CN105859740A - Resochin pharmaceutical composition and application thereof to biological medicine - Google Patents
Resochin pharmaceutical composition and application thereof to biological medicine Download PDFInfo
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- CN105859740A CN105859740A CN201610292150.3A CN201610292150A CN105859740A CN 105859740 A CN105859740 A CN 105859740A CN 201610292150 A CN201610292150 A CN 201610292150A CN 105859740 A CN105859740 A CN 105859740A
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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
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a resochin pharmaceutical composition and application thereof to biological medicine. The resochin pharmaceutical composition contains resochin and a natural product compound (I) which is separated out of dry roots and stems of radix salviae miltiorrhizae and is novel in structure, the resochin and the natural product compound (I) can improve macrophage functions of immunosuppressed mice and immune organ indexes, the macrophage functions of immunosuppressed mice and immune organ indexes can be further improved when the resochin and the compound (I) are used jointly, the effect is superior to that generated when the resochin or the compound (I) is used separately, the resochin pharmaceutical composition can be developed into medicine for improving immunity, and compared with the prior art, outstanding substantive features and remarkable progresses are achieved.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of chloroquine diphosphate, be specifically related to chloroquine diphosphate pharmaceutical composition and
Its application in biological medicine.
Background technology
Chloroquine diphosphate is 4 aminoquinolines, works plasmodium erythrocyte stage schizont, may be to disturb plasmodium to split
Grow duplication and the transcription of body DNA or hinder its endocytosis, so that polypide is dead due to lack amino acid.With
In treatment malignant malaria, tertian fever and malarlae malaria to chloroquine-sensitive.And can be used for the suppressive prophylaxis of malaria symptoms.Can also be used for
Treat parenteral amcbiasis, CTD, photosensitivity disease (such as sunburn) etc..
Up to now, there is not yet the correlation report of chloroquine diphosphate and pharmaceutical composition thereof and enhancing immunity.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of chloroquine diphosphate, containing chloroquine diphosphate and in this pharmaceutical composition
Plant the natural products of novel structure, chloroquine diphosphate and this natural products and can work in coordination with enhancing immunity.
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 chloroquine diphosphate, including chloroquine diphosphate, compound as claimed in claim 1 (I) and pharmacy
Upper acceptable carrier, is prepared as the formulation needed.
Further, pharmaceutically acceptable carrier includes diluent, excipient, filler, adhesive, wetting agent, collapses
Solve agent, sorbefacient, surfactant, absorption carrier or lubricant.
Further, described formulation include tablet, capsule, oral liquid, suck agent, granule, electuary, pill, powder,
Paste, sublimed preparation, supensoid agent, pulvis, solution, injection, suppository, spray, drops or patch.
The preparation method of above-claimed cpd (I), comprises following operating procedure: the dry rhizome of the red sage root is pulverized by (a), uses
85～95% alcohol heat reflux extract, merge extract, be concentrated into without alcohol taste, use petroleum ether, ethyl acetate and water saturated successively
Extracting n-butyl alcohol, respectively obtains petroleum ether extract, acetic acid ethyl ester extract and n-butyl alcohol extract；In (b) step (a)
N-butyl alcohol extract macroreticular resin removal of impurities, first with 10 column volumes of 8% ethanol elution, then with 12 posts of 70% ethanol elution
Volume, collects 70% eluent, and reduced pressure concentration obtains 70% ethanol elution concentrate；70% ethanol elution in (c) step (b)
Concentrate purification on normal-phase silica gel separates, successively with the methylene chloride-methanol gradient elution that volume ratio is 40:1,20:1,10:1 and 5:1
Obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 8:1,5:1 by volume ratio successively
3 components are obtained with the methylene chloride-methanol gradient elution of 2:1；Component 2 octadecylsilane key in (e) step (d)
The reverse phase silica gel closed separates, and with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%, collects 8～14 column volume wash-outs
Liquid, 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, merges extract.
Further, in the preparation method of compound (I), described macroreticular resin is AB-8 type macroporous absorbent resin.
Further, in the preparation method of compound (I), step (a) replace ethyl acetate to extract with dichloromethane,
Obtain dichloromethane extract.
The above-claimed cpd (I) application in preparation strengthens the medicine of immunity.
The application in preparation strengthens the medicine of immunity of the pharmaceutical composition of above-mentioned chloroquine diphosphate.
Advantages of the present invention:
Containing chloroquine diphosphate with a kind of separate from the dry rhizome of the red sage root in the pharmaceutical composition of the chloroquine diphosphate that the present invention provides
When the natural products of the novel structure arrived, chloroquine diphosphate and this natural products independent role, there is enhancing immunity；The two
During synergy, strengthen immunity effect and improve further, the medicine of enhancing immunity 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 scope with this.
Embodiment 1: compound (I) separates preparation and structural identification
Reagent source: ethanol, petroleum ether, ethyl acetate, n-butanol, dichloromethane are pure for analyzing, purchased from Shanghai Ling Feng chemistry
Reagent Co., Ltd, methyl alcohol, analyze pure, purchased from Jiangsu Han Bang chemical reagent Co., Ltd.
Separation method: the dry rhizome (2kg) of the red sage root is pulverized by (a), extracts (20L × 3 time) with 90% alcohol heat reflux,
Merge extract, be concentrated into without alcohol taste (4L), successively use petroleum ether (4L × 3 time), ethyl acetate (4L × 3 time) and
Water saturated n-butanol (4L × 3 time) extracts, and respectively obtains petroleum ether extract, acetic acid ethyl ester extract and extracting n-butyl alcohol
Thing；B n-butyl alcohol extract AB-8 type macroreticular resin removal of impurities in () step (a), first with 10 cylinders of 8% ethanol elution
Long-pending, then with 12 column volumes of 70% ethanol elution, collect 70% eluent, reduced pressure concentration obtains 70% ethanol elution concentrate；
In (c) step (b) 70% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 40:1 (8 column volumes),
The methylene chloride-methanol gradient elution of 20:1 (8 column volumes), 10:1 (8 column volumes) and 5:1 (10 column volumes) obtains
To 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel, be 8:1 (8 posts by volume ratio successively
Volume), the methylene chloride-methanol gradient elution of 5:1 (10 column volumes) and 2:1 (5 column volumes) obtain 3 components；
E reverse phase silica gel that in () step (d), component 2 is bonded by octadecylsilane separates, and is the first of 75% by concentration expressed in percentage by volume
Alcohol solution isocratic elution, collects 8～14 column volume eluents, eluent be concentrated under reduced pressure to give compound (I) (208mg,
HPLC normalization purity is more than 98%).
Structural identification: acicular crystal, HR-ESI-MS shows [M+H]+For m/z 313.1763, molecule can be obtained in conjunction with nuclear-magnetism feature
Formula is C20H24O3, degree of unsaturation is 9.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3, 500MHz): H-2 (2.77,
M), and H-3a (2.52, m), H-3b (1.84, dd, J=7.9,3.5Hz), H-6 (2.37, dd, J=14.7,7.5Hz),
H-7 (4.06, d, J=3.1Hz), H-8 (1.81, dd, J=5.6,3.1Hz), H-9 (2.07, m), H-10 (2.93,
Dd, J=11.4,2.2Hz), H-12 (6.07, d, J=10.5Hz), H-13 (6.62, dd, J=10.5,6.6Hz), H-14
(2.84, dd, J=5.6,6.6Hz), and H-16a (4.78, s), H-16b (4.74, s), H-17 (1.66, s), H-18a
(4.83, s) H-18b (4.47, s), H-19 (1.25, d, J=7.3Hz), H-20 (1.22, d, J=7.8Hz)；Core
Magnetic resonance carbon modal data δC(ppm, CDCl3, 125MHz): 210.1 (C, 1-C), 40.2 (CH, 2-C), 33.4
(CH2, 3-C), 84.6 (C, 4-C), 216.9 (C, 5-C), 43.2 (CH, 6-C), 82.3 (CH, 7-C),
47.2 (CH, 8-C), 41.3 (CH, 9-C), 55.2 (CH, 10-C), 144.6 (C, 11-C), 127.5 (CH,
12-C), 135.7 (CH, 13-C), 49.3 (CH, 14-C), 143.8 (C, 15-C), 114.8 (CH2, 16-C),
18.3(CH3, 17-C), 111.7 (CH2, 18-C), 14.6 (CH3, 19-C), 16.2 (CH3, 20-C).Infrared
Wave spectrum shows that this compound contains carbonyl (1735cm-1With 1675cm-1) and alkene (1632cm-1) group.13C-NMR、
DEPT and hsqc spectrum show 20 carbon signals, including three methyl, three methylene (two alkene carbon), nine
Methine (an oxygen-containing carbon and two alkene carbon), and five quaternary carbons (two carbonyl carbon, company's oxygen carbon and two alkene
Carbon), in conjunction with insatiable hunger sum, function above structure shows that this compound is tetracyclic structure.1H-NMR spectrum combines hsqc spectrum and shows
Show three methyl proton signal δH1.66 (3H, s), 1.25 (3H, d, J=7.3Hz), 1.22 (3H, d, J=7.8Hz),
One group of methene proton signal δH252 (1H, m) with 1.84 (1H, dd, J=7.9,3.5Hz), two groups of terminal olefine proton letters
Number δH4.78 (1H, s) with 4.74 (1H, s), 4.83 (1H, s) with 4.47 (1H, s), a pair olefinic proton signals
δH6.07 (1H, d, J=10.5Hz) and 6.62 (1H, dd, J=10.5,6.6Hz), company's oxygen methine proton signal
δH4.06 (1H, d, J=3.1Hz).1H-1There is H-12/H-13/H-14/H-8/H-7/H-6/H in H COSY spectrum3-20、
H-8/H-9/H-10 and H2-3/H-2/H3-19 coherent signals, show H in HMBC spectrum simultaneously2-3 with C-1, C-2, C-5
And C-10, H-7 and C-4, C-5, C-9 and C-20, H2-16 and C-14, H3-17 with C-14, C-15 and C-16, H2-18
With C-9, C-11 and C-12, H3-19 with C-1, C-2 and C-3, H3-20 with C-5, C-6 and C-7 coherent signal, pass through
Relevant information in above-mentioned H NMR spectroscopy can build the connected mode of this compound, and may determine that this compound is
Rhamnofolane type diterpene-kind compound.By coupling constant J=10.2 and the carbon chemical shifts δ of H-12 Yu H-13C 129.5
And it is double bond between C-12 and C-13 knowable to 137.2.H-7 to C-4, the relevant letter of C-5, C-9 and C-20 in HMBC spectrum
Number with1H-1In H COSY spectrum, H-9/H-10 and H-8/H-7 coherent signal can be confirmed C-4 and C-7 and connected the existence of oxygen bridged ring.
ROESY spectrum in, H-7 Yu Me-20, Me-17 and H-8, H-8 and H-10, the correlation of H-9 Yu H-14 show H-7,
H-8, H-10 and Me-20 are beta comfiguration, H-9 and H-14 is α configuration.Additionally, by consulting literatures (Naengchomnong
Et al., 1986) contrast carbon chemical shifts understands Me-19 configuration should be beta comfiguration.Comprehensive hydrogen spectrum, carbon spectrum, HMBC spectrum and
ROESY composes, and document is about correlation type nuclear magnetic data, can substantially determine that this compound is as follows, and spatial configuration enters one
Walking and determined by ECD test, theoretical value is basically identical with experiment value.This compound chemical formula and carbon atoms numbered are as follows:
Embodiment 2: pharmacological action
1, materials and methods
1.1 animal
Cleaning grade Kun Ming mice 120, body weight 20 ± 2g, male and female half and half, Sichuan Agricultural University's Experimental Animal Center provides.
1.2 reagent and sample
Chloroquine diphosphate is purchased from National Institute for Food and Drugs Control.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.Ring
Phosphamide (cyclophosphamide, CTX) (Jiangsu perseverance is auspicious), astragalus polyose (APS, East China, Jiangsu Bel's biology medicine company),
Trypan blue (Sigma), RPMI1640 nutrient solution (Hyclon), concanavalin A (ConA, Sigma), lipopolysaccharides (LPS,
Sigma), MTT (Sigma), dimethyl sulfoxide (DMSO), pH7.2PBS, 5% chicken red blood cell (CRBC), cavy
Serum (Guangzhou stamen spy is biological), mouse cytokine IL-2, IL-4 and IFN-γ detection kit (BOSTER), CD3+
(FITC Hamster anti-mouse) monoclonal antibody, CD4+ (PE rat anti-mouse) monoclonal antibody, CD8+ (PerCP
Rat anti-mouse) monoclonal antibody (BOSTER), hemolysin (VersalyseTM Lysing Solution)。
1.3 instrument
Ultra-violet and visible spectrophotometer (Shanghai precision scientific instrument), flow cytometer (BD FACSCcalibur TM),
Superclean bench (AIRTECH), inverted microscope (Motic), centrifuge (Thermo), enzyme-linked immunosorbent assay instrument (BIO-RAD),
CO2Incubator (Thermo).
1.4 animal packet and process
60 healthy mices are divided at random blank group, model group, positive group, chloroquine diphosphate group, compound (I) group, phosphoric acid
Chloroquine and compound (I) composition group, often group 10.Blank group and model group intraperitoneal injection of saline every day 0.2ml,
Positive group lumbar injection 20g L every day-1APS 0.2ml, chloroquine diphosphate group, compound (I) group, chloroquine diphosphate and compound
(I) composition component lumbar injection chloroquine diphosphate other every day 20g L-1, compound (I) 20g L-1, chloroquine diphosphate and chemical combination
Thing (I) composition [chloroquine diphosphate 20g L-1+ compound (I) 20g L-1] 0.2ml, continuous 7d；After administration, d5～7, removes
Blank group remaining each group lumbar injection CTX 100mg kg every day outer-1。
1.5 Peritoneal Macrophages Functions and Immune Organs Index detection
Process by " 1.4 ", each group after being administered d7 weigh, and 5% chicken red blood cell 0.5ml is penetrated in abdominal cavity, puts to death little after 8h
Mouse, Intraperitoneal injection PBS 2ml, gently rubs mouse web portion 1min, draws abdominal cavity liquid 0.5ml and hatch at 37 DEG C on slide
30min, 1:1 acetone-methanol is liquid-solid determines 5min, Giemsa dyeing, counts 200 macrophages, press under every smear oil mirror
Below equation calculating phagocytic rate and phagocytic index:
Phagocytic rate/%=(macrophage number/200 the macrophage number of phagocytosis chicken red blood cell) × 100%；
Phagocytic index=(chicken red blood cell sum/200 the macrophage numbers swallowed) ÷ 2.
Separately take each group of mice spleen and thymus gland weighed, calculate as follows:
Index and spleen index=spleen weight (mg)/body weight (g)；
Thymus index=thymic weight (mg)/body weight (g).
1.6 data statistic analysis
Use SPSS 19.0 to analyze software and carry out data statistics, variance analysis group difference.
2, experimental result
2.1 on immunosuppressed mice Peritoneal Macrophages Function and the impact of Immune Organs Index
Comparing with blank group, the indices of model group the most substantially reduces (P ＜ 0.01).Compared with model group, the Huang of positive group
Astragalus polysaccharides (APS), chloroquine diphosphate group, compound (I) group all can significantly improve phagocytic rate and phagocytic index (P ＜ 0.05)；
Compared with model group, chloroquine diphosphate and phagocytic rate, phagocytic index, index and spleen index and the chest of compound (I) composition group mouse
Gland index the most significantly raised (P ＜ 0.01).The results are shown in Table 1.
Table 1 is on immunosuppressed mice Peritoneal Macrophages Function and the impact of Immune Organs Index
| Group | Phagocytic rate/% | Phagocytic index | Index and spleen index | Thymus index |
| Blank group | 35.5±3.71 | 0.255±0.02 | 5.54±0.64 | 3.57±0.54 |
| Model group | 19.7±3.34 | 0.152±0.02 | 2.03±0.24 | 0.90±0.28 |
| Positive controls | 24.15±2.60 | 0.175±0.03 | 3.74±0.36 | 1.47±0.32 |
| Chloroquine diphosphate group | 24.15±4.67 | 0.183±0.02 | 3.32±0.53 | 1.55±0.28 |
| Compound (I) group | 23.75±4.56 | 0.197±0.04 | 3.90±0.52 | 1.51±0.20 |
| Chloroquine diphosphate and compound (I) composition group | 28.05±4.30 | 0.231±0.02 | 5.33±0.65 | 2.98±0.43 |
The above results shows, chloroquine diphosphate, compound (I) all can improve macrophage function and the immunity of immunosuppressed mice
Shoot formation, chloroquine diphosphate and compound (I) are used in combination the macrophage function that can improve immunosuppressed mice further
And Immune Organs Index, effect is better than chloroquine diphosphate or compound (I) independent role effect, can develop into raising immunity
Medicine, compared with prior art there is prominent substantive distinguishing features and significantly progressive.
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, technical scheme can be modified or equivalent, and not take off
Essence and protection domain from technical solution of the present invention.
Claims (10)
1. a compound (I) with following structural formula,
2. the pharmaceutical composition of a chloroquine diphosphate, it is characterised in that: include chloroquine diphosphate, chemical combination as claimed in claim 1
Thing (I) and pharmaceutically acceptable carrier, be prepared as the formulation needed.
The pharmaceutical composition of chloroquine diphosphate the most according to claim 2, it is characterised in that: pharmaceutically acceptable carrier
Including diluent, excipient, filler, adhesive, wetting agent, disintegrant, sorbefacient, surfactant, absorption
Carrier or lubricant.
The pharmaceutical composition of chloroquine diphosphate the most according to claim 2, it is characterised in that: described formulation includes tablet, glue
Wafer, oral liquid, suck agent, granule, electuary, pill, powder, paste, sublimed preparation, supensoid agent, pulvis, solution,
Injection, suppository, spray, drops or patch.
5. the preparation method of the compound (I) described in claim 1, it is characterised in that comprise following operating procedure: (a)
The dry rhizome of the red sage root is pulverized, with 85～95% alcohol heat reflux extract, merging extract, be concentrated into without alcohol taste, use stone successively
Oil ether, ethyl acetate and water saturated extracting n-butyl alcohol, respectively obtain petroleum ether extract, acetic acid ethyl ester extract and n-butanol
Extract；N-butyl alcohol extract macroreticular resin removal of impurities in (b) step (a), first with 10 column volumes of 8% ethanol elution,
Again with 12 column volumes of 70% ethanol elution, collecting 70% eluent, reduced pressure concentration obtains 70% ethanol elution concentrate；(c)
In step (b), 70% ethanol elution concentrate purification on normal-phase silica gel separates, and is 40:1,20:1,10:1 and 5:1 by volume ratio successively
Methylene chloride-methanol gradient elution obtain 4 components；D in () step (c), component 4 separates further by purification on normal-phase silica gel,
3 components are obtained successively with the methylene chloride-methanol gradient elution that volume ratio is 8:1,5:1 and 2:1；In (e) step (d)
The reverse phase silica gel that component 2 is bonded by octadecylsilane separates, with the methanol aqueous solution isocratic elution that concentration expressed in percentage by volume is 75%,
Collecting 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) 90% second
Alcohol circumfluence distillation, merges extract.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: described macroreticular resin is AB-8
Type macroporous absorbent resin.
The preparation method of compound the most according to claim 5 (I), it is characterised in that: step (a) is used dichloromethane
Alkane replaces ethyl acetate to extract, and obtains dichloromethane extract.
9. the application in preparation strengthens the medicine of immunity of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described chloroquine diphosphate of claim 2～4 application in preparation strengthens the medicine of immunity.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110917196A (en) * | 2020-02-05 | 2020-03-27 | 广州康健医学科技有限公司 | Chloroquine antibacterial disinfectant and application thereof |
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2016
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110917196A (en) * | 2020-02-05 | 2020-03-27 | 广州康健医学科技有限公司 | Chloroquine antibacterial disinfectant and application thereof |
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