Compounds and methods for treating HIV
Inhibitors of HIV-1 protease and compositions containing them are described. Use of the inhibitors and compositions containing them to treat HIV, AIDS, and AIDS-related diseases is described.
1. A compound of the formula (I)
or a pharmaceutically acceptable salt thereof, wherein
A is a group of the formula
wherein (*) indicates the point of attachment; in which R Q is amino or alkylamino, which is optionally substituted; or
a group of the formula
wherein (*) indicates the point of attachment; and wherein
m is an integer selected from 0, 1, 2 or 3;
Y 1 is oxygen and Y 2 is methylene; and R h amino or alkylamino, which is optionally substituted;
Q and W are each oxygen;
R 1 is hydrogen;
X is C(R a R b ) n , where n is 1, 2, or 3, and each of R a and R b is independently selected in each instance from the group consisting of hydrogen, alkyl, and alkoxy;
R 2 is phenyl substituted with one or more methoxy, isopropoxy, hydroxymethyl, methoxymethyl, methoxyethyl, halo or 2-(morpholino)ethoxy groups;
R 3 is hydrogen;
R 4 is alkyl, which is optionally substituted;
Z is S(O) 2 ;
R 5 is 4-aminophenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-hydroxymethylphenyl; 3-amino-4-methoxyphenyl, 3-amino-4-isopropoxyphenyl, 4-amino-3-fluorophenyl, 3-fluoro-4-methoxyphenyl, 3,4-methylenedioxyphenyl, or a group of the formula:
wherein (*) indicates the point of attachment; in which X 5 is O, S or NH; and R Y is (1-4C)alkylthio, (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl or NHR X or NR X R Z and each of R X and R Z is independently methyl, isopropyl, cyclopropyl, isobutyl, tert-butyl, cyclohexyl, 4-piperidinyl 1-cyclopentylpiperidin-4-yl, or the group NR X R Z is optionally substituted pyrrolidino, piperidino or piperazino.
2. The compound or salt of claim 1 wherein the phenyl is substituted with one or more methoxy, hydroxymethyl, fluoro or 2-(morpholino)ethoxy groups.
3. The compound or salt of claim 1 wherein R 4 is isobutyl.
4. The compound or salt of claim 1 wherein X 5 is O or S; and R Y is NHR X ; and R X is isopropyl, cyclopropyl or isobutyl.
5. The compound or salt of claim 1 , wherein
the group A is a group of the formula
wherein a is 0 or 1; and R A amino or NHR B in which R B is alkyl;
R 2 is phenyl substituted with one or more methoxy, isopropoxy, hydroxymethyl, methoxymethyl, methoxyethyl, fluoro or 2-(morpholino)ethoxy groups;
R 4 is isobutyl; and
R 5 is 4-aminophenyl, 4-methoxyphenyl, 4-isopropoxyphenyl, 4-hydroxymethylphenyl; 3-amino-4-methoxyphenyl, 3-amino-4-isopropoxyphenyl, 4-amino-3-fluorophenyl, 3-fluoro-4-methoxyphenyl, 3,4-methylenedioxyphenyl, or a group of the formula
in which X 5 is O, S or NH; and R Y is (1-4C)alkylthio, (1-4C)alkylsulfinyl, (1-4C)alkylsulfonyl or NHR X or NR X R Z and each of R X and R Z is independently isopropyl, cyclopropyl, isobutyl, tert-butyl, cyclohexyl, 4-piperidinyl or 1-cyclopentylpiperidin-4-yl, or the group NR X R Z is optionally substituted pyrrolidino, piperidino or piperazino.
6. The compound or salt of claim 5 wherein R 2 is 3-methoxyphenyl, 4-methoxyphenyl, 3-isopropoxyphenyl, 4-isopropoxyphenyl, 3-hydroxymethylphenyl, 3-methoxymethylphenyl, 4-methoxymethylphenyl, 3-methoxyethylphenyl, 4-methoxyethylphenyl, 3-fluorophenyl, 4-fluorophenyl, 3-[2-(morpholino)ethoxy]phenyl, 4-[2-(morpholino)ethoxy]phenyl.
7. The compound or salt of claim 5 wherein R B is methyl, ethyl or isopropyl.
8. The compound or salt of claim 5 wherein R 5 is
in which X 5 is O or S; and R Y is NHR X or NR X R Z and each of R X and R Z is isopropyl or cyclopropyl or the group NR X R Z is optionally substituted pyrrolidino, piperidino or piperazino.
9. The compound or salt of claim 5 , wherein a is 1.
10. The compound or salt of claim 1 wherein R 5 is
in which X 5 is O or S; and R Y is NHR X ; and R X is isopropyl or cyclopropyl.
11. A pharmaceutical composition comprising one or more compounds of claim 1 and one or more carriers, diluents, or excipients, or a combination thereof.
12. A method for treating a patient in need of relief from an HIV infection, the method comprising the step of administering to a patient in need of relief from the HIV infection a therapeutically effective amount of one or more compounds of claim 1 .
13. A pharmaceutical composition comprising one or more compounds of claim 5 and one or more carriers, diluents, or excipients, or a combination thereof.
14. A method for treating a patient in need of relief from an HIV infection, the method comprising the step of administering to a patient in need of relief from the HIV infection a therapeutically effective amount of one or more compounds of claim 5 .
15. The compound of claim 1 , wherein A is a group of the formula: