CN113956249B - Brain-targeted AChE inhibitor prodrug, and preparation method and application thereof - Google Patents
Brain-targeted AChE inhibitor prodrug, and preparation method and application thereof Download PDFInfo
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- CN113956249B CN113956249B CN202111364950.9A CN202111364950A CN113956249B CN 113956249 B CN113956249 B CN 113956249B CN 202111364950 A CN202111364950 A CN 202111364950A CN 113956249 B CN113956249 B CN 113956249B
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- tetrahydroacridin
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- salt
- amino
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- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- PHVXTQIROLEEDB-UHFFFAOYSA-N n-[2-(2-chlorophenyl)ethyl]-4-[[3-(2-methylphenyl)piperidin-1-yl]methyl]-n-pyrrolidin-3-ylbenzamide Chemical compound CC1=CC=CC=C1C1CN(CC=2C=CC(=CC=2)C(=O)N(CCC=2C(=CC=CC=2)Cl)C2CNCC2)CCC1 PHVXTQIROLEEDB-UHFFFAOYSA-N 0.000 description 1
- HBEDNENASUYMPO-LJQANCHMSA-N n-hydroxy-4-[[(2r)-3-oxo-2-(thiophen-2-ylmethyl)-2,4-dihydroquinoxalin-1-yl]methyl]benzamide Chemical compound C1=CC(C(=O)NO)=CC=C1CN1C2=CC=CC=C2NC(=O)[C@H]1CC1=CC=CS1 HBEDNENASUYMPO-LJQANCHMSA-N 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 1
- 230000002314 neuroinflammatory effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- JNYFTRHOIQYVSN-UHFFFAOYSA-M sodium sulfonatosulfanylmethylbenzene Chemical compound [Na+].[O-]S(=O)(=O)SCC1=CC=CC=C1 JNYFTRHOIQYVSN-UHFFFAOYSA-M 0.000 description 1
- IFVCHJIOPOZEBO-UHFFFAOYSA-M sodium;sulfonatosulfanylethane Chemical compound [Na+].CCSS([O-])(=O)=O IFVCHJIOPOZEBO-UHFFFAOYSA-M 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000003977 synaptic function Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
- C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
- C07D219/08—Nitrogen atoms
- C07D219/10—Nitrogen atoms attached in position 9
- C07D219/12—Amino-alkylamino radicals attached in position 9
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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- General Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a thiazole salt compound shown in a formula II or pharmaceutically acceptable salt and solvate thereof; the invention also discloses a thiamine disulfide precursor compound of the AChE inhibitor shown in the formula I or pharmaceutically acceptable salts and solvates thereof, which can form thiazole salt compounds which can not penetrate through BBB and have AChE inhibition capacity under the action of reducing substances in the brain, can effectively inhibit AChE activity in the brain, reduce side effects on the periphery and can be used for preventing or treating central nervous system diseases, namely Alzheimer disease.
Description
Technical Field
The invention relates to a compound, a preparation method and application thereof, in particular to a preparation method and application of an AChE inhibitor or a precursor compound thereof.
Background
Alzheimer's Disease (AD) is a progressive neurodegenerative disease of the nervous system, which is complicated and difficult to cure. The global AD patient would reach 1.35 million people by 2050 and the global AD patient treatment cost would increase to $ 2 trillion in 2030 as predicted by the "2015 world alzheimer's disease report". The most prominent pathological changes in the brains of AD patients are brain atrophy, amyloid (aβ) plaque deposition in the extracellular brain parenchyma, neurofibrillary tangles (nerve fiber tangles, NFTs) within neurons, neuroinflammatory reactions such as oxidative stress, etc., abnormal synaptic function of neurons, massive loss of neurons, etc. The cause of AD is very complex and few effective drugs are available to treat AD. Currently, 4 out of the 5 drugs approved by the FDA for the treatment of AD are AChE inhibitors, which fully embody the clinical effectiveness of AChE targets. Indeed, the selective AChE inhibitor donepezil is the only first line drug approved for the treatment of light-medium AD by both the us FDA and the uk MCA. However, donepezil is also non-negligible as a second generation specific reversible central acetylcholinesterase (AChE) inhibitor, and its peripheral side effects are reported in the literature to be likely to cause rhinitis or nasopharyngitis in patients; women with early onset alzheimer's disease and no history of heart disease, develop secondary heart block after receiving donepezil treatment for several weeks; bradycardia, hypertension, aggression, increased tremors may occur; urinary incontinence; the high dose administration may cause unacceptable side effects of gastrointestinal tract, etc., and tacrine which has been marketed once is also returned to the market because of the risk of the adverse reaction being greater than the benefit due to the reversible liver enzyme abnormality. Therefore, the development of AChE inhibitors with high brain exposure is of great importance for the treatment of AD.
In recent years, students have successfully designed thiamine disulfide compounds by utilizing the rule that the concentration of the reducing substances in the brain of AD patients is higher than that in blood, and once the thiamine disulfide-containing prodrug enters the central nervous system, the thiamine disulfide-containing prodrug can be reduced by disulfide reductase and then closed to form thiazole salt compounds, and then the thiazole salt compounds are "locked" in the brain and cannot be transported outwards through the Blood Brain Barrier (BBB), so that the concentration of the active drug in the brain is increased.
Disclosure of Invention
The invention aims to: the inventor takes a thiazole ring formed by putting a prodrug containing thiamine disulfide into the brain as a part of thiazole salt compounds to perform AChE inhibition activity, designs and synthesizes the thiamine prodrug of the AChE inhibitor, so that other fragments are not generated when the thiamine prodrug plays a role, the medication economy is improved, the aim of increasing the concentration of the drug in the brain is fulfilled, the peripheral side effect is reduced, the drug concentration is ensured to be achieved in the center, the prodrug shows excellent brain targeting capability in an in-vivo blood brain distribution experiment, the possibility is provided for targeting the thiazole salt type AChE inhibitor which cannot penetrate through the blood brain barrier into the brain, the good pharmacokinetic property is realized, and the patentability is ensured.
The technical scheme is as follows:
the invention aims to provide an AChE inhibitor, which is a thiazole salt compound shown in a formula II or pharmaceutically acceptable salt and solvate thereof:
wherein R is 1 Each occurrence independently represents hydrogen, cl; m is an integer of 1 to 4;
R 3 each occurrence independently represents hydrogen, F or C1-C3 alkoxy; n is an integer of 1 to 5;
l is selected from- (CH) 2 ) p -or-CH 2 -O-CH 2 -p is 1 or 2;
x is selected from Cl - 、Br - 。
As a further preferable technical method of the AChE inhibitor, a thiazole salt compound shown in a formula IIa or pharmaceutically acceptable salt and solvate thereof is adopted:
wherein R is 1 Selected from hydrogen, cl;
R 3 selected from hydrogen, F or methoxy;
l is selected from- (CH) 2 ) n -or-CH 2 -O-CH 2 -, n is 1 or 2;
x is selected from Cl - 、Br - 。
More preferably, an AChE inhibitor is selected from any one of the following thiazole salt compounds or pharmaceutically acceptable salts, solvates thereof:
3-benzyl-4-methyl-5- (2- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) ethyl) -3-bromothiazole salt;
3-benzyl-5- (2- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) ethyl) -4-methyl-3-bromothiazole salt;
5- (2- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) ethyl) -3- (3-methoxybenzyl) -4-methyl-3-bromothiazole salt.
Another object of the present invention is to provide a thiamine disulfide precursor compound of an AChE inhibitor represented by formula i:
wherein R is 1 Each occurrence independently represents hydrogen, cl; m is an integer of 1 to 4;
R 2 a linear or linear alkyl group selected from C1 to C5, phenyl-substituted linear or linear alkyl groups of C1 to C5;
R 3 each occurrence independently represents hydrogen, F or C1-C3 alkoxy; n is an integer of 1 to 5;
l is selected from- (CH) 2 ) p -or-CH 2 -O-CH 2 -p is 1 or 2.
As a further preferred embodiment of the present invention, the thiamine disulfide precursor compound of the AChE inhibitor shown in formula la, or a pharmaceutically acceptable salt, solvate thereof:
wherein R is 1 Selected from hydrogen, cl;
R 2 a linear or linear alkyl group selected from C1 to C5, phenyl-substituted linear or linear alkyl groups of C1 to C5; specifically, R is 2 Selected from the group consisting of
R 3 Selected from hydrogen, F or C1-C3 alkoxy;
l is selected from- (CH) 2 ) p -or-CH 2 -O-CH 2 -p is 1 or 2.
More preferably, a thiamine disulfide precursor compound of an AChE inhibitor is selected from any one of the following compounds or pharmaceutically acceptable salts, solvates thereof:
N-benzyl-N- (5- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) -3- (isoglutaryl) pent-2-en-2-yl) carboxamide;
N-benzyl-N- (3- (benzyldithio) -5- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) pent-2-en-2-yl) carboxamide;
N-benzyl-N- (5- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) -3- (isobutyldithio) pent-2-en-2-yl) carboxamide;
N-benzyl-N- (5- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) -3- (ethyldithio) pent-2-en-2-yl) carboxamide;
n- (5- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) -3- (isoglutaryl) pent-2-en-2-yl) -N- (3-methoxybenzyl) carboxamide.
The invention also aims to provide a preparation method of the compound shown in the formula II, wherein the synthetic route is as follows:
the method comprises the following steps:
step (1) ofDioxane is used as a reaction solvent, pd 2 (dba) 3 (tris (dibenzylideneacetone) dipalladium), xantphos (4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene), cesium carbonate and under the protection of argon, a compound shown in a formula VI and a compound shown in a formula IV react to obtain a compound shown in a formula III; wherein the molar ratio of the compound shown in the formula VI to the compound shown in the formula IV is 1.05-1.1:1; the molar ratio of the compound shown in the formula IV to cesium carbonate is 1:2; the molar ratio of the tri (dibenzylideneacetone) dipalladium to the 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthene is 1:1.8-2; the molar ratio of the tri (dibenzylideneacetone) dipalladium to the compound shown in the formula IV is 1:22-22.5; the reaction temperature is 110 ℃;
step (2), acetonitrile is taken as a reaction solvent, and a compound shown in a formula III andobtaining a compound shown in a formula II through reaction; wherein the compound of formula III and +.>The molar ratio of (2) is 1:1.5-2; the reaction temperature was 80 ℃.
In the step (1), after the reaction is finished, adding a mixed solvent of dichloromethane and methanol in a volume ratio of 3:1 into the reaction liquid, carrying out suction filtration, standing, carrying out suction filtration, concentrating filtrate, adopting silica gel column chromatography, and carrying out V DCM :V MeOH And (2) purifying the compound shown in the formula III by using the eluent of which the ratio is between 25:1 and 19:1.
Specifically, the compound shown in the formula VI is selected from 9-chloro-1, 2,3, 4-tetrahydroacridine and 6, 9-dichloro-1, 2,3, 4-tetrahydroacridine. The compound of formula IV is selected from 2- (4-methylthiazol-5-yl) ethane-1-amine.Selected from benzyl bromide, m-methoxybenzyl bromide.
In the step (2), after the reaction is finished, suction filtration is carried out, and the filter cake is washed twice by acetonitrile, thus obtaining the compound shown in the formula II.
Another object of the present invention is to provide a process for the preparation of thiamine disulfide precursor compounds of the AChE inhibitors of formula i, the synthetic route being as follows:
the method comprises the following steps:
step (1), dissolving a compound shown in a formula II and sodium hydroxide in water, carrying out ice bath reaction under the protection of argon, and then adding a compound R under the protection of argon 2 -S 2 O 3 Reacting an aqueous solution of Na at room temperature to obtain a compound shown in a formula I; wherein, the mol ratio of the compound shown in the formula II to the sodium hydroxide is 1:2-3; compounds of formula II and R 2 -S 2 O 3 The molar ratio of Na is 1:2.8-3.
Specifically, R is 2 -S 2 O 3 Na is selected from sodium S-isopentyl thiosulfate, sodium S-benzyl thiosulfate, sodium S-isobutyl thiosulfate and sodium S-ethyl thiosulfate.
Compound R 2 -S 2 O 3 The preparation method of Na is as follows: to compound R 2 -Br was dissolved in ethanol and PEG400 was added at 0.7% of the volume of ethanol based on the volume of PEG400; dissolving sodium thiosulfate pentahydrate in water, and adding PEG400 according to the volume of the PEG400 being 1% of the volume of the water; dropwise adding an aqueous solution of sodium thiosulfate to the compound R under stirring 2 -in an alcoholic solution of Br, heating and refluxing; after the reaction, the solvent was removed, and methanol was added to dissolve the reaction product R 2 -S 2 O 3 Na, heating and refluxing, filtering while hot to remove salt impurities, evaporating the solvent, adding ethyl acetate, stirring at room temperature, vacuum filtering, and vacuum drying to obtain white crystalline powder to obtain compound R 2 -S 2 O 3 Na. Wherein said compound R 2 -Br and sodium thiosulfate pentahydrate in a molar ratio of 0.9:1; the volume ratio of water to ethanol is 1:3; PEG400 acts as a co-solvent and phase transfer catalyst.
The invention also aims to provide application of the thiazole salt compound or pharmaceutically acceptable salt and solvate thereof or a thiamine disulfide precursor compound of an AChE inhibitor shown in a formula I or pharmaceutically acceptable salt and solvate thereof in preparation of a medicament for treating Alzheimer's disease.
Preferably, the indicated application is in the preparation of AChE inhibitors.
A pharmaceutical composition comprising a thiamine disulfide precursor compound of the thiazole salt compound or a pharmaceutically acceptable salt, solvate thereof or the AChE inhibitor of the present invention or a pharmaceutically acceptable salt, solvate thereof.
Preferably, the pharmaceutical composition is prepared by adding one or more pharmaceutically acceptable auxiliary materials into the thiazole salt compound or pharmaceutically acceptable salts and solvates thereof or the thiamine disulfide precursor compound of the AChE inhibitor or pharmaceutically acceptable salts and solvates thereof serving as active components.
The preparation is in the form of capsule, pill, tablet, granule or injection.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, a thiazole ring formed by putting a thiamine disulfide-containing prodrug into the brain is used as a part of thiazole salt compounds for playing an AChE inhibitory activity, and the thiamine disulfide prodrug for synthesizing an AChE inhibitor is designed to play a role without generating other fragments, so that the medication economy is improved, under the action of a reducing substance in the brain, the thiamine disulfide precursor compounds can be converted into thiazole salt compounds which cannot pass through a blood brain barrier in the brain, the AChE activity in the brain can be effectively inhibited, and the side effects on the periphery are reduced.
Drawings
FIG. 1 shows the ratio of the peak areas of the parent drug corresponding to different prodrugs at different times to the peak areas of the parent drug at the first time (10 min) as measured by co-incubating the prodrug with reduced glutathione.
FIG. 2 shows the peak areas of different prodrugs measured at 10min and 270min by co-incubating the prodrug with reduced glutathione.
Fig. 3 shows the detection of 4b and 4c levels in the brain at various times after intraperitoneal injections of prodrugs 8a and 8 e.
Fig. 4 shows the 4b and 4c content detected in blood at various times after intraperitoneal injections of prodrugs 8a and 8 e.
Fig. 5 shows the detection of 4b content in blood and in brain at various times after intraperitoneal injection of prodrug 8 a.
Fig. 6 shows the detection of 4c content in blood and in brain at various times after intraperitoneal injection of prodrug 8 e.
FIG. 7 shows AChE activity in brain and intestine 10min after administration of compound (i.p., 10 mg/kg) to mice.
FIG. 8 shows the synthetic route of the compounds of the present invention.
Detailed Description
The solvents used in the present invention are commercially available chemical or analytical pure.
The structure of the compound was determined by Nuclear Magnetic Resonance (NMR). NMR was performed using Bruker AVANCE-300/500 NMR, and the solvent used was DMSO-d 6 The internal standard is TMS.
Example 1
N- (2- (4-methylthiazol-5-yl) ethyl) -1,2,3, 4-tetrahydroacridin-9-amine (3 a)
The reaction flask was evacuated with double discharge tube and filled with Ar, 9-chloro-1, 2,3, 4-tetrahydroacridine (compound 1a,840mg,3.86 mmol), tris (dibenzylideneacetone) dipalladium (145 mg,0.158 mmol), and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (181 mg,0.313 mmol), cesium carbonate (2.28 g,7.03 mmol) were charged into the reaction flask, argon was replaced, dioxane and 2- (4-methylthiazol-5-yl) ethane-1-amine (compound 2,454. Mu.L, 3.51 mmol) were added, and reacted at 110℃for 30 hours. DCM (dichloromethane) +MeOH (methanol) (volume ratio of 3:1) was added to the reaction solution, suction filtration was performed, the mixture was allowed to stand, impurities were precipitated, suction filtration was performed, the filtrate was concentrated, and silica gel column chromatography (eluent: V DCM :V MeOH =25:1 to 19:1) to give compound 3a as a tan oil in 60% yield.
1 H NMR(300MHz,DMSO-d 6 )δ8.79(s,1H),8.05(d,J=8.0Hz,1H),7.72(dd,J=8.4,0.9Hz,1H),7.58–7.51(m,1H),7.34(ddd,J=8.2,6.8,1.2Hz,1H),5.70(t,J=6.5Hz,1H),3.64(m,2H),3.03(t,J=7.2Hz,2H),2.90(t,J=6.1Hz,2H),2.63(t,J=5.9Hz,2H),2.19(s,3H),1.87–1.72(m,4H).
3-benzyl-4-methyl-5- (2- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) ethyl) -3-bromothiazole salt (4 a)
N- (2- (4-methylthiazol-5-yl) ethyl) -1,2,3, 4-tetrahydroacridin-9-amine (3 a,200mg,0.618 mmol) was dissolved with acetonitrile, benzyl bromide (132. Mu.L, 1.11 mmol) was added, heated, reflux reacted at 80℃for 15h, suction filtered, the filter cake was washed twice with acetonitrile, and the filter cake was collected as compound 4a as pale yellow powder in 45% yield.
1 H NMR(300MHz,DMSO-d 6 )δ10.18(s,1H),8.39(d,J=8.6Hz,1H),7.91–7.87(m,2H),7.60–7.52(m,1H),7.48–7.38(m,3H),7.32–7.23(m,2H),5.76(s,2H),4.21–4.10(m,2H),3.44–3.42(m,2H),3.05–2.97(m,2H),2.64–2.54(m,2H),2.25(s,3H),1.86–1.73(m,4H).; 13 C NMR(75MHz,DMSO-d 6 )δ158.0,156.0,145.8,143.3,139.9,138.2,135.4,133.3,129.6,129.4,128.3,125.9,125.3,119.8,116.2,112.2,56.2,47.4,28.5,27.4,21.9,20.7,12.0,1.6.
Example 2
6-chloro-N- (2- (4-methylthiazol-5-yl) ethyl) -1,2,3, 4-tetrahydroacridin-9-amine (3 b)
The reaction flask was evacuated with double discharge tube and filled with Ar, 6, 9-dichloro-1, 2,3, 4-tetrahydroacridine (compound 1b,976mg,3.87 mmol), tris (dibenzylideneacetone) dipalladium (145 mg,0.158 mmol) and 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (181 mg,0.313 mmol), cesium carbonate (2.28 g,7.03 mmol) were charged into the reaction flask, argon was substituted, and dioxane and 2- (4-methyl) were addedThiazol-5-yl) ethan-1-amine (compound 2,454 μl,3.51 mmol) was reacted at 110 ℃ for 30h. Adding DCM+MeOH (volume ratio of 3:1) into the reaction solution, suction-filtering, standing, precipitating impurities, suction-filtering, concentrating filtrate, and performing silica gel column chromatography (eluent is V) DCM :V MeOH =25:1 to 19:1) to give compound 3b as a tan oil in 65% yield.
1 H NMR(300MHz,DMSO-d 6 )δ8.78(s,1H),8.07(d,J=9.1Hz,1H),7.73(d,J=2.2Hz,1H),7.33(dd,J=9.1,2.2Hz,1H),5.81(t,J=6.5Hz,1H),3.71–3.61(m,2H),3.02(t,J=7.1Hz,2H),2.88(t,J=6.0Hz,2H),2.60(t,J=5.8Hz,2H),2.18(s,3H),1.83–1.74(m,4H).
3-benzyl-5- (2- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) ethyl) -4-methyl-3-bromothiazole salt (4 b)
The preparation of compound 4a of example 1 was followed, with the other conditions unchanged, by substituting 6-chloro-N- (2- (4-methylthiazol-5-yl) ethyl) -1,2,3, 4-tetrahydroacridin-9-amine (3 b) for N- (2- (4-methylthiazol-5-yl) ethyl) -1,2,3, 4-tetrahydroacridin-9-amine (3 a) to give compound 4b as a yellow powder in 65% yield.
1 H NMR(300MHz,DMSO-d 6 )δ10.20(s,1H),8.42(d,J=9.3Hz,1H),7.99–7.93(m,1H),7.91(d,J=1.9Hz,1H),7.61(dd,J=9.1,1.6Hz,1H),7.50–7.44(m,3H),7.33–7.28(m,2H),5.79(s,2H),4.22–4.12(m,2H),3.43–3.46(m,2H),3.06–2.98(m,2H),2.65–2.56(m,2H),2.28(s,3H),1.86–1.79(m,4H); 13 C NMR(151MHz,DMSO-d 6 )δ158.1,155.9,152.4,143.3,138.9,137.8,135.3,133.4,129.6,129.4,128.3,127.8,126.1,118.6,114.8,112.7,56.2,47.4,28.6,27.3,24.7,21.8,20.6,12.0.
Example 3
5- (2- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) ethyl) -3- (3-methoxybenzyl) -4-methyl-3-bromothiazole salt (4 c)
The preparation method of the compound 4b of the example 2 is referred to by replacing benzyl bromide with m-methoxybenzyl bromide, and other conditions are unchanged, so that the compound 4c is obtained as yellow powder with the yield of 60%.
1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),8.40(d,J=9.3Hz,1H),7.90(d,J=2.1Hz,1H),7.58(dd,J=9.2,2.1Hz,1H),7.36(t,J=7.9Hz,1H),7.00(dd,J=8.2,2.1Hz,1H),6.92(s,1H),6.80(d,J=7.7Hz,1H),5.72(s,2H),4.20–4.08(m,2H),3.76(s,3H),3.45–3.41(m,2H),3.05–2.95(m,2H),2.62–2.54(m,2H),2.27(s,3H),1.84–1.76(m,4H); 13 C NMR(75MHz,DMSO-d 6 )δ160.1,158.0,156.0,152.3,143.4,138.8,137.8,135.1,134.7,130.8,127.8,126.1,120.2,118.4,114.7,114.5,114.4,112.7,56.1,55.7,49.0,31.1,28.5,27.2,21.7,20.6,12.0.
Example 4
S-Isopentylsodium thiosulfate (7 a)
1-bromo-3-methylbutane (compound 6a,6.2mL,49.63 mmol) was dissolved in ethanol and PEG400 (PEG 400 volume 0.7% of ethanol volume) was added; sodium thiosulfate pentahydrate (compound 5,11.22g,45.21 mmol) was weighed into water, V Ethanol :V Water and its preparation method PEG400 was added (the volume of PEG400 was 1% of the volume of water) =3:1; the aqueous solution of sodium thiosulfate was added dropwise to the above-mentioned alcohol solution of 1-bromo-3-methylbutane under stirring, and the mixture was refluxed at 69℃for 6 hours. Evaporating the solvent, adding methanol, refluxing at 60 ℃ for 30min, filtering while the solvent is hot, evaporating the organic solvent, adding Ethyl Acetate (EA), stirring at room temperature for 30min, vacuum-filtering, and vacuum-drying to obtain white crystalline powder 7a with a yield of 56%.
N-benzyl-N- (5- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) -3- (isoglutaryl) pent-2-en-2-yl) carboxamide (8 a)
The reaction flask was evacuated with double-drain tube and filled with Ar, 3-benzyl-5- (2- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) ethyl) -4-methyl-3-bromothiazole salt (compound 4b,300mg,0.668 mmol), sodium hydroxide (53 mg,1.33 mmol) and water were added to the reaction flask, the concentration of sodium hydroxide in the system was kept at 36mg/mL, the reaction was replaced with argon and the ice bath was carried out for 30min, and an aqueous solution of S-isopentyl sodium thiosulfate (compound 7a,412mg,2 mmol) was added to the flask under an argon atmosphere and reacted at room temperature for 1h. Adding EA to the reaction solution, EA/H 2 O extraction, concentration of organic layer, silica gel column chromatography (eluent is V) DCM :V MeOH =30:1 to 24:1) to give compound 8a as a yellow oil in 45% yield.
1 H NMR(300MHz,DMSO-d 6 )δ8.18(d,J=9.1Hz,1H),7.85(s,1H),7.76(s,1H),7.37(dd,J=9.2,1.8Hz,1H),7.33(d,J=2.1Hz,1H),7.30–7.22(m,4H),5.86(t,J=6.4Hz,1H),4.54(s,2H),3.60–3.49(m,2H),2.97–2.88(t,J=6.4Hz,2H),2.78–2.69(m,4H),2.39–2.31(m,2H),1.88–1.83(m,2H),1.80(s,3H),1.50–1.39(m,1H),1.29–1.20(m,4H),0.77(d,J=6.6Hz,6H); 13 C NMR(75MHz,DMSO-d 6 )δ162.5,150.7,136.9,136.2,133.2,130.4,129.3,129.0,128.8,128.7,127.8,126.8,125.8,124.1,119.1,116.9,46.3,46.0,37.6,36.8,33.7,31.6,26.8,25.8,23.0,22.7,22.5,19.0.
Example 5
S-benzyl sodium thiosulfate (7 b)
The preparation method of (bromomethyl) benzene (compound 6 b) instead of 1-bromo-3-methylbutane (compound 6 a) was used, and the procedure of example 4S-isopentyl sodium thiosulfate was followed under the same conditions to obtain compound 7b as a white powder in 41% yield.
N-benzyl-N- (3- (benzyldithio) -5- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) pent-2-en-2-yl) carboxamide (8 b)
The preparation of compound 8a of example 4 was followed, except that the sodium S-benzylthiosulfate (compound 7 b) was used instead of sodium S-isopentylthiosulfate (compound 7 a), to give compound 8b as a yellow oil in 55% yield.
1 H NMR(300MHz,DMSO-d 6 )δ8.17(d,J=9.1Hz,1H),7.82(s,1H),7.75(d,J=1.7Hz,1H),7.40–7.30(m,3H),7.28–7.23(m,7H),7.07–7.03(m,1H),5.88(t,J=6.5Hz,1H),4.54(s,2H),3.60(s,2H),3.55–3.49(m,2H),2.94–2.88(t,J=6.0Hz,2H),2.73–2.60(m,4H),1.85–1.78(m,4H),1.76(s,3H); 13 C NMR(75MHz,DMSO-d 6 )δ162.6,159.8,150.6,147.6,137.0,136.9,136.0,133.1,130.2,129.8,129.5,129.1,128.8,128.7,127.9,127.0,125.7,124.1,119.2,117.0,46.2,45.8,43.4,33.8,31.5,25.8,23.0,22.7,18.9.
Example 6
S-sodium isobutyl thiosulfate (7 c)
The preparation of sodium isopentyl thiosulfate was carried out by substituting 1-bromo-2-methylpropane (compound 6 c) for 1-bromo-3-methylbutane (compound 6 a), and the procedure was as described in example 4, except that the conditions were unchanged, to give compound 7c as a white powder in 60% yield.
N-benzyl-N- (5- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) -3- (isobutyldithio) pent-2-en-2-yl) carboxamide (8 c)
The preparation of compound 8a of example 4 was followed, except that the other conditions were unchanged, by substituting sodium S-isobutylthiosulfate (7 c) for sodium S-isopentylthiosulfate (7 a), to give compound 8c as a yellow oil in 50% yield.
1 H NMR(300MHz,DMSO-d 6 )δ8.18(d,J=9.1Hz,1H),7.82(s,1H),7.75(d,J=1.9Hz,1H),7.38(dd,J=9.1,2.0Hz,1H),7.33(d,J=4.0Hz,1H),7.30–7.23(m,4H),5.88(t,J=6.5Hz,1H),4.53(s,2H),3.59–3.47(m,2H),2.92(t,J=6.0Hz,2H),2.80–2.66(m,4H),2.24(d,J=6.7Hz,2H),1.92–1.81(m,4H),1.80(s,3H),1.63–1.54(m,1H),0.80(d,J=6.5Hz,6H); 13 C NMR(151MHz,DMSO-d 6 )δ162.5,150.5,136.9,136.2,133.0,130.3,129.3,129.0,128.9,128.7,127.9,127.1,125.7,124.1,119.3,117.1,47.8,46.3,45.9,33.9,31.6,28.0,25.8,23.0,22.7,21.7,18.9.
Example 7
S-Ethyl sodium thiosulfate (7 d)
The preparation of bromoethane (compound 6 d) instead of 1-bromo-3-methylbutane (compound 6 a) was performed according to the preparation method of sodium isopentyl thiosulfate of example 4, under the same conditions, to give compound 7d as a white powder with a yield of 55%.
N-benzyl-N- (5- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) -3- (ethyldithio) pent-2-en-2-yl) carboxamide (8 d)
The preparation of compound 8a of example 4 was followed under the same conditions by substituting sodium S-ethylthiosulfate (compound 7 d) for sodium S-isopentylthiosulfate (compound 7 a), to give compound 8d as a yellow oil in 45% yield.
1 H NMR(300MHz,DMSO-d 6 )δ8.15(dd,J=9.1,3.4Hz,1H),7.81(s,1H),7.73(d,J=2.1Hz,1H),7.35(dd,J=9.0,2.2Hz,1H),7.31(d,J=1.9Hz,1H),7.29–7.21(m,4H),5.88(t,J=6.5Hz,1H),4.52(s,2H),3.51(m,2H),2.90(t,J=5.6Hz,2H),2.75–2.64(m,4H),2.30(q,J=7.4Hz,2H),1.93–1.78(m,4H),1.77(s,3H),0.96(t,J=7.3Hz,3H); 13 C NMR(151MHz,DMSO-d 6 )δ162.5,150.5,136.9,136.2,133.0,130.2,129.3,129.1,128.9,128.7,127.8,127.1,125.7,124.1,119.2,117.0,46.3,45.8,33.9,32.5,31.5,25.8,23.0,22.7,18.8,14.5.
Example 8
N- (5- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) -3- (isoglutaryl) pent-2-en-2-yl) -N- (3-methoxybenzyl) carboxamide (8 e)
The preparation of compound 4b was replaced with compound 4c, and the preparation of compound 8a of example 4 was followed under the same conditions to give compound 8e as a yellow oil in 45% yield.
1 H NMR(300MHz,DMSO-d 6 )δ8.17(d,J=9.1Hz,1H),7.84(s,1H),7.76(d,J=2.2Hz,1H),7.37(dd,J=9.1,2.1Hz,1H),7.22(t,J=8.1Hz,1H),6.90(s,1H),6.83(d,J=6.5Hz,2H),5.85(t,J=6.6Hz,1H),4.51(s,2H),3.72(s,3H),3.49–3.54(m,2H),2.92(t,J=5.4Hz,2H),2.80–2.68(m,4H),2.40–2.31(t,J=6.0Hz,2H),1.87–1.83(m,2H),1.82(s,3H),1.48–1.40(m,1H),1.29–1.25(m,4H),0.77(d,J=6.6Hz,6H); 13 C NMR(151MHz,DMSO-d 6 )δ162.6,159.5,150.5,138.4,136.2,133.0,130.4,130.0,129.7,127.1,125.7,124.1,121.5,121.2,119.3,117.2,114.7,113.2,55.5,55.4,46.4,45.9,37.6,36.8,31.6,26.8,25.8,23.0,22.7,22.4,19.0.
Example 9 in vitro cholinesterase (AChE) inhibition Activity test Using the Elman method
Test compounds (Compounds 4a,4b, 4 c) were first formulated at a concentration of 4X 10 using DMSO -2 M solution was diluted with methanol to give 10% strength solutions -4 、10 -5 、10 -6 、10 -7 、10 -8 、10 -9 M test compound solution, ready for use.
Preparing a buffer solution: 1.36g of potassium dihydrogen phosphate was dissolved in 100mL of water, and the buffer was adjusted to ph=8.0±0.1 with sodium hydroxide solution. The buffer is stored at 4 ℃ for standby.
Preparing a 10mM DTNB solution: to 100mL of distilled water, 0.396g of DTNB and 0.15g of sodium hydrogencarbonate were added, and the mixture was completely dissolved to prepare a 10mM DTNB solution, which was stored at-20℃for use.
75mM ATC solution was prepared: to 10mL of distilled water, 0.217g of ATC was added, and the mixture was completely dissolved to prepare 75mM of ATC solution, which was stored at-20℃for further use.
Preparing AChE solution: to 1mL of a 1% gel solution (1 g of gel was added to 100mL of water, immersed for ten minutes, and dissolved by heating again), 500 units of AChE was added, and then diluted with water to 200mL to prepare an AChE solution having a concentration of 2.5 units/mL, and stored at-20℃for use.
Before the experiment, all the required solutions were allowed to stand at room temperature, and each solution was diluted to the required concentration, and 40. Mu.L of buffer solution, 10. Mu.L of test compound solution, 10. Mu.L of AChE solution, 20. Mu.L of DTNB solution, and 20. Mu.L of ATC solution were sequentially added to a 96-well plate. The UV absorbance was measured at 405nM, and the blank was measured using an equal volume of methanol instead of the test compound solution. Donepezil (Donepezil) was tested as a control group instead of the test compound. All tests were run in duplicate and the results are shown in table 1.
Conclusion: experiments prove that the compound prepared by the invention can effectively inhibit AChE activity. The optimal compounds 4a,4b and 4c have strong inhibition activity on AChE, and IC thereof 50 Reaching the micromolar scale.
TABLE 1 AChE inhibitory Activity of target Compounds
Note that: eeAChE-acetylcholinesterase of electric eels; hAChE-human acetylcholinesterase.
EXAMPLE 10 case where the prodrug releases the parent drug (Compound 4b or 4 c) in reduced glutathione
The prodrug (compounds 8a to 8 e) was dissolved in dimethyl sulfoxide to prepare a solution with a final concentration of 40mM, diluted with methanol to 400. Mu.M, and prepared into a solution with a final concentration of 4. Mu.M using an aqueous solution containing 1mM of reduced glutathione, after incubation for a specified period of time at 37℃clear supernatant was collected and integrated with LC-MS/MS for further calculation. LC-MS/MS conditions were as follows: the chromatographic column was a Phenomenex Luna Phenyl-Hexyl column (150X 4.6mm,5 μm); the mobile phase is: phase a (0.1% formic acid in water) and phase B (methanol); isocratic elution is adopted, and the proportion of an organic phase is 90%; flow rate: 1mL/min, sample injection amount: 20.0 μl, column temperature: 35 ℃.
The results are shown in FIGS. 1 and 2. As shown in fig. 1, the ordinate is the ratio of the peak area of the parent drug at different moments to the peak area of the parent drug at the first moment (10 min), and the abscissa is time, and it can be seen from fig. 1 that the peak area of the parent drug corresponding to each prodrug generally increases within 10min to 270min, which indicates that the prodrug can gradually release the parent drug in the reducing substance. As can be seen from fig. 2, the prodrug has a smaller peak area at 270min than at 10 min; indicating that it is possible to convert part of the prodrug to the parent drug within 10min to 270 min.
EXAMPLE 11 detection of parent drug (Compound 4b or 4 c) content in blood and brain at various times after intraperitoneal injection of prodrug
Mice were randomly divided into 2 groups of 15 animals each, each animal was given a single dose of 10mg/kg of prodrug (Compounds 8a,8e, V DMSO :V PEG400 :V Physiological saline =2:55:43 to make up a solution with prodrug concentration of 0.8 mg/mL). Blood samples were taken from the eyes at appropriate time intervals and collected in heparinized centrifuge tubes. Centrifuging to obtain supernatant, adding methanol at a volume ratio of 1:3, swirling for 5min, centrifuging at 4deg.C and 15000rpm for 15min, collecting supernatant, and filtering to obtain filtrate. Taking out brain tissue samples, carefully rolling the brain on filter paper, weighing, adding methanol and physiological saline (the volume ratio of the methanol to the physiological saline is 3:7) according to the feed liquid ratio of 1:2 (g/mL), homogenizing each tissue sample, taking 0.3mL of homogenate, adding 0.6mL of methanol, swirling for 5min, centrifuging at 4 ℃ at 15000rpm for 15min, and taking the supernatantFiltering membrane, and analyzing by LC-MS/MS sample injection. LC-MS/MS conditions were as follows: the chromatographic column was a Phenomenex Luna Phenyl-Hexyl column (150X 4.6mm,5 μm); the mobile phase is: phase a (0.1% formic acid in water) and phase B (methanol); isocratic elution was used: when detecting the compound 4b, the organic phase proportion is 75%; when detecting the compound 4c, the organic phase proportion is 85%; flow rate: sample injection amount of 0.3 mL/min: 10.0 μl, column temperature: 35 ℃.
The results are shown in fig. 3, fig. 4, fig. 5 and fig. 6. The corresponding parent drug of the prodrug can be detected in blood and brain 20min after administration, the content is highest, the content of the parent drug is continuously reduced along with the subsequent extension of time, the content of the parent drug detected by the prodrug 8a in blood is 300-600 ng/mL, and the content of the parent drug detected by the prodrug 8e is 500-700 ng/mL; the prodrug 8a detected the parent drug content in the brain tissue ranged from 400 to 700ng/g, and the prodrug 8e detected the parent drug content in the brain tissue ranged from 300 to 500 ng/g. The disulfide bond-containing prodrug enters the central nervous system, can be reduced by disulfide bond reducing substances and then ring-closed to thiazole compounds (compounds 4b or 4 c), and then is "locked" in the brain and cannot be transported outwards through the BBB, so that AChE inhibitor compounds (compounds 4b or 4 c) which cannot penetrate the blood brain barrier can be targeted into the brain.
EXAMPLE 12 Activity of AChE in brain and intestine after 10min of intraperitoneal injection of prodrug
The prodrug (compounds 8a,8 e) was treated with V DMSO :V PEG400 :V Physiological saline =2:55:43 to prepare a solution with a concentration of 0.8 mg/mL; mice were divided into two groups (8 a,8 e), each group being given 3, respectively numbered, two compounds 10mg/kg respectively intraperitoneally; blank groups (no drug administration, physiological saline) were also set; mice were sacrificed 10min after administration, brains were taken, intestines were taken (connecting the stomach ends, the length was kept as consistent as possible, 1-2 cm), ice saline was added to the brains at 1:2g/mL, ice saline was added to the intestines at 1:4g/mL, the homogenates were homogenized, diluted in the corresponding proportions, and enzyme activity was tested according to the elman method in example 9.
The results are shown in fig. 7, which shows that: the administration of the prodrugs 8a,8e, respectively, has a certain inhibitory effect on AChE in the brain and intestines of mice, and it is notable that the effect on AChE in the intestines after the administration of the prodrugs 8a,8e is relatively low, so that the compounds 8a,8e are expected to reduce the side effects in the intestines.
Claims (6)
1. A thiazole salt compound represented by formula IIa:
wherein R is 1 Selected from hydrogen, cl; r is R 3 Selected from hydrogen, F or methoxy; l is selected from- (CH) 2 ) n -or-CH 2 -O-CH 2 -, n is 1 or 2; x is selected from Cl - 、Br - 。
2. An AChE inhibitor, characterized in that: a thiazole salt compound or a pharmaceutically acceptable salt thereof selected from any of the following:
3-benzyl-4-methyl-5- (2- ((1, 2,3, 4-tetrahydroacridin-9-yl) amino) ethyl) -3-bromothiazole salt;
3-benzyl-5- (2- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) ethyl) -4-methyl-3-bromothiazole salt;
5- (2- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) ethyl) -3- (3-methoxybenzyl) -4-methyl-3-bromothiazole salt.
A thiamine disulfide precursor compound of an ache inhibitor, characterized in that: a compound selected from any one of the following:
Nbenzyl-)N- (5- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) -3- (isoglutaryl) pent-2-en-2-yl) carboxamide;
Nbenzyl-)N- (3- (benzyldithio) -5- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) pent-2-en-2-yl) carboxamide;
Nbenzyl-)N- (5- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) -3- (isobutyldithio) pent-2-en-2-yl) carboxamide;
Nbenzyl-)N-(5-((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) -3- (ethyldithio) pent-2-en-2-yl) carboxamide;
N- (5- ((6-chloro-1, 2,3, 4-tetrahydroacridin-9-yl) amino) -3- (isoglutaryl) pent-2-en-2-yl) propan-yl)N- (3-methoxybenzyl) formamide.
4. Use of a thiazate compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof or a thiamine disulfide precursor compound of an AChE inhibitor according to claim 3 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of alzheimer's disease.
5. Use of a thiazole salt compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof for the preparation of an AChE inhibitor.
6. A pharmaceutical composition characterized by: a thiamine disulfide precursor compound comprising the thiazole salt compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or the AChE inhibitor according to claim 3 or a pharmaceutically acceptable salt thereof.
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