USE OF MACROCYCLIC BIS(3,3'-INDOLYL)-MALEIMIDE DERIVATIVES FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS TREATING AIDS

摘要

The present invention relates to the use of protein kinase inhibitors of the formula I, their pharmaceutically acceptable salts, esters and prodrugs, for the preparation of a medicament for the inhibition of latent human immunodeficiency virus (HIV) activation. The present invention also provides the use of PKC inhibitors for the preparation of a pharmaceutical composition for inhibiting HIV replication. More particularly, the present invention relates to the use of a selective class of protein kinase inhibitors for the preparation of a pharmaceutical composition for the treatment of HIV infection. In the formula I, W is -O-, -S-, -SO-, -SO2-, -CO- , optionally substituted alkylene, alkenylene, aryl, aryl (CH2) mO, heterocyclic, heterocyclic (CH2) mO, fused bicyclic, (fused bicyclic) - (CH2) mO, -NR3-, -NOR3-, -CONH- or -NHCO-; X and Y are each independently an optionally substituted alkylene, or X, Y and W together form - (CH 2) n -AA-; R 1 is hydrogen or up to 4 optional substituents independently selected from the group consisting of halogen, alkyl, hydroxy, alkoxy, halogenated alkyl, nitro, -NR 4 R 5, and -NHCO-alkyl; R2 is hydrogen, CH3CO-, -NH2 hydroxy; R3 is hydrogen, - (CH2) m-aryl, alkyl, -COO-alkyl, -CONR4R5, - (C = NH) NH2, -SO-alkyl, -SO2 (NR4R5) or -SO2-. alkyl; AA is an amino acid residue; m is independently 0, 1, 2 or 3; and n is independently selected from the group consisting of 2, 3, 4 and 5; and pharmaceutically acceptable salts, prodrugs and esters of the above compounds. Particularly preferred for the above application is the b-isozyme-selective PKC inhibitor compound, (S) -3,4- [N, N'-1,1 '- ((2' '-ethoxy) -3' '' (O) -4 '' - (N, N-dimethylamino) butane-bis (3,3'-indolyl)] - 1 (H) -pyrrole-2,5-dione hydrochloride salt. SHE