CN102807575B - 3-aryl-5-thienyl-5H-thiazolo [3,2-a] pyrimidine derivative and application thereof - Google Patents

3-aryl-5-thienyl-5H-thiazolo [3,2-a] pyrimidine derivative and application thereof Download PDF

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CN102807575B
CN102807575B CN201210281106.4A CN201210281106A CN102807575B CN 102807575 B CN102807575 B CN 102807575B CN 201210281106 A CN201210281106 A CN 201210281106A CN 102807575 B CN102807575 B CN 102807575B
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thienyl
methyl
aryl
thiazole
alkoxy
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CN102807575A (en
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刘斯婕
何敬宇
史兰香
张宝华
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Shijiazhuang University
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Abstract

The invention discloses 3-aryl-5-thienyl-5H-thiazolo [3,2-a] pyrimidine derivative or pharmaceutically acceptable hydrate, and salt therof, including stereomer or tautomer, wherein R1 is independently selected from C1-C6 alkyl and C1-C6 alkoxy; R2 is independently selected from C1-C6 alkyl and C1-C6 alkoxy; R3 can be selected from C1-C10 amino-alkoxy freely selectively substituted by one or two substituent groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, substituted or un-substituted formamyl alkoxy, and hydroxyl and halogen substituent group, and R4 is independently selected from hydrogen, C1-C6 alkyl, ethanoyl and halogen. The 3-aryl-5-thienyl-5H-thiazolo [3,2-a] pyrimidine derivative based on the invention has an obvious inbibitional effect on acetylcholinesterase. Therefore, the 3-aryl-5-thienyl-5H-thiazolo [3,2-a] pyrimidine derivative is used for enhancing memory of patients suffering from dementia and alzheimer's disease.

Description

Also [3,2-a] pyridine derivatives and the application thereof of 3-aryl-5-thienyl-5H-thiazole
Technical field
The invention belongs to medical art, relate to 3-aryl-5-thienyl-5 h-thiazole also [3,2-a] pyridine derivatives and preparation method thereof with as acetylcholinesteraseinhibitors inhibitors, for improving the application suffered from dull-witted and Alzheimer’s disease patient and remember.
Background technology
Alzheimer’s disease is relevant with the degeneration of the cholinergic neuron [it plays an important role in recognition function (comprising memory)] in basal forebrain.Due to the result of described degeneration, the patient suffering from this disease shows obvious decay in acetylcholine synthesis, choline acetyltransferase activity, acetylcholine esterase active and choline absorption.
Known acetylcholinesteraseinhibitors inhibitors is effective in raising cholinergic activity, therefore can be used for the memory improving person with Alzheimer's disease.By acetylcholine esterase inhibition, described compound can improve the level of neurotransmission transmitter acetylcholine in brain, therefore can hypermnesis.
Existing acetylcholinesteraseinhibitors inhibitors is as tacrine, and this bright, galantamine etc., still exist drug resistance or pharmacokinetic deficits.Compound of the present invention, as the acetylcholinesteraseinhibitors inhibitors 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 a kind of 3-aryl-5-thienyl-5 h-thiazole is [3,2-a] pyridine derivatives also, and it has good inhibiting activity of acetylcholinesterase.
Another object of the present invention is to provide above-mentioned 3-aryl-5-thienyl-5 hthe preparation method of-thiazole also [3,2-a] pyridine derivatives.
Another object of the present invention is to provide above-mentioned 3-aryl-5-thienyl-5 hthe purposes of-thiazole also [3,2-a] pyridine derivatives.
Below describe the present invention.
The invention provides the 3-aryl-5-thienyl-5 of following general formula I h-thiazole is [3,2-a] pyridine derivatives or the acceptable salt of its pharmacy also.Structure is shown in Fig. 1:
Wherein, R 1independently be selected from C 1-C 6alkyl and C 1-C 6alkoxyl; R 2independently be selected from C 1-C 6alkyl and C 1-C 6alkoxyl; R 3can select arbitrarily to be independently selected from C by 1 or 2 1-C 6alkyl, C 1-C 6alkoxyl, C 1-C 10the substituent group of any aminoalkoxy, substituted or non-substituted carbamoyl alkoxyl, hydroxyl and the halogen of selecting to replace replaces; R 4independently be selected from hydrogen, C 1-C 6alkyl, acetyl group and halogen.
" pharmaceutically acceptable salt " refers to the biopotency and the character that remain type I compound, and with the acid of suitable non-toxic organic or inorganic or the conventional acid addition salts that formed of organic or inorganic alkali or base addition salts.The example of acid-addition salts comprises acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, citrate, camphorate, camsilate, cipionate, digluconate, lauryl sulfate, esilate, fumarate, gluceptate, glycerophosphate, Hemisulphate, enanthate, caproate, hydrogen chlorate, hydrobromate, hydriodate, 2-isethionate, lactate, maleate, mesylate, 2-naphthalene sulfonate, nicotinate, nitrate, oxalates, pamoate, pectinic acid salt, persulfate, 3-phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, sulfate, tartrate, rhodanate, toluene fulfonate and undecylate.Alkali salt comprises ammonium salt, alkali metal salt, such as sodium and potassium salt, alkali salt, such as calcium and magnesium salt, the salt of organic base, such as hexanamine salt, N-methyl-D-glucamine salt, and amino acid whose salt, such as arginine, lysine etc., and, Basic nitrogen-containing groups can be quaternized with such reagent, and such as elementary alkyl halide, as methyl, ethyl, the chlorine of propyl group and butyl, bromine and iodide; Dialkyl sulfate, as dimethyl sulfate, diethylester, dibutyl ester and diamyl ester; Long chain halide, as decyl, lauryl, the chlorine of myristyl and stearyl, bromine and iodide; Aralkyl halide, as the bromide etc. of benzyl and phenethyl.The acid being preferred for generating acid-addition salts comprises hydrochloric acid and acetic acid.
" pharmaceutically acceptable ", as pharmaceutically acceptable ground carrier, excipient, prodrug etc., refers to pharmacologically acceptable and to the essentially no toxicity of the patient of administration particular compound.
Present invention also offers the preparation method of above-mentioned compound of Formula I, the method is shown in Fig. 2.
The invention still further relates to the method suppressing acetylcholinesterase in mammal, the method comprises takes the formula I compound of acetylcholine esterase inhibition effective dose or its stereoisomer or its acid-addition salts be pharmaceutically suitable for mammal.
The present invention also relates to the method for formula I hypermnesis or treatment or prevention Alzheimer’s disease, the method comprises the formula I compound or its stereoisomer or its acid-addition salts be pharmaceutically suitable for of taking hypermnesis or treatment or prevention Alzheimer’s disease effective dose.
Accompanying drawing explanation
Fig. 1 is 3-aryl-5-thienyl-5 hthe general structure figure of-thiazole also [3,2-a] pyridine derivatives;
Fig. 2 is 3-aryl-5-thienyl-5 hthe synthetic route chart of-thiazole also [3,2-a] pyridine derivatives;
Fig. 3 is the processing method figure of sample in inhibiting activity of acetylcholinesterase, determination test;
Fig. 4 is the result figure of sample segment acetylcholine ester enzyme inhibition rate.
Illustrate the present invention further by following examples, but scope of the present invention should be noted not by any restriction of these embodiments.
Specific embodiment
Embodiment 1
The preparation of 6-methyl-5-acetyl group-4-thienyl-2-thiopyrimidine
In the round-bottomed flask of 250 ml, add thiophenecarboxaldehyde 0.1 mol, thiourea 0.1 mol, acetylacetone,2,4-pentanedione 0.11 mol, ethanol 30 ml, concentrated hydrochloric acid 2, stir, 60 DEG C of reaction 10 h.Cooling, sucking filtration, filter cake dehydrated alcohol recrystallization, obtains yellow crystals 20.4 grams, yield 80.9%.MS m/z (M) 252。
Embodiment 2
The preparation of 6-methyl-4-thienyl-2-thiopyrimidine-5-carboxylic acid, ethyl ester
In the round-bottomed flask of 250 ml, add thiophenecarboxaldehyde 0.1 mol, thiourea 0.1 mol, acetylacetone,2,4-pentanedione 0.11 mol, ethanol 30 ml, concentrated hydrochloric acid 2, stir, 60 DEG C of reaction 10 h.Cooling, sucking filtration, filter cake dehydrated alcohol recrystallization, obtains yellow crystals 24.6 grams, yield 87.2%.MS m/z (M) 282。
Embodiment 3
7-methyl-5-thienyl-3-(4-hydroxy phenyl)-5 hthe preparation of-thiazole also [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester
By 6-methyl-4-thienyl-2-thiopyrimidine-5-carboxylic acid, ethyl ester 2.82 g (10 mmol), 4-hydroxyl chloroacetophenone 1.71 g (10 mmol), sodium acetate/glacial acetic acid (2 g/20 mL), heating reflux reaction 8-24 hour, TLC monitor reaction.After cooling, sucking filtration, dehydrated alcohol recrystallization, obtains 2.07 g white powders, yield 54 %.MS: 396； 1H-NMR(300MHz, DMSO)δ(ppm): 1.14(3H, t), 2.49(3H, s), 4.11(2H, q), 5.61(1H, d), 6.29(1H, s), 6.41(1H, d) 6.93(2H, d, J=8.4Hz), 7.28(2H, d, J=8.4Hz), 7.31(1H, d), 7.84(1H, d), 10.17(1H, s)。
Embodiment 4
7-methyl-5-thienyl-3-(4-chlorphenyl)-5 hthe preparation of-thiazole also [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester
By 6-methyl-4-thienyl-2-thiopyrimidine-5-carboxylic acid, ethyl ester 2.82 g (10 mmol), 4-chlorine chloroacetophenone 1.89 g (10 mmol), sodium acetate/glacial acetic acid (2 g/20 mL), heating reflux reaction 8-24 hour, TLC monitor reaction.After cooling, sucking filtration, dehydrated alcohol recrystallization, obtains 2.19 g white powders, yield 52.9 %.MS: 414； 1H-NMR(300MHz, DMSO)δ(ppm): 1.14(3H, t), 2.49(3H, s), 4.11(2H, q), 5.61(1H, d), 6.29(1H, s), 6.41(1H, d), 7.31(1H, d), 7.64(2H, d, J=8.7Hz), 7.68(2H, d, J=8.7Hz)，7.84(1H, d)。
Embodiment 5
7-methyl-5-thienyl-3-(4-aminomethyl phenyl)-5 hthe preparation of-thiazole also [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester
By 6-methyl-4-thienyl-2-thiopyrimidine-5-carboxylic acid, ethyl ester 2.82 g (10 mmol), 4-methyl chloroacetophenone 1.78 g (10 mmol), sodium acetate/glacial acetic acid (2 g/20 mL), heating reflux reaction 8-24 hour, TLC monitor reaction.After cooling, sucking filtration, dehydrated alcohol recrystallization, obtains 2.32 g white powders, yield 58.9 %.MS: 394； 1H-NMR(300MHz, DMSO)δ(ppm): 1.14(3H, t), 2.49(3H, s), 4.11(2H, q), 5.61(1H, d), 6.29(1H, s), 6.41(1H, d), 6.73(2H, d, J=8.7)，7.15(2H, d, J=8.7)，7.31(1H, d), 7.84(1H, d)。
Embodiment 6
7-methyl-3-[4-(2-dimethylamino) ethoxyl phenenyl]-5-thienyl-5 hthe preparation of-thiazole also [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester
By 7-methyl-5-thienyl-3-(4-hydroxy phenyl)-5 h-thiazole is [3,2-a] pyrimidine-6-carboxylic acid, ethyl ester 0.39 g(1 mmol also), 2-chloroethyl dimethylamino hydrochlorate 0.14 g(1 mmol) be first dissolved in dehydrated alcohol, add potassium iodide 0.22 g again, potassium carbonate 2.76 g, reflux 8 h, after stopped reaction, be cooled to room temperature.Sucking filtration removing potassium iodide and potassium carbonate, revolved by solvent and steam removing, obtain red solid, dehydrated alcohol recrystallization obtains white needle-like crystals 0.31 g, yield 72.8 %.MS:467。 1H-NMR(300MHz, DMSO)δ(ppm): 1.14(3H, t), 2.23(6H, s)，2.49(3H, s), 2.65(2H, m)，3.96(2H, q)，4.11(2H, q), 5.61(1H, d), 6.29(1H, s), 6.41(1H, d)，6.93(2H, d, J=8.4Hz), 7.28(2H, d, J=8.4Hz), 7.31(1H, d), 7.84(1H, d)。
Embodiment 7
6-acetyl group-7-methyl-3-(4-hydroxy phenyl)-5-thienyl-5 hthe preparation of-thiazole also [3,2-a] pyrimidine
By 6-methyl-5-acetyl group-4-thienyl-2-thiopyrimidine 2.52 g (10 mmol); 4-hydroxyl chloroacetophenone 1.89 g (10 mmol); sodium acetate/glacial acetic acid (2 g/20 mL), heating reflux reaction 8-24 hour, TLC monitor reaction.After cooling, sucking filtration, dehydrated alcohol recrystallization, obtains 2.57 g white powders, yield 70.2 %.MS: 366； 1H-NMR(300MHz, DMSO)δ(ppm): 2.22(3H, t), 2.48(3H, s), 5.61(1H, d), 6.29(1H, s), 6.41(1H, d), 6.73(2H, d, J=8.7)，7.15(2H, d, J=8.7)，7.31(1H, d), 7.84(1H, d)，10.15(1H, s)。
Embodiment 8
6-acetyl group-7-methyl-3-(4-chlorphenyl)-5-thienyl-5 hthe preparation of-thiazole also [3,2-a] pyrimidine
By 6-methyl-5-acetyl group-4-thienyl-2-thiopyrimidine 2.52 g (10 mmol); 4-chlorine chloroacetophenone 1.89 g (10 mmol); sodium acetate/glacial acetic acid (2 g/20 mL), heating reflux reaction 8-24 hour, TLC monitor reaction.After cooling, sucking filtration, dehydrated alcohol recrystallization, obtains 2.57 g white powders, yield 70.2 %.MS: 384； 1H-NMR(300MHz, DMSO)δ(ppm): 2.22(3H, s), 2.49(3H, s), 5.61(1H, d), 6.29(1H, s), 6.41(1H, d), 7.31(1H, d), 7.64(2H, d, J=8.7Hz), 7.68(2H, d, J=8.7Hz)，7.84(1H, d)。
Embodiment 9
6-acetyl group-7-methyl-3-(4-aminomethyl phenyl)-5-thienyl-5 hthe preparation of-thiazole also [3,2-a] pyrimidine
By 6-methyl-5-acetyl group-4-thienyl-2-thiopyrimidine 2.52 g (10 mmol); 4-methyl chloroacetophenone 1.78 g (10 mmol); sodium acetate/glacial acetic acid (2 g/20 mL), heating reflux reaction 8-24 hour, TLC monitor reaction.After cooling, sucking filtration, dehydrated alcohol recrystallization, obtains 2.43 g white powders, yield 66.7%.MS: 364； 1H-NMR(300MHz, DMSO)δ(ppm): 2.22(3H, s), 2.49(3H, s), 5.61(1H, d), 6.29(1H, s), 6.41(1H, d), 6.73(2H, d, J=8.7)，7.15(2H, d, J=8.7)，7.31(1H, d), 7.84(1H, d)。
Embodiment 10
6-acetyl group-7-methyl-3-[4-(2-dimethylamino) ethoxyl phenenyl]-5-thienyl-5 hthe preparation of-thiazole also [3,2-a] pyrimidine
6-acetyl group-7-methyl-3-(4-hydroxy phenyl)-5-thienyl-5 h-thiazole is [3,2-a] pyrimidine 0.36 g(1 mmol also), 2-chloroethyl dimethylamino hydrochlorate 0.14 g(1 mmol) be first dissolved in dehydrated alcohol, add potassium iodide 0.22 g again, potassium carbonate 2.76 g, reflux 8 h, after stopped reaction, be cooled to room temperature.Sucking filtration removing potassium iodide and potassium carbonate, revolved by solvent and steam removing, obtain red solid, dehydrated alcohol recrystallization obtains white needle-like crystals 0.38 g, yield 86.9 %.MS:437。 1H-NMR(300MHz, DMSO)δ(ppm): 2.22(3H, s), 2.23(6H, s)，2.49(3H, s), 2.65(2H, m)，4.11(2H, q), 5.61(1H, d), 6.29(1H, s), 6.41(1H, d)，6.93(2H, d, J=8.4Hz), 7.28(2H, d, J=8.4Hz), 7.31(1H, d), 7.84(1H, d)。
Embodiment 11
The active determination test of acetylcholinesteraseinhibitors inhibitors
Materials and methods:
The preparation of test sample: positive control drug is set as hydrobromic acid neostigmine (SigmaN-2001), is formulated as 0.1M solution;
Acetylcholinesterase (people source) (SigmaC-1682) 0.5 unit;
Buffer solution is 100mM PBS solution (pH7.4), 10mM bis-sulfur dinitrobenzoic acid DTNB(D-8130) (with 100mM PBS preparation) ,-20 DEG C keep in Dark Place, now-making-now-using;
12.5mM acetylthiocholine ATCh(A-5751) be dissolved in the water ,-20 DEG C keep in Dark Place, now-making-now-using;
Test medicine DMSO is prepared into 10 μMs of solution after dissolving.
Method and result:
1. processing sample (see figure 3) as follows;
2. 37 DEG C of continuously jolting preheatings 15 minutes gently;
3. add 50mL ATCh and 50mL DTNB;
4. 37 DEG C of continuously joltings about 20 minutes gently, until reactant liquor occurs yellow;
5. measure the OD value at its 412nm place;
6. calculate suppression ratio, sample segment suppression ratio (see figure 4) as shown below.

Claims (3)

1. an acetylcholine enzyme inhibitor or the acceptable salt of its pharmacy; comprise 7-methyl-3-[4-(2-dimethylamino) ethoxyl phenenyl]-5-thienyl-5H-thiazole also [3; 2-a] pyrimidine-6-carboxylic acid, ethyl ester, 6-acetyl group-7-methyl-3-(4-hydroxy phenyl)-5-thienyl-5H-thiazole also [3; 2-a] pyrimidine or 6-acetyl group-7-methyl-3-(4-chlorphenyl)-5-thienyl-5H-thiazole also [3,2-a] pyrimidine.
2. a pharmaceutical composition, is characterized in that: it comprises any one compound and medicine acceptable carrier or excipient in the claim 1 as active component.
3. the application of compound described in claim 1 in preparation treatment degenerative dementia disease drug.
CN201210281106.4A 2012-08-09 2012-08-09 3-aryl-5-thienyl-5H-thiazolo [3,2-a] pyrimidine derivative and application thereof Expired - Fee Related CN102807575B (en)

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CN103044460B (en) * 2013-01-30 2015-02-25 石家庄学院 3,5,7-triphenyl-5H-thiazolo[3,2-a]pyrimidin derivatives and application thereof
CN104844628B (en) * 2015-04-16 2017-01-18 石家庄学院 2H,6H-pyrimido[2,1-b][1,3]thiazine derivative and application thereof
CN104892640B (en) * 2015-05-28 2017-06-23 石家庄学院 Simultaneously [3,2 b] [1,2,4] triazole derivative and the application of the benzoyl thiazole of 2 phenyl 6
CN104926838B (en) * 2015-05-31 2017-04-12 石家庄学院 5H-[1, 2, 4] triazole [5, 1-b] [1, 3] thiazide derivative and application
CN104945415B (en) * 2015-06-17 2017-05-17 石家庄学院 7H-benzo-isoxazole-[7,6-e][1,3]oxazine derivatives and application

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