CN110204592A - A kind of isopimarane type diterpene compound and the preparation method and application thereof - Google Patents

A kind of isopimarane type diterpene compound and the preparation method and application thereof Download PDF

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Publication number
CN110204592A
CN110204592A CN201910483321.4A CN201910483321A CN110204592A CN 110204592 A CN110204592 A CN 110204592A CN 201910483321 A CN201910483321 A CN 201910483321A CN 110204592 A CN110204592 A CN 110204592A
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type diterpene
isopimarane
preparation
diterpene compound
methanol
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CN110204592B (en
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段金廒
王益民
朱振华
钱大玮
王明耿
赵明
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Shandong Buchang Pharmaceuticals Co Ltd
Nanjing University of Chinese Medicine
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Shandong Buchang Pharmaceuticals Co Ltd
Nanjing University of Chinese Medicine
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/006—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by sulfur as hetero atom

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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Neurosurgery (AREA)
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Abstract

The invention discloses the isopimarane type diterpene compounds with anti-convulsant activity and anti-myocardial hypoxia activity.The compound is isolated from amber, and structural formula is as follows.The experiment of zebra fish convulsion model shows that isopimarane type diterpene compound provided by the invention has anticonvulsant effect；External anti anoxia damagine activity shows the ability that isopimarane type diterpene compound provided by the invention has protection cardiac muscle cell's anti anoxia.

Description

A kind of isopimarane type diterpene compound and the preparation method and application thereof
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of isopimarane type diterpene compound and its treat in preparation Application in terms of convulsions and cardiovascular disease medicine.
Background technique
At B.C. 2000, about the record of epilepsy, also there is epilepsy in the history of attack of different human civilizations Record.As one of the common disease in the nervous system disease, epilepsy disease incidence in the nervous system disease is only second to the cerebrovascular Disease.There are about 70,000,000 epileptics, the generations of epileptic condition can not only cause health problem in the whole world, makes patient's holistic health shape Condition is low, intelligence and impaired body function, accident occurs and the risk of injury is higher, and the mood of adjoint epilepsy generation, family A series of social mentality's problems such as front yard, occupation cause tremendous influence to the whole quality of life of patient.In addition, epilepsy is directly cured Treat spend and because caused by quality of life and production work Disability indirect costs it is huge, cause more heavy wealth Political affairs burden.
Cardiovascular disease, also known as circulation system disease refer to a series of diseases of the circulatory system；The circulatory system refers to human body Interior hemophoric organ and tissue include mainly heart, blood vessel (artery, vein, capilary), can be subdivided into acute and slow Property, it is generally related with atherosclerosis.The most common cardiovascular disease has arrhythmia cordis, myocardial ischemia, angina pectoris, cardiac muscle Infarct etc..Cardiovascular disease is one of most important cause of death of the mankind, and one of the disease of the huge medical resource of consumption.Entirely Ball dies of the number of cardiovascular disease every year, and there are about 17,000,000.Chinese cardiovascular disease illness rate, which is in, continues ascent stage, " China Cardiovascular disease report 2017 " calculate cardiovascular disease number of patients 2.9 hundred million, wherein 13,000,000 people of cerebral apoplexy, coronary heart disease 1100 Ten thousand people, 2.7 hundred million people of hypertension.
The resin of amber system ancient times Pinaceae pine genus plant is imbedded in the ambrite being transformed in underground prolonged year.Mainly have Tranquilizing and allaying excitement, promoting blood circulation to remove blood stasis, the effect of inducing diuresis for treating strangurtia.For palpitation and insomnia, convulsion, epilepsy, difficult urination, hematuria, urine Bitterly.It is recorded according to Compendium of Materia Medica: gas sweet taste, nontoxic.Five viscera settling is cured mainly, soul, the evil ghost of spermicidal evil spirit are determined, dispersing blood stasis blood leads to five leaching, strengthens Screen is ground in the heart, improving eyesight, only pained insane heresy, treats disease due to noxious agents produced by various parasites, breaks knot lump in the abdomen, blood pillow pain, hemostasia and promoting granulation after managing property.Cure mainly heart tonifying and tranquilizing, blood-breaking Myogenic, controls gynecological mass in abdomen, and children ward off evil, the mill drop red barrier of mesh screen with it.
Summary of the invention
Goal of the invention: the technical problem to be solved in the present invention provides a kind of isopimarane type diterpene noval chemical compound, originally passes through Many experiments filter out its application in terms for the treatment of convulsions and cardiovascular disease medicine, another purpose of the invention is to provide Preparation method.
Technical solution, in order to solve the above technical problems, the technical solution adopted by the present invention is that:
A kind of isopimarane type diterpene compound, with structure shown in following formula (1):
It is of the invention another solution is that a kind of treat convulsions and cardiovascular disease medicine, which includes formula (1) institute The isopimarane type diterpene compound or its salt shown.
Preferably, a kind of pharmaceutical preparation, be formula (1) shown in isopimarane type diterpene compound with it is pharmaceutically acceptable Pharmaceutic adjuvant clinical applicable spray, tablet, capsule, granule, pill or injection etc. is made.
For isopimarane type diterpene in the purposes for preparing anticonvulsant drug, the neurogenic disease includes convulsions, epilepsy.
For isopimarane type diterpene in the purposes of preparation treatment cardiovascular disease medicine, the cardiovascular disease includes that the heart twists Bitterly, myocardial infarction, myocardial ischemia, heart failure and arrhythmia cordis.Particularly preferred cardiovascular disease is myocardial ischemia.
The preparation method of isopimarane type diterpene compound provided by the invention the following steps are included:
(1) amber is taken, is extracted after crushing with ethyl acetate, extracting solution concentration obtains ethyl acetate extract；
(2) ethyl acetate extract of step (1) is taken to separate using AB-8 macroporous resin column chromatography, first with 50% methanol solution Elution, again with methanol elution collect meoh eluate, obtain methanol after recycling methanol and elute position；
(3) the methanol elution position for taking step (2) to obtain, is dissolved with acetonitrile, isolated different using high pressure preparation liquid phase Korean pine alkane type diterpenoid.
Preferably, isopimarane type diterpene compound provided by the invention preparation method the following steps are included:
(1) amber 100g is taken, the ethyl acetate measured after crushing with 10 times extracts twice, and 2 hours every time, combined ethyl acetate Extracting solution recycles ethyl acetate, obtains ethyl acetate extract；
(2) take the ethyl acetate extract of step (1) using AB-8 macroporous resin column chromatography, first with the elution of 50% methanol solution 3 column volumes, again with methanol elute 5 volumes, collect methanol and elute position, obtain methanol position after recycling methanol；
(3) 40% acetonitrile of the methanol position volumetric concentration dissolution for taking step (2) to obtain, prepares liquid phase separation using high pressure Obtain isopimarane type diterpene compound.
As the preferably described high pressure preparation condition are as follows: SEPAX GP-C18(10 × 250mm, 5 μm) chromatographic column, 40% second Nitrile isocratic elution, flow velocity 3mL/min, Detection wavelength 227nm.
In method made above, step (1) extracting method can be cold soaking, diacolation, Microwave Extraction, ultrasonic extraction, reflux Extract etc..
The utility model has the advantages that
The present invention is by carrying out system further investigation to amber medicinal material chemical component, by wave spectrum, mass spectrum and x single crystal diffraction Analysis shows the isolated isopimarane type diterpene from amber medicinal material, is retrieved it as noval chemical compound.
And show that isopimarane type diterpene provided by the invention is insane with significantly resisting by internal and external activity research Epilepsy and convulsion effect is included, and also there is good protective effect to ischemic cardiac myocyte.
And by toxicity test studies have shown that the different Korean pine provided by the invention with anti-epileptic and activity against myocardial ischemia Alkane type diterpenoid toxicity is low, and safety is good.
Detailed description of the invention
Fig. 1 is the structural schematic diagram of amber eo-acid.
Fig. 2 is amber eo-acid1HNMR spectrogram.
Fig. 3 is amber eo-acid13C NMR spectra.
Fig. 4 is the inhibiting effect that the zebra fish that amber eo-acid pentetrazole induces is fainted from fear；A is to shorten swimming distance, B in figure It is to reduce high speed swimming ratio.
Fig. 5 is that amber eo-acid increases H9C2 anti-anoxia ability.
Specific embodiment
For a further understanding of the present invention, the preferred embodiment of the invention is described below with reference to embodiment, still It should be appreciated that these descriptions are only further explanation the features and advantages of the present invention, rather than to the claims in the present invention Limitation.
The preparation of 1 isopimarane type diterpene compound of embodiment, comprising the following steps:
(1) amber 100g is taken, the ethyl acetate measured after crushing with 10 times extracts twice, 2 hours every time, recycles acetic acid second Ester obtains ethyl acetate extract.
(2) ethyl acetate extract for taking step (1) is first washed using AB-8 macroporous resin column chromatography with 50% methanol solution 3 column volumes are taken off, again with methanol elutes 5 volumes, collects alcohol elution, concentration；
(3) the methanol position for taking step (2) is redissolved with 40% acetonitrile, prepares the isolated different Korean pine of liquid phase using high pressure Alkane type diterpenoid (is named as amber eo-acid), structural formula such as Fig. 1.High pressure prepares liquid phase actual conditions are as follows:: SEPAX GP- C18(10 × 250mm, 5 μm) chromatographic column, 40% acetonitrile isocratic elution, flow velocity 3mL/min, Detection wavelength 227nm.
The structure elucidation of amber eo-acid: acicular crystal (acetonitrile).Ultraviolet spectra has characteristic absorption at λ max 227nm. HR-ESI-MS m/z:353.2153[M+H]+(calcd for C20H33O3S+, 353.2150；Δ=0.85ppm), Ω=6.
Such as Fig. 2,1H-NMR(400MHz,DMSO-d6) spectrum display three methyl signals δ of high field regionppm 1.10(3H,s,H- 17), 1.08 (3H, s, H-19), 0.86 (3H, s, H-20)；
Such as Fig. 3,13C-NMR(100MHz,DMSO-d6) compose and contain 20 carbon with DEPT spectrum information announcement compound, wherein wrapping Include 3 methyl carbon: δppm23.1 (C-17), 16.8 (C-19) and 0.86 (C-20)；8 mesomethylene carbon δppm37.9 (C-1), 17.6 (C-2), 23.8 (C-6), 33.2 (C-7), 19.7 (C-11), 32.0 (C-12), 40.4 (C-15) and 48.5 (C-16)；5 A methine carbon δppm46.3 (C-4), 48.9 (C-5), 32.6 (C-8), 51.1 (C-9) and 84.2 (C-14)；3 quaternary carbons: δppm44.80 (C-4), 35.8 (C-10) and 42.6 (C-13)；1 carbonyl carbon: δppm180.4 (C-18) and a thionyl Base.
X single crystal diffraction:
On BrukerAPEX-II CCD diffractometer, the MoK alpha ray Jing Guo graphite monochromator monochromatization is used (wavelength λ=0.71073A) is used as incident radiation.Within the scope of 2.01 < θ < 27.50deg., with w-20 scanning mode, Acquire 18426 reflection points altogether at 296 (2) K, wherein 4482 are independent considerable measuring point [of I > 2 s (I)], R (int)= 0.0305, whole intensity datas use SADABS correction to program.The crystal belongs to rhombic system, space group Pnma, a= 11.2366 (8), b=11.4228 (8), c=14.8442 (10), α=90deg., β=90deg., γ=90deg., V= 1905.3 (2), Z=4, Dc=1.229Mg/m3.Crystal structure is solved by direct method (SHELXL-97), is taken turns Fourier conjunction more At whole non-hydrogen atoms are obtained, hydrogen atom is obtained by direct hydrogenation after theoretical calculation.Whole non-hydrogen atom coordinates and anisotropic Thermal parameter is corrected using complete matrix least square method to convergence.Final discrepancy factor is R=0.0287, wR=0.0800.Point Minor structure is desired to make money or profit is drawn with SHELXl-97 program bag.
The anticonvulsion experiment of 2 zebra fish of embodiment
AB strain zebra fish, experimental group and administration are divided into 6 groups: (pentylenetetrazol is dry for control group (Control), model group In advance), the amber neo-acid compound that positive drug group (phenobarbital, PB), embodiment 1 are prepared it is high, in, 3, bottom concentration (10, 5,1 μM) dosage group, every group of 10 4-7dpf juvenile fish, each medicine group first gave drug 72 as a child, then plus 6mM pentylenetetrazol intervention 10 minutes, video recording in 10 minutes is then acquired, carries out carry out image procossing using Matlab 2018a self-compiling program, counts total trip Swimming distance, speed, the information such as swimming area distribution.
Statistical method: calculate data information withIt indicates, it is for statistical analysis using SPSS statistical software, between multiple groups Compare using one-way analysis of variance, two comparison among groups are examined using T, inspection level p=0.05.
It is as shown in Figure 4: Fig. 4 A amber eo-acid can significantly shorten under 5 μM, 10 μM of dosage the swimming of zebra fish always away from From Fig. 4 B can significantly reduce the ratio of zebra fish high speed swimming.(control group Control, model group model, positive drug group PB, Amber neo-acid compound low dose group C3N1- 1 μM, amber neo-acid compound middle dose group C3N1- 5 μM, amber neo-acid compound height Dosage group C3N1-10μM)
Above the experimental results showed that isolated noval chemical compound amber eo-acid of the invention has good anticonvulsant work With.
The experiment of 3 anti-myocardial H9C2 anoxic of embodiment
It chooses rat myocardial cell (H9C2).Experimental group and administration are divided into 8 groups: (600 μm of blank group, model group CoCl2Intervene), 6 concentration of amber neo-acid compound (50,15,5,1.5, the 0.5,0.15 μm) dosage that is prepared of embodiment 1 Group.Each medicine group first gave drug 48 as a child, then plus CoCl2Intervene for 24 hours.Cell activity is detected by mtt assay.
Statistical method: calculating data information is to indicate, more comparison among groups for statistical analysis using SPSS statistical software Using one-way analysis of variance, two comparison among groups are examined using T, inspection level p=0.05.
Such as Fig. 5 experimental result: rat myocardial cell H9C2 anoxic can be improved in 5~50 μM of concentration of amber neo-acid compound In the case of survival rate.Depositing under rat myocardial cell H9C2 anaerobic condition can be significantly improved when especially concentration is 015 μM Motility rate.P<0.05.
Above the experimental results showed that isolated amber eo-acid of the invention has the function of protecting cardiac muscle cell.

Claims (9)

1. the isopimarane type diterpene compound with anti-convulsant activity and protection cardiac muscle cell's Substituted phenyl-lactic acid, feature exist In structural formula are as follows:
2. a kind of treat epilepsy, convulsive disorder and cardiovascular disease medicine, which is characterized in that including described in claim 1 different Korean pine alkane type diterpenoid or its salt.
3. treatment epilepsy, convulsive disorder and cardiovascular disease medicine according to claim 2, which is characterized in that described Pharmaceutical dosage form is spray, tablet, capsule, granule, pill, injection.
4. the preparation method of isopimarane type diterpene compound described in claim 1, which comprises the following steps:
(1) amber is taken, is extracted after crushing with ethyl acetate, extracting solution concentration obtains ethyl acetate extract；
(2) it takes the ethyl acetate extract of step (1) to separate using AB-8 macroporous resin column chromatography, is first washed with 50% methanol solution De-, again with methanol elution collects meoh eluate, obtains methanol after recycling methanol and elute position；
(3) the methanol elution position for taking step (2) to obtain, is dissolved with acetonitrile, prepares the isolated different Korean pine of liquid phase using high pressure Alkane type diterpenoid.
5. the preparation method of isopimarane type diterpene compound according to claim 4, which is characterized in that step (1) mentions Taking method is cold-maceration, percolation, microwave loss mechanisms, ultrasonic extraction or reflux extraction.
6. the preparation method of isopimarane type diterpene compound according to claim 4, which is characterized in that step (3) is high Press preparation condition are as follows:: SEPAX GP-C18, 10 × 250mm of specification, 5 μm of chromatographic columns, 40% acetonitrile isocratic elution, flow velocity 3mL/ Min, Detection wavelength 227nm.
7. isopimarane type diterpene compound described in claim 1 prepare anti-epileptic, the application in anticonvulsant drug.
8. application of the isopimarane type diterpene compound described in claim 1 in preparation treatment cardiovascular disease medicine.
9. application according to claim 8, which is characterized in that the cardiovascular disease is angina pectoris, myocardial infarction, cardiac muscle Ischemic, heart failure and arrhythmia cordis.
CN201910483321.4A 2019-06-04 2019-06-04 Isopimarane diterpenoid compound and preparation method and application thereof Active CN110204592B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110934889A (en) * 2019-12-30 2020-03-31 嘉兴怡萃生物科技有限公司 Efficient and comprehensive extraction method of effective components in amber

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CN107021942A (en) * 2016-02-01 2017-08-08 复旦大学 Bark extract of pinus fenzeliana var dabeshanensis and preparation method thereof and the purposes in pharmacy
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CN107021942A (en) * 2016-02-01 2017-08-08 复旦大学 Bark extract of pinus fenzeliana var dabeshanensis and preparation method thereof and the purposes in pharmacy
CN108530281A (en) * 2018-06-11 2018-09-14 云南大学 A kind of isopimarane type forskolin, medical composition and its use

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Cited By (1)

* Cited by examiner, † Cited by third party
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CN110934889A (en) * 2019-12-30 2020-03-31 嘉兴怡萃生物科技有限公司 Efficient and comprehensive extraction method of effective components in amber

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