CN103626692B - 3,5-双芳基甲叉基哌啶酮衍生物及其在制备降糖降脂药物中的应用 - Google Patents
3,5-双芳基甲叉基哌啶酮衍生物及其在制备降糖降脂药物中的应用 Download PDFInfo
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- CN103626692B CN103626692B CN201310561814.8A CN201310561814A CN103626692B CN 103626692 B CN103626692 B CN 103626692B CN 201310561814 A CN201310561814 A CN 201310561814A CN 103626692 B CN103626692 B CN 103626692B
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- piperidin
- methylene
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- piperidone
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- 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
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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Abstract
本发明涉及医药技术领域。本发明提供了一类3,5-双芳基甲叉基哌啶酮衍生物及其药理上可接受的盐或水合物，该化合物的化学结构式如通式I所示。本发明的化合物对PTP1B有显著抑制作用，可用于制备降糖药物、降脂药物、治疗和预防糖尿病、肥胖症的药物或保健品。
Description
技术领域
本发明涉及医药技术领域，具体涉及一类3,5-双芳基甲叉基哌啶酮衍生物，及其在制备降糖、降脂、治疗或预防糖尿病、肥胖症的药物或保健品中的应用。
背景技术
蛋白酪氨酸磷酸化是一种重要的调节信号转导的翻译后修饰方式。在体内酪氨酸的磷酸化是可逆的动态过程，其磷酸化和去磷酸化分别由蛋白酪氨酸激酶(protein tyrosine kinases,PTKs)和蛋白酪氨酸磷酸酯酶(protein tyrosinephosphatases,PTPs)来调节。PTPs是信号转导途径中的重要成员，在人类健康和疾病的发生发展中起着关键作用。
蛋白酪氨酸磷酸酯酶1B(protein tyrosine phosphatase1B,PTP1B)是最早被纯化和确定生物学特征的蛋白酪氨酸磷酸酯酶。糖尿病和肥胖症都伴随着胰岛素敏感组织中的胰岛素敏感性降低即胰岛素抵抗，目前实验证据表明，PTP1B对胰岛素受体及其底物的磷酸化水平起着重要的负调控作用，通过抑制PTP1B的活性，有助于提高外周组织对胰岛素的敏感性。遗传学证据表明，PTP1B基因缺失的小鼠能维持正常的生理状态，并且能够改善对血糖的控制并对高脂类食物诱导的肥胖有一定的抵抗能力。两篇具有里程碑意义的文献报道了具有PTP1B缺陷的小鼠对胰岛素的具有更高的敏感性，可以显著的提高对血糖的控制能力，并且对饮食诱导的肥胖具有明显的抑制作用（Elchebly M.et al.Increased insulin sensitivity and obesity resistance in micelacking the protein tyrosine phosphatase1B gene.Science1999;283:1544-8.;Klaman LD.et al.Increased energy expenditure decreased adiposity andtissue-specific insulin sensitivity in protein-tyrosine phosphatase1B defcient mice.Mol Cell Biol2000;20:5479-89.）。而且PTP1B反义寡核苷酸能够显著减少PTP1B酶水平的表达，从而使得血糖水平正常化，提高对胰岛素的敏感性（Zinker BA et.al.,PTP1B antisense oligonucleotide lowers PTP1B protein,normalizes blood glucose,and improves insulin sensitivity in diabetic mice.ProcNatl Acad Sci USA2002;99:11357-62.;Gum RJ et al.,Reduction of proteintyrosine phosphatase1b increases insulin-dependent signaling in ob/ob mice.Diabetes2003;52:21-8）。因此，PTP1B是一个有效的治疗糖尿病和肥胖症等胰岛素抵抗类疾病的药物作用靶点，寻找具有成药性的高活性抑制剂对于糖尿病和肥胖症等疾病的治疗中有着广阔的应用前景。
到目前为止，有少量文献或专利公开3,5-双芳基甲叉基哌啶酮衍生物的具有抗肿瘤、抗炎（Swagatika Das et.al.,Europ J Med Chem,2013,64:321-328；Martina Bazzaro et.al.,J Med Chem.2011,54:449-456;Babasaheb Yadav et.al.,Bioorg Med Chem,2010,18:6701–6707;PCT专利申请WO2012021692A1，发明名称为CURCUMIN ANALOGS AND METHODS OF USE THEREOF；中国专利申请CN201110139209.2，发明名称为“新型成纤维细胞生长因子受体酪氨酸激酶抑制剂”，公开号CN102293770A；中国专利申请CN201310032627.0，发明名称为“一种（3E，5E）-3,5-双哌啶-4-酮类似物及其制备方法与应用”，公开号CN103044322A）。前述的中国专利申请CN201310032627.0中公开了一种3,5-二(2，6-二卤代苯亚甲基)-哌啶-4-酮类衍生物具有11β-HSD1抑制作用。
本技术领域一直致力于寻找新的3,5-双芳基甲叉基哌啶酮衍生物，能够具有抑制PTP1B的活性，进一步开发成为降糖、降脂、治疗或预防糖尿病、肥胖症的药物或保健品。
发明内容
本发明的目的是在于提供一类新的3,5-双芳基甲叉基哌啶酮衍生物及其药理上可接受的盐或水合物，本发明的另一目的是提供上述化合物在制备降血糖、降血脂、预防或治疗高脂血症、糖尿病的药物或保健品中的应用。
本发明提供了一类3,5-双芳基甲叉基哌啶酮衍生物及其药理上可接受的盐或水合物，其特征在于，该化合物的化学结构式如通式I所示：
其中R，代表H、甲基、乙基、丙基、丁基、乙酰基、丙酰基、丁酰基、桂皮酰基；3’-氟桂皮酰基；3’-氯桂皮酰基；3’-溴桂皮酰基；3’-碘桂皮酰基；4’-三氟甲基桂皮酰基；
Ar，代表呋喃基、5-羟甲基呋喃基、噻吩基、2-萘基、2-苯基乙烯基、3,4-亚甲二氧基苯基；或如下示的取代的苯基：
其中，R1代表H、甲氧基、氟、氯、溴、碘；
R2代表H、氟、氯、溴、碘、甲氧基、羟基；
R3代表H、氟、氯、溴、碘、甲氧基、乙氧基、丙氧基、羟基、三氟甲基；
R4代表H、氟、氯、溴、碘、甲氧基、羟基；
R5代表H、氟、氯、溴、碘、甲氧基。
本发明的3,5-双芳基甲叉基哌啶酮衍生物的药理上可接受的盐，可以是其盐酸盐、硫酸盐、磷酸盐、氢溴酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、乳酸盐、对甲苯磺酸盐、水杨酸盐、草酸盐等。
本发明的3,5-双芳基甲叉基哌啶酮衍生物的药理上可接受的水合物，可以是其一水合物、二水合物。
本发明的优选化合物如下：
(3E,5E)-3,5-双(3,4-二氯苯亚甲基)-哌啶-4-酮、
(3E,5E)-3,5-双(4-三氟甲基苯亚甲基)-哌啶-4-酮、
(3E,5E)-3,5-双(4-溴苯亚甲基)-哌啶-4-酮、
(3E,5E)-3,5-双(2,4-二氯苯亚甲基)-哌啶-4-酮、
(3E,5E)-3,5-双(2-萘亚甲基)-哌啶-4-酮、
(3E,5E)-3,5-双(2-氯苯亚甲基)-N-甲基哌啶-4-酮、
(3E,5E)-3,5-双(3-氯苯亚甲基)-N-甲基哌啶-4-酮、
(3E,5E)-3,5-双(4-氯苯亚甲基)-N-甲基哌啶-4-酮、
(3E,5E)-3,5-双(3，4-亚甲二氧苯亚甲基)-N-甲基哌啶-4-酮、
(3E,5E)-3,5-双(2，6-二氯苯亚甲基)-N-甲基哌啶-4-酮、
(3E,5E)-3,5-双(4-三氟甲基苯亚甲基)-N-甲基哌啶-4-酮、
(3E,5E)-3,5-双(3，4-二氯苯亚甲基)-N-甲基哌啶-4-酮、
(3E,5E)-3,5-双(2，4-二氯苯亚甲基)-N-甲基哌啶-4-酮、
(3E,5E)-3,5-双(4-溴苯亚甲基)-N-甲基哌啶-4-酮、
(3E,5E)-3,5-双(噻吩-2-亚甲基)-N-甲基哌啶-4-酮、
(3E,5E)-3,5-双苯乙烯亚甲基-N-甲基哌啶-4-酮、
(3E,5E)-1-乙酰基-3,5-双苯乙烯亚甲基哌啶-4-酮、
(3E,5E)-1-乙酰基-3,5-双(2-萘亚甲基)哌啶-4-酮、
(3E,5E)-1-乙酰基-3,5-双(2,6-二氯苯亚甲基)哌啶-4-酮、
(3E,5E)-1-丙酰基-3,5-双(2,4-二氯苯亚甲基)哌啶-4-酮、
(3E,5E)-1-丙酰基-3,5-双(呋喃-2-亚甲基)哌啶-4-酮、
(3E,5E)-1-((E)-3-(3-溴苯基)烯丙醛基-3,5-双(噻吩-2-亚甲基)哌啶-4-酮、
(3E,5E)-1-((E)-3-(4-三氟甲基苯基)烯丙醛基-3,5-双苯乙烯亚甲基哌啶-4-酮、
(3E,5E)-1-苯乙烯醛基-3,5-双(4-甲氧基苯亚甲基)哌啶-4-酮、
(3E,5E)-1-((E)-3-(3-溴苯基)烯丙醛基-3,5-双(3-氟苯亚甲基)哌啶-4-酮，或
(3E,5E)-1-((E)-3-(4-三氟甲基苯基)烯丙醛基-3,5-双(3-氟苯亚甲基)哌啶-4-酮。
本发明还提供了上述的3,5-双芳基甲叉基哌啶酮衍生物的合成路线如下：
采用哌啶酮或N-甲基哌啶酮为原料，在10%～50%NaOH溶液/乙醇中反应(a)得到部分式I化合物。其中由哌啶酮反应得到的式I化合物（即R=H）与各种酰氯在无水吡啶于0度到室温反应(b)得到N酰基取代产物。酰氯由市售相应的酸与SOCl2回流反应制备而得到。
本发明所公开的3,5-双芳基甲叉基哌啶酮衍生物，采用从大肠杆菌中表达并纯化的GST融合蛋白(PTP1B和CDC25B)进行活性筛选。结果显示本发明的通式I类化合物在浓度为20μg/ml时均有明显的PTP1B抑制作用。本发明的优选化合物1～37及其药理上可以接受的盐或水合物可用于制备降糖药物、降脂药物、治疗和预防糖尿病、肥胖症的药物或保健品。
本发明还提供了上述的3,5-双芳基甲叉基哌啶酮衍生物及其药理上可接受的盐或水合物在制备蛋白酪氨酸磷酸酯酶1B（PTP1B）抑制剂中的应用。
本发明还提供了上述的3,5-双芳基甲叉基哌啶酮衍生物及其药理上可接受的盐或水合物在制备降血糖、降血脂、预防或治疗高脂血症、糖尿病的药物或保健品中的应用。
具体实施方式
现结合实施例，对本发明作详细描述，但本发明的实施不仅限于此。
本发明所用试剂和原料均市售可得或可按文献方法制备。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。
实施例1：(3E,5E)-3,5-双(3,4-二氯苯亚甲基)-哌啶-4-酮的制备
取4-哌啶酮盐酸盐134mg，3,4-二氯苯甲醛383mg，加入到8ml乙醇中，然后加入20%NaOH2ml，于室温搅拌。TLC跟踪反应至基本完全（一般约需12～36h）。然后将反应液倒入到100ml水中。析出黄色沉淀，过滤，用乙醇重结晶，得到纯品210mg，收率51%。1H NMR（DMSO-d6）:3.96(4H,s,-CH2-);7.45-7.48(2H,dd,J=8.4Hz,J=1.8Hz,Ar-H);7.52(2H,s,=CH-);7.69-7.72(2H,d,J=8.4Hz,Ar-H);7.76-7.77(2H,d,J=1.8Hz,Ar-H)。
实施例2：(3E,5E)-3,5-双(4-三氟甲基苯亚甲基)-哌啶-4-酮的制备
除以4-哌啶酮和4-三氟甲基苯甲醛为原料外，其余同实施例1。黄色固体，收率37%。1H NMR(DMSO-d6):3.32(4H,s,-CH2-);7.63(2H,s,=CH-);7.68-7.71(4H,d,J=8.1Hz,Ar-H);7.79-7.82(4H,d,J=8.1Hz,Ar-H)。
实施例3：(3E,5E)-3,5-双(4-溴苯亚甲基)-哌啶-4-酮的制备
以4-哌啶酮和4-溴甲基苯甲醛为原料，方法同实施例1。黄色固体，收率63%。1H NMR(DMSO-d6):3.95(4H,s,-CH2-);7.42-7.44(4H,d,J=8.4Hz,Ar-H);7.52(2H,s,=CH-);7.64-7.66(4H,d,J=8.4Hz,Ar-H)。
实施例4：(3E,5E)-3,5-双(2,4-二氯苯亚甲基)-哌啶-4-酮的制备
除以4-哌啶酮和2,4-二氯苯甲醛为原料外，其余同实施例1。黄色固体，收率36%。1H NMR（DMSO-d6）:3.85(4H,s,-CH2-);7.43-7.46(2H,d,J=8.4Hz,Ar-H);7.50-7.53(2H,dd,J=8.4Hz,J=1.8Hz,Ar-H);7.65(2H,s,=CH-);7.76(2H,d,J=1.8Hz,Ar-H)。
实施例5：(3E,5E)-3,5-双(2-萘亚甲基)-哌啶-4-酮的制备
除以4-哌啶酮和2-萘甲醛为原料外，其余同实施例1。黄色固体，收率57%。1H NMR（DMSO-d6）:4.12(4H,s,-CH2-);7.57-7.65(6H,m,Ar-H);7.79(2H,s,Ar-H);7.94-8.05(6H,m,Ar-H);8.08(2H,s,CH=)。
实施例6：(3E,5E)-3,5-双(2-氯苯亚甲基)-N-甲基哌啶-4-酮的制备
除以N-甲基-4-哌啶酮和2-氯苯甲醛为原料外，其余同实施例1。黄色固体，收率59%。1H NMR（CDCl3）:2.37(3H,s,-CH3),3.61(4H,s,CH2-),7.23-7.26(3H,m,Ar-H),7.304-7.32(5H,m,Ar-H),8.00(2H,CH=)。
实施例7：(3E,5E)-3,5-双(3-氯苯亚甲基)-N-甲基哌啶-4-酮的制备
除以N-甲基-4-哌啶酮和3-氯苯甲醛为原料外，其余同实施例1。黄色固体，收率62%。1H NMR（CDCl3）:2.37(3H,s,-CH3),3.61-3.16(4H,m,-CH2-),7.46-7.47(2H,m,Ar-H),7.23-7.47(8H,m,Ar-H),8.00(2H,-CH=)。
实施例8：(3E,5E)-3,5-双(4-氯苯亚甲基)-N-甲基哌啶-4-酮的制备
除以N-甲基-4-哌啶酮和4-氯苯甲醛为原料外，其余同实施例1。黄色固体，收率55%。1H NMR（CDCl3）:2.50(3H,s,-CH3),3.75(4H,s,CH2-),7.33-7.37(4H,d,Ar-H),7.42-7.45(4H,d,Ar-H),7.78(2H,brs,-CH=)。
实施例9：(3E,5E)-3,5-双(3，4-亚甲二氧苯亚甲基)-N-甲基哌啶-4-酮(CHS286)的制备
除以N-甲基-4-哌啶酮和胡椒醛为原料外，其余同实施例1。黄色固体，收率68%。1H NMR（CDCl3）:2.49(3H,s,-CH3),3.75(4H,s,-CH2-),6.03(4H,s,O-CH2-O),6.87-6.96(6H,m,Ar-H),7.72(2H,-CH=)。
实施例10：(3E,5E)-3,5-双(2，6-二氯苯亚甲基)-N-甲基哌啶-4-酮的制备
除以N-甲基-4-哌啶酮和2，6-二氯苯甲醛为原料外，其余同实施例1。黄色固体，收率35%。1H NMR(CDCl3):2.32(3H,s,-CH3);3.40(4H,s,-CH2-);7.25-7.28(2H,m,Ar-H);7.37-7.39(4H,m,Ar-H);7.72(2H,s,Ar-H)。
实施例11：(3E,5E)-3,5-双(4-三氟甲基苯亚甲基)-N-甲基哌啶-4-酮的制备
除以N-甲基-4-哌啶酮和4-三氟甲基苯甲醛为原料外，其余同实施例1。黄色固体，收率11%。1H NMR(CDCl3):4.93(4H,s,-CH2-);7.15-7.18(4H,d,J=8.4Hz,Ar-H);7.40-7.43(4H,d,J=8.4Hz,Ar-H);7.82(2H,s,=CH-)。
实施例12：(3E,5E)-3,5-双(3，4-二氯苯亚甲基)-N-甲基哌啶-4-酮的制备
除以N-甲基-4-哌啶酮和3，4-二氯苯甲醛为原料外，其余同实施例1。黄色固体，收率35%。1H NMR(CDCl3):2.49(3H,s,-CH3),3.72(4H,s,-CH2-),7.21-7.24(2H,m,2’-Ar-H),7.47-7.52(4H,m,5’-Ar-H,6’-Ar-H),7.69(2H,-CH=)。
实施例13：(3E,5E)-3,5-双(2，4-二氯苯亚甲基)-N-甲基哌啶-4-酮的制备
除以N-甲基-4-哌啶酮和2，4-二氯苯甲醛为原料外，其余同实施例1。黄色固体，收率55%。1H NMR(CDCl3):2.39(3H,s,-CH3),3.56(4H,s,-CH2-),7.92(2H,-CH=),7.15-7.18(2H,d,J=8.4Hz,4’-Ar-H),7.28-7.31(2H,m,3’-Ar-H),7.49(2H,m,6’-Ar-H)。
实施例14：(3E,5E)-3,5-双(4-溴苯亚甲基)-N-甲基哌啶-4-酮的制备
除以N-甲基-4-哌啶酮和4-溴苯甲醛为原料外，其余同实施例1。黄色固体，收率68%。1H NMR(CDCl3):2.47(3H,s,-CH3),3.72(4H,s,N-CH2-),7.73(2H,brs,-CO-CH=),7.24-7.27(4H,d,J=8.4Hz,3’-Ar-H,5’-Ar-H),7.55-7.58(4H,d,J=8.4Hz,2’-Ar-H,6’-Ar-H)。
实施例15：(3E,5E)-3,5-双(噻吩-2-亚甲基)-N-甲基哌啶-4-酮的制备
除以N-甲基-4-哌啶酮和2-噻吩甲醛为原料外，其余同实施例1。黄色固体，收率97%。1H NMR:2.60(3H,s,-CH3);3.83(4H,s,-CH2-);7.14-7.17(2H,dd,J=5.1Hz,J=1.2Hz,Ar-H);7.33-7.34(2H,d,J=1.2Hz,Ar-H);7.55-7.57(2H,d,J=5.1Hz,Ar-H)，7.94(2H,s,=CH)。
实施例16：(3E,5E)-3,5-双苯乙烯亚甲基-N-甲基哌啶-4-酮的制备
除以N-甲基-4-哌啶酮和肉桂醛为原料外，其余同实施例1。收率49%。1H NMR:2.56(3H,s,-CH3);3.67(4H,s,-CH2-);7.00(2H,s,Ar-H);7.31-7.39(9H,m,Ar-H);7.50-7.52(5H,m,Ar-H)。
实施例17：(3E,5E)-1-乙酰基-3,5-双苯乙烯亚甲基哌啶-4-酮的制备
取(3E,5E)-3,5-二苯乙烯亚甲基哌啶-4-酮300mg，加入到8ml吡啶中，然后加入乙酸酐1ml，加热至60度反应2h。然后待反应液冷却后倒入到100ml的冰水中，搅拌，过滤，用乙醇重结晶得到黄色固体，收率71%。1H NMR:2.21-2.26(3H,s,-CH3);4.62(2H,s,-CH2-);4.80(2H,s,-CH2-);6.92-7.55(16H,m,Ar-H and-CH=).13C NMR:21.36(-CH3);41.79,45.97(-CH2-);121.40-143.50(Ar-C and–C=);169.10(-CO-N-);185.54(-CO-).ESI-MS:[2M+Na]+=762.68。
实施例18：(3E,5E)-1-乙酰基-3,5-双(2-萘亚甲基)哌啶-4-酮的制备
除以(3E,5E)-3,5-双(2-萘亚甲基)哌啶-4-酮为原料外，其余同实施例17。黄色固体，收率65%。1H NMR(DMSO-d6):2.13(3H,s,-CH3);4.67(2H,s,-CH2-);4.97(2H,s,-CH2-);7.522-7.55(2H,m,Ar-H);7.59-7.61(3H,m,Ar-H);7.69-7.71(2H,m,Ar-H);7.85-7.92(3H,m,Ar-H);7.97-8.04(4H,m,Ar-H)8.15(2H,s)。
实施例19：(3E,5E)-1-乙酰基-3,5-双(2,6-二氯苯亚甲基)哌啶-4-酮的制备
除以(3E,5E)-3,5-二(2,6-二氯苯亚甲基)哌啶-4-酮为原料外，其余同实施例17。黄色固体，收率82%。1H NMR:1.83-1.88(3H,s,-COCH3);4.24(2H,s,-CH2-);4.46(2H,s,-CH2-);7.23-7.44(6H,m,Ar-H);7.69(1H,s,-CH=);7.71(1H,s,-CH=).13C NMR:20.39(-CH3);42.65(-CH2-);46.42(-CH2-);127.76-135.13(Ar-C and–C=);168.59(-CO-N-);184.43(-CO-).ESI-MS:[2M+Na]+=929.25。
实施例20：(3E,5E)-1-丙酰基-3,5-双(2,4-二氯苯亚甲基)哌啶-4-酮的制备
除以(3E,5E)-3,5-二(2,4-二氯苯亚甲基)哌啶-4-酮和丙酸酐为原料外，其余同实施例17。黄色固体，收率72%。1H NMR:0.97-1.02(3H,t,J=7.5Hz,-CH3);2.08-2.15(2H,q,J=7.5Hz,-CO-CH2-);4.51(2H,s,-CH2-);4.71(2H,s,-CH2-);7.11-7.15(1H,m,Ar-H);7.31-7.34(2H,m,Ar-H);7.37-7.40(1H,m,Ar-H);7.46(1H,s,Ar-H);7.51(1H,s,Ar-H);7.89(2H,s,-CH=)。
实施例21：(3E,5E)-1-丙酰基-3,5-双(呋喃-2-亚甲基)哌啶-4-酮的制备
除以(3E,5E)-3,5-二(呋喃-2-亚甲基)哌啶-4-酮为原料外，其余同实施例20。黄色固体，熔点℃，收率67%。1H NMR:1.11-1.16(3H,t,J=7.5Hz,-CH3);2.41-2.49(2H,q,J=7.5Hz,-CO-CH2-);4.95(2H,s,-CH2-);5.04(2H,s,-CH2-);6.53-7.63(8H,m,Ar-H and-CH=).13C NMR:9.27(-CH3);26.37(-CO-CH2-);43.43(-CH2-);45.92(-CH2-);112.62-112.70(3-C);117.96-118.37(4-C);121.90,123.42(-CH=);128.00-128.42(5-C);145.61-145.78(-C=);151.70(2-C);172.61(-CO-N-);185.81(-CO-).ESI-MS：[2M+Na]+=645.44
实施例22：(3E,5E)-1-((E)-3-(3-溴苯基)烯丙醛基-3,5-双(噻吩-2-亚甲基)哌啶-4-酮的制备
3-溴肉桂酸1g，加入到5ml SOCl2中回流2h，减压蒸去过量SOCl2，待用。
氮气保护下(3E,5E)-3,5-二(噻吩-2-亚甲基)哌啶-4-酮300mg加入到新制无水吡啶中，然后于0度下加入3-溴肉桂酰氯222mg，于室温反应3h。然后将反应液倒入100ml水中，过滤，用乙醇重结晶，得到黄色固体，收率75%。1H NMR:5.01(4H,s,-CH2-);6.84-6.89(1H,d,J=15.6Hz,α-H);7.16-7.27(4H,m,Ar-H);7.43-7.49(4H,m,Ar-H);7.50-7.56(1H,d,J=15.6Hz,β-H);7.65(1H,s,-CH=);7.67(1H,s,-CH=);8.02(2H,s,5-H).ESI-MS：[2M+Na]+=1015.00
实施例23：(3E,5E)-1-((E)-3-(4-三氟甲基苯基)烯丙醛基-3,5-双苯乙烯亚甲基哌啶-4-酮的制备
除以(3E,5E)-3,5-二苯乙烯亚甲基哌啶-4-酮和4-三氟甲基肉桂酸为原料外，其余同实施例22。黄色固体，收率76%。1H NMR(DMSO-d6):4.90(2H,s),5.04(2H,s),7.32-7.44(12H,m),7.54-7.60(4H,d J=6.9),7.72-7.74(4H,dJ=6.9),7.89(1H,s,-CH=),7.92(1H,s,-CH=)。
实施例24：(3E,5E)-1-苯乙烯醛基-3,5-双(4-甲氧基苯亚甲基)哌啶-4-酮的制备
以(3E,5E)-3,5-二(4-甲氧基苯亚甲基)哌啶-4-酮(CHS63)和桂皮酰氯为原料，其余同实施例22，黄色固体，熔点196-198℃，收率72%。1H NMR:3.88(6H,s,-OCH3);4.88(2H,s,-CH2-);4.97(2H,s,-CH2-);6.41-6.46(1H,d,J=15.6Hz,α-H);6.99-7.48(13H,m,Ar-H);7.48-7.53(1H,d,J=15.6Hz,β-H);7.81(2H,s,-CH=).13C NMR:55.38(-OCH3and-CH2-);114.39-143.06(Ar-Cand–CH=);160.75(4-C);165.76(-CO-N-);187.17(-CO-).ESI-MS=[2M+H]+=931.54；[2M+Na]+=953.19。
实施例25：(3E,5E)-1-((E)-3-(3-溴苯基)烯丙醛基-3,5-双(3-氟苯亚甲基)哌啶-4-酮的制备
除以(3E,5E)-3,5-二(3-氟苯亚甲基)哌啶-4-酮和3-溴肉桂酸为原料外，其余同实施例22。黄色固体，收率78%。1H NMR(CDCl3):4.90(4H,br，s),6.36-6.41(1H,d,J=16.5Hz,α-H);7.04-7.27(9H,m,Ar-H);7.40-7.51(4H,m,Ar-H);7.81(2H,s,-CH=)。
实施例26：(3E,5E)-1-((E)-3-(4-三氟甲基苯基)烯丙醛基-3,5-双(3-氟苯亚甲基)哌啶-4-酮的制备
除以(3E,5E)-3,5-二(3-氟苯亚甲基)哌啶-4-酮和4-三氟甲基肉桂酸为原料外，其余同实施例22。黄色固体，收率75%。1H NMR(CDCl3):4.85-4.99(4H,br，s),6.44-6.49(1H,d,J=15.6Hz,α-H);7.19-7.26(8H,m,Ar-H);7.43-7.54(5H,m,Ar-H);7.82(2H,s,-CH=)。ESI-MS：[M-H]-=508.82。
实施例27：(3E,5E)-3,5-双(2,6-二氯苯亚甲基)-哌啶-4-酮的制备
除以4-哌啶酮和2,6-二氯苯甲醛为原料外，其余同实施例1。黄色固体，收率52%。1H NMR:1.61(1H,brs,-NH-);3.67(4H,s,-CH2-);7.20-7.26(2H,t,J=7.5Hz,4-H);7.35-7.37(4H,d,J=7.5Hz,3,5-H);7.60(2H,s,-CH=).13C NMR:47.65(-CH2-);128.04(4-C);129.75(3,5-C);130.71(2,6-C);133.20(1-C);134.40(-C=);138.49(-CH=);186.28(-CO-).
实施例28：(3E,5E)-3,5-双(2-溴苯亚甲基)-哌啶-4-酮的制备
除以4-哌啶酮和邻溴苯甲醛为原料外，其余同实施例1。黄色固体，收率56%。1H NMR:1.63(1H,brs,-NH-);3.96-4.02(4H,s,-CH2-);7.20-7.37(6H,m,Ar-H);7.64-7.67(2H,d,J=8.1Hz,Ar-H);7.91(2H,s,-CH=).13C NMR:47.87(-CH2-);125.22-136.06(Ar-C and-C=);187.49(-CO-).
实施例29：(3E,5E)-3,5-双(呋喃-2-亚甲基)-哌啶-4-酮的制备
除以4-哌啶酮和2-呋喃甲醛为原料外，其余同实施例1。黄色固体，收率49%。1H NMR:1.70-1.77(1H,brs,-NH-);2.89-2.97(2H,s,-CH2-);4.29(2H,s,-CH2-);6.52-6.54(2H,dd,J1=3.3Hz,J2=1.5Hz,4-H);6.67-6.68(2H,d,J=3.3Hz,3-H);7.51(2H,s,-CH=);7.59(2H,d,J=1.5Hz,5-H).
实施例30：(3E,5E)-3,5-双(5-羟甲基呋喃-2-亚甲基)-哌啶-4-酮(CHS74)的制备
除以4-哌啶酮和5-羟甲基-2-呋喃甲醛为原料外，其余同实施例1。黄色固体，收率12%。
实施例31：(3E,5E)-3,5-双(2-溴-6-氟苯亚甲基)-哌啶-4-酮的制备
参考CN103044322A方法，以4-哌啶酮和2-氟-6-溴苯甲醛为原料制备，柱层析分离化合物。
实施例32：(3E,5E)-3,5-双(4-甲氧基苯亚甲基)-N-甲基哌啶-4-酮的制备
除以N-甲基-4-哌啶酮和茴香醛为原料外，其余同实施例1。
实施例33：(3E,5E)-3,5-双(4-氟苯亚甲基)-N-甲基哌啶-4-酮的制备
除以N-甲基-4-哌啶酮和4-氟苯甲醛为原料外，其余同实施例1。
实施例34：(3E,5E)-3,5-双(2-溴苯亚甲基)-N-甲基哌啶-4-酮的制备
除以N-甲基-4-哌啶酮和2-溴苯甲醛为原料外，其余同实施例1。
实施例35：(3E,5E)-3,5-双(5-羟甲基呋喃-2-亚甲基)-N-甲基哌啶-4-酮的制备
除以N-甲基-4-哌啶酮和5-羟甲基-2-呋喃甲醛为原料外，其余同实施例1。
实施例36(3E,5E)-3,5-双噻吩亚甲基-哌啶-4-酮的制备
除以4-哌啶酮和噻吩甲醛为原料外，其余同实施例1。
实施例37：化合物的PTP1B抑制作用实验
将本发明所公开的化合物采用如下方法进行PTP1B的抑制活性测试（Chen et al.,Eur J Med Chem2013,69:399-412）。用于筛选的蛋白质酪氨酸磷酸酯酶PTP1B是从大肠杆菌中表达并纯化的GST融合蛋白。采用紫外底物pNPP，观察不同化合物对重组酶的活性抑制，以初步评价化合物的药用效果。PTP1B水解底物pNPP的磷酯得到的产物在405nm处有很强的光吸收。因此可以直接监测405nm处光吸收的变化以观察酶活性的变化以及化合物对其的抑制情况。首先计算酶初速度期内单位时间光吸收强度的增量（单位：mO.D./min），以此代表酶的初速度，然后根据公式1计算样品对酶活性的抑制率（%Inhibition）。
公式1：%Inhibition=(vDMSO-vSample)/vDMSO×100%
其中vSample表示加药组的初速度，vDMSO表示DMSO组（不加药组）的初速度。
在试验中，筛选纯化合物浓度为20μg/ml。抑制率大于等于50%认为有效。
本发明的化合物1～36(表1中的化合物序号与实施例1～36一一对应)对PTP1B的抑制作用如表1。
表1本发明的化合物在20μg/ml对PTP1B的抑制率（%）
可见，本发明的优选化合物1～26对PTP1B有显著抑制作用，可用于制备降糖药物、降脂药物、治疗和预防糖尿病、肥胖症的药物或保健品。
以上已对本发明创造的较佳实施例进行了具体说明，但本发明创造并不限于所述实施例，熟悉本领域的技术人员在不违背本发明创造精神的前提下还可作出种种的等同的变型或替换，这些等同的变型或替换均包含在本申请权利要求所限定的范围内。
Claims (4)
1.一类3,5-双芳基甲叉基哌啶酮衍生物及其药理上可接受的盐，其特征在于，所述的化合物为：
(3E,5E)-3,5-双(2，6-二氯苯亚甲基)-N-甲基哌啶-4-酮、
(3E,5E)-3,5-双(4-三氟甲基苯亚甲基)-N-甲基哌啶-4-酮、
(3E,5E)-3,5-双(3，4-二氯苯亚甲基)-N-甲基哌啶-4-酮、
(3E,5E)-1-乙酰基-3,5-双苯乙烯亚甲基哌啶-4-酮、
(3E,5E)-1-乙酰基-3,5-双(2-萘亚甲基)哌啶-4-酮、
(3E,5E)-1-乙酰基-3,5-双(2,6-二氯苯亚甲基)哌啶-4-酮、
(3E,5E)-1-丙酰基-3,5-双(2,4-二氯苯亚甲基)哌啶-4-酮、
(3E,5E)-1-丙酰基-3,5-双(呋喃-2-亚甲基)哌啶-4-酮、
(3E,5E)-1-((E)-3-(3-溴苯基)烯丙醛基-3,5-双(噻吩-2-亚甲基)哌啶-4-酮、
(3E,5E)-1-((E)-3-(4-三氟甲基苯基)烯丙醛基-3,5-双苯乙烯亚甲基哌啶-4-酮、
(3E,5E)-1-苯乙烯醛基-3,5-双(4-甲氧基苯亚甲基)哌啶-4-酮、
(3E,5E)-1-((E)-3-(3-溴苯基)烯丙醛基-3,5-双(3-氟苯亚甲基)哌啶-4-酮，或
(3E,5E)-1-((E)-3-(4-三氟甲基苯基)烯丙醛基-3,5-双(3-氟苯亚甲基)哌啶-4-酮。
2.根据权利要求1所示的一类3,5-双芳基甲叉基哌啶酮衍生物及其药理上可接受的盐，其特征在于，药理上可接受的盐是其盐酸盐、硫酸盐、磷酸盐、氢溴酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、乳酸盐、对甲苯磺酸盐、水杨酸盐，或草酸盐。
3.如权利要求1所述的一类3,5-双芳基甲叉基哌啶酮衍生物及其药理上可接受的盐在制备蛋白酪氨酸磷酸酯酶1B抑制剂中的应用。
4.如权利要求1所述的一类3,5-双芳基甲叉基哌啶酮衍生物及其药理上可接受的盐在制备降血糖、降血脂、预防或治疗高脂血症、糖尿病的药物或保健品中的应用。
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| CN105503709B (zh) * | 2015-12-10 | 2019-06-14 | 中国广州分析测试中心 | 3,5-双(芳基亚甲基)-1-取代-4-哌啶酮系列化合物及其在制备抗食管癌药物的应用 |
| CN106800547B (zh) * | 2017-01-03 | 2019-07-23 | 中国人民解放军第二军医大学 | 一种双取代芳基类化合物及其应用 |
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