阅读说明：本技术 含硒异唑胺类化合物及其制备方法和用途 (Selenium-containing isoxazolidine compound and preparation method and application thereof ) 是由 宋维彬 柳艳辉 于 2019-07-22 设计创作，主要内容包括：本发明提供一类具有式I所示结构的含硒异唑胺类化合物,试验表明该类化合物能有效抑制TNF-α活性和调节细胞铁死亡。本发明还提供了该类抑制剂的制备方法及在制备预防和治疗TNF-α及细胞铁死亡介导的疾病药物中的应用。(The invention provides selenium-containing isoxazolidine compounds with a structure shown in a formula I, and tests show that the compounds can effectively inhibit TNF- α activity and regulate cell iron death.)

1. A selenium-containing isoxazolidine compound with a structure shown in a general formula (I) or a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound or metabolite thereof:

in the formula (I), the compound is shown in the specification,

R₁、R₂、R₃and R₄Each independently selected from the group consisting of: H. d, halogen, hydroxyl, amino, nitro, cyano, carboxyl, seleno, sulfydryl and C₁~C₈Alkylseleno group, C₁~C₈Alkylselenium C₁~C₈Alkylamino radical, C₂~C₈An alkenylalkylseleno group,α-C₁~C₈Alkylseleno amino acid,α-C₁~C₈Alkylselenoyl amino acid, C₀~C₈Alkylamine C₁~C₈Alkylseleno group, C₀~C₈Alkylcarbamoylseleno, C₀~C₈Alkyl amine formyl, aryl selenium radical, C₀~C₈Alkoxy C₁~C₈Alkylseleno group, C₀~C₈Alcoxyl formyl radical C₁~C₈Alkylseleno group, C₀~C₈Alcoxyl formyl radical C₁~C₈Alkoxy, halo C₁~C₈Alkylseleno group, C₁~C₈Alkanesulfonyl group, C₁~C₈Alkanesulfonamide group, C₀~C₈Alkylaminosulfonyl radical, C₁~C₈Alkyl, halo C₁~C₈Alkyl, halo C₁~C₈Alkoxy radical, C₀~C₈Alkylethynyl group, C₁~C₈Alkoxy radical, C₁~C₈Alkanoyloxy group, C₁~C₈Alkoxy C₁~C₈Alkoxy radical, C₁~C₈Alkoxy C₁~C₈Alkyl radical, C₁~C₈Alkylamino radical, C₀~C₈Alkylamine C₁~C₈Alkyl, aryl C₁~C₈Alkylamine C₁~C₈Alkyl, amidino, guanidino, arylsulfonamide, arylaminosulfonyl, arylformyl, C₀~C₈Alkylselenoyl, aryl C₁~C₈Alkylamino radical, aryl C₁~C₈Alkanoylamino group, C₁~C₈Alcoxyl formyl radical, C₁~C₈Alkanoylamino group, C₁~C₈Alkylamino radical, arylselenium C₁~C₈Amide group, cyanogen selenium C₁~C₈Amide group, benzoselenazole C₁~C₈Alkylamide group, benzoselenazole C₁~C₈Alkanesulfonamide group, C₀~C₈Alkylcarbamoylseleno, C₀~C₈Alkylamino carboxamido radical, C₀~C₈Alkylamino formyl, C₁~C₈Alkylamino formyloxy, arylamino formylamino, arylamino formyl, arylamino formyloxy, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, quinolinyl, pyrimidinyl, pyrimidinylamino, thiazolyl, thienyl, furanyl, pyrrolyl, or absent; wherein R is₁、R₂、R₃And R₄The aryl is phenyl or substituted by 1-4 groups selected from halogen, hydroxyl, nitro, cyano, amino, trifluoromethyl, carboxyl, C₀~C₈Alkylaminosulfonyl radical, C₁~C₈Alkanesulfonamide group, C₁~C₈Alkyl, halo C₁~C₈Alkoxy radical, C₁~C₈Phenyl substituted by a group in alkoxy; the benzoselenazole C₁~C₈Alkylamide group is

Z can be any of:

w is: c or Se; wherein, when W is C, R₁、R₂、R₃、R₄And R₅At least one selenium-containing substituent is present in the substituent; when W is Se, R₁、R₂、R₃、R₄And R₅Is any of the groups described above;

x is: o or is absent;

the dotted line is: chemical bonds or absence.

2. The compound of formula (I), or a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotopic compound or metabolite thereof, as claimed in claim 1, wherein the compound is as shown in formula (I-a), (I-b), (I-c) and (I-d):

、

in the formulae (I-a), (I-b), (I-c), (I-d) and (I-e),

R₁、R₂、R₃、R₄and R₅Each independently is a group selected from: H. d, halogen, hydroxyl, amino, nitro, cyano, carboxyl, C₀~C₈Alkylamine C₁~C₈Alkylseleno group, C₀~C₈Alkyl carbamoyl radical, C₀~C₈Alcoxyl formyl radical C₁~C₈Alkoxy, amidino, guanidino, C₁~C₈Alkanesulfonyl group, C₁~C₈Alkanesulfonamide group, C₀~C₈Alkylaminosulfonyl radical, C₁~C₈Alkyl, halo C₁~C₈Alkyl, halo C₁~C₈Alkoxy radical, C₀~C₈Alkylethynyl group, C₁~C₈Alkoxy radical, C₁~C₈Alkanoyloxy group, C₁~C₈Alkoxy C₁~C₈Alkoxy radical, C₁~C₈Alkoxy C₁~C₈Alkyl radical, C₁~C₈Alkylamino radical, C₀~C₈Alkylamine C₁~C₈Alkyl, aryl C₁~C₈Alkylamine C₁~C₈Alkyl, arylsulfonamide group, arylaminosulfonyl group, arylformyl group, arylmethylamino group, arylcarboxamido group, amidino group and C₀~C₈Alcoxyl formyl radical, C₁~C₈Alkanoylamino group, C₁~C₈Alkylamino radical, C₀~C₈Alkylamino carboxamido, C₀~C₈Alkylamino formyl, C₁~C₈Alkylamino formyloxy, arylamino formylamino, arylamino formyl, arylamino formyloxy or not; wherein R is₁、R₂、R₃And R₄The aryl is phenyl or substituted by 1-4 substituents selected from halogen, hydroxy, nitro, cyano, trifluoromethyl, carboxy, aminosulfonyl, C₁~C₆Alkyl radical, C₁~C₆Phenyl substituted by a group in alkoxy; wherein Z is selected from

x is: o or is absent;

the dotted line is: chemical bonds or absence.

3. The selenium-containing isoxazolines of claim 1 or pharmaceutically acceptable salts, solvates, crystal forms, stereoisomers, isotopic compounds or metabolites thereof, wherein the compounds are selected from the group consisting of:

4. a pharmaceutical composition comprising at least one compound of formula I as defined in one of claims 1 to 4 or a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotopic compound or metabolite thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

5. A selenium-containing isoxazoline compound or a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotopic compound or metabolite thereof according to any one of claims 1 to 4, which is obtainable by:

a process for preparing tanshinone IIA piperazine compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, by:

the benzisoselenazolone compounds in the structural series of the formulas I-a, I-b, I-c and I-d are synthesized by mainly using substituted o-halobenzoyl chloride as a raw material, respectively reacting with 3-amido-1-adamantanol and 2-benzothiazolylamine to obtain a substituted benzamide intermediate, and carrying out [ Se ] reaction on the intermediate to obtain a target compound;

the benzisoselenazolone compounds in the structural series of the formulas I-a, I-b, I-c, I-d and I-e can also be synthesized by taking substituted o-selenium chlorobenzoyl chloride as a raw material to react with 3-amino-2, 6-piperidedione, 3-amino-1, 4-dihydropyridine-2- (1H) -ketone and 3-amino-2, 5-pyrroledione respectively to obtain a target compound;

the benzisoselenazole compounds in the structural series of the formulas I-a, I-b, I-c, I-d and I-e are synthesized by taking substituted 2, 2' -diselenide benzaldehyde as a raw material, and reacting with 3-amino-1-adamantanol, 2-benzothiazolamine, 3-amino-2, 6-piperidedione, 3-amino-1, 4-dihydropyridine-2- (1H) -one and 3-amino-2, 5-pyrroledione to obtain corresponding ene imine intermediates; performing reductive amination cyclization on the alkene imine intermediate to obtain a benzisoselenazole compound;

the synthesis of quadrivalent selenium type compounds in the structural series of formulas I-a, I-b, I-c, I-d and I-e takes substituted benzisoselenazole as raw material and is obtained by O peroxidation.

6. Use of the selenium-containing isoxazolines of any one of claims 1 to 3 or pharmaceutically acceptable salts, solvates, crystal forms, stereoisomers, isotopic compounds or metabolites thereof in the manufacture of a medicament for the prevention or treatment of autoimmune diseases, neurodegenerative diseases, hematological tumors, solid tumors, myelofibrosis and acute/chronic graft-versus-host reaction diseases caused by overexpression of TNF- α.

7. Use of the selenium-containing isoxazolines of any one of claims 1 to 3 or pharmaceutically acceptable salts, solvates, crystal forms, stereoisomers, isotopic compounds or metabolites thereof in the manufacture of a medicament for the prevention or treatment of neuronal degenerative diseases, hematological tumors, solid tumors, tissue ischemia-reperfusion injury, acute renal failure and aging diseases caused by selenase-dependent cellular iron death.

8. A method of treating a patient suffering from a disease associated with TNF- α overexpression and or apoptosis comprising administering to the patient a therapeutically effective amount of a selenoiszolamide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.

9. A selenoisazolidine compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, as TNF- α inhibitor and or iron death modulator.

10. The use, method or selenoiszolamide compound according to claims 7, 8 or 9, wherein the autoimmune disease comprises: myelofibrosis and acute/chronic graft-versus-host-disease, rheumatoid arthritis, inflammatory bowel disease, diabetes, psoriasis, ankylosing spondylitis, erythema nodosum leprosum and other infectious diseases including HBV, HCV, HIV; the nervous system degenerative disease refers to Alzheimer disease, senile dementia, multiple sclerosis and motor neuron disease; the hematological tumor is multiple myeloma; the solid tumor refers to liver cancer, lung cancer, kidney cancer, stomach cancer, colon cancer, ovarian cancer, pancreatic cancer, prostatic cancer, breast cancer, melanoma and brain glioma; the tissue ischemia reperfusion injury refers to cerebral apoplexy, coronary heart disease, myocardial infarction, pulmonary embolism and acute coronary syndrome.

Technical Field

The invention belongs to the technical field of medicines, and relates to selenium-containing isoxazolidine compounds with TNF- α and/or iron death regulation activity and pharmaceutically acceptable salts, solvates, crystal forms, stereoisomers, isotopic compounds or metabolites thereof, a preparation method of the compounds, and application of the compounds as TNF- α and/or iron death regulators in treatment and/or prevention of diseases or symptoms related to TNF- α and iron death pathways of human beings or other mammals.

Background

TNF- α (tumor necrosis factor) is a cytokine with multiple biological effects discovered in the last 70 th century, mainly secreted by activated monocytes/macrophages/T cells, and specific to the cell membraneTNF- α can also be produced by tumors and can play a role in promoting tumor formation and also in causing programmed death of tumor cells, in addition, TNF- α also affects processes such as apoptosis, necrosis, angiogenesis, immune cell activation, differentiation and cell migration, all of which play an important role in tumorigenesis and tumor progression, while inappropriate TNF- α production and continued activation of TNF- α signals will lead to systemic human pathological processes including systemic inflammatory response syndrome, inflammatory bowel disease, rheumatoid arthritis, neurodegenerative diseases (multiple sclerosis, motor neuropathy, Alzheimer's disease, Parkinson), cerebral malaria, diabetes, allogenic tumors, osteoporosis, transplantation, HCV, HBV, and HIV (Brenner's disease), etc.et. al.Nat Rev Immunol. 2015,15(6), 362; J. Blake Bartlett.et. al.Nat Rev Cancer.2004, 4314.). thus reducing or modulating levels of TNF- α is a promising therapeutic strategy for a number of immunological, inflammatory, neurodegenerative and malignant diseases (Front. Biosci. 2008,13, 5094;Results Prob. Cell Differ. 2009,49, 1)。

Clinical application studies show that the biomacromolecule TNF- α inhibitor has obvious (80%) and quick curative effect on rheumatoid arthritis, mandatory spondylitis, dry moss arthritis, psoriasis and inflammatory bowel disease, and usually has obvious improvement in about two weeksIn addition, small molecule TNF- α inhibitors such as thalidomide and lenalidomide are widely used for treating erythema nodosum leprosum, some blood and solid tumors such as myelodysplastic syndrome, myelofibrosis, mantle cell lymphoma, acute myeloid leukemia, acute/chronic graft-versus-host reaction, ovarian cancer, renal cell carcinoma and the like due to the demonstration that the inhibitors can inhibit the secretion of TNF- α and other proinflammatory cytokines, and have good clinical treatment effects (Palladino M.A).et. al. Anti-TNF-α therapies: the next generation.Nat Rev Drug Discov. 2003,2, 737). However, despite their clinical benefits, long-term use is limited, mainly by their clinical toxic effects, including peripheral neuropathy, lethargy, constipation, and thromboembolism and teratogenic risks, thus greatly reducing their overall therapeutic index. Therefore, there is a need in the art for structurally modified amines to optimize their performance.

Iron death is a recently discovered regulatory cell death induced by iron-dependent lipid peroxidation and Reactive Oxygen Species (ROS), and is largely different from death modes such as apoptosis, autophagy and programmed necrosis in aspects of cell morphological characteristics, biochemical indexes and the like, and mainly expressed by increased cytoplasm and lipid reactive oxygen species, smaller mitochondria and higher mitochondrial membrane density. The necrosis is strictly regulated by intracellular signal pathways, including the regulation pathway of iron homeostasis and the RAS pathway and cystine transport pathway, and is widely involved in various diseases such as tumor, nervous system, coronary heart disease, tissue ischemia-reperfusion injury, acute renal failure, aging, etc. Glutathione peroxidase (GPX 4) and thioredoxin reductase (TrxR), two important selenium-containing proteases in the redox system of organisms, play an important role in the process of cell iron death (DIXON, s.j).et al.Cell. 2012,5,1060；IIngold, I.et. al.Cell. 2018,172, 409; Llabani, E.et al.Nat Chem.2019,11, 521.). For example, GPX4 protects normal cells from oxidative stress and iron death, when GPX4 is absent, deficient in function or inhibitedResulting in normal cell iron death. In addition, TrxR is a protein associated with various hematological tumors (e.g., lymphoma, multiple myeloma) and solid tumors (e.g., lung cancer, liver cancer, breast cancer, glioma), and plays an important role in proliferation and differentiation of tumor cells, while inhibition of TrxR promotes iron death of tumor cells.

Aiming at the problems of thalidomide medicines, the invention creatively designs and synthesizes a series of novel selenium-containing isoxazolidine compounds by combining the action of different selenases in the regulation and control of cell iron death so as to inhibit the iron death of normal cells and promote the iron death of tumor cells while improving the inhibitory activity of TNF- α, thereby finally achieving the requirement of improving the comprehensive treatment index of diseases.

Disclosure of Invention

The invention aims to provide a novel selenium-containing isoxazolidine structure compound.

The invention also aims to provide a preparation method of the compound.

The invention also aims to provide application of the selenium-containing isoxazolidine structural compound, which has obvious intervention effect on TNF- α expression and cell iron death and can be used for preventing and/or treating diseases related to TNF- α overexpression and diseases related to cell iron death.

The invention provides a selenium-containing isoxazolidine compound with a novel structure or pharmaceutically acceptable salt thereof, a selenium-containing isoxazolidine compound with a structure shown in a general formula (I) or pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotope compound or metabolite thereof:

in the formula (I), the compound is shown in the specification,

R₁、R₂、R₃and R₄Each independently selected from the group consisting of: H. d, halogen, hydroxyl, amino, nitro, cyano, carboxyl, seleno, sulfydryl and C₁~C₈Alkylseleno group, C₁~C₈Alkylselenium C₁~C₈Alkylamino radical, C₂~C₈An alkenylalkylseleno group,α-C₁~C₈Alkylseleno amino acid,α-C₁~C₈Alkylselenoyl amino acid, C₀~C₈Alkylamine C₁~C₈Alkylseleno group, C₀~C₈Alkylcarbamoylseleno, C₀~C₈Alkyl amine formyl, aryl selenium radical, C₀~C₈Alkoxy C₁~C₈Alkylseleno group, C₀~C₈Alcoxyl formyl radical C₁~C₈Alkylseleno group, C₀~C₈Alcoxyl formyl radical C₁~C₈Alkoxy, halo C₁~C₈Alkylseleno group, C₁~C₈Alkanesulfonyl group, C₁~C₈Alkanesulfonamide group, C₀~C₈Alkylaminosulfonyl radical, C₁~C₈Alkyl, halo C₁~C₈Alkyl, halo C₁~C₈Alkoxy radical, C₀~C₈Alkylethynyl group, C₁~C₈Alkoxy radical, C₁~C₈Alkanoyloxy group, C₁~C₈Alkoxy C₁~C₈Alkoxy radical, C₁~C₈Alkoxy C₁~C₈Alkyl radical, C₁~C₈Alkylamino radical, C₀~C₈Alkylamine C₁~C₈Alkyl, aryl C₁~C₈Alkylamine C₁~C₈Alkyl, amidino, guanidino, arylsulfonamide, arylaminosulfonyl, arylformyl, C₀~C₈Alkylselenoyl, aryl C₁~C₈Alkylamino radical, aryl C₁~C₈Alkanoylamino group, C₁~C₈Alcoxyl formyl radical, C₁~C₈Alkanoylamino group, C₁~C₈Alkylamino radical, C₀~C₈Alkyl selenium formamido group, aryl selenium C₁~C₈Amide group, cyanogen selenium C₁~C₈Amide group, benzoselenazole C₁~C₈Alkylamide group, benzoselenazole C₁~C₈Alkanesulfonamide group, C₀~C₈Alkylcarbamoylseleno, C₀~C₈Alkyl amine methylAmide group, C₀~C₈Alkylamino formyl, C₁~C₈Alkylamino formyloxy, arylamino formylamino, arylamino formyl, arylamino formyloxy, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrazinyl, quinolinyl, pyrimidinyl, pyrimidinylamino, thiazolyl, thienyl, furanyl, pyrrolyl, or absent; wherein R is₁、R₂、R₃And R₄The aryl is phenyl or substituted by 1-4 groups selected from halogen, hydroxyl, nitro, cyano, amino, trifluoromethyl, carboxyl, C₀~C₈Alkylaminosulfonyl radical, C₁~C₈Alkanesulfonamide group, C₁~C₈Alkyl, halo C₁~C₈Alkoxy radical, C₁~C₈Phenyl substituted by a group in alkoxy;

z can be any of:、

、

、

、

、

or

(ii) a Wherein Z is selected from

、

、When radical, R₅Is H, D, C₁~C₈Alkyl radical, C₁~C₈Alkylselenium C₁~C₈Alkyl radical, C₂~C₈Alkenylene selenium C₁~C₈Alkyl, cyanoselenic acid C₁~C₈Alkyl, aryl, heteroaryl, and heteroaryl,

、(ii) a Z is selected from

OrWhen radical, R₅Is halogen, hydroxy, nitro, cyano, amino, trifluoromethyl, carboxy, C₁~C₈Alkylsulfonyl, aminosulfonyl, C₁~C₈Alkyl, halo C₁~C₈Alkoxy radical, C₁~C₈An alkoxy group;

w is: c or Se; wherein, when W is C, R₁、R₂、R₃、R₄And R₅At least one selenium-containing substituent is present in the substituent; when W is Se, R₁、R₂、R₃、R₄And R₅Is any of the groups described above;

x is: o or is absent;

the dotted line is: chemical bonds or absence.

Preferably, the present invention provides compounds having the structure of formula (I-a), (I-b), (I-c), (I-d), (I-e) and (I-f) or a pharmaceutically acceptable salt, solvate, crystal form, stereoisomer, isotopic compound or metabolite thereof:

、

、

、

、

R₁、R₂、R₃、R₄each independently is a group selected from: H. d, halogen, hydroxyl, amino, nitro, cyano, carboxyl, C₀~C₈Alkylamine C₁~C₈Alkylseleno group, C₀~C₈Alkyl carbamoyl radical, C₀~C₈Alcoxyl formyl radical C₁~C₈Alkoxy, amidino, guanidino, C₁~C₈Alkanesulfonyl group, C₁~C₈Alkanesulfonamide group, C₀~C₈Alkylaminosulfonyl radical, C₁~C₈Alkyl, halo C₁~C₈Alkyl, halo C₁~C₈Alkoxy radical, C₀~C₈Alkylethynyl group, C₁~C₈Alkoxy radical, C₁~C₈Alkanoyloxy group, C₁~C₈Alkoxy C₁~C₈Alkoxy radical, C₁~C₈Alkoxy C₁~C₈Alkyl radical, C₁~C₈Alkylamino radical, C₀~C₈Alkylamine C₁~C₈Alkyl, aryl C₁~C₈Alkylamine C₁~C₈Alkyl, arylsulfonamide group, arylaminosulfonyl group, arylformyl group, arylmethylamino group, arylcarboxamido group, amidino group and C₀~C₈Alcoxyl formyl radical, C₁~C₈Alkanoylamino group, C₁~C₈Alkylamino radical, C₀~C₈Alkylamino carboxamido, C₀~C₈Alkylamino formyl, C₁~C₈Alkylamino formyloxy, arylamino formylamino, arylamino formyl, arylamino formyloxy or not; wherein R is₁、R₂、R₃And R₄The aryl is phenyl or substituted by 1-4 substituents selected from halogen, hydroxy, nitro, cyano, trifluoromethyl, carboxy, aminosulfonyl, C₁~C₆Alkyl radical, C₁~C₆Phenyl substituted by a group in alkoxy;

wherein Z is selected from

、

、

When radical, R₅Is H, D, C₁~C₈An alkyl group; z is selected from

Or

When radical, R₅Is halogen, hydroxy, nitro, cyano, amino, trifluoromethyl, carboxy, C₁~C₈Alkylsulfonyl, aminosulfonyl, C₁~C₈Alkyl, halo C₁~C₈Alkoxy radical, C₁~C₈An alkoxy group.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

As used herein, the term "halo" may be monohalo or polyhalo.

As used herein, the term "alkylsulfonyl" refers to a linear or branched or cyclic saturated hydrocarbon sulfonyl group, said cyclic saturated hydrocarbon being from 3 to 8 carbon atoms.

As used herein, the term "alkanesulfonamide group" refers to a straight-chain or branched-chain or cyclic saturated alkanesulfonamide group, the cyclic saturated hydrocarbon being from 3 to 8 carbon atoms.

The term "alkylaminosulfonyl" as used herein refers toN-mono-or di-substituted straight or branched chain or cyclic saturated alkylaminosulfonyl, said cyclic saturated hydrocarbon being 3-8 carbon atoms.

The term "alkylaminocarbonyl" as used herein refers toN-mono-or di-substituted straight or branched chain or cyclic saturated alkane carbomoyl, said cyclic saturated hydrocarbon being 3-8 carbon atoms.

As used herein, the term "alkyl" refers to a straight or branched chain or cyclic saturated hydrocarbon group, the cyclic saturated alkane being from 3 to 8 carbon atoms.

As used herein, the term "alkoxy" refers to a straight or branched chain or cyclic saturated hydrocarbon oxy group, the cyclic saturated alkane being from 3 to 8 carbon atoms.

As used herein, the term "alkylenylethynyl" refers to a straight or branched chain or cyclic saturated hydrocarbon ethynyl group, the cyclic saturated alkane being from 3 to 8 carbon atoms.

As used herein, the term "alkanoyloxy" refers to a straight or branched chain or cyclic saturated hydrocarbon acyloxy group, the cyclic saturated alkane being 3 to 8 carbon atoms.

The term "alkylamino" as used herein refers toN-mono-or di-substituted straight or branched chain or cyclic saturated hydrocarbon amine groups, said cyclic saturated alkanes being 3-8 carbon atoms.

As used herein, the term "alkoxyformyl" refers to a straight or branched chain or cyclic saturated hydrocarbon alkoxyformyl, the cyclic saturated alkane being from 3 to 8 carbon atoms.

As used herein, the term "alkanoylamino" refers to a straight or branched chain or cyclic saturated hydrocarbon amide group, the cyclic saturated alkane being from 3 to 8 carbon atoms.

As used herein, the term "alkylaminocarboxamide group" isN-mono-or di-substituted refers to a straight chain or branched chain or cyclic saturated hydrocarbon amino carboxamide group, the cyclic saturated alkane is 3-8 carbon atoms.

As used herein, the term "stereoisomer" refers to a compound in which the chirality of one or more stereocenters is different. Stereoisomers include enantiomers and diastereomers.

As used herein, the "piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, pyrrolyl, imidazolyl, pyrimidinamino" groups are all at the N-position unless otherwise specified.

As used herein, the "pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazinyl, quinolinyl" all have a substitution attachment site on C, unless otherwise specified.

Where a compound of the invention is present as a stereoisomer, the invention includes all stereoisomers of the compound.

The invention also includes deuterated compounds produced by replacement of any one or more hydrogen atoms in said compounds with deuterium, which is a stable isotope thereof.

As used herein, the term "metabolite" refers to an active substance produced upon a change in the chemical structure experienced by a drug molecule in vivo, which active substance is typically a derivative of the aforementioned drug molecule, which may also be chemically modified.

As used herein and unless otherwise specified, the term "polymorph" (or "polymorph") refers to one or more crystal structures formed by molecules that differ in their arrangement in lattice space when crystallized.

As used herein, the term "solvate" refers to a crystal form of a compound of formula (I), a pharmaceutically acceptable salt, crystal form, stereoisomer, isotopic compound or metabolite thereof, which further comprises one or more solvent molecules incorporated into the crystal structure. Solvates may include stoichiometric or non-stoichiometric amounts of solvent, and solvent molecules in a solvent may exist in ordered or non-ordered arrangements. Solvates containing non-stoichiometric amounts of solvent molecules may result from solvates that lose at least one (but not all) of the solvent molecules. In a particular embodiment, a solvate is a hydrate, meaning that the crystalline form of the compound further comprises water molecules, with the water molecules acting as a solvent.

The compounds of general formula (I), pharmaceutically acceptable salts, solvates, crystal forms, stereoisomers, isotopic compounds or metabolites thereof, of the present invention may contain one or more asymmetric centers ("stereoisomers"). As used herein, the term "stereoisomer" refers to all stereoisomers, including enantiomers, diastereomers, epimers (epimers), endo-exoisomers (endo-exoisomers), atropisomers (atropisomers), regioisomers (regioisomers), cis-and trans-isomers, and the like. "stereoisomers" herein also includes "pure stereoisomers" as well as "enriched stereoisomers" or "racemates" of the aforementioned various stereoisomers. The stereoisomers can be separated, purified and enriched by an asymmetric synthesis method or a chiral separation method (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography and the like), and can also be obtained by chiral resolution in a mode of forming bonds (chemical bonding and the like) or salifying (physical bonding and the like) with other chiral compounds and the like.

As used herein, the term "pharmaceutically acceptable salt" refers to a non-toxic acid salt of a compound of formula I. These salts can be prepared in situ during the final isolation and purification of the compounds of formula I or separately by reacting a suitable organic or inorganic acid with a basic functional group. Representative salts include, but are not limited to: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthylsulfonate, oxalate, pamoate, pectate, thiocyanate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate.

Some preferred novel selenium-containing isoxazolines of the present invention are shown below. These examples are given solely for the purpose of further illustrating the present invention and are not to be construed as limiting the scope of the present invention in any way.

Wherein it is well known that any stereocenter of any of the above-listed compounds, when not explicitly indicated, may be absolute (CR) -or (S) Configuration, or a racemic mixture of the two. The present invention relates to: racemic mixtures of these compounds, mixtures enriched in any one of the enantiomers, and any one of the isolated enantiomers. In the context of the present invention, it is to be understood that the racemic mixture refers to a 50% to 50% mixture of the two R and S enantiomers, and that the isolated enantiomer is understood to be a pure enantiomer (i.e.100%) or a mixture highly enriched in one of the enantiomers (purity. gtoreq.98%,. gtoreq.95%,. gtoreq.90%,. gtoreq.88%,. gtoreq.85%,. gtoreq.80%).

The invention also provides a pharmaceutically acceptable salt of the novel benzoselenazole compound.

According to a second aspect of the present invention, there is provided a method for preparing the above selenium-containing isoxazolidines or pharmaceutically acceptable salts thereof, which comprises the following steps.

The following abbreviations are used throughout the specification and examples:

ac acetyl group

AcOH acetic acid

Base organic or inorganic bases

DMFN,N-dimethylformamide

EA Ethyl acetate

EtOH ethanol

EDC 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride

HA organic or inorganic acids, e.g. hydrochloric, sulfuric, maleic, tartaric acids, etc

H₂O₂Hydrogen peroxide solution

HOBt 1-hydroxybenzotriazole

OMs mesyloxy

LC-MS liquid chromatography-mass spectrometry

Nuclear Magnetic Resonance (NMR)

Pd/C-H₂Palladium carbon hydrogen reduction system

TLC thin layer chromatography

Volume of solution V

The compounds of formula I of the present invention can be prepared according to the following general procedure:

the benzisoselenazolone compounds in the structural series of the formulas I-a, I-b, I-c, I-d and I-e are synthesized by taking substituted benzoyl chloride as a raw material and respectively reacting the substituted benzoyl chloride with 3-amino-2, 6-piperidedione or 3-amino-1, 4-dihydropyridine-2- (1H) -one or 3-amino-1-adamantanol or 2-benzothiazolomine or 3-amino-2, 5-pyrroledione by heating (rt-120 ℃) under the alkaline (Base) condition by using tertiary amine such as triethylamine, diisopropylethylamine and the like, wherein the solvent comprises but is not limited toN,N-organic solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile, tetrahydrofuran, dichloromethane, chloroform and ethyl acetate (reference:Heteroatom Chemistry.2014, 35,320) (ii) a Wherein, when the ortho position Y = SeCl of the substituted benzoyl chloride is reacted with the substrate, the target products I-a, I-b and I-e can be directly obtained (reference:J. Med. Chem. 2013,569089); when the ortho-position Y = I or Br of the substituted benzoyl chloride is reacted with the substrate, the substituted o-halobenzamide intermediate is firstly obtained respectively and then is treated by [ Se [ (] E [ ]]The reaction was carried out as described to give the target compounds I-a, I-b, I-c and I-d (reference:Org. Lett. 2010,12, 23；J. Org. Chem. 2017,82, 3844；Tetrahedron. 2011,67, 9565）。

the benzisoselenazole compounds in the structural series of the formulas I-a, I-b, I-c, I-d and I-e are synthesized by taking substituted 2, 2' -diselenide benzaldehyde as a raw material, and reacting with 3-amino-1-adamantanol, 2-benzothiazolamine, 3-amino-2, 6-piperidedione, 3-amino-1, 4-dihydropyridine-2- (1H) -one and 3-amino-2, 5-pyrroledione to obtain corresponding ene imine intermediates; the benzisoselenazole compound is obtained by performing reductive amination cyclization on an eneimine intermediate (reference:Angew. Chem. Int. Ed. 2015,54, 1）。

the synthesis of quadrivalent selenium type compounds in the structural series of formulas I-a, I-b, I-c, I-d and I-e takes substituted benzisoselenazole as raw material and is carried out by [ O ]^-]Peroxidation reaction in the solvent of-20-0 deg.c and the peroxidation reagent of-20-0 deg.c including but not limited to H₂O₂、O₃M-chloroperoxybenzoic acid (reference:J. Org. Chem.2005,70, 868；J. Org. Chem. 2005,70,5023）。

the compounds of the structural types I-a, I-b, I-c, I-d and I-e contain-NH₂And the alkylamino or arylamine and HA form salt to obtain the medicinal salt of the benzoselenazole compound. HA is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid, malonic acid, salicylic acid, malic acid, fumaric acid, succinic acid, mandelic acid, ascorbic acid, maleic acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, or isethionic acid.

According to the third aspect of the invention, the compound with the structure of formula I has the effects of inhibiting the expression of TNF- α and the death of normal cell iron, and accordingly, can be used as a TNF- α and/or a cell iron death inhibitor for treating (including combined treatment) related diseases caused by the overexpression of TNF- α and/or the death of cell iron, such as autoimmune diseases, blood tumors, solid tumors, tissue ischemia reperfusion injury, acute renal failure and aging diseases.

Advantageous effects

Compared with the existing amine drugs, the compound not only has obvious inhibition effect on TNF- α, but also has the effects of simulating selenase to regulate oxidative stress and inhibiting normal cell iron death, and is more suitable for complex pathological processes of clinical complex diseases such as neurodegenerative diseases, autoimmune diseases and the like.

Drawings

FIG. 1 shows a general structural formula of a compound of formula I according to the present invention.

FIG. 2 shows the protective effect of the compound of formula I on ox-LDL induced human vascular endothelial cells.

FIG. 3 shows the protective effect of compounds of formula I according to the invention on Erastin induced HT22 iron death.

Detailed Description

The invention is further illustrated, but not limited, by the following specific examples. The experimental procedures of the present invention are of general utility and are not limited to the specific compounds mentioned in the examples below.

In the following preparation examples, 1H-NMR was measured by a Varian Mercury AMX300 type apparatus. MS was determined with VG ZAB-HS or VG-7070 type and Esquire 3000 Plus-01005. All reaction solvents were redistilled before use and the anhydrous solvents used were dried according to standard procedures. All reactions were carried out under argon atmosphere and followed by TLC except for the indication, and the work-up was carried out by drying with saturated brine and anhydrous sodium sulfate. Purification of the product column chromatography on silica gel (200-300 mesh) was used unless otherwise stated.