- Synthesis and lipid-lowering evaluation of 3-methyl-1 H-purine-2,6-dione derivatives as potent and orally available anti-obesityagents
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Obesity accompanied with metabolic disorder is often complicated with a strong link of dyslipidemia and insulin resistance, whose indicator is the excess accumulation of triglycerides (TG) in cells. Consideration the idea of lipid-lowering and improving insulin resistance, 34 novel compounds by combination the xanthine scaffold with the chain of Rosiglitazone have been synthesized. Among them, several compounds showed efficiency on reducing TG in 3T3-L1 adipoctyes, and 11c exhibited the most optimal capacity in lipid-lowering and improving obese clinical symptoms in DIO mice. Furthermore, the hydrochloride of 11c (11c·HCl) showed excellent bioavailability, 58.94%, over 2 folds than that (28.03%) of 11c, and the anti-obesity effect of 11c·HCl at 50 mg/kg dose was better than that of Metformin at 150 mg/kg dose in DIO mice, almost reversed HFD to a normal level. Thus, 11c·HCl might be a potent and orally available anti-obesity agent via alleviating the obese clinical symptoms, body fat, improving serum parameters and insulin resistance and TG clearance in liver.
- He, Linhong,Pei, Heying,Ma, Liang,Pu, Yuzhi,Chen, Jinying,Liu, Zhuowei,Ran, Yan,Lei, Lei,Fu, Suhong,Tang, Minghai,Peng, Aihua,Long, Chaofeng,Chen, Lijuan
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Read Online
- Synthesis of Novel Thiazolidin-4-ones and Thiazinan-4-ones Analogous to Rosiglitazone
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This work reports the synthesis of thiazolidin-4-ones and thiazinan-4-ones analogous to rosiglitazone, a potent antidiabetic drug. The desired compounds were synthesized with moderate to good yields by one-pot reactions between different primary amines, mercaptoacetic or mercaptopropionic acids, and the 4-(2-(methyl(pyridin-2-yl)amino)ethoxy)benzaldehyde. The cyclocondensation reactions were carried out for 20?h, and all the products were characterized by 1H and 13C nuclear magnetic resonance spectroscopy, mass spectrometry, and one example by X-ray diffraction.
- das Neves, Adriana M.,Campos, José C.,Gouvêa, Daniela P.,Berwaldt, Gabriele A.,Goulart, Taís B.,Avila, Cinara T.,Machado, Pablo,Zimmer, Geórgia C.,Cunico, Wilson
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Read Online
- Preparation method of rosiglitazone
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The invention provides a preparation method of rosiglitazone. The preparation method is characterized by comprising the following steps: reacting 2-chloropyridine with 2-methylaminoethanol under the catalysis of sodium triphenylmethyl to generate 2-[N-methyl-N-(2-pyridine) amino] ethanol; then carrying out Williamson synthesis reaction on the 2-[N-methyl-N-(2-pyridine) amino] ethanol and 4-fluorobenzaldehyde under the catalysis of bis (trimethylsilyl) amino potassium to obtain 4-[2-[N-methyl-N-(2-pyridine) amino] ethoxy] benzaldehyde; then carrying out condensation reaction with thiazoline-2,4-diketone to obtain 5-{4-[2-[N-methyl-N-(2-pyridine) amino] ethoxy] benzylidene} thiazoline-2, 4-diketone; and carrying out reduction reaction under the catalysis of an organic manganese reagent to obtain the rosiglitazone. The preparation method is simple, mild in condition, high in reaction yield and suitable for industrial production.
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Paragraph 0039; 0042; 0047; 0050; 0053; 0056; 0059; 0062
(2020/12/29)
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- Synthetic optimization of rosiglitazone and related intermediates for industrial purposes
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As an important newly Food and Drug Administration (FDA)-approved drug for treating diabetes, rosiglitazone (1) has received much attention from researchers in many areas. To search for an economical and convenient synthesis method for 1, we explored the reaction conditions and workup of a scalable five-step synthetic route by an orthogonal method to determine the best condition for each reaction step. The starting materials are commercially available, including 2-chloropyridine (2), N-methylethanolamine (3), 4-fluorobenzaldehyde (4a) or 4-hydroxybenzaldehyde (4b), and 1,3-thiazolidine-2,4-dione (5). The five sequential reaction steps are cyclization, alkylation, etherification, condensation, and reduction, having optimal yield of 90, 99, 59, 75, and 91 %, respectively. The best overall yield to synthesize rosiglitazone based on compound 2 was 40 %, being suitable for industrial purposes, using water as a green solvent and avoiding column chromatography during the last three reaction steps.
- Meng, Ge,Zheng, Meilin,Dong, Mengshu,Gao, Yang,Zheng, Aqun,Li, Zhenyu,Hu, Ruizhi
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p. 2023 - 2033
(2016/03/16)
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- Design and synthesis of new potent PTP1B inhibitors with the skeleton of 2-substituted imino-3-substituted-5-heteroarylidene-1,3-thiazolidine-4-one: Part I
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A new series of 2-substituted imino-3-substituted-5- heteroarylidene-1,3-thiazolidine-4-ones as the potent bidentate PTP1B inhibitors were designed and synthesized in this paper. All of the new compounds were characterized and identified by spectra analysis. The biological screening test against PTP1B showed that some of these compounds have the positive inhibitory activity against PTP1B. The activity of the compounds with 5-substituted pyrrole on 5-postion of 1,3-thiazolidine-4-one are more potent than that of those compounds with 5-substituted pyridine group. Compound 14b, 14h and 14i showed IC50values of 8.66?μM, 6.83?μM and 6.09?μM against PTP1B, respectively. Docking analysis of these active compounds with PTP1B showed the possible interaction modes of these biheterocyclic compounds with the active sites of PTP1B. The inhibition tests against oncogenetic CDC25B were also conducted on this set of compounds to evaluate the selectivity and possible anti-neoplastic activity. Compound 14b also showed the lowest IC50of 1.66?μM against CDC25B among all the possible inhibitors, including 14g, 14h, 14i and 15c. Some pharmacological parameters including VolSurf, steric and electric descriptors of all the compounds were calculated to give some hints about the relative relationship with the biological activity. The result of this study might give some light on designing the possible anti-cancer drugs targeting at phosphatases. The most active compound 14i might be used as the lead compound for further structure modification of the new low molecular weight PTP1B inhibitors with the N-containing heterocyclic skeleton.
- Meng, Ge,Zheng, Meilin,Wang, Mei,Tong, Jing,Ge, Weijuan,Zhang, Jiehe,Zheng, Aqun,Li, Jingya,Gao, Lixin,Li, Jia
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p. 756 - 769
(2016/08/18)
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- Thiazolidin-4-one and thiazinan-4-one derivatives analogous to rosiglitazone as potential antihyperglycemic and antidyslipidemic agents
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A number of thiazolidin-4-one and thiazinan-4-one derivatives were prepared by three component condensation in one pot reaction method. These compounds were evaluated for anti-hyperglycemic activity by in vitro and in vivo assay systems. The compounds with thiazolidin-4-one and thiazinan-4-one moieties exhibited significant anti-hyperglycemic activity. A few compounds (3a, 3b, 4a and 4b) have exhibited both anti-hyperglycemic and anti-dyslipidemic activities. Among them the thiazinan-4-one derivative 4a showed maximal (45%) improvement in oral glucose tolerance test in db/db mice at 30 mg/kg oral dose.
- Raza, Saman,Srivastava, Swayam P.,Srivastava, Daya S.,Srivastava, Arvind K.,Haq,Katti
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p. 611 - 620
(2013/07/27)
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- An alternative synthetic route for an antidiabetic drug, rosiglitazone
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A convenient and scalable four-step novel route has been developed for the synthesis of rosiglitazone (8), an antidiabetic drug. This multistep route requires 4-fluoro benzaldehyde (4), 2,4-thiazolidinedione (6) and 2-chloro pyridine (1) as key reactants and gives overall better yield of rosiglitazone. In addition, some steps have been accelerated, which leads to an overall time saving of 10 h.
- Jawale, Dhanaji V.,Pratap, Umesh R.,Mane, Ramrao A.
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scheme or table
p. 924 - 928
(2012/03/26)
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- Microwave-assisted synthesis of the antihyperglycemic drug rosiglitazone
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We developed a simple, rapid, high yielding, and environmentally benign microwave assisted total synthesis of rosiglitazone, an antihyperglycemic agent for diabetes mellitus Type II. We used microwave heating successfully to improve reactions in four of six steps and obtain quicker and higher yields. In addition, all intermediates were isolated in good yields with crystallizations only and did not require chromatographic separations.
- Gaonkar, Santosh L.,Shimizu, Hiroki
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experimental part
p. 3314 - 3317
(2010/06/21)
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- Synthesis of 4-[2-(methyl-2-pyridin-2yl-amino)-ethoxy]-Benzaldehyde derivatives
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Several 2,4-thiazolidindiones were prepared from corresponding aryl aldehydes by Knovengel condensation between Aldehydes and 2,4-thiazolidindione which shows anti-hyperglycemic potency such as Pioglitazone and Rosiglitazone. In our attempt we have prepared 4-[2-(methyl-2-pyridin-2yl-amino)-ethoxy]- benzaldehyde derivatives. Condensation of aryl Aldehydes with aryl ketones by Aldol condensation and the derivatives may have comparable biological importance.
- Ravindranath,Rangaraju,Srikanth,Radhakrishana
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experimental part
p. 47 - 52
(2011/06/21)
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- HETEROCYCLIC CARBOXYLIC ACID DERIVATIVES AND PHARMACEUTICAL COMPOSITION FOR INHIBITING LIPID ACCUMULATION CONTAINING SAME
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The present invention relates to a novel heterocyclic carboxylic acid derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the same as an active ingredient for inhibiting the accumulation of lipids in the body.
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Page/Page column 24-25
(2008/12/04)
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- An improved process for the preparation of 4-[2-(methyl-2-pyridinylamino) ethoxy] benzaldehyde, an intermediate for the preparation of rosiglitazone
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The invention relates to an improved process for the preparation of 4-[2-(methyl-2-pyridinylamino)ethoxy]-benzaldehyde via 4-[2-(methyl-2-pyridinylamino).ethoxy]-benzonitrile. The process of preparation of 4-[2-(methyl-2-pyridinylamino)ethoxy]-benzaldehyde comprises: (a) Reacting 2[methyl(pyridine-2-yl)amino]ethanol with 4-halobenzonitrile using a base in a solvent, to give 4-(2-[methyl(pyridine-2-yl)amino]ethoxy)benzonitrile, (b) reacting a solution of 4-(2-[methyl(pyridine-2-yl)amino]ethoxy)benzonitrile in formic acid with Raney nickel in water ,to give 4-[2-(methyl-2-pyridinylamino)ethoxy]-benzaldehyde.
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Page/Page column 5
(2010/11/30)
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- A PROCESS FOR THE PREPARATION OF SUBSTITUTED PHENYL ETHER COMPOUNDS AND ROSIGLITAZONE
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A novel process for the preparation of a compound of the formula (II), which is useful as intermediate compound for the preparation of thiazolidinedione derivatives, such as rosiglitazone, pioglitazone, troglitazone and ciglitazone, is disclosed. The novel process comprising reacting a compound of the formula (III) with a compound of the formula (IV) in a mixture of a non-polar water immiscible organic solvent and water (two phase system) with an alkali metal hydroxide or an alkali metal carbonate as a base in the presence of a phase transfer catalyst. In the first aspect of the present invention comprising reacting 2-(N-methyl-N-(2- pyridyl) ethanol with 4-fluorobenzaldehyde in the mixture of a non-polar water immiscible organic solvent, preferably toluene, and water with an alkali metal hydroxide or an alkali metal carbonate as a base, preferably potassium hydroxide, in the presence of a phase transfer catalyst, e.g. tetra n-butylammonium hydrogensulphate or benzyltriethylammonium chloride, to obtain 4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzaldehyde, which is the key intermediate for preparing rosiglitazone and its salts, e.g. maleate salt or phosphate salt, useful in the treatment of Type II diabetes.
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Page/Page column 11-12
(2008/06/13)
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- PROCESS FOR THE SYNTHESIS OF BENZYLIDENE ROSIGLITAZONE BASE
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Process for the synthesis of 5-{4-[N-methyl-N- (2-pyridyl)-amino-ethoxy]- 5 benzylidene}-thiazolidine-2, 4-dione (INN name: benzylidene-rosiglitazone) of formula (I), which consist of the following steps: (I) Step a) reaction of 2-chloro-pyridine and 2-(N-methylamino)-ethanol Step b) reaction of the obtained compound of formula (III) with 4- 0 fluorobenzaldehyde Step c) reaction of the obtained compound of formula (IV) with thiazolidine-2, 4-dione. (III), ((IV). characterized by - dissolving 4-{2-[N-methyl-N- (2-pyridyl) amino]-ethanol of formula (III) obtained in Step a) in toluene and using it in Step b) without isolation; - reacting the solution of compound of formula (III) in toluene in Step b) with 4-fluorobenzaldehyde in the presence of aqueous alkali hydroxide solution and phase transfer catalyst at 25-50 °C; - reacting the solution of the benzaldehyde derivative of formula (IV) obtained in Step b) in toluene in Step c) and isolating the desired product.
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(2008/06/13)
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- SYNTHESIS OF ANTIDIABETIC ROSIGLITAZONE DERIVATIVES
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A process of preparing rosiglitazone, or a pharmaceutically acceptable salt thereof, which process employs an intermediate metabisulphite complex of 4-[2-(N-methyl-N-(2-pyridyl)amino) ethoxy] benzaldehyde, which metabisulphite complex is represented by following formula (III); where X represents an alkali metal. The present invention further provides rosiglitazone, or a pharmaceutically acceptable salt thereof, prepared by the above process.
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Page/Page column 14-15
(2008/06/13)
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- PROCESS FOR PREPARING THIAZOLIDINEDIONES
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This invention provides a process for reducing an exocyclic double bond at the 5-position of a thiazolidinedione moiety of a thiazolidinedione precursor comprising the steps of: a) preparing a solution or suspension of the thiazolidinedione precursor in a non-ether solvent medium with a base, and b) combining the solution or suspension with a dithionite source. Preferred solvent media include aqueous N,N-dimethylformamide. Sodium dithionite is a preferred dithionite source. In particular the application discloses preparation processes for Pioglitazone, Rosilitazone and Troglitazone.
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Page/Page column 13-14
(2008/06/13)
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- Polymer-assisted solution phase synthesis of the antihyperglycemic agent Rosiglitazone (Avandia).
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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.
- Li, Xin,Abell, Chris,Warrington, Brian H,Ladlow, Mark
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p. 4392 - 4395
(2007/10/03)
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- Process for the preparation of pyridine derivative
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The invention discloses a process for the preparation of a pyridine derivative namely 5-{4-2(N-methyl-N(2-pyridyl) amino ethoxy]benzyl]thiazolidine-2,4-dione maleate comprising the steps of: (a) reacting 2-chloropyridine with 2-(N-methyl amino) ethanol; (b) coupling 2-N-methyl-N-(2-pyridyl)amino)ethanol) obtained in step (a) and 4-fluorobenzaldehyde in an aprotic polar solvent with an alkali metal hydroxide or an alkali metal alkoxide as base. (c) isolating the product of the coupling reaction viz 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde; (d) converting said isolated benzaldehyde compound of step (c) into 5-[4-[2-N-methyl-N-(2-pyridyl) amino)ethoxy]benzyl]thiazolidine-2,4-dione in a known manner and (e) converting said thiazolidine-2,4-dione compound obtained in step (d) into a pharmaceutically acceptable maleate salt.
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- benzyl>-2,4-thiazolidinediones as Potent Antihyperglycemic Agents
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A series of -2,4-thiazolidinediones and benzyl>-2,4-thiazolidinediones was synthesized from the corresponding aldehydes.Compounds from the urea series, exemplified by 16, showed antihyperglycemic potency comparable with known agents of the type such as pioglitazone and troglitazone (CS-045).The benzoxazole 49, a cyclic analogue of 16, was a very potent enhancer of insulin sensitivity, and by modification of the aromatic heterocycle, an aminopyridine, 37, was identified as a lead compound from SAR studies.Evaluation of antihyperglycemic activity together with effects on blood hemoglobin content, to determine the therapeutic index, was performed in 8-day repeat administration studies in genetically obese C57 BI/6 ob/ob mice.From these studies, BRL 49653 (37) has been selected, on the basis of antihyperglycemic potency combined with enhanced selectivity against reductions in blood hemoglobin content, for further evaluation.
- Cantello, Barrie C.C.,Cawthorne, Michael A.,Cottam, Graham P.,Duff, Peter T.,Haigh, David,et al.
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p. 3977 - 3985
(2007/10/02)
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- Compounds
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Compounds of formula (I): STR1 or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein: A1 represents a substituted or unsubstituted aromatic heterocyclyl group; R1 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group; R2 and R3 each represent hydrogen, or R2 and R3 together represent a bond; A2 represents a benzene ring having in total up to five substituents; and n represents an integer in the range of from 2 to 6; pharmaceutical compositions containing such compounds and the use of such compounds and compositions in medicine.
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- Compounds
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Compounds of formula (I): STR1 or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein: A1 represents a substituted or unsubstituted aromatic heterocyclyl group; R1 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group; R2 and R3 each represent hydrogen, or R2 and R3 together represent a bond; A2 represents a benzene ring having in total up to five substituents; and n represents an integer in the range of from 2 to 6; pharmaceutical compositions containing such compounds and the use of such compounds and compositions in medicine.
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- COMPOUNDS
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Compounds of formula (I) or a tautomeric form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, wherein: A1 represents a substituted or unsubstituted aromatic heterocyclyl group; R1 represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted or unsubstituted, or a substituted or unsubstituted aryl group; R2 and R3 each represent hydrogen, or R2 and R3 together represent a bond; A2 represents a benzene ring having in total up to five substituents; and n represents an integer in the range of from 2 to 6; pharmaceutical compositions containing such compounds and the use of such compounds and compositions in medicine
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