CN106074583B - A kind of application of phenylpropanoids and its pharmaceutically acceptable salt in the drug for preparing treatment diseases associated with inflammation - Google Patents
A kind of application of phenylpropanoids and its pharmaceutically acceptable salt in the drug for preparing treatment diseases associated with inflammation Download PDFInfo
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Abstract
The present invention relates to pharmaceutical technology field, a kind of application of phenylpropanoids and its pharmaceutically acceptable salt in the drug for preparing treatment diseases associated with inflammation is disclosed.The phenylpropanoids show the content that can inhibit cellular inflammation factor NO, inhibit cellular inflammation factor TNF α, 1 β of IL, the expressional function of IL 6, inhibiting effect with (OH) to hydroxyl radical free radical, and then there is anti-inflammatory and antioxidant activity, it is diseases associated with inflammation, such as the exploitation offer direction of the medicine of cervicitis, endometritis, pelvic infecton, mastitis, sphagitis and/or arthritis disease.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of phenylpropanoids and its pharmaceutically acceptable salt are being made
Application in the drug of standby treatment diseases associated with inflammation.
Background technology
It is various, active notable that isolated constituent structure is extracted from natural drug, it is isolated and purified, structure
Modification, transformation and it is fully synthetic, be always a main thought of new drug development.
TNF-α：Be it is a kind of can direct killing tumour cell and to cell factor of the normal cell without overt toxicity, be so far
One of strongest bioactie agent of direct killing function of tumor found until the present, however its toxic side effect is also very tight
Weight.
IL-1β：In local low concentration, collaboration stimulation APC and T cell activation, promote B cell proliferation and secretory antibody, into
Row immunological regulation.There is endocrine effect when a large amount of generations：Induced liver acute phase protein synthesizes, and causes fever and cachexia.
IL-6：Mankind's IL-6 genes are located on No. 7 chromosome；IL-6 molecular weight is between 21~30KD.Mainly by list
Core macrophage, Th2 cells, vascular endothelial cell, fibroblast generate.Activating B cell can be stimulated to be proliferated, secretion is anti-
Body；Stimulate T cell proliferation and CTL activation；Cell cultured supernatant synthesized acute phase albumen participates in inflammatory reaction；Promote haemocyte hair
It educates.
IL-6 can be synthesized by various kinds of cell, including the T cell of activation and B cell, monocytes/macrophages, endothelial cell,
Epithelial cell and fibroblast etc..There are many target cell of IL-6 effects, including macrophage, liver cell, static T thin
Born of the same parents, the B cell of activation and thick liquid cell etc.；Its biological effect is also sufficiently complex.
OH is most active reactive oxygen species in biosystem, can lead to DNA in cell and organism, protein and fat
Matter oxidative damage.
Macrophage can generate inflammation medium and participate in inflammatory reaction, wherein NO is the important cellular inflammation factor, NO
A variety of pathological processes are participated in, excessive NO can promote the generation and development of diseases associated with inflammation, and also can induce other inflammation
The factor.
Therefore, seek new compound, to inhibit the content of cellular inflammation factor NO, inhibit cellular inflammation factor TNF-
The expressional function of α, IL-1 β, IL-6 inhibit the activity of hydroxyl radical free radical (- OH), are applied to the treatment of diseases associated with inflammation, right and wrong
Often it is necessary to.
Waras medicinal material is that pulse family (Leguminosae) Moghania (Flemingl.Roxb. or Moghania) plant is big
The dry root of leaf waras (Moghaniamacrophylla (Willd.) O.Kuntze), the southeast is distributed mainly in China
Area.The plant is in Chinese Plants will (1995,41:313), TaiWan, China flora (1977,3:258), Hainan flora
(1965,2:311)、《Chinese Higher plant illustrated handbook》(1972,2:510), Chinese main plant figure is said (1955, pp707) and wide
State flora is included in (1956, pp361).Waras medicinal material is the genunie medicinal materials of Guangxi province, and history is loaded in《Plant name is real
Figure is examined》, there is extensive civil medication basis.Its nature and flavor is sweet, micro-puckery, puts down, and has removing damp-heat and other effects, is mainly used for treating
The gynecological diseases such as more than treating rheumatic ostealgia, traumatic injury, chronic nephritis, dysmenorrhoea and leukorrhea.The medicinal material has been recorded at present into version in 2005
《Chinese Pharmacopoeia》Annex.
The ingredient that Flemingia macrophylla has been reported mainly has flavonoids, steroid, terpene, Anthraquinones, volatile oil ingredient, has
There is certain pharmacological activity, pharmacological activity is various, reports the more neuroprotection that has, anti-inflammatory, antioxidation, to disease
Anthelmintic action, parahormone effect, cytotoxicity, antibacterial action and immunological enhancement, the antifatigue effect of pathogenic microorganism.
Waras is now widely used for the Chinese patent drug production of the types such as gynaecology, arthralgia pain due to rheumatism, such as FUKE QIANJIN PIAN, gynaecology
A thousand pieces of gold capsule, infusion of cherokee rose and spatholobus stem, JINJI JIAONANG etc., such Chinese patent drug is mainly used for gynaecological disease, and (dysmenorrhoea, cold uterus be infertile, uterus
Sagging, pelvic infecton, mastitis, leukorrhea be more, the postpartum deficiency of blood, arthralgia, postpartum waist and knee, hypogalactia and newborn sore etc.), weak anaemia
(woman anemia, deficient qi and blood and after being ill deficiency of vital energy etc.).In recent years, what clinical report was more is that FUKE QIANJIN PIAN is scorching in treatment gynaecology
Effect in terms of disease.
Currently, in the document of waras, report that the document of phenylpropanoids is few, finds effective Phenylpropanoid Glycosides class
Noval chemical compound isolates and purifies it, structural modification and synthesis, developing new drug are applied to the treatment of diseases associated with inflammation, meaning
It is great.
Invention content
The technical problem to be solved by the present invention is to find a kind of active ingredient, can inhibit containing for cellular inflammation factor NO
Amount inhibits cellular inflammation factor TNF-α, the expressional function of IL-1 β, IL-6 that there is the inhibition to (- the OH) of hydroxyl radical free radical to make
With, can apply to prepare treatment diseases associated with inflammation drug in.The present invention provides a kind of phenylpropanoids, can inhibit
The content of cellular inflammation factor NO inhibits cellular inflammation factor TNF-α, the expressional function of IL-1 β, IL-6 to have to hydroxyl certainly
By the inhibiting effect of (- OH) of base, and then there is anti-inflammatory and antioxidant activity, provides direction for the exploitation of anti-inflammatory drug, be used for
Treat related inflammation disease, such as cervicitis, endometritis, pelvic infecton, mastitis, sphagitis and/or arthritis.
The object of the present invention is to provide a kind of medical applications of phenylpropanoids.
A kind of phenylpropanoids and its pharmaceutically acceptable salt are provided as the medicine for preparing treatment diseases associated with inflammation
Application in object, shown in the structural formula such as formula (I) of the phenylpropanoids：
Shown in the structure such as formula (II) or formula (III) of the phenylpropanoids pharmaceutically acceptable salt：
Wherein, R is inorganic acid, R1Or R2Or R3For in sulfonate radical, alkali metal ion or ammonium root any one or arbitrary two
Kind is three kinds arbitrary.
Preferably, the phenylpropanoids and its pharmaceutically acceptable salt are preparing the inhibition cellular inflammation factor
The content of NO inhibits cellular inflammation factor TNF-α, the expression of IL-1 β, IL-6 or the active drug for inhibiting hydroxyl radical free radical
In application, be applied to treatment diseases associated with inflammation drug in.
Preferably, the diseases associated with inflammation is cervicitis, endometritis, pelvic infecton, mastitis, sphagitis and/or pass
Section is scorching.
The pharmaceutically acceptable salt is phenylpropanoids shown in formula (I) can pharmaceutically connect with what acid or alkali were formed
The salt received, wherein in formula (II), R is inorganic acid, in formula (III), R1Or R2Or R3In sulfonate radical, alkali metal ion or ammonium root
Any one is two kinds or three kinds arbitrary arbitrary.
The inorganic acid is hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid or lactic acid；It is described
Sulfonate radical is the sulfonate radical with aryl；The alkali metal ion is potassium ion, sodium ion, calcium ion, magnesium ion or lithium ion.
The sulfonate radical with aryl is benzene sulfonic acid root or p-methyl benzenesulfonic acid root.
The phenylpropanoids pharmaceutically acceptable salt is ammonium salt.
The drug contains the auxiliary material and/or carrier pharmaceutically allowed.
Preferably, the drug also contains other effective components.
Preferably, the drug is also containing in cherokee rose root, single side needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis
It is one or more of.
Preferably, the drug is also containing in cherokee rose root, single side needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis
One or more of extracts.
The extract be press patent announcement CN1078079C, CN1170549C, CN1158087C, CN1330335C,
Carrying described in any one of CN1296071C, CN1321631C, CN1296072C, CN1296073C or several patent documents
Method is taken to be prepared.
The dosage form of the drug is tablet, capsule, powder, granule, pill, solution, suspension, syrup, note
Penetrate agent, ointment, suppository or spray.
The purpose of the present invention is from traditional prescriptions of traditional Chinese medicine, pass through the prescription from FUKE QIANJIN PIAN and ' Qianjin ' capsule to treat ganopathy
In, by solvent extraction, column chromatography for separation, liquid phase separation, a kind of obtained new phenylpropanoids of purifying are prepared, and pass through reality
Verification is real, diseases associated with inflammation is can be applied to, such as cervicitis, endometritis, pelvic infecton, mastitis, sphagitis and/or pass
Save the treatment of the diseases such as inflammation.
Specifically, inventor is by from the prescription of FUKE QIANJIN PIAN, ' Qianjin ' capsule to treat ganopathy, choosing the dry of Flemingia macrophylla
Dry, by solvent extraction, column chromatography for separation, liquid phase separation, purifying are prepared, obtains phenylpropanoids of the present invention,
Then test cell line is carried out to the phenylpropanoids, measures it to cellular inflammation factor NO, TNF-α, IL-1 β, IL-6 and
The inhibition level of hydroxyl radical free radical (- OH), experiment show the phenylpropanoids in concentration (8.75-15.75 μ g/mL) model
Enclosing interior increased to NO contents caused by LPS has apparent inhibiting effect, and shows apparent dose-dependence.In concentration
264.7 cellular inflammation factor TNF-α of Raw, IL-1 β, IL-6 contents caused by LPS have in (8.75-15.75 μ g/mL) range
Apparent inhibiting effect (p ＜ 0.05), and apparent dose-dependence is shown, in concentration (5.25-15.75 μ g/mL) model
Enclose it is interior have apparent inhibiting effect (p ＜ 0.05) to OH changes of contents caused by LPS, and show dose-dependence.
Beneficial effects of the present invention：
The present invention from traditional Chinese medicine prescription angle, from traditional Chinese medicine FUKE QIANJIN PIAN, ' Qianjin ' capsule to treat ganopathy extraction,
Separation, purifying obtain a kind of phenylpropanoids, the experiment proved that, which, which shows, can inhibit cell
The content of inflammatory factor NO inhibits cellular inflammation factor TNF-α, the expressional function of IL-1 β, IL-6 to have to hydroxyl radical free radical
(- OH) inhibiting effect, be diseases associated with inflammation, as cervicitis, endometritis, pelvic infecton, mastitis, sphagitis and/or
The exploitation of the medicine of the diseases such as arthritis provides direction.
New phenylpropanoids provided by the invention are simple in structure, purity is high, and extraction separation method is easy, is easy to
Synthesis, is suitable for the commercial application of new drug.
Description of the drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of phenylpropanoids of the present invention.
Fig. 2 is the carbon-13 nmr spectra figure of phenylpropanoids of the present invention.
Fig. 3 is influence diagram of the phenylpropanoids of the present invention to cell activity.
Fig. 4 is inhibiting effect figure of the phenylpropanoids of the present invention to NO.
Fig. 5 is inhibiting effect figure of the phenylpropanoids of the present invention to TNF-α.
Fig. 6 is inhibiting effect figure of the phenylpropanoids of the present invention to IL-1 β.
Fig. 7 is inhibiting effect figure of the phenylpropanoids of the present invention to IL-6.
Fig. 8 is inhibiting effect figure of the phenylpropanoids of the present invention to OH.
Specific implementation mode
It is further illustrated the present invention below in conjunction with Figure of description and specific embodiment, but embodiment is not to the present invention
It limits in any form.Unless stated otherwise, the present invention uses reagent, method and apparatus routinely try for the art
Agent, method and apparatus.Unless stated otherwise, the raw material used in the present embodiment and equipment are the original of the art regular market purchase
Material and equipment.
The compound of the present invention is the change shown in phenylpropanoids and formula (II) or formula (III) shown in the formula (I)
Close object pharmaceutically acceptable salt.The method provided by the invention extracted as raw material using Flemingia macrophylla may be used in the compound
It is prepared, can also be combined according to structural formula provided by the invention and be prepared using the methods of the chemical synthesis of this field.
As the salt of phenylpropanoids of the present invention, as long as pharmaceutically acceptable salt, can be enumerated as
The inorganic acid salt formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid；With
The sulfonate that sulfonic acid is formed；The alkali metal salt formed with the hydroxide of the alkali metal such as potassium, sodium, calcium, magnesium, lithium is formed with ammonium
Ammonium salt etc..
Phenylpropanoids of the present invention can be used as cervicitis, endometritis, pelvic infecton, mastitis, sphagitis and/
Or the medicine of the diseases associated with inflammation such as arthritis.
The compounds of this invention can be used as pharmaceutical composition together with the auxiliary material and/or carrier that pharmaceutically allow, can also
Be added pharmaceutically allow auxiliary material and/or carrier in the case of with cherokee rose root, single side needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis,
The combination of one or more of Radix Angelicae Sinensis, Radix Codonopsis Chinese medicine or extract is used as pharmaceutical composition, and the compounds of this invention can be with
With together with other pharmaceutically acceptable effective components be used as pharmaceutical composition.
Can be tablet, capsule, powder, granule, pill, solution, suspension, syrup as pharmaceutical composition
Agent, injection, ointment, suppository, spray etc..
Further, tablet can be the manufactured sugar-coat in the case of auxiliary material and/or carrier that addition pharmaceutically allows
Piece, Film coated tablets, enteric coatings ply or two-ply, multilayer tablet.
The auxiliary material and/or carrier of the present invention can be as follows：
Solid pharmaceutical preparation is made, additive, such as sucrose, lactose, cellulose sugar, maltitol, glucose, shallow lake can be used
Powder class, agar, alginates, chitin, chitosan class, pectin class, gum arabic class, gelatin class, collagen class, junket egg
In vain, albumin, calcium phosphate, D-sorbite, glycine, glycerine, polyethylene glycol, sodium bicarbonate, talcum etc..
Semisolid preparation is made, of animal or plant nature grease (olive oil, corn oil, castor oil etc.), mineral oil can be used
It is fat (vaseline, albolene, solid paraffin etc.), wax class (jojoba oil, Brazil wax, beeswax etc.), partially synthetic or complete
Fatty acid glyceride (lauric acid, myristic acid, palmitic acid etc.) of synthesis etc..
Liquid preparation is made, additive, such as sodium chloride, glucose, D-sorbite, glycerine, olive oil, the third two can be used
Alcohol, ethyl alcohol etc..In the case of injection especially is made, aseptic aqueous solution, such as physiological saline, isotonic solution, oiliness can be used
Liquid, such as sesame oil, soybean oil.Furthermore it is also possible to as needed, suspending agent appropriate, such as sodium carboxymethylcellulose, nonionic be used in combination
Surfactant, cosolvent, such as Ergol, benzyl alcohol.
The amount of the active ingredient of these preparations is 0.01~80 weight % of preparation, is suitably 1~50 weight %, dosage
Symptom, weight, age according to patient etc. are different and change.
The preparation of 1 phenylpropanoids of embodiment
The present embodiment provides a kind of preparation methods of phenylpropanoids shown in formula (I), include the following steps：
S1. Flemingia macrophylla 50kg is taken, it is dry using root as raw material, it is cut into small pieces.Alcohol reflux through 8 times of amounts 60%
Extraction 3 times, 2 hours every time, extracting solution is merged, is concentrated into no alcohol taste, it is spare to obtain medicinal extract；
S2. the medicinal extract after being concentrated in step S1 is dissolved in 10L water, it is washed using D101 large pore resin absorption columns
De-, eluant, eluent is water, elutes 3 column volumes, collects eluent, is named as MM-1, spare；
S3. the flow point MM-1 being collected into step S2 is eluted with reverse phase ODS column chromatographies, eluant, eluent is methanol-water
System, volume ratio 25:75,18 column volumes are eluted, the eluent of a flow point are collected by every 3 column volumes, in order
6 flow points are collected, are respectively designated as：MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are spare；
S4. it is with liquid phase separation, preparative liquid chromatography column is prepared by the flow point MM-12 being collected into step S3：YMC,
20mm*250mm, flow velocity：5ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 25:75:
0.01, eluent is collected by peak sequence, 7 flow points is collected altogether, is respectively designated as MM-121, MM-122, MM-123, MM-
124, MM-125, MM-126, MM-127, it is spare；
S5. the flow point MM-126 being collected into step S4 is purified with liquid phase is prepared, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：5ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 15:85:
0.01, eluent is collected, the phenylpropanoids are obtained after recrystallization.
The preparation of 2 phenylpropanoids of embodiment
The present embodiment provides a kind of preparation methods of phenylpropanoids shown in formula (I), include the following steps：
S1. Flemingia macrophylla 40kg is taken, it is dry using root as raw material, it is cut into small pieces.Alcohol reflux through 6 times of amounts 50%
Extraction 2 times, 1 hour every time, extracting solution is merged, is concentrated into no alcohol taste, it is spare to obtain medicinal extract；
S2. the medicinal extract after being concentrated in step S1 is dissolved in 5L water, it is washed using D101 large pore resin absorption columns
De-, eluant, eluent is that the volume ratio of ethyl alcohol and water is 15:85,3 column volumes are eluted, eluent is collected, is named as MM-1, it is spare；
S3. the flow point MM-1 being collected into step S2 is eluted with reverse phase ODS column chromatographies, eluant, eluent is methanol-water
System, volume ratio 20:80,18 column volumes are eluted, the eluent of a flow point are collected by every 3 column volumes, in order
6 flow points are collected, are respectively designated as：MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are spare；
S4. it is with liquid phase separation, preparative liquid chromatography column is prepared by the flow point MM-12 being collected into step S3：YMC,
20mm*250mm, flow velocity：10ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 35:
65:0.01, eluent is collected by peak sequence, 7 flow points is collected altogether, is respectively designated as MM-121, MM-122, MM-123, MM-
124, MM-125, MM-126, MM-127, it is spare；
S5. the flow point MM-126 being collected into step S4 is purified with liquid phase is prepared, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：5ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 15:85:
0.01, eluent is collected, the phenylpropanoids are obtained after recrystallization.
The preparation of 3 phenylpropanoids of embodiment
The present embodiment provides a kind of preparation methods of phenylpropanoids shown in formula (I), include the following steps：
S1. Flemingia macrophylla 60kg is taken, it is dry using root as raw material, it is cut into small pieces.The alcohol reflux of 7 times of amounts 70% carries
It takes 4 times, 3 hours every time, extracting solution is merged, be concentrated into no alcohol taste, it is spare to obtain medicinal extract；
S2. the medicinal extract after being concentrated in step S1 is dissolved in 8L water, it is washed using D101 large pore resin absorption columns
De-, eluant, eluent is that the volume ratio of ethyl alcohol and water is 10:90,3 column volumes are eluted, eluent is collected, is named as MM-1, it is spare；
S3. the flow point MM-1 being collected into step S2 is eluted with reverse phase ODS column chromatographies, eluant, eluent is methanol-water
System, volume ratio 30:70,18 column volumes are eluted, the eluent of a flow point are collected by every 3 column volumes, in order
6 flow points are collected, are respectively designated as：MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are spare；
S4. it is with liquid phase separation, preparative liquid chromatography column is prepared by the flow point MM-12 being collected into step S3：YMC,
20mm*250mm, flow velocity：10ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 30:
70:0.01, eluent is collected by peak sequence, 7 flow points is collected altogether, is respectively designated as MM-121, MM-122, MM-123, MM-
124, MM-125, MM-126, MM-127, it is spare；
S5. the flow point MM-126 being collected into step S4 is purified with liquid phase is prepared, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：5ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 15:85:
0.01, eluent is collected, the phenylpropanoids are obtained after recrystallization.
The preparation of 4 phenylpropanoids of embodiment
The present embodiment provides a kind of preparation methods of phenylpropanoids shown in formula (I), include the following steps：
S1. Flemingia macrophylla 50kg is taken, it is dry using root as raw material, it is cut into small pieces.The alcohol reflux of 8 times of amounts 60% carries
It takes 2 times, 1.5 hours every time, extracting solution is merged, be concentrated into no alcohol taste, it is spare to obtain medicinal extract；
S2. the medicinal extract after being concentrated in step S1 is dissolved in 6L water, it is washed using D101 large pore resin absorption columns
De-, eluant, eluent is that the volume ratio of ethyl alcohol and water is 5:95,3 column volumes are eluted, eluent is collected, is named as MM-1, it is spare；
S3. the flow point MM-1 being collected into step S2 is eluted with reverse phase ODS column chromatographies, eluant, eluent is methanol-water
System, volume ratio 25:75,18 column volumes are eluted, the eluent of a flow point are collected by every 3 column volumes, in order
6 flow points are collected, are respectively designated as：MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are spare；
S4. it is with liquid phase separation, preparative liquid chromatography column is prepared by the flow point MM-12 being collected into step S3：YMC,
20mm*250mm, flow velocity：10ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 25:
75:0.01, eluent is collected by peak sequence, 7 flow points is collected altogether, is respectively designated as MM-121, MM-122, MM-123, MM-
124, MM-125, MM-126, MM-127, it is spare；
S5. the flow point MM-126 being collected into step S4 is purified with liquid phase is prepared, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：5ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 15:85:
0.01, eluent is collected, the phenylpropanoids are obtained after recrystallization.
The preparation of 5 phenylpropanoids of embodiment
The present embodiment provides a kind of preparation methods of phenylpropanoids shown in formula (I), include the following steps：
S1. Flemingia macrophylla 50kg is taken, it is dry using root as raw material, it is cut into small pieces.The alcohol reflux of 8 times of amounts 80% carries
It takes 2 times, 1.5 hours every time, extracting solution is merged, be concentrated into no alcohol taste, it is spare to obtain medicinal extract；
S2. the medicinal extract after being concentrated in step S1 is dissolved in 6L water, it is washed using D101 large pore resin absorption columns
De-, eluant, eluent is that the volume ratio of ethyl alcohol and water is 10:90,3 column volumes are eluted, eluent is collected, is named as MM-1, it is spare；
S3. the flow point MM-1 being collected into step S2 is eluted with reverse phase ODS column chromatographies, eluant, eluent is methanol-water
System, volume ratio 28:72,18 column volumes are eluted, the eluent of a flow point are collected by every 3 column volumes, in order
6 flow points are collected, are respectively designated as：MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are spare；
S4. it is with liquid phase separation, preparative liquid chromatography column is prepared by the flow point MM-12 being collected into step S3：YMC,
20mm*250mm, flow velocity：10ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 10:
90:0.01, eluent is collected by peak sequence, 7 flow points is collected altogether, is respectively designated as MM-121, MM-122, MM-123, MM-
124, MM-125, MM-126, MM-127, it is spare；
S5. the flow point MM-126 being collected into step S4 is purified with liquid phase is prepared, preparative liquid chromatography column is：YMC,
20mm*250mm, flow velocity：5ml/min, mobile phase are methanol-water-acetic acid system, methanol：Water：The volume ratio of acetic acid is 15:85:
0.01, eluent is collected, the phenylpropanoids are obtained after recrystallization.
The compound that embodiment 1 to embodiment 5 is prepared carries out mass spectrum, nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra
Detection, as a result prove gained compound be：4, the 5- alkene -2 ' of pyranoid ring -1 '-glucosyl group -1 ', 3 '-dihydroxy -2- methoxies
Base -3- hydroxybenzoic acids.Shown in its structural formula such as formula (I)：
Its mass spectrum, nuclear magnetic resonance spectroscopy, the spectral data of carbon-13 nmr spectra are as follows：
HR-ESIMS shows [M+Na]+be m/z 453.1158, and in conjunction with nuclear-magnetism feature, it is C that can obtain molecular formula18H22O12, no
Saturation degree is 8.
1H-NMR(600MHz,CD3OD):6.14(s,1H),4.73(d,1H),4.71(t,1H),3.79(s,3H)3.00-
4.00(H-2'-6'),2.59(d,2H)。
13C-NMR(150MHz,CD3OD):154.6(C-1),153.3(C-2),131.4(C-4),115.6(C-5),
131.4(C-3),128.2(C-6),114.7(C-2'),104.8(C-1”),93.2(C-1')78.7(C-3'),76.8-61.2
(C-2”-6”),50.4(C-4')。
The preparation of 6 phenylpropanoids salt of embodiment
The preparation of phenylpropanoids hydrochloride：
Saturation hydrochloric acid will be added dropwise under stirring in the phenylpropanoids methanol solution to pH value 2-3, stir lower dropwise addition second
Nitrile filters, is dried to obtain white powder solid, the as hydrochloride of phenylpropanoids.
The preparation of phenylpropanoids sulfonate：
Alkali metal is added in the reaction system containing the phenylpropanoids, solvent, sulfonic acid, neutral oil and accelerating agent
Hydroxide, solvent, lower alcohol and kicker is added, is passed through carbon dioxide, isolated white powder solid, as benzene
The sulfonate of third chlorins compound.
The preparation of phenylpropanoids sylvite or sodium salt：
The KOH being dissolved in ethyl alcohol or NaOH are added in the phenylpropanoids, lower heating reflux reaction, cold system are stirred
Room temperature, stir it is lower acetonitrile is added dropwise, filter, dry white solid, the as sylvite or sodium salt of phenylpropanoids.
The preparation of phenylpropanoids ammonium salt：
Saturation ammonium hydroxide will be added dropwise under stirring in the phenylpropanoids methanol solution to pH value 9-11, stir lower dropwise addition second
Nitrile filters, is dried to obtain white solid, the as ammonium salt of phenylpropanoids.
The spectral data of above compound salt：
Phenylpropanoids hydrochloride：ESIMS shows m/z 466.89, nuclear-magnetism feature1H-NMR(600MHz,
CD3OD):1H-NMR(600MHz,CD3OD):6.17(s,1H),4.77(d,1H),4.70(t,1H),3.78(s,3H)3.00-
4.00(H-2'-6'),2.44(d,2H)。
Phenylpropanoids sulfonate：ESIMS is shown as m/z 494.27, nuclear-magnetism feature1H-NMR(600MHz,
CD3OD):1H-NMR(600MHz,CD3OD):6.17(s,1H),4.78(d,1H),4.89(t,1H),3.66(s, 3H)3.00-
4.00(H-2'-6'),2.51(d,2H)。
Phenylpropanoids sylvite or sodium salt：
Sylvite：ESIMS shows m/z 468.33, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):1H-NMR(600MHz,
CD3OD):6.11(s,1H),4.69(d,1H),4.66(t,1H),3.73(s,3H)3.00-4.00(H-2'-6'),2.50(d,
2H)。
Sodium salt：ESIMS shows m/z 452.63, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):6.17(s,1H),4.50
(d,1H),4.61(t,1H),3.40(s,3H)3.00-4.00(H-2'-6'),2.10(d,2H)。
Phenylpropanoids ammonium salt：ESIMS shows m/z 445.26, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):1H-NMR(600MHz,CD3OD):6.18(s,1H),4.78(d,1H),4.46(t,1H),3.46(s,3H)3.00-4.00(H-
2'-6'),2.51(d,2H)。
Shown in the structural formula such as formula (IV) of above-mentioned phenylpropanoids salt~formula (VIII).
Wherein, formula (IV) is the phenylpropanoids hydrochloride being prepared, and formula (V) is the Phenylpropanoid Glycosides being prepared
The one of which sulfonate of class compound, formula (VI) are the one of which sylvite for the phenylpropanoids being prepared, formula
(VII) it is the one of which sodium salt for the phenylpropanoids being prepared, formula (VIII) is the phenylpropanoids being prepared
One of which ammonium salt.
7 application test of experimental example
Compound of the present invention and salt stress be with the shadows of inflammation to LPS 264.7 oxidative macrophages of RAW induced
It rings.(it is convenient in order to be recorded in experimentation, below by phenylpropanoids of the present invention marked as：Drug MM-126,
I.e. heretofore described drug MM-126 refers to phenylpropanoids shown in formula (I) or its is pharmaceutically acceptable
Salt.)
1 materials and methods
1.1 drugs and instrument
Lipopolysaccharides (lipopolysaccharide, LPS), MTT are purchased from Sigma companies；Mouse macrophage Raw264.7
Purchased from the refined cell bank in Hunan；PBS；DMEM high glucose mediums, fetal calf serum, penicillin and streptomysin；Full-automatic microplate reader；Constant temperature
CO2Incubator.
Mouse IL 1-β (IL-1- β) ELISA detection kit, lot number：2014/06(96T)；Small mIL6
(IL-6) ELISA detection kit, lot number：2014/06(96T)；Murine tumor necrosis factor-α (TNF-α) ELISA detection examinations
Agent box, lot number：2014/06(96T)；Mouse nitrous oxide (NO) ELISA detection kit, lot number：2014/10(96T)；Mouse
Hydroxyl radical free radical (OH) ELISA detection kit, lot number：2014/10(96T).
1.2 medicine preparation
It is dissolved first with a small amount of DMSO, certain concentration is then diluted to DMEM, DMSO contents in final concentration is made to be less than
1‰。
1.3 cell culture
Mouse macrophage Raw 264.7 be incubated at containing 10% heat inactivation (56 DEG C, 30min) fetal calf serum (FBS),
10U/mL Benzylpenicillin sodium salts, 100 μ g/mL streptomysins DMEM culture mediums in, 37 DEG C, 5%CO2Growth is incubated in constant incubator.
1.4 cell viabilities measure
Cell viability is measured by mtt assay.Cell suspension inoculation is made in cell to incubate in 96 orifice plates (1 × 104/hole)
It educates for 24 hours, resynchronization for 24 hours, then by the drug effect of various concentration in cell 2h, then adds LPS (30 μ g/mL) stimulations
For 24 hours, it inhales and abandons former culture medium, the MTT (0.5mg/mL) that 100 μ L are added per hole continues to be incubated 4h, and culture medium is abandoned in suction, is added per hole
The DMSO of 150 μ L, shaking table shake 10min, and absorbance is measured at 490nm.
1.5 NO assays
264.7 cell inoculations of Raw in 96 orifice plates for 24 hours, resynchronization for 24 hours, then by the drug effect of various concentration in thin
Then born of the same parents 2h adds LPS (30 μ g/mL) stimulations for 24 hours, finally collect supernatant, and on 10000rpm centrifugation 5min, packing
Clearly -80 DEG C are placed in save backup.Pass through mouse NO kit measurement NO contents.
1.6 inflammatory factor TNF-α, IL-1 β, IL-6 measurements
Sample takes 1.5 samples prepared for subsequent inflammation factor determination.Cell generation TNF-α, IL-1 β, IL-6's
By mouse TNF-α, IL-1 β, IL-6 kits measure for amount.
1.7 OH assays
Sample takes 1.5 samples prepared for OH factor determinations.Pass through OH kit measurement contents.
1.8 statistical analysis
Using SPSS17.0 softwares, experimental data is with (x ± s is indicated；The data obtained is by with one-way analysis of variance, side
Poor homogeneous is examined with LSD, and heterogeneity of variance is examined with Dunnett T3.
2 experimental results
2.1 cell viability
Influence of the drug to cell viability is evaluated by mtt assay.As shown in figure 3, drug MM-126 is in 1.75-15.75 μ
264.7 cell viabilities of Raw are had no significant effect in g/mL concentration ranges；Therefore the drug concentration pair under this range of concentrations
It is suitable in subsequent experimental.
The generation of 2.2 Drug inhibition NO
As shown in figure 4, by LPS stimulate 264.7 cells of Raw, generate NO (65.81 ± 2.93IU/mL) contents with
Normal group NO (33.61 ± 2.19IU/mL) is compared significantly raised (p ＜ 0.01).Drug MM-126 is in concentration (8.75-15.75 μ
G/mL) there is apparent inhibiting effect to NO contents raising caused by LPS in range, and show apparent dose-dependence.
2.3 Drug inhibition TNF-α, the generation of IL-1 β, IL-6
As shown in Figures 5 to 7,264.7 cells of Raw, 264.7 cellular inflammation factor TNF-α of Raw are stimulated by LPS
(132.16 ± 5.28pg/mL), IL-1 β (358.80 ± 24.64pg/mL), IL-6 (198.39 ± 5.97pg/mL) contents with just
Often group TNF-α (65.41 ± 6.29pg/mL), IL-1 β (172.67 ± 10.06pg/mL), IL-6 (103.34 ± 2.88pg/mL)
It is significantly raised (p ＜ 0.01) compared to content；Illustrate that LPS can stimulate 264.7 cells of Raw to generate a large amount of inflammatory factors.
Drug MM-126 generates inflammation in concentration (8.75-15.75 μ g/mL) range to LPS stimulation 264.7 cells of Raw
Factor TNF-α, IL-1 β, IL-6 contents have apparent inhibiting effect (p ＜ 0.05), and show apparent dose-dependant and close
System.
The generation of 2.4 Drug inhibition OH
As shown in figure 8, by LPS stimulate 264.7 cells of Raw, generate OH (113.58 ± 6.03ng/mL) contents with
Normal group OH (63.40 ± 1.19ng/mL) is compared significantly raised (p ＜ 0.01).
Drug MM-126 has significantly OH changes of contents caused by LPS in concentration (5.25-15.75 μ g/mL) range
Inhibiting effect (p ＜ 0.05), and show dose-dependence.
This experiment has studied drug MM-126 to mouse macrophage NO, TNF-α, IL-1 β, IL-6, OH through in vitro culture
The influence of generation.
Drug MM-126 need to have apparent inhibition, say in middle and high concentration to NO, the content of TNF-α, IL-1 β, IL-6
Bright its plays anti-inflammatory activity and higher drug concentration is needed to realize；It is apparent to the inhibitory activity of OH, illustrates that it has certain antioxygen
Change activity.
Embodiment 8
The preparation of tablet：Phenylpropanoids shown in formula (I) are first made by 1 method of embodiment, and utilize the change
Close object and inorganic acid (such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkali
Salt made of the hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium of metal, is pressed
The compound or its any one salt and excipient weight ratio are 1:Excipient, pelletizing press sheet is added in 10 ratio.
Embodiment 9
The preparation of powder：Phenylpropanoids shown in formula (I) are first made by 1 method of embodiment, and utilize the change
Close object and inorganic acid (such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkali
Salt made of the hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium of metal, is pressed
Powder is made in conventional powder preparation method.
Embodiment 10
The preparation of capsule or granule：Phenylpropanoids shown in formula (I) are first made by 1 method of embodiment, with
And utilize the compound and inorganic acid (such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid)
Or the hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium of sulfonic acid or alkali metal
Manufactured salt is 1 by the compound or its any one salt and excipient weight ratio:Excipient is added in 10 ratio, and glue is made
Wafer or granule.
Embodiment 11
The preparation of injection：Phenylpropanoids shown in formula (I) are first made by 1 method of embodiment, and utilizing should
Compound and inorganic acid (such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or
Salt made of the hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium of alkali metal,
Injection is made in routinely water for injection, refined filtration, embedding sterilizing.
Embodiment 12
A kind of pharmaceutical composition is made phenylpropanoids shown in formula (I) containing 1 method of embodiment, and utilizes
The compound and inorganic acid (such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid
Or made of the hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium of alkali metal
Salt and cherokee rose root, single side needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, powder and auxiliary material made of Radix Codonopsis.
Embodiment 13
Phenylpropanoids shown in formula (I), and golden cherry is made containing 1 method of embodiment in a kind of pharmaceutical composition
Root, single side needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, powder and auxiliary material made of Radix Codonopsis.
Embodiment 14
Phenylpropanoids shown in formula (I), and golden cherry is made containing 1 method of embodiment in a kind of pharmaceutical composition
Root, single side needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis extract and auxiliary material.Extract is by patent announcement number
CN1078079C、CN1170549C、CN1158087C、CN1330335C、CN1296071C、CN1321631C、CN1296072C、
Extracting method is prepared in any one of CN1296073C or several patent documents.
Embodiment 15
A kind of pharmaceutical composition is made phenylpropanoids shown in formula (I) containing 1 method of embodiment, and utilizes
The compound and inorganic acid (such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid
Or made of the hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide) or ammonium of alkali metal
Salt and cherokee rose root, single side needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis extract and auxiliary material.Extract be by
Patent announcement CN1078079C, CN1170549C, CN1158087C, CN1330335C, CN1296071C, CN1321631C,
Extracting method is prepared in any one of CN1296072C, CN1296073C or several patent documents.
The advantage of the basic principles and main features and the present invention of the present invention has been shown and described above.The technology of this field
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, this is to this
It is for field technology personnel it will be apparent that these changes and improvements all fall within the protetion scope of the claimed invention.This hair
Bright claimed range is defined by the appending claims and its equivalent thereof.
Claims (7)
1. a kind of phenylpropanoids and its pharmaceutically acceptable salt answering in the drug for preparing treatment diseases associated with inflammation
With shown in the structural formula such as formula (I) of the phenylpropanoids：
2. applying according to claim 1, which is characterized in that be to prepare the content for inhibiting cellular inflammation factor NO or inhibition
Application in cellular inflammation factor TNF-α, the expression of IL-1 β, IL-6 or the active drug of inhibition hydroxyl radical free radical.
3. applying according to claim 1, which is characterized in that the diseases associated with inflammation is cervicitis, endometritis, pelvic cavity
Inflammation, mastitis, sphagitis and/or arthritis.
4. according to the application of any one of claims 1 to 3, which is characterized in that the drug contains the auxiliary material pharmaceutically allowed.
5. applying according to claim 4, which is characterized in that the drug also contains cherokee rose root, single side needle, Caulis Spatholobi, work(
One or more of Lao Mu, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis.
6. applying according to claim 4, which is characterized in that the drug also contains cherokee rose root, single side needle, Caulis Spatholobi, work(
The extract of one or more of Lao Mu, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis.
7. applying according to claim 4, which is characterized in that the dosage form of the drug is tablet, capsule, powder, particle
Agent, pill, solution, suspension, syrup, injection, ointment, suppository or spray.
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| CN104274578A (en) * | 2014-09-05 | 2015-01-14 | 株洲千金药业股份有限公司 | Traditional Chinese medicinal composition with antimicrobial and antiinflammation effects and preparation method thereof |
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| CN104274578A (en) * | 2014-09-05 | 2015-01-14 | 株洲千金药业股份有限公司 | Traditional Chinese medicinal composition with antimicrobial and antiinflammation effects and preparation method thereof |
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| 千斤拔化学成分研究;李华等;《中草药》;20090430;第40卷(第4期);第512-516页 * |
| 千斤拔的镇痛和抗炎作用;陈一等;《广西医学》;19930430;第15卷(第2期);第77-79页 * |
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