Thieno-pyrimidines

摘要

Novel thieno[3,2-d]pyrimidines of the formula and their tautomers of the formulae (wherein R1 is hydrogen, halogen, alkyl, aralkyl, hydroxy, which may be alkyl-, alkenyl-, alkoxyalkyl-, mono- or di-alkyl-aminoalkyl-, aryl- or aralkyl-substituted, mercapto, alkyl mercapto or an amino group of the formula -NR5R6 in which R5 is hydrogen, amino, alkyl, hydroxyalkyl, alkoxyalkyl, mono- or di-alkyl-aminoalkyl wherein the dialkylamino group can be replaced by a saturated heterocyclic ring attached through a nitrogen atom, amidino, aryl, aralkyl, cycloalkyl or alkenyl, and R6 is hydrogen, alkyl, alkenyl or hydroxyalkyl, or R5 and R6 form together with the nitrogen atom a saturated heterocyclic ring which may be C1- 10 alkyl or aryl substituted; R2 is halogen, mercapto, alkylmercapto or an amino group of the above formula; R3 and R4 are hydrogen, alkyl, aralkyl or aryl which may be substituted in the aromatic ring by halogen or alkyl of 1 to 10 carbon atoms) and their acid-addition salts and alkali metal salts, are prepared (1) for compounds (I) where R2 is NH2, OH or SH, by reaction of 3-aminothiophene-2-carboxylic acid (hereinafter called VII) or a reactive derivative, e.g. an ester, amide, thioamide or nitrile thereof with a compound R1-CX-NH2 wherein R1 has the above meanings except halogen and X is oxygen or sulphur (the use of urea or thiourea gives products wherein R1 is OH or SH, ammonia being split out); (2) for compounds (I) where R1 is alkyl or aralkyl and R2 is OH, SH or NH2, by reaction of a compound (VII) or a functional derivative thereof with an alkyl or aralkyl nitrile; (3) for compounds (III) where R1 is OH or SH, by reaction of a compound (VII) or a functional derivative, e.g. an ester or amide, thereof with an alkali metal cyanate or thiocyanate or a compound R4NCX, the initially formed urea or thiourea being ring closed, for example with alkali; (4) for compounds (III) where R1 is hydrogen, alkyl, aralkyl or free or substituted amino, reaction of 3-R1CONH-thiophene-2-carboxylic acid or an ester thereof with an amine R4NH2, with subsequent ring-closure of the amide so formed with a dehydrating agent; (5) for the compounds (I), (III) and (IV) where R1 and R2 are not halogen, by reaction of a compound of formulae in which one of A1 and A2 is a halogen, mercapto or alkylmercapto and the other, where present, is a similar group or has one of the other meanings of R1, with compounds R1H or R2H in which R1 and R2 are not hydrogen, halogen, alkyl or aralkyl. Products wherein R1 (or R2) is a free hydroxyl group can be halogenated, halogen compounds can be reacted with alkali metal hydrogen sulphides or thiourea to give mercapto compounds, and these can also be obtained from the hydroxy compounds and phosphorus pentsulphide. Alkylthio compounds can be prepared by alkylation of free mercapto compounds or from the halogen compounds. Tautomers (II), (III) and (IV) can be alkylated and aralkylated on the N atoms. Free hydroxy, amino and mercapto compounds can be substituted by conventional methods. The compounds of the invention, which are stated to have cardiovascular, central-stimulating, diuretic, analgesic, sedative, antirheumatic, antiphlogistic, cytostatic, bacteriostatic and fungistatic properties, may be made up into pharmaceutical compositions, for oral, rectal or parenteral administration, with suitable carriers.