WO2007009389A2 - Substituted propanamide derivatives, preparation and use thereof - Google Patents

Abstract

The present invention provides compounds of formula (I), the preparation thereof and their use as peroxisome proliferator activated receptor-Ϝ (PPAR-Ϝ) agonist in the treatment of diabetes and diabetic complications.

Description

一类取代丙酰胺衍生物、 其制备方法和用途 技术领域 本发明涉及一类过氧化物酶体增殖子 γ 活化受体 （Peroxisome Proliferator-activated Receptor-γ, PPAR-γ)激动剂， 具体指一类取代丙 （烯）酰胺类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  FIELD OF THE INVENTION The present invention relates to a class of peroxisome proliferator-activated Receptor-γ (PPAR-γ) agonists, specifically A small molecule organic compound that is substituted with a propylene (olefin) amide derivative, which serves as a PPAR-gamma agonist for medical use 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 型糠尿病占患病群体的 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 贝 (J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^ 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 excess insulin, but the sensitivity of target cells to insulin is reduced (also known as "insulin resistance"). , leading to relatively 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 neurological damage, and severe shellfish (J causes gangrene in the extremities. Statistics show that diabetes has become the third largest human after cancer and cardiovascular disease Killer. Based on the study of insulin signal transduction pathway, designing and developing insulin sensitizer to improve insulin resistance is the focus of new drugs for the treatment of 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 ) 噻唑垸二酮 (Thiazolidinediones, TZD) 类， 如曲格列酮 （Troglitazone)、 罗格列酮 （Rosiglitazone)和 吡格列酮 （PiogHtazone)等； 2)双胍类， 如二甲双胍、 苯乙双胍和丁双胍等； 3 ) β 3-肾上 腺素受体激动剂和胰髙血糖素受体拮抗剂； 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 ( PiogHtazone); 2) biguanides, such as metformin, phenformin and buformin; 3) β 3-adrenoreceptor agonists and glucagon receptor antagonists; 4) fatty acid metabolism interfering agents, such as relying on 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（Clofibmte, 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) [Lelimann 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 Clofibmte (hypolipidemic), and subsequent studies have shown that TZD significantly enhances insulin-targeted tissue reactivity to insulin, whereas in the absence of insulin, TZD does not lower blood glucose. . In 1995, Lehmann et al. found that the molecular target of TZD drugs in vivo is peroxisome proliferator activation. γ (Peroxisome Proliferator Activated Receptor-γ, PPAR-γ) [Lelimann 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 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 O., Frachart 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'-flanking region. J Biol Chem. 1997, 272(40): 25252-9]。  The PPAR-γ single copy gene is encoded on human chromosome 3 and has 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 Receptors: nuclear control of metabolism. Endocr Rev. 1999, 20(5): 649-88]. Upon activation of small molecule ligands, PPAR-γ forms a heterodimer with retinoic acid receptor X (RXR) and then binds to a specific DNA sequence called PPAR Response Element (PPRE). Transcriptional factors regulate the transcription of target genes [Blanquart C., Barbier O., Frachart 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'-flanking region. J Biol Chem. 1997, 272(40): 25252-9].

PPAR-γ主要分布于脂肪、 免疫***、 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.] o 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。 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 JH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。 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 terms of insulin resistance and glucose metabolism, activation of PPAR-γ promotes glucose uptake and transport by adipocytes and skeletal muscle cells, regulates adipocyte signal transduction, induces differentiation of brown adipose tissue, and increases uncoupling protein UCP1 and Expression of 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.] o There are also reports in the literature that PPAR-γ has a certain role in inhibiting tumors and improving atherosclerosis. In addition to rosiglitazone and pioglitazone, PPAR-gamma agonists currently used in the treatment of type 2 diabetes have multiple drug JHs in preclinical or clinical research, including Darglitazone of TZD and Farglitazar of non-TZD. 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丙（烯）酰胺类衍生物的小分子化合物。受体结合活力试验和报告 基因活化检测均证明这类化合物与 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 substituted with propylene (acrylamide) derivatives by applying various PPAR-γ-based high-throughput drug screening models and structure-activity relationship studies of active samples. Both the receptor binding activity assay and the reporter gene activation assay demonstrated that these compounds specifically bind 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化合物的取代丙（烯）酰胺衍生物及其药学上可 以接受的盐；  It is an object of the present invention to provide a substituted propylene (en)amide derivative having a compound of formula I and a pharmaceutically acceptable salt thereof;

本发明的另一目的在于提供了一种制备式 I衍生物的方法；  Another object of the present invention is to provide a process for the preparation of a derivative of formula I;

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

本发明的再一目的在于提供了式 I衍生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 derivative of the formula I for the treatment or prevention of a peroxisome proliferator-activated receptor gamma agonist for 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： '  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:

其中 为下列任意一种取代基： 包括 d- ( 的烷基、 硝基、 羧基、 酯基、 醛基、 卤素、 羟基、 d-Cd的垸氧基、胺基、酰胺基、碳酰胺基、 巯基、 甲硫基、 乙硫基和包括以下在内的任意一 个、 两个或者三个取代基： ' Wherein is any of the following substituents: including d-(alkyl, nitro, carboxy, ester, aldehyde, halogen, hydroxy, d-Cd decyloxy, amine, amide, carboxamide, Sulfhydryl, methylthio, ethylthio and any one, two or three substituents including: '

其中 Ar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^- ( 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 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 2-、 3-、 或 4-位吡啶基； 含有包括 C, - 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呋喃基； 含有包括(^- C₄的垸 基、 硝基、 敷基、 酯基、 酸基、 素、 轻基、 焼氧基、 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吡喃基； 含有包括 Cr 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噻吩基； 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吡咯基。 为11、 CH₃。 为甲酰胺基、氰基、硫代甲酰胺基。

Wherein Ar is: aryl; 2-, 3-, or 4-position of the pyridine group; furyl; tetrahydropyranyl; thienyl; pyrrolyl; ^ contains include - ₍₄ alkyl group, a nitro group, a carboxyl group, an ester group Any one, two or three substituted aryl groups, 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 thiol, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio, etc. , two or three substituted 2-, 3-, or 4-position pyridyl groups; containing an alkyl group including a C, -C ₄ group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, a decyloxy group Any one, two or three substituted furanyl groups, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, and a fluorenyl group including (^-C ₄ , a nitro group, Substrate, ester group, acid group, element, light group, decyloxy group, amine group, amide group, carboxamide group, sulfhydryl group Methylthio, ethylthio, including any one, two or three substituents pyran group; an alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, halogen, hydroxy, oxo embankment comprising Cr C ₄ to Any one, two or three substituted thienyl 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 (^-(: ₄ ) Any one, two or three substitutions of a 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 decyl group, a methylthio group, an ethylthio group The pyrrolyl group is 11. CH ₃ . Is a carboxamide group, a cyano group, a thiocarboxamide group.

C₂-C₃为饱和或不饱和双键。 C ₂ -C ₃ is a saturated or unsaturated double bond.

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 compounds for use in the treatment or prevention of diabetes and its complications.

再一方面， 本发明涉及联合制剂， 该联合制剂包括一种具有选择性的激动过氧化物酶体 增殖子 γ活化受体， 尤其是激活该受体功能的化合物， 或其药物学上可接受的盐， 或单独， 或与药物学上可接受的载体或赋形剂组合存在。 该化合物具有以下分子式 I：

In a further aspect, the present invention relates to a combination preparation comprising a selective agonistic peroxisome proliferator gamma activating receptor, in particular a compound which activates the function of the receptor, or a pharmaceutically acceptable compound thereof The salt, either alone or in combination with a pharmaceutically acceptable carrier or excipient. This compound has the following formula I:

I  I

其中 R为下列任意一种取代基： 包括 CrC的'垸基、硝基、 羧基、 酯基、 醛基、 卤素、 羟基、 d-C₄的烷氧基、 胺基、 酰胺基、碳酰胺基、 巯基、 甲硫基、 乙硫基和包括以下在内的任意一 个、 两个或者三个取代基： Wherein R is any one of the following substituents: including a fluorenyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen, a hydroxyl group, an alkoxy group of dC ₄ , an amine group, an amide group, a carboxamide group, a fluorenyl group , methylthio, ethylthio and any, two or three substituents including:

\₀ ^·_ΑΓ η-0~5 \ ₀ ^· _ΑΓ η-0~5

其中 Ar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 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芳基； 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 2-、 3-、 或 4-位吡啶基； 含有包括

Wherein Ar is: aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing alkyl, nitro, carboxyl, ester, aldehyde including C ₄ Any one, two or three substituted aryl groups including 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; any alkyl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including a _4, two Or three substituted 2-, 3-, or 4-position pyridyl groups;

CrC 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呋喃基； 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吡喃基； 含有包括 Cr ( 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 - (^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。 为 CH₃。 R₃为甲酰胺基、氰基、硫代甲酰胺基。 Any one or two of CrC alkyl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, decyloxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio three or substituted furanyl; ^ contains include - C ₄ alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen, hydroxy, alkoxy, amine, amide, carboxamide, mercapto, a Any one, two or three substituted pyranyl groups including a thio 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, an alkoxy group including Cr ( ₄ ) Any one, two or three substituted thienyl groups, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, and an alkyl 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. is CH _3. R ₃ is a carboxamide, cyano, thio formamido

C₂-C₃为饱和或不饱和双键。 C ₂ -C ₃ is a saturated or unsaturated double bond.

本发明提供了包括上述联合制剂的药盒。本发明还进一步提供了应用上述联合制剂治疗 或预防糖尿病及其并发症的方法和药盒，达到选择性地激活过氧化物酶体增殖子 γ活化受体 的药效， 改善糠尿病患者的胰岛素抵抗状态。 The present invention provides a kit comprising the above combined preparation. The present invention still further provides a method and a kit for treating or preventing diabetes and its complications by using the above combined preparation, to selectively activate the peroxisome proliferator γ-activated receptor The efficacy of the drug improves the insulin resistance of patients with diabetes.

生物活性测试  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 K Hoc表达质粒为獒国 Addgene 公司产品' (Addgene. . A_SUSA); 人***上皮细胞 HeLa购自美国模式菌种收集中心 (American Type Culture Collection, ATCC); Biotin-PPRE脱氧核苷酸片段为人工合成。 The human PPAR-γ expression plasmid, the human K Hoc expression plasmid is the product of the Addgene company of Australia [Addgene. . A _S USA); the human cervical cancer epithelial cell HeLa is purchased from the American Type Culture Collection (American Type Culture Collection). , ATCC); Biotin-PPRE deoxynucleotide fragments are synthetic.

1.2 试剂和材料：  1.2 Reagents and materials:

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) ; 荧光素酶检测试剂盒 (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 BRL4965 (Cayman, USA); [³H]BRL49653 (53 Ci/mmol, American Radiolabeled Chemicals, Inc., USA)； 生物素结合蛋白包被的 SPA微球（ Amersham, USA); 96孔同位素检测板 （FlashPlate™, PerkinElmer, USA)。 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 protein is an insect cell transfected PPAR-γ gene expression product; positive control BRL4965 (Cayman, USA); [ 3 H] BRL49653 (53 Ci/mmol, American Radiolabeled Chemicals, Inc., USA); Biotin-binding protein-coated SPA microspheres (Amersham, USA); 96-well isotope assay plate (FlashPlateTM, PerkinElmer, USA).

1.3 仪器：  1.3 Instrument:

Walkc 1420 读板机 （PeridnEImer, USA) ; 二氧化碳培养箱 （Forma, USA ) ; Wallac MicroBeta®液闪计数仪（TriLux 1450, PerkinElmer, USA)。  Walkc 1420 plate reader (PeridnEImer, USA); carbon dioxide incubator (Forma, USA); Wallac MicroBeta® liquid scintillation 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 NaH₂PO₄,, , 80 mM KCL， 0.5 mM MgCl₂和 10%甘油， 4°C调 pH值到 7.4)加入 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 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 Fl shPlat_e™ 置于 4°C备用。 在一定量的反应缓冲液中加入 DTT、 CHAPS ^ EDTA、 aprotinin、 leupeptin 和 [³H]BRL49653，使它们的浓度分别达到 1 mmoI/L、5 mmol/L、 1 mmol/L、2 mg/L, 100 mol/L 和 10 nmol/L,随后加入受体 PPAR-y(73 g/mL)与 RXRa(6 g/niL)，充分混匀，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, ΙΟ Μ, 100 μΜ八个梯度， 阳性药浓度设定为 0， 0.3 πΜ， 1.6 nM, 8 ηΜ, 40 η , 200 ηΜ, 1000 ηΜ, 10000 ηΜ八个 梯度。 实验结果见表 1。 化合物 mwwl 073具较好的受体结合活性， 其 IC_5Q值小于 1 μΜ。 表 1 活性化合物与 PPAR-γ的结合活力

Add Biotin-PPRE and squid DNA to the reaction buffer (25 mM NaH ₂ PO ₄ , , , 80 mM KCL, 0.5 mM MgCl ₂ and 10% glycerol, adjusted to pH 7.4 at 4 ° C) to make them The concentrations were 0.2 mg L and 10 mg/L, respectively. After mixing well, add FlashPlate to each well 200, incubate at 4 °C overnight, and then aspirate the solution in the well the next day, then add 200 buffer to wash twice. After the buffer, 5 positive control drugs or samples to be sieved were added to each well, and Fl shPlat _e TM was placed at 4 ° C for use. DTT, CHAPS ^ EDTA, aprotinin, leupeptin and [ ³ H]BRL49653 were added to a certain amount of reaction buffer to achieve concentrations of 1 mmoI/L, 5 mmol/L, 1 mmol/L, 2 mg/L, respectively. , 100 mol/L and 10 nmol/L, then add the receptor PPAR-y (73 g/mL) and RXRa (6 g/niL), mix well, add 195 above solution to FlashPlateTM, incubate at 4 °C The data was read on a MicroBeta liquid scintillation counter after 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, ΙΟ Μ, 100 μΜ eight gradients, and the positive drug concentration was set to 0, 0.3 πΜ, 1.6 nM, 8 ηΜ, 40 η , 200 ηΜ, 1000 ηΜ, 10000 ηΜ eight gradients. The experimental results are shown in Table 1. The compound mwwl 073 has better receptor binding activity and its IC _5Q value is less than 1 μΜ. Table 1 Binding activity of active compound to PPAR-γ

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-glutamine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、 RXRct表达质粒和荧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， 混合均匀后逐滴加入细胞中。 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， 应用荧光素酶检测试剂盒检测酶活性， 以此评估化合物对 PPA -γ的药理活性。阳性药和化合物浓度均设定为 4 μΜ、 20 μΜ和 100 μΜ，结果见附图 2。 化合物 mwwl073显示激动活性。 HeLa cells were cultured in DMEM medium containing 10% FBS and 2 mM L-glutamine. 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 RXRct expression plasmid and the luciferase reporter plasmid were mixed at a ratio of 1: 1:10, and the ratio of the plasmid to Fugene 6 was 1:3, and the mixture was uniformly mixed and added dropwise 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 cultured for 24 hours, and the activity of the compound against PPA-γ was evaluated by measuring the enzyme activity using a luciferase assay kit. The positive drug and compound concentrations were set to 4 μΜ, 20 μΜ and 100 μΜ, and the results are shown in Figure 2. Compound mwwl073 showed agonistic activity.

3. 实验结论 3. Experimental conclusion

( 1 ) 化合物 mwwl073可与罗格列酮（BRL49653 )竞争结合 PPAR-γ受体， 其 IC₅₀值 小于 1 μΜ ； (1) Compound mwwl073 can compete with rosiglitazone (BRL49653) for binding to PPAR-γ receptor with an IC ₅₀ value of less than 1 μΜ;

(2) 报告基因表达测实验证实 mwwl073为 PPAR-γ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。 附图说明  (2) Reporter gene expression assay confirmed that mwwl073 is a PPAR-γ agonist, suggesting its potential to be further developed into a novel insulin sensitizer. DRAWINGS

图 1是 PPAR-γ的蛋白结构域。  Figure 1 is the protein domain of PPAR-γ.

图 2.化合物对 PPAR-γ反应元件调控的荧光素酶报告基因表达的影响： 被测化合物在 100 μΜ时对 PPAR-γ产生激动效应。 具体实施方式  Figure 2. Effect of compounds on luciferase reporter gene expression regulated by PPAR-γ response elements: The test compound produced an agonistic effect on PPAR-γ at 100 μΜ. 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.

Α、 定义 ' Α, 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 related to the source of this patent All patents, applications, published applications and other publications and sequences in the Gene Bank and other databases are reversed by the definitions of income and citations, or when they are inconsistent, the definitions set forth in this section 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， 特点是慢性髙血糖， 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、 ***、 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 blood sugar, 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, 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 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 organism readily available to 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。 '  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. '

本文所用， 给予某一特定药物组合物 "改善" 某一特定疾病的症状是指任何减轻， 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, administration of a particular pharmaceutical composition to "improve" the symptoms of a particular disease means any reduction, whether permanent, temporary, prolonged, transient, can be attributed to or associated with the pharmaceutical composition. Relevant 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 物的药物前体。 [# J¾ Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, 1985， pages 388-392]。 术语 "基本上"相同或均匀或相似， 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。 As used herein, "prodrug" refers to a compound that is administered in vivo and which can be metabolized or converted to a biologically, pharmaceutically 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 of the drug in the body, 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]. The term "substantially" is the same or uniform or similar, and the understanding of the relevant art by those skilled in the art may vary in the context, and is generally at least 70%, preferably at least 80%, more preferably at least 90%, most Excellent 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 ¾、 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, a suspension, a liquid, a powder, an oil, an aqueous, a 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.

B、 过氧化物酶体增殖子 γ活化受体激动剂 B, peroxisome proliferator γ-activated receptor agonist

本发明提供过氧化物酶体增殖子 γ活化受体功能的激动剂，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：  The present invention provides an agonist of peroxisome proliferator gamma activating receptor function, which increases members of an insulin sensitizer. The present invention relates to a compound of the formula I, or a pharmaceutically acceptable salt thereof:

I  I

其中 R,为下列任意一种取代基： 包括 C「 C₄的垸基、 硝基、 羧基、 酯基、 醛基、 素、 羟基、 CrC₄的烷氧基、胺基、酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基和包括以下在内的任意一 个、 两个或者三个取代基- Wherein R is any of the following substituents: including C"C ₄ thiol, nitro, carboxyl, ester, aldehyde, hydroxy, hydroxy, CrC ₄ alkoxy, amine, amide, carboxamide Base, thiol, methylthio, ethylthio and any, two or three substituents including -

其中 Ar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- (：₄的焼基、 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(^- ( 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 2-、 3-、 或 4-位吡啶基； 含有包括 d-a 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 CrC₄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喃基； 含有包括 CrC 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。 为 C¾。 R₃为甲酰胺基、氰基、硫代甲酰胺基。 (：₂-(：₃为饱和或不饱和双键。 Wherein Ar is: aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing fluorenyl, nitro, carboxyl, ester including d- (: ₄ ) Base, aldehyde group, halogen, hydroxyl group, decyloxy group, amine group, amide group, carbon amide Any one, two or three substituted aryl groups including a thiol group, a thiol group, an alkylthio group, an ethylthio group, and an alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen, Any one, two or three substituted 2-, 3-, or 4-position pyridyl groups including a hydroxyl group, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, and an ethylthio group. Containing any one including da thiol, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio , two or three substituted furyl groups; containing an alkyl group including a CrC ₄ , 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, Any one, two or three substituted pyranyl groups including a methylthio group, an ethylthio group; containing a CrC alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen, a hydroxyl group, an alkoxy group, an amine Base, amide group, carboxamide group, sulfhydryl group, methylthio group, B Group, including any one, two or three substituents thienyl; dC containing alkyl with ₄ comprising, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen, hydroxy, alkoxy, amine, amide, Any one, two or three substituted pyrrolyl groups such as a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group. It is C3⁄4. R ₃ is a carboxamide group, a cyano group or a thiocarboxamide group. ₂ -(: ₃ is a saturated or unsaturated double bond.

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。  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. The 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 different amounts of bound water molecules.

本发明的化合物可按照任何合适的方法来制备或合成。 优选地， 用以下面 D节中引证 的合成法制备该化合物。  The compounds of the invention may be prepared or synthesized according to any suitable method. Preferably, the compound is prepared by the synthetic method cited in Section D below.

另外优选地， 该化合物或其药物学上可接受的盐以药物组合物的形式提供， 或者单独， 或者与一种药物学上可接受的载体或赋形剂结合。  Further preferably, the 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.

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。  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.

C、 联合制剂， 药盒 C, combined preparation, kit

另一方面， 本发明也涉及联合制剂， 这种联合包括一种选择性激动过氧化物酶体增殖子 γ活化受体功能的化合物， 或其药物学上可接受的盐， 和一种或多种糖尿病治疗药物包括胰 岛素增敏剂。  In another aspect, the invention also relates to a combination formulation comprising a compound that selectively agonizes the function of a peroxisome proliferator gamma activating receptor, or a pharmaceutically acceptable salt thereof, and one or more Diabetes treatments include insulin sensitizers.

优选地，这种联合用药包括本发明化合物或其药物学上可接受的盐和一种或多种糖尿病 治疗药物包括胰岛素增敏剂， 该化合物具有以下分子式 I：

Preferably, such a combination comprises a compound of the present invention or a pharmaceutically acceptable salt thereof and one or more therapeutic agents for diabetes, including an insulin sensitizer, which has the following formula I:

I  I

其中 为下列任意一种取代基： 包括 C「 ( ₄的烷基、 硝基、 羧基、 酷基、 醛基、 素、 羟基、 CrC₄的烷氧基、 胺基、 酰胺基、 碳酰胺基、 巯基、 甲硫基、 乙硫基和包括以下在内的任意一 个、 两个或者三个取代基: Wherein any one of the following substituents: a C "(alkyl, nitro, carboxyl, cool, aldehyde,, hydroxy, CrC ₄ alkoxy, amine, amide, carboxamide group _4, Sulfhydryl, methylthio, ethylthio and any one, two or three substituents including:

其中 Ar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(「 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芳基； 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 2-、 3-、 或 4-位吡啶基； 含有包括 Cr ( 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呋喃基； 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吡喃基； 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噻吩基； 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吡咯基。 为11、 C 。 R₃为甲酰胺基、 氰基、硫代甲酰胺基。 Wherein Ar is: aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing ("C ₄ alkyl, nitro, carboxyl, ester group" Any one, two or three substituted aryl groups, 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; ^_( ₄ alkyl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, decyloxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio, etc. one, two or three substituents 2-, 3-, or 4-position of the pyridine group; comprising containing Cr (group ₄ of the embankment, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy, Any one, two or three substituted furyl groups including an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; and a thiol group, a nitro group, a carboxyl group including (^-C ₄ ) , ester group, aldehyde group, halogen, hydroxy group, alkoxy group, amine group, amide group, carboxamide group, fluorenyl group Methylthio, ethylthio, including any one, two or three of the substituents pyranyl; comprising comprising (^ - (] ₄ alkyl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy Any one, two or three substituted thienyl groups, an anthracene group, an amino group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group, and an alkyl group including (^-C ₄ ) Any one, two or three of nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio Substituted pyrrolyl group is 11. C. R ₃ is a carboxamide group, a cyano group or a thiocarboxamide group.

C₂ - C₃为饱和或不饱和双键。 C ₂ - C ₃ is a saturated or unsaturated double bond.

在本发明的联合制剂中可以使用任何合适的糖尿病治疗药物包括胰岛素增敏剂。在一个 特定实施方案中，用于本发明联合制剂中可以包括上述糖尿病治疗药物包括胰岛素增敏剂中 的一种或多种。 Any suitable therapeutic agent for diabetes, including insulin sensitizers, can be used in the combination formulations of the invention. In a specific embodiment, the above-mentioned diabetes therapeutic agent, including an insulin sensitizer, may be included in the combined preparation of the present invention. One or more.

在另一个特定实施方案中， 提供了一种治疗或预防由胰岛素分泌和 /或功能紊乱引起或 伴随的疾病或症状的方法，该方法包括对需要和愿意接受治疗或预防的对象给予有效量的上 述联合制剂， 或其药物学上可接受的盐， 从而治疗或预防上述疾病或症状。  In another specific embodiment, a method of treating or preventing a disease or condition caused or accompanied by insulin secretion and/or dysfunction is provided, the method comprising administering an effective amount to a subject in need and willing to receive treatment or prevention The above combined preparation, or a pharmaceutically acceptable salt thereof, thereby treating or preventing the above diseases or symptoms.

在另一个特定实施方案中，提供了一个药盒，其中包括本发明的化合物或其药物学上可 接受的盐以及使用上述化合物或其药物学上可接受的盐来防治由胰岛素分泌和 /或功能紊乱 引起或伴随的疾病或症状的使用说明。  In another specific embodiment, there is provided a kit comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and the use of the above compound or a pharmaceutically acceptable salt thereof for controlling secretion and/or secretion by insulin Instructions for the use of a disease or condition caused by or associated with a dysfunction.

再一个实施方案中，提供了一个药盒，包括上述联合制剂及使用所述联合制剂治疗或预 防由胰岛素分泌和 /或功能紊乱引起或伴随的疾病或症状的使用说明。  In still another embodiment, a kit is provided comprising the combination described above and instructions for using the combination to treat or prevent a disease or condition caused or accompanied by insulin secretion and/or dysfunction.

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。 制剂可采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沬， 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 preparation of the present invention may be a foam, a gel, an ointment, an ointment, a transdermal patch, or a paste.

治疗或预防的剂量大小会因病情的严重性和给药途径而有所变化。剂量和用药频度会因 年龄、 体重、 健康状况和病人个体反应不同而不同。  The size of the dose to be treated or prevented will vary depending on the severity of the condition and the route of administration. The frequency of dosing and medication will vary depending on age, weight, health status and individual patient response.

需要指出的是 （诊治医生也应知道）， 根据毒性和副反应， 必须采取必要措施终止、 中 断或降低治疗剂量。 相反， 如果临床反应不明显 （排除毒性和副反应）， 医生应适当调整治 疗方案， 提高剂量。  It should be noted that (the doctor should also know), according to toxicity and side effects, necessary measures must be taken to terminate, interrupt or reduce the therapeutic dose. Conversely, if the clinical response is not obvious (excluding toxicity and side effects), the doctor should adjust the treatment plan appropriately to increase the dose.

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—环糊精和 2—羟基一丙基— 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。 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。 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-hydroxypropyl-β-cyclodextrin. Finely mixed. 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. 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 solutions are physiological saline and dextrose solutions.

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.

D、 实施例 D, embodiment

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（具体方法参见 Journal of Medicinal Chemistry, 1989,32(10):2344-52 )： The compounds encompassed by the chemical structural formula of the present invention can be produced by the following general methods (for details, see Journal of Medicinal Chemistry, 1989, 32(10): 2234-52):

l eq取代的丙酰胺， l~1.5 eq芳香醛，溶于适量乙醇、甲醇或异丙醇中，数滴哌啶， 60-100 °C反应 2小时以上。 实验仪器及试剂  l eq substituted propionamide, l~1.5 eq aromatic aldehyde, dissolved in appropriate amount of ethanol, methanol or isopropanol, several drops of piperidine, reacted at 60-100 °C for more than 2 hours. Experimental instruments and reagents

HP1100 HPLC***， 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； 1HNMR 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 Fiimigan MAT95型质谱仪测得。 合成中所用原 料均为市售产品。 实施例一: 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. Melting point was determined by IA6304 melting point apparatus; 1H NMR was measured by Varian Mercury-300 nuclear magnetic resonance spectrometer (solvent is 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 Fiimigan MAT95 mass spectrometer. The raw materials used in the synthesis are all commercially available products. Embodiment 1:

称取 l eq取代的丙酰胺， l eq芳香醛， 适量乙醇， 数滴哌啶， 加热回流 2小时以上， 冷却， n Weigh 1 eq of substituted propionamide, 1 eq of aromatic aldehyde, an appropriate amount of ethanol, a few drops of piperidine, heated to reflux for more than 2 hours, and cooled. n

°(H ^cs)560'8 '(HN 's)g08 '(HI ^RYZ=[ 'Ρ)889·乙 _ί89·乙 '(HI VZ °(H ^c s)560'8 '(HN 's)g08 '(HI ^RYZ=[ 'Ρ)889·B_ί89·B' (HI VZ

i Z 's  i Z 's

。(m

'ρρ)ιεΐ'8-ΠΓ8. (m

'ρρ)ιεΐ'8-ΠΓ8

(HI 'ZHS'I 'zH6X=f 'ΡΡ)ΚΟ·8_8εθ·8 '(HN 's)A08 '(HI ^)9L L '(HI ^UVS=£ ^iWL^WL '(HI

L-Oli' L XU£ 's)l£8 :(⁹P_0S1A[CI) NH_T (HI 'ZHS'I 'zH6X=f 'ΡΡ)ΚΟ·8_8εθ·8 '(HN 's)A08 '(HI ^)9L L '(HI ^UVS=£ ^iWL^WL '(HI

L-Oli' L XU£ 's)l£8 :( ⁹ P_0S1A[CI) NH _T

°(Ht 's)on'8 '(HN 'δ)0ΐ8·Ζ, '(HZ '^69^ '(Ηΐ ^H/8=f 'v ^ L- L (HI ^)9\VL '(HI ^£zHA*8=r 'P)9 ) "ZJ0 %ΕΖ 'S)HS '(H£ 'S)S£8'£••(⁹P-OSlA[a)¾nA[HH_! °(Ht 's)on'8 '(HN 'δ)0ΐ8·Ζ, '(HZ '^69^ '(Ηΐ ^H/8=f 'v ^ L- L (HI ^)9\VL '( HI ^£ zHA*8=r 'P)9 ) "ZJ0 %ΕΖ 'S)HS '(H£ 'S)S£8'£••( ⁹ P-OSlA[a)3⁄4nA[HH _!

°(HI ^cs)880-8 '(HN ^)6U'L '(HI '^IWL '(HI '∞)9乙 9·Λ '(Ηΐ ¾^'8=1 ^eV)SZ9'L-L6^'L '(Ht°(HI ^c s)880-8 '(HN ^)6U'L '(HI '^IWL '(HI '∞)9乙9·Λ '(Ηΐ 3⁄4^'8=1 ^e V)SZ9'L- L6^'L '(Ht

■^)lSVL-6Pi'L '(HI ⁽ VS=£ 'Ρ)902·/τ8乙 ΓL '(Η2 ^)iZVS '(Η£ 's)g 8'£••(⁹P"OSHa)¾[]AilvH₁ ■^)lSVL-6Pi'L '(HI ⁽ VS=£ 'Ρ)902·/τ8 ΓL '(Η2 ^)iZVS '(Η£ 's)g 8'£••( ⁹ P"OSHa)3⁄4 []AilvH ₁

•■ ^^r^^ m 。啄 '蒈 ^囂 'Ψ氺 γ「§ •■ ^^r^^ m .啄 '蒈 ^嚣 'Ψ氺 γ"§

^8.l00/900ZN3/X3d 68C600/.00Z OAV

^8.l00/900ZN3/X3d 68C600/.00Z OAV

¹HNMR(t>MSO-d₆): 3.808(s, 3H), 5.206(s, 2H), 7.231-7.259(dd, J=8.4Hz, 1.2Hz, IH), 7.352- 7.385(m, IH), 7.412(s, IH), 7.427-7.477(m, 2H), 7.534-7.562(d, J=8.4Hz, IH), 7.684(s, 2H), 7.793(s, NH), 8.104(s, 1H)。

2H), 7.174-7.203(d, J=8.7Hz, IH), 7.225-7.250(d, J=6.6Hz, IH), 7.288-7.358(m, 5H), 7.534-7.562(d J=8.4Hz, IH), 7.665(s, NH), 7.787(s, NH), 8.096(s, 1H)。 ¹ H NMR (t>MSO-d ₆ ): 3.808 (s, 3H), 5.206 (s, 2H), 7.231-7.259 (dd, J = 8.4 Hz, 1.2 Hz, IH), 7.352 - 7.385 (m, IH) , 7.412(s, IH), 7.427-7.477(m, 2H), 7.534-7.562(d, J=8.4Hz, IH), 7.684(s, 2H), 7.793(s, NH), 8.104(s, 1H ).

2H), 7.174-7.203(d, J=8.7Hz, IH), 7.225-7.250(d, J=6.6Hz, IH), 7.288-7.358(m, 5H), 7.534-7.562(d J=8.4Hz, IH), 7.665(s, NH), 7.787(s, NH), 8.096(s, 1H).

mwwl091  Mwwl091

¹蘭 MR(DMSO-d₆): 3.053-3.099(t, J=6.9Hz, 2H), 3.857(s, 3H), 4.187-4.234(t, J=6.9Hz, 2H), 7.145-7.173 (d, J=8.4Hz, IH), 7.224-7.247(d, J=6.9Hz, IH), 7.3 0-7.357(m, 3H), 7.559-7.588(d J=8.7Hz, IH), 7.688(m, 2H), 7.768(s, NH), 8.094(s, 1H)。

¹ blue MR (DMSO-d ₆ ): 3.053-3.099 (t, J = 6.9 Hz, 2H), 3.857 (s, 3H), 4.187-4.234 (t, J = 6.9 Hz, 2H), 7.145-7.173 (d , J=8.4Hz, IH), 7.224-7.247(d, J=6.9Hz, IH), 7.3 0-7.357(m, 3H), 7.559-7.588(d J=8.7Hz, IH), 7.688(m, 2H), 7.768(s, NH), 8.094(s, 1H).

mww!097  Mww!097

'HNMRCDMSO-dg): 3.029-3.071(t, J=6.3Hz, 2H), 4.372-4.415(t, J=6.3Hz, 2H), 7.154-7.183 (d J=8.7Hz, 2H), 7.512-7.534(d, J=6.6Uz, 2H), 7.672(s, IH), 7.800(s, IH), 7.937-7.98 l(m, 4H), 8.058(s, IH), 8.104(s, 1H)。  'HNMRC DMSO-dg): 3.029-3.071 (t, J = 6.3 Hz, 2H), 4.372-4.415 (t, J = 6.3 Hz, 2H), 7.154-7.183 (d J = 8.7 Hz, 2H), 7.512-7.534 (d, J = 6.6 Uz, 2H), 7.672 (s, IH), 7.800 (s, IH), 7.937-7.98 l (m, 4H), 8.058 (s, IH), 8.104 (s, 1H).

Claims

权 利 要 求 Rights request

1. —类结构式如下的取代丙酰胺衍生物及其药学上可接受的盐：  1. A substituted propionamide derivative having the following structural formula: and a pharmaceutically acceptable salt thereof:

I  I

其中 为下列任意一种取代基： 包括 Cr ^的垸基、 硝基、 羧基、 酯基、 醛基、 卤素、 羟基、 C, - 的烷氧基、 胺基、酰胺基、碳酰胺基、 巯基、 甲硫基、 乙硫基和包括以下在内的任意一 个、 两个或者三个取代基： Wherein is any one of the following substituents: a mercapto group including a Cr ^ group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, a C, an alkoxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group , methylthio, ethylthio and any, two or three substituents including:

n=0 5  n=0 5

其中 Ar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 -( 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芳基； 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 2-、 3-、 或 4-位吡啶基； 含有包括 C, - (^的垸基、 硝基、 羧棊、 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^- 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喃基； 含有包括 C,- 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噻吩基； 含有包括 d- ( 的烷基、 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吡咯基。 为 C¾。 R₃为甲酰胺基、 氰基、 硫代甲酰胺 基。 c₂-c₃为饱和或不饱和双键。 Wherein Ar is: aryl; 2-, 3-, or 4-pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing alkyl, nitro, carboxy, ester, aldehyde Any one, two or three substituted aryl groups including 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; Any one or two of a mercapto 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 a three-substituted 2-, 3-, or 4-position pyridyl group; containing a thiol group, a nitro group, a carboxy group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, an alkoxy group, an amine group Any one, two or three substituted furanyl groups, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; an alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group including ?- Base, halogen, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio Any one, two or three substituted pyranyl groups including an ethylthio group; a mercapto group including a C, a C ₄ group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, a decyloxy group Any one, two or three substituted thienyl groups including an amino group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group, and an alkyl group, a nitro group, a carboxyl group, and the like 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 fluorenyl group, a methylthio group or an ethylthio group. C3⁄4. R ₃ is carboxamide, cyano, thiocarboxamide Base. c ₂ -c ₃ is a saturated or unsaturated double bond.

2. 根据权利要求 1所述的取代丙酰胺衍生物， 其特征在于 当 1^为\₀^^ 时， 其中 Ar为芳基； 2-、 3-、 或 4-位吡啶基； 呋喃基； 吡喃 基； 噬吩基； 吡咯基； 含有包括 C「 (：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、 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 d- ( 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呋 喃基； 含有包括 d- C₄ 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喃基； 含 有包括 C「 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噻吩基； 含有包括 C「C 烷基、 硝基、 羧基、 酯基、 醛基、 齒素、 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； 为 H、 CH_{3 ;} R₃ 为甲酰胺基、 氰基、 硫代甲酰胺基； C₂-C₃为饱和或不饱和双键。 2. The substituted propionamide derivative according to claim 1, wherein when 1^ is \ ₀ ^^, wherein Ar is an aryl group; 2-, 3-, or 4-pyridyl; furan; Pyranyl; phenylenyl; pyrrolyl; containing C" (: ₄ alkyl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, decyloxy, amine, amide, carboxamide Any one, two or three substituted aryl groups including a fluorenyl group, a methylthio group, an ethylthio group; containing an alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, and a halogen group including (^-( ₄ ) Any one, two or three substituted 2-, 3, or 4-position pyridyl groups such as hydroxy, decyloxy, amino, amido, carboxamide, decyl, methylthio, ethylthio Containing d-( ₄ alkyl, nitro, carboxy, ester, aldehyde, halogen, hydroxy, decyloxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio within any one, two or three substituents furanyl; containing d- C ₄ include alkyl, nitro, carboxyl, ester Any one, two or three substituted pyranyl groups, 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; C "C ₄ alkyl, nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethylthio, etc. One, two or three substituted thienyl groups; containing C"C alkyl, nitro, carboxy, ester, aldehyde, dentate, hydroxy, decyloxy, amine, amide, carboxamide, Any one, two or three substituted pyrrolyl groups including a mercapto group, a methylthio group, an ethylthio group; H, CH _{3 ;} R ₃ is a carboxamide group, a cyano group, a thiocarboxamide group; C ₂ - C ₃ is a saturated or unsaturated double bond.

3. 根据权利要求 1所述的取代丙酰胺衍生物， 其特征在于  3. A substituted propionamide derivative according to claim 1 wherein

0 '  0 '

当 1^为\₀入 时， 其中 Ar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 d- ( 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 C「 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 d- (：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噻吩基； 含有包括^-(：₄ 的垸基、 硝基、 接基、 酷基、 酸基、 素、 轻基、 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吡咯基； 为11、 CH₃; 为甲酰胺 基、 ¾基、 硫代甲酰胺基； c₂-c₃为饱和或不饱和双键。 When 1^ is "_0" , wherein Ar is an aryl group; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing a fluorenyl group including d-C 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, a decyloxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group or an ethylthio group. Substituted aryl; containing alkyl, nitro, carboxy, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, sulfhydryl, methylthio, ethyl sulphide including CrC ₄ Any one, two or three substituted 2-, 3-, or 4-position pyridyl groups, including an alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, 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 sulfhydryl group containing a C"group; , carboxyl group, ester group, aldehyde group, halogen, hydroxyl group, alkoxy group, amine group, amide group, carbon amide , Any mercapto, methylthio, ethylthio, including one, two or three of the substituents pyranyl; comprising containing d- (: ₄ alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen , any hydroxy, embankment group, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents thienyl; ^ contains include - (: ₄ Any one or two of a fluorenyl group, a nitro group, a sulfhydryl group, a thiol group, an acid group, a aryl group, a light 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; 11, CH ₃ ; a group, a 3⁄4 group, a thiocarboxamide group; c ₂ -c ₃ is a saturated or unsaturated double bond.

4、 根掂权利要求 1所述的取代丙酰胺衍生物， 其特征在于 当 为

时， 其中 Ar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 c「a^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 d- ( 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 2-、 3-、 或 4 -位吡啶基； 含有包括 C「C₄ 烷基、 硝基、 羧基、 酯基、 醛基、 素、 羟基、 烷氧基、 胺 基、 酰胺基、 碳 m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 C「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喃基； 含有 包括 C「 C₄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噻吩基； 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吡咯基； ₂为11、 CH₃ 4. A substituted propionamide derivative according to claim 1 which is characterized in that

Wherein Ar is an aryl group; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing c"a^ thiol, nitro, carboxy, esteryl Any one, two or three substituted aryl groups, 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, carboxamido, sulfhydryl, methylthio, ethylthio, etc.) , two or three substituted 2-, 3-, or 4-position pyridyl; containing C"C ₄ alkyl, nitro, carboxy, ester, aldehyde, hydroxy, alkoxy, amine groups, amide group, carbon group m, mercapto, methylthio, ethylthio, including one, two or three substituents furanyl; include C containing "C ₄ alkyl group, a nitro group, a carboxyl group, Ester group, aldehyde group, halogen, hydroxyl group, alkoxy group, amine group, amide group, carboxamide group, sulfhydryl group, A Group, ethylthio, including any one, two or three of the substituents pyranyl; C comprising including "C 1-6 alkyl, nitro, carboxyl, ester, aldehyde,, hydroxy, alkoxy ₄ Any one, two or three substituted thienyl groups including an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; an alkyl group, a nitro group, a carboxyl group, and an ester including ?- group, any aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents pyrrolyl; ₂ 11, CH ₃

为甲酰胺基、 氰基、 硫代甲酰胺基； C₂-C₃为饱和或不饱和双键。 Is a carboxamide group, a cyano group, a thiocarboxamide group; C ₂ -C ₃ is a saturated or unsaturated double bond.

5. 根据权利要求 1所述的取代丙酰胺衍生物， 其特征在于  5. The substituted propionamide derivative according to claim 1, which is characterized in that

0  0

当 ^为^^^ ⁿ⁼°~⁵时， 其中 Ar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 C「C₄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 代的芳基； 含有包括(：「 C₄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^- 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呋 喃基； 含有包括 Cr ( 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吡喃基； 含 有包括 C- ( 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噻吩基； 含有包括 d- 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； 为11、 CH₃ 为甲酰胺基、 铳基、 硫代甲酰胺基； C₂-C₃为饱和或不饱和双键。 When ^ is ^^^ ⁿ⁼ °~ ⁵ , where Ar is aryl; 2-, 3_, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing C"C ₄ Any one or two of a thiol group, a nitro group, a carboxyl group, an ester group, an aldehyde group, a hydroxy group, an hydroxy group, an alkoxy group, an amine group, an amide group, a carboxamide group, a thiol group, a methylthio group, an ethylthio group, or an ethylthio group. Or a three-substituted aryl group; including (including "C ₄ alkyl group, nitro group, carboxyl group, ester group, aldehyde group, hydroxy group, alkoxy group, amine group, amide group, carboxamide group, sulfhydryl group, 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, and an ester group including ^-C ₄ Any one, two or three substituted furanyl groups, 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, carbon Any amino, mercapto, methylthio, ethylthio, including one, two or three of the substituents pyranyl; comprising comprising C- ₍₄ alkyl group, a nitro group, a carboxyl group, an ester group, an aldehyde group, Any one, two or three substituted thienyl groups including a halogen, a hydroxyl group, a decyloxy group, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; , nitro, carboxyl, ester, aldehyde, halogen, hydroxy, alkoxy, amine, amide, carboxamide, Any one, two or three substituted pyrrolyl groups including a fluorenyl group, a methylthio group, an ethylthio group; 11, a CH ₃ is a carboxamide group, a fluorenyl group, a thiocarboxamide group; and C ₂ - C ₃ is Saturated or unsaturated double bond.

6. 根据权利要求 1所述的取代丙酰胺衍生物， 其特征在于 当！^为、^^ 时， 其中 Ar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- 的垸基、 硝基、 羧基、 酷基、 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 CrC^ 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 2-、 3-、 或 4 -位 吡啶基； 含有包括 d- 0₄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 d- 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喃基； 含有包括 - 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噻吩基； 含有包括 C, C₄的垸 基、 硝基、 羧基、 酯基、 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吡咯基； 为 CH_{3 ;} R₃为甲酰胺基、 氰基、 硫代甲酰胺基； C₂-C₃为饱和或不饱和双键。 6. A substituted propionamide derivative according to claim 1 characterized in that when! Wherein is ^, wherein R is aryl; 2-, 3-, or 4-position pyridyl; furyl; pyranyl; thienyl; pyrrolyl; containing fluorenyl, nitro, including d- Any one, two or three substituted aryl groups of a carboxyl group, a ketone 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. Any one containing a CrC sulfhydryl 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, and the like. One, two or three substituted 2-, 3-, or 4-position pyridyl groups; containing a fluorenyl group including a d- ₀₄ , a nitro group, a carboxyl group, an ester group, an aldehyde group, a halogen group, a hydroxyl group, an alkoxy group Any one, two or three substituted furanyl groups, an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; an alkyl group, a nitro group, a carboxyl group, and an ester including d- Base, aldehyde group, halogen, hydroxy group, alkoxy group, amine group, amide group, carboxamide group, thiol group, Any one, two or three substituted pyranyl groups including a methylthio group and 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, a decyloxy group, Any one, two or three substituted thienyl groups including an amine group, an amide group, a carboxamide group, a decyl group, a methylthio group, an ethylthio group; a thiol group including a C, C ₄ group, a nitro group, a carboxyl group, Any one, two or three substituted pyrrolyl groups including an ester group, an aldehyde group, a hydroxy group, a hydroxy group, an amine group, an amide group, a carboxamide group, a fluorenyl group, a methylthio group, an ethylthio group; CH _{3 ;} R ₃ is a carboxamide group, a cyano group, a thiocarboxamide group; and C ₂ -C ₃ is a saturated or unsaturated double bond.

7. 根据权利要求 1所述的取代丙酰胺衍生物， 其特征在于 当！^为\^^ n=o~5 时， 其中 Ar为芳基； 2-、 3-、 或 4-位吡啶基； 呋喃基； 吡喃 基； 噻吩基； 吡咯 含有包括 CrC 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 代的芳基； 含有包括 d- C₄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^-(：₄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呋 喃基； 含有包括 c「 ( ₄的垸基、 硝基、 羧基、 酯基、 醛基、 m, 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 ^的浣基、 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； 为 H、 CH_{3 ;} R₃ 为甲酰胺基、 ^基、 硫代甲酰胺基； C₂-C₃为饱和或不饱和双键'。 7. A substituted propionamide derivative according to claim 1 characterized in that when! ^ is ^^^ n=o~5, where Ar is aryl; 2-, 3-, or 4-pyridyl; furyl; pyranyl; thienyl; pyrrole containing CrC thiol, nitro Any one, two or three substituted aromatic groups such as 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. An alkyl group, a nitro group, a carboxyl group, an ester 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, an ethylthio group, including d-C ₄ including any one, two or three substituents 2, 3 - or 4-position of pyridyl; ^ contains include - (: ₄ embankment, nitro, carboxyl, ester, aldehyde, halogen, hydroxy any embankment group, amine, amide, carboxamide, mercapto, methylthio, ethylthio, including one, two or three substituents furanyl; containing comprising c "(group ₄ of the embankment, Nitro, carboxyl, ester, aldehyde, m, hydroxy, decyloxy, amine, amide, carboxamide, sulfhydryl, Any one, two or three substituted pyranyl groups including a methylthio group and 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 including ( ₄ ) Any one, two or three substituted thienyl 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, a nitro group, a carboxyl group, and an ester Base, aldehyde group, halogen, hydroxyl group, decyloxy group, amine group, amide group, carboxamide group, Any one, two or three substituted pyrrolyl groups including a mercapto group, a methylthio group and an ethylthio group; H, CH _{3 ;} R ₃ is a carboxamide group, a ^ group, a thiocarboxamide group; C ₂ - C ₃ is a saturated or unsaturated double bond '.

8、 根据权利要求 1所述的取代丙酰胺衍生物， 其特征在于当分子中存在手性碳时， 所 述化合物为消旋体或光学活性体。 .  The substituted propionamide derivative according to claim 1, wherein when the chiral carbon is present in the molecule, the compound is a racemate or an optically active substance. .

9、 如权利要求 1所述的取代丙酰胺衍生物及其药学上可接受盐的制备方法， 包括如下 步骤：  9. A method of preparing a substituted propionamide derivative according to claim 1 and a pharmaceutically acceptable salt thereof, comprising the steps of:

等当量取代丙 （烯）酰胺衍生物 2与等当量取代的芳香醛化合物 3， 在有机溶剂中在催化剂 存在下加热反应， 反应完毕后， 冷却， 反应液倒入水中， 析出固体， 纯化， 得目标化合物 I。 Equivalently substituted propylene (acryl) amide derivative 2 and equivalent-substituted aromatic aldehyde compound 3, heated in an organic solvent in the presence of a catalyst, after completion of the reaction, cooling, the reaction solution is poured into water, a solid is precipitated, and purified. Target compound I.

10.根据权利要求 1所述的取代丙酰胺衍生物及其药学上可接受盐的制备方法，其特征 在于取代丙 （烯）酰胺与取代芳香醛在乙醇、 甲醇或异丙醇中， 在哌啶存在下反应。  The process for preparing a substituted propionamide derivative according to claim 1, wherein a substituted acrylamide and a substituted aromatic aldehyde are used in ethanol, methanol or isopropanol, in the piperidine, and a pharmaceutically acceptable salt thereof. The reaction is carried out in the presence of pyridine.

11. 一种用于制备治疗或预防由胰岛素分泌和 /或功能紊乱引起或伴随的疾病或症状的 药物组合物或联合制剂含有作为活性成分的权利要求 1至 2中任一权项所述的化合物以及该 化合物药学上可接受的盐或药学上可接受的载体或赋形剂或载体的连结物，以及治疗糖尿病 药物、 胰岛素增敏剂。  A pharmaceutical composition or a combination preparation for the treatment or prevention of a disease or a symptom caused or accompanied by insulin secretion and/or dysfunction, which comprises as an active ingredient, according to any one of claims 1 to 2. A compound and a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable carrier or excipient or carrier, and a therapeutic agent for diabetes, an insulin sensitizer.

12. 如权利要求 1至 2中任一权项所述化合物或其可药用盐用于制备治疗和 /或预防胰 岛素分泌和 /或功能紊乱引起或伴随的疾病或症状药物的用途。  12. Use of a compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of a disease or condition caused or accompanied by insulin secretion and/or dysfunction.