CN110003142A - A kind of synthesis and application thereof - Google Patents
A kind of synthesis and application thereof Download PDFInfo
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- CN110003142A CN110003142A CN201810007904.5A CN201810007904A CN110003142A CN 110003142 A CN110003142 A CN 110003142A CN 201810007904 A CN201810007904 A CN 201810007904A CN 110003142 A CN110003142 A CN 110003142A
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- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
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Abstract
The present invention provides a kind of synthesis and its for preventing or the purposes for the treatment of cancer, the synthesis has Formulas I structure.The present invention also provides the preparation method of the compound of formula I and it includes the pharmaceutical compositions of the compound of formula I.
Description
Technical field
The invention belongs to biomedicine fields, more particularly to a kind of synthesis and its preparation method and application.
Background technique
Cancer is whole world disease and the first cause for leading to death, and since modern technologies extend the expected longevity
Life, it is therefore expected that cancer still will increase.In the lifetime of cell, the DNA minor change referred to as " being mutated " occurs for occasional.
In these mutation, certain mutation (referred to as " silent mutation ") do not lead to any essential change of cell function, and other are prominent
Become the mode of action of changeable cell.Number of mechanisms can prevent the cell to have mutated from continuing the cell cycle, and
And if hereditary mistake cannot correct, these cells will pass through the process " suicide " of referred to as " Apoptosis ".However, such as
Fruit mutation occurs in the protein for participating in cell cycle regulating, this can lead to cell Proliferation out of control (referred to as tumour is formed),
It can be further developed into cancer.
Cancer cell usually has adverse effect body.Cancer can invade adjacent tissue by malignant cell to expand
It dissipates, can also be spread by the process for being known as " shifting ", malignant cell is detached from and spreads from tumor mass during " transfer "
To farther away position.In many different types of tissues, cancer displays are diversified forms, and can be with its intrusion and invasion degree
To characterize.
Cancer occurs as abnormal structure's block in host organism living, it nutrition is received from host and independent of place
Main ground hyper-proliferative, and destroy host body.Human organ is by a large amount of cell compositions.When the normal cell of human body becomes abnormal
When cell and the abnormal cell are divided and are proliferated inspection is not added, cancer just occurs.Although the morbidity of inherent cause and cancer
It is closely related, but environmental factor also has an important influence on to whether individual occurs cancer.Cancer is especially universal in developed country.Have
According to the report, the reason of leading to cancer is that the use to pesticide, agrochemical increases (therefore residual quantity of this substance in food
Increase), the consumption of the processed food comprising additive (such as food preservative and colorant) is increased, to water, soil and air
Pollution increase, pressure of modern life, movable reduction, obesity caused by greasy eating habit, etc..In recent years
Come, somebody points out, when the cell signaling system of normal cell breaks down, when cancer gene is activated, or works as tumor suppressor gene
When breaking down, just cause cancer.
Presently, there are kinds cancer treatment method, such as operative treatment, chemotherapy and radiotherapy.Therapeutic method of surgery exists
Early stage is effectively removed cancer, and still, the disadvantage is that sometimes having to extract organ, this will lead to side effect, and have
Cancer diffuses to the uncertainty of other organs.Radiotherapy is conducive to effectively treat the cancer occurred in a certain organs
Disease, but have the disadvantage that: so that patient is exposed to other risk of cancer because of radiation, cancer cell can not be prevented to be diffused into other
Organ, and patient will bear very big pain over the course for the treatment of.Chemotherapy is carried out usually using anticancer drug, but
Know that the toxicity of anticancer drug acts not only on cancer cell, also acts on the normal cell of patient, cause side effect.Therefore, it to open
Hair has the new anti-cancer drug object of higher cancer cell selectivity and toxicity as small as possible.
Selenium is a kind of indispensable microelement of body vital movement.In recent years, people especially have selenium compound
Machine selenium compound is studied, it is intended to which therefrom discovery has the compound of anticancer or anti-tumor activity.For example, EI-Bayoumy etc.
[KEl-Bayoumy, DrugsFuture, 1997,22 (5): 539~545] the study found that benzyl selenium cyanide is induced in DMBA
Breast cancer mouse model in show antitumor action.Compared with sodium selenite, the anticancer activity of benzyl selenium cyanide is higher,
But itself there is strong peculiar smell, and there is the side effect for causing patient's weight to be remarkably decreased.
Ebselen (- 3 (2H) -one of ebselen, 2- phenyl -1,2- benzisoxa selenazoles) and Ethaselen (1,2- [two (1,
2- benzisoxa selenazoles -3 (2H) -one)] ethane is two organic selenium compounds for coming into clinical experimental stage.Studies have shown that
The mechanism of action of ebselen mainly passes through inhibition target enzyme-sulphur oxygen cyclase protein reductase activity, adjusts signal downstream and passes
Guiding path and its antitumor apoptosis pathway realize the antitumor action of drug, and bioactivity and hypotoxicity then may be with its ring-types
Selenium amide structure or Benzisoelenazolone heterocycle containing selenium it is related (H J Reich waits J.Am.Chem.Soc., 1987,109 (18):
5549-5551);Ethaselen is thioredoxin reductase inhibiter, contains 2 Benzisoelenazolones in Ethaselen molecule
Structure, has received synergistic effect, and activity is better than ebselen.
Although having found above-mentioned organic selenium compounds, existing organic selenium compounds there are still antitumor effect need into
The problems such as one step improves, anticancer spectrum is limited and compound structure limited types, is far from satisfying the mankind for tumor prevention
With the growing demand for the treatment of.Therefore, the pharmaceutical compound with better tumor prevention and/or therapeutic effect is developed
Object, especially organic selenium compounds have become urgent need.
Therefore, still there is an urgent need to the new new chemical combination for being used to prevent and/or treat tumour for having good result for the prior art
Object.
Summary of the invention
The present inventor passes through lot of experiments, has had been surprisingly found that a kind of selenium cyanogen organic compound, has unexpected
The bioactivity of prevention and/or treatment tumour.The compound can be effectively used for the prevention and/or treatment of kinds cancer.
Selenium cyanogen organic compound of the present invention is the compound with following formula I structure
Or its officinal salt, wherein R is the alkyl or hydrogen of the linear chain or branched chain of 1 to 6 carbon atom.
On the other hand, the present invention also provides the preparation methods of above-mentioned compound of formula I, comprising the following steps:
(i) make Formula II compound
It reacts to obtain compound III in organic solvent with halogenated acyl halide representated by X '-CO-CHR-X
(ii) formula III compound is made to react to obtain compound of formula I with Potassium Selenocyanate
Wherein R is as defined in claim 1;X and X ' can be identical or different, independently is selected from fluorine, chlorine, bromine and iodine
The halogen of atom.
In another aspect of this invention, a kind of pharmaceutical composition is additionally provided, it includes compound of formula I of the present invention
Or its officinal salt and pharmaceutically acceptable excipient or carrier.
In still another aspect of the invention, compound of formula I or its officinal salt of the invention are additionally provided in preparation for pre-
Purposes in anti-and/or treatment tumour drug.
Specific embodiment
It in the preparation process in accordance with the present invention, the use of sodium bicarbonate is catalyst preferably in step (i).
Illustrative reaction route is as follows:
Preparation method of the invention is simple, yield is higher, and compound of formula I can easily be made.
The present invention also provides compound of formula I or its officinal salt to prepare the drug for preventing and/or treating tumour
In purposes;Preferably, the tumour is selected from colon cancer, breast cancer, prostate cancer, cervical carcinoma, gastric cancer, liver cancer, lung cancer and white
Blood disease;It is particularly preferred that the tumour is selected from gastric cancer, lung cancer, liver cancer and leukaemia.
On the other hand, the present invention provides a kind of pharmaceutical composition, it includes compound of formula I or its officinal salt,
And optionally pharmaceutically acceptable excipient and/or carrier.
Specific embodiment
The present invention provides the compounds described in following formula I
Or its officinal salt,
Wherein R is the alkyl or hydrogen of the linear chain or branched chain of 1 to 6 carbon atom.Preferably, R is 1 to 4 carbon atom
The alkyl or hydrogen of linear chain or branched chain;It is highly preferred that R is selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, uncle
Butyl and hydrogen;In an especially preferred embodiment, R is selected from methyl, ethyl, n-propyl, isopropyl and hydrogen;It is outstanding at one
In its preferred embodiment, R is selected from methyl, ethyl and hydrogen;In a further preferred embodiment, R is selected from methyl and hydrogen.
Pharmaceutical composition of the invention includes compound of formula I or its officinal salt of the invention, and optionally pharmaceutically acceptable
Excipient and/or carrier.In pharmaceutical composition of the invention, other than compound of formula I of the invention or its officinal salt, also
Other drugs active constituent can be additionally comprised.Pharmaceutical composition of the invention can be prepared by routine techniques, such as
Remington:The Science and Practice of Pharmacy, the 19th edition, method described in 1995 is led to
It crosses and is incorporated herein by reference.The composition can occur with conventionally form, such as capsule, tablet, aerosol, solution, suspension
Agent or Topical application forms.
Typical composition includes compound of formula I or its salt and pharmaceutically acceptable excipient or carrier of the invention.For example, active
Compound is usually mixed with carrier, and perhaps being diluted or being sealed in by carrier can be ampoule, capsule, sachet
(sachet), in the carrier of paper or other vessel forms.When reactive compound is mixed with carrier, or when carrier serve as it is dilute
When releasing agent, the carrier can be the solid, semisolid or liquid material of the carrier for serving as reactive compound, excipient or medium
Material.The reactive compound can be adsorbed in particulate solid carrier (such as being contained in sachet).Suitable carrier
Some examples be water, salting liquid, alcohol, polyethylene glycol, poly- hydroxyl-oxethyl castor oil, peanut oil, olive oil, gelatin, lactose,
Carclazyte, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talcum, gelatin, agar, pectin, Arab
Glue, the lower alkyl ether of stearic acid or cellulose, silicic acid, fatty acid, fatty acid amine, fatty mono glyceride and diglyceride,
Pentaerythritol fatty ester, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.Similarly, the carrier or dilution
Agent may include any sustained release materials known in the art, such as individual glycerin monostearate or glycerol disterate
The mixture of ester or itself and wax.
The preparation can be mixed with the adjuvant that adverse reaction or not does not occur the reactive compound.These additives can
To include wetting agent, emulsifier and suspending agent, influence salt, buffer and/or coloring material, preservative, the sweetener of osmotic pressure
Or flavoring agent.If desired, can also sterilize to the composition.
Administration method, which can be, is effectively transported to appointing for appropriate or desired site of action for formula Compound I
What approach, such as oral, intranasal, lung, mouth containing, subcutaneous, intradermal, transdermal or parenteral route, such as rectum, reservoir
(depot), subcutaneous, intravenous, urethra is interior, the approach of intramuscular, intranasal, ophthalmic solution or ointment, oral route is preferred.
If said preparation can be tabletting, be set with pulvis or pellet form using solid carrier for being administered orally
In hard gelatin capsule or its form that can be lozenge (troche) or pastille.If using liquid-carrier, the system
Agent can be the form of syrup, emulsion, Perle or sterile injection liquid, such as aqueous or non-aqueous liquid is suspended
Agent or solution.
The dosage form of injectable generally includes aqueous suspension or Oil suspensions, and suitable dispersing agent or profit can be used
It is prepared by humectant and suspending agent.The form of injectable can be the suspension either prepared with solvent or diluent in solution phase
The form of agent.Acceptable solvent or carrier include sterile water, Ringer's solution or normal isotonic saline solution.Alternatively, nothing can be applied
Bacterium oil is as solvent or suspending agent.Preferably, the oil or fatty acid are fixedness, including natural oil or synthetic oil, rouge
Fat acid, monoglyceride, diglyceride or triglycerides.
For injection, the preparation can also be the powder for being suitable for being reconstructed with above-mentioned appropriate solution.These reality
Example include but is not limited to freeze-drying, rotary drying or spray drying powder, amorphous powder, particle, sediment or
Particle.For injection, the preparation can optionally include stabilizer, pH adjusting agent, surfactant, biological utilisation
Spend the combination of regulator and these reagents.The compound can be formulated as being used to carry out parenteral administration, example by injection
As by injecting or continuous infusion.Unit dosage forms for injection can be in ampoule or in multi-dose container.
It can be by formulation design of the invention at activity can be provided after being applied to patient by methods known in the art
Quick, the lasting or sustained release of ingredient.And hence it is also possible to which the preparation is configured to be used for controlled release release or slow release.
Compound of formula I of the invention is all effective in wide dosage range.It, can be with for example, in the treatment of adult
Use daily about 0.05 to about 5000mg, preferably from about 1 to about 2000mg, more preferably from about 2 to about 2000mg dosage.Typical agent
Amount is daily about 10mg to about 1000mg.When selecting patient treatment protocol, can usually must since higher dosage, and
Dosage is reduced when illness obtains control.Accurate dosage will depend on method of application, desired treatment, application form, to
The preference and experience of the weight and supervisor doctor of the object for the treatment of and object to be treated.
In general, per unit dose includes about 0.05mg to about by the distribution of formula Compound I in unit dosage forms
1000mg active constituent and pharmaceutical acceptable carrier.
In general, the dosage form for being suitable for oral, intranasal, lung or transdermal administration includes about 125 μ g to about 1250mg, preferably from about
The Formulas I chemical combination of 250 μ g to about 500mg, more preferably from about 2.5mg to about 250mg mixed with pharmaceutical acceptable carrier or diluent
Object.
Dosage form can be for example twice daily or three times a day to be applied above once a day or once a day.Alternatively, dosage form
It can be applied less than frequency once a day, such as every other day or weekly, if the doctor to prescribe thinks properly.
Pharmaceutical composition of the invention can be in the form of tablet, capsule, pulvis, granule, pastille, liquid or jelly.For
Oral tablet and capsule may be adapted to the form of unit dose medication, and can contain conventional excipient, these examples have:
Bonding agent such as syrup, gum arabic, gel, sorbierite, yellow work glue, polyvinylpyrrolidone (PVP);Filler such as lactose, sugar
Class, corn flour, calcium phosphate, sorbierite or glycine;Tablet lubricants for example magnesium stearate, silica, talcum, polyethylene glycol or
Silica;Disintegrating agent such as potato starch;Acceptable lubricant such as NaLS.Tablet can be according to known routine
Method in pharmaceutical practice is coated.Oral liquid can make watery or oleaginous suspension, solution, emulsion, syrup or
Tincture may be made as a kind of dry matter, be re-modulated again with water or other suitable carriers before the use.These liquid preparations
Containing conventional additive, such as suspending agent is (such as: sorbierite, syrup, methylcellulose, glucose syrup, gelatin, hydrogenated
Edible oil and fat).Emulsifier (such as incubates phosphatide, sorbierite list oleate or gum arabic), nonaqueous phase carrier (including edible oil
Such as apricot kernel oil, the coconut oil of rectifying, grease such as glycerol, propylene glycol or ethyl alcohol), preservative (such as methyl or propyl p-hydroxy benzene first
Acid or sorbic acid), if necessary to contain conventional flavouring agent or colorant.
Dosage can be with administrated method and dosage form and age, weight, and the state of patient is different with sensibility and changes.?
In the case where oral medication, effective daily dose range, for example, can be from 0.1mg to 1g.Single dosage unit containing compound of formula I or
The amount of its officinal salt is 0.1mg to 100mg, it is convenient to for meeting the needs of daily dose.The dosage and dosage list used
Position can exceed above range.
It is swollen for preventing and/or treating in preparation that the present invention also provides compound of formula I of the invention or its officinal salt
Purposes in the drug of tumor.Preferably, the tumour is selected from gastric cancer, lung cancer, liver cancer and leukaemia.
On the other hand, the present invention provides a kind of prevention or the method for the treatment of tumour or cancer, the method includes to having
This object needed applies a effective amount of compound of formula I of the invention or its officinal salt.
The percentage of active material is variable in pharmaceutical composition of the present invention, because medicaments dispensing must be made to be made centainly
The dosage of proper ratio, to obtain ideal curative effect.In short, pharmaceutical preparation of the invention is by oral administration or drug administration by injection can be by every
Daily 0.1 to the 100 milligram of compound of formula I of 70kg weight.Embodiment below be in order to illustrate the purpose of some aspects of the present invention,
It is all not considered as limiting the scope of the invention in any way.
Embodiment
It is synthetically prepared example
Prepare embodiment 1: the synthesis of compound I-a
Reaction equation is as follows:
In three-necked flask, taxol (200mg, 0.23mmol) is dissolved in the in the mixed solvent of methylene chloride and water
(CH2Cl2(V): H2O (V)=1:1) in, be added sodium bicarbonate (42mg, 0.2mmol), at room temperature be added bromoacetyl bromide (56mg,
0.28mmol), it stirs 1 hour, TLC detects fully reacting.Reaction solution is washed twice with 1N HCl (35ml) respectively, and 1%
NaHCO3Na after (35ml) is washed twice2SO3It is dry.Solid is dissolved by heating after solvent evaporated with EtOAc, places crystallization.It is obtained by filtration
Light tan solid, compound II (191mg, yield 71%).It is directly dissolved in anhydrous acetonitrile, Potassium Selenocyanate 145 is added portionwise
(33mg, 0.23mmol) is stirred at room temperature 16 hours.It is instilled in 150ml water after reaction solution concentration, obtained solid is filtered, with 5%
CH3OH/CH2Cl2Plate layer chromatography separation is carried out for solvent, finally obtains white solid, compound I-a (125mg, yield 54%).
Nuclear magnetic resonance:1H NMR(CDCl3)δ(ppm):1.14(s,3H,-CH3),1.23(s,3H,-CH3), 1.69 (s,
3H,-CH3), 1.87 (s, 3H ,-CH3), 1.93 (m, 1H), 2.18 (s, 3H ,-CH3), 2.39-2.41 (m, 2H), 2.46 (s,
3H,-CH3), 3.58 (d, J=7.2Hz, 1H), 3.76-3.84 (m, 2H), 4.23 (d, 1H, J=8.0Hz), 4.33 (d, 1H, J
=8.0Hz), 4.45-4.48 (m, 1H), 4.98 (d, 1H, J=8.0Hz), 5.58 (s, 1H), 5.70 (d, 1H, J=4.0Hz),
6.18 (d, 1H, J=4.2Hz), 6.20-6.32 (m, 2H), 7.32-7.45 (m, 4H), 7.46-7.54 (m, 5H), 7.55-7.62
(m, 3H), 7.78 (d, 2H, J=8.0Hz), 8.17 (d, 2H, J=8.0Hz)
13C NMR(CDCl3)δ(ppm):9.6,14.8,20.85,22.2,22.8,26.2,26.8,35.6,43.2,
45.6,52.4,58.5,72.1,72.2,73.5,74.9,75.1,76.3,79.1,82.3,84.5,101.8,126.4,
127.5,128.5,128.6,128.8,129.1,129.2,130.3,132.1,136.5,142.5,166.9,167.0,
167.2,167.4,170.0,171.3,203.8.
MS [ESI]: calculated value (C50H52N2O15Se) (M+Na), 1022.91, measured value: 1022.83.
Prepare embodiment 2: the synthesis of compound I-b
Reaction equation is as follows:
In three-necked flask, taxol (200mg, 0.23mmol) is dissolved in the in the mixed solvent of methylene chloride and water
(CH2Cl2(V): H2O (V)=1:1) in, it is added sodium bicarbonate (42mg, 0.2mmol), 2 bromo propionyl bromide is added at room temperature
(60mg, 0.28mmol) is stirred 1 hour, and TLC detects fully reacting.Reaction solution is washed twice with 1N HCl (35ml) respectively,
1%NaHCO3Na2SO3 is dry after (35ml) is washed twice.Solid is dissolved by heating after solvent evaporated with EtOAc, places crystallization.Filtering
Obtain light tan solid, compound II (191mg, yield 71%).It is directly dissolved in anhydrous acetonitrile, Potassium Selenocyanate is added portionwise
145
(33mg, 0.23mmol) is stirred at room temperature 16 hours.It is instilled in 150ml water after reaction solution concentration, filtering gained is solid
Body, with 5%CH3OH/CH2Cl2Plate layer chromatography separation is carried out for solvent, finally obtains white solid, (140mg is produced compound I-b
Rate 60%).
Nuclear magnetic resonance:1H NMR(CDCl3)δ(ppm):1.14(s,3H,-CH3),1.23(s,3H,-CH3), 1.64 (s,
3H,-CH3), 1.77 (s, 3H ,-CH3),1.87(s,3H,-CH3), 1.97 (m, 1H), 2.15 (s, 3H ,-CH3), 2.39-2.41
(m,2H),2.46(s,3H,-CH3), 3.56 (d, J=7.2Hz, 1H), 3.73-3.85 (m, 2H), 4.22 (d, 1H, J=
8.0Hz), 4.34 (d, 1H, J=8.0Hz), 4.46-4.49 (m, 1H), 4.99 (d, 1H, J=8.0Hz), 5.57 (s, 1H),
5.72 (d, 1H, J=4.0Hz), 6.19 (d, 1H, J=4.2Hz), 6.21-6.33 (m, 2H), 7.33-7.44 (m, 4H), 7.46-
7.55 (m, 5H), 7.55-7.64 (m, 3H), 7.80 (d, 2H, J=8.0Hz), 8.18 (d, 2H, J=8.0Hz)
13C NMR(CDCl3)δ(ppm):9.6,14.8,16.6,18.3,20.8,26.8,35.5,35.6,37.8,38.4,
43.2,45.6,52.3,52.4,53.5,58.5,72.0,72.1,73.4,74.8,75.3,76.4,79.3,82.4,84.5,
101.6,102.3,126.4,127.5,128.5,128.6,128.8,129.1,129.1,130.3,132.1,136.5,
136.6,142.6,167.0,167.1,167.2,167.2,170.0,171.3,203.8.
[01] MS [ESI]: calculated value (C51H54N2O15Se) (M+Na), 1036.93, measured value: 1036.88
Pharmacological activity
Experimental example 1: anti tumor activity in vitro screens (preliminary inhibiting rate experiment)
[02] positive control drug: paclitaxel injection (TAXOL), 5ml:30mg/ branch, Jiangsu Olympic Competition health medicine company share are limited
Company, lot number: 171211.Test cell strain select the low differentiation gastric adenocarcinoma cells BGC-823 of people, human liver cancer cells Hep G2,
Tetra- kinds of cell strains of human lung cancer cell A549 and human promyelocytic leukemia HL-60.
[03] test method: taking in exponential phase of growth in good condition one bottle of cell, and 0.25% trypsase is added and disappears
Change liquid, digestion makes attached cell fall off, and counts 2~4 × 104A/ml, is made cell suspension.Take cell suspension inoculation in 96 holes
On plate, constant temperature CO is set in 180 holes μ l/2It is cultivated 24 hours in incubator.Liquid is changed, test medicine is added, it is small to cultivate 48 for 20 holes μ l/
When.MTT is added in 96 orifice plates, 20 holes μ l/, is reacted 4 hours in incubator.Supernatant is sucked, DMSO is added by 150 holes μ l/,
It is shaken 5 minutes on plate shaker.Tested material investigates three concentration (1 × 10-7, 1 × 10-6,1×10-5;Mol/L), microplate reader is used
In the light absorption value that wavelength is the every hole of measurement at 570nm, the cell inhibitory rate under each concentration is calculated separately.
[04] cell inhibitory rate %=(negative control group OD value-susceptibility group OD value)/negative control group OD value × 100%
Table 1
[05] test result is shown, compound I-a and I-b has In-vitro Inhibitory Effect to four kinds of tumor cell lines, right
The action intensity of BGC-823, SMMC-7721, A549 and HL-60 cell line is superior to control drug taxol (TAXOL), especially
It is IC of the compound I-b to SMMC-772150Value is only 0.09 μM.
Experimental example 2: internal anti-tumor activity
[06] experimental animal selects SPF grades of male mice in kunming, weight 19-22g, by Wuhan University's zoopery
The heart provides, and tumor strain mouse S 180 sarcoma introduced by institute of Materia Medica,Chinese Academy of Medical Sciences, in laboratory cryopreservation conservation,
The cell suspension in the 4th generation is passed in experiment after being recovery with S180 cell, positive control medicine selects topological former times health.
[07] foundation of S180 bearing mouse model uses aseptic aspiration mice bearing S180 ascites, cell suspension is set micro-
It is counted under mirror, adjustment cell concentration is 2.0 × 107/ mL, in the above-mentioned S180 ascitic tumor fluid of the subcutaneous aseptic inoculation of right side of mice armpit
0.2mL/ only, healthy mice 20, is grouped at random according to weight.
[08] calculating of medication and tumour inhibiting rate: the 2nd day after mouse inoculation tumour cell starts to be administered, random by weight
It is divided into high, medium and low each 3 dosage groups of compound I, positive controls (taxol 1.5mg/kg) and negative control group, daily abdomen
Chamber is administered once, and only, the experimental administration time is 9 days to administered volume 0.5mL/, puts to death animal for 24 hours after the last administration, weighs constitution
Amount, and dissect tumor mass and weigh quality, inhibition rate of tumor growth is calculated according to the following formula.
Inhibiting effect of the 2 compound I of table to mouse S180
[09] results of animal shows that compound I-a and I-b has the work for inhibiting tumour growth to mice bearing S180
With, and the tumor-inhibiting action is significant, and (5mg/kg) antitumor action is better than control compound taxol under same dose.
Therefore, compound I-a and I-b shows Tumor growth inhibition efficiency more higher than taxol.
Claims (7)
1. Formulas I compound represented:
Or its officinal salt,
Wherein R is the alkyl or hydrogen of the linear chain or branched chain of 1 to 6 carbon atom.
2. compound according to claim 1, wherein the compound of formula I be compound selected from following formula I-a or I-b or
It can medication salt:
3. the method for preparing compound of formula I described in claim 1, comprising the following steps:
(i) make Formula II compound
It reacts to obtain compound III in organic solvent with halogenated acyl halide representated by X '-CO-CHR-X
(ii) formula III compound is made to react to obtain compound of formula I with Potassium Selenocyanate
Wherein R is as defined in claim 1;X and X ' can be identical or different, independently is selected from fluorine, chlorine, bromine and iodine atom
Halogen.
4. according to the method described in claim 3, wherein making in step (i) representated by Formula II compound and X '-CO-CHR-X
Halogenated acyl halide react in organic solvent, reaction sodium bicarbonate catalysis under carry out.
5. a kind of pharmaceutical composition, it includes the compound of formula I or its officinal salt as described in any one of claims 1 or 2,
And pharmaceutically acceptable excipient or carrier.
6. compound of formula I according to claim 1 or 2 or its officinal salt are in preparation for preventing and/or treating tumour
Drug in purposes.
7. purposes according to claim 6, wherein the tumour is selected from gastric cancer, lung cancer, liver cancer and leukaemia.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110938032A (en) * | 2018-09-21 | 2020-03-31 | 深圳福山生物科技有限公司 | Organic selenium compound and use thereof |
CN110938033A (en) * | 2018-09-21 | 2020-03-31 | 深圳福山生物科技有限公司 | Selenocyanine compounds and uses thereof |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5977386A (en) * | 1996-12-24 | 1999-11-02 | Bristol-Myers Squibb Company | 6-thio-substituted paclitaxels |
CN1821245A (en) * | 2005-09-05 | 2006-08-23 | 合肥中科大生物技术有限公司 | Camptothecine derivative and its preparation |
CN110041342A (en) * | 2018-01-16 | 2019-07-23 | 深圳福山生物科技有限公司 | A kind of selenium-containing compound and application thereof |
CN110862410A (en) * | 2018-08-27 | 2020-03-06 | 深圳福山生物科技有限公司 | Trifluoromethyl selenium compound and application thereof |
CN110938032A (en) * | 2018-09-21 | 2020-03-31 | 深圳福山生物科技有限公司 | Organic selenium compound and use thereof |
-
2018
- 2018-01-04 CN CN201810007904.5A patent/CN110003142A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5977386A (en) * | 1996-12-24 | 1999-11-02 | Bristol-Myers Squibb Company | 6-thio-substituted paclitaxels |
CN1821245A (en) * | 2005-09-05 | 2006-08-23 | 合肥中科大生物技术有限公司 | Camptothecine derivative and its preparation |
CN110041342A (en) * | 2018-01-16 | 2019-07-23 | 深圳福山生物科技有限公司 | A kind of selenium-containing compound and application thereof |
CN110862410A (en) * | 2018-08-27 | 2020-03-06 | 深圳福山生物科技有限公司 | Trifluoromethyl selenium compound and application thereof |
CN110938032A (en) * | 2018-09-21 | 2020-03-31 | 深圳福山生物科技有限公司 | Organic selenium compound and use thereof |
Non-Patent Citations (2)
Title |
---|
肖颖歆 等: "有机硒药物的研究进展及开发应用前景", 《中国现代应用药学》 * |
韩利文 等: "巴西蜂胶3种单体成分的体内抗肿瘤实验", 《中药材》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110938032A (en) * | 2018-09-21 | 2020-03-31 | 深圳福山生物科技有限公司 | Organic selenium compound and use thereof |
CN110938033A (en) * | 2018-09-21 | 2020-03-31 | 深圳福山生物科技有限公司 | Selenocyanine compounds and uses thereof |
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