Diamineplatinum(II) complex compounds with a hydroxylated 2-phenylindole ring, procedure for their preparation, pharmaceutical compositions containing them, and their use as antitumor agents

Abstract

The title compds. I [R1 = H, OH, C2-6 alkanoyloxy; R2, R5, R6 = H, halo; R3 = H, C1-6 alkyl; R4 = OH, C2-6 alkanoyloxy; Alk = C2-10 alkylene (4 neighboring CH2 can be replaced by 1,4-phenylene); AB = NHCH2CH2NH2, (H2NCH2)2CH, Q (R7 = H, C1-6 alkyl, Ph); X = equiv. physiol. tolerable anion], useful as antitumor agents with good tolerability, were prepd. by reaction of a tetrahaloplatinum (II) acid, a tetrahaloplatinum (II) complex salt with 2 monovalent or 1 divalent cation or a Pt(II) halide with indole compd. II. NaH in DMF was treated with 5-methoxy-2-(4-methoxyphenyl)-3-methylindole, then with Br(CH2)6Br to give 84% 1-(6-bromohexyl)-5-methoxy-2-(4-methoxyphenyl)-3-methylindole which reacted with (H2NCH2)2 in MeOH to give 1-[6-(2-aminoethylamine)hexyl]-5-methoxy-2-(4-methoxyphenyl)-3-methylindole (III). Ether cleavage of III with BBr3 gave 1-(2-aminoethylamino)-6-[5-hydroxy-2-(4-hydroxyphenyl)-3-methylindol-1-yl]hexane which reacted in DMF with K2PtCl4 in 5:2 DMF-H2O with light exclusion to give I [R1 = 5-OH, R2 = R5 = R6 = H, R3 = Me, R4 = 4-OH, Alk = (CH2)6, AB = NHCH2CH2NH2, X = Cl]. I, at 20 mg/kg (mice), reduced tumor wt. by 89%. An injection formulation contained 100 mg III in 10 mg of 1:1 polyethylene glycol 400/0.9% of NaCl.