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

Chem Pharm Bull (Tokyo). 2000 Jan;48(1):131-9. doi: 10.1248/cpb.48.131.


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.

MeSH terms

  • 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
  • Carrageenan
  • Chromones / chemical synthesis*
  • Chromones / pharmacology
  • Chromones / toxicity
  • Chronic Disease
  • Collagen
  • Edema / chemically induced
  • Edema / drug therapy*
  • Male
  • Mice
  • Mice, Inbred DBA
  • Rats
  • Rats, Inbred Lew
  • Rats, Wistar
  • Stomach Ulcer / chemically induced
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / pharmacology*
  • Sulfonamides / toxicity


  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzopyrans
  • Chromones
  • Sulfonamides
  • T 614
  • Carrageenan
  • Collagen