| Abstract | 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. |
| Authors | T Inaba, K Tanaka, R Takeno, H Nagaki, C Yoshida, S Takano
(Affiliation: Research Laboratories, Toyama Chemical Co., Ltd., Japan.)
|
| Journal | Chemical & pharmaceutical bulletin
(Chem Pharm Bull (Tokyo))
Vol. 48
Issue 1
Pg. 131-9
(Jan 2000)
ISSN: 0009-2363 JAPAN |
| PMID | 10705489
(Publication Type: Journal Article)
|
| Chemical References |
- Anti-Inflammatory Agents, Non-Steroidal
- Benzopyrans
- Chromones
- Sulfonamides
- T 614
- Carrageenan
- Collagen
|
| Topics |
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
(chemical synthesis, pharmacology, toxicity)
- Arthritis, Experimental
(drug therapy)
- Benzopyrans
(chemical synthesis, pharmacology, toxicity)
- Carrageenan
- Chromones
(chemical synthesis, pharmacology, toxicity)
- Chronic Disease
- Collagen
- Edema
(chemically induced, drug therapy)
- Male
- Mice
- Mice, Inbred DBA
- Rats
- Rats, Inbred Lew
- Rats, Wistar
- Stomach Ulcer
(chemically induced)
- Structure-Activity Relationship
- Sulfonamides
(chemical synthesis, pharmacology, toxicity)
|
