WO2007009353A1

WO2007009353A1 - Substituted thiazol-4-one compounds, preparation methods and use thereof

Info

Publication number: WO2007009353A1
Application number: PCT/CN2006/001657
Authority: WO
Inventors: Mingwei Wang; Qing Liu; Caihong Zhou; Mengneng Ning; Bin Wu; Xin Hui
Original assignee: Shanghai Institute of Materia Medica of CAS
Current assignee: Shanghai Institute of Materia Medica of CAS
Priority date: 2005-07-15
Filing date: 2006-07-13
Publication date: 2007-01-25
Anticipated expiration: 2008-01-15
Also published as: CN1896069B; CN1896069A

Abstract

Compounds of the following general formula, their preparation methods, and their use as new peroxisome proliferator-actived receptor-Ϝ(PPAR-Ϝ) agonist in the treatment of diabetes and their deuteropathy are provided. (formula)

Description

一类取代噻唑 -4酮化合物、制备方法和用途技术领域 A type of substituted thiazole-4 ketone compound, preparation method and use thereof

本发明涉及一类过氧化物酶体增殖子活化受体 γ ( Peroxisome Proliferator-activated Receptor-γ, PPAR-γ)激动剂，具体指一类取代噻唑 -4-酮衍生物的小分子有机化合物，其作为 PPAR-γ激动剂在治疗和预防糖尿病及其并发症中的医学用途。本发明还涉及该类化合物的制备方法。技术背景 The present invention relates to a peroxisome Proliferator-activated Receptor-γ (PPAR-γ) agonist, specifically a small molecule organic compound substituted with a thiazol-4-one derivative. It serves as a medical use of PPAR-gamma agonists in the treatment and prevention of diabetes and its complications. The invention also relates to a process for the preparation of such compounds. technical background

糖尿病是一组由遗传和环境因素相互作用而引起的临床综合症，主要分为 1型和 2型，其中 1型糖尿病的基本病理生理为绝对性胰岛素分泌不足，临床治疗以补充胰岛素为主； 2 型糖尿病占患病群体的 95%以上，临床研究发现绝大多数 2型糖尿病患者可合成正常甚至过量的胰岛素，但因靶细胞对胰岛素的敏感性降低（也称 "胰岛素抵抗")，导致胰岛素相对不足。胰岛素抵抗是 2型糖尿病发生和发展过程中的关键因素，目前除严格的血糖控制外尚无理想的治疗方法。糖尿病会引起多种致命性的并发症，包括脑中风、失明、糖尿病性肾病、高血压和冠心病等。在糖尿病患者中，约有 60〜70%的人都有一定程度的神经损害，严重的则导致肢端坏疽。统计数据表明，糖尿病已成为继肿瘤和心血管疾病之后的人类第三大杀手。在研究胰岛素信号转导途径的基础上，设计开发胰岛素增敏剂，以改善胰岛素抵抗状态，是治疗 2型糖尿病新药的研究重点，也是其主攻方向之一 [Saltiel A.R. New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell, 2001, 104(4): 517-29]。 Diabetes is a group of clinical syndromes caused by the interaction of genetic and environmental factors. It is mainly divided into type 1 and type 2. The basic pathophysiology of type 1 diabetes is absolute insulin secretion, and clinical treatment is mainly supplemented with insulin. Type 2 diabetes accounts for more than 95% of the diseased population. Clinical studies have found that most patients with type 2 diabetes can synthesize normal or even excess insulin, but the sensitivity of target cells to insulin is reduced (also known as "insulin resistance"). Insufficient insulin. Insulin resistance is a key factor in the development and progression of type 2 diabetes. Currently, there is no ideal treatment other than strict glycemic control. Diabetes can cause a variety of fatal complications, including stroke, blindness, diabetic nephropathy, hypertension, and coronary heart disease. In diabetic patients, about 60 to 70% of people have a certain degree of nerve damage, and severe cases cause gangrene. Statistics show that diabetes has become the third largest human killer after cancer and cardiovascular disease. Based on the study of insulin signal transduction pathway, designing and developing insulin sensitizer to improve insulin resistance is the focus of research on new drugs for type 2 diabetes, and it is also one of its main directions [Saltiel AR New perspectives into the molecular pathogenesis and Treatment of type 2 diabetes. Cell, 2001, 104(4): 517-29].

目前，对胰岛素增敏剂的研究主要侧重于以下几个方面： 1 ) 噻唑烷二酮 ( Thiazolidinediones, TZD )类，如曲格列酮（Troglitazone)、罗格列酮（Rosiglitazone)和吡格列酮（Pioglitazone ) 等； 2 )双胍类，如二甲双胍、苯乙双胍和丁双胍等； 3 ) β -肾上腺素受体激动剂和胰高血糖素受体拮抗剂； 4 ) 脂肪酸代谢干扰剂，如依托莫司（Etomoxir) 等。临床常用双胍类与磺酰脲类胰岛素分泌促进剂联合治疗，具有较好的初始疗效，但长期服用易产生耐受且无法根本阻止胰岛 β细胞的进一步坏死，导致胰岛素依赖；而受体调节和代谢干扰药物的适应症有限，疗效也并不显著。 TZD类药物作为一类新型的胰岛素增敏剂，临床应用时可显著改善胰岛素抵抗，纠正糖和脂质代谢异常，因而显示了巨大的市场价值。 At present, the research on insulin sensitizers mainly focuses on the following aspects: 1) Thiazolidinediones (TZD), such as Troglitazone, Rosiglitazone and Pioglitazone (Pioglitazone) ); 2) biguanides, such as metformin, phenformin, and buformin; 3) β-adrenergic receptor agonists and glucagon receptor antagonists; 4) fatty acid metabolism interfering agents, such as etomimus (Etomoxir) and so on. The combination of clinically used biguanide and sulfonylurea insulin secretion promoter has a good initial effect, but long-term use is easy to produce tolerance and can not prevent the further necrosis of islet β cells, leading to insulin dependence; and receptor regulation and The indications for metabolic interference drugs are limited and the efficacy is not significant. As a new class of insulin sensitizers, TZD drugs can significantly improve insulin resistance and correct abnormalities in sugar and lipid metabolism during clinical application, thus showing great market value.

TZD最初作为氯贝特（Clofibrate, 降血脂药）的类似物被发现，随后的研究表明， TZD 可明显增强胰岛素靶向组织对胰岛素的反应性，而在没有胰岛素的情况下， TZD不能降低血糖。 1995年， Lehmann等人发现 TZD类药物在体内的分子靶点为过氧化物增殖子活化受体 γ (Peroxisome Proliferator Activated Receptor-γ, PPAR-γ) [Lehmann J.M., Moore L.B., Oliver S" et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). 1995, J. Biol. Chem., Vol. (270): 12953-12956]。 TZD was originally discovered as an analog of clofibrate, and subsequent studies have shown that TZD significantly enhances the insulin-targeting tissue's response to insulin, whereas in the absence of insulin, TZD does not lower blood sugar. . In 1995, Lehmann et al. found that the molecular target of TZD drugs in vivo was Peroxisome Proliferator Activated Receptor-γ (PPAR-γ) [Lehmann JM, Moore LB, Oliver S" et al An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). 1995, J. Biol. Chem., Vol. (270): 12953-12956].

PPAR-γ由单拷贝基因编码，位于人类第 3号染色体上，其蛋白分别有 468、 441 和 479个氨基酸，由 A到 F共六个结构域组成（图 1 )。氨基端的 A/B结构域是激活转录区， C结构域是 DNA结合区（DBD)，羧基端的 E/F结构域是配体结合区（LBD) [Desvergne B., Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev. 1999, 20(5): 649-88] PPAR-γ被小分子配体激活后，与类维甲酸受体 X (RXR)形成异二聚体，然后结合于被称为 PPAR反应元件（PPAR Response Element, PPRE)的特定 DNA序列，在共转录因子的辅助下调控靶基因的转录 [Blanquart C, Barbier 0.， Fruchart J.C., et al. Peroxisome proliferator-activated receptors: regulation of transcriptional activities and roles in inflammation. J Steroid Biochem Mol Biol. 2003, 85(2-5): 267-73]。 PPRE存在于多个调控脂代谢和糖代谢相关基因的上游 [Juge-Aubry C, Pernin A., Favez T" et al. DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance of the 5'-flanldng region. J Biol Chem. 1997, 272(40): 25252-9]。 PPAR-γ is encoded by a single-copy gene located on human chromosome 3, with 468, 441 and 479 amino acids, respectively, consisting of six domains from A to F (Fig. 1). The A/B domain at the amino terminus is the activated transcribed region, the C domain is the DNA binding region (DBD), and the E/F domain at the carboxy terminus is the ligand binding region (LBD) [Desvergne B., Wahli W. Peroxisome proliferator-activated Endorser: nuclear control of metabolism. Endocr Rev. 1999, 20(5): 649-88] PPAR-γ is activated by small molecule ligands, forms a heterodimer with retinoic acid receptor X (RXR), and then binds The specific DNA sequence called PPAR Response Element (PPRE) regulates transcription of target genes with the help of co-transfer factors [Blanquart C, Barbier 0., Fruchart JC, et al. Peroxisome proliferator-activated receptors : regulation of transcriptional activities and roles in inflammation. J Steroid Biochem Mol Biol. 2003, 85(2-5): 267-73]. PPRE is present upstream of multiple genes involved in regulation of lipid metabolism and glucose metabolism [Juge-Aubry C, Pernin A., Favez T" et al. DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements. Importance Of the 5'-flanldng region. J Biol Chem. 1997, 272(40): 25252-9].

PPAR-γ主要分布于脂肪、免疫系统、大肠和视网膜等组织。大量的研究证明， PPAR-γ 是脂肪细胞分化的关键调控因子，对脂肪细胞的分化起正向调节作用，能诱导脂肪细胞的形成,抑制瘦素的表达，促使 3T3-L1前脂肪细胞向终末期脂肪细胞转化 [Chawla A., Schwarz EJ., Dimaculangan D.D., et al. Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology. 1994， 135(2): 798-800.]。 PPAR-γ基因敲除的小鼠在胚胎发育早期即死亡。体外实验证实 PPAR-γ 为胚胎干细胞分化为脂肪细胞所必需。在胰.岛素抵抗和糖代谢方面，通过激活 PPAR-γ可以促进脂肪细胞和骨骼肌细胞对葡萄糖的摄取和转运，调节脂肪细胞的信号转导，诱导棕色脂肪组织的分化，增加解偶联蛋白 UCP1和 UCP2的表达，进而增加能量消耗，降低血糖和血脂，改善 2型糖尿病人的胰岛素抵抗症状 [Motojima K.， Passilly P., Peters J.M., et al. Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner. J Biol Chem. 1998, 273(27): 16710-4; Kelly L.J., Vicario P.P., Thompson G.M., et al. Peroxisome proliferator-activated receptors gamma and alpha mediate in vivo regulation of uncoupling protein (UCP-1, UCP-2, UCP-3) gene expression. Endocrinology. 1998, 139(12): 4920-7.]。也有文献报道 PPAR-γ具有一定的抑制肿瘤及改善动脉粥样硬化作用。 PPAR-γ is mainly distributed in tissues such as fat, immune system, large intestine and retina. A large number of studies have proved that PPAR-γ is a key regulator of adipocyte differentiation, which positively regulates the differentiation of adipocytes, induces the formation of adipocytes, inhibits the expression of leptin, and promotes the end of 3T3-L1 preadipocytes. End stage fat cell transformation [Chawla A., Schwarz EJ., Dimaculangan DD, et al. Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology. 1994, 135(2): 798 -800.]. PPAR-γ knockout mice die early in embryonic development. In vitro experiments confirmed that PPAR-γ is essential for the differentiation of embryonic stem cells into adipocytes. In the pancreas, island resistance and glucose metabolism, activation of PPAR-γ can promote glucose uptake and transport by adipocytes and skeletal muscle cells, regulate signal transduction of adipocytes, induce differentiation of brown adipose tissue, and increase uncoupling Expression of proteins UCP1 and UCP2, which in turn increases energy expenditure, lowers blood sugar and blood lipids, and improves insulin resistance in people with type 2 diabetes [Motojima K., Passilly P., Peters JM, et al. Expression of putative fatty acid transporter genes are regulated By peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner. J Biol Chem. 1998, 273(27): 16710-4; Kelly LJ, Vicario PP, Thompson GM, et al. Peroxisome proliferator- Activated receptors gamma and alpha mediate in vivo regulation of uncoupling protein (UCP-1, UCP-2, UCP-3) gene expression. Endocrinology. 1998, 139(12): 4920-7.]. It has also been reported in the literature that PPAR-γ has a certain role in inhibiting tumors and improving atherosclerosis.

目前市场上用来治疗 2型糖尿病的 PPAR-γ激动剂除罗格列酮和吡格列酮外，还有多个药物正处于临床前或临床研究阶段，包括 TZD类的 Darglitazone与非 TZD类的 Farglitazar 等，它们都表现出了良好的降糖作用，且无明显的毒副作用。除了 Troglitazone因少见的严重肝毒性而被撤出市场外，这些药物普遍存在的包括导致肥胖和水肿在内的副作用 [Lebovitz H.E. Differentiating members of the thiazolidinedione class: a focus on safety. Diabetes Metab Res Rev. 2002, 18(Suppl 2): S23-9]限制了它们的广泛使用 [Gershell L. Type 2 diabetes market. Nature Reviews Drug Discovery 2005, 4(5): 367-368]。因此，以 PPAR-γ为靶点寻找毒副作用更小的胰岛素增敏剂已成为各大跨国医药公司竞争的热点。 In addition to rosiglitazone and pioglitazone, PPAR-gamma agonists currently used in the treatment of type 2 diabetes are in preclinical or clinical research, including Darglitazone in the TZD category and Farglitazar in the non-TZD category. They all showed good hypoglycemic effects without obvious side effects. In addition to Troglitazone being withdrawn from the market due to rare severe hepatotoxicity, these drugs are ubiquitous, including side effects leading to obesity and edema [Lebovitz HE Differentiating members of the thiazolidinedione class: a focus on safety. Diabetes Metab Res Rev. 2002 , 18 (Suppl 2): S23-9] limits their widespread use [Gershell L. Type 2 diabetes market. Nature Reviews Drug Discovery 2005, 4(5): 367-368]. Therefore, the use of PPAR-γ as a target to find insulin sensitizers with less toxic side effects has become a hot spot for major multinational pharmaceutical companies.

本发明通过应用多种基于 PPAR-γ的高通量药物筛选模型和活性样品的构效关系研究，发现和合成了一系列取代噻唑 -4-酮衍生物的小分子化合物。受体结合活力试验、报告基因活化检测以及脂肪细胞诱导分化实验证明这类化合物与 PPAR-γ特异性结合，为 PPAR-γ的激动剂，提示其具有进一步开发成为新型胰岛素增敏剂的潜力。发明内容 The present invention discovers and synthesizes a series of small molecule compounds of substituted thiazol-4-one derivatives by applying various PPAR-γ-based high-throughput drug screening models and structure-activity relationships of active samples. Receptor binding viability assays, reporter gene assays, and adipocyte-induced differentiation assays have demonstrated that these compounds bind specifically to PPAR-γ and are agonists of PPAR-γ, suggesting their potential to be further developed into novel insulin sensitizers. Summary of the invention

本发明的目的在于提供了一类具有式 I结构的取代噻唑 -4酮化合物。 It is an object of the present invention to provide a class of substituted thiazole-4-one compounds having the structure of Formula I.

本发明的另一目的在于提供了一种制备式 I化合物的方法。 Another object of the invention is to provide a process for the preparation of a compound of formula I.

本发明的另一目的在于提供了一种含有式 I化合物的药物组合物。 Another object of the present invention is to provide a pharmaceutical composition comprising a compound of formula I.

本发明的再一目的在于提供了式 I化合物用于治疗或预防糖尿病及其并发症的过氧化物酶体增殖子活化受体 γ激动剂的用途。 A further object of the present invention is to provide the use of a compound of formula I for the treatment or prevention of a peroxisome proliferator-activated receptor gamma agonist of diabetes and its complications.

本发明提供过氧化物酶体增殖子活化受体 γ激动剂，增加了胰岛素增敏剂的成员。本发明涉及具有以下分子式 I的化合物，或其药物学上可接受的盐：

其中 Ar为下列任意一种取代基：芳基； 2-、 3-、或 4-位吡啶基；呋喃基；吡喃基；噻吩基；吡咯基；含有包括 d- 的垸基、硝基、羧基、酯基、醛基、卤素、羟基、垸氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的芳基; 含有包括 CrC₄ ½焼基、硝基、羧基、酯基、醛基、素、羟基、烷氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的 2-、 3-、或 4-位吡啶基；含有包括(^- C₄的垸基、硝基、羧基、酯基、醛基、卤素、羟基、烷氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的呋喃基；含有包括^-( ₄的垸基、硝基、羧基、酯基、醛基、卤素、羟基、烷氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的吡喃基；含有包括 c「c₄的焼基、確基、幾基、酷基、醛基、 , 轻基、烷氧基、胺基、酷胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的噻吩基；含有包括(^- C₄的烷 '基、硝基、羧基、酯基、醛基、卤素、羟基、垸氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的吡咯基。 The present invention provides a peroxisome proliferator-activated receptor gamma agonist that increases the membership of an insulin sensitizer. The present invention relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof:

Wherein Ar is any one of the following substituents: aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing fluorenyl, nitro, including d- Any one, two or three substituted aryl groups such as a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group. Containing CrC ₄ 1⁄2 fluorenyl, nitro, carboxyl, ester, aldehyde, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio Any one, two or three substituted 2-, 3-, or 4-position pyridyl groups; containing (^-C ₄ sulfhydryl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkane any group, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents furanyl; ^ contains include - ₍₄ embankment group, a nitro group , carboxyl group, ester group, aldehyde group, halogen, hydroxyl group, alkoxy group, amine group, amide group, carboxamide group , Any mercapto, methylthio, ethylthio, including one, two or three of the substituents pyranyl; c comprising comprising _{"c. 4} groups of firing, indeed group, several groups, cool, aldehyde,, any light, alkoxy, amino, cool group, carbonamide group, a mercapto group, methylthio, ethylthio, including one, two or three substituents thienyl; comprising comprising (^ - C ₄ Any one of the alkyl group, the nitro group, the carboxyl group, the ester group, the aldehyde group, the halogen group, the hydroxyl group, the decyloxy group, the amine group, the amide group, the carboxamide group, the thiol group, the methylthio group, the ethylthio group, Or three substituted pyrrolyl groups.

X为 0、 S、腿或者 H。 X is 0, S, leg or H.

Y为 0、 S o z为下列任意一种取代基: Y is 0, S o z is any of the following substituents:

其中！^为：芳基； 2-、 3-、或 4 -位吡啶基；呋喃基；吡喃基；噻吩基；吡咯基；含有包括烷基、硝基、羧基、酯基、醛基、卤素、羟基、烷氧基、胺基、酰胺基、碳酰胺基、琉基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的芳基；含有包括 CrC₄的垸基、硝華、羧基、酯基、醛基、卤素、羟基、垸氧基、 '胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的 2-、 3-、或 4-位吡啶基；含有包括的烷基、硝基、羧基、酯基、醛基、卤素、羟基、烷氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的呋喃基；含有包括 d-c₄的垸基、硝基、幾基、酷基、酸基、轻基、焼氧基、胺基、酰胺基、碳酷胺基、琉基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的吡喃基；含有包括 C,- 的烷基、硝基、羧基、酯基、醛基、卤素、羟基、烷氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的噻吩基；含有包括 d- C₄的垸基、硝基、羧基、酯基、醛基、卤素、羟基、烷氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的吡咯基。 among them! ^ is: aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing alkyl, nitro, carboxyl, ester, aldehyde, halogen, Any one, two or three substituted aryl groups including a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; a thiol group including CrC ₄ , Any one, two or three of nitrate, carboxyl, ester, aldehyde, halogen, hydroxy, decyloxy, 'amine, amide, carboxamide, thiol, methylthio, ethylthio Substituted 2-, 3-, or 4-position pyridyl; containing alkyl, nitro, carboxy, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, Any one, two or three substituted furanyl groups including a fluorenyl group, a methylthio group, an ethylthio group; a fluorenyl group including a dc ₄ group, a nitro group, a aryl group, a sulfo group, an acid group, a light group, and an anthracene group Base, amine group, amide group, carboamine group, sulfhydryl group, methylthio group, ethylthio group Any one, two or three substituted pyranyl groups; containing an alkyl group including a C,-, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carbon amide Any one, two or three substituted thienyl groups including a thiol group, a thiol group, a methylthio group, an ethylthio group, a thiol group including a d-C ₄ group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen, Any one, two or three substituted pyrrolyl groups such as a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group.

此外优选地，该类化合物或其在药物学上可接受的盐是以药物组合物的形式，或单独，或与药物学上可接受的载体或赋形剂联合提供。本发明还提供了包括上述化合物的药盒，用于治疗或预防糖尿病及其并发症。 Further preferably, such a compound or a pharmaceutically acceptable salt thereof is provided in the form of a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier or excipient. The present invention also provides a kit comprising the above compound for use in the treatment or prevention of diabetes and its complications.

本发明通过如下步骤实施的： The invention is implemented by the following steps:

(1) 药学杂志， 1955， 75 (12) : 1535-9.

(1) Journal of Pharmacy, 1955, 75 (12): 1535-9.

(2) 反应条件： l eq噻唑， l〜2 eq芳香醛， 2〜4 eq醋酸钠或醋酸钾，适量的冰醋酸，加热回流 2小时以上。 (2) Reaction conditions: l eq thiazole, l~2 eq aromatic aldehyde, 2~4 eq sodium acetate or potassium acetate, an appropriate amount of glacial acetic acid, heated to reflux for more than 2 hours.

AriCONH H-iLsK+AriCONH H-iLsK+

(³) l eq氯乙酸， l〜2 eq碳酸钠或碳酸第钠， leq钾盐，用水作溶剂， 15— 60°C反应 5小时以上，稀 HC1调节至酸性，析出固体，过滤后溶入二氧六环或二氯甲垸，加热回流 1小时以上 ( ³ ) l eq chloroacetic acid, l~2 eq sodium carbonate or sodium carbonate, leq potassium salt, water as solvent, react at 15 - 60 ° C for more than 5 hours, dilute HC1 to acidity, precipitate solids, filter and dissolve Dioxane or dichloromethane, heated to reflux for 1 hour On

(4)本发明的化合物可用任何合适的酸以其药物学上可接受的盐的形式来制备。例如，无机酸如盐酸、氢溴酸、硝酸、硫酸、磷酸等；有机酸诸如甲酸、乙酸、丙酸、苯甲酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸等；烷基磺酸如甲基磺酸、乙基磺酸等；芳基磺酸如苯磺' 酸、对甲苯磺酸等均可使用。附图说明 (4) The compounds of the present invention can be prepared in the form of their pharmaceutically acceptable salts with any suitable acid. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.; A sulfonic acid such as methanesulfonic acid or ethylsulfonic acid; an arylsulfonic acid such as benzenesulfonic acid, p-toluenesulfonic acid or the like can be used. DRAWINGS

图 1. PPAR-γ的蛋白结构域示意图。 ' Figure 1. Schematic representation of the protein domain of PPAR-γ. '

图 2. 化合物诱导分化的 3T3-L1细胞内甘油三酯含量的检测：部分化合物具有诱导前脂肪细胞分化的能力。 *与空白对照进行 t检验， P<0.05。具体实施方式 Figure 2. Detection of intracellular triglyceride levels in 3T3-L1 cells induced by compounds: Some compounds have the ability to induce differentiation of pre-lipocytes. * t test with blank control, P < 0.05. detailed description

为了阐明发明内容且不受其局限，对发明分成以下几个小节进行详细描述。 In order to clarify the contents of the invention and not to be limited thereto, the invention will be described in detail in the following subsections.

定义 Definition

除非另有定义，本发明所用的技术和科学上的术语，与本发明所属领域的通用技术的一般理解具有相同意义。本处提到的来源于基因库和其他数据库的所有专利，申请，公布的申请和其他出版物和序列被全面收入引用作为参考。如果本节阐明的定义与本专利参用的来源于基因库和其他数据库的所有专利，申请，公布的申请和其他出版物和序列被收入和引用的定义阐述相反，或不一致时，以本节阐明的定义为准。 The technical and scientific terms used in the present invention have the same meaning as the general understanding of the general art in the field to which the invention pertains, unless otherwise defined. All patents, applications, published applications and other publications and sequences derived from the Gene Bank and other databases referred to herein are referenced in full revenue. If the definitions set forth in this section are inconsistent with, or inconsistent with, all patents, applications, published applications, and other publications and sequences derived from the Gene Bank and other databases referenced in this patent, or inconsistent, The definition of clarification shall prevail.

本文所用， "一"或 "一个"指 "至少一个" 或 "一个或多个"。 As used herein, "a" or "an" refers to "at least one" or "one or more."

本文所用， "糖尿病"指一种多病因的代谢性疾病，特点是慢性高血糖，伴随因胰岛素分泌及 /或作用缺陷引起的糖、脂肪和蛋白质代谢紊乱。随着糖尿病得病时间的延长，身体内的代谢紊乱如得不到很好地控制，可导致眼、肾、神经、血管和心脏等组织等器官的慢性并发症，以致最终发生失明、下肢坏疽、尿毒症、脑中风或心肌梗死，甚至危及生命。 As used herein, "diabetes" refers to a multi-pathogenic metabolic disease characterized by chronic hyperglycemia accompanied by disorders of sugar, fat and protein metabolism caused by defects in insulin secretion and/or function. As the time of diabetes is prolonged, the metabolic disorders in the body are not well controlled, leading to chronic complications of tissues such as the eyes, kidneys, nerves, blood vessels and heart, resulting in blindness and gangrene in the lower limbs. Uremic, stroke or myocardial infarction, even life-threatening.

本文所用， "并发症" 指伴随一些重大疾病发生的相关组织和器官的病理症状。 As used herein, "complication" refers to the pathological symptoms of related tissues and organs that occur with some major diseases.

本文所用的用于治疗某一特定疾病的化合物的 "有效量" 指足够改善或在某种程度上减轻与此病相伴的症状的量。这一剂量可以单一剂量给药，也可按照治疗方案给药。这一剂量可治愈疾病，但典型的是为了改善该症状而给药。为改善症状重复给药可能是需要的。 An "effective amount" of a compound for treating a particular disease as used herein refers to an amount sufficient to ameliorate or to some extent alleviate the symptoms associated with the disease. This dose can be administered in a single dose or in accordance with a therapeutic regimen. This dose cures the disease, but is typically administered to improve the condition. Repeated administration to improve symptoms may be desirable.

本文所用， "药物学上可接受的盐、酯或其他衍生物" 包括领域技术人员用已知方法易于制备的任何盐，酯或衍生物。这样衍生和生成的化合物可对动物和人给药，不具有毒性作用。该化合物或是具有药物活性，或是药物前体。 As used herein, "pharmaceutically acceptable salts, esters or other derivatives" includes any salt, ester or derivative that is readily prepared by those skilled in the art by known methods. The compounds thus derived and produced can be administered to animals and humans without toxic effects. The compound is either pharmaceutically active or a prodrug.

本文所用， "治疗"指疾病和症状用任何方式得以改善，或其他有益的改变。治疗也包括本发明化合物在药物上的应用。本文所用，给予某一特定药物组合物 "改善" 某一特定疾病 ¾]症状是指任何减轻，无论永久的，临时的，长时期的，短暂的，都能归因于或与该药物组合物的施用有关。 As used herein, "treatment" means that the disease and symptoms are improved in any way, or other beneficial changes. Treatment also includes the use of the compounds of the invention in medicine. As used herein, administration of a particular pharmaceutical composition "improves" a particular disease 3⁄4] symptom means any relief, whether permanent, temporary, prolonged, transient, can be attributed to or associated with the pharmaceutical composition Related to the application.

本文所用， "基本上纯" 是指足够均匀，通过本领域技术人员为评价纯度使用的标准分析方法探测不出杂质，所述标准分析方法有如薄层层析法（TLC)，凝胶电泳和高效液相色谱法（HPLC)。或者足够纯也指即使进一步纯化也不能改变该物质可探测到的理化特性，例如酶活性和生物活性。用于纯化化合物制得基本上化学纯的方法，是本领域技术人员所公知的。然而基本上化学纯的化合物可以是立体异构体或同分异构体的混合物。在这种情况下，进一步纯化也许会增加化合物的比活性。 As used herein, "substantially pure" means sufficiently uniform that no impurities can be detected by standard analytical methods used by those skilled in the art to evaluate purity, such as thin layer chromatography (TLC), gel electrophoresis, and High performance liquid chromatography (HPLC). Or sufficiently pure also means that even further purification does not alter the physicochemical properties detectable by the substance, such as enzymatic activity and biological activity. Methods for producing substantially chemically pure compounds for purification are well known to those skilled in the art. However, a substantially chemically pure compound can be a stereoisomer or a mixture of isomers. In this case, further purification may increase the specific activity of the compound.

本文所用， "药物前体"是指一种体内给药的化合物，该化合物可被代谢，或转化为生物学上、药物学上或治疗学上的活性形式。为了制造药物前体，药物活性化合物将被修饰，使该活性化合物通过代谢过程再产生。药物前体可被设计成改变其代谢稳定性，或运输特性的前体，以掩盖其副作用或毒性，改良药物的味觉，或改变其他特性。凭借药代动力学及药物体内代谢的知识，一旦药物学上活性化合物为已知，本领域技术人员就可以设计出该化合物白勺药物前体。 [#J¾ Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, 1985, pages 388-392]。 As used herein, "prodrug" refers to a compound that is administered in vivo and which can be metabolized or converted into a biological, pharmacologically or therapeutically active form. To produce a prodrug, the pharmaceutically active compound will be modified to reproduce the active compound by metabolic processes. Prodrugs can be designed to alter their metabolic stability, or precursors of transport properties, to mask their side effects or toxicity, to improve the taste of the drug, or to alter other properties. By virtue of knowledge of pharmacokinetics and metabolism within the drug, once the pharmaceutically active compound is known, one skilled in the art can design a prodrug of the compound. [#J3⁄4 Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, 1985, pages 388-392].

术语 "基本上"相同或均勾或相似，按照本领域技术人员对相关技术的理解可在上下文中有所改变，并且一般为至少 70%，优选为至少 80%，更优为至少 90%，最优为至少 95% 相同。 The terms "substantially" are the same or are either hooked or similar, and the understanding of the relevant art may vary in the context, and is generally at least 70%, preferably at least 80%, more preferably at least 90%, The optimal is at least 95% identical.

这里所用的 "组合物"指任何混合物。可以是溶液、混悬液、液体、粉末、油膏、水性的、非水性的或它们的任何组合。 ' As used herein, "composition" refers to any mixture. It may be a solution, suspension, liquid, powder, ointment, aqueous, non-aqueous or any combination thereof. '

这里所用的 "联合"指两种或多种之间的任何联合。 As used herein, "union" refers to any association between two or more.

这里使用的术语 "对象"包括人和动物；例如，狗，猫，牛，猪，啮齿动物等。有经验的实施者应可理解对象为适于并愿意对糖尿病及其并发症进行治疗和预防。 The term "object" as used herein includes humans and animals; for example, dogs, cats, cows, pigs, rodents, and the like. Experienced practitioners should understand that the subject is suitable and willing to treat and prevent diabetes and its complications.

这里使用的任何保护性基团，氨基酸和其他化合物的缩写，与它们通用的、公认的缩写或 IUPAC-IUB委员会颁布生化命名一致，除非特别说明。 Any of the protective groups, abbreviations for amino acids and other compounds used herein, are consistent with their general, recognized abbreviations or the biochemical nomenclature issued by the IUPAC-IUB committee, unless otherwise stated.

过氧化物酶体增殖子活化受体 γ激动剂 Peroxisome proliferator-activated receptor gamma agonist

本发明提供过氧化物酶体增殖子活化受体 γ的激动剂，增加了胰岛素增敏剂类药物的成员。本发明涉及具有以下分子式 I的化合物，或其药物学上可接受的盐-

其中 Ar为下列任意一种取代基：芳基； 2-、 3-、或 4-位吡啶基；呋喃基；吡喃基；噻吩基；吡咯基；含有包括 -( ₄的烷基、硝基、羧基、酯基、醛基、 '卤素、羟基、垸氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个两个或者三个取代的芳基；含有包括^- (：₄的烷基、硝基、羧基、酯基、醛基、素、羟基、烷氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的 2-、 3-、或 4 -位吡啶基；含有包括(^ -( 的垸基、硝基、羧基、酯基、醛基、素、羟基、烷氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的呋喃基；含有包括 Cr ( ₄的烷基、硝基、羧基、酯基、醛基、卤素、羟基、垸氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的吡喃基；含有包括 (^-( ₄的烷基、硝基、羧基、酯基、醛基、卤素、羟基、烷氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的噻吩基；含有包括^- C₄的垸基、硝基、羧基、酯基、醛基、卤素、羟基、垸氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的吡咯基。 The present invention provides an agonist of peroxisome proliferator-activated receptor gamma, which increases the membership of insulin sensitizers. The present invention relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof -

Wherein Ar is any one of the following substituents: aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing alkyl group containing -( ₄ , nitro , carboxyl group, ester group, aldehyde group, 'halogen, hydroxyl group, decyloxy group, amine Group, one of the two amide groups, carboxamide, mercapto, methylthio, ethylthio, including three or substituted aryl; ^ contains include - (: ₄ alkyl, nitro, carboxyl, ester Any one, two or three substituted 2-, 3- groups including an aldehyde group, an aldehyde group, a hydroxy group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, and an ethylthio group. Or 4- 4-pyridyl; containing (^-(indolyl, nitro, carboxy, ester, aldehyde, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, A any thio, ethylthio, including one, two or three substituents furanyl; comprise containing Cr ₍₄ alkyl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy embankment, Any one, two or three substituted pyranyl groups including an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; and an alkyl group, a nitro group, including (^-( ₄ ) Carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide , Any mercapto, methylthio, ethylthio, including one, two or three substituents thienyl; ^ contains include - C ₄ alkyl with a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen, hydroxy Any one, two or three substituted pyrrolyl groups, an anthraceneoxy group, an amino group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group.

X为 0、 S、 NH或者 H。. X is 0, S, NH or H. .

Y为 0、 S。 ' Y is 0, S. '

Z为下列任意一种取代基： Z is any of the following substituents:

其中 A_ri为'. 芳基； 2-、 3-、或 4-位吡啶基；呋喃基；吡喃基；噻吩基；吡咯基；含有包括 d-C₄ ½烷基、確基、羧基、酷基、醛基、素、羟基、垸氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的芳基；含有包括(^- C₄的烷基、硝基、羧基、酯基、醛基、卤素、羟基、烷氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的 2-、 3-、或 4-位吡啶基；含有包括 (^-(^的垸基、硝基、羧基、酯基、醛基、卤素、羟基、烧氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的呋喃基；含有包括^-^的垸基、硝基、羧基、酯基、醛基、卤素、羟基、烷氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的吡喃基；含有包括^- ( 的垸基、硝基、羧基、酯基、醛基、卤素、羟基、烷氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的噻吩基；含有包括 d- C₄的'烷基、硝基、羧基、酯基、醛基、卤素、羟基、烷氧基、胺基、酰胺基、碳酰胺基、巯基、甲硫基、乙硫基在内的任意一个、两个或者三个取代的吡咯基。本发明的化合物可以是一个特定的立体异构体，例如 R-或 S-构型，或它们的混合物，例如，外消旋混合物。这里考虑的化合物包括所有具有药物活性的化合物种类，或其溶液或混合物。还包括其水合类型，例如这些化合物的水溶液，水解产物或电离产物；并且这些化合物可含有不同数量的结合水分子。 Wherein A _ri is '. aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing dC ₄ 1⁄2 alkyl, exact, carboxyl, thiol Any one, two or three substituted aryl groups, an aldehyde group, a hydroxy group, a methoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; ^-C ₄ alkyl, nitro, carboxy, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio One, two or three substituted 2-, 3-, or 4-position pyridyl groups; containing (^-(^ thiol, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, oxynitride) Any one, two or three substituted furyl groups including an amino group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; a thiol group including a thiol group, a nitro group and a carboxyl group; , ester group, aldehyde group, halogen, hydroxy group, alkoxy group, amine group, amide group, carboxamide group, sulfhydryl group, methyl sulfide Any one, two or three substituted pyranyl groups including an ethylthio group; containing a fluorenyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen, a hydroxyl group, an alkoxy group, an amine Any one, two or three substituted thienyl groups including a amide group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; an alkyl group including a d-C ₄ group, a nitro group, a carboxyl group, Any one, two or three substituted pyrrolyl groups such as an ester group, an aldehyde group, a halogen, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group or an ethylthio group. The compound of the present invention may be a specific stereoisomer, such as the R- or S-configuration, or a mixture thereof, for example, a racemic mixture. Compounds contemplated herein include all classes of pharmaceutically active compounds, or solutions or mixtures thereof. Also included are hydration types thereof, such as aqueous solutions, hydrolysates or ionized products of these compounds; and these compounds may contain varying amounts of bound water molecules.

本发明的化合物可用任何合适的酸以其药物学上可接受的盐的形式来制备。例如，无机酸如盐酸、氢溴酸、硝酸、硫酸、磷酸等；有机酸诸如甲酸、乙酸、丙酸、苯甲酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸等；烷基磺酸如甲基磺酸、乙基磺酸等；芳基磺酸如苯磺酸、对甲苯磺酸等均可使用。组合物 The compounds of the invention may be prepared in the form of their pharmaceutically acceptable salts with any suitable acid. For example, inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, etc.; A sulfonic acid such as methanesulfonic acid or ethylsulfonic acid; an arylsulfonic acid such as benzenesulfonic acid or p-toluenesulfonic acid can be used. combination

本发明药物组合物即包括一种选择性式 I取代噻唑 -4酮化合物或其药物学上可接受的盐的治疗有效量和一种或几种糖尿病治疗药物包括胰岛素增敏剂、赋形剂、辅料组成的药物组合物。 The pharmaceutical composition of the present invention comprises a therapeutically effective amount of a selective I substituted thiazol-4-one compound or a pharmaceutically acceptable salt thereof, and one or more diabetes therapeutic agents including insulin sensitizers, excipients And a pharmaceutical composition composed of an auxiliary material.

根据本发明，本发明的化合物，单独或与其它药剂，载体或赋形剂联合，为任何合适的给药途径制定制剂，例如腔内注射、皮下注射、静脉内注射、肌内注射、真皮内注射、口服或局部用药。本方法可以使用注射给药制剂，以单剂量的形式在安瓿，或多剂量容器中与添加的缓冲剂注射给药。制剂可釆取以下形式如混悬液、溶液或在油性或水性媒介中的乳液。制剂可以含有配方试剂如混悬剂、稳定剂和 /或分散剂。此外，使用前，活性成分可以粉末形式与合适的载体，无菌无热源水或其他溶剂构成剂型。本发明的局部用药可采用泡沫，凝胶，软膏，油膏，转皮膜片，或膏状物。 According to the invention, the compounds of the invention, alone or in combination with other agents, carriers or excipients, are formulated for any suitable route of administration, for example, intraluminal, subcutaneous, intravenous, intramuscular, intradermal Injection, oral or topical. The method can be administered by injection in a single dose in an ampoule, or in a multi-dose container with an additional buffer. The formulations may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles. The formulations may contain formulating agents such as suspending, stabilizing and/or dispersing agents. In addition, prior to use, the active ingredient may be in the form of a powder in the form of a suitable carrier, sterile non-pyrogenic water or other solvent. The topical medicament of the present invention may be a foam, a gel, an ointment, an ointment, a transdermal patch, or a paste.

任何合适的给药途径均可被采用。剂型包括片剂，锭剂，豆状胶囊，分散剂，悬浮剂，溶液，胶囊，膜片及类似物等。 Any suitable route of administration can be employed. Dosage forms include tablets, lozenges, lenticular capsules, dispersing agents, suspending agents, solutions, capsules, films and the like.

在实际应用中，本发明的化合物，单独或与其他制剂联合，可以按照一般药物学混合技术与药物载体或赋形剂，例如 β一环糊精和 2—羟基一丙基一 β—环糊精紧密混和'。根据投药的需要，可釆用通用载体、局部或非肠道途径的特殊载体。制备非肠道剂型，例如静脉内注射或灌输的组合物，可采用类似的药物媒质，本领域技术人员所公知的水，乙二醇，油，缓冲剂，糖，防腐剂，脂质体等。这种非肠道组合物的例子包括，但不限制于 5%W/V的右旋糖，生理盐水或其他溶液。本发明的化合物的总剂量，单独或和其他制剂联合给药，可用小瓶静脉注射液给药，体积大约从 1毫升到 2000毫升。根据给药的总剂量，稀释液量也会不同。 In a practical application, the compound of the present invention, alone or in combination with other preparations, may be in accordance with a general pharmaceutical mixing technique with a pharmaceutical carrier or excipient such as β-cyclodextrin and 2-hydroxy-propyl-β-cyclodextrin. Finely blended'. Depending on the needs of the administration, a special carrier, a special carrier for the local or parenteral route can be used. For the preparation of parenteral dosage forms, such as compositions for intravenous injection or infusion, similar pharmaceutical vehicles can be employed, water, glycols, oils, buffers, sugars, preservatives, liposomes, etc., which are well known to those skilled in the art. . Examples of such parenteral compositions include, but are not limited to, 5% w/v dextrose, physiological saline or other solutions. The total dose of the compound of the present invention, alone or in combination with other preparations, can be administered in vial vials in a volume of from about 1 ml to about 2000 ml. The amount of diluent will vary depending on the total dose administered.

本发明还提供了实现治疗方案的药盒。该药盒将有效剂量的本发明化合物以药物学上可接受的形式单独或与其他试剂联合，包含在一个或多个容器中。优选的药物形式是与无菌盐水，右旋糖溶液，缓冲溶液，或其他药物学上可接受的无菌液体合用。或者，组合物可被冻干或干燥；在这种情况下，药盒任选地进一步将一种药物学上可接受的溶液，优选无菌的溶液包含在一个容器中，以重新组成复合物形成用于注射目的的溶液。典型的药物学上可接受的溶液是生理盐水和右旋糖溶液。 The invention also provides a kit for achieving a therapeutic regimen. The kit comprises an effective amount of a compound of the invention in a pharmaceutically acceptable form, alone or in combination with other agents, in one or more containers. A preferred pharmaceutical form is in combination with sterile saline, dextrose solution, buffered solution, or other pharmaceutically acceptable sterile liquid. Alternatively, the composition may be lyophilized or dried; in this case, the kit optionally further comprises a pharmaceutically acceptable solution, preferably a sterile solution, in a container to reconstitute the complex A solution for injection purposes is formed. Typical pharmaceutically acceptable The solution is saline and dextrose solution.

在另一个实施方案中，本发明的药盒进一步包含用于注射组合物的优选以无菌形式包装的针或针筒和 /或包装的酒精垫。可任选地包括供医生或患者使用的说明书。 In another embodiment, the kit of the present invention further comprises a needle or syringe and/or a packaged alcohol pad for injection of the composition, preferably in a sterile form. Instructions for use by a doctor or patient may optionally be included.

下面结合实施例对本发明作进一步的描述，但不限制本发明。 The invention is further described below in conjunction with the examples without restricting the invention.

实施例 Example

本发明的化学结构通式中所涵盖的化合物可用下述通法制备：

The compounds encompassed by the chemical structural formula of the present invention can be prepared by the following general methods:

称取 l eq噻唑， 1. 7 eq芳香醛， 2. 8 eq醋酸钠，适量的冰醋酸，加热回流 1天，冷却，倒入水中，乙酸乙酯提取，水洗,干燥，过滤,浓缩后用乙酸乙酯 /石油醚重结晶，得产物。实验仪器及试剂 Weigh 1 eq thiazole, 1. 7 eq aromatic aldehyde, 2. 8 eq sodium acetate, appropriate amount of glacial acetic acid, heat reflux for 1 day, cool, pour into water, extract with ethyl acetate, wash with water, dry, filter, concentrate and use The ethyl acetate/petroleum ether was recrystallized to give the product. Experimental instruments and reagents

HP1100 HPLC系统，具备二元梯度泵、在线真空脱气机、自动进样器、柱温箱和光二极管阵列检测器。色谱柱为 ZORBAX ODS (4.6 x 250 mm), 流动相为甲醇 /水 =80:20，流速为 1 ml/min，检测波长为 254 nm。熔点采用 IA6304型熔点仪测定； iHNMR 由 Varian Mercury-300型核磁共振仪测得（溶剂为 CDC1₃，其内标为 TMS或 CD₃OD或 DMSO-d₆); ESI-MS由 AB Mariner型质谱仪测得， EI由 Finnigan MAT95型质谱仪测得。合成中所用原料均为市售产品。 HP1100 HPLC system with binary gradient pump, online vacuum degasser, autosampler, column oven and photodiode array detector. The column was ZORBAX ODS (4.6 x 250 mm), the mobile phase was methanol/water = 80:20, the flow rate was 1 ml/min, and the detection wavelength was 254 nm. The melting point was measured by a IA6304 melting point apparatus; the iHNMR was measured by a Varian Mercury-300 nuclear magnetic resonance spectrometer (solvent CDC1 ₃ with internal standard TMS or CD ₃ OD or DMSO-d ₆ ); ESI-MS by AB Mariner mass spectrometry The instrument was measured by EI by a Finnigan MAT95 mass spectrometer. The raw materials used in the synthesis are all commercially available products.

下面结合具体实施例对本发明作进一步阐述，但不限制本发明。 The invention is further illustrated by the following specific examples, without limiting the invention.

实施例一： Embodiment 1:

Ar_ICONHNH-^ll-S + C1CH₂C00H-

Ar _I CONHNH- ^ll -S + C1CH ₂ C00H-

称取 1 eq碳酸钠溶于适量的水中，加入 1 eq的氯乙酸，反应液冒泡，搅拌半小时后加入化合物 1的水溶液 (le q化合物 1加适量水)，搅拌过夜.加入 1 N HC1调节 pH至酸性，冷却, 析出固体，过滤，烘干，得浅黄色固体。加入二氧六环，加热回流 1小时，冷却，减压蒸去溶剂，乙醇重结晶，获得以下化合物：

Weigh 1 eq of sodium carbonate dissolved in an appropriate amount of water, add 1 eq of chloroacetic acid, the reaction solution is bubbling, stir for half an hour, then add the aqueous solution of compound 1 (le q compound 1 plus appropriate amount of water), stir overnight. Add 1 N HC1 The pH was adjusted to be acidic, cooled, solids were precipitated, filtered and dried to give a pale yellow solid. Dioxane was added, and the mixture was heated under reflux for 1 hour, cooled, and the solvent was evaporated under reduced pressure.

iHNMR (300MHz, DMSO-d₆): δ 4.505(s, 1H), 7.506-7.666(m, 4H) iHNMR (300MHz, DMSO-d ₆ ): δ 4.505 (s, 1H), 7.506-7.666 (m, 4H)

EI (m/e): 286, 251, 141, 139。

01 EI (m/e): 286, 251, 141, 139.

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'(HI 's) II '(HI ^es) 6i7£ I '(IK '^ZH8 H ' W 'PP) ^L-m'L '(HI 's) OWL XUZ ' ZL=i 'Ρ) 66VLSLVL %RZ '∞) iVL- WL '(H£ '∞) lei'L-H^L '(Ηΐ '^ZH8'A=f 'P) nZL- 'L HZ '^)9Z&9-L6 '9 '(IK's) 66Γζ '(H£'s) 6L '£ 9 :(⁹P"OS a ¾iW 00£) "H1A [腿工 '(HI 's) II '(HI ^e s) 6i7£ I '(IK ' ^Z H8 H ' W 'PP) ^L-m'L '(HI 's) OWL XUZ ' ZL=i 'Ρ) 66VLSLVL %RZ '∞) iVL- WL '(H£ '∞) lei'LH^L '(Ηΐ ' ^Z H8'A=f 'P) nZL- 'L HZ '^)9Z&9-L6 '9 '(IK's) 66Γζ '(H£'s) 6L '£ 9 :( ⁹ P"OS a 3⁄4iW 00£) "H1A [leg work

'(HI 's)i08'll XUZ

'P)966'/,- 6"L '(HI 's)906'乙 '( HI ' L H6'9=f 'VV)H L-L99'L XHZ HS 'WL=[ 'ΡΡ)9Ι9·乙- UZ 'ΖΗ6·9=1" 'Ρ) Z0^L-6LYL '(HI ¾9'9=£ ^lWL-eiYL '(HI ¾9"9=£ 'v Z' L-ZLi' L XUZ ^e^)Z £'L '(HZ 'zH/8-f 'V^ZZ'L- eVL '(HZ's) ςθΖ'ξ '(H£'s) £88'£ S ^:(⁹P"OSIA[a '^ΗΙΜ 00£) ΉΙΙΝΗ, '(HI 's)i08'll XUZ

'P)966'/,- 6"L '(HI 's)906'B'( HI ' L H6'9=f 'VV)H L-L99'L XHZ HS 'WL=[ 'ΡΡ)9Ι9· B - UZ 'ΖΗ6·9=1"'Ρ) Z0^L-6LYL '(HI 3⁄49'9=£ ^lWL-eiYL '(HI 3⁄49"9=£ 'v Z'L-ZLi' L XUZ ^e ^ ) Z £ 'L' (HZ 'zH / 8-f' V ^ ZZ'L- eVL '(HZ's) ςθΖ'ξ' (H £ 's) £ 88' £ S: (9 P "OSIA [a ' ^ΗΙΜ 00£) Oh,

.S9T00/900ZM3/X3d CSC600/Z.00Z OAV ει

.S9T00/900ZM3/X3d CSC600/Z.00Z OAV Ει

"(HN ^ss) iSfU '(Η£ ' ) -L~9S6'L '(Η£ ' L—U9' L '(HK '∞) WL-e^L m ∞) I 'Z, Χϊίί '∞) 6LVL-\5VL '(HS 'sq ) SZi^ ΧΉΖ 'sq ) 8Λ0·£ S :(⁹P-OS I 'z丽 oo ε) ^IAI H,

^{"(HN s s) iSfU '} (Η £') -L ~ 9S6'L '(Η £' L-U9 'L' (HK '∞) WL-e ^ L m ∞) I' Z, Χϊίί '∞ 6LVL-\5VL '(HS 'sq ) SZi^ ΧΉΖ 'sq ) 8Λ0·£ S :( ⁹ P-OS I 'z丽oo ε) ^IAI H,

•(Hl's)l9e'8 '(IK 'Ρ)096·Α— 9 £6·乙 '(Ηΐ 's) 008·乙 '(HZ '∞) \WL-i6^L•(Hl's)l9e'8 '(IK 'Ρ)096·Α— 9 £6·B '(Ηΐ 's) 008·B '(HZ '∞) \WL-i6^L

(HZ, '∞) ίζς -ίςζ-L '(He '∞) XRZ ^£S) SZYS S :(⁹P-os \ta 'ZHW οοε) ^NH.

LYL - OZYL '(Hi ' 'L=i ' ) ^TL-MZL '(IK § :(⁹P_OSIAia '^HH 00£)

(HZ, '∞) ίζς -ίςζ-L '(He '∞) XRZ ^£ S) SZYS S :( ⁹ P-os \ta 'ZHW οοε) ^NH.

LYL - OZYL '(Hi ''L=i' ) ^TL-MZL '(IK § :( ⁹ P_OSIAia '^HH 00£)

•(HI 's) WU '(HI 's) 606·乙 XUZ »1* 'Ρ) ίί^ί-ξ ^ί '(Η9 '«ι) LL H L UZ '∞) iiZL-e^YL '(HI 's) 19VL '(HI 's) 826"9 '(Ηΐ 's) 006.9 '(IK ¾6'9 =f ¾ 9^Z-f-6£ '(HE 's) XUZ 'ΖΗ6'9=Γ ¾ 60r£-£90X 9 ^:(⁹P"OSWa '^ΐΏΝ.00 £) "S NHr

•(HI 's) WU '(HI 's) 606·B XUZ »1* 'Ρ) ίί^ί-ξ ^ί '(Η9 '«ι) LL HL UZ '∞) iiZL-e^YL '( HI 's) 19VL '(HI 's) 826"9 '(Ηΐ 's) 006.9 '(IK 3⁄46'9 =f 3⁄4 9^Zf-6£ '(HE 's) XUZ 'ΖΗ6'9=Γ 3⁄4 60r£-£90X 9 ^: ( ⁹ P"OSWa '^ΐΏΝ.00 £) "S NHr

"(HI 's) LSVU '(HI 's) £S£ l '(H2 9l6'Z,-S06-/, '(HZ iLS'L-li^L '(HS '∞) 6εε·/τΖ6Γ \ΥίΖ 9Ζ '(HZ '∞) 6Ζ6·9_906·9 \ΉΖ ¾9'£=1"(HI 's) LSVU '(HI 's) £S£ l '(H2 9l6'Z,-S06-/, '(HZ iLS'L-li^L '(HS '∞) 6εε·/τΖ6Γ \ ΥίΖ 9Ζ '(HZ '∞) 6Ζ6·9_906·9 \ΉΖ 3⁄49'£=1

¾ 06z -8/,3 '(Ηε 's) zwz '(ΗΖ ^W£=[ i80'£-oz.o'£ s :(⁹P-os a ' οοε) ¾HNH_T ¾ 06z -8 /, 3 '( Ηε' s) zwz '(ΗΖ ^ W £ = [i80' £ -oz.o '£ s :( 9 P-os a' οοε) ¾HNH T

'(HI 's)8S8'n '(HI 's) LZ

'(HI '(HI 's)8S8'n '(HI 's) LZ

'(HI

Z.S9T00/900Z 3/13d CSC600/-00Z OAV PI Z.S9T00/900Z 3/13d CSC600/-00Z OAV PI

•(HN's) 9Ϊ6-Π '(HI 's) L '(HI H6'9=f 'Ρ) 'L-\L 'L '(HI '∞) Κ9·乙 -009 i '∞) it ' L-IW L '(HZ- IWL-QZ L \YiZ 's) ΙΙΖ'ξ 9 :(⁹P—OSWa 'z麵 00£)丽腿 !

•(HN's) 9Ϊ6-Π '(HI 's) L '(HI H6'9=f 'Ρ) 'L-\L 'L '(HI '∞) Κ9·B-009 i '∞) it ' L -IW L '(HZ- IWL-QZ L \YiZ 's) ΙΙΖ'ξ 9 :( ⁹ P-OSWa 'z face 00 £) Leg!

"(HN 's) 8*n '(HI 's) WL '(HZ 'Z/8=f 'Ρ) WLL-Z^L '(H6 ZWL-l^L '(He ^Ηί'Ζ=ΐ 'Ρ) m L '(He 's) ίΖΖ'ς δ :(⁹P_OS願 00 £)爾腿 _t "(HN 's) 8*n '(HI 's) WL '(HZ 'Z/8=f 'Ρ) WLL-Z^L '(H6 ZWL-l^L '(He ^Ηί'Ζ=ΐ 'Ρ' m L '(He 's) ίΖΖ'ς δ :( ⁹ P_OS will 00 £) er leg _t

•(HN 's) 9£8'n '(H£ '∞) 966·Α·0Α6·Α '(ΗΙ'^) £69 -699 Χ ίΖ ：∞) 819'乙 -£6ς·乙 '(ΗΙ'∞) OOS' ,-^-/, '(Η9 '^m) i9ZL-^lZL '(RZ '∞) LSYL-Z£VL UZ '^sc09S0 '■(HZ 'ΖΗ6·9=Γ Ί) \6LZ-Z Z XtiZ ¾9'9=1 ¾ I80 _6S0'2 S ^:(⁹P"OSIMa ^H 00£) ΉΗΝΗ_Τ goo

• (HN 's) 9£8'n '(H£ '∞) 966·Α·0Α6·Α '(ΗΙ'^) £69 -699 Χ ίΖ :∞) 819'B-£6ς·B'( ΗΙ'∞) OOS' , -^-/, '(Η9 ' ^m ) i9ZL-^lZL '(RZ '∞) LSYL-Z£VL UZ ' ^sc 09S0 '■(HZ 'ΖΗ6·9=Γ Ί) \ 6LZ-ZZ XtiZ 3⁄49'9=1 3⁄4 I80 _6S0'2 S ^: ( ⁹ P"OSIMa ^H 00£) ΉΗΝΗ _Τ goo

•(HN 's) SSfll '(PK '∞) 066·乙 _£96·乙 '(Η£ ' L_ 9' L '(ΕΚ Π9'ί-Ζ6ζ'ί '(HA ς Ζί-Ζ 'ί '(HZ; 'sq) 060 '(EK ^csq) 6£L'Z RZ 990Z, 9 :(⁹P"OS^ia H 00£) ¾ ΝΗ_Τ • (HN 's) SSfll '(PK '∞) 066·B_£96·B'(Η£ 'L_ 9' L '(ΕΚ Π9'ί-Ζ6ζ'ί '(HA ς Ζί-Ζ 'ί '(HZ;'sq)060' (EK c sq) 6 £ L'Z RZ 990Z, 9 :( 9 P "OS ^ ia H 00 £) ¾ ΝΗ Τ

'(HN'^s)6£8'n'(HN' ^s )6£8'n

( ZL6'L '(HI £697 SI9'A '(IK '∞) 69'L '(HI '∞) '(HA '∞) LWL-^ZL(ZL6'L '(HI £697 SI9'A '(IK '∞) 69'L '(HI '∞) '(HA '∞) LWL-^ZL

(HI '∞) 19YL-9ZYL '(RZ 'sq) Z,8S '(HK 'sq) 6L0'£ δ ^:(⁹P_OSWa ¾I 00C) ¾ NH_T

(HI '∞) 19YL-9ZYL '(RZ 'sq) Z,8S '(HK 'sq) 6L0'£ δ ^: ( ⁹ P_OSWa 3⁄4I 00C) 3⁄4 NH _T

.S9l00/900ZN3/X3d CSC600/.00i OAV £1 .S9l00/900ZN3/X3d CSC600/.00i OAV £1

"(HI 's) ZZS '∞) £8· τΙ8·Α '(IK ¾5"8=： 'Ρ) ί9·ί_Ρ9·ί XHZ ¾8'8=£ 'Ρ) ZS'L-eVL (m '« WL-e^L '(HZ; 'ΖΗ8'8=Γ 'p) IYL- 0'L '(IK 's) ζΥζ s :(^£DGD ^HW 00£) ¾PMNH_T "(HI 's) ZZS '∞) £8· τΙ8·Α '(IK 3⁄45"8=: 'Ρ) ί9·ί_Ρ9·ί XHZ 3⁄48'8=£ 'Ρ) ZS'L-eVL (m '« WL-e^L '(HZ;'ΖΗ8'8=Γ'p) IYL- 0'L '(IK 's) ζΥζ s :( ^£ DGD ^HW 00£) 3⁄4PMNH _T

"(HI 's) 8^8 '(HI 'ζΗίΉ 'Ρ) L^L~WL '(HI 's) Z 'L '(HI¾K =r ' ) Z^L-\^L UL '∞) WL-iZL '(HI

"(HI 's) 8^8 '(HI 'ζΗίΉ 'Ρ) L^L~WL '(HI 's) Z 'L '(HI3⁄4K =r ' ) Z^L-\^L UL '∞) WL -iZL '(HI

t70 -00 ΗΖ 'zHS'Z,=f L -Z-ZS'Z '(ΙΚ ' ) 0ZZ-£VZ S -(^£\DQD 謂 00£) 顺顧 _T

T70 -00 ΗΖ 'zHS'Z,=f L -Z-ZS'Z '(ΙΚ ' ) 0ZZ-£VZ S -( ^£ \DQD 00£) Follow _T

'(HI 's) LV2 '(Ηΐ 'ΖΗΓ =Γ 'Ρ) 9^L~WL '(HI 's) Z 'L XUi '∞) L-IVL '(H9 '∞) iZ'L-lcL ΧΚΖ 8'8-f 'Ρ) ¾)·Ζτ86·9 '(HK ¾K'9=f'(HI 's) LV2 '(Ηΐ 'ΖΗΓ =Γ 'Ρ) 9^L~WL '(HI 's) Z 'L XUi '∞) L-IVL '(H9 '∞) iZ'L-lcL ΧΚΖ 8'8-f 'Ρ) 3⁄4)·Ζτ86·9 '(HK 3⁄4K'9=f

¾ 90 -^o Xm ' vi^s: ¾ 98 -ΐ8τ 'OFK '∞) οζτ-ςοτ g :( α。腦 οοε)湖腿【 3⁄4 90 -^o Xm ' vi^s: 3⁄4 98 -ΐ8τ 'OFK '∞) οζτ-ςοτ g :( α. 脑 οοε) Lake Leg [

'P) 96'L-WL '(HI 's)

\m 'z腦 'ε=Γ 'ρ) ζς-ι-ις-ί '(HS ςνι-θ£-ί '(HI 'S) VL'L '(HI ^nfi=i 'p) w ir乙 '(HS '∞) εθ'Α-10'A '(HZ; Γε 9 ^:(^£ QD 'ΖΗ 00£) ¾[ NH_t

\m 'z brain'ε=Γ 'ρ) ζς-ι-ις-ί '(HS ςνι-θ£-ί '(HI 'S) VL'L '(HI ^nfi=i 'p) w ir B '(HS '∞) εθ'Α-10'A '(HZ; Γε 9 ^: ( ^£ QD 'ΖΗ 00£) 3⁄4[ NH _t

'(HI 's) 9 8 '(HI 'ΖΗ£· =Γ 'Ρ) £6 '(HI 's) 8 ^C(H£ 0S'Z W£ '(H9 '∞) Α£·Ζτ6ζ·乙 (HZ 'ΖΗ5·8=Γ 'Ρ) 00'Z, '(ΗΚ Η6·9=ί '(HK'ZH6'9=JT ¾ PV£ S ^:(^£10QO 'zH ^i 00£) ¾WNH_T

'(HI 's) 9 8 '(HI 'ΖΗ£· =Γ 'Ρ) £6 '(HI 's) 8 ^C (H£ 0S'ZW£ '(H9 '∞) Α£·Ζτ6ζ·B ( HZ 'ΖΗ5·8=Γ 'Ρ) 00'Z, '(ΗΚ Η6·9=ί '(HK'ZH6'9=JT 3⁄4 PV£ S ^: ( ^£ 10QO 'zH ^i 00£) 3⁄4WNH _T

Z.S9T00/900ZN3/X3d ε¾ε6θο/ζ.οοζ OAV

Z.S9T00/900ZN3/X3d ε3⁄4ε6θο/ζ.οοζ OAV

¾6zδ),H() §£6mfASZs-.. •.

3⁄46zδ), H() §£6mfASZs-.. •.

™MR (300 MHz, DMSO-d₆): δ 2.03-2.08 (m, 2H), 2.73-2.78 (t, J=7.1Hz, 2H), 1224.09 (bs, 2H) 7.13-7.32 (m， 7H), 7.52-7.68 (m, 6H)， 8.05 (s, IH).

TMMR (300 MHz, DMSO-d ₆ ): δ 2.03-2.08 (m, 2H), 2.73-2.78 (t, J=7.1Hz, 2H), 1224.09 (bs, 2H) 7.13-7.32 (m, 7H) , 7.52-7.68 (m, 6H), 8.05 (s, IH).

mww7020 Mww7020

¹HNMR (300 MHz, DMSO-d₆): δ 2.01-2.08 (m, 2H), 2.74-2.79 (t， J=7.4Hz, 2H), 4.03-4.07 (t, J=6.3Hz, 2H), 7.11-7.14 (d, J=7.4Hz, 2H), 7.19-7.32 (m, 6H), 7.47-7.62 (m， 5H), 8.07 (s, IH). ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 2.01-2.08 (m, 2H), 2.74-2.79 (t, J = 7.4 Hz, 2H), 4.03-4.07 (t, J = 6.3 Hz, 2H), 7.11-7.14 (d, J=7.4Hz, 2H), 7.19-7.32 (m, 6H), 7.47-7.62 (m, 5H), 8.07 (s, IH).

'HNMR (300 MHz, DMSO-d₆): δ 3.06-3.10 (t, J=6.9Hz, 2H), 4.26-4.30 (t, J=6.9Hz, 2H), 7.11-7.15 (dd， J=2.75Hz, J=8.5Hz, 1H)， 7.24-7.37 (m, 7H), 7.46-7.62 (m, 5H), 8.08 (s, IH).

'HNMR (300 MHz, DMSO-d ₆ ): δ 3.06-3.10 (t, J=6.9 Hz, 2H), 4.26-4.30 (t, J=6.9 Hz, 2H), 7.11-7.15 (dd, J=2.75 Hz, J=8.5Hz, 1H), 7.24-7.37 (m, 7H), 7.46-7.62 (m, 5H), 8.08 (s, IH).

mww7022 Mww7022

^IHNMR (300 MHz, DMSO-d₆): δ 5.187 (s, 2H), 7.215-7.294 (m, 3H), 7.336-7.536 (m， 8H)_; 7.593-7.611 (m, 2H), 8.048 (s, IH).

^I H NMR (300 MHz, DMSO-d ₆ ): δ 5.187 (s, 2H), 7.215-7.294 (m, 3H), 7.336-7.536 (m, 8H) _; 7.593-7.611 (m, 2H), 8.048 (s , IH).

mww7023 Mww7023

'HNMR (300 MHz, DMSO-d₆): δ 1.95-2.17 (m, 2H), 2.732-2.782 (t, J=8.1Hz, 2H), 4.042 (bs, 2H), 7.095-7.146 (m, IH), 7.18-7.344 (m,7H), 7.422-7.545 (m, 1H)， 7.743-7.961 (m, 4H), 8.062 (s: IH). 'HNMR (300 MHz, DMSO-d ₆ ): δ 1.95-2.17 (m, 2H), 2.732-2.782 (t, J=8.1Hz, 2H), 4.042 (bs, 2H), 7.095-7.146 (m, IH ), 7.18-7.344 (m,7H), 7.422-7.545 (m, 1H), 7.743-7.961 (m, 4H), 8.062 (s: IH).

实施例三：生物活性测试 Example 3: Biological activity test

1. 材料设备 Material equipment

1.1 质粒和细胞株： 1.1 Plasmids and cell lines:

人源性 PPAR-γ 表达质粒、人源 RXR 表达质粒为美国 Addgene 公司产品 (Add_gene.MA,USA);非洲绿猴肾细胞 CV-1和小鼠前脂肪细胞 3T3-L1购自美国模式菌种收集中心 (American Type Culture Collection, ATCC); 含 PPAR-γ反应元件的萤光素酶报告基因载体购自美国 Panomics公司 (Panomics, USA)。 The human PPAR-γ expression plasmid and the human RXR expression plasmid were added to the American Addgene company (Add _gene. MA, USA); the African green monkey kidney cell CV-1 and the mouse pre-adipocyte 3T3-L1 were purchased from the American model strain. Collection center (American Type Culture Collection, ATCC); Luciferase reporter vector containing PPAR-gamma response elements was purchased from Panomics, USA (Panomics, USA).

1.2试剂和材料： - 胎牛血清（Fetal bovine serum, FBS, GIBCO/BRL, USA); 活性炭和葡聚糖处理胎牛血清（CD-FBS, Hyclone， USA); DMEM培养基（GIBCO/BRL, USA); 萤光素酶检测试剂盒 1.2 Reagents and materials: - Fetal bovine serum (FBS, GIBCO/BRL, USA); Activated carbon and dextran treatment of fetal bovine serum (CD-FBS, Hyclone, USA); DMEM medium (GIBCO/BRL, USA); Luciferase Assay Kit

(Promega Corporation, USA); Fugene 6 (Roche Ltd., USA); PPAR-γ蛋白为 PPAR-γ基因转染的昆虫细胞表达产物；阳性对照药物罗格列酮（BRL4965, Cayman, USA); [1H]BRL49653 (53 Ci/mmol, American Radiolabeled Chemicals, Inc., USA); 生物素结合蛋白包被的 SPA微球(Promega Corporation, USA); Fugene 6 (Roche Ltd., USA); PPAR-γ protein is a PPAR-γ gene transfected insect cell expression product; positive control drug rosiglitazone (BRL 4965, Cayman, USA); 1H]BRL49653 (53 Ci/mmol, American Radiolabeled Chemicals, Inc., USA); Biotin-binding protein-coated SPA microspheres

(Amersham, USA); 96孔同位素检测板（FlashPlate™, PerkinElmer, USA); 甘油三酯检测试剂盒（亚太生物技术有限公司，中国）。 (Amersham, USA); 96-well isotope assay plate (FlashPlateTM, PerkinElmer, USA); Triglyceride assay kit (Asia Pacific Biotechnology Co., Ltd., China).

1.3 仪器： 1.3 Instrument:

Wallac 1420 读板机（PerkinElmer, USA) ; 二氧化碳培养箱（Forma, USA ) ; Wallac MicroBeta®液闪计数仪（TriLux 1450, PerkinElmer, USA) Wallac 1420 Plate Reader (PerkinElmer, USA); Carbon Dioxide Incubator (Forma, USA); Wallac MicroBeta® Liquid Flash Counter (TriLux 1450, PerkinElmer, USA)

2. 实验方法和结果 2. Experimental methods and results

2.1 受体结合活力测试 2.1 Receptor binding viability test

在反应缓冲液中（25 mM NaH₂P0₄， 80 mM KCL, 0.5 mM MgCl₂和 10%甘油， 4°C调 pH值到 7.4) 加入生物素标记的 PPAR-γ反应元件（Biotin-PPRE) 与鲑鱼精 DNA，使它们的浓度分别达到 0.2 mg/L与 10 mg/L, 充分混匀后以每孔 200 μΐ加入 FlashPlate, 4°C孵育过夜，次日吸弃孔中溶液后，加入 200 缓冲液清洗两次，吸净孔中的缓冲液后每孔加入 5 阳性对照药或待筛样品，将 FlashPlate™置于 4°C备用。在一定量的反应缓冲液中加入 DTT、 CHAPS、 EDTA、抑肽酶（Aprotinin) 、亮抑酶肽（Leupeptin)和 [³H]BRL49653 (罗格列酮），使它们的浓度分别达到 1 mmol/L、 5 mmol/L、 1 mmol/L、 2 mg/L、 ΙΟΟ μηιοΙ/L和 10 nmol/L,随后加入受体 PPAR-y(73 g/mL)与 RXRa (6 g/mL) ,充分混勾，向 FlashPlate™ 中加入 195 上述溶液， 4°C孵育一定时间后在 MicroBeta液闪计数仪上读取数据。化合物浓度设定为 0， 0.003 μΜ, 0.016 μΜ, 0.08 μΜ, 0.4 μΜ, 2 μΜ, 10 μΜ, 100 μΜ八个梯度，阳性药浓度设定为 0， 0.3 ηΜ, 1.6 ηΜ, 8 ηΜ, 40 ηΜ, 200 ηΜ, 1000 ηΜ, 10000 ηΜ八个梯度。实验结果见表 1。化合物 mww7008、 7012、 7018、 7020、 7022和 mww7023具较好的受体结合活性，其 IC_5Q值均小于 300 nM。 Add biotin-labeled PPAR-γ response element (Biotin-PPRE) in reaction buffer (25 mM NaH ₂ P0 ₄ , 80 mM KCL, 0.5 mM MgCl ₂ and 10% glycerol, adjusted to pH 7.4 at 4 ° C) With salmon sperm DNA, make them concentration of 0.2 mg / L and 10 mg / L, mix well, add FlashPlate at 200 μΐ per well, incubate overnight at 4 ° C, aspirate the solution in the well the next day, add 200 buffer The solution was washed twice. After the buffer in the well was removed, 5 positive control drugs or samples to be sieved were added to each well, and the FlashPlateTM was placed at 4 ° C for use. Add DTT, CHAPS, EDTA, aprotinin, Leupeptin and [ ³ H]BRL49653 (Rosiglitazone) to a certain amount of reaction buffer to a concentration of 1 mmol /L, 5 mmol/L, 1 mmol/L, 2 mg/L, ΙΟΟ μηιοΙ/L and 10 nmol/L, followed by the addition of the receptor PPAR-y (73 g/mL) and RXRa (6 g/mL), Fully mix the hook, add 195 to the FlashPlateTM solution, and read the data on a MicroBeta liquid scintillation counter after incubation at 4 °C for a certain period of time. The compound concentration was set to 0, 0.003 μΜ, 0.016 μΜ, 0.08 μΜ, 0.4 μΜ, 2 μΜ, 10 μΜ, 100 μΜ eight gradients, and the positive drug concentration was set to 0, 0.3 ηΜ, 1.6 ηΜ, 8 ηΜ, 40 ηΜ , 200 ηΜ, 1000 ηΜ, 10000 ηΜ eight gradients. The experimental results are shown in Table 1. The compounds mww7008, 7012, 7018, 7020, 7022 and mww7023 have better receptor binding activities with IC _5Q values of less than 300 nM.

表 1 活性化合物与 PPAR-γ的结合活力 Table 1 Binding activity of active compounds with PPAR-γ

化合物编号 IC_So (nM) Compound number IC _S o (nM)

罗格列酮（阳性对照） 181 Rosiglitazone (positive control) 181

mww7008 30 Mww7008 30

mww7012 39 mww7018 34 Mww7012 39 Mww7018 34

mww7020 188.7 Mww7020 188.7

mww7022 209.9 Mww7022 209.9

mww7023 236.9 Mww7023 236.9

SH0012671 211 SH0012671 211

2.2报告基因表达检测 2.2 Report gene expression detection

HeLa细胞培养在含 10%FBS和 2 mM L型谷氨酸盐的 DMEM培养基中。转染前一天换成含 10%CD-FBS的 DMEM培养基，转染采用 Fugene6转染试剂。将人源性 PPAR-γ表达质粒、 RXR表达质粒和蛮光素酶报告基因质粒以 1:1:10的比例混勾，质粒和 Fugene6的比例为 1:3，混合均匀后加入细胞中。在 37°C及 5%C0₂条件下培养 6小时。细胞消化后以 5000 个 /100 μΐ/孔接入 96孔培养板，用含 10%CD-FBS的 DMEM培养基于 37°C培养 2小时。加入待测化合物，培养 24小时后，应用萤光素酶检测试剂盒检测酶活性，以此评估化合物对 PPAR-γ的药理活性。阳性药和化合物浓度均设定为 50 μΜ， ΙΟμΜ, 2 μΜ， 0.4μΜ, 0.08μΜ, 0.016μΜ, 0.0032μΜ, 结果见表 2。化合物 mww7008、 7012、 7018、 7020、 7022和 7023 均显示激动活性，且其 EC_5C)值小于 10 μ Μ。计算化合物效能时，以 50 μ Μ的罗格列酮引起的荧光素酶活性为 100%，其中 mww7012的相对活性最高，为 BRL49653的 68%。 HeLa cells were cultured in DMEM medium containing 10% FBS and 2 mM L-type glutamate. The day before transfection, the cells were replaced with DMEM medium containing 10% CD-FBS, and transfected with Fugene6 transfection reagent. The human PPAR-γ expression plasmid, the RXR expression plasmid and the luciferase reporter gene plasmid were mixed at a ratio of 1:1:10, and the ratio of the plasmid to Fugene6 was 1:3, and the cells were uniformly mixed and added to the cells. Incubation was carried out for 6 hours at 37 ° C and 5% CO ₂ . After the cells were digested, the cells were inserted into a 96-well culture plate at 5000 cells/100 μM/well, and cultured in DMEM medium containing 10% CD-FBS at 37 ° C for 2 hours. The test compound was added, and after 24 hours of culture, the luciferase assay kit was used to detect the enzyme activity, thereby evaluating the pharmacological activity of the compound against PPAR-γ. The concentration of the positive drug and the compound were set to 50 μΜ, ΙΟμΜ, 2 μΜ, 0.4 μΜ, 0.08 μΜ, 0.016 μΜ, 0.0032 μΜ, and the results are shown in Table 2. Compounds mww7008, 7012, 7018, 7020, 7022 and 7023 all showed agonistic activity with an EC _5C) value of less than 10 μΜ. When calculating the potency of the compound, the luciferase activity caused by 50 μM of rosiglitazone was 100%, and the relative activity of mww7012 was the highest, which was 68% of BRL49653.

表 2化合物在细胞水平对 PPAR-γ的激动活性 The agonistic activity of the compounds of Table 2 on PPAR-γ at the cellular level

2.3前脂肪细胞诱导分化实验 2.3 pre-adipocyte differentiation experiment

3T3-L1细胞接入 24孔板，待长满 2天后，以含 10%胎牛血清的 DMEM培养基培养，同时加入 Ι μΜ地塞米松、 1 g/mL胰岛素和不同浓度的待测化合物，于 37°C及 10%CO₂条件下培养 3天，换同样培养液和化合物继续培养两天，弃培养液，以含 10%胎牛血清和 1 g/inL胰岛素的 DMEM培养基培养 2天，弃培养液， PBS洗一遍。细胞样品按甘油三酯检测试剂盒的说明进行检测。吸收波长 505 nM，参比波长 690 nM。阳性药和化合物浓度均设为 5 μΜ，结果见附图 2。化合物 mww7008、 7012和 7020的数值显著高于空白孔，表明它们可诱导前脂肪细胞分化和脂肪贮积，为 PPAR-γ激动剂。 *表示与空白对照进行 t检验， P<0.05 o . 实验结论 3T3-L1 cells were inserted into 24-well plates. After 2 days, they were cultured in DMEM medium containing 10% fetal bovine serum, and ΙμΜ dexamethasone, 1 g/mL insulin and different concentrations of test compounds were added. Incubate for 3 days at 37 ° C and 10% CO ₂ , continue to culture for the same culture medium and compound for two days, discard the culture solution, and culture for 2 days in DMEM medium containing 10% fetal bovine serum and 1 g/inL insulin. Discard the culture solution and wash it with PBS. Cell samples were tested as described in the Triglyceride Assay Kit. The absorption wavelength is 505 nM and the reference wavelength is 690 nM. The positive drug and compound concentrations were set to 5 μΜ, and the results are shown in Figure 2. The values of the compounds mww7008, 7012 and 7020 were significantly higher than those of the blank wells, indicating that they induced pre-adipocyte differentiation and fat accumulation as PPAR-gamma agonists. * indicates t test with blank control, P < 0.05 o . Experimental results

(1)化合物 mww7008、 7012、 7018、 7020、 7022和 7023可与罗格列酮竞争结合 PPAR-γ 受体，其中化合物 _mwW7008、 7012、 7018具有较好的结合活性， IC₅o值小于 50 ηΜ ；(1) Compounds mww7008, 7012, 7018, 7020, 7022 and 7023 can compete with rosiglitazone for binding to PPAR-γ receptors, wherein compounds _mwW 7008, 7012, 7018 have good binding activity and IC ₅ o values are less than 50. ΜΜ;

(2)报告基因表达检测证实化合物 mww7008、7012、 7018、7020、 7022和 7023为 PPAR-γ 激动剂，在前脂肪细胞诱导分化实验中，化合物 mww7008、 7012和 7020可诱导前脂肪细胞分化，显示 PPAR-γ激动活性，提示其具有进一步开发成为新型胰岛素增敏剂的潜力。 SH0012671在本发明使用的细胞水平筛选模型中未显示生物活性。 ' (2) Reporter gene expression assay confirmed that compounds mww7008, 7012, 7018, 7020, 7022 and 7023 were PPAR-γ agonists. In the pre-adipocyte differentiation assay, compounds mww7008, 7012 and 7020 induced preadipocyte differentiation, showing PPAR-γ agonistic activity suggests a potential for further development as a novel insulin sensitizer. SH0012671 does not show biological activity in the cell level screening model used in the present invention. '

Claims

Rights request

1. A substituted thiazol-4-one derivative having the following structural formula: and a pharmaceutically acceptable salt:

Wherein Ar is any one of the following substituents: aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing alkyl containing (^-(: ₄ ) Any one, two or three of a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group. Substituted aryl; containing (: ₄ alkyl, nitro, carboxy, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, B Any one, two or three substituted 2, 3-, or 4-position pyridyl groups including a thio group; containing an alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, or a group including (^-C ₄ ) , any hydroxy, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents furanyl; comprising comprising (^ - ₍₄ Alkyl, nitro, carboxy, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, Amide groups, mercapto, methylthio, ethylthio, including one, two or three of the substituents pyranyl; include C containing _'4 C embankment group, a nitro group, a carboxyl group, an ester group, an aldehyde group, any of halogen, hydroxy, alkoxy embankment, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents thienyl; include d- C ₄ containing the Any one or two of an alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, or Three substituted pyrrolyl groups;

X is 0, S, NH or H;

Y is 0, S;

Z is any of the following substituents:

Ar, - n=0~4

Ar,

Wherein Ar is: aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing alkyl, nitro, carboxyl, ester group including d-, Any one, two or three substituted aryl groups including an aldehyde group, a halogen, a hydroxyl group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; ₄ alkyl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, Any one, two or three substituted 2-, 3-, or 4-position pyridyl groups including a methylthio group and an ethylthio group; containing an alkyl group, a nitro group, a carboxyl group, an ester group, and an aldehyde group including Cr Any one, two or three substituted furanyl groups such as halogen, hydroxy, decyloxy, amino, amido, carboxamido, decyl, methylthio, ethylthio; including C'-C any of a group ₄ of the embankment, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy embankment, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including two Or three substituted pyranyl groups; containing Cr ( ₄ alkyl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, Any one, two or three substituted thienyl groups including a methylthio group or an ethylthio group; containing an alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, and an alkyl group including d-(: ₄ ) Oxyl, amine, amide, carboxamide, sulfhydryl, methylthio, ethyl sulphide Any one, two or three substituted pyrrolyl groups within the base.

2. A substituted thiazole-4-one derivative according to claim 1 wherein:

0 When Z is ^Αί ', Ar and An each independently substitute an aryl group; 2-, 3-, or 4-position pyridyl; furyl; P-pyranyl; thienyl; pyrrolyl; Containing an alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, etc. including a C1-C4 group. Any one, two or three substituted aryl groups; containing an alkyl group including a C1-C4 group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, a decyloxy group, an amine group, an amide group, a carboxamide group Any one, two or three substituted 2-, 3-, or 4-position pyridyl groups including a mercapto group, a methylthio group, an ethylthio group; an alkyl group, a nitro group, a carboxyl group, including a C1-C4 group; Any one, two or three substituted furyl groups including an ester group, an aldehyde group, a halogen, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Including C1-C4 alkyl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, 'alkane Any one, two or three substituted pyranyl groups including an amino group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group, and an alkyl group including a C1-C4 group, a nitro group, Any one, two or three substituted thiophenes including a carboxyl group, an ester group, an aldehyde group, a halogen, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Containing an alkyl group including a C1-C4 group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Any one, two or three substituted pyrrolyl groups;

X is 0, S, NH or H;

Y is 0, S.

3. A substituted thiazol-4-one derivative according to claim 1 wherein:

When Ar and An are each substituted by an aryl group, respectively, or the same one;

3-, or 4-pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing alkyl, nitro, carboxy, ester, aldehyde, halogen, hydroxy, alkoxy including C1-C4 Any one, two or three substituted aryl groups, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; an alkyl group including a C1-C4 group, a nitro group, a carboxyl group, Ester group, Any one, two or three substituted 2-, 3-, or an aldehyde group, a halogen, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, or 4-position pyridyl; containing alkyl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, Any one, two or three substituted furanyl groups including an ethylthio group; containing an alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, an alkoxy group, an amine group, and the like, including a C1-C4 group; Any one, two or three substituted pyranyl groups including an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; a thiol group including a C1-C4 group, a nitro group, a carboxyl group, an ester group, Any one, two or three substituted thienyl groups including an aldehyde group, a halogen, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; C4 alkyl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, Any one, two or three substituted pyrrolyl groups including an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a 'methylthio group, an ethylthio group;

X is 0, S, NH or H;

Y is 0, S.

4. A substituted thiazol-4-one derivative according to claim 1 wherein: Z is

When, each of Ar, each independently or the same is substituted for an aryl group; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing an alkyl group including C1-C4, Any one, two or three substitutions of a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group An aryl group; containing a C1-C4 alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methyl group, an ethyl group Any one, two or three substituted 2-, 3-, or 4-position pyridyl groups including a thiol group including a C1-C4 group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, and a hydroxyl group. Any one, two or three substituted furyl groups including an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; a thiol group including a C1-C4 group, a nitrate Base, carboxyl group, ester group, aldehyde group, halogen, hydroxyl group, decyloxy group, amine group, amide Any one, two or three substituted pyranyl groups including a carboxamide group, a mercapto group, a methylthio group, an ethylthio group; a mercapto group including a C1-C4 group, a nitro group, a carboxyl group, an ester group, and an acid group Any one, two or three substituted thienyl groups, including a C1-C4 group, a hydroxy group, a methoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; Any one or two of an alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, or Three substituted pyrrolyl groups;

X is 0, S, NH or H;

Y is 0, S.

5. A substituted thiazol-4-one derivative according to claim 1 wherein:

Each of Ati is substituted with an aryl group, either alone or in the same group; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing alkyl, nitro, including C1-C4, Any one, two or three substituted aryl groups such as a carboxyl group, an ester group, an aldehyde group, a halogen, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group. Containing alkyl, nitro, carboxyl, ester, aldehyde groups including C1-C4, Any one, two or three substituted 2-, 3-, or 4-positions of a halogen, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group Pyridyl; containing alkyl, nitro, carboxy, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio, including C1-C4 Any one, two or three substituted furanyl groups; containing an alkyl group including a C1-C4 group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, an alkoxy group, an amine group, an amide group, Any one, two or three substituted pyranyl groups including a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; a thiol group including a C1-C4 group, a nitro group, a carboxyl group, an ester group, an acid group, Any one, two or three substituted thiopanyl groups including a halogen, a hydroxyl group, an alkoxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; Sulfhydryl, nitro, carboxyl, ester, aldehyde, hydroxy, methoxy, Any one, two or three substituted pyrrolyl groups including an amine group, an amide group, a carboxamide group, a benzyl group, a methylthio group, and an ethylthio group;

X is 0, S, recommended or H;

Y is 0, s.

The substituted thiazole-4-one derivative according to Claim 1, which is characterized in that when a chiral carbon is present in the molecule, the compound is a racemate or an optically active substance.

7. A process for the preparation of a substituted thiazol-4-one derivative according to Claim 1 and a pharmaceutically acceptable salt thereof, comprising the steps of:

l eq thiazole, l~2 eq aromatic aldehyde, 2~4 eq sodium acetate or potassium acetate, an appropriate amount of glacial acetic acid, heated to reflux for more than 2 hours.

l eq chloroacetic acid, 1~2 eq sodium carbonate or sodium bicarbonate, leq potassium salt, water as solvent, react at 15 - 60 °C for more than 5 hours, dilute HC1 to acidity, precipitate solids, filter and dissolve into dioxane Ring or dichloromethane, heated to reflux for more than 1 hour.

8. A pharmaceutical composition for treating or preventing a disease or a symptom caused or accompanied by insulin secretion and/or dysfunction, the composition comprising as an active ingredient, according to any one of claims 1 to Substituted Thiazol-4-one Derivative Substituted Thiazol-4-one Derivative Substituted Thiazol-4-one Derivatives and pharmaceutically acceptable salts of such compounds and their association with other molecules or carriers.

9. The pharmaceutical composition according to claim 8, further comprising a pharmaceutically acceptable carrier and an excipient.

The substituted thiazole-4 ketone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 for use in the preparation of a disease or a symptom caused or accompanied by the treatment and/or prevention of insulin secretion and/or dysfunction The use of the drug.

11. Use according to claim 10, wherein the disease or condition is caused or accompanied by insulin secretion and/or dysfunction.

12. Use according to claim 1.1, wherein the disease or condition caused or accompanied by insulin secretion and/or dysfunction comprises, but is not limited to, diabetes and its complications, insulin resistance or obesity and the like.

13. The method of claim 12, wherein the disease or condition is caused by resistance or toxic side effects to an already marketed diabetes therapeutic, including an insulin sensitizer.

A joint preparation comprising the substituted thiazole-4-one derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 and other diabetes therapeutic agents including insulin sensitizers.

15. The combination according to claim 14, wherein the insulin sensitizer comprises, but is not limited to, rosiglitazone, troglitazone, pioglitazone and the like.

16. A method of treating or preventing a disease or condition caused or accompanied by insulin secretion and/or dysfunction, the method comprising administering to a subject in need or willingness to receive treatment or prevention an effective amount of the combination preparation of claim 14 or A pharmaceutically acceptable salt thereof, thereby treating or preventing the disease or condition.

A kit comprising the substituted thiazol-4-one derivative according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and the use of the substituted thiazol-4-one derivative or A pharmaceutically acceptable salt thereof is used to treat or prevent an indication of a disease or condition caused or accompanied by insulin secretion and/or dysfunction.

18. A kit comprising the combination of claim 14 and instructions for using the combination to treat or prevent a disease or condition caused or accompanied by insulin secretion and/or dysfunction.