thienopyrimidine and dicyanmethane

Thienopyrimidine-based bisphosphonates were identified as a new class of nitrogen-containing bisphosphonate (N-BP) inhibitors of the human farnesyl pyrophosphate synthase (hFPPS). Analogs were prepared via cyclization of 2-(1-(trimethylsilyl)ethylidene)malononitrile to 2-amino-4-(trimethylsilyl)thiophene-3-carbonitrile in the presence of elemental sulfur. Direct ipso-iododesilylation of this intermediate led to selective iodination at Cβ of the sulfur atom in high efficiency. The synthetic protocols developed were used in the parallel synthesis of structurally diverse thieno[2,3-d]pyrimidin-4-amine-based bisphosphonate inhibitors of hFPPS.

Topics: Cyclization; Enzyme Inhibitors; Geranyltranstransferase; Humans; Models, Molecular; Nitriles; Pyrimidines; Structure-Activity Relationship

Treatment of 2-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)ethanal with malononitrile, cyanoacetamide and 2-cyano-N-(4-methoxyphenyl)acetamide, respectively, in the presence of aluminium oxide yielded 2-cyano-4-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)crotonic acid derivatives. Cyclization with sulfur and triethylamine was performed to synthesize the 2-amino-5-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)thiophene-3-carbonic acid derivatives, which were treated with triethyl orthoformate/ammonia and triethyl orthoformate, respectively, to furnish 6-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)thieno[2.3-d]pyrimidine derivatives. Deprotection in two steps afforded 2-amino-5-(1,6-anhydro-3-deoxy-beta-D-altropyranos-3-yl)thiophene-3-carbonitrile and 6-(1,6-anhydro-3-deoxy-beta-D-altropyranos-3-yl)thieno[2.3-d]pyrimidine derivatives, respectively.

Topics: Aluminum Oxide; Carbohydrate Conformation; Carbohydrate Sequence; Glycosides; Molecular Structure; Nitriles; Nucleosides; Pyrimidines; Stereoisomerism; Structure-Activity Relationship; Sulfur