Synthesis and antiinflammatory activity of 7-methanesulfonylamino-6-phenoxychromones. Antiarthritic effect of the 3-formylamino compound (T-614) in chronic inflammatory disease models.
A group of derivatives of 7-methanesulfonylamino-6-phenoxychromone (1) at the pyrone and phenoxy rings was synthesized starting with 4-chloro-3-nitroanisole and evaluated against acute and chronic inflammations in oral administration in animals. Significant potency in the rat models of carrageenin-induced edema (CPE) and adjuvant-induced arthritis (AA) was realized with 2'-fluoro and 2',4'-difluoro derivatives (9a and 9d), and 3-formylamino derivative (19a) and its 2'-fluoro and 2',4'-difluoro compounds (22a and 22d), displaying AA therapeutic effect of ED40 = 2.5-7.1 mg/kg/d for 7 d and AA prophylactic effect of 53-70% inhibition at the dosage of 3 mg/kg/d for 22 d. To identify a candidate for further pharmacological study, the five compounds were subjected to evaluation of their gastro-ulcerogenic liability, leading to selection of the fluorine-free compound 19a which did not cause acute ulceration at 300 mg/kg in oral administration in rats. Compound 19a (ED40 = 3.6 mg/kg in established AA) possessed good therapeutic efficacy against type II collagen-induced arthritis in DBA/1J mice with doses of 30 and 100 mg/kg, suggesting the development of 19a (designated T-614) as a prospective disease-modifying antirheumatic agent. In addition, a preparative-scale synthetic route to T-614 has been established.
Inaba
T
T
Research Laboratories, Toyama Chemical Co., Ltd., Japan.
Tanaka
K
K
Takeno
R
R
Nagaki
H
H
Yoshida
C
C
Takano
S
S
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D002351:Carrageenan; D002867:Chromones / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002908:Chronic Disease; D003094:Collagen; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D051381:Rats; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001578:Benzopyrans; D002867:Chromones; D013449:Sulfonamides; C077313:T 614; D002351:Carrageenan; D003094:Collagen