CN107021946A - A kind of compound and its preparation and application with antitussive effect - Google Patents
A kind of compound and its preparation and application with antitussive effect Download PDFInfo
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- CN107021946A CN107021946A CN201710409126.8A CN201710409126A CN107021946A CN 107021946 A CN107021946 A CN 107021946A CN 201710409126 A CN201710409126 A CN 201710409126A CN 107021946 A CN107021946 A CN 107021946A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 230000000954 anitussive effect Effects 0.000 title abstract description 16
- 239000000284 extract Substances 0.000 claims abstract description 36
- 241000234435 Lilium Species 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 26
- 229940079593 drug Drugs 0.000 claims abstract description 18
- 238000000605 extraction Methods 0.000 claims abstract description 9
- 238000000926 separation method Methods 0.000 claims abstract description 3
- 206010011224 Cough Diseases 0.000 claims description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 35
- 101100175487 Glycine max CG-1 gene Proteins 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 239000000243 solution Substances 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 5
- 239000002002 slurry Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 229910001868 water Inorganic materials 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 3
- 238000000825 ultraviolet detection Methods 0.000 claims description 3
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 230000000295 complement effect Effects 0.000 claims description 2
- 239000001257 hydrogen Chemical group 0.000 claims description 2
- 229910052739 hydrogen Chemical group 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 238000002137 ultrasound extraction Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 241000935230 Cardiocrinum giganteum var. yunnanense Species 0.000 abstract description 3
- 238000012360 testing method Methods 0.000 abstract description 3
- 239000000575 pesticide Substances 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 201000010099 disease Diseases 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 241000046585 Aristolochia clematitis Species 0.000 description 5
- 229960004126 codeine Drugs 0.000 description 5
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 5
- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical class C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 4
- 229960001985 dextromethorphan Drugs 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 241001648246 Cardiocrinum Species 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000005553 drilling Methods 0.000 description 3
- 235000013399 edible fruits Nutrition 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229910021642 ultra pure water Inorganic materials 0.000 description 3
- 239000012498 ultrapure water Substances 0.000 description 3
- DKSZLDSPXIWGFO-BLOJGBSASA-N (4r,4ar,7s,7ar,12bs)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-ol;phosphoric acid;hydrate Chemical group O.OP(O)(O)=O.OP(O)(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC.C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC DKSZLDSPXIWGFO-BLOJGBSASA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000234280 Liliaceae Species 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 229940124584 antitussives Drugs 0.000 description 2
- BBFQZRXNYIEMAW-UHFFFAOYSA-N aristolochic acid I Chemical compound C1=C([N+]([O-])=O)C2=C(C(O)=O)C=C3OCOC3=C2C2=C1C(OC)=CC=C2 BBFQZRXNYIEMAW-UHFFFAOYSA-N 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 208000013116 chronic cough Diseases 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 201000004897 cough variant asthma Diseases 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 241000411851 herbal medicine Species 0.000 description 2
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000726094 Aristolochia Species 0.000 description 1
- 208000034657 Convalescence Diseases 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- 206010065563 Eosinophilic bronchitis Diseases 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 206010044314 Tracheobronchitis Diseases 0.000 description 1
- 206010046555 Urinary retention Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960004415 codeine phosphate Drugs 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 208000017574 dry cough Diseases 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 238000011841 epidemiological investigation Methods 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000000396 hypokalemic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 208000009928 nephrosis Diseases 0.000 description 1
- 231100001027 nephrosis Toxicity 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229960003447 pseudoephedrine hydrochloride Drugs 0.000 description 1
- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical compound [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000002893 slag Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000007483 tonsillectomy Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/40—Separation, e.g. from natural material; Purification
-
- 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)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
- A61K36/8967—Lilium, e.g. tiger lily or Easter lily
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of compound and its preparation and application with antitussive effect as shown in formula (I).Present invention also offers the preparation method of the compound and purposes.The compounds of this invention derives from the compound after extraction separation and purification in Yunnan giant lily (Cardiocrinum giganteum var.yunnanense), Yunnan giant lily is distributed mainly on China Yun-Gui Plateau, it is readily available, and extract convenient, simple to operate, cost is low, and the test of pesticide effectiveness is proved, the compounds of this invention has good antitussive activity, and a kind of new medication selection is provided to be clinical。
Description
Technical field
The invention belongs to field of natural medicinal chemistry, more particularly to a kind of compound of antitussive effect and preparation method thereof,
And its application in the medicine of preventing cough or/and antibechic is prepared.
Background technology
Cough is a kind of guarding reflex action of human body, can remove pathological discharge thing and the external world in respiratory tract and enter breathing
Foreign matter in road, its sensitiveness increases or function is impaired can all damage to human body.Cough is different according to duration, can be divided into
Acute cough's (course of disease is less than 3 weeks), subacute cough (course of disease 3~8 weeks) and chronic cough (course of disease is more than 8 weeks).Acute cough
Common disease factor be common cold and acute tracheobronchitis；The common disease factor of subacute cough is postinfectious cough, upper gas
Road cough syndrome and cough variant asthma；The common disease factor of chronic cough is cough variant asthma, epithelium healing cough is comprehensive
Close disease, Eosinophilic bronchitis and gastroesophageal reflux induced cough etc..Zhong Nanshan teaches (Chen Ruchong, Lai Kefang, Liu Chun
Beautiful, Luo Wei, epidemiology survey [J] .2006,22 (2) of the 1087 university student's coughs in Zhong Nanshan In Guangzhou Areas:123-126.)
The epidemiological investigation of the 1087 university student's coughs in Guangzhou is shown：The illness rate of acute cough is 7.6%, chronic to cough
The illness rate coughed is 3.3%.This result is pointed out, and compares university student, common community-based population be more easy to touch dust in environment and
Deleterious particle, cough illness rate is higher.But cough illness rate is stepped up with advancing age, the harm of cough is not allowed to neglect
Depending on.
And some antitussives sold on the market, generally codeine, dextromethorphan, pseudoephedrine hydrochloride solution and some contain
The Chinese patent drug of birthwort.Most common codeine, with good antibechic curative effect, the dry cough for treating interference rest.But it
Adverse reaction such as Hypokalemic paralysis, poisoning, dependence syndrome and the retention of urine etc. is well-known.On 2 20th, 2013, FDA was at it
Official website formally sends black surround warning, to warn tonsillotome or the postoperative children of mammary gland excision to use the fatal risk of codeine
FDA.Drug Safety Podcast:Safety review update of codeine use in children；new
Boxed Warning and Contraindication on use after tonsillectomy and/or
adenoidectomy.There is also such safety issue, the U.S. in 1997 for cold drug dextromethorphan with antitussive action
Society of Pediatrics delivers statement, it is believed that children should disable the antitussive No authors containing codeine or dextromethorphan
listed.Use of codeine-and dextromethorphan-containing cough remedies in
children.American Academy of Pediatrics.Committee on Drugs[J].Pediatrics,
1997,99(6):918..A assessment report of CDC of the U.S. (CDC) claims：There are about 7000 youngsters every year
Child is admitted to hospital's first aid because of cold drug and cough medicine.And some contain the antibechic Chinese patent drug of birthwort, also because " birthwort
Nephrosis " is affected.1999-2001, Britain medicine safety committee (CSM), Britain medicine Surveillance center, United States drug with
Food control office (FDA), Australian FAD (TGA) etc. are announced to Chinese herbal medicine containing aristolochic acid and products thereof in succession
Carry out indefinite duration disabling.
The fitochemical studies of traditional herbal medicines show that other types of compound also has beneficial antitussive activity, and
With the side effect fewer than above-mentioned synthesis compound.Yunnan giant lily (Cardiocrinum giganteum
Var.yunnanense it is) herbaceos perennial of Liliaceae (Liliaceae) Cardiocrinum (Cardiocrinum), is big
Lily is mainly distributed on the areas such as Yunnan Province of China, Guizhou in the mutation of China.With cough-relieving, relieving asthma and the effects such as clearing lung-heat, be used for
The illnesss such as treatment cough, asthma, spitting of blood and pulmonary tuberculosis.The fruit of Yunnan giant lily is commonly called as " pocket bell ", pharmaceutically acceptable, in Taiwan
Area is used as the substitute of birthwort fruit.Ming Li,Ka-Ho Ling,Hilary Lam,Pang-Chui Shaw,et
al.2010,Cardiocrinum seeds as a replacement for Aristolochia fruits in
treating cough,Journal of Ethnopharmacology,130:429-432. researchs show, in the antibechic of cavy
In experiment, it is found that birthwort and Yunnan giant lily seed have antitussive effect, the ethanol solution of Yunnan giant lily seed is to cavy
There is gentle antitussive effect.But, the antitussive activity composition of Yunnan giant lily seed is still not clear.
The content of the invention
The present invention is in view of the deficienciess of the prior art, provide a kind of compound and its preparation side with antitussive activity
Method, and its application in the medicine of preventing cough or/and antibechic is prepared.
The invention provides the compound as shown in formula (I),
Wherein, R is alkyl or hydrogen.
Further, the alkyl is C1~C5Alkyl.
Further, the structure of the compound is shown in CGY-1 or CGY-2：
A kind of preparation method of compound, it is characterised in that：It is comprised the steps of：
(1) crude drug is crushed, with 50~95% ethanol solution ultrasonic extraction 3~4 times, filter cleaner obtains crude drug
Extract solution；
(2) extract solution is concentrated under reduced pressure as slurry, obtains total extract；
(3) total extract is suspended with water, petroleum ether extraction is then extracted with ethyl acetate, vacuum distillation removes ethyl acetate
After obtain extract；
(4) extract chromatogram neat solvent is dissolved, HPLC is isolated and purified, and finally obtains compound CGY-1, compound
CGY-2。
Further, crude drug described in above-mentioned preparation method is Yunnan giant lily seed.
Further, final product described in above-mentioned preparation method contains two kinds of structures of formula CGY-1 and CGY-2.
Further, the ethanol solution in above-mentioned preparation method described in step (1) is that volume fraction of ethanol is 50~95%
Ethanol solution.
Further, each ultrasonic time in above-mentioned preparation method described in step (1) is 1~2h.
Further, in above-mentioned preparation method：Chromatogram neat solvent described in step (4) is methanol or acetonitrile.
Further, in above-mentioned preparation method step (4) it is described prepare mobile phase condition that HPLC isolates and purifies for acetonitrile-
The aqueous solution, flow velocity is 8ml/min, and ultraviolet detection wavelength is 254nm.
Present invention also offers purposes of the described compound in the medicine of preventing cough or/and antibechic is prepared.
Present invention also offers a kind of preventing cough or/and the medicine of antibechic, it is above-claimed cpd plus pharmaceutically may be used
The auxiliary material of receiving or complementary composition are prepared into pharmaceutically conventional preparation.
The compounds of this invention is derived from Yunnan giant lily (Cardiocrinum giganteum var.yunnanense)
Compound after extraction separation and purification, Yunnan giant lily is distributed mainly on China Yun-Gui Plateau, it is easy to obtain, and extraction side
Just, simple to operate, cost is low, and the test of pesticide effectiveness is proved, the compounds of this invention has good antitussive activity, and one kind is provided for clinic
New medication selection.
According to the above of the present invention, according to the ordinary technical knowledge and customary means of this area, this hair is not being departed from
Under the premise of bright above-mentioned basic fundamental thought, the modification of other diversified forms can also be made, replaces or changes.
Brief description of the drawings
Fig. 1 is the total LC-MS chromatograms of Yunnan giant lily seed ethyl acetate extract；Wherein, upper figure is mass signal, under
Figure is efficient liquid phase signal, and compound CGY-1 and CGY-2 are index components.
Fig. 2 is compound CGY-1 Advances in crystal X-ray diffraction structure chart.
Fig. 3 is compound CGY-1 ESI-MS mass spectrograms.
Fig. 4 is compound CGY-2 ESI-MS mass spectrograms.
Fig. 5 CGY-1 and CGY-2 influences preclinical on guinea pig cough (N=8, M：Solvent group；P：Positive drug salt
Sour codeine group, 12mg/kg；A：CGY-1 low dose groups, 100mg/kg；B CGY-1 high dose groups, 200mg/kg；C：CGY-2
Low dose group, 100mg/kg；D：CGY-2 high dose groups, 200mg/kg.
Fig. 6 CGY-1 and CGY-2 to guinea pig cough's number of times influence (N=8, M：Solvent group；P：Positive drug hydrochloric acid can
Treat because of group, 12mg/kg；A：CGY-1 low dose groups, 100mg/kg；B：CGY-1 high dose groups, 200mg/kg；C：Low dose of CGY-2
Amount group, 100mg/kg；D：CGY-2 high dose groups, 200mg/kg.
The embodiment of form, remakes further specifically to the above of the invention by the following examples
It is bright.But the scope that this should not be interpreted as to above-mentioned theme of the invention is only limitted to following example.It is all to be based on the above of the present invention
The technology realized belongs to the scope of the present invention.
Embodiment
The CGY-1 of embodiment 1 and CGY-2 preparation method
(1) preparation of extract
A, Yunnan giant lily seed 100g crushed, in room temperature KQ- is passed through for 50% ethanol solution with percent by volume
250DE types ultrasonic drilling machine is extracted 3 times, and ethanol 1000ml is used every time, and each time is 2 hours, merges No. three extract solutions, filtering
Slagging-off, obtains Yunnan giant lily seed extract solution；
B, extract solution carried out being concentrated under reduced pressure into constant weight with N-1100V-W types Rotary Evaporators, obtain yellow slurry, be
Yunnan giant lily seed total extract 12g；
C, Yunnan giant lily seed total extract is suspended with ultra-pure water, 100ml petroleum ether extractions then use 100ml acetic acid
Ethyl ester is extracted, and vacuum distillation obtains extract 1g after removing ethyl acetate；
(2) extract that step (1) is obtained is analyzed
The extract that step (1) is obtained is dissolved in methanol, is made into 1mg/ml solution, and anti-phase preparation, tool are carried out with HPLC
Body preparation condition is：LP-C18Welch Ultimate reverse phase preparative columns (21.2mm × 250mm, 5 μm), ultraviolet detection wavelength is
254nm, flow velocity is 8ml/min, and gradient system is：A:Water, B:Acetonitrile；0~35min, 25% (v/v%) → 60% (v/v%)
Acetonitrile solution；36~50min, the acetonitrile of 60% (v/v%) → 100% (v/v%)；Respectively at 13.986min,
Chromatographic peak is collected at 21.211min minutes (see Fig. 1).Be concentrated under reduced pressure (N-1100V-W with Rotary Evaporators to collection liquid
Type), respectively obtain compound CGY-1 (95mg) and compound CGY-2 (86mg).Compound 1~2 can be carried out according to spectral data
Identification.
(3) CGY-1 and CGY-2 identification
CGY-1：Yellow column crystallization (methanol-water)；Vanillic aldehyde-strong sulfuric acid response is in yellow；Advances in crystal X-ray diffraction knot
Composition and ESI-MS mass spectrograms are shown in Fig. 2 and Fig. 3 respectively, and molecular formula is C31H22O11, HR-ESI-MS m/z:569.1093[M-H]-
(calcd for[M-H]-:569.1084)；UV(MeOH)λmax:209,267,340nm；IR(KBr):νmax 3396,1643,
1603cm-1。1H NMR (400MHz, DMSO-d6) and13C NMR (75MHz, DMSO-d6)(δ)：It is shown in Table 1.
CGY-2：Pale yellow powder；Vanillic aldehyde-strong sulfuric acid response is in yellow；ESI-MS mass spectrograms are shown in Fig. 4, and molecular formula is
C30H20O11, HR-ESI-MS m/z:555.0922[M-H]-(calcd for[M-H]-:555.0927)；UV(MeOH)λmax:
209,267,298,340nm；IR(KBr):νmax 3403,1643,1615cm-1。1H NMR (400MHz, DMSO-d6) and13C
NMR (75MHz, DMSO-d6)(δ)：It is shown in Table 1.
Table 1：CGY-1's and 21H NMR and13C NMR datas (δ, in DMSO-d6,J in Hz)
The CGY-1 of embodiment 2 and CGY-2 preparation method
(1) preparation of extract
A, Yunnan giant lily seed 100g crushed, in room temperature KQ- is passed through for 95% ethanol solution with percent by volume
250DE types ultrasonic drilling machine is extracted 2 times, and ethanol 1000ml is used every time, and each time is 1 hour, merges No. three extract solutions, filtering
Slagging-off, obtains Yunnan giant lily seed extract solution；
B, extract solution carried out being concentrated under reduced pressure into constant weight with N-1100V-W types Rotary Evaporators, obtain yellow slurry, be
Yunnan giant lily seed total extract 11g；
C, Yunnan giant lily seed total extract is suspended with ultra-pure water, 100ml petroleum ether extractions then use 100ml acetic acid
Ethyl ester is extracted, and removes under reduced pressure and extract 0.9g is obtained after ethyl acetate；
(2) extract obtained to step (1) carries out HPLC analyses and prepared by HPLC, analysis and preparation condition be the same as Example
1, finally respectively obtain compound CGY-1 (98mg) and compound CGY-2 (90mg).To the identification be the same as Example of two compounds
1。
The CGY-1 of embodiment 3 and CGY-2 preparation method
(1) preparation of extract
A, Yunnan giant lily seed 100g crushed, in room temperature KQ- is passed through for 75% ethanol solution with percent by volume
250DE types ultrasonic drilling machine is extracted 3 times, and ethanol 1000ml is used every time, and each time is 1.5 hours, merges No. three extract solutions, mistake
Slag is filtered out, Yunnan giant lily seed extract solution is obtained；
B, extract solution carried out being concentrated under reduced pressure into constant weight with N-1100V-W types Rotary Evaporators, obtain yellow slurry, be
Yunnan giant lily seed total extract 10.5g；
C, Yunnan giant lily seed total extract is suspended with ultra-pure water, 100ml petroleum ether extractions then use 100ml acetic acid
Ethyl ester is extracted, and removes under reduced pressure and extract 0.95g is obtained after ethyl acetate；
(2) extract obtained to step (1) carries out HPLC analyses and prepared by HPLC, analyzes and preparation condition is with example 1,
Finally respectively obtain compound CGY-1 (94mg) and compound CGY-2 (89mg).To the identifications of two compounds with example 1.
Beneficial effects of the present invention are proved below by way of specific pharmacodynamics test.
The compounds of this invention antibechic of experimental example 1 is tested
- the 350g of body weight 250 cavy is taken, male and female half and half, adaptability is raised 3~5 days, is randomly divided into 6 groups, respectively solvent
Group, codeine phosphate group, CGY-1 low dose groups, CGY-1 high doses group, CGY-2 low dose groups, CGY-2 high dose groups.
Animal mark is placed in 24L closed box, constant speed is sprayed into 0.5M citric acids in box by shower nozzle, spraying
The cough number of times of cavy in 10min, observed and recorded 10min, experimental animal of the cough number between 18 and 30 times is chosen as subsequently
Antibechic experimental subjects.After the convalescence of 5 days, selected 48 animals are randomly divided into 6 groups by body weight and sex, every group 8, female
Hero half and half.Low dosage is administered by 100mg/kg, 200mg/kg dosage respectively with high doses of compounds；Positive drug codeine phosphate
By 12mg/kg；Solvent group gives distilled water.Administered volume be 1.0ml/100g body weight, gastric infusion after 60 minutes in 0.5M
Citric acid spray carries out induction cough, then the cough latent period of cavy and cough number of times in observed and recorded 10min.
After atomization terminates, with 20% urethane by 1.5g/kg intraperitoneal administrations by laboratory animal anesthesia, and abdominal aorta is carried out
Blood sampling, serum sample is placed in ice chest preservation；Put to death after animal, dissected immediately, carry out pulmonary lavage liquid collection, BALF samples
It is placed in ice chest；Bronchus and lung tissue sample are gathered, in formalin-fixed.
Data are represented with mean ± standard error (X ± SEM), and data statistic analysis, two groups are carried out using SPSS18.0 softwares
Compare, the t compared using two sample averages is examined, and is compared between group using one-way analysis of variance (ANOVA).
Antitussive activity evaluation result：
As shown in figure 5, in this experiment, in atomization excitation process, compared with solvent group, 100 and 200mg/kg i.g.
CGY-1 make respectively cough latent period extend 46.1% and 53.8% (P<0.01).And 100 and 200mg/kg i.g. CGY-2
Cough latent period is set to extend 73.1% and 80.8% (P respectively<0.01).
As shown in Figure 6 in the influence to coughing number of times, compared with solvent group, 100 and 200mg/kg i.g. CGY-1
Cough number of times is reduced into by 41.1% and 44.6% (P respectively respectively<0.01).And 100 and 200mg/kg i.g. CGY-2 difference
Cough number of times is reduced into by 51.8% and 66.1% (P respectively<0.01).
These results indicate that two compounds are respectively provided with antibechic property, therefore expand the application of Yunnan giant lily seed
Scope.First demonstration that their antitussive effect.Because CGY-1 and CGY-2 are the main components of Yunnan giant lily, it
Content it is high, it is easy to prepare.
The present invention is not limited by the embodiment above, and the embodiment is only provided as example, it is possible to by institute
Changed in a variety of ways in the protection domain that attached claim is defined.
Claims (10)
1. a kind of compound as shown in formula (I),
Wherein, R is alkyl or hydrogen.
2. compound according to claim 1, it is characterised in that：The alkyl is C1~C5Alkyl.
3. compound according to claim 2, it is characterised in that：The structure of the compound is CGY-1 or CGY-2：
4. the preparation method of compound described in claim 3, it is characterised in that：It is comprised the steps of：
(1) crude drug is crushed, with 50~95% ethanol solution ultrasonic extraction 3~4 times, filter cleaner obtains crude drug extraction
Liquid；
(2) extract solution is concentrated under reduced pressure as slurry, obtains total extract；
(3) total extract is suspended with water, petroleum ether extraction is then extracted with ethyl acetate, vacuum distillation is removed and obtained after ethyl acetate
To extract；
(4) extract chromatogram neat solvent is dissolved, HPLC is isolated and purified, and finally obtains compound CGY-1, compound CGY-2.
5. preparation method according to claim 4, it is characterised in that：The crude drug is Yunnan giant lily seed.
6. the preparation method of compound according to claim 4, it is characterised in that：Each ultrasonic time described in step (1)
For 1~2h.
7. the preparation method of compound according to claim 4, it is characterised in that：Chromatogram neat solvent described in step (4) is
Methanol or acetonitrile.
8. the preparation method of compound according to claim 4, it is characterised in that：Step (4) the preparation HPLC separation is pure
The mobile phase condition of change is acetonitrile-aqueous solution, and flow velocity is 8ml/min, and ultraviolet detection wavelength is 254nm.
9. purposes of the compound described in claim 1-3 any one in the medicine of preventing cough or/and antibechic is prepared.
10. the pharmaceutical composition of a kind of preventing cough or/and antibechic, it is as the chemical combination described in claim 1-3 any one
Thing is prepared into pharmaceutically conventional preparation plus pharmaceutically acceptable auxiliary material or complementary composition.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101049301A (en) * | 2007-05-14 | 2007-10-10 | 湖北中医学院 | Pharmaceutical preparation of biflavone compound for anti gout |
| CN101361733A (en) * | 2008-09-17 | 2009-02-11 | 暨南大学 | Use of flavone derivates and preparation method thereof |
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2017
- 2017-06-02 CN CN201710409126.8A patent/CN107021946B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101049301A (en) * | 2007-05-14 | 2007-10-10 | 湖北中医学院 | Pharmaceutical preparation of biflavone compound for anti gout |
| CN101361733A (en) * | 2008-09-17 | 2009-02-11 | 暨南大学 | Use of flavone derivates and preparation method thereof |
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|---|
| LI-LI YU ET AL: "A new biflavonoid from Aristolochiacontorta", 《PHARMAZIE》 * |
| 崔树德: "《中药大全》", 30 June 1989 * |
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