C-3 substituted bicyclooctane based HIV protease inhibitors
C3-functionalized-cyclopentanyltetrahydrofuranyl carbamates that inhibit HIV proteolytic enzymes and processes for preparing the compounds are described. Compositions comprising the disclosed compound and methods of using the compounds and/or compositions for treating patients infected with HIV are also described.
1. A compound having the formula
or a pharmaceutically acceptable salt, isomer, mixture of isomers, crystalline form, non crystalline form, hydrate, or solvate thereof; wherein
X 1 is C(O), S(O), S(O) 2 , HNS(O) 2 , HNC(O), or C(O)NH;
R 1 and R 2 are in each instance independently selected from the group consisting of hydrogen, and a prodrug forming group;
R A represents from 0 to 4 substituents independently selected in each instance from the group consisting of hydroxy, alkyl, heteroalkyl, alkyloxy, heteroalkyloxy, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted; or R A represents from 2 to 4 substituents where two of the substituents are vicinal substituents and taken with the attached carbons form a carbocycle or heterocycle; and the remaining substituents, if present, are independently selected in each instance from the group consisting of alkyl, heteroalkyl, alkyloxy, heteroalkyloxy, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted;
R B represents from 0 to 4 substituents independently selected in each instance from the group consisting of amino, alkyl, heteroalkyl, alkyloxy, heteroalkyloxy, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted; or R B represents from 2 to 4 substituents where two of the substituents are vicinal substituents and taken with the attached carbons form a carbocycle or heterocycle; and the remaining substituents, if present, are independently selected in each instance from the group consisting of alkyl, heteroalkyl, alkyloxy, heteroalkyloxy, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted;
R 3 is alkyl, cycloalkyl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted;
R 4 and R 5 are independently selected in each instance from hydrogen, halogen, oxo, hydroxy, or the group consisting of alkyl, heteroalkyl, alkyloxy, hydroxyalkyl, acyloxy, —OC(C))-amino, acyl, amino, sulfonylamino, acylamino, alkyloxy-C(O)-amino, and alkoxyamino, each of which is optionally substituted, where at least one of R 4 or R 5 is not hydrogen.
2. The compound of claim 1 wherein the compound has the formula
3. The compound of claim 1 wherein the compound has the formula
4. The compound of claim 1 wherein R 4 is alkyl or an oxygen containing substituent.
5. The compound of claims 1 wherein R 5 is alkyl or an oxygen containing substituent.
6. The compound of claim 1 wherein R B is a substituent at the 4-position selected from the group consisting of amino, alkyloxy, and hydroxyalkyl.
7. The compound of claim 1 wherein R B is NH 2 , CH 3 O, or CH 2 OH; X 1 is S(O) 2 ; R 3 is branched alkyl; and R A represents 0 substituents.
8. The compound of claim 4 wherein R 4 is hydroxy or methoxy.
9. The compound of claim 5 wherein R 5 is hydroxy or methoxy.
10. The compound of claim 7 wherein R 3 is iso-butyl.
11. The compound of claim 1 wherein R 5 is amino or methylamino.
12. The compound of claim 1 wherein R 4 is hydrogen.
13. The compound of claim 1 wherein R 5 is selected from the group consisting of hydroxy, alkyloxy, —OC(O)-amino, acylamino, and sulfonylamino.
14. The compound of claim 1 wherein R 5 is hydroxy, methoxy, or acetamido.
15. The compound of claim 1 wherein the compound binds to HIV-1 protease, where the binding includes a direct or indirect interaction between the compound and an Asp29, Asp30, or Gly48 amino acid residues in the protease.
16. A pharmaceutical composition comprising one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more carriers, diluents, or excipients, or a combination thereof.
17. A method for treating HIV in a patient, the method comprising the step of administering to the patient a therapeutically effective amount of one or more compounds of claim 1 .