CN109467560A - A kind of synthesis and application thereof - Google Patents
A kind of synthesis and application thereof Download PDFInfo
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- CN109467560A CN109467560A CN201710806471.5A CN201710806471A CN109467560A CN 109467560 A CN109467560 A CN 109467560A CN 201710806471 A CN201710806471 A CN 201710806471A CN 109467560 A CN109467560 A CN 109467560A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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Abstract
The present invention relates to a kind of synthesis shown in formula I, preparation method and its preparing the purposes in the drug for treating and preventing tumour.
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
Deng [ K El-Bayoumy, Drugs Future, 1997,22 (5): 539~545 ] the study found that benzyl selenium cyanide exists
Antitumor action is shown in the breast cancer mouse model of DMBA induction.Compared with sodium selenite, the anticancer of benzyl selenium cyanide
Activity is higher, but itself has 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 benzisoxas in Ethaselen molecule
Selenazoles ketone 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, spectrum of disease 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 anti-tumor drug of more preferable effect is developed, especially organic selenium compounds have become
For urgent need.
Therefore, still there is an urgent need to the new noval chemical compounds for being used to treat or prevent tumour for having good result for the prior art.
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 prevention
With the bioactivity for the treatment of tumour.The compound can be effectively used for the treatment and/or prevention of kinds cancer.
The present invention provides entitled (S) -4- ethyl -4- (selenium the cyanoacetate) -1H- pyrans of chemistry simultaneously [3', 4':6,7] Yin
Piperazine simultaneously [1,2-b] quinoline -3,14- (4H, 12H)-diketone compounds of Formula I or its officinal salt:
I
On the other hand, it the present invention also provides the preparation method of above-mentioned compound of formula I, the described method comprises the following steps:
(i) formula III compound is made
III
Formula II compound is obtained by substitution reaction；
With
(ii) make Formula II compound react to obtain compound of formula I with Potassium Selenocyanate.
In the preparation process in accordance with the present invention, preferably react Formula II compound with Potassium Selenocyanate in step (ii)
To compound of formula I.
In an especially preferred embodiment, using following methods preparation of compounds of formula I: first make compound III with
Bromoacetic acid DMAP catalysis under reaction obtains compound II(i.e. (S) -4- ethyl -4-(bromacetate) -1H- pyrans simultaneously [3', 4':
6,7] indolizine simultaneously [1,2-b] quinoline -3,14- (4H, 12H)-diketone), then react Formula II compound with Potassium Selenocyanate
To compound I.
Wherein, the molar ratio of formula III compound and bromoacetic acid is 1:3~1:6, and the molar ratio of DMAP and camptothecine is 1:2
~1:6, reaction temperature are -10oC~0 oC, reaction time are 4 hours；Molar ratio 1:1~1 of compound of formula I and Potassium Selenocyanate:
2, reaction temperature 0 oC~40 oC, reaction time are 16~24 hours.
Reaction equation is as follows:
Preparation method of the invention is simple, yield is high, and compound of formula I can easily be made.
In another aspect of the invention, providing can with optional comprising formula Compound I or its officinal salt
The pharmaceutical composition of pharmaceutical excipient and/or carrier.In pharmaceutical composition of the invention, in addition to compound of formula I of the invention
Or outside its officinal salt, other drugs active constituent can also be additionally comprised.Pharmaceutical composition of the invention can pass through routine
Technology preparation, for example, in Remington:The Science and Practice of Pharmacy, the 19th edition, in 1995
Described method, is incorporated herein by reference.The composition can occur with conventionally form, such as capsule, tablet, gas
Mist agent, solution, suspension 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 the dosage of daily about 0.05 to about 5000 mg, preferably from about 1 to about 2000 mg, more preferably from about 2 to about 2000 mg.It is typical
Dosage be daily about 10 mg to about 1000 mg.When selecting patient treatment protocol, must usually can be opened from higher dosage
Begin, and reduces dosage when illness obtains control.Accurate dosage will depend on method of application, desired treatment, application
Form, the weight of object to be treated and object to be treated and the preference and experience of being responsible for doctor.
In general, per unit dose includes about 0.05 mg to about by the distribution of formula Compound I in unit dosage forms
1000 mg active constituents 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 1250 mg, preferably from about
The Formulas I of 250 μ g to about 500 mg, more preferably from about 2.5 mg to about 250 mg mixed with pharmaceutical acceptable carrier or diluent
Compound.
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 20mg to 1g.Single dosage unit containing compound of formula I or its
The amount of officinal salt is 20mg to 200mg, it is convenient to for meeting the needs of daily dose.The dosage and dosage unit used can
Beyond above range.
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 1 to the 15 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,
Any aspect is all not considered as limiting the scope of the invention.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of Formula II compound；
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of compound of formula I；
Fig. 3 is the carbon-13 nmr spectra figure of compound of formula I；
Fig. 4 is the mass spectrogram of compound of formula I；
Fig. 5 is the HPLC purity detecting spectrogram of the compound of formula I synthesized in embodiment 2.
Specific embodiment
Embodiment
It is synthetically prepared example
Embodiment 1: the synthesis of Formula II compound
In three-necked flask, camptothecine (200mg, 0.57mmol) is dissolved in anhydrous methylene chloride (100ml), DMAP is added
(139 mg, 1.14mmol) are added bromoacetic acid (240 mg, 1.72 mmol) under ice bath, stir 5 hours, TLC detection reaction
Completely.Reaction solution is washed twice with 1N HCl (35 ml) respectively, 1% NaHCO3Na after (35 ml) is washed twice2SO3It is dry.It steams
Solid is dissolved by heating after dry solvent with EtOAc, places crystallization.Light tan solid, compound II (191 mg, yield is obtained by filtration
71%)。
Nuclear magnetic resonance:1H NMR (CDCl3) δ(ppm): 1.06 (s, 3H, -CH3), 2.06-2.36 (m, 2H,
-CH2- ), 3.97 (s, 2H, -CH2-), 5.34 (s, 2H, -CH2-), 5.4-5.7 (dd, 2H, -CH2-),
7.27 (s, 1H, Ar-H), 7.6-7.7 (t, 1H, Ar-H), 7.86-7.9 (t, 1H, Ar-H), 7.97-7.99
(d, 1H, Ar-H), 8.24-8.28 (d, 1H, Ar-H), 8.65 (s, 1H, Ar-H)
Embodiment 2: the synthesis of compound of formula I
In three hole flasks, compound II (180 mg, 0.38mmol) is dissolved in acetonitrile (20 ml), Potassium Selenocyanate is added
(55 mg, 0.38mmol) are stirred at room temperature 16 hours.It is instilled in 100 ml 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 (95 mg, yield 51%).
Nuclear magnetic resonance:1H NMR (CDCl3) δ(ppm): 1.02 (s, 3H, -CH3), 2.16-2.38 (m, 2H,
-CH2- ), 3.97 (s, 2H, -CH2-), 5.26 (s, 2H, -CH2-), 5.3-5.7 (dd, 2H, -CH2-),
7.27 (s, 1H, Ar-H), 7.6-7.7 (t, 1H, Ar-H), 7.82-7.86 (t, 1H, Ar-H), 7.93-7.95
(d, 1H, Ar-H), 8.22-8.24 (d, 1H, Ar-H), 8.41 (s, 1H, Ar-H).
13C NMR (CDCl3) δ(ppm): 7.59, 27.12, 31.75, 50.07, 67.23, 78.00, 95.57,
99.95, 120.21, 128.18, 128.22, 128.43, 129.72, 130.78, 131.26, 144.79,
146.72, 148.92, 152.15, 157.27, 166.50, 166.69
MS [ESI]: C23H17N3O5Se [M+H]+ = 495.03
HPLC: purity 93.15%
Pharmacological activity
Experimental example 1: anti tumor activity in vitro screens (preliminary inhibiting rate experiment)
Positive control drug: alkyl camptothecine injection (HCPT), 5ml:5mg/ branch, Medisan Pharmaceutical Co., Ltd. Harbin,
Lot number: 170501.Test cell strain selects the low differentiation gastric adenocarcinoma cells BGC-823 of people, human liver cancer cells Hep G2, people's lung
Tetra- kinds of cell strains of cancer cell A549 and human promyelocytic leukemia HL-60.
Test method: taking in exponential phase of growth in good condition one bottle of cell, 0.25% tryptic digestive juice be added,
Digestion makes attached cell fall off, and counts 2 ~ 4 × 104A/ml, is made cell suspension.Take cell suspension inoculation on 96 orifice plates,
180 holes μ l/, set constant temperature CO2It is cultivated 24 hours in incubator.Liquid is changed, test medicine is added, 20 holes μ l/ are cultivated 48 hours.It will
MTT is added in 96 orifice plates, 20 holes μ l/, reacts 4 hours in incubator.Supernatant is sucked, DMSO, plate is added by 150 holes μ l/
It is shaken 5 minutes on shaking table.Tested material investigates three concentration (1 × 10-7, 1 × 10-6, 1×10-5；Mol/L), with microplate reader in wave
The light absorption value that every hole is measured at a length of 570nm, calculates separately the cell inhibitory rate under each concentration.
Cell inhibitory rate %=(negative control group OD value-susceptibility group OD value)/negative control group OD value × 100%
Table 1
Test result shows that compound I has In-vitro Inhibitory Effect to four kinds of tumor cell lines, to BGC-823, SMMC-7721
It is better than control drug 10- Hydroxycamptothecin (HCPT) with the action intensity of A549 cell line, especially to SMMC-7721's and A549
Inhibiting effect is substantially better than HCPT, wherein to the IC of SMMC-772150Value is only 0.06 μM.
Experimental example 2: internal anti-tumor activity
Experimental animal selects SPF grades of male mice in kunming, and weight 19-22 g is mentioned by Wuhan University's animal experimental center
For tumor strain mouse S 180 sarcoma is introduced by institute of Materia Medica,Chinese Academy of Medical Sciences, real in laboratory cryopreservation conservation
It tests after being recovery with S180 cell and passes on the cell suspension in the 4th generation, positive control medicine selects topological former times health.
The foundation of bearing mouse model uses aseptic aspiration mice bearing S180 ascites, and cell suspension is set and is counted under microscope
Number, adjustment cell concentration are 2.0 × 107/ mL, in the above-mentioned S180 ascitic tumor fluid 0.2 of the subcutaneous aseptic inoculation of right side of mice armpit
ML/ only, healthy mice 20, is grouped at random according to weight.
The calculating of medication and tumour inhibiting rate: the 2nd day after mouse inoculation tumour cell starts to be administered, and divides at random by weight
For high, medium and low each 3 dosage groups of compound I, positive controls (topological 1.5 mg/kg of former times health) and negative control group, daily
Intraperitoneal administration 1 time, only, the experimental administration time is 9 days to 0.5 mL/ of administered volume, and 24 h put to death animal after the last administration, is claimed
Weight is measured, and dissects tumor mass and weighs quality, calculates inhibition rate of tumor growth according to the following formula.
Inhibiting effect of the 2 compound I of table to mouse S180
Results of animal shows that compound I has the function of mice bearing S180 to inhibit tumour growth, and the tumor suppression is made
With significant, and under same dose, (5mg/kg) antitumor action is better than control compound Hycamtin.Therefore, compound 1
Show Tumor growth inhibition efficiency more higher than Hycamtin.
Claims (6)
1. Formulas I compound represented:
Or its officinal salt.
2. the method for preparing compound described in claim 1, comprising the following steps:
(i) formula III compound is made
Formula II compound is obtained by substitution reaction
；With
(ii) make Formula II compound react to obtain compound of formula I with Potassium Selenocyanate.
3. according to the method described in claim 2, wherein formula III compound is made to react to obtain formula with bromoacetic acid in step (i)
II compound.
4. a kind of pharmaceutical composition, it includes compound of formula I as described in claim 1 or its officinal salts, and optional
Pharmaceutically acceptable excipient and/or carrier.
5. compound of formula I according to claim 1 or its officinal salt are preparing the drug for treating or preventing tumour
In purposes.
6. purposes according to claim 5, wherein the tumour be selected from colon cancer, breast cancer, prostate cancer, cervical carcinoma,
Liver cancer and lung cancer.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| 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 |
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| WO2012066578A2 (en) * | 2010-11-18 | 2012-05-24 | Kasina Laila Innova Pharmaceuticals Private Limited | Substituted 4-(selenophen-2(or 3)-ylamino)pyrimidine compounds and methods of use thereof |
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| WO2012066578A2 (en) * | 2010-11-18 | 2012-05-24 | Kasina Laila Innova Pharmaceuticals Private Limited | Substituted 4-(selenophen-2(or 3)-ylamino)pyrimidine compounds and methods of use thereof |
| CN106620717A (en) * | 2016-12-13 | 2017-05-10 | 上海交通大学 | Amphipathic conjugate anti-tumor nano-drug with function of reversing multidrug resistance of tumors and preparation method and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
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