CN102807575A - 3-芳基-5-噻吩基-5H-噻唑并[3,2-a]嘧啶类衍生物及其应用 - Google Patents
3-芳基-5-噻吩基-5H-噻唑并[3,2-a]嘧啶类衍生物及其应用 Download PDFInfo
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- CN102807575A CN102807575A CN2012102811064A CN201210281106A CN102807575A CN 102807575 A CN102807575 A CN 102807575A CN 2012102811064 A CN2012102811064 A CN 2012102811064A CN 201210281106 A CN201210281106 A CN 201210281106A CN 102807575 A CN102807575 A CN 102807575A
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- thienyl
- alkyl
- independently selected
- thiazolo
- aryl
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Abstract
本发明公开了通式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水合物、盐，包括其立体异构体或互变异构体，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。基本发明的3-芳基-5-噻吩基-5H-噻唑并[3,2-a]嘧啶类衍生物对乙酰胆碱酯酶有明显的抑制作用，因此，3-芳基-5-噻吩基-5H-噻唑并[3,2-a]嘧啶类衍生物用于增强患有痴呆和阿尔茨海默症病人的记忆力。
Description
技术领域
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。
背景技术
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。
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。
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。
发明内容
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。
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。
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。
以下对本发明进行详细描述。
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：
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。
“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。
“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。
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。
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。
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。
附图说明
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；
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；
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；
图4为部分样品乙酰胆碱酯酶抑制率的结果图。
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。
具体实施例
实施例1
6-甲基-5-乙酰基-4-噻吩基-2-硫代嘧啶的制备
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。
实施例2
6-甲基-4-噻吩基-2-硫代嘧啶-5-羧酸乙酯的制备
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。
实施例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
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)。
实施例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
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)。
实施例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
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)。
实施例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
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)。
实施例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
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)。
实施例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
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)。
实施例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
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)。
实施例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
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)。
实施例11
乙酰胆碱酯酶抑制剂的活性测定试验
材料与方法：
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；
乙酰胆碱酯酶（人源）（SigmaC-1682）0.5单位；
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；
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；
受试药物用DMSO溶解后制备成10μM溶液。
方法与结果：
1. 按如下方法处理样品（见图3）；
2. 37℃连续轻轻振摇预热15分钟；
3. 加入50mL ATCh和50mL DTNB；
4. 37℃连续轻轻振摇约20分钟,直到反应液出现黄色；
5. 测定其412nm处的OD值；
6. 计算抑制率，部分样品抑制率如下图所示（见图4）。
Claims (7)
1.通式I的芳基烷酸并环磷酰胺衍生物或其药学可接受的水合物、盐，包括其立体异构体或互变异构体，其特征是它具有如下通式（I）：
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。
2.一种药物组合物，包括作为活性成分的权力要求1中任何一个的化合物和药物可接受的载体或赋性剂。
3.根据权利要求1所述此类衍生物，其特征在于：R1优选甲基。
4. 根据权利要求1所述此类衍生物，其特征在于：R2优选甲基。
5.根据权利要求1所述此类衍生物，其特征在于：其中R3优选4-[2-(1-哌啶)乙氧基]。
6. 根据权利要求1所述此类衍生物，其特征在于：其中R4优选氢。
7. 权力要求1中任何一个化合物及其组合物在制备治疗退化性痴呆症药物中的应用。
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044460A (zh) * | 2013-01-30 | 2013-04-17 | 石家庄学院 | 3,5,7-三苯基-5H-噻唑并[3,2-a]嘧啶类衍生物及应用 |
| CN104844628A (zh) * | 2015-04-16 | 2015-08-19 | 石家庄学院 | 2H,6H-嘧啶并[2,1-b][1,3]噻嗪类衍生物及其应用 |
| CN104892640A (zh) * | 2015-05-28 | 2015-09-09 | 石家庄学院 | 2-苯基-6-苯甲酰基-噻唑并[3,2-b][1,2,4]-三氮唑类衍生物及应用 |
| CN104926838A (zh) * | 2015-05-31 | 2015-09-23 | 石家庄学院 | 5H-[1,2,4]三氮唑并[5,1-b][1,3]噻嗪类衍生物及应用 |
| CN104945415A (zh) * | 2015-06-17 | 2015-09-30 | 石家庄学院 | 7H-苯并异噁唑并[7,6-e][1,3]噁嗪类衍生物及应用 |
Citations (1)
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| CN101503414A (zh) * | 2009-03-04 | 2009-08-12 | 沈阳药科大学 | 噻唑并[3,2-b]-1,2,4-三嗪衍生物及其应用 |
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| CN101503414A (zh) * | 2009-03-04 | 2009-08-12 | 沈阳药科大学 | 噻唑并[3,2-b]-1,2,4-三嗪衍生物及其应用 |
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| 陈兰妹: "噻唑并[3,2-a]嘧啶类化合物的设计、合成及生物活性研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044460A (zh) * | 2013-01-30 | 2013-04-17 | 石家庄学院 | 3,5,7-三苯基-5H-噻唑并[3,2-a]嘧啶类衍生物及应用 |
| CN104844628A (zh) * | 2015-04-16 | 2015-08-19 | 石家庄学院 | 2H,6H-嘧啶并[2,1-b][1,3]噻嗪类衍生物及其应用 |
| CN104892640A (zh) * | 2015-05-28 | 2015-09-09 | 石家庄学院 | 2-苯基-6-苯甲酰基-噻唑并[3,2-b][1,2,4]-三氮唑类衍生物及应用 |
| CN104926838A (zh) * | 2015-05-31 | 2015-09-23 | 石家庄学院 | 5H-[1,2,4]三氮唑并[5,1-b][1,3]噻嗪类衍生物及应用 |
| CN104926838B (zh) * | 2015-05-31 | 2017-04-12 | 石家庄学院 | 5H‑[1,2,4]三氮唑并[5,1‑b][1,3]噻嗪类衍生物及应用 |
| CN104945415A (zh) * | 2015-06-17 | 2015-09-30 | 石家庄学院 | 7H-苯并异噁唑并[7,6-e][1,3]噁嗪类衍生物及应用 |
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