CN106977472A - Benzisoelenazolone modifies nitrosourea compound synthesis and its application - Google Patents
Benzisoelenazolone modifies nitrosourea compound synthesis and its application Download PDFInfo
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- CN106977472A CN106977472A CN201610030546.0A CN201610030546A CN106977472A CN 106977472 A CN106977472 A CN 106977472A CN 201610030546 A CN201610030546 A CN 201610030546A CN 106977472 A CN106977472 A CN 106977472A
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- chloroethyl
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- benzisoxas
- nitroso ureas
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- 0 *c(ccc(Cl)c1)c1SSc(cc(cc1)Cl)c1C(O)=O Chemical compound *c(ccc(Cl)c1)c1SSc(cc(cc1)Cl)c1C(O)=O 0.000 description 5
- HJLACUXEFDENME-UHFFFAOYSA-N O=C(c(c(SCl)c1)ccc1Cl)Cl Chemical compound O=C(c(c(SCl)c1)ccc1Cl)Cl HJLACUXEFDENME-UHFFFAOYSA-N 0.000 description 1
- PYYZYFNQNTUJAY-UHFFFAOYSA-N O=C(c1cc(F)ccc1SCl)Cl Chemical compound O=C(c1cc(F)ccc1SCl)Cl PYYZYFNQNTUJAY-UHFFFAOYSA-N 0.000 description 1
- HDNJJFBIIZAUQH-UHFFFAOYSA-N O=C(c1ccccc1SCl)Cl Chemical compound O=C(c1ccccc1SCl)Cl HDNJJFBIIZAUQH-UHFFFAOYSA-N 0.000 description 1
- NVPJTHQRGCOMHH-UHFFFAOYSA-N OC(c(cc(cc1)F)c1SSc(ccc(F)c1)c1C(O)=O)=O Chemical compound OC(c(cc(cc1)F)c1SSc(ccc(F)c1)c1C(O)=O)=O NVPJTHQRGCOMHH-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D293/00—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms
- C07D293/10—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D293/12—Selenazoles; Hydrogenated selenazoles
Abstract
The present invention relates to Benzisoelenazolone modification nitrosourea compound and its application.The Benzisoelenazolone of the present invention modifies nitrosourea compound as shown in formula I.The Benzisoelenazolone modification nitrosourea compound of the present invention has excellent antitumor activity, can be widely used for preparing antineoplastic.
Description
Technical field
The present invention relates to a kind of nitrosourea compounds process for production thereof of Benzisoelenazolone modification and application, belong to chemical field
Background technology
Nitroso ureas series antineoplastic medicament is a kind of quite varied alkylating agent of application, the clinical treatment applied to diseases such as brain tumor, leukaemia, malignant lymphoma, gliomas.
Nitroso ureas series antineoplastic medicament largely belongs to difunctional alkylating agent.Its mechanism of action is：Nitrosourea is decomposed rapidly in aqueous, produces azo hydroxide intermediate.This intermediate can be further broken into carbonium ion.Because the macromoleculars such as DNA belong to electron rich molecules, it can be combined with carbonium ion, such as the O in guanine6Position or N7Position forms alkanisation damage, or even further reacts the covalent cross-linked thing formed between complementary base pair.These crosslinked actions can produce damage to DNA duplication, finally cause Apoptosis.
By taking methyl-nitroso-urea as an example, nitrosourea and DNA mechanism of action are as follows：
BCNU is a kind of alkylating agent, is the representative medicine in nitroso ureas series antineoplastic medicament.Due to have the advantages that molecular weight it is small, it is fat-soluble it is good, can be high through blood-brain barrier, blood plasma Percentage bound, be widely used in clinic.It is all proved to play the role of anti-central nerve neuroma in mouse experiment and clinical research, is the choice drug for treating glioblastoma.In addition, it is also used for the treatment of the diseases such as Huppert's disease, malignant mela noma.
BCNU is bifunctional alkylating agents.It can be decomposed rapidly in water, generation chloroethyl diazohydroxide (Cl-CH2-CH2- N=N-OH) and chloroethyl isocyanates (O=C=N-CH2-CH2-Cl).The former can crosslink effect with DNA, and isocyanates can be protein carbamylation i.In addition, BCNU also has inhibitory action to TrxR, TrxR can also turn into the target spot of its effect, and it has Irreversible inhibition to TrxR.
BCNU has very strong CDCC.When standard metering is administered, its restricted toxicity is to produce delayed toxicity to hemopoietic system.And during long term administration, possible fatal pulmonary fibrosis can be caused.In heavy dose administration, the restricted toxicity of BCNU is hepatotoxicity wind agitation and pulmonary toxicity, and venous embolism disease occurs in the patient for having 5%~20%.
Benzisoelenazolone representation compound Ethaselen is targeting thioredoxin reductase, the organic selenium compounds for antitumor action, clinical research is carried out now, the clinical I phases show that Ethaselen toxicity is low, compared with Carmustine toxicity is showed, preferable tolerance is shown.Early-stage Study shows, Benzisoelenazolone structure initiative recognition target enzyme activated centre and can embody targeting to tumour and linked groups as the main pharmacodynamics group of the medicine.The internal metabolism studies have shown that Ethaselen of medicine is far above Plasma in the concentration of tumor tissues, shows good tumor-targeting.
This patent innovative point passes through in nitrous urea structure N Benzisoelenazolone structure is introduced on atom, obtains that a class is new, nitrosourea compound with Benzisoelenazolone structureAccording to Benzisoelenazolone medicine (Ethaselen) feature, such compound can target thioredoxin reductase, and with tumor-targeting, and thioredoxin reductase activity is the key factor of tumour growth, therefore such compound will have Mutiple Targets feature, while the class formation improves the targeting of medicine relative to nitrous urea structure, therefore can reach the effect of Synergy and attenuation.
This research employs the brand-new structure type of the Nitrosourea with Benzisoelenazolone structure, and its meaning is as follows
1
, this series compound remain the active pharmacophore of Ethaselen and BCNU.Research shows that Benzisoelenazolone is the active pharmacophore in Ethaselen, can be with initiative recognition
TrxR
In avtive spot and in combination, so as to play pair
TrxR
Inhibitory action.Therefore, we remain the Benzisoelenazolone structure in Ethaselen.One of decomposition fragment of BCNU --- chloroethyl diazohydroxide is to play
DNA
The group of crosslinked action.
2
, as a kind of prodrug forms, this series compound is decomposed effect in water, produces two molecule fragments.Benzisoelenazolone structure and isocyanates structure in the former can cooperate with generation
TrxR
Inhibitory activity.Another fragment can be with
DNA
Produce crosslinked action.The two pharmacophores can produce anti-tumor synergetic effect, so as to improve antitumor activity.
3
, there is preferable tumor-targeting due to Benzisoelenazolone structure, therefore targeting drug effect can be produced, and after being combined with nitrosourea structure so that the molecule of new range has high targeting, while further reducing toxicity of compound.
4
, carry out due to Nitrosourea compound and have preferable water-soluble, and with after Benzisoelenazolone structure split, changing symmetry molecular structure in Ethaselen, improve compound dissolubility, enhance druggability.
Such compound activity test is shown inBenzisoelenazoloneThe compounds that part C-5 and C-6 are substituted by F, simultaneouslyBenzisoelenazoloneLinking arm more short better (n=2) between part and Nitrosourea part can obtain more obvious antitumor activity.Wherein, 3- [2- (5- fluoro- 1,2- benzisoxas selenazoles -3 (2H) -one) ethyl] -1- chloroethyl -1- nitroso ureas and 3- [2- (6- fluoro- 1,2- benzisoxas selenazoles -3 (2H) -one) ethyl] -1- chloroethyl -1- nitroso ureas is in LoVo, RKO, there is preferable antitumor activity in MIA PaCa-2, PANC-1 cell lines, with antitumor action meaning.And introduceBenzisoelenazoloneAfterwards, compound target tropism gets a promotion, and is conducive to the realization of attenuation synergistic target.Therefore, the application has carried out special application to such compound.Because as newNitrosourea with Benzisoelenazolone structureStructure medicament solubility has compared with Ethaselen largely to be lifted, and targeting has larger lifting compared with Carmustine, Synergy and attenuation effect is served, while adding druggability.AndBenzisoelenazolone structure and nitrosoureaStructure can play a part of Synergistic in pharmacological action, therefore this kind of compound shows external good antitumor activity, its IC50Value is also below Carmustine or suitable therewith.
The content of the invention
A kind of Benzisoelenazolone modification nitrosourea compound is provided it is an object of the invention to theoretical based on more than, and its antitumor activity is determined by experiment.
The present invention is achieved through the following technical solutions：
The compound of following structure,
N is the number of carbon between linking arm
Formula I
Wherein, R1、R2、R3、R4Respectively H, C1-4Alkyl group, C1-4Chain alkoxy group, C1-4Acyloxy group, NO2, OH or halogen substitution.
N is that the number of carbon between linking arm is 2-4.
2nd, compound according to claim 1, it is characterised in that the C1-4Alkyl group be methyl, ethyl or propyl group；C1-4Chain alkoxy group be methoxyl group, ethyoxyl or propoxyl group.
3rd, compound according to claim 1, it is characterised in that the halogen is F, Cl, Br.
4th, compound according to claim 1, it is characterised in that R1, R2, R3, R4 are H, Me, OCH3, F, Cl, Br
5th, the compound according to claim 1, it is characterised in that n is that the carbon number between linking arm is 2-4.
6th, application of the compound in antineoplastic is prepared any one of claim 1-5.
In a preferred embodiment of the invention, described pharmaceutical composition is applied to enteral (for example orally or rectally), part or parenteral, for example, orally, injection, implantation, external application, spraying, suction etc..
In a preferred embodiment of the invention, the combination of oral medication is selected from tablet (ordinary tablet, lozenge, sublingual tablet, mouth paster, chewable tablets, dispersible tablet, fuse, effervescent tablet, vaginal tablets or vagina effervescence, sustained release tablets, controlled release tablet, enteric coatel tablets, oral dosage form etc.), capsule (hard shell capsules, soft capsule, spansule, controlled release capsule, capsulae enterosolubilis etc.), pill (dripping pill, sugar-pill, piller), oral liquid (syrup, supensoid agent, oral solution, oral suspensions, Orally taken emulsion, syrup, mixture, distillate medicinal water or medicinal tea), granule (mix suspension grain, effervescence granular, enteric coated particles, slow-releasing granules, controlled release granule etc.), powder it is any.
In a preferred embodiment of the invention, the injection include parenteral solution, injection sterile powder or sterile block (including being prepared using techniques such as solvent crystallization, spray drying process or freeze-dryings), transfusion, concentrated solution for injection it is any.
In a preferred embodiment of the invention, the external preparation be selected from suppository, aerosol, powder spray, spray, film, gel, patch, jelly, emplastrum, plaster, ointment, liniment, lotion, liniment, solidifying paste it is any.
In a preferred embodiment of the invention, the present composition can be prepared using preparation technique means well known in the art.
In a preferred embodiment of the invention, described pharmaceutical composition is selected from inclusion preparation or pharmaceutical dispersions.
In a preferred embodiment of the invention, described pharmaceutically acceptable carrier is well known in the art usual excipients or auxiliary material for preparing above-mentioned preparation, wherein, oral formulations or the conventional excipient of external preparation or auxiliary material include but are not limited to filler or diluent, lubricant or glidant or antitack agent, dispersant, wetting agent, adhesive, conditioning agent, solubilizer, antioxidant, bacteriostatic agent, emulsifying agent etc..Adhesive, such as syrup, Arabic gum, gelatin, sorbierite, tragacanth, cellulose and its derivates, gelatine size, syrup, starch slurry or polyvinylpyrrolidone, cellulose derivative preferably is microcrystalline cellulose, sodium carboxymethylcellulose, ethyl cellulose, HPMC；Filler, such as lactose, Icing Sugar, dextrin, starch and its derivative, cellulose and its derivates, inorganic calcium salt, sorbierite or glycine, preferably inorganic calcium salt are calcium sulfate, calcium phosphate, calcium monohydrogen phosphate, precipitated calcium carbonate；Lubricant, such as superfine silica gel powder, magnesium stearate, talcum powder, aluminium hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol；Disintegrant, such as starch and its derivative, polyvinylpyrrolidone or microcrystalline cellulose, starch derivatives preferably is sodium carboxymethyl starch, Explotab, pregelatinized starch, modified starch, hydroxypropul starch, cornstarch；Wetting agent, such as lauryl sodium sulfate, water or alcohol, preferably pharmaceutically acceptable carrier is cyclodextrin (alpha-cyclodextrin, beta-schardinger dextrin or gamma-cyclodextrin), Celldone 102 CG, Polyplasdone XL-10, talcum powder, magnesium stearate or ethanol etc..
In a preferred embodiment of the invention, the conventional excipient of the injection or auxiliary material are included but are not limited to：Antioxidant, such as sodium thiosulfate, sodium sulfite, sodium hydrogensulfite, dibutyl benzoic acid or sodium pyrosulfite；Bacteriostatic agent, such as 0.5% phenol, 0.3% cresols, 0.5% anesin；PH adjusting agent, such as hydrochloric acid, citric acid, potassium hydroxide (sodium), sodium citrate and buffer phosphoric acid dioxy sodium and disodium hydrogen phosphate；Emulsifying agent, such as Tween-80, do not have that sour sorb is smooth, pluronic gram F-68, lecithin, Fabaceous Lecithin；Solubilizer, such as Tween-80, glycerine.
In a preferred embodiment of the invention, also with pharmaceutically acceptable slow controlled release carrier by it can be prepared by active component into requirement to be mixed, according still further to the preparation method of sustained-release preparation well known in the art, retarding agent is such as added to be coated or micropill, such as sustained release pellet or controlled release micro pill will be made after active principle microcapsules again；Described slow controlled release carrier includes but are not limited to oily cured property dopant, hydrophilic colloid or is coated retarding agent etc., and described oil dopant is glycerin monostearate, rilanit special, Dormant oils, polysiloxanes, dimethyl siloxane；Described hydrophilic colloid is the cellulose derivative such as sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, or PVP, Arabic gum, tragcanth or carbopol etc.；Described coating retarding agent is ethyl cellulose (EC), HPMC (HMPC), polyvinylpyrrolidone (PVP), cellulose acetate-phthalate (CAP), acrylic resin etc..
In a preferred embodiment of the invention, according to required administering mode, compound 1-18 of the pharmaceutically acceptable composition comprising about 1-99 weight % or its pharmaceutically acceptable salt any or its combination, and the suitable pharmaceutical excipients of 1-99 weight %.
In a preferred embodiment of the invention, the compound 1-18 comprising about 5-75 weight % or its pharmaceutically acceptable salt any or its combination in described pharmaceutical composition, surplus is pharmaceutical excipient.
Another aspect of the present invention be to provide compound 1-18 or its pharmaceutically acceptable salt or its pharmaceutical composition are used to prepare the application in anti-tumor drug.
In a preferred embodiment of the invention, the antitumor action refers to be used to prevent or treat abnormal cell growth, the abnormal cell growth can show as tumour, the tumour is selected from brain tumor, lung cancer, liver cancer, leukemia, osteocarcinoma, cancer of pancreas, cutaneum carcinoma, melanoma, uterine cancer, oophoroma, the carcinoma of the rectum, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of fallopian tube, carcinoma of endometrium, cervix cancer, carcinoma of vagina, carcinoma of vulva, cancer of the esophagus, carcinoma of small intestine, internal system cancer, soft tissue sarcoma, carcinoma of urethra, prostate cancer, lymphocytoma, carcinoma of urinary bladder, kidney, carcinoma of ureter, Vertebral Neoplasmss, brain stem glioma, pituitary adenoma, lung cancer, liver cancer, leukemia it is any.
In a preferred embodiment of the invention, dosage of the Benzisoelenazolone modification nitrosourea compound of the present invention when treating tumour is about 0.05-250mg/Kg body weight, preferably 0.5-200mg/Kg body weight, more preferably 2-125mg/Kg body weight, most more preferably 5-85mg/Kg body weight.
The compound is
3-【2- (1,2- benzisoxa selenazoles -3 (2H) -one) ethyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (1,2- benzisoxa selenazoles -3 (2H) -one) propyl group】- 1- chloroethyl -1- nitroso ureas
3-【2- (1,2- benzisoxa selenazoles -3 (2H) -one) butyl】- 1- chloroethyl urea -1- nitroso ureas
3-【2- (fluoro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) ethyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (fluoro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) propyl group】- 1- chloroethyl -1- nitroso ureas
3-【2- (fluoro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) butyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (fluoro- 1,2- benzisoxas selenazoles -3 (2H) -one of 6-) ethyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (chloro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) ethyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (chloro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) propyl group】- 1- chloroethyl -1- nitroso ureas
3-【2- (chloro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) butyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (chloro- 1,2- benzisoxas selenazoles -3 (2H) -one of 6-) ethyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (5- methyl isophthalic acids, 2- benzisoxas selenazoles -3 (2H) -one) ethyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (5- methyl isophthalic acids, 2- benzisoxas selenazoles -3 (2H) -one) propyl group】- 1- chloroethyl -1- nitroso ureas
3-【2- (5- methyl isophthalic acids, 2- benzisoxas selenazoles -3 (2H) -one) butyl】- 1- chloroethyl -1- nitroso ureas
3-【2- ((2H) -one of 5- methoxyl group -1,2- benzisoxas selenazoles -3) ethyl】- 1- chloroethyl -1- nitroso ureas
3-【2- ((2H) -one of 5- methoxyl group -1,2- benzisoxas selenazoles -3) propyl group】- 1- chloroethyl -1- nitroso ureas
3-【2- ((2H) -one of 5- methoxyl group -1,2- benzisoxas selenazoles -3) butyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (bromo- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) ethyl】- 1- chloroethyl -1- nitroso ureas
A further object of the present invention is a kind of method for preparing compound described above of offer, specifically includes following steps：
(1) prepare compound 1
Compound 1
Make in the presence of natrium nitrosumReacted with hydrochloric acid under ice bath, obtain diazol, gained diazol is set to keep reactant mixture in alkalescence with sodium diselenide reaction, the acidifying of gained mixture hydrochloric acid is obtained into solid, then gained solid is made to be flowed back in thionyl chloride and DMF, revolving removes thionyl chloride and obtains residue, residue obtained use petroleum ether extraction, cooling separates out crystal, as compound 1.
(2) compound 1 is dissolved in ether, dropwise addition N-BOC-1,2- ethylenediamines, stirring reaction, there is solid precipitation at room temperature.Suction filtration obtains intermediate.
(3) intermediate obtained in step (2) is added into dichloromethane, trifluoroacetic acid is added dropwise, at room temperature stirring reaction.Use saturation NaHCO3PH to 7-8 is adjusted, layer of fetching water.Concentration, dichloromethane extraction (a small amount of multiple).Dry, concentration is added dropwise chloroethyl isocyanate, there is Precipitation.Suction filtration obtains intermediate.
(4) intermediate obtained in step (3) is dissolved in 2ml anhydrous formic acids, is added at 0 DEG C at NaNO2 (mol ratio 1: 4), 0 DEG C and react 40min, plus have solid precipitation after suitable quantity of water, suction filtration, obtains white powdery solids, i.e. compound of Formula I
Embodiment
With reference to embodiment, the invention will be further described, it should be understood that these embodiments are only used for the purpose of illustration, are never limited in protection scope of the present invention.
The following is the synthetic route of the compounds of this invention：
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
Illustrate preparation and the antitumor activity of compound of Formula I by taking 28 kinds of compounds as an example below.
This 28 kinds of compounds are as shown in table 1.
Table 1
----------------------------
The preparation of the double benzoic acid of the selenizing of embodiment 12,2 '-two
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
(1) sodium hydroxide 16g, sodium hydrosulfite 18g, selenium powder 16g, are sequentially added in water, are warming up to 50 DEG C, and reaction, which is finished, obtains double selenizing sodium solutions.
(2) under condition of ice bath, ortho-aminobenzoic acid 28g adds 1: 1 hydrochloric acid 80ml stirring mixing, and the natrium nitrosum 18.0g aqueous solution is slowly instilled wherein, chlorination 2- benzoic acid diazols are obtained.
(3) solution for the chlorination 2- benzoic acid diazols for obtaining step 1 under ice-water bath stirring is added drop-wise in double selenizing sodium solutions that step 2 is obtained, and mixture continues to stir.PH test paper proves solution alkaline.Diatomite is filtered, and adjusts pH to 3, and filtering, filter cake is washed with water, and dries, obtains yellow-brown solid.
1H NMR (400MHz, DMSO-d6)：δ δ 7.34 (t, 2H), 7.46 (t, 2H), 7.67 (d, 2H), 8.02 (d, 2H), 13.69 (s, br, 2H)
The preparation of the 2- selenium chlorobenzoyl chlorides of embodiment 2
The double benzoic acid 40g of 2,2 '-two selenizings, thionyl chloride 200ml and DMF are stirred at reflux for few drops, and reaction finishes revolving and removes unnecessary thionyl chloride, and residue is recrystallized with petroleum ether, obtains yellow needles.
1H NMR (400MHz, CDCl3)：(d, J=7.7Hz, 1H, the Ar-H) of δ δ 7.39 (t, J=7.7Hz, 1H, Ar-H), 7.67 (t, J=7.7Hz, 1H, Ar-H), 7.85 (d, J=7.7Hz, 1H, Ar-H), 8.09
Embodiment 35,5 '-two fluoro- 2, the preparation of the double benzoic acid of 2 '-two selenizings
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
The compound is obtained in the same manner as example 1.
1H NMR (400MHz, DMSO-d6)：δ δ 7.23 (m, 2H), 7.40 (dd, 2H), 8.11 (m, 2H), 13.93 (s, br, 2H)
The preparation of the chloro- 5- fluorobenzoyl chlorides of the 2- selenium of embodiment 4
The compound is obtained in the same way as in example 2.
1H NMR (400MHz, CDCl3)：(dd, J=9.0,2.7Hz, 1H, the Ar-H) of δ δ 7.42 (td, J=8.3,2.7Hz, 1H, Ar-H), 7.65 (dd, J=8.3,5.4Hz, 1H, Ar-H), 7.78
Embodiment 55,5 '-two chloro- 2, the preparation of the double benzoic acid of 2 '-two selenizings
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
The compound is obtained in the same manner as example 1.
1H NMR (400MHz, DMSO-d6) d 14.12 (br, 2H, COOH), 8.00 (d, J=2.2,2H, ArH), 7.64 (d, J=8.6,2H, ArH), 7.60 (dd, J1=8.6, J2=2.2,2H, ArH)
The preparation of the chloro- 5- chlorobenzoyl chlorides of the 2- selenium of embodiment 6
The compound is obtained in the same way as in example 2.
1(dd, J1=8.6, J2=2.2,1H, the ArH) of H NMR (400MHz, CDCl3) d 8.12 (d, J=8.6,1H, ArH), 7.69 (d, J=2.2,1H, ArH), 7.65
Embodiment 75,5 '-dimethyl -2, the preparation of the double benzoic acid of 2 '-two selenizings
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
The compound is obtained in the same manner as example 1.
1H NMR (400MHz, DMSO-d6)：δ δ 2.30 (s, 3H), 7.43 (m, 2H), 7.66 (m, 2H), 7.79 (dd, 2H), 13.50 (s, br, 2H)
The preparation of the chloro- 5- methyl benzoyl chlorides of the 2- selenium of embodiment 8
The compound is obtained in the same way as in example 2.
1H NMR (400MHz, CDCl3)：δ δ 2.37 (s, 3H, CH3), 7.48 (d, J=8.2Hz, 1H, Ar-H), 7.65 (s, 1H, Ar-H), 7.96 (d, J=8.2Hz, 1H, Ar-H)
Embodiment 95,5 '-dimethoxy -2, the preparation of the double benzoic acid of 2 '-two selenizings
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
The compound is obtained in the same manner as example 1.
1H NMR (400MHz, DMSO-d6)：δ δ 2.30 (s, 3H), 7.43 (m, 2H), 7.66 (m, 2H), 7.79 (dd, 2H), 13.50 (s, br, 2H)
The preparation of the 2- selenium chloro-5-methoxyl chlorobenzoyl chlorides of embodiment 10
The compound is obtained in the same way as in example 2.
1H NMR (400MHz, CDCl3)：(d, J=8.8Hz, 1H, the Ar-H) of δ 3.80 (s, 3H, OCH3), 7.33 (dd, J=8.8,2.7Hz, 1H, Ar-H), 7.39 (d, J=2.7Hz, 1H, Ar-H), 7.90
The preparation of the double benzoic acid of embodiment 11 5,5 '-bromo- 2,2 '-two selenizing
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
The compound is obtained in the same manner as example 1.
1H NMR (400MHz, DMSO-d6) d 14.06 (br, 2H, COOH), 8.10 (d, J=2.3,2H, ArH), 7.69 (dd, J1=8.6, J2=2.3,2H, ArH), 7.55 (d, J=8.6,2H, ArH)
The preparation of the chloro- 5- bromo-benzoyl chlorides of the 2- selenium of embodiment 12
The compound is obtained in the same way as in example 2.
1H NMR (400MHz, CDCl3) d 8.14 (d, J=2.2,1H, ArH), 7.65 (dd, J1=8.6, J2=2.2,1H, ArH), 7.49 (d, J=8.6,1H, ArH)
Embodiment 13 4,4 '-two fluoro- 2, the preparation of the double benzoic acid of 2 '-two selenizings
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
The compound is obtained in the same manner as example 1.
1H NMR (400MHz, DMSO-d6)：δ δ 7.23 (m, 2H), 7.40 (dd, 2H), 8.11 (m, 2H), 13.93 (s, br, 2H)
The preparation of the chloro- 4- fluorobenzoyl chlorides of the 2- selenium of embodiment 14
The compound is obtained in the same way as in example 2.
1H NMR (400MHz, CDCl3)：(dd, J=9.9,2.3Hz, 1H, the Ar-H) of δ δ 7.19 (td, J=8.4,2.3Hz, 1H, Ar-H), 7.80 (dd, J=8.4,5.7Hz, 1H, Ar-H), 7.86
Embodiment 15 4,4 '-two chloro- 2, the preparation of the double benzoic acid of 2 '-two selenizings
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
The compound is obtained in the same manner as example 1.
1H NMR (400MHz, DMSO-d6) d 14.08 (br, 2H, COOH), 8.03 (d, J=8.3,2H, ArH), 7.60 (d, J=1.7,2H, ArH), 7.44 (dd, J1=8.3, J2=1.7,2H, ArH)
The preparation of the chloro- 4- chlorobenzoyl chlorides of the 2- selenium of embodiment 16
The compound is obtained in the same way as in example 2.
1H NMR (400MHz, CDCl3) d 8.13 (d, J=1.8,1H, ArH), 7.74 (d, J=8.1,1H, ArH), 7.40 (dd, J1=8.1, J2=1.8,1H, ArH)
The 3- of embodiment 17 [2- (1,2- benzisoxa selenazoles -3 (2H) -one) ethyl] -1- chloroethyl -1- nitroso ureas
(1) 2- selenium chlorobenzoyl chlorides are dissolved in ether, dropwise addition N-BOC-1,2- ethylenediamines, stirring reaction, there is solid precipitation at room temperature.Suction filtration obtains intermediate.
(2) intermediate obtained in step (1) is added into dichloromethane, trifluoroacetic acid is added dropwise, at room temperature stirring reaction.Use saturation NaHCO3PH to 7-8 is adjusted, layer of fetching water.Concentration, dichloromethane extraction (a small amount of multiple).Dry, concentration is added dropwise chloroethyl isocyanate, there is Precipitation.Suction filtration obtains intermediate.
(3) intermediate obtained in step (2) is dissolved in 2ml anhydrous formic acids, NaNO is added at 0 DEG C2(mol ratio 1: 4), reacting after 40min, plus suitable quantity of water at 0 DEG C has solid precipitation, and suction filtration obtains white powdery solids, i.e. compound of Formula I
1H NMR (400MHz, DMSO) d 8.87 (t, J=5.6Hz, 1H), 8.01 (d, J=8.0Hz, 1H), 7.77 (d, J=7.0Hz, 1H), 7.66-7.52 (m, 1H), 7.41 (t, J=7.1Hz, 1H), 4.04 (t, J=5.7Hz, 2H), 3.76 (t, J=5.6Hz, 2H), 3.66-3.42 (m, 4H)
MS(EI)m/z：376.0(M+).
The 3- of embodiment 18 [2- (1,2- benzisoxa selenazoles -3 (2H) -one) propyl group] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.92 (t, J=5.7Hz, 1H), 8.05 (d, J=8.0Hz, 1H), 7.80 (d, J=6.9Hz, 1H), 7.62 (t, J=7.6Hz, 1H), 7.42 (t, J=7.4Hz, 1H), 3.85-3.78 (m, 2H), 3.76 (t, J=6.3Hz, 2H), 3.70-3.57 (m, 3H), 2.06-1.94 (m, 1H), (1.76-1.63 m, 2H)
MS(EI)m/z：390.0(M+).
The 3- of embodiment 19 [2- (1,2- benzisoxa selenazoles -3 (2H) -one) butyl] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.91 (t, J=5.5Hz, 1H), 8.04 (d, J=8.0Hz, 1H), 7.79 (d, J=6.8Hz, 1H), 7.61 (t, J=7.6Hz, 1H), 7.42 (t, J=7.0Hz, 1H), 3.77 (dt, J=12.8,6.5Hz, 3H), 3.68 (t, J=6.9Hz, 2H), 3.61 (dd, J=12.2,6.1Hz, 2H), 2.04-1.93 (m, 1H), 1.54-1.43 (m, 2H), 1.36 (dd, J=19.7,12.8Hz, 2H)
MS(EI)m/z：404.0(M+).
The 3- of embodiment 20 [2- (fluoro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) ethyl] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.88 (t, J=5.6Hz, 1H), 8.12-7.95 (m, 1H), 7.57-7.40 (m, 2H), 4.04 (t, J=5.6Hz, 2H), 3.76 (t, J=5.6Hz, 2H), 3.63 (t, J=6.2Hz, 2H), 3.54-3.43 (m, 2H) .MS (EI) m/z：393.9(M+).
The 3- of embodiment 21 [2- (fluoro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) propyl group] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.99-8.66 (m, 1H), 8.10 (dd, J=8.6,4.6Hz, 1H), 7.61-7.28 (m, 2H), 3.81 (ddd, J=22.4,13.7,7.2Hz, 4H), 3.69-3.51 (m, 4H), 1.76-1.60 (m, 2H) .MS (EI) m/z：408.0(M+).
The 3- of embodiment 22 [2- (fluoro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) butyl] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.89 (t, J=18.7Hz, 1H), (8.17-7.98 m, 1H), 7.52 (t, J=8.9Hz, 2H), 3.91-3.51 (m, 8H), 1.53-1.29 (m, 4H) .MS (EI) m/z：422.0(M+).
The 3- of embodiment 23 [2- (fluoro- 1,2- benzisoxas selenazoles -3 (2H) -one of 6-) ethyl] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.86 (t, J=5.6Hz, 1H), 7.79 (dt, J=8.5,4.4Hz, 2H), 7.34-7.17 (m, 1H), 4.03 (t, J=5.6Hz, 2H), 3.75 (t, J=5.7Hz, 2H), 3.62 (t, J=6.3Hz, 2H), 3.53 (dd, J=12.1,6.1Hz, 2H) .MS (EI) m/z：394.0(M+).
The 3- of embodiment 24 [2- (chloro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) ethyl] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, CDCl3) d 8.01 (t, J=4.6Hz, 1H), 7.63-7.42 (m, 2H), 4.31-4.10 (m, 2H), 3.88 (dd, J=15.2,9.7Hz, 2H), 3.83-3.70 (m, 2H), 3.64 (t, J=5.6Hz, 2H) .MS (EI) m/z：409.9(M+).
The 3- of embodiment 25 [2- (chloro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) propyl group] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.92 (s, 1H), 8.18-8.00 (m, 1H), 7.80-7.59 (m, 2H), 3.90-3.70 (m, 4H), 3.62 (dt, J=12.8,6.1Hz, 4H), (2.05-1.87 m, 2H)
MS(EI)m/z：424.0(M+).
The 3- of embodiment 26 [2- (chloro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) butyl] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.89 (dd, J=21.6,16.0Hz, 1H), 8.04 (dd, J=18.4,8.6Hz, 1H), 7.79-7.53 (m, 2H), 4.08 (t, J=6.4Hz, 1H), 3.87-3.51 (m, 6H), 2.00 (dd, J=14.5,6.8Hz, 1H), 1.60-1.28 (m, 4H) .MS (EI) m/z：438.0(M+)
The 3- of embodiment 27 [2- (chloro- 1,2- benzisoxas selenazoles -3 (2H) -one of 6-) ethyl] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.12 (d, J=31.9Hz, 1H), 7.54-7.41 (m, 1H), 7.21 (s, 1H), (6.67 s, 1H), 3.68 (dd, J=34.6,28.6Hz, 4H), (3.05 t, J=5.9Hz, 2H), 2.63 (d, J=31.7Hz, 2H) .MS (EI) m/z：410.0(M+).
The 3- of embodiment 28 [2- (5- methyl isophthalic acids, 2- benzisoxas selenazoles -3 (2H) -one) ethyl] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.87 (t, J=5.4Hz, 1H), 7.89 (t, J=10.8Hz, 1H), 7.61 (d, J=19.9Hz, 1H), 7.43 (d, J=8.0Hz, 1H), 4.03 (t, J=5.6Hz, 2H), 3.74 (t, J=5.6Hz, 2H), 3.68-3.57 (m, 2H), 3.53 (dd, J=12.0,6.0Hz, 2H), 2.36 (d, J=22.8Hz, 3H) .MS (EI) m/z：390.0(M+).
The 3- of embodiment 29 [2- (5- methyl isophthalic acids, 2- benzisoxas selenazoles -3 (2H) -one) propyl group] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.91 (dd, J=19.6,14.3Hz, 1H), 7.92 (d, J=8.2Hz, 1H), 7.67-7.54 (m, 1H), 7.44 (d, J=8.3Hz, 1H), 3.92-3.69 (m, 4H), 3.69-3.50 (m, 4H), 2.36 (d, J=26.8Hz, 3H), 1.68 (dd, J=14.0,7.0Hz, 2H)
MS(EI)m/z：404.0(M+).
The 3- of embodiment 30 [2- (5- methyl isophthalic acids, 2- benzisoxas selenazoles -3 (2H) -one) butyl] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.89 (dd, J=21.3,15.6Hz, 1H), 7.90 (dd, J=16.5,8.3Hz, 1H), 7.72-7.56 (m, 1H), 7.41 (dt, J=41.3,20.7Hz, 1H), 3.75 (dt, J=28.9,14.9Hz, 4H), 3.62 (tt, J=19.3,6.4Hz, 4H), 2.36 (d, J=25.5Hz, 3H), 1.59-1.44 (m, 2H), 1.36 (dt, J=13.4,6.6Hz, 2H) .MS (EI) m/z：418.0(M+).
The 3- of embodiment 31 [2- ((2H) -one of 5- methoxyl group -1,2- benzisoxas selenazoles -3) ethyl] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.89 (dd, J=23.3,17.5Hz, 1H), 8.08 (dd, J=26.5,14.3Hz, 1H), 7.78-7.58 (m, 2H), 4.18-3.98 (m, 2H), 3.74 (dt, J=13.0,5.8Hz, 2H), 3.67-3.57 (m, 2H), 3.57-3.43 (m, 2H), 3.34 (s, 3H) .MS (EI) m/z：406.0(M+).
The 3- of embodiment 32 [2- ((2H) -one of 5- methoxyl group -1,2- benzisoxas selenazoles -3) propyl group] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.92 (t, J=5.6Hz, 1H), 7.91 (d, J=8.7Hz, 1H), 7.27 (ddd, J=11.5,7.9,3.6Hz, 2H), 3.85-3.71 (m, 6H), 3.69-3.55 (m, 4H), 2.05-1.95 (m, 1H), 1.75-1.62 (m, 2H) .MS (EI) m/z：420.0(M+).
The 3- of embodiment 33 [2- ((2H) -one of 5- methoxyl group -1,2- benzisoxas selenazoles -3) butyl] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.91 (s, 1H), 7.90 (d, J=8.6Hz, 1H), 7.37-7.19 (m, 2H), 3.93-3.71 (m, 5H), 3.70-3.55 (m, 3H), 2.33 (s, 1H), 2.05-1.94 (m, 2H), 1.47 (m, 2H), 1.39 (m, 2H) .MS (EI) m/z：434.0(M+).
The 3- of embodiment 34 [2- (bromo- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) ethyl] -1- chloroethyl -1- nitroso ureas
To obtain the compound with the identical mode of embodiment 17.
1H NMR (400MHz, DMSO) d 8.86 (s, 1H), 7.97 (d, J=8.5Hz, 1H), 7.91-7.83 (m, 1H), 7.77 (dd, J=8.6,2.1Hz, 1H), 4.05 (dd, J=10.5,5.5Hz, 2H), 3.82-3.70 (m, 2H), 3.62 (t, J=6.1Hz, 2H), 3.53 (d, J=5.8Hz, 2H) .MS (EI) m/z：453.9(M+).
The measure of the anti tumor activity in vitro of 35 18 kinds of compounds of experimental example
Using mtt assay, first by the LoVo in exponential phase, RKO, MIA PaCa-2, PANC-1 cells are inoculated in 96 orifice plates, and inoculum density is 4 × 104Individual/ml.After after cell attachment, 20 microlitres of decoctions are added per hole, it is 0 to make medicine ultimate density, 1,5,10,50, microlitre/milliliter, after acting on 48 hours, 5mg/ml MTT solution (20ul/ holes) is added, after being put into the culture of carbon dioxide incubator 3~4 hours, supernatant is carefully abandoned, after residual liquid is air-dried, DMSO, 200 microlitres/hole are added, in being shaked on shaking table 0.5~1 hour, it is to be crystallized be completely dissolved after, absorbance OD values are surveyed at ELIASA 492nm.
Inhibitory rate of cell growth=(negative control OD value-dosing group OD values)/(negative control OD value-blank group OD values) × 100%
Table 2
The experimental result of table 2 is shown, in RKO cell lines, the IC for having 16 compounds (numbering is outside 9,18)50It is worth low 30uM；In LOVO cell lines, there is the IC of 14 compounds (numbering is outside 10,11,17,18)50Value is less than 30uM；In Mia-Paca2 cell lines, there is the IC of 14 compounds (numbering is outside 9,10,11,18)50Value is less than 30uM；In PAN C-1 cell lines, there is the IC of 14 compounds (numbering is outside 9,10,17,18)50It is worth low 30uM；It can be seen that, the nitrosourea compound of this class Benzisoelenazolone modification shows good antitumor activity.
Presently preferred embodiments of the present invention is the foregoing is only, is merely illustrative for the purpose of the present invention, and it is nonrestrictive.Those skilled in the art understands, can carry out many changes to it in the spirit and scope that the claims in the present invention are limited, and changes, or even equivalent, but falls within protection scope of the present invention.
Claims (7)
1. below structure compound,
Wherein, R1、R2、R3、R4Respectively H, C1-4Alkyl group, C1-4Chain alkoxy group, C1-4Acyloxy group, NO2, OH or halogen substitution.
N is that the number of carbon between linking arm is 2-4.
2. compound according to claim 1, it is characterised in that the C1-4Alkyl group be methyl, ethyl or propyl group；C1-4Chain alkoxy group be methoxyl group, ethyoxyl or propoxyl group.
3. compound according to claim 1, it is characterised in that the halogen is F, Cl, Br.
4. compound according to claim 1, it is characterised in that R1, R2, R3, R4 are H, Me, OCH3, F, Cl, Br.
5. the compound according to claim 1, it is characterised in that n is that the carbon number between linking arm is 2-4.
6. the compound according to claim any one of 1-4, it is characterised in that the compound is
3-【2- (1,2- benzisoxa selenazoles -3 (2H) -one) ethyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (1,2- benzisoxa selenazoles -3 (2H) -one) propyl group】- 1- chloroethyl -1- nitroso ureas
3-【2- (1,2- benzisoxa selenazoles -3 (2H) -one) butyl】- 1- chloroethyl urea -1- nitroso ureas
3-【2- (fluoro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) ethyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (fluoro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) propyl group】- 1- chloroethyl -1- nitroso ureas
3-【2- (fluoro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) butyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (fluoro- 1,2- benzisoxas selenazoles -3 (2H) -one of 6-) ethyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (chloro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) ethyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (chloro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) propyl group】- 1- chloroethyl -1- nitroso ureas
3-【2- (chloro- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) butyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (chloro- 1,2- benzisoxas selenazoles -3 (2H) -one of 6-) ethyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (5- methyl isophthalic acids, 2- benzisoxas selenazoles -3 (2H) -one) ethyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (5- methyl isophthalic acids, 2- benzisoxas selenazoles -3 (2H) -one) propyl group】- 1- chloroethyl -1- nitroso ureas
3-【2- (5- methyl isophthalic acids, 2- benzisoxas selenazoles -3 (2H) -one) butyl】- 1- chloroethyl -1- nitroso ureas
3-【2- ((2H) -one of 5- methoxyl group -1,2- benzisoxas selenazoles -3) ethyl】- 1- chloroethyl -1- nitroso ureas
3-【2- ((2H) -one of 5- methoxyl group -1,2- benzisoxas selenazoles -3) propyl group】- 1- chloroethyl -1- nitroso ureas
3-【2- ((2H) -one of 5- methoxyl group -1,2- benzisoxas selenazoles -3) butyl】- 1- chloroethyl -1- nitroso ureas
3-【2- (bromo- 1,2- benzisoxas selenazoles -3 (2H) -one of 5-) ethyl】- 1- chloroethyl -1- nitroso ureas.
7. a kind of method for preparing compound any one of claim 1-5, it is characterised in that comprise the following steps：
(1) prepare compound 1
Make in the presence of natrium nitrosumReacted with hydrochloric acid under ice bath, obtain diazol, gained diazol is set to keep reactant mixture in alkalescence with sodium diselenide reaction, the acidifying of gained mixture hydrochloric acid is obtained into solid, then gained solid is made to be flowed back in thionyl chloride and DMF, revolving removes thionyl chloride and obtains residue, residue obtained use petroleum ether extraction, cooling separates out crystal, as compound 1.
(2) compound 1 is dissolved in ether, dropwise addition N-BOC-1,2- ethylenediamines, stirring reaction, there is solid precipitation at room temperature.Suction filtration obtains intermediate.
(3) intermediate obtained in step (2) is added into dichloromethane, trifluoroacetic acid is added dropwise, at room temperature stirring reaction.Use saturation NaHCO3PH to 7-8 is adjusted, layer of fetching water.Concentration, dichloromethane extraction (a small amount of multiple).Dry, concentration is added dropwise chloroethyl isocyanate, there is Precipitation.Suction filtration obtains intermediate.
(4) intermediate obtained in step (3) is dissolved in 2ml anhydrous formic acids, is added at 0 DEG C at NaNO2 (mol ratio 1: 4), 0 DEG C and react 40min, plus have solid precipitation after suitable quantity of water, suction filtration, obtains white powdery solids, i.e. compound of Formula I.
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| WO2021223780A3 (en) * | 2020-05-06 | 2021-12-30 | 上海元熙医药科技有限公司 | Use of benzisoselazole derivative for anti-coronavirus and control of interstitial lung disease (ild) related to coronavirus |
| CN113616642B (en) * | 2020-05-06 | 2023-02-28 | 上海元熙医药科技有限公司 | Use of benzisoselenazole derivatives for preparing anti-coronavirus medicines |
| CN112707917A (en) * | 2020-12-24 | 2021-04-27 | 石家庄学院 | Benzisoselenazolone dihydroartemisinin derivative and preparation method and application thereof |
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