CN103012182B - N-acyl-sphingosine compound, preparation method and application of N-acyl neuro sphingosine compound - Google Patents
N-acyl-sphingosine compound, preparation method and application of N-acyl neuro sphingosine compound Download PDFInfo
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- CN103012182B CN103012182B CN201210563660.1A CN201210563660A CN103012182B CN 103012182 B CN103012182 B CN 103012182B CN 201210563660 A CN201210563660 A CN 201210563660A CN 103012182 B CN103012182 B CN 103012182B
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Abstract
The invention discloses an N-acyl-sphingosine compound capable of restraining activity of angiotensin I-converting enzyme. A preparation method comprises the following steps in sequence: pulverized tamarix ramosissima is taken, soaked in ethanol or methanol with a volume fraction of 50-100%, and then subjected to heating backflow extraction for 2-3 times; each extraction time is 2-3h; extracting solutions are mixed; the obtained extracting solution is extracted by petroleum ether, normal hexane or cyclohexane for 2-4 times; a volume ratio of an extracting solvent to the extracting solution is (1-2):(1-2); extracting solutions are mixed; the extracting solvent is recovered, and an extractant is obtained; the obtained extractant is separated by silicagel column chromatography, and subjected to gradient elution by a petroleum ether and ethyl acetate mixed solvent; and elution distillment of petroleum ether and ethyl acetate at the volume ratio of 100:(0-2) is collected.
Description
Technical field
The present invention relates to a kind of N-acyl group schwann's sheath amine alcohol compound, preparation method and suppress the application in angiotensin i-converting enzyme active medicine in preparation.
Background technology
Hypertension is modal cardiovascular disorder, is the principal element threatening grownup's health.In human body, angiotensin I-converting Enzyme (Angiotensin I-converting enzyme, ACE) is angiotonase-angiotensin system (Renin-angiotension system, RAS) most important adjustment hinge.On the one hand ACE can by the angiotensin I(Angiotensin I from hepatic secretion) cut off be converted into angiotensin II(Angiotensin II), angiotensin II impels vasoconstriction, causes hypertension; On the other hand, the kallikrein in blood plasma cuts off kininogen proteins and produces bradykinin (Bradykinin), and bradykinin promotes vasodilation, make blood pressure drops, but ACE but makes bradykinin decompose, passivation bradykinin; All cause elevation of blood pressure in human body these two of ACE, if inhibit the activity of ACE, just can suppress hypertensive generation.
Current antihypertensive drugs is divided into five large classes: interference adrenergic nerve medicine, vasodilation medicine, calcium antagonist medicine, diuretic antihypertensive medicine and angiotensin-conerting enzyme (ACE) inhibitor.After wherein angiotensin-conerting enzyme (ACE) inhibitor acts on renin-angiotensin system, effectively can regulate, control human blood-pressure, be applied to the treatment of multiple cardiovascular disorder, as congestive heart disease, myocardial infarction, diabetic nephropathy and renal tubal dysfunction etc., represent medicine as captopril (captopril).Although captopril can stop the activity of ACE, the also side effect of various degrees, as cough, maldigestion reaction, hepar damnification, postural hypotension, kidney injury, oligoleukocythemia etc.Natural drug have stable curative effect, action temperature and, the advantage such as toxicity is little, in treatment diabetes, there is the irreplaceable advantage of Western medicine.Halophytes is the most valuable economic plant resources in Xinjiang, but also lacks the Halophyte Resources that Xinjiang is abundant at present and go deep into systematic research, especially in the exploitation of medicinal halophytes.
Tamarix
tamarixlinn. plant is the host of Cistanche Tubulosa, is that suspend distribution is the widest, the genus of most species.Congener Tamarix ramosissima
t. ramosissimaledeb. be one of main host plants plant of Cistanche Tubulosa, be also one of the Tamarix the most widely that distributes, be mainly distributed in the arid areas such as the Inner Mongol, Ningxia, Gansu, Qinghai, at source also do Chinese tamarisk and use.Record according to " Harbin Pharmaceuticals ", the branches and leaves of Tamarix ramosissima can be used as medicine, and are used for the treatment of rheumatosis and jaundice; Branch can be used as astringent matter, and for flu, measles goes out saturating from the beginning of, rash, the diseases such as rheumatic pain, sprains, and wound is downright bad, all have good curative effect.Number of patent application is the Chinese invention patent application of 200910249032.4, discloses one and " extracts from plant
the method of-glucosidase activity inhibitor "; disclosed in it, concrete grammar is: put into extractor after dry for Tamarix ramosissima cauline leaf is shredded grinding; add alcohol-water or acetone-water solution soaking that volume and Tamarix ramosissima cauline leaf mass ratio are 8 ~ 30ml/g; heating and refluxing extraction; Extracting temperature is for reaching to boiling temperature, and extraction time is 1 ~ 3 time, and each extraction time is 1.0 ~ 3.0h; discard extracting solution, and dries for extract by remaining cauline leaf; In extract, add the water that volume and extract quality ratio are 5 ~ 30ml/g carry out second extraction, Extracting temperature causes boiling temperature for reaching, and extraction time is 1 ~ 3 time, and each extraction time is 1.0 ~ 3.0h; Collect and merge cooled extracting solution, concentrating under reduced pressure, lyophilize obtains plant milk extract.This extract has suppression
-glucosidase activity, can be widely used in preparing and reduce in the medicine of diabetes and healthcare products.But also not do not obtain N-acyl group schwann's sheath amine alcohol compound and it is for suppressing the relevant report of angiotensin i-converting enzyme about being separated from Tamarix ramosissima up to now.
Summary of the invention
The present invention is the above-mentioned technical problem in order to solve existing for prior art, provides a kind of N-acyl group schwann's sheath amine alcohol compound, preparation method and suppresses the application in angiotensin i-converting enzyme active medicine in preparation.
Technical solution of the present invention is:
A preparation method for N-acyl group schwann's sheath amine alcohol compound, is characterized in that carrying out as follows successively:
A. get the Tamarix ramosissima of pulverizing, employing volume fraction is ethanol or the methyl alcohol immersion post-heating refluxing extraction of 50 ~ 100%, each extraction time 2 ~ 3h, extraction time 2 ~ 3 times, united extraction liquid, reclaim under reduced pressure extracting solution is to determining alcohol lower than 5 %, and contained crude drug concentration is 50 ~ 100g/ml;
B. extracted 2 ~ 4 times through sherwood oil, normal hexane or hexanaphthene by the extracting solution of gained, the volume ratio of extraction solvent and extracting solution is 1 ~ 2: 1 ~ 2, combining extraction liquid, and recycling design obtains extract;
C. be separated through silica gel column chromatography by the extract obtained, with the mixed solvent gradient elution of sherwood oil, ethyl acetate, collection sherwood oil and ethyl acetate volume ratio are the eluting fraction of 100:0 ~ 2.
The amount ratio of the Tamarix ramosissima of described pulverizing and ethanol or methyl alcohol is 1 Kg:6 ~ 20 L.
An above-mentioned N-acyl group schwann's sheath amine alcohol compound, is characterized in that the application suppressed in preparation in angiotensin i-converting enzyme active medicine.
The present invention is the reflux extracting liquid utilizing Tamarix ramosissima; from Tamarix ramosissima, separation and purification goes out the new N-acyl group schwann's sheath amine alkylol cpd of a class first; by method provided by the invention, separating-purifying is carried out to such N-acyl group schwann's sheath amine alkylol cpd, simple and convenient, easily operate.The N-acyl group schwann's sheath amine alkylol cpd extracted derives from common natural drug, and having no side effect, is 11.7 ~ 187 μm of olmL in concentration
-1have and comparatively significantly suppress angiotensin i-converting enzyme active, can apply in the functional food of preparation auxiliary adjustment blood pressure and treatment hypertension drug.
Accompanying drawing explanation
Fig. 1 is the mass spectrum of N-acyl group schwann's sheath amine alcohol compound.
Embodiment
The extraction and isolation of embodiment 1 N-acyl group schwann's sheath amine alcohol compound
A. get 3.1 kg Tamarix ramosissimas (
tamarix.ramosissimaledeb.) over-ground part is pulverized with pulverizer, and employing 24.8L volume fraction is the alcohol immersion post-heating refluxing extraction of 100%, each extraction time 2h, extraction time 2 times, united extraction liquid, reclaim under reduced pressure extracting solution is to determining alcohol lower than 5 %, and contained crude drug concentration is 50 ~ 100g/ml;
B. by the extracting solution of gained through petroleum ether extraction 3 times, the volume ratio of extraction solvent and extracting solution is 2:1, combining extraction liquid, and recycling design obtains extract;
C. be separated through silica gel column chromatography by the extract 30g obtained, with the mixed solvent gradient elution of sherwood oil, ethyl acetate, collection sherwood oil and ethyl acetate volume ratio are the eluting fraction of 100:0 ~ 2, solvent flashing under room temperature, separate out white powder.
TLC detects the composition in elutriant, and the merging that chemical composition is identical obtains N-acyl group schwann's sheath amine alcohol compound 10 mg(formula 1).
Embodiment 2:
A. get 4 kg Tamarix ramosissimas (
tamarix.ramosissimaledeb.) over-ground part is pulverized with pulverizer, adopt 24 volume fractions be 80% methyl alcohol soak post-heating refluxing extraction, each extraction time 2h, extraction time 2 times, united extraction liquid, reclaim under reduced pressure extracting solution is to determining alcohol lower than 5 %, and contained crude drug concentration is 50 ~ 100g/ml;
B. by the extracting solution of gained through n-hexane extraction 2 times, the volume ratio of extraction solvent and extracting solution is 1:2, combining extraction liquid, and recycling design obtains extract;
C. be separated through silica gel column chromatography by the extract 30g obtained, with the mixed solvent gradient elution of sherwood oil, ethyl acetate, collection sherwood oil and ethyl acetate volume ratio are the eluting fraction of 100:0 ~ 2, solvent flashing under room temperature, separate out white powder.
TLC detects the composition in elutriant, and the merging that chemical composition is identical obtains N-acyl group schwann's sheath amine alcohol compound.
Embodiment 3:
A. get 1 kg Tamarix ramosissima (
tamarix.ramosissimaledeb.) over-ground part is pulverized with pulverizer, and employing 20L volume fraction is the methyl alcohol immersion post-heating refluxing extraction of 50%, each extraction time 3h, extraction time 3 times, united extraction liquid, reclaim under reduced pressure extracting solution is to determining alcohol lower than 5 %, and contained crude drug concentration is 50 ~ 100g/ml;
B. by the extracting solution of gained through n-hexane extraction 4 times, the volume ratio of extraction solvent and extracting solution is 1:1, combining extraction liquid, and recycling design obtains extract;
C. be separated through silica gel column chromatography by the extract 30g obtained, with the mixed solvent gradient elution of sherwood oil, ethyl acetate, collection sherwood oil and ethyl acetate volume ratio are the eluting fraction of 100:0 ~ 2, solvent flashing under room temperature, separate out white powder.
TLC detects the composition in elutriant, and the merging that chemical composition is identical obtains N-acyl group schwann's sheath amine alcohol compound.
The Structural Identification of N-acyl group schwann's sheath amine alcohol compound:
The white powder that embodiment 1 ~ 3 obtains, EI-MS: providing molecular weight is 535.According to mass spectrum (Fig. 1) fracture mode, molecular weight in turn reduces 28,26,28,18,28,15,27,27,27,16 from 535, etc., the group ruptured successively is C=O, C-N, C=O, H
2o, C=O, CH
3, CH
2-CH, CH
2-CH, CH
2-CH, CH
4, etc.In conjunction with
1h NMR composes (DMSO-
d 6) and
13c NMR composes, and δ 1.15-1.34 has strong proton signal and δ 0.81(3H, q), infer there are two aliphatic alkyl chains; δ 7.24(1H, s, NH) and δ 174.17(CONH) and δ 5.31(1H, m), δ 39.60(CH-NH) and connect oxygen carbon signal δ 77.65,77.43,76.81, amido linkage and polyhydric existence in 77.23,61.42 display structures, above data show that this composition is ceramide type compound.
With n in structural formula, and n is greater than 0 integer being less than 4.
The suppression angiotensin i-converting enzyme of N-acyl group schwann's sheath amine alcohol compound is active:
Concrete active testing process is as follows: with containing 608 mmolL
-10.2 molL of NaCl
-1borate buffer solution, is made into 7.6 mmolL by Hip-His-Leu
-1solution; Get 5 μ l N-acyl group schwann's sheath amine alcohol compounds, be placed in 0.5 mL centrifuge tube, add ACE 15 μ l, after reacting 5 min at 37 DEG C, add 25 μ l Hip-His-Leu solution, at mixing 37 DEG C, react 30 min; By 5 μ l10 % trifluoroacetic acid termination reactions, obtain reaction solution.Do blank assay, except adding equivalent distilled water and replacing sample, other operation is identical simultaneously.This reaction solution is directly analyzed at HPLC system sample introduction.The urobenzoic acid obtained by ACE substrate specificity is come quantitatively by HPLC.Moving phase: 30 % methyl alcohol-1 ml trifluoroacetic acid-0.5 ml glacial acetic acids (adjusting pH 3.0 ~ 3.3), 70 % methyl alcohol-1 ml trifluoroacetic acid-0.5 ml glacial acetic acids (adjusting pH 3.0 ~ 3.3) carry out gradient elution; Determined wavelength: 228 nm.
Inhibiting rate (%)=(A-B)/A × 100 (%)
In formula, A is not containing the urobenzoic acid liquid phase peak area of inhibitor, and B is the urobenzoic acid liquid phase peak area containing inhibitor.
Be 11.7,23.4,46.8,93.6,187 μm of olmL to concentration respectively by aforesaid method
-1the suppression angiotensin i-converting enzyme activity of N-acyl group schwann's sheath amine alcohol compound measure, inhibiting rate is respectively 13 %, 57 %, 74 %, 63% and 54%.Result shows that such compound on vascular Angiotensin I converting enzyme activity has comparatively significantly inhibit activities.
The extract that the embodiment of the present invention 1 ~ 3 prepares can as treatment and preventing hypertension and related cardiovascular disease medicine thereof various preparations, suppression elevation of blood pressure functional food and as the foodstuff additive etc. reduced blood pressure.Medicine and healthcare products are mixed to form various forms of pill, powder, tablet, paste, pulvis with auxiliary material, injection, aqua, granule, capsule, injection etc.; Protective foods form can be liquid such as refreshment drink, soda pop, seasonings; Can join wheaten food class as additive, jelly, ice-creams, curing food, ham, point in the heart.
Claims (2)
1. a preparation method for N-acyl group schwann's sheath amine alcohol compound, is characterized in that carrying out as follows successively:
A. get the Tamarix ramosissima of pulverizing, employing volume fraction is ethanol or the methyl alcohol immersion post-heating refluxing extraction of 50 ~ 100%, each extraction time 2 ~ 3h, extraction time 2 ~ 3 times, united extraction liquid, reclaim under reduced pressure extracting solution is to determining alcohol lower than 5 %, and contained crude drug concentration is 50 ~ 100g/ml;
B. extracted 2 ~ 4 times through sherwood oil, normal hexane or hexanaphthene by the extracting solution of gained, the volume ratio of extraction solvent and extracting solution is 1 ~ 2: 1 ~ 2, combining extraction liquid, and recycling design obtains extract;
C. be separated through silica gel column chromatography by the extract obtained, with the mixed solvent gradient elution of sherwood oil, ethyl acetate, collection sherwood oil and ethyl acetate volume ratio are the eluting fraction of 100:0 ~ 2.
2. the preparation method of N-acyl group schwann's sheath amine alcohol compound according to claim 1, is characterized in that the Tamarix ramosissima of described pulverizing and the amount ratio of ethanol or methyl alcohol are 1 Kg:6 ~ 20 L.
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Non-Patent Citations (4)
| Title |
|---|
| 10种盐生植物对血管紧张肽I-转化酶活性的影响;刘宇等;《中国药学杂志》;20100531;第45卷(第10期);736-738 * |
| RN 123065-40-7;CAS;《STN REGISTRY》;19891006;全文 * |
| 南海海绵Gellius cymiformis 化学成分的研究;肖定军等;《天然产物研究与开发》;19991231;第11卷(第1期);6-9 * |
| 多枝柽柳化学成分研究;张媛等;《中草药》;20061231;第37卷(第12期);1764-1768 * |
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