Synthesis of 3-aminorhodanine derivatives as aldose reductase inhibitors

A number of 5-condensated 3-acylaminorhodanines 3 was prepared as potential inhibitors of the aldose reductase by acylation of the amino group of 3-aminorhodanine 1 and subsequent condensation of the 5-methylene function with appropriate aldehydes. Some of these compounds displayed interesting activity.     

Studies on aldose reductase inhibitors from natural products. IV. Constituents and aldose reductase inhibitory effect of Chrysanthemum morifolium, Bixa orellana and Ipomoea batatas.

The hot water extracts of Chrysanthemum morifolium, Bixa orellana and Ipomoea batatas, were found to have potent inhibitory activity towards lens aldose reductase (AR). Ellagic acid (4) was isolated from C. morifolium and I. batatas, isoscutellarein (7) from B. orellana and 3,5-dicaffeoylquinic acid (10) from I. batatas, respectively, as potent inhibitors.     

Preparation of fused 1,3-oxazine-2,4-diones as potential antitumor agents

A series of indole, thiophene and pyrrole-fused 1,3-oxazine-2,4-diones, 2-methyl-1,3-oxazin-4-ones and 2-dimethylamino-1,3-oxazin-4-ones were synthesized and evaluated as antitumor agents.     

Studies on antidiabetic agents. IX. A new aldose reductase inhibitor, AD-5467, and related 1,4-benzoxazine and 1,4-benzothiazine derivatives: synthesis and biological activity

N-Acetic acid derivatives (I) of 2-substituted 1,4-benzoxazines and benzothiazines were designed and synthesized for evaluation as new aldose reductase inhibitors. In general, 3-thioxo derivatives were more potent inhibitors of aldose reductase from human palcenta in vitro than the corresponding 3-oxo derivatives. While many compounds (I) were not very effective in inhibiting sorbitol accumulation in the rat sciatic nerve in vivo, the 3-thioxo compounds bearing an isopropyl group at the 2-position showed highly potent activity in the in vivo assay. Compound 46 (AD-5467) was selected from this series as a candidate for further development.     

CoMFA and docking studies on glycogen phosphorylase a inhibitors as antidiabetic agents

Glycogen phosphorylase (GP(a)) is a specific target for the design of inhibitors and may prevent glycogenolysis under high glucose conditions in type II diabetes. The carboxamides first reported by Hoover D. J. et al. (J. Med. Chem. 1998, 41, 2934-2938) are one of the major classes of GP(a) inhibitors other than glucose derivatives. The recent, X-ray crystallographic analyses (Oikonomakos et al. Biochim. Biophys. Acta 2003, 1647, 325-332) have revealed a distinct mechanism of action for these inhibitors, which bind at a new allosteric site away from the inhibitory and catalytic sites. To elucidate the essential structural and physicochemical requirements responsible for binding to the GP(a) enzyme and to develop predictive models, CoMFA and docking studies have been carried out on a series of indole-2-carboxamide derivates. The CoMFA model developed using pharmacophoric alignments and hydrogen-bonding fields demonstrated high predictive ability against the training (r2 = 0.98, q2 = 0.68) and the test set (r2pred = 0.85). Further the superimposition of PLS coefficient contour maps from CoMFA with the GP(a) active site (PDB: 1lwo) has shown a high level of compatibility.     

Efficient synthesis of bicyclo[3.2.1]octane-2,4-diones and their incorporation into potent HPPD inhibitors

Herein we report a very efficient access to a variety of bicyclic 1,3-diones as key intermediates to be incorporated into very potent HPPD inhibitors. In particular, we have developed a one-pot process for the synthesis of the bicyclo[3.2.1]octane-2,4-dione, the parent dione of Bicyclopyrone.     

A series of diarylsubstituted oximes as potential substrate for new aldose reductase inhibitors

In the course of our research aimed at the discovery of new compounds acting as aldose reductase inhibitors, we tested a series of some (E)‐ and (Z)‐ω‐[[(aryldiazinylmethylene)amino]oxy]alkanoic acids, which were found to have moderate in vitro inhibitory activity. On this basis we have now prepared several new derivatives modified both at the length of the chain and at its terminal carboxylic group, together with compounds carrying various substituents at the phenyl ring. This paper describes their synthesis and biological properties.     

Nuclear magnetic resonance spectra of psychotherapeutic agents. III.. Stereochemistry of 1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2,4-diones

The stereochemistry of some 1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-2,4-diones was determined by proton magnetic resonance using the paramagnetic shift reagent tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium [Eu(fod)₃] two of these compounds, clobazam and triflubazam, are clinically used as psychotherapeutic agents. Several model structures, with intermediate stereochemistry in the range of the possible limit situations of benzocycloheptene, -cycloheptadiene or -cycloheptatriene type, are considered; LIS (3) are computer simulated on the basis of proton geometric parameters. It was found that at room temperature, these derivatives exist in only one pseudo-boat cycloheptadiene-like conformation, showing the 5-phenyl group directed pseudo-axially. This conformational preference is interpreted in terms of a balance between the steric requirements of the bulky substituent and electronic repulsion in the ring π-system.     

天然活性吡咯烷-2,4-二酮类化合物研究进展

吡咯烷-2,4-二酮类化合物广泛存在于陆上及海洋生物中,其复杂多变的分子结构和广谱独特的生物活性引起人们的极大关注.结合本研究组在这一邻域的工作综述了天然吡咯烷-2,4-二酮类化合物的结构、生物活性,重点介绍此类化合物的全合成等方面的新进展.     

Studies on non-thiazolidinedione antidiabetic agents. 1. Discovery of novel oxyiminoacetic acid derivatives

A novel series of oxyiminoacetic acid derivatives were synthesized in an effort to develop a potent antidiabetic agent, which does not contain the 2,4-thiazolidinedione moiety. These compounds were evaluated for glucose and lipid lowering effects in genetically obese and diabetic KKA(y) mice. Several of the compounds showed strong antidiabetic activity, including functional potency at peroxisome proliferator-activated receptor (PPAR)-gamma. (Z)-2-[4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino]-2-(4-phenoxyphenyl)acetic acid (25) significantly reduced plasma glucose (33%, p<0.01) and plasma triglycelide levels (43%, p<0.01) even at a dosage of 0.001% in diet. Pharmacokinetic analyses of 25 are also reported.     

Synthesis of 5-(4-substituted benzyl)-2,4-diaminoquinazolines as inhibitors of candida albicans dihydrofolate reductase

Several 5-(4-substituted benzyl)-2,4-diaminoquinazolines were prepared as potentially selective inhibitors of Candida albicans dihydrofolate reductase. These compounds were synthesized by a novel route, which included as a key step the displacement of a fluoro group in 2,6-difluorobenzonitrile by the anions of ethyl or methyl 4-substituted phenylacetates. The resultant diarylacetates were saponified and decarboxylated to the 2-fluoro-6-(4-substituted phenyl)benzonitriles. Ring closure of these benzonitriles with guanidine carbonate gave the 5-(4-substituted benzyl)-2,4-diaminoquinazolines.     

2,4-Dithiouracil as Complexing Agent. III

Pd(0), Rh(I), Rh(II), and Ru(II) complexes of 2,4-dithiouracil have been prepared. The structures of the complexes have been postulated on the basis of chemical analyses, infrared, visible spectral and magnetic susceptibility data.     

Studies in ring-opening polymerization. IV. Thermal polymerization of phenyl-substituted 1,3-dioxolan-2,4-diones

The effect of C-5 phenyl substituents on the thermal decomposition of the 1,3-dioxolan-2,4-dione ring has been examined. Unlike the dimethyl-substituted ring, 5-methyl-5-phenyl-1,3-dioxolan-2,4-dione decomposes smoothly in dry nonhydroxylic solvents to yield polymer and carbon dioxide. The introduction of a second C-5 phenyl substituent produces a similar but more rapid decomposition, with the added complication of a competing ring fragmentation leading to ketone formation. An analogy is drawn between the observed behavior of the phenyl-substituted 1,3-dioxolan-2,4-diones and that of the previously studied 1,3,2-dioxanthiolan-4-one 2-oxides. These monomers therefore provide another example of the thermal polymerisation mechanism first observed with 5,5-dimethyl-1,3,2-dioxathiolan-4-one 2-oxides. In these reactions the rate-determining step is the first-order ring-scission process leading to the formation of an α-lactone intermediate. This intermediate then takes part in a very rapid chain-growth process which governs the characteristics of the polymer formed.     

Preparation of 5-alkyl-3-carboxymethylrhodanines and their aldose reductase inhibitory activity.

5-Alkyl-3-carboxymethylrhodanines (2) were prepared from 5-alkylmethylidene-3-carboxymethylrhodanines (1). The exo double bond of 1 was successfully reduced with NaBH4. The 1,4-addition reaction path was confirmed on the basis of proton nuclear magnetic resonance spectrum of the product (4b) obtained from the reduction of 3 using NaBD4. Optical resolution of the tert-butyl compound (2i) was achieved upon epimerization-crystallization method using L-3-amino-epsilon-caprolactam. The alkyl compounds (2) and the optical active compounds ((+)-2i, (-)-2i) were evaluated for aldose reductase inhibitory potency.     

Studies on aldose reductase inhibitors from natural products. II. Active components of a Paraguayan crude drug "Para-parai mí," Phyllanthus niruri

Aldose reductase (AR) inhibitory activity-directed fractionation of the 70% ethanolic extract of Para-parai mí, Phyllanthus niruri, has led to the isolation of three active components, ellagic acid (1), brevifolin carboxylic acid (4) and ethyl brevifolin carboxylate (5). Among them, 1 showed the highest inhibitory activity, being about 6 times more potent than quercitrin, which is a known natural inhibitor of AR.     

Studies on antidiabetic agents. X. Synthesis and biological activities of pioglitazone and related compounds

Various analogues of a new antidiabetic agent, pioglitazone (AD-4833, U-72107), were synthesized in order to study in more detail the structure-activity relationships of this class of drug. 5-(4-Pyridylalkylthiobenzyl)-2,4-thiazolidinediones (I), thia-analogues of pioglitazone, were prepared via Meerwein arylation of the alkylthioanilines (IV). 5-(4-Pyridylalkoxybenzylidene)-2,4-thiazolidinediones (IIa) and related heterocyclic analogues (IIb) were synthesized by Knoevenagel condensation of the aldehydes (VIII) with the corresponding azolidinones. Compounds I and II were evaluated for hypoglycemic and hypolipidemic activity in genetically obese and diabetic yellow KK (KKAy) mice. Several 5-[4-[2-(2-pyridyl)ethoxy]-benzylidene]-2,4- thiazolidinediones (IIa) were equipotent to pioglitazone. However, the thia-analogues (I) and the benzylideneheterocycles (IIb) had decreased activity. Catalytic hydrogenation of the 5-benzylidene analogue (14) was found to be a convenient new synthetic method for pioglitazone. The configuration of 14 is also discussed.