Synthesis and oral hypoglycemic effect of novel thiazine containing trisubstituted benzenesulfonylurea derivatives

A new series of 3-(4-substituted phenyl)-1-(4-(4,6-dimethyl-6H-1,3-thiazin-2-yl)phenylsulfonyl)-1-substituted urea (5a–o) was synthesized by an effectual route via sulfonylcarbamates and explores the novel site for substitution in sulfonylurea as well as the way of thiazine can be prepared. The molecules were established by elemental analysis and spectroscopic viz. IR, ¹H NMR, ¹³C NMR and MS techniques. All the fifteen derivatives were shown very prominent oral hypoglycemic effect at the dose of 40 mg/kg body weight (p.o.) in respect of standard drug glibenclamide and control. The hypoglycemic effect was studied using oral glucose tolerance test in normal and NIDDM in STZ-rat model. The compounds 5a, 5d, 5f, 5i, 5k and 5n were dominant out of fifteen derivatives for blood glucose lowering activity (more than 80%) when comparing with NIDDM control. These derivatives were either containing simply phenyl ring (5a, 5f and 5k) on to the second amine of sulfonylurea (R′ = H) or nitro group at the para position in compound 5d, 5i and 5n (R′ = NO₂) to produce significant oral hypoglycemic effect. Other structural activity relationship is also observed regarding the heteroaromatic and substituted aromatic group at R and R′ position respectively.     

Synthesis and hypoglycemic activity of azolopyrimidine derivatives

Translted from Khimiko-Farmatsevticheskii Zhurnal, Vol. 29, No. 4, pp. 37–38, April, 1995.     

Synthesis and hypoglycemic activity evaluation of rhein amide derivatives

In order to investigate the relationship of the structure and hypoglycemic activity, rhein amide derivatives 2a–2e were synthesized and their hypoglycemic activities were evaluated by glucose consumption in HepG2. Their structures were characterized by ¹H-, ¹³C NMR, IR, mass and elemental analysis. All the compounds exhibited strong hypoglycemic activity in improving glucose consumption in HepG2 cell assays in vitro, which was influenced by the diversity of rhein amide derivatives. The compounds 2a–c, 2f, and 2g bearing heterocyclic ring were proved to be more potentially useful in glucose consumption than dimethyldiguanide. Among all the compounds, compound 2f exhibited the strongest activity on glucose consumption, while compound 2d showed the weakest activity.     

5-羟甲基-2-呋喃甲醛衍生物的合成及降血糖活性评价

目的设计合成5-羟甲基-2-呋喃甲醛（5-HMF）衍生物,并评价其降血糖活性,寻找新型降血糖化合物。方法以5-羟甲基-2-呋喃甲醛为起始原料,分别经缩合、酯化、苄基化、脱苄基等反应合成目标化合物。通过测试目标化合物对葡萄糖促吸收率的影响评价化合物的活性。结果合成了14个未见文献报道的新化合物,其化学结构经。H—NIVlR、MS谱确证。结论生物活性评价结果显示,8个目标化合物（1～7、14）具有良好的降血糖活性,其中,化合物6的降血糖活性最好,其葡萄糖促吸收率为87．45％。     

Synthesis and hypoglycemic activity of S-acyl derivatives of 3-mercaptopicolinic acid.

A series of S-alkanoyl and benzoyl derivatives of 3-mercaptopicolinic acid (3-MPA) was prepared and studied for hypoglycemic activity. Three alkanoyl derivatives (propionyl, pivaloyl, and 1-adamantanecarbonyl, 19-21) were prepared with increasing bulk around the thio ester bond. The benzoyl derivatives contained aromatic substituents chosen from a sigma-pi cluster chart so that the esters prepared had a wide range of electronic and solubility properties. In general, compounds with substituents which increased lipid solubility [p-chlorobenzoyl (4), p-trifluoromethylbenzoyl (6), and pivaloyl (20)] had the greatest potency at a dose of 300 mg/kg. Hydrolysis rates, measured at pH 6 and 8, indicated that in vivo breakdown to 3-MPA probably did not account for the observed hypoglycemic activity of the esters. 4, 6, and 20 were less potent than 3-MPA in comparative dose range studies.     

Pyridine derivatives possessing hypoglycemic and analgesic activity

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 23, No. 9, pp. 1076–1080, September, 1989.     

Synthesis and hypoglycemic activity of N-alkylated hydrazonopropionic acids

A series of N-alkylated 2-hydrazonopropionic acids have been synthesized and evaluated for their hypoglycemic activity. Most of the compounds exhibit a remarkable blood glucose lowering activity in fasted guinea pigs. Some of the structural variables studied were the effects of branching, unsaturation, or substitution on the alkyl side chain and the effect of nuclear substitution on the aralkyl analogues. From these compounds, 2-[[(E)-2-methyl-3-phenyl-2-propenyl]hydrazono]propionic acid (BM 42.304; 42) was selected for further investigation.     

Synthesis and hypoglycemic activity of pyridyl alcohols.

The potent hypoglycemic activity of 3-(3-methyl-2-pyridyl)propan-1-ol (1) prompted us to synthesize and study related structures. Some of the variables studied were the position of the methyl and alcohol side chains, the distance between the heterocyclic ring and the hydroxyl group, the effect of additional nuclear substitution, and the effects of branching and substitution on the alcohol side chain. The compounds were tested in 48-h fasted rats, usually at a dose of 150 mg/kg po. 1, the corresponding propionic acid 12, the acetate and methyl ether of 1 (22 and 23), and the 5-methyl analogue of 1 (29) were of comparable hypoglycemic potency. However, these compounds all caused a concomitant elevation of hepatic triglycerides and/or death in the test animals when observations were continued for 4--24 h.     

Synthesis and hypoglycemic activity evaluation of 7-alkoxyl-rhein

A four-step microwave-assisted procedure was used to synthesize 7-alkoxyl-rhein derivatives 5a–e starting from emodin and 1-bromoalkanes. These compounds exhibited hypoglycemic activity by inhibiting α-glucosaccharase, which were influenced by the aliphatic chain length. Results showed that 5c displayed remarkable activity in vitro and in vivo.     

酪醇衍生物的合成、抑菌及降血糖活性评价

目的探讨酪醇衍生物的抑菌和α-葡萄糖苷酶抑制活性。方法以酪醇为起始原料设计合成一系列酪醇衍生物,考察化合物的体外抑菌活性以及α-葡萄糖苷酶抑制活性。结果与结论合成了10个目标化合物,其结构经1H-NMR、13C-NMR和ESI-MS表征。对20个酪醇衍生物体外抑菌活性研究显示,化合物3i对金黄色葡萄球菌的MIC (minimum inhibitory concentration)和MBC(minimum bactericidal concentration)分别为8和16 mg·L~(-1);对李斯特菌的MIC和MBC分别为8和16 mg·L~(-1);对大肠埃希菌的MIC和MBC分别为32和64 mg·L~(-1);对沙门氏菌的MIC和MBC分别为64和128 mg·L~(-1),接近氯霉素。体外α-葡萄糖苷酶抑制活性研究显示,化合物3t对α-葡萄糖苷酶抑制活性IC50值为42. 6μmol·L~(-1),强于阳性对照,说明化合物3t具有潜在降血糖活性。     

Synthesis and blood glucose lowering activity of some novel benzenesulfonylurea derivatives substituted with 6-aryl-4,5-dihyropyridazin-3(2H)-ones

Five (2a–e) benzenesulfonylurea derivatives bearing pyridazinone were synthesized by refluxing the appropriate 6-aryl-2-(p-sulfamylphenyl)-4,5-dihydropyridazine-3(2H)-one with benzylisocyanate in dry acetone over anhydrous K₂CO₃. These compounds were characterized by elemental analysis and various spectroscopic techniques viz; IR, ¹H NMR, ¹³C NMR, and MS data. These compounds (2a–e) at the dose of 20?mg/kg were tested for blood glucose lowering activity in glucose-fed hyperglycemic normal rats. Compound 2b showed more potent anti-hyperglycemic activity than the standard drug gliclazide. The compound 2b was also tested for its hypoglycemic effect in fasted normal rats. It also showed significant hypoglycemic effect (but less than that of gliclazide).     

Synthesis of some new amidine derivatives as potent hypoglycemic agents

A series of S-arylformamidino-N-(alkyl/arylisothiourea) Cyclicamino dihydrochlorides were synthesised and screened for their hypoglycemic activity in normal as well as alloxanized diabetic rats. Some of the compounds (Id, Ie, Ih-1) showed more than 30% lowering of blood sugar level of Albino rats.