CN102351854A - Amino thiazole derivative and preparation method and medical purpose thereof - Google Patents
Amino thiazole derivative and preparation method and medical purpose thereof Download PDFInfo
- Publication number
- CN102351854A CN102351854A CN2011102163442A CN201110216344A CN102351854A CN 102351854 A CN102351854 A CN 102351854A CN 2011102163442 A CN2011102163442 A CN 2011102163442A CN 201110216344 A CN201110216344 A CN 201110216344A CN 102351854 A CN102351854 A CN 102351854A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- preparation
- normal
- organic bases
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 *c1ccc2c(NCN)c(CCCC3)c3nc2c1 Chemical compound *c1ccc2c(NCN)c(CCCC3)c3nc2c1 0.000 description 1
- RKXNOCVEXXJMLH-UHFFFAOYSA-N CCN(CCCCCCNc1c(CCCC2)c2nc2ccccc12)CC(Nc1nc(-c(cc2)ccc2OC)c[s]1)=O Chemical compound CCN(CCCCCCNc1c(CCCC2)c2nc2ccccc12)CC(Nc1nc(-c(cc2)ccc2OC)c[s]1)=O RKXNOCVEXXJMLH-UHFFFAOYSA-N 0.000 description 1
- SWNXUFFUARZIDF-UHFFFAOYSA-N CCN(CCCCNc1c(cccc2)c2nc2c1CCCC2)CC(Nc1nc(-c(cc2)ccc2Cl)c[s]1)=O Chemical compound CCN(CCCCNc1c(cccc2)c2nc2c1CCCC2)CC(Nc1nc(-c(cc2)ccc2Cl)c[s]1)=O SWNXUFFUARZIDF-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an amino thiazole derivative compound, a tautomer thereof, a medicinal salt thereof and a preparation method thereof. The amino thiazole derivative compound, the tautomer thereof, or the medicinal salt thereof provided by the invention has effects of inhibiting acetylcholinesterase and senile plaque aggregated by beta- amyloid (A beta), and can be used for treating, improving or preventing cognitive decline related neurological diseases, such as Alzheimer disease, vascular dementia, slight cognitive impairment and other dementia with oxidative stress participation.
Description
Technical field
The invention belongs to field of medicaments, relate to aminothiazole derivs and preparation method and medicinal use.
Background technology
Along with the world population aging, and the nervous system disorders, particularly alzheimer's disease that the cognitive function decline is relevant (Alzheimer ' s disease, AD) sickness rate significantly improves.Alzheimer's disease is as a kind of multifactor inductive nerve degenerative diseases, and its definite pathogenesis it be unclear that.For this reason, pathogeny and the therapeutics research to alzheimer's disease has become the focus that people pay close attention to.Alzheimer's disease is that a kind of the damage with carrying out property cognitive disorder and learning memory is master's central nervous system degenerative disease, and main pathological characters is that cerebral atrophy, A beta peptide aggregation form senile plaque, the excessive phosphorylation of Protein tau forms neurofibrillary tangles.Medical circle has proposed the Different types of etiopathogenises hypothesis in recent years, comprises that mainly choline function decline hypothesis, A beta peptide aggregation form the amyloid beta deposition hypothesis, the free radical overload causes nerve injury hypothesis, neural inflammation hypothesis etc.
Some medicines that improve the AD symptom are developed listing in succession based on " cholinergic hypothesis ", and wherein modal medicine is anticholinesterase (chEI).ChEI delays cholinolytic speed through suppressing Pseudocholinesterase (ChE) activity, improves the improvement effect of the level performance of synaptic cleft choline to AD patient's cognitive function.The acetylcholinesterase depressant of food and drug administration (FDA) approval listing comprises: tacrine (Tacrine), aricept (Donpezil), Exelon (Rivastigmine), lycoremine (Galantamine) etc.
The hydrolysis of beta amyloid precursor protein generates that amyloid-beta (A β) is assembled and the senile plaque that forms is the important pathological characters of AD.The outer A beta peptide aggregation of born of the same parents has mediated multiple neurotoxic effect, and suppressing its gathering can its neurotoxic effect of antagonism.Mostly the medicine that is applied to AD treatment at present is that some improve symptom class medicine, is difficult to fundamentally cure nerve degenerative diseases.The gathering and the depolymerization that suppress the sick paraprotein A β (amyloid) of AD have become one of sick important means of treatment AD.
To the multifactor property of nerve degenerative diseases morbidity, the medicine of many target spots effect will help improving curative effect of medication, reduce side effect.The many target drugs that have successfully to nerve degenerative diseases get into clinical study at present, as draw replace lucky (Ladostigil) more, and its activity through acetylcholine esterase inhibition and monoamine oxidase-B is brought into play the effect of treatment AD.Other has some drug molecules to be in preclinical study, and for example, existing report closes antioxidant and AChEIs contraction the drug molecule of many target treatments of design AD.The methene chain of investigator through different lengths is connected tacrine with Thioctic Acid, designed and synthesized out a series of compounds that have AChE inhibition and oxidation resistant many target spots effect simultaneously (J.Med.Chem.2005,48,360-363).
Summary of the invention
Task of the present invention provides a kind of aminothiazole derivs compound, and the pharmaceutical salts of the tautomer of this aminothiazole derivs compound and this aminothiazole derivs compound.
Another task of the present invention provides the preparation method of this aminothiazole derivs compound.
Another task of the present invention provides the medical applications of this aminothiazole derivs compound.
Realize that technical scheme of the present invention is:
This aminothiazole derivs compound provided by the invention has the structure shown in the formula I, comprises the tautomer of this aminothiazole derivs compound, also comprises the pharmaceutical salts of this aminothiazole derivs compound:
Wherein
M=1,2,3 or 4;
N=3,4,5,6,7 or 8;
R
2Be H or Cl
Above-described pharmaceutical salts is meant parent compound and the sour salify of formula I.Compound provided by the present invention contains the alkali part, and pharmaceutical salts can be synthetic by the parent compound of formula I through ordinary method.Usually, this salt is through preparing the formula I compound of free alkali form and the suitable acid of stoichiometric quantity in water or in the organic solvent.Usually non-aqueous media such as ether, ethyl acetate, ethanol, Virahol are preferred solvent.Wherein pharmaceutical salts can be: mineral acid salify, for example hydrochloride, hydrobromate, hydriodate, vitriol; Or organic acid salify, for example acetate, maleate, fumarate, Citrate trianion, oxalate, succinate, tartrate, malate, mandelate and tosilate.
Aminothiazole derivs compound provided by the invention or its tautomer or its pharmaceutical salts; Can be used for preparing the medicine of treatment, improvement, nervous system disorders that the decline of prevention cognitive function is relevant, the relevant nervous system disorders of described cognitive function decline comprises the dementia that alzheimer's disease, vascular dementia, mild cognitive damage and other oxidative stresss are participated in etc.
Compound involved in the present invention contains two main structural units: aminothiazole part and tacrine part, they connect through suitable intermediate chain.Type and the length that can adjust intermediate chain on the one hand combined with the dual site of enzyme with the while, improved inhibition activity and selectivity to Pseudocholinesterase, lowered toxic side effect; On the other hand, bring into play the inhibition A β peptide pathologic accumulative effect of aminothiazole derivs simultaneously.Give full play to the superiority of many target drug treatment nerve degenerative diseases, make them become the drug candidate that is used to treat the dementia of preventing AD and the participation of other A beta peptide aggregations.
The preparation method of aminothiazole derivs compound provided by the invention may further comprise the steps:
1) makes formula (1) compound and alkyl diamine do at Pentyl alcohol under the condition of solvent nucleophilic substitution reaction takes place; Obtain formula (2) compound; Formula (1) compound and alkyl diamine are done the concrete steps that nucleophilic substitution reaction takes place under the condition of solvent at Pentyl alcohol can be synthetic according to reported method [referring to: J.Med.Chem.2008; 51,713-716];
2) make formula (2) compound and monobromethane under the catalysis of potassiumiodide and organic bases or mineral alkali,, in dinethylformamide, ethanol or the methylene dichloride nucleophilic substitution reaction takes place, get formula (3) compound at solvent N.
3) make formula (4) compound and bromacyl chloride under the catalysis of organic bases or mineral alkali, the condensation reaction that acyl chlorides and amine take place in solvents tetrahydrofurane or methylene dichloride gets formula (6) compound.
4) make formula (5) compound and bromacyl chloride under the catalysis of organic bases or mineral alkali, the condensation reaction that acyl chlorides and amine take place in solvents tetrahydrofurane or methylene dichloride gets formula (7) compound.
5) make formula (6) compound or formula (7) compound and formula (3) compound under the catalysis of potassiumiodide and organic bases or mineral alkali,, nucleophilic substitution reaction takes place in dinethylformamide or the methylene dichloride get formula (8) compound at solvent N.
Above-mentioned steps 1) to 5) reaction scheme and formula (1), (2), (3), (4), (5), (6), the structure of (7) and (8) compound be:
Wherein
M=1,2,3 or 4;
N=3,4,5,6,7 or 8;
R
2Be H or Cl.
Above-mentioned steps 1) the described order concrete grammar that nucleophilic substitution reaction obtains formula (2) compound takes place under formula (1) compound and alkyl diamine make solvent at Pentyl alcohol the condition can be: formula (1) compound and alkyl diamine are done under the condition of solvent at Pentyl alcohol; Temperature control refluxed 18 hours for 180 ℃, nucleophilic substitution reaction takes place obtain formula (2) compound; Concrete steps can be synthetic according to reported method (referring to: J.Med.Chem.2008,51,713716).
Above-mentioned steps 2) described formula (2) compound and the monobromethane of making is under the catalysis of potassiumiodide and organic bases or mineral alkali; At solvent N; The concrete grammar that nucleophilic substitution reaction gets formula (3) compound takes place in dinethylformamide or the methylene dichloride can be: 1 times of normal formula (2) compound and 1 times of equivalent monobromethane are at one times of normal alkali, a spot of potassiumiodide catalysis N at 10mL; Normal-temperature reaction is 5 hours in dinethylformamide or the methylene dichloride, obtains formula (3) compound through column chromatography purification again.Wherein alkali can be that organic bases is triethylamine, diisopropyl ethyl amine, pyridine, 2,6 lutidine or 4-Dimethylamino pyridine, perhaps mineral alkali salt of wormwood or yellow soda ash.The condition of column chromatography is a sherwood oil: ethyl acetate=1: 1 (1-2% triethylamine).
Above-mentioned steps 3) described formula (4) compound and the bromacyl chloride of making in that the concrete grammar that the condensation reaction of acyl chlorides with amine get formula (6) compound takes place under the catalysis of organic bases or mineral alkali can be: 1 times of normal formula (4) and 1.2 times of normal bromacyl chlorides obtain formula (6) compound through column chromatography purification again in 1.5 times of normal base catalyzed reactions solvents normal-temperature reaction 12 hours in the tetrahydrofuran (THF) of 20mL or methylene dichloride.Wherein alkali can be that organic bases is triethylamine, diisopropyl ethyl amine, pyridine, 2,6 lutidine or 4-Dimethylamino pyridine, perhaps mineral alkali salt of wormwood or yellow soda ash.The condition of column chromatography is a sherwood oil: ethyl acetate=10: 1.
Above-mentioned steps 4) described formula (5) compound and the bromacyl chloride of making in that the concrete grammar that the condensation reaction of acyl chlorides with amine get formula (7) compound takes place under the catalysis of organic bases or mineral alkali can be: 1 times of normal formula (5) and 1.2 times of normal bromacyl chlorides under 1.5 times of normal base catalysiss in the tetrahydrofuran (THF) of 20mL or methylene dichloride normal-temperature reaction 12 hours, obtain formula (7) compound through column chromatography purification again.Wherein alkali can be that organic bases is triethylamine, diisopropyl ethyl amine, pyridine, 2,6 lutidine or 4-Dimethylamino pyridine, perhaps mineral alkali salt of wormwood or yellow soda ash.The condition of column chromatography is a sherwood oil: ethyl acetate=10: 1.
Above-mentioned steps 5) described formula (6) compound or formula (7) compound and formula (3) compound of making is under the catalysis of potassiumiodide and organic bases or mineral alkali; The concrete grammar that nucleophilic substitution reaction gets formula (8) compound takes place is: 1 times of normal formula (6) compound or formula (7) compound and 1 times of normal formula (3) compound are at one times of normal alkali; A spot of potassiumiodide catalysis is at the N of 10mL; Dinethylformamide; 70 ℃ of reactions of temperature control are 2 hours in ethanol or the methylene dichloride; Obtain formula (8) compound through column chromatography purification again; Wherein alkali can be that organic bases is a triethylamine; Diisopropyl ethyl amine; Pyridine; 2; 6 lutidine or 4-Dimethylamino pyridine, perhaps mineral alkali salt of wormwood or yellow soda ash.The condition of column chromatography is that sherwood oil, ethyl acetate and triethylamine are with arbitrary proportion.
Aminothiazole derivs compound provided by the invention or its tautomer or its pharmaceutical salts; Have simultaneously that acetylcholinesteraseinhibition inhibition, amyloid-beta (A β) are assembled and the effect of the senile plaque that forms; Can be used for treating, improve or prevent the relevant nervous system disorders of cognitive function decline, like alzheimer's disease, vascular dementia, mild cognitive damage, and other oxidative stresss dementia of participating in.
With aminothiazole derivs compound provided by the invention or its tautomer or its pharmaceutical salts is activeconstituents, can process pharmaceutical composition.With aminothiazole derivs compound provided by the invention or its tautomer or its pharmaceutical salts is activeconstituents; Add pharmaceutically acceptable additive or/and carrier; Can be prepared into various pharmaceutical preparations; Like solid orally ingestible, comprise tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule or granule etc.; Liquid oral medicine comprises oral solution; Injection comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions, primary infusion etc.
Embodiment
The universal method that is used to prepare The compounds of this invention has below been described.Provide the following example further to illustrate the present invention, rather than to the qualification of the scope of the invention.
Embodiment 1:
The preparation of 2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) butyl) amido)-N-(4-phenyl thiazole-2-yl) ethanamide
Reagent: 2-bromo-N-(4-phenyl thiazole-2-yl) ethanamide (0.4g, 1.57mmol), DMF (10mL), salt of wormwood (0.26g), potassiumiodide (0.136g), and N-(4-(ethylamino) butyl)-1,2,3,4-tetrahydro acridine-9-amine (0.5g, 1.57mmol).Method: get 2-chloro-N-(4-phenyl thiazole-2-yl) ethanamide and N-(4-(ethylamino) butyl)-1,2,3,4-tetrahydro acridine-9-amine is dissolved in N, in the dinethylformamide, adds salt of wormwood, 70 ℃ of reactions of temperature control 2 hours.The methylene dichloride dilution, direct purification by silica gel column chromatography behind the washing and drying.Purification process: silica gel column chromatography, use petrol ether/ethyl acetate (2: 1,0.3% triethylamine), get faint yellow oily thing 0.51g, productive rate 55%.H
1Nuclear magnetic resonance result is: H
1-NMR (CDCl
3, 400MHz, δ ppm): 7.92 (d, J=7.6Hz, 1H), 7.91 (d, J=7.6Hz; 1H), 7.83 (d, J=7.2Hz, 2H), 7.54 (m, 1H), 7.40 (t; J=7.6Hz, 2H), 7.33 (m, 2H), 7.16 (s, 1H), 3.50 (t; J=7.2Hz, 2H), 3.29 (s, 2H), 2.69 (m, 4H); 2.61 (t, J=7.2Hz, 2H), 1.88 (m, 4H), 1.73 (m; 2H), 1.62 (m, 2H), 1.11 (t, J=7.2Hz, 3H) .C
13Nuclear magnetic resonance result is: C
13-NMR (CDCl
3, 100MHz, δ ppm): 170.1,158.5,157.0,150.5,150.2,147.4,134.4,128.7 (3C); 128.3,128.0,126.1 (2C), 123.8,122.6,120.4,116.4,107.8,57.4,54.9; 49.3,49.1,40.0,29.6,24.8,24.7,23.0,22.7,11.9.
Embodiment 1-1:
The preparation of N-(4-(4-chloro-phenyl-) thiazol-2-yl)-2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) butyl) amido) ethanamide
Reagent: 2-bromo-N-((4-chloro-phenyl-) thiazol-2-yl) ethanamide (0.34g, 117mmol), DMF (10mL), salt of wormwood (0.2g), potassiumiodide (0.05g), and N-(4-(ethylamino) butyl)-1,2,3,4-tetrahydro acridine-9-amine (0.35g, 1.17mmol).Except that reagent, all the other preparation purification process get light brown oily thing 0.6g, productive rate 85.7% with embodiment 1.H
1Nuclear magnetic resonance result is: H
1-NMR (CDCl
3, 400MHz, δ ppm): 7.90 (d, J=7.6Hz, 1H), 7.88 (d, J=7.6Hz; 1H), 7.74 (d, J=8.4Hz, 2H), 7.52 (m, 2H), 7.33 (d; J=8.4Hz, 2H), 7.29 (m, 1H), 7.11 (s, 1H), 3.47 (t; J=7.2Hz, 2H), 3.27 (s, 2H), 3.03 (t, J=6.0Hz, 2H); 2.66 (m, 4H), 2.59 (m, 2H), 1.85 (m, 4H), 1.69 (m; 2H), 1.59 (m, 2H), 1.08 (t, J=7.2Hz, 3H) .C
13Nuclear magnetic resonance result is: C
13-NMR (CDCl
3, 100MHz, δ ppm): 170.1,158.3,157.2; 150.5,148.9,147.2,133.7,132.9; 128.8 (2C), 128.6,128.4,127.3 (2C), 123.8; 122.6,120.2,116.3,108.1,57.4; 54.9,49.3,49.1,33.8,29.5; 24.8,24.7,22.9,22.7,11.9.
Embodiment 1-2:
The preparation of N-(4-(4-p-methoxy-phenyl) thiazol-2-yl)-2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) butyl) amido) ethanamide
Reagent: 2-bromo-N-((4-p-methoxy-phenyl) thiazol-2-yl) ethanamide (0.43g, 1.5mmol), DMF (10mL), salt of wormwood (0.22g), potassiumiodide (0.01h), and N-(4-(ethylamino) butyl)-1,2,3,4-tetrahydro acridine-9-amine (0.45g, 1.5mmol).Except that reagent, all the other preparation purification process get light brown oily thing 0.35g, productive rate 43.8% with embodiment 1.H
1Nuclear magnetic resonance result is: H
1-NMR (CDCl
3, 400MHz, δ ppm): 7.95 (d, J=7.6Hz, 1H), 7.93 (d, J=7.6Hz, 1H); 7.75 (d, J=8.8Hz, 2H), 7.55 (m, 1H), 7.34 (m, 1H); 7.02 (s, 1H), 6.92 (d, 2H), 3.84 (s, 3H), 3.52 (t; J=7.2Hz, 2H), 3.29 (s, 2H), 3.07 (t, J=6.0Hz, 2H); 2.68 (m, 4H), 2.61 (t, J=7.2Hz, 2H), 1.88 (m, 4H); 1.74 (m, 2H), 1.62 (m, 2H), 1.11 (t, J=7.2Hz, 3H) .C
13Nuclear magnetic resonance result is: C
13-NMR (CDCl
3, 100MHz, δ ppm): 170.0,159.5,158.2,156.9; 150.7,149.9,128.6,128.4,128.3; 127.4 (2C), 127.7,123.9,122.7,120.1; 116.1,114.1 (2C), 106.1,57.4,55.3; 54.9,49.3,49.1,33.7,29.6; 24.8,24.7,22.9,22.6,11.9.
Embodiment 1-3:
The preparation of 2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) butyl) amido)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) ethanamide
Reagent: 2-bromo-N-(4,5,6; 7-tetrahydro benzo [d] thiazol-2-yl) ethanamide (0.39g, 1.68mmol), DMF (10mL); Salt of wormwood (0.26g), potassiumiodide (0.01g), and N-(4-(ethylamino) butyl)-1; 2,3,4-tetrahydro acridine-9-amine (0.5g; 1.68mmol); All the other preparation purification process get light yellow oil 0.4g, productive rate 47.1% with embodiment 1.H
1Nuclear magnetic resonance result is: H
1-NMR (CDCl
3, 400MHz, δ ppm): 7.92 (d, J=8.0Hz, 2H), 7.91 (d, J=8.0Hz; 2H), 7.55 (m, 1H), 7.33 (m, 1H), 3.46 (t; J=7.2Hz, 2H), 3.22 (s, 2H), 3.07 (m, 2H); 2.70 (m, 4H), 2.62 (m, 4H), 2.55 (t, J=7.6Hz; 2H), 1.91 (m, 4H), 1.84 (m, 4H), 1.67 (m; 2H), 1.56 (m, 2H), 1.05 (t, J=7.2Hz, 3H.C
13Nuclear magnetic resonance result is: C
13-NMR (CDCl
3, 100MHz, δ ppm): 169.5,158.3,154.3,150.6,147.1,144.3,128.5,128.4; 123.8,123.1,122.7,120.2,116.2,57.5,54.9,49.3,49.0,33.8; 29.7,29.4,26.4,24.9,24.7,23.3,23.0,22.7,19.1,11.9.
Embodiment 1-4:
The preparation of N-(4-(4-chloro-phenyl-) thiazol-2-yl)-2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) butyl) amido) propionic acid amide
Reagent: 3-bromo-N-((4-chloro-phenyl-) thiazol-2-yl) propionic acid amide (0.58g, 1.68mmol), N, dinethylformamide (10mL); Salt of wormwood (0.2g), potassiumiodide (0.05g), and N-(4-(ethylamino) butyl)-1,2; 3, and 4-tetrahydro acridine-9-amine (0.5g, 1.68mmol).Except that reagent, all the other preparation purification process get light brown oily thing 0.57g, productive rate 57.2% with embodiment 1.H
1Nuclear magnetic resonance result is: H
1-NMR (CDCl
3, 400MHz, δ ppm): 7.89 (d, J=8.0Hz, 1H), 7.84 (d, J=8.0Hz, 1H); 7.55 (d, J=8.0Hz, 2H), 7.52 (d, J=8.0Hz, 1H), 7.27 (m, 2H); 7.24 (m, 1H), 7.10 (s, 1H), 3.91 (bs, 1H), 3.51 (t, J=6.8Hz; 2H), 3.01 (t, J=6.4Hz, 2H), 2.81 (t, J=6.4Hz, 2H), 2.72 (q; J=7.2Hz, 2H), 2.60 (m, 4H), 2.48 (t, J=6.4Hz, 2H); 1.84 (m, 4H), 1.75 (m, 4H), 1.18 (t, J=7.2Hz, 3H) .C
13Nuclear magnetic resonance result is: C
13-NMR (CDCl
3, 100MHz, δ ppm): 170.4,158.3,157.7,150.6; 148.8,147.2,133.5,133.0,128.7 (2C); 128.6,128.3,127.1 (2C), 123.7,122.6; 120.2,116.2,107.6,52.4,49.3; 48.9,46.2,33.9,31.7,29.7; 24.6,24.3,22.9,22.7,10.8.
Embodiment 1-5:
The preparation of 2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) butyl) amido)-N-(4-phenyl thiazole-2-yl) propionic acid amide
Reagent: 3-bromo-N-(4-phenyl thiazole-2-yl) propionic acid amide (0.52g, 1.68mmol), N, dinethylformamide (10mL); Salt of wormwood (0.2g), potassiumiodide (0.06g), and N-(4-(ethylamino) butyl)-1,2; 3, and 4-tetrahydro acridine-9-amine (0.5g, 1.68mmol).Except that reagent, all the other preparation purification process get light brown oily thing 0.85g, productive rate 811% with embodiment 1.H
1Nuclear magnetic resonance result is: H
1-NMR (CDCl
3, 400MHz, δ ppm): 7.85 (d, J=8.0Hz, 1H), 7.84 (d, J=8.0Hz; 1H), 7.79 (d, J=8.0Hz, 2H), 7.47 (t, J=8.0Hz, 2H); 7.22 (m, 4H), 7.07 (s, 1H), 3.47 (t, J=7.2Hz, 2H); 2.96 (t, J=6.4Hz, 2H), 2.75 (t, J=6.0Hz, 2H), 2.64 (q; J=7.2Hz, 2H), 2.53 (m, 4H), 2.42 (t, J=6.4Hz, 2H); 1.78 (m, 4H), 1.67 (m, 4H), 1.11 (t, J=7.2Hz, 3H) .C
13Nuclear magnetic resonance result is: C
13-NMR (CDCl
3, 100MHz, δ ppm): 170.4,158.2,157.5,150.7; 149.8,147.1,134.5,128.5 (2C), 128.4; 128.3,127.8,125.8 (2C), 123.6,122.8; 120.1,116.0,107.2,52.3,49.2; 48.9,46.2,33.8,31.8,29.6; 24.5,24.3,22.9,22.6,10.8.
Embodiment 1-6:
The preparation of N-(4-(4-p-methoxy-phenyl) thiazol-2-yl)-2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) butyl) amido) propionic acid amide
Reagent: 3-bromo-N-((4-p-methoxy-phenyl) thiazol-2-yl) propionic acid amide (0.72g, 2.08mmol), N, dinethylformamide (10mL); Triethylamine (0.25g), and N-(4-(ethylamino) butyl)-1,2; 3, and 4-tetrahydro acridine-9-amine (0.62g, 2.08mmol).Except that reagent, all the other preparation purification process get light yellow oil 0.98g, productive rate 75.4% with embodiment 1.H
1Nuclear magnetic resonance result is: H
1-NMR (CDCl
3, 400MHz, δ ppm): 7.87 (d, J=8.4Hz, 2H), 7.75 (d, J=8.4Hz, 2H); 7.51 (m, 1H), 7.27 (m, 1H), 6.98 (s, 1H), 6.79 (d, J=8.4Hz; 2H), 3.92 (bs, 1H), 3.74 (s, 3H), 3.51 (t, J=6.8Hz; 2H), 2.99 (t, J=6.4Hz, 2H), 2.80 (t, J=6.4Hz, 2H); 2.71 (q, J=7.2Hz, 2H), 2.59 (m, 4H), 2.46 (t, J=6.4Hz; 2H), 1.83 (m, 4H), 1.73 (m, 4H), 1.17 (J=7.2Hz, 3H) .C
13Nuclear magnetic resonance result is: C
13-NMR (CDCl
3, 100MHz, δ ppm): 170.3,159.3,158.4,157.4; 150.6,149.7,147.4,128.7,128.2,127.5; 127.2 (2C), 123.6,122.7,120.3,116.3; 113.9 (2C), 105.5,55.2,52.4,49.3; 48.9,46.1,33.9,31.8,29.7; 24.5,24.3,22.9,22.7,10.7.
Embodiment 1-7:
The preparation of 2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) propyl group) amido)-N-(4-phenyl thiazole-2-yl) ethanamide
Reagent: 2-bromo-N-(4-phenyl thiazole-2-yl) ethanamide (0.45g, 1.76mmol), N, dinethylformamide (10mL); Salt of wormwood (0.25g), potassiumiodide (0.01g), and N-(4-(ethylamino) propyl group)-1,2; 3, and 4-tetrahydro acridine-9-amine (0.5g, 1.76mmol).Except that reagent, all the other preparation purification process get light brown oily thing 0.98g, productive rate 75.8% with embodiment 1.H
1Nuclear magnetic resonance result is: H
1-NMR (CDCl
3, 400MHz, δ ppm): 7.96 (d, J=8.8Hz, 1H), 7.94 (d, J=8.8Hz; 1H), 7.72 (d, J=7.6Hz, 2H), 7.54 (t, J=7.6Hz, 1H); 7.39 (m, 2H), 7.32 (m, 2H), 7.15 (s, 1H); 3.57 (t, J=6.8Hz, 2H), 3.34 (s, 2H), 3.05 (t; J=6.8Hz, 2H), 2.72 (m, 6H), 1.91 (t, J=7.2Hz; 2H), 1.86 (m, 4H), 1.13 (t, J=7.2Hz, 3H) .C
13Nuclear magnetic resonance result is: C
13-NMR (CDCl
3, 100MHz, δ ppm): 169.9,158.4,156.9,150.6,150.2,147.1,134.3,128.7 (3C); 128.5,128.0,126.0 (2C), 124.1,122.5,120.3,116.7,107.7,57.5; 52.8,49.3,47.4,33.7,29.3,24.9,22.9,22.6,11.9.
Embodiment 1-8:
The preparation of N-(4-(4-p-methoxy-phenyl) thiazol-2-yl)-2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) propyl group) amido) ethanamide
Reagent: 2-bromo-N-((4-p-methoxy-phenyl) thiazol-2-yl) ethanamide (0.4g, 1.4mmol), N, dinethylformamide (10mL); Salt of wormwood (0.2g), potassiumiodide (0.1g), and N-(4-(ethylamino) propyl group)-1,2; 3, and 4-tetrahydro acridine-9-amine (0.4g, 1.4mmol).Except that reagent, all the other preparation purification process get light brown oily thing 0.45g, productive rate 60.5% with embodiment 1.H
1Nuclear magnetic resonance result is: H
1-NMR (CDCl
3, 400MHz, δ ppm): 7.95 (d, J=8.0Hz, 1H), 7.92 (d, J=8.0Hz; 1H), 7.65 (d, J=8.8Hz, 2H), 7.54 (t, J=8.0Hz, 1H); 7.34 (t, J=8.0Hz, 1H), 7.01 (s, 1H), 7.65 (d, J=8.8Hz; 2H), 4.00 (brs, 1H), 3.85 (s, 3H), 3.55 (t, J=7.2Hz; 2H), 3.33 (s, 2H), 3.06 (t, J=6.0Hz, 2H), 2.71 (m; 6H), 1.88 (m, 6H), 1.12 (t, J=7.2Hz, 3H) .C
13Nuclear magnetic resonance result is: C
13-NMR (CDCl
3, 100MHz, δ ppm): 169.8,159.5,158.7; 156.8,150.4,150.0,147.4,128.9; 128.4,127.3 (2C), 127.2,124.0,122.5; 120.5,116.9,114.1 (2C), 106.0,57.6; 55.3,52.8,49.4,47.5,34.0; 29.3,24.9,22.9,22.7,11.8.
Embodiment 1-9:
The preparation of N-(4-(4-chloro-phenyl-) thiazol-2-yl)-2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) propyl group) amido) propionic acid amide
Reagent: 3-bromo-N-((4-chloro-phenyl-) thiazol-2-yl) propionic acid amide (0.7g, 2.0mmol), N, dinethylformamide (10mL); Salt of wormwood (0.3g), potassiumiodide (0.01g), and N-(4-(ethylamino) propyl group)-1,2; 3, and 4-tetrahydro acridine-9-amine (0.64g, 2.0mmol).Except that reagent, all the other preparation purification process get light brown oily thing 0.4g, productive rate 30.8% with embodiment 1.H
1Nuclear magnetic resonance result is: H
1-NMR (CDCl
3, 400MHz, δ ppm): 7.92 (m, 2H), 7.72 (d, J=8.8Hz, 2H); 7.51 (t, J=7.2Hz, 1H), 7.27 (m, 2H), 7.25 (m, 2H); 7.11 (s, 1H), 4.41 (brs, 1H), 3.73 (m, 2H), 3.02 (t; J=6.0Hz, 2H), 2.84 (t, J=6.0Hz, 2H), 2.75 (q, J=7.2Hz; 2H), 2.68 (t, J=6.8Hz, 2H), 2.59 (m, 4H), 1.96 (m; 2H), 1.81 (m, 4H), 1.17 (t, J=7.2Hz, 3H) .C
13Nuclear magnetic resonance result is: C
13-NMR (CDCl
3, 100MHz, δ ppm): 170.2,158.6,157.6; 150.1,148.8,147.4,133.5,132.9; 128.8,128.7 (2C), 128.3,127.2 (2C), 123.8; 122.3,120.3,116.4,107.7,50.5; 48.9,47.0,46.2,34.0,31.9; 28.8,24.9,22.9,22.7,10.6.
Embodiment 1-10:
The preparation of 2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) propyl group) amido)-N-(4-phenyl thiazole-2-yl) propionic acid amide
Reagent: 2-bromo-N-(4-phenyl thiazole-2-yl) propionic acid amide (0.4g, 1.74mmol), methylene dichloride (10mL), salt of wormwood (0.2g), potassiumiodide (0.01g), and N-(4-(ethylamino) propyl group)-1,2,3,4-tetrahydro acridine-9-amine (0.55g, 1.76mmol).Except that reagent, all the other preparation purification process get light brown oily thing 0.4g, productive rate 44.0% with embodiment 1.H
1Nuclear magnetic resonance result is: H
1-NMR (CDCl
3, 400MHz, δ ppm): 7.91 (d, J=8.4Hz, 1H); 7.89 (d, J=8.4Hz, 1H), 7.81 (d, J=7.6Hz; 2H), 7.51 (t, J=7.6Hz, 1H), 7.31 (t; J=7.6Hz, 2H), 7.25 (m, 2H), 7.13 (s; 1H), 4.33 (bs, 1H), 3.71 (t, J=6.8Hz; 2H), 2.99 (t, J=6.4Hz, 2H), 2.82 (t; J=6.0Hz, 2H), 2.72 (q, J=7.2Hz, 2H); 2.65 (t, J=6.8Hz, 2H), 2.58 (m, 4H); 1.95 (t, J=6.8Hz, 2H), 1.79 (m; 4H), 1.15 (t, J=7.2Hz, 3H) .C
13Nuclear magnetic resonance result is: C
13-NMR (CDCl
3, 100MHz, δ ppm): 170.2,158.5,157.5; 150.2,150.0,147.3,134.4,128.7; 128.6 (2C), 128.2,127.8,126.0 (2C), 123.7; 122.4,120.3,116.3,107.4,50.5; 48.9,46.9,46.2,33.9,31.8; 28.8,24.9,22.9,22.7,10.6.
Embodiment 1-11:
The preparation of N-(4-(4-p-methoxy-phenyl) thiazol-2-yl)-2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) propyl group) amido) propionic acid amide
Reagent: 2-bromo-N-((4-p-methoxy-phenyl) thiazol-2-yl) propionic acid amide (0.51g, 1.7mmol), N, dinethylformamide (10mL); Salt of wormwood (0.2g), potassiumiodide (0.1g), and N-(4-(ethylamino) propyl group)-1,2; 3, and 4-tetrahydro acridine-9-amine (0.58g, 1.7mmol).Except that reagent, all the other preparation purification process get light brown foaming material 0.51g, productive rate 48.6% with embodiment 1.H
1Nuclear magnetic resonance result is: H
1-NMR (CDCl
3, 400MHz, δ ppm): 7.92 (d, J=8.4Hz, 2H), 7.72 (d, J=8.8Hz, 2H); 7.52 (m, 1H), 7.27 (m, 1H), 7.25 (m, 1H), 6.99 (s, 1H); 6.82 (d, J=8.8Hz, 2H), 4.48 (bs, 1H), 3.80 (s, 3H), 3.75 (m; 2H), 3.01 (t, J=6.0Hz, 2H), 2.83 (t, J=6.0Hz, 2H), 2.73 (q; J=7.2Hz, 2H), 2.66 (t, J=6.4Hz, 2H), 2.58 (m, 4H), 1.96 (t; J=7.2Hz, 2H), 1.79 (m, 4H), 1.16 (t, J=7.2Hz, 3H) .C
13Nuclear magnetic resonance result is: C
13-NMR (CDCl
3, 100MHz, δ ppm): 170.2,159.4,158.5,157.5; 150.2,149.8,147.3,128.7,128.3; 127.4,127.2 (2C), 123.7,122.5,120.3; 116.3,114.0 (2C), 105.6,55.3,50.6; 48.9,47.0,46.2,33.9,31.9; 28.8,24.9,22.9,22.7,10.6.
Implement 1-12:
The preparation of 2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) hexyl) amido)-N-(4-phenyl thiazole-2-yl) ethanamide
Reagent: 2-bromo-N-(4-phenyl thiazole-2-yl) ethanamide (0.4g, 1.74mmol), N, dinethylformamide (10mL), triethylamine (0.25g), and N-(4-(ethylamino) hexyl)-1,2,3,4-tetrahydro acridine-9-amine (0.55g, 1.6mmol).Except that reagent, all the other preparation purification process get light brown oily thing 0.45g, productive rate 47.4% with embodiment 1.H
1Nuclear magnetic resonance result is: H
1-NMR (CDCl
3, 400MHz, δ ppm): 7.96 (d, J=8.0Hz, 1H); 7.92 (d, J=8.4Hz, 1H), 7.83 (d, J=7.6Hz; 2H), 7.56 (t, J=7.6Hz, 1H), 7.40 (t; J=7.6Hz, 2H), 7.32 (m, 2H), 7.14 (s; 1H), 4.06 (brs, 1H), 3.49 (t, J=7.2Hz; 2H), 3.29 (s, 2H), 3.08 (m, 2H); 2.68 (q, J=7.2Hz, 2H), 2.63 (m, 2H); 2.57 (t, J=7.2Hz, 2H), 1.89 (m, 4H); 1.70 (m, 2H), 1.53 (m, 2H), 1.42 (m; 4H), 1.12 (t, J=7.2Hz, 3H) .C
13Nuclear magnetic resonance result is: C
13-NMR (CDCl
3, 100MHz, δ ppm): 170.3,157.1,150.1,134.4,128.7 (2C), 128.0,126.0 (2C), 123.8,122.9,119.7,107.7,57.5,55.1,49.3,49.2,33.4,31.7,27.2,27.1,26.8,24.6,22.9,22.5,12.0.
Embodiment 1-13:
The preparation of N-(4-(4-p-methoxy-phenyl) thiazol-2-yl)-2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) hexyl) amido) ethanamide
Reagent: 2-bromo-N-((4-p-methoxy-phenyl) thiazol-2-yl) ethanamide (0.35g, 1.3mmol), N, dinethylformamide (10mL); Salt of wormwood (0.2g), potassiumiodide (0.1g), and N-(4-(ethylamino) hexyl)-1,2; 3, and 4-tetrahydro acridine-9-amine (0.5g, 1.4mmol).Except that reagent, all the other preparation purification process get light brown oily thing 0.41g, productive rate 51.3% with embodiment 1.H
1Nuclear magnetic resonance result is: H
1-NMR (CDCl
3, 400MHz, δ ppm): 7.91 (d, J=8.4Hz, 2H); 7.76 (d, J=8.8Hz, 2H), 7.54 (t, J=8.4Hz; 1H), 7.32 (t, J=8.4Hz, 1H), 7.00 (s; 1H), 6.92 (d, J=8.8Hz, 2H), 3.92 (brs; 1H), 3.82 (s, 3H), 3.46 (t, J=7.2Hz; 2H), 3.28 (s, 2H), 3.06 (m, 2H); 2.67 (q, J=7.2Hz, 2H), 2.66 (m, 2H); 2.56 (t, J=7.2Hz, 2H), 1.90 (m, 4H); 1.68 (m, 2H), 1.52 (m, 2H), 1.41 (m; 4H), 1.11 (t, J=7.2Hz, 3H) .C
13Nuclear magnetic resonance result is: C
13-NMR (CDCl
3, 100MHz, δ ppm): 170.3,159.5,158.3,156.9; 150.7,149.9,147.4,128.6,128.3,127.4; 127.3 (2C), 123.6,122.8,120.2,115.8,114.1 (2C); 106.0,57.5,55.3,55.1,49.3; 49.2,33.9,31.7,27.2,27.1; 26.9,24.7,23.0,22.7,12.0.
Embodiment 2: external cholinesterase inhibition research:
Ellman (Ellman, G.L.; Courtney, K.D.; Andres, B.; Featherstone; R.M.Biochem.Pharmacol.1961; 7; 88-95) Bao Dao colorimetry is active 30 ℃ of inhibition of measuring acetylcholinesterase, and test soln is made up of and the following: the phosphate buffered saline buffer pH=7.4 of 50mM, 5 of 1.5mM; 5 '-two (2-the nitrobenzoic acid) (DTNB of dithio; Ellman ' s reagent), the acetylcholinesterase of 0.22U/ml (deriving from electric eel), the sulfo-Acetylcholine iodide of 30mM is as the substrate of enzymatic reaction.With at room temperature hatching 5min in the compound adding mensuration solution that detects and with enzyme, add 5,5 of 1.5mM '-dithio two (2-nitrobenzoic acid) again and hatch 10min, add subsequently under the substrate sulfo-Acetylcholine iodide room temperature and hatch 5min.Be determined at the absorbancy (OD value) at 415nm place with the microplate reader of Biotek, calculate because the per-cent inhibiting rate that existence caused of test compounds.The acetylcholinesterase of measuring generation 50% suppresses the compound concentration (pIC of effect
50), pIC
50The activity of big more reflection acetylcholine esterase inhibition is strong more.
It is active that identical method is measured butyrylcholine esterase; Just replace the acetylcholinesterase (deriving from electric eel) of 0.22U/ml with the butyrylcholine esterase (deriving from bovine serum) of 0.12U/ml, the sulfo-iodate BuCh of 30mM replaces the substrate of the sulfo-Acetylcholine iodide of 30mM as enzymatic reaction.Experimental result is seen table 1.
Table 1, each embodiment compound acetylcholine esterase inhibition and butyrylcholine esterase be table as a result
Embodiment 3: suppress A beta peptide aggregation activity research
A β (1-42) lyophilized powder of handling through hexafluoroisopropanol (HFIP) is dissolved among the DMSO; Mother liquid concentration 200 μ M; Get among the phosphoric acid buffer PBS (pH=7.4) that joins 40 μ l under the A β mother liquor 5 μ l room temperatures and hatched 24 hours; The testing compound (final concentration 20 μ M) that in the application of sample group, adds 5 μ l, every pipe final volume 50 μ l.Use thioflavin T (thioflavin T) fluorescence detection method quantitative test amyloid fiber to form.After hatching, sample is diluted to 150 μ l with glycine-NaOH damping fluid of 5 μ l thioflavin T.Adopt λ exc=435nm, λ em=485nm calculates every cell mean after deducting thioflavin T fluorescence background.The result sees the following form 2, and the ability that the high more reflection of inhibiting rate suppresses the A beta peptide aggregation is strong more.
Table 2, each embodiment compd A beta peptide aggregation inhibiting rate be table as a result
Embodiment 4:
Injection: activeconstituents 1mg
Sodium-chlor 9mg
Preparing method: activeconstituents and sodium-chlor are dissolved in the proper amount of water for injection, filter gained solution, in the ampoule of under aseptic condition, packing into.
Above-mentioned described activeconstituents is N-(4-(4-p-methoxy-phenyl) thiazol-2-yl)-2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) hexyl) amido) ethanamide
Embodiment 5:
Tablets:
Above-mentioned described activeconstituents is N-(4-(4-p-methoxy-phenyl) thiazol-2-yl)-2-(ethyl (4-(1,2,3,4-tetrahydrochysene-acridine-9-amido) hexyl) amido) ethanamide
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds basic V-Pyrol RC solution, mixes; The system softwood sieves, and the system wet granular is in 50-60 ℃ of drying; With the hydroxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
All the other preparations of the present invention adopt the routine prescription in pharmaceutical formulations field equally, by the preparation of conventional working method.
Claims (14)
1. the aminothiazole derivs compound or its tautomer or its pharmaceutical salts that have formula I structure,
Wherein
M=1,2,3 or 4;
N=3,4,5,6,7 or 8;
R
2Be H or Cl.
2. aminothiazole derivs compound or its tautomer or its pharmaceutical salts with formula I structure according to claim 1 is characterized in that described pharmaceutical salts is meant any pharmaceutical salts.
3. the preparation method of the described compound of claim 1 comprises the steps:
1) makes formula (1) compound and alkyl diamine do at Pentyl alcohol under the condition of solvent nucleophilic substitution reaction takes place, obtain formula (2) compound;
2) make formula (2) compound and monobromethane in DMF, nucleophilic substitution reaction takes place under the catalysis of organic bases or mineral alkali, get formula (3) compound;
3) make formula (4) compound and bromacyl chloride in THF, under the catalysis of organic bases or mineral alkali, react formula (6) compound;
4) make formula (5) compound and bromacyl chloride in THF, under the catalysis of organic bases or mineral alkali, react formula (7) compound;
5) make formula (6) compound or formula (7) compound and formula (3) compound in DMF, nucleophilic substitution reaction takes place under the catalysis of organic bases or mineral alkali, get formula (8) compound;
Wherein
M=1,2,3 or 4;
N=3,4,5,6,7 or 8;
R
1Be H, Cl or OCH
3
R
2Be H or Cl.
4. preparation method according to claim 3, wherein step 2), 3), 4) and 5) described in organic bases can be triethylamine, diisopropyl ethyl amine, pyridine, 2,6 lutidine or 4-Dimethylamino pyridine; Described mineral alkali can be salt of wormwood or yellow soda ash.
5. preparation method according to claim 3; It is characterized in that: the concrete grammar that nucleophilic substitution reaction obtains formula (2) compound takes place under the condition that step 1) is described to make formula (1) compound and alkyl diamine make solvent at Pentyl alcohol can be: formula (1) compound and alkyl diamine are done under the condition of solvent at Pentyl alcohol; Temperature control refluxed 18 hours for 180 ℃, nucleophilic substitution reaction takes place obtain formula (2) compound.
6. preparation method according to claim 3; It is characterized in that: step 2) described formula (2) compound and the monobromethane of making be under the catalysis of potassiumiodide and organic bases or mineral alkali; At solvent N; The concrete grammar that nucleophilic substitution reaction gets formula (3) compound takes place in dinethylformamide or the methylene dichloride can be: 1 times of normal formula (2) compound and 1 times of equivalent monobromethane are at one times of normal alkali, a spot of potassiumiodide catalysis N at 10mL; Normal-temperature reaction is 5 hours in dinethylformamide or the methylene dichloride, obtains formula (3) compound through column chromatography purification again.Wherein alkali can be that organic bases is triethylamine, diisopropyl ethyl amine, pyridine, 2,6 lutidine or 4-Dimethylamino pyridine, perhaps mineral alkali salt of wormwood or yellow soda ash.The condition of column chromatography is a sherwood oil: ethyl acetate=1: 1 (1-2% triethylamine).
7. preparation method according to claim 3; It is characterized in that: step 3) is described to make formula (4) compound and bromacyl chloride in that the concrete grammar that the condensation reaction of acyl chlorides with amine get formula (6) compound takes place under the catalysis of organic bases or mineral alkali can be: 1 times of normal formula (4) and 1.2 times of normal bromacyl chlorides obtain formula (6) compound through column chromatography purification again in 1.5 times of normal base catalyzed reactions solvents normal-temperature reaction 12 hours in the tetrahydrofuran (THF) of 20mL or methylene dichloride.Wherein alkali can be that organic bases is triethylamine, diisopropyl ethyl amine, pyridine, 2,6 lutidine or 4-Dimethylamino pyridine, perhaps mineral alkali salt of wormwood or yellow soda ash, and the condition of column chromatography is a sherwood oil: ethyl acetate=10: 1.
8. preparation method according to claim 3; It is characterized in that: step 4) is described to make formula (5) compound and bromacyl chloride in that the concrete grammar that the condensation reaction of acyl chlorides with amine get formula (7) compound takes place under the catalysis of organic bases or mineral alkali can be: 1 times of normal formula (5) and 1.2 times of normal bromacyl chlorides under 1.5 times of normal base catalysiss in the tetrahydrofuran (THF) of 20mL or methylene dichloride normal-temperature reaction 12 hours, obtain formula (7) compound through column chromatography purification again.Wherein alkali can be that organic bases is triethylamine, diisopropyl ethyl amine, pyridine, 2,6 lutidine or 4-Dimethylamino pyridine, perhaps mineral alkali salt of wormwood or yellow soda ash, and the condition of column chromatography is a sherwood oil: ethyl acetate=10: 1.
9. preparation method according to claim 3; It is characterized in that: described formula (6) compound or formula (7) compound and formula (3) compound of making of step 5) is under the catalysis of potassiumiodide and organic bases or mineral alkali; The concrete grammar that nucleophilic substitution reaction gets formula (8) compound takes place is: 1 times of normal formula (6) compound or formula (7) compound and 1 times of normal formula (3) compound are at one times of normal alkali; A spot of potassiumiodide catalysis is at the N of 10mL; Dinethylformamide; 70 ℃ of reactions of temperature control are 2 hours in ethanol or the methylene dichloride; Obtain formula (8) compound through column chromatography purification again; Wherein alkali can be that organic bases is a triethylamine; Diisopropyl ethyl amine; Pyridine; 2; 6 lutidine or 4-Dimethylamino pyridine, perhaps mineral alkali salt of wormwood or yellow soda ash.The condition of column chromatography is that sherwood oil, ethyl acetate and triethylamine are with arbitrary proportion.
10. a pharmaceutical composition contains described aminothiazole derivs compound or its tautomer or its pharmaceutical salts with formula I structure of claim 1.
11. a pharmaceutical preparation is characterized in that, contain described aminothiazole derivs compound or its tautomer or its pharmaceutical salts with formula I structure of claim 1, and pharmaceutically acceptable additive is or/and carrier.
12. pharmaceutical preparation according to claim 11; It is characterized in that; Its formulation is solid orally ingestible, liquid oral medicine or injection, and described solid orally ingestible can be tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule or granule; Described liquid oral medicine can be an oral solution; Described injection can be injection liquid drugs injection, injection freeze-dried powder, infusion solutions or primary infusion.
Have aminothiazole derivs compound or its tautomer of formula I structure or its pharmaceutical salts is used for treating, improving or prevent the medicine of the relevant nervous system disorders of cognitive function decline in preparation application 13. claim 1 is described.
14. application according to claim 13 is characterized in that, the relevant nervous system disorders of described cognitive function decline is the dementia that alzheimer's disease, vascular dementia, mild cognitive damage or other oxidative stresss are participated in.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110216344.2A CN102351854B (en) | 2011-07-29 | 2011-07-29 | Amino thiazole derivative and preparation method and medical purpose thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110216344.2A CN102351854B (en) | 2011-07-29 | 2011-07-29 | Amino thiazole derivative and preparation method and medical purpose thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102351854A true CN102351854A (en) | 2012-02-15 |
| CN102351854B CN102351854B (en) | 2014-06-04 |
Family
ID=45575523
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110216344.2A Expired - Fee Related CN102351854B (en) | 2011-07-29 | 2011-07-29 | Amino thiazole derivative and preparation method and medical purpose thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102351854B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103382190A (en) * | 2013-07-16 | 2013-11-06 | 浙江医药高等专科学校 | Thiazole-cyclohexane compound of same category and preparation method and purpose thereof |
| CN103408541A (en) * | 2013-07-16 | 2013-11-27 | 浙江医药高等专科学校 | Indole-substituted thiazolo cyclohexane compound and antineoplastic applications thereof |
| CN103435573A (en) * | 2013-07-16 | 2013-12-11 | 浙江医药高等专科学校 | Benzyl-substituted thiazolocyclohexane compounds, and preparation methods and antitumor uses thereof |
| CN103435572A (en) * | 2013-07-16 | 2013-12-11 | 浙江医药高等专科学校 | Thiazolocyclohexane compounds, and preparation methods and antitumor uses thereof |
| RU2675794C1 (en) * | 2017-11-01 | 2018-12-25 | Федеральное Государственное Бюджетное Учреждение Науки Институт Физиологически Активных Веществ Российской Академии Наук (Ифав Ран) | Multifunctional conjugates of tacrine and its analogues with derivatives of 1,2,4-tiadiazole, the way of their synthesis and application for the treatment of neurodegenerative diseases |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993000342A1 (en) * | 1991-06-21 | 1993-01-07 | Boehringer Mannheim Italia S.P.A. | 2-amino-4-aryl-thiazoles with antiasthmatic and anti-inflammatory activities on the respiratory tract |
| CN1688557A (en) * | 2002-10-09 | 2005-10-26 | 辉瑞产品公司 | Thiazole compounds for treatment of neurodegenerative disorders |
| CN101415681A (en) * | 2006-03-29 | 2009-04-22 | 弗·哈夫曼-拉罗切有限公司 | Pyridine and pyrimidine derivatives as mGluR2 antagonists |
-
2011
- 2011-07-29 CN CN201110216344.2A patent/CN102351854B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993000342A1 (en) * | 1991-06-21 | 1993-01-07 | Boehringer Mannheim Italia S.P.A. | 2-amino-4-aryl-thiazoles with antiasthmatic and anti-inflammatory activities on the respiratory tract |
| CN1688557A (en) * | 2002-10-09 | 2005-10-26 | 辉瑞产品公司 | Thiazole compounds for treatment of neurodegenerative disorders |
| CN101415681A (en) * | 2006-03-29 | 2009-04-22 | 弗·哈夫曼-拉罗切有限公司 | Pyridine and pyrimidine derivatives as mGluR2 antagonists |
Non-Patent Citations (3)
| Title |
|---|
| KENNETH L DAVIS，等: "Tacrine", 《LANCET》 * |
| MICHELA ROSINI,等: "Design, synthesis, and biological evaluation of substituted 2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamine related compounds as fructose-1,6-bisphosphatase inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| MICHELA ROSINI，等: "Rational Approach to discover multipotent anti-Alzheimer Drugs", 《J. MED. CHEM》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103382190A (en) * | 2013-07-16 | 2013-11-06 | 浙江医药高等专科学校 | Thiazole-cyclohexane compound of same category and preparation method and purpose thereof |
| CN103408541A (en) * | 2013-07-16 | 2013-11-27 | 浙江医药高等专科学校 | Indole-substituted thiazolo cyclohexane compound and antineoplastic applications thereof |
| CN103435573A (en) * | 2013-07-16 | 2013-12-11 | 浙江医药高等专科学校 | Benzyl-substituted thiazolocyclohexane compounds, and preparation methods and antitumor uses thereof |
| CN103435572A (en) * | 2013-07-16 | 2013-12-11 | 浙江医药高等专科学校 | Thiazolocyclohexane compounds, and preparation methods and antitumor uses thereof |
| CN103382190B (en) * | 2013-07-16 | 2015-01-14 | 浙江医药高等专科学校 | Thiazole-cyclohexane compound of same category and preparation method and purpose thereof |
| CN103408541B (en) * | 2013-07-16 | 2015-04-01 | 浙江医药高等专科学校 | Indole-substituted thiazolo cyclohexane compound and antineoplastic applications thereof |
| CN103435573B (en) * | 2013-07-16 | 2015-04-01 | 浙江医药高等专科学校 | Benzyl-substituted thiazolocyclohexane compounds, and preparation methods and antitumor uses thereof |
| RU2675794C1 (en) * | 2017-11-01 | 2018-12-25 | Федеральное Государственное Бюджетное Учреждение Науки Институт Физиологически Активных Веществ Российской Академии Наук (Ифав Ран) | Multifunctional conjugates of tacrine and its analogues with derivatives of 1,2,4-tiadiazole, the way of their synthesis and application for the treatment of neurodegenerative diseases |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102351854B (en) | 2014-06-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4694834B2 (en) | 8-hydroxyquinoline derivatives | |
| JP4690043B2 (en) | Nerve active compounds | |
| CN103087024B (en) | Flavone alkylamine compounds as well as preparation method and application thereof | |
| CN102351854B (en) | Amino thiazole derivative and preparation method and medical purpose thereof | |
| IL279020B2 (en) | Use of chloroquine and clemizole compounds for treatment of inflammatory and cancerous conditions | |
| De Los Ríos et al. | Synthesis, inhibitory activity of cholinesterases, and neuroprotective profile of novel 1, 8-naphthyridine derivatives | |
| KR102051485B1 (en) | Hydantoins that modulate bace-mediated app processing | |
| CN101284812A (en) | Tacrine-ferulaic acid hetero-blend, preparation method and pharmaceutical compositions thereof | |
| Ghafary et al. | Design, synthesis, and evaluation of novel cinnamic acid-tryptamine hybrid for inhibition of acetylcholinesterase and butyrylcholinesterase | |
| EA015249B1 (en) | Compounds with a combination of cannabinoid-cbantagonism and acetylcholinesterase inhibition | |
| Sun et al. | Development of 5-hydroxyl-1-azabenzanthrone derivatives as dual binding site and selective acetylcholinesterase inhibitors | |
| CN113651805A (en) | 1,2, 4-oxadiazole-pyridine compound and application thereof in treating Alzheimer's disease | |
| JP2021120391A (en) | Enantiomer of 8-hydroxyquinoline derivative and synthesis thereof | |
| El Ati et al. | Novel benzene sulfonamides with acetylcholinesterase and carbonic anhydrase inhibitory actions | |
| CN104447682A (en) | Bilastine compound | |
| EP3883935A1 (en) | Compositions and methods for treating neurodegenerative, myodegenerative, and lysosomal storage disorders | |
| CN102816151A (en) | Levorotatory meptazinol derivative, preparation method and pharmaceutical application thereof | |
| Abdullaha et al. | Methoxy-naphthyl-Linked N-Benzyl Pyridinium Styryls as Dual Cholinesterase Inhibitors: Design, Synthesis, Biological Evaluation, and Structure–Activity Relationship | |
| CN113582911B (en) | Multi-target donepezil-hydroxamic acid compound, and preparation method and application thereof | |
| US20130172346A1 (en) | Use of kynurenic acid amide derivatives for the treatment of huntington's disease | |
| CN101575341B (en) | Amidocyanogen amido xanthone pyridine derivant, and preparation method and application thereof | |
| CN102391180B (en) | Sulfydryl-containing tacrine derivative and preparation method and application thereof | |
| CN105111195A (en) | Tacrine-bifendate heterocomplex as well as preparation method and application thereof | |
| CN114072380A (en) | Carbamate substituted styryl sulfone compound and preparation method and application thereof | |
| CN108276332A (en) | A kind of double twin pharmaceutical compounds of asafoetide amide and its preparation method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140604 Termination date: 20200729 |