CN105646613A - Phenylpropanoid compound and pharmaceutically acceptable salt and medicinal composition thereof - Google Patents

Phenylpropanoid compound and pharmaceutically acceptable salt and medicinal composition thereof Download PDF

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CN105646613A
CN105646613A CN201610153553.XA CN201610153553A CN105646613A CN 105646613 A CN105646613 A CN 105646613A CN 201610153553 A CN201610153553 A CN 201610153553A CN 105646613 A CN105646613 A CN 105646613A
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phenylpropanoids
salt
pharmaceutical composition
pharmaceutically acceptable
acid
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CN105646613B (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 invention relates to the technical field of medicine, and discloses a phenylpropanoid compound and pharmaceutically acceptable salt and a medicinal composition thereof. The structure of the phenylpropanoid compound is as shown in a formula (I). The phenylpropanoid compound and the pharmaceutically acceptable salt have an effect of inhibiting content of a macrophage inflammatory cytokine NO so as to achieve the anti-inflammatory activity by an NO inhibiting approach, and has very wide application prospect on the aspects of preparing medicaments for treating diseases related to the macrophage inflammatory cytokine NO, such as inflammatory diseases of cervicitis, endometritis, pelvic inflammation, mastitis, sphagitis and/or arthritis and the like. (referring to the specification) (I).

Description

Phenylpropanoids and pharmaceutically acceptable salt thereof and pharmaceutical composition
Technical field
The present invention relates to pharmaceutical technology field, more particularly, to a kind of phenylpropanoids and pharmaceutically acceptable salt thereof and pharmaceutical composition.
Background technology
From natural drug, extract that to separate the constituent structure that obtains various, active significantly, it is easily separated purification, structural modification, transformation and complete synthesis, is always up a main thought of new drug development.
TNF-��: be a kind of can direct killing tumor cell and to the normal cell cytokine without overt toxicity, be one of bioactie agent that the direct killing function of tumor found up to now is the strongest, but its toxic and side effects be also very serious.
IL-1 ��: collaborative APC and the T cell activation of stimulating, promotion B cell proliferation and secretory antibody when local low concentration, carries out immunomodulating. There is endocrine effect during a large amount of generation: induced liver acute phase protein synthesizes, cause heating and cachexia.
IL-6: mankind's IL-6 gene is positioned on No. 7 chromosome; IL-6 molecular weight is between 21��30KD. Main by mononuclear phagocyte, Th2 cell, vascular endothelial cell, fibroblast generation. Activating B cell can be stimulated to breed, secretory antibody; Stimulate T cell propagation and CTL activation; Cell cultured supernatant synthesized acute phase albumen, participates in inflammatory reaction; Promote blood cell development.
IL-6 can be synthesized by various kinds of cell, including T cell and B cell, monocytes/macrophages, endotheliocyte, epithelial cell and the fibroblast etc. of activation. The target cell of IL-6 effect is a lot, including macrophage, hepatocyte, static T cell, the B cell of activation and plasma cell etc.; Its biological effect is also sufficiently complex.
Macrophage can produce inflammation medium and participate in inflammatory reaction, and wherein, NO is the important cellular inflammation factor, and NO participates in multiple pathological processes, and excessive NO can promote generation and the development of diseases associated with inflammation, and can also induce other inflammatory factors.
Therefore, seek new compound, to suppress the content of cellular inflammation factor NO, be applied to the treatment of diseases associated with inflammation, be necessary.
Radix Flemingiae Philippinensis medical material is the dry root of pulse family (Leguminosae) Moghania (Flemingl.Roxb. or Moghania) plant Flemingia macrophylla (Moghaniamacrophylla (Willd.) O.Kuntze), is distributed mainly on region of Southeast in China.This 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), China main plant figure says (1955, and Guangzhou flora (1956, pp361) is all included pp707). Radix Flemingiae Philippinensis medical material is the genuine medicinal materials of Guangxi province, and history is loaded in " Zhiwu Mingshi Tukao ", has the basis of medication among the people widely. Its nature and flavor are sweet, micro-puckery, flat, have the effects such as removing damp-heat, are mainly used in the gynaecopathias such as treatment rheumatic ostalgia, traumatic injury, chronic nephritis, dysmenorrhea and leucorrhea be many. This medical material has recorded at present into version " Chinese Pharmacopoeia " annex in 2005.
The composition that Flemingia macrophylla has been reported mainly has flavonoid, steroid class, terpenoid, Anthraquinones, volatile oil composition; it is respectively provided with certain pharmacologically active; its pharmacologically active is various; reporting more has neuroprotective; antiinflammatory, antioxidation; to the anthelmintic action of pathogenic microorganism, parahormone effect, cytotoxicity, antibacterial action and immunological enhancement, antifatigue effect.
Radix Flemingiae Philippinensis is now widely used for the Chinese patent medicine of the type such as gynecological, rheumatic arthralgia and produces, such as FUKE QIANJIN PIAN, FUKE QIANJIN JIAONANG, JINJI CHONGJI, JINJI JIAONANG etc., this type of Chinese patent medicine be mainly used in gynaecopathia (dysmenorrhea, cold uterus be infertile, uterine prolapse, pelvic inflammatory disease, mastitis, leucorrhea are many, puerperal blood deficiency, arthralgia, puerperal waist and knee, hypogalactia and breast ulcer etc.), weak anemia (woman anemia, deficient qi and blood and the after being ill deficiency of vital energy etc.). In recent years, what clinical report was more is FUKE QIANJIN PIAN effect in treatment gynecological inflammation.
At present, in the document of Radix Flemingiae Philippinensis, the document of report phenylpropanoids is few, finds effective Phenylpropanoid Glycosides class noval chemical compound, it is easily separated purification, structural modification and synthesis, developing new drug, be applied to the treatment of diseases associated with inflammation, significant.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of new phenylpropanoids and pharmaceutically acceptable salt thereof.
Another technical problem that the invention solves the problems that is to provide the pharmaceutical composition containing described phenylpropanoids and/or pharmaceutically acceptable salt.
The purpose of the present invention is achieved by the following technical programs:
The structural formula of a kind of phenylpropanoids is such as shown in formula I:
The pharmaceutically acceptable salt that phenylpropanoids shown in a kind of above-mentioned formula I is formed.
Preferably, the inorganic acid salt that described pharmaceutically acceptable salt is phenylpropanoids shown in formula I to be formed with mineral acid, or the sulfonate formed with sulfonic acid, or the alkali metal salt formed with alkali metal hydroxide, or the ammonium salt formed with ammonium.
Preferably, described inorganic acid salt is hydrochlorate, hydrobromate, hydrofluoride, hydriodate, sulfate, nitrate, carboxylate, phosphate or lactate; Described alkali metal salt is potassium salt, sodium salt, calcium salt, magnesium salt or lithium salts.
Present invention simultaneously provides a kind of pharmaceutical composition, described pharmaceutical composition contains phenylpropanoids shown in above-mentioned formula I and/or its pharmaceutically acceptable salt.
Preferably, described pharmaceutical composition contains phenylpropanoids shown in above-mentioned formula I and/or its pharmaceutically acceptable salt and the adjuvant pharmaceutically allowed and/or carrier.
Preferably, described pharmaceutical composition contains phenylpropanoids shown in above-mentioned formula I and/or its pharmaceutically acceptable salt and other property of medicine compositions.
Preferably, described pharmaceutical composition is possibly together with one or more in Radix Rosae Laevigatae, Fructus Zanthoxyli Dissiti, Caulis Spatholobi, Caulis Mahoniae, Herba Andrographis, Radix Angelicae Sinensis, Radix Codonopsis.
Preferably, described pharmaceutical composition is possibly together with the extract of one or more in Radix Rosae Laevigatae, Fructus Zanthoxyli Dissiti, Caulis Spatholobi, Caulis Mahoniae, Herba Andrographis, Radix Angelicae Sinensis, Radix Codonopsis.
Described extract is that the extracting method described in any one by patent announcement CN1078079C, CN1170549C, CN1158087C, CN1330335C, CN1296071C, CN1321631C, CN1296072C, CN1296073C or several patent documents prepares.
The dosage form of described pharmaceutical composition can be tablet, capsule, powder, granule, pill, solution, suspensoid, syrup, injection, ointment, suppository or spray, and the attainable dosage form of other prior aries.
Described phenylpropanoids and pharmaceutically acceptable salt thereof have the content suppressing cellular inflammation factor NO, and then by suppressing NO approach to realize anti-inflammatory activity, can be applicable to the medicine of the preparation treatment diseases associated with inflammation relevant to cellular inflammation factor NO, described diseases associated with inflammation includes but not limited to cervicitis, endometritis, pelvic inflammatory disease, mastitis, pharyngolaryngitis and/or arthritis etc.
It is an object of the invention to from traditional prescriptions of Chinese medicine, by in the prescription from FUKE QIANJIN PIAN and FUKE QIANJIN JIAONANG, a kind of new phenylpropanoids is prepared by solvent extraction, column chromatography for separation, preparation liquid phase separation, purification, and experiments prove that, it can apply to diseases associated with inflammation, such as the treatment of the diseases such as cervicitis, endometritis, pelvic inflammatory disease, mastitis, pharyngolaryngitis and/or arthritis.
Specifically, inventor by from FUKE QIANJIN PIAN, FUKE QIANJIN JIAONANG prescription, choose the dry root of Flemingia macrophylla, by solvent extraction, column chromatography for separation, preparation liquid phase separation, purification, obtain phenylpropanoids of the present invention, then this phenylpropanoids is carried out test cell line, measure its suppression degree to cellular inflammation factor NO, experiments show that, the NO content that LPS is caused by this compound in concentration (4.87 14.62 �� g/mL) scope raises obvious inhibitory action, and shows obvious dose-dependence.
The invention has the beneficial effects as follows:
The invention provides a kind of new phenylpropanoids, provide described phenylpropanoids pharmaceutically acceptable salt simultaneously, this change Phenylpropanoid Glycosides class compound or its pharmaceutically acceptable salt can suppress the content of cellular inflammation factor NO, and then by suppressing NO approach to realize anti-inflammatory activity, the medicine of preparation treatment diseases associated with inflammation aspect can be advantageously applied to, include but not limited to such as cervicitis, endometritis, pelvic inflammatory disease, mastitis, the medicine of the diseases associated with inflammation such as pharyngolaryngitis and/or arthritis, for the technical foundation that the development offer of anti-inflammatory drug is strong.
Accompanying drawing explanation
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 that cytoactive is affected figure by phenylpropanoids of the present invention.
Fig. 4 is the phenylpropanoids of the present invention inhibitory action figure to NO.
Fig. 5 is the phenylpropanoids of the present invention inhibitory action figure to TNF-��.
Fig. 6 is the phenylpropanoids of the present invention inhibitory action figure to IL-1 ��.
Fig. 7 is the phenylpropanoids of the present invention inhibitory action figure to IL-6.
Fig. 8 is the phenylpropanoids of the present invention inhibitory action figure to OH.
Detailed description of the invention
Further illustrate the present invention below in conjunction with Figure of description and specific embodiment, but the present invention is not limited in any form by embodiment. Unless stated otherwise, the present invention adopts reagent, method and apparatus are the art conventional reagent, method and apparatus. Unless stated otherwise, raw material used by the present embodiment and equipment are the conventional commercial raw material of the art and equipment.
The compound of the present invention is the phenylpropanoids shown in described formula I and this compound pharmaceutically acceptable salt. This compound can adopt the method extracted for raw material with Flemingia macrophylla provided by the invention to prepare, it is also possible to prepares according to methods such as the chemosynthesis of structural formula provided by the invention combination employing this area.
As the salt of phenylpropanoids of the present invention, as long as pharmaceutically acceptable salt, the inorganic acid salt formed with the mineral acid such as hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid can be enumerated as; Sulfonate with sulfonic acid formation; The alkali metal salt formed with the alkali-metal hydroxide such as potassium, sodium, calcium, magnesium, lithium, the ammonium salt etc. formed with ammonium.
Phenylpropanoids of the present invention can be used as such as the medicine of the diseases associated with inflammation such as cervicitis, endometritis, pelvic inflammatory disease, mastitis, pharyngolaryngitis and/or arthritis.
The compounds of this invention can be used as pharmaceutical composition together with the adjuvant pharmaceutically allowed and/or carrier, can also being used as pharmaceutical composition when adding the adjuvant and/or carrier that pharmaceutically allow with the combination of one or more Chinese crude drugs in Radix Rosae Laevigatae, Fructus Zanthoxyli Dissiti, Caulis Spatholobi, Caulis Mahoniae, Herba Andrographis, Radix Angelicae Sinensis, Radix Codonopsis or extract, the compounds of this invention can also be used as pharmaceutical composition together with other pharmaceutically acceptable active ingredient.
As pharmaceutical composition, it is possible to be tablet, capsule, powder, granule, pill, solution, suspensoid, syrup, injection, ointment, suppository, spray etc.
Further, tablet can be make when adding the adjuvant that pharmaceutically allows and/or carrier coated tablet, Film coated tablets, enteric coatings ply or two-ply, multilayer tablet.
Adjuvant and/or the carrier of the present invention can be such that
Make solid preparation, additive can be used, for instance sucrose, lactose, cellulose sugar, maltose alcohol, glucose, starch based, agar, alginates, chitin, chitosan class, pectin class, Radix Acaciae senegalis class, gelatin class, collagen class, casein, albumin, calcium phosphate, Sorbitol, glycine, glycerol, Polyethylene Glycol, sodium bicarbonate, Talcum etc.
Make semi-solid preparation, it is possible to use of animal or plant nature oils and fats (olive oil, Semen Maydis oil, Semen Ricini wet goods), mineral oils and fats (vaseline, white vaseline, solid paraffin etc.), wax class (Jojoba oil, Brazil wax, Cera Flava etc.), partial synthesis or complete synthesis fatty acid glyceride (lauric acid, myristic acid, Palmic acid etc.) etc.
Make liquid preparation, additive can be used, for instance sodium chloride, glucose, Sorbitol, glycerol, olive oil, propylene glycol, ethanol etc. When especially making injection, it is possible to use aseptic aqueous solution, for instance normal saline, isotonic solution, oiliness liquid, such as Oleum Sesami, soybean oil.Furthermore it is also possible to as required, and with suitable suspending agent, such as sodium carboxymethyl cellulose, nonionic surfactant, cosolvent, such as benzyl benzoate, benzyl alcohol etc.
0.01��80 weight % that amount is preparation of the effective ingredient of these preparations, is suitably 1��50 weight %, and dosage changes according to differences such as the symptom of patient, body weight, ages.
The preparation of embodiment 1 phenylpropanoids
The present embodiment provides a kind of preparation method of phenylpropanoids shown in formula I, comprises the steps:
S1. Flemingia macrophylla 50kg is taken, with root for raw material, dry, it is cut into small pieces. Through the alcohol reflux 3 times of 8 times amount 60%, each 2 hours, extracting solution is merged, is concentrated into without alcohol taste, obtains extractum standby;
S2. being dissolved in 10L water by the extractum after concentration in step S1, adopt D101 macroporous adsorptive resins that it is carried out eluting, eluant is water, 3 column volumes of eluting, collection eluent, and called after MM-1 is standby;
S3. the flow point MM-1 collected in step S2 is carried out eluting with anti-phase ODS column chromatography, eluant is methanol-water system, and its volume ratio is 25:75,18 column volumes of eluting, the eluent of a flow point is collected by every 3 column volumes, collect 6 flow points in order, be respectively designated as: MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are standby;
S4. being prepared by the flow point MM-12 collected in step S3 liquid phase separation, preparative liquid chromatography post is: YMC, 20mm*250mm, flow velocity: 5ml/min, mobile phase is methanol-water-acetic acid system, methanol: water: the volume ratio of acetic acid is 25:75:0.01, collect eluent by peak sequence, collect 7 flow points altogether, be respectively designated as MM-121, MM-122, MM-123, MM-124, MM-125, MM-126, MM-127, standby;
S5. the flow point MM-124 collected in step S4 is prepared liquid phase purification, preparative liquid chromatography post is: YMC, 20mm*250mm, flow velocity: 5ml/min, mobile phase is methanol-water-acetic acid system, methanol: water: the volume ratio of acetic acid is 15:85:0.01, collects eluent, obtains described phenylpropanoids after recrystallization.
The preparation of embodiment 2 phenylpropanoids
The present embodiment provides a kind of preparation method of phenylpropanoids shown in formula I, comprises the steps:
S1. Flemingia macrophylla 40kg is taken, with root for raw material, dry, it is cut into small pieces. Through the alcohol reflux 2 times of 6 times amount 50%, each 1 hour, extracting solution is merged, is concentrated into without alcohol taste, obtains extractum standby;
S2. being dissolved in 5L water by the extractum after concentration in step S1, adopt D101 macroporous adsorptive resins that it is carried out eluting, the volume ratio that eluant is ethanol and water is 15:85,3 column volumes of eluting, collection eluent, and called after MM-1 is standby;
S3. the flow point MM-1 collected in step S2 is carried out eluting with anti-phase ODS column chromatography, eluant is methanol-water system, and its volume ratio is 20:80,18 column volumes of eluting, the eluent of a flow point is collected by every 3 column volumes, collect 6 flow points in order, be respectively designated as: MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are standby;
S4. being prepared by the flow point MM-12 collected in step S3 liquid phase separation, preparative liquid chromatography post is: YMC, 20mm*250mm, flow velocity: 10ml/min, mobile phase is methanol-water-acetic acid system, methanol: water: the volume ratio of acetic acid is 35:65:0.01, collect eluent by peak sequence, collect 7 flow points altogether, be respectively designated as MM-121, MM-122, MM-123, MM-124, MM-125, MM-126, MM-127, standby;
S5. the flow point MM-124 collected in step S4 is prepared liquid phase purification, preparative liquid chromatography post is: YMC, 20mm*250mm, flow velocity: 5ml/min, mobile phase is methanol-water-acetic acid system, methanol: water: the volume ratio of acetic acid is 15:85:0.01, collects eluent, obtains described phenylpropanoids after recrystallization.
The preparation of embodiment 3 phenylpropanoids
The present embodiment provides a kind of preparation method of phenylpropanoids shown in formula I, comprises the steps:
S1. Flemingia macrophylla 60kg is taken, with root for raw material, dry, it is cut into small pieces. The alcohol reflux of 7 times amount 70% 4 times, each 3 hours, merges extracting solution, is concentrated into without alcohol taste, obtains extractum standby;
S2. being dissolved in 8L water by the extractum after concentration in step S1, adopt D101 macroporous adsorptive resins that it is carried out eluting, the volume ratio that eluant is ethanol and water is 10:90,3 column volumes of eluting, collection eluent, and called after MM-1 is standby;
S3. the flow point MM-1 collected in step S2 is carried out eluting with anti-phase ODS column chromatography, eluant is methanol-water system, and its volume ratio is 30:70,18 column volumes of eluting, the eluent of a flow point is collected by every 3 column volumes, collect 6 flow points in order, be respectively designated as: MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are standby;
S4. being prepared by the flow point MM-12 collected in step S3 liquid phase separation, preparative liquid chromatography post is: YMC, 20mm*250mm, flow velocity: 10ml/min, mobile phase is methanol-water-acetic acid system, methanol: water: the volume ratio of acetic acid is 30:70:0.01, collect eluent by peak sequence, collect 7 flow points altogether, be respectively designated as MM-121, MM-122, MM-123, MM-124, MM-125, MM-126, MM-127, standby;
S5. the flow point MM-124 collected in step S4 is prepared liquid phase purification, preparative liquid chromatography post is: YMC, 20mm*250mm, flow velocity: 5ml/min, mobile phase is methanol-water-acetic acid system, methanol: water: the volume ratio of acetic acid is 15:85:0.01, collects eluent, obtains described phenylpropanoids after recrystallization.
The preparation of embodiment 4 phenylpropanoids
The present embodiment provides a kind of preparation method of phenylpropanoids shown in formula I, comprises the steps:
S1. Flemingia macrophylla 50kg is taken, with root for raw material, dry, it is cut into small pieces. The alcohol reflux of 8 times amount 60% 2 times, each 1.5 hours, merges extracting solution, is concentrated into without alcohol taste, obtains extractum standby;
S2. being dissolved in 6L water by the extractum after concentration in step S1, adopt D101 macroporous adsorptive resins that it is carried out eluting, the volume ratio that eluant is ethanol and water is 5:95,3 column volumes of eluting, collection eluent, and called after MM-1 is standby;
S3. the flow point MM-1 collected in step S2 is carried out eluting with anti-phase ODS column chromatography, eluant is methanol-water system, and its volume ratio is 25:75,18 column volumes of eluting, the eluent of a flow point is collected by every 3 column volumes, collect 6 flow points in order, be respectively designated as: MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are standby;
S4. being prepared by the flow point MM-12 collected in step S3 liquid phase separation, preparative liquid chromatography post is: YMC, 20mm*250mm, flow velocity: 10ml/min, mobile phase is methanol-water-acetic acid system, methanol: water: the volume ratio of acetic acid is 25:75:0.01, collect eluent by peak sequence, collect 7 flow points altogether, be respectively designated as MM-121, MM-122, MM-123, MM-124, MM-125, MM-126, MM-127, standby;
S5. the flow point MM-124 collected in step S4 is prepared liquid phase purification, preparative liquid chromatography post is: YMC, 20mm*250mm, flow velocity: 5ml/min, mobile phase is methanol-water-acetic acid system, methanol: water: the volume ratio of acetic acid is 15:85:0.01, collects eluent, obtains described phenylpropanoids after recrystallization.
The preparation of embodiment 5 phenylpropanoids
The present embodiment provides a kind of preparation method of phenylpropanoids shown in formula I, comprises the steps:
S1. Flemingia macrophylla 50kg is taken, with root for raw material, dry, it is cut into small pieces. The alcohol reflux of 8 times amount 80% 2 times, each 1.5 hours, merges extracting solution, is concentrated into without alcohol taste, obtains extractum standby;
S2. being dissolved in 6L water by the extractum after concentration in step S1, adopt D101 macroporous adsorptive resins that it is carried out eluting, the volume ratio that eluant is ethanol and water is 10:90,3 column volumes of eluting, collection eluent, and called after MM-1 is standby;
S3. the flow point MM-1 collected in step S2 is carried out eluting with anti-phase ODS column chromatography, eluant is methanol-water system, and its volume ratio is 28:72,18 column volumes of eluting, the eluent of a flow point is collected by every 3 column volumes, collect 6 flow points in order, be respectively designated as: MM-11, MM-12, MM-13, MM-14, MM-15, MM-16 are standby;
S4. being prepared by the flow point MM-12 collected in step S3 liquid phase separation, preparative liquid chromatography post is: YMC, 20mm*250mm, flow velocity: 10ml/min, mobile phase is methanol-water-acetic acid system, methanol: water: the volume ratio of acetic acid is 10:90:0.01, collect eluent by peak sequence, collect 7 flow points altogether, be respectively designated as MM-121, MM-122, MM-123, MM-124, MM-125, MM-126, MM-127, standby;
S5. the flow point MM-124 collected in step S4 is prepared liquid phase purification, preparative liquid chromatography post is: YMC, 20mm*250mm, flow velocity: 5ml/min, mobile phase is methanol-water-acetic acid system, methanol: water: the volume ratio of acetic acid is 15:85:0.01, collects eluent, obtains described phenylpropanoids after recrystallization.
Compound embodiment 1 to embodiment 5 prepared carries out the detection of mass spectrum, proton nmr spectra, carbon-13 nmr spectra, and result proves that gained compound is: and 4 '-glucosyl group (6 "-glucosyl group)-3 '-methoxyphenyl 3-hydroxy-4-methyl methyl valerate. Its structural formula is such as shown in formula I:
Its mass spectrum, proton nmr spectra, carbon-13 nmr spectra spectral data as follows:
HR-ESIMS shows [M+Na]+for m/z601.2243, and in conjunction with nuclear-magnetism feature, can obtain molecular formula is C25H38O15, degree of unsaturation is 7.
1HNMR (400MHz, MeOD) �� 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),5 5.1(-OCH3),37.7(C-4),24.8(C-5),20.2(-CH3),61.5-77.8(glc-C)��
The preparation of embodiment 6 phenylpropanoids salt
The preparation of phenylpropanoids hydrochlorate:
This compound methanol solution will drip saturated hydrochloric acid to pH value 2-3 under stirring, drip acetonitrile, sucking filtration under stirring, dry and obtain white powder solid, be the hydrochlorate of compound.
The preparation of phenylpropanoids sulfonate:
Reaction system containing this phenylpropanoids, solvent, sulfonic acid, neutral oil and accelerator adds alkali-metal hydroxide, add solvent, lower alcohol and kicker, pass into carbon dioxide, separate and obtain white powder solid, be the sulfonate of compound.
The preparation of phenylpropanoids potassium salt or sodium salt:
KOH or NaOH being dissolved in ethanol is added in this compound, the lower heating reflux reaction of stirring, cold room temperature processed, under stirring, drip acetonitrile, sucking filtration, dry to obtain white solid, be potassium salt or the sodium salt of this compound.
The preparation of phenylpropanoids ammonium salt:
This compound methanol solution will drip saturated ammonia to pH value 9-11 under stirring, drip acetonitrile, sucking filtration under stirring, dry and obtain white solid, be the ammonium salt of compound.
The spectral data of above-mentioned phenylpropanoids salt:
Phenylpropanoids hydrochlorate: ESIMS shows m/z614.38, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):1HNMR (400MHz, MeOD) �� 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/z642.77, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):1HNMR (400MHz, MeOD) �� 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 potassium salt or sodium salt:
Potassium salt ESIMS shows m/z616.17, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):1HNMR (400MHz, MeOD) �� 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/z600.67,1HNMR (400MHz, MeOD) �� 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/z593.49, nuclear-magnetism feature1H-NMR(600MHz,CD3OD):1HNMR (400MHz, MeOD) �� 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).
The partial structural formula of above-mentioned phenylpropanoids salt is such as shown in formula II��formula VI.
Wherein, formula II is the phenylpropanoids hydrochlorate prepared, formula III is the one of which sulfonate of the phenylpropanoids prepared, formula IV is the one of which potassium salt of the phenylpropanoids prepared, formula (V) is the one of which sodium salt of the phenylpropanoids prepared, and formula VI is the one of which ammonium salt of the phenylpropanoids prepared.
Experimental example 7 application test
The RAW264.7 oxidative macrophage of phenylpropanoids of the present invention and salt pair LPS induction stress with the impact of inflammation. (in order in experimentation, record is convenient, being numbered by phenylpropanoids of the present invention below: medicine MM-124, namely namely heretofore described medicine MM-124 refers to phenylpropanoids shown in formula I of the present invention or its pharmaceutically acceptable salt.)
1 materials and methods
1.1 medicines and instrument
Lipopolysaccharide (lipopolysaccharide, LPS), MTT available from Sigma; Mouse macrophage Raw264.7 is purchased from the refined cell bank in Hunan; PBS; DMEM high glucose medium, hyclone, penicillin and streptomycin; Full-automatic microplate reader; Constant temperature CO2 incubator.
Mice IL-1�� (IL-1-��) ELISA detection kit, lot number: 2014/06 (96T); Little mIL6 (IL-6) ELISA detection kit, lot number: 2014/06 (96T); Murine tumor necrosis factor-�� (TNF-��) ELISA detection kit, lot number: 2014/06 (96T); Mouse nitrous oxide (NO) ELISA detection kit, lot number: 2014/10 (96T); Mice hydroxyl radical free radical (OH) ELISA detection kit, lot number: 2014/10 (96T).
Prepared by 1.2 medicines
First dissolve with a small amount of DMSO, be then diluted to certain concentration with DMEM, make in final concentration DMSO content less than 1 ��.
1.3 cells are cultivated
Mouse macrophage Raw264.7 is incubated in the DMEM culture medium inactivateing the hyclone (FBS) of (56 DEG C, 30min), 10U/mL penicillin sodium, 100 �� g/mL streptomycins containing 10% heat, 37 DEG C, 5%CO2Constant incubator is hatched growth.
1.4 cell viabilities measure
Cell viability is measured by mtt assay. Cell is made cell suspension inoculation and hatches 24h in 96 orifice plates (1 �� 104/hole), resynchronization 24h, then the medicine of variable concentrations is acted on cell 2h, then adding LPS (30 �� g/mL) and stimulate 24h, inhale and abandon former culture medium, every hole adds the MTT (0.5mg/mL) of 100 �� L and continues to hatch 4h, culture medium is abandoned in suction, every hole adds the DMSO of 150 �� L, shaking table jolting 10min, measures absorbance at 490nm place.
1.5NO assay
Raw264.7 cell is inoculated in 96 orifice plate 24h, resynchronization 24h, then the medicine of variable concentrations is acted on cell 2h, then add LPS (30 �� g/mL) and stimulate 24h, finally collect supernatant, and in the centrifugal 5min of 10000rpm, subpackage supernatant is placed in-80 DEG C and saves backup. By mice NO kit measurement NO content.
1.6 inflammatory factor TNF-��, IL-1 ��, IL-6 measure
Sample takes 1.5 samples prepared for subsequent inflammation factor determination. Cell produces TNF-��, and the amount of IL-1 ��, IL-6 is by mice TNF-��, and IL-1 ��, IL-6 test kit measures.
1.7OH assay
Sample takes 1.5 samples prepared for OH factor determination. By OH kit measurement content.
1.8 statistical analysiss
Adopting SPSS17.0 software, experimental data is so that (x �� s represents; The data obtained is by using one factor analysis of variance, and homogeneity of variance LSD checks, and heterogeneity of variance DunnettT3 checks.
2 experimental results
2.1 cell viabilities
The impact of cell viability is evaluated by medicine by mtt assay. As it is shown on figure 3, Raw264.7 cell viability is had no significant effect by medicine MM-124 in (1.62-14.62 �� g/mL) concentration range; Therefore the drug level under this range of concentrations is suitable for subsequent experimental.
The generation of 2.2 Drug inhibition NO
As shown in Figure 4, stimulating Raw264.7 cell by LPS, it produces NO (65.81 �� 2.93IU/mL) content significantly raised compared with normal group NO (33.61 �� 2.19IU/mL) (p < 0.01). The NO content that LPS is caused by medicine MM-124 in concentration (4.87-14.62 �� g/mL) scope raises obvious inhibitory action, and shows obvious dose-dependence.
2.3 Drug inhibition TNF-��, the generation of IL-1 ��, IL-6
As shown in Figures 5 to 7, Raw264.7 cell is stimulated by LPS, Raw264.7 cellular inflammation factor TNF-�� (132.16 �� 5.28pg/mL), IL-1 �� (358.80 �� 24.64pg/mL), IL-6 (198.39 �� 5.97pg/mL) content and normal group TNF-�� (65.41 �� 6.29pg/mL), IL-1 �� (172.67 �� 10.06pg/mL), IL-6 (103.34 �� 2.88pg/mL) compare content significantly raised (p < 0.01);Illustrate that LPS can stimulate Raw264.7 cell to produce a large amount of inflammatory factors.
LPS is stimulated the Raw264.7 cellular inflammation factor TNF-�� caused by medicine MM-124 at various concentrations, and IL-1 ��, IL-6 content is all without obvious inhibitory action (p > 0.05).
The generation of 2.4 Drug inhibition OH
As shown in Figure 8, stimulating Raw264.7 cell by LPS, it produces OH (113.58 �� 6.03ng/mL) content significantly raised compared with normal group OH (63.40 �� 1.19ng/mL) (p < 0.01).
Medicine MM-124 at various concentrations to OH all without obvious inhibitory action.
This experiment, through In vitro culture, have studied medicine MM-124 to mouse macrophage NO, TNF-��, the impact that IL-1 ��, IL-6, OH generate.
Factor NO is had stronger inhibition by medicine MM-124, and to cellular inflammation factor TNF-��, IL-1 ��, IL-6 content all has no significant effect, and illustrates that its anti-inflammatory activity is mainly through suppressing NO approach to realize; It, to the basic unrestraint effect of OH, illustrates that its antioxidant activity is inconspicuous.
Embodiment 8
The preparation of tablet: first prepare the phenylpropanoids shown in formula I by embodiment 1 method, and utilize the salt that this compound and mineral acid (example hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkali-metal hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, Lithium hydrate) or ammonium make, excipient, pelletizing press sheet is added with excipient weight than the ratio for 1:10 in this compound or its any one salt.
Embodiment 9
The preparation of powder: first prepare the phenylpropanoids shown in formula I by embodiment 1 method, and utilizing the salt that this compound and mineral acid (example hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkali-metal hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, Lithium hydrate) or ammonium make, powder method for making makes powder routinely.
Embodiment 10
The preparation of capsule or granule: first prepare the phenylpropanoids shown in formula I by embodiment 1 method, and utilize the salt that this compound and mineral acid (example hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkali-metal hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, Lithium hydrate) or ammonium make, add excipient with excipient weight than the ratio for 1:10 in this compound or its any one salt, make capsule or granule.
Embodiment 11
The preparation of injection: first prepare the phenylpropanoids shown in formula I by embodiment 1 method, and utilize the salt that this compound and mineral acid (example hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkali-metal hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, Lithium hydrate) or ammonium make, water for injection routinely, fine straining, injection is made in embedding sterilizing.
Embodiment 12
A kind of pharmaceutical composition, the phenylpropanoids shown in formula I is prepared containing embodiment 1 method, and utilize the salt that this compound and mineral acid (example hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkali-metal hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, Lithium hydrate) or ammonium make, and the powder that Radix Rosae Laevigatae, Fructus Zanthoxyli Dissiti, Caulis Spatholobi, Caulis Mahoniae, Herba Andrographis, Radix Angelicae Sinensis, Radix Codonopsis are made, and adjuvant.
Embodiment 13
A kind of pharmaceutical composition, prepares the phenylpropanoids shown in formula I containing embodiment 1 method, and the powder that Radix Rosae Laevigatae, Fructus Zanthoxyli Dissiti, Caulis Spatholobi, Caulis Mahoniae, Herba Andrographis, Radix Angelicae Sinensis, Radix Codonopsis are made, and adjuvant.
Embodiment 14
A kind of pharmaceutical composition, prepares the phenylpropanoids shown in formula I containing embodiment 1 method, and Radix Rosae Laevigatae, Fructus Zanthoxyli Dissiti, Caulis Spatholobi, Caulis Mahoniae, Herba Andrographis, Radix Angelicae Sinensis, Radix Codonopsis extract, and adjuvant. Extract is that in any one by patent announcement CN1078079C, CN1170549C, CN1158087C, CN1330335C, CN1296071C, CN1321631C, CN1296072C, CN1296073C or several patent documents, extracting method prepares.
Embodiment 15
A kind of pharmaceutical composition, the phenylpropanoids shown in formula I is prepared containing embodiment 1 method, and utilize the salt that this compound and mineral acid (example hydrochloric acid, hydrobromic acid, Fluohydric acid., hydroiodic acid, sulphuric acid, nitric acid, carboxylic acid, phosphoric acid, lactic acid) or sulfonic acid or alkali-metal hydroxide (such as potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, Lithium hydrate) or ammonium make, and Radix Rosae Laevigatae, Fructus Zanthoxyli Dissiti, Caulis Spatholobi, Caulis Mahoniae, Herba Andrographis, Radix Angelicae Sinensis, Radix Codonopsis extract, and adjuvant. Extract is that in any one by patent announcement CN1078079C, CN1170549C, CN1158087C, CN1330335C, CN1296071C, CN1321631C, CN1296072C, CN1296073C or several patent documents, extracting method prepares.
The ultimate principle of the present invention and the advantage of principal character and the present invention have more than been shown and described. Skilled person will appreciate that; the present invention is not restricted to the described embodiments; described in above-described embodiment and description is that principles of the invention is described; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications; this will be apparent to those skilled in the art, and these changes and improvements both fall within the claimed scope of the invention. Claimed scope is defined by appending claims and equivalent thereof.

Claims (9)

1. a phenylpropanoids, it is characterised in that the structural formula of described phenylpropanoids is such as shown in formula I:
(I).
2. the pharmaceutically acceptable salt that phenylpropanoids is formed according to claim 1.
3. the pharmaceutically acceptable salt that phenylpropanoids is formed according to claim 2, it is characterized in that, described pharmaceutically acceptable salt is inorganic acid salt that in claim 1, phenylpropanoids described in formula I and mineral acid are formed or the sulfonate formed with sulfonic acid or the alkali metal salt formed with alkali metal hydroxide or the ammonium salt formed with ammonium.
4. the pharmaceutically acceptable salt that phenylpropanoids is formed according to claim 3, it is characterised in that described inorganic acid salt is hydrochlorate, hydrobromate, hydrofluoride, hydriodate, sulfate, nitrate, carboxylate, phosphate or lactate; Described alkali metal salt is potassium salt, sodium salt, calcium salt, magnesium salt or lithium salts.
5. a pharmaceutical composition, it is characterised in that containing the pharmaceutically acceptable salt that phenylpropanoids described in phenylpropanoids described in claim 1 and/or any one of claim 2 to 4 is formed.
6. pharmaceutical composition according to claim 5, it is characterised in that described pharmaceutical composition is possibly together with the adjuvant pharmaceutically allowed and/or carrier.
7. pharmaceutical composition according to claim 5, it is characterised in that described pharmaceutical composition is possibly together with one or more in Radix Rosae Laevigatae, Fructus Zanthoxyli Dissiti, Caulis Spatholobi, Caulis Mahoniae, Herba Andrographis, Radix Angelicae Sinensis, Radix Codonopsis.
8. pharmaceutical composition according to claim 5, it is characterised in that described pharmaceutical composition is possibly together with the extract of one or more in Radix Rosae Laevigatae, Fructus Zanthoxyli Dissiti, Caulis Spatholobi, Caulis Mahoniae, Herba Andrographis, Radix Angelicae Sinensis, Radix Codonopsis.
9. pharmaceutical composition according to claim 5, it is characterised in that the dosage form of described pharmaceutical composition is tablet, capsule, powder, granule, pill, solution, suspensoid, syrup, injection, ointment, suppository or spray.
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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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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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