CN115215881B - 唐古特瑞香中制备的愈创木烷型倍半萜类化合物及其制备方法和应用 - Google Patents
唐古特瑞香中制备的愈创木烷型倍半萜类化合物及其制备方法和应用 Download PDFInfo
- Publication number
- CN115215881B CN115215881B CN202210904653.7A CN202210904653A CN115215881B CN 115215881 B CN115215881 B CN 115215881B CN 202210904653 A CN202210904653 A CN 202210904653A CN 115215881 B CN115215881 B CN 115215881B
- Authority
- CN
- China
- Prior art keywords
- guaiane
- daphne
- thangustifolia
- tanguticum
- prepared
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- -1 Guaiane sesquiterpene compound Chemical class 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 239000003814 drug Substances 0.000 claims abstract description 12
- 206010061218 Inflammation Diseases 0.000 claims abstract description 9
- 230000004054 inflammatory process Effects 0.000 claims abstract description 9
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 17
- 238000004458 analytical method Methods 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000000284 extract Substances 0.000 claims description 9
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 6
- 238000010828 elution Methods 0.000 claims description 6
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 6
- 230000003959 neuroinflammation Effects 0.000 claims description 6
- 238000010898 silica gel chromatography Methods 0.000 claims description 6
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 claims description 5
- 238000004007 reversed phase HPLC Methods 0.000 claims description 5
- 101100313763 Arabidopsis thaliana TIM22-2 gene Proteins 0.000 claims description 3
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 3
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 150000000176 guaiane derivatives Chemical class 0.000 claims 4
- 229930004725 sesquiterpene Natural products 0.000 claims 3
- 238000010992 reflux Methods 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 6
- 238000011161 development Methods 0.000 abstract description 2
- 230000003287 optical effect Effects 0.000 abstract description 2
- MCNAURNYDFSEML-UHFFFAOYSA-N Guaiane Natural products CC1CCC(C(C)=C)C(O)C2=C(C)C(=O)CC12 MCNAURNYDFSEML-UHFFFAOYSA-N 0.000 abstract 2
- QAQCPAHQVOKALN-RMEBNNNOSA-N guaiane Chemical compound C1[C@H](C(C)C)CC[C@H](C)[C@@H]2CC[C@H](C)[C@@H]21 QAQCPAHQVOKALN-RMEBNNNOSA-N 0.000 abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 31
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 24
- 241000934856 Daphne Species 0.000 description 16
- 238000001211 electron capture detection Methods 0.000 description 13
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 13
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 12
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 12
- 238000003929 heteronuclear multiple quantum coherence Methods 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- 239000013078 crystal Substances 0.000 description 8
- 230000004770 neurodegeneration Effects 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 4
- 208000015122 neurodegenerative disease Diseases 0.000 description 4
- 241000744675 Daphne tangutica Species 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 230000003215 anti-neuroinflammatory effect Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- 238000005084 2D-nuclear magnetic resonance Methods 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010007953 Central nervous system lymphoma Diseases 0.000 description 1
- FDJCVHVKXFIEPJ-JCNFZFLDSA-N Delapril hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N(CC(O)=O)C1CC2=CC=CC=C2C1)CC1=CC=CC=C1 FDJCVHVKXFIEPJ-JCNFZFLDSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000003501 co-culture Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 238000002212 electronic circular dichroism spectrum Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000002025 microglial effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 208000016800 primary central nervous system lymphoma Diseases 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/83—Thymelaeaceae (Mezereum family), e.g. leatherwood or false ohelo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/743—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups having unsaturation outside the rings, e.g. humulones, lupulones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
- C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
- C07C2602/30—Azulenes; Hydrogenated azulenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
- C07C2603/78—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing seven-membered rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Medical Informatics (AREA)
- Neurosurgery (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Botany (AREA)
- Emergency Medicine (AREA)
- Biotechnology (AREA)
- Alternative & Traditional Medicine (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
唐古特瑞香中制备的愈创木烷型倍半萜类化合物及其制备方法和应用，属于医药技术领域，具体涉及如下所示，从植物唐古特瑞香中制备得到的新的愈创木烷型倍半萜类化合物及这类化合物在抗炎方面的应用。进一步的，所述愈创木烷型倍半萜类化合物或包含上述化合物的药物组合物在制备抑制LPS诱导的BV‑2细胞炎症药物中的应用。本发明的优点在于，所述化合物均为新化合物，结构新颖，且均为立体构型确定的光学纯化合物，同时其抗炎活性强，具有进一步开发的价值。
Description
技术领域
本发明属于医药技术领域，具体涉及植物唐古特瑞香中制备得到的新的愈创木烷型倍半萜类化合物及这类化合物在抗炎方面的应用。
背景技术
唐古特瑞香：唐古特瑞香[Daphne tangutica Maxim.]，为瑞香科瑞香属的常绿灌木。唐古特瑞香主要分布于山西、陕西、甘肃、青海、四川、贵州、云南、西藏。生于海拔1000-3800米的润湿林中。1977年版《中国药典》及《陕西中药志》记载黄瑞香、唐古特瑞香和凹叶瑞香可用作祖师麻入药。目前市售制剂有注射液、片剂、贴剂等，临床上主要用于治疗跌打损伤、风湿性关节炎及止痛等。
炎症(inflammation)：机体对于刺激的一种防御反应，表现为红、肿、热、痛和功能障碍。炎症分为两类，可以是感染引起的感染性炎症，也可以不是由于感染引起的非感染性炎症。例如对人体自身组织的攻击、发生在透明组织的炎症等等。神经退行性疾病(Neurodegenerative diseases)与炎症：神经退行性疾病是由于大脑和脊髓的神经元丧失而引起的一类不可逆转的神经系统疾病，特征表现为发作迟缓和选择性神经元的功能障碍。大脑中的慢性炎症环境是阿尔茨海默病、帕金森病等神经退行性疾病的标志。
发明内容
本发明的目的在于提供一种从唐古特瑞香中制备得到的愈创木烷型倍半萜类化合物，以及其在抑制神经炎症方面的应用。
本发明所述从瑞香科瑞香属植物唐古特瑞香[Daphne tangutica Maxim.]中分离得到的新愈创木烷型倍半萜类化合物为如下所示结构中任一种：
本发明的所述愈创木烷型倍半萜类化合物的制备技术方案包括如下步骤：
取干燥的唐古特瑞香全草以乙醇提取，合并提取液浓缩得浸膏，浸膏采用乙酸乙酯萃取并将所得组分经硅胶柱色谱，以二氯甲烷-甲醇系统100:0-0:100进行等度梯度洗脱，共收集到四个组分Fr.A-Fr.D；
流份Fr.B经HP20柱色谱，以乙醇-水系统0:100-90:10进行梯度洗脱，得三个组分Fr.B1-Fr.B3；
利用ODS柱色谱将组分Fr.B1-Fr.B3以乙醇-水系统10:90-90:10进行梯度洗脱，得5个组分Fr.R1-Fr.R5；
所得组分Fr.R3经硅胶柱色谱以石油醚-乙酸乙酯系统100:1-10:1在TLC分析的基础上得到15个亚组分Fr.R3-1-Fr.R3-15；
在制备性反相高效液相色谱上使用乙腈-水的流动相来分离Fr.R3-2、Fr.R3-5和Fr.R3-7得到化合物1-12。
上述制备方法中，采用的唐古特瑞香为瑞香科瑞香属植物唐古特瑞香[Daphanetangutica Maxim]。
干燥的唐古特瑞香全草以70％-80％工业乙醇回流提取2-3次，每次2-3h。
在制备性反相高效液相色谱上以55:45-35:65的乙腈-水流动相分离Fr.R3-2、Fr.R3-5和Fr.R3-7。
所得化合物经过系统结构鉴定结果如下：
利用高分辨质谱，一维NMR、二维NMR、计算ECD及X单晶衍射方法对化合物1-12的结构鉴定，相应谱图如图1-15所示。
Tanguticatin A(1):白色块状结晶；+88.5(c 0.20,MeOH)；HRESIMS(m/z287.1249[M+Na]+,calcd 287.1254)确定分子式为C15H20O4；通过分析tanguticatin A的1HNMR、13C NMR、HMQC谱、HMBC谱、计算ECD及X射线单晶衍射，确定了tanguticatin A的结构，为一个新化合物。
Tanguticatin B(2):无色油状物；-90.5(c 0.20,MeOH)；HRESIMS(m/z235.1689[M+H]+,calcd for C15H23O2,235.1693)确定分子式为C15H23O2；通过分析tanguticatin B的1H NMR、13C NMR、HMQC谱、HMBC谱及计算ECD，确定了tanguticatin B的结构，为一个新化合物。
Tanguticatin C(3):无色油状物；+90.0(c 0.20,MeOH)；HRESIMS(m/z235.1638[M+H]+,calcd for C15H23O2,235.1693)确定分子式为C15H23O2；通过分析tanguticatin C的1H NMR、13C NMR、HMQC谱、HMBC谱及计算ECD，确定了tanguticatin C的结构，为一个新化合物。
Tanguticatin D(4):无色油状物；-88.5(c 0.20,MeOH)；HRESIMS(m/z255.1361[M+Na]+,calcd for C15H20NaO2,255.1356)确定分子式为C15H20O2；通过分析tanguticatin D的1H NMR、13C NMR、HMQC谱、HMBC谱及计算ECD，确定了tanguticatin D的结构，为一个新化合物。
Tanguticatin E(5):无色油状物；+30(c 0.20,MeOH)；HRESIMS(m/z287.1619[M+Na]+,calcd for C16H24NaO3,287.1618)确定分子式为C16H24O3；通过分析tanguticatin E的1H NMR、13C NMR、HMQC谱、HMBC谱及计算ECD，确定了tanguticatin E的结构，为一个新化合物。
Tanguticatin F(6):无色油状物；-28(c 0.20,MeOH)；HRESIMS(m/z271.1213[M+Na]+,calcd for C15H20NaO3,271.1305)确定分子式为C15H20O3；通过分析tanguticatin F的1H NMR、13C NMR、HMQC谱、HMBC谱及计算ECD，确定了tanguticatin F的结构，为一个新化合物。
Tanguticatin G(7):无色油状物；-37.0(c 0.20,MeOH)；HRESIMS(m/z277.1399[M+H]+,calcd for C16H21O4,277.1434)确定分子式为C16H20O4；通过分析tanguticatin G的1H NMR、13C NMR、HMQC谱、HMBC谱及计算ECD，确定了tanguticatin G的结构，为一个新化合物。
Tanguticatin H(8):无色块晶；+39.2(c 0.10,MeOH)；HRESIMS(299.1259[M+Na]+,calcd for C16H20NaO4,299.1254)确定分子式为C16H20O4；通过分析tanguticatin H的1H NMR、13C NMR、HMQC谱、HMBC谱、计算ECD及X射线单晶衍射，确定了tanguticatin H的结构，为一个新化合物。
Tanguticatin I(9):无色块晶；-39.8(c 0.10,MeOH)；HRESIMS(m/z235.1687[M+H]+,calcd for C15H23O2,235.1693确定分子式为C15H22O2；通过分析tanguticatin I的1H NMR、13C NMR、HMQC谱、HMBC谱、计算ECD及X射线单晶衍射，确定了tanguticatin I的结构，为一个新化合物。
Tanguticatin J(10):无色油状；-83.0(c 0.30,MeOH)；HRESIMS(m/z287.1615[M+Na]+,calcd for C15H20NaO2,287.1618)确定分子式为C16H24O3；通过分析tanguticatin J的1H NMR、13C NMR、HMQC谱、HMBC谱、计算ECD，确定了tanguticatin J的结构，为一个新化合物。
Tanguticatin K(11):无色油状；+85.0(c 0.30,MeOH)；HRESIMS(m/z255.1361[M+Na]+,calcd for C15H20NaO2,255.1356)确定分子式为C15H20O2；通过分析tanguticatin K的1H NMR、13C NMR、HMQC谱、HMBC谱、计算ECD，确定了tanguticatin K的结构，为一个新化合物。
Tanguticatin L(12):无色油状；-19.7(c 0.10,MeOH)；HRESIMS(m/z233.1510[M+H]+,calcd for C15H21O2,233.1536)确定分子式为C15H20O2；通过分析tanguticatin L的1H NMR、13C NMR、HMQC谱、HMBC谱、计算ECD，确定了tanguticatin L的结构，为一个新化合物。
表1化合物1-3的1H NMR数据(600MHz,in CDCl3,δin ppm,J in Hz)
表2化合物4-6的1H NMR数据(600MHz,in CDCl3,δin ppm,J in Hz)
表3化合物7-9的1H NMR数据(600MHz,in CDCl3,δin ppm,J in Hz)
表4化合物10-12的1H NMR数据(600MHz,in CDCl3,δin ppm,J in Hz)
表5化合物1-6的13C NMR数据(150MHz,in CDCl3,δin ppm,J in Hz)
表6化合物1-6的13C NMR数据(150MHz,in CDCl3,δin ppm,J in Hz)
对本发明所述12个新化合物的抗神经炎症活性进行了考察，其中化合物1-12均展现良好的抗炎活性，因此本发明所述的新愈创木烷型倍半萜类化合物具有进一步开发预防和治疗神经炎症药物的前景。
一种药物组合物，包含上述从唐古特瑞香中制备得到的愈创木烷型倍半萜类化合物或其在药学上可接受的盐和药学上可接受的载体或赋形剂。
本发明还提供所述从唐古特瑞香中制备得到的愈创木烷型倍半萜类化合物或包含上述化合物的药物组合物在制备抑制神经炎症药物中的应用。
本发明还提供所述从唐古特瑞香中制备得到的愈创木烷型倍半萜类化合物或包含上述化合物的药物组合物在制备抑制LPS诱导的BV-2细胞炎症药物中的应用。
一种唐古特瑞香提取物，包含所述愈创木烷型倍半萜类化合物，应用于制备抑制神经炎症药物中。
本发明的优点在于，所述化合物均为新化合物，结构新颖，且均为立体构型确定的光学纯化合物，同时其抗炎活性强，具有进一步开发的价值。
附图说明
图1化合物1的HRESIMS、1H、13C-NMR和HMBC谱；
图2化合物2的HRESIMS、1H、13C-NMR和HMBC谱；
图3化合物3的HRESIMS、1H、13C-NMR和HMBC谱；
图4化合物4的HRESIMS、1H、13C-NMR和HMBC谱；
图5化合物5的HRESIMS、1H、13C-NMR和HMBC谱；
图6化合物6的HRESIMS、1H、13C-NMR和HMBC谱；
图7化合物7的HRESIMS、1H、13C-NMR和HMBC谱；
图8化合物8的HRESIMS、1H、13C-NMR和HMBC谱；
图9化合物9的HRESIMS、1H、13C-NMR和HMBC谱；
图10化合物10的HRESIMS、1H、13C-NMR和HMBC谱；
图11化合物11的HRESIMS、1H、13C-NMR和HMBC谱；
图12化合物12的HRESIMS、1H、13C-NMR和HMBC谱；
图13化合物1、8、9的X单晶数据图；
图14化合物1-12的HMBC相关；
图15化合物1-12的实测与计算ECD谱图；
图16化合物1-12在体外抑制LPS诱导的小鼠小胶质细胞BV-2细胞炎症作用。对照组相比于模型组的NO产物浓度###P<0.001；实验组相比于模型组的细胞存活百分比*P<0.1,**P<0.05,***P<0.001。
具体实施方式
下面所列实施例有助于本领域技术人员更好地理解本发明，但不以任何方式限制本发明。
实施例1
化合物1-12的制备方法，具体操作如下：
取干燥的唐古特瑞香全草以80％工业乙醇回流提取，2次，每次2h，合并提取液浓缩得浸膏，浸膏采用乙酸乙酯萃取并将所得组分经硅胶柱色谱，以二氯甲烷-甲醇系统100:0,90:10,80:20,70:30,60:40,50:50,40:60,30:70,20:80,10:90,0:100(v/v)进行等度梯度洗脱，共收集到四个组分Fr.A-Fr.D；
流份Fr.B经HP20柱色谱，以乙醇-水系统0:100,10:90,20:80,30:70,40:60,50:50,60:40,70:30,80:20,90:10(v/v)进行梯度洗脱，得三个组分Fr.B1-Fr.B3；
利用ODS柱色谱将组分Fr.B1-Fr.B3以乙醇-水系统10:90,20:80,30:70,40:60,50:50,60:40,70:30,80:20,90:10(v/v)进行梯度洗脱，得5个组分Fr.R1-Fr.R5；
所得组分Fr.R3经硅胶柱色谱以石油醚-乙酸乙酯系统100:1,80:1,60:1,40:1,20:1,10:1(v/v)在TLC分析的基础上得到15个亚组分Fr.R3-1-Fr.R3-15；
在制备性反相高效液相色谱上使用乙腈-水55:45-35:65的流动相来分离Fr.R3-2、Fr.R3-5和Fr.R3-7得到化合物1-12(化合物1-4采用55:45，化合物2-8采用45:55，化合物9-12采用35:65)。化合物1-12的量分别为11.2mg,3.2mg,5.6mg,4.3mg,3.1mg,1.8mg,10.0mg,18.7mg,21.2mg,30.0mg,1.5mg,1.6mg。
实施例2
化合物1-12的抗神经炎症的活性考察：
用Griess法检测LPS诱导的BV-2细胞内的NO产物含量。BV-2细胞系置于含10％胎牛血清以及1％双抗的DMEM培养基内，37℃，5％CO2的培养箱中进行培养。稳定传代培养至对数生长的细胞用于实验。取对数生长期的BV-2小胶质瘤细胞以5×103个/孔的密度接种于96孔板中，待细胞生长至60％时加入10μM的受试化合物，共培养1h后观察细胞生长状态良好，加入10μg/mL的LPS，24h后取上清液用NO试剂盒检测NO浓度。利用紫外分光光度计(Thermo Scientific Multiskan MK3，上海，中国)在540nm处测定吸光度。结果显示，多数化合物表现出比阳性药地塞米松更好的抗炎作用，如图16所示。
Claims (9)
1.唐古特瑞香中制备的愈创木烷型倍半萜类化合物，其特征在于，其为如下所示结构中任一种：
2.一种权利要求1所述唐古特瑞香中制备的愈创木烷型倍半萜类化合物的制备方法，其特征在于，包括如下步骤：
取干燥的唐古特瑞香全草以乙醇提取，合并提取液浓缩得浸膏，浸膏采用乙酸乙酯萃取并将所得组分经硅胶柱色谱，以二氯甲烷-甲醇系统100:0-0:100进行等度梯度洗脱，共收集到四个组分Fr.A-Fr.D；
流份Fr.B经HP20柱色谱，以乙醇-水系统0:100-90:10进行梯度洗脱，得三个组分Fr.B1-Fr.B3；
利用ODS柱色谱将组分Fr.B1-Fr.B3以乙醇-水系统10:90-90:10进行梯度洗脱，得5个组分Fr.R1-Fr.R5；
所得组分Fr.R3经硅胶柱色谱以石油醚-乙酸乙酯系统100:1-10:1在TLC分析的基础上得到15个亚组分Fr.R3-1-Fr.R3-15；
在制备性反相高效液相色谱上使用乙腈-水的流动相来分离Fr.R3-2、Fr.R3-5和Fr.R3-7得到化合物1-8、10、12。
3.根据权利要求2所述唐古特瑞香中制备的愈创木烷型倍半萜类化合物的制备方法，其特征在于，采用的唐古特瑞香为瑞香科瑞香属植物唐古特瑞香[Daphane tanguticaMaxim]。
4.根据权利要求2所述唐古特瑞香中制备的愈创木烷型倍半萜类化合物的制备方法，其特征在于，干燥的唐古特瑞香全草以70％-80％工业乙醇回流提取2-3次，每次2-3h。
5.根据权利要求2所述唐古特瑞香中制备的愈创木烷型倍半萜类化合物的制备方法，其特征在于，在制备性反相高效液相色谱上以55:45-35:65的乙腈-水流动相分离Fr.R3-2、Fr.R3-5和Fr.R3-7。
6.一种药物组合物，其特征在于，包含权利要求1所述的唐古特瑞香中制备得到的愈创木烷型倍半萜类化合物或其在药学上可接受的盐和药学上可接受的载体或赋形剂。
7.一种唐古特瑞香提取物，其特征在于，包含权利要求1所述愈创木烷型倍半萜类化合物，应用于制备抑制神经炎症药物中。
8.权利要求1所述唐古特瑞香中制备得到的愈创木烷型倍半萜类化合物或权利要求6所述药物组合物在制备抑制神经炎症药物中的应用。
9.权利要求1所述唐古特瑞香中制备得到的愈创木烷型倍半萜类化合物或权利要求6所述药物组合物在制备抑制LPS诱导的BV-2细胞炎症药物中的应用。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210904653.7A CN115215881B (zh) | 2022-07-29 | 2022-07-29 | 唐古特瑞香中制备的愈创木烷型倍半萜类化合物及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210904653.7A CN115215881B (zh) | 2022-07-29 | 2022-07-29 | 唐古特瑞香中制备的愈创木烷型倍半萜类化合物及其制备方法和应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115215881A CN115215881A (zh) | 2022-10-21 |
| CN115215881B true CN115215881B (zh) | 2023-11-03 |
Family
ID=83614464
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210904653.7A Active CN115215881B (zh) | 2022-07-29 | 2022-07-29 | 唐古特瑞香中制备的愈创木烷型倍半萜类化合物及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115215881B (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116687914B (zh) * | 2023-08-07 | 2024-01-16 | 山东师范大学 | 一种治疗非酒精性脂肪肝的药物 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108503521A (zh) * | 2018-02-12 | 2018-09-07 | 新疆维吾尔自治区中药民族药研究所 | 愈创木烷型倍半萜a及其制备方法和作为制备预防肿瘤和抗肿瘤药物的应用 |
| CN113248361A (zh) * | 2020-02-10 | 2021-08-13 | 沈阳药科大学 | 倍半萜类化合物及其医药用途 |
| CN113683507A (zh) * | 2021-08-24 | 2021-11-23 | 沈阳药科大学 | 岷江瑞香中的愈创木烷倍半萜衍生物及其应用 |
| CN113912482A (zh) * | 2020-07-09 | 2022-01-11 | 沈阳药科大学 | 愈创木烷型倍半萜类化合物及其制备和应用 |
-
2022
- 2022-07-29 CN CN202210904653.7A patent/CN115215881B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108503521A (zh) * | 2018-02-12 | 2018-09-07 | 新疆维吾尔自治区中药民族药研究所 | 愈创木烷型倍半萜a及其制备方法和作为制备预防肿瘤和抗肿瘤药物的应用 |
| CN113248361A (zh) * | 2020-02-10 | 2021-08-13 | 沈阳药科大学 | 倍半萜类化合物及其医药用途 |
| CN113912482A (zh) * | 2020-07-09 | 2022-01-11 | 沈阳药科大学 | 愈创木烷型倍半萜类化合物及其制备和应用 |
| CN113683507A (zh) * | 2021-08-24 | 2021-11-23 | 沈阳药科大学 | 岷江瑞香中的愈创木烷倍半萜衍生物及其应用 |
Non-Patent Citations (3)
| Title |
|---|
| A cyperane and trixanes from Jungia polita;Ybarra, Maria Ines等;Phytochemistry;第31卷(第10期);第3627页 * |
| Bioactive sesquiterpenoids and sesquiterpenoid glucosides from the flowers of Inula japonica;Zhi-Pu Yu等;Fitoterapia(第138期);第2页图1，第8页左栏第3.5节 * |
| Four New Sesquiterpenoids from the Roots of Diarthron Tianschanica with Their Antineoplastic Activity;Dong-Xue Sun等;molecules(第23期);第1383/1页图1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115215881A (zh) | 2022-10-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103816296B (zh) | 紫珠总苷提取物及其制备方法和用途 | |
| DE60115032T2 (de) | Verwendung von spermatophyte pflanzenextrakte mit immunomoduelierender wirkung | |
| US9884884B2 (en) | Compound extracted from husk and fruit stem of xanthoceras sobifolia and its extracting method and use thereof | |
| CN115215881B (zh) | 唐古特瑞香中制备的愈创木烷型倍半萜类化合物及其制备方法和应用 | |
| CN115611839B (zh) | 白花地胆草中的倍半萜内酯类化合物的制备及其应用 | |
| CN115160337B (zh) | 1α-烷基瑞香烷型二萜类化合物及其制备方法和应用 | |
| CN113912482B (zh) | 愈创木烷型倍半萜类化合物及其制备和应用 | |
| CN105017345A (zh) | 从夏枯草中同时提取四种化合物的方法及应用 | |
| CN1247855A (zh) | 丹参多酚酸盐的制备方法和用途 | |
| CN111205302B (zh) | 一种大果木姜子果实提取物、提取方法及制备方法和应用 | |
| CN102688261A (zh) | 一种凤尾草提取物及其制备方法和用途 | |
| CN105311085B (zh) | 忍冬藤或其基源植物忍冬的叶或花提取物及其制备方法和应用 | |
| CN111205347A (zh) | 齐墩果烷型三萜皂苷类化合物及其提取方法和用途 | |
| CN105712844A (zh) | 杜松烷型倍半萜Salicifoliusin A及其制备方法和应用 | |
| CN105712963A (zh) | 一种香豆素二聚体及其制备方法和应用 | |
| Gorai | Bioactive constituents from Peltophorum pterocarpum (DC.) flowers | |
| CN110759882B (zh) | 二氢沉香呋喃倍半萜及医药用途 | |
| CN115716836B (zh) | 瑞香狼毒中的愈创木烷型倍半萜类化合物及其应用 | |
| CN115716812B (zh) | 瑞香狼毒中的没药烷型倍半萜类化合物及其应用 | |
| CN108948040B (zh) | 一种烟管头草中提取的吉玛烷型倍半萜化合物及其应用 | |
| CN107722087B (zh) | 一种绞股蓝黄酮类化合物及其制备与在抗肿瘤药物中的应用 | |
| CN111067924A (zh) | 一种具有抑制醛糖还原酶活性的琼花果实总木脂素提取物及其活性成分和用途 | |
| CN113402528A (zh) | 西松烷型大环二萜化合物及制备方法、药物组合物及用途 | |
| CN112920146B (zh) | 倍半萜类化合物及其制备方法和在制备抗炎药物中的应用 | |
| KR101733048B1 (ko) | 차즈기 추출물을 포함하는 콜레스테롤 대사 관련 혈관질환 개선용 식품 조성물 및 이의 제조방법 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |