THIENO-PYRIMIDINES

摘要

1384161 Thiero[2,3-d]pyrimidines DR KARL THOMAE GmbH 7 April 1972 [10 April 1971] 16211/72 Heading C2C [Also in Division A5] 4 - Amino - 2 - (5 - nitro - 2 - furyl) - thieno- [2,3-d] pyrimidines (I) and the acid addition salts thereof in which R is amino, C 2-4 acylamino optionally substituted by one or two chlorine atoms, straight or branched chain mono-C 1-5 alkylamino, di-C 1-4 alkyl-amino in which the alkyl groups may be the same or different, straight or branched chain mono- or di-hydroxy-C 1-5 alkyl-amino in which the N atom is optionally substituted by C 1-4 alkyl, straight or branched chain di(hydroxy C 1-3 alkyl)amino, C 1-2 alkoxy- C 1-3 alkylamino, amino C 1-3 alkylamino N- acetyl-amino-alkylene-amino in which the alkylene chain contains 1 to 3 C atoms or a piperidino group optionally substituted by hydroxy and R1 and R 2 which may be the same or different are hydrogen, methyl or ethyl are prepared by (1) reacting a compound II in which Z is halogen or a free or substituted mercapto group with an amine R1-H in which R1 is R with the exception of a C 2-4 acylamino group optionally substituted by one or two chlorine atoms (in the presence of a hydrogen halide binding agent when Z is halogen), (2) reacting compound (IV) with a nitrating agent such as preferably nitric acid or a mixture of nitric acid with sulphuric acid or acetic anhydride, (3) reacting compound (V) with a salt of nitrous acid in a polar solvent, (4) reacting compound (VI) with nitric acid or with a salt of nitric acid in the presence of a mineral acid or (5) acylating a compound (I) in which R is amino with an acid chloride or acid anhydride to form compound (I) in which R is C 2-4 acylamino optionally substituted by one or two chlorine atoms. In reactions (2) and (4) in which R contains free hydroxy or amino groups, these groups are protected prior to the reaction by acylation and the protecting groups are removed subsequently by action of an acid. Compound (I) in which R is aminoalkylamino may be prepared by acid hydrolysis of the corresponding compound (I) containing a N-acylaminoalkyleneamine radical. Compounds (II) in which Z is halogen are prepared by reacting 5-nitrofuran-2-imino carboxylic acid esters with 2-amino thiophene-3- carboxylic acid esters and halogenating the resulting 2-(5-nitro-2-furyl)-4-hydroxy-thieno- [2,3-d]pyrimidines with phosphorus oxychloride. Compounds (II) in which Z is a free or substituted mercapto group are prepared by reacting the corresponding 4-halo-thieno[2,3-d]pyrimidine with thiourea and optionally alkylating the resulting compound using a potassium alcoholate. 2 - (2 - Furyl) - 4 - hydroxy - thieno[2,3-d]- pyrimidine, prepared by the above cyclization reaction is halogenated to form the corresponding 4-halo compound which is either reacted (1) with an amine R-H to form compounds (IV) or (2) with bromine in the presence of a hydrogen halide binding agent and subsequently with an amine R-H to form compounds (V). Compounds (VI) are prepared by reaction of 5-carbalkoxyfuran-2-imino carboxylic acid ester with 2- amino thiophene 3-carboxylic acid ester; the resulting compound is halogenated, reacted with an amine R-H and saponified in the presence of an acid. Compounds (I) are active against bacteria, moulds and trichomonads and form with a suitable carrier a pharmaceutical composition which may be administered orally, parenterally, rectally, vaginally or topically. A dragee comprises 4 - (2 - hydroxy - ethylamino) - 2 - (5- vitro - 2 - furyl) thieno[2,3-d]pyrimidine and papaverine.