WO2016086496A1 - 五环三萜类化合物及其作为人肠羧酸酯酶抑制剂的应用 - Google Patents

五环三萜类化合物及其作为人肠羧酸酯酶抑制剂的应用 Download PDF

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WO2016086496A1
WO2016086496A1 PCT/CN2015/000327 CN2015000327W WO2016086496A1 WO 2016086496 A1 WO2016086496 A1 WO 2016086496A1 CN 2015000327 W CN2015000327 W CN 2015000327W WO 2016086496 A1 WO2016086496 A1 WO 2016086496A1
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carboxylesterase
acid
deoxy
pentacyclic triterpenoid
ester
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杨凌
邹立伟
葛广波
李耀光
宁静
王平
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Dalian Institute of Chemical Physics of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
    • C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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  • the invention belongs to the technical field of biomedicine, and mainly relates to a pentacyclic triterpenoid compound and application thereof as a potent inhibitor of human intestinal carboxylate.
  • Carboxylesterases belong to group B esterases, and CEs involved in the metabolism of ester drugs in humans are mainly carboxylesterase 1 (hCE-1) and carboxylesterase 2 (hCE-2).
  • hCE-1 is highly expressed in the liver and is present in tissues such as macrophages, lung epithelial cells, heart, testis, etc., but is rarely expressed in the gastrointestinal tract.
  • hCE-2 is present in the small intestine, colon, kidney, liver, heart and brain tissue.
  • CEs participate in the hydrolytic metabolism of various endogenous and exogenous compounds in the body, and interact with other metabolic enzymes or carriers to play an important role in the metabolism and elimination process of ester drugs.
  • CEs can hydrolyze a variety of drug- or ester-containing prodrugs, such as angiotensin converting enzyme inhibitors (temoripril, cilazapril, quinapril), antineoplastic agents (irinotecan and card) Peitabin) and anesthetics (cocaine, heroin and meperidine).
  • hCE-1 and hCE-2 possess 48% amino acid homologous sequences, but the substrate characteristics of the two are quite different.
  • irinotecan and heroin exhibit a small acyl end and a large hydroxyl end, which is a good substrate for hCE-2, it has been reported that about 99% of irinotecan in human duodenum, jejunum, ileum and kidney tissues Biotransformation is the responsibility of hCE-2.
  • Irinotecan is a prodrug of the camptothecin derivative SN38.
  • CPT-11 is widely used in the chemotherapy of various cancers due to its broad-spectrum anticancer activity.
  • its clinical application is affected by its severe and unpredictable diarrhea response.
  • Diarrhea caused by CPT-11 includes acute diarrhea (occurring within 24 hours after administration) and delayed diarrhea (occurring after 24 hours after administration) [Mol Pharmacol, 2004, 65(6): 1336-34331].
  • the incidence of grade 3 and grade 4 delayed diarrhea caused by CPT-11 clinical medication is as high as 40%, which severely limits the clinical use of CPT-11.
  • irinotecan As a prodrug of SN-38, irinotecan is only 1/1000 of the SN-38 due to its active/active group being blocked. Therefore, if the hydrolysis of irinotecan can be reduced locally (intestine), it is very beneficial to reduce the damage to the body. Therefore, it has become necessary to develop a safe and potent inhibitor of carboxylesterase 2, which is used to reduce the excessive hydrolysis of irinotecan to the toxic component SN-38.
  • Licorice is the root of the perennial herb licorice (Glycyrrhiza urlensis Fisch) Rhizome, sweet taste, heart, lung, spleen, stomach, is an important traditional Chinese herbal medicine.
  • the traditional Chinese medicine formula is known as “ten noodles and nine grasses, no grass is not square”.
  • Licorice, one of the famous Chinese medicines in China is also one of the food and food homologous foods approved by the Ministry of Health. Modern medical research shows that the main pharmacological active substance of licorice is Glycyrrhizic acid and its glycorrhetinic acid (GA).
  • the former is a kind of triterpenoid saponin, which accounts for about 4% of the dry weight of licorice root. ⁇ 5%.
  • the metabolic process of glycyrrhizic acid in the human body has been clear. After intravenous injection of glycyrrhizic acid, it enters the liver and is metabolized by ⁇ -D-glucuronidase in lysosome to 3-mono-glucaldehyde in liver cells. After the acid glycyrrhetinic acid, it is discharged into the intestine with the bile, and is metabolized by the intestinal flora into glycyrrhetinic acid, and then absorbed into the blood.
  • glycyrrhetinic acid and its derivatives have anti-allergic, analgesic, anti-inflammatory, anti-cancer, anti-HIV, anti-ulcer, anti-oxidation, liver protection and other activities.
  • analgesic anti-inflammatory, anti-cancer, anti-HIV, anti-ulcer, anti-oxidation, liver protection and other activities.
  • the inhibitory effect of glycyrrhetinic acid and its derivatives on human carboxylesterase has not been reported, and there is no report on the use of glycyrrhetinic acid and its derivatives to alleviate delayed diarrhea caused by CPT-11.
  • the present invention relates to a pentacyclic triterpenoid and its use as an inhibitor of human carboxylesterase.
  • This compound has a 11-deoxy-glycyrrhetic acid skeleton structure which potently and selectively inhibits the activity of human carboxylesterase subtype 2. Determination of in vitro activity of such compounds found to inhibit human carboxylesterase 2 IC 50 of up to 0.02 [mu] M, inhibit the human carboxylesterase 1 IC 50 IC 50 ratio of inhibition of human carboxylesterase 2 up to 1020.
  • the inhibitor can increase the bioavailability of the oral ester prodrug and prolong its metabolic half-life and reduce the intake of intestinal esters. In addition, the inhibitor can also alleviate delayed diarrhea caused by a variety of clinical chemotherapy drugs.
  • the present invention provides a pentacyclic triterpenoid having a 11-deoxy-glycyrrhetic acid skeleton structure, which has the following structural formula:
  • R is any one of a methyl group, an ethyl group and a propyl group.
  • a method for preparing a pentacyclic triterpenoid compound the synthesis of which is carried out according to the following steps:
  • the acid binding agent can be potassium carbonate or sodium carbonate, and the selective esterification of the 30-position carboxyl group can be achieved to obtain 18 ⁇ -11-deoxy-glycyrrhiza. Hypo- 30-ester;
  • the preparation method of the step (3) 18 ⁇ -(3-carboxypropanoyl)-11-deoxy-glycyrrhetic acid-30-ester is specifically as follows:
  • a pentacyclic triterpenoid for use as a human intestinal carboxylesterase inhibitor as a potent inhibitor of human intestinal carboxylesterase which potently and selectively inhibits human carboxylic acid 2 isoenzyme activity, which inhibits human carboxylesterase IC 1 '50 and the IC 50 for inhibiting human acid esterase 2 ratio of up to 1020 times.
  • a pentacyclic triterpenoid as a human intestinal carboxylesterase inhibitor can prepare a drug containing a pentacyclic triterpenoid compound, which can enhance oral esters by potently inhibiting human intestinal carboxylesterase
  • the bioavailability of the prodrug further exerts the efficacy of the ester prodrug synergist.
  • a pentacyclic triterpenoid as a human intestinal carboxylesterase inhibitor can prepare a drug containing a pentacyclic triterpenoid compound, which can slow down fatty acid substances by potently inhibiting human intestinal carboxylesterase
  • the intestinal absorption is used for the adjuvant treatment of metabolic disorders such as obesity and diabetes.
  • a pentacyclic triterpenoid as a human intestinal carboxylesterase inhibitor can prepare a drug containing a pentacyclic triterpenoid compound, which potently inhibits human intestinal carboxylesterase, In addition, it can alleviate delayed diarrhea caused by various clinical chemotherapy drugs.
  • chemotherapeutic drugs include, but are not limited to, irinotecan hydrochloride, cisplatin, 5-fluorouracil, paclitaxel, topotecan, methotrexate, doxorubicin, etoposide, cyclophosphamide, carmustine, gemcitabine , epirubicin, vinorelbine and so on.
  • the present invention provides the use of the pentacyclic triterpenoid as a human intestinal carboxylesterase inhibitor, which mainly inhibits the carboxylesterase 2 which is highly expressed in the human intestinal tract, thereby further improving the prodrug (carboxylic acid) Oral bioavailability of the esterase substrate:
  • the inhibitor reduces the prodrug by inhibiting the carboxylesterase of the human gastrointestinal system when co-administered with the prodrug (carboxyesterase substrate)
  • the gastrointestinal hydrolysis and first-pass effect of the enzyme substrate enhances its bioavailability.
  • the present invention provides another use of the pentacyclic triterpenoid as a human intestinal carboxylesterase inhibitor which attenuates diarrhea caused by the antitumor drug irinotecan: the inhibitor and
  • the combination of irinotecan anti-tumor drugs inhibits the hydrolysis of irinotecan in the gastrointestinal tract, thereby reducing the local exposure of irinotecan active metabolite SN-38 in the gastrointestinal system and slowing down the serious adverse reactions caused by delayed diarrhea.
  • the carboxylesterase inhibitor provided by the invention can reduce the anti-tumor drug causing diarrhea and improve the oral bioavailability of the prodrug, and the component can be used as a monomer or a compound mixed with a common excipient to prepare a dosage form, or It is used as a pharmaceutical composition after being mixed with antitumor drugs in different ratios.
  • the present invention relates to a pentacyclic triterpenoid and its use as a human carboxylesterase inhibitor, the advantages of which are as follows:
  • the novel carboxylate esterase inhibitor provided by the invention is obtained by chemical synthesis by using cheap glycyrrhetinic acid as raw material, and the synthesis process is simple and easy, and the yield is high.
  • the novel carboxylesterase inhibitor has good safety, and the oral LD 50 of the mouse is greater than 1 g/kg.
  • the apparatus and model of the invention are: fluorescence emission/excitation spectroscopy is completed by SynergyH1 full-function microplate detector; 1 H-NMR spectrum and 13 C-NMR spectrum are obtained by NMR spectrometer (Avance) II 400MHz) Detection completed.
  • the nuclear magnetic resonance spectrum of the product is as follows:
  • the substrate was added to the reaction system (final concentration 10 ⁇ M) to initiate the reaction; after reacting at 37 ° C for 30 minutes, 200 ⁇ l of acetonitrile was added, and the reaction was terminated after vigorous shaking;
  • the IC 50 of inhibition of carboxylesterase 1 by glycyrrhetinic acid and its derivatives was determined by hydrolytic metabolism of fluorescein diacetate as a probe reaction and by human liver microsome in vitro incubation system:
  • the substrate was added to the reaction system (final concentration 10 ⁇ M) to initiate the reaction; after reacting at 37 ° C for 30 minutes, 200 ⁇ l of acetonitrile was added, and the reaction was terminated after vigorous shaking;
  • Glycyrrhetinic acid and its derivatives showed good inhibitory activity against hCE2, and the half-inhibitory concentration of each compound is shown in Table 1. It can be seen from the experimental data that the modification of glycyrrhetinic acid (3 hydroxyl acylation, removal of 11 carbonyl group, 30 carboxyl esterification) can significantly enhance its inhibitory activity on hCE2, and significantly enhance the selectivity to hCE2.
  • mice purchased from the Experimental Animal Center of Dalian Medical University
  • mice were selected, male and female, weighing 19-22 g.
  • Mice were randomized into groups of 20, half male and half female.
  • the test compound was suspended in 0.5% CMC-Na at a concentration of 1 g/L.
  • the experimental group included different dose groups of test compounds (0.1-1 g/kg) and 0.5% CMC-Na blank control group.
  • the behavioral state of the mice after administration was continuously observed until 14 days, and on the 14th day, the mice of the different administration groups were roughly dissected and the visceral condition was observed. Only 4 of the mice in the maximal dose group (1 g/kg) were killed, and no deaths were observed in the other dose groups.
  • the anatomy of the dead individual did not reveal obvious lesions of the main organs such as liver and kidney.
  • the experimental results indicate that the mouse is orally administered (3-carboxypropionyl)-11-
  • the LD50 value of deoxy-glycyrrhetinic acid -29-carboxylate is greater than 1.0 g/kg, suggesting that the novel carboxylesterase inhibitor has good safety.
  • the normal diet group continued to give a high-fat diet to the normal-feed, high-fat diet group, while the deoxyglycyrrhetinic acid group was orally administered (3-carboxypropionyl)-11 at a dose of 300 mg/kg (daily, three times).
  • - Deoxy-glycyrrhetinic acid-30-carboxylic acid ethyl ester.
  • rat (3-carboxypropionyl)-11-deoxy-glycyrrhetinic acid-30-carboxylic acid ethyl ester can effectively alleviate the excessive weight gain of rats induced by high-fat diet, suggesting that it may inhibit intestinal tract.
  • Highly expressed CES2 regulates the homeostatic balance of lipid compounds and inhibits the occurrence of obesity.
  • mice Eighteen Balb/c mice were randomly divided into three groups: normal control group, irinotecan diarrhea model group and (3-carboxypropionyl)-11-deoxy-glycyrrhetinic acid-30-carboxylic acid ethyl ester + irinotecan
  • the diarrhea model group (hereinafter referred to as the deoxyglycyrrhetinic acid group), each group of 6 each.
  • the diarrhea status of the normal control group, the diarrhea model group and the deoxyglycyrrhetinic acid group were observed, and the intestinal tissues of the mice were examined by tissue biopsy.
  • the diarrhea model group was treated with Trifan method (Cancer Res 2002; 62: 5778-84.), and the diarrhea model was intraperitoneally injected with irinotecan (100 mg/kg/d) for 3 days (d), and delayed diarrhea at 3rd. The day appeared, the most serious on the fourth day.
  • the deoxyglycyrrhetinic acid group started 3 days before CPT-11 injection once a day, and was intragastrically administered with 100 mg/kg. The other two groups were given an equal volume of distilled water to prevent the effects of emergency on mice.
  • the normal control group was injected with an equal volume of normal saline in the tail vein. The diarrhea status of the normal control group, the diarrhea model group and the deoxyglycyrrhetic acid group were observed. The mice were sacrificed on the 7th day, and the intestinal tissues were taken and examined by tissue section staining.
  • mice were sacrificed on the 9th day after injection of CPT-11.
  • the intestine was taken 3 cm from the ileocecal valve, the cecum was 1 cm, the anus was 7 to 9 cm, and the colon tissue was 3 cm.
  • the 10% formaldehyde was fixed for light microscope observation.
  • the degree of damage to the intestinal mucosa was evaluated as shown in Table 3.
  • the results of the experiment showed that the degree of diarrhea was significantly decreased, and the degree of intestinal mucosal damage in the deoxyglycyrrhetinic acid group was slightly lower than that in the model group.
  • the above experimental results confirmed that (3-carboxypropionyl)-11-deoxy-glycyrrhetinic acid-30-carboxylic acid ethyl ester can not only reduce the degree of CPT-11-induced delayed diarrhea and intestinal mucosal damage in mice, but also Better inhibition of diarrhea. Therefore, (3-carboxypropionyl)-11-deoxy-glycyrrhetic acid-30-carboxylate has a certain preventive effect on CPT-11-induced delayed diarrhea in mice.

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Abstract

本发明提供了一种五环三萜类化合物及其作为人羧酸酯酶抑制剂的应用，属生物医药技术领域。该五环三萜类化合物具有11-脱氧-甘草次酸骨架结构，其可以强效地、选择性地抑制人肠道羧酸酯酶亚型2的活性，进而提高口服前药的生物利用度，并减少肠道酯类物质的摄取。此外，该抑制剂还可减缓伊立替康引发的迟发型腹泻。体外活性测定发现该类化合物抑制人羧酸酯酶2的IC50可达0.02微摩，抑制人羧酸酯酶1的IC50与抑制人羧酸酯酶2的IC50比率可达1020，且该类化合物的安全性较好，同时还具有制备工艺简单、收率高等优势，提示该类化合物显示具有良好的应用前景。

Description

五环三萜类化合物及其作为人肠羧酸酯酶抑制剂的应用 技术领域
本发明属于生物医药技术领域，主要涉及一种五环三萜类化合物及其作为人肠羧酸酯强效抑制剂应用。
背景技术
羧酸酯酶(CEs)属于B族酯酶，人体内参与酯类药物代谢的CEs主要为羧酸酯酶1(hCE-1)和羧酸酯酶2(hCE-2)。hCE-1在肝脏中高表达，并在巨噬细胞、肺上皮细胞、心脏、睾丸等组织中存在，但在胃肠道表达甚微。hCE-2在小肠、结肠、肾、肝脏、心脏和脑组织中存在。CEs参与机体多种内源性和外源性化合物的水解代谢，并与其他代谢酶或运载体共同作用，在酯类药物的体内代谢与清除过程发挥着重要作用。CEs可水解多种含酯键的药物或酯类前药，例如血管紧张肽转化酶抑制药(替莫普利、西拉普利、喹那普利)，抗肿瘤药(伊立替康和卡培他滨)以及麻醉药(可卡因、海洛因和哌替啶)等。hCE-1与hCE-2拥有48％的氨基酸同源序列，但两者的底物特征有较大差异。由于伊立替康和海洛因表现出小酰基端和大羟基端，是hCE-2的良好底物，有报道称，人体十二指肠、空肠、回肠、肾组织中约99％的伊立替康的生物转换由hCE-2负责。
伊立替康(CPT-11)是喜树碱类衍生物SN38的前体药物。目前，由于CPT-11广谱的抗癌活性使其被广泛地应用于各种癌症的化疗之中。但是，由于其严重且不可预测的腹泻反应，使它的临床应用受到 了一定限制。CPT-11所致的腹泻包括急性腹泻(给药后24h内发生)和迟发性腹泻(给药后24h后发生)两种[Mol Pharmacol，2004，65(6)：1336-13431]。CPT-11临床用药所导致的3级和4级迟发性腹泻发生率高达40％，严重限制了CPT-11的临床使用。国内外大量研究表明CPT-11导致的迟发型腹泻的发生原因是由于活性代谢产物SN-38在肠道中过多积聚。人肠道羧酸酯酶，尤其是hCE-2在此发病机制中起了重要作用。因此，开发一种强效的、选择性的hCE-2抑制剂，降低CPT-11向SN-38的转化，从而可以降低腹泻等肠道的毒副反应[J Med Chem，2009，52(12)：3742-37521]。
国内外许多学者致力于研究伊立替康不良反应的发生与缓解机制，以求提高伊立替康使用的安全性和疗效。目前，对伊立替康所导致的腹泻主要采取的是给予洛哌丁胺来进行治疗。洛哌丁胺通过抑制肠道平滑肌的收缩，减少肠蠕动，减少肠壁神经末梢释放乙酰胆碱，直接抑制蠕动反射而发挥减轻腹泻的作用。但需要特别指出的是，腹泻作为机体的一种防御措施，是在将毒性较大的SN-38排出体外，减少腹泻次数，对于降低其对机体的毒性并没有根本性的益处。而伊立替康作为SN-38的前药，由于其活性/活性基团被封闭，其毒性仅为SN-38的1/1000。因此，如果能在局部(肠道)减少伊立替康的水解，对于降低对机体的损害程度是十分有益的。因此，开发出一种安全强效的羧酸酯酶2的抑制剂，用来减少肠道局部伊立替康过多地水解成毒性成分SN-38，显得尤为必要。
甘草为多年生草本植物甘草(Glycyrrhiza urlensis Fisch)的根及 根茎，性味甘平，归心、肺、脾、胃经，是一味重要的传统中药材。在2000多种中草药中甘草的用量最大，中药配方中素有“十方九草，无草不成方”之说。作为我国著名的国药之一的甘草，也是国家卫生部批准的药食同源食物之一。现代医学研究表明甘草的主要药理学活性物质为甘草酸(Glycyrrhizic acid)及其苷元甘草次酸(Glycyrrhetinic acid，GA)，前者是一类三萜类皂苷，约占甘草根干重的4％～5％。甘草酸类药物在人体内的代谢过程已经比较清楚，甘草酸静脉注射后，进入肝脏，在肝细胞内由溶酶体中的β-D-葡萄糖醛酸苷酶代谢成3-单-葡萄糖醛酸甘草次酸后，随胆汁排入肠内，由肠内菌群代谢成甘草次酸，再吸收入血。近些年，大量的研究表明，甘草次酸及其衍生物具有抗过敏、镇痛、抗炎、抗癌、抗艾滋病毒、抗溃疡、抗氧化、保肝等活性。然而，甘草次酸及其衍生物对人羧酸酯酶的抑制作用一直未见报道，也没有利用甘草次酸及其衍生物缓解CPT-11所致迟发型腹泻的报道。此外，许多含有羧酸酯键的口服药物常会被胃肠道中分布的羧酸酯酶代谢，易在吸收入血之前就被水解成水溶性较大的活性药物，从而降低了其吸收入血的药物量，影响了生物利用度。若同时共服安全的人羧酸酯酶抑制剂，可减少前药在吸收过程中的水解，从而提高其口服生物利用度。
发明内容
本发明涉及一种五环三萜类化合物及其作为人羧酸酯酶的抑制剂的应用。该化合物具有11-脱氧-甘草次酸骨架结构，其可强效地、选择性地抑制人羧酸酯酶亚型2的活性。体外活性测定发现该类化合 物抑制人羧酸酯酶2的IC50可达0.02微摩，抑制人羧酸酯酶1的IC50与抑制人羧酸酯酶2的IC50比率可达1020。该抑制剂可以提高口服酯类前药的生物利用度并延长其代谢半衰期，并减少肠道酯类物质的摄取。此外该抑制剂还可缓解临床多种化疗药物导致的迟发型腹泻。
本发明提供了一种五环三萜类化合物，该衍生物具有11-脱氧-甘草次酸骨架结构，其结构式如下：
Figure PCTCN2015000327-appb-000001
其中，R为甲基、乙基、丙基中的任意一种。
一种五环三萜类化合物的制备方法，该化合物的合成按照以下步骤进行：
1)采用锌粉-盐酸还原体系，高选择性地脱除甘草次酸11位羰基；获得11-脱氧-甘草次酸；
2)以卤代烷(碘甲烷、溴乙烷、溴丙烷)为酯化试剂，缚酸剂可为碳酸钾、碳酸钠，实现了30位羧基的选择性酯化，获得18β-11-脱氧-甘草次酸-30-酯；
3)以琥珀酸酐为酯化试剂，4-二甲氨基吡啶为高效的反应促进剂，高效地在3位引入琥珀酸，得到产物18β-(3-羧丙酰基)-11-脱氧-甘草次酸-30-酯；
所述步骤(3)18β-(3-羧丙酰基)-11-脱氧-甘草次酸-30-酯的制备方法具体如下：
室温下，依次将18β-11-脱氧-甘草次酸-30-酯、4-二甲氨基吡啶、琥珀酸酐加入到二氯甲烷溶液中，加完室温反应，薄板层析(TLC)监测反应；反应完全后，加水，1M HCl溶液调pH＝2-3，乙酸乙酯萃取三次，合并有机相水洗、饱和氯化钠溶液洗，无水硫酸钠干燥，蒸除溶剂，粗产物柱层析得产物18β-(3-羧丙酰基)-11-脱氧-甘草次酸-30-酯3；各反应试剂的用量按摩尔比为18β-11-脱氧-甘草次酸-30-酯∶琥珀酸酐∶4-二甲氨基吡啶＝1.0∶1.5-3.0∶1.5-3.0。
一种五环三萜类化合物作为人肠羧酸酯酶抑制剂的应用，该化合物作为一种人肠道羧酸酯酶的强效抑制剂，可强效地、选择性地抑制人羧酸酯酶亚型2的活性，其抑制人羧酸酯酶1的IC50与抑制人羧酸酯酶2的IC50比率可达1020倍。
一种五环三萜类化合物作为人肠羧酸酯酶抑制剂的应用，可制备含五环三萜类化合物的药物，该药物可通过强效抑制人肠道羧酸酯酶提高口服酯类前药的生物利用度，进而发挥酯类前药增效剂的功效。
一种五环三萜类化合物作为人肠羧酸酯酶抑制剂的应用，可制备含五环三萜类化合物的药物，该药物可通过强效抑制人肠道羧酸酯酶减缓脂肪酸类物质的肠道吸收，进而用于肥胖、糖尿病等代谢紊乱性疾病的辅助治疗。
一种五环三萜类化合物作为人肠羧酸酯酶抑制剂的应用，可制备含五环三萜类化合物的药物，该药物通过强效抑制人肠道羧酸酯酶， 进而可以缓解临床多种化疗药物导致的迟发型腹泻。
所述的化疗药物包括但不限于盐酸伊立替康、顺铂、5-氟尿嘧啶、紫杉醇、拓扑替康、甲氨蝶呤、阿霉素、依托泊苷、环磷酰胺、卡莫司汀、吉西他滨、表柔比星、长春瑞滨等。
本发明提供了所述的五环三萜类化合物作为人肠羧酸酯酶抑制剂的应用，该衍生物主要抑制人体肠道高表达的羧酸酯酶2，进而可以提高前药(羧酸酯酶底物)的口服生物利用度：该抑制剂在与前药(羧酸酯酶底物)共服时，通过抑制人胃肠体系的羧酸酯酶，可减少前药(羧酸酯酶底物)的胃肠水解及首过效应，提高其生物利用度。
本发明提供了所述的五环三萜类化合物作为人肠羧酸酯酶抑制剂的另一个应用，该羧酸酯酶抑制剂能减弱抗肿瘤药伊立替康导致的腹泻：该抑制剂与伊立替康抗肿瘤药物合用，抑制伊立替康在胃肠道中的水解，进而降低伊立替康活性代谢物SN-38在胃肠体系的局部暴露量，减缓其导致的迟发型腹泻严重不良反应。
本发明提供的羧酸酯酶抑制剂在减弱抗肿瘤药导致腹泻与提高前药口服生物利用度方面的应用，该类成分可作为单体或复方与常用辅料混合后制成剂型使用，也可与抗肿瘤药按不同比例混合后作为药物组合物使用。
本发明涉及一种五环三萜类化合物及其作为人羧酸酯酶抑制剂的应用，优点如下：
1、价廉易得：本发明提供的新型羧酸酯酶抑制剂以廉价的甘草次酸为原料，经化学合成获得，合成工艺简单易行，收率较高。
2、高抑制活性：该新型羧酸酯酶抑制剂在人组织微粒体中对羧酸酯酶2的半数抑制浓度IC50可达nM级。
3、高选择性：体外活性测定发现该类化合物抑制羧酸酯酶1的IC50与抑制羧酸酯酶2的IC50比率可达1020。
4、高安全性：该新型羧酸酯酶抑制剂具有良好的安全性，其小鼠口服LD50大于1g/kg。
附图说明
图1.甘草次酸衍生物的结构通式；
图2.(3-羧丙酰基)-11-脱氧-甘草次酸-30-乙酯的1H-NMR谱图；
图3.(3-羧丙酰基)-11-脱氧-甘草次酸-30-乙酯的13C-NMR谱图；
图4.(3-羧丙酰基)-11-脱氧-甘草次酸-30-乙酯的合成路线；
图5.(3-羧丙酰基)-11-脱氧-甘草次酸-30-乙酯抑制hCE2的抑制曲线；
具体实施方式
下面的实施例将对本发明予以进一步的说明，但并不因此而限制本发明。
本发明所采用的设备及其型号为：荧光发射/激发光谱是由SynergyH1全功能微孔板检测仪检测完成；1H-NMR谱图和13C-NMR谱图是由核磁共振波谱仪(Avance II 400MHz)检测完成。
实施例1
(3-羧丙酰基)-11-脱氧-甘草次酸-30-羧酸酯的合成
(1)化合物1(11-脱氧-甘草次酸)的合成
室温，将18β-甘草次酸(235.3mg，0.5mmol)、锌粉(526.5mg，16.2mmol)加入到1，4-二氧六环(9mL)溶液中，冷却反应体系到8-12℃，缓慢滴加浓盐酸(1.45mL)，加完保持体系8-12℃反应，薄板层析(TLC)监测反应。反应完全后，减压蒸除溶剂，加水(25mL)，二氯甲烷萃取三次(30mL×3)，合并有机相饱和氯化钠溶液洗(20mL×1)，无水硫酸钠干燥，蒸除溶剂，粗产物柱层析(石油醚/乙酸乙酯＝20/1-5/1)得化合物1，白色固体，产率65-75％。
(2)化合物2(11-脱氧-甘草次酸-30-乙酯)的合成
室温，将化合物1(167.0mg，0.37mmol)、无水碳酸钾(51.1mg，0.37mmol)加入到丙酮(10mL)和四氢呋喃(5mL)的混合溶液中，搅拌5min后滴加溴乙烷(41μL，0.55mmol)，加完升温到35℃反应，薄板层析(TLC)监测反应。反应完全后，减压蒸除溶剂，加水(20mL)，二氯甲烷萃取三次(25mL×3)，合并有机相饱和氯化钠溶液洗(15mL×1)，无水硫酸钠干燥，蒸除溶剂，粗产物柱层析(石油醚/乙酸乙酯＝50/1-10/1)得化合物2，白色固体，产率85-95％。(3)化合物3((3-羧丙酰基)-11-脱氧-甘草次酸-30-乙酯)的合成
室温，依次将化合物2(89.0mg，0.18mmol)、4-二甲氨基吡啶(45.0mg，0.36mmol)、琥珀酸酐(91.9mg，0.92mmol)加入到二氯甲烷(2mL)溶液中，加完室温反应，薄板层析(TLC)监测反应。反应完全后，加水(10mL)，1M HCl溶液调pH＝2-3，乙酸乙酯萃取三次(25mL×3)，合并有机相水洗(15mL×1)、饱和氯化钠溶液洗(15mL×1)，无水硫酸钠干燥，蒸除溶剂，粗产物柱层析(二 氯甲烷/甲醇＝100/1-20/1梯度洗脱)得化合物3，白色固体，产率70-80％。
产物的核磁共振波谱具体如下：
1H NMR(400MHz，CDCl3)δ5.26(s，1H)，4.61-4.43(m，1H)，4.29-3.98(m，2H)，2.69-4.24(m，4H)，2.03-1.82(m，6H)，1.80-1.74(m，1H)，1.69-1.47(m，7H)，1.47-1.38(m，1H)，1.37-1.21(m，8H)，1.14(s，3H)，1.12(s，3H)，1.09-0.99(m，2H)，0.96(s，6H)，0.83-0.87(m，8H)，0.78(s，3H)；13C NMR(101MHz，CDCl3)δ177.2，171.9，144.6，122.4，81.6，60.0，55.3，48.2，47.56，44.1，42.8，41.5，39.8，38.3，38.2，37.8，36.8，32.6，31.9，31.3，29.4，28.8，28.5，28.2，28.0，27.0，26.2，25.9，23.5，18.2，16.8，16.7，15.5，14.3.
实施例2.
(3-羧丙酰基)-11-脱氧-甘草次酸-30-羧酸酯对羧酸酯酶2抑制能力的定量评估
以对荧光素二乙酸酯的水解代谢为探针反应，借助人肝微粒体体外孵育体系，测定甘草次酸及其衍生物对羧酸酯酶2抑制的IC50：
a.200微升体外代谢反应体系中，含有pH为7.4的磷酸缓冲液，人肝微粒体蛋白浓度为2μg/ml，抑制剂终浓度范围为0.001μM-100μM，于37℃条件下震荡预孵10分钟；
b.向反应体系中加入底物(终浓度10μM)，起始反应；于37℃条件下反应30分钟后，加入200μl乙腈，剧烈震荡后，终止反应；
c.采用高速冷冻离心机，在20,000×g的条件下，高速离心上述 体系5分钟后，取上清，进行酶标仪检测分析；对代谢水解产物进行定量检测。
实施例3.
(3-羧丙酰基)-11-脱氧-甘草次酸-30-羧酸酯对羧酸酯酶1抑制能力的定量评估
以对荧光素二乙酸酯的水解代谢为探针反应，借助人肝微粒体体外孵育体系，测定甘草次酸及其衍生物对羧酸酯酶1抑制的IC50：
a.200微升体外代谢反应体系中，含有pH为7.4的磷酸缓冲液，人肝微粒体蛋白浓度为2μg/ml，抑制剂终浓度范围为0.001μM-120μM，于37℃条件下震荡预孵10分钟；
b.向反应体系中加入底物(终浓度10μM)，起始反应；于37℃条件下反应30分钟后，加入200μl乙腈，剧烈震荡后，终止反应；
c.采用高速冷冻离心机，在20,000×g的条件下，高速离心上述体系5分钟后，取上清，进行酶标仪检测分析；对代谢水解产物进行定量检测。
表1 甘草次酸及其衍生物对羧酸酯酶的抑制
Figure PCTCN2015000327-appb-000002
Figure PCTCN2015000327-appb-000003
Figure PCTCN2015000327-appb-000004
甘草次酸及其衍生物对hCE2呈现出很好的抑制活性，各化合物的半数抑制浓度如表1所示。从所得实验数据可以看出，改造甘草次酸(3位羟基酰化、脱除11位羰基、30位羧基酯化)可以明显提高其对hCE2的抑制活性，同时显著增强对hCE2的选择性。改造后(3-羧丙酰基)-11-脱氧-甘草次酸-30-乙酯对hCE2抑制活性是甘草次酸的3463倍，抑制羧酸酯酶1的IC50与抑制羧酸酯酶2的IC50比率可达1020.5。
实施例4.
(3-羧丙酰基)-11-脱氧-甘草次酸-30-羧酸乙酯的小鼠口服急性毒性评估
选取Balb/c小鼠(购于大连医科大学实验动物中心)，雌雄各半，体重19-22g。将小鼠随机分组，每组20只，雌雄各半。测试化合物混悬于0.5％CMC-Na中，浓度为1g/L。实验组包括测试化合物不同剂量组(0.1～1g/kg)以及0.5％CMC-Na空白对照组。连续观察给药后小鼠的行为状态直至14天，并于第14天对不同给药组小鼠进行大体解剖并观察内脏情况。最大剂量组(1g/kg)给药组小鼠中只有4例死亡，其他剂量组均无死亡例。对死亡个体进行解剖并未发现肝、肾等主要器官的明显病变。实验结果表明小鼠口服(3-羧丙酰基)-11- 脱氧-甘草次酸-29-羧酸乙酯的LD50值大于1.0g/kg，提示该新型羧酸酯酶抑制剂具有良好的安全性。
实施例5.
(3-羧丙酰基)-11-脱氧-甘草次酸-30-羧酸乙酯对减缓高脂饮食诱发大鼠营养性肥胖的研究
选取45只成年SD雄性大鼠，采用D12492配方所制作的高脂肪、高热量食物进行限制饲喂，第1周内每只鼠13g，以后每周增加2g，至第6周为止。每日饲养分2次供给，吃完后不再添加，自由饮水。于3周后将体重增加排在后1/3的大鼠作为肥胖抵抗大鼠剔除。其余大鼠按照随机分组原则分为正常饲料组、高脂饮食模型组和(3-羧丙酰基)-11-脱氧-甘草次酸-30-羧酸乙酯给药组(以下简称脱氧甘草次酸组)，每组10只大鼠。正常饲料组只给于正常饲料、高脂饮食组继续给予高脂饮食，而脱氧甘草次酸组于按300mg/kg(每日，三次)剂量口服灌胃给予(3-羧丙酰基)-11-脱氧-甘草次酸-30-羧酸乙酯。连续操作4周(即第4-7实验周)，并分别对体重和Lee’s指数(麻醉后测量大鼠从鼻至肛门的长度，并根据公式[Lee’s指数＝体重(g)1/3×103/体长(cm)]计算Lee’s指数)进行观察。
表2.大鼠体重及Lee’s指数观察
Figure PCTCN2015000327-appb-000005
实验结果证实，给予大鼠(3-羧丙酰基)-11-脱氧-甘草次酸-30-羧酸乙酯能够有效缓解高脂饮食导致的大鼠体重过度增长，提示其可能通过抑制肠道中高表达的CES2而对脂质化合物体内平衡进行调节，抑制肥胖的发生。
实施例6.
(3-羧丙酰基)-11-脱氧-甘草次酸-30-羧酸乙酯对减缓伊立替康导致的小鼠腹泻研究
18只Balb/c小鼠随机分为3组：正常对照组、伊立替康腹泻模型组和(3-羧丙酰基)-11-脱氧-甘草次酸-30-羧酸乙酯+伊立替康腹泻模型组(以下简称脱氧甘草次酸组)，每组各6只。分别观察正常对照组、腹泻模型组和脱氧甘草次酸组小鼠的腹泻状况，并对小鼠肠道组织进行组织切片检查。腹泻模型组按Trifan方法(Cancer Res 2002；62：5778-84.)，腹泻模型采用腹腔注射伊立替康(100mg/kg/d)，连续用药3天(d)，迟发性腹泻于第3天出现，于第4天最严重。脱氧甘草次酸组于CPT-11注射前3天开始，每天1次，灌胃100mg/kg，其余两组用等体积蒸馏水灌胃来防止应急对小鼠造成的影响。正常对照组尾静脉注射等体积生理盐水。分别观察正常对照组、腹泻模型组和脱氧甘草次酸组小鼠的腹泻状况，于第7天处死小鼠，进行肠道组织取材，组织切片染色检查。
注射CPT-11后第9天处死小鼠，距回盲瓣5cm处取回肠3cm、盲肠1cm、肛门至上7～9cm取结肠组织3cm，10％甲醛固定，以备光镜观察。常规HE染色观察各组小鼠肠粘膜组织结构变化；根据Chiu 肠粘膜损伤评分方法(Arch Surg 1970；101：478-83)，对肠粘膜损伤程度进行分级：1级：正常肠粘膜绒毛；2级：上皮下间隙扩大，通常在肠绒毛顶端，常有上皮充血；3级：上皮下间隙扩张，伴有中等程度上皮层从肠粘膜固有层脱离；4级：肠粘膜侧面大块上皮脱离，大部分肠绒毛顶端变光滑；5级：肠绒毛变光滑，毛细血管扩张，肠粘膜固有层细胞构成增加；6级：肠粘膜固有层消化和分解，出血和出现溃疡。
对肠粘膜损伤程度进行评估如表3所示，实验结果显示，腹泻程度显著下降，脱氧甘草次酸组肠粘膜损坏程度较模型组轻微。以上实验结果证实，(3-羧丙酰基)-11-脱氧-甘草次酸-30-羧酸乙酯不仅能够降低CPT-11诱发的小鼠迟发性腹泻及肠粘膜损伤的程度，还能较好地抑制腹泻的发生。因此，(3-羧丙酰基)-11-脱氧-甘草次酸-30-羧酸酯对CPT-11诱发的小鼠迟发性腹泻具有一定的预防作用。
表3.小鼠盲肠肠粘膜损伤程度分级n(％)
Figure PCTCN2015000327-appb-000006

Claims (7)

  1. 一种五环三萜类化合物，其特征在于：该化合物为11-脱氧-甘草次酸-3-O-琥珀酰衍生物的羧酸酯，其结构式如下：
    Figure PCTCN2015000327-appb-100001
    其中，R为甲基、乙基、丙基中的任意一种。
  2. 一种如权利要求1所述的五环三萜类化合物制备方法，其特征在于该化合物的合成按照以下步骤进行：
    1)采用锌粉-盐酸还原体系，高选择性地脱除甘草次酸11位羰基；获得11-脱氧-甘草次酸；
    2)以卤代烷(碘甲烷、溴乙烷、溴丙烷)为酯化试剂，缚酸剂可为碳酸钾、碳酸钠，实现了30位羧基的选择性酯化，获得18β-11-脱氧-甘草次酸-30-酯；
    3)以琥珀酸酐为酯化试剂，4-二甲氨基吡啶为高效的反应促进剂，高效地在3位引入琥珀酸，得到产物18β-(3-羧丙酰基)-11-脱氧-甘草次酸-30-酯。
  3. 按照权利要求2所述的五环三萜类化合物制备方法，其特征在于所述步骤(3)18β-(3-羧丙酰基)-11-脱氧-甘草次酸-30-酯的制备方法 具体如下：
    室温下，依次将18β-11-脱氧-甘草次酸-30-酯、4-二甲氨基吡啶、琥珀酸酐加入到二氯甲烷溶液中，加完室温反应，薄板层析(TLC)监测反应；反应完全后，加水，1M HCl溶液调pH＝2-3，乙酸乙酯萃取三次，合并有机相水洗、饱和氯化钠溶液洗，无水硫酸钠干燥，蒸除溶剂，粗产物柱层析得产物18β-(3-羧丙酰基)-11-脱氧-甘草次酸-30-酯3；
    各反应试剂的用量按摩尔比为18β-11-脱氧-甘草次酸-30-酯∶琥珀酸酐∶4-二甲氨基吡啶＝1.0∶1.5-3.0∶1.5-3.0。
  4. 一种五环三萜类化合物作为人肠羧酸酯酶抑制剂的应用，其特征在于：该化合物作为一种人肠道羧酸酯酶的强效抑制剂，可强效地、选择性地抑制人羧酸酯酶亚型2的活性，其抑制人羧酸酯酶1的IC50与抑制人羧酸酯酶2的IC50比率可达1020倍。
  5. 按照权利要求4所述的五环三萜类化合物作为人肠羧酸酯酶抑制剂的应用，其特征在于可制备含五环三萜类化合物的药物，该药物可通过强效抑制人肠道羧酸酯酶提高口服酯类前药的生物利用度，进而发挥酯类前药增效剂的功效。
  6. 按照权利要求4所述的五环三萜类化合物作为人肠羧酸酯酶抑制剂的应用，其特征在于可制备含五环三萜类化合物的药物，该药物可通过强效抑制人肠道羧酸酯酶减缓脂肪酸类物质的肠道吸收，进而用于肥胖、糖尿病等代谢紊乱性疾病的辅助治疗。
  7. 按照权利要求4所述的五环三萜类化合物作为人肠羧酸酯酶抑制剂的应用，其特征在于可制备含五环三萜类化合物的药物，该药物可通过强效抑制人肠道羧酸酯酶，进而可以缓解临床多种化疗药物导致的迟发型腹泻等副作用。
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