CN105732364A - Domperidone pharmaceutical composition and application thereof in biological medicine - Google Patents
Domperidone pharmaceutical composition and application thereof in biological medicine Download PDFInfo
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- CN105732364A CN105732364A CN201610283902.XA CN201610283902A CN105732364A CN 105732364 A CN105732364 A CN 105732364A CN 201610283902 A CN201610283902 A CN 201610283902A CN 105732364 A CN105732364 A CN 105732364A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/40—Unsaturated compounds
- C07C59/76—Unsaturated compounds containing keto groups
- C07C59/80—Unsaturated compounds containing keto groups containing rings other than six-membered aromatic rings
- C07C59/82—Unsaturated compounds containing keto groups containing rings other than six-membered aromatic rings the keto group being part of a ring
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract
The invention discloses a domperidonepharmaceutical composition and an application thereof in a biological medicine. The domperidone pharmaceutical composition provided by the invention contains domperidone and a natural product compound (I) of a novel structure. When the domperidone and the compound (I) are used separately, benign prostatic hyperplasia can be treated; when the domperidone and the compound (I) are used together, the treatment effect on benign prostatic hyperplasia can be further improved, a medicine for treating benign prostatic hyperplasia can be developed, and thus compared with the prior art, the domperidone pharmaceutical composition has outstanding practical characteristics and remarkable improvement.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of domperidone, be specifically related to the pharmaceutical composition of domperidone and the application in biological medicine thereof.
Background technology
The chemical name of domperidone is the chloro-1-of 5-[1-[3-(2,3-dihydro-2-oxo-1H-benzimidazole-1-base) propyl group] piperidin-4-yl]-1,3-dihydro-2H-2-ketone benzimidaozole, for gastrointestinal dynamics-promoting medicine class nonprescription drugs medicine.
Up to now, there is not yet the dependency of domperidone and pharmaceutical composition thereof and prostatic hyperplasia report.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of domperidone, containing the natural product of domperidone and a kind of novel structure, domperidone and this natural product in this pharmaceutical composition can Synergistic treatment prostatic hyperplasia.
The above-mentioned purpose of the present invention is achieved by the techniques below scheme:
A kind of compound (I) with following structural formula,
The pharmaceutical composition of a kind of domperidone, including domperidone, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepares into the dosage form of needs.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form includes tablet, capsule, oral liquid, sucks agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
The preparation method of above-claimed cpd (I), comprise following operating procedure: Rhizoma Cibotii is pulverized by (a), extract with 85～95% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste, successively with petroleum ether, ethyl acetate and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B in () step (a), n-butyl alcohol takes thing macroporous resin remove impurity, first with 8 column volumes of 35% ethanol elution, then with 12 column volumes of 90% ethanol elution, collect 90% eluent, and concentrating under reduced pressure obtains 90% ethanol elution concentrate；In (c) step (b) 90% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 120:1,60:1,30:1 and 15:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel, successively with volume ratio be 40:1,30:1 and 10:1 methylene chloride-methanol gradient elution obtain 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 85%, collecting 14～18 column volume eluents, eluent concentrating under reduced pressure obtains compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 90% alcohol heat reflux, united extraction liquid.
Further, in the preparation method of compound (I), described macroporous resin is D101 type macroporous adsorbent resin.
Further, in the preparation method of compound (I), step (a) replaces ethyl acetate to extract with dichloromethane, obtains dichloromethane extract.
The above-claimed cpd (I) application in the medicine of preparation treatment prostatic hyperplasia.
The application in the medicine of preparation treatment prostatic hyperplasia of the pharmaceutical composition of above-mentioned domperidone.
Advantages of the present invention: when containing the natural product of domperidone and a kind of novel structure, domperidone and this natural product independent role in the pharmaceutical composition of domperidone provided by the invention, prostatic hyperplasia is had therapeutical effect；During the two synergy, the therapeutic effect of prostatic hyperplasia is improved further, it is possible to develop into the medicine for the treatment of prostatic hyperplasia.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit scope with this.
Embodiment 1: compound (I) separates preparation and structural identification
Separation method: Rhizoma Cibotii (2kg) is pulverized by (a), (15L × 3 time) are extracted with 90% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste (3L), extract with petroleum ether (3L × 3 time), ethyl acetate (3L × 3 time) and water saturated n-butyl alcohol (3L × 3 time) successively, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B acetic acid ethyl ester extract D101 type macroporous resin remove impurity in () step (a), first with 8 column volumes of 35% ethanol elution, then with 12 column volumes of 90% ethanol elution, collects 90% eluent, concentrating under reduced pressure obtains 90% ethanol elution concentrate；C in () step (b), 90% ethanol elution concentrate purification on normal-phase silica gel separates, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 120:1 (11 column volumes), 60:1 (9 column volumes), 30:1 (9 column volumes) and 15:1 (8 column volumes) successively；D in () step (c), component 3 separates further by purification on normal-phase silica gel, obtain 3 components with the methylene chloride-methanol gradient elution that volume ratio is 40:1 (6 column volumes), 30:1 (8 column volumes) and 10:1 (6 column volumes) successively；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 85%, collecting 14～18 column volume eluents, eluent concentrating under reduced pressure obtains compound (I) (HPLC normalization purity is more than 98%).
Structural identification: white amorphous powder, HR-ESI-MS shows [M+Na]+For m/z285.1108, can obtain molecular formula in conjunction with nuclear-magnetism feature is C15H18O4, degree of unsaturation is 7.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-3 (5.83, br, s), H-5 (2.87, br, d, J=12.7Hz), H-6 (1.35, m), H-6 (2.11, m), H-7 (2.63, br, t, J=12.1Hz), H-8 (1.62, m), H-8 (1.75, m), and H-9 (1.75, m), H-9 (2.43, m), H-13 (6.38, br, s), H-13 (6.73, br, s), H-14 (1.19, s), and H-15 (1.95, s)；Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz): 181.6 (C, 1-C), 182.5 (C, 2-C), 124.9 (CH, 3-C), 176.5 (C, 4-C), 42.3 (CH, 5-C), 29.7 (CH2, 6-C), 39.6 (CH, 7-C), 26.1 (CH2, 8-C), 34.2 (CH2, 9-C), 47.5 (C, 10-C) 144.3 (C, 11-C), 171.3 (C, 12-C), 125.6 (CH2, 13-C), 17.4 (CH3, 14-C), 23.3 (CH3, 15-C).Infrared spectrum shows that this compound contains hydroxyl (3320cm-1), carbonyl (1646cm-1) and alkene key (1620cm-1)。13C-NMR, DEPT and hsqc spectrum show 15 carbon signals, including two methyl δC17.4,23.3；Four methylene (an alkene carbon) δC29.7,26.1,34.2,125.6；Three methine (an alkene carbon) δC124.9,42.3,39.6；And six quaternary carbon (three carbonyl carbon, an alkene carbon) δC181.6,182.5,176.5,47.5,144.3,171.3；In conjunction with insatiable hunger sum, function above structure shows that this compound is two ring structures.1H-NMR spectrum two methyl proton signal δ of displayH-141.19 (3H, s) and δH-151.95 (3H, s), an olefinic methene proton signal δH-136.38 (1H, br, s) and δH-136.73 (1H, br, s), an olefinic methine proton signal δH-35.83 (1H, br, s).In hsqc spectrum, all proton signals have all belonged to corresponding carbon, according to1H-1H in HCOSY spectrum2-6/H-7/H2-8/H2-9 coherent signals, H-3 and C-1, C-2, C-4 and C-5 in composing in conjunction with HMBC, H-7 and C-11, H2-13 and C-11, H3-14 with C-1, C-5 and C-9, H3-15 with C-4 and C-5 coherent signal, it is possible to build the connected mode of this compound.H-5 and H2The coupling constant J of-6H-5=12.7Hz and H2-6 with the coupling constant J of H-7H-7=12.1Hz illustrates that H-5 and H-7 is all axial bond in this compound chair conformation.Additionally, further by analyzing H-5 and H in NOESY spectrum3-14 are absent from coherent signal, it is possible to confirmation H3-14 is beta comfiguration.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, and document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows, spatial configuration is determined by ECD test further, and theoretical value is basically identical with experiment value.
This compound chemistry formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
The present embodiment adopts Kunming mouse castration, continuous 3 weeks sc Testosterone Propionate 5mg kg-1·d-1, make prostatic hyperplasia model, observe the medicine therapeutical effect to prostatic hyperplasia.
1, materials and methods
1.1 animals
Mice, Kunming kind, male, 20～23g, 80, Hebei province's Experimental Animal Center provide.
1.2 reagent and sample
Domperidone is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.Pentobarbital sodium, Solution on Chemical Reagents in Shanghai company of Chinese Medicine group；Benzylpenicillin sodium for injection, Huabei Pharmaceutic Co., Ltd；Testosterone Propionate injection, Shanghai General Pharmaceutical Co., ltd.；Longbishu Jiaonang., Kedi Pharmaceutical Co., Ltd., Shijiazhuang；Mice testosterone (T) ELISA detection kit, Kemei Dongya Biological Technology Co., Ltd., Beijing；Mouse E2 (E2) ELISA detection kit, Kemei Dongya Biological Technology Co., Ltd., Beijing.
1.3 instruments
FA (N)/JA (N) series electronic balance, Shanghai Min Qiao precision instrument company limited；TGL-16G High speed refrigerated centrifuge, Anting Scientific Instrument Factory, Shanghai；Electric homogenate machine, NingBo XinZhi Biology Science Co., Ltd；Sn-895B type intelligence is put and is exempted from γ measuring instrument: Fourth Ring instrument one factory of Shanghai nuclear research institute.
Prepared by 1.4 mice group and model
Taking body weight 20～23g male mice 80, take 10 at random and be only used as blank group, rehearse surgical procedure；All the other mices make prostatic hyperplasia model, and mouse weights pneumoretroperitoneum injects 2% pentobarbital sodium (30mg kg-1) anesthesia, routine disinfection skin, under aseptic condition, extract bilateral testes, the ligation of stump place, skin suture, During Intramuscular Injection of Penicillin 200,000 u kg through scrotum-1；Post operation the 3rd day, removes gesture success, mice 50 in good condition, is randomly divided into 5 groups for making prostatic hyperplasia model, respectively model control group, positive controls (Longbishu Jiaonang. suspension 450mg kg-1) and domperidone group (80mg kg-1), compound (I) group (80mg kg-1), domperidone and compound (I) compositions group [40mg kg-1Domperidone+40mg kg-1Compound (I)], continuous 3 week every day sc Testosterone Propionate 5mg kg-1(being dissolved in soybean oil) modeling, blank group injection equivalent solvent.In modeling type the 1st day, model control group ig normal saline；Positive controls ig Longbishu Jiaonang. suspension (450mg kg-1)；The medicine of domperidone group, compound (I) group, domperidone and the above-mentioned dosage of compound (I) compositions group ig, administration volume is 20mL kg-1；Blank group gavages the normal saline of same volume；Daily 1 time, successive administration 3 weeks.2h (water 12h is can't help in fasting) after last is administered, mouse weights posterior orbit takes blood, centrifugal, separates serum, surveys T, E2 level in serum；Then de-cervical vertebra puts to death mice, takes rapidly prostata tissue, each group of mouse prostate body of gland carries out three-dimensional meterological and measures, measure the body density of body of gland.
The mensuration of T in 1.5 serum
The content of T in serum is measured: test kit adopts double antibody one step sandwich assay elisa (ELISA) by mice TELISA detection kit, it is coated in micropore toward what be coated T antibody in advance, it is sequentially added into the detection antibody of specimen, reference substance, HRP labelling, through incubation and thoroughly wash.Developing the color with substrate TMB, TMB changes into blueness under the catalysis of peroxidase, and changes into final yellow under the action of an acid.T in the depth of color and sample is proportionate.Under 450nm wavelength, measure absorbance (A) by microplate reader, calculate sample concentration, namely obtain the content of T in mice serum.
E in 1.6 serum2Mensuration
Use mice E2ELISA detection kit measures the content of estradiol in serum: test kit adopts double antibody one step sandwich assay elisa (ELISA), toward being coated E in advance2Antibody be coated in micropore, be sequentially added into the detection antibody of specimen, reference substance, HRP labelling, through incubation and thoroughly wash.Developing the color with substrate TMB, TMB changes into blueness under the catalysis of peroxidase, and changes into final yellow under the action of an acid.E in the depth of color and sample2It is proportionate.Under 450nm wavelength, measure A by microplate reader, calculate sample concentration, namely obtain E in mice serum2Content.
The body density of 1.7 prostate gland measures
Adopt General stereoscopic meterological assay method, application testing lattice point analytic process, calculate the intersection on body of gland and count the percentage ratio counted with intersecting in reference frame, for the body density (Vv) of body of gland in this tissue.
1.8 statistical methods
Experimental data adopts SPSS13.0 statistical software to process.Data withRepresent, between measurement data group, compare employing one factor analysis of variance.P < 0.05 is statistically significant.
2, experimental result
2.1 couples of mouse prostate model of hyperplasia serum T, E2The impact of level
With blank group ratio, in model group mice serum, T level significantly raises (P < 0.01), E2Level significantly reduces (P < 0.01), and modeling success is described.Comparing with model control group, domperidone and T level in compound (I) compositions group and positive controls mice serum significantly reduce, E2Level significantly raises (P < 0.01)；With model control group ratio, the reduction of T level, E in domperidone group, compound (I) group mice serum2Level raises (P < 0.05).Result is in Table 1.
2.2 impacts on the body density of prostatic hyperplasia model mouse prostate body of gland
With blank group ratio, model group prostate gland body density significantly raises (P < 0.01), illustrates to make prostatic hyperplasia model success.With model control group ratio, the body density of domperidone group, compound (I) group mouse prostate body of gland reduces (P < 0.05)；Comparing with model control group, the body density of domperidone and compound (I) compositions group, positive controls mouse prostate body of gland significantly reduces (P < 0.01).Result is in Table 1.
The table 1 impact on mouse prostate model of hyperplasia serum testosterone, estradiol level and prostate gland density
After this experiment adopts mice castration, subcutaneous injection Testosterone Propionate is successfully established prostatic hyperplasia model, after mice castration, and the rapid atrophy of prostate, then give exogenous androgen, sex hormone level in animal body can be caused disorderly, make prostate generation hypertrophy.Testosterone (T) is androgen main in human body, becomes dihydrotestosterone (DHT) under 5α-reductase effect, and intraprostatic DHT concentration increase may result in glandular hyperplasia.Basic fibroblast growth factor (bFGF) increases release by the effect of DHT, short prostatic stromal hyperplasia, the epithelical cell growth factor (EGF) stimulating prostate epithelial cell growth is proportionate with androgenic content in blood plasma, cause prostatic hypertrophy, cause prostatic hyperplasia model.The change of estrogen and androgen ratio is the crucial inducement of prostatic hyperplasia, and testosterone in serum, estradiol level are significant to reaction prostatic hyperplasia situation.Prostate weight in wet base and prostate index are one of reflection prostatic hyperplasia the most objective indexs of degree, and prostatic histomorphology is to determine whether the key of hypertrophy；Prostatic hyperplasia is chronic disease, and long-term pathological change may involve relevant internal organs.Prostatic hyperplasia may involve body's immunity, and the tectology change of thymus and lymphocytic number thereof can effecting reaction prostatic hyperplasia situations.
The above results shows, when domperidone, compound (I) independent role, it is possible to treatment prostatic hyperplasia；When domperidone and compound (I) synergy, the therapeutic effect of prostatic hyperplasia is improved further, it is possible to develop into the medicine for the treatment of prostatic hyperplasia.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit protection scope of the present invention with this.It will be understood by those within the art that, it is possible to technical scheme is modified or equivalent replacement, without deviating from essence and the protection domain of technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a domperidone, it is characterised in that: include domperidone, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepare into the dosage form of needs.
3. the pharmaceutical composition of domperidone according to claim 2, it is characterised in that: pharmaceutically acceptable carrier includes diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
4. the pharmaceutical composition of domperidone according to claim 2, it is characterised in that: described dosage form includes tablet, capsule, oral liquid, sucks agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, injection, suppository, spray, drop or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterized in that, comprise following operating procedure: Rhizoma Cibotii is pulverized by (a), extract with 85～95% alcohol heat reflux, united extraction liquid, it is concentrated into without alcohol taste, successively with petroleum ether, ethyl acetate and water saturated n-butanol extraction, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；B in () step (a), n-butyl alcohol takes thing macroporous resin remove impurity, first with 8 column volumes of 35% ethanol elution, then with 12 column volumes of 90% ethanol elution, collect 90% eluent, and concentrating under reduced pressure obtains 90% ethanol elution concentrate；In (c) step (b) 90% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 120:1,60:1,30:1 and 15:1 methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 3 separates further by purification on normal-phase silica gel, successively with volume ratio be 40:1,30:1 and 10:1 methylene chloride-methanol gradient elution obtain 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 85%, collecting 14～18 column volume eluents, eluent concentrating under reduced pressure obtains compound (I).
6. the preparation method of compound according to claim 5 (I), it is characterised in that: step (a) is extracted with 90% alcohol heat reflux, united extraction liquid.
7. the preparation method of compound according to claim 5 (I), it is characterised in that: described macroporous resin is D101 type macroporous adsorbent resin.
8. the preparation method of compound according to claim 5 (I), it is characterised in that: step (a) replaces ethyl acetate to extract with dichloromethane, obtains dichloromethane extract.
9. the application in the medicine of preparation treatment prostatic hyperplasia of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described domperidone of claim 2～4 application in the medicine of preparation treatment prostatic hyperplasia.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112425568A (en) * | 2020-12-11 | 2021-03-02 | 上海市计划生育科学研究所 | Method for establishing benign prostatic hyperplasia BPH dog model with EMT characteristics |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112425568A (en) * | 2020-12-11 | 2021-03-02 | 上海市计划生育科学研究所 | Method for establishing benign prostatic hyperplasia BPH dog model with EMT characteristics |
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Application publication date: 20160706 |