The reaction of phthalazino(2,3-b)phthalazine-5,12(7H, 14H)-diones with nitrous acid.

3,4-Dihydrophthalazin-1(2H)-one (I) was oxidized to phthalazin-1(2H)-one (III) with nitrous acid or with ferric chloride . Phthalazino [2,3-b] phthalazine-5,12(7H, 14H)-diones (IV) did not react with ferric chloride but they were oxidized with nitrous acid to 2-[1(2H)-oxo-2-phthalazinyl] methylbenzoic acids (V) and (VI). The formation of (V) or (VI) depends upon the substituents of compounds (IV). Strucutres (V) and (VI) were established by pKa measurements in methylcellosolve and by mass and N.M.R. spectra.     

Synthesis and immunomodulating activity of 5H-thiazolo[2,3-b]quinazolin-3(2H)-one

The synthesis and immunomodulating activity of 5H-thiazolo[2,3-b]quinazoline-3(2H)-one (7) are described. When tested in the Kennedy plaque assay, 7 exerted immunosuppressive activity on IgM production in female C3H mice sensitized with sheep erythrocytes.     

Synthesis and antitumor activity of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones

The synthesis of 3-(5-imidazo]2,1-blthiazolylmethylene)-2-indolinones, analogs of compounds recently published, is described. The EIZ isomerism was studied by means of nuclear Overhauser effect experiments and X-ray crystallography. All the compounds were tested as potential antitumor agents. They were also tested as potential inhibitors of cyclin-dependent kinase 1 (CDK1), in order to determine if the antitumor activity was related to this mechanism of action. The results showed that under certain substitution conditions (5-methoxy group for the indole benzene ring and 2-methyl group for the imidazothiazole system), an interesting antitumor activity was found for some compounds. From the analysis of the antitumor data, 3-1(2,6-dimethylimidazo[2,1-bJ-thiazol-5-yl)methylenel-5-methoxy-2-indolinone was the most active of the whole series.     

Synthesis and antiulcer activity of novel 5-(2-ethenyl substituted)-3(2H)-furanones.

In order to investigate new antiulcer agents, spizofurone 1 (AG-629) was fragmented and reassembled to generate 5-phenyl-2,2-dimethyl-3(2H)-furanone (bullatenone, 2). Because of the antiulcer activity of 2,5-phenyl-substituted 2,2-dimethyl-3(2H)-furanones (3-6) were made and shown to have poor activity. Insertion of an ethenyl link between the furanone and phenyl rings gave 5-(2-phenylethenyl)-2,2-dimethyl-3(2H)- furanone (7). This compound had better activity than 2. Compounds 8-41 were synthesized to evaluate the SAR in 5-(2-ethenyl substituted)-3(2H)-furanones. Electron-withdrawing substituents on the aromatic ring (8, 10, 19, and 20) gave 2-3-fold higher activity. Further increases in the activity were found when the phenyl ring was replaced by heterocyclic nuclei. Compounds that contained a thiophene (29), pyridine (24-26), or quinoline ring (32) had the best activity. Replacement of the methyl group on the furanone ring with a phenyl (34) or p-fluorophenyl (40) substituent in the 2-pyridine series gave compounds with activity that ranked with the best obtained in this study. The best compounds from the above SAR studies were evaluated in the ethanol-necrosis model for duration of cytoprotection action. Compounds 19, 24, and 29, which had the best duration of action, were tested with AG-629 in the acidified aspirin and indomethacin-induced lesion models. Only compound 24 had equivalent activity with AG-629 in both models.     

Synthesis and biological activity of pyrido(2,3-e)-1,4-diazepine and of pyrido(2,3-b)(1,4)diazepine]

The Schmidt reaction on tetrahydro-1,8-naphthyridin-4-ones gave pyrido [2,3-e]-1,4-diazepines and pyrido[2,3-b][1,4]diazepines. The preliminary pharmacological screening of some of these compounds showed no appreciable activity.     

In vitro metabolism of the novel antiinflammatory agent 6-(4'-fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo-[2,1-b]-thiazole

6-(4'-Fluorophenyl)-5-(4'-pyridyl)-2,3-dihydroimidazo-[2,1-b]-thia zole (SK&F 86002) is a dual inhibitor of arachidonic acid metabolism which has therapeutic potential for the treatment of inflammatory diseases. Previous studies in rats, in vivo, demonstrated that SK&F 86002 metabolism proceeds by sequential steps of sulfur and nitrogen oxidation. Therefore, these studies were designed to 1) identify the enzymes (flavin vs. cytochrome P-450-dependent monooxygenases) which were responsible for SK&F 86002 metabolism in vitro in hepatic microsomal suspensions from Sprague-Dawley rats, 2) characterize sex-dependent differences, and 3) quantitate the effect of pretreatment with SK&F 86002. All three steps in the sequential metabolism of SK&F 86002 to the N-oxide sulfone metabolite were quantitated individually. The three oxidation steps appeared to be catalyzed primarily by cytochrome P-450; heat inactivation (used to destroy flavin monooxygenase) had little effect on the metabolism of each compound. Further,N-octylamine failed to stimulate the metabolism of any compound and the cytochrome P-450 inhibitors (SK&F 525-A, metyrapone, and alpha-naphthoflavone) resulted in a marked inhibition of the metabolism of all three substrates. Maximal velocities for metabolism of all three substrates (SK&F 86002, sulfoxide, and sulfone) in microsomes isolated from male rats, were 3- to 5-fold greater than observed in female rats. Furthermore, pretreatment of male rats with SK&F 86002 (60 mg/kg/day for 3 days) resulted in a change in the in vitro metabolism of all three substrates generally characterized by an increase in Vmax and/or a fall in km.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synthesis and pharmacological evaluations of N-(substituted benzoylamino)-5-carbethoxymethyl-1,2,3,6-tetrahydropyridines as potential antiinflammatory agents

In a continuing effort to enhance antiinflammatory activities, a series of 1,2,3,6-tetrahydropyridines, 4-tert butyl (9a), 4-methoxy (9b), 2-fluoro (9c), 3-chloro (9d) and 3,4-dichloro (9e) benzoylamino-5-carbethoxymethyl-1,2,3,6-tetrahydropyridines, were synthesized and evaluated for their antiinflammatory activities. Antiinflammatory activities were screened in animal models employing carrageenan induced paw-edema assay on the male Sprague-Dawley rat. Relative potencies for carrageenan induced paw-edema assay were 1, 0.07, > 0.03, 0.14, 0.4 and 0.12 for indomethacin (IC50 = 3 mg/kg), 9a, 9b, 9c, 9d and 9e, respectively. These novel tetrahydropyridines were assessed for nonsteroidal antiinflammatory drug-mediated inhibition of nitric oxide generation in RAW 264.7 macrophage cell line using Griess' reagent. Relative potencies for inhibition of nitric oxide generation by macrophages stimulated with lipopolysaccharide (1 microgram/ml) were 1, 0.48, 0.44, 0.43, 0.45 and 0.45 for indomethacin (IC50 = 0.434 mM), 9a, 9b, 9c, 9d and 9e, respectively. The results show that novel tetrahydropyridines have moderate antiinflammatory activities and that they inhibit nitric oxide production by inhibiting inducible nitric oxide synthase.     

Synthesis and Pharmacological Activity of 1-Hydroxy-, 1-Amino-, and 1-Hydrazino-Substituted 2,3-Dihydro-1H-pyrazolo[1,2-a]pyridazine-5,8-diones and 2,3-Dihydro-1H-pyrazolo[1,2-b]phthalazine-5,10-diones

Pharmaceutical Chemistry Journal -     

Antiinflammatory activity of a series of substituted 2,3-dihydro-6-hydroxypyrimido[2,1-f]purine-4,8(1H,9H)-diones

A series of substituted analogues based on the novel 2,3-dihydro-6-hydroxypyrimido[2,1-f]purine-4,8(1H,9H)-dione ring system have been synthesized and shown to exhibit antiinflammatory activity in the adjuvant-induced arthritis rat model (AAR). The activity exhibited by the pyrimidopurinediones in this model of chronic inflammation is comparable to that of their previously studied 2-oxo congeners, the 6-hydroxypyrimido[2,1-f]purine-2,4,8-(1H,3H,9H)-triones, the best of which show potency levels approximately equal to that of naproxen. On the basis of its potency in the AAR assay, 9-benzyl-2,3-dihydro-1,3-dimethyl-6-hydroxy-7-(3-methyl-2-butenyl) pyrimido-[2,1-f]purine-4,8(1H,9H)-dione was selected for further evaluation and found to exhibit cyclooxygenase inhibitory activity in the in vitro rat neutrophil model. With respect to side-effect liability, this prenylated derivative has been shown to be devoid of gastric ulcer inducing potential, as well as the ocular toxicity observed previously with the 2-oxo series.     

2-甲基-5-(E)-(邻甲氧基苯亚甲基)环戊酮Mannich碱类化合物的合成及其抗炎活性

目的 设计合成2-甲基-5-（E）-（邻甲氧基苯亚甲基）环戊酮曼尼希碱类化合物，并对其抗炎活性进行初步评价。方法 以N-环戊烯基吗啉、邻甲氧基苯甲醛及多种胺类为原料，经多步反应全成目标化合物，并以二甲苯致小鼠耳肿胀模型测试目标化合物的抗炎活性。结果 共合成8个新化合物，经IR，^1H-NMR和MS确证其结构。其中两个化合物的抗炎活性与阿司匹林相当。结论 羧基a位被烷基取代的环戊酮曼尼希碱仍具有较强的抗炎作用。