CN105820046A - Pharmaceutical composition containing acipimox and medical application of pharmaceutical composition - Google Patents
Pharmaceutical composition containing acipimox and medical application of pharmaceutical composition Download PDFInfo
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- CN105820046A CN105820046A CN201610322145.2A CN201610322145A CN105820046A CN 105820046 A CN105820046 A CN 105820046A CN 201610322145 A CN201610322145 A CN 201610322145A CN 105820046 A CN105820046 A CN 105820046A
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- acipimox
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- 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
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- 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
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
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- 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)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/534—Mentha (mint)
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- General Health & Medical Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a pharmaceutical composition containing acipimox and medical application of the pharmaceutical composition. The pharmaceutical composition containing acipimox contains acipimox and a natural product compound (I) which is obtained through separation from dry leaves of herba menthae and is novel in structure, and when acipimox and the natural product compound (I) independently act, the neuron protection effect is weak; when acipimox and the natural product compound (I) jointly act, the neuron protection effect is significantly improved, and the pharmaceutical composition can be developed into a neuron protection drug. Compared with the prior art, the prominent substantive features and significant progress are achieved.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of acipimox, be specifically related to the pharmaceutical composition of a kind of acipimox and the medical usage of neuroprotective thereof.
Background technology
Acipimox is the blood fat reducing new drug of a kind of lipotropism.It act as: 1. suppression total body fat tissue release free fatty, makes cholesterol and triglyceride synthesis material reduce, so that total plasma cholesterol, first oily three esters, low density lipoprotein, LDL, very low density lipoprotein (VLDL) content reduce.2. transhipment and the removing of blood plasma middle-high density lipoprotein content, beneficially cholesterol are increased.3. increase hepatic glycogen synthesis, make blood sugar content reduce, and promote fatty acid decomposition to maintain blood glucose so that cholesterol and triglyceride synthesis material more become reduction.4. antioxidation, the oxidation of membrane lipid capable of inhibiting cell, protect cell membrane.
Acipimox is used for various constitutionales and Secondary Hyperlipidemia, it is possible to decrease total plasma cholesterol, triglyceride, low density lipoprotein, LDL and very low density lipoprotein (VLDL) content, improves hdl concentration, and persistent is stable.This product can not only be used for first-selected fat-reducing medicament, treats slight hyperlipemia, again can based on fat-reducing medicament, share to improve curative effect with other fat-reducing medicaments.This product still can play assosting effect as hypoglycemic medicine in treatment diabetes.
Up to now, there is not yet the pharmaceutical composition of acipimox and the dependency report of neuroprotective.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of acipimox; containing acipimox and a kind of natural product of the novel structure of isolated from mentha leave in this pharmaceutical composition; acipimox and this natural product can work in coordination with the effect playing neuroprotective, develop into the medicine of neuroprotective.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
The pharmaceutical composition of a kind of acipimox, including acipimox, compound as above (I) and pharmaceutically acceptable carrier.
The preparation method of compound (I) as above, comprise following operating procedure: the dried leaves of Herba Menthae is pulverized by (a), with 70～80% alcohol heat reflux extract, united extraction liquid, it is concentrated into without alcohol taste, successively with petroleum ether, ethyl acetate and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B in () step (a), n-butyl alcohol takes thing macroporous resin remove impurity, first with 6 column volumes of 8% ethanol elution, then with 8 column volumes of 70% ethanol elution, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate purification on normal-phase silica gel separates, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 50:1,25:1,15:1 and 5:1 successively；D in () step (c), component 4 separates further by purification on normal-phase silica gel, obtain 3 components with the methylene chloride-methanol gradient elution that volume ratio is 10:1,5:1 and 2:1 successively；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 70%, collecting 8～12 column volume eluents, eluent is concentrated under reduced pressure to give pure compound (I).
Further, in step (a), extract with 75% alcohol heat reflux, united extraction liquid.
Further, described macroporous resin is D101 type macroporous adsorbent resin.
The compound (I) application in the medicine preparing neuroprotective as above.
The application in the medicine preparing neuroprotective of the pharmaceutical composition of acipimox as above.
Advantages of the present invention:
Time in the pharmaceutical composition of the acipimox that the present invention provides containing acipimox and a kind of natural product of the novel structure of isolated from mentha leave, acipimox and this natural product independent role, neuroprotective is more weak；During the two synergy, neuroprotective significantly improves, and can develop into the medicine of neuroprotective.The present invention compared with prior art has prominent substantive distinguishing features and significantly progress.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit scope with this.Although the present invention being explained in detail with reference to preferred embodiment, it will be understood by those within the art that, technical scheme can be modified or equivalent, without deviating from the spirit and scope of technical solution of the present invention.
Embodiment 1: compound (I) separates preparation and structural identification
Reagent source: ethanol, petroleum ether, ethyl acetate, n-butyl alcohol, dichloromethane are analytical pure, purchased from Shanghai Ling Feng chemical reagent company limited, methanol, analytical pure, purchased from Jiangsu Han Bang chemical reagent company limited.
Separation method: the dried leaves (5kg) of Herba Menthae is pulverized by (a), (20L × 3 time) are extracted with 75% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste (4L), successively with petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and water saturated n-butyl alcohol (4L × 3 time) extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B acetic acid ethyl ester extract D101 type macroporous resin remove impurity in () step (a), first with 6 column volumes of 8% ethanol elution, then with 8 column volumes of 70% ethanol elution, collects 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate purification on normal-phase silica gel separates, successively with volume ratio be 50:1 (8 column volumes), the methylene chloride-methanol gradient elution of 25:1 (8 column volumes), 15:1 (8 column volumes) and 5:1 (10 column volumes) obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 10:1 (8 column volumes), the methylene chloride-methanol gradient elution of 5:1 (10 column volumes) and 2:1 (5 column volumes) obtain 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 70%, collect 8～12 column volume eluents, eluent is concentrated under reduced pressure to give compound (I) (265mg, HPLC normalization purity is more than 98%).
Structural identification: white powder, HR-ESIMS shows [M+H]+For m/z301.2026, can obtain molecular formula in conjunction with nuclear-magnetism feature is C20H28O2, degree of unsaturation is 7.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3null，500MHz): H-2 (1.65，m)，H-3(1.59，m)，H-3(2.21，m)，H-4(1.92，dd，J=7.1，17.3Hz)，H-4(2.31，m)，H-7(2.21，m)，H-7(2.26，m)，H-8(2.01，d，J=13.2Hz)，H-8(2.57，dt，J=4.6，13.2Hz)，H-10(5.02，s)，H-12(3.37，s，2H)，H-14(6.72，dd，J=2.4，12.2Hz)，H-15(1.97，d，J=15.6Hz)，H-15(2.82，ddd，J=6.6，12.2，15.6Hz)，H-16(0.87，s)，H-17(0.97，s)，H-18(1.73，s)，H-19(9.94，s)，H-20(1.63，s)；Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz): 37.8 (C, 1-C), 42.5 (CH, 2-C), 27.2 (CH2, 3-C), 31.6 (CH2, 4-C), 127.5 (C, 5-C), 136.4 (C, 6-C), 26.5 (CH2, 7-C), 38.4 (CH2, 8-C), 145.8 (C, 9-C), 136.1 (CH, 10-C), 196.8 (C, 11-C), 43.5 (CH2, 12-C), 131.4 (C, 13-C), 163.8 (CH, 14-C), 33.7 (CH2, 15-C), 24.6 (CH3, 16-C), 33.1 (CH3, 17-C), 22.2 (CH3, 18-C), 193.3 (CH, 19-C), 18.9 (CH3, 20-C).Infrared spectrum shows that this compound contains carbonyl (1755cm-1), aldehyde radical (1655cm-1) and alkene (1610cm-1) group.13C-NMR, DEPT and hsqc spectrum show 20 carbon signals, including four methyl δ C24.6,33.1,22.2,18.9；Six methylene δ C27.2,31.6,26.5,38.4,43.5,33.7；Four methine (aldehyde radical, two alkene carbon) δ C42.5,163.8,193.3；And six quaternary carbon (carbonyl carbon, four alkene carbon) δ C37.8,127.5,136.4,145.8,196.8,131.4.H in HMBC spectrum2-7 with C-6, H2-12 with C-13, H-14 and C-12 and C-13, H3-16 and C-1, C-2, C-6 and C-17, H3-17 and C-1, C-2, C-6 and C-16, H3-18 and C-4, C-5 and C-6, H-19 Yu C-13 and C-14, H3-20 and the coherent signal of C-8, C-9 and C-10, and1H-1H-14/H in HCOSY spectrum2-15/H-2/H2-3/H2-4、H2-7/H2The coherent signal of-8 shows that this compound is to be connected, with ring 12 carbon dienone, the endocyclic compound formed by cyclohexene by C-1, C-2 and C-6 position.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, and document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows, spatial configuration is determined by ECD test further, and theoretical value is basically identical with experiment value.
Embodiment 2: neuroprotective
One, material and instrument
PC12 cell strain, gifts in Anhui Chinese Medicine College experimental center.Aβ1-40Albumen is purchased from Sigma company.Compound (I) is self-control, and HPLC normalization purity is more than 98%.(import subpackage is purchased from Beijing match Mo Feishier biochemistry Products Co., Ltd to DMEM/F12 culture medium.NewbomCalfSerum is purchased from BeijingSolarbioScience&TechnologyCo., Ltd.MTT is purchased from Amresco company of the U.S..Triumphant base AnnexinV-FITC cell apoptosis detection kit is purchased from Nanjing Kai Ji Bioisystech Co., Ltd.Paraformaldehyde is purchased from chemical reagent company limited of Chinese Medicine group.Bcl-2 polyclonal antibody is purchased from Wuhan doctor's moral Bioisystech Co., Ltd.Bax polyclonal antibody is purchased from Beijing Bo Aosen Bioisystech Co., Ltd.Cyt-c polyclonal antibody is purchased from Wuhan doctor's moral Bioisystech Co., Ltd.Goat anti-rabbit igg/FITC is purchased from Beijing Bo Aosen Bioisystech Co., Ltd.Sheep anti-mouse igg/(H+L) is purchased from the green skies, Jiangsu biotech firm.Normal Goat Serum is purchased from Wuhan doctor's moral Bioisystech Co., Ltd.SABC immunohistochemical kit is purchased from Wuhan Boster Biological Technology Co., Ltd..
Electronic analytical balance (FA2004 type, Shanghai Lei Ci precision scientific instrument company), microplate reader (ELx-800 type, U.S. Bio-Tek), flow cytometer (EPICXL-MCL type, BeckmanCouiter company of the U.S.), High speed refrigerated centrifuge (3K30 type, Sigma Co., USA, CO2 gas incubator (CO-150 type, NBS company limited of the U.S.), OLYMPUS fluorescence microscope (BX41 type, band DP70 camera system, Japan's Olympus Products).
Two, test method
1、Aβ1-40Hatch
Aβ1-40It is configured to 1000 μm ol/L with deionized water and stores liquid subpackages, be positioned over storages of-20 DEG C of refrigerator, face and hatch 7d with taking-up the last week at 37 DEG C of incubators, be allowed to assemble aging.
2, the cultivation of cell
PC12 cell strain is cultivated in glass culture bottle with containing 10% hyclone, 100U/ and the DMEM/F12 culture medium of penicillin, 100U/mL streptomycin, CO2The condition of culture of cell culture incubator is 37 DEG C, 5%CO2Concentration, saturated humidity, pass on 1 time (about 2-3d) with the trypsinization of 0.25% after cell length to 80% abundance, inverted microscope observation of cell upgrowth situation, trophophase cell of taking the logarithm during experiment is tested.Seed cells into 96 well culture plate serum-free mediums before carrying out MTT experiment to cultivate；Cell is seeded to before flow cytomery 6 well culture plate serum-free cultures both cultivated；Immunohistochemical experiment all cultivates cell by 24 well culture plate creep plate methods, and culture medium is serum-free medium.
3, cell administration processes and packet
Cell is divided into five groups, carries out pharmaceutical intervention: 1. Normal group: normal PC12 cell after serum-free medium inoculation 24h；2. model control group: 25 μm ol/LA β1-40；3. acipimox group: 25 μm ol/LA β1-40+ 50mg/L acipimox；4. compound (I) group: 25 μm ol/LA β1-40+ 50mg/L compound (I)；5. acipimox and compound (I) compositions group: 25 μm ol/LA β1-40+ 25mg/L acipimox+250mg/L compound (I).Carry out after drug treating 24h detecting indices.
4, MTT detects each group of cell viability
Take the logarithm the cell of trophophase, with 1 × 10 after trypsinization5The cell density of individual/mL, every hole 100 μ L is inoculated in serum-free culture 24h in 96 orifice plates, then according to above-mentioned group technology carries out pharmaceutical intervention, often group arranges 6 multiple holes, and after 24h, every hole adds the MTT solution 20 μ L of 5mg/mL and continues at CO2Hatching 4h in cell culture incubator, then take out 96 well culture plates, abandoning supernatant, every hole adds the DMSO of 150 μ L, is placed on shaking table vibration 10min, detects the light absorption value in each hole after purple crystal is completely dissolved by microplate reader at 490nm wavelength.With the hole that only adds culture fluid for zeroing reference, cell viability percentage expression, regard the cytoactive of matched group as 100%.Result calculates: cell survival rate=(experimental group OD value-blank group OD value)/(matched group OD value-blank group OD value) × 100%.
5, statistical analysis
Use SPSS17.0 analyze software statistical result is processed, data acquisition one factor analysis of variance, with mean scholar's standard deviation () represent, using LSD to compare between group, P < 0.05 is for having significant difference, and P < 0.01 is extremely significant difference, and chart is drawn by Excel2003.
Three, result and conclusion
MTT test result shows, compares with normal group cell, and model control group cytoactive substantially reduces (P < 0.01).Comparing with model control group, acipimox significantly improves (P ＜ 0.01) with the cytoactive of compound (I) compositions group；Comparing with model control group, acipimox group, compound (I) group cytoactive increases (P ＜ 0.05).The results are shown in Table 1.
The table 1 impact (x ± s, n=6) on A β 1-40 induction PC12 cytoactive
| Group | Cytoactive (%) |
| Normal group | 100±0.0 |
| Model control group | 50.08±7.45 |
| Acipimox group | 62.78±9.84 |
| Compound (I) group | 63.77±8.96 |
| Acipimox and compound (I) compositions group | 93.43±9.58 |
Conclusion: this study demonstrates that A β1-40Toxicity damage neurocyte, cause a large amount of apoptosis of PC12, cytoactive declines；After acipimox, compound (I), acipimox and compound (I) compositions intervention, apoptosis situation is improved, and the improvement effect of acipimox and compound (I) compositions is significantly higher than acipimox or the improvement effect of compound (I) independent role.Synergism is there is between acipimox and compound (I).
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit protection scope of the present invention with this.It will be understood by those within the art that, technical scheme can be modified or equivalent, without deviating from essence and the protection domain of technical solution of the present invention.
Claims (7)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of an acipimox, it is characterised in that: include acipimox, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier.
3. the preparation method of the compound (I) described in claim 1, it is characterized in that, comprise following operating procedure: the dried leaves of Herba Menthae is pulverized by (a), with 70～80% alcohol heat reflux extract, united extraction liquid, it is concentrated into without alcohol taste, successively with petroleum ether, ethyl acetate and water saturated n-butanol extraction, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B in () step (a), n-butyl alcohol takes thing macroporous resin remove impurity, first with 6 column volumes of 8% ethanol elution, then with 8 column volumes of 70% ethanol elution, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；C in () step (b), 70% ethanol elution concentrate purification on normal-phase silica gel separates, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 50:1,25:1,15:1 and 5:1 successively；D in () step (c), component 4 separates further by purification on normal-phase silica gel, obtain 3 components with the methylene chloride-methanol gradient elution that volume ratio is 10:1,5:1 and 2:1 successively；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 70%, collecting 8～12 column volume eluents, eluent is concentrated under reduced pressure to give pure compound (I).
The preparation method of compound the most according to claim 3 (I), it is characterised in that: in step (a), extract with 75% alcohol heat reflux, united extraction liquid.
The preparation method of compound the most according to claim 3 (I), it is characterised in that: described macroporous resin is D101 type macroporous adsorbent resin.
6. the application in the medicine preparing neuroprotective of the compound (I) described in claim 1.
7. the pharmaceutical composition of the acipimox described in claim 2 application in the medicine preparing neuroprotective.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105461782A (en) * | 2016-01-14 | 2016-04-06 | 郑平珍 | Novel triterpene compound and preparation and medical application thereof |
| CN106188217A (en) * | 2016-07-19 | 2016-12-07 | 袁肇斌 | The pharmaceutical composition of a kind of aminoglutethimide and the medical usage of neuroprotective thereof |
-
2016
- 2016-05-16 CN CN201610322145.2A patent/CN105820046A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| YU-CHI LIN等: "Verticillane-Type Diterpenoids and an Eudesmanolide-Type Sesquiterpene from the Formosan Soft Coral Cespitularia hypotentaculata", 《HELVETICA CHIMICA ACTA》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105461782A (en) * | 2016-01-14 | 2016-04-06 | 郑平珍 | Novel triterpene compound and preparation and medical application thereof |
| CN106188217A (en) * | 2016-07-19 | 2016-12-07 | 袁肇斌 | The pharmaceutical composition of a kind of aminoglutethimide and the medical usage of neuroprotective thereof |
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Application publication date: 20160803 |