WO2024031997A1 - 一种n-n-双-恶唑烷酮生物碱类化合物、制备方法及在医药领域的应用 - Google Patents

一种n-n-双-恶唑烷酮生物碱类化合物、制备方法及在医药领域的应用 Download PDF

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WO2024031997A1
WO2024031997A1 PCT/CN2023/083469 CN2023083469W WO2024031997A1 WO 2024031997 A1 WO2024031997 A1 WO 2024031997A1 CN 2023083469 W CN2023083469 W CN 2023083469W WO 2024031997 A1 WO2024031997 A1 WO 2024031997A1
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oxazolidinone
bis
preparation
alkaloid
compound
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PCT/CN2023/083469
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English (en)
French (fr)
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王晓
于金倩
刘伟
赵恒强
闫慧娇
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山东省分析测试中心
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the invention belongs to the technical field of oxazolidinone alkaloid compounds, and specifically relates to an N-N-bis-oxazolidinone alkaloid compound, a preparation method of the compound, a pharmaceutical composition containing the alkaloid compound and Its application in the field of medicine.
  • Alkaloids are a class of nitrogen-containing alkaline organic compounds and an important class of active ingredients in natural products. They are widely distributed in Ranunculaceae, Papaveraceae, Fanggenaceae, Solanaceae, Apocynaceae, Rutaceae, Leguminosae, etc. Among plants such as Berberidaceae and Berberidaceae, alkaloids can be divided into more than 60 categories according to their basic structures, such as organic amines, pyrrolidines, pyridines, etc. Literature survey found that alkaloids have numerous pharmacological activities, mainly including anti-tumor, anti-inflammatory, analgesic, antibacterial, antiviral, etc. This type of compounds has good development and application prospects.
  • Lonicera japonica Thunb. is a perennial semi-evergreen twining shrub of the genus Lonicera in the Caprifoliaceae family. It is a commonly used traditional Chinese medicine with a long history. Its flowers, stems and leaves can be used. Lonicera leaves are the dried leaves of Lonicera japonica, i.e. honeysuckle leaves, with thick texture, opposite leaves, oval, elliptical or oblong, and covered with downy hairs. As a by-product of honeysuckle, the yield is large. Modern research shows that honeysuckle leaves contain chemical components such as iridoids, flavonoids, organic acids, and volatile oils.
  • honeysuckle leaves have anti-pathogenic microorganisms, anti-inflammatory, antioxidant, and hypolipidemic effects.
  • the present invention studied the chemical components of Lonicera japonica leaves, and obtained N-N-bis-oxazolidinone alkaloid isomers with new structures, and the obtained compounds have significant Antioxidant and hepatoprotective activities are expected to be used in the development of chemical drugs.
  • the present invention provides an NN-bis-oxazolidinone alkaloid compound, which has a structure represented by the following formula 1 or formula 2:
  • N-N-bis-oxazolidinone alkaloid compounds described in the first aspect also include pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs of the compounds represented by Formula 1 or Formula 2; wherein, the above Pharmaceutically acceptable compounds or esters mainly include salt-forming or ester-forming modifications in order to improve the physical and chemical properties of the compound, for example, in order to improve water solubility.
  • a second aspect of the present invention provides a method for preparing the N-N-bis-oxazolidinone alkaloid compounds described in the first aspect, which is obtained by isolating the ethanol extract of Lonicera japonica leaves as raw material.
  • the separation includes the following steps:
  • the preparation method of the ethanol extract of Lonicera japonica leaves is as follows: add 30 to 50% ethanol solution to the crushed Lonicera japonica leaves and heat it to reflux. The solid-liquid ratio is 1:2.5 to 3.5. The alcohol solutions extracted by refluxing are combined, filtered and concentrated. until there is no mellow taste, and the above-mentioned honeysuckle leaf extract is obtained.
  • the heating temperature of reflux is 95-105°C; the number of reflux times and the reflux extraction time can be routinely determined according to the extraction situation of the medicinal materials. Considering the extraction efficiency, the number of reflux extractions can be three times, and the reflux time each time is 1.8 ⁇ 2.2h.
  • the macroporous resin is a weakly polar adsorption macroporous resin, and further, a styrene-type weakly polar copolymer.
  • a specific example is AB-8 macroporous resin.
  • the water elution part and silica gel are mixed with a mass ratio of 1:0.8 to 1.2.
  • the volume ratio of dichloromethane and methanol in the eluent is 15:1, 10:1, 5:1, 1:1, or 16:1, 11:1, 6: 1, 1.2:1, or 14:1, 9:1, 4:1, 0.8:1.
  • the solubility of methanol is 5%, 15%, 25%, 35%, 100%, or 4%, 13%, 23%, 33%, 96%, or 6%, 16%, 26%, 36%, 100%.
  • the volume ratio of acetonitrile to formic acid aqueous solution is 8-12:88-92, and further, it is 10:90.
  • the present invention provides a pharmaceutical composition, which includes an active dose of the N-N-bis-oxazolidinone alkaloid compound described in the first aspect.
  • Possible modes of administration of the pharmaceutical composition described in the third aspect include but are not limited to the preparation of pharmaceutical preparations, nutritional products or skin care products.
  • One of the functions of the above pharmaceutical preparations, nutritional products or skin care products is to prevent, improve or treat chronic diseases.
  • diseases related to oxidative pathways another function is to prevent, improve, repair or treat liver damage and liver damage-related diseases.
  • diseases related to the peroxidation pathway include but are not limited to tumors, diabetes and its complications, vascular sclerosis, cardiovascular and cerebrovascular diseases, kidney disease, radiation damage or immune diseases; the liver damage or liver damage-related diseases include but are not limited to drugs. Liver damage caused by alcohol, alcohol or other disease factors.
  • the pharmaceutical composition also includes a pharmaceutically acceptable carrier;
  • the pharmaceutical carrier includes but is not limited to excipients, lubricants, binders, disintegrants, solvents, solubilizers, and suspending agents. , isotonic agents, buffers, soothing agents, preservatives, antioxidants, colorants, sweeteners or other additives, etc.
  • the fourth aspect of the present invention provides applications of the N-N-bis-oxazolidinone alkaloid compounds described in the first aspect and the pharmaceutical compositions described in the third aspect in the medical field.
  • the two new N-N-bis-oxazolidinone alkaloid isomers obtained have good antioxidant and hepatoprotective activities, low toxic and side effects, and have good medicinal prospects. .
  • Figure 1 is the 1 H NMR spectrum of compound 1
  • Figure 2 is the 13 C NMR spectrum of compound 1;
  • Figure 5 is the NOESY spectrum of compound 1
  • Figure 6 is the ICD spectrum of compound 1
  • Figure 7 is the HRESIMS spectrum of compound 1
  • Figure 8 is the 1 H NMR spectrum of compound 2
  • Figure 9 is the 13 C NMR spectrum of compound 2;
  • Figure 11 is the HMBC spectrum of compound 2;
  • Figure 12 is the NOESY spectrum of compound 2
  • Figure 13 is the ICD spectrum of compound 2
  • Figure 14 is the HRESIMS spectrum of compound 2.
  • the infrared spectrum has absorption at 3361 cm -1 indicating the presence of hydroxyl functional groups, absorption at 2932 cm -1 indicating the possible presence of -CH 2 groups, and absorption at 1737 cm -1 indicating the presence of carbonyl functional groups.
  • the 13 C-NMR spectrum shows the presence of 8 carbon signals, including 2 carbonyl carbon signals ⁇ C 176.7 (C-2), ⁇ C 173.6 (C-2'), and 2 oxygenated CH signals ⁇ C 88.7 (C-5 ) and ⁇ C 68.2 (C-6), 4 CH 2 signals (including 2 oxygenated CH 2 signals ⁇ C 61.2 (C-7) and ⁇ C 57.5 (C-5'), 2 connected N CH 2 Signals ⁇ C 38.4(C-4) and ⁇ C 38.2(C-4')). It was inferred from 1 H-NMR and 13 C-NMR spectra that the compound contained structural fragments of oxazolidin-2-one and ethylene glycol, and the inference was further confirmed by two-dimensional spectra.
  • ⁇ H (H-4) is related to ⁇ C 173.6 (C-2), ⁇ C 88.7 (C-5), ⁇ C 68.2 (C-6), and ⁇ H 4.28 (H-5) is related to ⁇ C 176.7 (C-2), ⁇ C 38.4 (C-4), ⁇ C 68.2 (C-6), ⁇ C 61.2 (C-7) are related, ⁇ H 4.26 (H-6) is related to ⁇ C 88.7 ( C-5), ⁇ C 38.4 (C-4), ⁇ C 61.2 (C-7) are related, ⁇ H 3.55 (H 2 -7) is related to ⁇ C 88.7 (C-5), ⁇ C 68.2 (C-6 ), ⁇ H 2.35 (H-4') is related to ⁇ C 173.6 (C-2'), ⁇ C 88.7 (C-5'), ⁇ H 3.61 (H-5') is related to ⁇ C 173.6 (C- 2') and ⁇ C 38.2 (C-4'
  • the three-dimensional structure of compound 1 was determined by measuring circular dichroism spectra after reacting with Mo 2 (OAc) 4 reagent. From the CD spectrum after 40 minutes of reaction, positive chirality can be observed at 320 nm, indicating that the dihedral torsion angle of the diol system is clockwise, and the configuration of C-6 position is determined to be R. Further, through the related signals in the NOE spectrum: H-5 is related to H-4b, H-6 is related to H-4a, it is determined that the configuration of C-5 position is R.
  • compound 1 is determined to be (5R, 6R)-5-(1,2-dihydroxyethyl)-[3,3'-bisoxazolidine]-2,2'-dione ( (5R,6R)-5-(1,2-dihydroxyethyl)-[3,3'-bioxazolidine]-2,2'-dione).
  • the infrared spectrum has absorption at 3341 cm -1 indicating the presence of hydroxyl functional groups, absorption at 2938 cm -1 indicating the possible presence of -CH 2 groups, and absorption at 1753 cm -1 indicating the presence of carbonyl functional groups.
  • the 13 C-NMR spectrum shows the presence of 8 carbon signals, including 2 carbonyl carbon signals ⁇ C 176.7 (C-2), ⁇ C 173.6 (C-2'), and 2 oxygenated CH signals ⁇ C 88.7 (C-5 ) and ⁇ C 68.2 (C-6), 4 CH 2 signals (including 2 oxygenated CH 2 signals ⁇ C 61.2 (C-7) and ⁇ C 57.5 (C-5'), 2 connected NCH 2 signals ⁇ C 38.4(C-4) and ⁇ C 38.2(C-4')). Comparing the NMR spectra of compounds 1 and 2 shows that they are isomers. The three-dimensional structure of compound 2 was determined by measuring circular dichroism spectroscopy after reacting with Mo 2 (OAc) 4 reagent.
  • compound 2 is determined to be (5S, 6R)-5-(1,2-dihydroxyethyl)-[3,3'-bisoxazolidine]-2,2'-dione ( (5S,6R)-5-(1,2-dihydroxyethyl)-[3,3'-bioxazolidine]-2,2'-dione).
  • the HepG2 cell line was cultured using RPMI-1640 medium and 10% fetal bovine serum (FBS), and was cultured in a cell culture incubator with 5% CO 2 and 37°C until the cell coverage reached more than 90% for passage. Take a 96-well cell culture plate, add 100 ⁇ L of cell suspension at a concentration of 3 ⁇ 10 5 cells/mL to each well, and culture for 24 hours in a 37°C, 5% CO 2 incubator, then aspirate the original culture medium and discard it. Set up a blank group, AAPH model group, positive control group, and drug administration group to conduct research.
  • FBS fetal bovine serum
  • the blank group was given 100 ⁇ L serum-free medium
  • the AAPH model group was given 100 ⁇ L 100 mmol/L concentration of AAPH (serum-free medium dissolved)
  • the positive control group was given 100 ⁇ L 50 ⁇ mol/L quercetin
  • the drug group was given 100 ⁇ L 50 ⁇ mol/L Compounds 1 and 2, each sample has 3 duplicate wells.
  • the HepG2 cell line was cultured using RPMI-1640 medium and 10% fetal bovine serum (FBS), and was cultured in a cell culture incubator with 5% CO 2 and 37°C until the cell coverage reached more than 90% for passage. Take a 96-well cell culture plate, add 100 ⁇ L of cell suspension with a concentration of 2 ⁇ 10 5 cells/mL to each well, and culture for 24 hours in a 37°C, 5% CO 2 incubator, then aspirate the original culture medium and discard it. Set up a blank group, APAP model group, positive control group, and drug administration group to conduct research.
  • FBS fetal bovine serum
  • the blank group was given 100 ⁇ L of medium containing 10% fetal calf serum
  • the APAP model group was given 100 ⁇ L of 7.5 mmol/L APAP (dissolved in medium containing 10% fetal calf serum)
  • the positive control group was given 100 ⁇ L of 2.5 mg/mL magnesium isoglycyrrhizinate.
  • the treatment group was given 100 ⁇ L of 50 ⁇ mol/L compound 1 and 2 culture medium (containing 7.5mmol/L APAP), each sample had 3 duplicate wells, and after 48 h of culture, each well was added
  • Add 50 ⁇ L of 15 mg/mL MTT solution discard the cell supernatant after 4 hours, add 100 ⁇ L DMSO to each well, and shake to fully dissolve the crystals.

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Abstract

本发明涉及一种N-N-双-恶唑烷酮生物碱类化合物、制备方法及在医药领域的应用。本发明提供了从忍冬叶中分离纯化的两种新的N-N-双-恶唑烷酮生物碱同分异构体及其制备方法；所述化合物结构如下式1或式2所示。经验证，上述化合物1和2对AAPH所致肝癌细胞氧化损伤具有显著保护作用，并且化合物1和2均可不同程度抑制APAP对HepG2细胞的损伤，有望应用于医药途径的开发。

Description

一种N-N-双-恶唑烷酮生物碱类化合物、制备方法及在医药领域的应用
本发明要求于2022年8月11日提交中国专利局、申请号为202210961137.8、发明名称为“一种N-N-双-恶唑烷酮生物碱类化合物、制备方法及在医药领域的应用”的中国专利申请的优先权，其全部内容通过引用结合在本发明中。
技术领域
本发明属于恶唑烷酮生物碱类化合物技术领域，具体涉及一种N-N-双-恶唑烷酮生物碱类化合物、所述化合物的制备方法、包含所述生物碱类化合物的药物组合物及其在医药领域的应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解，而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
生物碱类化合物是一类含氮的碱性有机化合物，是天然产物中重要的一类有效成分，广泛分布于毛茛科、罂粟科、防己科、茄科、夹竹桃科、芸香科、豆科、小檗科等植物中，根据生物碱基本结构的不同可分为60多类，如有机胺类、吡咯烷类、吡啶类等。文献调研发现生物碱的药理活性众多，主要包括抗肿瘤、抗炎、镇痛、抗菌、抗病毒等，该类化合物有良好的开发应用前景。
忍冬(Lonicera japonica Thunb.)为忍冬科(Caprifoliaceae)忍冬属(Lonicera)多年生半常绿缠绕灌木，是一种具有悠久历史的常用中药，其花、茎、叶均可入。忍冬叶为忍冬科植物忍冬的干燥叶，即金银花叶，质地较厚，叶对生，呈卵形、椭圆形或长椭圆形，被覆绒毛。作为金银花的副产品，产量较大。现代研究表明忍冬叶中含有环烯醚萜类、黄酮类、有机酸、挥发油等化学成分，药理活性实验发现忍冬叶具有抗病原微生物、抗炎、抗氧化、降血脂等作用。文献报道金银花中存在生物碱类成分，而忍冬叶中生物碱类成分未见报道。
发明内容
为了充分发掘忍冬叶的药效物质基础，本发明对忍冬叶化学成分进行了研究，从中得到新型结构的N-N-双-恶唑烷酮生物碱类同分异构体，且所得化合物具有显著的抗氧化和保肝活性，有望应用于化药的开发。
基于上述技术成果，本发明提供以下技术方案：
本发明第一方面，提供一种N-N-双-恶唑烷酮生物碱类化合物，所述化合物具有如下式1或式2所示的结构：
上述第一方面所述N-N-双-恶唑烷酮生物碱类化合物，还包括式1或式2所示化合物药学上可接受的盐、酯、溶剂化物、代谢产物或前药；其中，上述化合物药学上可接受的或酯主要包括为了改善所述化合物物理、化学性质所进行的成盐或成酯修饰，例如，为了改善水溶性等。
本发明第二方面，提供第一方面所述N-N-双-恶唑烷酮生物碱类化合物的制备方法，以忍冬叶乙醇提取物为原料分离得到，所述分离包括如下步骤：
(1)采用大孔树脂对忍冬叶乙醇提取物进行梯度洗脱，洗脱液依次为水、35～45％乙醇、55～65％乙醇、75～85％乙醇和92～98％乙醇，获取水洗脱部分，加入硅胶拌样；
(2)制备硅胶柱色谱，所述柱色谱中硅胶采用二氯甲烷混匀后装柱；将上述步骤(1)中拌样后的硅胶加入柱色谱，并采用二氯甲烷-甲醇进行梯度洗脱，所述洗脱液中二氯甲烷、甲醇两试剂的洗脱梯度依次为13～17:1、8～12:1、4～6:1、0.8～1.2:1(v/v)；合并上述各部分洗脱液并浓缩依次得到Fr.1～Fr.4四个部分；
(3)将上述Fr.1部分加入甲醇溶液溶解，通过MCI中压制备色谱进行分离，以甲醇-水体系进行梯度洗脱，上述洗脱液中甲醇的浓度依次为4～6％、13～17％、23～27％、33～37％、96～100％；收集上述洗脱液通过HPLC进行检查将相似馏分进行合并，得到Fr.1-1～Fr.1-10共十个组分，取组分Fr.1-1通过半制备色谱进行分离纯化，流动相为乙腈-0.0.08～0.12％甲酸水，得到化合物1和化合物2.
上述步骤(1)中，一些优选的实施方式如下：
所述忍冬叶乙醇提取物的制备方法如下：向粉碎后的忍冬叶中加入30～50％乙醇溶液进行加热回流，固液比为1：2.5～3.5，将回流提取的醇溶液合并过滤并浓缩至无醇味，得到上述忍冬叶提取物。
上述制备方法中，回流的加热温度为95～105℃；回流次数及回流提取时间可根据药材提取情况常规确定，考虑到提取效率，所述回流提取的次数可以为三次，每次回流时间为1.8～2.2h。
所述大孔树脂采用弱极性吸附型大孔树脂，进一步的，为苯乙烯型弱极性共聚体，具体的实例如AB-8大孔树脂。
另外，上述步骤(1)中，所述水洗脱部分与硅胶以质量比1：0.8～1.2进行拌样。
上述步骤(2)中，所述洗脱液中二氯甲烷及甲醇的体积比为15:1、10:1、5:1、1:1，或为16:1、11:1、6:1、1.2:1，或14:1、9:1、4:1、0.8:1.
上述步骤(3)中，一些优选的技术方案如下:
所述洗脱液中，甲醇的溶度依次为5％、15％、25％、35％、100％，或为4％、13％、23％、33％、96％，或为6％、16％、26％、36％、100％。
所述流动相中，乙腈与甲酸水溶液的体积比为8～12：88～92，进一步的，为10：90.
本发明第三方面，提供一种药物组合物，所述组合物中，包括活性剂量的第一方面所述N-N-双-恶唑烷酮生物碱类化合物。
上述第三方面所述药物组合物可行的施用方式包括但不限于用于药物制剂、营养品或护肤品的制备，上述药物制剂、营养品或护肤品的其中一个功效在于预防、改善或治疗过氧化途径相关的疾病，另一个功效在于预防、改善、修复或治疗肝损伤及肝损伤相关疾病。其中，过氧化途径相关疾病包括但不限于肿瘤、糖尿病及其并发症、血管硬化、心脑血管疾病、肾病、辐射损伤或免疫性疾病；所述肝损伤或肝损伤相关疾病包括但不限于药物原因、酒精原因或其他疾病因素导致的肝损伤。
优选的方案中，所述药物组合物中还包括药学上可接受的载体；所述药物载体包括但不限于赋形剂、润滑剂、粘合剂、崩解剂、溶剂、增溶剂、悬浮剂、等渗剂、缓冲剂、舒缓剂、防腐剂、抗氧化剂、着色剂、甜味剂或其他添加剂等。
本发明第四方面，提供第一方面所述N-N-双-恶唑烷酮生物碱类化合物、第三方面所述药物组合物在医药领域的应用。
上述第四方面所述医药领域的应用，其应用方式包括至少包括以下几种：
(1)将上述N-N-双-恶唑烷酮生物碱类化合物、药物组合物应用于制备药物制剂、营养品、食品或护肤品；
(2)将活性剂量的上述N-N-双-恶唑烷酮生物碱类化合物、药物组合物施用于有需求的个体以实现预防、改善疾病症状或治疗疾病的作用，所述疾病为过氧化相关疾病或肝部疾病；所述施用手段为剂量可精确调控的给药方式，包括手术、口服、注射或介入等；
(3)将上述N-N-双-恶唑烷酮生物碱类化合物、药物组合物应用于疾病模型的制备，如过氧化抑制模型或肝损伤抑制模型。
以上一个或多个技术方案的有益效果是：
提供了上述从忍冬叶中分离纯化的两个新N-N-双-恶唑烷酮生物碱同分异构体的结构鉴定方法及其制备方法，以忍冬叶为原料，来源广泛，制备工艺简单，经济、安全，得率高，所得的两个新N-N-双-恶唑烷酮生物碱同分异构体具有较好的抗氧化和保肝活性，而且毒副作用低，具有良好的药用前景。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。
图1为化合物1的1H NMR图谱；
图2为化合物1的13C NMR图谱；
图3为化合物1的HMQC图谱；
图4为化合物1的HMBC图谱；
图5为化合物1的NOESY图谱；
图6为化合物1的ICD谱；
图7为化合物1的HRESIMS图谱；
图8为化合物2的1H NMR图谱；
图9为化合物2的13C NMR图谱；
图10为化合物2的HMQC图谱；
图11为化合物2的HMBC图谱；
图12为化合物2的NOESY图谱；
图13为化合物2的ICD谱；
图14为化合物2的HRESIMS图谱。
具体实施方式
应该指出，以下详细说明都是例示性的，旨在对本发明提供进一步的说明。除非另有指明，本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。
需要注意的是，这里所使用的术语仅是为了描述具体实施方式，而非意图限制根据本发明的示例性实施方式。如在这里所使用的，除非上下文另外明确指出，否则单数形式也意图包括复数形式，此外，还应当理解的是，当在本说明书中使用术语“包含”和/或“包括”时，其指明存在特征、步骤、操作、器件、组件和/或它们的组合。
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案，以下将结合具体的实施例详细说明本发明的技术方案。
实施例1
式1或式2所示结构的化合物，其制备方法具体步骤如下：
(1)取忍冬叶药材10kg，粉碎，40％乙醇加热回流提取三次，固液比为1:3，每次2h，将提取液合并过滤，浓缩至无醇味，得忍冬叶乙醇提取物1.2kg。
(2)采用AB-8大孔树脂柱色谱对忍冬叶乙醇提取物进行分离，依次采用水、40％乙醇、60％乙醇、80％乙醇和95％乙醇进行梯度洗脱，每个梯度洗脱体积为30L，合并各部分洗脱液， 分别浓缩后得水、40％、60％、80％和95％乙醇洗脱部分。
(3)取水部位洗脱样品(1kg)与硅胶1:1拌匀备用，采用硅胶柱色谱进行分离，5kg硅胶填料用15L二氯甲烷混匀后装柱，密封静置4h，用1.5L二氯甲烷将水部位硅胶拌样样品匀后的上样，静置1h，依次采用二氯甲烷-甲醇(15:1、10:1、5:1、1:1,v/v)进行洗脱，每个梯度洗脱体积为20L，合并各部分洗脱液，分别浓缩后得4个部位(Fr.1～4)。
(4)取Fr.1(80g)用甲醇水溶解成50mL溶液，采用MCI中压制备色谱(柱体积1500mL)进行分离，以甲醇-水体系(5％、15％、25％、35％、100％)进行梯度洗脱，每1500mL洗脱液为一馏分，每个梯度洗脱体积为4500mL，用HPLC对各馏分进行检测，将成分峰组成类似的馏分进行合并，共得到10段(Fr.1-1～Fr.1-10)，取Fr.1-1(2.5g)采用岛津半制备色谱进行分离纯化，流动相为乙腈-0.1％甲酸水(10:90，v/v，288nm)，得到化合物1(20mg)和化合物2(32mg)。
结构鉴定：对分离得到的单体成分应用Bruker Impact II质谱仪和Burker 400MHz核磁共振波谱仪分别进行HR-ESI-MS，NMR谱的测定，所得核磁数据见表1，鉴定该两个新N-N-双-恶唑烷酮生物碱同分异构体的结构。
式1所示化合物的结构认定
(5R，6R)-5-(1,2-二羟基乙基)-[3,3'-双恶唑烷]-2,2'-二酮((5R,6R)-5-(1,2-dihydroxyethyl)-[3,3'-bioxazolidine]-2,2'-dione)(1)：黄色油状物；HR-ESI-MS:m/z231.0558[M-H]-(理论值：231.0612，C8H11N2O6)，确定其分子式为：C8H12N2O6，不饱和度为4。红外光谱在3361cm-1处有吸收表明存在羟基官能团，2932cm-1处有吸收表明可能存在-CH2基团，1737cm-1处的吸收表明存在羰基官能团。
1H-NMR谱显示4组连氧氢信号δH 4.28(1H,m,H-5)、δH 4.26(1H,m,H-6)、δH3.55(2H,dd,J＝3.6,6.4Hz,H-7)、δH3.61(2H,t,J＝6.4Hz,H-5')，以及2组连N氢信号δH 2.81(1H,dd,J＝17.6,6.4Hz,H-4a)、δH 2.23(1H,dd,J＝17.6,2.0Hz,H-4b)、δH 2.35(2H,t,J＝6.4Hz,H-4')。13C-NMR谱显示存在8个碳信号，包括2个羰基碳信号δC 176.7(C-2)、δC 173.6(C-2')，2个连氧CH信号δC 88.7(C-5)和δC68.2(C-6)，4个CH2信号(包括2个连氧CH2信号δC61.2(C-7)和δC57.5(C-5'),2个连N CH2信号δC38.4(C-4)和δC38.2(C-4'))。通过1H-NMR和13C-NMR谱推断该化合物含有oxazolidin-2-one和乙二醇的结构片段，并通过二维谱图进一步确定该推断。在HMBC谱中，δH(H-4)与δC 173.6(C-2)、δC 88.7(C-5)、δC 68.2(C-6)相关，δH 4.28(H-5)与δC 176.7(C-2)、δC 38.4(C-4)、δC 68.2(C-6)、δC 61.2(C-7)相关，δH 4.26(H-6)与δC 88.7(C-5)、δC 38.4(C-4)、δC 61.2(C-7)相关，δH 3.55(H2-7)与δC 88.7(C-5)、δC 68.2(C-6)相关，δH 2.35(H-4')与δC 173.6(C-2')、δC 88.7(C-5')相关，δH 3.61(H-5')与δC 173.6(C-2')、δC 38.2(C-4')相关，进一步确定化合物21含有1个 oxazolidin-2-one结构和1个5-(1,2-dihydroxyethyl)oxazolidin-2-one结构。根据化合物2的分子式确定oxazolidin-2-one和5-(1,2-dihydroxyethyl)oxazolidin-2-one结构片段通过N-N相连，最终确定化合物1的平面结构为5-(1,2-dihydroxyethyl)-[3,3'-bioxazolidine]-2,2'-dione。
化合物1的立体结构通过与Mo2(OAc)4试剂反应后测定圆二色谱确定。通过反应40min后的CD谱可观察到320nm处为正手征性，表明二醇体系的二面角扭角为顺时针，进而确定C-6位构型为R。进一步通过NOE谱中相关信号：H-5与H-4b相关，H-6与H-4a相关，确定C-5位构型为R。综上所述，化合物1的结构确定为(5R，6R)-5-(1,2-二羟基乙基)-[3,3'-双恶唑烷]-2,2'-二酮((5R,6R)-5-(1,2-dihydroxyethyl)-[3,3'-bioxazolidine]-2,2'-dione)。
式2所示化合物的结构认定
(5S，6R)-5-(1,2-二羟基乙基)-[3,3'-双恶唑烷]-2,2'-二酮((5S,6R)-5-(1,2-dihydroxyethyl)-[3,3'-bioxazolidine]-2,2'-dione)(2)：黄色油状物；HR-ESI-MS:m/z231.0557[M-H]-(理论值：231.0612，C8H11N2O6)，确定其分子式为：C8H12N2O6，不饱和度为4。红外光谱在3341cm-1处有吸收表明存在羟基官能团，2938cm-1处有吸收表明可能存在-CH2基团，1753cm-1处的吸收表明存在羰基官能团。
1H-NMR谱显示4组连氧氢信号δH 4.29(1H,m,H-5)、δH 4.29(1H,m,H-6)、δH 3.53(2H,dd,J＝3.6,6.4Hz,H-7)、δH 3.62(2H,t,J＝6.4Hz H-5')，以及2组连N氢信号δH 2.80(1H,dd,J＝17.6,6.4Hz,H-4a)、2.23(1H,dd,J＝17.6,2.0Hz,H-4b)、δH 2.35(1H,t,J＝6.4Hz,H-4')。13C-NMR谱显示存在8个碳信号，包括2个羰基碳信号δC176.7(C-2)、δC173.6(C-2')，2个连氧CH信号δC88.7(C-5)和δC68.2(C-6)，4个CH2信号(包括2个连氧CH2信号δC61.2(C-7)和δC57.5(C-5'),2个连NCH2信号δC38.4(C-4)和δC38.2(C-4'))。通过比较化合物1和2的核磁谱图表明两者为同分异构体。化合物2的立体结构通过与Mo2(OAc)4试剂反应后测定圆二色谱确定。通过反应40min后的CD谱可观察到320nm处为正手征性，表明二醇体系的二面角扭角为顺时针，进而确定C-6位相对构型为R。进一步通过NOE谱中相关信号：H-5与H-4a相关，H-6与H-4b相关，确定C-5位构型为S。综上所述，化合物2的结构确定为(5S，6R)-5-(1,2-二羟基乙基)-[3,3'-双恶唑烷]-2,2'-二酮((5S,6R)-5-(1,2-dihydroxyethyl)-[3,3'-bioxazolidine]-2,2'-dione)。
表1化合物1和2的1H NMR(400MHz,DMSO-d6)和13C NMR数据(100MHz,DMSO-d6)

药效活性验证
一、式1、式2所示化合物的抗氧化和保肝活性研究
1、偶氮二异丁脒盐酸盐(AAPH)诱导肝细胞氧化应激损伤模型的建立及抗氧化活性筛选
HepG2细胞株采用RPMI-1640培养基、10％胎牛血清(FBS)进行培养，置于5％CO2，37℃的细胞培养箱中培养至细胞覆盖率达90％以上时用于传代。取96孔细胞培养板，每孔加入浓度为3×105个/mL的细胞悬液100μL，在37℃、5％CO2培养箱中贴壁培养24h后，吸出原培养液弃去。设置空白组、AAPH模型组、阳性对照组、给药组，进行研究。空白组加100μL无血清的培养基，AAPH模型组给予100μL 100mmol/L浓度的AAPH(无血清的培养基溶解)，阳性对照组给予100μL 50μmol/L槲皮素，给药组给予100μL 50μmol/L化合物1和2，每个样品3个复孔，培养24h后，在不吸出原来培养基的条件下，空白组加入100μL新鲜无血清培养基，模型组、阳性对照组和给药组各加入100μL的100mmol/L AAPH(无血清培养基)，继续培养4h后。每孔加入15mg/mL的MTT溶液50μL，4h后弃去细胞上清液，每孔加入100μL DMSO，振荡，使结晶物充分溶解。多功能酶标仪490nm处测量各孔的吸光度(A)值，试验重复进行3次，计算细胞存活率。
2、对乙酰氨基酚(APAP)诱导HepG2细胞肝损伤模型的建立及保肝活性筛选
HepG2细胞株采用RPMI-1640培养基、10％胎牛血清(FBS)进行培养，置于5％CO2，37℃的细胞培养箱中培养至细胞覆盖率达90％以上时用于传代。取96孔细胞培养板，每孔加入浓度为2×105个/mL的细胞悬液100μL，在37℃、5％CO2培养箱中贴壁培养24h后，吸出原培养液弃去。设置空白组、APAP模型组、阳性对照组、给药组，进行研究。空白组加100μL含10％胎牛血清的培养基，APAP模型组给予100μL 7.5mmol/L浓度的APAP(含10％胎牛血清的培养基溶解)，阳性对照组给予100μL 2.5mg/mL异甘草酸镁的培养基(含7.5mmol/L APAP)，给药组给予100μL 50μmol/L化合物1和2的培养基(含7.5mmol/L APAP)，每个样品3个复孔，培养48h后，每孔加入15mg/mL的MTT溶液50μL，4h后弃去细胞上清液，每孔加入100μL DMSO，振荡，使结晶物充分溶解。多功能酶标仪490nm处测量各孔的吸光度(A)值，试验 重复进行3次，计算细胞存活率。
二、实验结果
1、式1、式2所示化合物的抗氧化活性筛选结果
表2抗氧化抑制结果
2、式1、式2所示化合物的保肝活性筛选结果
表3抗氧化抑制结果
结论：从图中数据可以看知，化合物1和2对AAPH所致肝癌细胞氧化损伤具有显著保护作用，其中化合物1的抗氧化活性优于阳性对照槲皮素；采用对乙酰氨基酚(APAP)处理HepG2细胞建立体外药物性肝损伤模型，对化合物的保肝能力进行评价，化合物1和2均可不同程度抑制APAP对HepG2细胞的损伤，其中化合物2的保肝活性优于化合物1，均略低于阳性对照药。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种N-N-双-恶唑烷酮生物碱类化合物，其特征在于，所述化合物具有如下式1或式2所示的结构：
  2. 如权利要求1所述N-N-双-恶唑烷酮生物碱类化合物，其特征在于，所述N-N-双-恶唑烷酮生物碱类化合物，还包括式1或式2所示化合物药学上可接受的盐、酯、溶剂化物、代谢产物或前药。
  3. 权利要求1或2所述N-N-双-恶唑烷酮生物碱类化合物的制备方法，其特征在于，以忍冬叶乙醇提取物为原料分离得到，所述分离包括如下步骤：
    (1)采用大孔树脂对忍冬叶乙醇提取物进行梯度洗脱，洗脱液依次为水、35～45％乙醇、55～65％乙醇、75～85％乙醇和92～98％乙醇，获取水洗脱部分，加入硅胶拌样；
    (2)制备硅胶柱色谱，所述柱色谱中硅胶采用二氯甲烷混匀后装柱；将上述步骤(1)中拌样后的硅胶加入柱色谱，并采用二氯甲烷-甲醇进行梯度洗脱，所述洗脱液中二氯甲烷、甲醇两试剂的洗脱梯度依次为13～17:1、8～12:1、4～6:1、0.8～1.2:1；合并上述各部分洗脱液并浓缩依次得到Fr.1～Fr.4四个部分；
    (3)将上述Fr.1部分加入甲醇溶液溶解，通过MCI中压制备色谱进行分离，以甲醇-水体系进行梯度洗脱，上述洗脱液中甲醇的浓度依次为4～6％、13～17％、23～27％、33～37％、96～100％；收集上述洗脱液通过HPLC进行检查将相似馏分进行合并，得到Fr.1-1～Fr.1-10共十个组分，取组分Fr.1-1通过半制备色谱进行分离纯化，流动相为乙腈-0.0.08～0.12％甲酸水，得到化合物1和化合物2。
  4. 权利要求3所述N-N-双-恶唑烷酮生物碱类化合物的制备方法，其特征在于，步骤(1)中，所述忍冬叶乙醇提取物的制备方法如下：向粉碎后的忍冬叶中加入30～50％乙醇溶液进行加热回流，固液比为1：2.5～3.5，将回流提取的醇溶液合并过滤并浓缩至无醇味，得到上述忍冬叶提取物；
    优选的，上述制备方法中，回流的加热温度为95～105℃；所述回流提取的次数为三次，每次回流时间为1.8～2.2h；
    或，步骤(1)中，所述大孔树脂采用弱极性吸附型大孔树脂；进一步的，为苯乙烯型弱极性共聚体，具体的实例如AB-8大孔树脂；
    或，步骤(2)中，所述水洗脱部分与硅胶以质量比1：0.8～1.2进行拌样。
  5. 权利要求3所述N-N-双-恶唑烷酮生物碱类化合物的制备方法，其特征在于，步骤(2)中，所述洗脱液中二氯甲烷及甲醇的体积比为15:1、10:1、5:1、1:1，或为16:1、11:1、6:1、1.2:1，或14:1、9:1、4:1、0.8:1。
  6. 权利要求3所述N-N-双-恶唑烷酮生物碱类化合物的制备方法，其特征在于，步骤(3)所述洗脱液中，甲醇的溶度依次为5％、15％、25％、35％、100％，或为4％、13％、23％、33％、96％，或为6％、16％、26％、36％、100％；
    或，乙腈与甲酸水溶液的体积比为8～12：88～92，进一步的，为10：90。
  7. 一种药物组合物，其特征在于，所述组合物中，包括活性剂量的权利要求1或2所述N-N-双-恶唑烷酮生物碱类化合物。
  8. 如权利要求7所述药物组合物，其特征在于，所述药物组合物的施用方式包括但不限于用于药物制剂、营养品或护肤品的制备；所述药物制剂、营养品或护肤品的其中一个功效在于预防、改善或治疗过氧化途径相关的疾病，或，所述功效在于预防、改善、修复或治疗肝损伤及肝损伤相关疾病；
    优选的，所述药物组合物中还包括药学上可接受的载体，包括但不限于赋形剂、润滑剂、粘合剂、崩解剂、溶剂、增溶剂、悬浮剂、等渗剂、缓冲剂、舒缓剂、防腐剂、抗氧化剂、着色剂、甜味剂或其他添加剂。
  9. 权利要求1或2所述N-N-双-恶唑烷酮生物碱类化合物、第三方面所述药物组合物在医药领域的应用。
  10. 权利要求9所述N-N-双-恶唑烷酮生物碱类化合物、药物组合物在医药领域的应用，其特征在于，其应用方式包括至少包括以下几种：
    (1)将上述N-N-双-恶唑烷酮生物碱类化合物、药物组合物应用于制备药物制剂、营养品、食品或护肤品；
    (2)将活性剂量的上述N-N-双-恶唑烷酮生物碱类化合物、药物组合物施用于有需求的个体以实现预防、改善疾病症状或治疗疾病的作用，所述疾病为过氧化相关疾病或肝部疾病；所述施用手段为剂量可精确调控的给药方式，包括手术、口服、注射或介入；
    (3)将上述N-N-双-恶唑烷酮生物碱类化合物、药物组合物应用于疾病模型的制备，如过氧化抑制模型或肝损伤抑制模型。
PCT/CN2023/083469 2022-08-11 2023-03-23 一种n-n-双-恶唑烷酮生物碱类化合物、制备方法及在医药领域的应用 WO2024031997A1 (zh)

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