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Polymers, containing 5-(4-O-methylacryloylbenzyl)thiazolidine-2,4-dione [MABTZD]; poly (MABTZD), poly(MABTZD-co-AA) and poly(MABTZD-co-AMAA), were prepared, and identified by FT-IR, 1H- and 13C-NMR spectra. The MABTZD unit contents in poly(MABTZD-co-AA) and poly(MABZD-co-AMAA) were 11.3 and 27.7 mol %, respectively. The number average molecular weights of the polymers, as determined by GPC, ranged from 16,800 to 22,300, and with polydispersity indices of 1.2-1.4.

A series of substituted 5-[4-[2-(6,7-dimethyl-1,2,3,4-tetrahydro-2-oxo-4-quinoxalinyl)ethoxy]phenyl]methylene]thiazolidine-2,4-diones were synthesized and their euglycemic and hypolipidemic activities were investigated in Wistar male rats. Based on the in vivo data in rats, compound 4a was identified as a potent euglycemic and hypolipidemic agent.

The 1,2,4-dithiazolidine-3,5-dione heterocycle, also referred to as a dithiasuccinoyl (Dts)-amine, serves as a readily removable amino protecting group for building blocks used in syntheses of peptides, glycopeptides, and PNA; it is also useful as a masked isocyanate and (inversely) as a sulfurization reagent for trivalent phosphorus. Bis(chlorocarbonyl)disulfane, the two-sulfur analogue of succinyl chloride, has been envisioned as a reagent for facile single-step elaboration of the heterocycle. However, reactions of bis(chlorocarbonyl)disulfane directly with primary amines fail to yield Dts-amines for reasons that are discussed. Inspired by several precedents from the organosilicon chemistry literature that a trimethylsilyl group may serve as a "large proton," a successful, high-yield preparation of Dts-amines through reactions of bis(chlorocarbonyl)disulfane with bis(trimethylsilyl)amines has been developed. Studies aimed at elucidating mechanistic reasons for these observations are also presented.

Pharmaceutical preparation of a hydrophobic aldose reductase inhibitor 5-(3-ethoxy-4-pentyloxyphenyl)-2,4-thiazolidinedione (CT112) was investigated. CT112 dissolved in a basic solution with different kinds of polymers was neutralized by acid to obtain a suspension preparation. In particular, the addition of a polymer, hydroxypropyl methyl cellulose (HPMC) provided a stable CT112 suspension with a homogeneous particle size, and there seemed to be an optimal concentration of HPMC for the stable suspension. The addition of polysorbate 80 brought higher CT112 solubility in water, but did not provide a stable suspension. X-ray diffraction, IR spectrum, and thermal analysis revealed that the particles in the suspension with HPMC had lower degree of crystallinity, less hydrophobic particle surface, and lower melting point and decreased fusion enthalpy than the suspension without HPMC. These results suggested that the highly stable CT112 suspension could be attained by the adsorption of the polymer.

A number of thiazolidine-2,4-diones derivatives having carboxylic ester appendage at N-3 were synthesized and their antihyperglycemic activity was evaluated. Many of these derivatives as well as their corresponding carboxylic acid showed significant improvement on post-prandial hyperglycemia in normal rats, in contrast to their poor agonist activity at PPARgamma.

In the pioglitazone bulk drug three prominent impurities I-III were detected up to concentrations of 0.1% (ranging from 0.05-0.1%) by reversed phase HPLC. These impurities were isolated from enriched mother liquor samples and characterized as 5-(4-hydroxybenzyl)-1,3-thiazolidine-2,4-dione (I) 5-(4-fluorobenzyl)-1,3-thiazolidine-2,4-dione (II), 2-[2-(4-bromophenoxy) ethyl-5-ethyl pyridine (III) based on their 1H, and 13C NMR, DEPT, Mass and IR spectral data. Structure elucidation and synthesis of these impurities is discussed.

Microwave irradiation of a mixture of benzylidene-anilines and mercaptoacetic acid in benzene gives 1,3-thiazolidin-4-ones in very high yield (65-90%), whereas the same reaction performed through using the conventional method, at reflux temperature, requires a much longer time and gives a much lower yield (25-69%). This difference seems to be due to some intermediates and by-products formed during the conventional reaction. On the basis of 1H NMR studies, two different mechanisms, acting in benzene and in DMF, respectively, have been hypothesized for the thiazolidin-4-one system formation., (Copyright 2004 The Royal Society of Chemistry)

Multi-substituted benzylidenethiazolidine-2,4-diones 3a-h were synthesized by Knoevenagel condensation of di- or tri-substituted 4-hydroxybenzaldehydes [or 1-(3,5-di-tert-butyl-4-hydroxyphenyl)ethanone] 1 with thiazolidine-2,4-dione (2) and evaluated for antioxidant activities of Cu(2+)-induced oxidation of human low-density lipoproteins (LDL). Among compounds 3a-h, 3a was superior to probucol in LDL-antioxidant activities and found to be ninefold more active than probucol. Due to its potency, compound 3a was tested for complementary in vitro investigations, such as TBARS assay (IC(50) = 0.1 microM), lag time (240 min at 1.5 microM), relative electrophoretic mobility (REM) of ox-LDL (inhibition of 83% at 10 microM), fragmentation of apoB-100 (inhibition of 61% at 5 microM), and radical DPPH scavenging activity on copper-mediated LDL oxidation. In macrophage-mediated LDL oxidation, the TBARS formation was also inhibited by compound 3a.

Depletion of calcium from the endoplasmic reticulum has shown to affect protein synthesis and cell proliferation. The anticancer effect of troglitazone was reported to be mediated by depletion of intracellular calcium stores resulting in inhibition of translation initiation. The unsaturated form of troglitazone displays similar anticancer properties in vitro. In this letter, we report our findings on the minimum structural requirements for both compounds to retain their calcium release and antiproliferative activities.

Troglitazone (TGZ) was the first glitazone used for the treatment of type II diabetes mellitus. TGZ undergoes an oxidative chroman ring-opening reaction to form a quinone product. Recently, cytochrome P450 (P450) was shown to be able to catalyze the formation of TGZ quinone. TGZ quinone was the major metabolite formed by dexamethasone-induced rat liver microsomes or myeloperoxidase (MPO) incubated with TGZ. The ultimate source for the quinone carbonyl oxygen atom of TGZ quinone was investigated using (18)O water in both enzyme reaction systems followed by liquid chromatography/tandem mass spectometry analysis of the TGZ quinone product. The resultant TGZ quinone formed by either liver microsomes or MPO contained a single atom of (18)O. The (18)O atom was determined to be the quinone carbonyl oxygen by collision-induced dissociation fragmentation of the (18)O-labeled TGZ quinone. The formation of TGZ quinone was inhibited approximately 90% by coincubation with ascorbic acid or cysteine in the MPO reaction system but only 10 to 20% in liver microsomes, which might reflect the difference in the mechanism by which TGZ quinone is formed by P450 and peroxidase. These results suggest that P450 catalyze an atypical reaction to form TGZ quinone, involving the incorporation of an oxygen from water into the quinone carbonyl position.

Molecular modeling on various well-known glitazones carrying a pyridine ring instead of benzene ring as the middle linker unit showed conformational rigidity as compared to their parent molecules. Blocking the lone pair of electrons on the pyridine N, made them flexible once again. A few representatives of these analogues were synthesized and their efficacy as PPARgamma agonists evaluated.

A novel series of substituted sulfanyldihydroimidazolones (1) that modulates high-density lipoprotein cholesterol (HDL-C) has been reported to have HDL-elevating properties in several animal models. Concerns about the chemical and metabolic stability of 1 directed us to explore the structure-activity relationship (SAR) of a related series of substituted thiohydantoins (2). Expansion of the scope of the thiohydantoin series led to exploration of compounds in related thio-containing ring systems 3-7 and the N-cyanoguanidine derivative 8. Compounds were tested sequentially in three animal models to assess their HDL-C elevating efficacy and safety profiles. Further evaluation of selected compounds in a dose-response paradigm culminated in the identification of compound 2.39 as a candidate compound for advanced preclinical studies.

The regioselective syntheses of 3-alkyl(aryl)-2-(anthracen-9'-ylimino)-1,3-thiazolidin-4-ones (2) and 2-alkyl(aryl)imino-3-(anthracen-9'-yl)-1,3-thiazolidin-4-ones (3) from N-(anthracen-9-yl)-N'-alkyl(aryl)thioureas were accomplished effectively using methyl bromoacetate and bromoacetyl bromide, respectively. Detailed structural characteristics were confirmed mainly by NMR techniques. The mass spectrometric behavior of the resulting sets of compounds of known structures was shown to be characteristic for each set. Some interesting fragmentation pathways involving the transfer and rearrangements of various moieties were also revealed, as well as regioisomerization for particular substituent-specific fragmentations., (Copyright 2003 John Wiley & Sons, Ltd.)

1. To assess the involvement of volume overload in the development of cardiac hypertrophy during treatment with an antidiabetic thiazolidinedione, changes in cardiac anatomy and parameters of cardiac volume overload were evaluated in female Sprague-Dawley rats treated with the thiazolidinedione derivative T-174. 2. Two week administration of T-174 (13 and 114 mg/kg per day) increased absolute and relative heart weights by 11-24%, demonstrating the development of cardiac hypertrophy. There was no evidence of oedema in hearts from treated rats. 3. Both plasma and blood volumes were increased in T-174-treated rats without any changes in systolic blood pressure and heart rate, whereas haematocrit was decreased. In accordance with the existence of volume overload, both left ventricular end-diastolic pressure and right atrial pressure were increased. Morphometric analysis of hearts revealed that T-174 induced eccentric heart hypertrophy, as characterized by a small increase in wall thickness and a large increase in the chamber volume, which is characteristic of volume overload. Volume overload is suggested as the possible trigger mechanism because blood volume expansion preceded cardiac hypertrophy and there was a high correlation between heart weight and blood volume. 4. T-174-treated streptozotocin-induced diabetic rats also exhibited blood volume expansion and cardiac hypertrophy. 5. These findings suggest that cardiac volume overload is induced by plasma volume expansion and contributes to the development of eccentric cardiac hypertrophy during treatment with antidiabetic thiazolidinediones. Although thiazolidinediones are insulin-sensitizing agents, these cardiac effects are likely to be mediated independently of insulin.

The commercially important antihyperglycemic agent Rosiglitazone 1(Avandia) has been prepared in high purity by a multi-step, polymer-assisted solution phase (PASP) synthesis without the need for the conventional chromatographic purification of any intermediates.

A novel benzylidenethiazolidinedione has been discovered with antimicrobial activity. Here, we present the results of a structure-activity study on this compound with respect to its antimicrobial activity.

A number of 2,4-thiazolidinedione derivatives of -phenyl substituted cinnamic acid were synthesized and studied for their PPAR agonist activity. The E-isomer of cinnamic acid, 11, showed moderate PPAR transactivation. The corresponding Z-isomer, 23, and double bond reduced derivative, 15, were found to be much less potent. Although the E-isomer showed a moderate PPAR gamma transactivation, it demonstrated a strong glucose-lowering effect in a genetic rodent model of diabetes. Results of pharmacokinetic, metabolism and permeability studies are consistent with 11 being an active prodrug with an active metabolite, 14, that has similar glucose lowering and PPAR gamma agonist properties.

Ethyl (coumarin-4-oxy)acetate 1 was prepared through the reaction of 4-hydroxycoumarin with ethyl bromoacetate. Compound 1 was allowed to react with hydrazine hydrate to produce coumarin-4-oxyacetic hydrazide 2. The synthesis of N-(arylidene and alkylidene)-coumarin-4-oxyacetic hydrazones 3-20 was performed. The preparation of 2-substituted-3-[(coumarin-4-oxy) acetamido]thiazolidinones 21-26 and 2-[(coumarin-4-oxy)methyl]-4-acetyl-5-substituted-delta2-1,3,4-oxadiazolines 27-33 was performed by the reaction of the hydrazones 3, 4, 7, 9, 12, 14 with mercaptoacetic acid and the hydrazones 3, 4, 5, 7, 12, 15, 16 with acetic anhydride, respectively. The antiviral activities, cytotoxicities and structure-activity relationship (SAR) towards different microorganisms of the prepared compounds were studied.

A novel series of 5-aryl thiazolidine-2,4-diones based dual PPARalpha/gamma agonists was identified. A number of highly potent and orally bioavailable analogues were synthesized. Efficacy study results of some of these analogues in the db/db mice model of type 2 diabetes showed them superior to rosiglitazone in correcting hyperglycemia and hypertriglyceridemia.

A series of 5-aryl thiazolidine-2,4-diones containing 4-phenoxyphenyl side chains was designed, synthesized, and evaluated for PPAR agonist activities. One such compound 28 exhibited comparable levels of glucose correction to rosiglitazone in the db/db mouse type 2 diabetes animal model.

A new series of furochromone-2,4-thiazolidinedione derivatives (VIIa-h) was prepared by Knoevenagel reaction of substituted-2,4-thiazolidinediones (VIa-h) with Khellin-2-carboxaldehyde (IV). The prepared compounds were tested for their insulinotropic activities in INS-1 cells. Compounds VIId and VIIf (at lower concentration; 1 microgram/ml) were able to increase insulin release in the presence of 5.6 mmol/l glucose. Both these compounds (VIId and VIIf) and VIIg increased glucose uptake in NIH-3T3 cells. Thus these 3 compounds should be tested for antidiabetic effects in vivo.