HIV protease inhibitors, compositions containing the same, their pharmaceutical uses and materials for their synthesis
The present invention concerns processes for preparing compounds of formula (I-H), or a prodrug, pharmaceutically active metabolite, or pharmaceutically active salt or solvate thereof, which are useful as inhibitors of the HIV protease enzyme.
1. A process for preparing a compound of formula (I-H), or a prodrug, or pharmaceutically active salt or solvate thereof,
wherein:
R 1 is a 5- or 6-membered mono-cyclic carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is saturated, partially unsaturated or fully unsaturated and is optionally substituted by at least one substituent chosen from C 1-6 alkyl, hydroxyl, C 1-6 alkylcarbonyloxy, C 6-10 arylcarbonyloxy, and heteroarylcarbonyloxy;
R 2 is C 1-6 alkyl substituted with at least one halogen; and
R 4 , R 5 , R 6 and R 7 are independently chosen from H and C 1 –C 6 alkyl;
comprising:
reacting a compound of formula (II), wherein Y 1 is hydroxyl or a leaving group, with a compound of formula (III), or a salt or solvate thereof,
2. A process according to claim 1 , wherein Y 1 is hydroxyl.
3. A process according to claim 1 , wherein R 1 is phenyl optionally substituted by at least one substituent chosen from C 1-6 alkyl, hydroxyl, C 1-6 alkylcarbonyloxy, C 6-10 arylcarbonyloxy, and heteroarylcarbonyloxy.
4. A process according to claim 3 , wherein in the compound of formula (I-H):
R 2 is C 1-6 alkyl substituted with at least one halogen;
R 4 and R 5 are H; and
R 6 and R 7 are independently chosen from H and C 1 –C 6 alkyl.
5. A process according to claim 4 , wherein in the compound of formula (I-H) R 6 and R 7 are C 1 –C 6 alkyl.
6. A process according to claim 5 , wherein in the compound of formula (I-H) R 6 and R 7 are methyl.
7. A process according to claim 6 , wherein in the compound of formula (I-H) R 2 is C 1-6 alkyl substituted with at least one fluorine.
8. A process according to claim 7 , wherein in the compound of formula (I-H) R 1 is phenyl substituted by at least one substituent chosen from C 1-6 alkyl, hydroxyl, and C 1-6 alkylcarbonyloxy.
9. A process according to claim 8 , wherein in the compound of formula (I-H) R 1 is phenyl substituted by at least one substituent chosen from methyl, hydroxyl, and methycarbonyloxy.
10. A process according to claim 9 , wherein in the compound of formula (I-H) R 2 is —CH 2 CF 3 .
11. A process according to claim 10 , wherein in the compound of formula (I-H) R 1 is phenyl substituted by methyl and methylcarbonyloxy.
12. A process according to claim 11 , wherein the compound of formula (I-H) is:
13. A process according to claim 10 , wherein in the compound of formula (I-H) R 1 is phenyl substituted by methyl and hydroxyl.
14. A process according to claim 13 , wherein the compound of formula (I-H) is:
15. A process for preparing a compound of formula (I-J),
comprising:
reacting a compound of formula (II-A) with a compound of formula (III-A).
16. A process for preparing a compound of formula (I-K),
comprising:
(i) reacting a compound of formula (II-A) with a compound of formula (III-A),
to afford a compound of formula (I-J); and
(ii) deprotecting the compound of formula (I-J).