Novel synthesis of [1]-benzothiepino[5,4-b]pyridine-3-carbonitriles and their anti-inflammatory properties.
Reaction of 4-arylmethylene-3,4-dihydro-[1]-benzothiepin-5(2H)-ones 1 with malononitrile in the appropriate alcohol in the presence of sodium afforded the 2-alkoxy-4-aryl-5,6-dihydro-[1]-benzothiepino[5,4-b]pyridine-3-carbonitriles 2 and not the isomeric forms [1]-benzothiepino[4,5-c]pyridine-1-carbonitriles 3 in high regioselective manner. The assumed structure of 2 was inferred through independent synthetic reaction of 3,4-dihydro-[1]-benzothiepin-5(2H)-one (4) with ylidenemalononitriles 5 under the same applied reaction conditions and confirmed by single crystal X-ray diffraction studies. However, reaction of 4 with arylidenecyanothioacetamides 6 in refluxing ethanol in the presence of basic catalyst (piperidine or morpholine) does not afford the expected 4-aryl-3-cyano-5,6-dihydro-[1]-benzothiepino[5,4-b]pyridine-2(1H)-thiones 7 and instead 4-aryl-3,5-dicyano-6-thioxo-2(1H)-pyridinethiolate monohydrates were isolated as piperidinium or morpholinium salts 8. On the other hand, reaction of 6 with cyanothioacetamide in the presence of a sufficient amount of basic catalyst yielded exclusively 2-amino-4-aryl-3,5-dicyano-2-pyridinethiolates as piperidinium or morpholinium salts 9. Meanwhile, 7 were prepared through the reaction of 1 with cyanothioacetamide in refluxing ethanol in the presence of a catalytic amount of piperidine. Anti-inflammatory activity screening of the prepared compounds using in vivo acute carrageenan-induced paw oedema in rats exhibited that all the tested compounds possess considerable activity. In addition, few synthesized derivatives reveal remarkable anti-inflammatory properties (2d, k, l) comparable with indomethacin which was used as a reference standard during the pharmacological activity screening studies.
Girgis
Adel S
AS
Pesticide Chemistry Department, National Research Centre, Dokki, 12622 Cairo, Egypt. girgisas10@yahoo.com
Mishriky
Nawal
N
Ellithey
Mohey
M
Hosni
Hanaa M
HM
Farag
Hanaa
H
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001582:Benzothiepins / Q000737:chemistry*; D002351:Carrageenan / Q000633:toxicity; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005260:Female; D008297:Male; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001582:Benzothiepins; D009570:Nitriles; D011725:Pyridines; C509176:pyridine-3-carbonitrile; D002351:Carrageenan