CN106188179A - There is sharp leaf vacation Radix Gentianae extract, compound and the pharmaceutical composition of anti-diarrhea effect - Google Patents

There is sharp leaf vacation Radix Gentianae extract, compound and the pharmaceutical composition of anti-diarrhea effect Download PDF

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CN106188179A
CN106188179A CN201610536509.7A CN201610536509A CN106188179A CN 106188179 A CN106188179 A CN 106188179A CN 201610536509 A CN201610536509 A CN 201610536509A CN 106188179 A CN106188179 A CN 106188179A
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compound
agent
represent
pharmaceutical composition
radix gentianae
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CN106188179B (en
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王涛
张祎
刘艳霞
倪雅娟
于海洋
韩立峰
郝佳
刘二伟
高秀梅
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Tianjin University of Traditional Chinese Medicine
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 9
    • C07D311/86—Oxygen atoms, e.g. xanthones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C07H1/08—Separation; Purification from natural products
    • 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)
    • A61K36/51—Gentianaceae (Gentian family)
    • A61K36/515—Gentiana

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Abstract

The embodiment of the invention discloses the compound of a kind of logical formula I purposes in preparing antidiarrheal, the compound of logical formula I, and comprise the sharp leaf vacation Radix Gentianae extract of described compound, and comprise described compound or the pharmaceutical composition of point leaf vacation Radix Gentianae extract.Show after deliberation, the present invention obtained compound from point leaf vacation Radix Gentianae has anti-diarrhea effect in various degree, it is expected to the compound obtained by the present invention or may be used for antidiarrheal, it is possible to further be used for preparing antidiarrheal containing its sharp leaf vacation Radix Gentianae extract, pharmaceutical composition.

Description

There is sharp leaf vacation Radix Gentianae extract, compound and the pharmaceutical composition of anti-diarrhea effect
Technical field
The present invention relates to field of phytochemistry, particularly to having the sharp leaf vacation Radix Gentianae extract of anti-diarrhea effect, compound And pharmaceutical composition.
Background technology
Diarrhoea is a kind of common sympton, refer to defecation frequency significantly more than the frequency being on ordinary days accustomed to, excrement matter is thin, and moisture increases Adding, every day, feces volume was more than 200g, or containing not digesting food or pus and blood, mucus.Diarrhoea is often accompanied by defecation urgency sense, anus not The symptoms such as suitable, incontinence.Acute and chronic two classes of diarrhoea point, drastically, the course of disease is within 2～3 weeks in acute diarrhea morbidity；Chronic diarrhea Refer to the recurrent diarrhoea that the course of disease is more than two months or the intermission is in 2～4 weeks.For violent acute diarrhea or long-term chronic Diarrhoea, needs to take antidiarrheal to prevent the imbalance of body excessive dehydration, water-electrolyte metabolism, digestion and malnutrition.
Point leaf vacation Radix Gentianae (Gentianella acuta (Michx.) Hulten), false for Gentianaceae (Gentiananceae) Gentiana (Gentianella Moench.) plant, has another name called bitter Radix Gentianae, and the entitled A Gute of medicine-its its lattice are annual for Gentianaceae Herbaceous plant, all herbal medicine.It is distributed widely in the areas such as China Hebei, northeast, the Inner Mongol, Shanxi, Shandong, the Soviet Union, Mongolia, north Also there is distribution in America.It is used in illiteracy, Tibetanmedicine, mongolian medicine is referred to as " A Gute-its its lattice ", there is effect of heat-clearing and toxic substances removing, Treatment icterohepatitis, have a headache, the principal agent of fever etc..The hunter of Ewenki and the Oroqen loses with its treatment rhythm of the heart for a long time Often etc. heart disease and effect are notable, are a kind of plants with treatment heart disease effect of this genus, have not in Mongolia Medicine Alternative status.
Summary of the invention
Point leaf vacation Radix Gentianae is extracted and has been separated by inventor, has obtained extract and a series ofization of sharp leaf vacation Radix Gentianae Compound, and surprisingly it has been found that obtained extract and/or compound have anti-diarrhea effect.And based on this, complete this Invention.
A first aspect of the present invention provides the compound of logical formula I purposes in preparing antidiarrheal,
Wherein, R1、R2、R3、R4、R5The most independent representative-H ,-OH ,-OCH3、 In this article, in unit structure formulaRepresent the connection of this group and molecule other parts Point.
In some preferred implementations of first aspect present invention, R1Represent-OH ,-OCH3OrR2Represent- OH orR3Represent-H ,-OH orR4Represent-H or-OH；R5Represent-H or-OH.
First aspect present invention other preferred embodiment in, the compound of logical formula I is selected from:
A second aspect of the present invention provides the compound of logical formula I,
Wherein,
R1Represent-OH orR2Represent-OH orR3Represent-OH, R4Representative-H, R5 Representative-OH.
In one preferred implementation of second aspect present invention, the compound of logical formula I is selected from:
A third aspect of the present invention provides the sharp leaf vacation Radix Gentianae extract comprising aforementioned formula (I) compound.
A fourth aspect of the present invention provides a kind of pharmaceutical composition for antidiarrheal, and wherein said pharmaceutical composition comprises There are active constituents of medicine and pharmaceutically acceptable carrier or excipient；Described active constituents of medicine is selected from aforesaid logical formula I Compound or aforesaid point leaf vacation Radix Gentianae extract.
In one preferred implementation of fourth aspect present invention, logical formula I compound extracts from point leaf vacation Radix Gentianae Arrive.
In another preferred implementation of fourth aspect present invention, wherein said pharmaceutically acceptable carrier or excipient Selected from solvent, diluent, dispersant, suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, binding agent, Lubricant, stabilizer, hydrating agents, emulsifying accelerator, buffer agent, absorbent, coloring agent, flavouring agent, sweeting agent, ion exchange Agent, releasing agent, smears, correctives and antioxidant.
In another preferred implementation of fourth aspect present invention, pharmaceutical composition described herein is preferably made following dose Type: tablet, capsule, powder, granule, lozenge, pill, solution, suspensoid, Emulsion, syrup, powder, granula subtilis, little Pill, elixir, injection, medicinal drops, ointment, lotion, gel, emulsifiable paste, spray, suppository or patch.
Showing after deliberation, the present invention obtained compound from point leaf vacation Radix Gentianae has anti-diarrhea effect in various degree, It is expected to the compound obtained by the present invention or only may be used for containing its sharp leaf vacation Radix Gentianae extract, pharmaceutical composition Rush down, it is possible to further be used for preparing antidiarrheal.
Detailed description of the invention
Being described technical scheme below in conjunction with specific embodiment, described embodiment is only this Invent a part of embodiment rather than whole embodiments.Based on the embodiment in the present invention, those of ordinary skill in the art exist Do not make the every other embodiment obtained under creative work premise, broadly fall into the scope of protection of the invention.
Embodiment 1 point leaf vacation Radix Gentianae extract and the preparation of chemical composition
Through 14 times amount 70% alcohol heating reflux, 3 times (it is little that the time of backflow is respectively 3 to point leaf vacation Radix Gentianae herb (3.0kg) Time, 2 hours, 2 hours), merging filtrate, decompression and solvent recovery, obtain extractum 1053.4g.Take above-mentioned extractum 868.5g, use CHCl3- H2O (1:1, v/v) extracts, and obtains CHCl respectively3And H2O extract 64.5g and 804.0g.Take H2O extract (670.0g) warp (eluent is followed successively by H to the process of D101 macroporous adsorbent resin2O → 95% ethanol → acetone), obtain H2O, 95% ethanol and acetone are washed De-thing is respectively 332.4g, 294.9g and 5.1g.
Above-mentioned 95% ethanol elution thing (200g) is through silica gel column chromatography [CHCl3→CHCl3-methanol (100:1 → 100:5, v/ v)→CHCl3-methanol-H2O (10:3:1 → 7:3:1 → 6:4:1, lower floor, v/v/v)], 16 components of isolated (component 1～ Component 16, is named by elution order, first named component 1 flowed out, the named component 16 finally flowed out, group below Point nomenclature principle is all identical with this).Centrifuged 1,3,5, the 8-Tetrahydroxyxanthones of component 7 (25.7g) (compound 4, 15.9g) with component 7-2 (9.8g), component 7-2 (9.8g) separates preparation through preparative high performance liquid chromatography (PHPLC) [CH3CN-H2O (18:82 → 35:65 → 42:58, v/v)+1% acetic acid], obtain 27 components (component 7-2-1～components 7-2- 27).Component 7-2-22 (54.4mg) separates (methanol) through Sephadex LH-20 gel filtration chromatography, obtains 1,3,5-trihydroxy oxygen Miscellaneous anthrone (compound 3,25.6mg).
Component 11 (20.0g) prepares [CH through PHPLC separation3CN-H2O (15:85 → 25:75 → 42:58, v/v)+1% vinegar Acid], obtain 29 components (component 11-1～component 11-29).Component 11-17 (790.7mg) through PHPLC separation prepare [methanol- H2O (42:58, v/v)+1% acetic acid], obtain climing Radix GentianaeKetone glycoside A (compound 7,14.6mg).
Component 13 (20.0g) through PHPLC from preparation [methanol-H2O (35:65 → 45:55 → 55:45, v/v)+1% vinegar Acid], obtain 20 components (component 13-1～component 13-20).Component 13-17 (504.0mg) separates preparation through PHPLC [CH3CN-H2O (22:78, v/v)+1% acetic acid], obtain 9 components (component 13-17-1～component 13-17-9), component 13- 17-5 (35.4mg) prepares [methanol-H through PHPLC separation2O (50:50, v/v)+1% acetic acid], obtain compound 1, (by chemical combination 1 Named point leaf vacation Radix GentianaeKetone A1, 7.1mg).
Component 14 (15.3g) through PHPLC from preparation [CH3CN-H2O (15:85 → 25:75, v/v)+1% acetic acid], obtain 20 Individual component (component 14-1～component 14-20).Component 14-17 (72.6mg) prepares [methanol-H through PHPLC separation2O (50:50, V/v)+1% acetic acid], obtain Swertianolin (compound 6,27.9mg).
Component 15 (14.4g) separates [methanol-H through Sephadex LH-20 gel filtration chromatography2O (1:1, v/v)], obtain 9 Individual component (component 15-1～component 15-9).Component 15-4 (2.4g) prepares [methanol-H through PHPLC separation2O (40:60, v/v)+ 1% acetic acid], there are 17 components (component 15-4-1～component 15-4-17).Component 15-4-6 (215.7mg) is divided through PHPLC From preparation [CH3CN-H2O (13:87, v/v)+1% acetic acid], obtain compound 2 (by named for chemical combination 2 point leaf vacation Radix GentianaeKetone A2, 19.4mg).Component 15-4-7 (284.5mg) prepares [CH through PHPLC separation3CN-H2O (15:85, v/v)+1% acetic acid], To the nor-Swertianolin of compound (compound 5,139.8mg).
It should be noted that herein, when relating to percent ethanol, without special explanation, each mean percentage by volume, such as, 70% ethanol refers to the ethanol water that percentage by volume is 70%.
The qualification of embodiment 2 compound 1-7
True by multiple spectroscopic techniques such as ultraviolet-visible spectrum, infrared spectrum, NMR (Nuclear Magnetic Resonance) spectrum (NMR), mass spectrums (MS) Determine compound 1-7 structure；Determined by compound 1-7 structure as shown in table 1 below.
The structural formula of table 1 compound 1-7
Embodiments result for compound 1-7 is as follows:
The characterization result of compound 1:
Yellow powder；[α]25 D-89.5 ° (c 0.11, methanol)；UVλmax(methanol) nm (log ε): 252 (4.41), 274 (4.30), 331 (4.07)；IR(KBr)νmax3362,2922,2852,1635,1612,1587,1499,1289,1243, 1209,1173,1073cm–1；It is m/z 421.0796 [M H] that high-resolution Q-TOF-ESI-MS provides its quasi-molecular ion peak–, really Its molecular formula fixed is C19H18O11(C19H17O11, value of calculation 421.0776).
1H NMR(DMSO-d6, 500MHz) δ: 6.47 (1H, br.s, H-2), 6.68 (1H, br.s, H-4), 7.29 (1H, d, J=8.0Hz, H-6), 6.66 (1H, d, J=8.0Hz, H-7), 11.09 (1H, br.s, 1-OH), 5.14 (1H, d, J=7.0Hz, H-1'), 3.28 (1H, dd, J=7.0,8.0Hz, H-2'), 3.30 (1H, dd, J=7.0,8.0Hz, H-3'), 3.19 (1H, dd, J=7.0,8.0Hz, H-4'), 3.48 (1H, m, overlapped, H-5'), [3.48 (1H, m, overlapped), 3.71 (1H, Br.d, ca.J=10Hz), H2-6']。
13C NMR(DMSO-d6, 125MHz) and δ: 161.9 (C-1), 99.0 (C-2), 164.8 (C-3), 94.6 (C-4), 157.1 (C-4a), 143.4 (C-4b), 137.3 (C-5), 123.9 (C-6), 109.5 (C-7), 151.7 (C-8), 107.5 (C- 8a), 102.8 (C-8b), 184.1 (C-9), 99.6 (C-1'), 73.0 (C-2'), 76.2 (C-3'), 69.4 (C-4'), 77.1 (C-5'), 60.5 (C-6').
The characterization result of compound 2:
Yellow powder；[α]25 D-55.7 ° (c 0.23, methanol)；UVλmax(methanol) nm (log ε): 252 (4.41), 274 (4.30), 331 (4.07)；IR(KBr)νmax3356,2922,2852,1648,1610,1585,1490,1457,1294, 1243,1209,1073cm–1；High-resolution Q-TOF-ESI-MS provides its quasi-molecular ion peak m/z 583.1325 [M H]–, determine Its molecular formula is C25H28O16(C28H27O16, value of calculation 583.1305).
1H NMR(DMSO-d6, 500MHz) δ: 6.69 (1H, br.s, H-2), 6.46 (1H, br.s, H-4), 7.15 (1H, d, J=8.5Hz, H-6), 6.54 (1H, d, J=8.5Hz, H-7), 12.54 (1H, br.s, 8-OH), 4.94 (1H, d, J=7.5Hz, H-1'), 3.42 (1H, dd, J=7.5,8.5Hz, H-2'), 3.33 (1H, dd, J=8.5,8.5Hz, H-3'), 3.28 (1H, dd, J=8.5,8.5Hz, H-4'), 3.62 (1H, m, H-5'), [3.66 (1H, m, overlapped), 4.03 (1H, br.d, ca.J= 11Hz), H2-6'], 4.25 (1H, d, J=7.5Hz, H-1 "), 3.03 (1H, dd, J=7.5,8.5Hz, H-2 "), 3.17 (1H, Dd, J=8.5,8.5Hz, H-3 "), 3.08 (1H, m, overlapped, H-4 "), 3.08 (1H, m, overlapped, H-5 "), [3.43 (1H, dd, J=5.0,11.5Hz), 3.67 (1H, br.d, ca.J=12Hz), H2-6”]。
13C NMR(DMSO-d6, 125MHz) and δ: 159.6 (C-1), 101.5 (C-2), 167.1 (C-3), 97.0 (C-4), 158.6 (C-4a), 142.7 (C-4b), 136.5 (C-5), 122.3 (C-6), 108.7 (C-7), 152.6 (C-8), 108.6 (C- 8a), 103.3 (C-8b), 180.2 (C-9), 101.6 (C-1'), 73.3 (C-2'), 76.0 (C-3'), 69.4 (C-4'), 75.9 (C-5'), 68.2 (C-6'), 103.4 (C-1 "), 73.5 (C-2 "), 76.5 (C-3 "), 70.0 (C-4 "), 76.8 (C-5 "), 60.9(C-6”)。
The characterization result of compound 3:
Yellow powder；High-resolution Q-TOF-ESI-MS provides its quasi-molecular ion peak m/z 243.0295 [M H]–, determine Its molecular formula is C13H8O5(C13H7O5, value of calculation 243.0299).
1H NMR(DMSO-d6, 500MHz) and δ: 6.22 (1H, d, J=2.0Hz, H-2), 6.44 (1H, d, J=2.0Hz, H- 4), 7.32 (1H, dd, J=1.5,7.5Hz, H-6), 7.25 (1H, dd, J=7.5,7.5Hz, H-7), 7.56 (1H, dd, J= 1.5,7.5Hz, H-8), 12.91 (1H, br.s, 1-OH).
13C NMR(DMSO-d6, 125MHz) and δ: 162.8 (C-1), 98.1 (C-2), 165.9 (C-3), 94.0 (C-4), 157.2 (C-4a), 144.8 (C-4b), 146.1 (C-5), 120.9 (C-6), 124.0 (C-7), 114.4 (C-8), 120.5 (C- 8a), 102.0 (C-8b), 180.0 (C-9).
The characterization result of compound 4:
Yellow powder；High-resolution Q-TOF-ESI-MS provides its quasi-molecular ion peak m/z 259.0258 [M H]–, determine Its molecular formula is C13H8O6(C13H7O6, value of calculation 259.0248).
1H NMR(DMSO-d6, 500MHz) and δ: 6.24 (1H, d, J=1.5Hz, H-2), 6.41 (1H, d, J=1.5Hz, H- 4), 7.24 (1H, d, J=8.5Hz, H-6), 6.60 (1H, d, J=8.5Hz, H-7), 11.14 (1H, br.s, 8-OH), 11.90 (1H, br.s, 1-OH).
13C NMR(DMSO-d6, 125MHz) and δ: 162.3 (C-1), 98.5 (C-2), 166.6 (C-3), 94.3 (C-4), 157.4 (C-4a), 143.3 (C-4b), 137.2 (C-5), 123.5 (C-6), 109.3 (C-7), 151.9 (C-8), 107.3 (C- 8a), 101.1 (C-8b), 183.7 (C-9).
The characterization result of compound 5:
Yellow powder；High-resolution Q-TOF-ESI-MS provides its quasi-molecular ion peak m/z 421.0795 [M H]–, determine Its molecular formula is C19H18O11(C19H17O11, value of calculation 421.0776).
1H NMR(DMSO-d6, 500MHz) and δ: 6.23 (1H, d, J=2.0Hz, H-2), 6.43 (1H, d, J=2.0Hz, H- 4), 7.30 (1H, d, J=9.0Hz, H-6), 7.20 (1H, d, J=9.0Hz, H-7), 13.11 (1H, s, 1-OH), 4.87 (1H, D, J=7.5Hz, H-1'), 3.48 (1H, dd, J=7.5,8.5Hz, H-2'), 3.41 (1H, dd, J=8.5,9.0Hz, H-3'), 3.31 (1H, dd, J=9.0,9.0Hz, H-4'), 3.44 (1H, m, H-5'), [3.63 (1H, dd, J=5.0,11.0Hz), 3.84 (1H, br.d, ca.J=11Hz), H2-6']。
13C NMR(DMSO-d6, 125MHz) and δ: 163.0 (C-1), 98.3 (C-2), 165.5 (C-3), 93.6 (C-4), 156.5 (C-4a), 144.9 (C-4b), 141.1 (C-5), 120.9 (C-6), 112.7 (C-7), 149.4 (C-8), 111.9 (C- 8a), 102.7 (C-8b), 180.8 (C-9), 103.5 (C-1'), 73.6 (C-2'), 76.0 (C-3'), 69.8 (C-4'), 77.4 (C-5'), 60.9 (C-6').
The characterization result of compound 6:
Yellow powder；High-resolution Q-TOF-ESI-MS provides its quasi-molecular ion peak m/z 435.0935 [M H]–, determine Its molecular formula is C20H20O11(C20H19O11, value of calculation 435.0933).
1H NMR(DMSO-d6, 500MHz) and δ: 3.89 (3H, s, 3-OCH3), 6.35 (1H, s, H-2), 6.56 (1H, s, H- 4), 7.27 (1H, d, J=9.0Hz, H-6), 7.14 (1H, d, J=9.0Hz, H-7), 13.08 (1H, br.s, 1-OH), 4.82 (1H, d, J=7.5Hz, H-1'), 3.37 (1H, dd, J=7.5,8.0Hz, H-2'), 3.31 (1H, dd, J=8.0,9.5Hz, H- 3'), 3.21 (1H, dd, J=9.0,9.5Hz, H-4'), 3.34 (1H, m, H-5'), [3.53 (1H, dd, J=6.0,12.0Hz), 3.75 (1H, br.d, ca.J=12Hz), H2-6']。
13C NMR(DMSO-d6, 125MHz) and δ: 162.6 (C-1), 97.1 (C-2), 166.2 (C-3), 92.1 (C-4), 156.3 (C-4a), 144.9 (C-4b), 140.9 (C-5), 121.0 (C-6), 112.3 (C-7), 149.4 (C-8), 111.8 (C- 8a), 103.5 (C-8b), 181.0 (C-9), 56.0 (C-OCH3), 103.1 (C-1'), 73.5 (C-2'), 76.0 (C-3'), 69.7 (C-4'), 77.4 (C-5'), 60.8 (C-6').
The characterization result of compound 7:
Yellow powder；High-resolution Q-TOF-ESI-MS provides its quasi-molecular ion peak m/z 421.0775 [M H]–, determine Its molecular formula is C19H18O11(C19H17O11, value of calculation 421.0776).
1H NMR(DMSO-d6, 500MHz) and δ: 7.39 (1H, d, J=9.0Hz, H-3), 7.28 (1H, d, J=9.0Hz, H- 4), 6.19 (1H, s, H-5), 6.06 (1H, s, H-7), 12.97 (1H, br.s, 8-OH), 4.96 (1H, d, J=7.5Hz, H- 1'), 3.48 (1H, m, H-2'), 3.30 (1H, m, H-3'), 3.23 (1H, dd, J=8.5,9.0Hz, H-4'), 3.30 (1H, m, H-5'), [3.48 (1H, m), 3.68 (1H, br.d, ca.J=12Hz), H2-6']。
13C NMR(DMSO-d6, 125MHz) and δ: 141.8 (C-1), 146.1 (C-2), 124.6 (C-3), 114.3 (C-4), 149.3 (C-4a), 156.9 (C-4b), 93.8 (C-5), 169.0 (C-6), 98.9 (C-7), 162.8 (C-8), 101.4 (C- 8a), 114.0 (C-8b), 179.4 (C-9), 105.0 (C-1'), 73.6 (C-2'), 75.8 (C-3'), 69.3 (C-4'), 77.5 (C-5'), 60.5 (C-6').
Embodiment 3 point leaf vacation Radix Gentianae extract and the monomer component shadow to mice rat small intestine in vitro Spontaneously contractive activities of the smooth muscle Ring
1. the preparation of mice rat small intestine in vitro smooth muscle specimen
Utilizing the healthy male mice of body weight 25～30g, after mice fasting 24 hours, cervical dislocation is put to death, rapidly along abdomen Median line opens abdominal part, takes nearly ileocecus small intestinal 10cm.Be placed in fill room temperature (about 25 DEG C) tyrode's solution (NaCl 8.0g/L, CaCl2 0.2g/L,KCl 0.2g/L,MgCl2 0.1g/L,NaHCO3 1.0g/L,KH2PO40.05g/L, glucose 1.0g/L, PH 7.4) culture dish in, clean intestinal contents.It is cut into the intestinal segment of 1cm as experimental specimen.
2. the recording method of contraction movement
One end of specimen is fixed on L-shaped hook, is placed in the smooth muscle groove filling 10mL tyrode's solution；The other end connects to be opened Power transducer, persistently leads to mixed gas (95%O2+ 5%CO2, 1～2 bubble per second), temperature (37.0 ± 0.5 DEG C), tension force is born Lotus 1g, balances 15 minutes, after system stability, starts experiment.
3. experiment packet
Preparation mice rat small intestine in vitro smooth muscle specimen, after contraction movement is stable, it is positive right to be separately added in smooth muscle groove According to medicine loperamide hydrochloride (final concentration of 10 μMs, dimethyl sulfoxide content 0.1%), point leaf vacation Radix Gentianae total extract, D101 are big Macroporous adsorbent resin 95% ethanol elution thing (final concentration of 150 μ g/mL), and compound 1-7 (final concentration of 40 μMs, dimethyl sulfoxide Content 0.1%, percentage by volume), 4 minutes observed and recorded mouse small intestine smooth muscle tension, frequently after first 1 minute of dosing and dosing The activity change of rate etc..
Using labchart 7 software records each time period contract tension force and contraction frequency, shrink tension calculates average Value, is set as 100% by shrink tension meansigma methods and the contraction frequency of normal group, uses below equation to calculate relative constriction tension force And relative frequency, experimental result is reported in Table 2 below.
Relative constriction tension force (%)=(administration group tension force meansigma methods/normal group tension force meansigma methods) × 100
Relative frequency (%)=(being administered class frequency/normal group frequency) × 100
The table 2 point leaf each extract of vacation Radix Gentianae and the monomer component impact on mice rat small intestine in vitro Spontaneously contractive activities of the smooth muscle
Data represent with meansigma methods ± standard deviation, compare with blank group: * p < 0.05, * * p < 0.01, * * * P < 0.001, n =6.Normal group: blank mice rat small intestine in vitro smooth muscle；Positive controls: loperamide hydrochloride, final concentration 10 μMs；Point leaf vacation dragon Gallbladder 70% ethanol extraction, D101 macroporous adsorbent resin 95% ethanol elution thing: final concentration 150 μ g/mL；Compound 17 is the denseest Spend 40 μMs.It is in terms of 100% by shrink tension and the frequency of normal group, calculates relative constriction tension force and the frequency of each administration group.
From Table 2, it can be seen that point leaf vacation Radix Gentianae 70% ethanol extraction, D101 macroporous adsorbent resin 95% ethanol elution Thing and 17 pairs of rat small intestine in vitro smooth muscle Spontaneous Contraction frequency changes of compound do not make significant difference, but they all energy appreciable impacts are little The tension variation of intestinal smooth muscle, its level and positive drug group quite or are better than positive drug group, have anti-diarrhea effect.
It should be noted that general diarrhea such as loperamide hydrochloride is both at the tension force of appreciable impact intestinal smooth muscle Again the change of intestinal smooth muscle Spontaneous Contraction frequency is had a significant impact while change, and to intestinal smooth muscle Spontaneous Contraction frequency Change has a significant impact and can have adverse effect on the normal absorption of food nutrition, is disadvantageous to human body, and in the present invention Sharp leaf vacation Radix Gentianae 70% ethanol extraction, D101 macroporous adsorbent resin 95% ethanol elution thing and the compound 1 of institute's isolated 7 pairs of rat small intestine in vitro smooth muscle Spontaneous Contraction frequency changes do not make significant difference, and can avoid this problem, thus can also infer, bag Containing point leaf vacation Radix Gentianae 70% ethanol extraction, D101 macroporous adsorbent resin 95% ethanol elution thing or the medicine of compound 17 Compositions can also avoid this problem.
Above to sharp leaf vacation Radix Gentianae extract, compound and the pharmaceutical composition with anti-diarrhea effect provided by the present invention It is described in detail.Principle and the embodiment of the present invention are set forth by specific embodiment used herein, above The explanation of embodiment is only intended to help to understand method and the central idea thereof of the present invention.It should be pointed out that, for this area is general For logical technical staff, under the premise without departing from the principles of the invention, it is also possible to the present invention is carried out some improvement and modification, this A little improvement and modification also fall into the protection of the claims in the present invention.

Claims (10)

1. lead to the compound of the formula I purposes in preparing antidiarrheal,
Wherein, R1、R2、R3、R4、R5The most independent representative-H ,-OH ,-OCH3、
2. the purposes of the compound of logical formula I as claimed in claim 1, wherein,
R1Represent-OH ,-OCH3OrR2Represent-OH orR3Represent-H ,-OH orR4Represent-H or-OH；R5Represent-H or-OH.
3. the purposes of the compound of logical formula I as claimed in claim 1, wherein, the compound of logical formula I is selected from:
4. lead to the compound of formula I,
Wherein,
R1Represent-OH orR2Represent-OH orR3Represent-OH, R4Representative-H, R5Represent- OH。
5. leading to the compound of formula I as claimed in claim 4, it is selected from:
6. the sharp leaf vacation Radix Gentianae extract of the compound of the logical formula I comprised as according to any one of claim 1-5.
7., for a pharmaceutical composition for antidiarrheal, wherein said pharmaceutical composition includes active constituents of medicine and pharmaceutically may be used The carrier accepted or excipient；Described active constituents of medicine is selected from the chemical combination of the logical formula I according to any one of claim 1-5 Sharp leaf vacation Radix Gentianae extract described in thing or claim 6.
8. pharmaceutical composition as claimed in claim 7, the compound of wherein said logical formula I extracts from point leaf vacation Radix Gentianae Arrive.
9. pharmaceutical composition as claimed in claim 7, wherein said pharmaceutically acceptable carrier or excipient are selected from solvent, dilute Release agent, dispersant, suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, binding agent, lubricant, stablize Agent, hydrating agents, emulsifying accelerator, buffer agent, absorbent, coloring agent, flavouring agent, sweeting agent, ion-exchanger, releasing agent, painting Cloth agent, correctives and antioxidant.
10., according to the pharmaceutical composition according to any one of claim 7-9, the dosage form of wherein said pharmaceutical composition is sheet Agent, capsule, powder, granule, lozenge, pill, solution, suspensoid, Emulsion, syrup, powder, granula subtilis, pilule, Elixir, injection, medicinal drops, ointment, lotion, gel, emulsifiable paste, spray, suppository or patch.
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