Novel methotrexate (MTX) derivatives bearing dihydro-2H-1,4-benzothiazine or dihydro-2H-1,4-benzoxazine were synthesized and tested for in vitro antiproliferative activities against human synovial cells (hSC) and human peripheral blood mononuclear cells (hPBMC) obtained from patients with rheumatoid arthritis and healthy volunteers, respectively. In vivo antiarthritic activities of these derivatives were also evaluated in a rat adjuvant arthritis model. N-[[4-[(2,4-Diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzothiazin-7-yl]carbonyl]-L-glutamic acid (3c) exhibited more potent antiproliferative activities in hSC and hPBMC than MTX in vitro. Antiproliferative activities of N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzoxazin-7-yl]carbonyl]-L-homoglutamic acid (3b) and N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzothiazin-7-yl]carbonyl]-L-homoglutamic acid (3d) (MX-68) were comparable to that of MTX in these in vitro assays. Compounds 3b,d (MX-68) significantly suppressed progression of the adjuvant arthritis in a dose-dependent manner ranging from 0.5 to 2.5 mg/kg (po). In addition, 3d (MX-68) completely suppressed this progression at the dose of 2.5 mg/kg (po). Importantly, 3d (MX-68) having benzothiazine and homoglutamate, as expected, did not undergo polyglutamation, a process which may be responsible for the associated side effects of MTX. These results suggest that 3d (MX-68) is a potent and safe candidate antirheumatic agent, absent of the side effects of MTX.

A number of 4-substituted 2-[omega-(1-imidazolyl)alkyl]-1(2H)-phthalazinones were synthesized in order to develop agents possessing both thromboxane A2 synthetase inhibitory and bronchodilatory activities. The pharmacological evaluation of these compounds disclosed that they have both activities to various extents. Both activities were slightly dependent on the length of the 2-substituents and largely affected by the nature of the 4-substituents. Compounds bearing phenyl and thienyl groups exhibited relatively high and well-rounded activities. Among these compounds, 12j and 15f were found to be the most effective agents having well-rounded activities in vitro and in vivo. Introduction of a carboxyl group reduced both activities contrary to our expectation. 4-(3-Pyridyl)phthalazinone 18b was of particular interest because of unexpectedly high in vivo activities in spite of an absence of significant in vitro activities.

CP-060 (1), 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3- [3-[N-methyl-N-[2-[3,4-(methylenedioxy)phenoxy]ethyl]amino]propyl]-1,3-thiazolidin-4-one, is a novel type of Ca 2+ antagonist possessing both Ca 2+ overload inhibition and antioxidant activity. The structure-activity relationships for this series of compounds were studied by synthesizing the analogues and evaluating these three kinds of activity. Ca 2+ antagonistic activity was largely determined by the lipophilicity of the phenyl group at the 2-position and the length of the alkyl chains. As for the antioxidant activity, it was demonstrated that the phenolic hydroxyl group is an essential structural element. Compounds with potent activity were evaluated for their effect on the coronary blood flow in vivo. Among these compounds, compound 1 was shown to be the most potent. Furthermore, the enantiomers of 1 were resolved by high-performance liquid chromatography with a chiral column. Compound (-)-1 showed about 10 times higher Ca 2+ antagonistic activity than (+)-1, though both enantiomers had similar potency in Ca 2+ overload inhibition and antioxidant activity. An X-ray crystal structure determination of (-)-1 hydrogen fumarate identified (-)-1 as having S configuration at the 2-position.

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The synthesis and antibacterial activity of new ureidopenicillin derivatives having catechol moieties in the 6-acyl side chain are described. These compounds showed remarkably strong VOL. XXXIX NO. 2 THE JOURNAL OF ANTIBIOTICS 231