Synthesis and antiinflammatory activity of 7-methanesulfonylamino-6-phenoxychromones. Antiarthritic effect of the 3-formylamino compound (T-614) in chronic inflammatory disease models

• Published in: Chemical & pharmaceutical bulletin Vol. 48; no. 1; pp. 131 - 139
• Main Authors: Inaba, T, Tanaka, K, Takeno, R, Nagaki, H, Yoshida, C, Takano, S
• Format: Journal Article
• Language: English
• Published: TOKYO Pharmaceutical Soc Japan 01.01.2000; Maruzen
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - toxicity; Arthritis, Experimental - drug therapy; Benzopyrans - chemical synthesis; Benzopyrans - pharmacology; Benzopyrans - toxicity; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carrageenan; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Chromones - chemical synthesis; Chromones - pharmacology; Chromones - toxicity; Chronic Disease; Collagen; Edema - chemically induced; Edema - drug therapy; Life Sciences & Biomedicine; Male; Medical sciences; Mice; Mice, Inbred DBA; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; Rats; Rats, Inbred Lew; Rats, Wistar; Science & Technology; Stomach Ulcer - chemically induced; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - pharmacology; Sulfonamides - toxicity; COLLAGEN-INDUCED ARTHRITIS; CGP-28238; methanesulfoanilide; COX-2; RATS; INTERLEUKIN-6; antiarthritic activity; chromone; AGENT; PHARMACOLOGICAL PROPERTIES; NIMESULIDE; PROFILE; T-614; DRUGS; antiinflammatory activity; structure-activity relationship; Rat; Diseases of the osteoarticular system; Chromone derivatives; Inflammatory joint disease; Arthritis; Oxygen heterocycle; Gastroduodenal; Structure activity relation; Bicyclic compound; Ulcer; Adjuvant; Aromatic compound; Antirheumatic agent; Chemical synthesis; Edema; Sulfonamide; Rodentia; Antiinflammatory agent; Oral administration; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Treatment; Mouse; Animal; Carboxamide
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.48.131

A group of derivatives of 7-methanesulfonylamino-6-phenoxychrome (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'-diffuoro compounds (22a and 22d), displaying AA therapeutic effect of ED40 = 2.5-7.1 mg/kg/d for 7 d and AA prophylarrtic 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.