CN106083881A - The pharmaceutical composition of Granisetron Hydrochloride and the application in biological medicine thereof - Google Patents
The pharmaceutical composition of Granisetron Hydrochloride and the application in biological medicine thereof Download PDFInfo
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- CN106083881A CN106083881A CN201610396728.XA CN201610396728A CN106083881A CN 106083881 A CN106083881 A CN 106083881A CN 201610396728 A CN201610396728 A CN 201610396728A CN 106083881 A CN106083881 A CN 106083881A
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
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Abstract
The invention discloses the pharmaceutical composition of Granisetron Hydrochloride and the application in biological medicine thereof, containing Granisetron Hydrochloride and the natural product compound (I) of a kind of novel structure in the pharmaceutical composition of the Granisetron Hydrochloride that the present invention provides, when Granisetron Hydrochloride, compound (I) independent role, can be with enhancing human body immunity function；When Granisetron Hydrochloride and compound (I) synergy, the potentiation of body's immunity is improved further, the medicine of enhancing immunologic function can be developed into, compared with prior art there is prominent substantive distinguishing features and significantly progress.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of Granisetron Hydrochloride, be specifically related to Granisetron Hydrochloride
Pharmaceutical composition and application in biological medicine.
Background technology
Granisetron Hydrochloride is a kind of high selective 5-HT3 receptor antagonist, to cause because of radiotherapy, chemotherapy and operation
Nausea and vomiting has good preventive and therapeutic action.The factors such as radiotherapy, chemotherapy and surgical operation can cause enterochromaffin cell
Release 5-HT, 5-HT can activate maincenter or vagal 5-HT3 receptor and the reflection that causes vomiting.This product controls nausea and vomiting
Mechanism, be the 5-HT3 receptor by antagonism Central chemoreception district and periphery vagus nerve ending, thus suppression felt sick, vomitted
The generation told.This product selectivity is high, without the untoward reaction such as the extrapyramidal symptoms, excess sedation.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of Granisetron Hydrochloride, containing salt in this pharmaceutical composition
Acid granisetron and the natural product of a kind of novel structure, Granisetron Hydrochloride and this natural product can work in coordination with enhancing immunity merit
Energy.
The above-mentioned purpose of the present invention is achieved by techniques below scheme:
A kind of compound (I) with following structural formula,
The pharmaceutical composition of a kind of Granisetron Hydrochloride, including Granisetron Hydrochloride, compound as claimed in claim 1
(I) and pharmaceutically acceptable carrier, is prepared as the dosage form needed.
Further, pharmaceutically acceptable carrier include diluent, excipient, filler, binding agent, wetting agent,
Disintegrating agent, absorption enhancer, surfactant, absorption carrier or lubricant.
Further, described dosage form include tablet, capsule, oral liquid, suck 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), comprises following operating procedure: Herba Lysimachiae is pulverized by (a), with 85～95% second
Alcohol circumfluence distillation, united extraction liquid, it is concentrated into without alcohol taste, successively by petroleum ether, ethyl acetate and water saturated n-butyl alcohol extraction
Take, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；N-butyl alcohol extract in (b) step (a)
Use macroporous resin remove impurity, first with 10 column volumes of 8% ethanol elution, then with 12 column volumes of 70% ethanol elution, collect 70%
Eluent, concentrating under reduced pressure obtains 70% ethanol elution concentrate；70% ethanol elution concentrate purification on normal-phase silica gel in (c) step (b)
Separate, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 40:1,20:1,10:1 and 5:1 successively；(d)
In step (c), component 4 separates further by purification on normal-phase silica gel, is the methylene chloride-methanol of 8:1,5:1 and 2:1 by volume ratio successively
Gradient elution obtains 3 components；E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, and uses volume
Percentage concentration is the methanol aqueous solution isocratic elution of 75%, collects 8～14 column volume eluents, and eluent is concentrated under reduced pressure to give
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 AB-8 type macroporous adsorbent resin.
Further, in the preparation method of compound (I), step (a) replace ethyl acetate to extract with dichloromethane
Take, obtain dichloromethane extract.
The above-claimed cpd (I) application in preparation strengthens the medicine of immunologic function.
The application in preparation strengthens the medicine of immunologic function of the pharmaceutical composition of above-mentioned Granisetron Hydrochloride.
Advantages of the present invention: in the pharmaceutical composition of the Granisetron Hydrochloride that the present invention provides containing Granisetron Hydrochloride and
When the natural product of a kind of novel structure, Granisetron Hydrochloride and this natural product independent role, there is enhancing immunologic function and make
With；During the two synergy, strengthen immunologic function effect and improve further, the medicine of enhancing immunologic function can be developed into.
Detailed description of the invention
Further illustrate the essentiality content of the present invention below in conjunction with embodiment, but do not limit the present invention with this and protect model
Enclose.
Embodiment 1: compound (I) separates preparation and structural identification
Reagent source: ethanol, petroleum ether, ethyl acetate, n-butyl alcohol, dichloromethane are analytical pure, insults peaking purchased from Shanghai
Learning reagent company limited, methanol, analytical pure, purchased from Jiangsu Han Bang chemical reagent company limited.
Separation method: Herba Lysimachiae (2kg) is pulverized by (a), extracts (20L × 3 time) with 90% alcohol heat reflux, united extraction
Liquid, is concentrated into without alcohol taste (4L), successively with petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and water saturated n-butyl alcohol
(4L × 3 time) extract, and respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；In (b) step (a)
N-butyl alcohol extract AB-8 type macroporous resin remove impurity, first with 10 column volumes of 8% ethanol elution, then with 70% ethanol elution 12
Individual column volume, collects 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；70% ethanol elution in (c) step (b)
Concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 40:1 (8 column volumes), 20:1 (8 column volumes), 10:1 (8 posts
Volume) and the methylene chloride-methanol gradient elution of 5:1 (10 column volumes) obtain 4 components；D in () step (c), component 4 is used
Purification on normal-phase silica gel separates further, successively with volume ratio be 8:1 (8 column volumes), 5:1 (10 column volumes) and 2:1 (5 cylinders
Long-pending) methylene chloride-methanol gradient elution obtain 3 components；In (e) step (d) component 2 with octadecylsilane be bonded anti-
Phase silica gel separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collects 8～14 column volume eluents,
Eluent is concentrated under reduced pressure to give compound (I) (purity is more than 98%).
Structural identification: HR-ESI-MS shows [M+Na]+For m/z 383.1816, can obtain molecular formula in conjunction with nuclear-magnetism feature is
C21H28O5, degree of unsaturation is 8.Hydrogen nuclear magnetic resonance modal data δH(ppm, DMSO-d6, 600MHz): H-1 (3.06, m), H-2
(1.04, m), H-2 (1.88, m), H-3 (1.57, m), H-3 (1.96, m), H-6 (1.58, m), H-6 (1.92, m), H-7
(3.91, td, J=10.8,5.4), and H-8 (2.43, m), H-9 (2.74, td, J=11.8,5.6), H-11 (2.43, m), H-11
(2.65, m), H-14 (3.42, d, J=8.7), H-15 (6.07, d, J=1.8), H-16 (7.16, d, J=1.8), H-18
(1.03, s), H-19 (0.98, s), H-20 (1.07, s), 17-OCH3(3.71, s)；Carbon-13 nmr spectra data δC(ppm,
DMSO-d6, 150MHz): 81.7 (CH, 1-C), 29.5 (CH2, 2-C), 26.1 (CH2, 3-C), 38.3 (C, 4-C), 86.8 (C, 5-
C), 36.6 (CH2, 6-C), 73.7 (CH, 7-C), 42.1 (CH, 8-C), 36.2 (CH, 9-C), 43.3 (C, 10-C), 21.5 (CH2,
11-C), 150.6 (C, 12-C), 113.4 (C, 13-C), 46.3 (CH, 14-C), 108.1 (CH, 15-C), 141.2 (CH, 16-
C), 176.2 (C, 17-C), 24.8 (CH3, 18-C), 27.7 (CH3, 19-C), 17.3 (CH3, 20-C), 52.1 (CH3, 17-
OCH3).Infrared spectrum shows that this compound contains hydroxyl and carbonyl (3422 and 1720cm-1)。1H-NMR spectrum shows three first
Base signal δ H0.98 (s, H3-19), 1.03 (s, H3-18) and 1.07 (s, H3-20), methoxyl group δ H3.71 (3H, s,
OCH3), two oxygen-containing methines δ H3.06 (m, H-1) and 3.91 (td, J=10.8,5.4Hz, H-7), and one 1,2-is double
Substituted furan nucleus δ H6.07 (d, J=1.8Hz, H-15) and 7.16 (d, J=1.8Hz, H-16).13C-NMR spectrum demonstrates 21
Carbon signal, including three methyl (δ C17.3,24.8 and 27.7), a methyl-O-carbonyl group (δ C176.2 and 52.1),
Three oxygen-containing carbon (δ C73.7,81.7 and 86.8) and furan ring structure part (δ C108.1,113.4,141.2, and 150.6).
In HMBC spectrum, H-1 (δ H3.06) and C-2 (δ C29.5), C-5 (δ C86.8), C-10 (δ C43.3) and the phase of C-20 (δ C17.3)
Guan Xing, and the chemical shift of C-1 with C-5 shows that leading to peroxide bridge between the two is connected.Additionally, H-7 (δ H3.91) and C-14 (δ
C46.3) Long-Range Correlation shows that C-7 position is connected with a hydroxyl.In NOESY spectrum, the dependency of H-14 and H-7/H-9 shows
C7-OH and C14-C17OOCH3For beta comfiguration.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and NOESY spectrum, and document is about correlation type core
Magnetic data, can determine that this compound is as follows substantially, and spatial configuration is determined by ECD test further, theoretical value and experiment
It is worth basically identical.
This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
The present embodiment uses cyclophosphamide to prepare immunodeficient mouse model, observes medicine and improves IL-6, IFN-γ, immunity
The effect of the raising immunologic function of the aspects such as globulin (IgA, IgM, IgG) and complement (C3, C4) level.
1, materials and methods
1.1 animal
Healthy Kunming kind adult mice, male and female half and half, University Of Suzhou's Experimental Animal Center provide, weight (20.0 ±
2.0) g, after packet, every mouse is listed numbering.
1.2 reagent and sample
Granisetron Hydrochloride is purchased from Nat'l Pharmaceutical & Biological Products Control Institute.Compound (I) is made by oneself, and preparation method is shown in embodiment
1.Cyclophosphamide (cyclophosphamide, CY), interleukin-6 (interleukin6, IL-6), interferon-γ
SigmaAldrich company of (interferon-γ, IFN-γ) ELISA kit U.S.；Immunoglobulin reagents box (IgA,
IgG, IgM), Ortho-Clinical Diagnostics company of complement reagent box (C3, C4) U.S..
1.3 instrument
XP2001S precision balance prunus mume (sieb.) sieb.et zucc. Teller-torr benefit (Shanghai) Instrument Ltd.；In 79-3 type constant temperature blender with magnetic force
Hai Sile instrument plant；Thermo3111 CO2 gas incubator U.S. Thermo Fisher Scientific company；Spectra
Molecular Devices company of the MaxM5 microplate reader U.S.；SN-CJ-ZF type double two-sided clean work station Suzhou cleaning equipment
Company limited；UV2600 ultraviolet-visible spectrophotometer Shanghai Techcomp Instrument Ltd.；Hitachi 7100 full-automatic biochemical
Analyser HIT；24,96 well culture plate Sai Ye bio tech ltd；BXM-30R vertical pressure steam sterilization
Device, Eppendorf company of Centrufuge5415R type High speed refrigerated centrifuge Germany.
Prepared by 1.4 mice group and model
According to experiment Testing index, fed-batch mice, and it is randomly divided into 5 groups after adaptability feeds 4d, is respectively
Normal group, model control group, Granisetron Hydrochloride group (80mg kg-1), compound (I) group (80mg kg-1), hydrochloric acid
Granisetron and compound (I) compositions group [40mg kg-1Granisetron Hydrochloride+40mg kg-1Compound (I)].Empty weekly
Abdomen claims quality once, and in addition to Normal group and model control group give normal saline, remaining organizes gastric infusion, successive administration
14d, free choice feeding.19th day starts intraperitoneal injection of cyclophosphamide 100mg/ (kg d), continuously except Normal group remaining 4 groups
4d。
The determination experiment of 1.5 immunodeficient mouse immune factors
After mice process terminates, claiming on an empty stomach quality, eye socket takes blood, and blood sample stands 12h in 4 DEG C, after separating out serum, in 4 DEG C,
3000r/min is centrifuged 10min, collects serum and is sub-packed in Eppendorf pipe, in 20 DEG C of preservations.Go bail for the serum deposited, according to examination
Agent box description measures immunodeficient mouse immune factor.Wherein cytokine IL-6, IFN-γ all characterize with OD450nm value.
Complement C_3, C4, Immunoglobulin IgA, IgM, the unit of IgG content are mg/100mL.
1.6 statistical method
Experimental data mean ± standard deviation (x ± s) represents, application SPSS18.0 version statistical software carries out single factor test variance
Analyze and t checks, statistically significant for difference with P ＜ 0.05.
2, experimental result
2.1 impacts on immunodeficiency model mice IL-6 content
Comparing with Normal group, in model control group mice serum, the content of IL-6 substantially reduces (P ＜ 0.01), shows
The injection of cyclophosphamide can make the content of IL-6 in normal growth mice serum reduce, and causes mouse immune system dysfunction,
Immunity of organisms is caused to decline；Compare with model control group, Granisetron Hydrochloride and IL-6 in compound (I) compositions group serum
Content significantly raised (P ＜ 0.01)；Compare with model control group, IL-6 in Granisetron Hydrochloride group, compound (I) group serum
Content raise (P ＜ 0.05).The results are shown in Table 1.
2.2 impacts on immunodeficiency model mice IFN-γ content
Comparing with Normal group, in model control group mice serum, the content of IFN-γ substantially reduces (P ＜ 0.05), table
The injection of bright cyclophosphamide can make the content of IFN-γ in normal growth mice serum reduce, and causes mouse immune system function disorderly
Disorderly, immunity of organisms is caused to decline；Compare with model control group, Granisetron Hydrochloride and compound (I) compositions group Mouse Blood
The content significantly raised (P ＜ 0.01) of IFN-γ in clear；Compare with model control group, Granisetron Hydrochloride group, compound (I) group
In mice serum, the content of IFN-γ raises (P ＜ 0.05).The results are shown in Table 1.
2.3 impacts on immunodeficient mouse complement
Comparing with Normal group, model control group mouse complement C3, C4 content substantially reduces (P ＜ 0.01)；With model
Matched group compares, Granisetron Hydrochloride and compound (I) compositions group Complement C_3, C4 content significantly raised (P ＜ 0.01)；With mould
Type matched group compares, and Granisetron Hydrochloride group, compound (I) group mouse complement C3, C4 content raises (P ＜ 0.05).Result is shown in
Table 1.
2.4 impacts on immunodeficient mouse immunoglobulin
Comparing with Normal group, immunoglobulin (IgA, IgM, IgG) content of model control group mice substantially to drop
Low (P ＜ 0.01)；Compare with model control group, Granisetron Hydrochloride and compound (I) compositions group mouse immuning ball protein
(IgA, IgM, IgG) content significantly raised (P ＜ 0.01)；Compare with model control group, Granisetron Hydrochloride group, compound (I)
Group mouse immuning ball protein (IgA, IgM, IgG) content raises (P ＜ 0.05).The results are shown in Table 2.
Table 1 is on immunodeficiency model mice IL-6 content, IFN-γ content and the impact of complement content
| Group | IL-6 | IFN-γ | C3 content | C4 content |
| Normal group | 0.172±0.008 | 0.077±0.007 | 25.6±1.2 | 6.2±0.3 |
| Model control group | 0.081±0.011 | 0.046±0.006 | 17.4±2.2 | 3.1±0.8 |
| Granisetron Hydrochloride group | 0.134±0.013 | 0.054±0.006 | 21.3±3.2 | 4.8±0.9 |
| Compound (I) group | 0.136±0.010 | 0.061±0.012 | 22.5±2.1 | 4.7±0.3 |
| Granisetron Hydrochloride and compound (I) compositions group | 0.163±0.014 | 0.083±0.013 | 25.2±1.1 | 5.8±0.4 |
The table 2 impact on immunodeficiency model mice immunoglobulin content
| Group | IgA content | IgM content | IgG content |
| Normal group | 30.17±1.23 | 31.34±1.72 | 65.31±2.37 |
| Model control group | 20.44±2.05 | 19.16±1.26 | 40.36±3.36 |
| Granisetron Hydrochloride group | 24.32±3.12 | 24.37±2.01 | 49.84±3.25 |
| Compound (I) group | 25.86±1.37 | 25.73±1.35 | 51.28±2.56 |
| Granisetron Hydrochloride and compound (I) compositions group | 29.33±2.05 | 30.84±1.71 | 63.85±4.27 |
Cytokine (cytokine) refers to albumen that mainly secreted, that have immunoregulation effect by immune cell
Matter and micromolecule polypeptide.These minute amount of polypeptide class factors being synthesized by immunocyte and secreting, during immunne response, for
Cell-cell interaction, the growth of cell and differentiation have important regulative.They not only have maintenance organism physiology balance
Function, additionally it is possible to resist the invasion and attack of pathogen and suppression growth of tumour cell, induction host to the reaction of tumor cell or tune
The expression etc. of control oncogene.Cytokine has specific target cell, by the receptor on target cell membrane, passes information to
Cell produces responsing reaction, improves the immunocompetence of body, but also can cause the pathological phenomenons such as flu, fever under abnormal conditions.
Body is resisted disease and maintains organism balance aspect to have great importance by the generation of cytokine and interaction.
The above results shows, when Granisetron Hydrochloride, compound (I) independent role, and can be with enhancing human body immunity function；Salt
When acid granisetron and compound (I) synergy, the potentiation of body's immunity is improved further, can develop into
Strengthen the medicine of immunologic function.
The effect of above-described embodiment indicates that the essentiality content of the present invention, but does not limit the protection of the present invention with this
Scope.It will be understood by those within the art that, technical scheme can be modified or equivalent,
Essence and protection domain without deviating from technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a Granisetron Hydrochloride, it is characterised in that: include Granisetron Hydrochloride, such as claim 1 institute
The compound (I) stated and pharmaceutically acceptable carrier, be prepared as the dosage form needed.
The pharmaceutical composition of Granisetron Hydrochloride the most 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.
The pharmaceutical composition of Granisetron Hydrochloride the most according to claim 2, it is characterised in that: described dosage form includes sheet
Agent, capsule, oral liquid, suck agent, granule, electuary, pill, powder, unguentum, sublimed preparation, suspensoid, powder, solution, note
Penetrate agent, suppository, spray, drop or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a) is by gold
Money grass meal is broken, with 85～95% alcohol heat reflux extract, united extraction liquid, be concentrated into without alcohol taste, successively use petroleum ether, acetic acid second
Ester and water saturated n-butanol extraction, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；(b)
N-butyl alcohol extract macroporous resin remove impurity in step (a), first with 10 column volumes of 8% ethanol elution, then washes with 70% ethanol
De-12 column volumes, collect 70% eluent, and concentrating under reduced pressure obtains 70% ethanol elution concentrate；70% ethanol in (c) step (b)
Eluting concentrate purification on normal-phase silica gel separates, successively by the methylene chloride-methanol gradient that volume ratio is 40:1,20:1,10:1 and 5:1
Afford 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, successively with volume ratio be 8:1,5:1 and
The methylene chloride-methanol gradient elution of 2:1 obtains 3 components；In (e) step (d) component 2 with octadecylsilane be bonded anti-
Phase silica gel separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collects 8～14 column volume eluents,
Eluent is concentrated under reduced pressure to give compound (I).
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) is returned by 90% ethanol heat
Stream extracts, united extraction liquid.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: described macroporous resin is AB-8 type
Macroporous adsorbent resin.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) uses dichloromethane generation
Extract for ethyl acetate, obtain dichloromethane extract.
9. the application in preparation strengthens the medicine of immunologic function of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described Granisetron Hydrochloride of claim 2～4 strengthens the medicine of immunologic function in preparation
In application.
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