WO2020108480A1 - Composés de thiamine, procédé de préparation et composition pharmaceutique associés - Google Patents

Composés de thiamine, procédé de préparation et composition pharmaceutique associés Download PDF

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Publication number
WO2020108480A1
WO2020108480A1 PCT/CN2019/120947 CN2019120947W WO2020108480A1 WO 2020108480 A1 WO2020108480 A1 WO 2020108480A1 CN 2019120947 W CN2019120947 W CN 2019120947W WO 2020108480 A1 WO2020108480 A1 WO 2020108480A1
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group
ring
substitution
thiamine
substituted
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PCT/CN2019/120947
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English (en)
Chinese (zh)
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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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    • 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
    • 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
    • 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
    • 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
    • C07F9/65586—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 at least one of the hetero rings does not contain nitrogen as ring hetero atom

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 its structure is as follows (1),
  • ring A is a saturated or unsaturated 3-8 membered non-aromatic ring
  • the ring atoms of ring A include 0-3 O, N and/or S heteroatoms;
  • the ring A does not contain a substituent, or is substituted by a double bond, or has one or more independent substituents, or has a cyclic substitution sharing one or two carbon atoms;
  • the substituent is a halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, ester group, carboxyl group, hydroxyl group, mercapto group, hydrocarbon mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, Or acyl, amide.
  • the ring A is a five-membered ring or a six-membered ring.
  • the cyclic substitution having two carbon atoms in common is benzene ring substitution.
  • only one ring carbon atom of the ring A has a substituent.
  • the substituent is a hydrocarbon group or a halogen atom.
  • the thiamine compound has one of the following structural formulas:
  • the thiamine compound has a structural formula of formulas 1-4, 1-6, 1-11, 1-13, 1-15, 1-16, 1-17, 1-18, or 1-19.
  • the method for preparing the thiamine compound is obtained by reacting the thiamine phosphate represented by formula (1a) with the acid chloride represented by formula (1b);
  • ring A is a saturated or unsaturated 3-8 membered non-aromatic ring
  • the ring atoms of ring A include 0-3 O, N and/or S heteroatoms;
  • the ring A does not contain a substituent, or is substituted by a double bond, or has one or more independent substituents, or has a cyclic substitution sharing one or two carbon atoms;
  • the substituents are halogen atom, nitro group, cyano group, sulfonic acid group, amino group, substituted amine group, ester group, carboxyl group, hydroxyl group, mercapto group, hydrocarbylthio group, hydrocarbyl group, substituted hydrocarbyl group, hydrocarbyloxy group, substituted hydrocarbyloxy group , 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 with a non-aromatic ring A, which have an inhibitory effect on A ⁇ 40 and/or A ⁇ 42; further, the ring A is a five-membered ring Or a six-membered ring, or the ring A has a benzene ring substitution sharing two carbon atoms, or the ring A has only one substituent and is trans-substituted, its inhibitory effect is strengthened; further, the thiamine compound Specifically, the compounds are represented by formulas 1-4, 1-6, 1-11, 1-13, 1-15, 1-16, 1-18, 1-19, especially formulas 1-4, 1-11, 1 The compound shown in -16 has prominent inhibitory effects on A ⁇ 40 and A ⁇ 42.
  • the thiamine compound of the embodiment of the present invention has a structure of the following formula (1),
  • ring A is a saturated or unsaturated 3-8 membered non-aromatic ring; the ring atoms of ring A include 0-3 O, N and/or S heteroatoms; ring A contains no substituents, Or having one or more independent substituents, or having a cyclic substitution sharing one or two carbon atoms; the substituents are halogen atoms, nitro groups, cyano groups, sulfonic acid groups, amino groups, substituted amine groups, Ester group, carboxyl group, hydroxyl group, mercapto group, hydrocarbon mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbonoxy group, substituted hydrocarbonoxy group, acyl group or amide group.
  • the ring A has a double bond substitution of the following formula (X):
  • R1 and R2 are independently hydrogen atom, halogen atom, nitro group, cyano group, sulfonic acid group, amino group, carboxyl group, hydroxyl group, mercapto group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, or acyl group , As shown in formula 1-10.
  • the ring A has a cyclic substitution that shares two carbon atoms, and is specifically represented by structural compounds represented by formulas 1-5, 1-12, 1-13, and 1-20.
  • 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, cyclopentyl, hexanoyl, 1-methylvaleryl, 1-ethylbutyryl, cyclohexyl, 2-heptanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl , Dodecanoyl, tridecanoyl, tetrade
  • 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 ring A is a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring, a seven-membered ring or an eight-membered ring, etc.
  • the ring A is a five-membered ring or a six-membered ring
  • the element ring may have a better inhibitory effect on A ⁇ 40 and/or A ⁇ 42 due to its more stable ring.
  • the cyclic substitution having one or two carbon atoms is benzene ring substitution, spiro ring substitution, bridge ring substitution, preferably the cyclic substitution having two carbon atoms is benzene ring substitution .
  • only one ring carbon atom of the ring A has a substituent, and the substituent is preferably an alkane group or a halogen atom, and further preferably a mono-substituted C1-C20 alkane group or a di-substituted halogen atom.
  • the mono-substituted C1-C20 alkane group is further preferably a C1-C10 alkane group, and still more preferably a C1-C4 alkane group.
  • the mono-substituted C1-C20 alkane group may be cis substitution or trans substitution, preferably trans substitution.
  • the thiamine compound has one of the following structural formulas:
  • the formulas 1-4, 1-6, 1-11, 1-13, 1-15, 1-16, 1-17 are preferred .
  • the present invention also provides a method for preparing the above-mentioned thiamine compound, which is obtained by reacting a thiamine phosphate represented by formula (1a) with an acid chloride represented by formula (1b);
  • ring A is a saturated or unsaturated 3-8 membered non-aromatic ring; the ring atoms of ring A include 0-3 O, N and/or S heteroatoms; ring A contains no substituents, Or double bond substitution, or one or more independent substituents, or a cyclic substitution that shares one or two carbon atoms; the substituents are halogen atoms, nitro, cyano, sulfonate, amino , Substituted amine group, ester group, carboxyl group, hydroxyl group, mercapto group, hydrocarbon thio group, hydrocarbon group, substituted hydrocarbon group, hydrocarbon oxy group, substituted hydrocarbon oxy group, acyl group 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.
  • Example 2 Using the synthetic route of Example 1, the raw material 1-1b compound was replaced with the 1-2b compound to prepare the product 1-2.
  • 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.
  • Example 2 Using the synthetic route of Example 1, the raw material 1-1b compound was replaced with the 1-3b compound to prepare the product 1-3.
  • 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.
  • Example 2 Using the synthetic route of Example 1, the raw material 1-1b compound was replaced with the 1-4b compound to prepare the product 1-4.
  • 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.
  • Example 2 Using the synthetic route of Example 1, the raw material 1-1b compound was replaced with the 1-6b compound to obtain the product 1-6.
  • 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.
  • 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 aqueous phase was adjusted to pH 4-5 with 31% hydrochloric acid.
  • Dichloromethane was extracted twice, concentrated and dried, methanol and ethyl acetate were slurried, filtered, and the filter cake was dried at 45°C to obtain the product. 1-16.
  • 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 used to prepare a stock solution of the test product for biological testing. The results are listed in Table 1.
  • 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 (1HNMR) and mass spectrometry (MS) tests. The results are as follows. The product 1-20 was prepared for the biological test of the test 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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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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Abstract

Selon des modes de réalisation, la présente invention concerne une série de composés de thiamine ayant un cycle non aromatique A, les composés de thiamine ayant un effet inhibiteur sur Aβ40 et/ou Aβ42.
PCT/CN2019/120947 2018-11-28 2019-11-26 Composés de thiamine, procédé de préparation et composition pharmaceutique associés WO2020108480A1 (fr)

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JP2022511468A (ja) * 2018-11-28 2022-01-31 上海日馨医▲薬▼科技股▲分▼有限公司 チアミン化合物、製造方法及びその医薬組成物

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CN116531373A (zh) * 2022-01-26 2023-08-04 上海日馨医药科技股份有限公司 噻唑类化合物、其药物组合物及应用
CN116531381A (zh) * 2022-01-26 2023-08-04 上海日馨医药科技股份有限公司 一种含硫类化合物及其药物组合物

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US11591354B2 (en) 2018-11-28 2023-02-28 Shanghai Raising Pharmaceutical Co., Ltd. Thiamine compound, preparation method and pharmaceutical composition thereof
JP7307979B2 (ja) 2018-11-28 2023-07-13 上海日馨医▲薬▼科技股▲分▼有限公司 チアミン化合物、製造方法及びその医薬組成物

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