CN108069898B - 含烟酸辣椒碱酯衍生物、制备方法及其用途 - Google Patents
含烟酸辣椒碱酯衍生物、制备方法及其用途 Download PDFInfo
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- CN108069898B CN108069898B CN201611008597.XA CN201611008597A CN108069898B CN 108069898 B CN108069898 B CN 108069898B CN 201611008597 A CN201611008597 A CN 201611008597A CN 108069898 B CN108069898 B CN 108069898B
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- methyl
- phenyl
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- nonenamide
- nicotinate
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Classifications
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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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一类具有结构通式I的含烟酸辣椒碱酯衍生物及其制造方法,及此类衍生物具有镇痛、抗肿瘤、抗炎、抗动脉粥样硬化、降血脂、促进食欲、改善消化、抗菌杀虫、抗氧化、抗病毒方面的用途。
Description
技术领域
本发明涉及一类含烟酸辣椒碱酯衍生物及其制造方法,及此类衍生物具有镇痛、抗肿瘤、抗炎、抗动脉粥样硬化、降血脂、促进食欲、改善消化、抗菌杀虫、抗氧化、抗病毒方面的用途。
背景技术
辣椒碱是辣椒果实辣味成分中的一种主要活性成分,目前该类物质在化学工业中作为添加剂和医药工业中已得到广泛使用。辣椒碱具有镇痛、抗肿瘤、抗炎、抗动脉粥样硬化、降血脂、促进食欲、改善消化、抗菌杀虫、抗氧化、抗病毒作用及对神经递质具有选择性等多种药理活性和药理作用。辣椒碱具有良好的镇痛作用,但由于辣椒碱的水溶性差,口服难以吸收且刺激性大,限制了它的应用。此外,进一步的研究发现辣椒碱在体内的活性不够高、吸收少、代谢快以及生物利用度低,进一步限制了它的应用。
发明内容
本发明提供具有通式Ia或通式Ib的化合物:
或其药学上可接受的盐、水合物、溶剂化物、立体异构体,其中:
R1、R2、R3、R4各自独立地是或选自氢、卤素、羟基、C1-C8烷基、C1-C8烷氧基、C1-C8酰基C1-C8烷氧基、C2-C8炔基、C2-C8链烯基、C3-C8环烷基、C7-C10芳烷基、苯基、氰基C1-C8烷基、硝基C1-C8烷基、羧基、卤代C1-C8烷基、单或多羟基C1-C8烷基、C1-C8烷基硫代C1-C8烷基、C1-C8烷基磺酰C1-C8烷基、C1-C8酰氧基C1-C8烷基、C1-C8酰基C1-C8烷基或磺酸基;
R5、R6、R7、R8各自独立地是或选自氢、卤素、羟基、C1-C8烷基、C1-C8烷氧基、C1-C8酰基C1-C8烷氧基、C2-C8炔基、C2-C8链烯基、C3-C8环烷基、C7-C10芳烷基、苯基、氰基C1-C8烷基、硝基C1-C8烷基、羧基、卤代C1-C8烷基、单或多羟基C1-C8烷基、C1-C8烷基硫代C1-C8烷基、C1-C8烷基磺酰C1-C8烷基、C1-C8酰氧基C1-C8烷基、C1-C8酰基C1-C8烷基或磺酸基;
R9是或选自C1-C25烷基、C1-C25烷氧基、C1-C10酰基C1-C8烷氧基、C2-C12炔基、C2-C12链烯基、C3-C10环烷基、C7-C12芳烷基、苯基、氰基C1-C12烷基、硝基C1-C12烷基、羧基、卤代C1-C12烷基、单或多羟基C1-C12烷基、C1-C8烷基硫代C1-C8烷基、C1-C8烷基磺酰C1-C8烷基、C1-C8酰氧基C1-C8烷基、C1-C8酰基C1-C8烷基或磺酸基。
优选的是:
R1、R2、R3、R4各自独立地是或选自氢、卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6酰基C1-C6烷氧基、C2-C6炔基、C2-C6链烯基、C3-C6环烷基、C7-C8芳烷基、苯基、氰基C1-C6烷基、硝基C1-C6烷基、羧基、卤代C1-C6烷基、单或多羟基C1-C6烷基、C1-C6烷基硫代C1-C6烷基、C1-C6烷基磺酰C1-C6烷基、C1-C6酰氧基C1-C6烷基、C1-C6酰基C1-C6烷基或磺酸基;
R5、R6、R7、R8各自独立地是或选自氢、卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6酰基C1-C6烷氧基、C2-C6炔基、C2-C6链烯基、C3-C6环烷基、C7-C8芳烷基、苯基、氰基C1-C6烷基、硝基C1-C6烷基、羧基、卤代C1-C6烷基、单或多羟基C1-C6烷基、C1-C6烷基硫代C1-C6烷基、C1-C6烷基磺酰C1-C6烷基、C1-C6酰氧基C1-C6烷基、C1-C6酰基C1-C6烷基或磺酸基;和
R9是或选自C1-C12烷基、C1-C12烷氧基、C1-C6酰基C1-C6烷氧基、C4-C10炔基、C4-C10链烯基、C5-C8环烷基、C7-C10芳烷基、苯基、氰基C1-C10烷基、硝基C1-C10烷基、羧基、卤代C1-C10烷基、单或多羟基C1-C10烷基、C1-C6烷基硫代C1-C6烷基、C1-C6烷基磺酰C1-C6烷基、C1-C6酰氧基C1-C6烷基、C1-C6酰基C1-C6烷基或磺酸基。
优选,R2为羟基、甲氧基或乙氧基,其余取代基团R1、R3和R4为氢。R9为辛烷基、壬烷基、癸烷基、十二烷基、辛烯基、壬烯基、癸烯基或十二碳烯基中的任一种。取代基R8为羟基或乙酰氧基,其余取代基R5、R6、R7为氢。
优选,R2为羟基或甲氧基。
具体地说,以上所述化合物是选自下列这些中的一种或多种:
8-甲基-N-[(3-羟基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物1);
8-甲基-N-[(4-羟基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物2);
8-甲基-N-[(3-甲氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物3);
8-甲基-N-[(4-甲氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物4);
8-甲基-N-[(3-乙氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物5);
8-甲基-N-[(4-乙氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物6);
8-甲基-N-[(3-丙氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物7);
8-甲基-N-[(4-丙氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物8);
8-甲基-N-[(3-苄氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物9);
8-甲基-N-[(4-苄氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物10);
8-甲基-N-[(3-庚氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物11);
8-甲基-N-[(4-庚氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物12);
8-甲基-N-[(3-辛氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物13);
8-甲基-N-[(4-辛氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物14);
8-甲基-N-[(3-癸氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物15);
8-甲基-N-[(4-癸氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物16);
8-甲基-N-[(3-羟基-4-2’-氯烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物17);或
8-甲基-N-[(4-羟基-3-2’-氯烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物18)。
本发明还提供以上所述通式(Ia)或(Ib)化合物的制备方法,该方法包括以下步骤:
步骤1:通式(a)的烟酸在溶剂中与氯化剂或酰氯化剂进行反应,制得通式(b)的烟酰氯:
步骤2:通式(b)的烟酰氯与通式(c)或通式(d)的酰胺化合物在溶剂中进行反应,制得通式(Ia)或通式(Ib)化合物;
或者
其中:
R1、R2、R3、R4各自独立地是或选自氢、卤素、羟基、C1-C8烷基、C1-C8烷氧基、C1-C8酰基C1-C8烷氧基、C2-C8炔基、C2-C8链烯基、C3-C8环烷基、C7-C10芳烷基、苯基、氰基C1-C8烷基、硝基C1-C8烷基、羧基、卤代C1-C8烷基、单或多羟基C1-C8烷基、C1-C8烷基硫代C1-C8烷基、C1-C8烷基磺酰C1-C8烷基、C1-C8酰氧基C1-C8烷基、C1-C8酰基C1-C8烷基或磺酸基;
R5、R6、R7、R8各自独立地是或选自氢、卤素、羟基、C1-C8烷基、C1-C8烷氧基、C1-C8酰基C1-C8烷氧基、C2-C8炔基、C2-C8链烯基、C3-C8环烷基、C7-C10芳烷基、苯基、氰基C1-C8烷基、硝基C1-C8烷基、羧基、卤代C1-C8烷基、单或多羟基C1-C8烷基、C1-C8烷基硫代C1-C8烷基、C1-C8烷基磺酰C1-C8烷基、C1-C8酰氧基C1-C8烷基、C1-C8酰基C1-C8烷基或磺酸基;
R9是或选自C1-C25烷基、C1-C25烷氧基、C1-C10酰基C1-C8烷氧基、C2-C12炔基、C2-C12链烯基、C3-C10环烷基、C7-C12芳烷基、苯基、氰基C1-C12烷基、硝基C1-C12烷基、羧基、卤代C1-C12烷基、单或多羟基C1-C12烷基、C1-C8烷基硫代C1-C8烷基、C1-C8烷基磺酰C1-C8烷基、C1-C8酰氧基C1-C8烷基、C1-C8酰基C1-C8烷基或磺酸基。
优选,在步骤1中使用的氯化剂或酰氯化剂是或选自于:三氯氧磷、三氯化磷、五氯化磷、二氯亚砜、磺酰氯、氯气、硫酰氯SO2Cl2或光气COCl2。
优选,步骤1中还使用催化剂,该催化剂是DMF、三乙胺、吡啶、碳酸钾或碳酸钠中的一种或多种,优选是吡啶。
本发明还提供以上所述通式(Ia)或(Ib)化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体在制备治疗镇痛、抗肿瘤、抗炎、抗动脉粥样硬化、降血脂、促进食欲、改善消化、抗菌杀虫、抗氧化、抗病毒作用的药物中的用途。
本发明还提供一种药物组合物,它包括以上所述通式(Ia)或(Ib)化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体,以及一种或几种药学上可接受的辅料。
对于通式(c)或(d)的化合物,可使用从市场上购买的产品,当然,也可以自己合成:
或
另外,也可以通过酯化反应,从(c)或(d)制备化合物(Ia)或(Ib):
或者,
在上述反应历程中,R2可以为羟基。
例如,从通式(e)化合物制备通式(f)的化合物的反应中,通式(e)的苯甲醛与甲酸铵(HCO2NH4)反应。一般,在水中反应,反应温度在100-200℃,反应时间为1~12h。并且加入碱(优选KOH、NaOH、Ca(OH)2中的任一种或者多种,更优选NaOH),制得通式(f)的氨甲基苯。
另外,在从通式(f)化合物制备通式(c)化合物的反应中,通式(f)的氨甲基苯与R9取代的酰氯(R9-COCl)进行反应。优选在无水***中反应,反应温度0-100℃,反应时间为1~6h,制得通式(c)的酰胺化合物。
在通式(c)酰胺化合物与通式(b)化合物的反应中,通式(c)酰胺化合物与通式(b)烟酸化合物在溶剂中(溶剂优选为二氯亚砜、DMF、丙酮中的任一种或者多种,更优选二氯亚砜),加入催化剂(优选吡啶、三乙胺中的任一种或者多种,更优选吡啶),进行反应。一般,反应温度为0-100℃,反应时间为1~48h。从而制得通式Ia化合物。
本发明还提供通式(Ia)或(Ib)的化合物的盐。该盐是由上述化合物与碱(优选KOH、NaOH、Ca(OH)2中的任一种或者多种,更优选NaOH)进行反应所获得。反应温度5-85℃。
本发明还提供上述通式(Ia)或(Ib)的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体在制备治疗镇痛、抗肿瘤、抗炎、抗动脉粥样硬化、降血脂、促进食欲、改善消化、抗菌杀虫、抗氧化、抗病毒作用的药物中的应用。
本发明还提供一种药物组合物,其包括上述通式(Ia)或(Ib)的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体,和一种或几种药学上可接受的辅料。
对本发明的化合物进行药理实验:
镇痛方面:采用雌性小白鼠,用热板法测定了通式I化合物的镇痛作用。注射或涂抹0.005-0.50mg/kg通式I的化合物,其给药后痛反应时间延长,表明其具有良好的镇痛作用。
降血脂方面:采用ApoE敲除小鼠动脉粥样硬化模型,用HITACHI7060全自动生物化学分析仪酶法(Zhang C,et al.J Lipid Res.2006;47(9):2055-63)测定了通式I的化合物的降血脂作用及抗动脉粥样硬化作用。口服20mg/Kg/天(混入饲料中),连续给药10周,可显著降低血浆LDL-C、TC水平,对TG也有一定降低作用;同时,还有升高HDL-C的作用,其效能与洛伐他汀相当;且明显抑制粥样斑块形成。
抗肿瘤方面:包括体内和体外实验。其中体外实验系用MTT法与SRB法检测通式I的化合物具有显著的细胞毒作用,其IC50值为0.03~30.0nM。体内实验是这样进行的:给荷Lewis肺瘤小鼠腹腔注射通式I的化合物,连续10天,可显著抑制Lewis肺瘤的生长,抑制率为93.1%。若腹腔注射0.3-30mg/kg通式I的化合物,可抑制ICR-Jc1小鼠皮下接种的S-180瘤生长,半数抑制率为0.05-15mg/kg。
促消化方面:将实验小鼠随机分为对照组和通式I化合物不同剂量组。观察各组实验动物的小肠推进率、胃蛋白酶活性、胃液及胃蛋白酶分泌情况。结果显示,通式I化合物剂量组对小鼠小肠推进有促进作用,且随着剂量的增加,作用逐渐增强;通式I化合物不同剂量组能促进胃液及胃蛋白酶的分泌。说明通式I化合物具有促进消化吸收的作用。
抗菌方面:通式I的化合物具有显著的抗菌作用,其MIC为0.0012-20.32μg/ml。
抗炎方面:采用小白鼠-巴豆油涂耳刺激法,口服0.01-0.50mg/kg通式I化合物的小鼠耳肿胀程度要显著低于空白对照组(p<0.01),表明其抗炎作用良好。
抗病毒方面:通式I的化合物能显著抑制HIV-1病毒的生长繁殖。
急性毒性实验:以1次大剂量给小白鼠灌胃通式I的化合物,连续观察小白鼠行为活动等指标和毒性反应程度,并在实验结束时处死小白鼠进行剖解,以获得通式I的化合物毒性资料。连续观察15天,小白鼠无明显行为异常,也未出现死亡,实验设定的最高剂量1000mg/kg及其以下剂量对小白鼠均无明显毒性。
通过以上药理实验证明,本发明的化合物具有不同程度的镇痛、抗肿瘤、抗炎、降血脂、抗菌、抗病毒作用。并且毒性较低。
本发明的化合物可以组合物的形式施用于需要治疗的患者,所说的组合物包括治疗有效量的本发明的化合物及其盐和医药学上可接受的载体,所说的载体包括稀释剂,如水、填充剂,如淀粉、润湿剂,如甘油、粘合剂,如纤维素衍生物等,并以本领域公知的方法制备成片剂、胶囊剂、丸剂、颗粒剂、糖浆、乳剂、悬浊液和溶液,按常规给药,优先口服给药。剂量为0.005~20mg/kg体重。
与现有技术相比,本发明具有以下优点:
1、本发明提供的一种新的含烟酸辣椒碱酯衍生物及其盐,可以制备治疗镇痛、抗肿瘤、抗炎、抗动脉粥样硬化、降血脂、促进食欲、改善消化、抗菌杀虫、抗氧化、抗病毒作用的药物,且毒性较低。
2、本发明将烟酸基团引入辣椒碱类化合物中,获得一种新型的含烟酸辣椒碱酯衍生物,本发明还提供了上述含烟酸辣椒碱酯衍生物的制备方法,可以提高辣椒碱类化合物的生物活性并改善刺激性,以满足临床用药的需要。
3、采用热板法测定镇痛作用,采用ApoE敲除小鼠动脉粥样硬化模型测定降血脂作用,并测定了本发明化合物的细胞毒作用(抗癌细胞作用)、促消化作用、抗菌作用、抗炎作用,实验结果证明,本发明的化合物及其盐具有不同程度的镇痛、抗肿瘤、抗炎、降血脂、抗菌、抗病毒作用,并且毒性较低。
综上所述,本发明的化合物及其盐具有优良的镇痛、抗肿瘤、抗炎、降血脂、抗菌、抗病毒作用,并且毒性较小,制备方法容易,便于工业化生产,能够满足医药领域的需要。本发明的化合物具有疗效高、毒性低等优点。
具体实施方式
实施例1
8-甲基-N-[(3-羟基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物1,即代号1)与8-甲基-N-[(4-羟基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物2,即代号2)的制备:
将0.1mol 8-甲基-N-[(3,4-二羟基苯基)-甲基]-(反)-6-壬烯基酰胺在100ml二氯亚砜中于80℃下与0.15mol烟酸反应10小时,倒入冰水浴中,用乙酸乙酯萃取3次,无水硫酸钠干燥,然后用乙酸乙酯:石油醚=1:2~1:5柱层析,获得目标产物8-甲基-N-[(3-羟基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺,产率48.8%;以及8-甲基-N-[(4-羟基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺,得率44.3%。相关数据如下:
8-甲基-N-[(3-羟基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物1)MS(EI,70ev)m/z:370;Anal.Calcd.for C21H26O4N2:C,68.21,H,7.03,N 7.57;Found C,68.19,H,6.99,N 7.53.
8-甲基-N-[(4-羟基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物2)MS(EI,70ev)m/z:370;Anal.Calcd.for C21H26O4N2:C,68.21,H,7.03,N 7.57;Found C,68.19,H,6.99,N 7.53.
实施例2
8-甲基-N-[(3-甲氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物3)的制备:
将0.2mol碘甲烷与0.1mol的8-甲基-N-[(3-甲氧基-4-羟基苯基)-甲基]-(反)-6-壬烯基酰胺溶解于300ml丙酮中,加入12克催化剂K2CO3,与0.15mol烟酸在80℃反应3小时,得目标产物8-甲基-N-[(3-甲氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。相关数据如下:
MS(EI,70ev)m/z:384;Anal.Calcd.for C22H28O4N2:C,68.75,H,7.29,N 7.29;Found C,68.70,H,7.25,N 7.24.
实施例3
8-甲基-N-[(4-甲氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物4)的制备
按照实施例2的操作,只是使用8-甲基-N-[(4-甲氧基-3-羟基苯基)-甲基]-(反)-6-壬烯基酰胺代替8-甲基-N-[(3-甲氧基-4-羟基苯基)-甲基]-(反)-6-壬烯基酰胺,得到化合物8-甲基-N-[(4-甲氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。相关数据如下:
MS(EI,70ev)m/z:384;Anal.Calcd.for C22H28O4N2:C,68.75,H,7.29,N 7.29;Found C,68.70,H,7.25,N 7.24.
实施例4
8-甲基-N-[(3-乙氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物5)的制备
用溴乙烷代替碘甲烷,按照实施例2的操作,得到化合物8-甲基-N-[(3-乙氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。相关数据如下:
MS(EI,70ev)m/z:398;Anal.Calcd.for C23H30O4N2:C,69.35,H,7.54,N 7.04;Found C,69.31,H,7.49,N 7.01.
实施例5
8-甲基-N-[(4-乙氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物6)的制备
重复实施例4,只是使用8-甲基-N-[(4-甲氧基-3-羟基苯基)-甲基]-(反)-6-壬烯基酰胺代替8-甲基-N-[(3-甲氧基-4-羟基苯基)-甲基]-(反)-6-壬烯基酰胺,得到化合物8-甲基-N-[(4-乙氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。相关数据如下:
MS(EI,70ev)m/z:398;Anal.Calcd.for C23H30O4N2:C,69.35,H,7.54,N 7.04;Found C,69.31,H,7.49,N 7.01.
实施例6
8-甲基-N-[(3-丙氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物7)的制备
用溴丙烷代替碘甲烷,按照实施例2的操作,得到化合物8-甲基-N-[(3-丙氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。相关数据如下:
MS(EI,70ev)m/z:412;Anal.Calcd.for C24H32O4N2:C,69.90,H,7.77,N 6.80;Found C,69.87,H,7.75,N 6.79.
实施例7
8-甲基-N-[(4-丙氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物8)的制备
用溴丙烷代替碘甲烷,按照实施例3的操作,得到化合物8-甲基-N-[(4-丙氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。相关数据如下:
MS(EI,70ev)m/z:412;Anal.Calcd.for C24H32O4N2:C,69.90,H,7.77,N 6.80;Found C,69.87,H,7.75,N 6.79.
实施例8
8-甲基-N-[(3-苄氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物9)的制备
用溴苄烷代替碘甲烷,按照实施例2的操作,得到化合物8-甲基-N-[(3-苄氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。相关数据如下:
MS(EI,70ev)m/z:488;Anal.Calcd.for C30H36O4N2:C73.77,H,7.38,N 5.73;Found C,73.75,H,7.37,N 5.70.
实施例9
8-甲基-N-[(4-苄氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物10)的制备
用溴苄烷代替碘甲烷,按照实施例3的操作,得到化合物8-甲基-N-[(4-苄氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。相关数据如下:
MS(EI,70ev)m/z:488;Anal.Calcd.for C30H36O4N2:C73.77,H,7.38,N 5.73;Found C,73.75,H,7.37,N 5.70.
实施例10
8-甲基-N-[(3-庚氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物11)的制备
用溴庚烷代替碘甲烷,按照实施例2的操作,得到化合物8-甲基-N-[(3-庚氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。相关数据如下:
MS(EI,70ev)m/z:468;Anal.Calcd.for C28H40O4N2:C,71.79,H,8.55,N 5.98;Found C,71.78,H,8.52,N 5.97.
实施例11
8-甲基-N-[(4-庚氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物12)的制备
用溴庚烷代替碘甲烷,按照实施例3的操作,得到化合物8-甲基-N-[(4-庚氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。相关数据如下:
MS(EI,70ev)m/z:468;Anal.Calcd.for C28H40O4N2:C,71.79,H,8.55,N 5.98;Found C,71.78,H,8.52,N 5.97.
实施例12
8-甲基-N-[(3-辛氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物13)的制备
用溴辛烷代替碘甲烷,按照实施例2的操作,得到化合物8-甲基-N-[(3-辛氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。相关数据如下:
MS(EI,70ev)m/z:482;Anal.Calcd.for C29H42O4N2:C,72.20,H,8.71,N 5.81;Found C,72.17,H,8.68,N 5.79.
实施例13
8-甲基-N-[(4-辛氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物14)的制备
用溴辛烷代替碘甲烷,按照实施例3的操作,得到化合物8-甲基-N-[(4-辛氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。相关数据如下:
MS(EI,70ev)m/z:482;Anal.Calcd.forC29H42O4N2:C,72.20,H,8.71,N 5.81;Found C,72.17,H,8.68,N 5.79.
实施例14
8-甲基-N-[(3-癸氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物15)的制备
用溴癸烷代替碘甲烷,按照实施例2的操作,得到化合物8-甲基-N-[(3-癸氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。相关数据如下:
MS(EI,70ev)m/z:510;Anal.Calcd.for C31H46O4N2:C,72.94,H,9.02,N 5.49;Found C,72.91,H,9.01,N 5.48.
实施例15
8-甲基-N-[(4-癸氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物16)的制备
用溴癸烷代替碘甲烷,按照实施例3的操作,得到化合物8-甲基-N-[(4-癸氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。相关数据如下:
MS(EI,70evm/z:510;Anal.Calcd.for C31H46O4N2:C,72.94,H,9.02,N 5.49;Found C,72.91,H,9.01,N 5.48.
实施例16
8-甲基-N-[(3-羟基-4-2’-氯烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物17)与8-甲基-N-[(4-羟基-3-2’-氯烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物18)的制备
用2-氯烟酸代替烟酸,重复实施例1的操作,得到化合物8-甲基-N-[(3-羟基-4-2’-氯烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物17)与8-甲基-N-[(4-羟基-3-2’-氯烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物18)。相关数据如下:
8-甲基-N-[(3-羟基-4-2’-氯烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物17)
MS(EI,70evm/z:404.5;Anal.Calcd.for C21H25O4N2Cl:C,62.30,H,6.18,N6.98,Cl,8.78;Found C,62.29,H,6.19,N 6.90,Cl,8.79.
8-甲基-N-[(4-羟基-3-2’-氯烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺(化合物18)
MS(EI,70evm/z:404.5;Anal.Calcd.for C21H25O4N2Cl:C,62.30,H,6.18,N6.98,Cl,8.78;Found C,62.29,H,6.19,N 6.90,Cl,8.79.
实施例17(实验)
采用热板法测定了所合成通式(I)的六种化合物(实施例1-3、实施例16的化合物)的镇痛作用,结果见表1。采用雌性小白鼠,注射或涂抹0.01mg/kg通式I的化合物,给药后痛反应时间延长,表明其具有良好的镇痛作用。
表1 小鼠注射本发明合成的六种化合物痛阈提高百分率
实施例18
采用ApoE敲除小鼠动脉粥样硬化模型,采用HITACHI7060全自动生物化学分析仪酶法(Zhang C,et al.J Lipid Res.2006;47(9):2055-63)测定了通式I化合物(实施例1-2、实施例15-16的化合物)的降血脂作用及抗动脉粥样硬化作用。所获的一些结果见表2。口服20mg/Kg/天(混入饲料中),连续给药10周,结果表明通式I化合物可显著降低血浆LDL-C、TC水平,对TG也有一定降低作用;同时,还有升高HDL-C的作用,其效能与洛伐他汀相当;且明显抑制粥样斑块形成。
表2 通式(I)的四种化合物对动脉粥样硬化小鼠(ApoE-/-)血脂的影响
TC=总胆固醇;TG=三酰甘油;LDL-C=低密度脂蛋白胆固醇;
DL-C=低高密度脂蛋白胆固醇;*,p<0.05;**,p<0.01vs模型组
实施例19
参照Mosman的方法(Mosman,T.J.Immunol Methods.1983,65,55),通过MTT比色法测定了本发明化合物的细胞毒作用,其IC50值为0.03~30.0nM。结果见表3。
表3
实施例20
参照文献(张均田主编,现代药理实验方法。)研究不同剂量通式I的化合物对细菌、真菌的作用。其MIC为0.0012-20.32μg/ml。其结果见表4。
表4
实施例21
含有通式(I)的化合物(例如化合物1)的片剂,可由本领域公知的方法制备。
实施例22
含有通式(I)的化合物的胶囊剂,可由本领域公知的方法制备。
Claims (8)
2.根据权利要求1所述的化合物,其中所述化合物是选自下列这些中的一种或多种:
8-甲基-N-[(3-羟基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺;
8-甲基-N-[(4-羟基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺;
8-甲基-N-[(3-乙氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺;
8-甲基-N-[(4-乙氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺;
8-甲基-N-[(3-丙氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺;
8-甲基-N-[(4-丙氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺;
8-甲基-N-[(3-庚氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺;
8-甲基-N-[(4-庚氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺;
8-甲基-N-[(3-辛氧基-4-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺;
8-甲基-N-[(4-辛氧基-3-烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺;
8-甲基-N-[(3-羟基-4-2’-氯烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺;或
8-甲基-N-[(4-羟基-3-2’-氯烟酸酯苯基)-甲基]-(反)-6-壬烯基酰胺。
4.根据权利要求3所述的方法,其特征在于,步骤1中使用的氯化剂或酰氯化剂选自于:三氯氧磷、三氯化磷、五氯化磷、二氯亚砜、磺酰氯、氯气、硫酰氯SO2Cl2或光气COCl2。
5.根据权利要求3或4所述的方法,其特征在于,步骤1中还使用催化剂,该催化剂是DMF、三乙胺或吡啶中的一种或多种。
6.根据权利要求5所述的方法,其特征在于,所述催化剂是吡啶。
7.根据权利要求1或2所述的化合物在制备治疗镇痛、抗肿瘤、抗炎、抗动脉粥样硬化、降血脂、抗菌的药物中的用途。
8.一种药物组合物,它包括权利要求1或2所述化合物,以及一种或几种药学上可接受的辅料。
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