Synthesis of thiophenecarboxamides, thieno [3,4-c] pyridin-4(5H)-ones and thieno[3,4-d]pyrimidin-4(3H)-ones and preliminary evaluation as inhibitors of poly(ADP-ribose)polymerase (PARP)

Inhibitors of poly(ADP-ribose)polymerase (PARP) inhibit repair of damaged D NA and thus potentiate radiotherapy and chemotherapy of cancer. Treatment o f 3-cyanothiophene with potassium nitrate and concentrated sulphuric acid g ave 5-nitrothiophene-3-carboxamide. 4-Nitrothiophene-2-carboxamide and 5-ni trothiophene-2-carboxamide were formed similarly from 2-cyanothiophene. Red uction with tin(II) chloride gave the corresponding aminothiophenecarboxami de salts which were isolated via their N-Cbz derivatives. Lithiation of 3,4 -dibromothiophene at -116 degrees C and quenching with alkyl chloroformates gave 4-bromothiophene-3-carboxylates, which were hydrolysed to 4-bromothio phene-3-carboxylic acid. Hurtley reactions with the enolates of pentane-2,4 -dione and of 1-phenylbutane-1,3-dione, followed by acyl cleavage, led to 4 -(2-oxopropyl)thiophene-3-carboxylic acid and 4-phenacylthiophene-3-carboxy lic acid, respectively. Condensation with ammonia in acetic acid gave 6-met hyl- and 6-phenyl-thieno[3,4-c]pyridin-4-ones, which were selectively nitra ted at the 1- and 7-positions or were dinitrated. Ethyl 4-acetamido- and 4- benzamido-thiophene-3-carboxylates were cyclised to 2-methyl- and 2-phenyl- thieno[3,4-d][1,3]oxazin-4-ones, respectively. Ring opening with ammonia an d recyclisation led to 2-substituted thieno[3,4-d]pyrimidin-4-ones. The ami nothiophenecarboxamides are analogues of 3-aminobenzamide, a selective inhi bitor of poly(ADP-ribose)polymerase (PARP); the thienopyridinones and the t hienopyrimidinones are analogues of isoquinolin-1-ones and quinazolin-4-one s, respectively, which inhibit this enzyme. In preliminary assays, several thienopyridinones and thienopyrimidinones showed potent inhibitory activity against PARP. (C) 1999 Published by Elsevier Science Ltd. All rights reser ved.