methyl, R 1 and R 5 are fluorine, and R 2 , R 3 , and R 4 are hydrogen.
12 ) The method of claim 1 wherein, in formula (A), —X—R is —N-Me 2 Y is methyl, Z is methyl, R 1 and R 5 are fluorine, and R 2 , R 3 , and R 4 are hydrogen.
13 ) The method of claim 1 wherein, in formula (A), —X—R is —NH-cPe, Y is methyl, Z is methyl, R 1 and R 5 are fluorine, and R 2 , R 3 , and R 4 are hydrogen.
14 ) The method of claim 1 wherein, in formula (A), —X—R is —N═O, Y is methyl, Z is methyl, R 1 and R 5 are fluorine, and R 2 , R 3 , and R 4 are hydrogen.
15 ) The method of claim 1 wherein, in formula (A), —X—R is —S-Me, Y is methyl, Z is methyl, R 1 and R 5 are fluorine, and R 2 , R 3 , and R 4 are hydrogen.
16 ) The method of claim 1 wherein, in formula (A), —X—R is —S-MeSMe, Y is methyl, Z is methyl, R 1 and R 5 are fluorine, and R 2 , R 3 , and R 4 are hydrogen.
17 ) A topical composition in the form of a cream, lotion, gel, or foam, comprising a dihydro-allkyloxy-benzyl-oxopyrmdine of formula (A):
wherein:
X is —O, —CH 2 , —CHK 1 (wherein K 1 is —H, —C 1-4 alkyl, —C 3-6 Cycloalkyl), —S, —NK 2 (wherein K 2 is —H, —C 1-4 alkyl, —C 3-6 cycloalkyl, or a bond when X—R is nitro), -aryl, or -arylalkyl;
R is —H, —C 1-4 alkyl (optionally containing one or more of heteroatoms selected from O, S, and N), —C 3-6 cycloalkyl (optionally containing one or more of heteroatoms selected from O, S, N), -aryl, -arylakl, heterocycle, oxo thio, or a primary amine;
Y is —H, —C 1-4 alkyl, or —C 3-6 cycloalkyl;
Z is —H, —C 1-4 alkyl, or —C 3-6 cycloalkyl;
R 1 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , aryl), or —SW
(wherein W is —H, —CH 3 , -aryl);
R 2 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl); or —SW
(wherein W is —H, —CH 3 , -aryl);
R 3 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl); or —SW
(wherein W is —H, —CH 3 , -aryl);
R 4 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl); or —
(wherein W is —H, CH 3 , -aryl); and
R 5 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl), or —SW (wherein W is —H, —CH 3 , -aryl).
18 ) The composition of claim 17 further comprising a second anti-HIV agent.
19 ) The composition of claim 17 further comprising a viruside effective against viral infections other than HIV.
20 ) The composition of claim 17 further comprising a spermicide.
21 ) The composition of claim 17 further comprising a lubricant.
22 ) A composition in the form of an intra-vaginal or intra-rectal pill or suppository comprising a dihydro-alkyloxy-benzyl-oxopyrimidine of formula (A):
wherein:
X is —O, —CH 2 , —CHK 1 (wherein K 1 is —H, —C 1-4 alkyl, —C 3-6 Cycloalkyl), —S, —NK 2 (wherein K 2 is —H, —C 1-4 alkyl, —C 3-6 cycloalkyl, or a bond when X—R is nitro), -aryl, or -arylalkyl;
R is —H, —C 1-4 alkyl (optionally containing one or more of heteroatoms selected from O, S, and N), —C 3-6 cycloalkyl (optionally containing one or more of heteroatoms selected from O, S, N), -aryl, -arylakl, hetero cycle, oxo, thio, or a primary amine;
Y is —H, —C 1-4 alkyl, or —C 3-6 cycloalkyl;
Z is —H, —C 1-4 alkyl, or —C 3-6 cycloalkyl;
R 1 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , aryl), or —SW
(wherein W is —H, —CH 3 , -aryl);
R 2 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl); or —SW
(wherein W is —H, —CH 3 , -aryl);
R 3 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl); or —SW
(wherein W is —H, —CH 3 , -aryl);
R 4 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl); or —SW
(wherein W is —H, —CH 3 , -ary); and
R 5 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl), or —SW (wherein W is —H, —CH 3 , -aryl).
23 ) The composition of claim 22 further comprising a second anti-HIV agent.
24 ) The composition of claim 22 further comprising a viruside effective against viral infections other than HIV.
25 ) The composition of claim 22 further comprising a spermicide.
26 ) A device for inhibiting the sexual transmission of HIV comprising:
a) a barrier structure for insertion into the vaginal cavity, and
b) a composition comprising a dihydro-alkyloxy-benzyl-oxopyrimidine of formula (A):
wherein:
X is —O, —CH 2 , —CHK 1 (wherein K 1 is —H, —C 1-4 alkyl, —C 3-6 Cycloalkyl), —S, —NK 2 (wherein K 2 is —H, —C 1-4 alkyl, —C 3-6 cycloalkyl, or a bond when X—R is nitro), -aryl, or -arylalkyl;
R is —H, —C 1-4 alkyl (optionally containing one or more of heteroatoms selected from O, S, and N), —C 3-6 cycloalkyl (optionally containing one or more of heteroatoms selected from O, S, N), -aryl, -arylakl, heterocycle, oxo, thio, or a primary amine;
Y is —H, —C 1-4 alkyl, or —C 3-6 cycloalkyl;
Z is —H, —C 1-4 alkyl, or —C 3-6 cycloalkyl;
R 1 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , aryl), or —SW
(wherein W is —H, —CH 3 , -aryl);
R 2 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl); or —
(wherein W is —H, —CH 3 , -aryl);
R 3 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl); or —SW
(wherein W is —H, —CH 3 , -aryl);
R 4 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl); or —SW
(wherein W is —H, —CH 3 , -aryl); and
R 5 is —H, —C 1-4 alkyl, -halogen, —NO 2 , —OW (wherein W is —H, —CH 3 , -aryl), or —SW (wherein W is —H, —CH 3 , -aryl).
27 ) The device of claim 26 wherein the barrier structure is a vaginal sponge, diaphram, cervical cap, or condom.
28 ) The device of claim 26 wherein the composition further comprises a second anti-HIV agent, a viruside effective against viral infections other than HIV, and/or a spermicide.
29 ) A compound of formula (A):
wherein:
a) —X—R is —N-Me 2 , Y is methyl, Z is methyl, R 1 and R 5 are fluorine, and R 2 , R 3 , and R 4 are hydrogen;
b) —X—R is —N═O, Y is methyl, Z is methyl, R 1 and R 5 are fluorine, and R 2 , R 3 , and R 4 are hydrogen; or
c) —X—R is —S-MeSMe, Y is methyl, Z is methyl, R 1 and R 5 are fluorine, and R 2 , R 3 , and R 4 are hydrogen.