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Synthesis and antimalarial effects of 5,6‐dichloro‐2‐[(4‐||4‐(diethylamino)‐i‐methylbutyl] amino||‐6‐methyl‐2‐pyrirnidinyl)amino] benzimidazole and related benzimidazoles and l H ‐imidazo[4,5‐ b ] pyridines
Author(s) -
Werbel Leslie M.,
Curry Ann,
Elslager Edward F.,
Hess Carolyn
Publication year - 1973
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.5570100316
Subject(s) - chemistry , yield (engineering) , amino acid , benzimidazole , pyridine , medicinal chemistry , amine gas treating , pyrimidine , stereochemistry , organic chemistry , biochemistry , materials science , metallurgy
A group of fifty‐five 2‐[(4‐11[(dialkylamino)alkyI]amino11‐6‐methyl‐2‐pyrimidinyl)amino]‐benzimidazoles (VII) was synthesized in 3‐88% yield by the condensation of the requisite 2‐[(2‐benzimidazolyl)amino]‐4‐chloro‐6‐methylpyrimidine (VI) with the appropriate polyamine in ethanol‐hydrochloric acid or neat with excess amine containing potassium iodide. The 2‐[(2‐benzimidazolyl)amino]‐6‐methyl‐4‐pyrirnidinol precursors (V), obtained in 11‐51% yield by cyclization of 2‐(cyanoamino)‐4‐hydroxy‐6‐methylpyrimidine with a suitably substituted o ‐phenylenediamine, were chlorinated with phosphorus oxychloride to give the intermediate 2‐[(2‐benzimidazolyl)amino]‐4‐chloro‐6‐rnethylpyrimidines (VI) (27‐99%). Oxidation of 5,6‐dichloro‐2‐[(4‐11[4‐(diethylamino)‐l‐methylbutyl] amino 11‐6‐methyl‐2‐pyrimidinyl) amino ]benzimidazole ( 29 ) with m ‐chloroperbenzoic acid gave the distal N 4 '‐oxide ( 31 ) (19%). Fusion of 2,3‐uiaminopyridine with 2‐(cyanoamino)‐4‐hydroxy‐6‐methylpyrimidine provided 2‐[(4‐hydroxy‐6‐tnethyl‐2‐pyrimidinyl)amino]‐l H ‐imitlazo[4,5‐ b ]pyrimidine (VIII) (30%), which upon chlori‐nation with phosphorus oxychloride (63%) followed by amination with i N, N ‐diethylethylene‐diamine afforded 2‐(4‐11[2‐(diethylamino)ethyl] amino 11‐6‐methyl‐2‐pyrimidinyl)‐l H ‐imidazo [4,5‐ b ]pyridine (X) (8%). Thirty‐eight of the novel 2‐[(4‐amino‐6‐methyl‐2‐pyrimidinyl)amino]‐benzimidazoles possessed “curative” activity against Plasmodium berghei at single subcutaneous doses ranging from 20.640 mg./kg. Orally, thirty‐one compounds exhibited suppressive activity against P. berghei comparable with or superior to the reference drugs 1‐( p ‐chlorophenyl)‐3‐(4‐11[2‐(diethylarnino)ethyl]amino 11‐6‐methyl‐2‐pyrimidinyl)guanidine (I) and quinine hydrochloride, while twelve of them were 5 to 28 times as potent as I and quinine hydrochloride. Eight compounds also displayed strong suppressive activity against P. gallinaceum in chicks. 5,6‐Dichloro‐2‐[(4‐112‐(diethylamino)ethyl]amino11‐6‐methyl‐2‐pyrimidinyl] benzimidazole (18) showed marked activity against a cycloguanil‐resistant line of P. berghei , and the most promising member of the series, namely 5,6‐dichloro‐2‐[(4‐11[4‐(diethylamino)‐l‐methylbutyl]amino11‐6‐methyl‐2‐pyrimidinyl)amino]benzimidazole ( 29 ) (Q = 28), was designated for preclinical toxico‐logical studies and clinical trial. Structure‐activity relationships are discussed.