TUMOUR CHEMOTHERAPY ⅩⅫⅠ.PREPARATION OF SOME 5 (AND 7)-BIS-(β-HALOGENOETHYL)-AMINO-INDOLE-2-CARBOXYLIC ACIDS AND THEIR ETHYL ESTERS OWEN

In the previous paper, 5(and 7)-bis-(β-chloroethyl)-amino-indole-2-carboxylic acids (I_a and I_b) were reported to possess pronounced inhibiting action against Sarcoma-180 and melanoma in mice. Compound I_a has been recommended for clinical trials. Since the cytostatic effect of nitrogen mustard derivatives is usually parallel to the rate of hydrolysis of halogen atoms of bis-(β-chloroethyl)-amino group. Vargha et al.had replaced the chlorine atoms of Degranol (Ⅲ) with the more active bromine atoms, this bromine derivative (Ⅳ) does inhibit the growth of rat and mouse tumours to a greater extent than Ⅲ. In this communication, a series of 5 (and 7)-bis-(β-halogenoethyl)-amino-2-carboxylic acids (I_c-f) and their ethyl esters (Ⅱ_a-f) have been prepared to see whether more potent antitumour agents could be found. Ethyl 5 (and 7)-bis-β-chloro(or bromo)-ethyl-amino-indole-2-carboxylate (Ⅱ_a—d) were readily prepared from ethyl 5 (and 7)-bis-(β-hydroxyethyl)-amino-indole- 2-carboxylate (Ⅶ_a and Ⅶ_b) through chlorination by phosphorus oxychloride or bromination by phosphorus tribromide in the usual way. Ⅱ_a—d were converted to their acids (I_a—d) with hydrochloric acid or hydrobromic acid. 5 (and 7)-bis-(β-iodoethyl)-amino- indole-2-carboxylic acids (I_e and I_f) and their ethyl esters (Ⅱ_e