Synthetic methods for aplidine and new antitumoral derivatives, methods of making and using them

A compound of formula:

• wherein:
• X is independently —C(R)2—, —O—, —S—, or —NR—, in which each R is independently H or an organic group selected from an alkyl group, an alkenyl group, an aryl group, an aralkyl group, and their substituted derivatives substituted with one or more of a heterocyclic group, an alkoxy group, an hydroxy group, a mercapto group, an optionally protected amino group, a guanidino group, or a halogen group;
• Y is CO or —COCHCH3CO—;
• R4 is H or an organic group selected from a group RSO2—, an amido group RCONH— or an acyl group RCO—, an alkyl group, an alkenyl group, an aryl group, an aralkyl group, and substituted derivatives substituted with one or more of a heterocyclic group, an alkoxy group, an hydroxy group, a mercapto group, an optionally protected amino group, a guanidino group, or a halogen group;
• wherein R is H or an organic group selected from an alkyl group, an alkenyl group, an aryl group, an aralkyl group, and their substituted derivatives substituted with one or more of a heterocyclic group, an alkoxy group, an hydroxy group, a mercapto group, an optionally protected amino group, a guanidino group, or a halogen group;
• when Y is CO, then R3 is an organic group selected from an alkyl group, an alkenyl group, an aryl group, an aralkyl group, a group RSO2— or an acyl group RCO—, where R is an alkyl group, an alkenyl group, an aryl group, an aralkyl group, and substituted derivatives substituted with one or more of a mercapto group, an optionally protected amino group, a guanidino group, or a halogen group;
• when Y is —COCHCH3CO—, then R3 is RSO2— where R is alkyl, or R3 is an alkenyl group, an aralkyl group, and substituted derivatives substituted with one or more of a carbonyl group, an hydroxy group, a mercapto group, an optionally protected amino group, a guanidino group, or a halogen group;
• and pharmaceutically acceptable salts thereof.