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.

No abstract

No abstract

The synthesis and in vitro antibacterial and 13-lactamase inhibitory activity of the 2-azetidinone-l-oxysulfonic acids having a substituent at C-4 position of the p-lactam ring are described. The influence of C-4 substituents on the antibacterial activity was examined for the compounds having a-ureidoacetyl or a-oxyiminoacetyl group as acyl side chain at C-3 position. The antibacterial activity is correlated with the C-4 substituents and acyl side chain. Especially, 4(R)-methyl substituted derivatives exhibited excellent activity against Gram-negative bacteria and 4-dimethyl substituted derivatives exhibited strong activity against resistant Gram-negative bacteria except for Pseudomonas aeruginosa. 39 and 40 showed strong inhibitory activity against cephalosporinase of Enterobacter cloacae H-27.Since the discovery of monocyclic j3-lactam antibiotics represented by nocardicinl' and sulfazecin2,3) and monobactam4,5), many of their derivatives have been reported. As a general characteristic of them, they showed strong activity against Gram-negative bacteria and excellent stability against j3-lactamase. However, they showed weak activity against Gram-positive bacteria. To overcome this insufficiency, various chemical modifications have been tried at N-i, C-3 and C-4 position of (3-lactam. SYKES et al.6,7), and we have independently reported the synthesis and antibacterial activity of the title compounds in a patent literature' . In this paper, we report the chemical modification at C-3 and C-4 position, and the interesting results of antibacterial activity and 3-lactamase inhibitory activity as well. ChemistryOur objective compounds, 3-acylamino-2-azetidinone-l-oxysulfonic acids (12,, were synthesized by the route shown in Schemes 1 and 2. A general synthetic method of f3-lactam from f3-hydroxyl amino acid through cyclization has already been established by MILLER et We modified the method and applied it to the synthesis of 3-tert-butoxycarbonyl-i-hydroxy-2-azetidinones (4).Mixed anhydride of N-Boc-(3-hydroxyamino acids (1) coupled with ethylchloroformate was reacted with O-benzylhydroxylamine to give hydroxamates (2) in good yield. Then, the hydroxamates were cyclized with carbon tetrachloride (CC14)-triphenylphosphine (Ph3P) to give 3-lactams (3). Since optically inactive amino acids were used as starting materials, the obtained /3-lactams (3e ti 3i) were a mixture of two diastereomers. Cis form (3e, 3g, 3j) and traps form (3f, 3h, 3i) were easily isolated by recrystallization or column chromatography on silica gel. However, the cis isomer represented by 3j was not formed in this cyclization reaction. 1-Hydroxy-2-azetidinones (4) were quantitatively ob-

The relationship between structure and antibacterial activity among monocyclic i3-lactams having a pyridyl, pyrimidinyl, thiazolyl, imidazolyl, or a tetrazolyl group at N-1 position was investigated. N-(Tetrazol-5-yl)azetidin-2-ones were found to posses excellent activity.