CN111233926A - Thiamine compound, preparation method and pharmaceutical composition thereof - Google Patents
Thiamine compound, preparation method and pharmaceutical composition thereof Download PDFInfo
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- CN111233926A CN111233926A CN201811435614.7A CN201811435614A CN111233926A CN 111233926 A CN111233926 A CN 111233926A CN 201811435614 A CN201811435614 A CN 201811435614A CN 111233926 A CN111233926 A CN 111233926A
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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
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- 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
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- 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
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- 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 System
- 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
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- 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 System
- 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
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- 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 System
- 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
Abstract
The embodiment of the invention provides a series of thiamine compounds with non-aromatic rings A, and the thiamine compounds have an inhibiting effect on A β 40 and/or A β 42.
Description
Technical Field
The invention belongs to the field of medical chemistry, and particularly relates to a thiamine compound, a preparation method and a pharmaceutical composition thereof.
Background
Alzheimer's Disease (AD) is a progressive neurodegenerative disease with cognitive and behavioral disorders as main clinical manifestations, and is the most common senile dementia, and the main manifestations are cognitive dysfunction and rapid decline of memory function.
Studies have shown that benfotiamine can reduce the deposition of β -amyloid protein (β -amyloid, A β) in brain and the phosphorylation of Tau protein by inhibiting the activity of sugar synthase kinase-3 (GSK-3), thereby reducing the occurrence of pathological damage of Alzheimer disease.
Disclosure of Invention
The specific embodiment of the invention provides a novel thiamine compound, a preparation method and a technical scheme of a pharmaceutical composition thereof:
a thiamine compound has a structure shown in formula (1),
wherein ring A is a saturated or unsaturated 3-8 membered non-aromatic ring;
the ring A ring atoms include 0-3O, N and/or S heteroatoms;
ring a is unsubstituted or double-bond substituted, or has one or more substituents independently of each other, or has cyclic substitution sharing one or two carbon atoms;
the substituent is halogen atom, nitryl, cyano, sulfonic group, amino, substituted amino, ester group, carboxyl, hydroxyl, sulfydryl, hydrocarbon sulfydryl, alkyl, substituted alkyl, hydrocarbonoxy, substituted hydrocarbonoxy, or acyl, acylamino.
Optionally, the ring a is a five-membered ring or a six-membered ring.
Alternatively, the cyclic substitution having a common two carbon atoms is a phenyl ring substitution.
Alternatively, only one ring carbon atom of the ring a may have a substituent.
Optionally, the substituent is a hydrocarbon group or a halogen atom.
Optionally, the thiamine compound has one of the following structural formulas:
optionally, the thiamine compound has a structural formula of 1-4, 1-6, 1-11, 1-13, 1-15, 1-16, 1-17, 1-18 or 1-19.
The preparation method of the thiamine compound is obtained by reacting thiamine phosphate shown in a formula (1a) with acyl chloride shown in a formula (1 b);
wherein ring A is a saturated or unsaturated 3-8 membered non-aromatic ring;
the ring A ring atoms include 0-3O, N and/or S heteroatoms;
ring a is unsubstituted or double-bond substituted, or has one or more substituents independently of each other, or has cyclic substitution sharing one or two carbon atoms;
the substituent is halogen atom, nitryl, cyano, sulfonic group, amino, substituted amino, ester group, carboxyl, hydroxyl, sulfydryl, sulfenyl, alkyl, substituted alkyl, oxyl, substituted oxyl, acyl or amido.
A pharmaceutical composition comprising any one of the above thiamine compounds and isomers thereof or salts of thiamine compounds and isomers thereof.
Optionally, the pharmaceutical composition is used for preparing a medicament for preventing and treating neurodegenerative diseases.
Optionally, the pharmaceutical composition is used for preparing a medicament for preventing and treating Alzheimer disease or aging.
Compared with the prior art, the embodiment of the invention provides a series of thiamine compounds with non-aromatic rings A, which have an inhibiting effect on A β 40 and/or A β 42, further, the inhibition effect is enhanced when the rings A are five-membered rings or six-membered rings, or the rings A share two carbon atom benzene rings for substitution, or the rings A only have one substituent and are in trans-substitution, and further, the thiamine compounds are specifically shown as formulas 1-4, 1-6, 1-11, 1-13, 1-15, 1-16, 1-18 and 1-19, particularly as formulas 1-4, 1-11 and 1-16, and have outstanding inhibiting effects on A β 40 and A β 42.
Detailed Description
The thiamin compound of the embodiment of the present invention has the following structure (1),
wherein ring A is a saturated or unsaturated 3-8 membered non-aromatic ring; the ring A ring atoms include 0-3O, N and/or S heteroatoms; ring a is unsubstituted or has one or more substituents independently of each other or has cyclic substitution sharing one or two carbon atoms; the substituent is halogen atom, nitryl, cyano, sulfonic group, amino, substituted amino, ester group, carboxyl, hydroxyl, sulfydryl, hydrocarbon sulfydryl, alkyl, substituted alkyl, hydrocarbonoxy, substituted hydrocarbonoxy, acyl or amido.
In a particular embodiment of the invention, said ring A has double bond substitution of formula (X) as follows:
wherein, R1 and R2 are respectively independent of each other, hydrogen atom, halogen atom, nitro, cyano, sulfonic group, amino, carboxyl, hydroxyl, sulfydryl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, or acyl, and are structural compounds shown in formulas 1-10.
In a specific embodiment of the present invention, the ring A has a cyclic substitution sharing two carbon atoms, specifically structural compounds represented by formulas 1-5, 1-12, 1-13, and 1-20.
In a specific embodiment of the present invention, the substituent includes a linear, branched or cyclic hydrocarbon group, which may be an alkane group, and may also be an alkene group, an alkyne group or an aromatic hydrocarbon group, and in some embodiments, the hydrocarbon group is an alkane group, specifically, for example, methyl group, ethyl group, ethenyl group, propenyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, isobutyl group, pentyl group, 1-ethylpropyl group, 1-methylbutyl group, cyclopentyl group, hexyl group, 1-methylpentyl group, 1-ethylbutyl group, cyclohexyl group, 2-heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, eicosyl group, heneicosyl group, docosyl group, tricosyl group, etc.; in some embodiments, the hydrocarbon group is an aromatic hydrocarbon group, such as, specifically, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 1-naphthyl, 2-naphthyl, benzyl, 2-phenylethyl, or the like.
In a specific embodiment of the present invention, the substituted hydrocarbon group includes halogen atom substitution, nitro group substitution, cyano group substitution, sulfonic group substitution, hydrocarbyloxy group substitution, amino group substitution, carboxyl group substitution, hydroxyl group substitution, mercapto group substitution, and the like of the above-mentioned hydrocarbon group, and specifically, for example, methoxyethyl group, ethoxyethyl group, butoxyethyl group, trifluoromethyl group, pentafluoroethyl group, and the like.
In a specific embodiment of the present invention, the hydrocarbyloxy group includes a straight-chain, branched-chain or cyclic hydrocarbyloxy group, specifically, for example, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, t-butoxy group, isobutoxy group, pentyloxy group, 1-ethylpropoxy group, 1-methylbutyloxy group, cyclopentyloxy group, hexyloxy group, 1-methylpentyloxy group, 1-ethylbutoxy group, cyclohexyloxy group, 2-heptyloxy group, octyloxy group, nonyloxy group, decyloxy group, undecyloxy group, dodecyloxy group, tridecyloxy group, tetradecyloxy group, pentadecyloxy group, hexadecyloxy group, heptadecyloxy group, octadecyloxy group, nonadecyloxy group, icosyloxy group, heneicosyloxy group, docosyl group, tricosyloxy group, phenoxy group, 2-methylphenoxy group, 3-methylphenoxy, 1-naphthyloxy group, 2-naphthyloxy group, benzyloxy group, 2-phenethyloxy group and the like.
In a specific embodiment of the present invention, the substituted hydrocarbyloxy group includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic group substitution, hydrocarbyloxy substitution, amino substitution, carboxyl substitution, hydroxyl substitution, mercapto substitution, or the like of the above-mentioned hydrocarbyloxy group, and specifically, for example, methoxyethoxy group, ethoxyethoxy group, butoxyethoxy group, trifluoromethoxy group, pentafluoroethoxy group, or the like.
In a specific embodiment of the present invention, the hydrocarbon mercapto group includes a straight-chain, branched-chain or cyclic hydrocarbon mercapto group, specifically, for example, methylmercapto, ethylmercapto group, n-propylmercapto group, isopropylmercapto group, n-butylmercapto group, t-butylmercapto group, isobutylmercapto group, pentylmercapto group, 1-ethylpropylmercapto group, 1-methylbutylthio group, cyclopentylmercapto group, hexylmercapto group, 1-methylpentylmercapto group, 1-ethylbutylmercapto group, cyclohexylmercapto group, 2-heptylmercapto group, octylmercapto group, nonylmercapto group, decylthio group, undecylmercapto group, dodecylmercapto group, tridecylmercapto group, tetradecylmercapto group, pentadecylmercapto group, hexadecylmercapto group, heptadecylthio group, octadecylmercapto group, nonadecylthio group, eicosylmercapto group, heneicosylmercapto group, docosylthio group, tricosylmercapto group, benzenemercapto group, 2-methylbenzylmercapto group, 3-methylbenzylmercapto, 4-methylbenzmercapto group, 1-naphthylmercapto group, 2-naphthylmercapto group, benzylmercapto group, 2-phenethylmercapto group, or the like.
In a specific embodiment of the present invention, the substituted hydrocarbon mercapto group includes halogen atom substitution, nitro group substitution, cyano group substitution, sulfonic group substitution, hydrocarbon mercapto group substitution, amino group substitution, carboxyl group substitution, hydroxyl group substitution, mercapto group substitution, and the like of the above-mentioned hydrocarbon mercapto group, and specifically, for example, methoxyethylmercapto group, ethoxyethylmercapto group, butoxyethylmercapto group, trifluoromethylmercapto group, pentafluoroethylmercapto group, and the like.
In a specific embodiment of the present invention, the acyl group includes various kinds of hydrocarbon acyl groups or various kinds of substituted hydrocarbon acyl groups, and the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic group substitution, amino substitution, carboxyl substitution, hydroxyl substitution, mercapto substitution, or the like, specifically, for example, formyl group, acetyl group, n-propionyl group, iso-propionyl group, n-butyryl group, t-butyryl group, iso-butyryl group, valeryl group, 1-ethylpropionyl group, 1-methylbutyryl group, cyclopentoyl group, hexanoyl group, 1-methylpentanoyl group, 1-ethylbutyryl group, cyclohexylacyl group, 2-heptanoyl group, octanoyl group, nonanoyl group, decanoyl group, undecanoyl group, dodecanoyl group, tridecanoyl group, tetradecanoyl group, pentadecanoyl group, hexadecanoyl group, heptadecanoyl group, octadecanoyl group, nonadecanoyl group, decanoyl group, dodecanoyl group, aralkanoyl, eicosanoyl, heneicosanoyl, docosanoyl, tricosanoyl, benzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 1-naphthoyl, 2-naphthoyl, benzylformyl, 2-phenylacetyl, methoxyacetyl, ethoxyacetyl, butoxyacetyl or trifluoroacetyl, and the like.
In a specific embodiment of the present invention, the ester group includes various hydrocarbon ester groups or various substituted hydrocarbon ester groups, and the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic group substitution, amino substitution, carboxyl substitution, hydroxyl substitution, or mercapto substitution, and the like, specifically, for example, methyl ester group, ethyl ester group, n-propyl ester group, isopropyl ester group, n-butyl ester group, t-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, 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, heptadecyl ester group, octadecyl ester group, nonadecyl ester group, Aralkyl ester group, eicosyl ester group, heneicosanyl ester group, docosanyl ester group, tricosanyl ester group, benzyl ester group, 2-methylbenzyl ester group, 3-methylbenzyl ester group, 4-methylbenzyl ester group, 1-naphthylmethyl ester group, 2-naphthylmethyl ester group, benzyl ester group, 2-phenethyl ester group, methoxyethyl ester group, ethoxyethyl ester group, butoxyethyl ester group or trifluoroethyl ester group and the like.
In a specific embodiment of the present invention, the substituted amino group includes various kinds of alkyl-substituted amino groups or various kinds of substituted alkyl-substituted amino groups, and the substitution includes halogen atom substitution, nitro group substitution, cyano group substitution, sulfonic group substitution, amino group substitution, carboxyl group substitution, hydroxyl group substitution, or mercapto group substitution, and the like, such as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, tert-butylamino, isobutylamino, pentylamino, 1-ethylpropylamino, 1-methylbutylamino, cyclopentylamino, hexylamino, 1-methylpentylamino, 1-ethylbutylamino, cyclohexylamino, 2-heptylamino, octylamino, nonylamino, decylamino, undecylamino, dodecylamino, tridecylamino, tetradecylamino, pentadecylamino, hexadecylamino, heptadecylamino, octadecylamino, Nonadecylamino group, aralkylamino group, eicosylamino group, heneicosyl group, docosanylamino group, tricosyl group, benzylamino group, 2-methylbenzylamino group, 3-methylbenzylamino group, 4-methylbenzylamino group, 1-naphthylmethylamino group, 2-naphthylmethylamino group, benzylamino group, 2-phenylethylamino group, methoxyethylamino group, ethoxyethylamino group, butoxyethylamino group, or trifluoroethylamino group, and the like.
In a specific embodiment of the present invention, the amide group includes various kinds of hydrocarbon amide groups or various kinds of substituted hydrocarbon amide groups, and the substitution includes halogen atom substitution, nitro substitution, cyano substitution, sulfonic group substitution, amide group substitution, carboxyl substitution, hydroxyl substitution, mercapto substitution, or the like, specifically, for example, a carboxamide group, an acetamide group, an n-propionamide group, an isopropanamide group, an n-butylamide group, a tert-butylamide group, an isobutanamide group, a pentanoamide group, a 1-ethylpropanamide group, a 1-methylbutanamide group, a cyclopentyl amide group, a hexanoamide group, a 1-methylpentanamide group, a 1-ethylbutanamide group, a cyclohexyl amide group, a 2-heptylamino group, a heptanoamide group, an octanoamide group, a nonanamide group, a decanoamide group, a undecanamide group, a dodecanamide group, pentadecanoamido, hexadecanoylamino, heptadecanoylamino, octadecanoylamino, nonadecanoylamino, aralkylamido, eicosanoylamino, heneicosanoylamino, docosanoylamino, tricosanoylamino, benzamido, 2-methylbenzamido, 3-methylbenzamido, 4-methylbenzamido, 1-naphthoylamino, 2-naphthoylamino, benzamido, 2-phenylacetylamino, methoxyacetamido, ethoxyacetamido, butoxyacetamido or trifluoroacetamido, and the like.
In a specific embodiment of the present invention, the ring a is a three-membered ring, a four-membered ring, a five-membered ring, a six-membered ring, a seven-membered ring, an eight-membered ring, or the like, and when the ring a is a five-membered ring or a six-membered ring, it may have a better inhibitory effect on a β 40 and/or a β 42 because the ring is more stable.
In a specific embodiment of the present invention, the cyclic substitution having a common carbon atom or two carbon atoms is a benzene ring substitution, a spiro ring substitution, a bridged ring substitution, and preferably the cyclic substitution having a common carbon atom is a benzene ring substitution.
In a particular embodiment of the invention, only one ring carbon atom of the ring A has a substituent, preferably an alkyl group or a halogen atom, more preferably a mono-substituted C1-C20 alkyl group or a di-substituted halogen atom. The mono-substituted C1-C20 alkyl is more preferably C1-C10 alkyl, and even more preferably C1-C4 alkyl. The mono-substituted C1-C20 alkyl can be cis-substituted or trans-substituted, and is preferably trans-substituted.
In a specific embodiment of the present invention, the thiamine compound has one of the following structural formulas:
among the thiamine compounds having the structures represented by the above formulae 1-1 to 1-20, the compounds having the structures represented by the formulae 1-4, 1-6, 1-11, 1-13, 1-15, 1-16, 1-17, 1-18 and 1-19 are preferable, and the compounds having the structures represented by the formulae 1-4, 1-11 and 1-16 are more preferable, and when the thiamine compounds are specifically the compounds represented by the formulae 1-4, 1-6, 1-11, 1-13, 1-15, 1-16, 1-17, 1-18 and 1-19, particularly the compounds represented by the formulae 1-4, 1-11 and 1-16, they have outstanding inhibitory effects on A β and A β.
The invention also provides a preparation method of the thiamine compound, which is prepared by reacting thiamine phosphate shown in the formula (1a) with acyl chloride shown in the formula (1 b);
wherein ring A is a saturated or unsaturated 3-8 membered non-aromatic ring; the ring A ring atoms include 0-3O, N and/or S heteroatoms; ring a is unsubstituted or double-bond substituted, or has one or more substituents independently of each other, or has cyclic substitution sharing one or two carbon atoms; the substituent is halogen atom, nitryl, cyano, sulfonic group, amino, substituted amino, ester group, carboxyl, hydroxyl, sulfydryl, sulfenyl, alkyl, substituted alkyl, oxyl, substituted oxyl, acyl or amido.
In the specific embodiment of the preparation method of thiamine compounds of the present invention, the specific experimental conditions can be performed by referring to the experimental condition method disclosed in EP2918593a1 in the prior art, and the method for preparing benfotiamine through the reaction of thiamine phosphate and benzoyl chloride, specifically, for example, the thiamine phosphate shown in formula (1a) is dissolved in water, 30% sodium hydroxide solution is added dropwise, the pH value is adjusted to 10-12, and the mixture is stirred and dissolved; dropwise adding an acyl chloride solution shown in the formula (1b) at 0-15 ℃, and controlling and adjusting the pH value to be 10-12 in the dropwise adding process; and reacting for 0.5-3 hours after the dropwise adding is finished, and then extracting and purifying reactants to obtain the thiamine compound. For different acyl chlorides shown in the formula (1b), conventional selection and adjustment can be performed on reaction conditions according to actual conditions, and the selection is compared with the selection of a solvent prepared from an acyl chloride solution shown in the formula (1b), the selection of an extraction solvent and the like.
Further, the invention also provides a pharmaceutical composition, which comprises the thiamine compound and the isomer thereof or the salt of the thiamine compound and the isomer thereof, and is preferably used for preparing a medicament for preventing and treating neurodegenerative diseases, and is further preferably used for preparing a pharmaceutical composition for preventing and treating alzheimer disease or aging. The salt is pharmaceutically acceptable salt, such as lithium salt, sodium salt, potassium salt or calcium salt. The composition can be made into tablet, powder, spray, injection, powder for injection, rectal suppository or skin patch (transdermal administration) by conventional method.
Examples
Description of the tests of the invention:
nuclear magnetism (1H NMR): NMR shifts (. delta.) are given in ppm units. NMR was measured using a Bruker AVANCE-500 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated methanol (CD)3OD), deuterated water (D)2O), and the internal standard is Tetramethylsilane (TMS).
Mass Spectrum (MS): MS was determined using an Agilent (ESI) mass spectrometer (manufacturer: Agilent, model: Agilent 6110).
1. Biological assay
Test materials and methods
(1) BCA protein concentration determination kit is purchased from Biyun Tian, A β 40 and A β 42 detection kit is purchased from wako company, and cell culture related reagents are purchased from Gibico company.
(2) HEK293APP/sw overexpressing cell culture: the cells were cultured in 48-well plates in DMEM (containing 10% FBS, 100. mu.g/mLG 418(Geneticin, Geneticin) and diabody), and at 70% cell density, 4mM stock solution of the test article (prepared by dissolving the test article in DMEM) was diluted to 400. mu.M in DMEM, and 500. mu.L of each well was added and cultured for 24 hours.
(3) Taking culture solution supernatant, adding BCA reagent, incubating at room temperature for 30min, measuring the light absorption value of each hole at OD 570nm of an enzyme labeling instrument, calculating the total protein concentration according to a protein standard curve, simultaneously taking supernatant to measure the concentrations of A β 40 and A β 42, adding supernatant into a coated 96-well plate, incubating overnight at 4 ℃, removing and washing reagent, adding HRP (horse radish oxidase) labeled antibody, incubating at 4 ℃ for 2h, removing and washing reagent, adding TMB (TMB) color solution, incubating at room temperature for 30min, adding light absorption solution to stop reaction, measuring the hole values at OD 450nm of the enzyme labeling instrument, calculating the concentrations of A β 40 and A β 42 according to the standard curves of A β 40 and A β 42, and finally adjusting the concentrations of A β 40 and A β 42 by using the total protein concentration to obtain the final concentrations.
The compounds synthesized in the following examples are based on the compounds represented by the formula, and the names in Chinese and English are only used as references.
Example 1
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) cyclopropanecarboxylate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamide) -5- (phosphoryloxy) pent-2-en-3-yl) thiocyclopropanecarboxylate 1-1 Synthesis:
dissolving 6.1g of thiamine phosphate in 12.8g of water, stirring for dissolving, beginning to dropwise add a sodium hydroxide solution (30%) to adjust the pH value to 10-12, stirring for 0.5 hour, repeatedly measuring the pH value, adjusting the pH value to 10-12 until the pH value is stable, stirring for 0.5 hour, dropwise adding a tetrahydrofuran solution of the compound of the formula 1-1b below 10 ℃, adding the sodium hydroxide solution to maintain the pH value to 10-12 in the dropwise adding process, finishing dropwise adding, carrying out heat preservation reaction for 1 hour, adding ethyl acetate for extraction twice, separating an organic phase, adjusting the pH value to 3-4 by 31% hydrochloric acid, separating out a product, filtering, pulping a filter cake by using a small amount of methanol, filtering, and drying the filter cake at 40 ℃ to obtain a product 1-1.
Subjecting said product 1-1 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are shown in table 1, were as follows, and the test stock solutions were formulated with the product 1-1 for bioassay.
MS m/z(ESI):431.0[M+1]
1H NMR(DMSO-d6):δ7.91(s,1H),7.79(s,1H),7.69(s,2H),4.45(d,2H),3.81-3.77(m,2H),2.60(d,2H),2.39(s,3H),2.12(s,3H),1.99-1.95(m,1H),0.97-0.95(m,2H),0.92-0.90(m,2H)。
Example 2
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) cyclobutanecarbothioate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamide) -5- (phosphoryloxy) pent-2-en-3-yl) thiocyclobutylformate 1-2 Synthesis:
using the synthetic route of example 1, the starting material 1-1b compound was replaced with 1-2b compound to give product 1-2.
Subjecting said product 1-2 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are shown in table 1, were as follows, and the test stock solutions were formulated with the products 1-2 for bioassay.
MS m/z(ESI):445.1[M+1]
1H NMR(DMSO-d6):δ7.88(s,1H),7.78(s,1H),7.51(s,2H),4.43(d,2H),3.80-3.76(m,2H),3.30-3.26(m,1H),2.60(d,2H),2.37(s,3H),2.13(s,3H),2.09-2.04(m,4H),1.91-1.85(m,1H),1.79-1.72(m,1H)。
Example 3
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) cyclopentanecarbothioate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- (phosphonooxy) pent-2-en-3-yl) thiocyclopentylcarbamate 1-3 Synthesis:
using the synthetic route of example 1, starting material 1-1b compound was replaced with 1-3b compound to afford product 1-3.
Subjecting said product 1-3 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are shown in table 1, were as follows, and the test stock solutions were formulated with the products 1-3 for bioassay.
MS m/z(ESI):459.1[M+1]
1H NMR(DMSO-d6)δ7.94(s,1H),7.77(s,1H),4.45(s,2H),3.78-3.76(m,2H),2.89-2.85(m,1H),2.59(s,2H),2.40(s,3H),2.13(s,3H),1.81-1.75(m,2H),1.60-1.51(m,6H)。
Example 4
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) cyclohexecarboxylate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- (phosphonooxy) pent-2-en-3-yl) thiocyclohexyl formate 1-4 synthesis:
using the synthetic route of example 1, starting material 1-1b compound was replaced with 1-4b compound to afford products 1-4.
Subjecting said product 1-4 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are shown in table 1, were as follows, and the test stock solutions were formulated with the products 1 to 4 for bioassay.
MS m/z(ESI):473.0[M+1]
1H NMR(DMSO-d6):δ7.89(s,1H),7.75(s,1H),4.42(d,2H),3.80-3.76(m,2H),2.59(d,2H),2.38-2.36(m,4H),2.13(s,3H),1.78-1.73(m,2H),1.66-1.64(m,2H),1.56(d,1H),1.28-1.22(m,4H)。
Example 5
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) bicyclo [2.2.1] pt-5-ene-2-carbothioate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- (phosphonooxy) pent-2-en-3-yl) thiobicyclo [2.2.1] hex-5-ene-2-carbonate 1-5 synthesis:
2.8g of 5-norbornene-2-carboxylic acid was added to 30mL of dichloromethane, 0.5g of dimethylformamide and 4.8g of thionyl chloride were added, the mixture was heated to 60 ℃ and refluxed for 3 hours, thionyl chloride and dichloromethane were distilled off under reduced pressure, and 30mL of dichloromethane was added for further use. Dissolving 5.5g of thiamine phosphate in 12.8g of water, stirring for dissolving, beginning to dropwise add a sodium hydroxide solution (30%) to adjust the pH value to 10-12, stirring for 0.5 hour, re-measuring the pH value, adjusting the pH value to 10-12 until the pH value is stable, stirring for 0.5 hour, keeping the temperature below 10 ℃, dropwise adding the prepared solution, adding the sodium hydroxide solution to keep the pH value to 10-12 in the dropwise adding process, dropwise adding the solution to finish heat preservation reaction for 1 hour, adjusting the pH value to 4-5 by using 31% hydrochloric acid, extracting dichloromethane for two times, concentrating an organic phase to obtain a yellow solid, dissolving the methanol into clear solution, adding methyl tert-butyl ether to separate out a white solid, filtering, and drying a filter cake at 45 ℃ to obtain a product 1.
Subjecting said product 1-5 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are shown in table 1, were as follows, and the test stock solutions were formulated with the products 1-5 for bioassay.
MS m/z(ESI):483.0[M+1]
1H NMR(DMSO-d6):δ7.98(s,1H),7.72(s,1H),6.18-6.16(m,1H),5.87-5.85(m,1H),4.62(d,2H),3.82-3.76(m,2H),3.20-3.17(m,1H),3.09(s,1H),2.85(s,1H),2.61-2.54(m,2H),2.44(s,3H),2.15(s,3H),1.84-1.70(m,1H),1.44(s,1H),1.26-1.23(m,2H)。
Example 6
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) 4, 4-difluorooxocyclohexane carboxylate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pent-2-en-3-yl) thio 4, 4-difluorocyclohexanecarboxylate 1-6 Synthesis:
using the synthetic route of example 1, starting material 1-1b compound was replaced with 1-6b compound to afford products 1-6.
Subjecting said products 1-6 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are shown in table 1, were as follows, and the test stock solutions were formulated with the products 1-6 for bioassay.
MS m/z(ESI):509.0[M+1]
1H NMR(DMSO-d6)δ7.88(s,1H),7.77(s,1H),7.39(s,2H),4.43(s,2H),3.79-3.75(m,2H),2.67-2.63(m,1H),2.58(s,2H),2.34(s,3H),2.13(s,3H),1.97(d,2H),1.89-1.81(m,4H),1.53-1.44(m,2H)。
Example 7
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) 4-propylhexenecarbothioate (1S,4r) -S- ((Z) -2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) 4-propylhexenecarbothioate, (1S,4r) -S- ((Z) -2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) 4-propylhexenecarbothioate (1S,4r) -S- ((Z) -2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pent-2-en-3-yl) thio 4-N-propylcyclohexanecarboxylate 1-7-yl The composition is as follows:
adding 1.1g of 4-propylcyclohexane-2-formic acid into a 50mL single-neck flask, adding 1.5g of thionyl chloride, 30mL of dichloromethane and 0.3g of dimethylformamide, heating to 60 ℃, carrying out reflux reaction for 3 hours, carrying out reduced pressure distillation to remove dichloromethane and thionyl chloride to obtain a compound 1-7b, and adding tetrahydrofuran for later use. Dissolving 6.6g of thiamine phosphate in 8.8g of water, stirring for dissolving, beginning to dropwise add a sodium hydroxide solution (30%) to adjust the pH value to 10-12, stirring for 1 hour, repeatedly measuring the pH value, adjusting the pH value to 10-12 until the pH value is stable, dropwise adding 1-7b of a compound tetrahydrofuran solution at the temperature of below 10 ℃, keeping the temperature for reaction for 1 hour after the dropwise adding is finished, adjusting the pH value to 7-8, adding dichloromethane for extraction, separating, adjusting the pH value to 4 by using a water phase, adding dichloromethane, separating, spin-drying a dichloromethane phase, scraping out solids to obtain yellow solid powder, pulping by using n-heptane, performing suction filtration, and drying to obtain a product 1-7.
Subjecting said product 1-7 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are listed in table 1, were as follows, and the test stock solutions were formulated with the products 1 to 7 for bioassay.
MS m/z(ESI):515.2[M+1]
1H NMR(DMSO-d6)δ7.98(s,1H),7.77(s,1H),4.46(s,2H),3.78(s,2H),2.58-2.51(m,2H),2.41(s,3H),2.33-2.29(m,1H),2.14(s,3H),1.79-1.71(m,4H),1.28-1.12(m,9H),0.91-0.83(m,3H)。
Example 8
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) cyclohex-3-enecarboxylate (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- (phosphonooxy) pent-2-en-3-yl) thiocyclohex-3-enecarboxylate 1-8 Synthesis:
using the synthetic route of example 7, starting materials 1-7b were replaced with 1-8b compounds to afford products 1-8.
Subjecting said product 1-8 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are shown in table 1, were as follows, and the test stock solutions were formulated with the products 1 to 8 for bioassay.
MS m/z(ESI):471.1[M+1]
1H NMR(DMSO-d6)δ7.90(s,1H),7.76(s,1H),5.67-5.61(m,2H),4.44(s,2H),3.79-3.76(m,2H),2.60-2.60(m,3H),2.37(s,3H),2.13(s,3H),2.10(s,1H),2.03-1.99(m,3H),1.75-1.78(m,1H),1.48-1.46(m,1H)。
Example 9
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) cyclopent-3-enecarbothioate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphoryloxy) pent-2-en-3-yl) thiocyclopent-3-ene carbonate 1-9 Synthesis:
using the synthetic route of example 7, starting materials 1-7b were replaced with 1-9b compounds to afford products 1-9.
Subjecting said product 1-9 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results are as followsThe products 1-9 were used to prepare stock solutions for biological testing, the results of which are shown in Table 1.
MS m/z(ESI):457.0[M+1]
1H NMR(DMSO-d6):δ7.83(s,1H),7.78(s,1H),5.63(s,2H),4.45(d,2H),3.81-3.77(m,2H),3.28-3.24(m,1H),2.60(d,2H),2.54(d,2H),2.43(d,2H),2.38(s,3H),2.14(s,3H)。
Example 10
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) 3-methylenebutyrecarboxylate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- (phosphonooxy) pent-2-en-3-yl) thio-3-methylenecyclobutyrate 1-10 Synthesis:
using the synthetic route of example 7, starting materials 1-7b were replaced with 1-10b compounds to afford products 1-10.
Subjecting said product 1-10 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are listed in table 1, were as follows, and the test stock solutions were formulated with the products 1 to 10 for bioassay.
MS m/z(ESI):457.0[M+1]
1H NMR(DMSO-d6)δ7.91(s,1H),7.80(s,1H),4.80(s,2H),4.44(s,2H),3.80-3.76(m,2H),3.33-3.28(m,1H),2.86-2.77(m,4H),2.61(s,2H),2.37(s,3H),2.14(s,3H)。
Example 11
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) cyclohex-1-enecarboxylate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- (phosphonooxy) pent-2-en-3-yl) thiocyclohex-1-enecarboxylate 1-11 synthesis:
using the synthetic route of example 7, starting materials 1-7b were replaced with 1-11b compounds to afford products 1-11.
Subjecting said product 1-11 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are shown in table 1, were as follows, and the test stock solutions were formulated with the products 1 to 11 for bioassay.
MS m/z(ESI):471.1[M+1]
1H NMR(DMSO-d6)δ7.91(s,1H),7.80(s,1H),6.80(s,1H),4.45(s,2H),3.80-3.73(m,2H),2.59(s,2H),2.36(s,3H),2.19(d,2H),2.14(s,3H),2.07(s,2H),1.57-1.52(m,4H)。
Example 12
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) 1,2,3, 4-tetrahydronaphtalene-1-carbothioate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- (phosphonooxy) pent-2-en-3-yl) thio-1, 2,3, 4-tetrahydronaphthalene-1-carboxylate 1-12:
dissolving 4.1g of thiamine phosphate in 6.0g of water, stirring for dissolving, beginning to dropwise add a sodium hydroxide solution (30%) to adjust the pH value to 10-12, stirring for 0.5 hour, repeatedly measuring the pH value, adjusting the pH value to 10-12 until the pH value is stable, stirring for 1 hour, keeping the temperature below 0 ℃, dropwise adding a dichloromethane solution of the compound shown in the formula 1-12b, adjusting the pH value to 10-12, reacting for 1 hour, adjusting the pH value to 3-4 by using a water phase, separating out solids, filtering to obtain a filter cake, pulping the filter cake with water for 0.5 hour, and drying the filter cake at 45 ℃ after filtering to obtain a product.
Subjecting said product 1-12 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are listed in table 1, were as follows, and the test stock solutions were formulated with the products 1 to 12 for bioassay.
MS m/z(ESI):521.1[M+1]
1H NMR(DMSO-d6)δ8.12(s,1H),7.83(s,1H),7.19–7.11(m,3H),7.02(s,1H),4.48(d,2H),3.84(d,3H),2.73-2.66(m,3H),2.53(s,1H),2.44(s,3H),2.14(s,3H),1.91(s,2H),1.69(s,2H)。
Example 13
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) 1,2,3, 4-tetrahydronaphtalene-2-carbothioate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pent-2-en-3-yl) thio-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate 1-13:
using the synthetic route of example 12, starting materials 1-12b were replaced with 1-13b compounds to afford products 1-13.
Subjecting said products 1-13 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are shown in table 1, were as follows, and the test stock solutions were formulated with the products 1-13 for bioassay.
MS m/z(ESI):521.0[M+1]
1H NMR(DMSO-d6)δ7.85(s,1H),7.81(s,1H),7.09-7.05(m,6H),4.43(s,2H),3.79-3.75(m,2H),2.87-2.86(m,2H),2.83-2.79(m,2H),2.77-2.76(m,1H),2.70-2.58(m,2H),2.34(s,3H),2.13(s,3H),2.03-2.00(m,1H),1.64-1.62(m,1H)。
Example 14
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) 4-pentylbenzothioate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) carboxamido) -5- (phosphonooxy) pent-2-en-3-yl) thio-4-pentylcyclohexyl-1-carboxylate 1-14 Synthesis:
using the synthetic route of example 7, starting materials 1-7b were replaced with 1-14b compounds to afford products 1-14.
Subjecting said products 1-14 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS) tests, the results of which are shown below, were performed by formulating test stock solutions with the products 1 to 14 as described above1 in (c).
MS m/z(ESI):543.0[M+1]
1H NMR(DMSO-d6)δ7.89(s,1H),7.74(s,1H),4.42(s,2H),3.79-3.77(m,2H),2.58(s,2H),2.38(s,3H),2.20(t,1H),2.13(s,3H),1.79-1.71(m,4H),1.26-1.13(m,8H),1.13(s,3H),0.87-0.84(m,5H)。
Example 15
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) 1-methylcyclohexanecarbothioate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pent-2-en-3-yl) -1-methylcyclohexylthioate 1-15:
using the synthetic route of example 7, starting materials 1-7b were replaced with 1-15b compounds to afford products 1-15.
Subjecting said product 1-15 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are listed in table 1, were as follows, and the test stock solutions were formulated with the products 1 to 15 for bioassay.
MS m/z(ESI):487.0[M+1]
1H NMR(500MHz,DMSO-d6)δ7.88(s,1H),7.73(s,1H),4.46(s,2H),3.78(s,2H),2.53(s,2H),2.39(s,3H),2.14(s,3H),1.99(s,1H),1.77(s,2H),1.44(d,3H),1.21(d,6H),1.05(s,3H)。
Example 16
(1r,4r) -S- ((Z) -2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) 4-methoxycyclohexanecarboxylate, (1r,4r) -S- ((Z) -2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pent-2-en-3-yl) thio-4-methylcyclohexanecarboxylate 1-16:
2.8g of trans 4-methylcyclohexanecarboxylic acid was added to 30mL of methylene chloride, 0.5g of dimethylformamide and 4.8g of thionyl chloride were added, and the mixture was heated to 60 ℃ and refluxed for 3 hours, thionyl chloride and methylene chloride were distilled off under reduced pressure, 30mL of methylene chloride was added for backup, 6.2g of thiamine phosphate was dissolved in 12.8g of water, stirring and dissolving, beginning to dropwise add sodium hydroxide solution (30%) to adjust the pH value to 10-12, stirring for 0.5 hour, and (2) repeatedly measuring the pH value, adjusting the pH value to 10-12 until the pH value is stable, stirring for 0.5 hour, keeping the temperature below 10 ℃, dropwise adding the prepared solution, adding a sodium hydroxide solution in the dropwise adding process to keep the pH value of 10-12, dropwise adding the solution to finish the heat preservation reaction for 1 hour, extracting dichloromethane twice, adjusting the pH value of a water phase to 4-5 by 31% hydrochloric acid, extracting dichloromethane twice, concentrating to dry, pulping by using ethyl acetate and methanol, filtering, and drying a filter cake at 45 ℃ to obtain a product 1-16.
Subjecting said product 1-16 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are listed in table 1, were as follows, and the test stock solutions were formulated with the products 1 to 16 for bioassay.
MS m/z(ESI):487.0[M+1]
1H NMR(DMSO-d6):δ7.91(s,1H),7.74(s,1H),4.42(d,2H),3.78-3.74(m,2H),2.58(d,2H),2.38(s,3H),2.32-2.27(m,1H),2.13(s,3H),1.75-1.73(m,2H),1.68-1.66(m,2H),1.26-1.21(m,3H),0.91-0.88(m,2H),0.85(d,3H)。
Example 17
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) 4- (trifluoromethylthio) cycloheximide, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pent-2-en-3-yl) thio-4-trifluoromethylcyclohexanoate methyl 1-17 Synthesis:
using the synthetic route of example 7, starting materials 1-7b were replaced with 1-17b compounds to afford products 1-17.
Subjecting said product 1-17 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), resultsTest stocks were prepared from the products 1-17 as described below for bioassay, the results of which are shown in Table 1.
MS m/z(ESI):541.0[M+1]
1H NMR(DMSO-d6)δ7.89(s,1H),7.76(s,1H),4.43(s,2H),3.79-3.78(m,2H),2.60(s,2H),2.45(s,1H),2.38(s,3H),2.26(s,1H),2.14(s,3H),1.89-1.80(m,4H),1.36-1.25(m,4H)。
Example 18
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) tetrahydro-2H-pyran-4-carbothioate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pent-2-en-3-yl) thio-tetrahydro-2H-pyran-4-carboxylate 1-18 Synthesis:
using the synthetic route of example 7, starting materials 1-7b were replaced with 1-18b compounds to afford products 1-18.
Subjecting said product 1-18 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are listed in table 1, were as follows, and the test stock solutions were formulated with the products 1 to 18 for bioassay.
MS m/z(ESI):475.0[M+1]
1H NMR(DMSO-d6)δ7.96(s,1H),7.78(s,1H),7.54(s,2H),4.46(s,2H),3.81-3.76(m,4H),3.33-3.23(m,2H),2.71-2.67(m,1H),2.58(d,2H),2.39(s,3H),2.15(s,3H),1.67-1.64(m,2H),1.48-1.41(m,2H)。
Example 19
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) tetrahydro-2H-pyran-3-carbothioate, (Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pent-2-en-3-yl) thio-tetrahydro-2H-pyran-3-carboxylate 1-19 Synthesis:
using the synthetic route of example 7, starting materials 1-7b were replaced with 1-19b compounds to afford products 1-19.
Subjecting said product 1-19 to nuclear magnetism (1H NMR) and Mass Spectrometry (MS), the results of which are shown in table 1, were as follows, and sample stocks were prepared from the products 1-19 for bioassay.
MS m/z(ESI):475.0[M+1]
1H NMR(DMSO-d6)δ7.87(s,1H),7.75(s,1H),4.43(s,2H),3.79-3.68(m,4H),3.33-3.29(m,2H),2.51-2.50(m,3H),2.36(s,3H),2.13(s,3H),1.87-1.85(m,1H),1.57-1.55(m,3H)。
Example 20
(Z) -S- (2- (N- ((4-amino-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphonooxy) pen-2-en-3-yl) 2H-chromene-3-carbothioate, (Z) -S- (2- (N- ((4-amine-2-methylpyrimidin-5-yl) methyl) formamido) -5- (phosphoryloxy) pent-2-en-3-yl) thio-2H-benzopyran-3-carboxylic acid acetate 1-20 Synthesis:
using the synthetic route of example 7, starting materials 1-7b were replaced with 1-20b compounds to afford products 1-20.
Nuclear magnetic (1H NMR) and Mass Spectrometry (MS) tests were performed on the products 1 to 20, and the results were as follows, and the results of biological tests were performed on test stock solutions prepared from the products 1 to 20, and are shown in Table 1.
MS m/z(ESI):521.0[M+1]
1H NMR(DMSO-d6):δ7.90(s,1H),7.87(s,1H),7.45-7.43(m,2H),7.34-7.32(m,1H),7.02(d,1H),6.89(d,1H),4.83(s,2H),4.46(s,2H),3.85(s,2H),2.66(s,2H),2.32(s,3H),2.17(s,3H)。
Comparative example 1
The bioassay was carried out without adding the stock solutions of the test products and with the medium as a blank, and the results are shown in Table 1.
Comparative example 2
The result of the biological test using the benfotiamine to prepare the stock solution of the test article is shown in Table 1.
TABLE 1 content of A β 40 and A β 42 proteins secreted by APP/293 cells treated with thiamine compounds
According to the above experimental results, the structurants have the inhibiting effect of A β or/and A β both as compared with the blank of comparative example 1, the effects of the five-membered ring and the six-membered ring are superior to those of the three-membered rings of examples 1 and 2 in examples 3 and 4, the inhibiting effect of A β is enhanced as compared with the benfotiamine of comparative example 2 by the content of A β 040 in examples 6, 13, 15, 16, 17 and 18, particularly in examples 6 and 18, which is substantially the same as that of comparative example 2, but the content of A6335 is remarkably reduced, as compared with the benfotiamine of comparative example 2, the inhibiting effect of A β is enhanced by the content of A58342 of example 19 is substantially the same as that of comparative example 2, but the content of A6340 is slightly reduced, as compared with the content of A6340, as compared with the benfotiamine of comparative example 2, both examples 4 and 11, A β and A β are remarkably reduced, as compared with the inhibiting effect of A4640 and A β is greatly enhanced by the inhibiting effect of A6342 and A6342, as compared with the inhibiting effect of β.
Although the present invention is disclosed above, the present invention is not limited thereto. Various changes and modifications may be effected therein by one skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (11)
1. A thiamine compound has a structure shown in formula (1),
wherein ring A is a saturated or unsaturated 3-8 membered non-aromatic ring;
the ring A ring atoms include 0-3O, N and/or S heteroatoms;
ring a is unsubstituted or double-bond substituted, or has one or more substituents independently of each other, or has cyclic substitution sharing one or two carbon atoms;
the substituent is halogen atom, nitryl, cyano, sulfonic group, amino, substituted amino, ester group, carboxyl, hydroxyl, sulfydryl, sulfenyl, alkyl, substituted alkyl, oxyl, substituted oxyl, acyl or amido.
2. The thiamine compound according to claim 1, wherein ring A is a five-membered ring or a six-membered ring.
3. The thiamine compound of claim 1, wherein said cyclic substitution having a common two carbon atoms is a benzene ring substitution.
4. The thiamine compound according to claim 1, wherein only one ring carbon atom of said ring A has a substituent.
5. The thiamine compound according to claim 4, wherein said substituent is a hydrocarbon group or a halogen atom.
6. The thiamin-based compound according to claim 1, characterized in that said thiamin-based compound has one of the following structural formulae:
7. the thiamin compound of claim 6, wherein the thiamin compound has a structural formula of 1-4, 1-6, 1-11, 1-13, 1-15, 1-16, 1-17, 1-18, or 1-19.
8. A process for producing thiamin compounds according to any one of claims 1 to 7, which comprises reacting thiamin phosphate represented by formula (1a) with an acid chloride represented by formula (1 b);
wherein ring A is a saturated or unsaturated 3-8 membered non-aromatic ring;
the ring A ring atoms include 0-3O, N and/or S heteroatoms;
ring a is unsubstituted or double-bond substituted or has one or more substituents independently of each other, or has cyclic substitution sharing one or two carbon atoms;
the substituent is halogen atom, nitryl, cyano, sulfonic group, amino, substituted amino, ester group, carboxyl, hydroxyl, sulfydryl, sulfenyl, alkyl, substituted alkyl, oxyl, substituted oxyl, acyl or amido.
9. A pharmaceutical composition comprising the thiamine compound and its isomer or a salt of the thiamine compound and its isomer according to any one of claims 1 to 7.
10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is used for the preparation of a medicament for the prevention and treatment of neurodegenerative diseases.
11. The pharmaceutical composition according to claim 10, characterized in that it is used for the preparation of a medicament for the prevention and treatment of alzheimer's disease or of aging.
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| PCT/CN2019/120947 WO2020108480A1 (en) | 2018-11-28 | 2019-11-26 | Thiamine compounds, preparation method, and pharmaceutical composition thereof |
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| JPS3921526B1 (en) * | 1960-09-20 | 1964-10-01 | ||
| GB1019124A (en) * | 1963-04-22 | 1966-02-02 | Ciba Ltd | Quinazolines and process for their manufacture |
| CN103772432A (en) * | 2014-01-03 | 2014-05-07 | 湖北瑞锶科技有限公司 | Production method of benfotiamine |
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| JPS3921526B1 (en) * | 1960-09-20 | 1964-10-01 | ||
| GB1019124A (en) * | 1963-04-22 | 1966-02-02 | Ciba Ltd | Quinazolines and process for their manufacture |
| CN103772432A (en) * | 2014-01-03 | 2014-05-07 | 湖北瑞锶科技有限公司 | Production method of benfotiamine |
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| CN116531373A (en) * | 2022-01-26 | 2023-08-04 | 上海日馨医药科技股份有限公司 | Thiazole compound, pharmaceutical composition and application thereof |
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