WO2022252392A1 - 磺酰胺基烟酸衍生物、酰胺基烟酸衍生物及其制备方法和应用 - Google Patents

磺酰胺基烟酸衍生物、酰胺基烟酸衍生物及其制备方法和应用 Download PDF

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WO2022252392A1
WO2022252392A1 PCT/CN2021/111477 CN2021111477W WO2022252392A1 WO 2022252392 A1 WO2022252392 A1 WO 2022252392A1 CN 2021111477 W CN2021111477 W CN 2021111477W WO 2022252392 A1 WO2022252392 A1 WO 2022252392A1
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nicotinic acid
cycloalkyl
alkoxy
acid derivative
group
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French (fr)
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李环球
朱一凡
胡庆华
董进
延南俊
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苏州大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the technical field of medicinal chemistry, in particular to a sulfonamide nicotinic acid derivative, an amido nicotinic acid derivative and a preparation method and application thereof.
  • Bile acids have a variety of physiological functions, not only play an important role in the absorption, transport and distribution of fat and fat-soluble vitamins, but also act as a signaling molecule to activate nuclear receptors and then regulate the metabolism of bile acids and cholesterol.
  • the enterohepatic circulation of bile acids is an important regulatory mechanism that regulates the rate of bile acid synthesis. Bile acids are synthesized from the liver into the gallbladder, secreted into the small intestine, reabsorbed in the ileum, and transported back to the liver through the portal vein.
  • Ursodeoxycholic acid is the most commonly used drug for cholestasis in clinical practice. It is a steroidal compound and an analogue of cholic acid. Stone formation, but UDCA has poor activating effect on bile acid nuclear receptor FXR, so it has limitations in the treatment of cholestasis, and some patients with cholestasis are not sensitive to UDCA.
  • FXR receptor farnesoid X receptor
  • FXR farnesoid X receptor
  • FXR is a member of the hormone nuclear receptor superfamily.
  • FXR is a bile acid sensor.
  • bile acid is an endogenous ligand of FXR under physiological conditions. They found that bile acid can not only directly bind to FXR, but also the interaction between the two can lead to synergistic activators and co-inhibitors.
  • the recruitment of bile acids which indicates the endogenous FXR ligands of bile acids, so FXR is also known as bile acid receptors.
  • FXR can maintain the internal environment of bile acids by regulating the expression of genes involved in bile acid metabolism.
  • FXR is a key regulator of cholesterol homeostasis, triglyceride synthesis, and lipogenesis (Crawley, Expert Opinion Ther. Patents (2010), 20(8): 1047-1057).
  • FXR-related diseases include treatment of liver disease, diabetes, vitamin D-related diseases, drug-induced side effects, and hepatitis.
  • Bile excretion so it has a therapeutic effect on diseases related to bile excretion disorder; at the same time, it can also reduce the values of ALT, AST, and ALP accordingly, and has a certain effect on repairing liver damage.
  • This type of compound can also reduce portal pressure.
  • Hypertension has a therapeutic effect, and according to the description of the instructions, it can be known that the compound is superior in pharmacodynamic activity.
  • the compound has a low melting point and is not suitable for heating or grinding, which brings great difficulties to the preparation research, and its poor solubility is not conducive to storage and weighing, which brings a lot of inconvenience to the later development.
  • the technical problem to be solved by the present invention is to provide a kind of sulfonamide nicotinic acid derivatives, amido nicotinic acid derivatives and their preparation method and application, the prepared sulfonamido nicotinic acid derivatives, amido nicotinic acid derivatives It has good activity in treating atherosclerosis.
  • the present invention provides a nicotinic acid sulfonamide derivative, which has the structure shown in formula (I), or its anion form, pharmaceutically acceptable salt:
  • R is selected from H, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclyl;
  • n is any integer from 0 to 5;
  • R2 is selected from H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclyl, C2-C6 alkenyl, alcoholic hydroxyl or phenyl ;
  • the C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, C1-C6 heterocyclic group, C2-C6 alkenyl group, alcoholic hydroxyl group or phenyl substituent are selected from cyano, Hydroxy, cycloalkyl, alkenyl or alkoxy.
  • the anion form refers to the carboxylic acid anion form formed after the carboxyl group loses H ions.
  • the anion form has a structure shown in the following formula (I-a):
  • the pharmaceutically acceptable salt is preferably one or more of hydrochloride, sulfate and phosphate.
  • the R1 is preferably H, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclic; more preferably H, halogen, nitro, cyano, C1 ⁇ A C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group or a C1-C6 heterocyclic group; more preferably a methyl group.
  • n is preferably any integer from 0 to 5, more preferably 1 or 2, even more preferably 1.
  • the R2 is preferably H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclic group, C2-C6 alkenyl, alcoholic hydroxyl group or phenyl.
  • the C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, C1-C6 heterocyclic group, C2-C6 alkenyl group, alcoholic hydroxyl group or phenyl substituent is preferably cyano, Hydroxy, cycloalkyl, alkenyl or alkoxy; more preferably cyano, hydroxyl, C3-C6 cycloalkyl, C2-C6 alkenyl or C1-C6 alkoxy; more preferably cyano, hydroxyl , C3-C6 cycloalkyl, C2-C3 alkenyl or C1-C3 alkoxy.
  • the R2 is preferably H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropylethyl, Allyl, methoxy, methoxyethyl, ethanol, propylcyano or pyrrolidinyl.
  • the nicotinic acid sulfonamide derivative has any of the following structures, or an anionic form or a pharmaceutically acceptable salt thereof:
  • the present invention provides a preparation method of the above-mentioned sulfonamide nicotinic acid derivatives, comprising the following steps:
  • the compound of the formula (III) is prepared by reacting 6-chloro-5-nitronicotinic acid and piperazine, and then reducing the nitro group of the obtained intermediate.
  • R 1 , R 2 , and n are the same as above, and will not be repeated here.
  • the present invention provides a nicotinic acid amido derivative, which has the structure shown in formula (IV), or its anion form, pharmaceutically acceptable salt:
  • R is selected from H, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclyl;
  • n is any integer from 0 to 5;
  • R4 is selected from H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclyl, C2-C6 alkenyl, alcoholic hydroxyl or phenyl ;
  • the C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, C1-C6 heterocyclic group, C2-C6 alkenyl group, alcoholic hydroxyl group or phenyl substituent are selected from cyano, Hydroxy, cycloalkyl, alkenyl or alkoxy.
  • the anion form refers to the carboxylic acid anion form formed after the carboxyl group loses H ions.
  • the pharmaceutically acceptable salt is preferably one or more of hydrochloride, sulfate and phosphate.
  • the R3 is preferably H, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl or heterocyclic; more preferably H, halogen, nitro, cyano, C1 ⁇ A C6 alkyl group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group or a C1-C6 heterocyclic group; more preferably a methyl group.
  • M is preferably any integer from 0 to 5; more preferably 1 or 2, even more preferably 2.
  • the R4 is preferably H, substituted or unsubstituted C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 heterocyclic group, C2-C6 alkenyl, alcoholic hydroxyl group or phenyl.
  • the C1-C6 alkyl group, C3-C6 cycloalkyl group, C1-C6 alkoxy group, C1-C6 heterocyclic group, C2-C6 alkenyl group, alcoholic hydroxyl group or phenyl substituent is preferably cyano, Hydroxy, cycloalkyl, alkenyl or alkoxy. More preferably cyano, hydroxyl, C3-C6 cycloalkyl, C2-C6 alkenyl or C1-C6 alkoxy; more preferably cyano, hydroxyl, C3-C6 cycloalkyl, C2-C3 alkene group or C1-C3 alkoxy group.
  • the R2 is preferably H, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropylethyl, Allyl, methoxy, methoxyethyl, ethanol, propylcyano or pyrrolidinyl; more preferably H, isopropyl, methoxy, ethanol, propylcyano or cyclopropylethyl .
  • said amide nicotinic acid derivative has any of the following structures, or an anionic form or a pharmaceutically acceptable salt thereof:
  • the invention discloses a preparation method of the above-mentioned amide nicotinic acid derivatives, comprising the following steps:
  • the compound of the formula (VI) is prepared by reacting 6-chloro-5-nitronicotinic acid and piperazine, and then reducing the nitro group of the obtained intermediate.
  • the present invention provides the above-mentioned sulfonamido-nicotinic acid derivative or the sulfonamido-nicotinic acid derivative prepared by the above-mentioned preparation method, or the above-mentioned amido-nicotinic acid derivative or the amido-nicotinic acid derivative prepared by the above-mentioned preparation method in the preparation and treatment of arterial Application in atherosclerotic drugs.
  • the present invention provides a drug for treating atherosclerosis, comprising the above-mentioned sulfonamido-nicotinic acid derivative or the sulfonamido-nicotinic acid derivative prepared by the above-mentioned preparation method, or the above-mentioned amido-nicotinic acid derivative or the above-mentioned preparation method Aminonicotinic acid derivatives and excipients.
  • the auxiliary materials can be pharmaceutically acceptable auxiliary materials.
  • the above-mentioned drugs for treating atherosclerosis provided by the present invention can also be used in combination with other drugs for treating atherosclerosis.
  • the present invention provides sulfonamide nicotinic acid derivatives and amido nicotinic acid derivatives, and the experimental results show that the sulfonamido nicotinic acid derivatives and amido nicotinic acid derivatives provided by the present invention have relatively
  • the good activity of treating atherosclerosis can be used as a medicine for the preparation of related atherosclerosis diseases.
  • Fig. 1 is a diagram showing that the compound of the present invention inhibits abnormal blood lipid levels in atherosclerotic mice
  • Fig. 2 is a diagram showing that the compound of the present invention improves pathological and morphological changes of the aorta in mice with atherosclerosis.
  • 6-Chloro-5-nitronicotinic acid (2.02g), di-tert-butyl dicarbonate (2.18g), DMAP (2.7ml) were dissolved in 20ml of pyridine solution, stirred at room temperature, monitored by TLC, after the reaction was completed, use acetic acid Extracted with ethyl ester, dried, spin-dried, and passed through the column to obtain pure tert-butyl 6-chloro-5-nitronicotinate;
  • 6-(4-(2-cyanoethyl)piperazin-1-yl)-5-((3-methylphenyl)sulfonamide) tert-butyl nicotinate (4.86g) was dissolved in 40ml of dichloromethane in 1.5ml trifluoroacetic acid, stirred at room temperature, monitored by TLC, extracted with ethyl acetate after the reaction was completed, dried, spin-dried, and passed through the column to obtain the pure target compound.
  • the NMR data are as follows:
  • Example 1 Using 1-isobutylpiperazine as a raw material, see Example 1 for the synthesis method.
  • the NMR data are as follows:
  • the NMR data are as follows:
  • Example 1 Using 1-(2-cyclopropylethyl)piperazine as raw material, see Example 1 for the synthesis method.
  • the NMR data are as follows:
  • Example 1 Using 1-allylpiperazine as a raw material, see Example 1 for the synthesis method.
  • the NMR data are as follows:
  • the NMR data are as follows:
  • Example 1 Using 1-isopropylpiperazine as raw material, see Example 1 for the synthesis method.
  • the NMR data are as follows:
  • the NMR data are as follows:
  • the NMR data are as follows:
  • Example 1 Using 1-methoxypiperazine as raw material, refer to Example 1 for the synthesis method.
  • the NMR data are as follows:
  • Example 1 Using 1-ethylpiperazine as a raw material, see Example 1 for the synthesis method.
  • the NMR data are as follows:
  • the NMR data are as follows:
  • 6-Chloro-5-nitronicotinic acid (2.02g), di-tert-butyl dicarbonate (2.18g), DMAP (2.7ml) were dissolved in 20ml of pyridine solution, stirred at room temperature, monitored by TLC, after the reaction was completed, use acetic acid Extracted with ethyl ester, dried, spin-dried, and passed through the column to obtain pure tert-butyl 6-chloro-5-nitronicotinate;
  • tert-butyl 5-nitro-6-(piperazin-1-yl)nicotinate (3.08g) in an autoclave, dissolve it with ethanol, cover the device, pump H2 for three times, and finally fill the autoclave with Make hydrogen gas, seal it well, heat and stir for 4 hours, extract with ethyl acetate after the reaction is completed, dry, spin dry, and pass through the column to obtain pure tert-butyl 5-amino-6-(piperazin-1-yl)nicotinate;
  • 5-(3,5-Dimethylbenzamide)-6-(piperazin-1-yl) tert-butyl nicotinate (4.10g) was dissolved in 40ml of dichloromethane and added dropwise to 1.5ml of trifluoroacetic acid , stirred at room temperature, and monitored by TLC. After the reaction was completed, it was extracted with ethyl acetate, dried, spin-dried, and passed through the column to obtain the pure target compound.
  • the NMR data are as follows:
  • the NMR data are as follows:
  • the NMR data are as follows:
  • the NMR data are as follows:
  • Example 13 Using 1-isopropylpiperazine as raw material, see Example 13 for the synthesis method.
  • the NMR data are as follows:
  • the NMR data are as follows:
  • the previously constructed human P2Y6R stably transfected HEK293 cells were cultured in DMEM medium (containing 10% fetal bovine serum, 100 U/ml penicillin and 100 ⁇ g/ml streptomycin), and inoculated into 6-well culture plates before the experiment at a seeding density of 5 ⁇ 105cells/ml, cells were cultured at 37°C, 95% O 2 , 5% CO 2 humidity conditions. Before the experiment, the serum-free medium was starved for 12 hours, and 1 ⁇ M compound was added to each well. After 30 minutes of reaction, 10 ⁇ M UDP was added to incubate for 12 hours, and samples were collected to detect the content of intracellular inositol 3-phosphate (IP3).
  • IP3 intracellular inositol 3-phosphate
  • IP3 enzyme-linked immunosorbent assay kit adopts competition ELISA method.
  • the IP3 antigen is coated on the microtiter plate, and the IP3 in the sample or standard competes with the coated IP3 for the binding site on the biotin-labeled anti-IP3 monoclonal antibody during the experiment, and the free components are washed away.
  • Add horseradish peroxidase-labeled avidin, biotin and avidin specifically combine to form an immune complex, and free components are washed away.
  • Chromogenic substrate (TMB) is added, and TMB turns blue under the catalysis of horseradish peroxidase, and turns yellow after adding stop solution.
  • High-fat diet was used to establish the AS model of LDLR-/- mice, and 20 mg/kg of compound 1 was used for intervention treatment.
  • the results show that compound 1 can effectively inhibit the abnormal changes of TC, TG, LDL-C and HDL-C in atherosclerotic blood lipid levels caused by HFD ( Figure 1); at the same time, compound 1 can effectively improve the lipid profile of the main plaque in mice Pathological changes such as increased plasma deposition, thickening of the arterial wall, stenosis of the lumen, high content of collagen fibers, and intimal fibrosis (Fig. 2). It is proved that compound 1 has a good therapeutic effect in the mouse model of atherosclerosis, showing its potential as a drug for the treatment of atherosclerosis.
  • the sulfonamide nicotinic acid and amido nicotinic acid derivatives prepared by the present invention have better activity in treating atherosclerosis.

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Abstract

本发明提供了烟酸磺酰胺基衍生物和烟酸酰胺基衍生物，分别具有式(Ⅰ)和式(Ⅳ)所示结构。实验结果表明，本发明提供的磺酰胺基烟酸衍生物和酰胺基烟酸衍生物具有较好的治疗动脉粥样硬化活性，可以作为制备相关动脉粥样硬化治疗药物。

Description

磺酰胺基烟酸衍生物、酰胺基烟酸衍生物及其制备方法和应用
本申请要求于2021年06月01日提交中国专利局、申请号为202110610206.6、发明名称为“磺酰胺基烟酸衍生物、酰胺基烟酸衍生物及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物化学技术领域，尤其涉及一种磺酰胺基烟酸衍生物、酰胺基烟酸衍生物及其制备方法和应用。
背景技术
胆汁酸具有多种生理功能，不仅在脂肪和脂溶性维生素的吸收、转运和分配中发挥重要的作用，而且可作为一种信号分子激活核受体继而调节胆汁酸和胆固醇的代谢。胆汁酸的肝肠循环是调节胆汁酸合成速率的重要调节机制。胆汁酸从肝脏合成进入胆囊，分泌入小肠，在回肠重吸收再通过门静脉循环运回肝脏。
胆汁淤积症主要发生于妊娠中晚期、肝纤维化、肝硬化以及胆道阻塞等患者，临床表现为瘙痒、黄疸(Choleplania)、血清碱性磷酸酶(ALP)升高等。针对胆汁淤积的药物，目前临床最常用的是熊去氧胆酸(Ursodesoxycholic acid,UDCA)，其为甾体化合物，系胆酸的类似物，有利胆作用，用于治疗胆固醇结石，预防药物性结石形成，但UDCA对胆汁酸核受体FXR激动作用较差，因而在治疗胆汁淤积的方面有局限性，部分胆汁淤积症的患者对UDCA不敏感。
经研究，FXR受体(法尼酯X受体)，属于激素核受体超家族的一员。FXR是胆汁酸感受器，多个研究小组报道生理状态下胆汁酸是FXR内源性配体，他们发现胆汁酸不仅与FXR可以直接结合，而且两者的相互作用可以导致协同活化因子和辅助抑制因子的募集，这说明胆汁酸的内源性FXR配体，因此FXR又被称为胆汁酸受体。FXR作为胆汁酸的受体可以通过调控参与胆汁酸代谢基因的表达来维持胆汁酸的内环境稳定。FXR是胆固醇动态平衡、甘油三酯合成以及脂肪生成的关键调节者(Crawley，Expert Opinion Ther.Patents(2010)，20(8)：1047-1057)。FXR相关的疾病包括治疗肝脏疾病、糖尿病、维生素D-相关疾病、药物导致的副作用以及肝炎。
本申请的申请人于2018年08月15日提交的申请(CN201810930184.X) 中公开了用于代谢性疾病治疗的胆汁酸衍生物类化合物，该类化合物对于胆汁淤积具有明显改善作用，可以促进胆汁排泄，因此对于胆汁排泄障碍相关疾病具有治疗作用；同时还可相应的降低ALT、AST、ALP的值，对于修复肝损伤也具有一定效果，该类化合物还可以降低门脉压力，对于门脉高压症具有治疗作用，且根据说明书的记载也可知，该化合物在药效活性方面表现较优。但该化合物熔点较低不适于受热或研磨，为制剂研究带来较大困难，且溶解性欠佳，不利于贮存、称量，给后期的开发带来诸多不便。
因此，在保证该化合物药效的情况下，如何得到该化合物更好成药性的固体形式具有重要意义。
发明内容
有鉴于此，本发明要解决的技术问题在于提供一种磺酰胺基烟酸、酰胺基烟酸衍生物及其制备方法和应用，制备的磺酰胺基烟酸衍生物、酰胺基烟酸衍生物具有较好的治疗动脉粥样硬化活性。
为达到上述目的，本发明提供了一种烟酸磺酰胺基衍生物，具有式(I)所示结构，或其阴离子形式、药学上可接受的盐：
Figure PCTCN2021111477-appb-000001
其中，R 1选自H、卤素、硝基、氰基、烷基、烷氧基、环烷基或杂环基；
n为0～5的任意整数；
R 2选自H、取代或非取代C1～C6的烷基、C3～C6的环烷基、C1～C6烷氧基、C1～C6杂环基、C2～C6烯基、醇羟基或苯基；
所述C1～C6的烷基、C3～C6的环烷基、C1～C6烷氧基、C1～C6杂环基、C2～C6烯基、醇羟基或苯基的取代基选自氰基、羟基、环烷基、烯基或烷氧基。
本发明中，所述阴离子形式指羧基失去H离子后形成的羧酸阴离子形式。
本发明中，所述阴离子形式具有以下式(I-a)所示结构：
Figure PCTCN2021111477-appb-000002
本发明中，所述药效上可接受的盐优选为盐酸盐、硫酸盐、磷酸盐中的一种或多种。
本发明中，所述R 1优选为H、卤素、硝基、氰基、烷基、烷氧基、环烷基或杂环基；更优选为H、卤素、硝基、氰基、C1～C6的烷基、C1～C6的烷氧基、C3～C6的环烷基或C1～C6的杂环基；进一步优选为甲基。
所述n优选为0～5的任意整数，更优选为1或2，进一步优选为1。
所述R 2优选为H、取代或非取代C1～C6的烷基、C3～C6的环烷基、C1～C6烷氧基、C1～C6杂环基、C2～C6烯基、醇羟基或苯基。
所述C1～C6的烷基、C3～C6的环烷基、C1～C6烷氧基、C1～C6杂环基、C2～C6烯基、醇羟基或苯基的取代基优选为氰基、羟基、环烷基、烯基或烷氧基；更优选为氰基、羟基、C3～C6的环烷基、C2～C6烯基或C1～C6的烷氧基；进一步优选为氰基、羟基、C3～C6的环烷基、C2～C3烯基或C1～C3的烷氧基。
在本发明的一些具体实施例中，所述R 2优选为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基乙基、烯丙基、甲氧基、甲氧基乙基、乙醇基、丙氰基或吡咯烷基。
本发明优选的，所述烟酸磺酰胺基衍生物具有以下任一结构，或其阴离子形式、药学上可接受的盐：
Figure PCTCN2021111477-appb-000003
Figure PCTCN2021111477-appb-000004
本发明提供了上述磺酰胺基烟酸衍生物的制备方法，包括以下步骤：
将式(II)结构的化合物和式(III)结构的化合物反应，得到式(I)所示的磺酰胺基烟酸衍生物；
Figure PCTCN2021111477-appb-000005
其中，R 1、n、R 2的范围同上，在此不再赘述。
其中，所述式(III)结构的化合物由6-氯-5-硝基烟酸和哌嗪反应，得到的中间体后再还原硝基，制备得到。
上述制备方法的反应方程式如下：
Figure PCTCN2021111477-appb-000006
所述R 1、R 2、n的范围同上，在此不再赘述。
本发明提供了一种烟酸酰胺基衍生物，具有式(Ⅳ)所示结构，或其阴离 子形式、药学上可接受的盐：
Figure PCTCN2021111477-appb-000007
其中，R 3选自H、卤素、硝基、氰基、烷基、烷氧基、环烷基或杂环基；
m为0～5的任意整数；
R 4选自H、取代或非取代C1～C6的烷基、C3～C6的环烷基、C1～C6烷氧基、C1～C6杂环基、C2～C6烯基、醇羟基或苯基；
所述C1～C6的烷基、C3～C6的环烷基、C1～C6烷氧基、C1～C6杂环基、C2～C6烯基、醇羟基或苯基的取代基选自氰基、羟基、环烷基、烯基或烷氧基。
本发明中，所述阴离子形式指羧基失去H离子后形成的羧酸阴离子形式。
其中，所述阴离子形式具有以下式(Ⅳ-a)所示结构：
Figure PCTCN2021111477-appb-000008
本发明中，所述药效上可接受的盐优选为盐酸盐、硫酸盐、磷酸盐中的一种或多种。
本发明中，所述R 3优选为H、卤素、硝基、氰基、烷基、烷氧基、环烷基或杂环基；更优选为H、卤素、硝基、氰基、C1～C6的烷基、C1～C6的烷氧基、C3～C6的环烷基或C1～C6的杂环基；进一步优选为甲基。
M优选为0～5的任意整数；更优选为1或2，进一步优选为2。
所述R 4优选为H、取代或非取代C1～C6的烷基、C3～C6的环烷基、C1～C6烷氧基、C1～C6杂环基、C2～C6烯基、醇羟基或苯基。
所述C1～C6的烷基、C3～C6的环烷基、C1～C6烷氧基、C1～C6杂环基、C2～C6烯基、醇羟基或苯基的取代基优选为氰基、羟基、环烷基、烯基或烷氧基。更优选为氰基、羟基、C3～C6的环烷基、C2～C6烯基或C1～C6的烷氧基；进一步优选为氰基、羟基、C3～C6的环烷基、C2～C3烯基或C1～C3的烷氧基。
在本发明的一些具体实施例中，所述R 2优选为H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基乙基、烯丙基、甲氧基、甲氧基乙基、乙醇基、丙氰基或吡咯烷基；更优选为H、异丙基、甲氧基、乙醇基、丙氰基或环丙基乙基。
在本发明的一些具体实施例中，所述的酰胺基烟酸衍生物具有以下任一结构，或其阴离子形式、药学上可接受的盐：
Figure PCTCN2021111477-appb-000009
本发明公开了上述酰胺基烟酸衍生物的制备方法，包括以下步骤：
将式(Ⅴ)结构的化合物和式(Ⅵ)结构的化合物反应，得到式(Ⅳ)结 构的化合物；
Figure PCTCN2021111477-appb-000010
其中，R 3、m、R 4的范围同上，在此不再赘述。
其中，所述式(Ⅵ)结构的化合物由6-氯-5-硝基烟酸和哌嗪反应，得到的中间体后再还原硝基，制备得到。
上述制备方法的反应方程式如下：
Figure PCTCN2021111477-appb-000011
其中，所述R 3、R 4、m的范围同上，在此不再赘述。
本发明提供了上述磺酰胺基烟酸衍生物或上述制备方法制备的磺酰胺基烟酸衍生物，或上述酰胺基烟酸衍生物或上述制备方法制备的酰胺基烟酸衍生物在制备治疗动脉粥样硬化药物中的应用。
本发明提供了一种治疗动脉粥样硬化药物，包括上述磺酰胺基烟酸衍生物或上述制备方法制备的磺酰胺基烟酸衍生物，或上述酰胺基烟酸衍生物或上述制备方法制备的酰胺基烟酸衍生物以及辅料。
所述辅料可以为药学上可接受的辅料。
本发明提供的上述治疗动脉粥样硬化药物还可以与其他治疗动脉粥样硬化药物联合使用。
与现有技术相比，本发明提供了磺酰胺基烟酸衍生物和酰胺基烟酸衍生物，实验结果表明，本发明提供的磺酰胺基烟酸衍生物和酰胺基烟酸衍生物具有较好的治疗动脉粥样硬化活性，可以作为制备相关动脉粥样硬化疾病治疗药物。
附图说明
图1为本发明化合物抑制动脉粥样硬化小鼠血脂水平异常改变图；
图2为本发明化合物改善动脉粥样硬化小鼠主动脉病理组织形态学改变图。
具体实施方式
为了进一步说明本发明，下面结合实施例对本发明提供的磺酰胺基烟酸衍生物、酰胺基烟酸衍生物及其制备方法和应用进行详细描述。
实施例1
Figure PCTCN2021111477-appb-000012
6-(4-(2-氰基乙基)哌嗪-1-基)-5-((3-甲基苯基)磺酰胺基)烟酸的 合成：
将6-氯-5-硝基烟酸(2.02g)，二碳酸二叔丁酯(2.18g)，DMAP(2.7ml)溶于20ml吡啶溶液中，室温搅拌，TLC监测，反应完成后用乙酸乙酯萃取，干燥，旋干，过柱子，得到纯净6-氯-5-硝基烟酸叔丁酯；
在25ml甲苯中加入Pd 2(dba) 3(0.1g)，P(N(i-Bu)CH 2CH 2) 3(0.1g)，叔丁醇钠(1.92g)，6-氯-5-硝基烟酸叔丁酯(2.58g)，3-(哌嗪-1-基)丙腈(1.5g)，室温搅拌，TLC监测，反应完成后用乙酸乙酯萃取，干燥，旋干，过柱子，得到纯净6-(4-(2-(氰基乙基)哌嗪-1-基)-5-尼古丁酸酯；
把6-(4-(2-(氰基乙基)哌嗪-1-基)-5-尼古丁酸酯(3.61g)置于高压釜中，用乙醇溶解，盖好装置，H 2抽换气三次，最后釜内充好氢气，密封好，加热搅拌4小时，反应完成后用乙酸乙酯萃取，干燥，旋干，过柱子，得到纯净5-氨基-6-(4-(2-氰基乙基)哌嗪-1-基)烟酸叔丁酯；
将5-氨基-6-(4-(2-氰基乙基)哌嗪-1-基)烟酸叔丁酯(3.31g)溶于20ml吡啶溶液中，滴加入甲基苯磺酰氯(2.2ml)，室温搅拌，TLC监测，反应完成后用乙酸乙酯萃取，干燥，旋干，过柱子，得到纯净6-(4-(2-氰基乙基)哌嗪-1-基)-5-((3-甲基苯基)磺酰胺)烟酸叔丁酯；
6-(4-(2-氰基乙基)哌嗪-1-基)-5-((3-甲基苯基)磺酰胺)烟酸叔丁酯(4.86g)溶于40ml二氯甲烷中，滴加入1.5ml三氟乙酸中，室温搅拌，TLC监测，反应完成后用乙酸乙酯萃取，干燥，旋干，过柱子，得到纯净目标化合物。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ8.65(d,J＝1.1Hz,1H),7.73(ddd,J＝7.2, 3.5,1.4Hz,1H),7.61(d,J＝4.5Hz,3H),7.37(d,J＝1.3Hz,1H),3.50(t,J＝5.1Hz,4H),3.01(t,J＝7.6Hz,2H),2.73(t,J＝7.5Hz,2H),2.57(t,J＝5.1Hz,4H),2.42(s,3H).
13C NMR(125MHz,DMSO-d 6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,118.85,117.56,53.40,52.43,47.44,21.27,14.43.
实施例2
Figure PCTCN2021111477-appb-000013
6-(4-异丁基哌嗪-1-基)-5-((3-甲基苯基)磺酰胺)烟酸的合成：
以1-异丁基哌嗪为原料，合成方法参见实施例1。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ8.78(d,J＝1.3Hz,1H),7.78–7.71(m,1H),7.65–7.58(m,3H),7.37(d,J＝1.3Hz,1H),3.50(t,J＝5.1Hz,4H),2.57(t,J＝5.1Hz,4H),2.42(s,3H),2.08(d,J＝6.9Hz,2H),1.68(dp,J＝13.7,6.8Hz,1H),0.85(d,J＝6.8Hz,6H).
13C NMR(125MHz,DMSO-d 6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,66.88,52.83,47.44,25.20, 21.27,20.82.
实施例3
Figure PCTCN2021111477-appb-000014
6-(4-(2-羟乙基)哌嗪-1-基)-5-((3-甲基苯基)磺酰胺)烟酸的合成：
以2-(哌嗪-1-基)乙烷-1-醇为原料，合成方法参见实施例1。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ8.64(d,J＝1.3Hz,1H),7.73(ddt,J＝7.9,5.2,2.2Hz,1H),7.65–7.58(m,3H),7.37(d,J＝1.3Hz,1H),4.25(t,J＝4.9Hz,1H),3.58(td,J＝7.2,5.0Hz,2H),3.50(t,J＝5.1Hz,4H),2.64(t,J＝5.1Hz,4H),2.58(t,J＝7.2Hz,2H),2.42(s,3H).
13C NMR(125MHz,DMSO-d 6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,59.93,58.30,52.88,47.44,21.27.
实施例4
Figure PCTCN2021111477-appb-000015
6-(4-(2-环丙基乙基)哌嗪-1-基)-5-((3-甲基苯基)磺酰胺)烟酸的合成：
以1-(2-环丙基乙基)哌嗪为原料，合成方法参见实施例1。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ8.68(d,J＝1.3Hz,1H),7.71(tt,J＝5.3,2.6Hz,1H),7.61(d,J＝4.9Hz,2H),7.54–7.49(m,1H),7.37(d,J＝1.3Hz,1H),3.50(t,J＝5.1Hz,4H),2.57(t,J＝5.1Hz,4H),2.49–2.40(m,5H),1.42(q,J＝7.4Hz,2H),1.00(hept,J＝7.0Hz,1H),0.37(tt,J＝7.3,4.2Hz,2H),0.22(tt,J＝7.3,4.2Hz,2H).
13C NMR(125MHz,DMSO-d 6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,55.26,52.43,47.44,31.12,21.27,10.30,5.57.
实施例5
Figure PCTCN2021111477-appb-000016
6-(4-烯丙基哌嗪-1-基)-5-((3-甲基苯基)磺酰胺)烟酸的合成：
以1-烯丙基哌嗪为原料，合成方法参见实施例1。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ8.65(d,J＝1.1Hz,1H),7.73(td,J＝4.9,2.5Hz,1H),7.61(t,J＝4.1Hz,3H),7.37(d,J＝1.3Hz,1H),5.84(ddt,J＝14.3,12.4,6.2Hz,1H),5.19–5.12(m,2H),3.50(t,J＝5.1Hz,4H),3.01(dd,J＝6.1,1.2Hz,2H),2.55(t,J＝5.1Hz,4H),2.42(s,3H).
13C NMR(125MHz,DMSO-d 6)δ166.73,150.45,149.13,138.73,137.96,134.53,132.62,128.72,128.28,124.91,123.14,117.56,61.55,52.35,47.44,21.27.
实施例6
Figure PCTCN2021111477-appb-000017
5-((3-甲基苯基)磺胺基)-6-(4-(吡咯烷-1-基)哌嗪-1-基)烟酸的合成：
以1-(吡咯烷-1-基)哌嗪为原料，合成方法参见实施例1。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ8.67(d,J＝1.3Hz,1H),7.73(tt,J＝5.3,2.6Hz,1H),7.70–7.65(m,1H),7.61(d,J＝4.9Hz,2H),7.37(d,J＝1.3Hz,1H), 3.12(t,J＝5.1Hz,4H),2.79(ddd,J＝10.1,7.6,4.6Hz,8H),2.42(s,3H),1.97–1.87(m,4H).
13C NMR(125MHz,DMSO-d 6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,53.42,52.97,48.57,22.66,21.27.
实施例7
Figure PCTCN2021111477-appb-000018
6-(4-异丙基哌嗪-1-基)-5-((3-甲基苯基)磺酰胺)烟酸的合成：
以1-异丙基哌嗪为原料，合成方法参见实施例1。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ8.73(d,J＝1.3Hz,1H),7.71(tt,J＝5.2,2.6Hz,1H),7.67–7.58(m,3H),7.37(d,J＝1.3Hz,1H),3.50(t,J＝4.9Hz,4H),2.69(hept,J＝6.9Hz,1H),2.54(t,J＝4.9Hz,4H),2.42(s,3H),1.00(d,J＝6.8Hz,6H).
13C NMR(125MHz,DMSO-d 6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,54.57,50.90,47.75,21.27,18.30.
实施例8
Figure PCTCN2021111477-appb-000019
6-(4-(2-甲氧基乙基)哌嗪-1-基)-5-((3-甲基苯基)磺酰胺)烟酸的合成：
以1-(2-甲氧基乙基)哌嗪为原料，合成方法参见实施例1。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ8.65(d,J＝1.3Hz,1H),7.76–7.69(m,1H),7.65–7.59(m,3H),7.37(d,J＝1.3Hz,1H),3.53–3.43(m,6H),3.25(s,3H),2.98(t,J＝7.2Hz,2H),2.64(t,J＝5.1Hz,4H),2.42(s,3H).
13C NMR(125MHz,DMSO-d 6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,70.81,58.91,55.94,52.88,47.44,21.27.
实施例9
Figure PCTCN2021111477-appb-000020
5-((3-甲基苯基)磺酰胺)-6-(4-甲基哌嗪-1-基)烟酸的合成：
以为1-甲基哌嗪原料，合成方法参见实施例1。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ8.64(d,J＝1.3Hz,1H),7.72–7.64(m,2H),7.61(d,J＝4.9Hz,2H),7.37(d,J＝1.3Hz,1H),3.50(t,J＝5.1Hz,4H),2.60(s,3H),2.44–2.35(m,7H).
13C NMR(125MHz,DMSO-d 6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,54.46,46.96,44.73,21.27.
实施例10
Figure PCTCN2021111477-appb-000021
6-(4-甲氧基哌嗪-1-基)-5-((3-甲基苯基)磺酰胺)烟酸的合成：
以1-甲氧基哌嗪为原料，合成方法参见实施例1。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ8.79(d,J＝1.3Hz,1H),7.62(dd,J＝6.1,1.2Hz,4H),7.37(d,J＝1.3Hz,1H),3.49(s,3H),3.25(t,J＝5.1Hz,4H),2.78(t,J＝5.1Hz,4H),2.42(s,3H).
13C NMR(125MHz,DMSO-d 6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,60.71,55.29,48.14,21.27.
实施例11
Figure PCTCN2021111477-appb-000022
6-(4-乙基哌嗪-1-基)-5-((3-甲基苯基)磺胺基)烟酸的合成：
以1-乙基哌嗪为原料，合成方法参见实施例1。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ8.77(d,J＝1.3Hz,1H),7.78–7.71(m,1H),7.65–7.59(m,3H),7.37(d,J＝1.3Hz,1H),3.50(t,J＝5.1Hz,4H),2.57(t,J＝5.1Hz,4H),2.44–2.34(m,5H),0.96(t,J＝8.0Hz,3H).
13C NMR(125MHz,DMSO-d 6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,52.16,52.05,47.44,21.27,12.04.
实施例12
Figure PCTCN2021111477-appb-000023
5-((3-甲基苯基)磺酰胺)-6-(哌嗪-1-基)烟酸的合成：
以哌嗪为原料，合成方法参见实施例1。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ8.64(d,J＝1.3Hz,1H),7.72–7.63(m,2H),7.61(d,J＝4.9Hz,2H),7.37(d,J＝1.3Hz,1H),3.38(t,J＝5.0Hz,4H),2.65(t,J＝5.0Hz,4H),2.42(s,3H),1.80(s,1H).
13C NMR(125MHz,DMSO-d 6)δ166.73,150.45,149.13,138.73,137.96,132.62,128.72,128.28,124.91,123.14,117.56,47.97,45.61,21.27.
实施例13
Figure PCTCN2021111477-appb-000024
5-(3,5-二甲基苯甲酰胺)-6-(哌嗪-1-基)烟酸的合成：
将6-氯-5-硝基烟酸(2.02g)，二碳酸二叔丁酯(2.18g)，DMAP(2.7ml)溶于20ml吡啶溶液中，室温搅拌，TLC监测，反应完成后用乙酸乙酯萃取，干燥，旋干，过柱子，得到纯净6-氯-5-硝基烟酸叔丁酯；
在25ml甲苯中加入Pd 2(dba) 3(0.1g)，P(N(i-Bu)CH 2CH 2) 3(0.1g)，叔丁醇钠(1.92g)，6-氯-5-硝基烟酸叔丁酯(2.58g)，哌嗪(0.86g)，室温搅拌，TLC监测，反应完成后用乙酸乙酯萃取，干燥，旋干，过柱子，得到纯净5-硝基-6-(哌嗪-1-基)烟酸叔丁酯；
把5-硝基-6-(哌嗪-1-基)烟酸叔丁酯(3.08g)置于高压釜中，用乙醇溶 解，盖好装置，H 2抽换气三次，最后釜内充好氢气，密封好，加热搅拌4小时，反应完成后用乙酸乙酯萃取，干燥，旋干，过柱子，得到纯净5-氨基-6-(哌嗪-1-基)烟酸叔丁酯；
将5-氨基-6-(哌嗪-1-基)烟酸叔丁酯(2.78g)溶于20ml吡啶溶液中，滴加入3,5-二甲基苯甲酰氯(2.2ml)，室温搅拌，TLC监测，反应完成后用乙酸乙酯萃取，干燥，旋干，过柱子，得到纯净5-(3,5-二甲基苯甲酰胺)-6-(哌嗪-1-基)烟酸叔丁酯；
5-(3,5-二甲基苯甲酰胺)-6-(哌嗪-1-基)烟酸叔丁酯(4.10g)溶于40ml二氯甲烷中，滴加入1.5ml三氟乙酸中，室温搅拌，TLC监测，反应完成后用乙酸乙酯萃取，干燥，旋干，过柱子，得到纯净目标化合物。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ9.72(s,1H),9.16(d,J＝1.3Hz,1H),8.50(d,J＝1.3Hz,1H),7.54(d,J＝2.0Hz,2H),7.40–7.34(m,1H),3.38(t,J＝5.1Hz,4H),2.65(t,J＝5.1Hz,4H),2.34(s,5H),1.78(s,1H).
13C NMR(125MHz,DMSO-d 6)δ166.73,166.23,152.10,149.07,135.74,134.51,132.49,127.00,126.45,122.70,121.61,47.97,45.61,20.82.
实施例14
Figure PCTCN2021111477-appb-000025
6-(4-(2-环丙基乙基)哌嗪-1-基)-5-(3,5-二甲基苯甲酰胺基)烟酸的合成：
以1-(2-环丙基乙基)哌嗪为原料，合成方法参见实施例13。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ9.72(s,1H),9.15(d,J＝1.1Hz,1H),8.50(d,J＝1.3Hz,1H),7.55(d,J＝1.9Hz,2H),7.37(q,J＝1.8Hz,1H),3.50(t,J＝5.2Hz,4H),2.57(t,J＝5.2Hz,4H),2.45(t,J＝7.6Hz,2H),2.34(s,5H),1.42(q,J＝7.4Hz,2H),0.99(hept,J＝6.9Hz,1H),0.40–0.33(m,2H),0.24–0.16(m,2H).
13C NMR(125MHz,DMSO-d 6)δ166.73,166.23,152.10,149.07,135.74,134.51,132.49,127.00,126.45,122.70,121.61,55.26,52.43,47.44,31.12,20.82,10.30,5.57.
实施例15
Figure PCTCN2021111477-appb-000026
6-(4-(2-氰基乙基)哌嗪-1-基)-5-(3,5-二甲基苯甲酰胺基)烟酸的合成：
以3-(哌嗪-1-基)丙腈为原料，合成方法参见实施例13。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ9.71(s,1H),9.12(d,J＝1.3Hz,1H),8.49(d,J＝1.3Hz,1H),7.54(d,J＝2.0Hz,2H),3.50(t,J＝5.2Hz,4H),3.01(t,J＝7.6Hz,2H),2.73(t,J＝7.5Hz,2H),2.57(t,J＝5.2Hz,4H),2.34(s,5H).
13C NMR(125MHz,DMSO-d 6)δ166.73,166.23,152.10,149.07,135.74,134.51,132.49,127.00,126.45,122.70,121.61,118.85,53.40,52.43,47.44,20.82,14.43.
实施例16
Figure PCTCN2021111477-appb-000027
5-(3,5-二甲基苯甲酰胺基)-6-(4-(2-羟乙基)哌嗪-1-基)烟酸的合成：
以2-(哌嗪-1-基)乙烷-1-醇为原料，合成方法参见实施例13。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ9.77(s,1H),9.19(d,J＝1.3Hz,1H),8.51(d,J＝1.3Hz,1H),7.57–7.52(m,2H),7.40–7.35(m,1H),4.25(t,J＝4.9Hz,1H),3.58(td,J＝7.2,5.0Hz,2H),3.50(t,J＝5.1Hz,4H),2.67–2.55(m,6H),2.34(s,5H).
13C NMR(125MHz,DMSO-d 6)δ166.73,166.23,152.10,149.07,135.74,134.51,132.49,127.00,126.45,122.70,121.61,59.93,58.30,52.88,47.44,20.82.
实施例17
Figure PCTCN2021111477-appb-000028
5-(3,5-二甲基苯甲酰胺)-6-(4-异丙基哌嗪-1-基)烟酸的合成：
以1-异丙基哌嗪为原料，合成方法参见实施例13。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ9.77(s,1H),9.13(d,J＝1.3Hz,1H),8.46(d,J＝1.3Hz,1H),7.54(d,J＝2.0Hz,2H),7.37(tt,J＝2.2,1.2Hz,1H),3.50(t,J＝5.1Hz,4H),2.68(h,J＝6.8Hz,1H),2.54(t,J＝5.1Hz,4H),2.34(s,5H),1.00(d,J＝6.8Hz,6H).
13C NMR(125MHz,DMSO-d 6)δ166.73,166.23,152.10,149.07,135.74,134.51,132.49,127.00,126.45,122.70,121.61,54.57,50.90,47.75,20.82,18.30.
实施例18
Figure PCTCN2021111477-appb-000029
5-(3,5-二甲基苯甲酰胺基)-6-(4-甲氧基哌嗪-1-基)烟酸的合成：
以1-甲氧基哌嗪为原料，合成方法参见实施例13。
核磁数据如下：
1H NMR(500MHz,DMSO-d 6)δ9.77(s,1H),9.15(d,J＝1.1Hz,1H),8.49(d,J＝1.3Hz,1H),7.55(d,J＝2.0Hz,2H),7.40–7.35(m,1H),3.49(s,3H),3.25(t,J＝5.2Hz,4H),2.78(t,J＝5.2Hz,4H),2.34(s,5H).
13C NMR(125MHz,DMSO-d 6)δ166.73,166.23,152.10,149.07,135.74,134.51,132.49,127.00,126.45,122.70,121.61,60.71,55.29,48.14,20.82.
实施例19化合物对P2Y6R受体体外拮抗活性测试
将前期构建的人P2Y6R稳转HEK293细胞培养于DMEM培养基中(含10％胎牛血清、100U/ml青霉素和100μg/ml链霉素)，实验前接种至6孔培养板，接种密度为5×105cells/ml，细胞于37℃、95％O 2、5％CO 2湿度条件下培养。实验前换无血清培养基饥饿12h，每孔加入1μM化合物，反应30min后加入10μM UDP孵育12h后收集样品检测胞内3磷酸肌醇(IP3)含量。
3磷酸肌醇(IP3)酶联免疫吸附测定试剂盒采用竞争ELISA法。用IP3抗原包被于酶标板上，实验时样品或标准品中的IP3与包被的IP3竞争生物素标记的抗IP3单抗上的结合位点，游离的成分被洗去。加入辣根过氧化物酶标记的亲和素，生物素与亲和素特异性结合而形成免疫复合物，游离的成分被洗去。加入显色底物(TMB)，TMB在辣根过氧化物酶的催化下呈现蓝色，加终止液后变成黄色。用酶标仪在450nm波长处测OD值，IP3浓度与OD450值之间呈反比，通过绘制标准曲线计算出样品中IP3的浓度。最后计算每组复孔的平 均OD值。以浓度为横坐标，OD值为纵坐标，在双对数坐标纸上绘出四参数逻辑函数的标准曲线；通过标准曲线计算出样品中IP3的浓度。实验重复三次，取平均值并计算化合物对P2Y 6R的IC 50和SD。
实验结果如表1所示：
表1化合物对P2Y6R受体体外拮抗活性测试结果
Figure PCTCN2021111477-appb-000030
Figure PCTCN2021111477-appb-000031
实施例20化合物在动脉粥样硬化动物模型中的治疗效果研究
以6-(4-(2-氰基乙基)哌嗪-1-基)-5-((3-甲基苯基)磺酰胺基)烟酸(以下简称化合物1)为例，研究此类化合物在小鼠的动脉粥样硬化模型中的药效学研究
采用高脂饲料(HFD)建立LDLR-/-小鼠AS模型，并用20mg/kg的化合物1进行干预治疗。结果表明，化合物1能够有效地抑制HFD导致的动脉粥样硬化血脂水平TC、TG、LDL-C和HDL-C的异常改变(图1)；同时化合物1能有效改善小鼠主斑块的脂质沉积增加、动脉壁增厚、管腔狭窄、胶原纤维含量高、内膜纤维化等病理性改变(图2)。证明化合物1在小鼠动脉粥样硬化模型中有很好的治疗效果，展现了其作为动脉粥样硬化治疗药物的潜力。
由上述实施例可知，本发明制备的磺酰胺基烟酸、酰胺基烟酸衍生物具有较好的治疗动脉粥样硬化活性。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (10)

  1. 一种烟酸磺酰胺基衍生物，具有式(I)所示结构，或其阴离子形式、药学上可接受的盐：
    Figure PCTCN2021111477-appb-100001
    其中，R 1选自H、卤素、硝基、氰基、烷基、烷氧基、环烷基或杂环基；
    n为0～5的任意整数；
    R 2选自H、取代或非取代C1～C6的烷基、C3～C6的环烷基、C1～C6烷氧基、C1～C6杂环基、C2～C6烯基、醇羟基或苯基；
    所述C1～C6的烷基、C3～C6的环烷基、C1～C6烷氧基、C1～C6杂环基、C2～C6烯基、醇羟基或苯基的取代基选自氰基、羟基、环烷基、烯基或烷氧基。
  2. 根据权利要求1所述的烟酸磺酰胺基衍生物，其特征在于，所述R 1选自甲基；
    所述n为1或2；
    所述R 2选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基乙基、烯丙基、甲氧基、甲氧基乙基、乙醇基、丙氰基或吡咯烷基。
  3. 根据权利要求1所述的烟酸磺酰胺基衍生物，其特征在于，具有以下任一结构，或其阴离子形式、药学上可接受的盐：
    Figure PCTCN2021111477-appb-100002
    Figure PCTCN2021111477-appb-100003
  4. 权利要求1～3任一项所述的磺酰胺基烟酸衍生物的制备方法，包括以下步骤：
    将式(II)结构的化合物和式(III)结构的化合物反应，得到式(I)所示的磺酰胺基烟酸衍生物；
    Figure PCTCN2021111477-appb-100004
    其中，R 1选自H、卤素、硝基、氰基、烷基、烷氧基、环烷基或杂环基；
    n为0～5的任意整数；
    R 2选自H、取代或非取代C1～C6的烷基、C3～C6的环烷基、C1～C6烷氧基、C1～C6杂环基、C2～C6烯基、醇羟基或苯基；
    所述C1～C6的烷基的取代基选自氰基、羟基、环烷基、烯基或烷氧基。
  5. 一种烟酸酰胺基衍生物，具有式(Ⅳ)所示结构，或其阴离子形式、药学上可接受的盐：
    Figure PCTCN2021111477-appb-100005
    其中，R 3选自H、卤素、硝基、氰基、烷基、烷氧基、环烷基或杂环基；
    m为0～5的任意整数；
    R 4选自H、取代或非取代C1～C6的烷基、C3～C6的环烷基、C1～C6烷氧基、C1～C6杂环基、C2～C6烯基、醇羟基或苯基；
    所述C1～C6的烷基、C3～C6的环烷基、C1～C6烷氧基、C1～C6杂环基、C2～C6烯基、醇羟基或苯基的取代基选自氰基、羟基、环烷基、烯基或烷氧基。
  6. 根据权利要求5所述的酰胺基烟酸衍生物，其特征在于，所述R 3选自甲基；
    所述m为1或2；
    所述R 2选自H、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基乙基、烯丙基、甲氧基、甲氧基乙基、乙醇基、丙氰基或吡咯烷基。
  7. 根据权利要求5所述的酰胺基烟酸衍生物，其特征在于，具有以下任一结构，或其阴离子形式、药学上可接受的盐：
    Figure PCTCN2021111477-appb-100006
    Figure PCTCN2021111477-appb-100007
  8. 权利要求5～7任一项所述的酰胺基烟酸衍生物的制备方法，包括以下步骤：
    将式(Ⅴ)结构的化合物和式(Ⅵ)结构的化合物反应，得到式(Ⅳ)结构的化合物；
    Figure PCTCN2021111477-appb-100008
    其中，R 3选自H、卤素、硝基、氰基、烷基、烷氧基、环烷基或杂环基；
    m为0～5的任意整数；
    R 4选自H、取代或非取代C1～C6的烷基、C3～C6的环烷基、C1～C6烷氧基、C1～C6杂环基、C2～C6烯基、醇羟基或苯基；
    所述C1～C6的烷基的取代基选自氰基、羟基、环烷基、烯基或烷氧基。
  9. 权利要求1～3任一项所述的磺酰胺基烟酸衍生物或权利要求4所述的制备方法制备的磺酰胺基烟酸衍生物，或权利要求5～7任一项所述的酰胺基烟酸衍生物或权利要求8所述的制备方法制备的酰胺基烟酸衍生物在制备治疗动脉粥样硬化药物中的应用。
  10. 一种治疗动脉粥样硬化药物，包括权利要求1～3任一项所述的磺酰胺基烟酸衍生物或权利要求4所述的制备方法制备的磺酰胺基烟酸衍生物，或权利要求5～7任一项所述的酰胺基烟酸衍生物或权利要求8所述的制备方法制备的酰胺基烟酸衍生物以及辅料。
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