CN110225916A - 用于治疗衰老相关病症的化合物 - Google Patents
用于治疗衰老相关病症的化合物 Download PDFInfo
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- CN110225916A CN110225916A CN201780084785.7A CN201780084785A CN110225916A CN 110225916 A CN110225916 A CN 110225916A CN 201780084785 A CN201780084785 A CN 201780084785A CN 110225916 A CN110225916 A CN 110225916A
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Abstract
本发明涉及通式I的化合物
Description
技术领域
本发明涉及能够从活生物体中消除衰老细胞并且可用于治疗衰老相关病症的新型化合物。
背景技术
细胞衰老被认为是第一线肿瘤发生屏障,其阻止具有受损基因组的细胞的分裂。另一方面,衰老细胞在生物体中的持续存在由于这些细胞本身产生的物质而被认为是有害的。在伦纳德·海弗里克(Leonard Hayflick)的学说之后的半个世纪,最近的出版物明确证实了衰老细胞对生物体老化的影响(Baker等,Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan(天然存在的p16(Ink4a)阳性细胞缩短健康寿命),Nature.2016 530:184-189)。鉴于衰老细胞周期停滞并非完全不可逆转的事实,衰老细胞在组织中的持续存在可能代表了具有不可修复的DNA损伤的衰老细胞逃逸者的衰老绕过和转变成具有病理潜力的细胞的时间依赖性威胁。
各种衰老形式的基因表达特征的变化伴随着许多细胞因子、趋化因子、生长因子以及蛋白酶的mRNA水平和分泌的稳健增加。这种现象被称作衰老相关的分泌表型(SASP)。由于SASP主要由基因组损伤响应所引起,因此它的有益功能之一可能是经由分泌促炎性细胞因子,特别是TNFα、IL6、IL8以及IL1β与免疫系统的细胞进行通信,以发信号表明带有潜在病理发展风险的受损细胞的存在。除了这种功能之外,还发现了SASP在损伤之后组织再生中的作用。由受损组织中的衰老细胞分泌的基质金属蛋白酶防止胶原蛋白和纤连蛋白的积累,这两种蛋白质参与纤维化的扩展。
另一方面,衰老细胞在其中免疫系统被削弱的老年人或接受免疫抑制化疗的患者体内的积累会导致以年龄依赖性方式抑制各种器官功能(Vasto 等,Inflammatorynetworks in ageing,age-related diseases and longevity(老化、年龄相关疾病以及长寿中的炎症网络),Mech Ageing Dev.2007 128:83-91)或导致组织损伤,这是由于相邻细胞中的异常线粒体所引起的氧化应激增强所引起的促炎性细胞因子的信号传导增加所致(Campisi等,Senescent cells,tumor suppression,and organismal aging:goodcitizens,bad neighbors(衰老细胞、肿瘤抑制以及生物体老化:好公民,坏邻居),Cell.2005 120:513-522)。据描述,衰老细胞经由直接影响胰腺β细胞功能、SASP介导的组织损伤以及涉及脂肪组织功能障碍而在2型糖尿病发病机制中起作用(关于概述,参见Palmer等,Cellular Senescence in Type 2Diabetes:A Therapeutic Opportunity(2型糖尿病中的细胞衰老:一种治疗机会),Diabetes.2015 64:2289-2298)。由于进而在糖尿病中看到的代谢和信号传导变化可以促进衰老,因此显然,衰老细胞是糖尿病中的致病环的一部分,是代谢变化和组织损伤的原因和结果,并且它们的治疗靶向可能对预防疾病进展有很大的影响。还发现SASP通过自分泌方式或旁分泌方式扩增衰老表型,从而引起衰老经由组织和器官扩散。
到目前为止,只有两个小组报道了衰老细胞的消除和它的后果。首先,Baker等(Baker等,Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders(p16Ink4a阳性衰老细胞的清除延迟老化相关病症),Nature.2011479:232-236)使用在p16启动子下携带胱天蛋白酶8质粒的特异性转基因小鼠,这在细胞经历衰老时会激活细胞凋亡,从而消除生物体中的这些细胞。他们证实了衰老细胞消除在改善生活质量和延长寿命方面的作用。
衰老细胞上调来自Bcl-2家族的蛋白质以保护其自身防止细胞凋亡。Yosef等(Yosef等,Directed elimination of senescent cells by inhibition of BCL-W andBCL-XL(通过抑制BCL-W和BCL-XL定向消除衰老细胞),Nat Commun.7:11190)首次证实了可以使用Bcl-2抑制剂ABT-737以药理学方式消除衰老细胞,所述ABT-737由于它的不利的药理学特性而没有经过临床测试。
在体内以药理学方式消除衰老细胞的能力为研究衰老细胞在其中检测到它们的广泛范围的生理环境中的作用打开了大门。衰老细胞的化疗消除可以被证明是有益的,这是因为这些细胞在各种组织中的积累会导致年龄相关的病变。
因此,从生物体中清除衰老细胞在治疗和/或预防衰老相关疾病中起作用,如特发性肺纤维化、肌肉减少症、糖尿病、肥胖症、骨关节炎、慢性炎症、青光眼、白内障、放射诱发性口腔粘膜炎、肾移植(Munoz-Espin和Serrano,Cellular senescence:from physiologyto pathology(细胞衰老:从生理到病理),Nat Rev Mol Cell Biol.2014,15:482-496)以及前列腺增生(Castro等,Cellular senescence in the pathogenesis of benignprostatic hyperplasia(细胞衰老在良性前列腺增生的发病机制中),Prostate,55,30-8.(2003))。
发明内容
本发明提供了新一代的通式I的物质,其应当被认为包括所有异构结构(并且其中通式I中的交叉双键表示所述双键可以具有E构型和/或Z构型)和药学上可接受的盐
其中Z是选自亚烷基、亚烯基或亚炔基的直链烃基链,其含有1个至20个碳原子,优选地含有4个至14个碳原子,更优选地含有8个至12个碳原子,而任选地,所述烃基链中的一个或多个碳原子对可以被一个或多个5元或6元芳环或含有杂原子O、S和/或N的杂芳环,优选地亚苯基或亚吡啶基或三唑置换,和/或所述烃基链中的一个或多个碳原子可以被选自O、S、NH的一个或多个杂原子置换;而所述烃基链可以是未取代的或被独立地选自包括以下各项的组的一个或多个取代基取代:C1-C4烷基;N(H或C1-C4烷基)2,其中所述烷基是相同的或不同的;苯基;苯甲基;OH;=O;SH;=S;F;Cl;Br;I;C1-C4烷氧基;C1-C4酰氧基;C1-C4巯基;
并且R1、R2、R3中的每一个独立地选自包括以下各项的组:C1-C10烷基、C6-C12芳基、C6-C12芳基-C1-C2烷基、C5-C12杂芳基、C3-C8环烷基,其中R1、R2、R3中的每一个可以任选地(并且彼此独立地)被独立地选自包括以下各项的组的一个或多个取代基取代:C1-C4烷基;C1-C4烷氧基;N(H或C1-C4烷基)2,其中所述烷基是相同的或不同的;OH;=O;SH;=S;F;Cl;Br;I;C1-C4巯基。
优选的是,Z是选自亚烷基、亚烯基或亚炔基(优选地是亚烷基)的直链烃基链,其含有4个至14个碳原子,更优选地含有8个至12个碳原子,最优选地含有8个或10个或12个碳原子。
优选的是,Z是选自亚烷基、亚烯基或亚炔基(优选地是亚烷基)的直链烃基链,其含有4个至14个碳原子,更优选地含有8个至12个碳原子,其中所述烃基链中的一个或多个碳原子被选自O、S、NH(优选地是O)的一个或多个杂原子置换。
优选的是,Z是选自亚烷基、亚烯基或亚炔基(优选地是亚烷基)的直链烃基链,其含有4个至14个碳原子,更优选地含有8个至12个碳原子,其中所述烃基链中的一个或多个碳原子被选自以下各项的一个或多个取代基取代:C1-C4烷基;N(H或C1-C4烷基)2,其中所述烷基是相同的或不同的;OH;=O;SH;=S;F;Cl;Br;I;C1-C4烷氧基;C1-C4巯基。
优选的是,Z是选自亚烷基、亚烯基或亚炔基(优选地是亚烷基)的直链烃基链,其含有4个至14个碳原子,更优选地含有8个至12个碳原子,其中所述烃基链中的一个或多个碳原子被选自O、S、NH(优选地是N)的一个或多个杂原子置换,并且所述烃基链中的一个或多个碳原子被选自以下各项的一个或多个取代基取代:OH;=O;SH;=S;C1-C4烷氧基;C1-C4巯基。
优选的是,Z是选自亚烷基、亚烯基或亚炔基(优选地是亚烷基)的直链烃基链,其含有4个至14个碳原子,更优选地含有8个至12个碳原子,其中所述烃基链中的一个或多个碳原子对被一个或多个5元或6元芳环或杂芳环,优选地亚苯基和/或亚吡啶基和/或三唑置换。
优选的是,Z被选自以下各项的一个或多个取代基取代:C1-C4烷基;N(H或C1-C4烷基)2,其中所述烷基是相同的或不同的;OH;=O;SH;=S;F;Cl;Br;I;C1-C4烷氧基;C1-C4巯基;更优选的是,Z被选自以下各项的一个或多个取代基取代:OH;=O;SH;=S;F;Cl;Br;I。
为了保护所述化合物,因而,R1、R2以及R3不同时是未取代的苯基。
优选的是,R1、R2、R3中的每一个独立地选自包括甲基、丁基、辛基、苯基、甲氧基苯基、苯甲基、环己基、叔丁基的组。
X-是药学上可接受的阴离子,特别是无机酸或有机酸的阴离子,特别合适的阴离子选自下组:有机盐,如柠檬酸盐、乙酸盐、乳酸盐、酒石酸盐、草酸盐、抗坏血酸盐、甲磺酸盐、甲苯磺酸盐;或无机盐,如硫酸盐、卤化物、磷酸盐和/或它们的混合物。
本文以上所列的实施方案可以自由组合。
本发明的化合物是通过以下合成程序制备的。
制备通式I的2-(4-(1,2-二苯基乙烯基)苯氧基)-N,N-二甲基乙-1-胺衍生物的优选方法(当Z是亚烷基时,是特别合适的)是基于在-78℃的温度下在氩气气氛下在四氢呋喃(THF)中在有机碱(优选地是丁基锂)的处理下从具有通式II的叔丁基二甲基甲硅烷基-氧基-烷基-三苯基磷鎓
其中n=1-19,
并且Y是I、Br、Cl或甲磺酰基,
产生内鎓盐的反应以及随后与式III的醛的缩合
得到通式IV的甲硅烷基化的衍生物,
用四丁基氟化铵处理通式IV的甲硅烷基化的衍生物,得到通式V的烯醇,
将所述通式V的烯醇在氢气气氛中在氢化催化剂存在下还原成通式VI的醇,
将所述通式VI的醇取代成通式VII的相应衍生物,
将所述通式VII的相应衍生物通过与通式VIII的膦一起加热而转化成通式I的2-(4-(1,2-二苯基乙烯基)苯氧基)-N,N-二甲基乙-1-胺(或它的相应盐)的磷鎓衍生物,
其中R1、R2、R3中的每一个具有如式I中所定义的含义。
在一种优选的方法中,式III的衍生物在一锅法程序中与原位制备的内鎓盐反应以直接得到通式V的醇,所述内鎓盐是由通式IX的醇
其中Y是离去基(或如化合物II中所定义)
和三苯基膦在碱(优选地是双(三甲基甲硅烷基)氨基锂)存在下在有机溶剂中(优选地在二甲基甲酰胺/二甲亚砜混合物中)反应而得到的。
在另一种优选的方法中,将式VII的衍生物在用氨处理下,优选地在DMF/甲醇溶液中转化成通式X的胺,
所述通式X的胺与通式XI的羧酸衍生物和通式VIII的膦反应,优选地在DCM中反应,
以形成通式I的2-(4-(1,2-二苯基乙烯基)苯氧基)-N,N-二甲基乙-1-胺的磷鎓衍生物,
其中Y是离去基(或如化合物II中所定义)。
在另一种优选的方法中,使用奥伊拉-贝斯特曼试剂(Ohira-Bestmann reagent)或其他合适的试剂将醛III转化成炔烃衍生物XII
并且在标准点击反应条件下,优选地使用CuSO4·5H2O和抗坏血酸钠,优选地在乙醇/DMF混合物中与通式XIII的叠氮化物衍生物进行反应,
得到通式I的相应衍生物。
本发明还提供了式I的化合物,其用于治疗并且克服生物体不能消除衰老细胞的方法中。所述药物主要影响源自于各种组织,特别是乳腺、胰腺以及前列腺组织的衰老细胞。
因此,式I的化合物可用于治疗和/或预防衰老相关疾病和健康状况,如特发性肺纤维化、肌肉减少症、糖尿病、肥胖症、骨关节炎、慢性炎症、青光眼、白内障、放射诱发性口腔粘膜炎、肾移植(Munoz-Espin和Serrano,Cellular senescence:from physiology topathology(细胞衰老:从生理到病理),Nat Rev Mol Cell Biol.2014,15:482-496)以及前列腺增生(Castro等,Cellular senescence in the pathogenesis of benign prostatichyperplasia(细胞衰老在良性前列腺增生的发病机制中),Prostate,55,30-8.(2003))。
如上所述,年龄相关的慢性疾病,如糖尿病可能部分地由导致年龄相关的组织功能障碍、慢性“无菌性”炎症、大分子损伤或祖细胞功能障碍的基本老化机制的会聚所引起。使用体外模型和体内模型,我们观测到使用式I的化合物特异性消除衰老细胞。我们发现了蛋白质腺嘌呤核苷酸转位酶2(ANT2)的关键作用,其上调增加了衰老细胞对式I化合物的抗性。
式I的化合物选择性地在衰老细胞中诱导细胞死亡。它们非常有效地杀死在老化器官中积累的原代衰老细胞和响应于遗传突变、环境影响或可能最重要的是,病理状态而存在于较年轻的生物体中的过早衰老细胞。
具体实施方式
实施本发明的实施例
缩写:
ANT2:腺嘌呤核苷酸转位酶2
ATP:腺苷三磷酸
B-gal:β-半乳糖苷酶
BrdU:5-溴-2-脱氧尿苷
DCM:二氯甲烷
DMF:二甲基甲酰胺
DMSO:二甲亚砜
FCCP:羰基氰-4-(三氟甲氧基)苯腙
IBX:2-碘酰基苯甲酸
LiHMDS:六甲基二硅氮烷锂
mtATP:线粒体腺苷三磷酸
NAC:N-乙酰半胱氨酸
NMR:核磁共振
PAI:纤溶酶原激活物抑制因子
qRT PCR:定量逆转录聚合酶链反应
ROS:活性氧簇
TBAF:四丁基氟化铵
THF:四氢呋喃
TLC:薄层色谱
使用式III的醛作为起始材料来制备通式I的与以鏻鎓盐封端的接头连接的(Z)-2-(4-(1,2-二苯基乙烯基)苯氧基)-N,N-二甲基乙-1-胺,所述式III的醛是根据2003年公开的程序制备的((Z)-Tamoxifen and Tetrasubstituted Alkenes and Dienes via aRegio-and Stereospecific Three-Component Magnesium Carbometalation Palladium(0)Cross-Coupling Strategy(经由区域特异性和立体特异性三组分镁碳金属化钯(0)交叉偶联策略的(Z)-他莫昔芬以及四取代的烯烃和二烯);Pierre E.Tessier,AndreaJ.Penwell,Fabio E.S.Souza以及Alex G.Fallis*;ORGANIC LETTERS,2003,第5卷,第17期,2989-2992),
起始醛IIIa可以借助于除上述出版物中所用的氧化剂以外的另外的氧化剂来制备。使用稳定化的2-碘苯甲酸(SIBX)代替戴斯-马丁试剂(Dess-Martin agent)仅形成一种双键异构体。产率是相当的。
将SIBX(250g,401.757mmol)和起始烯丙醇(100.00g,267.744mmol)(参见上述出版物)溶解在乙酸乙酯(1L)中。在恒定搅拌下将悬浮液回流1.5小时的时间。将反应混合物冷却到室温,过滤并且在甲苯(2.5L)与氢氧化钠(2M,1L)之间洗涤。在添加木炭(25g)的情况下将有机层经过硫酸镁干燥,过滤并且在真空下浓缩,得到93g(93%)呈棕色固体形式的醛IIIa。
实施例1
将(9-((叔丁基二甲基甲硅烷基)氧基)壬基)三苯基溴化磷鎓(634mg,1.057mmol)溶解在无水四氢呋喃(THF)(6ml)中,用氩气气氛覆盖并且冷却到-78℃。在氩气气氛下将丁基锂(1.2ml,0.9M THF溶液)缓慢逐滴添加到反应混合物中。使溶液升温到0℃,颜色变成暗红色,再次冷却到-78℃并且逐滴添加溶解在无水THF(3ml)中的式IIIa的醛(160mg,0.430mmol)。然后,使反应混合物升温到实验室温度并且在氩气气氛下搅拌16小时。使用薄层色谱(TLC)在氯仿-甲醇(10:1)的混合物中监测反应的进展。然后,将氯化铵和水的饱和溶液添加到反应混合物中并且用乙酸乙酯萃取。将乙酸乙酯层用盐水洗涤并且经过硫酸镁干燥。将溶液过滤并且在减压下浓缩。在硅胶柱上在二氯甲烷(DCM)/甲醇(梯度0%至10%的甲醇)的体系中对浓缩物进行色谱分离,得到147mg的式4的产物(56%产率)。
1H NMR(500MHz,CDCl3)δ7.42-7.36(m,5H),7.18-7.28(m,5H),6.94(d,J=8.7,2H),6.73(d,J=8.7,2H),6.19(d,J=11.5,1H),5.47(dt,J=11.5,7.4,1H),4.09(t,J=5.8,2H),3.72(t,J=6.6,2H),2.80(t,J=5.8,2H),2.42(s,6H),1.69-1.57(m,4H),1.48-1.13(m,10H),1.03(s,9H),0.18(s,6H)。电喷雾电离质谱(ESI MS):612。
13C NMR(101MHz,CDCl3)δ156.64,143.81,142.75,140.29,138.42,135.65,131.80,129.58,129.51,128.04,127.83,126.45,125.94,113.38,77.34,77.02,76.71,65.49,63.34,58.04,45.61,35.88,32.90,29.71,29.65,29.56,29.45,29.41,29.24,28.84,26.00,25.80,18.39,-5.23。
C40H60O2NSi的HRMS计算值:614.43878,实测值:614.43869。
IR(KBr压片):ν=3056,3025,2927,2855,2821,2771,1943,1886,1607,1508,1471,1463,1443,1246,1174,1098,1031,835,774,703。
(9-((叔丁基二甲基甲硅烷基)氧基)壬基)三苯基溴化磷鎓根据文献中公开的程序来制备。(Tetrahedron Letters,2010,51,49,6426-6428。)
实施例2
方法A
将式4的甲硅烷基化的衍生物(147mg,2.240mmol)溶解在THF(5ml)中,然后用氩气气氛覆盖并且在0℃的温度下在搅拌下逐滴添加四丁基氟化铵(TBAF)(260μl,1M THF溶液)。然后,使反应混合物升温到实验室温度并且再搅拌6小时。使用TLC在氯仿-甲醇(10:1)的混合物中监测反应的进展。然后,添加水并且用乙酸乙酯萃取混合物。将乙酸乙酯层用苏打和盐水的饱和溶液洗涤并且经过硫酸镁干燥。过滤干燥剂并且在减压下浓缩溶液。将浓缩物用硅胶柱色谱在体系氯仿/甲醇(梯度0%至10%的甲醇)中纯化,得到115mg(96%产率)的所需的式5的烯醇。
方法B
将三苯基膦(161.5g,615.8mmol)添加到溴壬醇(125g,559.8mmol)于二甲基甲酰胺(500ml)中的溶液中。将反应混合物在氩气下在80℃搅拌16小时,然后冷却到35℃。在添加双(三甲基甲硅烷基)氨基锂于四氢呋喃中的溶液(1M,1L)(10分钟时间段)之前,添加另外的溶剂(1L二甲亚砜和1L四氢呋喃)。在搅拌10分钟之后,显现独特的橙红色,此时,经过5分钟的时间段添加醛IIIa(100g,269.2mmol)于四氢呋喃(500ml)中的溶液。将所得溶液在室温下搅拌1小时。在乙酸乙酯与饱和氯化铵之间洗涤的几滴反应混合物的TLC分析(在氯仿/甲醇/氨95:5:0.5中展开)表明起始材料完全转化。用冰(0.5kg)和冰冷饱和氯化铵溶液(1L)淬灭反应。混合物自发分成两层。用乙醚(1000ml+500ml)再萃取底部水层。将合并的有机层用HCl乙醚溶液(1M,500ml)酸化,用庚烷(1L)稀释并且用饱和氯化铵(1L)洗涤。棕色产物沉淀物在上部有机层与底部水层之间形成。在分液漏斗中分离所有层。将棕色油状沉淀物溶解在二氯甲烷中并且在饱和氯化铵(1L)、乙醚(1L)以及庚烷(2L)之间再次洗涤。将在上部有机层与底部水层之间形成的棕色产物沉淀物在分液漏斗中分离,溶解在二氯甲烷(1L)中并且加到柱(1L二氧化硅)上。在二氯甲烷(2L)→氯仿/甲醇100:10(4L)→100:15(2L)中进行色谱分离,得到含有大量二甲亚砜的精制产物的浅色油状物。然后将精制产物溶解在甲醇(1.5L)中,用碳酸氢钠(4%,1L)稀释并且萃取到庚烷(8×2L)中。在真空下浓缩合并的庚烷层,得到108.5g呈白色固体状的化合物5。
1H NMR(500MHz,CDCl3)δ7.43-7.14(m,5H),6.94(d,J=8.5,2H),6.72(d,J=8.5,2H),6.20(d,J=11.5,1H),5.48(dt,J=11.5,7.4,1H),4.12(t,J=5.9,2H),3.72(t,J=6.6,2H),2.86(t,J=5.9,2H),2.46(s,6H),1.71-1.58(m,4H),1.51-1.10(m,10H)。ESI MS:498。
13C NMR(101MHz,CDCl3)δ157.18,143.73,142.70,141.09,133.83,132.52,131.04,130.96,130.65,127.73,127.56,126.84,126.05,113.50,77.38,77.06,76.74,65.71,62.93,58.25,45.86,32.81,29.36,29.32,29.25,29.08,28.96,25.74。
C34H44O2N的HRMS计算值:498.33666,实测值:498.33656。
IR(KBr压片):ν=3411,3054,3019,2926,2853,2772,1605,1507,1464,1442,1287,1243,1172,1031,963,827,764。
实施例3
将式5的烯醇衍生物(115mg,0.231mmol)溶解在无水乙醇(6ml)中并且用氩气气氛覆盖。将10%Pd/C(10mg)添加到混合物中并且将容纳反应悬浮液的烧瓶反复抽空并用氢气气氛覆盖几次。然后,在实验室温度下在氢气气氛下将反应混合物搅拌24小时。使用TLC在氯仿-甲醇(10:1)的混合物中监测反应的进展。将混合物经由硅藻土层过滤并且用乙醇洗涤几次。蒸发乙醇,得到101mg(87%产率)所需的式6的醇,其不经任何进一步纯化而用于合成的下一步。
1H NMR(500MHz,CD3OD)δ7.40-7.01(m,10H),6.85(d,J=8.1,2H),6.68(d,J=8.1,2H),4.20(s,2H),3.55(t,J=6.4,2H),3.46(s,2H),2.89(s,6H),2.42(t,J=7.8,2H),1.57-1.48(m,2H),1.38-1.11(m,12H)。ESI MS:500。
13C NMR(101MHz,CDCl3)δ156.7,143.8,142.7,140.3,138.4,135.6,131.8,129.6,129.5,128.0,127.8,126.5,126.0,113.4,77.4,77.1,76.7,65.6,63.0,58.1,45.7,35.9,32.8,29.6,29.5,29.4,29.4,29.2,28.8,25.8。
C34H46O2N的HRMS计算值:500.35231,实测值:500.35208。
IR(KBr压片):ν=3411,3055,2925,2853,2773,1607,1508,1465,1442,1284,1242,1174,1100,1031,962,835,772,703,606。
实施例4
将式6的醇(230mg,0.460mmol)溶解在DCM(10ml)中。在实验室温度下在氩气气氛下将CBr4(480mg,1.447mmol)添加到混合物中。然后,逐滴添加溶解在DCM(3ml)中的三苯基膦(400mg,1.525mmol)。将混合物在实验室温度下搅拌2小时,然后在减压下浓缩。使用TLC在氯仿-甲醇(10:1)的混合物中监测反应的进展。在硅胶柱上在DCM/甲醇体系(梯度0%-10%)中对浓缩物进行色谱分离,得到273mg(92%产率)所需的式7的溴化物。在没有任何长期储存的情况下对溴化物进行下一步反应。
1H NMR(400MHz,CDCl3)δ7.46-6.96(m,10H),6.78(d,J=8.9Hz,2H),6.53(d,J=8.8Hz,2H),4.29(t,J=6.6Hz 2H),3.47-3.28(m,4H),2.82(s,6H),2.38(t,J=7.8Hz,2H),1.80(q,J=7.8Hz,2H),1.46-0.98(m,14H)。ESI MS:561。
13C NMR(101MHz,CDCl3)δ155.1,143.5,142.5,140.8,138.0,136.9,132.0,129.5,129.5,128.1,127.9,126.6,126.1,113.4,77.4,77.1,76.7,62.6,56.6,43.8,35.9,34.1,32.8,29.6,29.3,29.2,28.8,28.7,28.1。
C34H45NOBr的HRMS计算值:562.26790,实测值:562.26787。
IR(KBr压片):ν=3417,3017,2609,2456,1605,1574,1508,1465,1441,1284,1238,1174,1111,1071,1029,993,832,770,704,604。
实施例5
一般程序:
将通式结构VIII的膦(3当量)添加到式7的溴化物(1当量)中,并且在85℃的温度下在氩气气氛下将混合物搅拌12小时的时间。使用TLC在氯仿-甲醇(10:1)的混合物中监测反应的进展。将反应混合物冷却到实验室温度,溶解在最小量的DCM中并且在恒定搅拌下在0℃的温度下逐滴添加到己烷溶液(50ml)中。将所形成的沉淀物过滤,再次溶解在最小量的DCM中并且在恒定搅拌下在0℃的温度下逐滴添加到乙醚溶液(50ml)中。将沉淀物过滤并且在真空下干燥。产率在55%与85%之间变动。
实施例6
使用实施例5中所述的程序和三苯基膦,获得呈黄色粉末形式的式8的化合物。
1H NMR(400MHz,甲醇-d4)δ7.98-7.68(m,15H),7.37-7.29(m,2H),7.28-7.05(m,8H),6.82(d,J=8.8Hz,2H),6.67(d,J=8.8Hz,2H),4.27-4.07(t,J=5.2Hz,2H),3.44(t,J=5.2Hz,2H),3.42-3.34(m,2H),2.87(s,6H),2.38(t,J=8.0Hz,2H),1.70-1.57(m,2H),1.51(q,J=7.4Hz,2H),1.43-1.21(m,4H),1.21-1.06(m,6H)。
13C NMR(101MHz,甲醇-d4)δ157.19,144.91,143.93,141.89,139.94,137.98,136.25(d,J=3.0Hz),134.78(d,J=9.9Hz),132.99,131.51(d,J=12.6Hz),130.72,130.43,129.21,128.93,127.71,127.19,119.97(d,J=86.2Hz),114.65,63.32,57.88,49.64,49.43,49.21,49.00,48.79,48.57,48.36,44.12,36.76,31.50(d,J=15.9Hz),30.55,30.24,30.18,29.74(d,J=5.4Hz),23.50,23.46,22.94,22.43。
C52H59NOP的HRMS计算值:744.43288,实测值:744.43311。
IR(KBr压片):ν=3397,3051,3016,2923,2853,2596,2455,1605,1507,1485,1465,1438,1240,1174,1112,1072,1028,995,751,723,705,691。
实施例7
使用实施例5中所述的程序和三苯甲基膦,获得呈黄色泡沫形式的式9的化合物。
1H NMR(500MHz,CD3OD)δ7.45-7.37(m,9H),7.37-7.31(m,2H),7.30-7.19(m,9H),7.19-7.05(m,5H),6.78(d,J=8.8Hz,2H),6.58(d,J=8.9Hz,2H),3.96(t,J=5.5Hz,2H),3.80(d,J=14.7Hz,6H)-磷鎓亚甲基的信号可能由于溶剂化或水合而显著漂移,2.69(t,J=5.5Hz,2H),2.45-2.38(m,2H),2.30(s,3H),2.06-1.96(m,2H),1.42-1.27(m,6H),1.27-1.08(m,8H)。
13C NMR(126MHz,cd3od)δ158.17,145.09,144.04,141.45,140.17,136.96,132.88,131.44(d,J=5.2Hz),130.76,130.71(d,J=3.0Hz),130.49,129.80,129.77,129.18,128.92,127.66,127.15,114.45,66.38,59.05,45.78,36.76,31.64(d,J=15.3Hz),30.58,30.24,30.11(2C),29.76,29.61,29.9(2C),22.26(d,J=4.9Hz)。
HR-MS:m/z=393.74333,C55H66NOP2+的计算值:393.74355。
IR:1602,1584,1574,1508,1496,1442,1174,1031,702。
实施例8
使用实施例5中所述的程序和三环己基膦,获得呈黄色泡沫形式的式10的化合物。
1H NMR(500MHz,CD3OD)δ7.38-7.32(m,2H),7.29-7.24(m,1H),7.23-7.05(m,7H),6.77(d,J=8.9Hz,2H),6.58(d,J=8.9Hz,2H),3.96(t,J=5.5Hz,2H),2.70(t,J=5.5Hz,2H),2.53(qt,J=12.5 5Hz,J=2.5Hz,3H),2.44-2.39(m,2H),2.31(s,6H),2.26-2.18(m,2H),1.96(m,12H),1.80(m,3H),1.66-1.11(m,31H)。
13C NMR(126MHz,cd3od)δ158.14,145.07,144.02,141.45,140.14,136.95,132.86,130.73,130.48,129.15,128.89,127.62,127.12,114.43,66.33,59.03,45.76,36.73,32.14(d,J=14.0Hz),30.80(d,J=41.2Hz),30.60,30.33,30.30,30.25,29.76,29.72,27.98(d,J=3.8Hz),27.50(d,J=11.9Hz),26.55,26.54,23.36(d,J=5.1Hz),16.09(d,J=43.3Hz)。
HR-MS:m/z=2,381.78974,C52H78NOP2+的计算值:381.790505;m/z=1,762.57242,C52H77NOP+的计算值:762.57373。
IR:2929,2853,2772,1638,1606,1574,1508,1492,1473,1445,1443,1363,1243,1174,1113,1030,963,750,703。
实施例9
使用实施例5中所述的程序和三(邻甲氧基苯基)膦,获得呈黄色泡沫形式的式11的化合物。
1H NMR(500MHz,CD3OD)δ7.86-7.78(m,3H),7.37-7.01(m,19H),6.80-6.73(m,2H),6.61-6.55(m,2H),3.97(t,J=5.5Hz,2H),3.76(s,9H),3.17-3.06(m,2H),2.71(t,J=5.5Hz,2H),2.42-2.37(m,2H),2.31(s,6H),1.53-1.39(m,4H),1.32-1.27(m,2H),1.25-1.19(m,2H),1.19-1.05(m,8H)。
13C NMR(126MHz,CD3OD)δ163.07(d,J=2.4Hz),158.13,145.08,144.02,141.44,140.14,138.14(d,J=2.1Hz),136.96,135.90(d,J=8.20Hz),132.86,130.74,130.48,129.15,128.90,127.62,127.12,123.12(d,J=12.7Hz),114.44,113.87(d,J=6.6Hz),107.59(d,J=92.3Hz),66.30,59.02,56.62,45.74,36.69,31.61(d,J=17.6Hz),30.50,30.18(d,J=3.5Hz),30.11,29.90,29.67,25.13(d,J=54.2Hz),25.04,25.00。
HR-MS:m/z=2,417.73529,C55H66NO4P2+的计算值:417.735952;m/z=1,834.46307,C55H65NO4P+的计算值:834.46457。
IR:2924,2853,2845,2771,1640,1605,1589,1575,1508,1479,1432,1368,1172,1030,962,757,703。
实施例10
使用实施例5中所述的程序和甲基二苯基膦,获得呈黄色泡沫形式的式12的化合物。
1H NMR(500MHz,CD3OD)δ7.92-7.78(m,6H),7.76-7.68(m,4H),7.38-7.30(m,2H),7.28-7.04(m,8H),6.77(d,J=8.8Hz,2H),6.58(d,J=8.9Hz,2H),3.96(t,J=5.5Hz,2H),3.01-2.91(m,2H),2.70(t,J=5.5Hz,2H),2.59(d,J=13.9Hz,3H),2.42-2.37(m,2H),2.30(s,6H),1.60-1.51(m,2H),1.50-1.43(m,2H),1.34-1.23(m,4H),1.22-1.05(m,8H)。
13C NMR(126MHz,CD3OD)δ158.15,145.07,144.02,141.46,140.14,136.97,135.83(d,J=3.0Hz),133.38(d,J=10.0Hz),132.86,131.28(d,J=12.5Hz),130.74,130.47,129.16,128.90,127.63,127.13,121.42(d,J=85.6Hz),114.44,66.35,59.04,45.77,36.73,31.43(d,J=16.1Hz),30.56,30.27,30.19(d,J=2.8Hz),29.80,29.73,23.09(d,J=51.5Hz),22.84,22.81,6.29(d,J=56.2Hz)。
HR-MS:m/z=2,341.71149,C47H58NOP2+的计算值:341.71225;m/z=1,682.41522,C47H57NOP+的计算值:682.41723。
IR:2924,2853,2771,1606,1589,1574,1508,1491,1464,1438,1369,1242,1174,1116,1030,997,746,704,692。
实施例11
使用实施例5中所述的程序和二甲基苯基膦,获得呈黄色泡沫形式的式13的化合物。
1H NMR(500MHz,CD3OD)δ7.98-7.89(m,2H),7.84-7.76(m,1H),7.74-7.68(m,2H),7.37-7.31(m,2H),7.29-7.05(m,8H),6.77(d,J=8.8Hz,2H),6.58(d,J=8.8Hz,2H),3.96(t,J=5.5Hz,2H),2.69(t,J=5.5Hz,2H),2.56-2.46(m,2H),2.43-2.36(m,2H),2.29(s,6H),2.23(d,J=14.3Hz,6H),1.55-1.45(m,2H),1.44-1.35(m,2H),1.34-1.22(m,4H),1.21-1.07(m,8H)。
13C NMR(126MHz,CD3OD)δ158.16,145.07,144.02,141.46,140.14,136.96,135.52(d,J=3.0Hz),132.86,132.41(d,J=9.9Hz),131.09(d,J=12.4Hz),130.74,130.47,129.16,128.90,127.63,127.13,121.93(d,J=84.9Hz),114.44,66.39,59.06,45.79,36.73 31.41(d,J=15.9Hz),30.57,30.30,30.20(d,J=3.6Hz),29.79,29.74,24.61(d,J=51.6Hz),22.57,22.54,7.21(d,J=55.6Hz)。
HR-MS:m/z=2,310.70419,C42H56NOP2+的计算值:310.704425;m/z=1,620.40099,C42H55NOP+的计算值:620.40158。
IR:2922,2852,2824,2774,1636,1608,1574,1508,1491,1465,1452,1437,1368,1247,1175,1120,1028,964,744,690,480。
实施例12
使用实施例5中所述的程序和三丁基膦,获得呈黄色油形式的式14的化合物。
1H NMR(500MHz,CD3OD)δ7.38-7.32(m,2H),7.30-7.06(m,8H),6.77(d,J=8.9Hz,2H),6.58(d,J=8.9Hz,2H),3.96(t,J=5.5Hz,2H),2.69(t,J=5.5Hz,2H),2.44-2.38(m,2H),2.30(s,6H),2.27-2.15(m,8H),1.63-1.50(m,14H),1.49-1.42(m,2H),1.39-1.12(m,12H),1.01(t,J=7.1Hz,12H)。
13C NMR(126MHz,CD3OD)δ158.14,145.07,144.02,141.45,140.14,136.95,132.86,130.74,130.48,129.15,128.90,127.63,127.12,114.43,66.36,59.04,45.77,36.74,31.74(d,J=15.0Hz),30.62,30.37,30.28(d,J=6.8Hz),29.83,29.77,24.95(d,J=15.6Hz),24.39(d,J=4.6Hz),22.34,22.31,19.31(d,J=47.7Hz),19.12(d,J=48.0Hz),13.71。
HR-MS:m/z=2,342.76669,C46H72NOP2+的计算值:342.76703;m/z=1,684.52576,C46H71NOP+的计算值:684.52678。
IR:2957,2928,2858,2772,1606,1574,1492,1465,1410,1381,1243,1174,1030,704。
实施例13
使用实施例5中所述的程序和三辛基膦,获得呈黄色油形式的式15的化合物。
1H NMR(500MHz,CD3OD)δ7.35(t,J=7.4Hz,2H),7.29-7.24(m,1H),7.24-7.07(m,7H),6.77(d,J=8.8Hz,2H),6.58(d,J=8.8Hz,2H),3.97(t,J=5.4Hz,2H),2.72(t,J=5.4Hz,2H),2.46-2.38(m,2H),2.32(s,6H),2.27-2.09(m,8H),1.64-1.54(m,6H),1.53-1.45(m,6H),1.43-1.11(m,24H),0.96-0.87(m,9H)。
13C NMR(126MHz,CD3OD)δ158.11,145.07,144.01,141.45,140.13,136.97,132.87,130.73,130.48,129.15,128.90,127.64,127.13,114.43,79.47,66.25,59.01,45.73,36.75,32.92,31.77(d,J=14.8Hz),31.68(d,J=14.8Hz),30.62,30.39,30.28,30.25,30.13,29.89,29.80,29.78,23.69,22.35(d,J=4.7Hz),22.30(d,J=4.7Hz),19.28(d,J=47.6Hz),19.22(d,J=47.6Hz),14.45。
HR-MS:m/z=2,426.86991,C58H96NOP2+的计算值:426.86093。
IR:3075(w),3051(w),3019(w),2953(sh)2924(s),2868(s),2854(s),2802(sh),约2500(br)NH+,1605(m),1575(m),1508(s),1490(m),1466(m),1442(m),1410(m),1378(m),1241(s),1175(s),1030(m),834(m),720(sh),704(s)。
实施例14
使用实施例5中所述的程序和三甲基膦,获得呈黄色粉末形式的式16的化合物。
1H NMR(500MHz,CD3OD)δ7.35(t,J=7.4Hz,2H),7.29-7.24(m,1H),7.24-7.06(m,6H),6.79(d,J=8.8Hz,2H),6.60(d,J=8.8Hz,2H),4.02(t,J=5.4Hz,2H),2.88(t,J=5.4Hz,2H),2.44(s,6H),2.43-2.37(m,2H),2.27-2.13(m,2H),1.87(d,J=14.4Hz,9H),1.67-1.53(m,2H),1.45(dq,J=8.8,6.9Hz,2H),1.39-1.10(m,12H)。
13C NMR(126MHz,CD3OD)δ157.90,145.03,143.99,141.58,140.08,137.22,132.89,130.73,130.46,129.17,128.91,127.66,127.14,114.49,65.62,58.75,45.37,36.75,31.74,31.61,30.62,30.41,30.34,30.23,29.93,29.75,24.06(d,J=52.4Hz),22.35(d,J=4.3Hz),7.86(d,J=54.9Hz)。
HR-MS:m/z=2,276.69702,C37H54NOP2+的计算值:276.69660。
IR:3074(w),3050(w),3015(w),2959(sh)2923(s),2853(s),2790(sh),1605(m),1594(sh),1587(m),1574(m),1507(s),1490(sh),1484(m),1466(m),1438(m),1238(s),1175(s),1030(m),996(m),723(m),705(s),690(m)。
实施例15
将奥伊拉-贝斯特曼试剂添加到冷(4℃)的醛(0.1g;0.269mmol)和K2CO3(0.372g;2.694mmol)的溶液/悬浮液中。使反应混合物达到室温并且搅拌1小时。TLC分析(氯仿/甲醇10:1)在用茚三酮染色后显示出新的橙色斑点或在用磷钼酸染色后显示出新的蓝色斑点。然后将混合物过滤,在真空下浓缩并且在Et2O(2×30mL)与水(30mL)之间洗涤。将合并的有机层经过MgSO4干燥并且在真空下浓缩。将粗产物在氯仿/石油醚混合物(1:1)中加到柱(V(SiO2)=10mL)上。进行色谱分离(50mL氯仿→50mL氯仿/甲醇/氨100:1:0.1→50mL氯仿/甲醇/氨100:2:0.2),得到77mg(76%)呈无色油形式的式17的化合物。
1H NMR(500MHz,氯仿-d)δ7.52-7.46(m,2H),7.41-7.08(m,8H),6.87(d,J=8.7Hz,2H),6.67(d,J=8.7Hz,2H),3.99(t,J=5.8Hz,2H),2.69(t,J=5.8Hz,2H),2.32(s,6H)。
13C NMR(126MHz,氯仿-d)δ193.53,158.14,150.10,142.58,139.55,133.40,132.27,130.28,129.84,127.92,127.70,126.90,119.28,113.75,85.89,80.55,65.83,58.25,45.91。
HR-MS:m/z=1,368.19998,C26H26NO1+的计算值:368.20089。
实施例16
将叠氮化钠(231mg,0.3556mmol)添加到(10-溴癸基)三苯基磷鎓于二甲基甲酰胺/水混合物(1:1,1mL)中的溶液中。将混合物加热到90℃过夜。然后将反应混合物在二氯甲烷(2×15mL)与水(10mL)之间分配。将有机层在真空下浓缩并且溶解在水(10mL)中并且用盐水(20mL)稀释。用二氯甲烷(4×10mL)萃取所得的乳液。将合并的有机层经过MgSO4干燥,过滤并且在真空下浓缩。产物具有与起始材料基本上相同的Rf(氯仿/甲醇10:1),但是在用pernot染色时颜色不同。在氯仿/甲醇100:0(100mL)→100:2(200mL)→100:4(200mL)中进行色谱分离(10ml二氧化硅),得到128mg呈无色油状的式18的化合物。
1H NMR(500MHz,甲醇-d4)δ7.91(td,J=7.3,1.8Hz,3H),7.86-7.73(m,12H),3.49-3.38(m,2H),3.27(t,J=6.8Hz,2H),1.76-1.63(m,2H),1.57(p,J=7.2Hz,4H),1.43-1.22(m,10H)。
13C NMR(126MHz,甲醇-d4)δ136.23(d,J=3.0Hz),134.77(d,J=10.0Hz),131.50(d,J=12.5Hz),119.98(d,J=86.3Hz),52.41,31.53(d,J=16.0Hz),30.34,30.21,30.12,29.85,29.81(d,J=1.3Hz),27.73,23.51(d,J=4.4Hz),22.65(d,J=50.9Hz)。
实施例18
将式17的炔烃(0.020g;0.0544mmol)和(10-叠氮基癸基)三苯基溴化磷鎓18(0.026g;0.0544mmol)溶解在乙醇/DMF(2mL+1mL)中。用铝箔覆盖反应容器并且在以下操作的过程中维持氮气气氛。一次性添加CuSO4·5H2O(40mg),继而添加抗坏血酸钠(40mg)。在室温下将反应混合物搅拌1小时,此时,形成橙色沉淀物。在几滴的少量后处理(二氯甲烷/盐水洗涤)之后TLC分析(氯仿/甲醇/氨100:10:1)表明起始材料的完全消耗和新的产物斑点(RF=0.15)。将反应混合物在盐水(50mL)与二氯甲烷(3×30mL)之间洗涤。将合并的有机层经过MgSO4干燥并且在真空下浓缩。然后将粗产物在混合物(氯仿/甲醇/氨100:5:0.5)/石油醚1:1中加到柱(V(SiO2)=10mL)上。在180mL(氯仿/甲醇/氨100:5:0.5)中进行色谱分离→在180mL(氯仿/甲醇/氨100:7:0.7)中进行200mL色谱分离,得到呈黄色油状的式19的产物(35mg;78%)。
1H NMR(500MHz,CDCl3)δ7.90-7.74(m,12H),7.74-7.59(m,3H),7.24-7.00(m,10H),6.87(d,J=8.6Hz,2H),6.65(s,1H),6.61(d,J=8.6Hz,2H),4.11(t,J=6.8Hz,2H),3.98(t,J=5.6Hz,2H),3.74(m,2H),2.71(t,J=5.5Hz,3H),2.33(s,6H),2.07-1.97(m,2H),1.71-1.51(m,6H),1.47-0.98(m,8H)。
13C NMR(126MHz,CDCl3)δ157.42,149.21,143.85,142.27,141.18,139.17,134.88(d,J=2.8Hz),133.57(d,J=10.0Hz),132.06,130.94,130.38(d,J=12.5Hz),130.27,129.48,128.11,127.76,126.97,126.59,123.71,118.37(d,J=85.7Hz),113.60,70.46,65.62,58.12,45.74,33.72,31.83,30.28(d,J=15.7Hz),29.59,28.86,28.45,25.88,22.59,22.40(d,J=54.1Hz)。
IR:2924,2853,2772,1640,1605,1587,1573,1507,1493,1464,1438,1375,1244,1172,1112,1029,996,691。
HR-MS:m/z=2,406.22778,C54H61NOP2+的计算值:406.22860。
实施例19
将溴化物中间体7的氢溴酸盐(125mg,0.1942mmol)溶解在氨甲醇溶液(2mL,7N)和DMF(0.5mL)中。将反应混合物加热2小时达到50℃并且添加另外的氨甲醇溶液(8mL,7N)。将混合物加热过夜,在真空下浓缩。在12mL二氧化硅上进行色谱分离(氯仿→氯仿/甲醇/氨100:2:0.2(50mL)→100:4:0.4(150mL))。得到21mg(22%)呈无色油形式的式20的化合物。
1H NMR(500MHz,CD3OD)δ7.33(d,2H),7.29-7.24(m,1H),7.23-7.18(m,2H),7.18-7.06(m,5H),6.77(d,J=8.9Hz,1H),6.57(d,J=8.9Hz,1H),3.95(t,J=5.5Hz,2H),2.67(t,J=5.5Hz,2H),2.63(t,J=7.4Hz,2H),2.44-2.37(m,1H),2.28(s,6H),1.52-1.40(m,2H),1.38-1.05(m,14H)。
13C NMR(126MHz,CD3OD)δ158.15,145.08,144.04,141.49,140.12,136.97,132.88,130.75,130.49,129.16,128.90,127.64,127.12,114.43,66.42,59.07,45.82,42.43,36.75,33.44,30.60,30.58,30.53,30.45,30.25,29.74,27.98。
HR-MS:m/z=2-250.18761,C34H48N2O的计算值:250.187785。
实施例20
将胺20(50mg,0.100mmol)溶解在无水二氯甲烷(2mL)中并且添加溴乙酰溴(20μl,0.23mmol)于二氯甲烷(1mL)中的溶液。在反应30分钟之后TLC(氯仿/甲醇/氨100:5:0.5)表明起始材料完全转化成酰胺。将反应混合物用二氯甲烷(50mL)稀释并且用NaOH(50mL,1M)洗涤。用二氯甲烷(30mL)再萃取水层。将合并的有机层用HBr甲醇溶液(22μL的HBr于1mL甲醇中)酸化,经过MgSO4干燥并且在真空下浓缩。将粗产物溶解在二甲基甲酰胺(1mL)中并且添加三苯基膦(263mg,1.00mmol)。将所得混合物加热到50℃,持续1小时。TLC(氯仿/甲醇/氨100:10:1)表明起始材料完全转化。然后将混合物用乙醚/石油醚混合物(50mL,1:1)稀释并且在冰浴中沉淀2小时。然后滗析出溶剂并且将所得的油状物直接加到色谱柱(10mL二氧化硅)上。进行色谱分离(氯仿/甲醇10:1,100mL),得到90mg(93%)的产物。
1H NMR(500MHz,CD3OD)δ7.94-7.65(m,12H),7.35(td,J=7.4,2.9Hz,3H),7.30-7.01(m,10H),6.84(d,J=8.5Hz,2H),6.69(d,J=8.8Hz,2H),4.75(d,J=14.6Hz,2H),4.22(t,J=4.9Hz,2H),3.54(t,J=4.8Hz,m,2H),3.25(t,J=7.2Hz,1H),3.05(t,J=7.0Hz,1H),2.94(s,6H),2.43-2.38(m,2H),1.57-1.50(m,2H),1.42-1.25(m,6H),1.23-1.10(m,8H)。
13C NMR(126MHz,CD3OD)δ158.15,145.08,144.04,141.49,140.12,136.97,132.88,130.62(d,J=32.5Hz),129.03(d,J=32.6Hz),127.38(d,J=64.7Hz),114.43,66.42,59.07,45.82,42.43,36.75,33.44,30.60,30.58(2C),30.53,30.45,30.25,29.74,27.98。
IR:3377,2463,1669,1605,1588,1574,1543,1507,1485,1438,1415,1365,1240,1175,1113,996,704,690。
HR-MS:m/z=2,401.23091,C54H63N2O2P+的计算值:401.23081。
实施例21
为了证实式I的化合物还在体内消除衰老细胞中具有作用,我们使用自然年老的FVB小鼠(19个月)与年轻的2个月大的小鼠进行比较。我们首先分析了这两组中器官中衰老细胞的存在(使用B-半乳糖苷酶(B-gal)染色)。从所有测试的器官(肺、脑、白色脂肪组织以及胃)中,我们检测到肺中B-gal阳性细胞的存在有最大的差异(未示)。在下一步中,我们每周用1次剂量的化合物8(1μg的化合物8/1g小鼠)处理小鼠(6×19个月大的小鼠+6×2个月大的小鼠),持续4周的时间段。使用仅用玉米油而没有用化合物8处理的小鼠(5×19个月大的小鼠+6×2个月大的小鼠)作为对照。在4周之后,我们取出肺并且检测组织中B-gal阳性细胞的百分比。表1示出了与年轻小鼠相比年老小鼠中的B-gal阳性细胞增加并且在化合物8处理之后它们的数量减少,这是使用特定计算机程序在超薄切片上定量的。该结果得到了来自qRT PCR的数据的支持,其中我们检测了肺、肾脏以及脾脏中几种其他衰老标志物,如p16、p21以及纤溶酶原激活物抑制因子(PAI)的mRNA水平(表2)。这些数据再次表明年老小鼠组织中衰老细胞的增加和它们在化合物8处理之后的消除,这是因为所测试的标志物的水平几乎降低到对照水平。
表1
表2
实施例22
我们测试了化合物8对培养的衰老胰腺细胞的作用。我们使用暴露于100μM的BrdU6天以诱导衰老的三种胰腺细胞系(PANC-1、PaTu以及BxPC-3)。将这些衰老细胞用不同剂量的化合物8处理48小时并且评估它们的活力。表3示出了在更高剂量的化合物8中细胞死亡增加(被检测为膜联蛋白V/Hoechst阴性细胞的数量减少)。使用作为最敏感的测试细胞的RPE细胞作为对照来确定化合物8对非衰老细胞无毒的浓度。
表3
实施例23
惊人的是,不同于其他临床上使用的化疗药物,式I的化合物不诱导肿瘤细胞的衰老,这是这些药剂的一个重要特征,这是因为许多公认的化疗剂的这种副作用使治疗结果变得相当复杂。使用经过化合物8(0.2mg的化合物8/小鼠,每周2次,持续2周-3周的时间段)处理的带有4T1细胞衍生的肿瘤的Balb-c小鼠或带有自发肿瘤的FVB小鼠,我们在mRNA水平上没有观测到衰老标志物p16、p21以及PAI的任何增加(表4)。
表4
重要的是,我们使用源自于患者的异种移植物(PDX;三阴性乳腺肿瘤)重复该实验,所述异种移植物被移植到NOD scidγ小鼠体内并且用化合物8(0.375mg的化合物8/小鼠,每周两次,持续2周-3周的时间段)处理。使用qRT PCR,用特异性人类引物,我们发现即使在这种情况下,衰老标志物也没有增加(表5)。
表5
实施例24
由于经过化合物8处理的衰老细胞能够诱导糖酵解,如由它们倾向于增加作为糖酵解产物的乳酸盐的产生所表明(关于RPE细胞的表6),因此我们侧重于它们利用由糖酵解产生的ATP的能力。腺嘌呤核苷酸转位酶2(ANT2)是对于ATP从细胞质向线粒体转位来说重要的蛋白质,这不同于ANT家族的另外两个成员ANT1和ANT3,所述ANT1和ANT3参与线粒体呼吸期间ADP经由复合物V向线粒体中的经典转移。ANT2在维持线粒体电位和保持完整的线粒体中起着关键作用,特别是在肿瘤细胞中。mRNA水平的测量揭示了衰老细胞中ANT2的减少(关于RPE细胞的表7,BJ细胞的数据未示)。使用特异性siRNA下调抗性对照细胞中的ANT2引起在化合物8处理之后这些细胞的死亡增加(关于RPE细胞的表8,BJ细胞的数据未示),这表明了ANT2在对化合物8的抗性中的作用。为了证实该假设,我们制备了用诱导型ANT2转染的RPE细胞以提高它在衰老细胞中的水平。表9揭示了具有诱导的ANT2的衰老细胞对化合物8处理的抗性增加。所有这些实验都证实了ANT2在化合物8抗性中的关键作用。
表6
样品(化合物8) | 乳酸盐产生(诱导倍数) | 标准偏差(+/-) |
RPE对照,未处理 | 1.0 | 0.00 |
RPE对照,经处理 | 1.6 | 0.03 |
RPE BrdU,未处理 | 2.8 | 0.26 |
RPE BrdU,经处理 | 8.2 | 0.29 |
表7
表8
表9
实施例26
测试化合物7、化合物8、化合物10、化合物15对原代衰老细胞(用100μM的5-溴-2-脱氧尿苷(BrdU)处理8天的视网膜色素上皮细胞(RPE))的作用。只有式I的化合物(化合物8、化合物10以及化合物15)显示出消除衰老细胞的特异性作用(被检测为膜联蛋白V/Hoechst阴性细胞的数量减少,表10)而对对照细胞没有任何影响。还针对BJ细胞和HPF-1细胞确认了所有这些实验,得到了相同的结果(数据未示)。
表10
使用他莫昔芬(从US 2015/0151001中已知用于治疗衰老)重复相同的实验,得到了以下结果:
结果显示本发明的化合物选择性地对衰老细胞更具细胞毒性(特别是比较在以下化合物存在下对照细胞和衰老(BrdU)细胞的活力值:化合物8,浓度2.5μM;化合物7,浓度0.5μM;化合物10,浓度0.5μM;化合物15,浓度5μM)。来自现有技术的化合物他莫昔芬在任何测试浓度下对衰老细胞不都比对对照细胞具有显著更高的毒性。直到5μM的浓度为止,他莫昔芬没有显示出细胞毒性,在10μM时,它将衰老细胞和对照细胞这两者的活力都降低约一半,并且在20μM时,它对衰老细胞和对照细胞这两者都具有高度细胞毒性。本发明的化合物在低于他莫昔芬的浓度下对衰老细胞也显示出显著的细胞毒性作用。
Claims (11)
1.一种通式Ia的化合物,
其中Z是选自亚烷基、亚烯基或亚炔基的直链烃基链,其含有1个至20个碳原子,优选地含有4个至14个碳原子,更优选地含有8个至12个碳原子,而任选地,所述烃基链中的一个或多个碳原子对可以被一个或多个5元或6元芳环或含有杂原子O、S和/或N的5元或6元杂芳环,优选地亚苯基或亚吡啶基或三唑置换,和/或所述烃基链中的一个或多个碳原子可以被选自O、S、NH的一个或多个杂原子置换;而所述烃基链是未取代的或被独立地选自包括以下各项的组的一个或多个取代基取代:C1-C4烷基;N(H或C1-C4烷基)2,其中所述烷基是相同的或不同的;苯基;苯甲基;OH;=O;SH;=S;F;Cl;Br;I;C1-C4烷氧基;C1-C4酰氧基;C1-C4巯基;
并且R1、R2、R3中的每一个独立地选自包括以下各项的组:C1-C10烷基、C6-C12芳基、C6-C12芳基-C1-C2烷基、C5-C12杂芳基、C3-C8环烷基,其中R1、R2、R3中的每一个可以任选地并且彼此独立地被一个或多个独立地选自包括以下各项的组的取代基取代:C1-C4烷基;C1-C4烷氧基;N(H或C1-C4烷基)2,其中所述烷基是相同的或不同的;OH;=O;SH;=S;F;Cl;Br;I;C1-C4巯基;
X-是药学上可接受的阴离子;
其中所述通式I中的交叉双键表示所述双键可以具有E构型和/或Z构型;
前提条件是所有R1、R2以及R3不都同时是未取代的苯基;
以及所述通式Ia的化合物的药学上可接受的盐。
2.一种通式I的化合物,
其中Z是选自亚烷基、亚烯基或亚炔基的直链烃基链,其含有1个至20个碳原子,优选地含有4个至14个碳原子,更优选地含有8个至12个碳原子,而任选地,所述烃基链中的一个或多个碳原子对可以被一个或多个5元或6元芳环或含有杂原子O、S和/或N的5元或6元杂芳环,优选地亚苯基或亚吡啶基或三唑置换,和/或所述烃基链中的一个或多个碳原子可以被选自O、S、NH的一个或多个杂原子置换;而所述烃基链是未取代的或被一个或多个独立地选自包括以下各项的组的取代基取代:C1-C4烷基;N(H或C1-C4烷基)2,其中所述烷基是相同的或不同的;苯基;苯甲基;OH;=O;SH;=S;F;Cl;Br;I;C1-C4烷氧基;C1-C4酰氧基;C1-C4巯基;
并且R1、R2、R3中的每一个独立地选自包括以下各项的组:C1-C10烷基、C6-C12芳基、C6-C12芳基-C1-C2烷基、C5-C12杂芳基、C3-C8环烷基,其中R1、R2、R3中的每一个可以任选地并且彼此独立地被一个或多个独立地选自包括以下各项的组的取代基取代:C1-C4烷基;C1-C4烷氧基;N(H或C1-C4烷基)2,其中所述烷基是相同的或不同的;OH;=O;SH;=S;F;Cl;Br;I;C1-C4巯基;
X-是药学上可接受的阴离子;
其中所述通式I中的交叉双键表示所述双键可以具有E构型和/或Z构型;
以及所述通式I的化合物的药学上可接受的盐,
其用于治疗和/或预防衰老相关疾病和健康状况的方法中,所述疾病和健康状况特别是特发性肺纤维化、肌肉减少症、糖尿病、肥胖症、骨关节炎、慢性炎症、青光眼、白内障、放射诱发性口腔粘膜炎、肾移植、前列腺增生。
3.根据权利要求1所述的化合物或根据权利要求2所述的所使用的化合物,其中Z是选自亚烷基、亚烯基或亚炔基的直链烃基链,其含有4个至14个碳原子,更优选地含有8个至12个碳原子,最优选地含有8个或10个或12个碳原子;并且任选地,所述烃基链中的一个或多个碳原子被一个或多个独立地选自以下各项的取代基取代:C1-C4烷基;N(H或C1-C4烷基)2,其中所述烷基是相同的或不同的;OH;=O;SH;=S;F;Cl;Br;I;C1-C4烷氧基;C1-C4巯基。
4.根据权利要求1所述的化合物或根据权利要求2所述的所使用的化合物,其中Z是选自亚烷基、亚烯基或亚炔基的直链烃基链,其含有4个至14个碳原子,更优选地含有8个至12个碳原子,其中所述烃基链中的一个或多个碳原子被选自O、S、NH的一个或多个杂原子置换;并且任选地,所述烃基链中的一个或多个碳原子被一个或多个独立地选自以下各项的取代基取代:OH;=O;SH;=S;C1-C4烷氧基;C1-C4巯基。
5.根据权利要求1所述的化合物或根据权利要求2所述的所使用的化合物,其中Z是选自亚烷基、亚烯基或亚炔基的直链烃基链,其含有4个至14个碳原子,更优选地含有8个至12个碳原子,其中所述烃基链中的一个或多个碳原子被一个或多个杂原子NH置换;并且任选地,所述烃基链中的一个或多个碳原子被一个或多个独立地选自以下各项的取代基取代:OH;=O;SH;=S;C1-C4烷氧基;C1-C4巯基。
6.根据权利要求1所述的化合物或根据权利要求2所述的所使用的化合物,其中Z是选自亚烷基、亚烯基或亚炔基的直链烃基链,其含有4个至14个碳原子,更优选地含有8个至12个碳原子,其中所述烃基链中的一个或多个碳原子被一个或多个杂原子O、S置换;并且任选地,所述烃基链中的一个或多个碳原子被一个或多个独立地选自以下各项的取代基取代:OH;=O;SH;=S;C1-C4烷氧基;C1-C4巯基。
7.根据权利要求1所述的化合物或根据权利要求2所述的所使用的化合物,其中Z是选自亚烷基、亚烯基或亚炔基的直链烃基链,其含有4个至14个碳原子,更优选地含有8个至12个碳原子,其中所述烃基链中的一个或多个碳原子对被一个或多个亚苯基和/或亚吡啶基置换。
8.根据权利要求1所述的化合物或根据权利要求2所述的所使用的化合物,其中Z被一个或多个独立地选自以下各项的取代基取代:C1-C4烷基;N(H或C1-C4烷基)2,其中所述烷基是相同的或不同的;OH;=O;SH;=S;F;Cl;Br;I;C1-C4烷氧基;C1-C4巯基;更优选的是,Z被选自以下各项的一个或多个取代基取代:OH;=O;SH;=S;F;Cl;Br;I。
9.根据权利要求1和3-8中任一项所述的化合物或根据权利要求2-8中任一项所述的所使用的化合物,其中R1、R2、R3中的每一个独立地选自包括以下各项的组:C1-C8烷基、C6-C12芳基、C6-C12芳基-甲基、C5-C8环烷基,其中这些部分中的任一个可以任选地被一个或多个独立地选自包括以下各项的组的取代基取代:C1-C4烷基;C1-C4烷氧基;OH;SH;F;Cl;Br;I;C1-C4巯基。
10.根据权利要求1和3-8中任一项所述的化合物或根据权利要求2-8中任一项所述的所使用的化合物,其中R1、R2、R3中的每一个独立地选自包括甲基、丁基、辛基、苯基、甲氧基苯基、苯甲基、环己基的组。
11.根据权利要求1和3-10中任一项所述的化合物或根据权利要求2-10中任一项所述的所使用的化合物,其中X-选自包括柠檬酸根、乙酸根、乳酸根、酒石酸根、草酸根、抗坏血酸根、甲磺酸根、甲苯磺酸根、硫酸根、卤离子、磷酸根和/或它们的混合物的组。
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