技术领域technical field
本发明属于医药技术领域，涉及3-芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮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-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives and a preparation method thereof and as an inhibitor of acetylcholinesterase medicament for improving memory in 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-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类衍生物，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 kind of 3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives, which have good acetylcholinesterase inhibitory activity . the
本发明的再一目的在于提供上述3-芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类衍生物的用途。Another object of the present invention is to provide the use of the above-mentioned 3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one 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-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类衍生物或其药学可接受的盐。结构如下（见图1）：The present invention provides 3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives of the following general formula I or pharmaceutically acceptable salts thereof. The structure is as follows (see Figure 1):
其中in
R1可以任意选择地由 1 个， 2 个或3个独立地选自H，卤素，-OH，-OCH3，-CH3，-NO2，-O(CH2)n1NR3R4，-O(CH2)n2CONR5R6；R1 can optionally consist of 1, 2 or 3 independently selected from H, halogen, -OH, -OCH3 , -CH3 , -NO2 , -O(CH2 )n1 NR3 R4 ,-O(CH2 )n2 CONR5 R6 ;
R2可以任意选择地由 1 个， 2 个或3个独立地选自H，卤素，-OH，-OCH3，-CH3，-NO2，-O(CH2)n1NR3R4，-O(CH2)n2CONR5R6；R2 can optionally consist of 1, 2 or 3 independently selected from H, halogen, -OH, -OCH3 , -CH3 , -NO2 , -O(CH2 )n1 NR3 R4 ,-O(CH2 )n2 CONR5 R6 ;
X=为O, S等；X= is O, S, etc.;
R3R4独立的选自甲基或乙基，或R3R4与它们相连的氮原子一起组成吡咯烷基，甲基吡咯烷基，二甲基吡咯烷基，哌啶基，吗啉基，或六亚甲基亚胺基环；R3 R4 are independently selected from methyl or ethyl, or R3 R4 together with the nitrogen atom they are attached to form pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, piperidinyl, morpholine Base, or hexamethyleneimino ring;
n1为2至6的整数；n1 is an integer from 2 to 6;
R5R6独立的选自甲基或乙基，或R5R6与它们相连的氮原子一起组成吡咯烷基，甲基吡咯烷基，二甲基吡咯烷基，哌啶基，吗啉基，或六亚甲基亚胺基环；或分别独立的选自氢和取代或未取代的苯环基团；R5 R6 is independently selected from methyl or ethyl, or R5 R6 together with the nitrogen atom they are connected to form pyrrolidinyl, methylpyrrolidinyl, dimethylpyrrolidinyl, piperidinyl, morpholine group, or hexamethyleneimino ring; or independently selected from hydrogen and substituted or unsubstituted benzene ring groups;
n2为1至6的整数。n2 is an integer of 1 to 6.
“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. the
本发明还提供了上述通式I化合物的制备方法，该方法包括（见图2）。The present invention also provides a preparation method for the above-mentioned compound of general formula I, which method comprises (see Figure 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.
本发明化合物可以通过不同的方法给患者服用，例如以胶囊剂或片剂口服，以无菌溶液剂或混悬剂给药，并且在某些情况下，可以以溶液剂形式静脉注射。可以将本发明的游离碱化合物以其药学上适用的酸加成盐形式进行配制和服用。The compounds of the present invention can be administered to the patient by various methods, for example, orally as capsules or tablets, as sterile solutions or suspensions and, in some cases, as intravenous solutions. The free base compounds of the present invention may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts.
对于一般的成人而言，本发明化合物每天的剂量通常为约1-300毫克/公斤，并可以按单剂量或均分剂量给药。对于给药，如果服用溶液剂或混悬剂，那么本发明化合物的浓度至少为1%(重量)，以4-70%(重量)(以单位的总重量为基础)较好。非经胃肠道给药的剂量单位一般含有约5-100毫克有效化合物。For an average adult, the daily dose of the compound of the present invention is usually about 1-300 mg/kg, and can be administered in a single dose or in divided doses. For administration, if a solution or suspension is administered, the concentration of the compound of the invention is at least 1% by weight, preferably 4-70% by weight (based on the total weight of the unit). Dosage units for parenteral administration will generally contain about 5-100 mg of active compound.
本发明化合物可以与惰性稀释剂或可食用的载体一起口服给药，或者它们可以封装在明胶胶囊中，或者压成片剂。所述制剂应含有至少0.5%活性化合物，但是根据具体的剂型，浓度可以改变，可以为4-70%(重量)(以单位的总重量为基础)。口服剂量单位一般含有 1.0毫克-300毫克有效化合物。The compounds of this invention may be administered orally with an inert diluent or an edible carrier, or they may be enclosed in gelatin capsules, or compressed into tablets. The formulations should contain at least 0.5% active compound, but depending on the particular dosage form, concentrations may vary and may range from 4 to 70% by weight (based on the total weight of the unit). Oral dosage units will generally contain from 1.0 mg to 300 mg of the active compound.
对于药理应用，式 I 化合物优选以其药用酸加成盐的形式给药。当然化合物的有效剂量将根据所用每个化合物的效力、所要治疗疾病的严重性和性质、要治疗的特定患者而变化。一般，以约0.01mg到约 20mg/kg体重/天的剂量，化合物系统给药可得到有效的结果。应以较低剂量开始治疗。随后可以固体剂型如胶囊、片剂、或粉剂，或以液态形式如溶液或悬液口服给药。这些化合物还可以灭菌溶液或悬液的形式经肠外注射。For pharmacological use, the compounds of formula I are preferably administered in the form of their pharmaceutically acceptable acid addition salts. The effective dosage of the compound will of course vary depending on the potency of each compound employed, the severity and nature of the disease being treated, and the particular patient being treated. In general, effective results are obtained with systemic administration of the compounds at dosages of from about 0.01 mg to about 20 mg/kg body weight/day. Treatment should be started at a lower dose. It can then be administered orally in solid dosage forms such as capsules, tablets, or powders, or in liquid forms such as solutions or suspensions. The compounds can also be injected parenterally in the form of sterile solutions or suspensions.
附图说明Description of drawings
图1为3-芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类衍生物的结构通式图；Figure 1 is a general structural diagram of 3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives;
图2为3-芳基-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮类衍生物的合成路线图；Figure 2 is a synthetic route diagram of 3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one 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1 Example 1
2-甲基-4-亚甲基噻吩恶唑酮的制备Preparation of 2-methyl-4-methylenethienoxazolone
将2-噻吩甲醛0.1mol，乙酰甘氨酸0.12mol，无水醋酸钠0.12mol和醋酐50克依次加入到100三颈瓶中，加热回流搅拌反应5小时，冷至室温后，溶液变成固体，抽滤，滤饼用冷水洗涤，用丙酮重结晶，得所需的产品黄色结晶粉末19.3克，收率100%，MS m/z (M) 193。Add 0.1 mol of 2-thiophene carboxaldehyde, 0.12 mol of acetylglycine, 0.12 mol of anhydrous sodium acetate and 50 grams of acetic anhydride into a 100-degree three-necked flask in sequence, heat and reflux and stir for 5 hours to react. After cooling to room temperature, the solution becomes solid. Suction filtration, the filter cake was washed with cold water, and recrystallized with acetone to obtain 19.3 grams of the desired product yellow crystalline powder, yield 100%, MS m/z (M) 193.
实施例2 Example 2
α-乙酰氨基-β-噻吩丙烯酸的制备Preparation of α-Acetamido-β-thiophene Acrylic Acid
将2-甲基-4-亚甲基噻吩恶唑酮类化合物0.1mol，水100mL，丙酮80mL依次加入到100mL圆底烧瓶中，加热回流搅拌反应3小时，冷却到室温，析出大量黄色固体，抽滤，滤饼用冷水和少量丙酮冲洗，用丙酮重结晶，得所需的产品黄色晶体20.3克，收率96.2，MS m/z (M) 211。Add 0.1mol of 2-methyl-4-methylenethienoxazolone compound, 100mL of water, and 80mL of acetone into a 100mL round-bottomed flask in sequence, heat to reflux and stir for 3 hours, cool to room temperature, and a large number of yellow solids are precipitated. Suction filtration, the filter cake was rinsed with cold water and a small amount of acetone, and recrystallized with acetone to obtain 20.3 grams of yellow crystals of the desired product, yield 96.2, MS m/z (M) 211.
实施例3 Example 3
β-噻吩基丙酮酸的制备Preparation of β-thienylpyruvate
将α-乙酰氨基-β-噻吩丙烯酸0.1mol，1mol/L的HCl溶液60mL, 依次加入到100mL圆底烧瓶中，加热回流反应1小时，停止反应,趁热过滤,滤液中即有固体析出,冷却,抽滤，无水乙醇重结晶，得到所需要的产品红色晶体15.5克，收率91.2%，MS m/z (M) 170。Add 0.1mol of α-acetamido-β-thiophene acrylic acid, 60mL of 1mol/L HCl solution into a 100mL round-bottomed flask, heat and reflux for 1 hour, stop the reaction, filter while it is hot, and solids will precipitate out of the filtrate. Cooling, suction filtration, recrystallization from absolute ethanol to obtain 15.5 grams of the desired product red crystals, yield 91.2%, MS m/z (M) 170.
实施例4 Example 4
6-(2-噻吩甲基)-3-硫代-(2H,4H)-1,2,4-三嗪-5-酮的制备Preparation of 6-(2-thienylmethyl)-3-thioxo-(2H,4H)-1,2,4-triazin-5-one
将β-噻吩基丙酮酸0.1mol，硫代氨基脲0.1mol，乙醇30mL，水30mL依次加入到250mL圆底烧瓶中，搅拌，加热回流反应8小时后，冷却到室温，减压蒸馏蒸去溶剂，得到大量乳白色固体，抽滤，烘干，用乙醇重结晶，得到所需产品白色晶体19.7克，收率87.6%，MS m/z (M) 225。Add 0.1mol of β-thienylpyruvate, 0.1mol of thiosemicarbazide, 30mL of ethanol, and 30mL of water into a 250mL round-bottomed flask in turn, stir, heat to reflux for 8 hours, cool to room temperature, and distill off the solvent under reduced pressure , to obtain a large amount of milky white solid, suction filtration, drying, and recrystallization with ethanol to obtain 19.7 grams of white crystals of the desired product, yield 87.6%, MS m/z (M) 225.
实施例5Example 5
6-(2-噻吩甲基)-3-(4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备Preparation of 6-(2-thienylmethyl)-3-(4-hydroxyphenyl)-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one
向0.05mol醋酸钠的15mL冰醋酸溶液中加入6-（2-噻吩甲基）-3-硫代-(2H,4H)-1,2,4-三嗪-5-酮0.01mol和4’-羟基-α-氯代苯乙酮0.01mol，室温搅拌30分钟，缓慢升温至回流后继续反应2小时，TLC监测反应进程，反应完毕后冷却至室温，将反应液浓缩至干，加入饱和食盐水溶液，室温下搅拌30分钟，并用乙酸乙酯萃取。有机层经干燥和浓缩得到粗产品，乙醇重结晶，得到所需的产物黄色晶体2.0克，收率58.9%，MS m/z (M) 341；1HNMR(CDCl3)：δ4.0(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),。Add 0.01mol of 6-(2-thienylmethyl)-3-thio-(2H,4H)-1,2,4-triazin-5-one and 4' -Hydroxy-α-chloroacetophenone 0.01mol, stirred at room temperature for 30 minutes, slowly heated to reflux and continued to react for 2 hours, TLC monitored the reaction process, cooled to room temperature after the reaction was completed, concentrated the reaction solution to dryness, and added saturated salt aqueous solution, stirred at room temperature for 30 minutes, and extracted with ethyl acetate. The organic layer was dried and concentrated to obtain a crude product, which was recrystallized from ethanol to obtain 2.0 g of yellow crystals of the desired product, with a yield of 58.9%, MS m/z (M) 341;1 HNMR (CDCl3 ): δ4.0 (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), .
实施例6Example 6
6-(2-噻吩甲基)-3-(4-甲基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备Preparation of 6-(2-thienylmethyl)-3-(4-methylphenyl)-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one
向0.05mol醋酸钠的15mL冰醋酸溶液中加入6-(2-噻吩甲基)-3-硫代-(2H,4H)-1,2,4-三嗪-5-酮0.01mol和4’-羟基-α-氯代苯乙酮0.01mol，室温搅拌30分钟，缓慢升温至回流后继续反应2小时，TLC监测反应进程，反应完毕后冷却至室温，将反应液浓缩至干，加入饱和食盐水溶液，室温下搅拌30分钟，并用乙酸乙酯萃取。有机层经干燥和浓缩得到粗产品，乙醇重结晶，得到所需的产物2.17克，收率64.1%，MS m/z (M) 339；1HNMR(DMSO)：δ2.3(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)。Add 0.01mol of 6-(2-thienylmethyl)-3-thio-(2H,4H)-1,2,4-triazin-5-one and 4' -Hydroxy-α-chloroacetophenone 0.01mol, stirred at room temperature for 30 minutes, slowly heated to reflux and continued to react for 2 hours, TLC monitored the reaction process, cooled to room temperature after the reaction was completed, concentrated the reaction solution to dryness, and added saturated salt aqueous solution, stirred at room temperature for 30 minutes, and extracted with ethyl acetate. The organic layer was dried and concentrated to obtain a crude product, which was recrystallized from ethanol to obtain 2.17 g of the desired product, with a yield of 64.1%, MS m/z (M) 339;1 HNMR (DMSO): δ2.3 (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=8.4 Hz), 7.42 (1H, d).
实施例7Example 7
6-(2-噻吩甲基)-3-(4-氯苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备Preparation of 6-(2-thienylmethyl)-3-(4-chlorophenyl)-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one
向0.05mol醋酸钠的15mL冰醋酸溶液中加入6-(2-噻吩甲基)-3-硫代-(2H,4H)-1,2,4-三嗪-5-酮0.01mol和4’-羟基-α-氯代苯乙酮0.01mol，室温搅拌30分钟，缓慢升温至回流后继续反应2小时，TLC监测反应进程，反应完毕后冷却至室温，将反应液浓缩至干，加入饱和食盐水溶液，室温下搅拌30分钟，并用乙酸乙酯萃取。有机层经干燥和浓缩得到粗产品，乙醇重结晶，得到所需的产物2.29克，收率63.8%，MS m/z (M) 359；1HNMR(DMSO)：δ4.0(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)。Add 0.01mol of 6-(2-thienylmethyl)-3-thio-(2H,4H)-1,2,4-triazin-5-one and 4' -Hydroxy-α-chloroacetophenone 0.01mol, stirred at room temperature for 30 minutes, slowly heated to reflux and continued to react for 2 hours, TLC monitored the reaction process, cooled to room temperature after the reaction was completed, concentrated the reaction solution to dryness, and added saturated salt aqueous solution, stirred at room temperature for 30 minutes, and extracted with ethyl acetate. The organic layer was dried and concentrated to obtain a crude product, which was recrystallized from ethanol to obtain 2.29 g of the desired product, with a yield of 63.8%, MS m/z (M) 359;1 HNMR (DMSO): δ4.0 (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=8.7 Hz), 7.42 (1H, d).
实施例8Example 8
6-(2-噻吩甲基)-3-(4-溴苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备Preparation of 6-(2-thienylmethyl)-3-(4-bromophenyl)-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one
向0.05mol醋酸钠的15mL冰醋酸溶液中加入6-(2-噻吩甲基)-3-硫代-(2H,4H)-1,2,4-三嗪-5-酮0.01mol和4’-羟基-α-氯代苯乙酮0.01mol，室温搅拌30分钟，缓慢升温至回流后继续反应2小时，TLC监测反应进程，反应完毕后冷却至室温，将反应液浓缩至干，加入饱和食盐水溶液，室温下搅拌30分钟，并用乙酸乙酯萃取。有机层经干燥和浓缩得到粗产品，乙醇重结晶，得到所需的产物2.56克，收率63.5%，MS m/z (M) 403；1HNMR(DMSO)：δ4.0(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)。Add 0.01mol of 6-(2-thienylmethyl)-3-thio-(2H,4H)-1,2,4-triazin-5-one and 4' -Hydroxy-α-chloroacetophenone 0.01mol, stirred at room temperature for 30 minutes, slowly heated to reflux and continued to react for 2 hours, TLC monitored the reaction process, cooled to room temperature after the reaction was completed, concentrated the reaction solution to dryness, and added saturated salt aqueous solution, stirred at room temperature for 30 minutes, and extracted with ethyl acetate. The organic layer was dried and concentrated to obtain a crude product, which was recrystallized from ethanol to obtain 2.56 g of the desired product, with a yield of 63.5%, MS m/z (M) 403;1 HNMR (DMSO): δ4.0 (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=8.6 Hz), 7.42 (1H, d).
实施例9Example 9
6-(2-噻吩甲基)-3-{4-[2-(1-哌啶基)乙氧基]苯基}-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备6-(2-Thienylmethyl)-3-{4-[2-(1-piperidinyl)ethoxy]phenyl}-7H-thiazolo[3,2-b]-1,2,4 - Preparation of triazin-7-one
室温搅拌条件下，向1mmol 6-(2-噻吩甲基)-3-(4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的丙酮或乙醇溶液中加入相应的1mmol氯乙基哌啶盐酸盐，并加入1 mmol缚酸剂(无水碳酸钾或三乙胺)和0.1 mmol碘化钾催化剂后，回流反应，TLC跟踪反应进程，待反应完毕后冷却至室温，将反应液浓缩至干，加入饱和食盐水30mL，乙醚萃取。有机层经干燥和浓缩得到粗产品，乙醇重结晶，得到所需的产物0.24克，收率51.3%。MS m/z (M) 452；1HNMR(CDCl3)：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)。Under stirring at room temperature, 1 mmol 6-(2-thienylmethyl)-3-(4-hydroxyphenyl)-7H-thiazolo[3,2-b]-1,2,4-triazine-7- Add corresponding 1mmol chloroethylpiperidine hydrochloride to the acetone or ethanol solution of ketone, and after adding 1 mmol acid binding agent (anhydrous potassium carbonate or triethylamine) and 0.1 mmol potassium iodide catalyst, reflux reaction, TLC tracking reaction process, after the reaction is completed, cool to room temperature, concentrate the reaction solution to dryness, add 30 mL of saturated saline, and extract with ether. The organic layer was dried and concentrated to obtain a crude product, which was recrystallized from ethanol to obtain 0.24 g of the desired product with a yield of 51.3%. MS m/z (M) 452;1 HNMR (CDCl3 ): 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).
实施例10Example 10
6-(2-噻吩甲基)-3-[4-(2-二乙胺基乙氧基)苯基]-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的制备6-(2-thienylmethyl)-3-[4-(2-diethylaminoethoxy)phenyl]-7H-thiazolo[3,2-b]-1,2,4-triazine Preparation of -7-one
室温搅拌条件下，向1mmol 6-(2-噻吩甲基)-3-(4-羟基苯基)-7H-噻唑并[3,2-b]-1,2,4-三嗪-7-酮的丙酮或乙醇溶液中加入相应的1mmol氯乙基二乙胺盐酸盐，并加入1 mmol缚酸剂(无水碳酸钾或三乙胺)和0.1 mmol碘化钾催化剂后，回流反应，TLC跟踪反应进程，待反应完毕后冷却至室温，将反应液浓缩至干，加入饱和食盐水30毫升，乙醚萃取。有机层经干燥和浓缩得到粗产品，乙醇重结晶，得到所需的产物0.22克，收率50.0%。MS m/z (M) 440；1HNMR(CDCl3)：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)。Under stirring at room temperature, 1 mmol 6-(2-thienylmethyl)-3-(4-hydroxyphenyl)-7H-thiazolo[3,2-b]-1,2,4-triazine-7- Add corresponding 1mmol chloroethyldiethylamine hydrochloride to the acetone or ethanol solution of ketone, and after adding 1 mmol acid binding agent (anhydrous potassium carbonate or triethylamine) and 0.1 mmol potassium iodide catalyst, reflux reaction, TLC tracking Reaction process, after the reaction is completed, cool to room temperature, concentrate the reaction solution to dryness, add 30 ml of saturated saline, and extract with ether. The organic layer was dried and concentrated to obtain a crude product, which was recrystallized from ethanol to obtain 0.22 g of the desired product with a yield of 50.0%. MS m/z (M) 440;1 HNMR (CDCl3 ): 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).
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（见图4）。6. Calculate the inhibition rate, the inhibition rate of some samples (see Figure 4).
| Application Number | Priority Date | Filing Date | Title |
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| CN201210281120.4ACN102796121B (en) | 2012-08-09 | 2012-08-09 | 3-aryl-7H-thiazol[3,2-b]-1,2,4-triazinyl-7-one derivatives and application thereof |
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| CN201210281120.4ACN102796121B (en) | 2012-08-09 | 2012-08-09 | 3-aryl-7H-thiazol[3,2-b]-1,2,4-triazinyl-7-one derivatives and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| 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 |
| CN112047962B (en)* | 2020-10-18 | 2022-04-29 | 石家庄学院 | 2H-thiazolo [3,2-b ] -1,2, 4-triazine-3, 7-diketone derivative and application thereof |
| Title |
|---|
| 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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|---|---|
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