CN105687217B - A kind of application of phenylpropanoids and its pharmaceutically acceptable salt in the drug of preparation treatment diseases associated with inflammation - Google Patents
A kind of application of phenylpropanoids and its pharmaceutically acceptable salt in the drug of preparation 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 of preparation treatment diseases associated with inflammation is disclosed.The phenylpropanoids, which are shown, can inhibit cellular inflammation factor TNF-α, IL-1 β, the expressional function of IL-6, inhibiting effect with (- OH) to hydroxyl radical free radical, and then there is anti-inflammatory and antioxidant activity, for diseases associated with inflammation, such as the exploitation of therapeutic agent of cervicitis, endometritis, pelvic inflammatory disease, mazoitis, sphagitis and/or arthritis disease provides direction.
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 technique
It is significant that isolated constituent structure multiplicity, activity are extracted from natural drug, it are 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 the cell factor to 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：The synthesis of induced liver acute phase protein, causes fever and cachexia.
IL-6：Mankind's IL-6 gene is located on No. 7 chromosome；IL-6 molecular weight is between 21~30KD.Mainly by list
Core macrophage, Th2 cell, 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, T cell and B cell, monocytes/macrophages, endothelial cell including activation,
Epithelial cell and fibroblast etc..There are many target cell of IL-6 effect, thin including macrophage, liver cell, static T
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 rouge
Matter oxidative damage.
Therefore, seek new compound, cellular inflammation factor TNF-α can be inhibited, the expressional function of IL-1 β, IL-6 inhibit
The activity of hydroxyl radical free radical (- OH) is necessary applied to the treatment of diseases associated with inflammation.
Philippine flemingia root medicinal material is that pulse family (Leguminosae) Moghania (Flemingl.Roxb. or Moghania) plant is big
The dry root of leaf philippine flemingia root (Moghaniamacrophylla (Willd.) O.Kuntze), is distributed mainly on the southeast in China
Area.The plant is in Chinese Plants will (1995,41:313), Flora of Taiwan (1977,3:258), Hainan flora (1965,
2:311),《Chinese Higher plant illustrated handbook》(1972,2:510), Chinese main plant figure says (1955, pp707) and Guangzhou plant
Will is included in (1956, pp361).Philippine flemingia root medicinal material is the genunie medicinal materials of Guangxi province, and history is loaded in《The Illustrated Book on Plants》,
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 rheumatic bone
Bitterly, the gynecological diseases such as more than traumatic injury, chronic nephritis, dysmenorrhea and leukorrhea.The medicinal material has been recorded at present into version in 2005《Middle traditional Chinese medicines
Allusion quotation》Annex.
The reported ingredient of Flemingia macrophylla mainly has flavonoids, steroid, terpene, Anthraquinones, volatile oil component, has
There is certain pharmacological activity, pharmacological activity multiplicity reports the more neuroprotection that has, anti-inflammatory, antioxidation, to disease
The anthelmintic action of pathogenic microorganism, parahormone effect, cytotoxicity, antibacterial action and immunological enhancement, antifatigue effect.
Philippine flemingia root is now widely used for the Chinese patent drug production of the types such as gynaecology, rheumatic arthralgia, 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 (dysmenorrhea, cold uterus be infertile, uterus
Sagging, pelvic inflammatory disease, mazoitis, 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, reporting that the document of phenylpropanoids is few in the document of philippine flemingia root, effective Phenylpropanoid Glycosides class is found
Noval chemical compound isolates and purifies it, structural modification and synthesis, developing new drug, applied to the treatment of diseases associated with inflammation, meaning
It is great.
Summary of the invention
The technical problem to be solved by the present invention is to, a kind of effective component is found, cellular inflammation factor TNF-α can be inhibited,
The expressional function of IL-1 β, IL-6, and it is inhibited to hydroxyl radical free radical (- OH), it can apply to preparation and treat inflammatory disease
In the drug of disease.The present invention provides a kind of phenylpropanoids, can inhibit cellular inflammation factor TNF-α, IL-1 β, IL-
6 expressional function has the inhibiting effect to hydroxyl radical free radical (- OH), and then has anti-inflammatory and antioxidant activity, is anti-inflammatory agent
The exploitation of object provides direction, for treating related inflammation disease, such as cervicitis, endometritis, pelvic inflammatory disease, mazoitis, pharynx
Laryngitis and/or arthritis etc..
The object of the present invention is to provide a kind of medical applications of phenylpropanoids.
A kind of medicine of phenylpropanoids and its pharmaceutically acceptable salt as preparation treatment diseases associated with inflammation is provided
Application in object, shown in the structural formula of the phenylpropanoids such as formula (I)：
Shown in the structure such as formula (II) or formula (III) of the phenylpropanoids pharmaceutically acceptable salt：
Wherein, R is inorganic acid, R1Or R2For in sulfonate radical, alkali metal ion or ammonium root any one or it is two kinds any.
Preferably, the phenylpropanoids and its pharmaceutically acceptable salt are in the preparation inhibition cellular inflammation factor
Application in TNF-α, the expression of IL-1 β, IL-6 or the active drug of inhibition hydroxyl radical free radical, is applied to treat inflammatory disease
In the drug of disease.
Preferably, the diseases associated with inflammation is cervicitis, endometritis, pelvic inflammatory disease, mazoitis, sphagitis and/or pass
Section is scorching.
The pharmaceutically acceptable salt is that 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 R2For appointing in sulfonate radical, alkali metal ion or ammonium root
It anticipates a kind of or two kinds any.
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,
It is mentioned 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 pass through the prescription from FUKE QIANJIN PIAN and ' Qianjin ' capsule to treat ganopathy from traditional prescriptions of traditional Chinese medicine
In, a kind of new phenylpropanoids are made, and pass through reality by solvent extraction, column chromatography for separation, preparation liquid phase separation, purifying
Verifying is real, can be applied to diseases associated with inflammation, such as cervicitis, endometritis, pelvic inflammatory disease, mazoitis, 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, preparation liquid phase separation, purifying, phenylpropanoids of the present invention are obtained,
Then test cell line is carried out to the phenylpropanoids, measures it to cellular inflammation factor TNF-α, the inhibition of IL-1 β, IL-6
Degree, experiment show that the compound stimulates caused Raw 264.7 thin LPS in concentration (7.50-13.50 μ g/mL) range
Born of the same parents' inflammatory factor TNF-α content has apparent inhibiting effect (p < 0.05), and shows apparent dose-dependence；?
There is apparent inhibiting effect (p < to inflammatory factor IL-1 β and IL-6 content in concentration (10.50-13.50 μ g/mL) range
0.05) apparent dose-dependence, is shown.
Beneficial effects of the present invention：
The present invention from traditional Chinese medicine prescription angle, extracted from traditional Chinese medicine FUKE QIANJIN PIAN, ' Qianjin ' capsule to treat ganopathy,
Separation, purifying obtain a kind of phenylpropanoids, the experiment proved that, which, which shows, can inhibit cell
Inflammatory factor TNF-α, the expressional function of IL-1 β, IL-6 have the inhibiting effect to hydroxyl radical free radical (- OH), are inflammatory disease
Disease, such as cervicitis, endometritis, pelvic inflammatory disease, mazoitis, sphagitis and/or arthritis disease therapeutic agent exploitation
Provide direction.
New phenylpropanoids structure provided by the invention is simple, with high purity, and extraction separation method is easy, is easy to
Synthesis, is suitable for the industrial application of new drug.
Detailed description of the invention
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 embodiment
The present invention is further illustrated 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, raw material and equipment used in the present embodiment are the original of the art regular market purchase
Material and equipment.
The compound of the present invention is the change shown in phenylpropanoids shown in the formula (I) and formula (II) or formula (III)
Close object pharmaceutically acceptable salt.The compound can use the method provided by the invention extracted using Flemingia macrophylla as raw material
It is prepared, the structural formula that can also be provided according to the present invention is combined to 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 inflammatory disease, mazoitis, sphagitis and/
Or the therapeutic agent 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 with
Be added pharmaceutically allow auxiliary material and/or carrier in the case where 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
It is used as pharmaceutical composition together with other pharmaceutically acceptable effective components.
As pharmaceutical composition, tablet, capsule, powder, granule, pill, solution, suspension, syrup can be
Agent, injection, ointment, suppository, spray etc..
Further, tablet can be the manufactured sugar-coat in the case where auxiliary material and/or carrier that addition pharmaceutically allows
Piece, Film coated tablets, enteric coatings ply or two-ply, multilayer tablet.
Auxiliary material and/or carrier of the 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
White, albumin, calcium phosphate, D-sorbite, glycine, glycerol, 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 rouge (vaseline, albolene, solid paraffin etc.), wax class (jojoba oil, Brazil wax, beeswax etc.), partially synthetic or complete
Fatty acid glyceride (lauric acid, myristic acid, palmitinic acid etc.) of synthesis etc..
Liquid preparation is made, additive, such as sodium chloride, glucose, D-sorbite, glycerol, olive oil, the third two can be used
Alcohol, ethyl alcohol etc..In the case where 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, and with suspending agent appropriate, such as sodium carboxymethylcellulose, nonionic
Surfactant, cosolvent, such as Ergol, benzyl alcohol.
The amount of the effective component 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%
It extracts 3 times, 2 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 10L water, it is washed using D101 large pore resin absorption column
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 chromatographed with reverse phase ODS column and is eluted, 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. by the preparation liquid phase separation of the flow point MM-13 being collected into step S3, 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 25:75:
0.01, eluent is collected by peak sequence, 4 flow points is collected altogether, is respectively designated as MM-131, MM-132, MM-133, MM-
134, it is spare；
S5. the flow point MM-132 being collected into step S4 preparation liquid phase is purified, 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, obtains the phenylpropanoids 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%
It extracts 2 times, 1 hour 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 5L water, it is washed using D101 large pore resin absorption column
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 chromatographed with reverse phase ODS column and is eluted, 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. by the preparation liquid phase separation of the flow point MM-13 being collected into step S3, 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 35:65:
0.01, eluent is collected by peak sequence, 4 flow points is collected altogether, is respectively designated as MM-131, MM-132, MM-133, MM-
134, it is spare；
S5. the flow point MM-132 being collected into step S4 preparation liquid phase is purified, 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, obtains the phenylpropanoids 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% mentions
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 column
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 chromatographed with reverse phase ODS column and is eluted, 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. by the preparation liquid phase separation of the flow point MM-13 being collected into step S3, preparative liquid chromatography column is：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, 4 flow points is collected altogether, is respectively designated as MM-131, MM-132, MM-133, MM-
134, it is spare；
S5. the flow point MM-132 being collected into step S4 preparation liquid phase is purified, 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, obtains the phenylpropanoids 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% mentions
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 column
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 chromatographed with reverse phase ODS column and is eluted, 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. by the preparation liquid phase separation of the flow point MM-13 being collected into step S3, preparative liquid chromatography column is：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, 4 flow points is collected altogether, is respectively designated as MM-131, MM-132, MM-133, MM-
134, it is spare；
S5. the flow point MM-132 being collected into step S4 preparation liquid phase is purified, 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, obtains the phenylpropanoids 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% mentions
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 column
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 chromatographed with reverse phase ODS column and is eluted, 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. by the preparation liquid phase separation of the flow point MM-13 being collected into step S3, preparative liquid chromatography column is：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, 4 flow points is collected altogether, is respectively designated as MM-131, MM-132, MM-133, MM-
134, it is spare；
S5. the flow point MM-132 being collected into step S4 preparation liquid phase is purified, 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, obtains the phenylpropanoids 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：3- hydroxyl -4- methoxyl group -5- glucosyl group -9,9- dimethyl benzene propyl alcohol.It is tied
Shown in structure 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]+for m/z 411.1713, and in conjunction with nuclear-magnetism feature, can obtain molecular formula is C18H28O9, no
Saturation degree is 5.
1H-NMR(600MHz,CD3OD):6.97(d,1H),6.29(d,1H),4.89(d,1H),3.80(s,3H),3.56
(m,2H),3.12-3.89(5H,glc-H),3.03(m,2H),1.34(s,3H),1.18(s,3H)。
13C-NMR(150MHz,CD3OD):158.2(C-5),155.6(C-4),131.4(C-3),130.0(C-2),
129.5(C-1),117.5(C-6),102.2(C-1'),61.0-72.4(C2'-6'),68.7(C-9),58.1(-OCH3),
48.5(C-7),43.9(C-8),27.8(-CH3),21.0(-CH3)。
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 promotor
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 the 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 424.67, nuclear-magnetism feature1H-NMR(600MHz,
CD3OD):6.40(d,1H),6.19(d,1H),5.09(d,1H),3.90(s,3H),3.34(m,2H),3.13(m,2H),1.44
(s,3H),1.28(s,3H)。
Phenylpropanoids sulfonate：ESIMS is shown as m/z 452.17, nuclear-magnetism feature1H-NMR(600MHz,
CD3OD):6.28(d,1H),6.25(d,1H),4.87(d,1H),3.84(s,3H),3.51(m,2H),3.00(m,2H),1.24
(s,3H),1.11(s,3H)。
Phenylpropanoids sylvite or sodium salt：
Sylvite：ESIMS shows m/z 426.87, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):6.23(d,1H),6.20
(d,1H),4.41(d,1H),3.57(s,3H),3.41(m,2H),3.01(m,2H),1.15(s,3H),1.02(s,3H)。
Sodium salt：ESIMS shows m/z 411.17, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):6.25(d,1H),6.21
(d,1H),4.47(d,1H),3.58(s,3H),3.44(m,2H),3.01(m,2H),1.17(s,3H),1.08(s,3H)。
Phenylpropanoids ammonium salt：ESIMS shows m/z 403.47, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):
6.22(d,1H),6.21(d,1H),4.97(d,1H),3.80(s,3H),3.51(m,2H),3.03(m,2H),1.44(s,3H),
1.38(s,3H)。
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
One of sulfonate of class compound, formula (VI) are one of sylvite for the phenylpropanoids being prepared, formula
It (VII) is one of sodium salt for the phenylpropanoids being prepared, formula (VIII) is the phenylpropanoids being prepared
One of ammonium salt.
7 application test of experimental example
Compound and salt of the present invention stress be with the shadows of inflammation to LPS 264.7 oxidative macrophage 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-132,
I.e. heretofore described drug MM-132 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 company；Mouse macrophage Raw264.7
Purchased from the refined cell bank in Hunan；PBS；DMEM high glucose medium, fetal calf serum, penicillin and streptomysin；Full-automatic microplate reader；Constant temperature
CO2 incubator.
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 examination
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, is less than DMSO content in final concentration
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 salt, 100 μ g/mL streptomysins DMEM culture medium in, 37 DEG C, 5%CO2Growth is incubated in constant incubator.
The measurement of 1.4 cell viabilities
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) stimulation
For 24 hours, it inhales and abandons former culture medium, the MTT (0.5mg/mL) that 100 μ L are added in every hole continues to be incubated for 4h, inhales and abandons culture medium, and every hole is added
The DMSO of 150 μ L, shaking table shake 10min, and absorbance is measured at 490nm.
1.5 NO assays
264.7 cell inoculation 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) stimulation for 24 hours, finally collect supernatant, and on 10000rpm centrifugation 5min, packing
- 80 DEG C are placed in clearly to save backup.Pass through mouse NO kit measurement NO content.
1.6 inflammatory factor TNF-α, IL-1 β, IL-6 measurement
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 kit is measured for amount.
1.7 OH assays
Sample takes 1.5 samples prepared for OH factor determination.Pass through OH kit measurement content.
1.8 statistical analysis
Using SPSS17.0 software, 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-132 is in 1.50-13.50 μ
264.7 cell viability of Raw is had no significant effect in g/mL concentration range；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 cell of Raw, generate NO (65.81 ± 2.93IU/mL) content with just
Often group NO (33.61 ± 2.19IU/mL) compares significantly raised (p < 0.01).Drug MM-132 is under the concentration to caused by LPS
NO content increases no apparent inhibiting effect.
2.3 Drug inhibition TNF-α, the generation of IL-1 β, IL-6
As shown in Figures 5 to 7,264.7 cell 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) content 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 Raw264.7 cell to generate a large amount of inflammatory factors.
264.7 cell of Raw caused by drug MM-132 stimulates LPS in concentration (7.50-13.50 μ g/mL) range is scorching
Inflammation factor TNF-α content has apparent inhibiting effect (p < 0.05), and shows apparent dose-dependence；In concentration
There is apparent inhibiting effect (p < 0.05) to inflammatory factor IL-1 β and IL-6 content in (10.50-13.50 μ g/mL) range,
Show apparent dose-dependence.
The generation of 2.4 Drug inhibition OH
As shown in figure 8, by LPS stimulate 264.7 cell of Raw, generate OH (113.58 ± 6.03ng/mL) content with
Normal group OH (63.40 ± 1.19ng/mL) compares significantly raised (p < 0.01).
Drug MM-132 has significantly OH changes of contents caused by LPS in (4.50-13.50 μ g/mL) concentration range
Inhibiting effect (p < 0.05), and show dose-dependence.
This experiment has studied drug MM-132 to mouse macrophage NO, TNF-α, IL-1 β, IL-6, OH through in vitro culture
The influence of generation.
Drug MM-132 to the generation of factor NO without obvious inhibiting effect, to cellular inflammation factor TNF-α, IL-1 β, IL-6
Content shows inhibitory activity in middle and high concentration, illustrates that it plays anti-inflammatory activity and higher drug concentration is needed to realize；It is to OH's
Inhibitory activity is obvious, illustrates the antioxidant activity for having certain.
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, encapsulating 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.
Basic principles and main features of the invention and advantage of the 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 the technical staff of field 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 (12)
1. a kind of phenylpropanoids and its pharmaceutically acceptable salt answering in the drug of preparation treatment diseases associated with inflammation
With shown in the structural formula of the phenylpropanoids such as formula (I)：
2. applying according to claim 1, which is characterized in that be preparation inhibit cellular inflammation factor TNF-α, IL-1 β,
Application in the expression of 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, mazoitis, sphagitis and/or arthritis.
4. applying according to any one of the claim 1 to 3, which is characterized in that the pharmaceutically acceptable salt is formula (I) institute
Show the pharmaceutically acceptable salt that phenylpropanoids and acid or alkali are formed,
Shown in the structure such as formula (II) or formula (III) of the phenylpropanoids pharmaceutically acceptable salt：
Wherein, R is inorganic acid, R1Or R2For sulfonate radical, even in oxonium base metal ion or ammonium root any one or it is two kinds any.
5. applying according to claim 4, which is characterized in that the inorganic acid be hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid,
Sulfuric acid, nitric acid, phosphoric acid；The sulfonate radical is the sulfonate radical with aryl；The even oxonium base metal ion is potassium ion, sodium ion
Or lithium ion.
6. applying according to any one of the claim 1 to 3, which is characterized in that the pharmaceutically acceptable salt be carboxylate,
Lactate, calcium salt or magnesium salts.
7. applying according to claim 5, which is characterized in that the sulfonate radical with aryl is for benzene sulfonic acid root or to toluene
Sulfonate radical.
8. applying according to any one of the claim 1 to 3, which is characterized in that the drug contains the auxiliary material pharmaceutically allowed
And/or carrier.
9. applying according to claim 8, which is characterized in that the drug also contains cherokee rose root, single side needle, Caulis Spatholobi, function
One or more of Lao Mu, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis.
10. applying according to claim 8, which is characterized in that the drug also contains cherokee rose root, single side needle, Caulis Spatholobi, function
The extract of one or more of Lao Mu, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis.
11. applying according to claim 8, which is characterized in that the dosage form of the drug is tablet, capsule, powder, particle
Agent, pill, solution, suspension, injection, ointment, suppository or spray.
12. applying according to claim 8, which is characterized in that the dosage form of the drug is syrup.
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