CN101511804A - 对线粒体钠-钙交换体有作用的环状砜类 - Google Patents
对线粒体钠-钙交换体有作用的环状砜类 Download PDFInfo
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Abstract
本发明涉及新的游离碱形式或酸加成盐形式的式I杂环化合物、它们的制备、它们作为药物的用途和包含它们的药物。
Description
本发明涉及新的杂环化合物、它们的制备、它们作为药物的用途和包含它们的药物。
更具体地讲,本发明涉及游离碱形式或酸加成盐形式的式I化合物
例如由于存在于式I化合物中的不对称碳原子,式I化合物可以以纯的光学活性形式或光学异构体混合物的形式(例如外消旋混合物的形式)存在。所有此类纯的光学异构体和所有它们的混合物(包括外消旋混合物)都是本发明的组成部分。
式I化合物可以以游离碱形式或以酸加成盐形式存在。所有此类游离化合物和盐都是本发明的组成部分。
式I化合物可以以互变异构体形式存在。所有此类互变异构体都是本发明的组成部分。
在特别优选的实施方案中,本发明涉及一个或多个游离碱形式或酸加成盐形式的实施例中所述的式I化合物。
在另一方面,本发明涉及制备游离碱形式或酸加成盐形式的式I化合物的方法,所述方法包括下列步骤:使游离碱形式或酸加成盐形式的式II化合物
与氧化剂反应;接着任选裂解任何任选存在的保护基;和回收如此获得的游离碱形式或酸加成盐形式的式I化合物。
根据常规方法可以实现上述方法步骤,例如如实施例中所述那样。
在氧化步骤中可以使用下列氧化剂,例如,臭氧;双环氧乙烷衍生物,例如二甲基双环氧乙烷;氧化性吡啶鎓盐,例如氯铬酸吡啶鎓盐;过氧化物,例如H2O2或叔丁基过氧化氢;无机过酸或其盐,例如KHSO5;包含无机过酸或其盐的组合物,例如;或有机过酸例如过乙酸或间氯过苯甲酸。
氧化步骤可以在溶剂存在下进行,所述溶剂优选在所用的反应条件下是惰性的。
保护基的裂解可以根据已知的方法进行。
反应混合物的后处理和式I化合物的纯化可以根据已知的方法进行。
式I化合物的酸加成盐可以用已知的方式从相应的游离碱生成,并且式I化合物的游离碱也可以用已知的方式从相应的酸加成盐生成。
式II化合物的起始原料是公知的或者可以根据常规方法以已知化合物为原料制备。
式I化合物还可以通过其它的常规方法制备,这些方法是本发明的另外方面。
当在体外和在动物中测试时,式I化合物和它们的药学上可接受的酸加成盐(在下文中称为“本发明物质”)显示了有价值的药理学性质,并且因此它们作为药物是有用的。
本发明物质是线粒体钠钙交换体(mNCE)抑制剂,所述线粒体钠钙交换体是易兴奋组织中线粒体Ca-稳态的重要组分。因此,本发明物质可以用于治疗和/或预防受线粒体Ca-处理能力功能障碍影响的病症或疾病。
因此,本发明物质能用于治疗和/或预防神经学上的、血管的或代谢的病症或疾病,例如神经变性疾病如帕金森氏病(PD)、阿尔茨海默氏病(AD)、亨廷顿病、多发性硬化(MS)、唐氏(Down’s)综合征、记忆损害、认知损害、痴呆、神经元变性、脑炎症、重症肌无力、神经外伤、脑外伤、进行性核上性麻痹、肌萎缩侧索硬化(ALS)、肌萎缩侧索硬化(ALS)样综合征、衰老、Leber遗传性视神经病(LHON)综合征、Leigh综合征、线粒体脑肌病、乳酸中毒、卒中样发作(MELAS)综合征、家族性双侧纹状体坏死(FBSN)综合征、生长阻滞、氨基酸尿症、乳酸中毒和早期死亡(GRACILE)综合征、肌阵孪癫痫合并破碎红纤维(MERRF)综合症、神经病、共济失调和色素性视网膜炎(NARP)综合征、进行性外眼肌麻痹(PEO)综合征、Kearns-Sayre(KS)综合征、婴儿猝死(SID)综合征、显性视神经萎缩、mtDNA缺失(MD)综合征、Barth氏综合征、线粒体神经胃肠道脑肌病、Mohr-Tranebjaerg综合征、弗里德赖希(Friedreich)共济失调病、威尔森(Wilson)氏病、缺血再灌注后的病理学状况(例如心脏缺血或中风)、癫痫发作后的病理学状况、Niemann-Pick C型疾病、糖尿病(例如1型糖尿病、2型糖尿病或幼年型糖尿病)或动脉粥样硬化病。
对于上面所述的适应征而言,本发明物质的适当剂量当然会根据例如所用的化合物、宿主、给药方式或待治疗和/或预防的病患的性质或严重性而变化。然而,一般来讲,本发明物质约0.1至约100(优选大约1至大约50)mg/kg动物体重的日剂量预期会在动物中得到满意的结果。在更大的哺乳动物中,例如人类,推荐的日剂量是常规给药(例如以一天最多四次的分剂量或以缓释形式)的约10至约2000、优选约10至约200mg本发明物质。
本发明物质可以通过任何常规途径给药,特别是肠道给药,优选口服,例如以片剂或胶囊剂的形式;或肠胃外给药,例如以注射溶液剂或混悬剂的形式。
根据上面所述,本发明还提供用作药物的本发明物质,例如用于治疗和/或预防受线粒体Ca-处理能力功能障碍影响的病症或疾病。
本发明还提供包含本发明物质和至少一种药学载体或稀释剂的药物组合物。所述药物组合物可以以常规方式制备。单位剂量形式包含例如大约1至大约1000mg、优选大约1至大约500mg的本发明物质。
本发明物质可以单独给药或与至少一种其它药学物质一起作为组合产品给药,所述组合产品在治疗和/或预防上述病症中是有效的。
药物组合物可以以单位剂量形式存在,其中每个单位剂量形式应包括预定量的活性组分以及适当的药学载体或稀释剂。或者,组合产品可以为包装产品(package)的形式,该包装产品分别地包含活性成分,例如适于活性物质共同或分别给药的包装或分配器-装置,其中所述物质被分别地安排。
而且,本发明提供本发明物质在制备治疗和/或预防受线粒体Ca-处理能力功能障碍影响的病症或疾病的药物中的用途。
在另一方面,本发明提供在有此类治疗和/或预防需要的个体中治疗和/或预防受线粒体Ca-处理能力功能障碍影响的病症或疾病的方法,所述方法包括将治疗有效量的本发明物质给药至所述个体。
下面的实施例举例说明本发明,但不限制本发明。
实施例
简称
BSA 牛血清白蛋白
DMSO 二甲基亚砜
EDTA 乙二胺四乙酸
h 小时
Hepes 2-[4-(2-羟基乙基)-1-哌嗪子基]-乙磺酸
1H-NMR 质子核磁共振谱
min 分钟
MS 质谱
rt 室温
sec 秒
Tris α,α,α-三-(羟基甲基)-甲基胺盐酸盐
实施例1:2-氯-9-(2-氯苯基)-8,8-二氧代-5,7,8,9-四氢-8λ*6*-硫杂-5-氮杂-苯并环庚-6-酮
在室温,将间氯过氧苯甲酸(319mg,0.93mmol)加到搅拌的2-氯-9-(2-氯苯基)-5,9-二氢-8-硫杂-5-氮杂-苯并环庚-6-酮(200mg,0.62mmol)的二氯甲烷(5ml)溶液中。45min后,将混合物溶解在二氯甲烷中,用饱和的Na2S2O3溶液和饱和的Na2CO3溶液洗涤,用Na2SO4干燥,并浓缩。将残留物从甲醇/二氯乙烷(5ml/1ml)中重结晶,得到白色固体形式的标题化合物。
1H-NMR(400 MHz,DMSO-D6):4.27(d,J=13.7Hz,1H),4.46(d,J=13.3Hz,1H),5.96(s,1H),7.08(d,J=2.4Hz,1H),7.36(d,J=8.6Hz,1H),7.58-7.72(m,4H),8.27(dd,J=7.8Hz和1.6Hz,1H).
MS:[M+NH4]+=372.9,374.9.
实施例2:大鼠脑线粒体的分离
该方法采用Rosenthal等人的方法[J.Cereb.Blood Flow Metab.,7,752-758(1987)]。
溶液
MSH+:225mM甘露醇,75mM蔗糖,5mM Hepes,0.5mM EDTA,1mg/ml BSA(基本无游离脂肪酸);最终pH=7.3。
MSH-:同MSH+,但没有EDTA。
枯草菌蛋白酶溶液:溶解于1ml MSH+中的5mg枯草菌蛋白酶(细菌蛋白酶类型XXIV,购自Sigma,圣路易斯(St.Louis),USA,目录#P-8038)。
洋地黄皂苷溶液:10%W/V的DMSO溶液。
步骤
在冰上完成全部步骤。移出大鼠的全脑(1个脑=2g)。将组织加到在冰上烧杯里的冰冷的MSH+中。用剪刀把组织切成小块,并用MSH+冲洗组织2次。把组织转移至20ml Dounce匀浆器中,并用MSH+设定水平至大约9ml。加1ml新制的枯草菌蛋白酶溶液。匀浆化(用松弛的研杵击6次并用装紧的研杵击6次)。加MSH+至大约30ml/脑,并在2000g/3min离心。保留上清夜。将片状沉淀物再悬浮在大约30ml MSH+中,并再次在2000g/3min离心。收集上清夜,并在12000g/8min离心。将片状沉淀物(主要由线粒体和突触小体组成)悬浮于20ml MSH+/脑。加20μl洋地黄皂苷溶液,并在冰上孵育2min。在12000g/10min离心。将片状沉淀物再悬浮在10ml MSH-中,并在12000g/10min离心。将最终的片状沉淀物再悬浮在1.5ml MSH-/脑中。用Pierce BCA测定法(Pierce,Rockford IL,USA)测量蛋白质浓度。典型产量是10-15mg线粒体蛋白/大鼠脑(即最终的线粒体混悬液是大约8mg/ml)。将线粒体保持在冰上,并在2-3h内使用。
实施例3:大鼠脑线粒体Na-Ca交换体的测量
该方法基本如Chiesi等人[Biochem.Pharmacol.,37,4399-4403(1988)]所述那样,并且适用至微孔板。
培养基
120mM KCl,20mM Tris(pH=7.4),5μM鱼藤酮,10mM K-琥珀酸盐,1μM Oregon Green(购自分子探针(Molecular Probes))。
步骤
在典型实验中,使用了96-孔微孔板(平底)。在室温完成实验。在96-孔板分配5μl/孔2μM钌红[在120mM KCl和20mM Tris(pH=7.4)中]和待分析的化合物(在DMSO中)(1μl/孔)。对照得到相同量的溶媒。制备线粒体混悬液(将30μl新制的脑线粒体稀释在1ml培养基质中)。4min后,当被给予能量的线粒体蓄积了所有内源性和污染的Ca,将90μl/孔线粒体混悬液分配至微孔板的孔中,接着将上述微孔板放进装备注射器的荧光计里。将注射器充满200mM NaCl,并使荧光计按程序设置从注射器递送10μl/孔(终浓度:20mM)并进行20次测量(每3sec一次)。通过监测OregonGreen荧光来测量加入Na诱导的Ca-释放(485nm和538nm单色器分别用于激发和发射)。
数据分析
通过拟合和计算起始的衰变速率,对指数衰变的Ca-外流曲线进行评价。为了评价化合物的效力,使用Levenberg/Marqwardt方程拟合了Ca-外流速率的浓度依赖曲线,以得到IC50值。
本发明物质在该实验中显示低于20μM的IC50值。
尤其是,实施例1中描述的本发明物质在该实验中显示出3.8μM的IC50值。
Claims (9)
3.游离碱形式或药学上可接受的酸加成盐形式的权利要求1中所定义的化合物,其用作药物。
4.游离碱形式或药学上可接受的酸加成盐形式的权利要求1中所定义的化合物,其用于治疗和/或预防受线粒体Ca-处理能力功能障碍影响的病症和疾病。
5.药物组合物,该药物组合物包含作为活性成分的游离碱形式或药学上可接受的酸加成盐形式的权利要求1中所定义的化合物和药学载体或稀释剂。
6.作为药物的游离碱形式或药学上可接受的酸加成盐形式的权利要求1中所定义的化合物用于治疗和/或预防受线粒体Ca-处理能力功能障碍影响的病症和疾病的用途。
7.游离碱形式或药学上可接受的酸加成盐形式的权利要求1中所定义的化合物在制备治疗和/或预防受线粒体Ca-处理能力功能障碍影响的病症和疾病的药物中的用途。
8.在有此类治疗和/或预防需要的个体中治疗和/或预防受线粒体Ca-处理能力功能障碍影响的病症和疾病的方法,该方法包括将治疗有效量的游离碱形式或药学上可接受的酸加成盐形式的权利要求1中所定义的化合物给药至所述个体。
9.组合产品,该组合产品包含治疗有效量的游离碱形式或药学上可接受的酸加成盐形式的权利要求1中所定义的化合物和另外的药物,其用于同时或依次给药。
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EP06120389.9 | 2006-09-08 | ||
EP06120389 | 2006-09-08 |
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CN101511804A true CN101511804A (zh) | 2009-08-19 |
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CNA2007800326377A Pending CN101511804A (zh) | 2006-09-08 | 2007-09-07 | 对线粒体钠-钙交换体有作用的环状砜类 |
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US (1) | US20090281077A1 (zh) |
EP (1) | EP2069319A1 (zh) |
JP (1) | JP2010502680A (zh) |
KR (1) | KR20090049062A (zh) |
CN (1) | CN101511804A (zh) |
AU (1) | AU2007293674A1 (zh) |
BR (1) | BRPI0716842A2 (zh) |
CA (1) | CA2661975A1 (zh) |
MX (1) | MX2009002555A (zh) |
RU (1) | RU2009112724A (zh) |
WO (1) | WO2008028958A1 (zh) |
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EP2567959B1 (en) | 2011-09-12 | 2014-04-16 | Sanofi | 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors |
WO2018148629A2 (en) * | 2017-02-10 | 2018-08-16 | Temple University-Of The Commonwealth System Of Higher Education | Methods and compositions for treating neurodegeneration and fibrosis |
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AU2003286755A1 (en) * | 2002-10-30 | 2004-06-07 | Smithkline Beecham Corporation | Benzodiazepine derivatives for the treatment of diabetes mellitus |
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2007
- 2007-09-07 US US12/440,440 patent/US20090281077A1/en not_active Abandoned
- 2007-09-07 KR KR1020097004712A patent/KR20090049062A/ko not_active Application Discontinuation
- 2007-09-07 EP EP07803336A patent/EP2069319A1/en not_active Withdrawn
- 2007-09-07 RU RU2009112724/04A patent/RU2009112724A/ru not_active Application Discontinuation
- 2007-09-07 JP JP2009527149A patent/JP2010502680A/ja active Pending
- 2007-09-07 CN CNA2007800326377A patent/CN101511804A/zh active Pending
- 2007-09-07 AU AU2007293674A patent/AU2007293674A1/en not_active Abandoned
- 2007-09-07 CA CA002661975A patent/CA2661975A1/en not_active Abandoned
- 2007-09-07 MX MX2009002555A patent/MX2009002555A/es not_active Application Discontinuation
- 2007-09-07 BR BRPI0716842-0A2A patent/BRPI0716842A2/pt not_active Application Discontinuation
- 2007-09-07 WO PCT/EP2007/059394 patent/WO2008028958A1/en active Application Filing
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KR20090049062A (ko) | 2009-05-15 |
AU2007293674A1 (en) | 2008-03-13 |
EP2069319A1 (en) | 2009-06-17 |
US20090281077A1 (en) | 2009-11-12 |
CA2661975A1 (en) | 2008-03-13 |
BRPI0716842A2 (pt) | 2013-10-01 |
RU2009112724A (ru) | 2010-10-20 |
JP2010502680A (ja) | 2010-01-28 |
MX2009002555A (es) | 2009-03-20 |
WO2008028958A1 (en) | 2008-03-13 |
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