CN102351854B - Amino thiazole derivative and preparation method and medical purpose thereof - Google Patents
Amino thiazole derivative and preparation method and medical purpose thereof Download PDFInfo
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- KHSCRKWDOCATKY-UHFFFAOYSA-N CCN(CCCCNc1c(cccc2)c2nc2c1CCCC2)CC(Nc1nc(CCCC2)c2[s]1)=O Chemical compound CCN(CCCCNc1c(cccc2)c2nc2c1CCCC2)CC(Nc1nc(CCCC2)c2[s]1)=O KHSCRKWDOCATKY-UHFFFAOYSA-N 0.000 description 1
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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 world population aging, cognitive function relevant nervous system disorders, particularly alzheimer's disease (Alzheimer ' s disease, the AD) sickness rate that fails significantly improves.Alzheimer's disease is as a kind of nerve degenerative diseases of induce by multifactor, and its definite pathogenesis it be unclear that.For this reason, become for pathogeny and the therapeutics research of alzheimer's disease the focus that people pay close attention to.Alzheimer's disease is a kind of taking the damage of carrying out property cognitive disorder and learning memory as main central nervous system degenerative disease, and main pathological characters is that cerebral atrophy, A beta peptide aggregation form senile plaque, Protein tau Hyperphosphorylationof forms neurofibrillary tangles.Medical circle has proposed Different types of etiopathogenises hypothesis in recent years, mainly comprises that choline function decline hypothesis, A beta peptide aggregation form amyloid beta deposition hypothesis, free radical overload causes nerve injury hypothesis, neural inflammation hypothesis etc.
Based on " cholinergic hypothesis ", some medicines that improve AD symptom are developed listing in succession, and wherein modal medicine is anticholinesterase (chEI).ChEI, by suppressing Pseudocholinesterase (ChE) activity, delays cholinolytic speed, improves the level of synaptic cleft choline and brings into play the improvement effect to AD cognitive function of patients.The acetylcholinesterase depressant of food and drug administration (FDA) approval listing comprises: tacrine (Tacrine), aricept (Donpezil), Exelon (Rivastigmine), lycoremine (Galantamine) etc.
It is the important pathological characters of AD that beta amyloid precursor protein is hydrolyzed the senile plaque that generates amyloid-beta (A β) gathering and form.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 at present AD treatment is that some improve symptom class medicine, is difficult to fundamentally cure nerve degenerative diseases.The gathering and the depolymerization that suppress the paraprotein A β (amyloid) of AD disease have become one of important means for the treatment of AD disease.
For the multifactor property of nerve degenerative diseases morbidity, the medicine of multiple target effect will be conducive to improve curative effect of medication, reduce side effect.Enter clinical study for the existing successful many target drugs of nerve degenerative diseases at present, as draw replace lucky (Ladostigil) more, its activity by acetylcholine esterase inhibition and monoamine oxidase-B is brought into play the effect for the treatment of AD.Separately there are some drug molecules to be in preclinical study, for example, have been reported antioxidant and AChEIs contraction are closed to the drug molecule that designs many target treatments AD.Investigator is connected tacrine by the methene chain of different lengths with Thioctic Acid, designed and synthesized out a series of compounds (J.Med.Chem.2005,48,360-363) simultaneously with AChE inhibition and oxidation resistant multiple target effect.
Summary of the invention
Task of the present invention is to provide 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 is to provide the preparation method of this aminothiazole derivs compound.
Another task of the present invention is to provide the medical applications of this aminothiazole derivs compound.
Realizing technical scheme of the present invention is:
This aminothiazole derivs compound provided by the invention has the structure shown in 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
2for H or Cl
Above-described pharmaceutical salts, refers to parent compound and the sour salify of formula I.Compound provided by the present invention contains alkali part, and pharmaceutical salts can be synthetic by the parent compound of formula I by ordinary method.Conventionally, this salt by preparing the suitable acid of the formula I compound of free alkali form and stoichiometric quantity in water or in organic solvent.Conventionally non-aqueous media as ether, ethyl acetate, ethanol, Virahol be 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, the medicine that can be used for preparation treatment, improve, prevention cognitive function fails relevant nervous system disorders, the described cognitive function dementia that relevant nervous system disorders comprises that alzheimer's disease, vascular dementia, mild cognitive impairment and other oxidative stresss participate in etc. that fails.
Compound involved in the present invention contains two main structural units: aminothiazole part and tacrine part, they connect by suitable intermediate chain.Type and the length that can adjust on the one hand intermediate chain were combined with the dual site of enzyme with the while, improved the inhibition activity and selectivity to Pseudocholinesterase, lowered toxic side effect; On the other hand, bring into play the effect of the inhibition A β peptide pathologic gathering of aminothiazole derivs simultaneously.Give full play to the superiority of many target drug treatment nerve degenerative diseases, make them become the dull-witted drug candidate that is used for the treatment of prevention AD and the participation of other A beta peptide aggregations.
The preparation method of aminothiazole derivs compound provided by the invention, comprises the following steps:
1) make formula (1) compound and alkyl diamine do at Pentyl alcohol under the condition of solvent nucleophilic substitution reaction occurs, obtain formula (2) compound, formula (1) compound and alkyl diamine do at Pentyl alcohol under the condition of solvent, there are the concrete steps of nucleophilic substitution reaction can be synthetic according to the method for having reported [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 solvent DMF, ethanol or methylene dichloride, nucleophilic substitution reaction occurs, obtain formula (3) compound.
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 occur in solvents tetrahydrofurane or methylene dichloride obtains 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 occur in solvents tetrahydrofurane or methylene dichloride obtains 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, in solvent DMF or methylene dichloride, there is nucleophilic substitution reaction and obtain formula (8) compound.
Above-mentioned steps 1) to 5) reaction scheme and the structure of formula (1), (2), (3), (4), (5), (6), (7) and (8) compound be:
Wherein
r
1for H, Cl or OCH
3;
M=1,2,3 or 4;
N=3,4,5,6,7 or 8;
R
2for H or Cl.
Above-mentioned steps 1) there is the concrete grammar that nucleophilic substitution reaction obtains formula (2) compound under the described condition that makes formula (1) compound and alkyl diamine make solvent at Pentyl alcohol and can be: formula (1) compound and alkyl diamine do at Pentyl alcohol under the condition of solvent,, there is nucleophilic substitution reaction and obtain formula (2) compound in 180 DEG C of backflows of temperature control 18 hours; Concrete steps can be synthetic according to the method for having reported (referring to: J.Med.Chem.2008,51,713716).
Above-mentioned steps 2) described make formula (2) compound and monobromethane under the catalysis of potassiumiodide and organic bases or mineral alkali, at solvent N, the concrete grammar that nucleophilic substitution reaction obtains formula (3) compound occurs in dinethylformamide or methylene dichloride can be: formula (2) compound of 1 times of equivalent and 1 times of equivalent monobromethane be the N at 10mL at the alkali of one times of equivalent, a small amount of potassiumiodide catalysis, normal-temperature reaction 5 hours in dinethylformamide or methylene dichloride, then obtain formula (3) compound through column chromatography purification.Wherein alkali can be that organic bases is triethylamine, diisopropyl ethyl amine, pyridine, 2,6 lutidine or DMAP, or mineral alkali salt of wormwood or sodium carbonate.The condition of column chromatography is sherwood oil: ethyl acetate=1: 1 (1-2% triethylamine).
Above-mentioned steps 3) the described condensation reaction that makes formula (4) compound and bromacyl chloride that acyl chlorides and amine occur under the catalysis of organic bases or the mineral alkali concrete grammar that obtains formula (6) compound can be: the formula (4) of 1 times of equivalent and the bromacyl chloride of 1.2 times of equivalents be in the base catalyzed reactions solvent of 1.5 times of equivalents normal-temperature reaction 12 hours in the tetrahydrofuran (THF) of 20mL or methylene dichloride, then obtain formula (6) compound through column chromatography purification.Wherein alkali can be that organic bases is triethylamine, diisopropyl ethyl amine, pyridine, 2,6 lutidine or DMAP, or mineral alkali salt of wormwood or sodium carbonate.The condition of column chromatography is sherwood oil: ethyl acetate=10: 1.
Above-mentioned steps 4) the described condensation reaction that makes formula (5) compound and bromacyl chloride that acyl chlorides and amine occur under the catalysis of organic bases or the mineral alkali concrete grammar that obtains formula (7) compound can be: the formula (5) of 1 times of equivalent and the bromacyl chloride of 1.2 times of equivalents under the base catalysis of 1.5 times of equivalents in the tetrahydrofuran (THF) of 20mL or methylene dichloride normal-temperature reaction 12 hours, then obtain formula (7) compound through column chromatography purification.Wherein alkali can be that organic bases is triethylamine, diisopropyl ethyl amine, pyridine, 2,6 lutidine or DMAP, or mineral alkali salt of wormwood or sodium carbonate.The condition of column chromatography is sherwood oil: ethyl acetate=10: 1.
Above-mentioned steps 5) described make formula (6) compound or formula (7) compound and formula (3) compound under the catalysis of potassiumiodide and organic bases or mineral alkali, the concrete grammar that generation nucleophilic substitution reaction obtains formula (8) compound is: formula (3) compound of formula (6) compound of 1 times of equivalent or formula (7) compound and 1 times of equivalent is at the alkali of one times of equivalent, a small amount of potassiumiodide catalysis is at the N of 10mL, dinethylformamide, 70 DEG C of reactions of temperature control 2 hours in ethanol or methylene dichloride, obtain formula (8) compound through column chromatography purification again, wherein alkali can be that organic bases is triethylamine, diisopropyl ethyl amine, pyridine, 2, 6 lutidine or DMAP, or mineral alkali salt of wormwood or sodium carbonate.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 that acetylcholinesteraseinhibition inhibition, amyloid-beta (A β) are assembled and the effect of the senile plaque that forms simultaneously, can be used for treatment, improve or the prevention cognitive function relevant nervous system disorders that fails the dementia participating in as alzheimer's disease, vascular dementia, mild cognitive impairment and other oxidative stresss.
Taking aminothiazole derivs compound provided by the invention or its tautomer or its pharmaceutical salts as activeconstituents, can make pharmaceutical composition.Taking aminothiazole derivs compound provided by the invention or its tautomer or its pharmaceutical salts as activeconstituents, add pharmaceutically acceptable additive or/and carrier, can be prepared into various pharmaceutical preparations, as 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
Universal method for the preparation of the compounds of this invention has below been described.Provide the following example further to illustrate the present invention, instead of limiting 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
The bromo-N-of reagent: 2-(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 the chloro-N-of 2-(4-phenyl thiazole-2-yl) ethanamide and N-(4-(ethylamino) butyl)-1,2,3,4-tetrahydro acridine-9-amine is dissolved in N, in dinethylformamide, add salt of wormwood, 70 DEG C of reactions of temperature control 2 hours.Methylene dichloride dilution, direct purification by silica gel column chromatography after washing and drying.Purification process: silica gel column chromatography, use petrol ether/ethyl acetate (2: 1,0.3% triethylamine), obtain faint yellow oily matter 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
The bromo-N-of reagent: 2-((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 reagent, all the other prepare purification process with embodiment 1, obtain light brown oily thing 0.6g, productive rate 85.7%.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
The bromo-N-of reagent: 2-((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 reagent, all the other prepare purification process with embodiment 1, obtain light brown oily thing 0.35g, productive rate 43.8%.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
The bromo-N-of reagent: 2-(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 prepare purification process with embodiment 1, obtain light yellow oil 0.4g, productive rate 47.1%.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
The bromo-N-of reagent: 3-((4-chloro-phenyl-) thiazol-2-yl) propionic acid amide (0.58g, 1.68mmol), DMF (10mL), salt of wormwood (0.2g), potassiumiodide (0.05g), and N-(4-(ethylamino) butyl)-1,2,3,4-tetrahydro acridine-9-amine (0.5g, 1.68mmol).Except reagent, all the other prepare purification process with embodiment 1, obtain light brown oily thing 0.57g, productive rate 57.2%.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
The bromo-N-of reagent: 3-(4-phenyl thiazole-2-yl) propionic acid amide (0.52g, 1.68mmol), DMF (10mL), salt of wormwood (0.2g), potassiumiodide (0.06g), and N-(4-(ethylamino) butyl)-1,2,3,4-tetrahydro acridine-9-amine (0.5g, 1.68mmol).Except reagent, all the other prepare purification process with embodiment 1, obtain light brown oily thing 0.85g, productive rate 811%.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
The bromo-N-of reagent: 3-((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)-1,2,3,4-tetrahydro acridine-9-amine (0.62g, 2.08mmol).Except reagent, all the other prepare purification process with embodiment 1, obtain light yellow oil 0.98g, productive rate 75.4%.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
The bromo-N-of reagent: 2-(4-phenyl thiazole-2-yl) ethanamide (0.45g, 1.76mmol), DMF (10mL), salt of wormwood (0.25g), potassiumiodide (0.01g), and N-(4-(ethylamino) propyl group)-1,2,3,4-tetrahydro acridine-9-amine (0.5g, 1.76mmol).Except reagent, all the other prepare purification process with embodiment 1, obtain light brown oily thing 0.98g, productive rate 75.8%.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
The bromo-N-of reagent: 2-((4-p-methoxy-phenyl) thiazol-2-yl) ethanamide (0.4g, 1.4mmol), DMF (10mL), salt of wormwood (0.2g), potassiumiodide (0.1g), and N-(4-(ethylamino) propyl group)-1,2,3,4-tetrahydro acridine-9-amine (0.4g, 1.4mmol).Except reagent, all the other prepare purification process with embodiment 1, obtain light brown oily thing 0.45g, productive rate 60.5%.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
The bromo-N-of reagent: 3-((4-chloro-phenyl-) thiazol-2-yl) propionic acid amide (0.7g, 2.0mmol), DMF (10mL), salt of wormwood (0.3g), potassiumiodide (0.01g), and N-(4-(ethylamino) propyl group)-1,2,3,4-tetrahydro acridine-9-amine (0.64g, 2.0mmol).Except reagent, all the other prepare purification process with embodiment 1, obtain light brown oily thing 0.4g, productive rate 30.8%.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
The bromo-N-of reagent: 2-(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 reagent, all the other prepare purification process with embodiment 1, obtain light brown oily thing 0.4g, productive rate 44.0%.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
The bromo-N-of reagent: 2-((4-p-methoxy-phenyl) thiazol-2-yl) propionic acid amide (0.51g, 1.7mmol), DMF (10mL), salt of wormwood (0.2g), potassiumiodide (0.1g), and N-(4-(ethylamino) propyl group)-1,2,3,4-tetrahydro acridine-9-amine (0.58g, 1.7mmol).Except reagent, all the other prepare purification process with embodiment 1, obtain light brown foaming material 0.51g, productive rate 48.6%.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
The bromo-N-of reagent: 2-(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 reagent, all the other prepare purification process with embodiment 1, obtain light brown oily thing 0.45g, productive rate 47.4%.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
The bromo-N-of reagent: 2-((4-p-methoxy-phenyl) thiazol-2-yl) ethanamide (0.35g, 1.3mmol), DMF (10mL), salt of wormwood (0.2g), potassiumiodide (0.1g), and N-(4-(ethylamino) hexyl)-1,2,3,4-tetrahydro acridine-9-amine (0.5g, 1.4mmol).Except reagent, all the other prepare purification process with embodiment 1, obtain light brown oily thing 0.41g, productive rate 51.3%.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) colorimetry of report is in the inhibition activity of 30 DEG C of mensuration acetylcholinesterases, test soln is made up of the following: the phosphate buffered saline buffer pH=7.4 of 50mM, 5 of 1.5mM, two (2-the nitrobenzoic acid) (DTNB of 5 '-dithio, Ellman ' s reagent), the acetylcholinesterase (deriving from electric eel) of 0.22U/ml, the sulfo-Acetylcholine iodide of 30mM is as the substrate of enzymatic reaction.The compound of detection is added and measures in solution and at room temperature hatch 5min with enzyme, then add 5,5 of 1.5mM '-dithio two (2-nitrobenzoic acid) to hatch 10min, add subsequently under substrate sulfo-Acetylcholine iodide room temperature and hatch 5min.Be determined at the absorbancy (OD value) at 415nm place by the microplate reader of Biotek, calculate the per-cent inhibiting rate causing due to the existence of test compounds.Measure the compound concentration (pIC of the acetylcholinesterase inhibition that produces 50%
50), pIC
50the activity of larger reflection acetylcholine esterase inhibition is stronger.
Identical method is measured the activity of BuChE, 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 sulfo-Acetylcholine iodide of 30mM as the substrate of enzymatic reaction.Experimental result is in table 1.
Table 1, each embodiment compound acetylcholine esterase inhibition and butyrylcholine esterase result table
Embodiment 3: suppress A beta peptide aggregation activity research
A β (1-42) lyophilized powder of processing through hexafluoroisopropanol (HFIP) is dissolved in DMSO, mother liquid concentration 200 μ M, get in the phosphoric acid buffer PBS (pH=7.4) that joins 40 μ l under A β mother liquor 5 μ l room temperatures and hatch 24 hours, to the testing compound (final concentration 20 μ M) that adds 5 μ l in application of sample group, 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 Ts.Adopt λ exc=435nm, λ em=485nm, calculates every cell mean deducting after thioflavin T fluorescence background.The results are shown in following table 2, the ability that the higher reflection of inhibiting rate suppresses A beta peptide aggregation is stronger.
Table 2, each embodiment compd A beta peptide aggregation inhibiting rate result table
Embodiment 4:
Injection: activeconstituents 1mg
Sodium-chlor 9mg
Preparation method: activeconstituents and sodium-chlor are dissolved in appropriate water for injection, filter gained solution, pack in ampoule under aseptic condition.
Activeconstituents described above 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:
Tablet:
Activeconstituents described above 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, fully mix, add base V-Pyrol RC solution, mix, softwood processed, sieves, and wet granular processed is dry in 50-60 DEG C, by hydroxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, then join compressing tablet in above-mentioned particle.
All the other preparations of the present invention adopt the routine prescription in pharmaceutical formulations field, production method preparation routinely equally.
Claims (14)
1. there is the aminothiazole derivs compound or pharmaceutically acceptable salt thereof of formula I structure,
Wherein
R
1for H, Cl or OCH
3;
M=1,2,3 or 4;
N=3,4,5,6,7 or 8;
R
2for H or Cl.
2. the preparation method of compound claimed in claim 1, comprises the steps:
1) make formula (1) compound and alkyl diamine do at Pentyl alcohol under the condition of solvent nucleophilic substitution reaction occurs, obtain formula (2) compound;
2) make formula (2) compound and monobromethane in DMF, under the catalysis of organic bases or mineral alkali, nucleophilic substitution reaction occurs, obtain formula (3) compound;
3) make formula (4) compound and bromacyl chloride in THF, under the catalysis of organic bases or mineral alkali, react to obtain formula (6) compound;
4) make formula (5) compound and bromacyl chloride in THF, under the catalysis of organic bases or mineral alkali, react to obtain formula (7) compound;
5) make formula (6) compound or formula (7) compound and formula (3) compound in DMF, under the catalysis of organic bases or mineral alkali, nucleophilic substitution reaction occurs, obtain formula (8) compound;
Wherein
M=1,2,3 or 4;
N=3,4,5,6,7 or 8;
R
1for H, Cl or OCH
3;
R
2for H or Cl.
3. preparation method according to claim 2, wherein step 2), 3), 4) and 5) described in organic bases can be triethylamine, diisopropyl ethyl amine, pyridine, 2,6 lutidine or DMAP; Described mineral alkali can be salt of wormwood or sodium carbonate.
4. preparation method according to claim 2, it is characterized in that: the concrete grammar that nucleophilic substitution reaction obtains formula (2) compound that makes formula (1) compound and alkyl diamine do at Pentyl alcohol occurring under the condition of solvent described in step 1) can be: formula (1) compound and alkyl diamine do at Pentyl alcohol under the condition of solvent,, there is nucleophilic substitution reaction and obtain formula (2) compound in 180 DEG C of backflows of temperature control 18 hours.
5. preparation method according to claim 2, it is characterized in that: step 2) described make formula (2) compound and monobromethane under the catalysis of potassiumiodide and organic bases or mineral alkali, at solvent N, the concrete grammar that nucleophilic substitution reaction obtains formula (3) compound occurs in dinethylformamide can be: formula (2) compound of 1 times of equivalent and 1 times of equivalent monobromethane are at the alkali of one times of equivalent, a small amount of potassiumiodide catalysis is at the N of 10mL, normal-temperature reaction 5 hours in dinethylformamide, obtain formula (3) compound through column chromatography purification again, wherein alkali is organic bases or mineral alkali, the condition of column chromatography is sherwood oil: ethyl acetate=1:1.
6. preparation method according to claim 2, it is characterized in that: the concrete grammar that the condensation reaction that makes formula (4) compound and bromacyl chloride that acyl chlorides and amine occur under the catalysis of organic bases or mineral alkali described in step 3) obtains formula (6) compound can be: the formula (4) of 1 times of equivalent and the bromacyl chloride of 1.2 times of equivalents be normal-temperature reaction 12 hours in the tetrahydrofuran (THF) at 20mL at the base catalyzed reactions solvent of 1.5 times of equivalents, obtain formula (6) compound through column chromatography purification again, wherein alkali is organic bases or mineral alkali, the condition of column chromatography is sherwood oil: ethyl acetate=10:1.
7. preparation method according to claim 2, it is characterized in that: the concrete grammar that the condensation reaction that makes formula (5) compound and bromacyl chloride that acyl chlorides and amine occur under the catalysis of organic bases or mineral alkali described in step 4) obtains formula (7) compound can be: the formula (5) of 1 times of equivalent and the bromacyl chloride of 1.2 times of equivalents under the base catalysis of 1.5 times of equivalents in the tetrahydrofuran (THF) of 20mL normal-temperature reaction 12 hours, obtain formula (7) compound through column chromatography purification again, wherein alkali is organic bases or mineral alkali, and the condition of column chromatography is sherwood oil: ethyl acetate=10:1.
8. preparation method according to claim 2, it is characterized in that: described in step 5), make formula (6) compound or formula (7) compound and formula (3) compound under the catalysis of potassiumiodide and organic bases or mineral alkali, the concrete grammar that generation nucleophilic substitution reaction obtains formula (8) compound is: formula (3) compound of formula (6) compound of 1 times of equivalent or formula (7) compound and 1 times of equivalent is at the alkali of one times of equivalent, a small amount of potassiumiodide catalysis is at the N of 10mL, 70 DEG C of reactions of temperature control 2 hours in dinethylformamide, obtain formula (8) compound through column chromatography purification again, wherein alkali is organic bases or mineral alkali, the condition of column chromatography is the sherwood oil of arbitrary proportion, ethyl acetate and triethylamine.
9. according to the preparation method described in any one in claim 5 to 8, it is characterized in that: described organic bases is triethylamine, diisopropyl ethyl amine, pyridine, 2,6 lutidine or DMAP; Described mineral alkali is salt of wormwood or sodium carbonate.
10. a pharmaceutical composition, contains the aminothiazole derivs compound or pharmaceutically acceptable salt thereof with formula I structure claimed in claim 1.
11. a pharmaceutical preparation, is characterized in that, contain the aminothiazole derivs compound or pharmaceutically acceptable salt thereof with formula I structure claimed in claim 1, and pharmaceutically acceptable additive is or/and carrier.
12. pharmaceutical preparations according to claim 11, is characterized in that, its formulation is solid orally ingestible, liquid oral medicine or injection.
The 13. aminothiazole derivs compound or pharmaceutically acceptable salt thereofs with formula I structure claimed in claim 1 for the preparation for the treatment of, improve or application that prevention cognitive function fails in the medicine of relevant nervous system disorders.
14. application according to claim 13, is characterized in that, the described cognitive function relevant nervous system disorders that fails is the dementia that alzheimer's disease, vascular dementia, mild cognitive impairment or other oxidative stresss participate in.
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