CN104974118B - 韧革菌素一级醇酸酯衍生物及其药物组合物和其制备方法与应用 - Google Patents

韧革菌素一级醇酸酯衍生物及其药物组合物和其制备方法与应用 Download PDF

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CN104974118B
CN104974118B CN201410128811.XA CN201410128811A CN104974118B CN 104974118 B CN104974118 B CN 104974118B CN 201410128811 A CN201410128811 A CN 201410128811A CN 104974118 B CN104974118 B CN 104974118B
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vibralactone
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刘吉开
韦堃
汪钢强
白雪
李正辉
董泽军
汪秋安
陈贺平
冯涛
文春南
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Kunming Institute of Botany of CAS
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Abstract

本发明属于药物技术领域，具体涉及韧革菌素（Vibralactone）一级醇酸酯衍生物（式I），以通式I代表的化合物或其药学上可接受的盐为活性成分的药物组合物，它们的制备方法，以及它们在制备预防和治疗肥胖以及其它代谢性疾病如糖尿病的药物中的应用。

Description

韧革菌素一级醇酸酯衍生物及其药物组合物和其制备方法与 应用
技术领域
本发明属于药物领域，具体涉及韧革菌素一级醇酸酯衍生物作为一类强效的胰脂肪酶抑制剂，通过与胰脂肪酶结合而抑制酶的活性，阻止甘油三酯水解为可吸收的游离脂肪酸和单酰基甘油，使其不被吸收，从而减少热量摄入、控制体重。
背景技术
肥胖是一种由食欲、能量摄取、代谢调节紊乱引起的疾病，与糖尿病、心血管疾病、脂肪肝、某些肿瘤有明显的相关性，已成为危害人类健康的主要杀手。因此如何有效地减少肥胖成为了许多国家面临的重要研究课题。饮食中的脂肪摄取是导致肥胖的主要原因之一，食物中的主要脂类成分为甘油三酯，这类脂肪被吸收前，先被水解成对应的单甘油酯和脂肪酸。而在这一过程，胰脂肪酶可水解脂肪总量的50%-70%(Drug Discov Today,2007,12,879)。水解产生的单甘油酯和脂肪酸会与胆盐、胆固醇以及溶血磷脂酸形成胶束，从而被小肠上皮细胞吸收，一部分氧化生成二氧化碳和水，并放出能量，一部分在细胞中重新合成甘油三酯，进而形成乳糜微粒，进入血液。因此，抑制胰脂肪酶的活力可有效抑制膳食中的脂肪吸收，从而达到治疗肥胖的目的(Drugs,2006,66,1625)。
1987年Weibel等(The Journal of Antibiotics,1987,40,1081)在Streptomycestoxytricini中分离发现了胰脂肪酶抑制剂lipstatin（1），化合物1是一个具有两个顺式的双键的β内酯化合物。Weibel等同时还报道了一些化合物1的衍生物，其中包括lipstatin的饱和衍生物tetrahydrolipstatin（2），并研究发现lipstatin类化合物结构中的β内酯为抑制脂肪酶的活性所必须。由于lipstatin的结构不稳定，最终瑞士Hoffmann-La Roche公司开发了化合物2作为一种非全身性的减肥药物上市，商品名为Xenical，又称为奥利司他（Orlistat），化学名为(3S,4S)-3-己基-4-[(2S)-2-羟基十三烷基]-2-氧杂环丁酮-N-甲酰基-L-亮氨酸酯。奥利司他作为一种强效的胃肠道脂肪酶抑制剂，是FDA批准的减肥药。其作用机理是通过与胰脂肪酶的活性丝氨酸部位形成共价键，导致酶失活，从而阻断了人体对食物中脂肪的吸收。但奥利司他有一定副作用，主要为胃肠道不适，包括腹胀排气、内急、脂肪泻等(Drugs, 1998, 56, 241)。另外，奥利司他（Orlistat）除结构中亮氨酰基自带一个手性中心外，其酯基部分还有3个手性中心需要在合成过程中构建，不对称合成的难度较大，现目前临床上使用的奥利司他（Orlistat）原料药大多数仍由天然的lipstatin还原来制备，成本仍然很高(Organic Letters, 2008, 10, 1401)。因此，寻找安全有效的脂酶抑制剂成为肥胖治疗的一个热点。
本申请人在对褐盖韧革菌【褐盖韧革菌（Boreostereum vibrans）属于韧革菌科（Stereaceae），韧革菌属真菌】发酵液的化学成分研究时发现了一个结构新颖的化合物(Organic Letters, 2006, 8, 5749.)——韧革菌素（Vibralactone），其具有以下特点：结构独特，含有4/5环稠合体系的β-内酯型结构，官能团高度密集，除了含有活性官能团β-内酯，还有环外双键、环内双键和一个烯丙位的羟基。含量较高，比较容易累积。对褐盖韧革菌（Boreostereum vibrans）发酵液进行分离提取，得到韧革菌素（Vibralactone）。
迄今，现有技术中未见韧革菌素一级醇酸酯衍生物及其活性的报道。
发明内容
本发明的目的是提供一类具有良好的抑制脂肪酶活性作用且毒副作用低的新型韧革菌素一级醇酸酯衍生物，以它们为活性成分的药物组合物和胰脂肪酶抑制剂。同时提供它们的制备方法，以及它们在制备预防和/或治疗肥胖以及其它代谢性疾病如糖尿病的药物中的应用。
为了实现本发明的上述目的，本发明提供了如下的技术方案：
具有下述结构式（I）的韧革菌素（Vibralactone）一级醇酸酯衍生物，
其中：R1表示饱和的直链或支链（C1–C18）烷基、不饱和的直链或支链（C1–C18）烷基、氧杂或硫杂烷基、带有杂环或芳香环或取代芳香环的直链或支链烷基、甲酰化的氨基酸、直链羧酸。
本发明化合物通过猪胰脂肪酶试验研究，显示良好的胰脂肪酶抑制活性和较小的毒性，可进一步研制开发为治疗和预防肥胖的药物。
本发明优选的化合物是：
更优选的化合物是：
本发明的优选化合物通过猪胰脂肪酶试验研究，有更明显的胰脂肪酶抑制活性和较小的毒性。
本发明的另一目的提供涉及具有式I结构的韧革菌素衍生物的制备方法，用韧革菌素与相应的酰氯反应得结构式（I）所示化合物，
其中R1表示饱和的直链或支链（C1–C18）烷基、不饱和的直链或支链（C1–C18）烷基、氧杂或硫杂烷基、带有杂环或芳香环或取代芳香环的直链或支链烷基、甲酰化的氨基酸、直链羧酸。
本发明实施例1详细讲述了化合物1的制备方法。
本发明进一步提供包含至少一种本发明的式（I）所代表的韧革菌素一级醇酸酯衍生物或上述的韧革菌素一级醇酸酯衍生物其药学上可接受的盐作为活性成分，单独或结合一种或几种药学上可接受的载体的药物组合物。
本发明还提供了所述的韧革菌素一级醇酸酯衍生物在制备预防和治疗肥胖以及其它代谢性疾病如糖尿病的药物中的应用。
以及药物组合物在制备预防和治疗肥胖以及其它代谢性疾病如糖尿病的药物中的应用。
本发明还提供了以所述的韧革菌素一级醇酸酯衍生物为活性成分的胰脂肪酶抑制剂。以及，
用所述的韧革菌素一级醇酸酯衍生物作为胰脂肪酶抑制剂。
本发明以韧革菌素（Vibralactone）为母体，对韧革菌素（Vibralactone）δ位羟基进行结构修饰，合成了43个一级醇酸酯衍生物，从中获得一衍生物其胰脂肪酶抑制活性与原型化合物（Vibralactone）比较，提高了三个数量级，其IC50达到纳摩尔级（83nM）。该化合物与现在市售的OTC药物Orlistat具有类似的药效团和作用机制。
本发明化合物用作药物上时，可以直接使用，或者以药物组合物的形式使用。该药物组合物含有0.1～99%，优选为0.5～90%的本发明化合物，其余为药物学上可接受的，对人和动物无毒和惰性的可药用载体和/或赋形剂。
所述的药用载体或赋形剂是一种或多种选自固体、半固体和液体稀释剂、填料以及药物制品辅剂。将所述的药物组合物以单位体重服用量的形式使用。本发明的药物可经口服和注射（静注、肌注）两种形式给药。
口服可用其固体或液体制剂，如粉剂、片剂、糖衣剂、胶囊、溶液、糖浆、滴丸剂等。
注射可用其固体或液体制剂，如粉针剂、溶液形注射剂等。
具体实施方式
下面结合实施例进一步对本发明的实质性内容进行说明，但本发明的内容并不局限于此。
实施例1
1H-和13C-NMR由Bruker AVANCE III-600、DRX-500或AM-400测定，内标为TMS，其中1H NMR在400MHz，500MHz和600MHz下测定，13C NMR在100MHz，125MHz和150MHz下测定；质谱HREI-MS和EI-MS由Finnigan-MAT90质谱仪测定；HRESI-MS和ESI-MS由API QSTAR Pulsari质谱仪测定；旋转蒸发仪：Buchi R-200、R-201；DLSB5110型低温反应冷却液循环泵，IKARCT basic(安全控制型)加热磁力搅拌器。
柱色谱材料：柱层析用硅胶(80-100目和200-300目)与预制GF254TLC板均为青岛海洋化工厂生产；Sephadex LH-20为瑞典Amersham Biosciences公司产品；Chromatorex C-18(40-75μm)为日本Fuji Silysia化学公司产品。HPLC：Agilent1100，Zorbax SB-C18column，5μm，4.6mm×150mm；Prep-HPLC：Agilent1200，Zorbox SB-C18column，5μm，9.4mm×150mm。显色方法为荧光灯下波长254、365nm处观察荧光，I2蒸气显色，10%硫酸香草醛处理后加热显色。
其它试剂来自于Sigma Aldrich,J&K百灵威，或北京伊诺凯公司，均为商品化的分析纯或化学纯试剂，本发明实验部分所采用的无水试剂(如无水THF、DCM、Toluene、DMF等)均按无水溶剂标准处理程序制备。
1、化合物韧革菌素的制备：
褐盖韧革菌(Boreosterum vibrans)采自昆明植物所，标本保存于昆明植物研究所。采用斜面转三角瓶液体培养的方法培养褐盖韧革菌。培养基：去皮土豆200g(煮水)，葡萄糖20g，MgSO41.5g，KH2PO43g，VB110mg，猪肉蛋白胨1.0g，去离子水1000mL，用柠檬酸调pH至6.0～6.5；培养条件：温度24℃，转速150r/min，暗箱培养25天。培养所得发酵液用乙酸乙酯萃取三遍，过滤后减压浓缩得到浸膏，上硅胶柱分离，以石油醚—乙酸乙酯系统梯度洗脱即可以得到韧革菌素(vibralactone)。
2、(1R,5S)-3-(6'-苯已酸甲酯)-1-(3-甲基-2-丁烯-1-基)-6-氧杂二环[3.2.0]庚-2-烯-7-酮（化合物1）的制备：
在10mL的圆底烧瓶加入0.023g(0.12mmol)6-苯基己酸,N2保护条件下加入2mL无水DCM，再加入2mL(0.2mmol)SOCl2，室温条件反应5小时后，减压蒸馏除去溶剂DCM和过量的SOCl2，后再加入3mL韧革菌素vibralactone0.021g(0.10mmol)的DCM溶液，再加0.2ml Et3N，室温条件反应4小时后，加入少量的水淬灭反应，用乙酸乙酯萃取3次(20mL×3),合并有机层后，依次用水，盐水洗涤之后，再用无水Na2SO4干燥，减压蒸馏除去溶剂，用20:1的石油醚和乙酸乙酯洗脱液快速柱层析得到无色油状物。收率85%。
HR-EI-MS m/z:382.2146[M]+(Calcd.for C24H30O4:382.2144).1H NMR(500MHz,CDCl3)δ(ppm):7.28(2H,m),7.18(3H,m),5.63(1H,s),5.13(1H,m),4.78(1H,m),4.65(2H,s),2.74(2H,s),2.61(3H,t,J=7.5Hz),2.41(1H,m),2.34(2H,t,J=7.5Hz),1.73(3H,s),1.67(4H,m),1.63(3H,s),1.37(2H,m).13C NMR(100MHz,CDCl3)δ(ppm):173.1,172.3,142.4,141.5,136.1,128.4,128.3,125.7,125.1,117.2,78.2,75.4,61.8,37.7,35.7,34.0,31.0,28.7,27.6,25.7,24.8,18.0.
化合物2-43的合成步骤同化合物1。所使用的不同底物（羧酸）购自于SigmaAldrich，J&K百灵威，或北京伊诺凯科技有限公司等。
用上述的方法制备的化合物1－43的结构式如下所示：
化合物1-43的波谱数据为：
化合物1:HR-EI-MS m/z:382.2146[M]+(Calcd.for C24H30O4:382.2144).1H NMR(500MHz,CDCl3)δ(ppm):7.28(2H,m),7.18(3H,m),5.63(1H,s),5.13(1H,m),4.78(1H,m),4.65(2H,s),2.74(2H,s),2.61(3H,t,J=7.5Hz),2.41(1H,m),2.34(2H,t,J=7.5Hz),1.73(3H,s),1.67(4H,m),1.63(3H,s),1.37(2H,m).13C NMR(100MHz,CDCl3)δ(ppm):173.1,172.3,142.4,141.5,136.1,128.4,128.3,125.7,125.1,117.2,78.2,75.4,61.8,37.7,35.7,34.0,31.0,28.7,27.6,25.7,24.8,18.0.
化合物2:HR-EI-MS m/z:432.1927[M]+(Calcd.for C27H28O5:432.1937).1H NMR(400MHz,CDCl3)δ(ppm):7.34(2H,t,J=7.5Hz),7.25(1H,t,J=7.5Hz),7.10(1H,t,J=7.4Hz),7.00(2H,d,J=8.3Hz),6.94(1H,d,J=7.5Hz),6.85(2H,d,J=6.9Hz),5.57(1H,s),5.10(1H,t,J=7.3Hz),4.77(1H,s),4.65(2H,s),2.94(2H,t,J=7.6Hz),2.67(5H,m),2.40(1H,m),1.72(3H,s),1.63(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):172.4,172.1,157.4,157.0,142.2,141.2,136.2,129.8,129.7,125.2,123.3,123.1,118.9,118.6,117.1,116.7,78.1,75.4,62.0,37.6,35.4,30.7,27.5,25.8,18.0.
化合物3:ESI-MS:418[M]+.1H NMR(500MHz,CDCl3)δ(ppm):5.63(1H,s),5.11(1H,m),4.78(1H,t,J=2.9Hz),4.67(2H,s),2.75(2H,s),2.60(1H,m),2.41(1H,m),2.34(2H,t,J=7.6Hz),1.72(3H,s),1.63(3H,s),1.29(22H,m),0.87(3H,t,J=6.7Hz).13C NMR(125MHz,CDCl3)δ(ppm):173.3,172.4,141.5,136.2,125.0,117.1,78.1,75.4,61.7,37.7,34.1,31.9,29.7,29.6,29.5,29.4,29.3,29.2,29.1,29.0,27.5,25.8,24.9,22.7,18.0,14.1.
化合物4:HR-EI-MS m/z:400.2044[M]+(Calcd.for C24H29O4F:400.2050).1H NMR(400MHz,CDCl3)δ(ppm):7.11(2H,m),6.95(2H,m),5.63(1H,s),5.12(1H,brs),4.79(1H,s),4.65(1H,s),2.74(2H,s),2.60(3H,m),2.41(1H,m),2.34(2H,t,J=7.5Hz),1.72(3H,s),1.63(9H,m),1.35(2H,m).13C NMR(100MHz,CDCl3)δ(ppm):173.1,172.4,162.3,159.9,141.4,137.9,136.2,129.6,125.0,117.1,115.1,114.8,78.2,75.3,61.8,37.7,34.8,34.0,31.2,28.6,27.5,25.8,24.7,18.0.
化合物5:HR-ESI-MS m/z:411.2513[M+Na]+(Calcd.for C24H36O4Na:411.2511).1HNMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.34(2H,m),5.11(1H,t,J=6.9Hz),4.79(1H,s),4.66(2H,s),2.75(2H,s),2.61(1H,m),2.42(1H,m),2.35(2H,t,J=7.5Hz),2.04(4H,m),1.72(3H,s),1.63(3H,s),1.28(10H,m),0.87(3H,m).13CNMR(100MHz,CDCl3)δ(ppm):173.1,172.4,141.5,136.2,131.3,128.1,125.0,117.1,78.1,75.4,61.8,37.7,33.5,31.7,31.6,29.6,29.4,29.0,27.5,27.2,26.5,25.8,24.8,22.6,18.0,14.1.
化合物6:HR-EI-MS m/z:340.1657[M]+(Calcd.for C21H24O4:340.1675).1H NMR(400MHz,CDCl3)δ(ppm):7.30(2H,m),7.21(3H,m),5.54(1H,s),5.10(1H,m),4.75(1H,m),4.65(2H,s),2.97(2H,t,J=7.6Hz),2.67(4H,m),2.60(1H,m),2.42(1H,m),2.21(1H,m),1.71(3H,s),1.64(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):172.4,172.3,141.3,140.2,136.2,128.5,128.3,126.3,125.1,117.1,78.1,75.4,62.0,37.6,35.6,30.9,27.5,25.8,18.0.
化合物7:HR-EI-MS m/z:374.1557[M]+(Calcd.for C21H26O4S:374.1552).1H NMR(400MHz,CDCl3)δ(ppm):7.11(1H,d,J=4.8Hz),6.91(1H,q,J=3.6Hz),6.78(1H,s),5.63(1H,s),5.11(1H,m),4.78(1H,s),4.66(2H,s),2.86(2H,s),2.74(2H,s),2.60(1H,m),2.43(3H,m),1.72(3H,s),1.63(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):172.9,144.7,141.4,136.2,126.7,125.1,124.2,123.0,117.1,78.1,75.4,61.8,37.7,33.7,31.1,29.5,27.5,25.8,24.3,18.0.
化合物8:HR-ESI-MS m/z:485.1604[M+Na]+(Calcd.for C24H30O7SNa:485.1609).1H NMR(400MHz,CDCl3)δ(ppm):5.73(1H,s),5.11(1H,t,J=7.2Hz),4.80(1H,t,J=3.0Hz),4.56(2H,m),2.78(2H,s),2.63(1H,m),2.44(1H,m),1.72(3H,s),1.64(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):172.1,140.5,136.4,126.8,126.6,116.9,78.1,75.5,59.9,59.7,37.6,27.4,25.8,18.0.
化合物9:HR-EI-MS m/z:412.2253[M]+(Calcd.for C25H32O5:412.2250).1H NMR(400MHz,CDCl3)δ(ppm):7.24(2H,d,J=8.8Hz),6.85(2H,d,J=8.8Hz),5.58(1H,s),5.10(1H,m),4.77(1H,m),4.61(2H,s),3.79(3H,s),2.71(2H,s),2.61(1H,m),2.42(1H,m),2.09(2H,m),1.95(2H,m),1.72(3H,s),1.63(3H,s),1.30(6H,s).13C NMR(100MHz,CDCl3)δ(ppm):173.5,172.4,150.5,141.4,139.8,136.2,126.8,124.9,117.1,113.5,78.1,75.3,61.8,55.2,39.0,37.7,36.7,30.0,28.9,27.5,25.8,18.0.
化合物10:HR-EI-MS m/z:388.2609[M]+(Calcd.for C24H36O4:388.2614).1H NMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.53(2H,m),5.11(1H,t,J=7.3Hz),4.78(1H,t,J=2.9Hz),4.68(2H,s),3.12(1H,d,J=6.6Hz),3.06(1H,d,J=6.6Hz),2.74(2H,s),2.61(1H,m),2.41(1H,m),2.04(2H,m),1.72(3H,s),1.63(3H,s),1.27(12H,m),0.87(3H,t,J=6.4Hz).13C NMR(100MHz,CDCl3)δ(ppm):172.4,171.5,141.3,136.2,135.4,133.9,125.0,121.0,120.2,117.1,78.1,75.3,62.0,37.9,37.7,32.8,32.5,31.8,29.5,29.4,29.3,29.2,29.1,27.5,27.4,25.8,22.6,18.0,14.1.
化合物11:HR-EI-MS m/z:610.3502[M]+(Calcd.for C36H50O8:610.3506).1H NMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.11(1H,t,J=7.3Hz),4.78(1H,t,J=2.7Hz),4.65(2H,s),2.75(2H,s),2.60(1H,m),2.42(1H,m),2.33(2H,t,J=7.5Hz),1.72(3H,s),1.63(3H,s),1.29(6H,s).13C NMR(100MHz,CDCl3)δ(ppm):173.2,172.4,141.5,136.2,125.0,117.1,78.2,75.4,61.7,37.7,34.1,29.3,29.2,29.1,27.5,25.8,24.9,18.0.
化合物12:HR-ESI-MS m/z:367.1891[M+Na]+(Calcd.for C21H28O4Na:367.1885).1H NMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.11(1H,t,J=7.3Hz),4.79(2H,t,J=3.0Hz),4.65(2H,s),2.75(2H,s),2.60(1H,m),2.42(1H,m),2.35-2.14(3H,m),1.98(1H,s),1.87(1H.m),1.72(3H,s),1.64(3H,s),1.57(2H,s),1.50(2H,m),1.31-1.04(4H,m).13C NMR(100MHz,CDCl3)δ(ppm):172.6,141.5,136.2,125.0,117.1,78.2,75.3,61.7,41.1,41.0,38.4,37.8,37.7,36.7,35.2,29.7,28.5,27.5,25.8,18.0.
化合物13:HR-EI-MS m/z:398.2087[M]+(Calcd.for C24H30O5:398.2093).1H NMR(400MHz,CDCl3)δ(ppm):7.10(2H,d,J=8.6Hz),6.82(2H,d,J=8.6Hz),5.62(1H,s),5.11(1H,m),4.78(1H,m),4.67(2H,s),3.79(3H,s),2.74(2H,s),2.60(3H,m),2.41(3H,m),1.72(3H,s),1.67(3H,s),1.65(4H,m).13C NMR(100MHz,CDCl3)δ(ppm):173.1,172.5,157.7,141.4,136.2,134.0,129.2,125.0,117.1,113.7,78.1,75.4,61.8,55.2,37.7,34.6,33.9,31.1,27.5,25.8,24.4,18.0.
化合物14:HR-EI-MS m/z:582.3207[M]+(Calcd.for C34H46O8:582.3193).1H NMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.11(1H,m),4.80(1H,t,J=2.7Hz),4.66(2H,s),2.75(2H,s),2.60(1H,m),2.42(1H,m),2.34(2H,t,J=7.5Hz),1.72(3H,s),1.63(6H,s),1.30(4H,s).13C NMR(100MHz,CDCl3)δ(ppm):173.2,172.5,141.5,136.2,126.5,117.1,78.2,75.4,61.8,37.7,34.0,29.0,27.5,25.8,24.8,18.0.
化合物15:HR-EI-MS m/z:368.1978[M]+(Calcd.for C23H28O4:368.1988).1H NMR(400MHz,CDCl3)δ(ppm):7.29(2H,m),7.19(3H,m),5.63(1H,s),5.11(1H,m),4.77(1H,m),4.65(2H,s),2.74(2H,s),2.66(3H,m),2.42(3H,m),1.73(3H,s),1.68(4H,m),1.63(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):173.0,172.4,142.0,141.4,136.2,128.4,128.3,125.8,125.0,117.0,78.1,75.4,61.8,37.7,35.5,33.9,30.8,27.5,25.8,24.5,18.0,.
化合物16:HR-EI-MS m/z:354.1765[M]+(Calcd.for C22H26O4:354.1831).1H NMR(400MHz,CDCl3)δ(ppm):7.30(2H,m),7.21(3H,m),5.63(1H,s),5.11(1H,m),4.79(1H,m),4.69(2H,s),2.75(2H,s),2.66(2H,t,J=7.5Hz),2.60(1H,m),2.42(1H,m),2.37(2H,t,J=7.5Hz),1.98(2H,t,J=7.5Hz),1.71(3H,s),1.63(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):172.9,172.4,141.4,141.1,136.2,128.4,128.3,126.0,125.1,117.1,78.1,75.4,61.8,37.8,35.1,33.3,27.5,26.4,25.8,18.0,.
化合物17:HR-EI-MS m/z:390.1830[M]+(Calcd.for C24H26O4:390.1831).1H NMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.11(1H,m),4.78(1H,t,J=2.9Hz),4.65(2H,s),2.74(2H,s),2.60(1H,m),2.41(1H,m),2.34(2H,t,J=7.6Hz),1.72(3H,s),1.63(3H,s),1.29(18H,m),0.87(3H,t,J=6.7Hz).13C NMR(125MHz,CDCl3)δ(ppm):173.3,172.4,141.5,136.2,125.0,117.1,78.1,75.4,61.7,37.7,34.1,31.9,29.6,29.5,29.4,29.3,29.2,29.1,29.0,28.8,27.5,25.8,24.9,24.2,22.7,18.0,14.1.
化合物18:HR-EI-MS m/z:346.1238[M]+(Calcd.for C19H22O4S:346.1239).1HNMR(500MHz,CDCl3)δ(ppm):7.13(1H,t,J=0.9Hz),6.90(1H,q,J=3.5Hz),6.82(1H,d,J=3.5Hz),5.57(1H,s),5.10(1H,m),4.76(1H,t,J=3.5Hz),4.67(2H,s),3.17(2H,t,J=7.4Hz),2.73(2H,t,J=7.4Hz),2.69(2H,s),2.60(1H,m),2.40(1H,m),1.72(3H,s),1.63(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):172.4,171.8,142.7,141.2,136.2,126.9,125.2,124.8,123.6,117.1,78.1,75.4,62.1,37.7,35.9,27.5,25.8,25.1,18.0.
化合物19:ESI-MS:446[M]+.1H NMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.11(1H,m),4.78(1H,t,J=2.9Hz),4.60(2H,s),2.75(2H,s),2.60(1H,m),2.41(1H,m),2.34(2H,t,J=7.6Hz),1.75(3H,s),1.65(3H,s),1.29(26H,m),0.87(3H,t,J=6.7Hz).13C NMR(125MHz,CDCl3)δ(ppm):173.3,172.4,141.5,136.2,125.0,117.1,78.1,75.4,61.7,37.7,34.1,31.9,29.7,29.6,29.5,29.4,29.3,29.2,29.1,29.0,28.8,27.5,24.2,22.7,18.0,14.1.
化合物20:ESI-MS:493[M+Na]+.1H NMR(400MHz,CD3COCD3)δ(ppm):5.56(1H,s),5.17(1H,m),4.87(1H,d,J=4.6Hz),4.15(2H,m),4.08(1H,t,J=4.3Hz),2.60(3H,m),2.42(1H,m),1.69(3H,s),1.64(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):173.6,149.1,136.0,122.1,119.0,79.3,76.0,61.2,38.0,28.3,26.0,18.0.
化合物21:HR-EI-MS m/z:554.2889[M]+(Calcd.for C32H42O8:554.2880).1H NMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.11(1H,t,J=7.3Hz),4.78(1H,t,J=2.7Hz),4.65(2H,s),2.75(2H,s),2.60(1H,m),2.42(1H,m),2.33(2H,t,J=7.5Hz),1.72(3H,s),1.63(3H,s),1.35(4H,s).13C NMR(100MHz,CDCl3)δ(ppm):173.0,172.4,141.4,136.2,125.1,117.1,78.2,75.4,61.7,37.7,33.9,28.7,27.5,25.8,24.6,18.0.
化合物22:HR-ESI-MS m/z:325.1415[M+Na]+(Calcd.for C18H22O4Na:325.1415).1H NMR(400MHz,CDCl3)δ(ppm):6.33(1H,m),6.16(1H,m),5.79(1H,m),5.64(1H,s),5.14(3H,m),4.79(1H,t,J=3.0Hz),4.68(2H,s),3.17(2H,d,J=7.1Hz),2.75(2H,s),2.60(1H,m),2.42(1H,m),1.72(3H,s),1.63(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):172.4,170.9,141.1,136.2,136.1,134.7,125.2,124.9,117.3,117.0,78.1,75.4,62.2,37.7,37.6,27.5,25.8,18.0.
化合物23:HR-ESI-MS m/z:399.2513[M+Na]+(Calcd.for C23H36O4Na:399.2511).1H NMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.11(1H,m),4.78(1H,t,J=3.0Hz),4.66(2H,s),2.75(2H,s),2.62(1H,m),2.41(1H,m),2.34(2H,t,J=7.5Hz),1.72(3H,s),1.64(3H,s),1.29(16H,m),0.87(3H,t,J=6.5Hz).13C NMR(100MHz,CDCl3)δ(ppm):173.3,172.4,141.5,136.2,125.0,117.1,78.1,75.4,61.7,37.7,34.1,31.9,29.5,29.4,29.3,29.2,29.1,25.8,24.9,22.7,18.0,14.1.
化合物24:HR-ESI-MS m/z:397.2347[M+Na]+(Calcd.for C23H34O4Na:397.2354).1H NMR(400MHz,CDCl3)δ(ppm):5.80(1H,m),5.63(1H,s),5.11(1H,m),4.96(2H,m),4.79(1H,t,J=3.0Hz),4.66(2H,s),2.75(2H,s),2.62(1H,m),2.41(1H,m),2.34(2H,t,J=7.5Hz),2.04(2H,q,J=6.8Hz),1.72(3H,s),1.64(3H,s),1.60(2H,m),1.29(10H,m).13C NMR(100MHz,CDCl3)δ(ppm):173.3,172.4,141.5,139.1,136.2,125.0,117.1,114.1,78.1,75.4,61.7,37.7,34.1,33.7,29.2,29.1,29.0,28.8,27.5,25.8,24.9,18.0.
化合物25:HR-EI-MS m/z:498.2262[M](Calcd.for C28H34O8:498.2254).1H NMR(500MHz,CDCl3)δ(ppm):5.68(1H,s),5.13(1H,t,J=6.3Hz),4.81(1H,t,J=2.8Hz),4.71(2H,s),2.78(2H,s),2.71(2H,s),2.60(1H,m),2.42(1H,m),1.75(3H,s),1.66(3H,s).13CNMR(100MHz,CDCl3)δ(ppm):172.4,171.7,141.1,136.2,125.3,117.0,78.1,75.4,62.0,37.7,28.8,27.5,25.8,18.0.
化合物26:HR-ESI-MS m/z:493.3297[M+Na]+(Calcd.for C30H46O4Na:493.3293).1H NMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.35(4H,m),5.11(1H,m),4.78(1H,t,J=3.0Hz),4.66(2H,s),2.76(4H,m),2.60(1H,m),2.41(1H,m),2.33(2H,t,J=7.5Hz),2.05(4H,m),1.72(3H,s),1.63(3H,s),1.32(16H,m),0.88(3H,t,J=6.7Hz).13C NMR(100MHz,CDCl3)δ(ppm):173.2,172.4,141.5,136.2,130.2,130.0,128.0,127.9,125.0,117.1,78.2,75.3,61.8,37.7,34.1,31.5,29.6,29.3,29.1,29.0,27.5,27.2,27.1,25.8,25.6,24.9,22.6,18.0,14.1.
化合物27:HR-ESI-MS m/z:427.2824[M+Na]+(Calcd.for C25H40O4Na:427.2824).1H NMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.11(1H,m),4.78(1H,t,J=3.0Hz),4.66(2H,s),2.75(2H,s),2.60(1H,m),2.41(1H,m),2.34(2H,t,J=7.5Hz),1.72(3H,s),1.64(3H,s),1.25(20H,m),0.87(3H,t,J=6.4Hz).13C NMR(100MHz,CDCl3)δ(ppm):173.3,172.4,141.5,136.2,125.0,117.1,78.1,75.4,61.7,37.7,34.1,31.9,29.6,29.5,29.4,29.3,29.2,29.1,27.5,25.8,24.9,22.6,18.0,14.1.
化合物28:HR-EI-MS m/z:526.1998[M]+(Calcd.for C30H38O8:526.2567).1H NMR(400MHz,CDCl3)δ(ppm):5.67(1H,s),5.11(1H,s),4.78(2H,m),4.70(1H,m),2.78(2H,m),2.60(1H,m),2.42(1H,m),2.31(2H,m),2.15(1H,m),1.89(1H,m),1.72(3H,s),1.63(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):172.4,168.8,140.9,136.2,125.5,117.1,78.2,75.4,62.7,38.0,37.6,27.5,27.3,25.7,20.9.
化合物29:ESI-MS:474[M]+.1H NMR(500MHz,CDCl3)δ(ppm):5.63(1H,s),5.11(1H,m),4.78(1H,s),4.65(2H,s),2.75(2H,s),2.60(1H,m),2.41(1H,m),2.33(2H,t,J=7.5Hz),1.72(3H,s),1.63(3H,s),1.25(30H,m),0.87(3H,t,J=6.7Hz).13C NMR(125MHz,CDCl3)δ(ppm):173.3,172.4,141.5,136.2,125.0,117.1,78.1,75.4,61.7,37.7,34.1,31.9,29.7,29.6,29.5,29.4,29.3,29.2,29.1,28.8,27.5,25.8,24.9,22.7,18.0,14.1.
化合物30:HR-EI-MS m/z:330.1470[M]+(Calcd.for C19H22O5:330.1467).1H NMR(500MHz,CDCl3)δ(ppm):7.31(1H,s),6.28(1H,s),6.03(1H,s),5.60(1H,s),5.10(1H,t,J=6.4Hz),4.77(1H,t,J=3.0Hz),4.68(2H,s),2.98(2H,t,J=7.5Hz),2.71(3H,s),2.59(1H,m),2.40(1H,m),1.72(3H,s),1.63(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):172.4,172.0,153.8,141.3,136.2,125.2,117.1,110.2,105.4,78.1,75.4,62.1,37.7,325,27.5,25.8,23.4,18.0.
化合物31:HR-EI-MS m/z:333.1558[M]+(Calcd.for C18H23NO5:333.1576).1HNMR(500MHz,CDCl3)δ(ppm):8.29(1H,s),5.66(1H,m),5.10(1H,m),4.76(2H,m),4.46(1H,m),3.64(2H,m),2.74(2H,m),2.60(1H,m),2.40(1H,m),2.25(2H,m),2.00(2H,m),1.72(3H,s),1.63(3H,s),1.26(2H,m).13C NMR(100MHz,CDCl3)δ(ppm):171.2,161.4,160.7,140.9,136.2,125.5,117.1,78.2,75.4,62.7,56.4,46.3,37.7,29.4,27.5,25.8,22.8,16.9.
化合物32:HR-ESI-MS m/z:481.3290[M+Na]+(Calcd.for C29H46O4Na:481.3293).1H NMR(500MHz,CDCl3)δ(ppm):5.63(1H,s),5.34(2H,m),5.11(1H,m),4.78(1H,t,J=3.0Hz),4.66(2H,s),2.75(2H,s),2.60(1H,m),2.41(1H,m),2.33(2H,t,J=7.5Hz),2.00(4H,s),1.72(3H,s),1.63(3H,s),1.27(20H,m),0.88(3H,t,J=6.5Hz).13C NMR(125MHz,CDCl3)δ(ppm):173.2,172.3,141.6,136.2,123.0,129.8,125.1,117.2,78.2,75.5,61.8,37.8,34.1,31.8,29.7,29.3,29.2,29.1,29.0,27.5,27.2,27.1,25.7,24.9,22.6,18.0,14.0.
化合物33:HR-EI-MS m/z:396.2308[M]+(Calcd.for C25H32O4:396.2301).1H NMR(400MHz,CDCl3)δ(ppm):7.28(2H,m),7.18(3H,m),5.63(1H,s),5.13(1H,m),4.79(1H,m),4.66(2H,s),2.75(2H,s),2.61(3H,t,J=7.5Hz),2.44(1H,m),2.35(2H,t,J=7.5Hz),1.73(3H,s),1.64(7H,m),1.37(4H,m).13C NMR(100MHz,CDCl3)δ(ppm):179.7,173.2,142.6,141.5,136.2,128.4,128.3,125.6,125.0,117.0,78.1,75.4,61.8,37.7,35.5,33.9,31.2,28.8,27.5,25.8,24.5,18.0.
化合物34:HR-EI-MS m/z:362.1184[M]+(calcd for C19H22O5S362.1188).1H NMR(400MHz,CDCl3)δ(ppm):7.79(2H,d,J=8.3Hz),7.36(2H,d,J=8.3Hz),5.63(1H,s),5.06(1H,m),4.73(1H,d,J=5.6Hz),4.65(2H,s),2.72(2H,m),2.57(1H,m),2.46(3H,s),2.38(1H,m),1.71(3H,s),1.61(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):171.8,145.3,139.2,136.4,132.6,130.0,127.9,127.4,116.8,77.9,75.5,67.5,37.4,27.3,25.8,21.7,18.0.
化合物35:HR-EI-MS m/z:369.1556[M]+(Calcd.for C21H23NO5:369.1576).1HNMR(400MHz,CDCl3)δ(ppm):8.19(1H,s),7.97(2H,d,J=8.5Hz),7.63(2H,d,J=8.5Hz),5.69(1H,s),5.09(1H,t,J=7.2Hz),4.87(2H,s),4.83(1H,s),2.77(2H,s),2.60(1H,m),2.42(1H,m),2.18(3H,s),1.69(3H,s),1.61(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):172.7,168.9,165.4,142.7,141.6,136.2,130.8,124.9,118.8,116.9,78.3,75.4,62.2,37.8,27.5,25.7,24.6,17.9.
化合物36:HR-EI-MS m/z:336.1552[M]+(Calcd.for C18H24O6:336.1573).1H NMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.11(1H,m),4.78(1H,m),4.66(2H,s),3.68(3H,s),2.74(2H,s),2.62(1H,m),2.40(5H,m),1.95(2H,m),1.71(3H,s),1.64(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):173.2,172.3,141.3,136.2,125.2,117.0,78.1,75.4,62.0,51.6,37.7,33.0,32.9,27.5,25.7,18.0.
化合物37:HR-ESI-MS m/z:331.1152[M+Na]+(Calcd.for C16H20O6Na:331.1157).1H NMR(400MHz,CDCl3)δ(ppm):5.67(1H,s),5.11(1H,m),4.79(1H,m),4.74(2H,s),3.76(3H,s),3.44(2H,s),2.76(2H,s),2.62(1H,m),2.42(1H,m),1.72(3H,s),1.64(3H,s).13CNMR(100MHz,CDCl3)δ(ppm):172.3,140.6,136.3,125.8,117.0,78.1,75.4,62.9,52.6,41.1,37.6,27.5,25.8,18.0.
化合物38:HR-ESI-MS m/z:495.3443[M+Na]+(Calcd.for C30H48O4Na:495.3450).1H NMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.34(2H,m),5.11(1H,t,J=7.3Hz),4.78(1H,t,J=3.0Hz),4.65(2H,s),2.75(2H,s),2.59(1H,m),2.43(1H,m),2.34(2H,t,J=7.5Hz),2.00(4H,m),1.72(3H,s),1.63(3H,s),1.26(22H,m),0.87(3H,t,J=6.4Hz).13C NMR(100MHz,CDCl3)δ(ppm):173.1,172.4,141.5,136.2,130.5,128.9,125.0,117.1,78.1,75.4,61.8,37.7,34.0,31.9,29.7,29.6,29.5,29.3,29.2,29.1,27.5,27.2,26.8,25.8,24.5,22.7,18.0,14.1.
化合物39:HR-EI-MS m/z:383.1729[M]+(Calcd.for C22H25O5N:383.1733).1HNMR(600MHz,CDCl3)δ(ppm):8.17(1H,s),7.25(3H,m),7.10(2H,d,J=6.6Hz),6.02(1H,d,J=6.6Hz),5.53(1H,s),5.08(1H,t,J=7.2Hz),4.97(1H,q,J=6.6Hz),4.76(1H,s),4.72(1H,q,J=7.2Hz),3.12(1H,d,J=6.0Hz),2.65(2H,s),2.59(1H,m),2.41(1H,m),1.71(3H,s),1.62(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):172.4,171.0,160.7,140.4,136.6,135.4,129.4,129.3,127.7,126.1,117.1,78.3,75.6,63.3,52.1,38.1,37.9,27.7,26.1,18.0.
化合物40:HR-EI-MS m/z:349.1911[M]+(Calcd.for C19H27O5N:349.1889).1HNMR(400MHz,CDCl3)δ(ppm):8.22(1H,s),6.01(1H,d,J=7.4Hz),5.67(1H,s),5.11(1H,m),4.79(1H,m),4.72(3H,m),2.77(2H,s),2.62(1H,m),2.42(1H,m),1.72(3H,s),1.68(2H,m),1.64(3H,s),1.25(1H,m),0.96(6H,s).13C NMR(100MHz,CDCl3)δ(ppm):172.1,160.8,140.5,136.3,126.1,125.8,117.0,78.1,75.4,62.9,49.3,41.5,37.7,27.5,25.8,24.8,22.7,21.8,18.0.
化合物41:HR-ESI-MS m/z:495.3461[M+Na]+(Calcd.for C30H48O4Na:495.3450).1H NMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.34(2H,m),5.11(1H,t,J=7.4Hz),4.78(1H,t,J=3.0Hz),4.67(2H,s),2.75(2H,s),2.60(1H,m),2.41(1H,m),2.33(2H,t,J=7.5Hz),2.00(4H,s),1.72(3H,s),1.63(3H,s),1.27(22H,m),0.87(3H,t,J=6.5Hz).13C NMR(100MHz,CDCl3)δ(ppm):173.3,172.4,141.5,136.2,129.9,129.8,124.9,117.1,78.2,75.3,61.8,37.9,37.7,34.1,31.7,29.7,29.5,29.4,29.3,29.2,29.1,29.0,27.5,27.2,27.1,25.8,24.9,22.6,18.0,14.1.
化合物42:HR-ESI-MS m/z:455.3138[M+Na]+(Calcd.for C27H44O4Na:455.3137).1H NMR(400MHz,CDCl3)δ(ppm):5.63(1H,s),5.11(1H,t,J=7.0Hz),4.78(1H,s),4.65(2H,s),2.74(2H,s),2.60(1H,m),2.41(1H,m),2.33(2H,t,J=7.5Hz),2.17(1H,s),1.72(3H,s),1.63(3H,s),1.24(23H,m),0.87(3H,t,J=6.4Hz).13CNMR(100MHz,CDCl3)δ(ppm):173.3,172.4,141.5,136.2,124.9,117.1,78.1,75.3,61.7,37.7,34.1,31.9,29.6,29.5,29.4,29.3,29.2,29.1,27.5,25.8,24.9,22.7,18.0,14.1.
化合物43:HR-EI-MS m/z:341.1627[M]+(Calcd.for C20H23NO4:341.1627).1HNMR(400MHz,CDCl3)δ(ppm):8.48(2H,m),7.59(1H,d,J=7.7Hz),7.28(1H,m),5.58(1H,s),5.09(1H,t,J=7.3Hz),4.76(1H,t,J=3.2Hz),4.65(2H,s),2.98(2H,t,J=7.5Hz),2.70(4H,m),2.58(1H,m),2.39(1H,m),1.72(3H,s),1.63(3H,s).13C NMR(100MHz,CDCl3)δ(ppm):172.3,171.6,149.0,147.1,141.0,136.7,136.2,136.0,125.4,123.7,117.0,78.1,75.4,62.1,37.7,35.0,27.9,27.5,25.8,18.0
实施例2：
本发明化合物的抑制胰脂肪酶体外实验：
一、测定药物和化合物
测定化合物为实施例1所得韧革菌素(vibralactone)一级醇酸酯衍生物，共43个化合物；阳性药物为奥利司他（Orlistat，N-Formyl-L-leucine(1S)-1-[[(2S,3S)-3-hexyl-4oxo-2-oxetanyl]methyl]dodecyl ester）购自Sigma公司；化合物和Orlistat溶解于二甲基亚砜（DMSO）中，4℃保存。
二、试剂和溶液
（1）试剂
猪胰脂肪酶（PPL）购自阿拉丁试剂公司；p-nitrophenyl butyrate（p-NPB）、Tris购自Sigma公司；D-PBS购自Hyclone公司；无水氯化钙为成都市科龙化工试剂厂产品。
（2）溶液
Tris缓冲液含有100mM Tris，5mM CaCl2，pH值为7.0，4℃保存；PPL溶液以D-PBS配制成1000U/mL的贮存液，分装，-80℃保存；p-NPB溶液以二甲基甲酰胺（DMF）配制成10mM的溶液，-20℃保存。
三、优选化合物1-5对PPL的抑制作用检测
在96孔酶标板上，将不同浓度的待测化合物185μL与PPL溶液（250U/mL）5μL充分混合，每个浓度均设定3个重复孔，37℃，15min；加入p-NPB（10mM）10μL，混合均匀，37℃，15min；BioTek PowerWave XS酶标仪测定OD400nm/630nm值，检测波长为400nm，参考波长为630nm。实验同时设置空白对照孔和Orlistat阳性对照孔，实验共进行三次。计算的IC50值（50％Concentration of Inhibition），即抑制PPL50%活性的化合物浓度。计算如下：PPL活性抑制率（%）=（1–样品OD值/实验对照孔OD值）×100%
结果：
以韧革菌素(vibralactone)为母体，合成了43个一级醇酸酯衍生物，从中获得一衍生物其胰脂肪酶抑制活性与原型化合物（Vibralactone）比较，提高了三个数量级，其IC50达到纳摩尔级别（83nM）。该化合物与现在市售的OTC药物Orlistat具有类似的药效团和作用机制。
现在市售的OTC药物Orlistat以及韧革菌素（Vibralactone）的结构式为：
表1对照化合物与本发明化合物1-43的IC50值
名次 名次
Orlistat 0.004 22 1.428
Vibralactone 47.260 23 1.486
1 0.083 24 1.575
2 0.090 25 1.654
3 0.115 26 1.734
4 0.150 27 2.223
5 0.191 28 2.372
6 0.208 29 2.451
7 0.261 30 2.644
8 0.300 31 2.661
9 0.338 32 3.765
10 0.395 33 3.807
11 0.460 34 3.882
12 0.529 35 5.940
13 0.546 36 5.964
14 0.626 37 6.350
15 0.675 38 6.382
16 0.768 39 6.757
17 0.891 40 6.796
18 0.926 41 7.051
19 0.997 42 8.320
20 1.057 43 8.693
21 1.120
结论：
与现有技术相比，本发明具有下述突出特点：
1.本发明的化合物属于一新类型的胰脂肪酶抑制剂，与现在所有的胰脂肪酶抑制剂具有不同的结构。
2.本发明的化合物具有显著的胰脂肪酶抑制活性，且来源于天然产物，是从没有毒性的蘑菇发酵中分离得到的，相对安全性较高，预示着该化合物具有较好的药用前景。
3.本发明的物质原料来源丰富、价廉，制备工艺简单，通过对褐盖韧革菌进行发酵培养即可以得到母体化合物，物质原料的来源得到保证。
4.本发明以韧革菌素（Vibralactone）为母体，对韧革菌素（Vibralactone）δ位羟基进行结构修饰，合成了43个一级醇酸酯衍生物，从中获得一衍生物其胰脂肪酶抑制活性与原型化合物（Vibralactone）比较，提高了三个数量级，其IC50达到纳摩尔级（83nM）。
本发明化合物的剂型实施例：
实施例3：
按实施例1制得化合物，按化合物晶体与赋形剂重量比1：1的比例加入赋形剂，制粒压片。
实施例4：
按实施例1制得化合物，按常规胶囊制剂方法制成胶囊。
实施例5：
按实施例1制得化合物，按化合物晶体与赋形剂重量比1：2的比例加入赋形剂，制粒压片。
实施例6：
按实施例1制得化合物，按化合物晶体与赋形剂重量比1：3的比例加入赋形剂，制粒压片。
实施例7：
实施例8：
胶囊剂：实施例1制得化合物 100mg
淀粉 100mg
硬脂酸镁 适量
制备方法：将实施例1制得化合物与助剂混合，过筛，在合适的容器中均匀混合，把得到的混合物装入硬明胶胶囊。
实施例10：
安瓿剂：实施例1制得化合物50mg
制备方法：将实施例1制得化合物溶解于2毫升丙二醇中，过滤所得溶液在无菌条件下装入安瓿瓶中。

Claims (7)

1.如下结构式1、2所示的韧革菌素一级醇酸酯衍生物1、2，
2.制备权利要求1所述的韧革菌素一级醇酸酯衍生物1、2的方法，韧革菌素与相应的酰氯反应得化合物1、2，
3.药物组合物，包含至少一种权利要求1中所示的韧革菌素一级醇酸酯衍生物1、2或其药学上可接受的盐为活性成分，单独或结合一种或几种药学上可接受的载体。
4.权利要求1所述的韧革菌素一级醇酸酯衍生物1、2在制备预防和/或治疗肥胖以及其它代谢性疾病的药物中的应用。
5.权利要求1所述的韧革菌素一级醇酸酯衍生物1、2在制备预防和/或治疗糖尿病的药物中的应用。
6.权利要求3的药物组合物在制备预防和/或治疗肥胖以及其它代谢性疾病的药物中的应用。
7.以权利要求1所述的韧革菌素一级醇酸酯衍生物1或2为活性成分的胰脂肪酶抑制剂。
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