CN106279087A - A kind of compound and preparation method thereof, medical applications - Google Patents
A kind of compound and preparation method thereof, medical applications Download PDFInfo
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- CN106279087A CN106279087A CN201610670294.8A CN201610670294A CN106279087A CN 106279087 A CN106279087 A CN 106279087A CN 201610670294 A CN201610670294 A CN 201610670294A CN 106279087 A CN106279087 A CN 106279087A
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- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
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Abstract
The present invention relates to a kind of native compound, and the preparation method separated from Rhizoma Saururi (Herba Saururi), further relate to its application in acute gastric ulcer damages.The compound (I) that the present invention provides, separates from Rhizoma Saururi (Herba Saururi) and separates first, and this native compound (I) novel structure, structural formula is as follows；During this native compound (I) independent role, acute gastric ulcer damage had therapeutical effect.
Description
Technical field
The invention belongs to biomedicine field, relate to a kind of native compound and the preparation separated from Rhizoma Saururi (Herba Saururi) thereof
Method, further relates to its application in acute gastric ulcer damages.
Background technology
Rhizoma Saururi (Herba Saururi), formal name used at school: Saururus chinensis (Lour.) Baill, another name side of a pond Rhizoma Nelumbinis.It is distributed in Hebei, river
South, Shandong and the Yangtze river basin and on the south various places.This product rhizome is cylinder, slightly bent, has branch.Herb is medicinal, takes orally and controls
Urinary tract infection, lithangiuria, tinea pedis edema and trophedema；Ulcerative carbuncle furuncle and phyma, skin eczema etc. are controlled in external application.
Summary of the invention
It is an object of the invention to provide a kind of compound, this natural product can damage with Synergistic treatment acute gastric ulcer；
Meanwhile, the present invention also resides in the preparation method providing a kind of above-claimed cpd to separate from Rhizoma Saururi (Herba Saururi)；And also this is provided
Compound application in the medicine of preparation treatment acute gastric ulcer damage.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
The preparation method of above-claimed cpd (I), it is characterised in that comprise following operating procedure: Rhizoma Saururi (Herba Saururi) is pulverized by (a),
With 80～90% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, full with petroleum ether, ethyl acetate and water successively
The n-butanol extraction of sum, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；In (b) step (a)
N-butyl alcohol takes thing macroporous resin remove impurity, first with 6 column volumes of 30% ethanol elution, then with 12 cylinders of 85% ethanol elution
Long-pending, collect 85% eluent, concentrating under reduced pressure obtains 85% ethanol elution concentrate；85% ethanol elution concentrate in (c) step (b)
Separate by purification on normal-phase silica gel, obtain with the methylene chloride-methanol gradient elution that volume ratio is 100:1,50:1,25:1 and 12:1 successively
4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 20:1,12:1 and 2:1 by volume ratio successively
Methylene chloride-methanol gradient elution obtains 3 components；E anti-phase silicon that in () step (d), component 2 is bonded by octadecylsilane
Glue separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 88%, collects 13～16 column volume eluents, eluting
Liquid is concentrated under reduced pressure to give compound (I).
As preferably, described macroporous resin is D101 type macroporous adsorbent resin.
The application in the medicine of preparation treatment acute gastric ulcer damage of the above-mentioned compound (I).
Advantages of the present invention:
The present invention provides the natural product of a kind of novel structure, during this natural product independent role, damages acute gastric ulcer
Wound has therapeutical effect；It addition, this natural product can also can develop into treatment acute with other existing drug regimen medications
The medicine of gastric ulcer damage.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit the present invention with this and protect model
Enclose.Although the present invention being explained in detail with reference to preferred embodiment, it will be understood by those within the art that, can be right
Technical scheme is 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, insults peaking purchased from Shanghai
Learning reagent company limited, methanol, analytical pure, purchased from Jiangsu Han Bang chemical reagent company limited.
Separation method: Rhizoma Saururi (Herba Saururi) (2kg) is pulverized by (a), extracts (15L × 3 time) with 85% alcohol heat reflux, united extraction
Liquid, is concentrated into without alcohol taste (3L), successively with petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water saturated n-butyl alcohol
(3L × 3 time) extract, and respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；In (b) step (a)
Acetic acid ethyl ester extract D101 type macroporous resin remove impurity, first with 6 column volumes of 30% ethanol elution, then uses 85% ethanol elution
12 column volumes, collect 85% eluent, and concentrating under reduced pressure obtains 85% ethanol elution concentrate；C in () step (b), 85% ethanol is washed
De-concentrate purification on normal-phase silica gel separates, successively with volume ratio be 100:1 (12 column volumes), 50:1 (10 column volumes), 25:1
The methylene chloride-methanol gradient elution of (8 column volumes) and 12:1 (8 column volumes) obtains 4 components；Group in (d) step (c)
Points 4 separate further by purification on normal-phase silica gel, successively with volume ratio be 20:1 (6 column volumes), 12:1 (8 column volumes) and 2:1 (6
Individual column volume) methylene chloride-methanol gradient elution obtain 3 components；Component 2 octadecylsilane key in (e) step (d)
The reverse phase silica gel closed separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 88%, collects 13～16 column volumes
Eluent, eluent is concentrated under reduced pressure to give compound (I) (HPLC normalization purity is more than 98%).
Structural identification: HR-ESI-MS shows [M+H]+For m/z 405.1470, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C21H24O8, degree of unsaturation is 10.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-2 (6.18, d, J=
6.8Hz), H-3 (3.79, d, J=6.8Hz), H-5 (2.66, d, J=6.8Hz), H-6 (4.57, dd, J=6.8,9.6Hz), H-
7 (3.11, ddt, J=9.6,3.5,3.3Hz), H-8 (5.14, ddd, J=9.6,4.7,4.7Hz), H-9a (2.57, dd, J=
14.0,4.7Hz), H-9b (2.43, dd, J=14.0,4.7Hz), H-13a (6.01, d, J=3.5Hz), H-13b (5.51, d, J
=3.5Hz), and H-14a (5.14, s), H-14b (5.06, s), H-15a (4.75, d, J=12.5Hz), H-15b (4.33, d, J=
12.5Hz), and H-3 ' a (6.02, s), H-3 ' b (5.62, s), H-4 ' (1.95, s), 15-OAc (2.05, s)；Carbon-13 nmr spectra
Data δC(ppm, CDCl3, 125MHz): 141.2 (C, 1-C), 117.8 (CH, 2-C), 83.4 (CH, 3-C), 83.4 (C, 4-C),
57.4 (CH, 5-C), 77.2 (CH, 6-C), 48.7 (CH, 7-C), 74.6 (CH, 8-C), 38.7 (CH2, 9-C), 137.8 (C, 10-
C), 134.9 (C, 11-C), 168.2 (C, 12-C), 121.3 (CH2, 13-C), 116.4 (CH2, 14-C), 67.2 (CH2, 15-C),
164.6 (C, 1 '-C), 136.1 (C, 2 '-C), 122.4 (CH2, 3 '-C), 18.1 (CH3, 4 '-C), 172.8 (C, 15-COCH3),
21.7(CH3, 15-COCH 3 ).Infrared spectrum shows that this compound contains lactone ring five membered (1765cm-1) and hydroxyl (3600cm-1)。13C-NMR and hsqc spectrum show 21 carbon signals, including two methyl (acetonyl), five methylene (companies
Oxymethylene, three olefinic methylene), six methines (three even oxygen carbon and an olefinic carbon) and eight quaternary carbons (three
Ester carbonyl group, four alkene quaternary carbons and company's oxygen quaternary carbon).1H-NMR shows two distinctive single protons doublets signal [δH6.01 (1H, d, J=3.5Hz, H-13a) and 5.51 (1H, d, J=3.5Hz, H-13b)], and all with H-7 [δH3.11 (1H,
Ddt, J=9.6,3.5,3.3Hz)] it is connected it was confirmed the existence of alpha-methylene-gamma lactone structure.Additionally, the coupling of H-6 and H-7
Close constant (J6,7=9.6Hz) and the pi-allyl coupling constant (J of H-7 and H-137,13=3.5Hz) show that lactone is trans company
Connect.Heptatomic ring exocyclic double bond signal [δH5.14 (1H, s, H-14a) and 5.06 (1H, s, H-14b)].Two unimodal proton signal δH6.02 and 5.62 (H-3 ' a and H-3 ' b), and the sharp-pointed unimodal signal δ that three protons are formedH1.95(CH3-4 ') show
This compound contains a 2-methacryloxy side chain.H-8 (δ in HMBC spectrumH5.14) with carbonyl carbon C-1 ' (δC164.6)
Dependency show that side chain is positioned at C-8 position.Meanwhile, H2-15 and C-COCH3Dependency explanation C-15 position be connected with an acetyl oxygen
Base.Understanding this compound according to above-mentioned nuclear magnetic data is a sesquiterpenoids.By consulting literatures it appeared that this change
Compound and known compound 2 α 3 β 4 α-trihydroxy-4 β-(acetoxymethyl)-8 α (4-methacrylate)-1 α H, 5
α H, 6 β H, 7 α H-guai-10 (14), 11 (13)-dien-6,12-olide have similar structure.Relatively both nuclear-magnetism numbers
According to it is found that the difference of this noval chemical compound and known compound is, noval chemical compound has had more a double bond signal.Further
HMBC spectrum resolve, H-2 and C-1, H-3 and the dependency of C-2 and H-5 and the C-2 additional double bond signal of explanation is in
C-1 and C-2 position.In NOESY spectrum, the dependency between H-3/H-5, H-5/H-7 illustrates the 3-OH in this compound, and C-
Group on 7 is in β position.Additionally, dependency the explanation 4-OH, C-6 of H-15/H-6, H-6/H-13 and H-8/H-6
Group on position and the group on C-8 position are in α position.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, and document
About correlation type nuclear magnetic data, can substantially determine that this compound is as follows, spatial configuration is further by ECD test really
Fixed, theoretical value is basically identical with experiment value.This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
The present embodiment uses ethanol to prepare chmice acute gastric mucosa injury model, measures Gastric mucosal injury index and includes mice
Gastric tissue SOD activity, MAD and PEG2Content, observes the medicine therapeutical effect to acute gastric mucosal injury.
1, materials and methods
1.1 animal
Kunming mice, (25 ± 4) g, male and female half and half, Shandong Traditional Chinese Medicine University's animal center provides.
1.2 reagent and sample
Moclobemide is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.Three
Nine stomach Thailand granules are purchased from Sanjiu Pharmaceutical Co., Ltd.Superoxide dismutase (SOD) test kit, malonaldehyde (MAD) reagent
Box is purchased from sea blue base bio tech ltd.
1.3 instrument
Ultraviolet-uisible spectrophotometer (model: UV-2450/2550), Shimadzu Corporation of Japan produces.
Prepared by 1.4 mice group and model
Choose healthy mice 60 (male and female half and half), be randomly divided into 6 groups, respectively blank group, model control group, sun
Property matched group (SANJIU WEITAI KELI) and moclobemide group (80mg kg-1), compound (I) group (80mg kg-1), chlorine shellfish
Amine and compound (I) compositions group [40mg kg-1Moclobemide+40mg kg-1Compound (I)].Model control group and blank
Matched group gives normal saline, and other are administered continuous gavage 10d.After last is administered, fasting is not intake 24h, is administered the last time
After 1h, in addition to blank group, every equal gavage, to dehydrated alcohol, is administered by 0.1mL/10g.
1.5 gastric tissue SOD activity, MAD assay
The preparation of stomach gross specimen: at animal after death, is placed on ice chest, quickly takes full stomach, cuts off along greater gastric curvature, uses
Inside normal saline flushing coat of the stomach, flatten and be placed in body basis of microscopic observation gastric mucosa injury degree.Illustrate to measure according to test kit
Tissue SOD's activity, MAD assay.
1.6 gastric tissue PGE2Assay
Taking gastric tissue homogenate 2mL, 4 DEG C of 3000rpm take supernatant after being centrifuged 15min, with radioactivity determination PGE2Content.
1.7 statistical method
It is analyzed with Excel worksheet, between each test group and matched group, uses t inspection to compare.
2, experimental result
SOD, MAD, PGE in 2.1 pairs of acute gastric mucosal lesion model mice gastric tissues2The impact of content
With blank group ratio, model control group SOD content reduces (P < 0.05), MAD content raises (P < 0.05), PGE2
Content reduces (P < 0.05), and modeling success is described；With model control group ratio, positive controls SOD content significantly raise (P <
0.01), MAD content significantly reduces (P < 0.01), PGE2Content raises (P < 0.05)；With model control group ratio, moclobemide with
Compound (I) compositions group SOD content significantly raises (P < 0.01), MAD content significantly reduces (P < 0.01), PGE2Content is notable
Raise (P < 0.01)；With model control group ratio, moclobemide group, compound (I) group SOD content raises (P < 0.05), MAD content
Reduce (P < 0.05), PGE2Content raises (P < 0.05).
Result of the test is shown in Table 1.
Table 1 is to SOD, MAD, PGE in acute gastric mucosal lesion model mice gastric tissue2The impact of content
Acute gastric mucosal lesion is clinical common emergency case, finds that pathomechanism was mainly endogenous and exogenous attacks in recent years
The equilibrium relation hitting the factor and gastric mucosal protection mechanism is unbalance, at present it has proven convenient that OH free radical and O free radical and multiple types
The gastric mucosa injury of type is relevant, and research thinks that O free radical had both participated in histiocytic damage process, is also cell homergy
Intermediate product.Owing to oxygen-derived free radicals is relevant with gastric mucosa injury, i.e. participating in histiocytic damage is also cell homergy
Product.The height of MAD content reflects the degree that body is attacked by oxygen-derived free radicals indirectly, and SOD can eliminate free radical, and its activity is high
The low ability indirectly reflecting body scavenging activated oxygen.PGE2 has the effect of gastric acid secretion inhibiting, and can promote gastric mucus
Secrete and increase gastric mucosal blood flow and play protective effect, so its content height reflects the protective capability to gastric mucosa.
The above results shows, when moclobemide, compound (I) independent role, acute gastric ulcer damage is had protection and makees
With；When moclobemide and compound (I) synergy, the protective effect to acute gastric ulcer damage further enhances, Ke Yikai
Send out into the medicine treating acute gastric ulcer damage.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit the protection of the present invention with this
Scope.It will be understood by those within the art that, technical scheme can be modified or equivalent,
Essence and protection domain without deviating from technical solution of the present invention.
Claims (4)
1. a compound (I) with following structural formula,
2. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a) is by three
Pennisetum centrasiaticum Tzvel pulverize, with 80～90% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, successively use petroleum ether, acetic acid second
Ester 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 30% ethanol elution, then uses 85% ethanol elution
12 column volumes, collect 85% eluent, and concentrating under reduced pressure obtains 85% ethanol elution concentrate；C in () step (b), 85% ethanol is washed
De-concentrate purification on normal-phase silica gel separates, successively by the methylene chloride-methanol gradient that volume ratio is 100:1,50:1,25:1 and 12:1
Afford 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 20:1,12:1 by volume ratio successively
3 components are obtained with the methylene chloride-methanol gradient elution of 2:1；E in () step (d), component 2 is bonded by octadecylsilane
Reverse phase silica gel separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 88%, collects 13～16 column volume eluting
Liquid, eluent is concentrated under reduced pressure to give compound (I).
The preparation method of compound the most according to claim 2 (I), it is characterised in that: described macroporous resin is D101 type
Macroporous adsorbent resin.
4. the application in the medicine of preparation treatment acute gastric ulcer damage of the compound (I) described in claim 1.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030733A (en) * | 2010-12-30 | 2011-04-27 | 上海同田生物技术有限公司 | Method for preparing high-purity costuslactone and dehydrocostus lactone |
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- 2016-08-14 CN CN201610670294.8A patent/CN106279087A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102030733A (en) * | 2010-12-30 | 2011-04-27 | 上海同田生物技术有限公司 | Method for preparing high-purity costuslactone and dehydrocostus lactone |
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Application publication date: 20170104 |