CN108210491A - Cinchonain Ib is in the application for preparing prevention medicine for treating rheumatoid arthritis - Google Patents
Cinchonain Ib is in the application for preparing prevention medicine for treating rheumatoid arthritis Download PDFInfo
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- CN108210491A CN108210491A CN201711308008.4A CN201711308008A CN108210491A CN 108210491 A CN108210491 A CN 108210491A CN 201711308008 A CN201711308008 A CN 201711308008A CN 108210491 A CN108210491 A CN 108210491A
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- cinchonain
- rheumatoid arthritis
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- medicine
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- DKTDHUGOEJFFSN-BIENJYKASA-N Cinchonain Ib Chemical compound C1([C@@H]2CC(=O)OC3=CC(O)=C4C[C@H]([C@H](CC4=C32)C=2C=C(O)C(O)=CC=2)O)=CC=C(O)C(O)=C1 DKTDHUGOEJFFSN-BIENJYKASA-N 0.000 title claims abstract description 104
- NWZBNZUABGSPSN-UHFFFAOYSA-N Kandelin A2 Natural products C=12OC(C=3C=C(O)C(O)=CC=3)C(O)CC2=C(O)C=C(O)C=1C1C(O)C(C=2C=C(O)C(O)=CC=2)OC(C2=3)=C1C(O)=CC=3OC(=O)CC2C1=CC=C(O)C(O)=C1 NWZBNZUABGSPSN-UHFFFAOYSA-N 0.000 title claims abstract description 52
- LKCOZWLUAKSRQM-UHFFFAOYSA-N rhinchoin Ia Natural products C12=C3OC(C=4C=C(O)C(O)=CC=4)C(O)CC3=C(O)C=C2OC(=O)CC1C1=CC=C(O)C(O)=C1 LKCOZWLUAKSRQM-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 206010039073 rheumatoid arthritis Diseases 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 title claims abstract description 17
- 230000002265 prevention Effects 0.000 title claims abstract description 14
- 235000001497 healthy food Nutrition 0.000 claims abstract description 4
- 206010061218 Inflammation Diseases 0.000 claims description 8
- 230000004054 inflammatory process Effects 0.000 claims description 7
- 238000012360 testing method Methods 0.000 abstract description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 15
- 238000000034 method Methods 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 12
- 230000008961 swelling Effects 0.000 abstract description 11
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 abstract description 9
- 241000699670 Mus sp. Species 0.000 abstract description 8
- 206010030113 Oedema Diseases 0.000 abstract description 7
- 235000010418 carrageenan Nutrition 0.000 abstract description 6
- 229920001525 carrageenan Polymers 0.000 abstract description 6
- 239000002671 adjuvant Substances 0.000 abstract description 5
- 230000000202 analgesic effect Effects 0.000 abstract description 4
- 239000000679 carrageenan Substances 0.000 abstract description 4
- 229940113118 carrageenan Drugs 0.000 abstract description 4
- 230000006870 function Effects 0.000 abstract description 4
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 3
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- 239000000243 solution Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 5
- 241000220225 Malus Species 0.000 description 5
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 244000061508 Eriobotrya japonica Species 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 235000009008 Eriobotrya japonica Nutrition 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 240000009022 Smilax rotundifolia Species 0.000 description 3
- 235000003205 Smilax rotundifolia Nutrition 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
- 230000036592 analgesia Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 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 3
- 229960003957 dexamethasone Drugs 0.000 description 3
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- 231100000252 nontoxic Toxicity 0.000 description 3
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- 150000008442 polyphenolic compounds Chemical class 0.000 description 3
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- 238000004809 thin layer chromatography Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 241000605422 Asparagus asparagoides Species 0.000 description 2
- 238000007445 Chromatographic isolation Methods 0.000 description 2
- 208000009386 Experimental Arthritis Diseases 0.000 description 2
- 241001558017 Gynura Species 0.000 description 2
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- 240000002044 Rhizophora apiculata Species 0.000 description 2
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- 235000000485 Smilax china Nutrition 0.000 description 2
- 235000002634 Solanum Nutrition 0.000 description 2
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- 244000061458 Solanum melongena Species 0.000 description 2
- 235000002597 Solanum melongena Nutrition 0.000 description 2
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- 239000003435 antirheumatic agent Substances 0.000 description 2
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- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229930003944 flavone Natural products 0.000 description 2
- -1 flavone compound Chemical class 0.000 description 2
- 235000011949 flavones Nutrition 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000004262 preparative liquid chromatography Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- XOMKZKJEJBZBJJ-UHFFFAOYSA-N 1,2-dichloro-3-phenylbenzene Chemical group ClC1=CC=CC(C=2C=CC=CC=2)=C1Cl XOMKZKJEJBZBJJ-UHFFFAOYSA-N 0.000 description 1
- 240000006409 Acacia auriculiformis Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 101100313763 Arabidopsis thaliana TIM22-2 gene Proteins 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000195940 Bryophyta Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 241000709992 Potato virus X Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 244000042430 Rhodiola rosea Species 0.000 description 1
- 235000003713 Rhodiola rosea Nutrition 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- MHLMRBVCMNDOCW-UHFFFAOYSA-N acetic acid;butan-1-ol;hydrate Chemical compound O.CC(O)=O.CCCCO MHLMRBVCMNDOCW-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000146 antalgic effect Effects 0.000 description 1
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- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
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- 210000005069 ears Anatomy 0.000 description 1
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- 231100000321 erythema Toxicity 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229930015704 phenylpropanoid Natural products 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- 230000004224 protection Effects 0.000 description 1
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- 210000001258 synovial membrane Anatomy 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
- 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
-
- 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)
- A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Botany (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention discloses a kind of cinchonain Ib medicine for treating rheumatoid arthritis and the application in the healthy food of prevention rheumatoid arthritis are prepared in preparation prevention.Experiment proves that cinchonain Ib can significantly inhibit dimethylbenzene induced mice auricle edema, rat paw edema caused by effectively alleviating carrageenan, and confirm that cinchonain Ib has certain analgesic activity by acetic acid twisting experiment and hot plate method test, and with extended durations of action, function and effect are more notable, in addition cinchonain Ib has the primary pedal swelling that adjuvant induces good antagonism, and indication cinchonain Ib will have good application prospect in the prevention and treatment of rheumatoid arthritis.
Description
Technical field
The present invention relates to a kind of cinchonain Ib in the application for preparing prevention medicine for treating rheumatoid arthritis.
Background technology
Flavanolignan is the flavone compound of a kind of novel tool C-9 substituent groups, i.e., is spread out with flavones and Phenylpropanoid Glycosides class
The compound that forms of biology condensation, such compound have the bioactivity such as very strong anti-oxidant, liver protection, antitumor, sterilization[1]。
Cinchonain Ib is exactly a kind of flavanolignan's class compound, is spent from Meliaceae francolin and belongs to Brazil Hai Mu, polygonaceae Gynura Cass
Blood 37, Primulaceae Lysimachia loosestrife, Rhizophoraceae mangrove category Rhizophora stylosa root, Solanum autumn, eggplant autumn, Liliaceae smilax greenbrier
Root, stem, fruit, seed are raw material in 6 sections such as chinaroot greenbrier, rose family loquat category loquat, Malus apple, 8 platymisciums.It grinds at present
Display cinchonain Ib is studied carefully with stronger antiviral[2], antioxidant activity[3], the secretion of insulin can be promoted[4], but its
His activity research report is relatively fewer.
Rheumatoid arthritis（Rheumatoid arthritis, RA）It is a kind of Systemic inflammatory autoimmune disease,
Illness rate is 0.36%, and in China, there are about 5,000,000 patients[5].This disease pathological characteristic is the inflammatory reaction of articular cavity synovial membrane, sepage, increasing
It grows, late period can lead to destruction of joint, can also cause organs, Multisystem damage[6].Modern medicine to the treatment mode of RA
Through mitigating from non-steroidal anti-inflammatory drugs control symptom is used to evolve as antirheumatic drug and biological agent using the state of an illness is alleviated
Inflammatory reaction, control disease process[7].Biological agent is due to expensive, it is difficult to be generalized, alleviate the antirheumatic drug of the state of an illness
Since the presence of its toxic side effect has seriously affected the compliance of patient.Chinese medicine not only has anti-inflammatory and antalgic and immunological regulation work(
Effect, and there is too many levels, multi-level, multiple target point comprehensive function, therefore treatment RA has unique advantage[8].From biography
Active component or active ingredient treatment RA are found in the Chinese medicine and natural products of system has become research hotspot.Adjuvant-induced arthritis moves
Object model clinically similar to rheumatoid arthritis, is usually used in evaluating therapeutic effect and possible effect of the natural drug to RA
Mechanism study[9].The cinchonain Ib of present patent application is to extract to obtain using natural health food as raw material, safe and non-toxic, and is had
There is good anti-inflammatory and analgesic effect, adjuvant-induced arthritis can be inhibited, indicate its prevention and treatment in rheumatoid arthritis
In will have good application prospect.
Bibliography：
[1] Botany. Screening of biflavonoid compounds and British Columbian
bryophytes for antiviral activity against potato virus X[D]. The University
of British Columbia, 2000.
[2] Takara K, Kuniyoshi A, Wada K, et al. Antioxidative flavan-3-ol
glycosides from stems of Rhizophora stylosa[J]. Bioscience, biotechnology,
and biochemistry, 2008, 72(8): 2191-4.
[3]Qa’dan F, Verspohl EJ, Nahrstedt A, et al. Cinchonain Ib isolated from
Eriobotrya japonica induces insulin secretion in vitro and in vivo[J].
Journal of ethnopharmacology, 2009, 124(2): 224-7.
[4] Xavier R.J. Podolsky DKUnravelling the pathogenesis of inflammatory
bowel disease[J], Nature, 2007, 448:427-434.
[5] Zhang Zhuoli Diagnosis of Rheumatoid Arthritis and the progressive development Chinese medicines forward position magazine for the treatment of, 2013,5 (3):
30-32.
[6]Colmegna I,Olmta B R,Memmt H A.Current understanding of rheumatoid
arthritis therapy. Clin Pharmacol Ther, 2012, 9(4): 607-620.
[7] Zheng Zhi heavily fortified points rheumatoid arthritis traditional Chinese medicine Study of pathogenesis China TCM basis medical journal, 2000,7 (9):
13-14.
[8] Wei Zhiping, flood fragrance, willow dragon Chinese medicines treat the Recent Advances in Mechanism of rheumatoid arthritis, Aged in China
Magazine, 2017,37（4）: 1808-1812.
The Wistar rat freund adjuvant rheumatoid arthritis animal models such as [9] Zhu Yufang, Pei Yinhui, Zhou Fangyuan are ground
Study carefully North China Polytechnics journal（Medicine）, 2016,18（5）：337-340.
Invention content
The object of the present invention is to provide a kind of cinchonain Ib prepare prevention medicine for treating rheumatoid arthritis application and
Application in its healthy food in prevention rheumatoid arthritis.
Technical scheme of the present invention is summarized as follows.
Cinchonain Ib is in the application for preparing prevention medicine for treating rheumatoid arthritis.
Applications of the cinchonain Ib in the healthy food of prevention rheumatoid section inflammation.
It is observed that cinchonain Ib has the function of preferably analgesia, anti-inflammation, while more importantly have
There is anti-adjuvanticity rheumatoid arthritis.Cell in vitro experiment confirms that it can inhibit the release of the NO of macrophage
So as to disclose its anti-inflammatory, analgesia and inhibit the effect of adjuvanticity rheumatoid arthritis essentially from powerful oxidation resistance.
Many-sided effect makes its advantage in terms of rheumatoid arthritis disease is prevented more obvious possessed by cinchonain Ib.It is pungent
It is resistant to come from natural food because of Ib, high effect nontoxic, safety is high, therefore in clinical prevention rheumatoid arthritis disease
In have broad application prospects.
Specific embodiment
With reference to specific embodiment, the present invention is further illustrated.
Embodiment 1
（1）Extraction：80 DEG C of the water refluxing extraction 3 times of the black 40L of Fuji apple pomace fresh 5kg, extraction time is respectively 3,2,1
Hour, filtering, the mesh number of strainer is 120, and extracting solution merges filtering, and the mesh number of strainer is 100, obtains supernatant；Or choose city
The 200g apple polyphenols sold（Tianjin spike Natural products research research and development Co., Ltd provides, polyphenol content 80%）In plus
Enter the water stirring at normal temperature dissolving of 2000mL, it is spare；
（2）Macroporous resin adsorption detaches：It will（1）Middle apple polyphenol solution is through HP20 type macroporous resin adsorptions, with water, volume basis
Specific concentration is 10%, 30%, 50%, 70%, 95% ethanol water gradient elution, and every half of bed volume is as a receiving body
Product is detected by thin-layer chromatography method and binding analysis type HPLC, is collected the component rich in cinchonain Ib, is merged,
Temperature≤60 DEG C, vacuum degree are concentrated under reduced pressure for 0.06 ~ 0.08MPa, pol 40, obtain the enriched substance of cinchonain Ib；
（3）Silica gel post separation：The methanol of the enriched substance equimultiple of cinchonain Ib obtained after macroporous resin adsorption separation is molten
Solution measures ratio addition 60-100 mesh silica gel decompression with 1.5--2.5 times and mixes sample to dry, dry method loading, the silicagel column measured with 10-20 times
Chromatographic isolation is 95 with methylene chloride-methanol volume ratio:5,93:7,92:8,91:10 gradient elutions, half of bed volume conduct
One reception volume, is detected by thin-layer chromatography method and binding analysis type HPLC, collects the component rich in cinchonain Ib, will
It merges, and in temperature≤60 DEG C, vacuum degree is concentrated under reduced pressure into dry for 0.06 ~ 0.08MPa, obtains the enriched substance of cinchonain Ib, contains
Measure is 32.1%；
（4）Toyopearl HW-40 are detached：By the 2 times of water dissolutions of cinchonain Ib enriched substances, through Toyopearl HW-40 columns
Chromatographic isolation is 10%, 15%, 20% with the volume ratio of methanol-water, 25% gradient elution, per quart bed volume conduct
One reception volume, is detected by thin-layer chromatography method and binding analysis type HPLC, collects the component rich in cinchonain Ib, will
It merges, and in temperature≤60 DEG C, vacuum degree is concentrated under reduced pressure for 0.06 ~ 0.08MPa, and pol 20 obtains the enrichment of cinchonain Ib
Object, content 67.2%；
（5）Preparative liquid chromatography refines：It will（4）The enriched substance of middle cinchonain Ib is refined using preparative liquid chromatography,
Cosmosil ODS columns（5u, 10 × 250mm）254nm is detected, the separation of 50% methanol-water, collects the chromatographic peak of cinchonain Ib, and
By it in temperature≤60 DEG C, vacuum degree is concentrated under reduced pressure for 0.06 ~ 0.08MPa, and pol 16, freeze-drying obtains cinchonain Ib
（460mg）.
Using ESI-MS,1H-NMR and13The spectrum such as C-NMR means are simultaneously compareed in data in literature, are identified according to upper
State the structure of the isolated cinchonain Ib of method.It is demarcated on this basis using the area normalization of HPLC, Xin Ke
It is resistance to because Ib contents be 97%.Cinchonain Ib pale yellow powders, polyamide film is with n-Butanol acetic acid-water（4:1:3）Expansion,
Rf is 0.4, and 5% ferric trichloride ethanol solution shows single blue spot.HR ESI-MS：(negative) m/z：451.0986[M-
H]-, calculated value（451.1035）, it may be determined that the molecular weight of the compound is 452.The information provided is composed with reference to hydrogen spectrum carbon, really
Its fixed molecular formula is C24H20O9, it is 15 to calculate its degree of unsaturation.Its1H-NMR（300MHz, in DMSO）Middle signal overlaps relatively tight
Weight,13C-NMR（75MHz, in DMSO）Middle signal is clear, is contrasted with document and has carried out full ownership, is accredited as cinchonain
As a result Ib see the table below.
Compound in 1 present invention of table1H,13C-NMR data
Raw material in the present embodiment can also select：It is spent from Meliaceae francolin and belongs to the wooden extract in Brazil sea, polygonaceae Gynura Cass blood 37,
Primulaceae Lysimachia loosestrife, Rhizophoraceae mangrove category Rhizophora stylosa root, Solanum autumn, eggplant autumn, Liliaceae smilax chinaroot greenbrier, rose
Root, stem, fruit, seed are raw material in 6 sections such as section loquat category loquat, Malus apple, 8 platymisciums.
Embodiment 2
Mtd test and the anti-inflammatory activity test of cinchonain Ib.
1. test material：Animal：ICR mouse, 18 ~ 22g, male and female dual-purpose；Wistar rats, 160 ~ 190g of weight, male,
Beijing laboratory animal research center provides.
2. reagent：Cinchonain Ib（Laboratory is made by oneself according to method in embodiment, purity 95%）；Aspirin is purchased from
It Hunan forever can light industrial products Import and Export Co., Ltd.；Carrageenan is purchased from Chinese couple stars Industrial Co., Ltd.；Electronic analytical balance,
Swirl mixing device.
3. test method：（1）Mtd test：40 ICR mouse are divided into two groups, the 1st group, ordinary water compares
Group；2nd group, cinchonain Ib groups.Every group 20, half male and half female, after fasting 12h, to the pungent of intragastric administration on mice administration in 1 day
It is resistant to because of Ib maximum concentration 0.2g/mL solution, interval 4h is administered 1 time.It is administered 3 times, each 0.30ml/10g altogether within 1 day,
It is observed continuously 7 days.Normal granules material is raised after administration, free water, natural lighting 12h/12h, 20 ~ 24 DEG C of room temperature, humidity
60%.Observe reaction of animals.（2）Mice caused by dimethylbenzene xylene auricle edema is tested：Mouse 40, half male and half female, fill by random point 5 groups
It takes cinchonain Ib solution, aspirin aqueous solution or waits 1h after appearance water, in mouse right ear micro syringe melted paraxylene
0.02ml simultaneously enables dimethylbenzene be saturated with mouse ear two sides, and mouse draws neck to put to death after 40min, and two are cut with eye scissors along mouse the ear portion baseline
Ear weighs left and right auricle weight, and inflammatory reaction intensity is represented with the mg numbers of auris dextra and left ear weight difference.（3）Carrageenan causes big
Mouse foot swelling is tested：Rat 40 is only randomly divided into 5 groups, 1h after gastric infusion, and 1% is subcutaneously injected in every Rat Right rear foot vola pedis
Carrageenan 50mL causes are scorching, and the measurement of glass volumetric method causes scorching preceding and causes 1,3 and 5 h foot volumes after inflammation, calculates swelling and each group
Swelling inhibiting rate.
4. result of the test：
（1）None death of mouse in gastric infusion 7 days, administration the 3rd, 8 natural gift also known as weight, two groups of changes of weight do not have difference,
Animal increases weight.By dissection is only put to death after weighing within 8 days, it is without exception to visually observe each organ such as the heart, liver, spleen, lung, kidney.Xin Ke
The resistance to maximum dosage-feeding because of Ib gastric infusions is 6g/kg, illustrates that the extract is safe and non-toxic；
（2）Test result is as shown in table 2, and display cinchonain Ib can significantly inhibit dimethylbenzene induced mice auricle edema, and
Dose-effect dependence is presented, high dose group is suitable with the anti-inflammatory effect of aspirin group.
The influence of 2 cinchonain IB paraxylene induced mice auricle edemas of table
Compared with the control group, * P<0.05 ** P<0.01；It is examined (n=8) using T
（3）As a result each medicine group in cause it is scorching after 1h significant differences compared with the control group, cause it is scorching after 3h and 5h, cinchonain
Ib high dose groups still have significant difference compared with the control group, and suitable with positive drug aspirin group effect, and prompting is pungent can
The resistance to rat paw edema caused by Ib Carrageenans has obvious inhibiting effect, the results are shown in Table 3.
The influence of rat paw edema caused by 3 cinchonain Ib Carrageenans of table
Compared with the control group, * P<0.05 ** P<0.01;T examines (n=8)； EV：Swelling degree；EI：Swelling inhibiting rate.
Embodiment 3
The analgesic activities test of cinchonain Ib.
1. test material：Animal：ICR mouse, 18 ~ 22g, male and female dual-purpose；Beijing laboratory animal research center provides.
2. reagent：Cinchonain Ib（Laboratory self-control self-control, cinchonain Ib contents 95%）；Aspirin is purchased from Hunan
It forever can light industrial products Import and Export Co., Ltd.；Acetic acid is analyzes pure, electronic analytical balance, swirl mixing device.
3. test method：（1）Acetic acid twisting is tested：Mouse 40, half male and half female are randomly divided into 5 groups, respectively gavage drug
Or equivalent water, 1h after medicine, each mouse are injected intraperitoneally 0.7%HAC normal saline solution 0.2ml, it is small in 20min after observation injection HAC
The number of mouse writhing response, and calculate analgesia and inhibit percentage.
（2）Hot plate method in mice is tested：It is tested by one method of Zhao, female mice measures mouse in 60 ± 0.5 DEG C of hot plates and licks rear solid end
The incubation period of reaction, choose in do not jump in hot-plate instrument, in random point 5 groups of the mouse for occurring reacting in 5~15s 60, gavage
Mouse is put hot plate to measure the threshold of pain primary by drug or the water for injection for waiting capacity, 1h after medicine, 2h, and more than 60 s, reactor is not at once
It takes out, the reaction time is based on 60s.
4. result of the test：（1）Acetic acid writhing test result of the test shows that cinchonain Ib can inhibit acetic acid institute to a certain degree
Cause mouse writhing reaction.It the results are shown in Table 4.
The analgesic activity of 4 cinchonain Ib Dichlorodiphenyl Acetate induced mice writhings of table
Compared with the control group, * * P<0.01；* P<0.05；T examines (n=10).
（2）Hot plate method test result shows that cinchonain Ib has certain analgesic activity, and with extended durations of action,
Function and effect are more notable.Detailed results are shown in Table 5.
5 cinchonain Ib of table licks hot plate test mouse the influence in sufficient reaction time（X ± s, n=12）
Embodiment 4
The effect of the anti-adjuvanticity rheumatoid arthritis of cinchonain Ib.
1. test material：Animal：ICR mouse, 18 ~ 22g, male and female dual-purpose；SD rats, 180 ~ 200g of weight, male, Beijing
Laboratory animal research center provides.
2. reagent：Cinchonain Ib（Laboratory self-control self-control, hereinafter referred to as cinchonain IB, purity 95%）；Freund is complete
Full adjuvant, Sigma Products；Dexamethasone Injection, electronic analytical balance, swirl mixing device.
3. test method：Male rat 48 is taken, 160~180 g of weight is randomly divided into 6 groups by weight, respectively compares
Group (10 mL/kg of NS)；Model group (10 mL/kg of NS)；Dexamethasone group (0.85 mg/kg)；Middle and high dose of cinchonain Ib
Amount (25,50,100mg/kg) group.The daily ig of each group is administered once, continuous 24d.After experiment starts, first measured with volumetric method left and right
Vola pedis volume afterwards, 1 h after being then administered in the 1st day, in addition to control group, vola pedis SC Freund's complete adjuvants 0.1 after each group Rat Right
ML causes scorching.Hereafter vola pedis volume after Rat Right is measured, and observes mouse ear erythema, tail portion tubercle etc. and situation and weight occurs within every 3 day
Variation.It calculates and compares each group animal (vola pedis volume is unanimously scorching after swelling degree of the paw=cause inflammation in the swelling degree of the paw of different time
Preceding vola pedis volume).
4. result of the test：Significantly increase, and compared with the control group to model group Rat Right metapedes swelling degree of the paw after adjuvant
Significant difference (P<0.01)；And the middle and high dosage group Rat Right metapedes swelling degree of the paw of Dexamethasone group, cinchonain Ib administration
(P is obviously reduced<0.05、0.01).Show that cinchonain Ib has good confrontation to the primary pedal swelling that adjuvant induces
Effect.It the results are shown in Table 6.
Influences of the 6 cinchonain Ib of table to rat assist agent arthritis primary response（¯X ± s,n=8）
Compared with the control group：ΔΔP<0.01；Compared with model group：*P<0.05, * * P<0.01.
Claims (2)
1. cinchonain Ib is in the application for preparing prevention medicine for treating rheumatoid arthritis.
2. applications of the cinchonain Ib in the healthy food of prevention rheumatoid section inflammation.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101306003A (en) * | 2008-04-15 | 2008-11-19 | 天津市尖峰天然产物研究开发有限公司 | Use of cyaniding 3-0 glucoside in preparing medicament or food for preventing and curing atrophic arthritis |
| CN106046014A (en) * | 2016-05-26 | 2016-10-26 | 天津市科曼思特医药科技发展有限公司 | Preparation method and application of cinchonain Ib |
-
2017
- 2017-12-11 CN CN201711308008.4A patent/CN108210491A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101306003A (en) * | 2008-04-15 | 2008-11-19 | 天津市尖峰天然产物研究开发有限公司 | Use of cyaniding 3-0 glucoside in preparing medicament or food for preventing and curing atrophic arthritis |
| CN106046014A (en) * | 2016-05-26 | 2016-10-26 | 天津市科曼思特医药科技发展有限公司 | Preparation method and application of cinchonain Ib |
Non-Patent Citations (2)
| Title |
|---|
| C. WIRTH等: "Pharmacologically active Procyanidines from the bark of Uncaria tomentosa", 《PHYTOMEDICINE》 * |
| WENJIAN TANG等: "Two New Dihydrostilbenoid Glycosides Isolated from the Leaves of Litsea coreana and their Anti-inflammatory Activity", 《NATURAL PRODUCT COMMUNICATIONS》 * |
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