CN101914031B - Pregabalin derivative and application thereof - Google Patents

Pregabalin derivative and application thereof Download PDF

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CN101914031B
CN101914031B CN 201010242645 CN201010242645A CN101914031B CN 101914031 B CN101914031 B CN 101914031B CN 201010242645 CN201010242645 CN 201010242645 CN 201010242645 A CN201010242645 A CN 201010242645A CN 101914031 B CN101914031 B CN 101914031B
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pregabalin
derivatives
aminomethyl
pharmaceutically acceptable
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CN101914031A (en )
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俞亮
潘文龙
宋化灿
万一千
宋森川
陈智勇
陈泳
孙一峰
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中国广州分析测试中心
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Abstract

本发明涉及式I普瑞巴林衍生物及其在抗老年痴呆药物中的应用。 The present invention relates to derivatives of pregabalin and its Application of formula I in the anti-dementia drugs. 乙酰胆碱酯酶体外测试模型显示本发明中的普瑞巴林衍生物具有显著的抗乙酰胆碱酯酶活性,可用于制备抗老年痴呆药物。 Acetylcholinesterase in vitro test model display pregabalin derivative of the present invention has significant anti-acetylcholinesterase activity, can be used for the preparation of an anti-Alzheimer's drugs. 所述的普瑞巴林衍生物的化学结构式如式I所示,式中R如说明书所定义。 The chemical structural formula as pregabalin derivative of formula I, wherein R is as defined in the specification. 式I。 Type I.

Description

普瑞巴林衍生物及其应用 Pregabalin DERIVATIVES AND THEIR USE

技术领域 FIELD

[0001] 本发明涉及药物化学领域,具体而言,本发明涉及新的普瑞巴林衍生物及其应用。 [0001] The present invention relates to the field of pharmaceutical chemistry, in particular, the present invention relates to novel derivatives of pregabalin and its application. 技术背景 technical background

[0002] 随着全世界人口的老龄化,阿尔茨海默病(俗称老年痴呆,Alzhemer' sdisease, AD)成为威胁老人晚年生活的主要疾病之一。 [0002] With the aging of the world's population, Alzheimer's disease (commonly known as Alzheimer's, Alzhemer 'sdisease, AD) has become one of the major diseases of the elderly threat to life. AD是一种不可逆转的大脑进行性退变疾病。 AD is a progressive irreversible brain degenerative diseases. 临床表现为记忆力减退伴有其他认识功能损害的获得性智能减退,致使晚期患者丧失综合视、听、触、嗅等信息的能力,导致患者不能独立生活。 Clinical manifestations of memory loss associated with other intelligent knowledge acquired impairment loss, resulting in loss of the ability of patients with advanced integrated information visual, hearing, touch, smell, leading to the patient can not live independently. AD的发病机制复杂,病因学尚未完全清楚,至今没有好的根治或逆转病程的药物。 AD pathogenesis of complex etiology has not yet entirely clear, so far there is no good cure or reverse the course of medication. 目前,对于AD的病因主要有以下三种说法:其一,大脑皮层及其它脑区神经上出现淀粉样蛋白(βΑΡ)沉积和神经纤维缠结(NFT)。 Currently, the main cause of AD in the following three versions: amyloid (βΑΡ) deposition and neurofibrillary tangles (the NFT) appears on one, cerebral cortex and other brain regions nerve. β AP在AD的神经元损害中起了重要作用。 β AP plays an important role in the neuronal damage in AD. β AP沉积作用于神经细胞膜引起的细胞损害甚至死亡。 β AP deposition in the nerve cell membrane caused by cell damage or even death. 其二,AD的发生与衰老引起的生理、生化改变有密切的关系。 Second, AD occurrence and physiological, biochemical changes caused by aging are closely related. 钙平衡失调、自由基增多等都可导致神经元的损害。 Calcium imbalance, such as an increase in free radicals can lead to neuronal damage. 其三,AD与中枢神经递质如乙酰胆硷、5-羟色胺、兴奋性氨基酸等异常有关。 Third, as the AD and the central neurotransmitter acetylcholine, serotonin, excitatory amino acids and other abnormalities. 大量的研究证实,在AD病人中,学习和记忆能力的丧失与乙酰胆碱能神经功能的下降有直接关系。 Numerous studies confirm that in AD patients, loss of learning and memory ability and cholinergic nerve function decline has a direct relationship. 胆碱能假说为AD的治疗提供了理论依据,乙酰胆碱酯酶抑制剂成为目前治疗AD最有效的手段。 Cholinergic hypothesis provides a theoretical basis for the treatment of AD, acetylcholinesterase inhibitors become the most effective means of treating AD.

[0003] 乙酰胆碱酯酶抑制剂如它克林,毒扁豆碱,加兰他敏,齐多哌啶,石杉碱甲能够增强AD病人的认知能力,但是多数药物因其具有中枢或外周系统副作用而使其广泛应用受到限制。 [0003] It is an acetylcholinesterase inhibitor such as clindamycin, physostigmine, galantamine, homogeneous multi-piperidine, Huperzine A can enhance the cognitive ability of AD patients, but because most drugs have central or peripheral system side effects so widespread application is limited. 因此对老年痴呆疾病仍需继续研究寻找一类新型化合物,开发新一代毒副作用低、疗效高的乙酰胆碱酯酶抑制剂。 So for Alzheimer's disease remains to be studied to find a novel class of compounds, the development of a new generation of low toxicity, high efficacy of acetylcholinesterase inhibitors.

发明内容 SUMMARY

[0004] 本发明的目的之一是提供一类新的、对乙酰胆碱酯酶和丁酰胆碱酯酶具有高抑制活性的普瑞巴林衍生物。 [0004] One object of the present invention is to provide a new class, having high inhibitory activity pregabalin derivatives acetylcholinesterase and butyrylcholinesterase.

[0005] 实现上述目的的技术方案如下: [0005] The technical solution to achieve the above object are as follows:

[0006] 普瑞巴林衍生物为以下式I所示: [0006] Pregabalin derivative is shown in the following formula I:

[0007] [0007]

Figure CN101914031BD00031

[0008]式 I [0008] Formula I

[0009] 其中:R选自二烷基胺、一氮杂环、二氮杂环、吗啡啉环、或硫代吗啡啉环,即R = [0009] wherein: R is selected from dialkyl amine, a nitrogen heterocycle, diazepine ring, a morpholine ring, a morpholine ring or a thio, i.e. R =

Figure CN101914031BD00032

其中,m选自0 〜6,X选自1、2、3、4、5 ;y 选自0、1、2、3 ;z 选自0、1、2、3 ;n 选自I 〜14。 Wherein, m is selected from 0 ~6, X is selected from 1,2,3,4,5; y is selected from 0,1,2,3; z is selected from 0,1,2,3; n is selected from I ~14 .

[0010] 本发明的另一目的是提供上述4- 二乙基氨甲基酚衍生物及其在药学上可接受的酸或碱所形成的加成盐在制备抗老年痴呆症药物中的应用。 [0010] Another object of the present invention is to provide the above-ethyl-4-aminomethyl phenol derivatives and their addition salts in a pharmaceutically acceptable acid or base formed by the application in the treatment of senile dementia of making an anti- .

[0011] 本发明的另一目的是提供一种用于治疗老年痴呆症的药物。 [0011] Another object of the present invention is to provide a drug for treating Alzheimer's disease.

[0012] 具体技术方案如下: [0012] In particular the following technical solution:

[0013] 一种抗老年痴呆症的药物组合物,其活性成份为上述4-二乙基氨甲基酚衍生物及其在药学上可接受的酸或碱所形成的加成盐。 [0013] An anti-dementia drug compositions, addition salts of the active ingredients as above-ethyl-4-aminomethyl phenol derivatives and their pharmaceutically acceptable acid or base form.

[0014] 本发明中的普瑞巴林衍生物,是由普瑞巴林为起始原料合成得到。 [0014] Pregabalin derivative of the present invention, pregabalin is synthesized as a starting material.

[0015] 制备本发明的普瑞巴林衍生物的反应,如如下反应式I所示: [0015] The reaction for preparing pregabalin derivatives of the present invention, as shown in the following reaction formula I:

[0016] [0016]

Figure CN101914031BD00041

[0017] 普瑞巴林衍生物的结构说明如下表I。 [0017] Structure pregabalin derivative described below Table I.

[0018] 表1.普瑞巴林衍生物的结构说明 Structure Description [0018] Table 1. pregabalin derivative

[0019] [0019]

Figure CN101914031BD00051

[0020] 通过乙酰胆碱酯酶和丁酰胆碱酯酶抑制体外测试表明,本发明的普瑞巴林衍生物具有显著的抗乙酰胆碱酯酶和丁酰胆碱酯酶活性。 [0020] In vitro tests have indicated that inhibition of acetylcholinesterase and butyrylcholinesterase, pregabalin derivative of the invention has significant anti-AChE and BuChE. 其中化合物C4a,C4d的乙酰胆碱酯酶IC5tl值与对照物加兰他敏近似,而其丁酰胆碱酯酶IC5tl值明显高于对照物加兰他敏;同时当n > 3即n = 4、5、6、8时,化合物对丁酰胆碱酯酶抑制作用有明显的选择性。 Wherein the compound C4a, C4d acetylcholinesterase IC5tl with the control was approximately galantamine, butyrylcholinesterase IC5tl its value significantly higher than the control galantamine; while if n> 3 i.e. n = 4, 5,6,8, the compound has significant selectivity for inhibition of butyrylcholinesterase. 因此本发明的4-二乙基氨甲基酚衍生物,可用于制备治疗老年痴呆症的药物。 Thus 4-diethylamino-aminomethyl phenol derivative of the present invention, may be used medicament for the treatment of Alzheimer's disease.

具体实施方式 detailed description

[0021] 以下通过实施例对本发明作进一步说明。 [0021] The following invention is further illustrated by examples.

[0022] 实施例一:4-(8-溴代辛氧基)苯甲醛(If)的合成 4- (8-bromo-octyloxy) benzaldehyde (If) is: a [0022] Example

[0023] 先将2.4g(20mmol)对轻基苯甲醒,15ml 1.8_ 二溴辛烧和5.52g(40mmol)碳酸钾(微波活化)加入到IOOml的圆底烧瓶中,加入40ml无水丙酮,回流条件下搅拌24小时。 [0023] First 2.4g (20mmol) of benzyl group wake light, 15ml 1.8_ oct-dibromo burn and 5.52g (40mmol) of potassium carbonate (microwave activation) IOOml added to the round bottom flask, 40ml of anhydrous acetone was added It was stirred under reflux for 24 hours. TLC跟踪至反应至完全。 TLC tracking to the reaction to completion. 过滤,旋干溶剂,得到初产物。 Filtration, rotary evaporation, to give crude product. 再用硅胶柱层析分离得黄色固体粉末If,产率为63%。 By silica gel column chromatography to give a yellow solid powder If, in 63% yield. 其1Hnmr(Cdci3JOOmHz) δ,ppm 数据为:9.86 (S,1H, CH0),7.82 (d, J=8.8Hz,2H,ArH), 6.99 (d, J = 8.7Hz,2H,ArH), 4.04 (t, J = 6.5Hz,2H,HI) ,3.20 (t, J = Which 1Hnmr (Cdci3JOOmHz) δ, ppm data: 9.86 (S, 1H, CH0), 7.82 (d, J = 8.8Hz, 2H, ArH), 6.99 (d, J = 8.7Hz, 2H, ArH), 4.04 ( t, J = 6.5Hz, 2H, HI), 3.20 (t, J =

7.0Hz,2H,H8),1.88-1.78(m,4H,H7, H2),1.42-1.30(m,8H,H3, H4, H5, H6)。 7.0Hz, 2H, H8), 1.88-1.78 (m, 4H, H7, H2), 1.42-1.30 (m, 8H, H3, H4, H5, H6). 由此确定产物的结构。 Thereby determining the structure of the product.

[0024] 同上述方法制备得到la、lb、lc、Id、Ie。 [0024] to give la, lb, lc, Id, Ie prepared with the method described above.

[0025] 实施例二:B0C保护普瑞巴林对正辛氧基苯甲醛酯(2f)的合成 [0025] Second Embodiment: B0C protection Pregabalin Synthesis n-octyloxybenzaldehyde ester (2f) of

[0026] 取2mmol 4_ (8_溴代辛氧基)苯甲醒(Ie)和20ml干燥丙酮于50ml烧瓶中,加入 [0026] Take 2mmol 4_ (8_ bromo-octyloxy) benzoic awake (Ie) in 50ml of acetone and 20ml dried flask,

1.2g(5mmol)KI,室温下搅拌过夜。 1.2g (5mmol) KI, was stirred overnight at room temperature. 再将0.54g(2mmol)BOC保护的普瑞巴林和lg(7.5mmol)微波活化后的K2CO3加入反应体系,升温至60°C回流24小时。 Then 0.54g (2mmol) BOC protected pregabalin and lg (7.5mmol) K2CO3 microwave activation after the reaction system was heated to 60 ° C reflux for 24 hours. 后处理过滤除掉碳酸钾,减压蒸除溶剂,粗产品经硅胶柱层析(展开剂为1: 9乙酸乙酯:石油醚〜1: 2乙酸乙酯:石油醚梯度淋洗)得BOC保护普瑞巴林对正辛氧基苯甲醛酯(2f)。 After potassium carbonate was removed by filtration treatment, the solvent was distilled off under reduced pressure and the crude product purified by silica gel column chromatography (eluent 1: 9 ethyl acetate: petroleum ether ~ 1: 2 ethyl acetate: petroleum ether gradient elution) to give BOC protection pregabalin n-octyloxybenzaldehyde ester (2f). 产物结构经1HNMR分析数据确定。 The product structure determined by 1HNMR analysis data.

[0027] 1H NMR(CDCl3, 300MHz) δ,ppm:9.86 (s, 1H, CHO),7.82 (d, J = 8.6Hz,2H,ArH),6.99 (d, J = 8.6Hz,2H, ArH),3.92 (t,J = 6.2Hz,2H, CH2),3.72,3.56 (s, 2H, CH2),3.21-3.14 (m, 1H, CH2),3.04-2.97 (m, 1H, CH2),2.27-2.25 (m, 2H, CH2),2.04 (br s' 1H, CH),1.79-1.74 (m, 2H, CH2),1.73-1.65 (m, 2H, CH2),1.45-1.40 (m, 4H, 2CH2),1.39 (s, 9H, 3CHS), [0027] 1H NMR (CDCl3, 300MHz) δ, ppm: 9.86 (s, 1H, CHO), 7.82 (d, J = 8.6Hz, 2H, ArH), 6.99 (d, J = 8.6Hz, 2H, ArH) , 3.92 (t, J = 6.2Hz, 2H, CH2), 3.72,3.56 (s, 2H, CH2), 3.21-3.14 (m, 1H, CH2), 3.04-2.97 (m, 1H, CH2), 2.27- 2.25 (m, 2H, CH2), 2.04 (br s' 1H, CH), 1.79-1.74 (m, 2H, CH2), 1.73-1.65 (m, 2H, CH2), 1.45-1.40 (m, 4H, 2CH2 ), 1.39 (s, 9H, 3CHS),

1.38-1.30 (m, 5H, CH, 2CH2),1.17-1.12(m,2H,CH2), 0.88(t,6H,J = 6.2Hz, CH3)。 1.38-1.30 (m, 5H, CH, 2CH2), 1.17-1.12 (m, 2H, CH2), 0.88 (t, 6H, J = 6.2Hz, CH3).

[0028] 同上述方法制备得到2a、2b、2c、2d、2e。 [0028] prepared as above with the obtained 2a, 2b, 2c, 2d, 2e.

[0029] 实施例三:BOC保护普瑞巴林对乙氧基苄基二乙胺酯(3a)的合成。 [0029] Third Embodiment: BOC protected Pregabalin Synthesis diethylamine ethoxy-benzyl ester (3a) of.

[0030] 取lmmol BOC保护普瑞巴林对正丁氧基苯甲醒酯(2a),溶于20ml干燥的1,2- 二氯乙烷中,加入0.1ml(Immol)仲胺搅拌5分钟。 [0030] Take lmmol BOC protected pregabalin wake-n-butoxy benzyl ester (. 2A), dissolved in 20ml of dry 1,2-dichloroethane was added 0.1ml (Immol) a secondary amine stirred for 5 minutes. 后再加入0.7g三乙酰氧基硼氢化钠,搅拌过夜。 Then adding 0.7g sodium triacetoxy boron hydride, and stirred overnight. TLC检测反应完全后,加入饱和碳酸氢钠溶液终止反应,乙酸乙酯萃取三次。 After completion of the reaction by TLC, saturated sodium bicarbonate solution was added to terminate the reaction, and extracted three times with ethyl acetate. 合并有机相干燥。 The combined organic phase was dried. 旋干溶剂后粗产品经硅胶柱层析(展开剂为1: 50甲醇:二氯甲烷)得黄色油状BOC保护普瑞巴林对正丁氧基苄基二乙胺酯(3a)。 After rotary evaporation the crude product purified by silica gel column chromatography (developing solvent: 1:50 methanol: dichloromethane) to give a yellow oil of the BOC protecting pregabalin n-butoxy benzyl ester Diethylamine (3a). 产物结构经1HNMR分析数据确定。 The product structure determined by 1HNMR analysis data.

[0031] 1H NMR(CDCl3, 300MHz) δ,ppm:7.22 (d, J = 8.6Hz,2H,ArH), 6.84 (d, J = 8.6Hz,2H, ArH),4.42-4.35 (m, 4H, 2CH2),3.52 (s, 2H, CH2),3.03-2.99 (m, 1H, CH2),2.94-2.90 (m,1H, CH2),2.53-2.47 (m, 4H, NCH2CH3),2.39-2.36 (br s, 1H, CH),2.30-2.28 (m, 2H, CH2), [0031] 1H NMR (CDCl3, 300MHz) δ, ppm: 7.22 (d, J = 8.6Hz, 2H, ArH), 6.84 (d, J = 8.6Hz, 2H, ArH), 4.42-4.35 (m, 4H, 2CH2), 3.52 (s, 2H, CH2), 3.03-2.99 (m, 1H, CH2), 2.94-2.90 (m, 1H, CH2), 2.53-2.47 (m, 4H, NCH2CH3), 2.39-2.36 (br s, 1H, CH), 2.30-2.28 (m, 2H, CH2),

2.18-2.14 (m, 2H, CH2),1.65-1.60 (m, 1H, CH), 1.39 (s, 9H, 3CHS),1.19-1.12 (m, 2H, CH2),1.05(t,6H,J = 7.1Hz, NCH2CH3), 0.89(t,6H,J = 6.2Hz, CH3)。 2.18-2.14 (m, 2H, CH2), 1.65-1.60 (m, 1H, CH), 1.39 (s, 9H, 3CHS), 1.19-1.12 (m, 2H, CH2), 1.05 (t, 6H, J = 7.1Hz, NCH2CH3), 0.89 (t, 6H, J = 6.2Hz, CH3).

[0032]同上述方法制备得到 3b、3cl、3c2、3c3、3c4、3c5、3c6、3d、3e、3f。 [0032] to give 3b, 3cl, 3c2,3c3,3c4,3c5,3c6,3d, 3e, 3f was prepared with the method described above.

[0033] 实施例四:普瑞巴林对正丁氧基苄基二乙胺酯盐酸盐(4cl)的合成。 Synthesis of Pregabalin n-butoxy benzyl ester hydrochloride diethylamine (4CL) is: tetrakis [0033] Example.

[0034] 将BOC保护普瑞巴林对正丁氧基苄基二乙胺酯(3cl)0.5mmol溶于二氯甲烷,冰浴下加入Iml 4NHC1/甲醇搅拌半小时。 [0034] The BOC protected pregabalin n-butoxy benzyl ester Diethylamine (3cl) 0.5mmol dissolved in dichloromethane was added under ice Iml 4NHC1 / methanol was stirred for half an hour. 室温下继续搅拌过夜。 Stirring was continued at room temperature overnight. 旋干溶剂后加入乙醚20ml旋转搅拌,产物用乙醚反复洗涤5次。 20ml of diethyl ether was added After stirring for rotating rotary evaporation, product was washed repeatedly with ether 5 times. 最后在冰箱中低温放置,可得黄色油状普瑞巴林对正丁氧基苄基二乙胺酯盐酸盐(4cl)。 Finally, a low temperature placed in the refrigerator, can be obtained as a yellow oil pregabalin n-butoxy benzyl ester hydrochloride diethylamine (4cl). 产物结构经1HNMR,13CNMR, ES1-MS分析数据确定。 The product structure was confirmed by 1HNMR, 13CNMR, ES1-MS analysis of the data is determined.

[0035] 1H NMR (CDCl3, 300MHz) δ,ppm:7.22d, J = 8.6Hz,2H,ArH), 6.83 (d, J = 8.6Hz,2H, ArH) ,4.28 (t, J = 6.2Hz,2H, CH2) ,4.03 (t, J = 6.2Hz,2H, CH2),3.51 (s,2H,CH2), [0035] 1H NMR (CDCl3, 300MHz) δ, ppm: 7.22d, J = 8.6Hz, 2H, ArH), 6.83 (d, J = 8.6Hz, 2H, ArH), 4.28 (t, J = 6.2Hz, 2H, CH2), 4.03 (t, J = 6.2Hz, 2H, CH2), 3.51 (s, 2H, CH2),

3.10-3.05 (m, 1H, CH2),3.01-2.98 (m, 1H, CH2),2.54-2.47 (m, 4H, NCH2CH3),2.38-2.30 (brs' 1H, CH),2.29-2.27 (m, 2H, CH2),2.14-2.09 (m, 2H, CH2),2.08-1.95 (m, 2H, CH2),1.65-1.60 (m, 1H, CH),1.19-1.10(m,2H,CH2),1.05(t,6H,J = 7.1Hz, NCH2CH3), 0.88(t,6H,J = 6.2Hz, CH3) ;13C NMR(CDC13,75MHz) δ:172.8,160.0,132.8,130.3,115.3,67.5,64.6,55.5,46.2,43.5,41.2,36.9,31.5,28.6,25.5,25.3,22.8,9.2 ;ESI_MS m/z:394[M+H]+.[0036]同上述方法制备得到 4a、4b、4c2、4c3、4c4、4c5、4c6、4d、4e、4f。 3.10-3.05 (m, 1H, CH2), 3.01-2.98 (m, 1H, CH2), 2.54-2.47 (m, 4H, NCH2CH3), 2.38-2.30 (brs' 1H, CH), 2.29-2.27 (m, 2H, CH2), 2.14-2.09 (m, 2H, CH2), 2.08-1.95 (m, 2H, CH2), 1.65-1.60 (m, 1H, CH), 1.19-1.10 (m, 2H, CH2), 1.05 (t, 6H, J = 7.1Hz, NCH2CH3), 0.88 (t, 6H, J = 6.2Hz, CH3); 13C NMR (CDC13,75MHz) δ: 172.8,160.0,132.8,130.3,115.3,67.5,64.6, 55.5,46.2,43.5,41.2,36.9,31.5,28.6,25.5,25.3,22.8,9.2; ESI_MS m / z:. 394 [m + H] + [0036] to give 4a, 4b with the preparation method described above, 4c2,4c3 , 4c4,4c5,4c6,4d, 4e, 4f.

[0037] 实施例五:普瑞巴林衍生物胆碱酯酶抑制活性体外筛选 [0037] Example V: Pregabalin derivative inhibitory activity of in vitro screening

[0038] 本发明化合物,作为胆碱酯酶抑制剂的活性测试方法见Ellman等“A New andRapid Colorimetric Determination of Acetylcholineterase Activity”, Biochem.Pharm.1,88, (1961)。 [0038] The compounds of the present invention, see Ellman et al. "A New andRapid Colorimetric Determination of Acetylcholineterase Activity", Biochem.Pharm.1,88, (1961) as an active testing method of cholinesterase inhibitors.

[0039] 取5支1.5m L分别装有900 μ L 0.1M pH = 8.0磷酸盐缓冲液的梨型管,依次加入 [0039] 1.5m L 5 are taken with 900 μ L 0.1M pH = 8.0 phosphate buffer pear-shaped tube, were added sequentially

0、5、10、15、20 μ L的一定浓度的样品DMSO溶液,并用DMSO加至920 μ L。 0,5,10,15,20 μ L of DMSO solution of a certain concentration of sample, and with DMSO added to 920 μ L. 分别加入40 μ L4mg/mL 5,5- 二硫代双(2-硝基苯甲酸)和2 μ L乙酰胆碱酯酶(丁酰胆碱酯酶)溶液,并在37°C保温15分钟,立刻加入40 μ L 2mg/mL硫代乙酰胆碱(氯代丁酰胆碱)溶液,摇匀后测其在λ = 412nm处的A值(An)。 Were added 40 μ L4mg / mL 5,5- dithiobis (2-nitrobenzoic acid), and 2 μ L of acetylcholinesterase (butyrylcholinesterase) was added and incubated at 37 ° C for 15 minutes, and immediately after the test was added 40 μ L 2mg / mL acetylthiocholine (chloro-butyryl choline) was shaken in which λ = a value (An) 412nm at. 参比用0.1M pH = 8.0磷酸盐缓冲液,以未加样品所测得的A_tMl值作为100个活力单位: Reference with 0.1M pH = 8.0 phosphate buffer, A_tMl measured value of the sample not added to 100 activity units, as:

[0040]相对酶活力=(An/Acontrol) X 100 [0040] The relative enzyme activity = (An / Acontrol) X 100

[0041] 然后以酶的相对活力对抑制剂浓度作图,根据抑制曲线求得各种化合物的IC5tl值(抑制酶活力50%时的抑制剂浓度)。 [0041] The relative enzyme activity was then plotted against the concentration of inhibitor, to obtain values ​​for the various compounds according IC5tl curve inhibition (inhibitory concentration 50% of the enzyme inhibitor activity).

[0042] 加兰他敏氢溴酸盐为阳性对照物。 [0042] galanthamine hydrobromide salt as a positive control.

[0043] 普瑞巴林衍生物乙酰胆碱酯酶和丁酰胆碱酯酶体外抑制活性的测试数据(IC5tl值)如表2.。 [0043] Pregabalin derivative acetylcholinesterase and butyrylcholinesterase in vitro inhibitory activity of the test data (IC5tl value) as shown in Table 2 .. 同时,我们也求得了样品对乙酰胆碱酯酶与丁酰胆碱酯酶抑制活性的选择性,即乙酰胆碱酯酶抑制活性(IC5。值)与丁酰胆碱酯酶抑制活性(IC5tl值)的比值。 We also determined the selective inhibition of acetylcholinesterase samples butyrylcholinesterase activity, i.e. the ratio of the activity (IC5tl value) of acetylcholinesterase inhibition activity (IC5. Value) and BuChE inhibition .

[0044] 表2.普瑞巴林衍生物乙酰胆碱酯酶丁酰胆碱酯酶体外抑制活性(IC5tl值) [0044] Table 2. derivatives of pregabalin in vitro acetylcholinesterase inhibitory activity of butyrylcholinesterase (IC5tl value)

Figure CN101914031BD00071
Figure CN101914031BD00081

[0047] aAChE, EC3.1.1.7,from electric eel. [0047] aAChE, EC3.1.1.7, from electric eel.

[0048] bBChE, EC3.1.1.8,from horse serum.[0049] cIC50 values are means of three different experiments.[0050] dIC50 values of AChE reported in the literature:0.3-0.8 μ M.[0051] 从表2.可以得出如下结论: [0048] bBChE, EC3.1.1.8, from horse serum [0049] cIC50 values ​​are means of three different experiments [0050] dIC50 values ​​of AChE reported in the literature:.. 0.3-0.8 μ M. [0051] From Table 2. You can draw the following conclusions:

[0052] (I)大部分普瑞巴林衍生物均具有较强的乙酰胆碱酯酶(AChE)抑制活性,如4cl和4c4的IC5tl值(0.98uM、l.09uM)非常接近于阳性参比物加兰他敏氢溴酸盐的IC5tl值(0.67uM)。 [0052] (I) derivative most pregabalin showed strong acetylcholinesterase (AChE) inhibiting activity, as 4cl and 4c4 IC5tl value of (0.98uM, l.09uM) very close to the positive reference substance added galantamine hydrobromide salt IC5tl value (0.67uM).

[0053] (2)所合成的普瑞巴林衍生物对丁酰胆碱酯酶(BuChE)的抑制活性,要明显高于阳性参比物加兰他敏氢溴酸盐,尤其是4cl,其IC5tl值达到51nM。 [0053] (2) Synthesis of pregabalin derivatives butyrylcholinesterase (of BuChE) inhibition activity significantly higher than the positive reference substance galanthamine hydrobromide, especially 4CL, which IC5tl value reached 51nM.

[0054] (3)所合成的普瑞巴林衍生物对丁酰胆碱酯酶有很高的选择性,即对乙酰胆碱酯酶IC5tl值与对丁酰胆碱酯IC5tl值的比值较大。 [0054] (3) Synthesis of pregabalin derivative has a high selectivity to butyrylcholinesterase, acetylcholinesterase IC5tl i.e. the ratio of the value of butyryl cholinesterase IC5tl larger value. 阳性参比物加兰他敏氢溴酸盐的选择性值为 Positive reference substance galanthamine hydrobromide is a selective

0.44,4cl和4c2的选择性值高达19.21和18.35,分别为参比物的43.7倍和41.7倍。 0.44,4cl 4c2 and selectivity values ​​as high as 19.21 and 18.35, respectively, was 43.7 times the reference and 41.7 times.

Claims (7)

  1. 1.式I所示的3-氨甲基-5-甲基己酸衍生物及其在药学上可接受的酸或碱所形成的加成盐: 3-Aminomethyl-5-I shown in FIG 1. methylhexanoic acid addition salts of the derivatives and their pharmaceutically acceptable acid or base is formed:
    Figure CN101914031BC00021
    式IR=N [(CH2)fflCH3 Formula IR = N [(CH2) fflCH3
    Figure CN101914031BC00022
    中,m选自O〜6,X选自1、2、3、4、5 ;y选自0、1、2、3 ;z选自0、1、2、3 ;n选自I〜15。 , M is selected O~6, X is selected from 1,2,3,4,5; y is selected from 0,1,2,3; z is selected from 0,1,2,3; n is selected from I~15 .
  2. 2.根据权利要求1所述的3-氨甲基-5-甲基己酸衍生物及其在药学上可接受的酸或碱所形成的加成盐,其特征在于:所述m选自O〜5,X选自1、2、3、4 ;y选自0、1、2 ;z选自0、1、2 ;n 选自2 〜13。 The 3-aminomethyl-1 according to claim -5- methylhexanoic acid addition salts of the derivatives and their pharmaceutically acceptable acid or base form, wherein: m is selected from the O~5, X is selected from 1,2,3,4; y is selected from 0,1,2; z is selected from 0,1,2; n is selected from 2 ~ 13.
  3. 3.根据权利要求2所述的3-氨甲基-5-甲基己酸衍生物及其在药学上可接受的酸或碱所形成的加成盐,其特征在于:所述m选自O〜4,X选自1、2、3 ;y选自O、1、z选自1、2 ;η选自4〜12。 The 3-aminomethyl-2 according to claim -5- methylhexanoic acid addition salts of the derivatives and their pharmaceutically acceptable acid or base form, wherein: m is selected from the O~4, X is selected from 1,2,3; y is selected from O, 1, z is selected from 1,2; η selected 4~12.
  4. 4.根据权利要求3所述的3-氨甲基-5-甲基己酸衍生物及其在药学上可接受的酸或碱所形成的加成盐,其特征在于:R=N [ (CH2)mCH3] 2、 The 3-aminomethyl-3 according to claim -5- methylhexanoic acid addition salts of the derivatives and their pharmaceutically acceptable acid or base form, wherein: R = N [( CH2) mCH3] 2,
    Figure CN101914031BC00023
    其中,m 选自1、2、3 ;η 选自4 〜8。 Wherein, m is selected from 1,2,3; η 4 ~ 8 selected.
  5. 5.根据权利要求1所述的3-氨甲基-5-甲基己酸衍生物及其在药学上可接受的酸或碱所形成的加成盐,其特征在于,它选自下列化合物: 普瑞巴林对乙氧基苄基二乙胺酯盐酸盐; 普瑞巴林对正丙氧基苄基二乙胺酯盐酸盐; 普瑞巴林对正丁氧基苄基二乙胺酯盐酸盐; 普瑞巴林对正丁氧基苄基正二丙胺酯盐酸盐; 普瑞巴林对正丁氧基苄基正二丁胺酯盐酸盐; 普瑞巴林对正丁氧基苄基吡咯烷酯盐酸盐; 普瑞巴林对正丁氧基苄基哌啶酯盐酸盐; 普瑞巴林对正丁氧基苄基吗啡啉酯盐酸盐; 普瑞巴林对正戊氧基苄基二乙胺酯盐酸盐; 普瑞巴林对正己氧基苄基二乙胺酯盐酸盐; 普瑞巴林对正辛氧基苄基二乙胺酯盐酸盐。 The 3-aminomethyl-1 according to claim -5- methylhexanoic acid addition salts of the derivatives and their pharmaceutically acceptable acid or base is formed, characterized in that it is selected from the following compounds : pregabalin ethoxy-benzyl ester hydrochloride diethylamine; pregabalin n-propoxy-benzyl ester hydrochloride diethylamine; pregabalin n-butoxy benzyl ester diethylamine hydrochloride; pregabalin n-butoxy benzyl ester hydrochloride n-dipropylamine; pregabalin n-dibutylamine hydrochloride n-butoxy benzyl ester; pregabalin n-butoxy benzyl pyrrole alkyl ester hydrochloride; pregabalin piperidine hydrochloride n-butoxy benzyl ester; pregabalin n-butoxy benzyl ester hydrochloride morpholine; pregabalin benzyl n-pentoxy diethylamine ester hydrochloride; pregabalin diethylamine n-hexyl ester hydrochloride methoxybenzyl; pregabalin ester hydrochloride diethylamine n-octyl group, a benzyl group.
  6. 6.一种抗老年痴呆症的药物组合物,其特征是,其活性成份为权利要求1-5任一所述的3-氨甲基-5-甲基己酸衍生物及其在药学上可接受的酸或碱所形成的加成盐。 An anti-dementia pharmaceutical composition, characterized in that the active ingredient is a 3-Aminomethyl claims 1-5 on any -5- methylhexanoic acid derivatives and their pharmaceutically acceptable acceptable acid addition salt or base form.
  7. 7.权利要求1-5任一所述的3-氨甲基-5-甲基己酸衍生物及其在药学上可接受的酸或碱所形成的加成盐在制备抗老年痴呆症药物中的应用。 3-Aminomethyl claimed in any one of claim 1-5-5-methylhexanoic acid addition salts of the derivatives and their pharmaceutically acceptable acid or base formed in the preparation of anti-dementia drugs application.
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