Bendamustine derivatives and related compounds, and medical use thereof in cancer therapy

A process for preparing a compound of formula IX in the form of a salt,

• wherein R1 is alkyl, aryl or alkylaryl;
• R2 represents alkanediyl, arylene, alkylarylene or arylalkanediyl;
• Y1 and Y2 independently represent oxygen, and wherein the bis(2-chloroethyl)amino group is attached at position 6 of the benzimidazole ring structure, wherein the salt comprises 0.6 to 1.4 mol water relative to 1 mol of the compound,
• the process comprising the steps of:
• preparing a compound of formula V or an acid addition salt thereof
• wherein R1 represents alkyl, aryl or alkylaryl;
• R2 is alkanediyl, arylene, alkylarylene or arylalkanediyl;
• and R3 represents H, alkyl, aryl or alkylaryl;
• Y1 and Y2 independently represent oxygen, wherein the bis(2-chloroethyl)amino group is attached at position 6 of the benzimidazole ring structure, or an acid addition salt thereof,
• in which process a compound of formula II
• wherein R1 is defined as above, and the nitro group is attached to any one of positions 3, 4 and 6 of the aniline moiety,
• when R3, represents alkyl, aryl or alkylaryl, is reacted with a compound of formula III1
• wherein R2, Y1 and Y2 are defined as above, R3′ represents alkyl, aryl or alkylaryl, and R4 is selected from the group consisting of —Y2—H, chloro (—Cl) and —Y2—CY1—R2—CY1—Y2—R3′;
• or when R3 represents H, compound of formula II is reacted with a compound of formula III2 or a compound of formula III3
• wherein R2, Y1 and Y2 are defined as above, and R4′ independently from each other represent —Y2—H or chloro (—Cl), particularly both R4′ represent —Y2—H or one R4′═—Y2—H and the other R4′=chloro (—Cl), and more particularly both R4′═—Y2—H,
• with the proviso that in the case compound of formula III3 in which both R4′=chloro, the chloro group which did not form an amide with the amine compound of formula II is hydrolized in order to convert said chloro group to a hydroxy group (—OH), and
• converting compound of formula V to the compound of formula IX.