CN105646613B - Phenylpropanoids and its pharmaceutically acceptable salt and pharmaceutical composition - Google Patents

Phenylpropanoids and its pharmaceutically acceptable salt and pharmaceutical composition Download PDF

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CN105646613B
CN105646613B CN201610153553.XA CN201610153553A CN105646613B CN 105646613 B CN105646613 B CN 105646613B CN 201610153553 A CN201610153553 A CN 201610153553A CN 105646613 B CN105646613 B CN 105646613B
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phenylpropanoids
pharmaceutical composition
salt
acceptable salt
acid
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CN105646613A (en
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张鹏
彭开锋
林丽美
伍实花
夏博候
佘娜
廖爱玲
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Zhuzhou Qianjin Pharmaceutical Co Ltd
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Zhuzhou Qianjin Pharmaceutical Co Ltd
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Abstract

The present invention relates to pharmaceutical technology field, a kind of phenylpropanoids and its pharmaceutically acceptable salt and pharmaceutical composition are disclosed.Shown in the phenylpropanoids structure such as formula (I).The compound and its pharmaceutically acceptable salt have the content for inhibiting cellular inflammation factor NO, and then by inhibiting NO approach to realize anti-inflammatory activity, it has a good application prospect in terms of the drug of the diseases associated with inflammation such as preparation treatment and the cellular inflammation factor NO related disease, such as cervicitis, endometritis, pelvic inflammatory disease, mazoitis, sphagitis and/or arthritis.(I).

Description

Phenylpropanoids and its pharmaceutically acceptable salt and pharmaceutical composition
Technical field
The present invention relates to pharmaceutical technology fields, can more particularly, to a kind of phenylpropanoids and its pharmaceutically connect The salt and pharmaceutical composition received.
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-1 β: collaboration stimulation APC and T cell activation in local low concentration promote B cell proliferation and secretory antibody, into Row immunological regulation.Have 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, on Chrotoplast and fibroblast etc..IL-6 effect target cell it is very much, including macrophage, liver cell, static T cell, The B cell of activation and thick liquid cell etc.；Its biological effect is also sufficiently complex.
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, applied to controlling for diseases associated with inflammation It treats, is necessary.
Philippine flemingia root medicinal material is that pulse family (Leguminosae) Moghania (F1emingl.Roxb. or Moghania) plant is big The dry root of leaf philippine flemingia root (Moghaniamacrophylla (Willd.) 0.Kuntze), is distributed mainly on the southeast in China Area.The plant is in Chinese Plants will (1995,41:313), tw Taiwan flora (1977,3:258), Hainan flora (1965,2:311), " Chinese Higher plant illustrated handbook " (1972,2:510), Chinese main plant figure are said (1955, pp707) and wide State flora is included in (1956, pp361).Philippine flemingia root medicinal material is the genunie medicinal materials of Guangxi province, and history is loaded in " plant name reality 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, dysmenorrhea and leukorrhea.The medicinal material has been recorded at present into version in 2005 " Chinese Pharmacopoeia " 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 in the present invention is to provide a kind of new phenylpropanoids and its pharmaceutically acceptable Salt.
Another technical problem to be solved by the present invention is that providing containing the phenylpropanoids and/or can pharmaceutically connect The pharmaceutical composition for the salt received.
The purpose of the present invention is achieved by the following technical programs:
A kind of structural formula of phenylpropanoids such as formula (I) is shown:
The pharmaceutically acceptable salt that phenylpropanoids shown in a kind of above-mentioned formula (I) are formed.
Preferably, the pharmaceutically acceptable salt is the nothing that phenylpropanoids shown in formula (I) and inorganic acid are formed Machine hydrochlorate, or the sulfonate formed with sulfonic acid, or the alkali metal salt formed with alkali metal hydroxide, or the ammonium formed with ammonium Salt.
Preferably, the inorganic acid salt be hydrochloride, hydrobromate, hydrofluoride, hydriodate, sulfate, nitrate, Carboxylate, phosphate or lactate；The alkali metal salt is sylvite, sodium salt, calcium salt, magnesium salts or lithium salts.
Present invention simultaneously provides a kind of pharmaceutical composition, described pharmaceutical composition contains Phenylpropanoid Glycosides class shown in above-mentioned formula (I) Compound and/or its pharmaceutically acceptable salt.
Preferably, described pharmaceutical composition contains phenylpropanoids shown in above-mentioned formula (I) and/or its and can pharmaceutically connect The salt received and the auxiliary material and/or carrier that pharmaceutically allow.
Preferably, described pharmaceutical composition contains phenylpropanoids shown in above-mentioned formula (I) and/or its and can pharmaceutically connect The salt received and other pharmacological property ingredients.
Preferably, described pharmaceutical composition also contains cherokee rose root, single side needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, party One or more of ginseng.
Preferably, described pharmaceutical composition also contains cherokee rose root, single side needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, party The extract of one or more of ginseng.
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 described pharmaceutical composition can for tablet, capsule, powder, granule, pill, solution, suspension, Syrup, injection, ointment, suppository or spray and the achievable dosage form of other prior arts.
The phenylpropanoids and its pharmaceutically acceptable salt have the content for inhibiting cellular inflammation factor NO, into And anti-inflammatory activity is realized by inhibiting NO approach, it can be applied to preparation and treat diseases associated with inflammation relevant to cellular inflammation factor NO Drug, the diseases associated with inflammation include but is not limited to cervicitis, endometritis, pelvic inflammatory disease, mazoitis, sphagitis and/or Arthritis etc..
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 by solvent extraction, column chromatography for separation, preparation liquid phase separation, purifying It is experimentally confirmed that it can be applied to diseases associated with inflammation, as cervicitis, endometritis, pelvic inflammatory disease, mazoitis, sphagitis and/or The treatment of the diseases such as arthritis.
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 its inhibition level to cellular inflammation factor NO, experiment shows The compound has apparent inhibiting effect to the raising of NO content caused by LPS in concentration (4.87-14.62 μ g/mL) range, and And show apparent dose-dependence.
The beneficial effects of the present invention are:
The present invention provides a kind of new phenylpropanoids, while providing the phenylpropanoids pharmaceutically Acceptable salt, which, which closes object or its pharmaceutically acceptable salt, can inhibit the content of cellular inflammation factor NO, And then by inhibiting NO approach to realize anti-inflammatory activity, the drug in terms of preparation treatment diseases associated with inflammation, packet can be advantageously applied to It includes but is not limited to controlling for such as cervicitis, endometritis, pelvic inflammatory disease, mazoitis, sphagitis and/or arthritis diseases associated with inflammation Drug is treated, provides strong technical foundation for the development of anti-inflammatory 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 that phenylpropanoids shown in the formula (I) and the compound are pharmaceutically acceptable Salt.The compound can use the method provided by the invention extracted using Flemingia macrophylla as raw material to be prepared, can also root It combines according to structural formula provided by the invention and is 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 such that
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 elute 18 column volumes, the eluent of a flow point are collected by every 3 column volumes, in order 6 flow points are collected, be 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-12 being collected into step S3, preparative liquid chromatography column are as follows: YMC, 20mm*250mm, flow velocity: 5ml/min, mobile phase are methanol-water-acetic acid system, and 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-124 being collected into step S4 preparation liquid phase is purified, preparative liquid chromatography column are as follows: YMC, 20mm*250mm, flow velocity: 5ml/min, mobile phase are methanol-water-acetic acid system, and 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, elutes 3 column volumes, collects eluent, be 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 20: 80 elute 18 column volumes, the eluent of a flow point are collected by every 3 column volumes, in order 6 flow points are collected, be 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-12 being collected into step S3, preparative liquid chromatography column are as follows: YMC, 20mm*250mm, flow velocity: 10ml/min, mobile phase are methanol-water-acetic acid system, and 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-124 being collected into step S4 preparation liquid phase is purified, preparative liquid chromatography column are as follows: YMC, 20mm*250mm, flow velocity: 5ml/min, mobile phase are methanol-water-acetic acid system, and 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, elutes 3 column volumes, collects eluent, be 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 30: 70 elute 18 column volumes, the eluent of a flow point are collected by every 3 column volumes, in order 6 flow points are collected, be 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-12 being collected into step S3, preparative liquid chromatography column are as follows: YMC, 20mm*250mm, flow velocity: 10ml/min, mobile phase are methanol-water-acetic acid system, and 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-124 being collected into step S4 preparation liquid phase is purified, preparative liquid chromatography column are as follows: YMC, 20mm*250mm, flow velocity: 5ml/min, mobile phase are methanol-water-acetic acid system, and 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, elutes 3 column volumes, collects eluent, be 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 elute 18 column volumes, the eluent of a flow point are collected by every 3 column volumes, in order 6 flow points are collected, be 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-12 being collected into step S3, preparative liquid chromatography column are as follows: YMC, 20mm*250mm, flow velocity: 10ml/min, mobile phase are methanol-water-acetic acid system, and 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-124 being collected into step S4 preparation liquid phase is purified, preparative liquid chromatography column are as follows: YMC, 20mm*250mm, flow velocity: 5ml/min, mobile phase are methanol-water-acetic acid system, and 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, elutes 3 column volumes, collects eluent, be 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 28: 72 elute 18 column volumes, the eluent of a flow point are collected by every 3 column volumes, in order 6 flow points are collected, be 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-12 being collected into step S3, preparative liquid chromatography column are as follows: YMC, 20mm*250mm, flow velocity: 10ml/min, mobile phase are methanol-water-acetic acid system, and 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-124 being collected into step S4 preparation liquid phase is purified, preparative liquid chromatography column are as follows: YMC, 20mm*250mm, flow velocity: 5ml/min, mobile phase are methanol-water-acetic acid system, and 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 are as follows: -3 '-methoxyphenyl 3- hydroxyl -4- first of 4 '-glucosyl groups (6 "-glucosyl group) Base methyl valerate.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]+for m/z 601.2243, and in conjunction with nuclear-magnetism feature, can obtain molecular formula is C25H38O15, no Saturation degree is 7.
1H NMR (400MHz, MeOD) δ 6.77 (d, J=2.3Hz, 1H), 6.70 (d, J=8.6Hz, 1H), 6.57 (d, J =8.6Hz, 2.3Hz, 1H), 5.47 (s, 1H), 4.85 (s, 1H), 4.67 (t, 1H), 4.26 (m, 2H), 3.20-4.00 (glc- H), 2.81 (s, 1H), 1.43,1.14 (s, 6H).
13C-NMR (150MHz, CD3OD): 176.5 (C-1), 151.4 (C-4 '), 147.9 (C-1 '), 141.5 (C-3 '), 114.7 (C-2 '), 112.7 (C-6 '), 109.1 (C-5 '), 102.3 (C "), 101.1 (C " '), 88.4 (C-3), 60.5 (C-2), 55.1(-OCH3), 37.7 (C-4), 24.8 (C-5), 20.2 (- CH3), 61.5-77.8 (glc-C).
The preparation of 6 phenylpropanoids salt of embodiment
The preparation of phenylpropanoids hydrochloride:
Saturation hydrochloric acid will be added dropwise under stirring in the compound methanol solution to pH value 2-3, the lower dropwise addition acetonitrile of stirring filters, It is dried to obtain white powder solid, the as hydrochloride of compound.
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 is as changed Close the sulfonate of object.
The preparation of phenylpropanoids sylvite or sodium salt:
The KOH being dissolved in ethyl alcohol or NaOH are added in the compound, lower heating reflux reaction is stirred, cold room temperature processed is stirred Lower dropwise addition acetonitrile is mixed, is filtered, dry white solid, the as sylvite or sodium salt of the compound.
The preparation of phenylpropanoids ammonium salt:
Saturation ammonium hydroxide will be added dropwise under stirring in the compound methanol solution to pH value 9-11, the lower dropwise addition acetonitrile of stirring filters, It is dried to obtain white solid, the as ammonium salt of compound.
The spectral data of above-mentioned phenylpropanoids salt:
Phenylpropanoids hydrochloride: ESIMS shows m/z 614.38, nuclear-magnetism feature1H-NMR (600MHz, CD3OD):1H NMR (400MHz, MeOD) δ 6.74 (d, J=2.3Hz, 1H), 6.67 (d, J=8.6Hz, 1H), 6.44 (d, J= 8.6Hz, 2.3Hz, 1H), 5.41 (s, 1H), 4.80 (s, 1H), 4.60 (t, 1H), 4.21 (m, 2H), 3.20-4.00 (glc-H), 2.77 (s, 1H), 1.43,1.14 (s, 6H).
Phenylpropanoids sulfonate: ESIMS is shown as m/z 642.77, nuclear-magnetism feature1H-NMR (600MHz, CD3OD):1H NMR (400MHz, MeOD) δ 6.78 (d, J=2.3Hz, 1H), 6.72 (d, J=8.6Hz, 1H), 6.59 (d, J= 8.6Hz, 2.3Hz, 1H), 5.48 (s, 1H), 4.89 (s, 1H), 4.69 (t, 1H), 4.28 (m, 2H), 3.20-4.00 (glc-H), 2.83 (s, 1H), 1.43,1.14 (s, 6H).
Phenylpropanoids sylvite or sodium salt:
Sylvite ESIMS shows m/z 616.17, nuclear-magnetism feature1H-NMR (600MHz, CD3OD):1H NMR (400MHz, MeOD) δ 6.71 (d, J=2.3Hz, 1H), 6.66 (d, J=8.6Hz, 1H), 6.54 (d, J=8.6Hz, 2.3Hz, 1H), 5.44 (s, 1H), 4.81 (s, 1H), 4.61 (t, 1H), 4.26 (m, 2H), 3.20-4.00 (glc-H), 2.80 (s, 1H), 1.43,1.14 (s, 6H).
Sodium salt ESIMS shows m/z 600.67,1H NMR (400MHz, MeOD) δ 6.79 (d, J=2.3Hz, 1H), 6.63 (d, J=8.6Hz, 1H), 6.47 (d, J=8.6Hz, 2.3Hz, 1H), 5.34 (s, 1H), 4.84 (s, 1H), 4.67 (t, 1H), 4.20 (m, 2H), 3.20-4.00 (glc-H), 2.77 (s, 1H), 1.43,1.14 (s, 6H).
Phenylpropanoids ammonium salt: ESIMS shows m/z 593.49, nuclear-magnetism feature1H-NMR (600MHz, CD3OD):1H NMR (400MHz, MeOD) δ 6.70 (d, J=2.3Hz, 1H), 6.69 (d, J=8.6Hz, 1H), 6.49 (d, J=8.6Hz, 2.3Hz, 1H), 5.41 (s, 1H), 4.76 (s, 1H), 4.61 (t, 1H), 4.23 (m, 2H), 3.20-4.00 (glc-H), 2.77 (s, 1H), 1.43,1.14 (s, 6H).
Shown in the partial structural formula such as formula (II) of above-mentioned phenylpropanoids salt~formula (VI).
Wherein, formula (II) is the phenylpropanoids hydrochloride being prepared, and formula (III) is the Phenylpropanoid Glycosides being prepared One of sulfonate of class compound, formula (IV) are one of sylvite for the phenylpropanoids being prepared, formula (V) One of sodium salt for the phenylpropanoids being prepared, formula (VI) are its for the phenylpropanoids being prepared A kind of middle ammonium salt.
7 application test of experimental example
264.7 oxidative macrophage of RAW that phenylpropanoids and salt of the present invention induce LPS stress be with The influence of inflammation.(it is convenient in order to be recorded in experimentation, below by phenylpropanoids label of the present invention are as follows: medicine Object MM-124, i.e., heretofore described drug MM-124 refer to phenylpropanoids shown in formula (I) or its medicine Acceptable salt on.)
1 materials and methods
1.1 drugs and instrument
Lipopolysaccharides (1ipopolysaccharide, 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.
1.5NO assay
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-124 is in (1.62-14.62 μ g/mL) 264.7 cell viability of Raw is had no significant effect in concentration range；Therefore the drug concentration under this range of concentrations It is suitable for 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-124 is in concentration (4.87-14.62 μ g/ ML) there is apparent inhibiting effect to the raising of NO content 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 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 cellular inflammation factor TNF-α of Raw caused by drug MM-124 at various concentrations stimulates LPS, IL-1 β, IL-6 content is without apparent inhibiting effect (p > 0.05).
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-124 is at various concentrations to OH without apparent inhibiting effect.
This experiment has studied drug MM-124 to mouse macrophage NO, TNF-α, IL-1 β, IL-6, OH through in vitro culture The influence of generation.
Drug MM-124 has stronger inhibitory effect to factor NO, and to cellular inflammation factor TNF-α, IL-1 β, IL-6 contain Amount all has no significant effect, and illustrates that its anti-inflammatory activity mainly passes through and NO approach is inhibited to realize；It is to the basic unrestraint effect of OH, explanation Its antioxidant activity is unobvious.
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 Excipient, pelletizing press sheet is added in the ratio that the compound or its any one salt and excipient weight ratio are 1: 10.
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: being first made phenylpropanoids shown in formula (I) 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 added excipient in the ratio that the compound or its any one salt and excipient weight ratio are 1: 10, 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 (9)

1. a kind of phenylpropanoids, which is characterized in that shown in the structural formula of the phenylpropanoids such as formula (I):
2. the pharmaceutically acceptable salt that phenylpropanoids are formed according to claim 1.
3. the pharmaceutically acceptable salt that phenylpropanoids are formed according to claim 2, which is characterized in that the medicine On acceptable salt be inorganic acid salt that claim 1 Chinese style (I) phenylpropanoids and inorganic acid are formed or with The sulfonate that sulfonic acid is formed or the alkali metal salt formed with alkali metal hydroxide or the ammonium salt formed with ammonium.
4. the pharmaceutically acceptable salt that phenylpropanoids are formed according to claim 3, which is characterized in that the nothing Machine hydrochlorate is hydrochloride, hydrobromate, hydrofluoride, hydriodate, sulfate, nitrate, phosphate；The alkali metal salt is Sylvite, sodium salt or lithium salts.
5. a kind of pharmaceutical composition, which is characterized in that contain phenylpropanoids and/or claim 2 described in claim 1 The pharmaceutically acceptable salt formed to any one of 4 phenylpropanoids.
6. pharmaceutical composition according to claim 5, which is characterized in that described pharmaceutical composition also contains and pharmaceutically to allow Auxiliary material and/or carrier.
7. pharmaceutical composition according to claim 5, which is characterized in that described pharmaceutical composition also contains cherokee rose root, single side One or more of needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis.
8. pharmaceutical composition according to claim 5, which is characterized in that described pharmaceutical composition also contains cherokee rose root, list The extract of one or more of face needle, Caulis Spatholobi, leatherleaf mahonia, Herba Andrographitis, Radix Angelicae Sinensis, Radix Codonopsis.
9. pharmaceutical composition according to claim 5, which is characterized in that the dosage form of described pharmaceutical composition is tablet, capsule Agent, powder, granule, pill, solution, suspension, syrup, injection, ointment, suppository or spray.
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CN102274341A (en) * 2010-06-10 2011-12-14 上海中医药大学 Extracting and refining process for medicinal components of figwort root
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CN102274341A (en) * 2010-06-10 2011-12-14 上海中医药大学 Extracting and refining process for medicinal components of figwort root
CN102631390A (en) * 2012-04-12 2012-08-15 贵州师范大学 Preparation method of periploca forrestii schltr extract as well as product and application of periploca forrestii schltr extract

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