CN1449375A - 双羟萘酸或其一种衍生物或其一种类似物用于制备治疗以淀粉状蛋白聚集物沉积为特征的疾病的药物的用途 - Google Patents
双羟萘酸或其一种衍生物或其一种类似物用于制备治疗以淀粉状蛋白聚集物沉积为特征的疾病的药物的用途 Download PDFInfo
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- CN1449375A CN1449375A CN01812446A CN01812446A CN1449375A CN 1449375 A CN1449375 A CN 1449375A CN 01812446 A CN01812446 A CN 01812446A CN 01812446 A CN01812446 A CN 01812446A CN 1449375 A CN1449375 A CN 1449375A
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- naphthyl
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Abstract
描述了具有通式(I)的双羟萘酸或其一种衍生物(其中基团R1和R5如在说明书中所述),或者它们的一种药学上可接受的盐用于制备治疗以淀粉状蛋白聚集物沉积为特征的疾病的药物的用途。
Description
本文所述的发明涉及双羟萘酸或其一种衍生物,或其一种类似物,或这些化合物的一种药学上可接受的盐用于制备治疗以淀粉状蛋白聚集物沉积为特征的疾病的药物的用途。
淀粉状蛋白沉积和神经元细胞骨架异常的存在是阿尔茨海默氏病(AD)最显著的表现。这两种事件在早期主要影响大脑皮层,尽管这种疾病的最终病变涉及整个中枢神经系统,它们是这种疾病发生的必要但本身并不充分的条件(Chen M.(1998)Frontiers in Bioscience(生物科学前沿)3a,32-37)。
一般地,不管形成淀粉状蛋白的蛋白质如何,所述物质淀粉状蛋白的特征是由测量直径为7-8nm的纤维组成,对刚果红具有亲合力并不溶于水。在AD中,淀粉状蛋白纤维在细胞外、脑细胞内空间以及皮层和脑膜小动脉中层内蓄积,导致形成三种不同的肉眼可见的异常:老年斑和弥散斑,它们取决于围绕中央淀粉状蛋白沉积的神经元突起的异常存在与否而不同,以及淀粉状蛋白血管病,它是淀粉状蛋白纤维浸润到平滑肌纤维和内弹性层之间的动脉壁内的表现。
除了形成淀粉状蛋白和螺旋纤丝之外,已在患有AD的患者的皮层中检测到非常严重的突触稀疏。在此疾病的终末期大约80%-90%的神经元接触被破坏且这种异常实际上与痴呆具有病理学联系。在分析痴呆倾向时,似乎可以肯定淀粉状蛋白是疾病的早期、主要异常,而神经内螺旋纤丝是神经元遇难的中间表现,它们最终丧失其突触接触,所导致的临床效应是精神智力功能恶化。
可溶形式的特定类型的β淀粉状蛋白,βA1-42,至今认为仅其聚集形式具有毒性,它与阿尔茨海默氏病人的记忆和认知功能的渐进性丧失有关。在疾病初期产生的βA1-42抑制促成提供乙酰辅酶A转运的ACh合成的丙酮酸脱氢酶的活性,减少神经递质的释放,改变突触连接并造成导致疾病的胆碱能不足(Hoshi M.,Takashima A.,Murayama M.,Yasutake K.,Yoshida N.,Ishiguro K.,Hoshino T.,Imahori K.(1997)The Journal of Biological Chemistry(生物学化学杂志)272:4,2038-2041)。
已知许多染料以特定的方式与淀粉状蛋白纤维结合,其中最为重要的是刚果红(CR)(Lorenzo A.和Yankner B.A,1994 PNAS 91;12243-12247)。
该染料导致淀粉状蛋白纤维的双折射增加,并产生指示染料和底物(纤维)之间的特异性相互作用的特征性圆二色性,从而有利于对组织中的淀粉样变进行诊断性检测。
β-淀粉状蛋白(βA)是由多种特定的酶对淀粉状蛋白的前体(βAPP)的蛋白水解作用而产生的(Vassar R等人,1999 Science(科学)286;735-740)。
β-淀粉状蛋白片段可能诱导神经毒性作用的机理是多样的。首先,免疫组织化学研究已揭示老年斑中炎性白细胞介素(IL-1、IL-6)、补体因子、其它炎性因子和溶酶体水解酶的存在。已证明β-淀粉状蛋白能够刺激小神经胶质细胞合成和分泌IL-1、IL-6和IL-8,因而能够激活急性炎症的细胞毒性机制(Sabbagh M.N.,Galasko D.,Thal J.L.(1997)Alzheimer’s Disease Review(阿尔茨海默氏病综述)3,1-19)。
以淀粉状蛋白聚集物沉积为特征的疾病除阿尔茨海默氏病之外,包括唐氏综合征、与“荷兰型”淀粉样变有关的遗传性脑出血、与慢性炎症有关的淀粉样变、与多发性骨髓瘤和其它血B淋巴样细胞恶液质有关的淀粉样变、与II型糖尿病有关的淀粉样变、与朊病毒病有关的淀粉样变如克罗伊茨费尔特-雅各布病、格-施综合征、库鲁病和绵羊痒病。
但是一般地,由βA导致的损害可以概括为:
1.淀粉状蛋白产生异常;
2.神经元对细胞外毒性的易感性增加;
3.神经元对低血糖损伤的易感性增加;
4.钙体内平衡异常;
5.氧化性损伤增加;
6.炎症机制激活;
7.小神经胶质激活;
8.诱导溶酶体蛋白酶;
9.τ蛋白磷酸化异常;
10.诱导凋亡;
11.对膜的损伤。
从严格的理论观点来讲,降低βA诱导的损伤可以通过不同的治疗途径进行:
1.使用分泌酶抑制剂改变APP代谢而降低βA产生(增加α或减少β和γ分泌酶);
2.防止或阻断βA聚集;
3.增加βA清除率;
4.通过恢复钙体内平衡而阻断βA的神经毒性作用;
5.防止自由基产生的毒性;
6.防止细胞外毒性;
7.减少由炎性反应导致的损伤;
8.纠正改变的铜-锌平衡;
9.抑制神经元凋亡;
(Sabbagh M.N.,Galasko D.,Thal J.L.(1997)Alzheimer’sDisease Review(阿尔茨海默氏病综述)3,1-19)。
至今尚无特定的疗法能够预防、减缓或停止阿尔茨海默氏病潜在的淀粉状蛋白产生过程。
实际上,目前用于治疗这种疾病的疗法仅仅针对症状,且它虽然作用于不同的方面,但基本上只是干扰调节学习和记忆的神经递质机理。这些最常用的分子中有可逆性乙酰胆碱酯酶抑制剂如他克林、donezepil和利凡斯的明(rivastigmine)。
而且目前,可以获得的用于诊断阿尔茨海默氏病的唯一诊断工具是行为检查和临床评分,而放射摄影或闪烁成像方法仍不能精确区分阿尔茨海默氏类型的退化和其它变性现象,其准确的原因是缺乏适宜的示踪。
在阿尔茨海默氏病的治疗中遇到的困难、其严重性和在诊断中的困难使得人们期望鉴定能治愈该疾病或减缓其进程的新药,并期望发现用于对其进行诊断的放射摄影或闪烁成像方法的化合物。
因此令人惊奇的是,双羟萘酸,或其一种衍生物,或其一种类似物,或一种其药学上可接受的盐,或在文献中所述和已知的该酸的衍生物已证明在治疗和预防阿尔茨海默氏病和以淀粉状蛋白聚集物沉积为特征的疾病中是潜在有效的药物。
在此发现中,已发现新的双羟萘酸衍生物,如以下所述,其在治疗上述疾病中潜在有效,并已证明它是用于制备治疗以淀粉状蛋白聚集物沉积为特征的疾病的药物的有用药剂。
其中:
1 R1=R5=-COOCH2C6H5
R2=R4=-OH
R3=-CH2-
2 R1=R5=-COOCH(CH3)2
R2=R4=-OH
R3=-CH2-
3 R1=R5=-COOC2H5
R2=R4=-OH
R3=-CH2-
4 R1=R5=-COOC6H11
R2=R4=-OH
R3=-CH2-
5 R1=R5=-COOCH3
R2=R4=-OH
R3=-CH2-
6 R1=R5=-COOC(CH3)3
R2=R4=-OH
R3=-CH2-
在专利N°ES 432416中有所描述,而没有描述或要求保护这些化合物的用途;
7 R1=R5=-CONHC6H5
R2=R4=-OH
R3=-CH2-
在专利N° JP 7138347中描述上述化合物作为制备尼龙纤维的有用试剂;
8 R1=R5=-CONH-CH(CH(CH3)2)-COOH
R2=R4=-OH
R3=-CH2-
在Reetz,Manfred T.等人;Chem.Commun,(Cambridge)(1998),(19),2075-2076中描述该化合物作为HIV-1蛋白酶抑制剂;
9 R1=R5=-COOH
R2=R4=-OCOCH3
R3=-CH2-
在Poupelin,Jean Pierre;Eur.J.Med.Chem.-Chim.Ther.(1978),13(4),381-5中描述该化合物作为具有抗炎活性的药剂;
10 R1=R5=-COOH
R2=R4=-OCOCH2CH3
R3=-CH2-
在专利N° NE 1945254中描述了该化合物,指出此化合物的盐与链霉素联合使其作为治疗结核的药剂的效果更为持久;
11 R1=R5=-H
R2=R4=-OCOC6H5
R3=-CH2-
12 R1=R5=-H
R3=-CH2-
在Dorogov,M.V.;Khim.Khim.Tekhnol.(1996),39(4-5),170-172中描述了该化合物,没有说明它们的用途;
13 R1=R5=-H
R2=R4=-OCOCH=CH2
R3=-CH2-;
在Kielkiewicz,Jedrzej等人;Polimery(Warsaw)(1984),29(6),216-19中描述了该化合物,没有说明其用途;
14 R1=R5=-H
R2=R4=-OH
R3=-CH2-
此化合物是1,1’-亚甲基-二(2-萘酚),在US4,147,806中描述它是抗炎和止痛药物。
15 R1=R5=-COOH
R2=R4=-OH
R3=-CH2-
此化合物是双羟萘酸;它被描述为用作药物中的平衡离子,所述药物作为抗驱虫剂(双羟萘酸噻嘧啶)使用,或者用于治疗癌症(双羟萘酸奥曲肽)。
因此本文所述的本发明的目的是具有通式(I)的双羟萘酸,或其一种衍生物,或其一种类似物,或这些化合物的一种药学上可接受的盐用于制备治疗以淀粉状蛋白聚集物沉积为特征的疾病的药物的用途:
其中:
R1和R5,可以相同或不同,为COOR6、CONHR6、SO2R6、SO2NHR6、SO3R6、OR6、COR6、NHR6、R6;
其中R6为H或者具有1-5个碳原子的直链或支链、饱和或不饱和烷基链,或者苯基,被R7取代;
其中:
R8和R9可以相同或不同,为H、具有1-5个碳原子的烷基;
R2和R4可以相同或不同,为H、OH、NHR6、OCO-R10-NR8R9,
其中R10为具有1-5个碳原子的直链或支链、饱和或不饱和烷基链;
R3为-[CH2]n-、-CH2-O-、-CH(R11)-,
其中n为1-4的整数,
R11为具有1-5个碳原子的直链或支链烷基,所述基团被氨基、烷基氨基C1-C5、二烷基氨基C1-C5、OH、烷氧基C1-C5取代。
在式(I)化合物中,优选双羟萘酸,特别是双羧萘酸钠。
本文所述的本发明的另一目的是上述的式(I)化合物用于制备诊断以淀粉状蛋白聚集物沉积为特征的疾病的诊断试剂盒的用途。
实际上,本文所述的本发明的化合物在其分子结构中包含在诊断成像方法中常用的元素的原子。例如,可以将碳、氢、氮、氧、碘和铟的放射性同位素引入它们的分子结构。更准确地说,式(I)化合物自身分子结构中的至少一种元素,碳、氢、氮、氧可以被相应的放射性同位素置换;或者它携带至少一个放射性碘原子;或者它是与放射性铟形成的络合物的形式。
这些同位素可用于诸如PET(正电子发射断层成像术)、SPECT(单光子发射计算机断层成像术)和平面闪烁成像的技术。可选择地,不管是否包含放射性同位素或用作辐射不透性物质的元素的原子(如碘),本发明的化合物可以用作在诊断成像技术中常用元素如钆(NMR)和锝(闪烁成像技术)的络合剂。
在此诊断应用的基础上,本发明的化合物还用于预防上述的疾病。
本文所述的本发明的另一目的是具有通式(I)的新化合物
其中:
R1和R5可以相同或不同,为COOR6、CONHR6、SO2R6、SO2NHR6、SO3R6、OR6、COR6、NHR6、R6;
其中:
R6为H或具有1-5个碳原子的直链或支链、饱和或不饱和烷基链,或者苯基,被R7取代;
其中:
其中:
R8和R9可以相同或不同,为H、具有1-5个碳原子的烷基;
R2和R4可以相同或不同,为H、OH、NHR6、OCO-R10-NR8R9,
其中:
R10为具有1-5个碳原子的直链或支链、饱和或不饱和烷基链;
R3为-[CH2]n-、-CH2-O-、-CH(R11)-,
其中n为1-4的整数,
R11为具有1-5个碳原子的直链或支链烷基,所述基团被氨基、烷基氨基C1-C5、二烷基氨基C1-C5、OH、烷氧基C1-C5取代;
附带条件是取代基R1、R2、R3、R4和R5不是:
1 R1=R5=-COOCH2C6H5
R2=R4=-OH
R3=-CH2-
2 R1=R5=-COOCH(CH3)2
R2=R4=-OH
R3=-CH2-
3 R1=R5=-COOC2H5
R2=R4=-OH
R3=-CH2-
4 R1=R5=-COOC6H11
R2=R4=-OH
R3=-CH2-
5 R1=R5=-COOCH3
R2=R4=-OH
R3=-CH2-
6 R1=R5=-COOC(CH3)3
R2=R4=-OH
R3=-CH2-
7 R1=R5=-CONHC6H5
R2=R4=-OH
R3=-CH2-
11 R1=R5=-H
R2=R4=-OCOC6H5
R3=-CH2-
12 R1=R5=-H
R2=R4=
R3=-CH2-
13 R1=R5=-H
R2=R4=-OCOCH=CH2
R3=-CH2-;
14 R1=R5=-H
R2=R4=-OH
R3=-CH2-
15 R1=R5=-COOH
R2=R4=-OH
R3=-CH2-。
其中:
R1和R5为-COOR6,
其中R2、R3、R4和R5具有上述的含义,
其特征在于用卤化剂如SOCl2或PCl5处理其中的R6为H的通式(I)化合物以得到相应的酰氯,然后在搅拌下于25-60℃温度范围内与R6-OH醇以1-6的摩尔比反应2-24小时,或者在惰性无水溶剂如二甲基甲酰胺中与化学计算量的R6-OH反应。
其中R1和R5为CONHR6;
其中R2、R3、R4和R6具有上述含义,
其特征在于用卤化剂如SOCl2或PCl5处理其中的R6为H的通式(I)化合物以得到相应的酰氯,或者用偶联剂如DCC、EEDQ处理,然后在搅拌下,在25-60℃温度范围内与R6-NH2胺以6-1的摩尔比反应2-24小时,或在惰性无水溶剂中与化学计算量的R6-NH2反应。
其中R2和R4为OH;
其中R1和R5为SO3R6、SO2NHR6;
R3为-CH(R11)-,
其中R11具有上述含义;
其特征在于该方法根据以下的反应路线1进行,其中使式“a”化合物与R11-CHO醛在冰醋酸中在90℃-150℃的温度范围内反应从而得到具有通式“b”的化合物,然后用卤化剂如SOCl2或PCl5处理通式″b″化合物得到相应的磺酰氯,随后与R6-OH醇反应得到具有通式″d″的化合物,或者与R6-NH2胺反应得到具有通式″e″的化合物;
路线1
本文所述的本发明的另一目的是制备式(I)化合物的方法
其中:
R1、R2、R4和R5为OR6和/或NHR6;
R3为-CH(R11)-,
其中R6和R11具有上述含义;其特征在于该方法是根据以下的反应路线2进行的,其中使式A化合物与R11-CHO醛在酸性环境中如在乙酸中反应得到对应于结构B、C和D的化合物的混合物,通过色谱法将它们分离并纯化;在碱存在下使这些化合物与烷基卤R6-X反应,然后在酸性或碱性环境中去保护得到相应的萘基醚E、F和G;用在硫酸中的NaNO2对后者进行处理之后,得到化合物H、I和L;
本文所述的本发明的另一目的是包含具有通式(I)的化合物作为活性成分和药学上可接受的赋形剂和/或稀释剂的药物组合物其中R1、R2、R3、R4和R5具有上述含义,附带条件是R1、R2、R3、R4和R5不是:
1 R1=R5=-COOCH2C6H5
R2=R4=-OH
R3=-CH2-
2 R1=R5=-COOCH(CH3)2
R2=R4=-OH
R3=-CH2-
3 R1=R5=-COOC2H5
R2-R4=-OH
R3=-CH2-
4 R1=R5=-COOC6H11
R2=R4=-OH
R3=-CH2-
5 R1=R5=-COOCH3
R2=R4=-OH
R3=-CH2-
6 R1=R5=-COOC(CH3)3
R2=R4=-OH
R3=-CH2-
7 R1=R5=-CONHC6H5
R2=R4=-OH
R3=-CH2-
11 R1=R5=-H
R2=R4=-OCOC6H5
R3=-CH2-
12 R1=R5=-H
R2=R4=
R3=-CH2-
13 R1=R5=-H
R2=R4=-OCOCH=CH2
R3=-CH2-;
14 R1=R5=-H
R2=R4=-OH
R3=-CH2-
15 R1=R5=-COOH
R2=R4=-OH
R3=-CH2-。
本文以下给出多个进一步例示本发明的实施例。
实施例1
室温下将2.39g(0.01mol)氯化乙酰L-肉碱、2ml无水CH2Cl2和1.1ml(0.015mol)亚硫酰氯的溶液搅拌4小时。除去溶剂并用无水CH2Cl2洗涤残余固体三次。获得一种油,即氯化乙酰L-肉碱的酰氯,将此化合物直接用于下一步骤。
将2.58g(0.01mol)氯化乙酰L-肉碱的酰氯、3.88g(0.01mol)双羟萘酸和10ml N-甲基-2-吡咯烷二酮的悬浮液搅拌一夜。用乙醚沉淀后,得到一种黄色固体(7g)。使用硅胶柱色谱法纯化如此得到的粗产物,首先用CH2Cl2-MeOH 90∶10洗脱以收集未反应的双羟萘酸,然后用CH2Cl2-MeOH 85∶15洗脱以收集产物。除去溶剂后,得到1.2克(2R)-2-(乙酰氧基)-4-({3-羧基-1-[(3-羧基-2-羟基-1-萘基)甲基]-2-萘基}氧)-N,N,N-三甲基-4-氧代-1-丁烷氯化铵。
产率=19.7%,M.P.=185℃分解,[α]D 20=-17.5°,
1H NMR(DMSO,300MHz),δ7.1-8.5(m,10H,
H-Ar),5.50(m,1H,-C-C
H-C-N),4.76(s,2H,Ar-C
H 2-Ar),3.70(m,2H,-C
H 2-N),3.11(s,9H,-N-C
H 3),2.85(m,2H,-C
H 2-COO-),2.01(s,3H,C
H 3-COO-)。
K.F.=1.4%
C32H32NO9Cl的C、H、N计算值(校正水存在量):C,63.00;H,5.29;N,2.30;实测值C,60.45;H,5.83;N,2.87。
实施例2
室温下将2.39g(0.01mol)的氯化乙酰L-肉碱、2ml无水CH2Cl2和1.1ml(0.015mol)亚硫酰氯的溶液搅拌4小时。除去溶剂并用无水CH2Cl2洗涤残余固体三次。获得一种油,即氯化乙酰L-肉碱的酰氯,将此化合物直接用于下一步骤。
将3g(0.01mol)1,1’-亚甲基-二(2-萘酚)(ST1859)加入2.58g(0.01mol)氯化乙酰L-肉碱的酰氯在CH3CN(5ml)中的溶液。室温下将混合物搅拌过夜。用乙醚沉淀后得到粗产物。用乙醚洗涤该产物,真空干燥并用硅胶色谱法进行纯化(9∶1 CH2Cl2/MeOH混合物)。通过TLC控制合并包含产物的馏分。除去溶剂得到2g(0.0038mol)(2R)-2-(乙酰氧基)-4-({1-[(2-羟基-1-萘基)甲基]-2-萘基}氧)-N,N,N-三甲基-4-氧代-1-丁烷氯化铵(ST1745)。产率=38%
1H NMR(DMSO,300MHz),δ10.05(s,1H,-O
H),7.15-8.3(m,12H,
H-Ar),5.55(m,1H,-C-C
H-C-N),4.65(s,2H,Ar-C
H 2-Ar),3.6-3.9(m,2H,-C
H 2-N),3.10(s,9H,-N-C
H 3),2.95(m,2H,-C
H 2-COO-),2.00(s,3H,C
H 3-COO-)
K.F.=4.4%
C30H32NO5Cl的C、H、N计算值(校正水存在量):C,69.02;H,6.18;N,2.68;实测值C,68.6;H,6.3;N,2.61。
实施例3
将0.62g(0.011mol)KOH和2ml H2O加入在2ml甲苯中的2g(0.011mol)N-(叔丁氧羰基)-甘氨酸(BOC-GLY-OH)的溶液。
将混合物进行共沸蒸馏(150℃)以除去水。0℃下冷却所得的溶液并加入0.85ml异丁醇、11μl(d=0.92,0.1mmol)N-甲基吗啉和1.68ml氯甲酸异丁酯(d=1.044,0.0128mol)。0℃下将反应混合物搅拌2小时。
然后,制备在15ml H2O中的1.65g 1,1’-亚甲基-二(2-萘酚)(ST1859)(0.0055mol)和0.62g KOH的溶液。将此溶液加入反应混合物并在室温下搅拌。1小时后用HCl 3N调节pH至3,并进行相分离。使用20ml以NaOH 3N调节至pH9的H2O萃取有机相甲苯,并用H2O洗涤直至中性。用Na2SO4干燥分离的有机相并除去溶剂得到一种粗产物。用正己烷/乙酸乙酯8∶2重结晶后得到0.2g产物,将其溶于1ml三氟乙酸中进行叔丁氧基-羰基水解。20分钟后得到固体沉淀并过滤,用正己烷/乙酸乙酯8∶2的混合物洗涤。将所得的产物溶于甲醇并通过A21/Cl-树脂,用100ml MeOH洗脱得到60mg 2-({1-[(2-羟基-1-萘基)甲基]-2-萘基}氧)-2-氧代乙烷氯化铵(ST1913)。
1H NMR(DMSO,300MHz),δ9.6(s,1H,-O
H),8.7(s,3H,-N
H 3),7.2-8.4(m,12H,
H-Ar),4.7(s,2H,Ar-C
H 2-Ar),3.72(s,2H,C-C
H 2-N).
K.F.=1.2%
C23H20NO3Cl的C、H、N计算值(校正水存在量):C,70.14;H,5.12;N,3.56;实测值C,69.1;H,5.4;N,3.3。
实施例4
2-({4-[(3-{[2-(二乙基铵)乙氧基]羰基}-2-羟基-1-萘基)甲
基]-3-羟基-2-萘甲酰基}氧)-N,N-二乙基乙烷铵二氯化物(ST1800)
的制备
将3.88g(0.01mol)双羟萘酸(ST1641)悬浮在4.36ml亚硫酰氯(0.06mol)中并在80℃回流5小时。结束时,真空下除去溶剂并用乙醚洗涤残余物。将得到的酰氯悬浮在30ml CH2Cl2中并滴加0.7mlN,N-二乙醇。室温下将混合物搅拌过夜。结束时得到一种白色固体,将其过滤并用正己烷/乙酸乙酯8∶2的混合物洗涤得到0.5g2-({4-[(3-{[2-(二乙基铵)乙氧基]羰基}-2-羟基-1-萘基)甲基]-3-羟基-2-萘甲酰基}氧)-N,N-二乙基乙烷铵二氯化物(ST1800)。
1H NMR(CDCl3,300MHz),δ10.05(s,2H,-O
H),7.1-8.4(m,10H,
H-Ar),4.85(s,2H,Ar-C
H 2-Ar),4.55(t,4H,-O-C
H 2-CH2-N),3.0(t,4H,-O-CH2-C
H 2-N),2.75(m,8H,-N-C
H 2-CH3),1.0(t,12H,-N-CH2-C
H 3).
K.F.=0.8%
C35H44N2O6Cl2的C、H、N计算值(校正水存在量):C,63.72;H,6.72;N,4.24;实测值C,63.5;H,5.87;N,4.6。
实施例5
双羟萘酸钠(ST1641)对β-淀粉状蛋白
25-35
肽的抗聚集作用的评价
将250μl βa25-352mM(cat.Bachem n°H-1192.0001)水溶液加到250μl由双羟萘酸钠2mM和磷酸盐缓冲液200mM pH5组成的溶液中。如此得到500μl双羟萘酸钠1mM、βA25-35 1mM和磷酸盐缓冲液100mMpH5的溶液。
对于其中不存在双羟萘酸钠的对照样品进行同样的处理。
室温下24小时后,将样品和对照于12000rpm下离心20分钟,从上清液中分离沉淀的固体。往沉淀的固体加入250μl水。室温下3小时后将样品再次在12000rpm下离心20分钟。离心后,与对照物不同的是在样品中没有观察到任何固体的存在。此结果表明双羟萘酸钠完全抑制原纤维中βA25-35肽的聚集。
实施例6
双羟萘酸钠(ST1641)对β-淀粉状蛋白
1-42
肽的抗聚集作用的评价
根据以下方法通过测定硫黄素T(thioflavin T)结合来评价双羟萘酸钠对βA1-42肽的抗聚集作用。
37℃下在Tris缓冲液100mM pH7.4中,将浓度为0.22mM的βA1-42肽(cat.Bachem n°H-1368.0500)单独或在双羟萘酸钠存在下温育5天。肽与双羟萘酸钠的摩尔比一般为1∶8、1∶4和1∶2。
13000rpm下将溶液离心5分钟并除去上清液。用500μl的H2O洗涤沉淀物并在13000rpm下离心5分钟。在此沉淀物中,用600μl溶于甘氨酸-NaOH缓冲液50mM,pH9.4的硫黄素T(ThT)2μM检测原纤维形式的聚集物。温育5分钟后将500μl的样品转移到石英比色杯中并在荧光分光光度计中在420nm激发波长和480nm发射波长下检测荧光信号。在这些条件下,荧光信号与淀粉状蛋白聚集物的量成比例(Le Vine,Methods in Enzymology(酶学方法).vol.309 pp274-284)。
双羟萘酸钠在此实验中被证明能够一致地和剂量依赖性地降低原纤维形式的βA1-42聚集物的形成。这种效果是显著的,且与对照相比降低达到70%之多。
还测定了原纤维形成的抑制作用对温育时间的函数。在进行1-5天的温育时,双羟萘酸钠表现出降低硫黄素T结合的效力递增。
实施例7
ST化合物对β-淀粉状蛋白
1-42
肽的抗聚集作用的评价
采用以下方法(M.A.Findeis,S.M.Molineaux;Mehods inEnzymology(酶学方法)309,487-488(1999)),使用硫黄素“T”结合测定评价ST1641、ST1722、ST1859、ST1745、ST1800、ST1913抵抗βA1-42聚合的能力:将βA1-42肽(1mg/ml)溶于H2O/CH3CN(1∶1),冻干,溶于DMSO+PBS,并在37℃下温育8天。然后对肽进行超声处理并将其溶于PBS(1∶5)。用βA1-42(40μl/孔)和ST测试化合物(50μl/孔,浓度在0.8和100μM之间)的溶液制备96孔平板。15分钟后将50μl未聚集的βA1-42加到每孔,并在37℃振荡下将平板温育过夜。然后将200μl包含硫黄素“T”(10μM)和Na2HPO4×2H2O(50μM)溶液(pH6.5)的反应混合物加到每孔。60秒内在450nm的激发波长和482nm的发射波长下用96孔荧光平板读出器测定荧光。在此实验条件下,荧光测定结果与βA1-42聚合肽的量相关。
表1显示ST测试化合物的DE50值。
表1
化合物 | DE50(μM) |
ST1641 | 38.2 |
ST1745 | 90.3 |
ST1859 | 5.4 |
ST1745 | 8.0 |
ST1800 | >50 |
ST1913 | 7.8 |
实施例8
双羟萘酸钠(ST1641)对预先形成的原纤维形式的β-淀粉状蛋白
1-42
聚集物的溶解
根据以下方法进行此实验以评价双羟萘酸钠对事先聚集的βA1-42肽的抗聚集能力。
使βA1-42肽在实施例6所述的条件下于37℃下聚集48小时。加入双羟萘酸钠(肽∶双羟萘酸盐比值1∶8)。
在这些条件下,证明双羟萘酸钠在降低硫黄素T结合方面具有非常高的活性。
与不用双羟萘酸钠进行温育的对照相比,用双羟萘酸钠温育导致荧光降低70%。
此结果证实双羟萘酸钠能够对βA1-42的原纤维结构施加事后的抗聚集作用。
实施例9
双羟萘酸钠(ST1641)诱导的β-淀粉状蛋白
1-42
肽对胰蛋白酶消化
作用的抗性的降低
用15μl的NaOH 0.1M将βA1-42肽溶解。用15μl TRIS缓冲液100mM使溶液变为pH7.4,向其中加入30μl单独的缓冲液或30μl包含双羟萘酸钠的缓冲液。βA1-42肽的终浓度为0.22mM,双羟萘酸钠的终浓度范围为0.055-1.76mM,因而βA1-42肽∶双羟萘酸钠的比值范围为4∶1-1∶8。
将如此制备的样品在37℃下温育5天;在这些条件下βA1-42肽形成原纤维形式的聚集物,修饰其结构由无规卷曲变为β折叠(Zagorski M.G等人1999“Methodological and Chemical Factors AffectingAmyloid β Peptide Amyloidogenicity(影响淀粉状蛋白β肽淀粉样变形成的方法学和化学因素)″Methods in Enzymology(酶学方法)309:189-204)。5天温育后,将24μg胰蛋白酶(Merck)加到每份样品,搅拌并在13000rpm下离心1分钟;然后在37℃下将样品温育1小时。
当此段时期过去后,将混合物在13000rpm下离心5分钟,除去50μl上清液,并用40μl HCOOH和10μl包含0.1%三氟乙酸(TFA)的H2O溶解沉淀物。
此时样品准备就绪进行定量HPLC分析。将与双羟萘酸钠一起温育的样品的HPLC曲线与单独用肽得到的曲线进行比较,从而对βA1-42肽进行定量。
上述条件下胰蛋白酶能够水解30-50%的βA1-42肽。双羟萘酸钠在最高剂量(肽∶双羟萘酸盐比值1∶8)时将胰蛋白酶对βA1-42的水解增加50%以上,而在最低剂量(1∶4)时增加40%以上。
实施例10
双羟萘酸钠(ST1641)对由β-淀粉状蛋白
25-35
诱导的神经毒性的抑
制作用
为了证实双羟萘酸钠的潜在神经保护活性,使用通过显微解剖妊娠16-18天的大鼠胚胎脑而得到的原代皮层神经元培养物。在胎牛血清存在下培养脑组织并通过在第3和5天将抗有丝分裂剂阿糖胞苷加到培养基中而抑制神经胶质增生(Andreoni等人,1997 Exp.Neurology(实验神经学)148:281-287)。在双羟萘酸钠存在或不存在下使细胞培养物与βA25-35肽接触5-7天。在由红藻氨酸诱导的神经毒性条件下评价神经保护作用以证实双羟萘酸钠作用的特异性和它有效的针对神经毒性剂的抗聚集活性。还在培养基中缺乏胎牛血清的情况下培养的神经元中评价双羟萘酸钠保护细胞对抗变性的能力。在这种情况下,在接种后24小时,用含有谷氨酰胺、胰岛素、转铁蛋白、腐胺、孕酮、亚硒酸钠和Hepes的无血清培养基更换细胞培养基。
实验方法
从妊娠16-18天的大鼠胚胎脑中取出小脑皮层的神经元原代培养物并在胎牛血清中培养。在温育第3和5天时,使用阿糖胞苷作为抗有丝分裂剂抑制神经胶质增生。
从接种之后那天开始使培养物接触浓度为25和50μM的βA25-35肽5-7天。
将βA25-35肽与双羟萘酸钠一起加到培养物中,双羟萘酸钠具有与肽本身相同的摩尔浓度或较低的浓度。
使用比色法和采用图像分析仪进行光密度分析来评价对抗神经毒性的保护作用。
所得的结果表明双羟萘酸钠针对由βA25-35诱导的毒性能够提供完全的保护作用。所得的结果在表2中给出。
表2
对照 | βA25-3550μM | 双羟萘酸钠25μM | 双羟萘酸钠25μM+βA25-35 50μM |
%S | %S | %S | %S |
100 | 16 | 88 | 100 |
%S:存活百分率
实施例11
双羟萘酸钠(ST1641)减少由K
+
丧失诱导的小脑颗粒凋亡
从8天大的大鼠小脑中分离的颗粒在大约一周发生生化和形态学分化,形态学上变得成熟并具有谷氨酸能中间神经元表型(Gallo等人,1982 PNAS 79:7919-7923)。在除去培养基中的血清并将细胞外钾离子浓度(25mM)降至非去极化条件的程度(5mM)时,在大约24小时以后实现由于凋亡导致的细胞死亡。
编程性神经元死亡是一种不仅在多种生理过程而且在许多神经变性疾病如AD、帕金森病、亨廷顿氏舞蹈病和肌萎缩性脊髓侧索硬化症中观察到的现象。在AD的情况下,检测到凋亡与本身调节淀粉状蛋白产生的早老2(PS2)基因存在βA突变之间存在密切关系。实际上,在存在PS2突变的AD的情况下,还可以检测到典型的脑和血浆βA1-42增加(Scheuner D.,Eckman C.,Jensen M.,Song X.,Citron M.,SuzukiN.,Bird T.D.,Hardy J.,Hutton M.,Kukull W.,Laeson E.,Levy-Lahad E.,Viitanen M.,Peskind E.,Selkoe D.,Yunkin S.(1996)Nat.Med.2,864-870.);而且,在PC12中表达的突变形式的PS2基因导致凋亡(Wolozin B.,Iwasaki K.,D’Adamio L.(1996)Science(科学)274,1710-1713)。
这种实验模型能够获得“自我促成”βA产生体系,其中小脑颗粒的神经元凋亡致使淀粉状蛋白前体APP的加工发生变化,其性质有助于淀粉状蛋白产生代谢的过程。βA水平的增加进而促进编程性细胞死亡。在这个实验设计中,根据培养基中KCl减少之后既定时间(24、48和72小时)的细胞存活来测定研究物质的潜在效力。
实验方法
在处于含KCl 25mM的培养基中的8天大的大鼠的小脑颗粒原代培养物中,在培养6天之后用35S-蛋氨酸标记细胞。
通过除去血清和将KCl浓度从25mM降至5mM而诱导凋亡。
这种情况代表体外神经元去传入状态或进出神经组织细胞的树突和轴突的切除。
凋亡的结果是βA的过量产生。
将培养物与浓度范围从1μM至100μM的双羟萘酸钠一起温育。
以24、48和72小时的细胞生存来评价抗毒性保护作用。
结果
在这个实验中获得的结果表明浓度为10μM的双羟萘酸钠具有对抗在凋亡过程中淀粉状蛋白形成导致的损伤的保护作用(89%保护作用)。
实施例12
ST1859在“体内”穿透血脑屏障的能力
AD脑切片的尸检揭示其中存在大量由纤维状淀粉状蛋白聚集物组成的细胞外老年斑。β淀粉状蛋白肽的存在和疾病严重性之间的关系表明肽原纤维形成的抑制作用可能是治疗这种疾病的潜在的工具。ST1859在“体外”抑制β淀粉状蛋白聚集,为了测试它穿过完整血脑屏障的透性,将用14C标记的ST1859(S.A.50μCi/mM)以18μCi/大鼠的剂量静脉注射到正常大鼠体内。在注射后30分钟取出脑和血液,然后将血液离心(3000RPM×15分钟)并用水1∶20稀释所得的血清,同时在水中1∶20w/v均化脑组织。随后对于样品水溶液,将4ml闪烁液加入每份样品。用自动β计数器(Packard 4600)计数放射性的量。将以DPM报道的数据(表1)对每份样品的重量或体积进行标准化。此实验中所得的结果表明ST1859能够以比率血清/脑<1穿透血脑屏障(表3)。
表3
血清(DPM/ml) | 脑(DPM/g) | 血清/脑 | |
平均值 | 29.776 | 35.643 | 0.833 |
S.E. | ±1253 | ±1349 | ±0.042 |
Claims (27)
其中:
R1和R5,可以相同或不同,为COOR6、CONHR6、SO2R6、SO2NHR6、SO3R6、OR6、COR6、NHR6、R6;
其中R6为H或者具有1-5个碳原子的直链或支链、饱和或不饱和烷基链,或者苯基,被R7取代;
其中:
其中:
R8和R9可以相同或不同,为H、具有1-5个碳原子的烷基;
其中R10为具有1-5个碳原子的直链或支链、饱和或不饱和烷基链;
R3为-[CH2]n-、-CH2-O-、-CH(R11)-,
其中n为1-4的整数,R11为具有1-5个碳原子的直链或支链烷基,所述基团被氨基、烷基氨基C1-C5、二烷基氨基C1-C5、OH、烷氧基C1-C5取代;
附带条件是取代基R1、R2、R3、R4和R5不是:
1 R1=R5=-COOCH2C6H5
R2=R4=-OH
R3=-CH2-
2 R1=R5=-COOCH(CH3)2
R2=R4=-OH
R3=-CH2-
3 R1=R5=-COOC2H5
R2=R4=-OH
R3=-CH2-
4 R1=R5=-COOC6H11
R2=R4=-OH
R3=-CH2-
5 R1=R5=-COOCH3
R2=R4=-OH
R3=-CH2-
6 R1=R5=-COOC(CH3)3
R2=R4=-OH
R3=-CH2-
7 R1=R5=-CONHC6H5
R2=R4=-OH
R3=-CH2-
11 R1=R5=-H
R2=R4=-OCOC6H5
R3=-CH2-
12 R1=R5=-H
R3=-CH2-
13 R1=R5=-H
R2=R4=-OCOCH=CH2
R3=-CH2-;
14 R1=R5=-H
R2=R4=-OH
R3=-CH2-
15 R1=R5=-COOH
R2=R4=-OH
R3=-CH2-。
2.(2R)-2-(乙酰氧基)-4-({3-羧基-1-[(3-羧基-2-羟基-1-萘基)甲基]-2-萘基}氧)-N,N,N-三甲基-4-氧代-1-丁烷氯化铵。
3.(2R)-2-(乙酰氧基)-4-({1-[(2-羟基-1-萘基)甲基]-2-萘基}氧)-N,N,N-三甲基-4-氧代-1-丁烷氯化铵。
4.2-({1-[(2-羟基-1-萘基)甲基]-2-萘基}氧)-2-氧代乙烷氯化铵。
5.2-({4-[(3-{[2-(二乙基铵)乙氧基]羰基}-2-羟基-1-萘基)甲基]-3-羟基-2-萘甲酰基}氧)-N,N-二乙基乙烷铵二氯化物。
6.根据权利要求1-5的化合物用作药物。
7.具有通式(I)的化合物的制备方法
R1和R5为-COOR6,
其中R2、R3、R4和R5具有权利要求1中定义的含义,
其特征在于用卤化剂处理其中的R6为H的通式(I)化合物得到相应的酰氯,然后在搅拌下与R6-OH醇以1-6的摩尔比反应,或者在惰性无水溶剂中与化学计算量的R6-OH反应。
9.药物组合物,包含根据权利要求1-5的化合物作为其活性成分和至少一种药学上可接受的赋形剂和/或稀释剂。
其中:
R1和R5可以相同或不同,为COOR6、CONHR6、SO2R6、SO2NHR6、SO3R6、OR6、COR6、NHR6、R6;
其中R6为H或者具有1-5个碳原子的直链或支链、饱和或不饱和烷基链,或者苯基,被R7取代;
其中:R7为OH、COOH、SO3H、NR8R9,
其中:
R8和R9可以相同或不同,为H、具有1-5个碳原子的烷基;
其中R10为具有1-5个碳原子的直链或支链、饱和或不饱和烷基链;
R3为-[CH2]n-、-CH2-O-、-CH(R11)-,
其中n为1-4的整数,
R11为具有1-5个碳原子的直链或支链烷基,所述基团被氨基、烷基氨基C1-C5、二烷基氨基C1-C5、OH、烷氧基C1-C5取代。
11.根据权利要求12的用途,其中所述的以淀粉状蛋白聚集物的沉积为特征的疾病选自阿尔茨海默氏病、唐氏综合征、与荷兰型淀粉样变有关的遗传性脑出血、与慢性炎症有关的淀粉样变、与多发性骨髓瘤和其它血B淋巴样细胞恶液质有关的淀粉样变、与II型糖尿病有关的淀粉样变和与朊病毒疾病有关的淀粉样变、库鲁病或绵羊痒病。
12.根据权利要求13的用途,其中所述的与朊病毒疾病有关的淀粉样变选自克罗伊茨费尔特-雅各布病和格-施综合征。
13.根据权利要求12-14的用途,其中该化合物为双羟萘酸钠盐。
14.诊断试剂盒,包含至少一种权利要求12中所述的化合物,该诊断试剂盒用于诊断以淀粉状蛋白聚集物沉积为特征的疾病。
15.根据权利要求16的试剂盒,其中所述化合物的至少一种元素,碳、氢、氮或氧被相应的放射性同位素置换。
16.根据权利要求16的试剂盒,其中所述化合物携带至少一个放射性碘原子。
17.根据权利要求16的试剂盒,其中所述化合物无论是否携带根据权利要求17-18的同位素,其形式为与一种金属的放射性同位素形成的络合物。
18.根据权利要求19的试剂盒,其中所述金属选自铟、钆和锝。
19.根据权利要求16-20的试剂盒用于通过诊断成像技术进行诊断的用途。
20.根据权利要求21的用途,其中所述诊断成像技术选自PET、SPECT、NMR和闪烁成像技术。
21.根据权利要求22的用途,其中所述闪烁成像技术为平面闪烁成像。
22.如权利要求12中所述的化合物,其中至少一种元素,碳、氢、氮或氧被相应的放射性同位素置换。
23.如权利要求12中所述的化合物,该化合物携带至少一个放射性碘原子。
24.如权利要求12中所述的化合物,无论是否携带按照权利要求24-25的放射性同位素,它与诊断成像中所用的元素络合。
25.根据权利要求26的化合物,其中所述络合的元素选自铟、钆和锝。
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Cited By (3)
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CN102659577A (zh) * | 2012-04-07 | 2012-09-12 | 安徽绩溪县徽煌化工有限公司 | 一种亚甲基双羟基萘酸的制备方法 |
CN106074476A (zh) * | 2016-06-08 | 2016-11-09 | 天津大学 | 帕莫酸在制备BLyS拮抗剂的用途 |
CN114401935A (zh) * | 2019-12-14 | 2022-04-26 | 上海市东方医院(同济大学附属东方医院) | 离子通道拮抗剂/阻断剂及其用途 |
Families Citing this family (11)
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BRPI0617423A2 (pt) * | 2005-10-18 | 2011-07-26 | Sigma Tau Ind Farmaceuti | inibidores de derivados de naftila da agregaÇço de beta-amilàides |
CU23844B1 (es) | 2009-04-17 | 2012-10-15 | Ct De Neurociencias De Cuba | Procedimiento de obtención de nuevos derivados de naftaleno para el diagnóstico in vivo de la enfermedad de alzheimer |
US9040583B2 (en) | 2009-07-22 | 2015-05-26 | Temple University-Of The Commonwealth System Of Higher Education | Treatment of disorders associated with G protein-coupled receptor 35 (GPR35) |
EP2833866B1 (en) | 2012-04-04 | 2018-11-21 | Intervet International B.V. | Soft chewable pharmaceutical products |
RU2494750C1 (ru) * | 2012-06-20 | 2013-10-10 | Общество с ограниченной ответственностью "Научно-внедренческий центр Агроветзащита" | Способ получения стабилизированной формы антисептика-стимулятора дорогова - фракции 2 (асд-2) |
CU20130027A7 (es) | 2013-02-28 | 2014-10-30 | Ct De Neurociencias De Cuba | Chaperoninas químicas como nuevos moduladores moleculares de la beta agregación proteica presente en las enfermedades conformacionales |
EP3461488A1 (en) | 2017-09-27 | 2019-04-03 | Onxeo | Combination of a dbait molecule and a hdac inhibitor for treating cancer |
EP3461480A1 (en) | 2017-09-27 | 2019-04-03 | Onxeo | Combination of a dna damage response cell cycle checkpoint inhibitors and belinostat for treating cancer |
WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
WO2023041805A1 (en) | 2021-09-20 | 2023-03-23 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for improving the efficacy of hdac inhibitor therapy and predicting the response to treatment with hdac inhibitor |
WO2023194441A1 (en) | 2022-04-05 | 2023-10-12 | Istituto Nazionale Tumori Irccs - Fondazione G. Pascale | Combination of hdac inhibitors and statins for use in the treatment of pancreatic cancer |
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AU8897391A (en) * | 1990-12-12 | 1992-06-18 | Mitsubishi Kasei Corporation | Electrostatic image-developing toner |
US5276059A (en) * | 1992-07-10 | 1994-01-04 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibition of diseases associated with amyloid formation |
IT1299544B1 (it) * | 1998-07-03 | 2000-03-16 | Sigma Tau Ind Farmaceuti | Composizioni solide atte alla somministrazione orale comprendenti sali non igroscopici della l-carnitina e delle alcanoil l-carnitine |
EP0998946A1 (en) * | 1998-08-14 | 2000-05-10 | K.U. Leuven Research & Development | Non-porphyrin compound for use as a diagnosticum and/or pharmaceutical |
BR9904931A (pt) * | 1999-10-18 | 2001-06-12 | Sergio Teixeira Ferreira | Inibição de amiloidoses |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102659577A (zh) * | 2012-04-07 | 2012-09-12 | 安徽绩溪县徽煌化工有限公司 | 一种亚甲基双羟基萘酸的制备方法 |
CN102659577B (zh) * | 2012-04-07 | 2014-07-02 | 安徽绩溪县徽煌化工有限公司 | 一种亚甲基双羟基萘酸的制备方法 |
CN106074476A (zh) * | 2016-06-08 | 2016-11-09 | 天津大学 | 帕莫酸在制备BLyS拮抗剂的用途 |
CN114401935A (zh) * | 2019-12-14 | 2022-04-26 | 上海市东方医院(同济大学附属东方医院) | 离子通道拮抗剂/阻断剂及其用途 |
CN114401935B (zh) * | 2019-12-14 | 2024-04-05 | 上海市东方医院(同济大学附属东方医院) | 离子通道拮抗剂/阻断剂及其用途 |
Also Published As
Publication number | Publication date |
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US20040029963A1 (en) | 2004-02-12 |
CN1185210C (zh) | 2005-01-19 |
AU6942101A (en) | 2002-01-08 |
US20080293812A1 (en) | 2008-11-27 |
KR100764886B1 (ko) | 2007-10-09 |
ITRM20000340A0 (it) | 2000-06-23 |
SK18312002A3 (sk) | 2003-06-03 |
CZ20024123A3 (cs) | 2003-05-14 |
JP2004501893A (ja) | 2004-01-22 |
MXPA02012730A (es) | 2003-05-14 |
PL360492A1 (en) | 2004-09-06 |
AU784980B2 (en) | 2006-08-17 |
WO2002000603A1 (en) | 2002-01-03 |
CA2412568A1 (en) | 2002-01-03 |
EP1301463A1 (en) | 2003-04-16 |
BR0111933A (pt) | 2003-06-17 |
HK1058515A1 (en) | 2004-05-21 |
ITRM20000340A1 (it) | 2001-12-23 |
IT1317048B1 (it) | 2003-05-26 |
US20060205967A1 (en) | 2006-09-14 |
KR20030017554A (ko) | 2003-03-03 |
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