WO2020108481A1 - 硫胺类化合物、制备方法及其药物组合物 - Google Patents

硫胺类化合物、制备方法及其药物组合物 Download PDF

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WO2020108481A1
WO2020108481A1 PCT/CN2019/120950 CN2019120950W WO2020108481A1 WO 2020108481 A1 WO2020108481 A1 WO 2020108481A1 CN 2019120950 W CN2019120950 W CN 2019120950W WO 2020108481 A1 WO2020108481 A1 WO 2020108481A1
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group
hydrocarbon
substituted
amino
hydrogen atom
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PCT/CN2019/120950
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English (en)
French (fr)
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钟春玖
张寰
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上海日馨生物科技有限公司
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Publication of WO2020108481A1 publication Critical patent/WO2020108481A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a thiamine compound, a preparation method and a pharmaceutical composition thereof.
  • AD Alzheimer's disease
  • a ⁇ ⁇ -amyloid
  • phenothiamine can reduce the deposition of ⁇ -amyloid (A ⁇ ) and Tau protein phosphate in the brain by inhibiting the activity of Glycogensynthasekinase-3 (GSK-3) Reduce the occurrence of pathological damage to Alzheimer’s disease. Therefore, the synthetic methods and crystalline forms of benfotiamine and its application in the treatment of Alzheimer's disease have been successively researched and reported. However, no relevant research reports have been found on other phosphothiamine compounds.
  • the specific embodiments of the present invention provide a novel thiamine compound, a preparation method, and a technical solution of the pharmaceutical composition:
  • a thiamine compound its structure is as follows (1),
  • R 1 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a sulfonic acid group, an amino group, a substituted amine group, a carboxyl group, an ester group, a hydroxyl group, a mercapto group, a hydrocarbon group, a substituted hydrocarbon group, a hydrocarbonoxy group, a substituted hydrocarbonoxy group, Acyl, or amide;
  • R 2 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 3 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 4 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 5 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a sulfonic acid group, an amino group, a substituted amine group, a carboxyl group, an ester group, a hydroxyl group, a mercapto group, a hydrocarbon group, a substituted hydrocarbon group, a hydrocarbonoxy group, a substituted hydrocarbonoxy group, an acyl group, Or amide group;
  • R 6 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 7 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group.
  • the R 7 is a methyl group
  • the R 6 is a hydrogen atom
  • R 6 and R 7 are hydrogen atoms.
  • R 1 , R 2 , R 3 , R 4 and R 5 0, 1, 2, or 3 are halogen atoms.
  • one of R 1 and R 5 is a hydrogen atom, or two are hydrogen atoms.
  • the remaining groups other than halogen atoms are hydrogen atoms.
  • At least one of the halogen atoms is a fluorine atom.
  • the halogen atom is a fluorine atom, a chlorine atom or a bromine atom.
  • the thiamine compound has one of the following structural formulas:
  • R 1 , R 2 , R 3 , R 4 and R 5 1, 2, or 3 are hydrocarbon oxy groups, and the rest are hydrogen atoms.
  • the hydrocarbyloxy group is a C1-C7 hydrocarbyloxy group.
  • the hydrocarbyloxy group is methoxy, ethoxy or benzyloxy.
  • a method for preparing the thiamine compound is obtained by reacting a thiamine phosphate represented by formula (1a) with an acid chloride represented by formula (1b);
  • R 1 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a sulfonic acid group, an amino group, a substituted amine group, a carboxyl group, an ester group, a hydroxyl group, a mercapto group, a hydrocarbon group, a substituted hydrocarbon group, a hydrocarbonoxy group, a substituted hydrocarbonoxy group, Acyl, or amide;
  • R 2 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 3 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 4 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 5 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a sulfonic acid group, an amino group, a substituted amine group, a carboxyl group, an ester group, a hydroxyl group, a mercapto group, a hydrocarbon group, a substituted hydrocarbon group, a hydrocarbonoxy group, a substituted hydrocarbonoxy group, an acyl group, Or amide group;
  • R 6 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 7 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group.
  • the pharmaceutical composition comprises any of the above-mentioned thiamine compounds and their isomers or salts of thiamine compounds and their isomers.
  • the pharmaceutical composition is used to prepare drugs for preventing and treating neurodegenerative diseases.
  • the pharmaceutical composition is used to prepare drugs for preventing and treating Alzheimer's disease or aging.
  • the present invention provides a series of thiamine compounds that have an inhibitory effect on A ⁇ 40 and/or A ⁇ 42; further, when compared with When the connected styrene-based benzene ring is unsubstituted or a halogen atom, the compound has a prominent inhibitory effect on A ⁇ 40 and/or A ⁇ 42.
  • the thiamine compound of the present invention has the following formula (1),
  • R 1 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a sulfonic acid group, an amino group, a substituted amine group, a carboxyl group, an ester group, a hydroxyl group, a mercapto group, a hydrocarbon group, a substituted hydrocarbon group, a hydrocarbonoxy group, a substituted hydrocarbonoxy group, Acyl, or amide;
  • R 2 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 3 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 4 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 5 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a sulfonic acid group, an amino group, a substituted amine group, a carboxyl group, an ester group, a hydroxyl group, a mercapto group, a hydrocarbon group, a substituted hydrocarbon group, a hydrocarbonoxy group, a substituted hydrocarbonoxy group, an acyl group, Or amide group;
  • R 6 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 7 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group.
  • the hydrocarbon groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 each independently include a linear, branched or cyclic hydrocarbon group.
  • the hydrocarbon group may be an alkane group, or an alkene group, an alkyne group, or an aromatic hydrocarbon group. In some embodiments, the hydrocarbon group is an alkane group.
  • the hydrocarbon group is an aromatic hydrocarbon group, specifically, for example, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 1-na
  • the substituted hydrocarbyl groups at R 1 , R 2 , R 3 , R 4 , R 5 and R 6 or R 7 are independently of each other and include halogen atom substitution, nitro substitution, and cyano Group substitution, sulfonic acid substitution, hydrocarbyloxy substitution, amine substitution, carboxy substitution, hydroxyl substitution or mercapto substitution, etc.
  • Specific examples are methoxyethyl, ethoxyethyl, butoxyethyl, trifluoromethyl Base, or pentafluoroethyl, etc.
  • the hydrocarbyloxy groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 each independently include linear, branched or cyclic hydrocarbon oxygen Group, specifically, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, cyclobutoxy, tert-butoxy, isobutoxy, pentoxy, 1-ethyl Propyloxy, 1-methylbutoxy, cyclopentyloxy, hexyloxy, 1-methylpentyloxy, 1-ethylbutoxy, cyclohexyloxy, 2-heptyloxy, heptyl Oxygen, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy , Hepta
  • the substituted hydrocarbyloxy groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6, or R 7 are each independently substituted with a halogen atom including the above hydrocarbyloxy group, Nitro substitution, cyano substitution, sulfonic acid substitution, amine substitution, hydrocarbyloxy substitution, carboxy substitution, hydroxyl substitution or mercapto substitution, etc. Specific examples are methoxyethoxy, ethoxyethoxy, butoxy Ethoxy, trifluoromethoxy, or pentafluoroethoxy.
  • the acyl groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 each independently include various hydrocarbyl acyl groups or various substituted hydrocarbyl acyl groups.
  • the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, amine substitution, carboxy substitution, hydroxyl substitution, or mercapto substitution, etc.
  • Specific examples include formyl, acetyl, n-propionyl, isopropyl, N-butyryl, tert-butyryl, isobutyryl, valeryl, 1-ethylpropionyl, 1-methylbutyryl, cyclopentylyl, hexanoyl, 1-methylvaleryl, 1-ethylbutyryl , Cyclohexyl acyl, 2-heptanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecane Acyl, heptadecanoyl, octadecanoyl, nonadecanoyl, aralkanoyl, eicosanoyl, behenanoyl, behenyl, be
  • the substituted amine groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 are independently of each other and include various hydrocarbyl substituted amine groups or various substitutions Hydrocarbyl substituted amine group, the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, amine substitution, carboxy substitution, hydroxyl substitution or mercapto substitution, etc.
  • Specific examples include methylamino, ethylamino, N-propylamino, isopropylamino, n-butylamino, tert-butylamino, isobutylamino, pentylamino, 1-ethylpropylamino, 1-methylbutylamino, cyclopentylamino, hexylamino, 1 -Methylpentylamino, 1-ethylbutylamino, cyclohexylamino, 2-heptylamino, heptylamino, octylamino, nonylamino, decylamino, undecylamino, twelve Alkylamino, tridecylamino, tetradecylamino, pentadecylamino, hexadecylamino, heptadecylamino, octadecylamino, nona
  • the ester groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 are independently of each other and include various hydrocarbyl ester groups or various substituted hydrocarbyl esters Group, the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, amine substitution, carboxy substitution, hydroxy substitution or mercapto substitution, etc.
  • Specific examples include methyl ester group, ethyl ester group, n-propyl ester Group, isopropyl group, n-butyl ester group, tert-butyl ester group, isobutyl ester group, pentyl ester group, 1-ethyl propyl ester group, 1-methyl butyl ester group, cyclopentyl ester group, hexyl ester Group, 1-methylpentyl ester group, 1-ethylbutyl ester group, cyclohexyl ester group, 2-heptyl ester group, heptyl ester group, octyl ester group, nonyl ester group, decyl ester group, undecyl ester group , Dodecyl ester group, tridecyl ester group, tetradecyl ester group, pentadecyl ester group, hexadecyl ester group, hepta
  • the amide groups in R 1 , R 2 , R 3 , R 4 , R 5 , R 6 or R 7 are independently of each other and include various hydrocarbyl amide groups or various substituted hydrocarbyl amides Group, the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonate substitution, amine substitution, carboxyl substitution, hydroxyl substitution or mercapto substitution, etc., for example, formamide, acetamido, n-propionamide Group, isopropylamide group, n-butyramide group, tert-butyramide group, isobutyramide group, valeramide group, 1-ethylpropionamide group, 1-methylbutyramide group, cyclopentylamide group, caproamide Group, 1-methylvaleramide group, 1-ethylbutyramide group, cyclohexylamide group, 2-heptanamide group, heptamyl group,
  • the R 7 is a methyl group and the R 6 is a hydrogen atom.
  • R 6 and R 7 are hydrogen atoms.
  • R 1 , R 2 , R 3 , R 4 or R 5 there are 0, 1, 2, or 3 Halogen atoms, the rest are hydrogen atoms, further, one of R 1 and R 5 is a hydrogen atom, or two are hydrogen atoms, and further, at least one of the halogen atoms is a fluorine atom, further, the halogen atom is Fluorine atom, chlorine atom or bromine atom, the specific thiamine compound has formulas 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1- 11, 1-12, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 1-24, 1-25, 1-26, 1-27, 1-28, One of the structural formulas of 1-29 or 1-30.
  • R 6 and R 7 are hydrogen atoms, and 1 , 2 or 3 of R 1 , R 2 , R 3 , R 4 and R 5 are hydrocarbyloxy groups, and the rest It is a hydrogen atom.
  • the hydrocarbyloxy group is a C1-C7 hydrocarbyloxy group.
  • the hydrocarbyloxy group is methoxy, ethoxy, or benzyloxy.
  • the invention also provides a method for preparing a thiamine compound, which combines sulfur phosphate represented by formula (1a)
  • R 1 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a sulfonic acid group, an amino group, a substituted amine group, a carboxyl group, an ester group, a hydroxyl group, a mercapto group, a hydrocarbon group, a substituted hydrocarbon group, a hydrocarbonoxy group, a substituted hydrocarbonoxy group, Acyl, or amide;
  • R 2 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 3 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 4 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a sulfonic acid group, an amino group, a substituted amine group, a carboxyl group, an ester group, a hydroxyl group, a mercapto group, a hydrocarbon group, a substituted hydrocarbon group, a hydrocarbonoxy group, a substituted hydrocarbonoxy group, an acyl group, Or amide group;
  • R 5 is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a sulfonic acid group, an amino group, a substituted amine group, a carboxyl group, an ester group, a hydroxyl group, a mercapto group, a hydrocarbon group, a substituted hydrocarbon group, a hydrocarbonoxy group, a substituted hydrocarbonoxy group, an acyl group, Or amide group;
  • R 6 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group;
  • R 7 is a hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, carboxyl group, ester group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group, Or amide group.
  • the reaction conditions can be conventionally selected and adjusted according to the actual situation, such as the choice of the solvent for the preparation of the acid chloride solution represented by the formula (1b), the choice of the extraction solvent, and so on.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 may also be as described in the previous embodiment.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned thiamine compound and its isomer or a salt of the thiamine compound and its isomer, preferably the pharmaceutical composition is used for
  • the preparation of drugs for the prevention and treatment of neurodegenerative diseases is further preferably a pharmaceutical composition for the preparation of drugs for the prevention and treatment of Alzheimer's disease or aging.
  • the salt is a medically acceptable salt, such as lithium salt, sodium salt, potassium salt or calcium salt.
  • the composition can be made into tablets, powders, sprays, water injections, powder injections, rectal suppositories or skin patches (transdermal administration) according to a conventional method.
  • NMR shift ( ⁇ ) is given in ppm.
  • the measurement of NMR was performed using Bruker AVANCE-500 NMR instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD), deuterated water (D 2 O), etc., internal standard It is tetramethylsilane (TMS).
  • MS Mass spectrometry
  • BCA protein concentration determination kit was purchased from Biyuntian, A ⁇ 40 and A ⁇ 42 detection kits were purchased from Wako Company, and cell culture related reagents were purchased from Gibico Company.
  • HEK293APP/sw overexpression cell culture cells are cultured in 48-well plates with DMEM culture medium (containing 10% FBS, 100 ⁇ g/mL G418 (Geneticin, geneticin) and double antibody) at 70% cell density Take 4mM stock solution of test product (the test product is prepared by dissolving in DMEM culture solution), dilute to 400 ⁇ M with DMEM culture solution, add 500 ⁇ L per well, and culture for 24 hours.
  • DMEM culture medium containing 10% FBS, 100 ⁇ g/mL G418 (Geneticin, geneticin) and double antibody
  • the product 1-1 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-1 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-2 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-2 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-3 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-3 was prepared for the biological test of the test sample stock solution. The results are listed in Table 1.
  • the product 1-4 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-4 was prepared for the biological test of the stock solution of the test product. The results are listed in Table 1.
  • the product 1-5 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-5 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-6 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-6 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-7 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-7 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-8 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-8 was prepared for the biological test of the test sample stock solution. The results are listed in Table 1.
  • the product 1-9 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-9 was prepared for the biological test of the test sample stock solution. The results are listed in Table 1.
  • the products 1-10 were subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The products 1-10 were prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-12 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-12 was prepared for the biological test of the stock solution of the test product. The results are listed in Table 1.
  • the product 1-13 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-13 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-14 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-14 was prepared for the biological test of the test sample stock solution. The results are listed in Table 1.
  • the product 1-15 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-15 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-16 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-16 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the products 1-17 were subjected to nuclear magnetic (1HNMR) and mass spectrometry (MS) tests. The results are as follows.
  • the products 1-17 were prepared for the biological test of the stock solution of the test product.
  • the product 1-18 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-18 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-19 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-19 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-20 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-20 was prepared for the biological test of the test sample stock solution. The results are listed in Table 1.
  • the product 1-21 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-21 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-22 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-22 was prepared for biological testing with a stock solution of the test product. The results are listed in Table 1.
  • the product 1-23 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-23 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-24 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-24 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-25 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-25 was prepared for the biological test of the stock solution of the test product. The results are listed in Table 1.
  • the product 1-26 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows.
  • the product 1-26 was prepared as a test stock solution for biological testing. The results are listed in Table 1.
  • the product 1-27 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows.
  • the product 1-27 was prepared as a test stock solution for biological testing. The results are listed in Table 1.
  • the product 1-28 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-28 was prepared for the biological test of the test stock solution. The results are listed in Table 1.
  • the product 1-30 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-30 was prepared for the biological test of the test sample stock solution. The results are listed in Table 1.
  • the product 1-31 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-31 was prepared for the biological test of the stock solution of the test product. The results are listed in Table 1.
  • the product 1-32 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-32 was prepared for the biological test of the test sample stock solution. The results are listed in Table 1.
  • test sample stock solution was prepared with phenothiamine for biological testing, and the results are listed in Table 1.

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Abstract

本发明的具体实施方式提供一种硫胺类化合物、制备方法及其药物组合物，所述化合物对Aβ40和/或Aβ42具有抑制作用，特别当与其aa连接的苯乙烯基的苯环未取代、或卤素原子取代时，其化合物对Aβ40和Aβ42均有突出的抑制作用。

Description

硫胺类化合物、制备方法及其药物组合物
本申请要求于2018年11月28日提交中国专利局、申请号为201811469330.X、发明名称为“硫胺类化合物、制备方法及其药物组合物”，以及于2019年7月3日提交中国专利局、申请号为201910592261.X、发明名称为“硫胺类化合物、制备方法及其药物组合物”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明属于医药化学领域，具体涉及一种硫胺类化合物、制备方法及其药物组合物。
背景技术
阿尔茨海默病(俗称老年性痴呆，Alzheimer’s disease,AD)是一种以认知、行为失常为主要临床表现的进行性神经退行性疾病，是一种最常见的老年期痴呆，主要表现为识别能力障碍与记忆功能的迅速衰减。主要病理生理特征是脑内β-淀粉样蛋白(β-amyloid，Aβ)沉积形成老年斑、tau蛋白过度磷酸化形成神经纤维缠结、脑葡萄糖代谢障碍和神经元/突触丢失。由于病程长、患者生活自理能力差，给家庭、社会带来严重的精神和经济负担。但是，全球范围内目前没有能阻止或延缓疾病发展的药物，目前市场销售的治疗AD的药物仅为对症治疗药物，只能控制或改善认知和功能症状一段时间，不能阻止或延缓病情恶化。
已有研究表明，苯磷硫胺可以通过抑制糖合酶激酶-3(Glycogensynthasekinase-3，GSK-3)的活性，降低脑内β-淀粉样蛋白(β-amyloid，Aβ)沉积和Tau蛋白磷酸化，减少阿尔茨海默病的病理性损害发生。因而，有关苯磷硫胺的合成方法和晶型以及其在治疗阿尔茨海默病药物中应用相继研究和报道。但暂未发现有对其它磷硫胺类化合物的相关研究 报道。
发明内容
本发明的具体实施方式提供一种新型的硫胺类化合物、制备方法及其药物组合物的技术方案：
一种硫胺类化合物，其结构如下式(1)，
Figure PCTCN2019120950-appb-000001
其中，R 1为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 2为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 3为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 4为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 5为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 6为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 7为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基。
可选地，所述R 7为甲基，所述R 6为氢原子。
可选地，所述R 6和R 7为氢原子。
可选地，所述R 1、R 2、R 3、R 4和R 5中，有0个、1个、2个或3个为卤素原子。
可选地，R 1和R 5其中一个为氢原子、或两个为氢原子。
可选地，卤素原子外的其余基团为氢原子。
可选地，所述卤素原子至少有一个为氟原子。
可选地，所述卤素原子为氟原子、氯原子或溴原子。
可选地，所述硫胺类化合物具有如下结构式之一：
Figure PCTCN2019120950-appb-000002
Figure PCTCN2019120950-appb-000003
Figure PCTCN2019120950-appb-000004
可选地，所述R 1、R 2、R 3、R 4、R 5中，有1个、2个或3个为烃氧基，其余为氢原子。
可选地，所述的烃氧基为C1-C7的烃氧基。
可选地，所述烃氧基为甲氧基、乙氧基或苄氧基。
一种所述的硫胺类化合物的制备方法，将式(1a)所示的磷酸硫胺与式 (1b)所示的酰氯反应制备获得；
Figure PCTCN2019120950-appb-000005
其中，R 1为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 2为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 3为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 4为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 5为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 6为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 7为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基。
药物组合物，包含上述任一硫胺类化合物及其异构体或硫胺类化合物及 其异构体的盐。
可选地，所述药物组合物用于制备预防和治疗神经退行性疾病药物。
可选地，所述药物组合物用于制备预防和治疗阿尔茨海默病或衰老药物。
与现有技术相比，本发明提供了系列的对Aβ40和/或Aβ42具有抑制作用硫胺类化合物；进一步，当与其
Figure PCTCN2019120950-appb-000006
连接的苯乙烯基的苯环未取代、或卤素原子时，其化合物对Aβ40和/或Aβ42有突出的抑制作用。
具体实施方式
本发明的硫胺类化合物，其结构如下式(1)，
Figure PCTCN2019120950-appb-000007
其中，R 1为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 2为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 3为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 4为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 5为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 6为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 7为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基。
本发明的具体实施方式中，所述烃基在R 1、R 2、R 3、R 4、R 5、R 6或R 7中分别相互独立的包括直链、支链或环状烃基，所述烃基可以是烷烃基，也可以是烯烃基或炔烃基、芳烃基，在一些实施例中，所述烃基为烷烃基，具体例如，甲基、乙基、乙烯基、丙烯基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、1-乙基丙基、1-甲基丁基、环戊基、己基、1-甲基戊基、1-乙基丁基、环己基、2-庚基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、十九烷基、二十烷基、二十一烷基、二十二烷基、二十三烷基等；在一些实施例中，所述烃基为芳烃基，具体例如，苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、1-萘基、2-萘基、苄基或2-苯乙基等。
本发明的具体实施方式中，所述取代烃基在R 1、R 2、R 3、R 4、R 5和R 6或R 7分别相互独立的包括上述烃基的卤素原子取代、硝基取代、氰基取代、磺酸基取代、烃氧基取代、胺基取代、羧基取代、羟基取代或巯基取代等，具体例如甲氧基乙基、乙氧基乙基、丁氧基乙基、三氟甲基、或五氟乙基等。
本发明的具体实施方式中，所述烃氧基在R 1、R 2、R 3、R 4、R 5、R 6或R 7中分别相互独立的包括直链、支链或环状烃氧基，具体例如，甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、环丁氧基、叔丁氧基、异丁氧基、戊氧基、1-乙基丙氧基、1-甲基丁氧基、环戊氧基、己氧基、1-甲基戊氧基、1-乙基丁氧基、环己氧基、2-庚氧基、庚氧基、辛氧基、壬氧基、癸氧基、十一烷 氧基、十二烷氧基、十三烷氧基、十四烷氧基、十五烷氧基、十六烷氧基、十七烷氧基、十八烷氧基、十九烷氧基、二十烷氧基、二十一烷氧基、二十二烷氧基、二十三烷氧基、苯氧基、2-甲基苯氧基、3-甲基苯氧基、4-甲基苯氧基、1-萘氧基、2-萘氧基、苄氧基或2-苯乙氧基等。
本发明的具体实施方式中，所述取代烃氧基在R 1、R 2、R 3、R 4、R 5、R 6或R 7中分别相互独立的包括上述烃氧基的卤素原子取代、硝基取代、氰基取代、磺酸基取代、胺基取代、烃氧基取代、羧基取代、羟基取代或巯基取代等，具体例如甲氧基乙氧基、乙氧基乙氧基、丁氧基乙氧基、三氟甲氧基、或五氟乙氧基等。
本发明的具体实施方式中，所述酰基在R 1、R 2、R 3、R 4、R 5、R 6或R 7中分别相互独立的包括各种烃基酰基或各种取代烃基酰基，所述取代包括卤素原子取代、硝基取代、氰基取代、磺酸基取代、胺基取代、羧基取代、羟基取代或巯基取代等，具体例如甲酰基、乙酰基、正丙酰基、异丙酰基、正丁酰基、叔丁酰基、异丁酰基、戊酰基、1-乙基丙酰基、1-甲基丁酰基、环戊基酰基、己酰基、1-甲基戊酰基、1-乙基丁酰基、环己基酰基、2-庚酰基、庚酰基、辛酰基、壬酰基、癸酰基、十一烷酰基、十二烷酰基、十三烷酰基、十四烷酰基、十五烷酰基、十六烷酰基、十七烷酰基、十八烷酰基、十九烷酰基、芳烷酰基、二十烷酰基、二十一烷酰基、二十二烷酰基、二十三烷酰基、苯甲酰基、2-甲基苯酰基、3-甲基苯酰基、4-甲基苯酰基、1-萘甲酰基、2-萘甲酰基、苄甲酰基、2-苯乙酰基、甲氧基乙酰基、乙氧基乙酰基、丁氧基乙酰基或三氟乙酰基等。
本发明的具体实施方式中，所述取代胺基在R 1、R 2、R 3、R 4、R 5、R 6或R 7中分别相互独立的包括各种烃基取代胺基或各种取代烃基取代胺基，所述取代包括卤素原子取代、硝基取代、氰基取代、磺酸基取代、胺基取代、羧基取代、羟基取代或巯基取代等，具体例如甲胺基、乙胺基、正丙胺基、异丙胺基、正丁胺基、叔丁胺基、异丁胺基、戊胺基、1-乙基丙胺基、1-甲基丁胺基、环戊胺基、己胺基、1-甲基戊胺基、1-乙基丁胺基、环己胺基、2-庚胺基、庚胺基、辛胺基、壬胺基、癸胺基、十一烷胺基、十二烷胺基、十三烷胺基、十四烷胺基、十五烷胺基、十六烷胺基、十七烷胺基、十八烷胺基、 十九烷胺基、芳烷胺基、二十烷胺基、二十一烷胺基、二十二烷胺基、二十三烷胺基、苯甲胺基、2-甲基苯胺基、3-甲基苯胺基、4-甲基苯胺基、1-萘甲胺基、2-萘甲胺基、苄甲胺基、2-苯乙胺基、甲氧基乙胺基、乙氧基乙胺基、丁氧基乙胺基、三氟甲胺基、或五氟乙胺基等。
本发明的具体实施方式中，所述酯基在R 1、R 2、R 3、R 4、R 5、R 6或R 7中分别相互独立的包括各种烃基酯基或各种取代烃基酯基，所述取代包括卤素原子取代、硝基取代、氰基取代、磺酸基取代、胺基取代、羧基取代、羟基取代或巯基取代等，具体例如甲酯基、乙酯基、正丙酯基、异丙酯基、正丁酯基、叔丁酯基、异丁酯基、戊酯基、1-乙基丙酯基、1-甲基丁酯基、环戊基酯基、己酯基、1-甲基戊酯基、1-乙基丁酯基、环己基酯基、2-庚酯基、庚酯基、辛酯基、壬酯基、癸酯基、十一烷酯基、十二烷酯基、十三烷酯基、十四烷酯基、十五烷酯基、十六烷酯基、十七烷酯基、十八烷酯基、十九烷酯基、芳烷酯基、二十烷酯基、二十一烷酯基、二十二烷酯基、二十三烷酯基、苯甲酯基、2-甲基苯酯基、3-甲基苯酯基、4-甲基苯酯基、1-萘甲酯基、2-萘甲酯基、苄甲酯基、2-苯乙酯基、甲氧基乙酯基、乙氧基乙酯基、丁氧基乙酯基或三氟乙酯基等。
本发明的具体实施方式中，所述酰胺基在R 1、R 2、R 3、R 4、R 5、R 6或R 7中分别相互独立的包括各种烃基酰胺基或各种取代烃基酰胺基，所述取代包括卤素原子取代、硝基取代、氰基取代、磺酸基取代、胺基取代、羧基取代、羟基取代或巯基取代等，具体例如甲酰胺基、乙酰胺基、正丙酰胺基、异丙酰胺基、正丁酰胺基、叔丁酰胺基、异丁酰胺基、戊酰胺基、1-乙基丙酰胺基、1-甲基丁酰胺基、环戊基酰胺基、己酰胺基、1-甲基戊酰胺基、1-乙基丁酰胺基、环己基酰胺基、2-庚酰胺基、庚酰胺基、辛酰胺基、壬酰胺基、癸酰胺基、十一烷酰胺基、十二烷酰胺基、十三烷酰胺基、十四烷酰胺基、十五烷酰胺基、十六烷酰胺基、十七烷酰胺基、十八烷酰胺基、十九烷酰胺基、芳烷酰胺基、二十烷酰胺基、二十一烷酰胺基、二十二烷酰胺基、二十三烷酰胺基、苯甲酰胺基、2-甲基苯酰胺基、3-甲基苯酰胺基、4-甲基苯酰胺基、1-萘甲酰胺基、2-萘甲酰胺基、苄甲酰胺基、2-苯乙酰胺基、甲氧基乙酰胺基、乙氧基乙酰胺基、丁氧基乙酰胺基或三氟乙酰胺基等。
考虑到所述硫胺类化合物对Aβ40和Aβ42的抑制作用，具体地，在一些实施方式中，所述R 7为甲基，所述R 6为氢原子。在一些实施例中，所述R 6和R 7为氢原子，进一步，所述R 1、R 2、R 3、R 4或R 5中，有0个、1个、2个或3个为卤素原子，其余为氢原子，更进一步，R 1和R 5其中一个为氢原子、或两个为氢原子，再进一步，所述卤素原子至少有一个为氟原子，进一步，所述卤素原子为氟原子、氯原子或溴原子，具体的所述硫胺类化合物具有如式1-1、1-2、1-3、1-4、1-5、1-6、1-7、1-11、1-12、1-18、1-19、1-20、1-21、1-22、1-23、1-24、1-25、1-26、1-27、1-28、1-29或1-30的结构式之一。在一些实施例中，所述R 6和R 7为氢原子，所述R 1、R 2、R 3、R 4、R 5中，有1个、2个或3个为烃氧基，其余为氢原子，进一步，所述的烃氧基为C1-C7的烃氧基，更进一步，所述烃氧基为甲氧基、乙氧基或苄氧基。
本发明还提供一种硫胺类化合物的制备方法，将式(1a)所示的磷酸硫
Figure PCTCN2019120950-appb-000008
其中，R 1为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 2为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 3为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 4为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、 酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 5为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 6为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
R 7为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基。
本发明的硫胺类化合物的制备方法的具体实施方式中，具体实验条件可以参考现有技术中如EP2918593A1公开的实验条件方法，磷酸硫胺与苯甲酰氯反应制备苯磷硫胺的方法进行，具体来说例如，将式(1a)所示的磷酸硫胺溶解在水中，滴加30％的氢氧化钠溶液，调节pH值在8～12之间，搅拌溶解；-10～30℃下滴加式(1b)所示的酰氯溶液，在滴加过程中控制调节pH值在8～12之间；滴加完毕后反应0.5～8小时，然后对反应物进行萃取等提纯便得到所述硫胺类化合物。对于不同分子结构式的式(1b)所示的酰氯，可以根据实际情况对反应条件进行常规的选择调节，比如式(1b)所示的酰氯溶液配制的溶剂选择、萃取溶剂的选取等等。
本发明的硫胺类化合物的制备方法的具体实施方式中，其中R 1、R 2、R 3、R 4、R 5、R 6和R 7还可以如前实施方式所述。
进一步，本发明还提供一种药物组合物，所述药物组合物包含前述的硫胺类化合物及其异构体或硫胺类化合物及其异构体的盐，优选所述药物组合物用于制备预防和治疗神经退行性疾病药物，进一步优选为用于制备预防和治疗阿尔茨海默病或衰老药物的药物组合物。所述盐为医学上可接受的盐，如锂盐、钠盐、钾盐或钙盐等。所述组合物可以按常规方法制成片剂、粉剂、喷雾剂、水针剂、粉针剂、直肠栓剂或皮肤贴剂(透皮给药)。
实施例
本发明的测试说明：
核磁( 1H NMR)：NMR位移(δ)以ppm的单位给出。NMR的测定是用Bruker AVANCE-500核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代甲醇(CD 3OD)、氘代水(D 2O)等，内标为四甲基硅烷(TMS)。
质谱(MS)：MS的测定用安捷伦(ESI)质谱仪(生产商：安捷伦，型号：安捷伦6110)。
1.生物测试
试验材料与方法
(1)BCA蛋白浓度测定试剂盒购于碧云天，Aβ40及Aβ42检测试剂盒购于wako公司，细胞培养相关试剂均购于Gibico公司。
(2)HEK293APP/sw过表达细胞培养：细胞用DMEM培养液(含10％FBS、100μg/mL G418(Geneticin,遗传霉素)及双抗)培养于48孔板中，于70％细胞密度时，取4mM供试品储备液(供试品溶于DMEM培养液中配制得到),用DMEM培养液稀释至400μM，每孔加500μL，培养24小时。
(3)取培养液上清加入BCA试剂室温孵育30min后，在酶标仪OD570nm处测各个孔吸光值并根据蛋白标准曲线算出总蛋白浓度。同时取上清测定Aβ40及Aβ42浓度，将上清液加入到已包被的96孔板中4℃孵育过夜，除去并洗净试剂后加入HRP(辣根氧化物酶)标记抗体4℃孵育2小时，除去并洗净试剂后加入TMB显色液室温孵育30min后加入终止液终止反应，在酶标仪OD 450nm处测各个孔吸光值并根据Aβ40及Aβ42的标准曲线分别算出Aβ40及Aβ42的浓度，最后用总蛋白浓度对Aβ40及Aβ42的浓度进行调整得出最终浓度。
以下实施例中合成的化合物以分子式所表示的化合物为准，中英文名称仅作为参考。
实施例1
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(p hosphonooxy)pent-2-en-3-yl)3-phenylprop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-苯基丙-2-烯酸酯1-1合成：
Figure PCTCN2019120950-appb-000009
将10.9g磷酸硫胺1a溶解在12.0g水中，搅拌溶解，滴加氢氧化钠溶液(30％)调节pH至10～12，搅拌1小时，复测pH，调节pH至10～12直至稳定不变，保持在10℃以下滴加式1-1b化合物(溶于二氯甲烷),滴加完毕，保温反应8小时，减压蒸馏除去二氯甲烷，水相调节pH至4，大量固体产生，过滤，乙酸乙酯洗涤滤饼，滤饼用少量甲醇打浆，过滤，烘干滤饼得产物1-1。
对所述产物1-1进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-1配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):493.0[M +1]
1H NMR(DMSO-d 6)δ:7.89(d,2H),7.75(d,2H),7.49(s,1H),7.47-7.44(m,3H),6.84(d,1H),4.46(s,2H),3.88–3.84(m,2H),2.70(s,2H),2.32(s,3H),2.17(s,3H)。
实施例2
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(2-fluorophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(磷酰氧基)戊-2-烯-3-基)硫代3-(2-氟苯基)丙-2-烯酸酯1-2合成：
Figure PCTCN2019120950-appb-000010
将3.3g 2-氟肉桂酸加入至30mL二氯甲烷中，加入0.5g二甲基甲酰胺和4.8g二氯亚砜，加热到60℃回流1小时减压蒸馏除去二氯亚砜和二氯甲烷得式1-2b化合物，加入二氯甲烷30mL备用。将6.2g磷酸硫胺1a溶解在12g水中，搅拌溶解，开始滴加氢氧化钠溶液(30％)调节pH至10～12，搅拌10.5小时，复测pH，调节pH至10～12直至稳定不变，搅拌0.5小时，保持在10℃以下滴加上述制备的式1-2b化合物，滴加过程中加入氢氧化钠溶液保持调节pH至10～12，滴加完成保温反应1小时，乙酸乙酯萃取两次，丢弃有机相，水相用31％盐酸调节pH到4～5，产品析出，过滤，滤饼甲醇打浆，然后烘干，得到产物1-2。
对所述产物1-2进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-2配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):553.0[M +1]
1H NMR(D 2O):δ7.94(s,1H),7.65(s,1H),7.49-7.47(m,1H),7.36-7.34(m,2H),7.11-7.03(m,2H),6.53(d,1H),4.35(d,2H),3.72-3.69(m,2H),2.58(d,2H),2.15(s,3H),2.06(s,3H)。
实施例3
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(2,5-difluorophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(2,5-二氟苯基)丙-2-烯酸酯1-3合成：
Figure PCTCN2019120950-appb-000011
将1.6g磷酸硫胺1a溶解在2.2g水中，搅拌溶解，滴加2.5g氢氧化钠溶液(30％)调节pH至10～12，搅拌1小时，复测pH，调节pH至10～12直至稳定不变，保持在10℃以下滴加1-3b化合物(溶于四氢呋喃)，滴加完毕，保温反应1小时，调节pH至4，加入乙酸乙酯萃取，分液，分出水相中油状物，加入少量甲醇溶清，加入乙酸乙酯析出固体，过滤，滤饼用甲醇打浆1小时，过滤，滤饼烘干得产物1-3。
对所述产物1-3进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-3配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):529.0[M +1]
1H NMR(D 2O)δ7.92(s,1H),7.64(s,1H),7.31-7.28(d,1H),7.20(t,1H),7.06-7.02(m,2H),6.46(d,1H),4.34(s,2H),3.69-3.67(m,2H),2.54(s,2H),2.11(s,3H),2.05(s,3H)。
实施例4
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(2,4-difluorophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(2,4-二氟苯基)丙-2-烯酸酯1-4合成：
Figure PCTCN2019120950-appb-000012
把1.0g 2,4-二氟肉桂酸，1.3g氯化亚砜，0.1g二甲基甲酰胺和30mL二氯甲烷加入至100mL单口烧瓶中，60℃下加热回流3小时，把二氯甲烷蒸干后得式1-4b化合物，加4mL四氢呋喃溶解备用，将1.5g磷酸硫胺1a溶解在2.0g水中，搅拌溶解；开始滴加氢氧化钠溶液(30％)调节pH至10～12，搅拌0.5小时，复测pH，调节pH至10～12直至稳定不变，搅拌1小时，保持在0℃以下滴加式1-4b化合物，调节pH至10～12，滴加完毕，反应3小时，水相调节pH至7，用乙酸乙酯萃取后取水相调节pH至3～4，用二氯甲烷萃取，有机相用乙酸乙酯/甲醇打浆，过滤后滤饼45℃烘干得产物1-4。
对所述产物1-4进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-4配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):529.0[M +1]
1H NMR(DMSO-d 6)δ8.01-7.90(m,2H),7.90(s,1H),7.47-7.38(m,2H),7.22-7.19(m,1H),6.85(d,1H),4.47(s,2H),3.88-3.84(m,2H),2.68(s,2H),2.32(s,3H),2.17(s,3H)。
实施例5
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(3-bromo-4-fluorophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(磷酰氧基)戊-2-烯-3-基)硫代3-(3-溴-4-氟苯基)丙-2-烯酸酯1-5合成：
Figure PCTCN2019120950-appb-000013
将3-(3-溴-4-氟苯基)丙-2-烯酸(2.45g，0.01mol)加入30mL二氯甲烷中， 加入0.5g DMF和二氯亚砜(2.4g，0.02mol)，加热到60℃回流2小时，减压蒸馏除去二氯亚砜和二氯甲烷得式1-5b化合物，加入四氢呋喃10mL备用；将3.8g磷酸硫胺溶解在7.6g水中，搅拌溶解，开始滴加氢氧化钠溶液(30％)调节pH至10-12，搅拌10分钟，复测pH，调节pH至10-12直至稳定不变，搅拌0.1小时，保持在10℃以下滴加上述制备的溶液，滴加过程中加入氢氧化钠溶液保持pH至10～12，滴加结束后保温反应0.5小时，二氯甲烷萃取两次，丢弃有机相，水相用36％盐酸调节pH到4～5，产品析出，过滤，滤饼用甲醇打浆，过滤，滤饼45℃烘干得到产物1-5。
对所述产物1-5进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-5配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):591.0[M +1]
1H NMR(DMSO-d 6)δ7.93(s,1H),7.63(s,1H),7.57(d,1H),7.34(d,1H),7.12(m,2H),6.31(d,1H),4.24(s,2H),3.73(m,2H),2.53(s,2H),2.13(s,3H),2.09(s,3H)。
实施例6
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(5-bromo-2-fluorophenyl)prop-2-enethioate,(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(5-溴-2-氟苯基)丙-2-烯酸酯1-6合成：
Figure PCTCN2019120950-appb-000014
把1.2g 5-溴-2-氟肉桂酸，1.2g氯化亚砜，0.1g二甲基甲酰胺和30mL二氯甲烷加入至100mL单口烧瓶中，60℃下加热回流3小时，把二氯甲烷蒸 干后得式1-6b化合物，加4mL四氢呋喃溶解备用，将1.4g磷酸硫胺1a溶解在2.5g水中，搅拌溶解，开始滴加氢氧化钠溶液(30％)调节pH至10～12，搅拌0.5小时，复测pH，调节pH至10～12直至稳定不变，搅拌1小时，保持在0℃以下滴加1.3g式1-6b化合物，调节pH至10～12，滴加完毕，反应2小时，水相调节pH至7，用乙酸乙酯萃取后取水相调节pH至3～4，用二氯甲烷萃取，有固体析出，过滤后滤饼45℃烘干得产物1-6。
对所述产物1-6进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-6配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):591.0[M +1]
1H NMR(DMSO-d 6)δ8.21(s,1H),8.05(s,1H),7.96(s,1H),7.71(s,1H),7.42-7.34(m,2H),7.02(d,1H),4.51(s,2H),3.90(s,2H),2.69(s,2H),2.34(s,3H),2.20(s,3H)。
实施例7
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(4-chloro-2-fluorophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(2-氟-4-氯苯基)丙-2-烯酸酯1-7合成：
Figure PCTCN2019120950-appb-000015
将1.6g磷酸硫胺1a溶解在2.2g水中，搅拌溶解，滴加2.5g氢氧化钠溶液(30％)调节pH至10～12，搅拌1小时，复测pH，调节pH至10～12直至稳定不变，保持在10℃以下滴加式1-7b化合物(溶于四氢呋喃)，加毕，保温反应1小时，调节pH至4，析出固体，过滤，滤饼用甲醇打浆2小时，过滤， 滤饼烘干得产物1-7。
对所述产物1-7进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-7配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):545.0[M +1]
1H NMR(D 2O)δ7.97-7.94(d,1H),7.88(s,2H),7.60-7.58(d,1H),7.46-7.42(d,1H),7.40-7.38(d,1H),6.91-6.88(d,1H),4.45(s,2H),3.87-3.84(m,2H),2.69-2.66(m,2H),2.29(s,3H),2.17(s,3H)。
实施例8
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(2-ethoxyphenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(2-乙氧基苯基)丙-2-烯酸酯1-8合成：
Figure PCTCN2019120950-appb-000016
加入1.6g磷酸硫胺1a和水10mL，搅拌溶解。降温至10℃，加入氢氧化钠调节pH至11～12，稳定后搅拌1小时。将式1-8b化合物(溶于二氯甲烷)滴加入反应，控制体系pH在9～10，20℃减压蒸出有机溶剂，水相用二氯甲烷萃取两次，调节水相pH在2左右，有固体析出，过滤，滤饼用甲醇打浆，抽滤，滤饼烘干得到产物1-8。
对所述产物1-8进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-8配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):537.0[M +1]
1H NMR(DMSO-d 6):δ7.94(s,1H),7.88(s,1H),7.73-7.69(m,2H),7.43-7.41(m,1H),7.09(d,1H),6.99(t,1H),6.84(d,1H),4.46(d,2H),4.14-4.11(m,2H),3.86-3.82(m,2H),2.68(d,2H),2.33(s,3H),2.17(s,3H),1.40-1.35(m,3H)。
实施例9
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(2-methoxyphenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(磷酰氧基)戊-2-烯-3-基)硫代3-(2-甲氧基苯基)丙-2-烯酸酯1-9合成：
Figure PCTCN2019120950-appb-000017
采用实施例8的合成路线，将原料1-8b化合物替换为1-9b化合物，制得产物1-9。
对所述产物1-9进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-9配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):523.0[M +1]
1H NMR(D 2O):δ7.89(s,1H),7.61(s,1H),7.49-7.46(m,1H),7.35-7.33(m,1H),7.28(t,1H),6.89(d,1H),6.84(t,1H),6.46(d,1H),4.23(d,2H),3.72-3.69(m,5H),2.52(d,2H),2.08-2.07(m,6H)。
实施例10
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(2,5-dimethoxyphenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(磷酰氧基)戊-2-烯-3-基)硫代3-(2,5-二甲氧基苯基)丙-2-烯酸酯1-10合成：
Figure PCTCN2019120950-appb-000018
采用实施例8的合成路线，将原料1-8b化合物替换为1-10b化合物，制得产物1-10。
对所述产物1-10进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-10配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):553.0[M +1]
1H NMR(DMSO-d 6):δ7.88(s,1H),7.85(s,1H),7.68(d,1H),7.30(s,1H),7.02(s,2H),6.87(d,1H),6.71(s,2H),4.37(s,2H),3.80(s,3H),3.75(s,3H),3.71-3.67(m,2H),2.61-2.58(m,2H),2.23(s,3H),2.12(s,3H)。
实施例11
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(3-chlorophenyl)prop-2-enethioate，(E)-S-((Z)-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(3-氯苯基)丙-2-烯酸酯1-11合成：
Figure PCTCN2019120950-appb-000019
采用实施例2的合成路线，将原料1-2b化合物替换为1-11b化合物，制得产物1-11。
对所述产物1-11进行核磁( 1H NMR)和质谱(MS)测试，结果如下。
MS m/z(ESI):527.0[M +1]
1H NMR(DMSO-d 6):δ7.96(s,1H),7.90(s,1H),7.88(s,1H),7.72(d,,1H),7.52(m,1H),7.47(m,1H),7.43(d,1H),6.95(d,1H),4.48(s,2H),3.85(d,2H),2.68(s,2H),2.34(s,3H),2.17(s,3H)。
实施例12
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(3-chloro-4-fluorophenyl)prop-2-enethioate，(E)-S-((Z)-(2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(3-氯-4氟苯基)丙-2-烯酸酯1-12合成：
Figure PCTCN2019120950-appb-000020
采用实施例7的合成路线，将原料1-7b化合物替换为1-12b化合物，制得产物1-12。
对所述产物1-12进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-12配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):545.0[M +1]
1H NMR(DMSO-d 6):δ8.12(d,1H),8.08(s,1H),7.94(s,1H),7.82(s,1H),7.52(m,2H),6.92(d,1H),4.52(s,2H),3.89(d,2H),2.68(s,2H),2.38(d,3H),2.19(s,3H)。
实施例13
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(4-methoxyphenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(磷酰氧基)戊-2- 烯-3-基)硫代3-(4-甲氧基苯基)丙-2-烯酸酯1-13合成：
Figure PCTCN2019120950-appb-000021
采用实施例8的合成路线，将原料1-8b化合物替换为1-13b化合物，制得产物1-13。
对所述产物1-13进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-13配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):523.0[M +1]
1H NMR(DMSO-d 6):δ7.95(s,1H),7.90(s,1H),7.72(d,2H),7.48(d,1H),6.99(d,2H),6.73(d,1H),4.46(s,2H),3.84-3.81(m,5H),2.67(s,2H),2.38(s,3H),2.16(s,3H)。
实施例14
((E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2-methyl-3-phenylprop-2-enethioate，((E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(磷酰氧基)戊-2-烯-3-基)硫代2-甲基-3-苯基丙-2-烯酸酯1-14合成：
Figure PCTCN2019120950-appb-000022
采用实施例2的合成路线，将原料1-2b化合物替换为1-14b化合物，制得产物1-14。
对所述产物1-14进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述 产物1-14配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):507.0[M +1]
1H NMR(DMSO-d 6):δ7.89(s,1H),7.85(s,1H),7.52-7.40(m,6H),4.47(s,2H),3.84-3.83(m,2H),2.67(s,2H),2.36(s,3H),2.12(s,3H),1.84(s,3H)。
实施例15
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(4-ethoxyphenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(4-乙氧基苯基)丙-2-烯酸酯1-15合成：
Figure PCTCN2019120950-appb-000023
采用实施例8的合成路线，将原料1-8b化合物替换为1-15b化合物，制得产物1-15。
对所述产物1-15进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-15配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):537[M +1]
1H NMR(DMSO-d 6):δ7.89(s,1H),7.85(s,1H),7.52-7.40(m,6H),4.47(s,2H),3.84-3.83(m,2H),2.67(s,2H),2.36(s,3H),2.12(s,3H),1.84(s,3H)。
实施例16
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(2-fluoro-5-(trifluoromethyl)phenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基 -2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(2-氟-5-(三氟甲基)苯基)丙-2-烯酸酯1-16合成：
Figure PCTCN2019120950-appb-000024
采用实施例8的合成路线，将原料1-8b化合物替换为1-16b化合物，制得产物1-16。
对所述产物1-16进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-16配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):579.0[M +1]
1H NMR(500MHz,DMSO-d 6)δ8.40(d,1H),7.94(s,1H),7.90(s,2H),7.59–7.54(m,1H),7.50(d,1H),7.14(d,1H),4.48(s,2H),3.86(dd,2H),2.69(t,2H),2.34(d,3H),2.18(s,3H)。
实施例17
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(2-fluoro-4-(trifluoromethyl)phenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺)-5-(磷酰氧基)戊-2-烯-3-基)硫代3-(2-氟-4-(三氟甲基)苯基)丙-2-烯酸酯1-17合成：
Figure PCTCN2019120950-appb-000025
采用实施例8的合成路线，将原料1-8b化合物替换为1-17b化合物，制得产物1-17。
对所述产物1-17进行核磁(1H NMR)和质谱(MS)测试，结果如下，以所述产物1-17配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):579.0[M+1]
1H NMR(DMSO-d 6)δ8.16-8.13(dd,1H),7.94(s,1H),7.90(s,1H),7.82-7.80(d,1H),7.66-7.64(d,1H),7.51-7.48(d,1H),7.03-7.00(d,1H),4.47(s,2H),3.88-3.84(q,2H),2.70-2.66(t,2H),2.31(s,3H),2.18(s,3H)。
实施例18
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(2,3,4-trifluorophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(磷酰氧基)戊-2-烯-3-基)硫代3-(2,3,4-三氟苯基)丙-2-烯酸酯1-18合成：
Figure PCTCN2019120950-appb-000026
采用实施例8的合成路线，将原料1-8b化合物替换为1-18b化合物，制得产物1-18。
对所述产物1-18进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-18配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):547[M +1]
1H NMR(D 2O):δ7.99(s,1H),7.68(s,1H),7.28(m,2H),7.04(m,1H),6.51(d,1H),4.31(s,2H),3.73(m,2H),2.59(s,2H),2.08(s,3H),2.01(s,3H)。
实施例19
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(2,3,6-trifluorophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(2,3,6-三氟苯基)丙-2-烯酸酯1-19合成：
Figure PCTCN2019120950-appb-000027
采用实施例8的合成路线，将原料1-8b化合物替换为1-19b化合物，制得产物1-19。
对所述产物1-19进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-19配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):547[M +1]
1H NMR(D 2O)δ7.97(s,1H),7.73(s,1H),7.34–7.22(m,2H),6.94(t,1H),6.71(d,1H),4.39(s,2H),3.72(q,2H),2.57(dd,2H),2.13(d,6H)。
实施例20
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(3-chloro-2-fluorophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(3-氯-2-氟苯基)丙-2-烯酸酯1-20合成：
Figure PCTCN2019120950-appb-000028
采用实施例8的合成路线，将原料1-8b化合物替换为1-20b化合物，制得产物1-20。
对所述产物1-20进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-20配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):545[M +1]
1H NMR(DMSO-d 6):δ7.27(d,1H),7.03(s,1H),6.47(d,1H),4.25(s,2H),3.72(s,2H),2.56(s,2H),2.14(s,3H),2.09(s,3H)。
实施例21
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(3,4,5-trifluorophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(3,4,5-三氟苯基)丙-2-烯酸酯1-21合成：
Figure PCTCN2019120950-appb-000029
采用实施例8的合成路线，将原料1-8b化合物替换为1-21b化合物，制得产物1-21。
对所述产物1-21进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-21配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):547[M +1]
1H NMR(DMSO-d 6):δ7.98(s,1H),7.89–7.82(m,3H),7.44–7.39(m,1H),6.97(d,1H),4.48(s,2H),3.85(d,2H),2.68(s,2H),2.37(d,3H),2.18(s,3H)。
实施例22
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(3,4-difluorophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(3,4-二氟苯基)丙-2-烯酸酯1-22合成：
Figure PCTCN2019120950-appb-000030
采用实施例9的合成路线，将原料1-9b化合物替换为1-22b化合物，制得产物1-22。
对所述产物1-22进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-22配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):529[M +1]
1H NMR(DMSO-d 6):δ7.99–7.92(m,2H),7.87(s,1H),7.63(s,1H),7.53–7.42(m,2H),6.90(d,1H),4.46(s,2H),3.84(d,2H),2.68(s,2H),2.33(s,3H),2.17(s,3H)。
实施例23
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(3-fluorophenyl)prop-2-enethioate， (E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(3-氟苯基)丙-2-烯酸酯1-23合成：
Figure PCTCN2019120950-appb-000031
采用实施例8的合成路线，将原料1-8b化合物替换为1-23b化合物，制得产物1-23。
对所述产物1-23进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-23配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):511[M +1]
1H NMR(D 2O)δ7.96(s,1H),7.70(s,1H),7.35-7.22(m,4H),7.11(dd,1H),6.49(d,1H),4.41(s,2H),3.72(q,2H),2.61(s,2H),2.16(s,3H),2.07(s,3H)。
实施例24
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(3,5-difluorophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(3,5-二氟苯基)丙-2-烯酸酯1-24合成：
Figure PCTCN2019120950-appb-000032
采用实施例8的合成路线，将原料1-8b化合物替换为1-24b化合物，制 得产物1-24。
对所述产物1-24进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-24配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):529[M +1]
1H NMR(DMSO-d 6):δ7.98(s,1H),7.89(s,1H),7.58(d,2H),7.44(d,1H),7.34(t,1H),7.00(d,1H),4.48(s,2H),3.85(m,2H),2.68(s,2H),2.35(s,3H),2.18(s,3H)。
实施例25
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(4-fluorophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(4-氟苯基)丙-2-烯酸酯1-25合成：
Figure PCTCN2019120950-appb-000033
采用实施例8的合成路线，将原料1-8b化合物替换为1-25b化合物，制得产物1-25。
对所述产物1-25进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-25配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):511[M +1]
1H NMR(DMSO-d 6):δ7.86(d,2H),7.83(d,2H),7.45(d,1H),7.26(t,2H),6.80(d,1H),4.45(s,2H),3.85(t,2H),2.68(d,2H),2.36(s,3H),2.31(s,3H)。
实施例26
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(4-bromophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(4-溴苯基)丙-2-烯酸酯1-26合成：
Figure PCTCN2019120950-appb-000034
采用实施例8的合成路线，将原料1-8b化合物替换为1-26b化合物，制得产物1-26。
对所述产物1-26进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-26配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):573[M +1]
1H NMR(DMSO-d 6)δ7.97(s,1H),7.88(s,1H),7.71(d,2H),7.64(d,2H),7.44(d,1H),6.88(d,1H),4.46(s,2H),3.85(dd,2H),2.68(s,2H),2.34(s,3H),2.17(s,3H)。
实施例27
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(3-bromophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺)-5-(磷酰氧基)戊-2-烯-3-基)硫代3-(3-溴苯基)丙-2-烯酸酯1-27合成：
Figure PCTCN2019120950-appb-000035
采用实施例8的合成路线，将原料1-8b化合物替换为1-27b化合物，制得产物1-27。
对所述产物1-27进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-27配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):573[M +1]
1H NMR(DMSO-d 6):δ8.03(s,1H),7.95(s,1H),7.88(s,1H),7.76-7.76(d,1H),7.64-7.63(dd,1H),7.45-7.37(m,2H),6.96-6.93(d,1H),4.48(s,2H),3.87-3.83(q,2H),2.68(s,2H),2.33(s,3H),2.17(s,3H)。
实施例28
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(3-iodophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-
Figure PCTCN2019120950-appb-000036
烯-3-基)硫代3-(3-碘苯基)丙-2-烯酸酯1-28合成：
采用实施例8的合成路线，将原料1-8b化合物替换为1-28b化合物，制得产物1-28。
对所述产物1-28进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述 产物1-28配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):619[M +1]
1H NMR(DMSO-d 6):δ8.17(s,1H),7.87(d,2H),7.80(dd,2H),7.38(d,1H),7.23(d,1H),6.91(d,1H),4.45(s,2H),3.85(dd,2H),2.68(d,2H),2.31(s,3H),2.16(s,3H)。
实施例29
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(3,4-dichlorophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(3,4-二氯苯基)丙-2-烯酸酯1-29合成：
Figure PCTCN2019120950-appb-000037
采用实施例8的合成路线，将原料1-8b化合物替换为1-29b化合物，制得产物1-29。
对所述产物1-29进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-30配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):562[M +1]
1H NMR(500MHz,DMSO-d 6):δ8.11(d,1H),7.89(d,2H),7.76(dd,1H),7.69(d,1H),7.44(d,1H),7.00–6.96(m,1H),4.45(s,2H),3.84(dd,2H),2.68(s,2H),2.32(s,3H),2.16(s,3H)。
实施例30
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(4-chlorophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(磷酰氧基)戊-2-烯-3-基)硫代3-(4-氯苯基)丙-2-烯酸酯1-30合成：
Figure PCTCN2019120950-appb-000038
采用实施例8的合成路线，将原料1-8b化合物替换为1-30b化合物，制得产物1-30。
对所述产物1-30进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-30配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):527[M +1]
1H NMR(DMSO-d 6):δ7.94(s,1H),7.65(s,1H),7.39(m,2H),7.28(m,3H),6.42(d,1H),4.34(s,2H),3.71(m,2H),2.55(s,2H),2.13(s,3H),2.05(s,3H)。
实施例31
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(4-cyanophenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(4-氰基苯基)丙-2-烯酸酯1-31合成：
Figure PCTCN2019120950-appb-000039
采用实施例8的合成路线，将原料1-8b化合物替换为1-31b化合物，制得产物1-31。
对所述产物1-31进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-31配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):518[M +1]
1H NMR(DMSO-d 6)δ:8.02–7.93(m,3H),7.93–7.89(m,3H),7.51(d,1H),7.02(d，1H),4.48(s,2H),3.86(m,2H),2.68(d,2H),2.34(s,3H),2.18(s,3H)。
实施例32
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-(4-(benzyloxy)phenyl)prop-2-enethioate，(E)-S-((Z)-2-(N-((4-氨基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(膦酰氧基)戊-2-烯-3-基)硫代3-(4-苄氧基苯基)丙-2-烯酸酯1-32合成：
Figure PCTCN2019120950-appb-000040
采用实施例8的合成路线，将原料1-8b化合物替换为1-32b化合物，制得产物1-32。
对所述产物1-32进行核磁( 1H NMR)和质谱(MS)测试，结果如下，以所述产物1-32配制供试品储备液进行生物测试，其结果列于表1中。
MS m/z(ESI):599.0[M +1]
1H NMR(DMSO-d 6)δ:7.91(s,1H),7.86(s,1H),7.71(d,2H),7.45(t,3H),7.40(t,2H),7.35(d,1H),7.06(d,2H),6.68(d,1H),5.17(s,2H),4.45(s,2H),3.83(d,2H),2.67(s,2H),2.31(s,3H),2.15(s,3H)。
对比例1
不加供试品储备液，以培养基作为空白对照，进行生物测.试，其结果列于表1中。
对比例2
以苯磷硫胺配制供试品储备液进行生物测试，其结果列于表1中。
表1硫胺类化合物处理后APP/293细胞所分泌的Aβ40及Aβ42蛋白的含量
Figure PCTCN2019120950-appb-000041
Figure PCTCN2019120950-appb-000042
根据以上实验结果，与对比例1空白相比，所有实施例的Aβ42或/和Aβ40均有降低，表明所有实施例结构的硫胺化合物对Aβ42或/和Aβ40均具有抑制作用；与对比例2苯磷硫胺相比，实施例1-7、11-12、18-30的Aβ40和Aβ42值均降低，表明本发明结构的所述硫胺类化合物与其
Figure PCTCN2019120950-appb-000043
连接的苯乙烯基的苯环上不取代或取代原子为卤素原子时，其对Aβ40和Aβ42的抑制作用均得到明显加强。
虽然本发明披露如上，但本发明并非限定于此。任何本领域技术人员，在不脱离本发明的精神和范围内，均可作各种更动与修改，因此本发明的保护范围应当以权利要求所限定的范围为准。

Claims (15)

  1. 一种硫胺类化合物，其结构如下式(1)，
    Figure PCTCN2019120950-appb-100001
    其中，R 1为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
    R 2为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
    R 3为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
    R 4为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
    R 5为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
    R 6为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
    R 7为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基。
  2. 根据权利要求1所述的硫胺类化合物，其特征在于，所述R 7为甲基，所述R 6为氢原子。
  3. 根据权利要求1所述的硫胺类化合物，其特征在于，所述R 6和R 7为氢原子。
  4. 根据权利要求3所述的硫胺类化合物，其特征在于，所述R 1、R 2、R 3、R 4和R 5中，有0个、1个、2个或3个为卤素原子。
  5. 根据权利要求4所述的硫胺类化合物，其特征在于，R 1和R 5其中一个为氢原子、或两个均为氢原子。
  6. 根据权利要求4所述的硫胺类化合物，其特征在于，卤素原子外的其余基团为氢原子。
  7. 根据权利要求4所述的硫胺类化合物，其特征在于，所述卤素原子至少有一个为氟原子。
  8. 根据权利要求4所述的硫胺类化合物，其特征在于，所述卤素原子为氟原子、氯原子或溴原子。
  9. 根据权利要求4所述的硫胺类化合物，其特征在于，所述硫胺类化合物具有如下结构式之一：
    Figure PCTCN2019120950-appb-100002
    Figure PCTCN2019120950-appb-100003
    Figure PCTCN2019120950-appb-100004
  10. 根据权利要求3所述的硫胺类化合物，其特征在于，所述R 1、R 2、R 3、R 4和R 5中，有1个、2个或3个为烃氧基，其余为氢原子。
  11. 根据权利要求10所述的硫胺类化合物，其特征在于，所述烃氧基为甲氧基、乙氧基或苄氧基。
  12. 一种如权利要求1-11任意一项所述的硫胺类化合物的制备方法，其特征在 于，将式(1a)所示的磷酸硫胺与式(1b)所示的酰氯反应制备获得；
    Figure PCTCN2019120950-appb-100005
    其中，R 1为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
    R 2为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
    R 3为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
    R 4为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
    R 5为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
    R 6为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基；
    R 7为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基，羧基、酯基、羟基、巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基，或酰胺基。
  13. 一种药物组合物，其包含权利要求1-11中任一项的硫胺类化合物及其异构体或硫胺类化合物及其异构体的盐。
  14. 根据权利要求13的药物组合物，其特征在于，所述药物组合物用于制备预防和治疗神经退行性疾病药物。
  15. 根据权利要求13的药物组合物，其特征在于，所述药物组合物用于制备预防和治疗阿尔茨海默病或衰老药物。
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