技术领域technical field
本发明属于医药技术领域，涉及3-芳基-5-噻吩基-5H-噻唑并[3,2-a]嘧啶类衍生物及其制备方法与作为乙酰胆碱酯酶抑制剂，用于提高患有痴呆和阿耳茨海默氏病病人记忆的应用。The invention belongs to the technical field of medicine, and relates to 3-aryl-5-thienyl-5H -thiazolo[3,2-a]pyrimidine derivatives and a preparation method thereof and as an acetylcholinesterase inhibitor for improving the Memory application for patients with dementia and Alzheimer's disease.
背景技术Background technique
阿耳茨海默氏病与基底前脑中的胆碱能神经元[它在识别功能(包括记忆)中起重要作用]的退化有关。由于所述退化的结果，患有该疾病的患者在乙酰胆碱合成、胆碱乙酰基转移酶活性、乙酰胆碱酯酶活性和胆碱吸收方面表现出明显的衰减。Alzheimer's disease is associated with the degeneration of cholinergic neurons in the basal forebrain, which play an important role in recognition functions, including memory. As a result of said degeneration, patients suffering from this disease exhibit marked attenuations in acetylcholine synthesis, choline acetyltransferase activity, acetylcholinesterase activity, and choline absorption.
已知乙酰胆碱酯酶抑制剂在提高胆碱能活性方面是有效的，因此可用于改善阿耳茨海默氏病患者的记忆。通过抑制乙酰胆碱酯酶，所述化合物可提高大脑中神经传递递质乙酰胆碱的水平，因此可增强记忆。Acetylcholinesterase inhibitors are known to be effective in increasing cholinergic activity and thus may be used to improve memory in Alzheimer's disease patients. By inhibiting acetylcholinesterase, the compound increases levels of the neurotransmitter acetylcholine in the brain, thereby enhancing memory.
现有的乙酰胆碱酯酶抑制剂如他克林，斯的明，加兰他敏等，依然存在耐药性或药物动力学缺陷。本发明所述化合物作为全新结构类型的乙酰胆碱酯酶抑制剂，具有结构类型新颖，药效作用与现有药物相当或优于现有药物的特点，具有良好的应用价值和开发应用前景。The existing acetylcholinesterase inhibitors, such as tacrine, stigmine, galantamine, etc., still have drug resistance or pharmacokinetic defects. As an acetylcholinesterase inhibitor of a new structure type, the compound of the invention has the characteristics of novel structure type, pharmacodynamic effect equivalent to or better than the existing drugs, and has good application value and development and application prospect.
发明内容Contents of the invention
本发明的目的在于提供一种3-芳基-5-噻吩基-5H-噻唑并[3,2-a]嘧啶类衍生物，其具有良好的乙酰胆碱酯酶抑制活性。The object of the present invention is to provide a 3-aryl-5-thienyl-5H -thiazolo[3,2-a]pyrimidine derivative, which has good acetylcholinesterase inhibitory activity.
本发明的另一目的在于提供上述3-芳基-5-噻吩基-5H-噻唑并[3,2-a]嘧啶类衍生物的制备方法。Another object of the present invention is to provide a preparation method of the above-mentioned 3-aryl-5-thienyl-5H -thiazolo[3,2-a]pyrimidine derivatives.
本发明的再一目的在于提供上述3-芳基-5-噻吩基-5H-噻唑并[3,2-a]嘧啶类衍生物的用途。Another object of the present invention is to provide the use of the above-mentioned 3-aryl-5-thienyl-5H -thiazolo[3,2-a]pyrimidine derivatives.
以下对本发明进行详细描述。The present invention is described in detail below.
本发明提供以下通式I的3-芳基-5-噻吩基-5H-噻唑并[3,2-a]嘧啶类衍生物或其药学可接受的盐。结构见图1：The present invention provides 3-aryl-5-thienyl-5H -thiazolo[3,2-a]pyrimidine derivatives of the following general formula I or pharmaceutically acceptable salts thereof. The structure is shown in Figure 1:
其中，R1独立的选自C1-C6烷基和C1-C6烷氧基；R2 独立的选自C1-C6烷基和C1-C6烷氧基；R3可任意选择由1个或2个独立的选自C1-C6烷基、C1-C6烷氧基、C1-C10任意选择取代的氨基烷氧基、取代或非取代氨基甲酰基烷氧基、羟基和卤素的取代基取代；R4 独立的选自氢、C1-C6烷基、乙酰基和卤素。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 Optionally, one or two independently selected from C1 -C6 alkyl, C1 -C6 alkoxy, C1 -C10 optionally substituted aminoalkoxy, substituted or unsubstituted aminomethyl Substituents of acylalkoxy, hydroxy and halogen; R4 is independently selected from hydrogen, C1 -C6 alkyl, acetyl and halogen.
“药学上可接受的盐”指保留了式Ⅰ化合物的生物效力和性质，并与合适的非毒性有机或无机酸或有机或无机碱形成的常规酸加成盐或碱加成盐。酸加成盐的实例包括醋酸盐，己二酸盐，藻酸盐，天冬氨酸盐，苯甲酸盐，苯磺酸盐，硫酸氢盐，丁酸盐，柠檬酸盐，樟脑酸盐，樟脑磺酸盐，环戊丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，富马酸盐，葡庚糖酸盐，甘油磷酸盐，半硫酸盐，庚酸盐，己酸盐，氢氯酸盐，氢溴酸盐，氢碘酸盐，2-羟基乙磺酸盐，乳酸盐，马来酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，草酸盐，扑酸盐，果胶酯酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，新戊酸盐，丙酸盐，琥珀酸盐，硫酸盐，酒石酸盐，硫氰酸盐，甲苯磺酸盐和十一酸盐。碱盐包括铵盐，碱金属盐，例如钠和钾盐，碱土金属盐，例如钙和镁盐，有机碱的盐，例如二环己胺盐，N-甲基-D-葡糖胺盐，和氨基酸的盐，例如精氨酸，赖氨酸等，而且，碱性含氮基团可以用这样的试剂季铵化，例如低级烷基卤化物，如甲基，乙基，丙基和丁基的氯，溴和碘化物；硫酸二烷基酯，如硫酸二甲酯，二乙酯，二丁酯和二戊酯；长链卤化物，如癸基，月桂基，肉豆蔻基和硬脂酰基的氯，溴和碘化物；芳烷基卤化物，如苄基和苯乙基的溴化物等。优选用于生成酸加成盐的酸包括盐酸和醋酸。"Pharmaceutically acceptable salt" refers to conventional acid addition salts or base addition salts formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases while retaining the biological efficacy and properties of the compounds of formula I. Examples of acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphoric acid Salt, camphorsulfonate, cypionate, digluconate, lauryl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanate salt, hexanoate, hydrochlorate, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate , Nicotinate, Nitrate, Oxalate, Pamoate, Pectinate, Persulfate, 3-Phenylpropionate, Picrate, Pivalate, Propionate, Succinate , Sulfate, Tartrate, Thiocyanate, Tosylate and Undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts of organic bases such as dicyclohexylamine salts, N-methyl-D-glucosamine salts, and salts of amino acids such as arginine, lysine, etc. Also, basic nitrogen-containing groups can be quaternized with such reagents as lower alkyl halides such as methyl, ethyl, propyl and butyl chlorine, bromine and iodide; dialkyl sulfates such as dimethyl, diethyl, dibutyl and dipentyl; long-chain halides such as decyl, lauryl, myristyl and hard Acyl chlorine, bromine and iodide; aralkyl halides, such as benzyl and phenethyl bromide, etc. Preferred acids for the formation of acid addition salts include hydrochloric acid and acetic acid.
“药学上可接受的”如药学上可接受地载体、赋性剂、前体药物等，指药理学上可接受的、并对给药具体化合物的患者基本上无毒性。"Pharmaceutically acceptable", such as a pharmaceutically acceptable carrier, excipient, prodrug, etc., means pharmacologically acceptable and substantially non-toxic to the patient to whom the particular compound is administered.
本发明还提供了上述通式I化合物的制备方法，该方法见图2。The present invention also provides a preparation method of the above-mentioned compound of general formula I, and the method is shown in FIG. 2 .
本发明还涉及抑制哺乳动物中乙酰胆碱酯酶的方法，该方法包括给哺乳动物服用抑制乙酰胆碱酯酶有效剂量的式 I 化合物或其立体异构体或其药学上适用的酸加成盐。The present invention also relates to a method for inhibiting acetylcholinesterase in a mammal, the method comprising administering to the mammal a compound of formula I or its stereoisomer or a pharmaceutically applicable acid addition salt thereof at an effective dosage for inhibiting acetylcholinesterase.
本发明也涉及式 I增强记忆或治疗或预防阿耳茨海默氏病的方法，该方法包括服用增强记忆或治疗或预防阿耳茨海默氏病有效剂量的式 I 化合物或其立体异构体或其药学上适用的酸加成盐。The present invention also relates to a method for formula I to enhance memory or treat or prevent Alzheimer's disease, the method comprising taking a compound of formula I or its stereoisomer at an effective dose for enhancing memory or treating or preventing Alzheimer's disease body or its pharmaceutically acceptable acid addition salt.
附图说明Description of drawings
图1为3-芳基-5-噻吩基-5H-噻唑并[3,2-a]嘧啶类衍生物的结构通式图；Figure 1 is a general structural diagram of 3-aryl-5-thienyl-5H -thiazolo[3,2-a]pyrimidine derivatives;
图2为3-芳基-5-噻吩基-5H-噻唑并[3,2-a]嘧啶类衍生物的合成路线图；Figure 2 is a synthetic route diagram of 3-aryl-5-thienyl-5H -thiazolo[3,2-a]pyrimidine derivatives;
图3为乙酰胆碱酯酶抑制活性测定试验中样品的处理方法图；Fig. 3 is the treatment method diagram of sample in the acetylcholinesterase inhibitory activity assay test;
图4为部分样品乙酰胆碱酯酶抑制率的结果图。Figure 4 is a graph showing the results of the inhibition rate of acetylcholinesterase in some samples.
通过以下实施例进一步举例说明本发明，但应注意本发明的范围并不受这些实施例的任何限制。The invention is further illustrated by the following examples, but it should be noted that the scope of the invention is not limited in any way by these examples.
具体实施例specific embodiment
实施例1Example 1
6-甲基-5-乙酰基-4-噻吩基-2-硫代嘧啶的制备Preparation of 6-methyl-5-acetyl-4-thienyl-2-thiopyrimidine
在250 ml的圆底烧瓶中加入噻吩甲醛0.1 mol、硫脲0.1 mol、乙酰丙酮0.11 mol、乙醇30 ml、浓盐酸2滴，搅拌，60℃反应10 h。冷却，抽滤，滤饼无水乙醇重结晶，得到黄色晶体20.4克，收率80.9%。MS m/z (M) 252。Add 0.1 mol of thiophene formaldehyde, 0.1 mol of thiourea, 0.11 mol of acetylacetone, 30 ml of ethanol, and 2 drops of concentrated hydrochloric acid into a 250 ml round bottom flask, stir, and react at 60°C for 10 h. Cool, filter with suction, and recrystallize the filter cake from absolute ethanol to obtain 20.4 g of yellow crystals, with a yield of 80.9%. MS m/z (M) 252.
实施例2Example 2
6-甲基-4-噻吩基-2-硫代嘧啶-5-羧酸乙酯的制备Preparation of ethyl 6-methyl-4-thienyl-2-thiopyrimidine-5-carboxylate
在250 ml的圆底烧瓶中加入噻吩甲醛0.1 mol、硫脲0.1 mol、乙酰丙酮0.11 mol、乙醇30 ml、浓盐酸2滴，搅拌，60℃反应10 h。冷却，抽滤，滤饼无水乙醇重结晶，得到黄色晶体24.6克，收率87.2%。MS m/z (M) 282。Add 0.1 mol of thiophene formaldehyde, 0.1 mol of thiourea, 0.11 mol of acetylacetone, 30 ml of ethanol, and 2 drops of concentrated hydrochloric acid into a 250 ml round bottom flask, stir, and react at 60°C for 10 h. After cooling, suction filtration, and recrystallization of the filter cake from absolute ethanol, 24.6 g of yellow crystals were obtained, with a yield of 87.2%. MS m/z (M) 282.
实施例3Example 3
7-甲基-5-噻吩基-3-(4-羟基苯基)-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯的制备Preparation of 7-methyl-5-thienyl-3-(4-hydroxyphenyl)-5H -thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester
将6-甲基-4-噻吩基-2-硫代嘧啶-5-羧酸乙酯2.82 g (10 mmol)，4-羟基氯代苯乙酮1.71 g (10 mmol)，醋酸钠/冰醋酸（2 g/20 mL），加热回流反应8-24小时，TLC监测反应。冷却后，抽滤，无水乙醇重结晶，得2.07 g白色粉末，收率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)。2.82 g (10 mmol) of ethyl 6-methyl-4-thienyl-2-thiopyrimidine-5-carboxylate, 1.71 g (10 mmol) of 4-hydroxychloroacetophenone, sodium acetate/glacial acetic acid (2 g/20 mL), heat to reflux for 8-24 hours, and monitor the reaction by TLC. After cooling, filter with suction and recrystallize from absolute ethanol to obtain 2.07 g of white powder with a yield of 54%. MS: 396;1 H-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).
实施例4Example 4
7-甲基-5-噻吩基-3-(4-氯苯基)-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯的制备Preparation of 7-methyl-5-thienyl-3-(4-chlorophenyl)-5H -thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester
将6-甲基-4-噻吩基-2-硫代嘧啶-5-羧酸乙酯2.82 g (10 mmol)，4-氯氯代苯乙酮1.89 g (10 mmol)，醋酸钠/冰醋酸（2 g/20 mL），加热回流反应8-24小时，TLC监测反应。冷却后，抽滤，无水乙醇重结晶，得2.19 g白色粉末，收率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)。2.82 g (10 mmol) of ethyl 6-methyl-4-thienyl-2-thiopyrimidine-5-carboxylate, 1.89 g (10 mmol) of 4-chlorochloroacetophenone, sodium acetate/glacial acetic acid (2 g/20 mL), heat to reflux for 8-24 hours, and monitor the reaction by TLC. After cooling, filter with suction and recrystallize from absolute ethanol to obtain 2.19 g of white powder with a yield of 52.9%. MS: 414;1 H-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).
实施例5Example 5
7-甲基-5-噻吩基-3-(4-甲基苯基)-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯的制备Preparation of 7-methyl-5-thienyl-3-(4-methylphenyl)-5H -thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester
将6-甲基-4-噻吩基-2-硫代嘧啶-5-羧酸乙酯2.82 g (10 mmol)，4-甲基氯代苯乙酮1.78 g (10 mmol)，醋酸钠/冰醋酸（2 g/20 mL），加热回流反应8-24小时，TLC监测反应。冷却后，抽滤，无水乙醇重结晶，得2.32 g白色粉末，收率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)。2.82 g (10 mmol) of ethyl 6-methyl-4-thienyl-2-thiopyrimidine-5-carboxylate, 1.78 g (10 mmol) of 4-methylchloroacetophenone, sodium acetate/ice Acetic acid (2 g/20 mL), heated to reflux for 8-24 hours, TLC to monitor the reaction. After cooling, filter with suction and recrystallize from absolute ethanol to obtain 2.32 g of white powder with a yield of 58.9%. MS: 394;1 H-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).
实施例6Example 6
7-甲基-3-[4-(2-二甲氨基)乙氧基苯基]-5-噻吩基-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯的制备7-Methyl-3-[4-(2-dimethylamino)ethoxyphenyl]-5-thienyl-5H -thiazolo[3,2-a]pyrimidine-6-carboxylic acid ethyl ester preparation
将7-甲基-5-噻吩基-3-(4-羟基苯基)-5H-噻唑并[3,2-a]嘧啶-6-羧酸乙酯0.39 g（1 mmol），2-氯乙基二甲氨基盐酸盐0.14 g（1 mmol）先溶于无水乙醇中，再加入碘化钾0.22 g，碳酸钾2.76 g，加热回流8 h，停止反应后，冷却至室温。抽滤除去碘化钾和碳酸钾，将溶剂旋蒸除去，得红色固体，无水乙醇重结晶得白色针状晶体0.31 g，收率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)。0.39 g (1 mmol) of ethyl 7-methyl-5-thienyl-3-(4-hydroxyphenyl)-5H -thiazolo[3,2-a]pyrimidine-6-carboxylate, 2- Dissolve 0.14 g (1 mmol) of chloroethyl dimethylamino hydrochloride in absolute ethanol, then add 0.22 g potassium iodide and 2.76 g potassium carbonate, heat to reflux for 8 h, stop the reaction, and cool to room temperature. Potassium iodide and potassium carbonate were removed by suction filtration, and the solvent was removed by rotary evaporation to obtain a red solid, which was recrystallized from absolute ethanol to obtain 0.31 g of white needle-like crystals, with a yield of 72.8%. MS: 467.1 H-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).
实施例7Example 7
6-乙酰基-7-甲基-3-(4-羟基苯基)-5-噻吩基-5H-噻唑并[3,2-a]嘧啶的制备Preparation of 6-acetyl-7-methyl-3-(4-hydroxyphenyl)-5-thienyl-5H -thiazolo[3,2-a]pyrimidine
将6-甲基-5-乙酰基-4-噻吩基-2-硫代嘧啶2.52 g (10 mmol)，4-羟基氯代苯乙酮1.89 g (10 mmol)，醋酸钠/冰醋酸（2 g/20 mL），加热回流反应8-24小时，TLC监测反应。冷却后，抽滤，无水乙醇重结晶，得2.57 g白色粉末，收率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)。2.52 g (10 mmol) of 6-methyl-5-acetyl-4-thienyl-2-thiopyrimidine, 1.89 g (10 mmol) of 4-hydroxychloroacetophenone, sodium acetate/glacial acetic acid (2 g/20 mL), heated to reflux for 8-24 hours, and monitored by TLC. After cooling, filter with suction and recrystallize from absolute ethanol to obtain 2.57 g of white powder with a yield of 70.2%. MS: 366;1 H-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).
实施例8Example 8
6-乙酰基-7-甲基-3-(4-氯苯基)-5-噻吩基-5H-噻唑并[3,2-a]嘧啶的制备Preparation of 6-acetyl-7-methyl-3-(4-chlorophenyl)-5-thienyl-5H -thiazolo[3,2-a]pyrimidine
将6-甲基-5-乙酰基-4-噻吩基-2-硫代嘧啶2.52 g (10 mmol)，4-氯氯代苯乙酮1.89 g (10 mmol)，醋酸钠/冰醋酸（2 g/20 mL），加热回流反应8-24小时，TLC监测反应。冷却后，抽滤，无水乙醇重结晶，得2.57 g白色粉末，收率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)。2.52 g (10 mmol) of 6-methyl-5-acetyl-4-thienyl-2-thiopyrimidine, 1.89 g (10 mmol) of 4-chlorochloroacetophenone, sodium acetate/glacial acetic acid (2 g/20 mL), heated to reflux for 8-24 hours, and monitored by TLC. After cooling, filter with suction and recrystallize from absolute ethanol to obtain 2.57 g of white powder with a yield of 70.2%. MS: 384;1 H-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).
实施例9Example 9
6-乙酰基-7-甲基-3-(4-甲基苯基)-5-噻吩基-5H-噻唑并[3,2-a]嘧啶的制备Preparation of 6-acetyl-7-methyl-3-(4-methylphenyl)-5-thienyl-5H -thiazolo[3,2-a]pyrimidine
将6-甲基-5-乙酰基-4-噻吩基-2-硫代嘧啶2.52 g (10 mmol)，4-甲基氯代苯乙酮1.78 g (10 mmol)，醋酸钠/冰醋酸（2 g/20 mL），加热回流反应8-24小时，TLC监测反应。冷却后，抽滤，无水乙醇重结晶，得2.43 g白色粉末，收率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)。2.52 g (10 mmol) of 6-methyl-5-acetyl-4-thienyl-2-thiopyrimidine, 1.78 g (10 mmol) of 4-methylchloroacetophenone, sodium acetate/glacial acetic acid ( 2 g/20 mL), heated to reflux for 8-24 hours, and monitored by TLC. After cooling, filter with suction and recrystallize from absolute ethanol to obtain 2.43 g of white powder with a yield of 66.7%. MS: 364;1 H-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).
实施例10Example 10
6-乙酰基-7-甲基-3-[4-(2-二甲氨基)乙氧基苯基]-5-噻吩基-5H-噻唑并[3,2-a]嘧啶的制备Preparation of 6-acetyl-7-methyl-3-[4-(2-dimethylamino)ethoxyphenyl]-5-thienyl-5H -thiazolo[3,2-a]pyrimidine
6-乙酰基-7-甲基-3-(4-羟基苯基)-5-噻吩基-5H-噻唑并[3,2-a]嘧啶0.36 g（1 mmol），2-氯乙基二甲氨基盐酸盐0.14 g（1 mmol）先溶于无水乙醇中，再加入碘化钾0.22 g，碳酸钾2.76 g，加热回流8 h，停止反应后，冷却至室温。抽滤除去碘化钾和碳酸钾，将溶剂旋蒸除去，得红色固体，无水乙醇重结晶得白色针状晶体0.38 g，收率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)。6-acetyl-7-methyl-3-(4-hydroxyphenyl)-5-thienyl-5H -thiazolo[3,2-a]pyrimidine 0.36 g (1 mmol), 2-chloroethyl Dissolve 0.14 g (1 mmol) of dimethylamino hydrochloride in absolute ethanol first, then add 0.22 g potassium iodide and 2.76 g potassium carbonate, heat to reflux for 8 h, stop the reaction, and cool to room temperature. Potassium iodide and potassium carbonate were removed by suction filtration, and the solvent was removed by rotary evaporation to obtain a red solid, which was recrystallized from absolute ethanol to obtain 0.38 g of white needle-like crystals, with a yield of 86.9%. MS: 437.1 H-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).
实施例11Example 11
乙酰胆碱酯酶抑制剂的活性测定试验Activity Assay of Acetylcholinesterase Inhibitors
材料与方法：Materials and Methods:
供试样品的准备：阳性对照药设定为氢溴酸新斯的明（SigmaN-2001），配制为0.1M溶液；Preparation of test samples: the positive control drug was set as neostigmine hydrobromide (SigmaN-2001), prepared as a 0.1M solution;
乙酰胆碱酯酶（人源）（SigmaC-1682）0.5单位；Acetylcholinesterase (human source) (SigmaC-1682) 0.5 unit;
缓冲溶液为100mM PBS溶液（pH7.4），10mM 二硫二硝基苯甲酸DTNB（D-8130）（用100mM PBS配制），-20℃避光保存，现制现用；The buffer solution is 100mM PBS solution (pH7.4), 10mM dithiodinitrobenzoic acid DTNB (D-8130) (prepared with 100mM PBS), stored at -20°C in the dark, ready to use;
12.5mM硫代乙酰胆碱ATCh（A-5751）溶解于水中，-20℃避光保存，现制现用；12.5mM Thioacetylcholine ATCh (A-5751) dissolved in water, stored at -20°C in the dark, ready to use;
受试药物用DMSO溶解后制备成10μM溶液。The test drug was dissolved in DMSO to prepare a 10 μM solution.
方法与结果：Method and Results:
1. 按如下方法处理样品（见图3）；1. Treat the sample as follows (see Figure 3);
2. 37℃连续轻轻振摇预热15分钟；2. Preheat at 37°C for 15 minutes with continuous gentle shaking;
3. 加入50mL ATCh和50mL DTNB；3. Add 50mL ATCh and 50mL DTNB;
4. 37℃连续轻轻振摇约20分钟,直到反应液出现黄色；4. Continuously shake gently at 37°C for about 20 minutes until the reaction solution turns yellow;
5. 测定其412nm处的OD值；5. Measure the OD value at 412nm;
6. 计算抑制率，部分样品抑制率如下图所示（见图4）。6. Calculate the inhibition rate, and the inhibition rate of some samples is shown in the figure below (see Figure 4).
| Application Number | Priority Date | Filing Date | Title |
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| CN201210281106.4ACN102807575B (en) | 2012-08-09 | 2012-08-09 | 3-aryl-5-thienyl-5H-thiazolo [3,2-a] pyrimidine derivative and application thereof |
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