WO2021208865A1 - 含四嗪取代基的芳并异硒唑类化合物及其合成方法和应用 - Google Patents
含四嗪取代基的芳并异硒唑类化合物及其合成方法和应用 Download PDFInfo
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- WO2021208865A1 WO2021208865A1 PCT/CN2021/086688 CN2021086688W WO2021208865A1 WO 2021208865 A1 WO2021208865 A1 WO 2021208865A1 CN 2021086688 W CN2021086688 W CN 2021086688W WO 2021208865 A1 WO2021208865 A1 WO 2021208865A1
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention belongs to the field of medicine, and specifically relates to a method for synthesizing aromatic isoselenazole compounds containing tetrazine substituents, and its application in the preparation of drugs for treating tumors, especially gliomas .
- Glioma is a common orthotopic intracranial tumor, accounting for more than 50% of intracranial tumors, and its incidence is 1-3% of systemic malignant tumors. The median overall survival of patients is only 12-15 months. Because most gliomas grow infiltrating and have no obvious histological boundary with normal brain tissue, it is very difficult to cure gliomas by surgical resection.
- radiotherapy is also a common clinical treatment method, including conventional radiotherapy, three-dimensional conformal radiotherapy, and stereotactic radiotherapy.
- glioma cells themselves are not sensitive enough to radiotherapy, and there are differences between different subtypes. It is difficult to improve the effect of radiotherapy, and it must be combined with drug treatment to achieve a certain effect.
- Temozolomide as a new generation of alkylating agent, can be quickly absorbed by oral administration and has the characteristics of high efficiency, low toxicity and broad spectrum. Under physiological conditions, TMZ can finally be converted into cytotoxic diazomethane, methylation occurs at the position of guanine O 6 to produce cytotoxicity, which is the main reason for its killing effect. Regardless of whether it is used alone or in combination with radiotherapy in the treatment of glioma, TMZ has a relatively good therapeutic effect.
- the main clinical program of temozolomide is the "stupp" program, that is, radiation and adjuvant temozolomide chemotherapy are synchronized, and TMZ adjuvant chemotherapy is used one month after the end of radiotherapy. Every 28 days is a cycle.
- the medication time is 5 consecutive days, once a day, at intervals 23 days.
- the first cycle is 150 mg/m 2 /d ⁇ 5 days, and the second to sixth cycles are 200 mg/m 2 /d ⁇ 5 days.
- the median overall survival of patients treated with Stupp regimen was 14.6 months, while the median overall survival of patients treated with RT alone was 12.1 months.
- TMZ still has some shortcomings. The first is that efficiency is not ideal. Secondly, there are many side effects, and patients will have adverse reactions such as bone marrow suppression, gastrointestinal reactions, and peripheral neurotoxicity. Thirdly, there is also the problem of drug resistance. O 6 -methylguanine-DNA methyltransferase (MGMT) can directly cleave the methyl group, making TMZ useless. In addition, it is easy to develop multi-drug resistance (MDR). These are the main reasons for the failure of TMZ chemotherapy for glioma.
- MGMT methylguanine-DNA methyltransferase
- TRX system The thioredoxin system
- TrxR reduced nicotinamide adenine dinucleotide phosphate (NADPH), thioredoxin (Trx), and thioredoxin reductase (TrxR), where TrxR is a A NADPH-dependent dimeric selenozyme containing flavin adenine dinucleotide (FAD) domain.
- TrxR A NADPH-dependent dimeric selenozyme containing flavin adenine dinucleotide (FAD) domain.
- TrxR1 A NADPH-dependent dimeric selenozyme containing flavin adenine dinucleotide (FAD) domain.
- TrxR1 A NADPH-dependent dimeric selenozyme containing flavin adenine dinucleotide (FAD) domain.
- TrxR1 A NADPH-dependent dimeric selenozyme containing flavin
- the TRX system can directly resist oxidation and support the functions of other antioxidant enzymes. By defending against oxidative stress caused by exogenous substances or carcinogens, it helps prevent normal cells from transforming into malignant tumors. In terms of tumor development and metastasis, the elevated levels of TrxR/Trx have the functions of promoting cell proliferation, resisting cell apoptosis and promoting angiogenesis, so it may promote tumor growth.
- the TRX system is of great significance in the development and metastasis of tumors. It is an important system in tumor cells to maintain homeostasis, promote proliferation and angiogenesis.
- TrxR is highly expressed in brain tumors. Analysis of the clinical data of 433 cases of glioblastoma showed that thioredoxin reductase 1 (TrxR1) is up-regulated in more than 66% of cases, which is related to stronger proliferation. There is a clear correlation between activity and worse prognosis. Therefore, it is very urgent to carry out research on the treatment of glioma for the TrxR target.
- the present invention provides an aromatic isoselenazole compound containing a tetrazine substituent represented by formula (I) or a pharmaceutically acceptable salt thereof:
- a 1 , A 2 , A 3 and A 4 are the same or different, and are independently selected from CH or N, and at most one is N; when A 1 , A 2 , A 3 or A 4 is CH, it
- the hydrogen atom on can be substituted by R, wherein R is selected from hydrogen, cyano, hydroxyl, halogen, nitro or amino, mercapto, amido, alkyl, cycloalkyl, alkoxy substituted by one or more Ra , Heterocyclyl, aryl, heteroaryl, each Ra is independently selected from hydrogen, cyano, hydroxyl, halogen, amino, nitro, mercapto, alkyl, cycloalkyl, alkoxy, aryl, Heteroaryl; R 1 is selected from alkylene.
- R is selected from hydrogen, cyano, hydroxyl, halogen, nitro or amino, mercapto, amido, C 1-10 alkyl, C 3-10 cycloalkane substituted by one or more Ra Group, C 1-10 alkoxy group, 3-10 membered heterocyclic group, C 6-14 aryl group, 5-14 membered heteroaryl group, each Ra is independently selected from hydrogen, cyano, hydroxyl, halogen, Amino, nitro, mercapto, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkoxy, 3-10 membered heterocyclic group, C 6-14 aryl, 5-14 membered hetero Aryl; R 1 is selected from C 1-10 alkylene.
- R is selected from hydrogen, halogen or C 1-6 alkyl substituted by one or more Ra, C 3-6 cycloalkyl, C 1-6 alkoxy, phenyl, pyridyl ,
- Each Ra is independently selected from hydrogen, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, phenyl, pyridyl;
- R 1 is selected from C 1-6 Alkylene.
- R is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy.
- R is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, Isopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy and isopentoxy.
- the structure of the arylisoselenazole compound containing tetrazine substituents is as shown in formula (II):
- a 1 is selected from CH or N; n is 1, 2, 3, 4, 5 or 6; R has the above-mentioned definition.
- R is selected from hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy.
- R is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, Isopentyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy and isopentoxy.
- the aromatic isoselenazole compound containing a tetrazine substituent is selected from the compounds in Table 1 below:
- the pharmaceutically acceptable salt of the compound represented by formula (I) or formula (II) includes: an acid addition salt formed by the compound and an inorganic acid or an organic acid;
- the inorganic acid is selected From at least one of hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, perchloric acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, or nitric acid;
- the organic acid is selected from formic acid, acetic acid, acetoacetic acid, pyruvic acid, three Fluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclic Pentane propionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid,
- the pharmaceutically acceptable salt of the compound represented by formula (I) or formula (II) is an alkali metal salt, alkaline earth metal salt, ammonium salt, or a salt formed with an organic base that provides a physiologically acceptable cation ,
- the present invention also provides a method for preparing the compound represented by formula (I), which includes the following steps:
- a 1 , A 2 , A 3 , A 4 , R and R 1 have the above-mentioned definitions;
- Boc represents tert-butoxycarbonyl
- R 2 is selected from chlorine, bromine, hydroxyl or -OR 3 , wherein R 3 is selected from C 1-6 alkyl, succinimidyl, tert-butoxycarbonyl, methylsulfonyl, p-nitro Phenylbenzenesulfonyl, p-toluenesulfonyl, isobutyloxycarbonyl.
- the Na 2 Se 2 in step 1) can be prepared from elemental selenium and sodium dithionite.
- the step 2) can be carried out in the presence of a catalytic amount of DMF.
- the acid in step 4) may be hydrochloric acid.
- the step 4) can be carried out in an organic solvent such as ethyl acetate.
- Compound F is commercially available or can be obtained by conventional methods in the art, or can be prepared by the following steps:
- step c) is selected from the following steps c-1), step c-2), step c-3), step c-4) or step c-5):
- Step c-1) Compound F-1 and R 4 OH are reacted with acid to produce compound F-3 (that is, compound F in which R 2 is -OR 3 and R 3 is C 1-6 alkyl):
- R 4 is a C 1-6 alkyl group
- Step c-2) Compound F-1 and R 5 Cl are reacted with base to form compound F-4 (that is, where R 2 is -OR 3 and R 3 is methylsulfonyl, p-nitrobenzenesulfonyl or p-toluenesulfonyl Acyl compound F):
- R 5 is methylsulfonyl, p-nitrobenzenesulfonyl or p-toluenesulfonyl;
- Step c-3) Compound F-1 is reacted with N-hydroxysuccinimide to obtain compound F-5 (that is, compound F in which R 2 is -OR 3 and R 3 is a succinimide group):
- Step c-4) Compound F-1 is reacted with di-tert-butyl dicarbonate to obtain compound F-6 (ie, compound F in which R 2 is -OR 3 and R 3 is tert-butoxycarbonyl):
- Step c-5) Compound F-1 is reacted with isobutyl chloroformate to obtain compound F-7 (ie, compound F in which R 2 is -OR 3 and R 3 is isobutyloxycarbonyl):
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the tetrazine-substituted aromatic isoselenazole compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable a.
- the pharmaceutical composition is suitable for enteral, topical or parenteral administration, for example, oral administration, injection, implantation, external application, spraying or inhalation.
- the oral pharmaceutical composition may be any one of tablets, capsules, pills, oral liquid preparations, granules, injections, external preparations or powders.
- the tablets may be ordinary tablets, buccal tablets, sublingual tablets, buccal patches, chewable tablets, dispersible tablets, soluble tablets, effervescent tablets, vaginal tablets, vaginal effervescent tablets, sustained-release tablets, controlled-release tablets, enteric-coated tablets Tablets or oral quick-release tablets;
- the capsules can be hard capsules, soft capsules, sustained-release capsules, controlled-release capsules or enteric-coated capsules;
- the pills include drop pills, sugar pills or small pills;
- the oral liquid preparations can be Syrups, suspensions, oral solutions, oral suspensions, oral emulsions, syrups, mixtures, lotions or liniments;
- the granules can be suspended granules, effervescent granules, enteric-coated granules, sustained release Granules or controlled release granules.
- the injection can be any one of injection, sterile powder or lumps for injection, infusion and concentrated solution for injection.
- the external preparations can be suppositories, aerosols, powder mists, sprays, films, gels, patches, glues, plasters, plasters, ointments, liniments, lotions, smears and gels. Any of the ointments.
- the pharmaceutical composition can be prepared by using formulation techniques well known in the art.
- the pharmaceutical composition may be an inclusion formulation or a dispersion formulation.
- the pharmaceutically acceptable carrier is well known in the art as common excipients or adjuvants for preparing the above formulations, wherein the common excipients or adjuvants for oral preparations or topical preparations include but not only Limited to fillers, diluents, lubricants, glidants, anti-adhesive agents, dispersants, wetting agents, adhesives, regulators, solubilizers, antioxidants, bacteriostatic agents, emulsifiers, etc.
- the binder such as syrup, gum arabic, gelatin, sorbitol, tragacanth gum, cellulose and its derivatives, gelatin syrup, syrup, starch syrup, polyvinylpyrrolidone
- the preferred cellulose derivative is microcrystalline cellulose , Sodium carboxymethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose
- the fillers such as lactose, powdered sugar, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts , Sorbitol or glycine
- the inorganic calcium salt is preferably calcium sulfate, calcium phosphate, calcium hydrogen phosphate, precipitated calcium carbonate
- the lubricant such as micronized silica gel, magnesium stearate, talc, aluminum hydroxide, boric acid, Hydrogenated vegetable oil, polyethylene glycol
- the disintegrant such as starch and its derivatives, polyvinylpyrrolidone or microcrystalline
- the commonly used excipients or auxiliary materials for the injection include: antioxidants, bacteriostatic agents, pH regulators, emulsifiers, and solubilizers.
- the antioxidant includes sodium thiosulfate, sodium sulfite, sodium bisulfite, dibutyl benzoic acid or sodium metabisulfite;
- the bacteriostatic agent includes phenol, cresol, and chlorobutanol, preferably 0.5% Phenol, 0.3% cresol, 0.5% chlorobutanol;
- the pH adjusting agent includes hydrochloric acid, citric acid, potassium hydroxide, sodium hydroxide, sodium citrate, sodium dioxophosphate or disodium hydrogen phosphate
- the emulsifier includes polysorbate-80, fatty acid sorbitan, pluronic F-68, lecithin, soy phospholipid;
- the solubilizer includes Tween-80, glycerin.
- the compound represented by formula (I) or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable sustained and controlled release carrier can also be prepared into a sustained and controlled release formulation according to the conventional preparation method of sustained and controlled release formulations.
- Release preparations For example, a retarder coating can be added or the compound represented by formula (I) or the pharmaceutically acceptable salt thereof can be microencapsulated and then made into pellets, such as sustained-release pellets or controlled-release pellets.
- the sustained and controlled release carrier includes, but is not limited to, grease admixtures, hydrophilic colloids or coating blockers;
- the grease admixtures include glycerol monostearate, hydrogenated castor oil, mineral oil, poly Silicone or dimethylsiloxane;
- the hydrophilic colloid includes sodium carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone (PVP), gum arabic, western yellow Gum or Carbopol;
- the coating retarder includes ethyl cellulose (EC), hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP), cellulose acetate phthalate (CAP) , Acrylic resin.
- the pharmaceutical composition contains about 1-99% by weight of the compound represented by formula (I) or any one of the pharmaceutically acceptable salts thereof Combination, and 1-99% by weight of a pharmaceutically acceptable carrier.
- the present invention also provides an application of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same for inhibiting the activity of thioredoxin reductase (TrxR), or for preparing thioredoxin Application of reductase (TrxR) inhibitors.
- the present invention also provides an application of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing it for the treatment or alleviation of diseases or disorders related to the up-regulation or activity increase of TrxR, or in preparation of treatment Or to alleviate the application of drugs for diseases or disorders related to the up-regulation of TrxR expression or increased activity.
- the present invention also provides an application of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same for treating tumors or preparing drugs for treating tumors.
- the present invention also provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used to inhibit the activity of thioredoxin reductase (TrxR) for the treatment or alleviation of TrxR expression
- TrxR thioredoxin reductase
- Up-regulation or activity-enhancing related diseases or disorders are used in the treatment of tumors, in methods for the treatment of tumors, or in the preparation of drugs for the treatment of tumors.
- the present invention also provides a method for treating or alleviating a disease or condition related to the up-regulation or increased activity of TrxR in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula (I) or its A pharmaceutically acceptable salt or a pharmaceutical composition containing the same.
- the present invention also provides a method for treating tumors in a subject, comprising administering a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same to a subject in need thereof.
- the disease or disorder related to the up-regulation or increased activity of TrxR is a tumor
- the tumor includes, but is not limited to, glioma, 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, vagina cancer, vulvar cancer, esophagus cancer, small intestine cancer, endocrine cancer System cancer, soft tissue sarcoma, urethral deflation, prostate cancer, lymphoma, bladder cancer, kidney cancer, ureter cancer, spinal tumor, brainstem glioma, pituitary adenoma, lung cancer, liver cancer or blood cancer, Preferably, it is glioma.
- the arylisoselenazole compound containing tetrazine substituents of the present invention has the characteristic of targeting TrxR target. Because TrxR is a tumor growth regulating enzyme, it has the characteristics of a tumor growth marker. In addition, TrxR is highly expressed in brain gliomas as several recognized tumor markers. Therefore, compounds targeting TrxR inhibition will have good anti-tumor efficacy against brain glial. At present, the compounds can well inhibit the growth of various glioma cell lines both in vivo and in vitro.
- Figure 1 is a schematic diagram of the electron transfer inside the TRX system.
- Figure 2 shows the effect of compound 1 on the body weight of tumor-bearing (U87) mice.
- Figure 3 shows the effect of compound 1 on tumor volume in tumor-bearing (U87) mice.
- Figure 4 shows the effect of compound 1 on tumor weight in tumor-bearing (U87) mice.
- alkyl should be understood to mean a linear or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms.
- C 1-10 alkyl refers to straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.
- the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, etc. or their isomers.
- alkoxy should be understood as -OC 1-10 alkyl, wherein C 1-10 alkyl has the above definition.
- cycloalkyl should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3 to 20 carbon atoms.
- C 3-10 cycloalkyl should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
- the C 3-10 cycloalkyl group may be a monocyclic hydrocarbon group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic group. Hydrocarbyl such as decalin ring
- alkylene means a divalent alkyl group, for example, C 1-10 alkylene means a divalent C 1-10 alkyl group.
- heterocyclyl refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3 to 20 atoms, which contains 1-5 heteroatoms independently selected from N, O and S, preferably "3-10 membered hetero Cyclic group".
- 3-10 membered heterocyclic group means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S.
- the heterocyclic group may be connected to the rest of the molecule through any one of the carbon atoms or a nitrogen atom (if present).
- the heterocyclic group may include but is not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl Or trithiaalkyl; or 7-membered ring, such as diazepanyl.
- 4-membered ring such as azetidinyl, oxetanyl
- 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrol
- the heterocyclic group may be benzo-fused.
- the heterocyclic group may be bicyclic, such as but not limited to a 5, 5-membered ring, such as hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5, 6-membered bicyclic ring, such as hexahydropyrrole And [1,2-a]pyrazine-2(1H)-yl ring.
- the ring containing the nitrogen atom may be partially unsaturated, that is, it may contain one or more double bonds, such as but not limited to 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadi Azinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as but not limited to dihydroisoquinolinyl.
- the heterocyclic group is non-aromatic.
- aryl should be understood as a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6-20 carbon atoms, preferably 6-14 carbon atoms, preferably "C 6-14 aromatic base”.
- C 6-10 aryl should be understood as preferably meaning a monocyclic, bicyclic or partially aromatic monocyclic or partially aromatic monocyclic ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms.
- a tricyclic hydrocarbon ring (“C 6-14 aryl”), especially a ring having 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or one having 9 carbon atoms Ring (“C 9 aryl”), such as indanyl or indenyl, or a ring with 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring having 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring having 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
- the C 6-14 aryl group When the C 6-14 aryl group is substituted, it may be mono-substituted or multi-substituted. In addition, there is no restriction on the substitution site, for example, it may be ortho, para or meta substitution.
- heteroaryl should be understood as a monovalent monocyclic, bicyclic or tricyclic aromatic ring group having 3-20 ring atoms and containing 1-5 heteroatoms independently selected from N, O and S, for example "5-14 membered heteroaryl".
- the term “5-14 membered heteroaryl” should be understood as having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms-especially 5 or 6 or 9 or 10 carbon atoms ——And it contains 1-5—preferably 1-3—monovalent monocyclic, bicyclic or tricyclic aromatic ring groups independently selected from heteroatoms of N, O and S, and, additionally in each In one case, it may be benzo-fused.
- heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiol Diazolyl, etc.
- the solution turns into a white slurry, filtered with suction, washed with ice and water, and dried to obtain a white amorphous solid, namely 3,4-dihydro-3-methyl-4-oxo Pro-imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid (0.75 g, 75%).
- the solution turns into a white slurry, filtered with suction, washed with ice and water, and dried to obtain a white amorphous solid, namely 3,4-dihydro-3-methyl-4-oxo Pro-imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid (0.75 g, 75%).
- the solution turns into a white slurry, filtered with suction, washed with ice water, and dried to obtain a white amorphous solid, namely 3,4-dihydro-3-methyl-4 -Oxo-imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid (0.75 g, 80%).
- the solution turns into a white slurry, filtered with suction, washed with ice and water, and dried to obtain a white amorphous solid, namely 3,4-dihydro-3-methyl-4- Oxo-imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid (0.75 g, 80%).
- the solution turns into a white slurry, filtered with suction, washed with ice and water, and dried to obtain a white amorphous solid, namely 3,4-dihydro-3-methyl-4- Oxo-imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid (0.75 g, 80%).
- the solution turns into a white slurry, filtered with suction, washed with ice and water, and dried to obtain a white amorphous solid, namely 3,4-dihydro-3-methyl-4- Oxo-imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid (0.75 g, 75%).
- the solution turns into a white slurry, filtered with suction, washed with ice and water, and dried to obtain a white amorphous solid, namely 3,4-dihydro-3-methyl-4- Oxo-imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid (0.75 g, 80%).
- the mixture was acidified with hydrochloric acid, filtered to obtain a solid, washed with water and dried in a drying oven to obtain 4,4'-dimethyl-2,2'-diselenated bisbenzoic acid (5.88g, 55 %).
- the solution turns into a white slurry, filtered with suction, washed with ice and water, and dried to obtain a white amorphous solid, namely 3,4-dihydro-3-methyl-4- Oxo-imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid (0.75 g, 80%).
- Example 9 In vitro anti-tumor activity study of the compound of the present invention
- the MTT method was used to study the in vitro growth inhibitory activity of the compound 1-8 of the present invention on human glioma cells (U87 and LN229), human liver cancer cells (SMMC-7721) and human pancreatic cancer cells (Panc1).
- U87, LN229, SMMC-7721 and Panc1 cells in the logarithmic growth phase were respectively seeded in 96-well plates at a seeding density of 5 ⁇ 10 4 cells/mL, 180 ⁇ L/well; after the cells adhere to the wall, add 20 ⁇ L to each well Medicine solution, make the final concentration of the drug respectively 0 ⁇ M, 5 ⁇ M, 10 ⁇ M, 20 ⁇ M and 50 ⁇ M, after 48h of action, add 5mg/mL MTT solution (20 ⁇ L/well), put it in the CO 2 incubator and incubate for 3-4h, then discard it carefully Remove the supernatant, after the remaining liquid is air-dried, add acidified isopropanol (50 ⁇ L concentrated hydrochloric acid dissolved in 500mL isopropanol), 200mL/well, shake on a shaker for 30min, and after the crystals are completely dissolved, place it on the microplate reader at 570nm Measure the absorbance OD value, and the results are shown in Table
- Cell survival rate % (medicated cell OD-blank group OD)/(control cell OD-blank group OD) ⁇ 100
- the experimental results in Table 2 show that in the human glioma U87 cell line, the IC 50 of the compounds 1 and 3-8 of the present invention are significantly lower than that of TMZ.
- the compounds of the present invention all show good inhibitory activity, especially the IC 50 of compound 6 is significantly lower than that of TMZ, and the IC 50 of compounds 3, 5 and 8 is comparable to that of TMZ.
- the compounds of the present invention all show good inhibitory activity, especially the IC 50 of compounds 4, 5 and 8 are significantly lower than that of TMZ, and the IC 50 of compounds 2 and 6 are comparable to that of TMZ.
- the compounds of the present invention all show good inhibitory activity, especially the IC 50 of compounds 3, 5 and 8 are significantly lower than that of TMZ, and the IC 50 of the other compounds are comparable to TMZ.
- Example 10 Study on in vivo anti-tumor activity of compound 1 of the present invention
- the administration doses are: blank control group (5 ⁇ sodium carboxymethyl cellulose, once a day), temozolomide group (30mg ⁇ kg -1 ,ig,qd), 0409 low-dose group (45mg ⁇ kg -1 ,ig, qd), 0409 high-dose group (90mg ⁇ kg -1 , ig, qd).
- the solvent of temozolomide group, 0409 low-dose group, and 0409 high-dose group is acetic acid-sodium acetate buffer (pH 4.5), that is, take 18g of sodium acetate, add 9.8mL of glacial acetic acid, and then dilute to 1000mL with water. Available daily.
- the state of the mice was observed daily for 22 consecutive days, and the body weight and tumor volume were recorded. The tumor volume reached 100mm 3 as the standard to judge whether the mouse had a tumor.
- the results are shown in Table 3 and Figures 2, 3 and 4.
- the data are expressed as mean ⁇ standard deviation. *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001, indicating that there is a statistical difference compared with the control group.
- Figure 2 shows the changes in body weight of mice in each group before and 11 days after administration during the administration.
- temozolomide (TMZ) group, 0409 low-dose (0409L) group and 0409 high-dose (0409H) group the weight of the mice on the 11th day after administration was 1.01 times, 0.91 times, and the weight of the mice before administration, respectively. 1.02 times and 1.02 times.
- the weight loss of the TMZ group was obvious, reflecting the toxic reaction of TMZ.
- the drugs in the other groups had no obvious side effects on mice.
- the tumor volume and tumor weight of nude mice were counted, and the results are shown in Table 3, Figure 3 and Figure 4.
- the tumor volume and tumor weight of each administration group were statistically different compared with the control group.
- the tumor volume in the TMZ group was 209.18 ⁇ 57.83 mm 3 , and the tumor weight was 0.29 ⁇ 0.07 g;
- the tumor volume in the 0409 low-dose group was 96.70 ⁇ 24.08 mm 3 , and the tumor weight was 0.20 ⁇ 0.10 g;
- the tumor volume in the 0409 high-dose group was 90.00 ⁇ 32.64mm 3 , the tumor weight is 0.12 ⁇ 0.04g.
- the efficacy of 0409 is significantly improved.
- the tumor volume and tumor weight of the 0409 low and high dose groups decreased sequentially, and the tumor inhibition rates of the 0409 low and high dose groups were 82.78% and 83.97%, respectively, indicating that 0409 has a certain inhibitory effect on tumor growth. Concentration dependent phenomenon.
- Example 11 Compounds 1, 3, 6, and 8 are used to establish a subcutaneous model of human glioma cell U87 in Balb/c Nude nude mice Efficacy study
- test model and operation process were the same as in Example 10, and the inhibitory effect of compound 1, compound 3, compound 6, compound 8 and TMZ alone on the growth of Balb/c Nude human glioma cell U87 subcutaneous model tumor was explored.
- Administration method gavage (i.p., q.d. ⁇ 14 days). The results are as follows:
- the tumor inhibition rate of the compound 6 group was significantly higher than that of the other administration groups.
- the tumor inhibition rates of the compound 3, compound 6, and compound 8 groups were all above 80%.
- the tumor volume inhibition rates of the TMZ group, compound 1, compound 3, compound 6 and compound 8 groups were 14.26%, 81.42%, 88.01%, 92.48%, and 82.68%, respectively.
- Thioredoxin reductase is widely and highly expressed in tumor tissues, and the arylisoselazolone compounds of the present invention can choose to recognize thioredoxin reductase to show better targeting.
- the medicament of the present invention can well inhibit the growth of glioma cells both in vivo and in vitro, and significantly expand the application range of the existing aromatic isoselazolone compounds.
- Example 12 Study on in vitro anti-tumor activity of the compound of the present invention
- Example 13 Determination of thioredoxin reductase (TrxR) activity of the compounds of the present invention
- the measurement method is as follows:
- TrxR thioredoxin reductase
- compounds 8 and 50 of the IC 1,3,5,6 TrxR inhibitor and the IC 50 of the positive drug Butaselen On an order of magnitude, it shows excellent TrxR inhibitory activity.
- the aromatic isoselenazolone compounds of the present invention can be used as TrxR inhibitors for the treatment or alleviation of diseases or disorders related to the up-regulation of TrxR expression or increased activity.
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Abstract
本发明提供了式(I)和式(II)所示的含四嗪取代基的芳并异硒唑类化合物及其制备方法和应用。本发明的化合物具有TrxR抑制活性,具备靶向TrxR靶点特点,因此其对于肿瘤,特别是脑胶质瘤具有良好的抗肿瘤功效。本发明的化合物作为药物在体内和体外都能很好的抑制肿瘤细胞的生长。
Description
本申请要求2020年4月13日向中国国家知识产权局提交的,申请号为202010287745.6,发明名称为“含四嗪取代基的芳并异硒唑类化合物及其合成方法和应用”发明专利申请的优先权。该在先申请的全文通过引用的方式结合于本申请中。
本发明属于医药领域,具体涉及一种含四嗪取代基的芳并异硒唑类化合物的合成方法,以及其在制备用于治疗肿瘤——特别是脑胶质瘤——的药物中的应用。
脑胶质瘤是常见的原位颅内肿瘤,占颅内肿瘤50%以上,其发病率是全身恶性肿瘤的1-3%,患者的中位总生存期仅为12-15个月。由于脑胶质瘤大多呈浸润性生长,与正常脑组织无明显组织学边界,因此通过手术切除来根治脑胶质瘤非常困难。此外,放射治疗(RT)也是临床普遍应用的治疗方法,包括常规放疗、三维适形放疗及立体定向放疗等。而胶质瘤细胞本身对放疗敏感度不够高,不同亚型之间存在差异,放疗效果难以提升,必须结合药物治疗才能取得一定疗效。而由于血脑屏障的存在,大多数药物不能有效作用于肿瘤所在部位,对肿瘤杀伤效果有限。替莫唑胺(TMZ)作为新一代烷化剂,口服能够被快速吸收,具有高效、低毒、广谱的特点。在生理条件下,TMZ能够最终转化为具有细胞毒作用的重氮甲烷,在鸟嘌呤O
6位置发生甲基化而产生细胞毒性,是其发挥杀伤作用的主要原因。不管是单独应用还是联合放疗应用于胶质瘤的治疗中,TMZ都有较为不错的治疗效果。目前替莫唑胺的主要临床方案是“stupp”方案,即放射和辅助替莫唑胺化疗同步,在放疗结束后一个月采用TMZ辅助化疗,每28天为一周期,用药时间为连续5天,每日一次,间隔23天。第1周期150mg/m
2/d×5天,第2-6周期200mg/m
2/d×5天。Stupp方案治疗的患者的中位总生存期为14.6个月,而单独使用RT的患者的中位总生存期为12.1个月。
虽然取得了一定的成果,但是TMZ还存在一些缺点。首先是有效率还不理想。其次,副作用较多,患者会出现骨髓抑制、胃肠道反应、周围神经毒性等不良反应。再次,还存在耐药性问题,O
6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)能够直接将甲基切除,使TMZ失去作用。此外还容易产生多药耐药性(MDR)。这些是造成胶质瘤TMZ化疗失败的主要原因。
硫氧还蛋白系统(TRX系统)包括还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)、硫氧 还蛋白(Trx)以及硫氧还蛋白还原酶(TrxR)三个部分,其中TrxR是一种NADPH依赖的包含黄素腺嘌呤二核苷酸(FAD)结构域的二聚体硒酶。哺乳动物TrxR有三种亚型,细胞核中的TrxR1,线粒体中的TrxR2以及存在于睾丸内的TrxR3。整个TRX系统内部的电子转移如图1所示,完全氧化的酶从NADPH中接受电子,然后形成完全还原的酶。最后将底物还原,其中C-末端硒硫醇对起着传递电子的作用,是TrxR发挥调节氧化还原作用的基础。
TRX系统可以直接抗氧化并支持其他抗氧化酶的功能,通过防御外源性物质或致癌物引起氧化应激,有利于预防正常细胞转化为恶性肿瘤。在肿瘤发展和转移方面,由于TrxR/Trx水平升高具有促进细胞增殖、抵抗细胞凋亡和促进血管生成的功能,因此,可能促进肿瘤的生长。
TRX系统在肿瘤发生发展转移过程中具有重要的意义,是肿瘤细胞中维持内环境稳态、促进增殖和血管生成的重要系统。
TrxR在脑瘤呈高表达状态,对433例胶质母细胞瘤的临床数据的分析表明,硫氧还蛋白还原酶1(TrxR1)在超过66%的病例中发生上调,这与更强的增殖活性和更差的预后有明显关联。因此,针对TrxR靶点开展脑胶质瘤的治疗研究是十分紧迫的。
发明内容
本发明提供一种式(I)所示的含四嗪取代基的芳并异硒唑类化合物或其药学上可接受的盐:
其中,A
1、A
2、A
3和A
4相同或不同,彼此独立地选自CH或N,且最多有一个为N;当A
1、A
2、A
3或A
4为CH时,其上的氢原子可被R取代,其中R选自氢、氰基、羟基、卤素、硝基或者被一个或多个Ra取代的氨基、巯基、酰氨基、烷基、环烷基、烷氧基、杂环基、芳基、杂芳基,每个Ra彼此独立地选自氢、氰基、羟基、卤素、氨基、硝基、巯基、烷基、环烷基、烷氧基、芳基、杂芳基;R
1选自亚烷基。
根据本发明的实施方案,R选自氢、氰基、羟基、卤素、硝基或被一个或多个Ra取代的氨基、巯基、酰氨基、C
1-10烷基、C
3-10环烷基、C
1-10烷氧基、3-10元杂环基、C
6-14芳基、5-14元杂芳基,每个Ra彼此独立地选自氢、氰基、羟基、卤素、氨基、硝基、巯基、C
1-10烷基、C
3-10环烷基、C
1-10烷氧基、3-10元杂环基、C
6-14芳基、5-14元杂芳基;R
1选自C
1-10亚烷基。
根据本发明的实施方案,R选自氢、卤素或被一个或多个Ra取代的C
1-6烷基、C
3-6环烷基、C
1-6烷氧基、苯基、吡啶基,每个Ra彼此独立地选自氢、卤素、C
1-6烷基、C
3-6环烷基、C
1-6烷氧基、苯基、吡啶基;R
1选自C
1-6亚烷基。
根据本发明的实施方案,R选自氢、卤素、C
1-6烷基或C
1-6烷氧基。
根据本发明的实施方案,R选自氢、氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基和异戊氧基。
优选地,所述含四嗪取代基的芳并异硒唑类化合物的结构如式(II)所示:
其中,A
1选自CH或N;n为1、2、3、4、5或6;R具有上文所述的定义。
根据本发明的实施方案,R选自氢、卤素、C
1-6烷基或C
1-6烷氧基。
根据本发明的实施方案,R选自氢、氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基和异戊氧基。
优选地,所述含四嗪取代基的芳并异硒唑类化合物选自下表1中的化合物:
表1本发明的含四嗪取代基的芳并异硒唑类化合物
根据本发明的实施方案,式(I)或者式(II)所示的化合物的药学上可接受的盐包括:所述化合物与无机酸或有机酸形成的酸加成盐;所述无机酸选自盐酸、氢氟酸、氢溴酸、氢碘酸、高氯酸、硫酸、焦硫酸、磷酸或硝酸中的至少一种;所述有机酸选自甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺 酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸中的至少一种;
或者,式(I)或者式(II)所示的化合物的药学上可接受的盐为其碱金属盐、碱土金属盐、铵盐,或与提供生理学上可接受的阳离子的有机碱形成的盐,例如与如下物质中的至少一种形成的盐:钠离子、钾离子、钙离子、镁离子、吗啉、哌啶、三乙胺、三丙胺、三丁胺、二异丙基胺、二异丙基乙二胺、吡啶、二甲胺、二乙胺、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、葡甲胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、1-氨基-2,3,4-丁三醇。
本发明还提供式(Ⅰ)所示的化合物的制备方法,包括如下步骤,
1)将化合物A中的氨基重氮化,然后与Na
2Se
2反应制备得到化合物B:
其中,A
1、A
2、A
3、A
4、R和R
1具有上文所述的定义;
2)化合物B与二氯亚砜反应制备得到化合物C:
3)化合物C与H
2N-R
1-NHBoc反应制备得到化合物D:
其中,Boc表示叔丁氧羰基;
4)化合物D在酸存在下脱掉Boc保护基制备得到化合物E:
5)化合物E与化合物F反应制备得到式(I)所示化合物:
其中,在化合物F中,R
2选自氯、溴、羟基或-OR
3,其中R
3选自C
1-6烷基、琥珀酰亚胺基、叔丁氧羰基、甲磺酰基、对硝基苯磺酰基、对甲苯磺酰基、异丁基氧羰基。
根据本发明的实施方案,所述步骤1)中的Na
2Se
2可以通过单质硒和连二亚硫酸钠制备得到。
根据本发明的实施方案,所述步骤2)可在催化量的DMF存在下进行。根据本发明的实施方案,所述步骤4)中的酸可以为盐酸。此外,所述步骤4)可在有机溶剂如乙酸乙酯中进行。
根据本发明的实施方案,化合物F可商购获得或可通过本领域的常规方法获得,或者可以通过以下步骤制备得到:
a)化合物TMZ即替莫唑胺在硫酸和亚硝酸钠的作用下得到化合物F-1:
以及任选的步骤b):化合物F-1在催化量DMF存在下与二氯亚砜或二溴亚砜反应得到化合物F-2:
或者任选的步骤c):化合物F-1进一步反应得到其中R
2为-OR
3的化合物F,其中R
3为C
1-6烷基、琥珀酰亚胺基、叔丁氧羰基、甲磺酰基、对硝基苯磺酰基、对甲苯磺酰基或异丁基氧羰基。
所述步骤c)选自以下步骤c-1)、步骤c-2)、步骤c-3)、步骤c-4)或步骤c-5):
步骤c-1):化合物F-1与R
4OH在酸作用下生成化合物F-3(即其中R
2为-OR
3且R
3为C
1-6烷基的化合物F):
其中,R
4为C
1-6烷基;
步骤c-2):化合物F-1与R
5Cl在碱作用下生成化合物F-4(即其中R
2为-OR
3且R
3为甲磺酰基、对硝基苯磺酰基或对甲苯磺酰基的化合物F):
其中,R
5为甲磺酰基、对硝基苯磺酰基或对甲苯磺酰基;
步骤c-3):化合物F-1与N-羟基丁二酰亚胺反应得到化合物F-5(即其中R
2为-OR
3且R
3为琥珀酰亚胺基的化合物F):
步骤c-4):化合物F-1与二碳酸二叔丁酯反应得到化合物F-6(即其中R
2为-OR
3且R
3为叔丁氧基羰基的化合物F):
步骤c-5):化合物F-1与氯甲酸异丁酯反应得到化合物F-7(即其中R
2为-OR
3且R
3为异丁基氧羰基的化合物F):
本发明还提供了一种药物组合物,所述药物组合物包括所述式(I)所示含四嗪取代芳并异硒唑类化合物或其药学上可接受的盐,以及药学上可接受的载体。
根据本发明的实施方案,所述药物组合物适用于肠内、局部或肠胃外给药,例如,口服、注射、植入、外用、喷雾或吸入等给药方式。
根据本发明的实施方案,所述口服药物组合物可以为片剂、胶囊剂、丸剂、口服液体制剂、颗粒剂、注射剂、外用制剂或散剂的任意一种。
所述片剂可以为普通片、含片、舌下片、口腔贴片、咀嚼片、分散片、可溶片、泡腾片、阴道片、阴道泡腾片、缓释片、控释片、肠溶片或口腔速释片;所述胶囊剂可以为硬胶囊、软胶囊、缓释胶囊、控释胶囊或肠溶胶囊;所述丸剂包括滴丸、糖丸或小丸;所述口服液体制剂可以为糖浆剂、混悬剂、口服溶液剂、口服混悬剂、口服乳剂、糖浆剂、合剂、露剂或搽剂;所述颗粒剂可以为混悬颗粒、泡腾颗粒、肠溶颗粒、缓释颗粒或控释颗粒。所述注射剂可以为注射液、注射用无菌粉末或无菌块状物、输液和注射用浓溶液中的任意一种。所述 外用制剂可以为栓剂、气雾剂、粉雾剂、喷雾剂、膜剂、凝胶剂、贴剂、胶剂、贴膏剂、膏药、软膏剂、搽剂、洗剂、涂抹剂和凝膏剂中的任意一种。
根据本发明的实施方案,可采用本领域熟知的制剂技术手段来制备所述药物组合物。
根据本发明的实施方案,所述药物组合物可以为包合制剂或分散制剂。
根据本发明的实施方案,所述的药学上可接受的载体为本领域熟知用于制备上述制剂的常用赋形剂或辅料,其中,口服制剂或外用制剂常用的赋形剂或辅料包括但不仅限于填充剂、稀释剂、润滑剂、助流剂、抗粘着剂、分散剂、湿润剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂等。
所述粘合剂,例如糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物、明胶浆、糖浆、淀粉浆、聚乙烯吡咯烷酮,优选的纤维素衍生物为微晶纤维素、羧甲基纤维素钠、乙基纤维素、羟丙甲基纤维素;所述填充剂,例如乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐、山梨醇或甘氨酸,所述无机钙盐优选为硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙;所述润滑剂,例如微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇;所述崩解剂,例如淀粉及其衍生物、聚乙烯吡咯烷酮或微晶纤维素,所述淀粉衍生物优选为羧甲基淀粉钠、淀粉乙醇酸钠、预晈化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉;所述湿润剂,例如十二烷基硫酸钠、水或醇;所述赋形剂优选为α-环糊精、β-环糊精、γ-环糊精、Celadon102CG、聚维酮(PVP)-K系列(包括聚维酮K30(PVPK30))、滑石粉、硬脂酸镁或乙醇等。
根据本发明的实施方案,所述注射剂常用的赋形剂或辅料包括:抗氧剂、抑菌剂、pH调节剂、乳化剂、增溶剂。
所述抗氧剂,包括硫代硫酸钠、亚硫酸钠、亚硫酸氢钠、二丁基苯酸或焦亚硫酸钠;所述抑菌剂,包括苯酚、甲酚、三氯叔丁醇,优选为0.5%苯酚、0.3%甲酚、0.5%三氯叔丁醇;所述pH调节剂,包括盐酸、枸橼酸、氢氧化钾、氢氧化钠、枸橼酸钠、磷酸二氧钠或磷酸氢二钠;所述乳化剂,包括聚山梨酯-80、脂肪酸山梨坦、普朗尼克F-68、卵磷酯、豆磷脂;所述增溶剂,包括吐温-80、甘油。
根据本发明的实施方案,还可将式(I)所示化合物或所述其药学上可接受的盐与药学上可接受的缓控释载体按照缓控释制剂的常规制备方法制备成缓控释制剂。例如可以加入阻滞剂包衣或将式(I)所示化合物或所述其药学上可接受的盐微囊化后再制成微丸,如缓释微丸或控释微丸。
所述的缓控释载体包括但不仅限于油脂性掺入剂、亲水胶体或包衣阻滞剂;所述油脂性掺入剂包括单硬脂酸甘油酯、氢化蓖麻油、矿油、聚硅氧烷或二甲基硅氧烷;所述亲水胶体包括羧甲基纤维素钠、羟丙基纤维素、羟丙基甲基纤维素、聚乙烯吡咯烷酮(PVP)、阿拉伯胶、西黄耆胶或卡波普;所述包衣阻滞剂包括乙基纤维素(EC)、羟丙甲基纤维素(HPMC)、聚乙烯 吡咯烷酮(PVP)、邻苯二甲酸醋酸纤维素(CAP)、丙烯酸类树脂。
在本发明的优选实施方案中,根据所需给药方式,所述药物组合物包含约1-99重量%的式(Ⅰ)所示化合物或其药学上可接受的盐的任一种或其组合,以及1-99重量%的药学上可接受的载体。
本发明还提供式(I)所示化合物或其药学上可接受的盐或者包含其的药物组合物用于抑制硫氧还蛋白还原酶(TrxR)活性的应用,或者用于制备硫氧还蛋白还原酶(TrxR)抑制剂的应用。
本发明还提供式(I)所示化合物或其药学上可接受的盐或者包含其的药物组合物用于治疗或缓解与TrxR表达上调或活性提高相关的疾病或病症的应用,或者在制备治疗或缓解与TrxR表达上调或活性提高相关的疾病或病症的药物中的应用。
本发明还提供式(I)所示化合物或其药学上可接受的盐或者包含其的药物组合物用于治疗肿瘤或在制备治疗肿瘤的药物中的应用。
本发明还提供式(I)所示化合物或其药学上可接受的盐或者包含其的药物组合物,其用于抑制硫氧还蛋白还原酶(TrxR)活性,用于治疗或缓解与TrxR表达上调或活性提高相关的疾病或病症,用于治疗肿瘤,用于治疗肿瘤的方法中,或者用于制备治疗肿瘤的药物。
本发明还提供一种在受试者中治疗或缓解与TrxR表达上调或活性提高相关的疾病或病症的方法,包括给予需要其的受试者治疗有效量的式(I)所示化合物或其药学上可接受的盐或者包含其的药物组合物。
本发明还提供一种治疗受试者的肿瘤的方法,包括给予需要其的受试者治疗有效量的式(I)所示化合物或其药学上可接受的盐或者包含其的药物组合物。
根据本发明的实施方案,所述与TrxR表达上调或活性提高相关的疾病或病症为肿瘤,所述肿瘤包括但不限于脑胶质瘤、肺癌、肝癌、血癌、骨癌、胰腺癌、皮肤癌、黑素瘤、子宫癌、卵巢癌、直肠癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌系统癌、软组织肉瘤、尿道癟、前列腺癌、淋巴细胞瘤、膀胱癌、肾癌、输尿管癌、脊椎肿瘤、脑干神经胶质瘤、垂体腺瘤、肺癌、肝癌或血癌中的任一种,优选为脑胶质瘤。
本发明的含四嗪取代基的芳并异硒唑类化合物具备靶向TrxR靶点特点,由于TrxR是肿瘤生长调控酶,具有肿瘤生长标志物特征。且脑胶质瘤中TrxR是高表达的几个公认的肿瘤标志物,因此针对靶向TrxR抑制的化合物将具有良好的针对脑胶质的抗肿瘤功效。目前化合物在体内和体外水平上均能够较好的抑制各个脑胶质瘤细胞系的生长。
图1为TRX系统内部的电子转移示意图。
图2示出了化合物1对荷瘤(U87)小鼠体重的影响。
图3示出了化合物1对荷瘤(U87)小鼠肿瘤体积的影响。
图4示出了化合物1对荷瘤(U87)小鼠瘤重的影响。
术语定义与说明
术语“烷基”应理解为表示具有1~12个碳原子的直链或支链饱和一价烃基。例如,“C
1-10烷基”表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直链和支链烷基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。
术语“烷氧基”应理解为-O-C
1-10烷基,其中C
1-10烷基具有上述定义。
术语“环烷基”应理解为表示饱和的一价单环或双环烃环,其具有3~20个碳原子。术语“C
3-10环烷基”应理解为表示饱和的一价单环或双环烃环,其具有3、4、5、6、7、8、9或10个碳原子。所述C
3-10环烷基可以是单环烃基,如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基,或者是双环烃基如十氢化萘环
本文中,“亚烷基”表示二价烷基基团,例如C
1-10亚烷基表示二价C
1-10烷基基团。
术语“杂环基”指包含3至20个原子的饱和的一价单环或双环烃环,其包含1-5个独立选自N、O和S的杂原子,优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的一价单环或双环烃环,其包含1-5个,优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地,所述杂环基可以包括但不限于:4元环,如氮杂环丁烷基、氧杂环丁烷基;5元环,如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基;或6元环,如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基;或7元环,如二氮杂环庚烷基。任选地,所述杂环基可以是苯并稠合的。所述杂环基可以是双环的,例如但不限于5,5元环,如六氢环戊并[c]吡咯-2(1H)-基环,或者5,6元双环,如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的,即它可以包含一个或多个双键,例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基,或者,它可以是苯并稠合的,例如但不限于二氢异喹啉基。根据本发明,所述杂环基是无芳香性的。
术语“芳基”应理解为具有6~20个碳原子,优选6~14个碳原子的一价芳香性或部分芳香性 的单环、双环或三环烃环,优选“C
6-14芳基”。术语“C
6-10芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C
6-14芳基”),特别是具有6个碳原子的环(“C
6芳基”),例如苯基;或联苯基,或者是具有9个碳原子的环(“C
9芳基”),例如茚满基或茚基,或者是具有10个碳原子的环(“C
10芳基”),例如四氢化萘基、二氢萘基或萘基,或者是具有13个碳原子的环(“C
13芳基”),例如芴基,或者是具有14个碳原子的环(“C
14芳基”),例如蒽基。当所述C
6-14芳基被取代时,其可以为单取代或者多取代。并且,对其取代位点没有限制,例如可以为邻位、对位或间位取代。
术语“杂芳基”应理解为具有3~20个环原子且包含1-5个独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团,例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为具有5、6、7、8、9、10、11、12、13或14个环原子——特别是5或6或9或10个碳原子——且其包含1-5个——优选1-3个——独立选自N、O和S的杂原子的一价单环、双环或三环芳族环基团,并且,另外在每一种情况下可为苯并稠合的。特别地,杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基等以及它们的苯并衍生物,例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等,以及它们的苯并衍生物,例如喹啉基、喹唑啉基、异喹啉基等;或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
术语“酰氨基”是指Ra-C(=O)-NH-基团,其中,Ra具有上文所述的定义。
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
实施例1
3,4-二氢-3-甲基-4-氧代-N-(3(2H)-氧代-1,2-苯并异硒唑-2-基)-乙基-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰胺(编号1)
1)在烧杯中加入2-氨基苯甲酸28g,并加入40mL浓盐酸与40mL水组成的混合液,冰浴,保持反应温度在5℃以下,缓慢滴加NaNO
2(18g溶于40mL水中)的溶液,滴完后继续反应2h,制得重氮盐溶液,备用;取100mL水并在其中加入16g NaOH,置于50℃搅拌溶解后,少量多次加入连二亚硫酸钠17.6g,待澄清后加入16g硒粉,加完后继续反应3h,制得Na
2Se
2溶 液,备用;在搅拌条件下,将重氮盐滴加到Na
2Se
2溶液中,保持反应温度在5℃以下,滴完后继续反应2h,并保证溶液显碱性。反应完成后,混合物用盐酸酸化,过滤得固体,水洗后置于燥干箱中干燥,制得2,2’-二硒化双苯甲酸(25g,63%)。
2)向2,2’-二硒化双苯甲酸(4g,10mmol)中加入氯化亚砜(20mL)和DMF 1-2滴,搅拌回流5h,减压蒸去氯化亚砜,残渣用石油醚(100mL)重结晶,硅藻土过滤,滤液置于冰箱中得到黄色针状结晶2-硒氯苯甲酰氯(3g,59%)。
3)将Boc-乙二胺(1.60g,10mmol)溶于二氯甲烷(10mL)中,再加入三乙胺1.39mL,在冰浴下,向混合物中缓慢滴入2-硒氯苯甲酰氯(2.54g,10mmol)的二氯甲烷(10mL)溶液,升温至室温反应3h,减压蒸除溶剂,加乙醚搅拌析出白色固体,依次用水和石油醚洗涤,固体烘干后经柱层析(石油醚:二氯甲烷:甲醇=200:200:1),得到黄色固体,即(3(2H)-氧代-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(1.4g,41%))。
4)50mL单口瓶中加入(3(2H)-氧代-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(0.500g,1.47mmol),再加入2N盐酸乙酸乙酯溶液(5mL),反应1h,溶液先澄清后浑浊生成白色沉淀,抽滤,用乙酸乙酯洗涤,得白色固体,即2-氨乙基-[1,2-苯并异硒唑-3(2H)-酮]盐酸盐(0.405g,90%)。
5)在室温下,在搅拌下,将TMZ(0.97g,5.0mmol)分批加到浓硫酸中,完毕后,冰浴下滴加8mL NaNO
2(1.3g,18.8mmol)水溶液,控温于0℃,滴加完毕后,常温缓慢搅拌,体系溶液由棕黄色转为绿色胶状物再转为淡黄色胶状物。把胶状物倾入碎冰,剧烈搅拌,溶液转为白色浆状物,抽滤,冰水洗,干燥,得白色无定形固体,即3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.75g,75%)。
6)3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.585g,3mmol)、二氯亚砜30mL和2滴DMF反应5h,减压蒸除溶剂,加入少量甲苯,减压蒸除甲苯,得3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(0.545g,85%)。
7)将2-氨乙基-[1,2-苯并异硒唑-3(2H)-酮]盐酸盐(0.611g,2.2mmol)先与1mL三乙胺在二氯甲烷中反应1h,在冰浴下,加入3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(0.363g,1.7mmol)的二氯甲烷溶液,滴加完毕后升至室温,反应过夜,减压蒸除溶剂,二氯甲烷、水、丙酮洗涤固体,干燥后得目标化合物,其为黄色固体(441mg,62%)。
1H NMR(400MHz,DMSO-d
6)δ8.84(s,1H),8.67(s,1H),8.04(d,J=7.9Hz,1H),7.82(d,J=7.5Hz,1H),7.59(t,J=7.2Hz,1H),7.40(t,J=7.2Hz,1H),3.94(s,2H),3.86(s,3H),3.66–3.56(m,2H).
13C NMR(101MHz,DMSO-d
6)δ166.55,159.92,139.62,139.11,134.44,131.37,130.19,128.43,127.73,127.27,125.85,125.64,42.75,39.41,36.13.
实施例2
3,4-二氢-3-甲基-4-氧代-N-(3(2H)-氧代-5-氟-1,2-苯并异硒唑-2-基)-乙基-咪唑并 [5,1-d]-1,2,3,5-四嗪-8-甲酰胺(编号2)
1)在烧杯中加入2-氨基-5-氟苯甲酸7.75g,并加入15mL浓盐酸与15mL水组成的混合液,冰浴,保持反应温度在5℃以下,缓慢滴加NaNO
2(4.35g溶于10mL水中)的溶液,滴完后继续反应2h,制得重氮盐溶液,备用;取30mL水并在其中加入4g NaOH,置于50℃搅拌溶解后,少量多次加入连二亚硫酸钠4.35g,待澄清后加入4g硒粉,加完后继续反应2-3h,制得Na
2Se
2溶液,备用;在搅拌条件下,将重氮盐滴加到Na
2Se
2溶液中,保持反应温度在5℃以下,滴完后继续反应2h,并保证溶液显碱性。反应完成后,混合物用盐酸酸化,过滤得固体,水洗后置于燥干箱中干燥,制得5,5’-二氟-2,2’-二硒化双苯甲酸(6g,55%)。
2)向5,5’-二氟-2,2’-二硒化双苯甲酸(4.36g,10mmol)中加入氯化亚砜(20mL)和DMF1-2滴,搅拌回流5h,减压蒸去氯化亚砜,残渣用石油醚(100mL)重结晶,硅藻土过滤,滤液置于冰箱中得到黄色针状结晶,即5-氟-2-硒氯苯甲酰氯(3.25g,60%)。
3)将Boc-乙二胺(1.60g,10mmol)溶于二氯甲烷(10mL)中,再加入三乙胺1.39mL,在冰浴下,向混合物中缓慢滴入5-氟-2-硒氯苯甲酰氯(2.72g,10mmol)的二氯甲烷(10mL)溶液,升温至室温反应3h,减压蒸除溶剂,加乙醚搅拌析出白色固体,依次用水和石油醚洗涤,固体烘干后经柱层析(石油醚:二氯甲烷:甲醇=200:200:1),得到黄色固体,即(3(2H)-氧代-5-氟-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(1.22g,34%)。
4)25mL单口瓶中加入(3(2H)-氧代-5-氟-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(0.359g,1.00mmol),再加入2N盐酸乙酸乙酯溶液(5mL),反应1h,溶液先澄清后浑浊生成白色沉淀,抽滤,用乙酸乙酯洗涤,得白色固体,即2-(2-氨基乙基)-5-氟-1,2-苯并异硒唑-3(2H)-酮盐酸盐(0.251g,85%)。
5)在室温下,在搅拌下,将TMZ(0.97g,5.0mmol)分批加到浓硫酸中,完毕后,冰浴下滴加8mL NaNO
2(1.3g,18.8mmol)水溶液,控温于0℃,滴加完毕后,常温缓慢搅拌,体系溶液由棕黄色转为绿色胶状物再转为淡黄色胶状物。把胶状物倾入碎冰,剧烈搅拌,溶液转为白色浆状物,抽滤,冰水洗,干燥,得白色无定形固体,即3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.75g,75%)。
6)3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.585g,3mmol)、二氯亚砜30mL和2滴DMF反应5h,减压蒸除溶剂,加入少量甲苯,减压蒸除甲苯,得3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(0.545g,85%)。
7)将2-(2-氨基乙基)-5-氟-1,2-苯并异硒唑-3(2H)-酮盐酸盐(222mg,0.75mmol)先与三乙胺在二氯甲烷中反应1h,在冰浴下,加入3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(107mg,0.5mmol)的二氯甲烷溶液,滴加完毕后升至室温,反应过夜,减压蒸除溶剂,用二氯甲烷、水、丙酮洗涤固体,干燥后得目标化合物,其为白色固体(50mg,23%)。
1H NMR(400MHz,DMSO-d
6)δ8.84(s,1H),8.67(s,1H),8.04(dd,J=8.6,4.9Hz,1H),7.63–7.44(m, 2H),3.94(t,J=5.4Hz,2H),3.86(s,3H),3.66–3.55(m,2H).
13C NMR(101MHz,DMSO-d
6)δ165.62,165.59,162.25,159.95,159.84,139.13,134.61,134.46,130.17,129.40,129.33,128.46,127.88,127.81,119.63,119.39,113.07,112.84,43.01,38.98,36.15.
实施例3
3,4-二氢-3-甲基-4-氧代-N-(3(2H)-氧代-6-氟-1,2-苯并异硒唑-2-基)-乙基-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰胺(编号3)
1)在烧杯中加入2-氨基-6-氟苯甲酸7.75g,并加入15mL浓盐酸与15mL水组成的混合液,冰浴,保持反应温度在5℃以下,缓慢滴加NaNO
2(4.35g溶于10mL水中)的溶液,滴完后继续反应2h,制得重氮盐溶液,备用;取30mL水并在其中加入4g NaOH,置于50℃搅拌溶解后,少量多次加入连二亚硫酸钠4.35g,待澄清后加入4g硒粉,加完后继续反应3h,制得Na
2Se
2溶液,备用;在搅拌条件下,将重氮盐滴加到Na
2Se
2溶液中,保持反应温度在5℃以下,滴完后继续反应2h,并保证溶液显碱性。反应完成后,混合物用盐酸酸化,过滤得固体,水洗后置于燥干箱中干燥,制得4,4’-二氟-2,2’-二硒化双苯甲酸(5.5g,50%)。
2)向4,4’-二氟-2,2’-二硒化双苯甲酸(4.36g,10mmol)中加入氯化亚砜(20mL)和DMF1-2滴,搅拌回流5h,减压蒸去氯化亚砜,残渣用石油醚(100mL)重结晶,硅藻土过滤,滤液置于冰箱中得到黄色针状结晶,即4-氟-2-硒氯苯甲酰氯(3.00g,55%)。
3)将Boc-乙二胺(1.60g,10mmol)溶于二氯甲烷(10mL)中,再加入三乙胺1.39mL,在冰浴下,向混合物中缓慢滴入4-氟-2-硒氯苯甲酰氯(2.72g,10mmol)的二氯甲烷(10mL)溶液,升温至室温反应3h,减压蒸除溶剂,加乙醚搅拌析出白色固体,依次用水和石油醚洗涤,固体烘干后经柱层析(石油醚:二氯甲烷:甲醇=200:200:1),得到黄色固体,即(3(2H)-氧代-6-氟-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(1.07g,30%)。
4)25mL单口瓶中加入(3(2H)-氧代-6-氟-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(0.359g,1.00mmol),再加入2N盐酸乙酸乙酯溶液(5mL),反应1h,溶液先澄清后浑浊生成白色沉淀,抽滤,用乙酸乙酯洗涤,得白色固体,即2-(2-氨基乙基)-6-氟-1,2-苯并异硒唑-3(2H)-酮盐酸盐(0.275g,93%)。
5)在室温下,在搅拌下,将TMZ(0.97g,5.0mmol)分批加到浓硫酸中,完毕后,冰浴下滴加8mL NaNO
2(1.3g,18.8mmol)水溶液,控温于0℃,滴加完毕后,常温缓慢搅拌,体系溶液由棕黄色转为绿色胶状物再转为淡黄色胶状物。把胶状物倾入碎冰中,剧烈搅拌,溶液转为白色浆状物,抽滤,冰水洗涤,干燥,得白色无定形固体,即3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.75g,80%)。
6)3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.585g,3mmol)、二氯亚砜30mL和2滴DMF反应5h,减压蒸除溶剂,加入少量甲苯,减压蒸除甲苯,得3,4-二氢-3-甲 基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(0.545g,85%)。
7)将2-(2-氨基乙基)-6-氟-1,2-苯并异硒唑-3(2H)-酮盐酸盐(222mg,0.75mmol)先与三乙胺在二氯甲烷中反应1h,在冰浴下加入3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(107mg,0.5mmol)的二氯甲烷溶液,滴加完毕后升至室温,反应过夜,减压蒸除溶剂,用二氯甲烷、水、丙酮洗涤固体,干燥后得目标化合物,其为白色固体(120mg,55%)。
1H NMR(400MHz,DMSO-d
6)δ8.84(s,1H),8.68(t,J=5.5Hz,1H),7.82(ddd,J=16.4,8.8,3.8Hz,2H),7.26(td,J=8.7,2.1Hz,1H),3.93(t,J=5.7Hz,2H),3.86(s,3H),3.64–3.53(m,2H).
13C NMR(101MHz,DMSO-d
6)δ165.71,165.25,162.77,160.01,141.75,141.65,139.17,134.50,130.18,129.49,129.40,128.50,124.55,114.16,113.92,112.45,112.18,42.85,38.97,36.19.
实施例4
3,4-二氢-3-甲基-4-氧代-N-(3(2H)-氧代-5-氯-1,2-苯并异硒唑-2-基)-乙基-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰胺(编号4)
1)在烧杯中加入2-氨基-5-氯苯甲酸8.85g,并加入15mL浓盐酸与15mL水组成的混合液,冰浴,保持反应温度在5℃以下,缓慢滴加NaNO
2(4.35g溶于10mL水中)的溶液,滴完后继续反应2h,制得重氮盐溶液,备用;取30mL水并在其中加入4g NaOH,置于50℃搅拌溶解后,少量多次加入连二亚硫酸钠4.35g,待澄清后加入4g硒粉,加完后继续反应3h,制得Na
2Se
2溶液,备用;在搅拌条件下,将重氮盐滴加到Na
2Se
2溶液中,保持反应温度在5℃以下,滴完后继续反应2h,并保证溶液显碱性。反应完成后,混合物用盐酸酸化,过滤得固体,水洗后置于燥干箱中干燥,制得5,5’-二氯-2,2’-二硒化双苯甲酸(5.98g,51%)。
2)向5,5’-二氯-2,2’-二硒化双苯甲酸(4.69g,10mmol)中加入氯化亚砜(20mL)和DMF1-2滴,搅拌回流5h,减压蒸去氯化亚砜,残渣用石油醚(100mL)重结晶,硅藻土过滤,滤液置于冰箱中得到黄色针状结晶,即5-氯-2-硒氯苯甲酰氯(3.63g,63%)。
3)将Boc-乙二胺(1.60g,10mmol)溶于二氯甲烷(10mL)中,再加入三乙胺1.39mL,在冰浴下向混合物中缓慢滴入5-氯-2-硒氯苯甲酰氯(2.88g,10mmol)的二氯甲烷(10mL)溶液,升温至室温反应3h,减压蒸除溶剂,加乙醚搅拌析出白色固体,依次用水和石油醚洗涤,固体烘干后经柱层析(石油醚:二氯甲烷:甲醇=200:200:1),得到黄色固体,即(3(2H)-氧代-5-氯-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(1.12g,30%)。
4)25mL单口瓶中加入(3(2H)-氧代-5-氯-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(0.375g,1.00mmol),再加入2N盐酸乙酸乙酯溶液(5mL),反应1h,溶液先澄清后浑浊生成白色沉淀,抽滤,用乙酸乙酯洗涤,得白色固体,即2-(2-氨基乙基)-5-氯-1,2-苯并异硒唑-3(2H)-酮盐酸盐(0.284g,91%)。
5)在室温下,在搅拌下,将TMZ(0.93g,4.8mmol)分批加到浓硫酸中,完毕后,冰浴下滴加8mL NaNO
2(1.3g,18.8mmol)水溶液,控温于0℃,滴加完毕后,常温缓慢搅拌,体系溶 液由棕黄色转为绿色胶状物再转为淡黄色胶状物。把胶状物倾入碎冰中,剧烈搅拌,溶液转为白色浆状物,抽滤,冰水洗,干燥,得白色无定形固体,即3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.75g,80%)。
6)3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.585g,3mmol)、二氯亚砜30mL和2滴DMF反应5h,减压蒸除溶剂,加入少量甲苯,减压蒸除甲苯,得3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(0.545g,85%)。
7)将2-(2-氨基乙基)-5-氯-1,2-苯并异硒唑-3(2H)-酮盐酸盐(234mg,0.75mmol)先与三乙胺在二氯甲烷下反应1h,在冰浴下加入3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(147mg,0.5mmol)的二氯甲烷溶液,滴加完毕后升至室温,反应过夜,减压蒸除溶剂,用二氯甲烷、水、丙酮洗涤固体,干燥后得目标化合物,其为白色固体(147mg,65%)。
1H NMR(400MHz,DMSO-d
6)δ8.84(s,1H),8.67(t,J=5.1Hz,1H),8.03(d,J=8.6Hz,1H),7.77(s,1H),7.64(d,J=8.4Hz,1H),3.94(t,J=5.3Hz,2H),3.86(s,3H),3.60(d,J=5.6Hz,2H).
13C NMR(101MHz,DMSO-d
6)δ165.35,159.98,139.14,138.29,134.46,131.31,130.89,130.18,129.47,128.47,127.77,126.46,42.97,38.98,36.16.
实施例5
3,4-二氢-3-甲基-4-氧代-N-(3(2H)-氧代-5-溴-1,2-苯并异硒唑-2-基)-乙基-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰胺(编号5)
1)在烧杯中加入2-氨基-5-溴苯甲酸10.80g,并加入15mL浓盐酸与15mL水组成的混合液,冰浴,保持反应温度在5℃以下,缓慢滴加NaNO
2(4.35g溶于10mL水中)的溶液,滴完后继续反应2h,制得重氮盐溶液,备用;取30mL水并在其中加入4g NaOH,置于50℃搅拌溶解后,少量多次加入连二亚硫酸钠4.35g,待澄清后加入4g硒粉,加完后继续反应3h,制得Na
2Se
2溶液,备用;在搅拌条件下,将重氮盐滴加到Na
2Se
2溶液中,保持反应温度在5℃以下,滴完后继续反应2h,并保证溶液显碱性。反应完成后,混合物用盐酸酸化,过滤得固体,水洗后置于燥干箱中干燥,制得5,5’-二溴-2,2’-二硒化双苯甲酸(8.37g,60%)。
2)向5,5’-二溴-2,2’-二硒化双苯甲酸(5.58g,10mmol)中加入氯化亚砜(20mL)和DMF1-2滴,搅拌回流5h,减压蒸去氯化亚砜,残渣用石油醚(100mL)重结晶,硅藻土过滤,滤液置于冰箱中得到黄色针状结晶,即5-溴-2-硒氯苯甲酰氯(4.19g,63%)。
3)将Boc-乙二胺(1.60g,10mmol)溶于二氯甲烷(10mL)中,再加入三乙胺1.39mL,在冰浴下,向混合物中缓慢滴入5-溴-2-硒氯苯甲酰氯(3.33g,10mmol)的二氯甲烷(10mL)溶液,升温至室温反应3h,减压蒸除溶剂,加乙醚搅拌析出白色固体,依次用水和石油醚洗涤,固体烘干后经柱层析(石油醚:二氯甲烷:甲醇=200:200:1),得到黄色固体,即(3(2H)-氧代-5-溴-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(1.72g,41%)。
4)25mL单口瓶中加入(3(2H)-氧代-5-溴-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯 (0.420g,1.00mmol),再加入2N盐酸乙酸乙酯溶液(5mL),反应1h,溶液先澄清后浑浊生成白色沉淀,抽滤,用乙酸乙酯洗涤,得白色固体,即2-(2-氨基乙基)-5-溴-1,2-苯并异硒唑-3(2H)-酮盐酸盐(0.338g,95%)。
5)在室温下,在搅拌下,将TMZ(0.97g,5.0mmol)分批加到浓硫酸中,完毕后,冰浴下滴加8mL NaNO
2(1.3g,18.8mmol)水溶液,控温于0℃,滴加完毕后,常温缓慢搅拌溶液由棕黄色转为绿色胶状物再转为淡黄色胶状物。把胶状物倾入碎冰中,剧烈搅拌,溶液转为白色浆状物,抽滤,冰水洗,干燥,得白色无定形固体,即3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.75g,80%)。
6)3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.585g,3mmol)、二氯亚砜30mL和2滴DMF反应5h,减压蒸除溶剂,加入少量甲苯,减压蒸除甲苯,得3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(0.545g,85%)。
7)将2-(2-氨基乙基)-5-溴-1,2-苯并异硒唑-3(2H)-酮盐酸盐(267mg,0.75mmol)先与三乙胺在二氯甲烷中反应1h,冰浴下加入3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(107mg,0.5mmol)的二氯甲烷溶液,滴加完毕后升至室温,反应过夜,减压蒸除溶剂,用二氯甲烷、水、丙酮洗涤固体,干燥后得目标化合物,其为白色固体(151mg,61%)。
1H NMR(400MHz,DMSO-d
6)δ8.84(s,1H),8.66(t,J=5.7Hz,1H),8.12(d,J=8.6Hz,1H),7.92–7.84(m,1H),7.74(dd,J=8.5Hz,1H),3.92(t,J=5.8Hz,2H),3.86(s,3H),3.59(q,J=5.8Hz,2H).
13C NMR(101MHz,DMSO-d
6)δ165.18,159.93,139.25,139.13,134.45,130.21,130.16,129.25,129.06,128.57,128.45,118.74,42.76,39.05,36.16.
实施例6
3,4-二氢-3-甲基-4-氧代-N-(3(2H)-氧代-5-甲基-1,2-苯并异硒唑-2-基)-乙基-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰胺(编号6)
1)在烧杯中加入2-氨基-5-甲基苯甲酸7.75g,并加入15mL浓盐酸与15mL水组成的混合液,冰浴,保持反应温度在5℃以下,缓慢滴加NaNO
2(4.35g溶于10mL水中)的溶液,滴完后继续反应2h,制得重氮盐溶液,备用;取30mL水并在其中加入4g NaOH,置于50℃搅拌溶解后,少量多次加入连二亚硫酸钠4.35g,待澄清后加入4g硒粉,加完后继续反应3h,制得Na
2Se
2溶液,备用;在搅拌条件下,将重氮盐滴加到Na
2Se
2溶液中,保持反应温度在5℃以下,滴完后继续反应2h,并保证溶液显碱性。反应完成后,混合物用盐酸酸化,过滤得固体,水洗后置于燥干箱中干燥,制得5,5’-二甲基-2,2’-二硒化双苯甲酸(5.88g,54%)。
2)向5,5’-二甲基-2,2’-二硒化双苯甲酸(4.28g,10mmol)中加入氯化亚砜(20mL)和DMF1-2滴,搅拌回流5h,减压蒸去氯化亚砜,残渣用石油醚(100mL)重结晶,硅藻土过滤,滤液置于冰箱中得到黄色针状结晶5-甲基-2-硒氯苯甲酰氯(2.84g,53%)。
3)将Boc-乙二胺(1.60g,10mmol)溶于二氯甲烷(10mL)中,再加入三乙胺1.39mL,在 冰浴下,向混合物中缓慢滴入5-甲基-2-硒氯苯甲酰氯(2.68g,10mmol)的二氯甲烷(10mL)溶液,升温至室温反应3h,减压蒸除溶剂,加乙醚搅拌析出白色固体,依次用水和石油醚洗涤,固体烘干后经柱层析(石油醚:二氯甲烷:甲醇=200:200:1),得到黄色固体,即(3(2H)-氧代-5-甲基-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(1.31g,37%)。
4)25mL单口瓶中加入(3(2H)-氧代-5-甲基-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(0.355g,1.00mmol),再加入2N盐酸乙酸乙酯溶液(5mL),反应1h,溶液先澄清后浑浊生成白色沉淀,抽滤,用乙酸乙酯洗涤,得白色固体2-(2-氨基乙基)-5-甲基-1,2-苯并异硒唑-3(2H)-酮盐酸盐(0.262g,90%)。
5)在室温下,在搅拌下,将TMZ(0.97g,5.0mmol)分批加到浓硫酸中,完毕后,冰浴下滴加8mL NaNO
2(1.3g,18.8mmol)水溶液,控温于0℃,滴加完毕后,常温缓慢搅拌,溶液由棕黄色转为绿色胶状物再转为淡黄色胶状物。把胶状物倾入碎冰中,剧烈搅拌,溶液转为白色浆状物,抽滤,冰水洗,干燥,得白色无定形固体,即3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.75g,75%)。
6)3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.585g,3mmol)、二氯亚砜30mL和2滴DMF反应5h,减压蒸除溶剂,加入少量甲苯,减压蒸除甲苯,得3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(0.545g,85%)。
7)将2-(2-氨基乙基)-5-甲基-1,2-苯并异硒唑-3(2H)-酮盐酸盐(231mg,0.75mmol)先与三乙胺在二氯甲烷中反应1h,冰浴下加入3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(107mg,0.5mmol)的二氯甲烷溶液,滴加完毕后升至室温,反应过夜,减压蒸除溶剂,用二氯甲烷、水、丙酮洗涤固体,干燥后得目标化合物,其为白色固体(147mg,68%)。
1H NMR(400MHz,DMSO-d
6)δ8.84(s,1H),8.66(t,J=5.4Hz,1H),7.88(d,J=8.2Hz,1H),7.64(s,1H),7.42(d,J=8.2Hz,1H),3.92(t,J=6.1Hz,2H),3.86(s,3H),3.59(q,J=6.1Hz,2H),2.39(s,3H).
13C NMR(101MHz,DMSO-d
6)δ166.56,159.93,139.14,136.28,135.22,134.46,132.69,130.18,128.46,127.73,127.32,125.56,42.80,39.22,36.16,20.47.
实施例7
3,4-二氢-3-甲基-4-氧代-N-(3(2H)-氧代-5-甲氧基-1,2-苯并异硒唑-2-基)-乙基-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰胺(编号7)
1)在烧杯中加入2-氨基-5-甲氧基苯甲酸8.35g,并加入15mL浓盐酸与15mL水组成的混合液,冰浴,保持反应温度在5℃以下,缓慢滴加NaNO
2(4.35g溶于10mL水中)的溶液,滴完后继续反应2h,制得重氮盐溶液,备用;取30mL水并在其中加入4g NaOH,置于50℃搅拌溶解后,少量多次加入连二亚硫酸钠4.35g,待澄清后加入4g硒粉,加完后继续反应3h,制得Na
2Se
2溶液,备用;在搅拌条件下,将重氮盐滴加到Na
2Se
2溶液中,保持反应温度在5℃以下,滴完后继续反应2h,并保证溶液显碱性。反应完成后,混合物用盐酸酸化,过滤得固 体,水洗后置于燥干箱中干燥,制得5,5’-二甲氧基-2,2’-二硒化双苯甲酸(5.17g,45%)。
2)向5,5’-二氧甲基-2,2’-二硒化双苯甲酸(4.60g,10mmol)中加入氯化亚砜(20mL)和DMF1-2滴,搅拌回流5h,减压蒸去氯化亚砜,残渣用石油醚(100mL)重结晶,硅藻土过滤,滤液置于冰箱中得到黄色针状结晶,即5-甲氧基-2-硒氯苯甲酰氯(2.67g,47%)。
3)将Boc-乙二胺(1.60g,10mmol)溶于二氯甲烷(10mL)中,再加入三乙胺1.39mL,在冰浴下向混合物中缓慢滴入5-甲氧基-2-硒氯苯甲酰氯(2.84g,10mmol)的二氯甲烷(10mL)溶液,升温至室温反应3h,减压蒸除溶剂,加乙醚搅拌析出白色固体,依次用水和石油醚洗涤,固体烘干后经柱层析(石油醚:二氯甲烷:甲醇=200:200:1),得到黄色固体,即(3(2H)-氧代-5-甲氧基-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(1.67g,45%)。
4)25mL单口瓶中加入(3(2H)-氧代-5-甲氧基-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(0.371g,1.00mmol),再加入2N盐酸乙酸乙酯溶液(5mL),反应1h,溶液先澄清后浑浊生成白色沉淀,抽滤,用乙酸乙酯洗涤,得白色固体,即2-(2-氨基乙基)-5-甲氧基苯并[d][1,2]硒偶氮-3(2H)-酮盐酸盐(0.271g,88%)。
5)在室温下,在搅拌下,将TMZ(0.97g,5.0mmol)分批加到浓硫酸中,完毕后,冰浴下滴加8mL NaNO
2(1.3g,18.8mmol)水溶液,控温于0℃,滴加完毕后,常温缓慢搅拌,体系溶液由棕黄色转为绿色胶状物再转为淡黄色胶状物。把胶状物倾入碎冰中,剧烈搅拌,溶液转为白色浆状物,抽滤,冰水洗,干燥,得白色无定形固体,即3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.75g,80%)。
6)3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.585g,3mmol)、二氯亚砜30mL和2滴DMF反应5h,减压蒸除溶剂,加入少量甲苯,减压蒸除甲苯,得3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(0.545g,85%)。
7)将2-(2-氨基乙基)-5-甲氧基-1,2-苯并异硒唑-3(2H)-酮盐酸盐(231mg,0.75mmol)先与三乙胺在二氯甲烷中反应1h,冰浴下加入3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(107mg,0.5mmol)的二氯甲烷溶液,滴加完毕后升至室温,反应过夜,减压蒸除溶剂,用二氯甲烷、水、丙酮洗涤固体,干燥后得目标化合物,其为白色固体(159mg,71%)。
1H NMR(400MHz,DMSO-d
6)δ8.84(s,1H),8.67(t,J=5.7Hz,1H),7.91(d,J=8.8Hz,1H),7.32(d,J=2.7Hz,1H),7.23(dd,J=8.8,2.7Hz,1H),3.93(t,J=6.0Hz,2H),3.87(s,3H),3.82(s,3H),3.60(q,J=6.0Hz,2H).
13C NMR(101MHz,DMSO-d
6)δ166.36,159.93,158.14,139.14,134.46,130.43,130.19,128.72,128.46,126.80,120.46,109.69,55.46,42.96,39.23,36.16.
实施例8
3,4-二氢-3-甲基-4-氧代-N-(3(2H)-氧代-6-甲基-1,2-苯并异硒唑-2-基)-乙基-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰胺(编号8)
1)在烧杯中加入2-氨基-6-甲基苯甲酸7.75g,并加入15mL浓盐酸与15mL水组成的混合 液,冰浴,保持反应温度在5℃以下,缓慢滴加NaNO
2(4.35g溶于10mL水中)的溶液,滴完后继续反应2h,制得重氮盐溶液,备用;取30mL水并在其中加入4g NaOH,置于50℃搅拌溶解后,少量多次加入连二亚硫酸钠4.35g,待澄清后加入4g硒粉,加完后继续反应3h,制得Na
2Se
2溶液,备用;在搅拌条件下,将重氮盐滴加到Na
2Se
2溶液中,保持反应温度在5℃以下,滴完后继续反应2h,并保证溶液显碱性。反应完成后,混合物用盐酸酸化,过滤得固体,水洗后置于燥干箱中干燥,制得4,4’-二甲基-2,2’-二硒化双苯甲酸(5.88g,55%)。
2)向4,4’-二甲基-2,2’-二硒化双苯甲酸(4.28g,10mmol)中加入氯化亚砜(20mL)和DMF1-2滴,搅拌回流5h,减压蒸去氯化亚砜,残渣用石油醚(100mL)重结晶,硅藻土过滤,滤液置于冰箱中得到黄色针状结晶4-甲基-2-硒氯苯甲酰氯(2.84g,53%)。
3)将Boc-乙二胺(1.60g,10mmol)溶于二氯甲烷(10mL)中,再加入三乙胺1.39mL,在冰浴下向混合物中缓慢滴入4-甲基-2-硒氯苯甲酰氯(2.68g,10mmol)的二氯甲烷(10mL)溶液,升温至室温反应3h,减压蒸除溶剂,加乙醚搅拌析出白色固体,依次用水和石油醚洗涤,固体烘干后经柱层析(石油醚:二氯甲烷:甲醇=200:200:1),得到黄色固体,即(3(2H)-氧代-6-甲基-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(1.85g,52%)。
4)25mL单口瓶中加入(3(2H)-氧代-6-甲基-1,2-苯并异硒唑-2-基)-乙基-1-氨基甲酸叔丁酯(0.355g,1.00mmol),再加入2N盐酸乙酸乙酯溶液(5mL),反应1h,溶液先澄清后浑浊生成白色沉淀,抽滤,用乙酸乙酯洗涤,得白色固体,即2-(2-氨基乙基)-6-甲基-1,2-苯并异硒唑-3(2H)-酮盐酸盐(0.265g,91%)。
5)在室温下,在搅拌下,将TMZ(0.97g,5.0mmol)分批加到浓硫酸中,完毕后,冰浴下滴加8mL NaNO
2(1.3g,18.8mmol)水溶液,控温于0℃,滴加完毕后,常温缓慢搅拌,体系溶液由棕黄色转为绿色胶状物再转为淡黄色胶状物。把胶状物倾入碎冰中,剧烈搅拌,溶液转为白色浆状物,抽滤,冰水洗,干燥,得白色无定形固体,即3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.75g,80%)。
6)3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酸(0.585g,3mmol)、二氯亚砜30mL和2滴DMF反应5h,减压蒸除溶剂,加入少量甲苯,减压蒸除甲苯,得3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(0.545g,85%)。
7)将2-(2-氨基乙基)-6-甲基-1,2-苯并异硒唑-3(2H)-酮盐酸盐(219mg,0.75mmol)先与三乙胺在二氯甲烷中反应1h,冰浴下加入3,4-二氢-3-甲基-4-氧代-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰氯(107mg,0.5mmol)的二氯甲烷溶液,滴加完毕后升至室温,反应过夜,减压蒸除溶剂,用二氯甲烷、水、丙酮洗涤固体,干燥后得目标化合物,其为白色固体(153mg,71%)。
1H NMR(400MHz,DMSO-d
6)δ8.84(s,1H),8.67(t,J=5.7Hz,1H),7.84(s,1H),7.70(d,J=7.9Hz,1H),7.22(d,J=7.5Hz,1H),3.92(t,J=6.0Hz,2H),3.86(s,3H),3.59(q,J=5.9Hz,2H),2.40(s,3H).
13C NMR(101MHz,DMSO)δ166.55,159.92,141.55,139.78,139.13,134.45,130.18,128.45, 127.05,126.98,125.68,125.43,42.70,38.96,36.15,21.46.
实施例9:本发明化合物的体外抗肿瘤活性研究
采用MTT法,研究了本发明化合物1-8对人胶质瘤细胞(U87和LN229)、人肝癌细胞(SMMC-7721)和人胰腺癌细胞(Panc1)的体外生长抑制活性。
取处于对数生长期的U87、LN229、SMMC-7721和Panc1细胞分别接种于96孔板,接种密度均为5×10
4个/mL,180μL/孔;待细胞贴壁后,每孔加入20μL药液,使药物终浓度分别为0μM、5μM、10μM、20μM和50μM,作用48h后,加入5mg/mL的MTT溶液(20μL/孔),放入CO
2孵箱培养3-4h后,小心弃去上清,待残留液体风干后,加入酸化异丙醇(50μL浓盐酸溶于500mL异丙醇),200mL/孔,于摇床上振摇30min,待结晶完全溶解后,于酶标仪570nm处测吸光度OD值,结果见表2。
细胞存活率%=(加药细胞OD-空白组OD)/(对照细胞OD-空白组OD)×100
细胞杀伤率%=1-细胞存活率%
表2化合物1-8体外对U87和LN229细胞作用48h的抑制活性(IC
50)
表2中的实验结果表明,在人胶质瘤U87细胞系,本发明的化合物1以及3-8的IC
50都显著低于TMZ。在人胶质瘤LN229细胞系中,本发明的化合物都显示良好的抑制活性,特别是化合物6的IC
50显著低于TMZ,化合物3、5和8的IC
50与TMZ相当。在人肝癌SMMC-7721细胞系中,本发明的化合物都显示良好的抑制活性,特别是化合物4、5和8的IC
50显著低于TMZ,化合物2和6的IC
50与TMZ相当。在人胰腺癌Panc1细胞系中,本发明的化合物都显示良好的抑制活性,特别是化合物3、5和8的的IC
50显著低于TMZ,其余化合物的IC
50与TMZ相当。
实施例10:本发明化合物1的体内抗肿瘤活性研究
本实验考察了化合物1(即3,4-二氢-3-甲基-4-氧代-N-(3(2H)-氧代-苯并异硒唑-2-基)-乙基-咪唑并[5,1-d]-1,2,3,5-四嗪-8-甲酰胺(动物实验中代号0409)的体内抗肿瘤活性。
本研究采用体重为12-17g的4周龄健康雌性Balb/c Nude裸鼠随机分组,分别为对照组和替莫唑胺组各8只,0409低剂量组和0409高剂量组各4只。准备人源神经胶质瘤U87细胞悬液2×10
7/mL,于裸鼠右腋下接种0.1mL,即接种量为2×10
6个/只。出瘤率为100%。接种后第12天开始给药,连续给药11天。给药剂量为:空白对照组(5‰羧甲基纤维素钠,每天口服一次),替莫唑胺组(30mg·kg
-1,i.g.,q.d.),0409低剂量组(45mg·kg
-1,i.g.,q.d.),0409高剂量组(90mg·kg
-1,i.g.,q.d.)。其中,替莫唑胺组、0409低剂量组、0409高剂量组溶剂为醋酸-醋酸钠缓冲液(pH4.5),即取醋酸钠18g,加冰醋酸9.8mL,再加水稀释至1000mL。每日现用现配。连续22天每日观察小鼠状态,并记录体重和肿瘤体积。以肿瘤体积达到100mm
3为标准判断小鼠是否出瘤。结果见表3,图2,3,4。
表3实验结束时各组裸鼠肿瘤体积重量及抑瘤率
数据表示为平均值±标准差。*P<0.05,**P<0.01,***P<0.001,表示与对照组相比具有统计学差异。
结论
图2为给药过程中各组小鼠给药前和给药后11天的体重变化情况。对照组,替莫唑胺(TMZ)组,0409低剂量(0409L)组和0409高剂量(0409H)组,给药后第11天的小鼠体重分别为给药前小鼠体重的1.01倍、0.91倍、1.02倍和1.02倍。TMZ组体重下降明显,反映了TMZ的毒性反应,其他组药物对小鼠没有明显的毒副作用。
对裸鼠肿瘤体积及肿瘤重量进行统计,结果如表3,图3以及图4所示。各给药组肿瘤体积及肿瘤重量均与对照组相比具有统计学差异。首先,TMZ组肿瘤体积为209.18±57.83mm
3,肿瘤重量为0.29±0.07g;0409低剂量组肿瘤体积为96.70±24.08mm
3,肿瘤重量为0.20±0.10g;0409高剂量组肿瘤体积为90.00±32.64mm
3,肿瘤重量为0.12±0.04g。与替莫唑胺相比,0409的药效有明显的改善。其次,0409低和高两个剂量组的肿瘤体积及肿瘤重量依次减小,且0409低和高两个剂量组的抑瘤率分别为82.78%和83.97%,说明0409对肿瘤生长抑制作用存在一定浓度依赖现象。
此外,还同步采用低剂量0409(20mg·kg
-1,i.v.),和TMZ(10mg·kg
-1,i.v.)进行试验,测定其体积抑瘤率。结果见表4。
表4低剂量0409(20mg·kg
-1,i.v.)和TMZ(10mg·kg
-1,i.v.)的体积抑瘤率结果
实施例11:化合物1、3、6、8对Balb/c Nude裸鼠建立人源胶质瘤细胞U87皮下模型的药
效学研究
同实施例10试验模型和操作过程,同时探索了化合物1、化合物3、化合物6、化合物8和TMZ单独给药对Balb/c Nude的人源胶质瘤细胞U87皮下模型肿瘤生长的抑制作用。给药方式:灌胃(i.p.,q.d.×14天)。结果如下:
1)化合物1(20mg/Kg)、化合物3(20mg/Kg)、化合物6(20mg/Kg)、化合物8(20mg/Kg)在此研究剂量下未呈体重下降表现。提示该类型药物对裸鼠没有明显毒副作用。
给药第四天后,化合物6组抑瘤率明显高于其他给药组,给药第七天后,化合物3、化合物6、化合物8三组的肿瘤抑制率都在80%以上。试验结束时,各给药组,即TMZ组、化合物1组、化合物3组、化合物6组和化合物8组的肿瘤体积抑制率分别为14.26%、81.42%、88.01%、92.48%和82.68%。如表5所示:
表5各组抑瘤率(%)
硫氧还蛋白还原酶在肿瘤组织中广泛高表达,本发明的芳并异硒唑酮类化合物可选择识 别硫氧还蛋白还原酶而呈现较好的靶向性。本发明的药物在体内外都能很好的抑制胶质瘤细胞的生长,显著拓展已有芳并异硒唑酮类化合物的应用范围。
实施例12:本发明化合物的体外抗肿瘤活性研究
参考实施例9的方法,选择了人神经胶质瘤细胞U251MG和U251TR两种肿瘤细胞系,采用SRB法对替莫唑胺和本发明的化合物进行体外抗癌活性筛选。各化合物IC
50值(μM)如下表6所示:
表6化合物的体外抗肿瘤IC
50结果(μM)
注:*:胶质瘤阳性药,即替莫唑胺;**:TrxR抑制剂阳性药,即Butaselen;ND:未测定
表6的实验结果显示,在TrxR抑制方面,本发明的化合物1、3、6和8都在5μM以下,其中化合物1的TrxR抑制活性接近TrxR抑制剂阳性药BS。在人神经胶质瘤细胞系U251MG和U251TR中,本发明化合物的IC
50都优于TMZ,表明四嗪取代的芳并异硒唑类化合物表现出了良好的抗胶质瘤细胞系的活性。其中本发明的化合物1、3、5、6和8在这两个细胞系中,尤其是对耐药株U251TR的IC
50都很低,抑制活性很强。
实施例13:本发明化合物的硫氧还蛋白还原酶(TrxR)活性测定
测定方法如下:
1.提取细胞总蛋白(即硫氧还蛋白还原酶)并测量浓度,在96孔板中加入30μg蛋白样品(每个浓度设置3个复孔),用0.1M磷酸钠缓冲液补足体积至80μL,37℃烘箱中孵育30min。
2.加入20μL 5mM NADPH(对照组加入同等体积的0.1M磷酸钠缓冲液),最后加入100μL 10mM DTNB和待测化合物(常规采用5个以上的浓度测定IC
50),立即用酶标仪(FlexStation 3,Molecular Devices)检测405nm处吸光值,第一次读数前震荡10s,每15s测定一次,测定30次。取最大反应速率为酶活性指标。实验独立重复三次。
测定结果如下表7所示:
表7对硫氧还蛋白还原酶的抑制活性(IC
50(μM))
注:*:替莫唑胺;**:TrxR抑制剂阳性药,即Butaselen
该测定结果表明,本发明的化合物具有良好的硫氧还蛋白还原酶(TrxR)抑制活性;特别地,化合物1、3、5、6和8的IC
50与TrxR抑制剂阳性药Butaselen的IC
50在一个数量级水平上,显示极好的TrxR抑制活性。预期本发明的芳并异硒唑酮类化合物可用作TrxR抑制剂,用于治疗或缓解与TrxR表达上调或活性提高相关的疾病或病症。
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
- 一种式(I)所示的含四嗪取代基的芳并异硒唑类化合物或其药学上可接受的盐:其中,A 1、A 2、A 3和A 4相同或不同,彼此独立地选自CH或N,且最多有一个为N;当A 1、A 2、A 3或A 4为CH时,其上的氢原子可被R取代,其中R选自氢、氰基、羟基、卤素、硝基或者被一个或多个Ra取代的氨基、巯基、酰氨基、烷基、环烷基、烷氧基、杂环基、芳基、杂芳基,每个Ra彼此独立地选自氢、氰基、羟基、卤素、氨基、硝基、巯基、烷基、环烷基、烷氧基、芳基、杂芳基;R 1选自亚烷基;优选地,R选自氢、氰基、羟基、卤素、硝基或被一个或多个Ra取代的氨基、巯基、酰氨基、C 1-10烷基、C 3-10环烷基、C 1-10烷氧基、3-10元杂环基、C 6-14芳基、5-14元杂芳基,每个Ra彼此独立地选自氢、氰基、羟基、卤素、氨基、硝基、巯基、C 1-10烷基、C 3-10环烷基、C 1-10烷氧基、3-10元杂环基、C 6-14芳基、5-14元杂芳基;R 1选自C 1-10亚烷基;优选地,R选自氢、卤素或被一个或多个Ra取代的C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、苯基、吡啶基,每个Ra彼此独立地选自氢、卤素、C 1-6烷基、C 3-6环烷基、C 1-6烷氧基、苯基、吡啶基;R 1选自C 1-6亚烷基;优选地,R选自氢、卤素、C 1-6烷基或C 1-6烷氧基;优选地,R选自氢、氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基和异戊氧基。
- 根据权利要求1或2所述的化合物或其药学上可接受的盐,其特征在于,所述药学上可接受的盐包括:所述化合物与无机酸或有机酸形成的酸加成盐;所述无机酸选自盐酸、氢氟酸、氢溴酸、氢碘酸、高氯酸、硫酸、焦硫酸、磷酸或硝酸中的至少一种;所述有机酸选自甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡糖酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸中的至少一种;或者,所述药学上可接受的盐为其碱金属盐、碱土金属盐、铵盐,或与提供生理学上可接受的阳离子的有机碱形成的盐,例如与如下物质中的至少一种形成的盐:钠离子、钾离子、钙离子、镁离子、吗啉、哌啶、三乙胺、三丙胺、三丁胺、二异丙基胺、二异丙基乙二胺、吡啶、二甲胺、二乙胺、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、葡甲胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、1-氨基-2,3,4-丁三醇。
- 权利要求1-3中任一项所示化合物的制备方法,包括如下步骤,1)将化合物A中的氨基重氮化,然后与Na 2Se 2反应制备得到化合物B:其中,A 1、A 2、A 3、A 4、R和R 1具有权利要求1-3中任一项所述的定义;2)化合物B与二氯亚砜反应制备得到化合物C:3)化合物C与H 2N-R 1-NHBoc反应制备得到化合物D:其中,Boc表示叔丁氧羰基;4)化合物D在酸存在下脱掉Boc保护基制备得到化合物E:5)化合物E与化合物F反应制备得到式(I)所示化合物:其中,在化合物F中,R 2选自氯、溴、羟基或-OR 3,其中R 3选自C 1-6烷基、琥珀酰亚胺基、 叔丁氧羰基、甲磺酰基、对硝基苯磺酰基、对甲苯磺酰基、异丁基氧羰基;优选地,所述步骤1)中的Na 2Se 2可以通过单质硒和连二亚硫酸钠制备得到;优选地,所述步骤2)可在催化量的DMF存在下进行;所述步骤4)中的酸为盐酸;所述步骤4)可在有机溶剂如乙酸乙酯中进行。
- 根据权利要求4所述的制备方法,其特征在于,所述化合物F可商购获得或可通过本领域的常规方法获得,或者通过以下步骤制备得到:a)化合物TMZ即替莫唑胺在硫酸和亚硝酸钠的作用下得到化合物F-1:以及任选的步骤b):化合物F-1在催化量DMF存在下与二氯亚砜或二溴亚砜反应得到化合物F-2:或者任选的步骤c):化合物F-1进一步反应得到其中R 2为-OR 3的化合物F,其中R 3为C 1-6烷基、琥珀酰亚胺基、叔丁氧羰基、甲磺酰基、对硝基苯磺酰基、对甲苯磺酰基或异丁基氧羰基;所述步骤c)选自以下步骤c-1)、步骤c-2)、步骤c-3)、步骤c-4)或步骤c-5);步骤c-1):化合物F-1与R 4OH在酸作用下生成化合物F-3:其中,R 4为C 1-6烷基;步骤c-2):化合物F-1与R 5Cl在碱作用下生成化合物F-4:其中,R 5为甲磺酰基、对硝基苯磺酰基或对甲苯磺酰基;步骤c-3):化合物F-1与N-羟基丁二酰亚胺反应得到化合物F-5:步骤c-4):化合物F-1与二碳酸二叔丁酯反应得到化合物F-6步骤c-5):化合物F-1与氯甲酸异丁酯反应得到化合物F-7:
- 一种药物组合物,其特征在于,所述药物组合物包括权利要求1-3中任一项所述化合物或其药学上可接受的盐,以及药学上可接受的载体;优选地,所述药物组合物适用于肠内、局部或肠胃外给药,例如,口服、注射、植入、外用、喷雾或吸入给药方式;优选地,所述口服药物组合物为片剂、胶囊剂、丸剂、口服液体制剂、颗粒剂、注射剂、外用制剂或散剂的任意一种;优选地,所述片剂为普通片、含片、舌下片、口腔贴片、咀嚼片、分散片、可溶片、泡腾片、阴道片、阴道泡腾片、缓释片、控释片、肠溶片或口腔速释片;所述胶囊剂为硬胶囊、软胶囊、缓释胶囊、控释胶囊或肠溶胶囊;所述丸剂包括滴丸、糖丸或小丸;所述口服液体制剂为糖浆剂、混悬剂、口服溶液剂、口服混悬剂、口服乳剂、糖浆剂、合剂、露剂或搽剂;所述颗粒剂为混悬颗粒、泡腾颗粒、肠溶颗粒、缓释颗粒或控释颗粒;所述注射剂为注射液、注射用无菌粉末或无菌块状物、输液和注射用浓溶液中的任意一种;所述外用制剂为栓剂、气雾剂、粉雾剂、喷雾剂、膜剂、凝胶剂、贴剂、胶剂、贴膏剂、膏药、软膏剂、搽剂、洗剂、涂抹剂和凝膏剂中的任意一种;优选地,所述药物组合物为包合制剂或分散制剂。
- 根据权利要求6所述的药物组合物,其特征在于,权利要求1-3任一项所述化合物或所述其药学上可接受的盐可与药学上可接受的缓控释载体按照缓控释制剂的常规制备方法制备成缓控释制剂;例如可以加入阻滞剂包衣或将权利要求1-3任一项所述化合物或所述其药学上可接受的盐微囊化后再制成微丸,如缓释微丸或控释微丸。
- 权利要求1-3中任一项所述的化合物或其药学上可接受的盐或者权利要求6或7所述的药物组合物的应用,其用于抑制硫氧还蛋白还原酶(TrxR)活性的应用,或者在制备硫氧还蛋白还原酶(TrxR)抑制剂的应用;其用于治疗或缓解与TrxR表达上调或活性提高相关的疾病或病症的应用,或者在制备治疗或缓解与TrxR表达上调或活性提高相关的疾病或病症的药物中的应用;优选地,所述与TrxR表达上调或活性提高相关的疾病或病症是肿瘤;或者其用于治疗肿瘤或在制备治疗肿瘤的药物中的应用。
- 根据权利要求8的应用,其中所述肿瘤选自脑胶质瘤、肺癌、肝癌、血癌、骨癌、胰腺癌、皮肤癌、黑素瘤、子宫癌、卵巢癌、直肠癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌系统癌、软组织肉瘤、尿道癟、前列腺癌、淋巴细胞瘤、膀胱癌、肾癌、输尿管癌、脊椎肿瘤、脑干神经胶质瘤、垂体腺瘤、肺癌、肝癌或血癌中的任一种,优选为脑胶质瘤。
- 一种治疗受试者的与TrxR表达上调或活性提高相关的疾病或病症例如肿瘤的方法,包括给予需要其的受试者治疗有效量的权利要求1-3任一项所述的化合物或其药学上可接受的盐或者权利要求6或7所述的药物组合物;所述肿瘤选自脑胶质瘤、肺癌、肝癌、血癌、骨癌、胰腺癌、皮肤癌、黑素瘤、子宫癌、卵巢癌、直肠癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、食道癌、小肠癌、内分泌系统癌、软组织肉瘤、尿道癟、前列腺癌、淋巴细胞瘤、膀胱癌、肾癌、输尿管癌、脊椎肿瘤、脑干神经胶质瘤、垂体腺瘤、肺癌、肝癌或血癌中的任一种,优选为脑胶质瘤。
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US20230167120A1 (en) | 2023-06-01 |
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