MULTI-DRUG RESISTANCE FREE ISOQUINOLINE DERIVATIVES AND PREPARATION METHOD THEREOF

摘要

PURPOSE: Provided are novel multi-drug resistance free isoquinoline derivatives represented by the formula(XI), their pharmaceutically acceptable salts and compositions containing them. They suppress the activity of P-glycoprotein to decrease multi-drug resistance of a cancer cell. CONSTITUTION: The over-all synthesis comprises the steps of: obtaining a compound of the formula(II) by reacting a compound of the formula(I) with hydrazine; alkylating the compound of the formula(II) to obtain a substituted pyridazinone compound of the formula(III); methoxylating the compound of the formula(III) to get a substituted pyridazinone compound of the formula(IV); obtaining a hydroxypyridazinone compound of the formula(V) by hydrolyzing the compound of the formula(V); making an N-substituted amide compound of the formula(VIII) by reacting amine of the formula(VI) with a compound of the formula(VII); getting a cyclic oxazine compound of the formula(IX) by reacting the compound of the formula(V) and the compound of the formula(VIII); reducing the compound of the formula(IX) to obtain the compound of a formula(X) and reacting the compound of the formula(X) with Louis acid in Pictet-cyclization reaction to get a compound of the formula(XI). In the chemical formula(IX), R is methyl, ethyl, propyl, butyl, THP unsubstituted hydrocarbons such as vinyl, allyl, crotyl; substituted C1-100 unsaturated hydrocarbons with double and triple bonds; aryl containing aromatic rings, heterocyclic R1 is methyl, ethyl, phenyl and halogen.