CN105753833A - Medicine composition of amiodarone hydrochloride and application thereof in biological medicine - Google Patents
Medicine composition of amiodarone hydrochloride and application thereof in biological medicine Download PDFInfo
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- CN105753833A CN105753833A CN201610263836.XA CN201610263836A CN105753833A CN 105753833 A CN105753833 A CN 105753833A CN 201610263836 A CN201610263836 A CN 201610263836A CN 105753833 A CN105753833 A CN 105753833A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/70—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with ring systems containing two or more relevant rings
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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Abstract
The invention discloses a medicine composition of amiodarone hydrochloride and application thereof in biological medicine.The medicine composition of amiodarone hydrochloride contains amiodarone hydrochloride and a natural product compound (I) which is separated from dry rhizomes of acorus gramineus and is novel in structure, and amiodarone hydrochloride and the compound (I) act separately, so that a treatment effect on cough is achieved; amiodarone hydrochloride and the compound (I) act together, the treatment effect on cough is better, and the medicine composition can be developed into medicine for treating the cough, has prominent substantive features and makes a remarkable progress compared with the prior art.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of Amiodarone Hydrochloride, be specifically related to the pharmaceutical composition of Amiodarone Hydrochloride and the application in biological medicine thereof.
Background technology
Amiodarone Hydrochloride is anti-anginal drug, the property of can select that coronary artery dilator blood flow, reduces myocardial oxygen consumption, decreased heart rate, reduces Atrioventricular Conduction speed similar to the effect of beta-blocker.For supraventricular and ventricular tachycardia, paroxysmal auricular flutter and vibration, pre-excitation syndrome, it is also used for intractable paroxysmal tachycardia chronic coronary insufficiency and angina pectoris etc..
Up to now, there is not yet the dependency of Amiodarone Hydrochloride and pharmaceutical composition thereof and cough-relieving report.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of Amiodarone Hydrochloride, this pharmaceutical composition contains the natural product of Amiodarone Hydrochloride and a kind of novel structure, Amiodarone Hydrochloride and this natural product and can work in coordination with cough-relieving.
The above-mentioned purpose of the present invention is achieved by the techniques below scheme:
A kind of compound (I) with following structural formula,
The pharmaceutical composition of a kind of Amiodarone Hydrochloride, including Amiodarone Hydrochloride, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepares into the dosage form of needs.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form includes tablet, capsule, oral liquid, sucks agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
The preparation method of above-claimed cpd (I), comprise following operating procedure: the dry rhizome of Rhizoma Acori Graminei is pulverized by (a), extract with 85～95% alcohol heat reflux, 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 n-butyl alcohol extract macroporous resin remove impurity in () step (a), first with 10 column volumes of 8% ethanol elution, then with 12 column volumes of 70% ethanol elution, collects 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；In (c) step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 40:1,20:1,10:1 and 5:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 8:1,5:1 and 2:1 methylene chloride-methanol gradient elution 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 75%, collecting 8～14 column volume eluents, eluent concentrating under reduced pressure obtains compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 90% alcohol heat reflux, united extraction liquid.
Further, in the preparation method of compound (I), described macroporous resin is AB-8 type macroporous adsorbent resin.
Further, in the preparation method of compound (I), step (a) replaces ethyl acetate to extract with dichloromethane, obtains dichloromethane extract.
The above-claimed cpd (I) application in the medicine of preparation cough-relieving.
The application in the medicine of preparation cough-relieving of the pharmaceutical composition of above-mentioned Amiodarone Hydrochloride.
Advantages of the present invention: containing Amiodarone Hydrochloride and a kind of natural product separating the novel structure obtained from the dry rhizome of Rhizoma Acori Graminei in the pharmaceutical composition of Amiodarone Hydrochloride provided by the invention, when Amiodarone Hydrochloride and this natural product independent role, there is antitussive action；During the two synergy, cough suppressing effect improves further, it is possible to develop into the medicine of cough-relieving.
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.
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 dry rhizome (2kg) of Rhizoma Acori Graminei is pulverized by (a), (20L × 3 time) are extracted with 90% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste (4L), extract with petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and water saturated n-butyl alcohol (4L × 3 time) successively, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B n-butyl alcohol extract AB-8 type macroporous resin remove impurity in () step (a), first with 10 column volumes of 8% ethanol elution, then with 12 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, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 40:1 (8 column volumes), 20:1 (8 column volumes), 10:1 (8 column volumes) and 5:1 (10 column volumes) 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 8:1 (8 column volumes), 5:1 (10 column volumes) and 2:1 (5 column volumes) 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 75%, collect 8～14 column volume eluents, eluent concentrating under reduced pressure obtains compound (I) (334mg, HPLC normalization purity is more than 98%).
Structural identification: white amorphous powder；HR-ESI-MS shows [M+Na]+For m/z489.1902, can obtain molecular formula in conjunction with nuclear-magnetism feature is C27H30O7, degree of unsaturation is 13.Hydrogen nuclear magnetic resonance modal data δH(ppm, DMSO-d6, 500MHz): H-4 (6.54, s), H-6 (3.24, 2H, m), H-8 (2.68, m), H-9 (2.33, dd, J=14.2, 7.5), H-9 (2.61, dd, J=14.2, 2.6), H-11 (6.62, s), H-17 (0.81, d, J=7.2), H-18 (4.86, s), H-18 (5.02, s), H-3 ' (5.94, m), H-4 ' (1.76, dq, J=7.2, 1.2), H-5 ' (1.72, s), 1-OMe (3.45, s), 2-OMe (3.80, s), 3-OMe (3.85, s), 12, 13-OCH2O (5.85, s), 12,13-OCH2O (5.93, s)；Carbon-13 nmr spectra data δC(ppm, DMSO-d6, 125MHz): 151.3 (C, 1-C), 140.0 (C, 2-C), 152.2 (C, 3-C), 110.1 (CH, 4-C), 132.6 (C, 5-C), 42.8 (CH2, 6-C), 151.6 (C, 7-C), 39.6 (CH, 8-C), 36.3 (CH2, 9-C), 130.8 (C, 10-C), 108.4 (CH, 11-C), (147.2 C, 12-C), 137.3 (C, 13-C), 140.1 (C, 14-C), (123.2 C, 15-C), 122.4 (C, 16-C), 17.1 (CH3, 17-C), 108.7 (CH2, 18-C), 164.1 (C, 1 '-C), 126.5 (C, 2 '-C), 138.9 (CH, 3 '-C), 20.1 (CH3, 4 '-C), 15.8 (CH3, 5 '-C), 60.2 (CH3, 1-OMe), 60.4 (CH3, 2-OMe), 55.7 (CH3, 3-OMe), 101.6 (CH2, 12,13-OCH2O).Infrared spectrum shows that this compound contains carbonyl (1737cm-1) and phenyl ring (1642 and 1494cm-1) group.1H and13C-NMR spectrum one bimodal methyl signals (δ H0.81, d, J=7.2Hz, Me-17) of display, two benzyl methylene (δ H3.24,2H, m, H-6；δ H2.33, dd, J=14.2,7.5Hz, H-9 and 2.61, dd, J=14.2,2.6Hz, H-9), two fragrant simple substance subsignals (δ H6.54, H-4 and δ H6.62, H-11), one ring outer methylene signals (δ H4.86, s, H-18 and 5.02, s, H-18), a methylene-dioxy (δ H5.85, s, 12,13-OCH2O and 5.93, s, 12,13-OCH2O), three methoxyl groups (δ H3.45,3.80 and 3.85), and angeloyl groups [δ H5.94 (m, H-3 '), 1.72 (s, H-5 '), 1.76 (dq, J=7.2,1.2Hz, H-4 ')；δ C15.8 (C-5 '), 20.1 (C-4 '), 126.5 (C-2 '), 138.9 (C-3 '), 164.1 (C-1 ')].The peak that intersects of three methoxyl group signals in HMBC spectrum (δ H3.45,3.80 and 3.85) and C-1, C-2 and C-3, and the dependency of methylene-dioxy signal (δ H5.85 and 5.93) and C-12 and C-13 confirms these substituent groups position in biphenyl system.H in being composed by HMBC2-6 with C-4, C-5 and C-16, H2-9 with C-10, C-11 and C-15, H3-17 with C-7, C-8 and C-9, H2-18 with the dependency of C-6 and C-8, Yi Jicong1H-1The H observed in HCOSY spectrum3-17/H-8/H2-9 sequences this compound known contains cyclo-octadiene ring.The outer methylene signals (δ H4.86, s, H-18 and 5.02, s, H-18) of ring, and carbon signal (δ C108.7, C-18；δ C151.6, C-7) show to exist between C-7 and C-18 double bond.By spectrogram and nuclear magnetic data analysis, it is known that angeloyl groups can only be connected with C-14 position.In ROESY spectrum, the dependency of H-11 and H-9 α (δ H2.33) and Me-17 shows that Me-17 is α configuration.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and ROESY 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.This compound chemistry formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
1, materials and methods
1.1 animals
KM mice, SPF level, male and female half and half, body weight 18～22g, institute of lab animals of Sichuan Academy of Medical Sciences provide.Laboratory Animal Facility condition: animal observation ward of pharmaceutical college of Chengdu University of Traditional Chinese Medicine.
1.2 reagent and sample
Amiodarone Hydrochloride is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.Strong aqua ammonia (analytical pure), Chengdu Ke Long chemical reagent factory produces.NaHCO3(analytical pure), Chengdu Ke Long chemical reagent factory.Phenol red, Shanghai reagent three factory produces.
1.3 instruments
The multi-functional readout instrument of VARIOSKANFLASH2.4.3 all-wave length, Thermo company produces；BS323S electronic balance, Sartorius company produces；TGL-16G-A type high speed low temperature centrifugal machine, Hai'an booth scientific instrument factory produces；W201D thermostat water bath, Shen Shun bio tech ltd, Shanghai produces.Protocol is write and computer system record simultaneously by paper media.
Prepared by 1.4 antitussive experiment mice packets and model
Take healthy KM mice, male and female half and half, it is divided into 5 groups by sex, body weight stratified random, respectively model control group, positive controls (dromethan group 80mg/kg), Amiodarone Hydrochloride group (80mg/kg), compound (I) group (80mg/kg), Amiodarone Hydrochloride and compound (I) compositions group [40mg/kg Amiodarone Hydrochloride+40mg/kg compound (I)].Each treated animal gives given the test agent solution 1 time in set time gavage every day, and matched group gavage gives isometric(al) pure water, and each gavage amount of mice is 0.2mL/10g body weight.Successive administration 7 days, after last administration 20min, mice is put in the 250mL wide mouthed bottle equipped with Cotton Gossypii (drip and have 50 μ L strong aqua ammonia), bottleneck is airtight, timing immediately, observing and the record cough latent period of mice and cough number of times in 2min after starting cough, number of times of coughing in cough latent period and 2min is as the index evaluating medicine antitussive.
1.5 eliminate the phlegm experiment mice packet and model prepare
Take healthy KM mice, male and female half and half, it is divided into 5 groups by sex, body weight stratified random, respectively model control group, positive controls (ambroxol hydrochloride 80mg/kg), Amiodarone Hydrochloride group (80mg/kg), compound (I) group (80mg/kg), Amiodarone Hydrochloride and compound (I) compositions group [40mg/kg Amiodarone Hydrochloride+40mg/kg compound (I)].Each treated animal gives given the test agent solution 1 time in set time gavage every day, and matched group gavage gives isometric(al) pure water, and each gavage amount of mice is 0.2mL/10g body weight.Successive administration 7 days.Testing first 1 day, water 12h is can't help in mice fasting, after last administration 30min, and lumbar injection 0.5% phenol red solution 0.5mL.After injecting phenol red 30min, the de-cervical vertebra of mice is put to death, and faces upward position and is fixed on surgical plate, cervical region median incision, separating musculi colli, expose trachea, No. 7 syringe needles polished with head insert tracheal strips and are about 0.3cm, with silk thread, itself and trachea ligation are fixed, and be connected with syringe.By 5%NaHCO3Solution is sucking-off gently, collects in irrigating solution injecting tube after repeatedly rinsing 3 times.Operation 3 times in this approach, rinse 9 times altogether, merge irrigating solution to take supernatant after the centrifugal 10min of 2500r/min, adopt the VARIOSKANFLASH2.4.3 multi-functional readout instrument of all-wave length in 545nm place colorimetric, measure OD value.And make phenol red standard curve, from curve, find the phenol red concentration of its correspondence.
1.6 statistical methods
Experimental data mean ± standard deviation (x ± s) represents, application SPSS18.0 version statistical software carries out one factor analysis of variance and t inspection, statistically significant for difference with P < 0.05.
2, experimental result
2.1 impacts on strong aqua ammonia induced mice Respiratory frequency
Compare with model control group, Amiodarone Hydrochloride is obviously prolonged (P < 0.01) with compound (I) compositions group and positive controls Respiratory frequency incubation period, and Respiratory frequency number of times substantially reduces (P < 0.01)；Comparing with model control group, Amiodarone Hydrochloride group, compound (I) group Respiratory frequency prolongation of latency (P < 0.05), Respiratory frequency number of times reduces (P < 0.05).
Result of the test is in Table 1.
2.2 impacts on mice trachea phenols contents
Comparing with model control group, Amiodarone Hydrochloride remarkably promotes the phenol red excretion of Respiratory Tract of Mice (P < 0.01) with compound (I) compositions group and positive controls；Comparing with model control group, Amiodarone Hydrochloride group, compound (I) group promotes the excretion (P < 0.05) that Respiratory Tract of Mice is phenol red.
Result of the test is in Table 1.
The table 1 impact on strong aqua ammonia induced mice Respiratory frequency and mice trachea phenols contents
The above results shows, when Amiodarone Hydrochloride, compound (I) independent role, has therapeutical effect to what cough；When Amiodarone Hydrochloride and compound (I) synergy, the therapeutic effect of cough is more excellent, it is possible to develop into the medicine for the treatment of cough.
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, it is possible to technical scheme is modified or equivalent replacement, without deviating from essence and the protection domain of technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of an Amiodarone Hydrochloride, it is characterised in that: include Amiodarone Hydrochloride, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepare into the dosage form of needs.
3. the pharmaceutical composition of Amiodarone Hydrochloride according to claim 2, it is characterised in that: pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
4. the pharmaceutical composition of Amiodarone Hydrochloride according to claim 2, it is characterised in that: described dosage form includes tablet, capsule, oral liquid, sucks agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterized in that, comprise following operating procedure: the dry rhizome of Rhizoma Acori Graminei is pulverized by (a), extract with 85～95% alcohol heat reflux, 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 n-butyl alcohol extract macroporous resin remove impurity in () step (a), first with 10 column volumes of 8% ethanol elution, then with 12 column volumes of 70% ethanol elution, collects 70% eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；In (c) step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 40:1,20:1,10:1 and 5:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 8:1,5:1 and 2:1 methylene chloride-methanol gradient elution 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 75%, collecting 8～14 column volume eluents, eluent concentrating under reduced pressure obtains compound (I).
6. the preparation method of compound according to claim 5 (I), it is characterised in that: step (a) is extracted with 90% alcohol heat reflux, united extraction liquid.
7. the preparation method of compound according to claim 5 (I), it is characterised in that: described macroporous resin is AB-8 type macroporous adsorbent resin.
8. the preparation method of compound according to claim 5 (I), it is characterised in that: step (a) replaces ethyl acetate to extract with dichloromethane, obtains dichloromethane extract.
9. the application in the medicine of preparation cough-relieving of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described Amiodarone Hydrochloride of claim 2～4 application in the medicine of preparation cough-relieving.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105920521A (en) * | 2016-04-29 | 2016-09-07 | 陈芝维 | Cough-relieving traditional Chinese medicinal compound and preparation method thereof |
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| CN105384721A (en) * | 2015-12-07 | 2016-03-09 | 西宁意格知识产权咨询服务有限公司 | Novel biphenyl cyclooctene lignin compound, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105384721A (en) * | 2015-12-07 | 2016-03-09 | 西宁意格知识产权咨询服务有限公司 | Novel biphenyl cyclooctene lignin compound, and preparation method and application thereof |
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| CN105920521A (en) * | 2016-04-29 | 2016-09-07 | 陈芝维 | Cough-relieving traditional Chinese medicinal compound and preparation method thereof |
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Application publication date: 20160713 |