CN105753681A - Drug composition of citicoline sodium and medical application of drug composition - Google Patents
Drug composition of citicoline sodium and medical application of drug composition Download PDFInfo
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Abstract
The invention discloses a drug composition of citicoline sodium and medical application of the drug composition.The drug composition of the citicoline sodium comprises the citicoline sodium and a natural product chemical compound (I) of a novel structure, and the citicoline sodium and the chemical compound (I) have an inhibiting effect on transplanted tumor when acting independently; the citicoline sodium and the chemical compound (I) have a more remarkable inhibiting effect on transplanted tumor when acting jointly, the safety is high, the toxicity is low, the drug for inhibiting tumor can be developed, and compared with the prior art, the drug composition has prominent substantive features and remarkable advancement.
Description
Technical field
The invention belongs to biomedicine field, relate to the new application of C14H25N4NaO11P2, be specifically related to pharmaceutical composition and the medical usage thereof of a kind of C14H25N4NaO11P2.
Background technology
C14H25N4NaO11P2, by reducing cerebral vascular resistance, increases cerebral blood flow and promotes metabolism of brain, improve cerebral circulation.Also can strengthen the function of brain stem ARAS (ascending reticular activating system), strengthen the function of pyramidal system, improve paralysis motorica, therefore the recovery and promotion promoting brain function is revived and had certain effect.Clinic is mainly used in the disturbance of consciousness after Acute Brain Injury and brain surgery.
Up to now, there is not yet C14H25N4NaO11P2 and pharmaceutical composition thereof and antineoplastic dependency report.
Summary of the invention
It is an object of the invention to provide the pharmaceutical composition of a kind of C14H25N4NaO11P2, containing the natural product of C14H25N4NaO11P2 and a kind of novel structure, C14H25N4NaO11P2 and this natural product in this pharmaceutical composition can synergistic antitumor.
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 C14H25N4NaO11P2, including C14H25N4NaO11P2, 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: Concretio Silicea Bambusae is pulverized by (a), extract with 70～90% 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 12 column volumes of 20% ethanol elution, then with 15 column volumes of 80% ethanol elution, collect 80% eluent, and concentrating under reduced pressure obtains 80% ethanol elution concentrate；In (c) step (b) 80% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 80:1,40:1,20:1 and 10:1 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 25:1,20:1 and 15:1 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 65%, collecting 13～17 column volume eluents, eluent concentrating under reduced pressure obtains compound (I).
Further, in the preparation method of compound (I), step (a) is extracted with 80% 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 preparing anti-tumor drug.
The application in preparing anti-tumor drug of the pharmaceutical composition of above-mentioned C14H25N4NaO11P2.
Advantages of the present invention:
The pharmaceutical composition of C14H25N4NaO11P2 provided by the invention contains the natural product of C14H25N4NaO11P2 and a kind of novel structure, when C14H25N4NaO11P2 and this natural product independent role, there is antitumor action；During the two synergy, antitumor action improves further, it is possible to develop into anti-tumor drug.
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.Although the present invention being explained in detail with reference to preferred embodiment, it will be understood by those within the art that, it is possible to technical scheme is modified or equivalent replacement, without deviating from the spirit and scope of technical solution of the present invention.
Embodiment 1: compound (I) separates preparation and structural identification
Separation method: Concretio Silicea Bambusae (2kg) is pulverized by (a), (15L × 3 time) are extracted with 80% 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 12 column volumes of 20% ethanol elution, then with 15 column volumes of 80% ethanol elution, collects 80% eluent, concentrating under reduced pressure obtains 80% ethanol elution concentrate；C in () step (b), 80% ethanol elution concentrate purification on normal-phase silica gel separates, obtain 4 components with the methylene chloride-methanol gradient elution that volume ratio is 80:1 (10 column volumes), 40:1 (8 column volumes), 20:1 (8 column volumes) and 10:1 (9 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 25:1 (7 column volumes), 20:1 (8 column volumes) and 15:1 (7 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 65%, collecting 13～17 column volume eluents, eluent concentrating under reduced pressure obtains compound (I) (HPLC normalization purity is more than 98%)..
Structural identification: HR-ESI-MS shows [M+H]+For m/z253.1756, can obtain molecular formula in conjunction with nuclear-magnetism feature is C15H24O3, degree of unsaturation is 4.Hydrogen nuclear magnetic resonance modal data δH(ppm, CDCl3null，500MHz): H-3 (2.56，m)，H-4a(1.81，m)，H-4b(1.62，m)，H-5a(1.76，m)，H-5b(1.67，m)，H-6(2.10，m)，H-7(2.79，d，J=8.3Hz)，H-10a(2.45，d，J=15.7Hz)，H-10b(1.98，d，J=15.7Hz)，H-11a(4.22，d，J=11.4Hz)，H-11b(3.83，d，J=11.4Hz)，H-12a(3.98，dd，J=9.2，4.5Hz)，H-12b(3.58，dd，J=9.2，2.7Hz)，H-13(0.89，d，J=7.2Hz)，H-14(0.99，s)，H-15(1.15，s)；Carbon-13 nmr spectra data δC(ppm, CDCl3, 125MHz): 134.5 (C, 1-C), 127.6 (C, 2-C) 44.8 (CH, 3-C), 22.1 (CH2, 4-C), 36.3 (CH2, 5-C), 26.1 (CH, 6-C), 59.8 (CH, 7-C), 213.5 (C, 8-C), 48.2 (C, 9-C), 29.9 (CH2, 10-C), 58.4 (CH2, 11-C), 63.2 (CH2, 12-C), 10.5 (CH3, 13-C), 19.3 (CH3, 14-C), 25.8 (CH3, 15-C).Infrared spectrum shows that this compound contains hydroxyl (3340cm-1) and carbonyl (1735cm-1)。13C-NMR, DEPT and hsqc spectrum show 15 carbon signals, including three methyl, five methylene (two company's oxygen carbon), three methines, and four quaternary carbons (carbonyl carbon and two alkene carbon), in conjunction with insatiable hunger sum, function above structure shows that this compound is twin nuclei.1H-NMR spectrum shows three methyl proton signal δ in conjunction with hsqc spectrumH0.89 (3H, J=7.2Hz), 0.99 (3H, s), 1.15 (3H, s), three groups of methene proton signal δH1.81 (1H, m) with 1.62 (1H, m), 1.76 (1H, m) with 1.67 (1H, m), 2.45 (1H, d, J=15.7Hz) and 1.98 (1H, d, J=15.7Hz), two groups of methylol proton signal δH4.22 (1H, d, J=11.4Hz) and 3.83 (1H, d, J=11.4Hz), 3.98 (1H, dd, J=9.2,4.5Hz) and 3.58 (1H, dd, J=9.2,2.7Hz), three methine proton signal δH2.56 (1H, m), 2.10 (1H, m) with 2.79 (1H, d, J=8.3Hz).1H-1There is H-3/H in HCOSY spectrum2-12、H-3/H2-4/H2-5/H-6/H-7 coherent signal, shows H in HMBC spectrum simultaneously2-4 with C-2 and C-3, H2-5 and C-3, H-6 and C-8, H-7 and C-1, H2-10 with C-1, C-2, C-7, C-8 and C-14, H2-11 with C-1, C-2 and C-3, H2-12 and C-2, H3-13 with C-5 and C-7, H3-14 with C-8, C-9 and C-10, H3-15 with C-9 and C-10 coherent signal, the connected mode of this compound can be built by the relevant information in above-mentioned H NMR spectroscopy, and above-mentioned spectral data shows that this compound is tremulane type sesquiterpenoids.In tremulane type sesquiterpene, H-6 and H-7 is generally beta comfiguration, H3-14 usual places of configuration are β positions, H3-15 are configured as α position.H-6 and the H-7 embodied in the NOE of this compound tests and H-7 and H3-14 coherent signals meet the configuration relationship of tremulane type sesquiterpene, meanwhile, and H in NOESY spectrum2-12 with the coherent signal of H-7 hint H2-12 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
1, materials and methods
1.1 animals
Healthy ICR mice, cleaning grade, body weight 18～22g, male and female half and half, natural drug pharmacology key lab of province of unming Medical College provide.Animal feeding temperature (22 ± 1) DEG C, relative humidity 55%～65%, 12h periodicity of illumination aeration-drying environment in, adopt big mice maintain material 1022 raising.
1.2 reagent and sample
C14H25N4NaO11P2 is purchased from National Institute for Food and Drugs Control.Compound (I) is made by oneself, and preparation method is shown in embodiment 1.Cisplatin (DDP) is purchased from Gejiu Bio-Pharmaceutical Co., Ltd., Yunnan.
Prepared by 1.3 mice group and model
Take well-grown tumor cell, be adjusted to finite concentration (S180:6 × 10 with normal saline6/mL；H22:5 × 106/mL).Every mice is in forward right side limb axillary fossa subcutaneous vaccination 0.2mL, i.e. S180:1.2 × 106/ only；H22:1.0 × 106/ only.
The effect to S180 tumor-bearing mice of 1.4 medicines
ICR mice is randomly divided into 5 groups, often group 12, respectively negative control group, positive controls (DDP1mg/kg), C14H25N4NaO11P2 group (40mg kg-1), compound (I) group (40mg kg-1), C14H25N4NaO11P2 and compound (I) compositions group [20mg kg-1C14H25N4NaO11P2+20mg kg-1Compound (I)].Adapting to environment after 1 week, continuous gastric infusion 7d, Normal group and model control group mouse stomach give purified water.
The effect to H22 tumor-bearing mice of 1.5 medicines
ICR mice is randomly divided into 5 groups, often group 12, respectively negative control group, positive controls (DDP1mg/kg), C14H25N4NaO11P2 group (40mg kg-1), compound (I) group (40mg kg-1), C14H25N4NaO11P2 and compound (I) compositions group [20mg kg-1C14H25N4NaO11P2+20mg kg-1Compound (I)].Adapting to environment after 1 week, continuous gastric infusion 7d, Normal group and model control group mouse stomach give purified water.
1.6 Testing index and method
After last administration, next day puts to death mice, weighs, and peels off tumor block, takes thymus and spleen, weigh respectively, calculates tumor killing effect, thymus index and spleen index:
The average tumor weight × 100% of tumor control rate (%)=(negative control group average tumor weight-administration group average tumor weight)/negative control group；
Weight (g) after thymus index (mg/g)=thymic factor D injection (mg)/go tumor；
Weight (g) after spleen index (mg/g)=spleen quality (mg)/go tumor.
1.7 statistical methods
All data SPSS19.0 statistical packages process, and measurement data data represent with mean ± standard deviation, and data carry out test of normality；Many Sets of Measurement Datas adopt one-wayANOVA, adopt LSD and SNK method when variance is neat, adopt Tamhane'sT2 or Dunnett'sT3 method during heterogeneity of variance；The significance of difference between rate is determined in X2 inspection.P < 0.05 is statistically significant.
2, experimental result
The tumor-inhibiting action of 2.1 couples of mouse transplanted sarcoma S180
Comparing with negative control group, mouse transplanted sarcoma S180 is all shown certain tumor-inhibiting action by medicine.The growth of tumor is had obvious inhibitory action (P < 0.01) with compound (I) compositions group and positive controls by C14H25N4NaO11P2, and C14H25N4NaO11P2 group, compound (I) group are to the growth of tumor inhibited (P < 0.05).Result is in Table 1.
2.2 impacts on mouse transplanted sarcoma S180 thymus index and spleen index
S180 tumor-bearing mice thymus index and spleen index are had the impact slightly declined by medicine, compare with negative control group and there was no significant difference, and positive drug DDP can significantly reduce the organ coefficient of S180 tumor-bearing mice.
The tumor-inhibiting action of 2.3 couples of mouse bearing liver cancer H22
Comparing with negative control group, mouse bearing liver cancer H22 is all shown certain tumor-inhibiting action by medicine.The growth of tumor is had obvious inhibitory action (P < 0.01) with compound (I) compositions group and positive controls by C14H25N4NaO11P2, and C14H25N4NaO11P2 group, compound (I) group are to the growth of tumor inhibited (P < 0.05).Result is in Table 2.
2.4 impacts on H22 tumor-bearing mice thymus index and spleen index
Comparing with negative control group, H22 tumor-bearing mice thymus index and spleen index are had no significant effect by medicine, and positive control drug DDP then makes the thymus of tumor-bearing mice and spleen substantially alleviate (P < 0.01)；Prompting medicine is only small to mouse toxicity at this dose.
Table 1 is on the tumor-inhibiting action of mouse transplanted sarcoma S180 and the impact on thymus index and spleen index
| Group | Average tumor weight (g) |
| Negative control group | 1.54±0.32 |
| Positive controls | 0.34±0.13 |
| C14H25N4NaO11P2 group | 0.94±0.48 |
| Compound (I) group | 0.80±0.53 |
| C14H25N4NaO11P2 and compound (I) compositions group | 0.42±0.41 |
Table 2 is on the tumor-inhibiting action of mouse bearing liver cancer H22 and the impact on thymus index and spleen index
| Group | Average tumor weight (g) |
| Negative control group | 1.39±0.14 |
| Positive controls | 0.41±0.06 |
| C14H25N4NaO11P2 group | 0.84±0.12 |
| Compound (I) group | 0.73±0.05 |
| C14H25N4NaO11P2 and compound (I) compositions group | 0.54±0.19 |
The above results shows, when C14H25N4NaO11P2, compound (I) independent role, transplanted tumor is inhibited；When C14H25N4NaO11P2 and compound (I) synergy, the inhibition of transplanted tumor being become apparent from, and safety is high, toxicity is low, it is possible to develop into the medicine of suppression tumor.
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 C14H25N4NaO11P2, it is characterised in that: include C14H25N4NaO11P2, compound as claimed in claim 1 (I) and pharmaceutically acceptable carrier, prepare into the dosage form of needs.
3. the pharmaceutical composition of C14H25N4NaO11P2 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 C14H25N4NaO11P2 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: Concretio Silicea Bambusae is pulverized by (a), extract with 70～90% 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 12 column volumes of 20% ethanol elution, then with 15 column volumes of 80% ethanol elution, collect 80% eluent, and concentrating under reduced pressure obtains 80% ethanol elution concentrate；In (c) step (b) 80% ethanol elution concentrate with purification on normal-phase silica gel separate, successively with volume ratio be 80:1,40:1,20:1 and 10:1 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 25:1,20:1 and 15:1 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 65%, collecting 13～17 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 80% 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 preparing anti-tumor drug of the compound (I) described in claim 1.
10. the pharmaceutical composition of the arbitrary described C14H25N4NaO11P2 of claim 2～4 application in preparing anti-tumor drug.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105884773A (en) * | 2016-04-23 | 2016-08-24 | 何淑琼 | Benzocaine pharmaceutical composition and medical application thereof |
| CN106190965A (en) * | 2016-07-19 | 2016-12-07 | 袁肇斌 | A kind of mesenchymal stem cells MSCs In vitro culture liquid and cultivation amplification method |
-
2016
- 2016-04-23 CN CN201610258319.3A patent/CN105753681A/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105884773A (en) * | 2016-04-23 | 2016-08-24 | 何淑琼 | Benzocaine pharmaceutical composition and medical application thereof |
| CN106190965A (en) * | 2016-07-19 | 2016-12-07 | 袁肇斌 | A kind of mesenchymal stem cells MSCs In vitro culture liquid and cultivation amplification method |
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Application publication date: 20160713 |