CN102796121B - 3-aryl-7H-thiazol[3,2-b]-1,2,4-triazinyl-7-one derivatives and application thereof - Google Patents
3-aryl-7H-thiazol[3,2-b]-1,2,4-triazinyl-7-one derivatives and application thereof Download PDFInfo
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Abstract
The invention discloses 3-aryl-7H-thiazol[3,2-b]-1,2,4-triazinyl-7-one derivatives and application thereof, particularly 3-aryl-7H-thiazol[3,2-b]-1,2,4-triazinyl-7-one derivatives disclosed as general formula I or pharmaceutically acceptable hydrates and salts thereof, and application in enhancing memory of patients with dementia and Alzheimer's disease. In the general formula I, R1 and R2 are respectively and randomly one or two or three of H, halogens, hydroxy group, methoxy group, methyl group, nitro-group, -O(CH2)n1NR3R4 and -O(CH2)n2CONR5R6; R3, R4, R5 and R6 are respectively selected from methyl group, ethyl group, pyrrolidinyl group formed by the methyl or ethyl group and nitrogen atom connected with the methyl or ethyl, methylpyrrolidinyl group, dimethylpyrrolidinyl group, piperidyl group, morpholinyl group or hexamethylene imino group ring; n1 is a whole number ranging from 2 to 6; n2 is a whole number ranging from 1 to 6; and X is O or S.
Description
Technical field
The invention belongs to medical technical field, relate to also [3,2-b]-1,2 of 3-aryl-7H-thiazole, 4-triazine-7-ketones derivant and preparation method thereof with as acetylcholinesterase depressant, for improving, suffer from application dull-witted and that Alzheimer's patient remembers.
Background technology
Alzheimer's is relevant with the degeneration of cholinergic neuron [it plays an important role in recognition function (comprising memory)] in basal forebrain.Due to the result of described degeneration, the patient who suffers from this disease is synthetic at vagusstoff, show obvious decay aspect choline acetyltransferase activity, acetylcholine esterase active and choline absorption.
Known acetylcholinesterase depressant, being effectively aspect raising cholinergic activity, therefore can be used for improving person with Alzheimer's disease's memory.By acetylcholine esterase inhibition, described compound can improve the level of neurotransmission mediator vagusstoff in brain, therefore can hypermnesis.
Existing acetylcholinesterase depressant is as tacrine, this bright, and, still there is resistance or pharmacokinetics defect in lycoremines etc.Compound of the present invention, as the acetylcholinesterase depressant of brand new type, has structure type novelty, and drug action and existing medicine quite or be better than the feature of existing medicine, have good using value and development prospect.
Summary of the invention
The object of the present invention is to provide also [3,2-b]-1,2 of a kind of 3-aryl-7H-thiazole, 4-triazine-7-ketones derivant, it has good inhibiting activity of acetylcholinesterase.
A further object of the present invention is to provide also [3,2-b]-1,2 of above-mentioned 3-aryl-7H-thiazole, the purposes of 4-triazine-7-ketones derivant.
Below describe the present invention.
3-aryl-7H-the thiazole that the invention provides following general formula I is [3,2-b]-1,2 also, 4-triazine-7-ketones derivant or its pharmacologically acceptable salts.The following (see figure 1) of structure:
Wherein
R
1can be arbitrarily selectively by 1,2 or 3 are independently selected from H, halogen ,-OH ,-OCH
3,-CH
3,-NO
2,-O (CH
2) n
1nR
3r
4,-O (CH
2) n
2cONR
5r
6;
R
2can be arbitrarily selectively by 1,2 or 3 are independently selected from H, halogen ,-OH ,-OCH
3,-CH
3,-NO
2,-O (CH
2) n
1nR
3r
4,-O (CH
2) n
2cONR
5r
6;
X=is O, S etc.;
R
3r
4independently be selected from methyl or ethyl, or R
3r
4together with the nitrogen-atoms connected with them, form pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, or hexamethylene imine basic ring;
N
1it is 2 to 6 integer;
R
5r
6independently be selected from methyl or ethyl, or R
5r
6together with the nitrogen-atoms connected with them, form pyrrolidyl, methylpyrrole alkyl, alkyl dimethyl pyrrole, piperidyl, morpholinyl, or hexamethylene imine basic ring; Or be independently selected from respectively hydrogen and replacement or unsubstituted phenyl ring group;
N
2it is 1 to 6 integer.
" pharmacy acceptable salt " referred to retain biopotency and the character of formula I compound, and the conventional acid additive salt or the base addition salt that form with suitable non-toxicity organic or inorganic acid or organic or inorganic alkali.The example of acid salt comprises acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, Citrate trianion, camphorate, camsilate, cipionate, digluconate, dodecyl sulfate, esilate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, hexanoate, hydrogen chlorate, hydrobromate, hydriodate, 2-isethionate, lactic acid salt, maleate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinic acid salt, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, vitriol, tartrate, thiocyanate-, tosylate and undecylate.Alkali salt comprises ammonium salt, an alkali metal salt, for example sodium and sylvite, alkaline earth salt, for example calcium and magnesium salts, the salt of organic bases, dicyclohexyl amine salt for example, N-methyl-D-glucamine salt, and amino acid whose salt, arginine for example, Methionin etc., and, alkalescence nitrogen-containing group can be quaternized with such reagent, and elementary alkyl halide for example, as methyl, ethyl, the chlorine of propyl group and butyl, bromine and iodide; Sulfuric acid dialkyl, as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; Long-chain halogenide, as decyl, lauryl, the chlorine of myristyl and stearyl-, bromine and iodide; Aralkyl halide, as bromide of benzyl and styroyl etc.The acid that is preferred for generating acid salt comprises hydrochloric acid and acetic acid.
" pharmaceutically acceptable " as pharmaceutically acceptable ground carrier, excipient, prodrug etc., refers to acceptable on pharmacology and to the essentially no toxicity of the patient of administration particular compound.
The present invention also provides the preparation method of above-mentioned compound of Formula I, and the method comprises (see figure 2).
The invention still further relates to the method that suppresses acetylcholinesterase in Mammals, the method comprises to Mammals takes pharmaceutically applicable acid salt of the formula I compound of acetylcholine esterase inhibition effective dose or its steric isomer or its.
The present invention also relates to the method for formula I hypermnesis or treatment or prevention Alzheimer's, the method comprises takes pharmaceutically applicable acid salt of the formula I compound of hypermnesis or treatment or prevention Alzheimer's effective dose or its steric isomer or its.
The compounds of this invention can be taken to patient by diverse ways, for example oral with capsule or tablet, with sterile solution agent or suspensoid administration, and in some cases, can be with the intravenous injection of solution form.Can by free alkali compound of the present invention with its pharmaceutically applicable acid salt form prepare and take.
For general adult, the dosage of the compounds of this invention every day is generally about 1-300 mg/kg, and can or divide equally dosed administration by single dose.For administration, if take solution or suspensoid, the concentration of the compounds of this invention is at least 1% (weight) so, with 4-70% (weight) gross weight of unit (take as basis) better.The non-dose unit through gastrointestinal administration is generally containing having an appointment 5-100 milligram active compound.
The compounds of this invention can be together with inert diluent or edible carrier oral administration, or they can be encapsulated in gelatine capsule, or are pressed into tablet.Described preparation should contain at least 0.5% active compound, but according to concrete formulation, and concentration can change, and can be 4-70% (weight) gross weight of unit (take be basis).Oral dosage units generally contains 1.0 milligrams of-300 milligrams of active compounds.
For pharmacology action, formula I compound is preferably with the form administration of its medicinal acid addition salt.Certainly the effective dose of compound will change according to the effect of each compound used, the seriousness that treat disease and character, the particular patient that will treat.Generally, the dosage with about 0.01mg to about 20mg/kg body weight/day, system of compounds administration can obtain effective result.Should be with compared with low dosage begin treatment.Subsequently can solid dosage as capsule, tablet or pulvis, or with liquid form as solution or suspension oral administration.These compounds can also sterile solution or the form of suspension through intestines, inject outward.
Accompanying drawing explanation
Fig. 1 is also [3,2-b]-1,2 of 3-aryl-7H-thiazole, the general structure figure of 4-triazine-7-ketones derivant;
Fig. 2 is also [3,2-b]-1,2 of 3-aryl-7H-thiazole, the synthetic route chart of 4-triazine-7-ketones derivant;
Fig. 3 is the treatment process figure of sample in inhibiting activity of acetylcholinesterase, determination test;
Fig. 4 is the result figure of sample segment acetylcholinesterase inhibiting rate.
By following examples, further illustrate the present invention, but should notice that scope of the present invention is not subject to any restriction of these embodiment.
Specific embodiment
Embodiment 1
The preparation of 2-methyl-4-methylene radical thiophene oxazolone
By 2 thiophene carboxaldehyde 0.1mol, acetyl glycine 0.12mol, 50 grams of sodium acetate, anhydrous 0.12mol and aceticanhydrides join in 100 three-necked bottles successively, reflux stirring reaction 5 hours, be chilled to after room temperature, solution becomes solid, suction filtration, filter cake cold water washing, with acetone recrystallization, obtain 19.3 grams, required product yellow crystal powder, yield 100%, MS m/z (M) 193.
Embodiment 2
The acrylic acid preparation of alpha-acetamido--β-thiophene
By 2-methyl-4-methylene radical thiophene oxazolone compounds 0.1mol, water 100mL, acetone 80mL joins in 100mL round-bottomed flask successively, reflux stirring reaction 3 hours, cool to room temperature, separate out a large amount of yellow solids, suction filtration, cold water and a small amount of acetone rinsing for filter cake, with acetone recrystallization, obtain 20.3 grams of required product yellow crystals, yield 96.2, MS m/z (M) 211.
Embodiment 3
The preparation of β-thienyl pyruvic acid
By alpha-acetamido--β-thiophene vinylformic acid 0.1mol, the HCl solution 60mL of 1mol/L, joins in 100mL round-bottomed flask successively, heating reflux reaction 1 hour, stopped reaction, filtered while hot, has solid to separate out in filtrate, cooling, suction filtration, dehydrated alcohol recrystallization, obtains 15.5 grams of needed product red crystals, yield 91.2%, MS m/z (M) 170.
Embodiment 4
6-(2-thenyl)-3-sulfo--(2H, 4H)-1,2, the preparation of 4-triazine-5-ketone
By β-thienyl pyruvic acid 0.1mol, thiosemicarbazide 0.1mol, ethanol 30mL, water 30mL joins in 250mL round-bottomed flask successively, stirs, and heating reflux reaction is after 8 hours, cool to room temperature, underpressure distillation boils off solvent, obtains a large amount of Off-white solid, suction filtration, dry, with ethyl alcohol recrystallization, obtain 19.7 grams of desired product white crystals, yield 87.6%, MS m/z (M) 225.
Embodiment 5
6-(2-thenyl)-3-(4-hydroxy phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
In the 15mL glacial acetic acid solution of 0.05mol sodium-acetate, add 6-(2-thenyl)-3-sulfo--(2H, 4H)-1,2,4-triazine-5-ketone 0.01mol and 4 '-hydroxyl-alpha-chloroacetophenone 0.01mol, stirring at room 30 minutes, slowly be warming up to the rear reaction 2 hours that continues that refluxes, TLC monitors reaction process, is cooled to after completion of the reaction room temperature, reaction solution is concentrated into dry, add the saturated common salt aqueous solution, under room temperature, stir 30 minutes, and be extracted with ethyl acetate.Organic layer drying obtains thick product with concentrated, and ethyl alcohol recrystallization, obtains 2.0 grams of required product yellow crystals, yield 58.9%, MS m/z (M) 341;
1hNMR (CDCl
3): δ 4.0 (2H, s), 6.61 (1H, s), 6.72 (2H, d, J=8.7Hz), 6.84 (1H, d), 6.96 (1H, m), 7.20 (2H, d, J=8.7Hz), 7.28 (1H, s), 7.42 (1H, d).
Embodiment 6
6-(2-thenyl)-3-(4-aminomethyl phenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
In the 15mL glacial acetic acid solution of 0.05mol sodium-acetate, add 6-(2-thenyl)-3-sulfo--(2H, 4H)-1,2,4-triazine-5-ketone 0.01mol and 4 '-hydroxyl-alpha-chloroacetophenone 0.01mol, stirring at room 30 minutes, slowly be warming up to the rear reaction 2 hours that continues that refluxes, TLC monitors reaction process, is cooled to after completion of the reaction room temperature, reaction solution is concentrated into dry, add the saturated common salt aqueous solution, under room temperature, stir 30 minutes, and be extracted with ethyl acetate.Organic layer drying obtains thick product with concentrated, and ethyl alcohol recrystallization, obtains 2.17 grams of required products, yield 64.1%, MS m/z (M) 339;
1hNMR (DMSO): δ 2.3 (3H, s), 4.0 (2H, s), 6.51 (H, s), 6.65 (2H, d, J=8.4Hz), 6.84 (1H, d), 6.96 (1H, m), 6.95 (2H, d, J=8.4Hz), 7.42 (1H, d).
Embodiment 7
6-(2-thenyl)-3-(4-chloro-phenyl-)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
In the 15mL glacial acetic acid solution of 0.05mol sodium-acetate, add 6-(2-thenyl)-3-sulfo--(2H, 4H)-1,2,4-triazine-5-ketone 0.01mol and 4 '-hydroxyl-alpha-chloroacetophenone 0.01mol, stirring at room 30 minutes, slowly be warming up to the rear reaction 2 hours that continues that refluxes, TLC monitors reaction process, is cooled to after completion of the reaction room temperature, reaction solution is concentrated into dry, add the saturated common salt aqueous solution, under room temperature, stir 30 minutes, and be extracted with ethyl acetate.Organic layer drying obtains thick product with concentrated, and ethyl alcohol recrystallization, obtains 2.29 grams of required products, yield 63.8%, MS m/z (M) 359;
1hNMR (DMSO): δ 4.0 (2H, s), 6.65 (1H, s), 6.84 (1H, d), 6.96 (1H, m), 7.20 (2H, d, J=8.7Hz), 7.28 (1H, s), 7.29 (2H, d, J=8.7Hz), 7.42 (1H, d).
Embodiment 8
6-(2-thenyl)-3-(4-bromophenyl)-7H-thiazole is [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
In the 15mL glacial acetic acid solution of 0.05mol sodium-acetate, add 6-(2-thenyl)-3-sulfo--(2H, 4H)-1,2,4-triazine-5-ketone 0.01mol and 4 '-hydroxyl-alpha-chloroacetophenone 0.01mol, stirring at room 30 minutes, slowly be warming up to the rear reaction 2 hours that continues that refluxes, TLC monitors reaction process, is cooled to after completion of the reaction room temperature, reaction solution is concentrated into dry, add the saturated common salt aqueous solution, under room temperature, stir 30 minutes, and be extracted with ethyl acetate.Organic layer drying obtains thick product with concentrated, and ethyl alcohol recrystallization, obtains 2.56 grams of required products, yield 63.5%, MS m/z (M) 403;
1hNMR (DMSO): δ 4.0 (2H, s), 6.65 (1H, s), 6.84 (1H, d), 6.96 (1H, m), 7.19 (2H, d, J=8.6Hz), 7.28 (1H, s), 7.29 (2H, d, J=8.6Hz), 7.42 (1H, d).
Embodiment 9
6-(2-thenyl)-3-{4-[2-(piperidino) oxyethyl group] phenyl }-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
Under stirring at room condition, to 1mmol 6-(2-thenyl)-3-(4-hydroxy phenyl)-7H-thiazole also [3,2-b]-1,2, in the acetone or alcohol solution of 4-triazine-7-ketone, add corresponding 1mmol chloroethyl piperidine hydrochlorate, and add after 1 mmol acid binding agent (Anhydrous potassium carbonate or triethylamine) and 0.1 mmol potassium iodide catalyst, back flow reaction, TLC follows the tracks of reaction process, after question response, be cooled to room temperature, reaction solution is concentrated into dry, adds saturated aqueous common salt 30mL, extracted with diethyl ether.Organic layer drying obtains thick product with concentrated, and ethyl alcohol recrystallization, obtains 0.24 gram of required product, yield 51.3%.MS?m/z?(M)?452；
1HNMR(CDCl
3)：δ1.50(6H，m)，2.24(4H，m)，2.78(2H，t)，3.8(2H，s)，4.04(2H，t)，6.65?(1H，s)，6.72(2H，d,?J=8.7Hz)，6.84(1H，d)，6.96(1H，m)，7.20(2H，d，J=8.7Hz)?，7.42(1H，d)。
Embodiment 10
6-(2-thenyl)-3-[4-(2-diethylin oxyethyl group) phenyl]-7H-thiazole [3,2-b]-1,2 also, the preparation of 4-triazine-7-ketone
Under stirring at room condition, to 1mmol 6-(2-thenyl)-3-(4-hydroxy phenyl)-7H-thiazole also [3,2-b]-1,2, in the acetone or alcohol solution of 4-triazine-7-ketone, add corresponding 1mmol chloroethyl diethylamine hydrochloride, and add after 1 mmol acid binding agent (Anhydrous potassium carbonate or triethylamine) and 0.1 mmol potassium iodide catalyst, back flow reaction, TLC follows the tracks of reaction process, after question response, be cooled to room temperature, reaction solution is concentrated into dry, adds 30 milliliters of saturated aqueous common salts, extracted with diethyl ether.Organic layer drying obtains thick product with concentrated, and ethyl alcohol recrystallization, obtains 0.22 gram of required product, yield 50.0%.MS?m/z?(M)?440；
1HNMR(CDCl
3)：δ1.2(6H，t)，2.4(4H，q)，2.78(2H，t)，4.0(2H，s)，4.04(2H，t)，6.6?(1H，s)，6.72(2H，d,?J=8.7Hz)，6.84(1H，d)，6.96(1H，m)，7.20(2H，d，J=8.7Hz)，7.42(1H，d)。
Embodiment 11
The active determination test of acetylcholinesterase depressant
Materials and methods:
The preparation of test sample: positive control drug is set as Hydrogen bromide prostigmin(e) (SigmaN-2001), is formulated as 0.1M solution;
Acetylcholinesterase (people source) is 0.5 unit (SigmaC-1682);
Buffered soln is 100mM PBS solution (pH7.4), 10mM bis-sulphur dinitrobenzoic acid DTNB(D-8130) (with 100mM PBS preparation) ,-20 ℃ keep in Dark Place, now-making-now-using;
12.5mM acetylthiocholine ATCh(A-5751) be dissolved in the water ,-20 ℃ keep in Dark Place, now-making-now-using;
Tested medicine is prepared into 10 μ M solution after dissolving with DMSO.
Method and result:
1. processing sample (see figure 3) as follows;
2. 37 ℃ of jolting preheatings 15 minutes gently continuously;
3. add 50mL ATCh and 50mL DTNB;
4. 37 ℃ of joltings approximately 20 minutes gently continuously, until that reaction solution occurs is yellow;
5. measure the OD value at its 412nm place;
6. calculate inhibiting rate, sample segment inhibiting rate (see figure 4).
Claims (1)
1. a medical compounds, is characterized in that: its general structure is suc as formula shown in I:
Its concrete structure is expressed as:
A, 6-(2-thenyl)-3-[3-methyl-4-(4-morpholinyl) ethoxyl phenenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone, or,
B, 6-(2-thenyl)-3-[3-methyl-4-(piperidino) ethoxyl phenenyl]-7H-thiazole [3,2-b]-1,2 also, 4-triazine-7-ketone.
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| Title |
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| 刘斯婕，等.新型乙酰胆碱酯酶抑制剂7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成与生物活性.《中国药物化学杂志》.2009,第19卷(第4期),251-256. * |
| 金辄,等.3-(氨基烷氧基芳基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成与乙酰胆碱酯酶抑制活性.《沈阳药科大学学报》.2012,第29卷(第6期),416-422. * |
| 金辄，等.乙酰胆碱酯酶抑制剂3,6-二芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类化合物的设计、合成与生物活性.《中国药物化学杂志》.2011,第21卷(第1期),25-31. * |
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