CN106977472B - Synthesis and application of benzisoselenazolone modified nitrosourea compound - Google Patents
Synthesis and application of benzisoselenazolone modified nitrosourea compound Download PDFInfo
- Publication number
- CN106977472B CN106977472B CN201610030546.0A CN201610030546A CN106977472B CN 106977472 B CN106977472 B CN 106977472B CN 201610030546 A CN201610030546 A CN 201610030546A CN 106977472 B CN106977472 B CN 106977472B
- Authority
- CN
- China
- Prior art keywords
- nitrosourea
- chloroethyl
- benzisoselenazol
- compound
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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 invention relates to a benzisoselenazolone modified nitrosourea compound and application thereof. The benzisoselenazolone modified nitrosourea compound is shown as a general formula I. The benzisoselenazolone modified nitrosourea compound has excellent antitumor activity and can be widely used for preparing antitumor drugs.
Description
Technical Field
The invention relates to a preparation method and application of a benzisoselenazolone-modified nitrosourea compound, belonging to the field of chemistry
Background
Nitrosoureas antineoplastic is an alkylating agent with wide application, which is applied to the clinical treatment of diseases such as brain tumor, leukemia, malignant lymphoma, glioma, etc.
Most of nitrosourea antineoplastic drugs belong to bifunctional alkylating agents. The action mechanism is as follows: nitrosoureas rapidly decompose in aqueous solutions to produce azo hydroxide intermediates. This intermediate can be further decomposed into carbenium ions. Since macromolecules such as DNA belong to electron-rich molecules, they can bind to carbenium ions, such as O in guanine6Bit or N7The site forms an alkylating lesion and even further reactions form covalent crosslinks between complementary base pairs. These cross-linking events can cause damage to DNA replication and ultimately apoptosis.
Taking methyl nitrosourea as an example, the mechanism of action of nitrosourea drugs and DNA is as follows:
carmustine is an alkylating agent and is a representative drug in nitrosourea antineoplastic drugs. The blood-brain barrier-permeable plasma has the advantages of small molecular weight, good lipid solubility, capability of penetrating through the blood-brain barrier, high plasma binding rate and the like, and is widely applied to clinic. It is proved to have the function of resisting central nervous system tumor in mouse experiment and clinical research, and is the first choice medicine for treating malignant glioma. In addition, it is also used for the treatment of multiple myeloma and malignant melanoma.
Carmustine is a bifunctional alkylating agent. It will decompose rapidly in water to produce chloroethyl diazo hydroxide (Cl-CH)2-CH2-N-OH) and chloroethyl isocyanate (O ═ C ═ N-CH 2-CH)2-Cl). The former may be cross-linked with DNA and the isocyanate may be protein carbamoylation i. In addition, carmustine also has an inhibitory effect on TrxR, and TrxR can also be a target of the action and has an irreversible inhibitory effect on TrxR.
Carmustine has a very strong cytotoxic effect. Its limiting toxicity is a delayed toxicity to the hematopoietic system when administered in standard doses. And chronic administration of the drug can cause pulmonary fibrosis which can be fatal. The limiting toxicities of carmustine are hepatotoxicity and pulmonary toxicity at high dose administration, and venous embolic disease occurs in 5% to 20% of patients.
The benzisoselenazolone represents a compound, namely the ethaneselenone, is an organic selenium compound which targets thioredoxin reductase and has an anti-tumor effect, and clinical research is currently carried out, wherein the clinical phase I shows that the ethaneselenone has low toxicity and better tolerance compared with the toxicity of carmustine. Early researches show that the benzisoselenazolone structure as the main pharmacophore of the medicine can actively identify the active center of target enzyme and embody the targeting of tumors and related tissues. The in vivo metabolism research of the medicament shows that the concentration of the ethylselenoline in the tumor tissue is far higher than that in the blood plasma, and the medicament shows good tumor targeting.
The innovation point of the patent is that a benzisoselenazolone structure is introduced to the N atom of a nitrosourea structure to obtain a new class Nitrosoureas compound with benzisoselenazolone structureAccording to the characteristics of the benzisoselenazolone drug (ethylselenoline), the compound can target thioredoxin reductase and has tumor targeting property, and the thioredoxin reductase activity is an important factor of tumor growth, so that the compound has the characteristic of multiple targets, and the structure improves the targeting property of the drug compared with a nitrosourea structure, thereby achieving the effects of synergy and attenuation.
The research adopts a brand new structural form of nitrosourea with a benzisoselenazolone structure, and the significance of the structure is as follows
1. The series of compounds retain the active pharmacophores of the esselenoline and the carmustine. Studies show that benzisoselenium
The azolone is an active pharmacophore in the esoline, can actively recognize and combine with an active site in TrxR, and thereby exerts
Inhibition of TrxR. Thus, we retained the benzisoselenazolone structure in esselenoline. Decomposition tablet of carmustine
One of the paragraphs, chloroethyl diazo hydroxide, is a group that exerts a crosslinking effect on DNA.
2. As a prodrug form, this series of compounds undergoes decomposition in water to yield two molecular fragments. Front side
The benzisoselenazolone structure and the isocyanate structure in the compound can generate TrxR inhibitory activity synergistically. Another fragment will be produced with DNA
Cross-linking occurs. The two pharmacophores can generate the synergistic effect of anti-tumor, thereby improving the anti-tumor activity.
3. The benzisoselenazolone structure has better tumor targeting property, so that the benzisoselenazolone structure can generate targeting drug effect
After the structures of nitrosoureas are combined, a new series is madeThe molecule has high targeting property, and simultaneously, the toxicity of the compound is further weakened.
4. Because the nitrosourea compound has better water solubility, the nitrosourea compound is changed after being combined with the benzisoselenazolone structure
The symmetric molecular structure in the ethylselenoline is improved, the solubility of the compound is improved, and the pharmaceutical property is enhanced.
The activity test of the compounds shows thatBenzisoselenazoloneSome of the C-5 and C-6 positions are substituted by F, andbenzisoselenazoloneThe shorter the linker arm between the moiety and the nitrosourea moiety, the better (n ═ 2), the more pronounced the antitumor activity can be obtained. Wherein, 3- [2- (5-fluoro-1, 2-benzisoselenazol-3 (2H) -one) ethyl]-1-chloroethyl-1-nitrosourea and 3- [2- (6-fluoro-1, 2-benzisoselenazol-3 (2H) -one) ethyl]The-1-chloroethyl-1-nitrosourea has better anti-tumor activity in LoVo, RKO, MIA PaCa-2 and PANC-1 cell lines and has anti-tumor significance. And is introduced intoBenzisoselenazole KetonesAnd then, the targeting property of the compound is improved, and the realization of the target of attenuation and synergy is facilitated. Therefore, the application specially applies for the compounds. This is because of being novelNitrosoureas having benzisoselenazolone structureThe solubility of the structural drug is greatly improved compared with the solubility of the ethaneselenol, the targeting property is greatly improved compared with the carmustine, the synergistic attenuation effect is achieved, and the patent drug property is increased. WhileBenzisoselenazolone structures and nitrosoureasThe structure can play a role in synergy in pharmacological action, so that the compound shows good in vitro antitumor activity and IC of the compound50The values are also lower than or comparable to carmustine.
Disclosure of Invention
The invention aims to provide a benzisoselenazolone modified nitrosourea compound based on the theory, and the anti-tumor activity of the benzisoselenazolone modified nitrosourea compound is determined through experiments.
The invention is realized by the following technical scheme:
a compound of the structure (I) wherein,
n is the number of carbons between the linker arms
General formula I
Wherein R is1、R2、R3、R4Are respectively H, C1-4Alkyl radical of (2), C1-4Alkoxy radical of (A), C1-4Acyloxy group of (4), NO2OH or halogen.
n is the number of carbons between the linker arms from 2 to 4.
2. The compound of claim 1, wherein C is1-4The alkanyl radical of (a) is methyl, ethyl or propyl; c1-4The alkoxy group of (a) is methoxy, ethoxy or propoxy.
3. The compound of claim 1, wherein the halogen is F, Cl, Br.
4. The compound of claim 1, wherein R1, R2, R3, R4 are H, Me, OCH3, F, Cl, Br
5. The compound of claim 1, wherein n is the number of carbons between the linker arms is 2 to 4.
6. Use of a compound according to any one of claims 1 to 5 for the preparation of an anti-tumor medicament.
In a preferred embodiment of the invention, the pharmaceutical composition is suitable for enteral (e.g. oral or rectal), topical or parenteral administration, e.g. oral, injection, implantation, topical, spray, inhalation, etc.
In a preferred embodiment of the present invention, the oral pharmaceutical composition is selected from any one of tablets (plain tablets, buccal tablets, sublingual tablets, buccal patches, chewable tablets, dispersible tablets, soluble tablets, effervescent tablets, vaginal tablets or vaginal effervescent tablets, sustained release tablets, controlled release tablets, enteric-coated tablets, oral immediate release tablets, etc.), capsules (hard capsules, soft capsules, sustained release capsules, controlled release capsules, enteric-coated capsules, etc.), pills (dropping pills, dragees, pellets), oral liquid preparations (syrups, suspensions, oral solutions, oral suspensions, oral emulsions, syrups, mixtures, lotions or teas), granules (suspension granules, effervescent granules, enteric-coated granules, sustained release granules, controlled release granules, etc.), powders.
In a preferred embodiment of the present invention, the injection includes any one of injection solution, sterile powder or sterile block for injection (including preparation by solvent crystallization, spray drying or freeze drying), infusion solution, and concentrated solution for injection.
In a preferred embodiment of the present invention, the external preparation is selected from any one of suppository, aerosol, powder spray, film, gel, patch, glue, patch, plaster, ointment, liniment, lotion, liniment, and plaster.
In a preferred embodiment of the invention, the compositions of the invention may be prepared using formulation technology means well known in the art.
In a preferred embodiment of the invention, the pharmaceutical composition is selected from an inclusion or dispersion formulation.
In a preferred embodiment of the present invention, the pharmaceutically acceptable carrier is a common excipient or adjuvant known in the art for preparing the above-mentioned formulations, wherein the common excipient or adjuvant for oral or external preparations includes, but is not limited to, fillers or diluents, lubricants or glidants or anti-adherents, dispersants, wetting agents, binders, regulators, solubilizers, antioxidants, bacteriostats, emulsifiers, etc. Binders, such as syrup, acacia, gelatin, sorbitol, tragacanth, cellulose and its derivatives, gelatin syrup, starch syrup or polyvinylpyrrolidone, preferred cellulose derivatives being microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose, hydroxypropylmethylcellulose; fillers, such as lactose, powdered sugar, dextrin, starch and derivatives thereof, cellulose and derivatives thereof, inorganic calcium salts, sorbitol or glycine, preferably calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate; lubricants, such as aerosil, magnesium stearate, talc, aluminum hydroxide, boric acid, hydrogenated vegetable oils, polyethylene glycol; disintegrants, for example starch and its derivatives, polyvinylpyrrolidone or microcrystalline cellulose, preferred starch derivatives being sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch; wetting agents, such as sodium lauryl sulfate, water or alcohol, etc., preferably pharmaceutically acceptable carriers such as cyclodextrin (. alpha. -cyclodextrin,. beta. -cyclodextrin or. gamma. -cyclodextrin), Celldone 102 CG, Polyplasdone XL-10, talc, magnesium stearate or ethanol, etc.
In a preferred embodiment of the present invention, the excipients or adjuvants commonly used in the injection include, but are not limited to: antioxidants such as sodium thiosulfate, sodium sulfite, sodium bisulfite, dibutylbenzoic acid or sodium metabisulfite, and the like; bacteriostats such as 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol; pH adjusters such as hydrochloric acid, citric acid, potassium (sodium) hydroxide, sodium citrate, and buffering agents sodium dioxyphosphate and disodium hydrogen phosphate; emulsifiers such as polysorbate-80, sorbitan-kotate, pluronic F-68, lecithin, soy lecithin; solubilizers, for example, Tween-80, glycerol, etc.
In a preferred embodiment of the present invention, the active ingredient and the pharmaceutically acceptable sustained-release carrier can be mixed according to the preparation requirements, and then prepared into pellets, such as sustained-release pellets or controlled-release pellets, according to the preparation method of the sustained-release preparation well known in the art, such as adding a retardant coating or microencapsulating the active ingredient; the slow-release carrier comprises but is not limited to oil wax doping agent, hydrophilic colloid or coating retarder and the like, wherein the oil wax doping agent is glyceryl monostearate, hydrogenated castor oil, mineral oil, polysiloxane and dimethyl siloxane; the hydrophilic colloid is cellulose derivatives such as sodium carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc., or PVP, acacia, tragacanth or carbopol, etc.; the coating retarder is Ethyl Cellulose (EC), Hydroxypropyl Methylcellulose (HMPC), polyvinylpyrrolidone (PVP), Cellulose Acetate Phthalate (CAP), acrylic resin, etc.
In a preferred embodiment of the present invention, a pharmaceutically acceptable composition comprises about 1-99% by weight of any one or combination of compounds 1-18 or pharmaceutically acceptable salts thereof, and 1-99% by weight of a suitable pharmaceutical excipient, depending on the desired mode of administration.
In a preferred embodiment of the present invention, compounds 1-18, or any one or combination of pharmaceutically acceptable salts thereof, are included in the pharmaceutical composition in an amount of about 5-75% by weight, with the balance being pharmaceutically acceptable excipients.
Another aspect of the present invention provides the use of compounds 1-18 or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof for the manufacture of a medicament for the treatment of cancer.
In a preferred embodiment of the present invention, the anti-tumor effect means for preventing or treating abnormal cell growth which may be manifested as tumor selected from any one of brain tumor, lung cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, melanoma, uterine cancer, ovarian cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulva cancer, esophageal cancer, small intestine cancer, cancer of the endocrine system, soft tissue sarcoma, cancer of the urethra, prostate cancer, lymphocytic tumors, cancer of the bladder, cancer of the kidney, cancer of the ureter, spinal tumor, brain stem glioma, pituitary adenoma, lung cancer, liver cancer, blood cancer.
In a preferred embodiment of the invention, the benzisoselenazolone-modified nitrosoureas of the invention are administered in a dose of about 0.05-250mg/Kg of body weight, preferably 0.5-200mg/Kg of body weight, more preferably 2-125mg/Kg of body weight, and most preferably 5-85mg/Kg of body weight, for the treatment of tumors.
The compound is
3- [2- (1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
3- [2- (1, 2-benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
3- [2- (1, 2-benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethylurea-1-nitrosourea
3- [2- (5-fluoro-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-fluoro-1, 2-benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-fluoro-1, 2-benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethyl-1-nitrosourea
3- [2- (6-fluoro-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-chloro-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-chloro-1, 2-benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-chloro-1, 2-benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethyl-1-nitrosourea
3- [2- (6-chloro-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-methyl-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-methyl-1, 2-benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-methyl-1, 2-benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-methoxy-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-methoxy-1, 2-benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-methoxy-1, 2-benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-bromo-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
It is a further object of the present invention to provide a process for preparing the above compound, comprising the steps of:
(1) preparation of Compound 1
Compound 1
In the presence of sodium nitrite
Reacting with hydrochloric acid in an ice bath to obtain diazonium salt, reacting the obtained diazonium salt with sodium diselenide to keep a reaction mixture alkaline, acidifying the obtained mixture with hydrochloric acid to obtain solid, refluxing the obtained solid in thionyl chloride and DMF, removing the thionyl chloride by rotary evaporation to obtain residue, extracting the obtained residue with petroleum ether, cooling and precipitating crystals to obtain the compound 1.
(2) Dissolving the compound 1 in ether, dropwise adding N-BOC-1, 2-ethylenediamine, stirring at room temperature for reaction, and separating out a solid. And (5) carrying out suction filtration to obtain an intermediate.
(3) And (3) adding dichloromethane into the intermediate obtained in the step (2), dropwise adding trifluoroacetic acid, and stirring at room temperature for reaction. With saturated NaHCO3Adjusting pH to 7-8, and collecting water layer. Concentrate and extract with dichloromethane (small portions). Drying, concentrating, dripping chloroethyl isocyanate, and precipitating. And (5) carrying out suction filtration to obtain an intermediate.
(4) Dissolving the intermediate obtained in step (3) in 2ml of anhydrous formic acid, adding NaNO2 (molar ratio 1: 4) at 0 deg.C, reacting at 0 deg.C for 40min, adding appropriate amount of water to precipitate solid, and vacuum filtering to obtain white powdery solid, i.e. compound of formula I
Detailed Description
The present invention is further described below in conjunction with examples, which are to be understood as being illustrative only and in no way limiting to the scope of the invention.
The following is a synthetic route for the compounds of the invention:
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
the preparation and antitumor activity of the compounds of formula I are described below with reference to 28 compounds as examples.
These 28 compounds are shown in table 1.
TABLE 1
----------------------------
EXAMPLE 12 preparation of 2, 2' -Diselenized Bibenzoic acid
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
(1) Adding 16g of sodium hydroxide, 18g of sodium hydrosulfite and 16g of selenium powder into water in sequence, heating to 50 ℃, and obtaining the sodium diselenide solution after the reaction is finished.
(2) Under the ice-bath condition, 28g of anthranilic acid is added into 80ml of hydrochloric acid with the ratio of 1: 1, stirred and mixed, and 18.0g of aqueous solution of sodium nitrite is slowly dropped into the anthranilic acid, so that 2-benzoic acid diazonium chloride is obtained.
(3) And (3) dropwise adding the solution of the 2-benzoic acid diazonium chloride salt obtained in the step (1) into the sodium diselenide solution obtained in the step (2) under the stirring of an ice water bath, and continuously stirring the mixture. The solution was alkaline as demonstrated by PH paper. Filtering with diatomite, adjusting pH to 3, filtering, washing filter cake with water, and drying to obtain brown yellow solid.
1H NMR(400MHz，DMSO-d6)：δδ7.34(t，2H)，7.46(t，2H)，7.67(d，2H)，8.02(d，2H)，13.69(s，br，2H)
EXAMPLE 22 preparation of selenium chlorobenzoyl chloride
40g of 2, 2' -bis-selenobenzoic acid, 200ml of thionyl chloride and DMF are stirred and refluxed in a plurality of drops, after the reaction is finished, excessive thionyl chloride is removed by rotary evaporation, and the residue is recrystallized by petroleum ether to obtain yellow needle-shaped crystals.
1H NMR(400MHz，CDCl3)：δδ7.39(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(d，J＝7.7Hz，1H，Ar-H).
EXAMPLE 35 preparation of 5, 5 '-difluoro-2, 2' -diselenide bisbenzoic acid
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
This compound was obtained in the same manner as in example 1.
1H NMR(400MHz，DMSO-d6)：δδ7.23(m，2H)，7.40(dd，2H)，8.11(m，2H)，13.93(s，br，2H)
EXAMPLE 42 preparation of seleno-chloro-5-fluorobenzoyl chloride
This compound was obtained in the same manner as in example 2.
1H NMR(400MHz，CDCl3)：δδ7.42(td，J＝8.3，2.7Hz，1H，Ar-H)，7.65(dd，J＝8.3，5.4Hz，1H，Ar-H)，7.78(dd，J＝9.0，2.7Hz，1H，Ar-H).
EXAMPLE 55 preparation of 5, 5 '-dichloro-2, 2' -diselenide Bisbenzoic acid
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
This compound was obtained in the same manner as in 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).
EXAMPLE 62 preparation of seleno-chloro-5-chlorobenzoyl chloride
This compound was obtained in the same manner as in example 2.
1H NMR(400MHz，CDCl3)d 8.12(d，J＝8.6，1H，ArH)，7.69(d，J＝2.2，1H，ArH)，7.65(dd，J1＝8.6，J2＝2.2，1H，ArH).
EXAMPLE 75 preparation of 5, 5 '-dimethyl-2, 2' -diselenide bisbenzoic acid
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
This compound was obtained in the same manner as in example 1.
1H NMR(400MHz，DMSO-d6)：δδ2.30(s，3H)，7.43(m，2H)，7.66(m，2H)，7.79(dd，2H)，13.50(s，br，2H)
EXAMPLE 82 preparation of seleno-chloro-5-methylbenzoyl chloride
This compound was obtained in the same manner as in example 2.
1H NMR(400MHz，CDCl3)：δδ2.37(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).
EXAMPLE 95 preparation of 5, 5 '-dimethoxy-2, 2' -diselenide bisbenzoic acid
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
This compound was obtained in the same manner as in example 1.
1H NMR(400MHz，DMSO-d6)：δδ2.30(s，3H)，7.43(m，2H)，7.66(m，2H)，7.79(dd，2H)，13.50(s，br，2H)
EXAMPLE 102 preparation of seleno-chloro-5-methoxybenzoyl chloride
This compound was obtained in the same manner as in example 2.
1H NMR(400MHz，CDCl3)：δ3.80(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(d，J＝8.8Hz，1H，Ar-H).
EXAMPLE 115 preparation of 2, 2 ' -bis-selenoylbenzoic acid, 2 ' -bromo-2 ' -selenoylbenzoic acid
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
This compound was obtained in the same manner as in 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).
EXAMPLE 122 preparation of seleno-chloro-5-bromobenzoyl chloride
This compound was obtained in the same manner 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)
EXAMPLE 134, 4 '-difluoro-2, 2' -diselenide Bibenzoic acid preparation
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
This compound was obtained in the same manner as in example 1.
1H NMR(400MHz，DMSO-d6)：δδ7.23(m，2H)，7.40(dd，2H)，8.11(m，2H)，13.93(s，br，2H)
EXAMPLE 142 preparation of seleno-chloro-4-fluorobenzoyl chloride
This compound was obtained in the same manner as in example 2.
1H NMR(400MHz，CDCl3)：δδ7.19(td，J＝8.4，2.3Hz，1H，Ar-H)，7.80(dd，J＝8.4，5.7Hz，1H，Ar-H)，7.86(dd，J＝9.9，2.3Hz，1H，Ar-H).
EXAMPLE 154 preparation of 4, 4 '-dichloro-2, 2' -diselenide Bisbenzoic acid
2Se+4NaOH+Na2S2O4→Na2Se2+2Na2SO3+2H2O
This compound was obtained in the same manner as in 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).
EXAMPLE 162 preparation of seleno-chloro-4-chlorobenzoyl chloride
This compound was obtained in the same manner 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)
Example 173- [2- (1, 2-Benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
(1) Dissolving 2-selenium chlorobenzoyl chloride in ether, dripping N-BOC-1, 2-ethylenediamine, stirring at room temperature for reaction, and separating out solid. And (5) carrying out suction filtration to obtain an intermediate.
(2) And (2) adding dichloromethane into the intermediate obtained in the step (1), dropwise adding trifluoroacetic acid, and stirring at room temperature for reaction. With saturated NaHCO3Adjusting pH to 7-8, and collecting water layer. Concentrate and extract with dichloromethane (small portions). Drying, concentrating, dripping chloroethyl isocyanate, and precipitating. And (5) carrying out suction filtration to obtain an intermediate.
(3) Dissolving the intermediate obtained in step (2) in 2ml of anhydrous formic acid, and adding NaNO at 0 DEG C2(molar ratio 1: 4), reacting at 0 deg.C for 40min, adding appropriate amount of water to precipitate solid, and vacuum filtering to obtain white powdery solid, 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+).
Example 183- [2- (1, 2-Benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 193- [2- (1, 2-Benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 203- [2- (5-fluoro-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 213- [2- (5-fluoro-1, 2-benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 223- [2- (5-fluoro-1, 2-benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 233- [2- (6-fluoro-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 243- [2- (5-chloro-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 253- [2- (5-chloro-1, 2-benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 263- [2- (5-chloro-1, 2-benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+)
Example 273- [2- (6-chloro-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 283- [2- (5-methyl-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 293- [2- (5-methyl-1, 2-benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 303- [2- (5-methyl-1, 2-benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 313- [2- (5-methoxy-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 323- [2- (5-methoxy-1, 2-benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 333- [2- (5-methoxy-1, 2-benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Example 343- [2- (5-bromo-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
This compound was obtained in the same manner as in example 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+).
Experimental example 3518 Compounds
Adopting MTT method, firstly inoculating LoVo, RKO, MIA PaCa-2, PANC-1 cells in logarithmic growth phase into 96-well plate, the inoculation density is 4 multiplied by 104One per ml. After the cells adhere to the wall, 20 microliters of liquid medicine is added into each hole, so that the final concentration of the medicine is 0, 1, 5, 10, 50 microliter/ml, after 48 hours of action, 5mg/ml of MTT solution (20 ul/hole) is added, the mixture is placed into a carbon dioxide incubator for culture for 3-4 hours, the supernatant is carefully discarded, after the residual liquid is air-dried, DMSO (dimethyl sulfoxide) is added into the mixture, the mixture is shaken on a shaking table for 0.5-1 hour, and after the crystals are completely dissolved, the absorbance OD (optical density) value is measured at 492nm of an enzyme labeling instrument.
The cell growth inhibition rate (negative control OD value-adding medicine OD value)/(negative control OD value-blank group OD value) × 100%
TABLE 2
The results of the experiments in Table 2 show that there are 16 IC's of compounds (numbers other than 9, 18) in RKO cell line50The value was 30uM lower; in the LOVO cell line, there are ICs for 14 compounds (numbering other than 10, 11, 17, 18)50Values below 30 uM; in the Mia-Paca2 cell line, there are ICs for 14 compounds (numbering other than 9, 10, 11, 18)50Values below 30 uM; in PAN C-1 cell line, there are 14 compounds (numbering other than 9, 10, 17, 18) IC50The value was 30uM lower; therefore, the benzisoselenazolone modified nitrosourea compound shows good anti-tumor activity.
The foregoing is merely a preferred embodiment of the invention, which is intended to be illustrative and not limiting. It will be understood by those skilled in the art that various changes, modifications and equivalents may be made therein without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (7)
1. A compound of the structure (I) wherein,
wherein R is1、R2、R3、R4Are respectively H, C1-4Alkyl radical of (2), C1-4Is substituted with an alkoxy group or a halogen,
n is the number of carbons between the linker arms from 2 to 4.
2. The compound of claim 1, wherein C is1-4The alkanyl radical of (a) is methyl, ethyl or propyl; c1-4The alkoxy group of (a) is methoxy, ethoxy or propoxy.
3. The compound of claim 1, wherein the halogen is F, Cl, Br.
4. A compound of claim 1, wherein R is1，R2，R3，R4Is H, Me, OCH3、F、Cl、Br。
5. The compound of claim 1, wherein n is the number of carbons between the linker arms is 2 to 4.
6. The compound of any one of claims 1 to 4, wherein the compound is
3- [2- (1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
3- [2- (1, 2-benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
3- [2- (1, 2-benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethylurea-1-nitrosourea
3- [2- (5-fluoro-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-fluoro-1, 2-benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-fluoro-1, 2-benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethyl-1-nitrosourea
3- [2- (6-fluoro-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-chloro-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-chloro-1, 2-benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-chloro-1, 2-benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethyl-1-nitrosourea
3- [2- (6-chloro-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-methyl-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-methyl-1, 2-benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-methyl-1, 2-benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-methoxy-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-methoxy-1, 2-benzisoselenazol-3 (2H) -one) propyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-methoxy-1, 2-benzisoselenazol-3 (2H) -one) butyl ] -1-chloroethyl-1-nitrosourea
3- [2- (5-bromo-1, 2-benzisoselenazol-3 (2H) -one) ethyl ] -1-chloroethyl-1-nitrosourea.
7. A process for the preparation of a compound according to any one of claims 1 to 5, comprising the steps of:
(1) preparation of Compound 1
In the presence of sodium nitrite
Reacting with hydrochloric acid in an ice bath to obtain diazonium salt, reacting the obtained diazonium salt with sodium diselenide to keep a reaction mixture alkaline, acidifying the obtained mixture with hydrochloric acid to obtain solid, refluxing the obtained solid in thionyl chloride and DMF, removing the thionyl chloride by rotary evaporation to obtain residue, extracting the obtained residue with petroleum ether, and cooling to separate out crystals, namely the compound 1;
(2) dissolving the compound 1 in ether, dropwise adding N-BOC-1, 2-ethylenediamine, stirring at room temperature for reaction, separating out solids, and performing suction filtration to obtain an intermediate;
(3) adding dichloromethane into the intermediate obtained in the step (2), dropwise adding trifluoroacetic acid, stirring at room temperature for reaction, and reacting with saturated NaHCO3Adjusting the pH value to 7-8, taking a water layer, concentrating, extracting dichloromethane for a few times, drying, concentrating, dropwise adding chloroethyl isocyanate, precipitating out a precipitate, and performing suction filtration to obtain an intermediate;
(4) dissolving the intermediate obtained in step (3) in 2ml of anhydrous formic acid, and adding NaNO in a molar ratio of 1: 4 at 0 DEG C2Reacting at 0 deg.C for 40min, adding appropriate amount of water to precipitate solid, and vacuum filtering to obtain white powdery solid, i.e. compound of formula I.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610030546.0A CN106977472B (en) | 2016-01-19 | 2016-01-19 | Synthesis and application of benzisoselenazolone modified nitrosourea compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610030546.0A CN106977472B (en) | 2016-01-19 | 2016-01-19 | Synthesis and application of benzisoselenazolone modified nitrosourea compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106977472A CN106977472A (en) | 2017-07-25 |
| CN106977472B true CN106977472B (en) | 2021-09-07 |
Family
ID=59340247
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610030546.0A Active CN106977472B (en) | 2016-01-19 | 2016-01-19 | Synthesis and application of benzisoselenazolone modified nitrosourea compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106977472B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108503607B (en) * | 2018-06-22 | 2020-07-03 | 济源希健生物医药科技发展有限公司 | N, N-bis (2-chloroethyl) -2- (benzisoselenazol-3-one) -amide compound with anti-tumor activity |
| CN113527301A (en) * | 2020-04-13 | 2021-10-22 | 凯熙医药（武汉）股份有限公司 | Tetrazine substituent-containing aromatic isoselenazole compound and synthetic method and application thereof |
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1990475A (en) * | 2005-12-29 | 2007-07-04 | 曾慧慧 | Substituted benzisoselenazolone compounds and use thereof |
-
2016
- 2016-01-19 CN CN201610030546.0A patent/CN106977472B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1990475A (en) * | 2005-12-29 | 2007-07-04 | 曾慧慧 | Substituted benzisoselenazolone compounds and use thereof |
Non-Patent Citations (4)
| Title |
|---|
| Drug efficacy and pharmacological action of an organoselenium compound ethaselen,a novel antitumor drug;Jianing Fu;《Journal of Chinese Pharmaceutical Sciences》;20101231;第163-168页 * |
| N，N＇－ 双氯乙基脲和卡莫司汀的合成研究;南康立;《山东化工》;20121231;第41卷(第12期);第5-6页 * |
| Novel Antitumor Nitrosoureas and Related Compounds and Their Reactions with DNA;J. William Lown等;《Journal of Medicinal Chemistry》;19801231;第798-805-页 * |
| Nucleoside Analogs. 14. The Synthesis and Antitumor Activity in Mice of Molecular Combinations of 5-Fluorouracil and N-(2-Chloroethyl)-N-nitrosourea Moieties Separated by a Three-Carbon Chain;R. Stanley McElhinney等;《J. Med. Chem.》;19960329;第39卷(第7期);第1403-1412页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106977472A (en) | 2017-07-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7030093B2 (en) | How to make an oxathiadin-like compound | |
| AU2003251944B2 (en) | Compounds, compositions, and methods employing same | |
| CN106977472B (en) | Synthesis and application of benzisoselenazolone modified nitrosourea compound | |
| CN109134586B (en) | Tripterine derivative and application thereof | |
| US10011614B2 (en) | Bis-β-carboline compound and preparation method, pharmaceutical composition and use thereof | |
| JP2017534657A (en) | New cytidine derivatives and their applications | |
| TW201831191A (en) | Novel boric acid derivative and pharmaceutical composition using same | |
| WO2014008838A1 (en) | Bis-indolylacetic acid derivative attached with aryl substituted methyl, and preparation method and use thereof | |
| CN111662281B (en) | Salicylic acid berberine type alkaloid quaternary ammonium salt and application thereof in preparing medicines | |
| CN104230912B (en) | Quinoline, Its Preparation Method And Use | |
| CN103936762B (en) | Morpholine quinolines, Preparation Method And The Use | |
| CN111943906B (en) | Amidine derivatives, preparation method, pharmaceutical composition and application thereof | |
| EP1911451A1 (en) | Protein-kinase CK2 inhibitors and their therapeutic applications | |
| CN111410618A (en) | Compound with hexokinase 2 inhibitory activity and application | |
| CN110981865B (en) | Medicine for treating brain glioma and preparation method thereof | |
| CN116096372A (en) | EGFR inhibitor, preparation method and pharmaceutical application thereof | |
| US20160102066A1 (en) | Benzothiazole derivative and anti-tumor use thereof | |
| AU2011274194B2 (en) | Phenyl nitrone compounds containing stilbene segment and use thereof | |
| WO2008154801A1 (en) | A trans-cinnamic acid derivative, its preparation method and the use | |
| JP2004505899A (en) | 5'-Deoxy-N- (substituted oxycarbonyl) -5-fluorocytosine and derivatives thereof, method for producing the same, and anticancer composition containing the same as an active ingredient | |
| CN112250672B (en) | Nucleoside base derivative and preparation method and application thereof | |
| CN103012394A (en) | Rhodanine derivative and preparation method thereof | |
| WO2011103773A1 (en) | Pegylated cyclopamine analogue, preparation method and uses thereof | |
| CN112851679B (en) | 2, 4, 7-trisubstituted pyrimidoindole compound with antitumor effect | |
| CN106995368B (en) | non-ATP competitive FGFR1 inhibitor and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20211027 Address after: 210000 No. 199 shogundong Road, Gulou District, Nanjing, Jiangsu Patentee after: NANJING KAIXI MEDICAL TECHNOLOGY Co.,Ltd. Address before: 300457 n603, experimental building of Tianjin International Biomedical Joint Research Institute, No. 220 Dongting Road, Tianjin Economic and Technological Development Zone, Tianjin Patentee before: KAIXI MEDICINE (TIANJIN) CO.,LTD. |