CN100398506C - 用于治疗神经变性疾病的1-苯基烷羧酸衍生物 - Google Patents
用于治疗神经变性疾病的1-苯基烷羧酸衍生物 Download PDFInfo
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- CN100398506C CN100398506C CNB2004800047290A CN200480004729A CN100398506C CN 100398506 C CN100398506 C CN 100398506C CN B2004800047290 A CNB2004800047290 A CN B2004800047290A CN 200480004729 A CN200480004729 A CN 200480004729A CN 100398506 C CN100398506 C CN 100398506C
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- Prior art keywords
- chf
- cyclopropane
- carboxylic acid
- phenyl
- alkyl
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Abstract
本发明涉及1-苯基烷羧酸衍生物、其制备方法及其在治疗和/或预防神经变性疾病,诸如阿尔茨海默病中的应用。
Description
本发明涉及1-苯基烷羧酸类、在其羧酸部分上的前体药物和生物等排物。本发明还涉及它们的制备方法及其在预防或治疗神经变性疾病,特别是阿尔茨海默病中的应用。
引言
阿尔茨海默病是一种神经变性疾病,其特征在于大脑皮质萎缩和皮质神经元大量缺失以及基底核胆碱能投射向皮质。从组织病理学观点来看,阿尔茨海默病患者弥散性存在细胞外和血管周围神经斑和大脑实质中胞内神经原纤维缠结。
神经斑主要由带有39-43位氨基酸残基的称作β-淀粉状蛋白(βA)的蛋白质聚集物组成且随氨基酸数量的不同,所述的蛋白质为Aβ39、Aβ40、Aβ42和Aβ43。
除这些组织病理学损害外,还缺乏某些神经递质,特别是乙酰胆碱、5-羟色胺、去甲肾上腺素、多巴胺、谷氨酸和物质P。目的在于主要通过乙酰胆碱酯酶抑制剂增加乙酰胆碱大脑水平的药理学手段从临床观点来看获得的效果较差或无论如何不能获得显著防止该病发展的效果。由于这一原因,在近年中的注意力已经集中在患者大脑内主要病理损害形成的机制上,即神经斑和神经原纤维缠结,且已经寻求了更为有效的治疗手段。
现有技术
流行病学研究证实长期给予非类固醇消炎药(NSAIDs)在定期服用这些药物的人群中显著减少了阿尔茨海默病的发作。这类NSAID预防作用的机制尚未得到完全阐明,但明显与其抑制环加氧酶(COX)的能力相关。
近来已经描述了某些非类固醇消炎药(NSAIDs)的新药理学作用:吲哚美辛、舒林酸、布洛芬和氟比洛芬可以选择性地减少细胞培养物中β-淀粉状蛋白肽的大部分神经毒性同种型产生,即含有42个氨基酸的形式(Aβ42),由此有利于少量有害的同种型Aβ38释放(Weggen等,《自然》(Nature)2001;414(6860):212-6)。然而,已经在体外极高浓度下观察到了Aβ42产生受到抑制,这可以归因于这些药物与γ-分泌酶(具有天冬氨酰蛋白酶活性的大分子/多蛋白酶复合物)的相互作用。相当于体外实验中所用剂量的血浆和大脑浓度可以显著增加所治疗患者典型COX抑制剂副作用的危害,诸如胃肠道出血和穿孔性溃疡。
WO 01/78721中要求保护预防、延缓或逆转阿尔茨海默病发展的方法,通过在Aβ38水平增加而Aβ42水平保持不变的条件下给予降低Aβ42的活性剂来进行。此外,公开了用于鉴定和研发降低Aβ42的活性剂的方法和物质以及用于鉴定增加阿尔茨海默病发展或快速发展的危害的活性剂的方法。报导了涉及吲哚美辛和氟芬那酸衍生物的实施例,但无涉及氟比洛芬衍生物的实施例。
Jantzen等在《神经科学杂志》(J Neurosci)2002;22:2246-2254中描述了能够释放氧化氮的氟比洛芬衍生物。该文件一般性地描述了氟比洛芬衍生物显然比NSAIDs在清除β-淀粉状蛋白沉积物方面更为有效,但对任何降低Aβ42的选择活性均没有涉及。
在这种治疗方案中并根据常用NSAIDs可能存在的问题,对肽Aβ42更具有选择性和具有更有效的抑制活性、而对环加氧酶的抑制程度较低或完全没有抑制作用的新衍生物可以成为目的在于预防阿尔茨海默病发作和/或延缓代表早期疾病阶段的认知能力下降的疗法中的明显改进。
在GB 1,198,212、US 3,978,071、US 757,136、GB 1,352,723、JP49100089和JP 50046669中将取代的1-苯基-2,2-二烷基羧酸衍生物描述为抗炎药、止痛药和解热药。
JP-4,7047,375和FR-2,012,285中将3-卤代-4-烷基-或环烷基-取代的1-苯基环烷羧酸衍生物描述为具有相同活性的物质。
在来自涉及一系列苯乙酸衍生物的结构-活性研究的Kuzuna S等的文件中(Takeda Kenkyushoho 1975,34,467-473)一般性地描述了在α碳原子位置上引入环丙烷基降低了抗炎和止痛活性。
在WO 99/41224中,要求保护用于治疗许多疾病,包括阿尔茨海默病的具有抗炎活性的新双芳基-乙酸衍生物作为环加氧酶-2抑制剂
发明概述
本发明涉及1-苯基烷羧酸类、在其羧酸部分上的前体药物和生物等排物、其制备方法、含有它们的药物组合物及其在预防或治疗神经变性疾病,特别是阿尔茨海默病中的应用。
本发明的化合物抑制Aβ42肽释放,由此能够调节γ-分泌酶活性而不影响其它重要的代谢过程。
发明详述
本发明涉及通式(I)的化合物、其药物上可接受的盐和其它酯类:
其中:
R和R1相同且选自直链或支链C1-C4烷基;或它们与它们所连接的碳原子一起形成3-6个碳原子的环;
G为:
-COOR″基团,其中R″为H、直链或支链C1-C4烷基、C3-C6环烷基或抗坏血酸基(ascorbyl);
-CONH2或CONHSO2R″′基团,其中R″′为直链或支链C1-C4烷基或C3-C6环烷基;
-四唑残基;
R2为H、CF3、OCF3或选自F、Cl、Br、I的组的卤素,优选氟;
Ar为如下通式:
其中R3表示一个或多个独立地选自下列基团的基团:
-上述定义的卤素;
-CF3;
-任选被一个或多个C1-C4烷基和/或氧代基取代的C3-C8环烷基;
-CH=CH2;
-CN;
-CH2OH;
-亚甲二氧基或亚乙二氧基;
-NO2;
-任选被一个或多个如下基团取代的苯基:卤素;CF3;OCF3;OH;直链或支链C1-C4烷基;含有至少4个碳原子和至少1个杂原子的饱和杂环(eterocycle);任选依次被下列基团中的一个或多个取代的C3-C8环烷基:直链或支链C1-C4烷基、CF3或OH;OR4或NHCOR4,其中R4为CF3、直链或支链C2-C6链烯基或炔基;苄基;任选被如下基团中的一个或多个取代的苯基:卤素、CF3、OCF3、OH、直链或支链C1-C4烷基;含有至少4个碳原子和至少1个杂原子的饱和杂环(eterocycle);任选依次被下列基团中的一个或多个取代的C3-C8环烷基:直链或支链C1-C4烷基、CF3或OH;
-SR5、SO2R5或COR5,其中R5为直链或支链C1-C6烷基;
或Ar为选自如下的组的杂环(eterocycle):噻吩、苯并噻吩、二苯并噻吩、噻蒽、吡咯、吡唑、呋喃、苯并呋喃、二苯并呋喃、吲哚、异吲哚、苯并呋喃、咪唑、苯并咪唑、噁唑、异噁唑、苯并噁唑、噻唑、吡啶、嘧啶、吡嗪、哒嗪、喹啉、异喹啉、喹唑啉、喹喔啉、噌啉、吡唑、吡喃、苯并吡喃、pyrrolizine、2,3-二氮杂萘、1,5-二氮杂萘、1,3-间二氧杂环戊烯、1,3-苯并间二氧杂环戊烯,它们任选被一个或多个如上述定义的R3基团取代。
第一组优选化合物为,其中:
R和R1与它们所连接的碳原子一起形成3个碳原子的环;
R2为氟;
G为COOR″基团,其中R″为H、直链或支链C1-C4烷基、C3-C6环烷基或抗坏血酸基;
Ar为如上述所定义的苯基。
第二组优选化合物为,其中:
R和R1与它们所连接的碳原子一起形成3个碳原子的环;
R2为氟;
G为CONH2或CONHSO2R″′,其中R″′为直链或支链C1-C4烷基或C3-C6环烷基;
Ar为如上述所定义的苯基。
第三组优选化合物为,其中:
R和R1均为甲基;
R2为氟;
G为COOR″,其中R″如上述所定义;
Ar为如上述所定义的苯基。
第四组优选化合物为,其中:
R和R1均为甲基;
R2为氟;
G为CONH2或CONHSO2R″′,其中R″′如上述所定义;
Ar为如上述所定义的苯基。
第五组优选化合物为,其中:
R和R1与它们所连接的碳原子一起形成3个碳原子的环;
R2为氟;
G为COOR″,其中R″如上述所定义;
Ar为如上述所定义的杂环。
第六组优选化合物为,其中:
R和R1均为甲基;
R2为氟;
G为COOR″,其中R″如上述所定义;
Ar为如上述所定义的杂环。
特别优选如下化合物:
2-甲基-2(2-氟-4′-三氟甲基联苯-4-基)丙酸(CHF 4810);
2-甲基-2(2-氟-4′环己基联苯-4-基)丙酸(CHF 4961);
1-(2-氟-4′-三氟甲基联苯-4-基)环丙烷羧酸(CHF 5022);
1-(4′-环己基-2-氟联苯-4-基)环丙烷羧酸(CHF 5023);
1-(4′-苄氧基-2-氟联苯-4-基)环丙烷羧酸(CHF 5042);
1-(2-氟-4′-异丙氧基联苯-4-基)环丙烷羧酸(CHF 5044);
1-(2-氟-3′-三氟甲氧基联苯-4-基)环丙烷羧酸(CHF 5045);
1-(2-氟-4′-三氟甲氧基联苯-4-基)环丙烷羧酸(CHF 5046);
1-(2-氟-3′-三氟甲基联苯-4-基)环丙烷羧酸(CHF 5058);
1-(4′-环戊基-2-氟联苯-4-基)环丙烷羧酸(CHF 5059);
1-(4′-环庚基-2-氟联苯-4-基)环丙烷羧酸(CHF5060);
1-(2′-环己基-2-氟联苯-4-基)环丙烷羧酸(CHF 5061);
1-(2-氟-4′-羟基联苯-4-基)环丙烷羧酸(CHF 5070);
1-[2-氟-4′-(四氢吡喃-4-基氧基)联苯-4-基]-环丙烷-羧酸(CHF5071);
1-(2,3′,4′-三氟联苯-4-基)环丙烷羧酸(CHF 5073);
1-(3′,4′-二氯-2-氟联苯-4-基)环丙烷羧酸(CHF 5074);
1-(3′,5′-二氯-2-氟联苯-4-基)环丙烷羧酸(CHF 5075);
1-(3′-氯-2,4′-二氟联苯-4-基)环丙烷羧酸(CHF 5076);
1-(4-苯并[b]噻吩-3-基-3-氟苯基)环丙烷羧酸(CHF 5077);
1-(2-氟-4′-丙-2-炔氧基-联苯-4-基)-环丙烷羧酸(CHF 5078);
1-(4′-环己氧基-2-氟-联苯-4-基)-环丙烷羧酸(CHF 5079);
1-[2-氟-4′-(四氢吡喃-4-基)-联苯-4-基]-环丙烷羧酸(CHF5080);
1-[2-氟-4′-(4-氧代-环己基)-联苯-4-基]-环丙烷羧酸(CHF5081);
2-(2″-氟-4-羟基-[1,1′:4′,1″]叔苯基-4″-基)-环丙烷羧酸(CHF 5083);
1-[4′-(4,4-二甲基环己基)-2-氟[1,1′-联苯基]-4-基]-环丙烷-羧酸(CHF 5084);
1-[2-氟-4′-[[4-(三氟甲基)苯甲酰基]氨基][1,1′-联苯基]-4-基]-环丙烷羧酸(CHF 5094);
1-[2-氟-4′-[[4-(三氟甲基)环己基]氧基][1,1′-联苯基]-4-基]-环丙烷羧酸(CHF 5096);
1-[2-氟-4′-[(3,3,5,5-四甲基环己基)氧基][1,1′-联苯基]-4-基]-环丙烷羧酸(CHF 5102);
1-[4′-[(4,4-二甲基环己基)氧基]-2-氟[1,1′-联苯基]-4-基]-环丙烷羧酸(CHF 5103);
1-(2,3′,4″-三氟[1,1′:4′,1″-叔苯基]-4-基)-环丙烷羧酸(CHF5104);
1-(2,2′,4″-三氟[1,1′:4′,1″-叔苯基]-4-基)-环丙烷羧酸(CHF5105);
1-(2,3′-二氟-4″-羟基[1,1′:4′,1″-叔苯基]-4-基)-环丙烷-羧酸(CHF 5106);
1-(2,2′-二氟-4″-羟基[1,1′:4′,1″-叔苯基]-4-基)-环丙烷-羧酸(CHF 5107);
2-(2-氟-3′,5′-双(氯)联苯-4-基)丙酸酰胺(CHF 5125)。
更优选的一组化合物为,其中:
R和R1与它们所连接的碳原子一起形成3个碳原子的环;
R2为氟;
G为COOH;
Ar为被一个或多个基团取代的苯基,照此使得整个分子的logP(正辛醇与水之间的分配系数)等于或大于4.5,正如通过使用软件2.1版(Schrodinger Inc)所计算的。
已经发现分子的log P越高,则对Aβ42肽释放的抑制功效越大且特别有效的化合物为这类化合物,其log P等于或大于4.5,优选大于5.0。
这些化合物的实例为CHF 5022、CHF 5074、CHF 5096、CHF 5105、CHF 5106和CHF 5107。
本发明还涉及为增加跨过血脑屏障而制备的药物上可接受的盐和酯类。
本发明的另一个目的在于通式(I)的化合物作为药物的应用,特别是它们在制备用于治疗和/或预防神经变性疾病,诸如阿尔茨海默病的药物组合物中的应用。
本发明的另一个目的在于优选用于口服使用的固体或液体药物组合物,包括至少一种通式(I)化合物与药物上可接受的赋形剂和/或载体的混合物,所述的赋形剂和/或载体例如描述在《Remington氏药物科学手册》(Remington′s Pharmaceutical Sciences Handbook)XVIIEd.Mack Pub.N.Y.U.S.A.中。
可以按照文献方法,通过下列步骤制备一般通式(I)的化合物,其中R″为H:
在方案1中报导的条件下使通式(II)的芳基卤与硼酸或酯ArB(OL)2之间进行钯-催化的反应,其中通式(II)的结构式如下:
其中R、R1和R2如上述所定义且X为溴或碘,优选碘;
在ArB(OL)2中,L为烷基链。
方案1
通式(II)的化合物是商购的或可以按照下列合成途经制备。
衍生物,其中R和R
1
为直链或支链C
1
-C
4
烷基(IIa)
可以按照方案2中所示的合成途经以通式(III)的芳基乙酸类作为原料制备所述的化合物,在通式(III)中,R和R2如上述所定义且X为溴或碘。
使通式(III)的酸酯化、烷基化且任选进行水解,条件是终产物上的基团G为COOH。
方案2
衍生物,其中R和R
1
与它们所连接的碳原子形成3-6个碳的环
(IIb)
所述的化合物是商购的或可以按照方案3中报导的合成途经制备,其中n为1-4的整数。
方案3
硼酸或相应的硼酸盐是商购的或可以按照文献中已知的方法由相应的卤化物制备。
可以通过酯化G为COOH的通式(I)的化合物制备通式(I)的化合物,其中G为COOR″,其中R″为直链或支链C1-C4烷基、C3-C6环烷基或抗坏血酸基。
可以通过使相应的酯类与NH3或胺NH2SO2R″′反应制备通式(I)的化合物,其中G为CONH2或CONHSO2R″′,其中R″′为直链或支链C1-C4烷基或C3-C6环烷基。
可以按照已知方法,例如将羧酸转化成酰胺、使酰胺脱水得到腈并使后者与三丁基锡叠氮化物反应制备通式(I)的化合物,其中G为四唑基。
实施例
化学制备实施例
实施例1:2-甲基-2-(2-氟-4′-三氟甲基联苯-4-基)丙酸(CHF
4810)的制备
[2-(2-氟-4′-三氟甲基联苯-4-基)]丙酸甲酯的制备
向2-(2-氟-4′-三氟甲基联苯-4-基)丙酸(0.2g,0.64mmoles)在甲醇(3ml)中的溶液中加入98%硫酸(0.5g)并回流2.5小时。在真空中除去溶剂,将残余物溶于乙酸乙酯(5ml)并用5%NaHCO3溶液(5ml)、然后用水洗涤。用Na2SO4干燥该溶液并在真空中浓缩而得到油状物(0.2g,95%)。
HPLC-UV纯度(215nm):99%
[2-甲基-2-(2-氟-4′-三氟甲基联苯-4-基)丙酸甲酯的制备
向在0℃下和氮气环境中的[2-(2-氟-4′-三氟甲基联苯-4-基)]丙酸甲酯(0.2g,0.61mmoles)在无水THF(3ml)中的溶液中加入60%NaH(30mg,0.75mmoles)。将该混合物搅拌30分钟并加入CH3I(70μl,0.91mmoles)。3小时后,在真空中浓缩该混合物并使用乙酸乙酯(5ml)溶解。用5%NaHCO3溶液(5ml)、然后用水洗涤所得溶液,用Na2SO4干燥该溶液,并真空中浓缩而得到油状物(0.18g,87%),不经进一步纯化将其用于随后的反应。
2-甲基-2-(2-氟-4′-三氟甲基联苯-4-基)丙酸的制备
向[2-甲基-2-(2-氟-4′-三氟甲基联苯-4-基)]丙酸甲酯(0.18g,0.53mmoles)在乙醇(5ml)中的溶液中加入KOH(60mg,1mmol)并在室温下保持搅拌3小时。用H2O(5ml)稀释该混合物并用乙醚(5ml)洗涤该溶液。弃去有机相。用HCl将水相酸化至pH=2,然后用乙酸乙酯(10ml)提取。用Na2SO4干燥该有机相并在真空中浓缩而得到白色固体,将其通过快速SiO2色谱法纯化(洗脱剂己烷/乙酸乙酯8/2v/v)而得到产物,为白色固体(16mg,10%)。
HPLC-UV纯度(215nm):97%。
1H NMR(DMSO-d6):12.56(s br,1H);7.84(d,2H);7.78(d,2H);7.57(dd,1H);7.32(s,1H);7.29(m,1H);1.52(s,6H);MS(EI):326m/z(M+.),281,253。
按照相同步骤并使用合适的反应剂制备化合物CHF 4961。
实施例2:1-(2-氟联苯-4-基)环丙烷羧酸(CHF 5041)的制备
4-溴-3-氟苄基溴的制备
向4-溴-3-氟甲苯(10g,0.053moles)在四氯化碳(100ml)中的溶液中加入N-溴琥珀酰亚胺(NBS;14g,0.08moles)。回流该混合物,向其中加入过氧化二苯酰(100mg,0.4mmoles),回流1小时,然后在室温下冷却并用水提取。弃去水相,用盐水洗涤有机相,用硫酸钠干燥并在真空中浓缩而得到油状物(16g),使其进行硅胶柱色谱(150g),用己烷洗脱而得到产物。
4-溴-3-氟苯基乙腈的制备
向4-溴-3-氟苄基溴(12.2g,0.03moles)在乙醇(100ml)中的溶液中加入NaCN(2g,0.04moles)并回流2小时。在真空中浓缩该混合物;用水溶解所得残余物,然后用乙酸乙酯提取。用盐水洗涤有机相,用硫酸钠干燥并在真空中浓缩而得到深色油状物(10g),使其进行硅胶柱色谱(150g),用己烷∶乙醚7∶3洗脱而得到固体形式的产物。
4-溴-3-氟苯基环丙腈的制备
向4-溴-3-氟苯基乙腈(5g,23mmoles)在甲苯(20ml)中的溶液中加入35mmoles的1,2-二溴乙烷、50%NaOH水溶液(20ml)和溴化四丁基铵(1.6g,5mmoles)。将该混合物在室温下保持搅拌5-12小时,然后用水稀释并用乙酸乙酯提取。用1N HCl然后用盐水洗涤有机相,最终干燥并在真空中浓缩而得到棕色固体,使其进行硅胶柱色谱(200g),用己烷-乙醚1-1洗脱而得到固体形式的产物。
4-溴-3-氟苯基环丙烷羧酸的制备
向4-溴-3-氟苯基环丙腈(21mmoles)在甲醇(10ml)中的混悬液中加入35%NaOH水溶液(40ml)和35%H2O2水溶液(3ml),然后回流4小时,在室温下冷却并加入2N HCl(250ml)。通过过滤收集沉淀的固体并再溶于5%NaHCO3水溶液(300ml)。过滤出不溶性级分并用2N HCl将澄清滤液酸化至pH=2。产物沉淀,为白色固体,将其通过过滤回收并在真空中干燥。
1-(2-氟联苯-4-基)环丙烷羧酸的制备
将800mg(3.1mmoles)的4-溴-3-氟苯基环丙烷羧酸和650mg(3.4mmoles)的苯基硼酸悬浮于8ml的2M K2CO3水溶液中。向该混合物中加入溴化四丁基铵(960mg,3mmoles)和乙酸钯(II)(40mg,0.18mmoles)并在130℃下的封闭反应器中加热30分钟。在室温下冷却后,向该混合物中加入2MHC1(25ml)并用乙酸乙酯提取。用1NHC1,然后用盐水洗涤有机相,最终干燥并在真空中浓缩而得到油状物(1.7g),使其从异丙醚-己烷中结晶而得到产物,为白色固体(0.2g)。
HPLC(215nm)98%。
MS(EI;TSQ 700;参数180C;70V;200uA):256(M+.);210;196.
1H-NMR(DMSO):12.41(s br,1H);7.56-7.35(m,6H);7.27(m,1H);7.24(s,1H);1.48(m,2H);1.22(m,2H)。
按照与实施例1中所述相同的步骤,以合适的4-溴苯基环烷羧酸类为原料并使用合适的反应剂制备化合物CHF 5022、CHF 5023、CHF5042、CHF 5045、CHF 5046、CHF 5058、CHF 5059、CHF 5060、CHF 5061、CHF 5070、CHF 5071、CHF 5073、CHF 5074、CHF 5075、CHF 5076、CHF 5077、CHF 5078、CHF 5079、CHF 5080、CHF 5081、CHF 5083、CHF 5084、CHF 5094、CHF 5096、CHF 5102、CHF 5103、CHF 5104、CHF5105、CHF 5106、CHF 5107和CHF 5002。
实施例3-药理活性
H4-15x细胞上清液中Aβ
42
释放的抑制
在有潮霉素和杀稻瘟菌素存在下的烧瓶内(在37℃下的保温箱内,在水蒸气饱和的含有5%二氧化碳的气体环境中)培养H4-15x细胞(用编码β-淀粉状蛋白APP695前体的人基因转染的人神经胶质瘤细胞),该体系对连续表达所关注基因的细胞维持选择性压力。
当细胞达到约90%融合率时,收集它们并重新接种在24孔平板(各2×105个细胞)上的0.5ml完整培养基内。在约24小时后,当细胞与孔表面粘着并得到融合时,用0.5ml补充了至100微摩尔终浓度的化合物(I)的新鲜培养基取代各孔中的培养基。对每一测试浓度按照一式三份重复。预先将用于处理的分子溶于二甲亚砜(DMSO)或溶于二甲亚砜/水混合物,DMSO在孔中的终浓度不超过1%。因此,再次将制备的平板保温过夜(14-16小时);此后从各孔中取上清液并对Aβ42和Aβ40蛋白定量。使用用于微量培养板化学发光分析的仪器操作进行本试验,它允许对两种蛋白质分别定量且基于分析物-抗体复合物在顺磁微珠上的固定化。用钌化合物标记该复合物的抗体之一,在进行电化学激发时,这种化合物可以产生与存在的分析物的量成正比强度的光信号。
大鼠全血中环加氧酶-1(COX-1)的抑制
从大鼠腹主动脉取全血并立即放入肝素化试管。用100μM浓度的测试化合物或仅用载体(DMSO)将肝素化全血的等分部分(500μl)在37℃下预保温1小时。通过添加钙离子载体A23187(终浓度5×10-5M)诱导类二十烷酸产生并在30分钟后通过将样品快速放入干冰中而中断保温。此后离心样品(在4℃下12000g×3分钟)并通过放射性免疫测定法计算TxB2血栓烷B2的产量。
将表示为在100μM下Aβ42释放抑制百分比和在相同浓度下COX-1抑制活性百分比的结果报导在表1中。以相同浓度用作对比的氟比洛芬表现出约25%的Aβ42释放抑制作用和100%的COX-1抑制活性。
表1:本发明有代表性的化合物在100μM浓度下的Aβ42释放抑制百分比和COX-1抑制活性百分比
化合物 | Aβ<sub>42</sub>释放抑制% | COX-1抑制活性% |
CHF 4961 | 76.6 | 5.2 |
CHF 4810 | 58.0 | - |
CHF 5022 | 55.4 | 0.0 |
CHF 5045 | 56.4 | 8.3 |
CHF 5046 | 70.4 | 2.6 |
CHF 5058 | 54.8 | 0.0 |
CHF 5070 | 22.4 | 0.0 |
CHF 5071 | 28.1 | 0.4 |
CHF 5073 | 67.4 | 4.8 |
CHF 5074 | 79.2 | 0.5 |
CHF 5076 | 71.4 | 5.5 |
CHF 5078 | 57.5 | 3.6 |
CHF 5080 | 51.8 | 0.3 |
CHF 5081 | 52.3 | 6.1 |
CHF 5083 | 81.1 | - |
CHF 5096 | 70.0 | 0.8 |
CHF 5105 | 90.7 | 1.9 |
CHF 5106 | 79.9 | 0.0 |
CHF 5107 | 83.3 | 1.1 |
Claims (9)
1.通式(I)的化合物或其药物上可接受的盐:
其中:
R和R1相同且为直链或支链C1-C4烷基;或它们与它们所连接的碳原子一起形成3-6个碳原子的环;
G为:
-COOH基团;
R2为选自F、Cl、Br、I的卤素;
Ar为如下通式:
其中R3表示一个或多个独立地选自下列基团的基团:
-上述定义的卤素;
-CF3;
-任选被一个或多个C1-C4烷基和/或氧代基取代的C3-C8环烷基;
-任选被一个或多个如下基团取代的苯基:卤素;CF3;OCF3;OH;直链或支链C1-C4烷基;含有至少4个碳原子和至少1个杂原子的饱和杂环;任选依次被下列基团中的一个或多个取代的C3-C8环烷基:直链或支链C1-C4烷基、CF3或OH;
OR4或NHCOR4,其中R4为CF3、直链或支链C2-C6链烯基或炔基;苄基;任选被如下基团中的一个或多个取代的苯基:卤素、CF3、OCF3、OH、直链或支链C1-C4烷基;含有至少4个碳原子和至少1个杂原子的饱和杂环;任选依次被下列基团中的一个或多个取代的C3-C8环烷基:直链或支链C1-C4烷基、CF3或OH。
2.如权利要求1中所述的化合物,其中所述R2是氟。
3.如权利要求1中所述的化合物,其中所述R和R1与它们所连接的碳原子一起形成3个碳原子的环;R2为氟;G为COOH基团,Ar为如权利要求1中所定义的苯基。
4.如权利要求1中所述的化合物,其中R和R1与它们所连接的碳原子一起形成3个碳原子的环;R2为氟;G为COOH基团;Ar为如权利要求1中所定义的苯基。
5.如权利要求1中所述的化合物,其中R和R1为CH3;R2为氟;G为COOH基团;Ar为如权利要求1中所定义的苯基。
6.如权利要求1中所述的化合物,其选自:
1-(2-氟-4′-三氟甲基联苯-4-基)环丙烷羧酸;
1-(3′,4′-二氯-2-氟联苯-4-基)环丙烷羧酸;
1-[2-氟-4′-[[4-(三氟甲基)环己基]氧基][1,1′-联苯基]-4-基]-环丙烷羧酸;
1-(2,2′,4″-三氟[1,1′:4′,1″-叔苯基]-4-基)-环丙烷羧酸;
1-(2,3′-二氟-4″-羟基[1,1′:4′,1″-叔苯基]-4-基)-环丙烷-羧酸;
1-(2,2′-二氟-4″-羟基[1,1′:4′,1″-叔苯基]-4-基)-环丙烷-羧酸。
7.药物组合物,用于口服给药,其包含权利要求1-6任一项的化合物与至少一种药物上可接受的载体和/或赋形剂的混合物。
8.如权利要求7中所述的药物组合物制备预防或治疗神经变性疾病的药物的用途。
9.如权利要求8的用途,其中所述疾病是阿尔茨海默病。
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JPS4994680A (zh) * | 1973-01-22 | 1974-09-09 | ||
JPS5046669A (zh) * | 1973-03-28 | 1975-04-25 | ||
US3978071A (en) * | 1973-07-07 | 1976-08-31 | Yoshitomi Pharmaceutical Industries, Ltd. | Substituted phenylalkanoic acids and derivatives |
JPS58177977A (ja) * | 1982-04-09 | 1983-10-18 | Grelan Pharmaceut Co Ltd | 4−フエニルピラゾ−ル類 |
WO1999041224A1 (en) * | 1998-02-13 | 1999-08-19 | Merck Frosst Canada & Co. | Biaryl-acetic acid derivatives and their use as cox-2 inhibitors |
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JPS4994680A (zh) * | 1973-01-22 | 1974-09-09 | ||
JPS5046669A (zh) * | 1973-03-28 | 1975-04-25 | ||
US3978071A (en) * | 1973-07-07 | 1976-08-31 | Yoshitomi Pharmaceutical Industries, Ltd. | Substituted phenylalkanoic acids and derivatives |
JPS58177977A (ja) * | 1982-04-09 | 1983-10-18 | Grelan Pharmaceut Co Ltd | 4−フエニルピラゾ−ル類 |
WO1999041224A1 (en) * | 1998-02-13 | 1999-08-19 | Merck Frosst Canada & Co. | Biaryl-acetic acid derivatives and their use as cox-2 inhibitors |
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