WO2020108478A1 - 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

Info

Publication number
WO2020108478A1
WO2020108478A1 PCT/CN2019/120942 CN2019120942W WO2020108478A1 WO 2020108478 A1 WO2020108478 A1 WO 2020108478A1 CN 2019120942 W CN2019120942 W CN 2019120942W WO 2020108478 A1 WO2020108478 A1 WO 2020108478A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
thiamine
formula
methyl
mercapto
Prior art date
Application number
PCT/CN2019/120942
Other languages
English (en)
French (fr)
Inventor
钟春玖
张寰
Original Assignee
上海日馨生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海日馨生物科技有限公司 filed Critical 上海日馨生物科技有限公司
Priority to EP19888995.8A priority Critical patent/EP3889160A4/en
Priority to US17/298,214 priority patent/US11591354B2/en
Priority to JP2021531390A priority patent/JP7307979B2/ja
Publication of WO2020108478A1 publication Critical patent/WO2020108478A1/zh
Priority to JP2023039009A priority patent/JP7534814B2/ja

Links

Classifications

    • 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
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • 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

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 on other phosphothiamine compounds have been found.
  • 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 the structure of which is the following formula (1) or formula (2),
  • R 1 , R 2 , R 3 , R 4 , R 5 or R 6 are independently hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, ester group, carboxyl group, hydroxyl group , Mercapto, hydrocarbon mercapto, hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, substituted hydrocarbyloxy, acyl or amide.
  • the structure of the thiamine compound is as shown in formula (1), R 1 and R 2 are hydrogen atoms, and R 3 is benzyl or 1,5 difluorophenyl.
  • each of R 1 , R 2 , R 3 , R 4 , R 5 or R 6 is independently a hydrogen atom or a C1-C18 chain hydrocarbon group.
  • R 1 or R 2 are independently a hydrogen atom, a methyl group or an ethyl group, and R 3 is a C1-C10 chain hydrocarbon group.
  • the structure of the thiamine compound is as shown in formula (1), wherein R 1 is a hydrogen atom, R 2 is a methyl group, and R 3 is a methyl or ethyl group.
  • the structure of the thiamine compound is represented by formula (1), wherein R 1 is a methyl group, R 2 is a methyl group, and R 3 is a vinyl group.
  • the structure of the thiamine compound is as shown in formula (2), R 5 is a hydrogen atom, and R 4 is n-propyl group.
  • the preparation method of the thiamine compound is obtained by reacting the thioamine phosphate represented by formula (1a) with the acid chloride represented by formula (1b) or (2b);
  • R 1 , R 2 , R 3 , R 4 , R 5 or R 6 are independently hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, ester group, carboxyl group, hydroxyl group , Mercapto, hydrocarbon mercapto, hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, substituted hydrocarbyloxy, acyl or amide.
  • the pharmaceutical composition comprises any of the 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 embodiments of the present invention provide a series of thiamine compounds of formula (1) or formula (2), which have an inhibitory effect on A ⁇ 40 and/or A ⁇ 42; further, the thiamine
  • the structure of the compound is as shown in formula (1), wherein R 1 is a hydrogen atom, R 2 is a methyl group, R 3 is a methyl group or an ethyl group, or the R 1 is a methyl group, R 2 is a methyl group, and R 3 is a vinyl or n-butyl, or the sulphonamide compounds of formula (2), the R4 and R 5 is a hydrogen atom, R 6 is n-propyl, having a more prominent inhibition of A ⁇ 40 and A ⁇ 42.
  • the thiamine compound according to the embodiment of the present invention has the following formula (1) or formula (2),
  • R 1 , R 2 , R 3 , R 4 , R 5 or R 6 are independently hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, ester group, carboxyl group, hydroxyl group , Mercapto, hydrocarbon mercapto, hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, substituted hydrocarbyloxy, acyl or amide.
  • the substituent includes a linear, branched or cyclic hydrocarbon group
  • the hydrocarbon group may be an alkane group, or an alkene group, alkyne group or aromatic hydrocarbon group.
  • the The hydrocarbon group is an alkane group, specifically, for example, methyl, ethyl, vinyl, propenyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, 1-ethylpropyl , 1-methylbutyl, cyclopentyl, hexyl, 1-methylpentyl, 1-ethylbutyl, cyclohexyl, 2-heptyl, heptyl, octyl, nonyl, decyl, undecyl Alkyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexyl, hexyl, 2-h
  • the substituted hydrocarbon group includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, hydrocarbyloxy substitution, amine substitution, carboxyl substitution, hydroxyl substitution, or mercapto substitution of the above hydrocarbon group And the like, specifically, for example, methoxyethyl, ethoxyethyl, butoxyethyl, trifluoromethyl, pentafluoroethyl, or the like.
  • the hydrocarbyloxy group includes a linear, branched or cyclic hydrocarbyloxy group, specifically, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy Group, tert-butoxy, isobutoxy, pentyloxy, 1-ethylpropoxy, 1-methylbutoxy, cyclopentyloxy, hexyloxy, 1-methylpentyloxy, 1 -Ethylbutoxy, cyclohexyloxy, 2-heptyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy Radical, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, ei
  • the substituted hydrocarbyloxy group includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, hydrocarbyloxy substitution, amine substitution, carboxyl substitution, hydroxyl group of the above hydrocarbyloxy group Substitution or mercapto substitution, etc., specifically, for example, methoxyethoxy, ethoxyethoxy, butoxyethoxy, trifluoromethoxy, or pentafluoroethoxy.
  • the hydrocarbon mercapto group includes a linear, branched or cyclic hydrocarbon mercapto group, specifically, for example, methyl mercapto group, ethyl mercapto group, n-propyl mercapto group, isopropyl mercapto group, n-butyl mercapto group, tert-butyl mercapto group, isobutyl Butylmercapto, pentylmercapto, 1-ethylpropylmercapto, 1-methylbutylmercapto, cyclopentylmercapto, hexylmercapto, 1-methylpentylmercapto, 1-ethylbutylmercapto, cyclohexylmercapto, 2-heptylmercapto , Heptyl mercapto, octyl mercapto, nonyl mercapto, decyl mercapto, undecyl
  • the substituted hydrocarbon mercapto group includes the halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, hydrocarbon mercapto substitution, amine substitution, carboxy substitution, hydroxyl substitution or mercapto group of the above hydrocarbon mercapto group
  • the substitution and the like are specifically exemplified by methoxyethylmercapto, ethoxyethylmercapto, butoxyethylmercapto, trifluoromethylmercapto, or pentafluoroethylmercapto.
  • the acyl group includes various hydrocarbyl acyl groups or various substituted hydrocarbyl acyl groups, and the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, amine substitution, carboxy substitution , Hydroxy substitution or mercapto substitution, etc., for example, formyl, acetyl, n-propionyl, isopropionyl, n-butyryl, t-butyryl, isobutyryl, valeryl, 1-ethylpropionyl, 1-methyl Butyryl, cyclopentanoyl, hexanoyl, 1-methylvaleryl, 1-ethylbutyryl, cyclohexanoyl, 2-heptanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, Dodecanoyl, tridecanoyl,
  • the ester group includes various hydrocarbyl ester groups or various substituted hydrocarbyl ester groups, and the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, amine substitution , Carboxyl substitution, hydroxy substitution or mercapto substitution, etc.
  • Specific examples include methyl ester group, ethyl ester group, n-propyl ester group, isopropyl ester group, n-butyl ester group, tert-butyl ester group, isobutyl ester group, pentyl ester group, 1-ethylpropyl ester group, 1-methylbutyl ester group, cyclopentyl ester group, hexyl ester group, 1-methylpentyl ester group, 1-ethylbutyl ester group, cyclohexyl ester group, 2-heptyl Ester group, heptyl 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, ten Hexaalkyl ester group, heptade
  • the substituted amine group includes various hydrocarbyl substituted amine groups or various substituted hydrocarbyl substituted amine groups, and the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, Amino group substitution, carboxyl 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, dodecylamino, tridecylamino, tetradecylamino, pentadecylamino, hexadecane Amino, heptadecylamino, octadecylamino, nonade
  • the amide group includes various hydrocarbyl amide groups or various substituted hydrocarbyl amide groups, and the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic acid substitution, amide substitution , Carboxyl substitution, hydroxyl substitution or mercapto substitution, etc., for example, formamide, acetamide, n-propionamide, isopropionamide, n-butyramide, tert-butyramide, isobutyramide, valeramide, 1-ethylpropionamide, 1-methylbutyramide, cyclopentylamide, hexamide, 1-methylpentanamide, 1-ethylbutyramide, cyclohexylamide, 2-heptanoyl Amido, heptamido, octanamido, nonanoamido, decanamido, undecanoamido, dodecanoamido, tridecanoamid
  • the structure of the thiamine compound is represented by formula (1), R 1 and R 2 are hydrogen atoms, and R 3 is benzyl or 1,5 difluorophenyl.
  • the R 1 , R 2 , R 3 , R 4 or R 5 and R 6 independently represent a hydrogen atom or a C1-C18 chain hydrocarbon group, preferably the thiamine compound structure
  • R 1 or R 2 is independently a hydrogen atom or a C1-C4 chain hydrocarbon group
  • R 1 or R 2 is independently a hydrogen atom, methyl or ethyl
  • R 3 is C1- The C10 chain hydrocarbon group, considering the inhibitory effect on A ⁇ 40 and A ⁇ 42, further preferably, R 1 is a hydrogen atom
  • R 2 is a methyl group
  • R 3 is a methyl or ethyl group
  • R 1 is a methyl group
  • R 2 is a methyl group and R 3 is a vinyl group
  • the thiamine compound has the structure of formula (2)
  • R 4 and R 5 are hydrogen atoms
  • R 6 is n-propyl group.
  • the present invention also provides a method for preparing the above thiamine compound, which is obtained by reacting the thiamine phosphate represented by formula (1a) with the acid chloride represented by formula (1b) or (2b);
  • R 1 , R 2 , R 3 , R 4 or R 5 and R 6 are independently hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, ester group, carboxyl group, Hydroxyl, mercapto, hydrocarbon mercapto, hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, substituted hydrocarbyloxy, acyl or amide group.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned thiamine compounds and their isomers or salts of thiamine compounds and their isomers, preferably for the preparation of prevention and treatment
  • the drug for neurodegenerative diseases is further preferably a pharmaceutical composition for preparing a drug for preventing and treating 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 the 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 24h.
  • 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 1-6 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 1-11 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-11 was prepared for the biological test of the test sample stock solution. The results are listed in Table 1.
  • Example 4 Using the synthetic route of Example 4, the starting material 1-4b compound was replaced with 1-12b compound to obtain product 1-12.
  • 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 ethyl acetate was extracted once.
  • the aqueous phase was adjusted to pH 3-4.
  • Dichloromethane was extracted. After extraction, the dichloromethane was added with anhydrous sodium sulfate to remove water. , Spin dry, dissolve the solid in methanol, add methyl tert-butyl ether, after stirring for five hours, a solid precipitates, and filter cake is dried at 45 °C to obtain product 1-13.
  • 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 product 1-17 was subjected to nuclear magnetic ( 1 H NMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-17 was prepared for the biological test of the stock solution of the test product. 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.
  • the structured compounds compared with the blank of Comparative Example 1, the structured compounds all have A ⁇ 42 or/and A ⁇ 40 have an inhibitory effect; compared with Comparative Example 2 phenfosin, the content of A ⁇ 40 in Example 11 is comparable to that of Comparative Example 2.
  • the content is basically the same, but the content of A ⁇ 42 is reduced, indicating that it has a better inhibitory effect on A ⁇ 42; compared with Comparative Example 2 benfoti, Examples 5, 6 and 12, especially Example 12, A ⁇ 40 and A ⁇ 42 are both Significantly decreased, indicating that its inhibitory effect on A ⁇ 40 and A ⁇ 42 was greatly enhanced, indicating that its inhibitory effect on A ⁇ 40 and A ⁇ 42 was greatly enhanced.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明实施方式提供了系列的 (I) 上连有链烃基或取代链烃基的硫胺类化合物，所述化合物对Aβ40和/或Aβ42具有抑制作用。

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201811435584.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)或式(2)，
Figure PCTCN2019120942-appb-000001
其中，R 1、R 2、R 3、R 4、R 5或R6分别独立的为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基、酯基、羧基、羟基、巯基、烃巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基或酰胺基。
可选的，所述硫胺类化合物结构如式(1)，所述R 1和R 2为氢原子，R 3为苄基或1,5二氟苯基。
可选的，所述R 1、R 2、R 3、R 4、R 5或R6分别独立的为氢原子或C1-C18的链烃基。
可选的，所述硫胺类化合物结构如式(1)，R 1或R 2分别独立的为氢原子、甲基或乙基，R 3为C1-C10的链烃基。
可选的，所述硫胺类化合物结构如式(1)，所述R 1为氢原子，R 2为甲基，R 3为甲基或乙基。
可选的，所述硫胺类化合物结构如式(1)，所述R 1为甲基，R 2为甲基，R 3为乙烯基。
可选的，所述硫胺类化合物结构如式(2)，所述R 5为氢原子，R 4为正丙基。
上述硫胺类化合物的制备方法，将式(1a)所示的磷酸硫胺与式(1b) 或(2b)所示的酰氯反应制备获得；
Figure PCTCN2019120942-appb-000002
其中，R 1、R 2、R 3、R 4、R 5或R6分别独立的为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基、酯基、羧基、羟基、巯基、烃巯基、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。
可选的，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。
可选的，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，本发明实施方式提供了系列的如式(1)或式(2)的硫胺类化合物，所述化合物对Aβ40和/或Aβ42具有抑制作用；进一步，所述硫胺类化合物结构如式(1)，所述R 1为氢原子，R 2为甲基，R 3为甲基或乙基，或所述R 1为甲基，R 2为甲基，R 3为乙烯基或正丁基，或者所述硫胺类化合物结构如式(2)，所述R4和R 5为氢原子，R 6为正丙基时，具有比较突出的Aβ40和Aβ42抑制作用。
具体实施方式
本发明实施方式的硫胺类化合物，其结构如下式(1)或式(2)，
Figure PCTCN2019120942-appb-000003
其中，R 1、R 2、R 3、R 4、R 5或R6分别独立的为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基、酯基、羧基、羟基、巯基、烃巯基、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，所述取代基包括直链、支链或环状烃基，所述烃基可以是烷烃基，也可以是烯烃基、炔烃基或芳烃基，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、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、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，所述烃巯基包括直链、支链或环状烃巯基，具体例如，甲巯基、乙巯基、正丙巯基、异丙巯基、正丁巯基、叔丁巯基、异丁巯基、戊巯基、1-乙基丙巯基、1-甲基丁巯基、环戊基巯基、己巯基、1-甲基戊巯基、1-乙基丁巯基、环己基巯基、2-庚巯基、庚巯基、辛巯基、壬巯基、癸巯基、十一烷巯基、十二烷巯基、十三烷巯基、十四烷巯基、十五烷巯基、十六烷巯基、十七烷巯基、十八烷巯基、十九烷巯基、二十烷巯基、二十一烷巯基、二十二烷巯基、二十三烷巯基、苯巯基、2-甲基苯巯基、3-甲基苯巯基、4-甲基苯巯基、1-萘巯基、2-萘巯基、苄巯基或2-苯乙巯基等。
本发明的具体实施方式中，所述取代烃巯基包括上述烃巯基的卤素原子取代、硝基取代、氰基取代、磺酸基取代、烃巯基取代、胺基取代、羧基取代、羟基取代或巯基取代等，具体例如甲氧基乙巯基、乙氧基乙巯基、丁氧基乙巯基、三氟甲巯基、或五氟乙巯基等。
本发明的具体实施方式中，所述酰基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、环戊酰基、己酰基、1-甲基戊酰基、1-乙基丁酰基、环己酰基、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-甲基苯甲酰基、3-甲基苯甲酰基、4-甲基苯甲酰基、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，所述酯基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-甲基苯甲酯基、3-甲基苯甲酯基、4-甲基苯甲酯基、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，所述取代胺基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、环戊基胺基、己胺基、1-甲基戊胺基、1-乙基丁胺基、环己基胺基、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-甲基苯甲胺基、3-甲基苯甲胺基、4-甲基苯甲胺基、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、丁氧基乙胺基或三氟乙胺基等。
本发明的具体实施方式中，所述酰胺基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、酰胺基取代、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-甲基苯甲酰胺基、3-甲基苯甲酰胺基、4-甲基苯甲酰胺基、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。
本发明的具体实施方式中，所述硫胺类化合物结构如式(1)，所述R 1和R 2为氢原子，R 3为苄基或1,5二氟苯基。
本发明的具体实施方式中，所述R 1、R 2、R 3、R 4或R 5，R 6分别独立的为氢原子或C1-C18的链烃基，优选为所述硫胺类化合物结构如式(1)，R 1或R 2分别独立的为氢原子或C1-C4的链烃基，进一步，R 1或R 2分别独立的为氢原子、甲基或乙基，R 3为C1-C10的链烃基，考虑到对Aβ40和Aβ42的抑制作用，更进一步，优选所述R 1为氢原子，R 2为甲基，R 3为甲基或乙基，或所述R 1为甲基，R 2为甲基，R 3为乙烯基；或者优选所述硫胺类化合物结构如式(2)，所述R4和R 5为氢原子，R 6为正丙基。
本发明还提供一种上述硫胺类化合物的制备方法，将式(1a)所示的磷酸硫胺与式(1b)或(2b)所示的酰氯反应制备获得；
Figure PCTCN2019120942-appb-000004
其中，R 1、R 2、R 3、R 4或R 5，R 6分别独立的为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基、酯基、羧基、羟基、巯基、烃巯基、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10～12之间，搅拌溶解；0～15℃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10～12之间；滴加完毕后反应0.5～3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。
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，优先为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24h。
(3)取培养液上清加入BCA试剂室温孵育30min后，在酶标仪OD 570nm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2h，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
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)butanethioate，(Z)-S-(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)硫代丁酸酯1-1合成：
Figure PCTCN2019120942-appb-000005
将6.6g磷酸硫胺溶解在8.0g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10℃以下滴加2.3g式1-b的二氯甲烷溶液；分液，无水硫酸钠干燥二氯甲烷相，旋干二氯甲烷，黄色油状液体加入2mL甲醇溶清，加入30mL乙酸乙酯，搅拌，固体析出，过滤，滤饼45℃烘干的得到产物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):433.2[M +1]
1H NMR(DMSO-d 6)δ7.84(s,1H),7.81(s,1H),4.47(s,2H),3.78-3.82(m,2H),2.51-2.61(m,2H),2.43-2.41(m,2H),2.39(s,3H),2.13(s,3H),1.45-1.50(m,2H),0.82-0.85(m,3H)。
实施例2
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)decanethioate，(Z)-S-(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)硫代癸酸酯1-2合成：
Figure PCTCN2019120942-appb-000006
将6.6g磷酸硫胺溶解在10.0g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10℃以下滴加3.6g式1-2b的四氢呋喃溶液，滴加完毕反应0.5小时，调节pH至7～8，加入乙酸乙酯萃取分液两次，正庚烷一次，调节pH至7，正庚烷萃取分液一次，加入二氯甲烷，调节pH至不乳化，分液，干燥，旋干二氯甲烷，制得产物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):517.2[M +1]
1H NMR(DMSO-d 6)δ7.99(s,1H),7.81(s,1H),4.47(s,2H),3.82-3.81(m,2H),2.59-2.51(m,2H),2.43-2.42(m,5H),2.41(s,3H),1.45-1.44(m,2H),1.28-1.22(m,12H),0.87-0.84(m,3H)。
实施例3
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)dodecanethioate，(Z)-S-(2-(N-((4-胺基-2-甲基嘧啶-5-基)甲基)甲酰胺)-5-(磷酰氧基)戊-2-烯-3-基)硫代月桂酸酯1-3合成：
Figure PCTCN2019120942-appb-000007
将6.1g磷酸硫胺溶解在12.8g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0.5小时，保持在10℃以下滴加式1-3b的四氢呋喃溶液，滴加过程中加入氢氧化钠溶液保持pH 10～12，滴加完成，保温反应1小时；加入乙酸乙酯萃取两次，分掉有机相，31％盐酸调节pH到4～5，用二氯甲烷萃取产品，二氯甲烷相用无水硫酸钠干燥，过滤，滤液40℃浓缩，得到产物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):545.2[M +1]
1H NMR(DMSO-d 6):δ8.03(s,1H),7.83(s,1H),4.48(s,2H),3.83-3.81(m,2H),2.59(s,2H),2.43-2.40(m,5H),2.14(s,3H),1.45-1.43(m,2H),1.23-1.21(m,16H),0.85(t,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)2-methylbut-2-enethioate，(E)-S-((Z)-2-(N-((4-胺基-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-甲基丁-2-烯酸酯1-4合成：
Figure PCTCN2019120942-appb-000008
将3.0g 2-甲基丁-2-烯酸加入30mL二氯甲烷中，加入0.5g二甲基甲酰胺7.2g和二氯亚砜，加热到60℃回流1小时，减压蒸馏除去二氯亚砜和二氯甲烷，制得式1-4b的酰氯，加入二氯甲烷30mL备用，将8.3g磷酸硫胺 溶解在18.0g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0.5小时，保持在10℃以下滴加上述制备的酰氯溶液，滴加过程中加入氢氧化钠溶液保持pH 10～12，滴加完成保温10℃反应1小时，蒸馏掉二氯甲烷，水相，31％盐酸调节pH到4～5，无产品析出，丙酮洗两次，产品析出，过滤，滤饼用乙酸乙酯打浆一次，甲醇打浆两次过滤，滤饼45℃烘干，制得产物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):445.1[M +1]
1H NMR(DMSO-d 6):δ7.89(s,1H),7.80(s,1H),6.65(d,1H),4.44(d,2H),3.80-3.76(m,2H),2.59(d,2H),2.37(s,3H),2.14(s,3H),1.80-1.78(m,3H),1.72-1.69(m,3H)。
实施例5
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2-methylbutanethioate，产品名称：(Z)-S-(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2-甲基丁酸酯1-5合成：
Figure PCTCN2019120942-appb-000009
将6.6g磷酸硫胺溶解在10.0g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10℃以下滴加2.3g式1-5b的二氯甲烷溶液，滴加完毕，反应1小时，调节pH至7，加入50mL二氯甲烷，分液，水相调节pH至2.5，固体析出，过滤，乙酸乙酯打浆1小时，过滤，滤饼45℃烘干得产物1-5。
MS m/z(ESI):447.1[M +1]
1H NMR(DMSO-d 6)δ7.96(s,1H),7.77(s,1H),4.47(s,2H),3.81-3.77(m,2H),2.60-2.53(m,2H),2.47-2.46(m,1H),2.41(s,3H),2.14(s,3H),1.54-1.51(m,1H),1.37-1.36(m,1H),1.03-1.00(m,3H),0.84-0.79(m,3H)。
实施例6
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2-methylpropanethioate，(Z)-S-(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2-甲基丙酸酯1-6合成：
Figure PCTCN2019120942-appb-000010
采用实施例5的合成路线，将原料1-5b化合物替换为1-6b化合物，制得产物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):433.0[M +1]
1H NMR(DMSO-d 6)δ7.95(s,1H),7.76(s,1H),4.46(s,2H),3.80-3.76(m,2H),2.62-2.58(m,3H),2.40(s,3H),2.14(s,3H),1.05-1.02(m,6H)。
实施例7
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)octanethioate，(Z)-S-(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)硫代正辛酸酯1-7合成：
Figure PCTCN2019120942-appb-000011
采用实施例2的合成路线，将原料1-2b化合物替换为1-7b化合物，制得产物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):489.1[M +1]
1H NMR(DMSO-d 6)δ7.97(s,1H),7.81(s,1H),4.47(s,2H),3.81-3.78(m,2H),2.60-2.51(m,2H),2.44-2.41(m,1H),2.40(s,3H),2.20-2.17(m,1H),2.13(s,3H),1.47-1.43(m,2H),1.25-1.22(m,8H),0.87-0.84(m,3H)。
实施例8
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)3-phenylpropanethioate，(Z)-S-(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-苯基丙酸酯1-8合成：
Figure PCTCN2019120942-appb-000012
将6.6g磷酸硫胺溶解在8.8g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1-8b的二氯甲烷溶液，加毕，保温反应1小时，减压蒸馏除去二氯甲烷，水相调节pH至4，固体析出，过滤，滤饼使用乙酸乙酯打浆过滤，制得产物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):495.1[M +1]
1H NMR(DMSO-d 6)δ7.92(s,1H),7.81(s,1H),7.29-7.18(m,7H),4.43(s,2H),3.76-3.75(m,2H),2.75(m,4H),2.57(s,2H),2.37(s,3H),2.11(s,3H)。
实施例9
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)hex-5-enethioate，(Z)-S-(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)硫代己-5-烯酸酯1-9合成：
Figure PCTCN2019120942-appb-000013
将3.3g磷酸硫胺溶解在4.4g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1-9b酰氯的四氢呋喃溶液，滴加完毕，保温反应0.5小时，调节pH至7～8，加入二氯甲烷萃取，分液，水相，调节pH至4，搅拌析晶，过滤，水打浆0.5小时，过滤制得产物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):459.1[M +1]
1H NMR(DMSO-d 6)δ7.90(d,1H),7.80(d,1H),5.79-5.72(m,1H),5.10-5.00(m,2H),4.45(s,2H),3.8-3.76(m,2H),2.60(s,2H),2.45-2.42(m,2H),2.36(s,3H),2.12(s,3H),2.00-1.96(m,2H),1.57-1.53(m,2H)。
实施例10
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2-(2,6-difluorophenyl)ethanethioate，(Z)-S-(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)-2-(2,6-二氟苯基)乙酸硫酯1-10合成：
Figure PCTCN2019120942-appb-000014
将1.7g 2,6-二氟苯乙酸，2.4g二氯亚砜，0.2g二甲基甲酰胺，30mL二氯甲烷加入100mL单口烧瓶中，50℃下加热回流3小时，把二氯甲烷蒸干后，加四氢呋喃溶解得式1-10b的四氢呋喃溶液，将2.7g磷酸硫胺溶解在4g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1.9g式1-10b的四氢呋喃溶液，调节pH至10～12，滴加完毕，反应1小时，水相调节pH至3～4，有固体析出，过滤，得滤饼，滤饼用甲醇和水打浆，过滤后滤饼45℃烘干制得产物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):517.0[M +1]
1H NMR(DMSO-d 6)δ7.85(s,1H),7.76(s,1H),7.47-7.40(m,1H),7.13(t,2H),4.43(s,2H),3.87(s,2H),3.90-3.76(m,2H),2.60(s,2H),2.34(s,3H),2.11(s,3H)。
实施例11
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2,2-dimethylbut-3-enethioate，(Z)-S-(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-2,2-二甲基丁-3-烯酸酯1-11合成：
Figure PCTCN2019120942-appb-000015
采用实施例9的合成路线，将原料1-9b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，以所述产物1-11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):459.1[M +1]
1H NMR(DMSO-d 6)δ7.96(s,1H),7.74(s,1H),5.87-5.81(m,1H),5.20-5.17(m,2H),4.46(s,2H),3.78-3.74(m,2H),2.55-2.54(m,2H),2.40(s,3H),2.14(s,3H),1.17-1.15(m,6H)。
实施例12
(E)-S-((Z)-2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)hex-2-enethioate，(E)-S-((Z)-2-(N-((4-胺基-2-甲基嘧啶-5-基)甲基)甲酰胺基)-5-(磷酰氧基)戊-2-烯-3-基)硫代己-2-烯碳酸酯1-12合成：
Figure PCTCN2019120942-appb-000016
采用实施例4的合成路线，将原料1-4b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):459.1[M +1]
1H NMR(DMSO-d 6):δ7.94(s,1H),7.82(s,1H),6.77-6.71(m,1H),6.06(d,1H),4.45(d,2H),3.81-3.77(m,2H),2.62(d,2H),2.38(s,3H),2.17-2.14(m,5H),1.15-1.14(m,2H),0.90(t,3H)。
实施例13
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2-ethylhexanethioate，(Z)-S-(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2-乙基己酸酯1-13合成：
Figure PCTCN2019120942-appb-000017
将1.4g 2-乙基己酸，5.0g二氯亚砜，0.1mL二甲基甲酰胺，20mL二氯甲烷加入50mL单口烧瓶中，55℃下加热回流2小时，把二氯甲烷蒸干后，加二氯甲烷溶解得式1-13b的二氯甲烷溶液，将3.0g磷酸硫胺溶解在6.0g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1.44g 1-13b的二氯甲烷溶液，调节pH至10～12，滴加完毕，反应0.5小时，反应液调pH中性,乙酸乙酯萃取一次，水相调节pH至3～4，有油状固体析出，二氯甲烷萃取，萃取后二氯甲烷加无水硫酸钠除水，旋干，甲醇溶解固体，加甲基叔丁基醚，搅拌五个小时后有固体析出，过滤后滤饼45℃烘干得产物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):489.0[M +1]
1H NMR(DMSO-d 6):δ7.97(s,1H),7.78(s,1H),4.47(d,2H),3.76-3.75(m,2H),2.59(d,2H),2.37(s,3H),2.26(d,1H),2.13(s,3H),1.46-1.16(m,8H),0.84-0.79(m,6H)。
实施例14
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2-methylpentanethioate，(Z)-S-(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-2-甲基戊酸酯1-14合成：
Figure PCTCN2019120942-appb-000018
将2.3g 2-甲基戊酸，4.8g二氯亚砜，0.2g二甲基甲酰胺，60mL二氯甲烷加入100mL单口烧瓶中，60℃下加热回流3小时，把二氯甲烷蒸干后，加四氢呋喃溶解得式1-14b的四氢呋喃溶液，将5.5g磷酸硫胺溶解在8.0g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2.7g式1-14b四氢呋喃溶液，调节pH至10～12，滴加完毕，反应1小时，水相调节pH至7，用乙酸乙酯萃取2次，再把水相pH调为3～4，用二氯甲烷萃取2次，有机相用无水硫酸镁干燥后旋干，再用甲醇和乙酸乙酯重结晶，过滤，滤饼45℃烘干得产物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):461.0[M+1]
1H NMR(DMSO-d 6)δ7.97(s,1H),7.76(s,1H),4.47(s,2H),3.77(d,2H),2.54(s,2H),2.52(s,1H),2.41(s,3H),2.14(s,3H),1.52-1.45(m,1H),1.28-1.21(m,3H),1.00(d,3H),0.84(t,3H)。
实施例15
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2-methylhexanethioate，(Z)-S-(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-2-甲基己酸酯1-15合成：
Figure PCTCN2019120942-appb-000019
采用实施例14的合成路线，将原料1-14b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):475.0[M +1]
1H NMR(DMSO-d 6)δ7.95(s,1H),7.76(s,1H),4.46(s,2H),3.80-3.76(m,2H),2.60(s,2H),2.41(s,3H),2.13(s,3H),1.51-1.49(m,1H),1.26-1.16(m,6H),1.00(s,3H),0.86(s,3H)。
实施例16
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2,2-dimethylbutanethioate，(Z)-S-(2-(N-((4-胺基-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2，2-二甲基丁酸酯1-16合成：
Figure PCTCN2019120942-appb-000020
采用实施例4的合成路线，将原料1-4b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):461.0[M +1]
1H NMR(DMSO-d 6):δ7.87(s,1H),7.72(s,1H),4.45(d,2H),3.78-3.74(m,2H),2.64(d,2H),2.38(s,3H),2.13(s,3H),1.48-1.44(m,2H),1.04(s,6H),0.76(t,3H)。
实施例17
(Z)-S-(2-(N-((4-amino-2-methylpyrimidin-5-yl)methyl)formamido)-5-(phosphonooxy)pent-2-en-3-yl)2,2-dimethylhexanethioate，(Z)-S-(2-(N-((4-胺-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2,2-二甲基己酸酯1-17合成：
Figure PCTCN2019120942-appb-000021
将1.0g 2,2-二甲基己酸加入30mL二氯甲烷中，加入0.3g二甲基甲酰胺和1.7g二氯亚砜，加热到50℃回流2小时，减压蒸馏除去二氯亚砜和二氯甲烷制得式1-17b的酰氯，加入四氢呋喃10mL备用，将2.2g磷酸硫胺溶解在4.4g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0.5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 10～12，滴加完成保温5～10℃反应0.5小时，31％盐酸调节pH到4～5，用二氯甲烷萃取两次，有机相用无水硫酸钠干燥，减压浓缩干，剩余物加入正庚烷打浆，产品析出，过滤，滤饼用正庚烷洗涤一次，50℃真空干燥8小时，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):489.0[M +1]
1H NMR(DMSO-d 6):δ8.04(s,1H),7.78(s,1H),4.48(d,2H),3.84-3.80(m,2H),2.57(d,2H),2.44(s,3H),2.15(s,3H),1.42-1.41(m,2H),1.24-1.16(m,4H),1.04(s,6H),0.87-0.83(m,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 PCTCN2019120942-appb-000022
根据以上实验结果，与对比例1空白相比，所述结构化物均具有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11Aβ40的含量与对比例2的含量基本差不多，但Aβ42含量降低，表明其对Aβ42的更好的抑制作用；与对比例2苯磷硫胺相比，实施例5、6和实施例12特别是实施例12，Aβ40和Aβ42都明显降低，表明其对Aβ40和Aβ42的抑制作用得到大的加强，表明其对Aβ40和Aβ42的抑制作用得到大的加强。
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 (11)

  1. 一种硫胺类化合物，其结构如下式(1)或式(2)，
    Figure PCTCN2019120942-appb-100001
    其中，R 1、R 2、R 3、R 4、R 5或R6分别独立的为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基、酯基、羧基、羟基、巯基、烃巯基、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，所述硫胺类化合物结构如式(1)，所述R 1和R 2为氢原子，R 3为苄基或1,5二氟苯基。
  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 1、R 2、R 3、R 4、R 5或R 6分别独立的为氢原子或C1-C18的链烃基。
  4. 根据权利要求1所述的硫胺类化合物，其特征在于，所述硫胺类化合物结构如式(1)，R 1或R 2分别独立的为氢原子、甲基或乙基，R 3为C1-C10的链烃基。
  5. 根据权利要求4所述的硫胺类化合物，其特征在于，所述R 1为氢原子，R 2为甲基，R 3为甲基或乙基。
  6. 根据权利要求4所述的硫胺类化合物，其特征在于，所述R 1为甲基，R 2为甲基，R 3为乙烯基。
  7. 根据权利要求3所述的硫胺类化合物，其特征在于，所述硫胺类化合物结构如式(2)，所述R 4和R 5为氢原子，R 6为正丙基。
  8. 一种如权利要求1-7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)或(2b)所示的酰氯反应制备获得；
    Figure PCTCN2019120942-appb-100002
    其中，R 1、R 2、R 3、R 4、R 5或R 6分别独立的为氢原子、卤素原子、硝基、氰基、磺酸基、氨基、取代胺基、酯基、羧基、羟基、巯基、烃巯基、烃基、取代烃基、烃氧基、取代烃氧基、酰基或酰胺基。
  9. 一种药物组合物，其包含权利要求1-6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。
  10. 根据权利要求9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。
  11. 根据权利要求10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。
PCT/CN2019/120942 2018-11-28 2019-11-26 硫胺类化合物、制备方法及其药物组合物 WO2020108478A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP19888995.8A EP3889160A4 (en) 2018-11-28 2019-11-26 THIAMINE COMPOUND, METHOD FOR PREPARING IT AND PHARMACEUTICAL COMPOSITION RELATED
US17/298,214 US11591354B2 (en) 2018-11-28 2019-11-26 Thiamine compound, preparation method and pharmaceutical composition thereof
JP2021531390A JP7307979B2 (ja) 2018-11-28 2019-11-26 チアミン化合物、製造方法及びその医薬組成物
JP2023039009A JP7534814B2 (ja) 2018-11-28 2023-03-13 チアミン化合物、製造方法及びその医薬組成物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811435584.X 2018-11-28
CN201811435584.XA CN111233925B (zh) 2018-11-28 2018-11-28 硫胺类化合物、制备方法及其药物组合物

Publications (1)

Publication Number Publication Date
WO2020108478A1 true WO2020108478A1 (zh) 2020-06-04

Family

ID=70853867

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/120942 WO2020108478A1 (zh) 2018-11-28 2019-11-26 硫胺类化合物、制备方法及其药物组合物

Country Status (5)

Country Link
US (1) US11591354B2 (zh)
EP (1) EP3889160A4 (zh)
JP (2) JP7307979B2 (zh)
CN (1) CN111233925B (zh)
WO (1) WO2020108478A1 (zh)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111233925B (zh) 2018-11-28 2021-03-26 上海日馨生物科技有限公司 硫胺类化合物、制备方法及其药物组合物
WO2022242629A1 (zh) * 2021-05-20 2022-11-24 上海日馨医药科技股份有限公司 含有磷酸酯基团的化合物、包含其的药物组合物、其制备方法及其用途
CN118234735A (zh) * 2021-11-22 2024-06-21 上海日馨医药科技股份有限公司 苯磷硫胺衍生物的固体形式及其制备方法和用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS3921372B1 (zh) * 1961-07-14 1964-09-29
JPS3921526B1 (zh) * 1960-09-20 1964-10-01
JPS401396B1 (zh) * 1961-08-25 1965-01-26
CN103772432A (zh) * 2014-01-03 2014-05-07 湖北瑞锶科技有限公司 一种苯磷硫胺的生产方法
EP2918593A1 (en) 2012-10-17 2015-09-16 Shanghai Ri Xin Biotechnology Co., Ltd. Benfotiamine polymorphs, preparation method and use thereof

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE756255A (fr) * 1969-09-18 1971-03-17 Hoffmann La Roche Nouvelles 4-amino-2-methyl-pyrimidines
US20090060872A1 (en) * 2007-08-31 2009-03-05 Idenix Pharmaceuticals, Inc. Phosphadiazine hcv polymerase inhibitors v
JP6037330B2 (ja) * 2012-03-03 2016-12-07 国立研究開発法人理化学研究所 １１ｃ−標識チアミン及びその誘導体、１１ｃ−標識フルスルチアミン、チアミン前駆体、並びにｐｅｔ用プローブ及びそれらを用いたイメージング方法
CN112933101A (zh) * 2017-06-26 2021-06-11 上海日馨生物科技有限公司 苯磷硫胺衍生物、制备方法及其药物组合物
CN111233926B (zh) * 2018-11-28 2021-04-16 上海日馨生物科技有限公司 硫胺类化合物、制备方法及其药物组合物
CN111233925B (zh) 2018-11-28 2021-03-26 上海日馨生物科技有限公司 硫胺类化合物、制备方法及其药物组合物
WO2020108481A1 (zh) * 2018-11-28 2020-06-04 上海日馨生物科技有限公司 硫胺类化合物、制备方法及其药物组合物
US10947258B1 (en) * 2019-08-23 2021-03-16 Shanghai Rixin Biotechnology Co., Ltd. Benfotiamine derivatives, method for preparing the same and pharmaceutical composition comprising the same

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS3921526B1 (zh) * 1960-09-20 1964-10-01
JPS3921372B1 (zh) * 1961-07-14 1964-09-29
JPS401396B1 (zh) * 1961-08-25 1965-01-26
EP2918593A1 (en) 2012-10-17 2015-09-16 Shanghai Ri Xin Biotechnology Co., Ltd. Benfotiamine polymorphs, preparation method and use thereof
CN103772432A (zh) * 2014-01-03 2014-05-07 湖北瑞锶科技有限公司 一种苯磷硫胺的生产方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MITSURU KATAOKA; HIROO ITO: "Studies on the Allied Compounds of Vitamin B1. XXVI. On the S-Acylthiamine O-Disubstituted Phosphates", TAKAMINE KENKYUSHO NENPO = THE ANNUAL REPORT OF TAKAMINE LABORATORY, vol. 13, 31 December 1961 (1961-12-31), Tokyo, JP, pages 24 - 27, XP009528147 *

Also Published As

Publication number Publication date
US20220089621A1 (en) 2022-03-24
JP7534814B2 (ja) 2024-08-15
CN111233925A (zh) 2020-06-05
JP7307979B2 (ja) 2023-07-13
CN111233925B (zh) 2021-03-26
EP3889160A1 (en) 2021-10-06
JP2022511468A (ja) 2022-01-31
US11591354B2 (en) 2023-02-28
EP3889160A4 (en) 2022-07-27
JP2023085312A (ja) 2023-06-20

Similar Documents

Publication Publication Date Title
WO2020108480A1 (zh) 硫胺类化合物、制备方法及其药物组合物
WO2020108478A1 (zh) 硫胺类化合物、制备方法及其药物组合物
CN104262267B9 (zh) 用于治疗前列环素(pgi2)受体相关病症的pgi2受体调节剂
EP0082088B1 (fr) Nouveaux dérivés d'aminoacides, et leur application thérapeutique
CA2950452C (en) Amantadine nitrate compounds with neural protective effect, and preparation and medical use thereof
DE602004011255T2 (de) Phosphinsäurederivate, inhibitoren von beta-sekretase zur behandlung von alzheimer-krankheit
TW202019914A (zh) ２-（３，５-二氯-４-（（５-異丙基-６-側氧基-１，６-二氫噠嗪-３-基）氧）苯基）-３，５-二側氧基-２，３，４，５-四氫-１，２，４-三嗪-６-腈之固體型式
CA2398923A1 (en) A group of anti-cancer compounds with specific structure and their production method
CA2584610A1 (en) Novel dicarboxylic acid derivatives
US11820787B2 (en) Benfotiamine derivatives in the treatment of alzheimer's disease
CN109111478B (zh) 苯磷硫胺衍生物、制备方法及其药物组合物
WO2020108481A1 (zh) 硫胺类化合物、制备方法及其药物组合物
AU2002214978B2 (en) Beta-Thio-amino acids
DE69714056T2 (de) Cytostatische hydroxamsäurederivate
AU2008273923B2 (en) Amino acid derivatives
US20180148404A1 (en) Amantadine nitrate compounds with neural protective effect, and preparation and medical use thereof
KR20070114197A (ko) 씨피티를 억제하는 아미노부탄산의 유도체
CA2765462A1 (en) Mexiletine amino acid and peptide prodrugs and uses thereof
TW201912624A (zh) (E)-α,β-不飽和醯胺化合物及其製備方法和用途
DE68904203T4 (de) Cysteinderivate.
CN111233927B (zh) 硫胺类化合物、制备方法及其药物组合物
WO2017085733A2 (en) Improved process for the synthesis of 2, 6-xylidine and its derivatives
US2412966A (en) Chemical compounds
JPS6256860B2 (zh)
JPS62132845A (ja) Ｎ，ｎ−二置換フエニルセリン誘導体及びそれを有効成分とする中枢神経系用剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19888995

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2021531390

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2019888995

Country of ref document: EP

Effective date: 20210628