Purine studies. Part VII. The synthesis of purines as amplifiers of phleomycin against E. coli.

Abstract

Methylaminolysis of 4-chloro-2,6-dimethyl-5-nitropyrimidine and subsequent reduction gave 5-amino-2,5-dimethyl-6-methylaminopyrimidine (4; R = Me), which condensed with orthoesters to give 2,6,9-trimethyl- and 2,6,8,9-tetramethyl-purine (2d and e). Aminolysis or methoxylation of 2-chloro-4-methyl-6-methylamino-5-nitropyrimidine followed by reduction gave 5-amino-2-dimethylamino-(or methoxy-)4-methyl-6-methylaminopyrimidine (4; R = NMe₂ or OMe) which cyclized with appropriate orthoesters to give 2-dimethylamino-(or methoxy-)6,9-dimethylpurine (2f or h) and their 6,8,9-trimethyl homologues (2g and i). 4,5-Diamino-6-methylpyrimidine-2-thione and its 4-N-methyl derivative (6; R¹= Me, R²= NHMe), on treatment with carbon disulphide in pyridine gave 6-methyl- and 6,9-dimethyl-purine-2,8-dithione (5; X = S, R = H or Me), which underwent S-methylation to give the corresponding 2,8-bismethylthiopurines (2j and k); likewise, appropriate pyrimidinethiones with orthoesters gave 8-methyl-, 6,8-dimethyl-, and 6,8,9-trimethyl-purine-2-thione and thence the corresponding S-methyl derivatives (2l– n). Alkylation of 6,9-dimethylpurine-2-thione gave the 2-ethylthio- and 2-[¹⁴C]methylthio-derivatives (2o and a). Administered to mice, the latter thioether reached the urine mainly as the corresponding sulphoxide (2b), identified by unambiguous synthesis from the thioether with m-chloroperoxybenzoic acid; the urine contained neither the isomeric 6,9-dimethyl-2-methylthiopurin-8-one (8), made from the dimethyl-2-thioxopurin-8-one (5; X = O, R = Me), nor 5-amino-4-methyl-6-methylamino-2-methylthiopyrimidine (4; R = SMe), made by alkaline fission of the thioether.

The foregoing and related purines were tested as amplifiers of phleomycin against E. coli. Activities are discussed; ionization constants and u.v. spectra are recorded.