Methods of Making and Using Therapeutically Active Thiophenepyrimidinone Compounds

A method of preparing a compound corresponding to formula (I)

• wherein
• R1 and R2 represent the same or different alkyl, or one is alkyl and the other is H, or
• R1 and R2 together with their binding sites form a cyclic 5-, 6-, 7- or 8-membered ring system,
• which is saturated or contains one or more double bonds between the ring atoms, and
• which ring optionally contains up to two heteroatoms in addition to the nitrogen atom where R1 is attached, the number of N atoms being 0-2 and the number of O or S atoms each being 0-1,
• wherein said ring is optionally substituted with up to three substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl, or arylalkyl, wherein the aryl group is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl, and amido;
• R3 and R4 form together with their binding sites a cyclic 5-, 6-, 7- or 8-membered hydrocarbon ring system, which is saturated or contains one or more double bonds between the carbon atoms, and
• wherein said ring is optionally substituted with up to three substituents independently selected from the group consisting of alkyl, substituted alkyl, aryl or arylalkyl, wherein the aryl group is optionally substituted, alkoxy, aryloxy, acyloxy, arylthio, alkylthio, arylsulfonyl, alkylsulfonyl, hydroxyl, oxo, halogen, amino, oxime, acyl, carboxyl, thiocarboxyl, and amido;
• or a physiologically acceptable salt thereof;
• said method comprising:
• a) oxidizing a compound of formula 2
• or a ring-substituted or ring-modified analogue thereof to give an oxo-substituted compound of formula 3 or an analogue thereof,
• b) optionally further subjecting the oxo-substituted compound obtained in a) to a Vilsmeier reaction to give a carbonylsubstituted compound of formula 4 or an analogue thereof,
• c) optionally replacing the chlorosubstituent in the carbonylsubstituted compound obtained in b) by an alkylthio or an arylthio group by subjecting to an appropriate thiol in the presence of a base to give an arylthio- or alkylthiosubstituted compound of formula 5 or an analogue thereof,
• d) the arylthio- or alkylthiosubstituted compound obtained in c) is optionally further
• i) reduced to a compound of formula 6,
• ii) reacted with NH2OH to give a compound of formula 7,
• Or
• e) the compound obtained in b) is optionally further
• i) reduced so as to replace the carbonyl group with hydroxyalkyl, or
• ii) subjected to an appropriate thiol in the presence of a base and acetone, so as to replace the chloro substituent by a thiol group and to replace the carbonyl group with an oxosubstituted alkenyl.
• or
• f) optionally subjecting the compound obtained in a) to DMF acetal so as to introduce a dimethylaminomethylene substituent in the ring next to the oxo substituent.