TUMOUR CHEMOTHERAPY ⅩⅩⅧ.SYNTHESIS OF SOME N,N'-BISSUBSTITUTED PIPERAZINE CARBOXYLIC ACID DERIVATIVES

In veiw of the facts that HN₂(Ⅰ) can be selfcondensed to form piperazine derivative (Ⅱ) by chemical means and N,N'-bis(2-chloroethyl)amine (Ⅲ) to N,N'-bis(2-chloroethyl) piperazine (Ⅳ), the latter, though with two chloroethyl groups attached to different nitrogen atoms, still possesses inhibitory action towards the growth of sarcoma M45. Recently, some piperazine derivatives (Ⅴ) were reported to possess inhibitory action against many experimental tumours, and have been subjected to clinical trials. In this investigation, the authors utilized piperazine carboxylic acid, in view of its amphoteric nature, as the carrier of some antitumour groupings, hoping that the com- pounds thus obtained might possess more favourable antitumour activities and lower toxicities. The synthesis of ten N,N'-bissubstituted piperazine carboxylic acids and thir- teen related esters were described. N,N'-bis(benzenesulphonyl or tosyl) ethylenediamine condensed with methyl 2,3- dibromopropionate in the presence of sodium carbonate or triethylamine in methanol to give methyl N,N'-bis(benzenesulphonyl or tosyl)piperazine carboxylate (Ⅷ₂ or Ⅷ_e) in high yields. The latter was treated with the following procedure: (1) By heating with concentrated hydrochloric acid in a sealed tube to give piperazine carboxylic acid dihydrochloride (VI·2HCl), which was then reacted with an appropriate acid chloride by employing the Schotten-Baumann reaction to give compounds Ⅶ_a-b,f-h. Ⅶ_f-hwere then converted to methyl or ethyl esters (Ⅷ_1-m) by using diazomethane or diazoethane. Compound Ⅵ dihydrochloride was treated with ion exchange resin (Zerolite E) to afford Ⅵ, which was then formylated with formic acetic anhydride to give N,N'-bis(formyl) piperazine carboxylic acid Ⅶ_e. (2) By heating with a mixture of hydrochloric acid and glacial acetic acid or 10% potassium hydroxide solution to give N,N'-bis(benzenesul- phonyl or tosyl)piperazine carboxylic acid (Ⅶ_i or Ⅶ_j), which was first converted to acid chloride (X₂ Or X_b) by thionyl chloride and then treated with suitable alcohol, to afford the corresponding esters of N,N'-bis(benzenesulphonyl or tosyl)piperazine carboxy- lic acid (Ⅷ_b-d,f-h). (3) By treating with 37% hydrogen bromide in glacial acetic acid to give methyl piperazine carboxylate dihydrobromide (Ⅺ), which can also be con- verted to compound Ⅷ_i by employing the Schotten-Baumann reaction. Among these compounds, only Ⅷ_j showed a moderate inhibition against HeLa cell in vitro. The animal test is in progress. An unsuccessful attempt was made to prepare N,N'-bis(2-chloroethyl)piperazine car- boxylic acid (Ⅻ).