CN102317262B - 苯甲酸(1-苯基-2-吡啶基-4-基)乙酯作为磷酸二酯酶抑制剂 - Google Patents
苯甲酸(1-苯基-2-吡啶基-4-基)乙酯作为磷酸二酯酶抑制剂 Download PDFInfo
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- CN102317262B CN102317262B CN201080006643.7A CN201080006643A CN102317262B CN 102317262 B CN102317262 B CN 102317262B CN 201080006643 A CN201080006643 A CN 201080006643A CN 102317262 B CN102317262 B CN 102317262B
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Abstract
本发明涉及磷酸二酯酶4(PDE4)的酶抑制剂。更特别地,本发明涉及-苯基-2-吡啶基烷醇衍生物的化合物,制备该化合物的方法,包含它们的组合物,式(I)组合及其治疗用途,其中:n是0或1;R1和R2可以相同或不同,并且选自:-直链或支链C1-C6烷基;OR3,其中R3是任选被一个或多个C3-C7环烷基取代的直链或支链C1-C6烷基;和HNSO2R4,其中R4是任选被一个或多个卤素原子或C1-C4烷基取代的C1-C4烷基,其中R1和R2中的至少一个是HNSO2R4,其它变量如在权利要求中定义。
Description
发明领域
本发明涉及磷酸二酯酶4(PDE4)的酶抑制剂。更特别地,本发明涉及1-苯基-2-吡啶基烷醇衍生物,其制备方法,包含它们的组合物及其治疗用途。
背景技术
气道阻塞表征了许多严重的呼吸性疾病,其中包括哮喘和慢性阻塞性肺病(COPD)。导致气道阻塞的事件包括气道壁的水肿、增加的粘液产生和炎症。
目前通过吸入施用治疗呼吸性疾病,诸如哮喘和COPD的药物。与全身途径相比,吸入途径的优点之一是在作用位点处直接递送药物的可能性,避免了任何全身的副作用,从而提供更加快速的临床应答和更高的治疗比。
吸入的皮质类固醇是当前哮喘以及急性症状缓解用支气管扩张药β2-激动剂的维持治疗选择,它们形成了该疾病当前治疗的主流。当前COPD的治疗主要通过支气管扩张疗法,采用吸入的抗胆碱能药和吸入的β2-肾上腺素能受体激动剂进行对症治疗。然而,皮质类固醇没有降低COPD的炎性应答,而它们在哮喘中降低炎性应答。
鉴于在治疗炎性呼吸性疾病,诸如哮喘和COPD中的消炎效果而被广泛研究的另一类治疗剂以磷酸二酯酶(PDEs),尤其是磷酸二酯酶4型(下文称为PDE4)的酶抑制剂为代表。
现有技术中已经公开了充当PDE4抑制剂的各种化合物。然而,第一代的数种PDE4抑制剂,诸如咯利普兰和吡拉米司特的有效性因其非所需的副作用,诸如由于对中枢神经系统中PDE4的作用导致以及由于对在肠道内的肠壁细胞中PDE4的作用而导致的恶心、胃酸分泌和呕吐导致受到局限。
人们广泛研究了所述副作用的原因。
已发现,PDE4以代表不同构型的两种不同的形式存在,它们表示为高亲和力的咯利普兰结合位点或HPDE4,特别地存在于中枢神经系统和肠壁细胞内,和在免疫与炎性细胞中发现的低亲和力的咯利普兰结合位点或LPDE4(Jacobitz,S et al Mol.Pharmacol,1996,50,891-899)。尽管这两种形式显示出催化活性,但它们对抑制剂的灵敏度不同。特别地,对LPDE4具有较高亲和力的化合物似乎不那么容易诱导副作用,诸如恶心、呕吐和增加的胃分泌。
靶向LPDE4的努力导致第二代PDE4抑制剂,诸如西洛司特和罗氟司特的选择性的稍微改进。然而,即使这些化合物也没有提供对LPDE4良好的选择性。
WO2009/018909中公开了具有选择性LPDE4抑制活性的化合物。
WO 2008/006509中描述了1-苯基-2-吡啶基烯醇(alkylenealcohol)及其作为PDE4抑制剂的用途。
本发明提供一组具有优异LPDE4选择性的有效的新型PDE4抑制剂。
令人惊讶地,已发现苯甲酸酯残基上磺酰氨基(sulphonamido)取代基的存在显著改善效价。
此外,已经令人惊讶地发现本发明的磺酰氨基衍生物的(-)对映异构体(见下方用星号标记的碳原子)比相应的(+)对映异构体和外消旋体更有效。
目前已经发现本发明的化合物与长效β2-激动剂联用时,治疗呼吸道炎性或阻塞性疾病获得了预料不到的有益治疗效果,特别是协同效果。
发明内容
本发明涉及作为磷酸二酯酶4(PDE4)酶抑制剂起作用的、(-)对映异构体形式的通式(I)化合物,其制备方法,包含它们的组合物及其治疗用途
其中:
n是0或1;
R1和R2可以相同或不同,并且选自:
-直链或支链C1-C6烷基,任选被一个或多个卤素原子取代;
-OR3,其中R3是任选被一个或多个卤素原子或C3-C7环烷基取代的直链或支链C1-C6烷基;和
-HNSO2R4,其中R4是任选被一个或多个卤素原子取代的直链或支链C1-C4烷基,
其中R1和R2中的至少一个是HNSO2R4。
本发明还包括其药学上可接受的水合物、溶剂化物、加成络合物、无机或有机盐,例如钠、钾和赖氨酸盐。
本发明还涉及如方案1中所报道的式(I)化合物的制备方法,包括使醛(1)与甲基二氯吡啶(2)反应得到外消旋的醇(3)。然后按照方案1的路线1或2用诸如(S)-甲氧萘丙酸或(S)-乙酰基扁桃酸的手性酸将后者缩合分别得到非对映异构体混合物(10)或(5)。用色谱法、结晶或其它已知方法分别分离为单独的非对映异构体(11)和(13)或(6)和(8),裂解后,分别得到对映异构体的醇(-)(12)和(+)(14)或(+)(7)和(-)(9)。最后,通过使对映异构体(+)(14)或(+)(7)与合适的苯甲酸(15)反应得到通式(I)化合物。
本发明还涉及如方案1中报道的制备其中n是0的式(I)化合物的方法,包括使任一对映异构体醇,例如(+)(14)与苯甲酸(15)反应。
本发明还涉及如方案1中报道的制备其中n是1的式(I)化合物的方法,包括通过诸如3-氯过苯甲酸、过氧乙酸或过氧化氢的氧化剂氧化对映异构体醇(+)(14)以得到醇(+)对映异构体(7),其通过与式(15)的苯甲酸反应产生其中n是1的式(I)化合物。
本发明还涉及如方案1中报道的制备其中n是1的式(I)化合物的方法,包括通过诸如3-氯过苯甲酸、过氧乙酸或过氧化氢的氧化剂氧化其中n是0的式(I)的酯。
本发明还涉及通式(II)的中间体化合物
其中n是如上所定义的(ad defined above),并且下方以星号表示的碳原子显示(S)构型。
本发明还提供含有式(I)化合物和一种或多种药学上可接受的载体和/或赋形剂的药物组合物。
本发明特别提供适合吸入给药的药物配制剂。
本发明还提供式(I)化合物和选自长效β2激动剂、M3拮抗剂以及皮质类固醇的第二组分的组合。
本发明还提供式(I)化合物与选自卡莫特罗、GSK-642444、茚达特罗、milveterol、阿福特罗、福莫特罗、沙丁胺醇、福莫特罗、左旋沙丁胺醇、特布他林、AZD-3199、BI-1744-CL、LAS-100977、班布特罗、异丙肾上腺素、丙卡特罗、克仑特罗、瑞普特罗、非诺特罗和ASF-1020的长效β2激动剂的组合。
本发明还提供式(I)化合物与选自阿地铵(aclidinium)、噻托铵(tiotropium)、异丙托铵和氧托铵(oxitropium)的M3拮抗剂的组合。
本发明还提供式(I)化合物与选自地塞米松、氟替卡松、糠酸氟替卡松、泼尼松龙、倍他米松、布地奈德、莫米松、糠酸莫米松、曲安奈德、环索奈德、TPI-1020、倍氯米松、丙酸倍氯米松、泼尼松、地夫可特、氢化可的松、QAE-397和氟尼缩松的皮质类固醇的组合。
在一种优选的实施方式中,本发明提供式(I)化合物与福莫特罗或卡莫特罗的组合。
本发明还提供用作药物的式(I)化合物。
还提供式(I)化合物在制备用于预防或治疗任何涉及PDE4受体活性并且需要抑制PDE4受体活性的疾病的药物中的用途。
本发明还提供用于预防或治疗任何涉及PDE4受体活性并且需要抑制PDE4受体活性的疾病的方法,所述方法包括给予有此需要的患者治疗有效量的式(I)化合物。
上述用途或方法包括单独式(I)化合物或与上述报道的那些中的其它活性成分组合。
上述涉及PDE4受体活性以及抑制PDE4受体的疾病包括以气道阻塞为特征的呼吸道疾病,诸如哮喘和COPD。
此外,本发明还涉及使用式(I)化合物在体外抑制PDE4。
本发明还涉及含有式(I)化合物的可以是单-剂量或多-剂量的干粉吸入器、计量吸入器或软雾(soft mist)喷雾器的装置。
本发明还涉及含有与一种或多种药学上可接受的载体和/或赋形剂混合的单独存在的或与另外的药物成分组合的式(I)化合物以及可以是单-剂量或多-剂量的干粉吸入器、计量吸入器或软雾喷雾器的装置的试剂盒。
定义
本文中使用的术语“卤素原子”包括氟、氯、溴和碘。
本文中使用的表述“直链或支链(C1-Cx)烷基”(其中x是大于1的整数,诸如C1-C6或C1-C4烷基)是指直链或支链烷基,其中碳原子数范围为1-x(例如1-6或1-4)的范围。因此烷基的实例可以包括甲基、乙基、正丙基、异丙基和叔丁基、戊基、己基等等。
任选地,在所述基团中,一个或多个氢原子可被卤素原子,优选氯或氟置换。
本文中使用的表述“C3-C7环烷基”是指含有3-7个环碳原子的非芳族烃基。因此它们的实例可以包括环丙基、环丁基、环戊基、环己基和环庚基。
除非另外提供,当提及手性化合物时,纯度“基本上纯”的程度在此是指至少高于约97%的手性纯度,优选高于99%,最优选高于99.9%。
附图说明
附图显示了本发明优选的实施方式存在协同作用。
OA=卵白蛋白
C1=3-环丙基甲氧基-4-甲磺酰基氨基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)-乙酯
CARM=卡莫特罗
发明详述
本发明涉及充当磷酸二酯酶4(PDE4)的酶抑制剂的化合物。
所述化合物抑制环核苷酸,特别是环腺苷酸(cAMP)转化成它们的无活性的5’-单核苷酸形式。
在气道内,对升高的环核苷酸,特别是cAMP的胞内水平的生理应答将导致抑制免疫和促炎性细胞,诸如肥大细胞、巨噬细胞、T-淋巴细胞、嗜酸性粒细胞和中性粒细胞的活性,从而导致包括细胞因子,诸如IL-1、IL-3和肿瘤坏死因子-α(TNF-α)在内的炎症介质的释放降低。它还导致气道平滑肌松弛和水肿降低。
PDE4的催化位点已经得到预先鉴定:它主要包括其中存在两个亚口袋(sub-pocket),例如S0和S1的疏水区域,和其中含金属离子Zn2+和Mg2+的亲水区域,所述亲水区域相应地又包括在金属离子周围展布的亚口袋S2和在疏水口袋中间分叉约90°的亚口袋S3。
提供的大多数已知化合物具有能与疏水区域的亚口袋S0和S1相互作用的部分,诸如取代的儿茶酚(cathecol)基团,并具有能与S2亚口袋中的金属离子间接相互作用的另一部分,例如杂环,诸如吡啶或吡咯烷酮。
本发明涉及这样的化合物:它如同其它已知的PDE4抑制剂一样,可以通过取代的儿茶酚部分维持与亚口袋S0和S1的相互作用并通过吡啶环维持与金属离子区域的相互作用,但与所述PDE4抑制剂区别在于存在能使它们与亚口袋S3建立额外的相互作用的磺酰基氨基-苯甲酸基。
特别地本发明涉及如早先定义的通式(I)化合物,包括其药学上可接受的无机和有机盐、水合物、溶剂化物或加成络合物。
优选的式(I)化合物的组是那些,其中:
-R1是HNSO2R4,R2是OR3并且n是0;
-R1是HNSO2R4,R2是OR3并且n是1;
-R1是HNSO2R4,其中R4是甲基,R2是OR3,其中R3是环丙基甲基并且n是0;
-R1是HNSO2R4,其中R4是甲基,R2是OR3,其中R3是环丙基甲基并且n是1;
-R1是直链或支链C1-C6烷基,R2是HNSO2R4并且n是0;
-R1是甲基,R2是HNSO2R4,其中R4是甲基并且n是0;
-R1是直链或支链C1-C6烷基,R2是HNSO2R4并且n是1;
-R1是甲基,R2是HNSO2R4,其中R4是甲基并且n是1;
-R2是直链或支链C1-C6烷基,R1是HNSO2R4并且n是0;
-R2是甲基,R1是HNSO2R4,其中R4是甲基并且n是0;
-R2是直链或支链C1-C6烷基,R1是HNSO2R4并且n是1;
-R2是甲基,R1是HNSO2R4,其中R4是甲基并且n是1;
-R1是OR3,R2是HNSO2R4并且n是0;
-R1是OR3,R2是HNSO2R4并且n使1;
-R1是OR3,其中R3是环丙基甲基,R2是HNSO2R4并且R4是甲基n是1;
-R1是OR3,R2是HNSO2R4并且n是1;
-R1和R2均为HNSO2R4并且n是0;
-R1和R2均为HNSO2R4,其中R4是甲基并且n是0;
-R1和R2均为HNSO2R4并且n是1;
-R1和R2均为HNSO2R4,其中R4是甲基并且n是1。
显然对于本领域技术人员而言,通式(I)化合物至少含有一个不对称中心,目前以下方带有星号的碳原子表示,因此作为光学立体异构体存在。
本发明涉及式(I)化合物,其是下方以星号表示的碳原子为(S)构型的(-)对映异构体。
本发明还涉及式(II)的中间体化合物,其中下方以星号表示的碳原子显示(S)构型。
式(I)化合物在nM范围内显示出对PDE4酶的体外抑制活性,并且它们在COPD动物模型中气管内给药时被赋予对肺的显著活性。
它们还可以在肺中显示出持续的肺水平,而在血浆中无法检测到,这是短期全身作用的指标。
根据优选的实施方式,本发明提供以下报道的式(I)化合物:
但是,上述化合物已经被方便地鉴定为(-)对映异构体,其在以星号标记的碳原子处具有(S)构型。同样地,这些相同的化合物还可以根据下表鉴定:
有利地,本发明化合物的特征在于,对LPDE4的选择性高于HPDE4,这通过其IC50值的测定来获得。
在LPDE4的情况下,IC50是产生50%抑制cAMP消失的试验化合物的摩尔浓度,这根据Cortijo J et al Br J Pharmacol 1993,108:562-568中的描述来评价。而在HPDE4的情况下,IC50是产生50%抑制[H3]咯利普兰结合的试验化合物的摩尔浓度,这根据Duplantier AJet al J Med Chem 1996;39:120-125中的描述来评价。
优选地,本发明化合物的HPDE4/LPDE4IC50比高于5,更优选高于10,甚至更优选高于20,最优选高于100。
可方便地根据已知的方法制备式(I)化合物。以下在方案1中描述并报道了一些可以使用的方法。
制备式(I)化合物的方法
根据本发明的一种特别的实施方式,式(I)化合物可以按照例如方案1中描述的合成路线制备。
可以通过使醛(1)与甲基二氯吡啶(2)反应制备外消旋的醇(3)。
路线1-可以通过已知的方法,诸如使外消旋的混合物与合适的手性助剂反应可将外消旋的醇(3)分离成(-)(12)和(+)(14)对映异构体,从而获得非对映异构体的混合物。可以按照已知的方法通过结晶或通过色谱法或借助于酶分离该非对映异构体。随后,可以从非对映异构体中除去手性助剂得到希望的作为单独的对映异构体的手性醇。可供选择地,可以按照已知的方法(Ref:“Enantiomer Separation:Fundamentals and Practical Methods”F.Toda,Springer-Verlag 2004;“Drug Stereochemistry:Analytical Methods and Pharmacology”,Irving W.Wainer,CRC Press,1993)用手性固定相借助于色谱法拆分醇外消旋混合物。
特别地,可以用诸如(S)-甲氧萘丙酸的手性酸缩合外消旋的醇(3)并通过色谱法将得到的非对映异构体混合物(10)分离成两个单独的非对映异构体(11)和(13)。通过使用酸性或碱性条件,在含水溶剂中水解或在醇溶剂中醇解来裂解单独的非对映异构体酯(diastereomericester)后,可以获得对映异构体纯的醇中间体(-)(12)和(+)(14)。
路线2-可以将按照常规方法对外消旋体(3)进行氧化而获得的外消旋体(4)与诸如(S)-乙酰基扁桃酸的手性酸反应以获得两种非对映异构体的混合物(5)。通过用二乙醚研磨并在诸如异丙醇、乙醇或甲醇的溶剂中结晶,或通过色谱法分离可获得单独的非对映异构体酯(6)和(8)。
通过使用酸性或碱性条件,在含水溶剂中水解或在醇溶剂中醇解来裂解单独的非对映异构体酯后,可以获得对映异构体纯的醇中间体(+)(7)和(-)(9)。
其中n是0的通式(I)化合物可以通过使合适的对映异构体醇(+)(14)与苯甲酸(15)在存在合适的诸如二异丙氨基锂(LDA)、NaH或二甲基氨基吡啶(DMAP)的强碱以及诸如1-乙基-3-[3-二甲基氨基丙基]碳二亚胺盐酸盐(EDC)或N-羟基苯并三唑(HOBT)的缩合剂的情况下在诸如二氯甲烷的溶剂中反应来制备。可以使用其它溶剂,诸如二甲基甲酰胺(DMF)、四氢呋喃(THF)、氯仿、二烷或本领域技术人员已知的其它任何非质子溶剂。在一种特别的实施方式中,还可以在不存在溶剂的情况下进行反应。
其中n是1的式(I)化合物可以借助于诸如3-氯过苯甲酸、过氧乙酸或过氧化氢的氧化剂在诸如氯仿、二氯甲烷或乙酸的溶剂中通过氧化相应的其中n是0的式(I)化合物制备(路线B)。
可供选择地,其中n是1的式(I)化合物还可以借助于前述操作条件通过首先氧化醇对映异构体(+)(14)制备,从而得到醇对映异构体(+)(7)。随后的反应在给定的醇对映异构体与式(15)的苯甲酸中进行,从而提供其中n是0的上述式(I)化合物(路线A)。
可以使用已知的方法,如上面为分离外消旋醇(3)的对映异构体所描述的,从通过氧化外消旋醇(3)依次所获得的外消旋醇(4)分离(+)(7)和(-)(9)对映异构体。
本领域技术人员应当意识到也可以应用方案1中所报道的合成步骤的任选的变化方式同样地来制备本发明的化合物。
我们特别提及可以进行的反应的顺序以获得希望的化合物或其中间体,以及适合的操作条件,包括溶剂、任选的氧化剂、缩合剂等等的选择。
作为一个实例,在任何起始物质或其中间体中存在可能产生不需要的副反应的化学反应性取代基的情况下,可以在反应发生前进行那些同样取代基的适当保护。
以此类推,然后可以进行取代基的脱保护以再次获得游离形式的上述化学反应性取代基或基团。
官能团的保护与脱保护在″Protective Groups in OrganicChemistry″3rd edition,T.W.Greene and P.G.M.Wuts,Wiley-Interscience(1999)and″Protecting Groups″,P.J.Kocienski,Georg Thieme Verlag(1994)中描述。
根据当前的制备本发明化合物的方法及其变化形式,式(1)和(2)的起始物质以及任何附加的反应物[(例如式(15)的反应物)]、手性助剂、溶剂或应用的试剂都是已知的或可以按照已知方法容易地制备。
本发明还提供式(I)化合物与一种或多种药学上可接受的载体,例如在Remington′s Pharmaceutical Sciences Handbook,XVIIEd.,Mack Pub.,N.Y.,U.S.A.中所述的那些载体混合的药物组合物。
实例包括稀释剂(诸如蔗糖、甘露醇、乳糖、淀粉)和已知的赋形剂,其中包括悬浮剂、增溶剂、缓冲剂、粘合剂、崩解剂、防腐剂、着色剂、香料、润滑剂等等。在施用本发明的化合物中,同样有利的是定时释放的胶囊、片剂和凝胶。
可根据患者需求实现本发明化合物的施用,例如口服、经鼻、肠胃外,例如皮下、静脉内、肌肉内、胸骨内和通过输注、通过吸入、直肠、阴道、外用(topically)、局部(locally)、经皮,和通过眼内施用。各种固体口服剂型可用于施用本发明的化合物,其中包括诸如片剂、软胶囊、胶囊、小胶囊、颗粒、锭剂和整装散剂(bulk powder)的固体剂型。
也可使用各种液体口服剂型来施用本发明的化合物,其中包括含水和非含水溶液、乳液、悬浮液、糖浆和酏剂。这种剂型也可含有已知的合适的惰性稀释剂,诸如水和已知的合适的赋形剂,诸如防腐剂、润湿剂、增甜剂、香料以及乳化和/或悬浮本发明化合物的试剂。可例如以等渗灭菌溶液形式静脉内注射本发明的化合物。其他已知的配制剂也是可能的。
可通过混合该化合物与合适的赋形剂,诸如可可脂、水杨酸酯和聚乙二醇类,制备直肠施用本发明化合物的栓剂。
阴道施用的制剂也可以是除了活性成分以外,还含有常规载体的霜剂、凝胶、糊剂、泡沫或喷雾制剂形式。
对于外用施用而言,该药物组合物可以是适合于施用到皮肤、眼睛、耳朵或鼻子上的霜剂、软膏、擦剂、洗剂、乳液、悬浮液、凝胶、溶液、糊剂、粉末、喷雾剂和滴剂形式。外用施用也可涉及借助例如经皮贴剂之类的方式的经皮施用。
为了治疗呼吸道疾病,优选通过吸入来施用本发明的化合物。
可吸入的配制剂包括可吸入的粉末、含推进剂的计量气溶胶或不含推进剂的可吸入的制剂。
为了以干燥粉末形式施用,可使用已知的单-或多-剂量吸入器。在这一情况下,粉末可填充在明胶、塑料或其他胶囊、药筒或泡罩包装内或者容器内。
通常对本发明化合物呈化学惰性的稀释剂或载体,例如乳糖或适合于改进可吸入部分的任何其他添加剂可加入到本发明的粉末化合物中。
含推进剂气体,诸如氢氟烷烃的吸入气溶胶可含有溶液或分散形式的本发明化合物。推进剂驱动的制剂也可含有其它成分,诸如共溶剂、稳定剂和任选的其他赋形剂。
含本发明化合物的不含推进剂的可吸入制剂可以是在含水、醇或含水醇介质内的溶液或悬浮液形式,且它们可通过已知的喷射或超声喷雾器或者通过软雾喷雾器,诸如传输。
可作为唯一的活性剂或者与其它一种或更多种药物活性成分(包括目前治疗呼吸性疾病中使用的那些,例如β2-激动剂、皮质类固醇和M3拮抗剂)组合来施用本发明的化合物。
本发明化合物的剂量取决于各种因素,其中包括待治疗的特定疾病、症状的严重程度、施用途径、给药间隔的频率、所使用的特定化合物、效力、毒理学特征和该化合物的药物动力学特征。
有利地,可例如在包括0.001-1000mg/天,优选0.1-500mg/天的剂量下来施用式(I)化合物。
当通过吸入途径施用时,式(I)化合物的剂量有利地包括0.01-20mg/天,优选0.1-10mg/天。
优选地,可单独或与其他活性成分组合施用式(I)化合物,以供预防和/或治疗任何阻塞性呼吸疾病,诸如哮喘、慢性支气管炎和慢性阻塞性肺病(COPD)。
然而,可施用式(I)化合物以供预防和/或治疗其中涉及PDE4受体活性并且需要抑制PDE4受体活性的任何疾病,或由PDE4活性介导的疾病状态(例如PDE4过量表达或活性过度的疾病状态)。所述疾病的实例包括:变应性疾病状态,诸如特应性皮炎、寻麻疹、变应性鼻炎、变应性结膜炎、春季结膜炎、嗜酸细胞肉芽肿、银屑病、炎性关节炎、类风湿性关节炎、感染性休克、溃疡性结肠炎、局限性回肠炎、心肌和大脑的再灌注损伤、慢性肾小球肾炎、内毒素性休克、囊性纤维化、动脉再狭窄、动脉粥样硬化、角化病、类风湿性脊椎炎、骨关节炎、发热(pyresis)、糖尿病、尘肺、毒性和变应性接触湿疹、特应性湿疹、皮脂溢性湿疹、单纯苔癣、晒斑、肛门与生殖器区域内的搔痒症、斑秃、肥厚性瘢痕、盘状狼疮、系统性红斑狼疮、滤泡和大面积的脓皮病、内源性和外源性痤疮、红色痤疮、Beghet’s病、类过敏性紫癜性肾炎、炎性肠病、白血病、多发性硬化、肠胃病、自身免疫疾病等等。
它们还包括神经和精神疾病,诸如阿尔兹海默氏症、多发性硬化、肌萎缩性侧索硬化症(ALS)、多系统萎缩症(MSA)、精神裂解症、帕金森症、亨廷顿病、皮克病、抑郁症、中风和脊髓损伤。
通过下述实施例进一步描述本发明。
实施例1
制备1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)-乙醇(3)
将在50ml干燥THF中的3-环丙基甲氧基-4-二氟甲氧基-苯甲醛(5.00g)和3,5-二氯-4-甲基吡啶(2.57g)溶液冷却至-30℃。
分批加入固体叔丁醇钾(tBuOK,1.96g),维持温度在-30℃到-20℃之间,从而得到深红色溶液。加入完成后,将混合物于-30℃搅拌1h。然后向反应混合物中加入饱和的NH4Cl(50ml)水溶液,维持温度在-5℃到-10℃之间。反应混合物的颜色变为黄色。
然后用EtOAc提取混合物。在Na2SO4上干燥有机层并将溶剂蒸发掉。用30ml石油醚/EtOAc=8/2的混合物处理残余物;过滤并干燥沉淀,得到4.83g标题化合物,其无需进一步纯化而在下一步中使用。
MS/ESI+404-406[MH]+。
实施例2
制备1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)-乙醇(4)
将化合物(3)(13.0g)溶解在CH2Cl2(250ml)中然后加入间氯过苯甲酸(16.5g),并将得到的溶液于室温搅拌2小时。加入Na2S2O3(25.4g)并将混合物于室温剧烈搅拌1小时。将固体残余物滤除,用1NNaOH(3x100ml)洗涤溶液,然后在Na2SO4上干燥有机相并将溶剂蒸发掉,得到10.3g白色固体的希望产物(4),其无需进一步纯化而在下一步中使用。
MS/ESI+420-422[MH]+。
实施例3
制备乙酰氧基-苯基-乙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)-乙酯(5,非对映异构体混合物)
在N2气氛下,将化合物(4)(19.95g)、(S)-乙酰基扁桃酸(9.22g)、以及1-乙基-3-[3-二甲基氨基丙基]碳二亚胺盐酸盐(18g)和4-二甲基氨基吡啶(2.89g)溶解在干燥的CH2Cl2(300ml)中。将反应混合物于室温搅拌过夜。加入5%NaHCO3(200ml)水溶液并用CH2Cl2(3x 100ml)提取水相。将合并的有机相在Na2SO4上干燥并将溶剂减压蒸发得到两种非对映异构体混合物的标题化合物(5)(32g);两种非对映异构体的分离在实施例4和6中描述。
实施例4
制备(+)-乙酰氧基-苯基-乙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)-乙酯(6)
用Et2O(100ml)研磨非对映异构体的粗混合物(5)(32g),超声并过滤。将该步骤重复四次以得到富含非对映异构体(6)的固体混合物。将该固体从iPrOH(80ml)中结晶并过滤得到9.65g非对映异构体纯度>95%的化合物(6)。通过HPLC分析和在Chiracel OD柱(用己烷∶异丙醇=40∶60等度洗脱,流速0.45ml/min,保留时间=27.2min)上进行的分析手性HPLC测定非对映异构体纯度。
MS/E SI+596,598[MH]+
′1H NMR(300MHz,DMSO-d6)ppm 8.57(s,2H),7.27-7.44(m,5H),6.91-7.18(m,1H),7.03(t,1H),6.71-6.79(m,2H),5.95(dd,1H),5.85(s,1H),3.72(dd,1H),3.60(dd,1H),3.41(dd,1H),3.23(dd,1H),2.13(s,3H),1.07-1.31(m,1H),0.48-0.72(m,2H),0.21-0.44(m,2H)
[α]D=+14°(c=0.54,MeOH)
实施例5
制备(+)-1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)-乙醇(7)
将化合物(6)(6.42g)悬浮在甲醇(350ml)中然后加入饱和NaHCO3溶液(175ml)。将白色悬浮液于室温剧烈搅拌过夜。用CH2Cl2(700ml)稀释反应混合物并用5%NaHCO3水溶液(300ml)洗涤;用CH2Cl2(2x300ml)提取水相,将合并的有机层在Na2SO4上干燥,并将溶剂在真空下蒸发掉。用Et2O(2x100ml)研磨得到的白色粗固体并过滤得到3.88g对映异构体纯度>99%的化合物(7)。用在Chiracel OD柱(用己烷∶异丙醇=30∶70等度洗脱,流速0.35ml/min,保留时间=22.3min)上进行的分析手性HPLC测定对映异构体纯度。
MS/ESI+420-422[MH]+
′1H NMR(300MHz,DMSO-d6)ppm 8.51(s,2H),7.11(d,1H),7.05(d,1H),6.88(dd,1H),7.01(t,1H),5.59(d,1H),4.84(dd,1H),3.89(dd,1H),3.84(dd,1H),3.18(dd,1H),3.02(dd,1H),1.03-1.35(m,1H),0.46-0.67(m,2H),0.24-0.46(m,2H)
[α]D=+68°(c=0.5,MeOH)
实施例6
制备(+)-乙酰氧基-苯基-乙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)-乙酯(8)
用Et2O(100ml)研磨非对映异构体的粗混合物(5),超声并过滤。将该步骤重复四次,收集滤液并减压蒸发以得到富含非对映异构体(8)的固体混合物,将其从iPrOH(100ml)中结晶得到6.4g非对映异构体纯度>99%的化合物(8)。通过HPLC分析和在Chiracel OD色谱柱(用己烷∶异丙醇=40∶60等度洗脱,流速0.45ml/min,保留时间=21.6min)上进行的分析手性HPLC测定非对映异构体纯度。
MS/ESI+596,598[MH]+
1H NMR(300MHz,DMSO-d6)ppm 8.27(s,2H),7.27-7.45(m,5H),7.20(d,1H),7.08(d,1H),7.00(dd,1H),7.08(t,1H),5.97(dd,1H),5.85(s,1H),3.93(dd,1H),3.89(dd,1H),3.33(dd,1H),3.17(dd,1H),2.07(s,3H),1.14-1.38(m,1H),0.50-0.71(m,2H),0.21-0.47(m,2H)
[α]D=+26°(c=0.55,MeOH)
实施例7
制备(-)-1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)-乙醇(9)
将化合物(8)(1.18g)悬浮在甲醇(50ml)中然后加入饱和NaHCO3溶液(25ml)。将白色悬浮液于室温剧烈搅拌24h。用CH2Cl2(700ml)稀释反应混合物然后加入5%NaHCO3水溶液(300ml)并分离两相。用CH2Cl2(2x 100ml)提取水相,将合并的有机层在Na2SO4上干燥,并将溶剂在真空下蒸干。用Et2O(50ml)研磨两次得到的白色粗固体并用CH2Cl2(20ml)研磨一次,然后过滤得到0.74g对映异构体纯度>99%的化合物(7)。用在Chiracel OD柱(用己烷∶异丙醇=30∶70等度洗脱,流速0.35ml/min,保留时间=24.0min)上进行的分析手性HPLC测定对映异构体纯度。
MS/ESI+420-422[MH]+
′1H NMR(300MHz,DMSO-d6)ppm 8.51(s,2H),7.11(d,1H),7.05(d,1H),6.88(dd,1H),7.01(t,1H),5.59(d,1H),4.84(dt,1H),3.89(dd,1H),3.84(dd,1H),3.18(dd,1H),3.02(dd,1H),1.08-1.32(m,1H),0.47-0.66(m,2H),0.26-0.45(m,2H)
[α]D=-61°(c=0.5,MeOH)。
实施例8
2-(6-甲氧基-萘-2-基)-丙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)-乙酯(10,非对映异构体11和13的混合物)
将化合物(3)(12.0g)溶解在DMF(100ml)中然后加入(S)-2-(6-甲氧基-萘-2-基)-丙酸(7.5g)、4-二甲基氨基吡啶(3.6g)和1-乙基-3-[3-二甲基氨基丙基]碳二亚胺盐酸盐(5.7g)。室温搅拌4小时后,加入水(1000ml)。用EtOAc(500ml x 2)提取混合物,将合并的有机层在硫酸钠上干燥并将溶剂减压蒸发掉得到17.0g油,将其从EtOH中结晶从而得到11.5g非对映异构体(11)和(13)的混合物的标题化合物。
1H NMR(200MHz,CDCl3)ppm 8.43 and 8.60(2s,1H each,2H),7.51-7.68(m,3H),7.10-7.23(m,3H),6.85-6.97(m,2H),6.51-6.68(m,1H),6.22-6.97(t,1H,CHF2),6.00-6.13(m,1H),3.93-3.95(s,3H,OCH3),3.72-3.84(m,2H),3.07-3.57(m,3H),1.42-1.45(d,3H,CH3),0.94-1.25(m,1H),0.51-0.67(m,2H),0.12-0.36(m,2H)。
MS/ESI+616,618[MH]+。
实施例9
(+)-2-(6-甲氧基-萘-2-基)-丙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)-乙酯(第二个洗脱的非对映异构体)(13)
通过HPLC分离从实施例8的非对映异构体混合物中分离该化合物,其中使用Daisogel 10μm,50x300mm柱;洗脱剂:正己烷/甲基-叔-丁基-醚/异丙醇:90/9.9/0.1;流速:80ml/min.;上样量:每次注射300mg;洗脱时间:从11到20min。将收集的级分蒸发并将残余物从正己烷/异丙醇中结晶。
1H NMR(200MHz,CDCl3)ppm 8.60(s,2H),7.68-7.75(m,2H),7.58-7.59(m,1H),7.27-7.29(d,1H),7.12-7.24(m,2H),6.98-7.04(m,1H),6.73-6.78(dd,1H),6.67-6.68(d,1H),6.60-7.35(t,1H,CHF2),5.99-6.06(m,1H),3.84-3.87(m,4H),3.47-3.55(m,2H),3.32-3.41(dd,1H),3.22-3.29(m,1H),1.33-1.37(d,3H,CH3),0.96-1.03(m,1H),0.43-0.52(m,2H),0.13-0.21(m,2H)。
MS/ESI+616,618[MH]+。
[α]D=+52.8°(c=0.5,MeOH)
实施例10
(+)-2-(6-甲氧基-萘-2-基)-丙酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)-乙酯(第一个洗脱的非对映异构体)(11)
通过HPLC分离从实施例8的非对映异构体混合物中分离该化合物,其中使用Daisogel 10μm,50x300mm色谱柱;洗脱剂:正己烷/甲基-叔-丁基-醚/异丙醇:90/9.9/0.1;流速:80ml/min.;上样量:每次注射300mg;洗脱时间:从7到10min。将收集的级分蒸发并将残余物从正己烷/异丙醇中结晶。
1H NMR(200MHz,CDCl3)ppm 8.27(s,2H),7.64-7.80(m,2H),7.56-7.57(m,1H),7.28-7.29(d,1H),7.14-7.20(m,3H),6.68-7.42(t,1H,CHF2),6.93-6.98(m,2H),6.00-6.07(m,1H),3.88-3.92(m,4H),3.71-3.84(m,2H),3.39-3.51(dd,1H),3.16-3.25(dd,1H),1.33-1.37(d,3H,CH3),1.08-1.23(m,1H),0.50-0.59(m,2H),0.34-0.26(m,2H)。
MS/ESI+616,618[MH]+
[α]D=+45°(c=0.5,MeOH)。
实施例11
(+)-1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)-乙醇(14)
向(+)-2-(6-甲氧基-萘-2-基)-丙酸-1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)-乙酯(13)(14.0g)的甲醇悬浮液(110ml)中加入叔丁醇钾(5.1g)。将得到的混合物于室温搅拌2hrs,获得澄清溶液。在搅拌下向初始沉淀物(浑浊溶液)中缓慢加入水。
进一步搅拌60min后将沉淀的固体过滤,用水洗涤并溶解在氯仿中(100ml)。将溶液在硫酸钠上干燥并在真空下除去溶剂。将残余物在氯仿/己烷=1/2.5中结晶获得8.1g白色固体。
1H NMR(200MHz,CDCl3)ppm δ8.45(s,2H),7.19-7.08(d,1H),7.06-7.00(d,1H),6.95-6.85(dd,1H),6.99-6.24(t,1H,CHF2),5.18-5.00(m,1H),3.98-3.78(m,2H),3.54-3.35(m,1H),3.31-3.15(m,1H),2.04-1.94(d,1H,OH),1.40-1.14(m,1H),0.75-0.53(m,2H),0.50-0.29(m,2H).
MS/ESI+404,406[MH]+。
[α]D=+9.35°(c=1,CHCl3)。
实施例12
(-)-1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)-乙醇(12)
从非对映异构体(11)起始,按照实施例10的操作获得醇(12)。
MS/ESI+404,406[MH]+。
[α]D=-9.15°(c=1,CHCl3)。
实施例13
通过氧化醇(14)制备醇(7)
将化合物(14)(3.0g)溶解在CH2Cl2(100ml)中。加入70%间氯过苯甲酸(5.4g)并将得到的溶液于室温搅拌18小时。然后加入固体Na2S2O3(5g)并将混合物于室温剧烈搅拌30min。滤除固体残余物;用额外的100ml CH2Cl2稀释有机溶液并用饱和的NaHCO3水溶液洗涤(3x100ml)。将有机相在Na2SO4上干燥并将溶剂蒸发掉。在EtOAc(20ml)中研磨残余物得到1.9g白色固体的希望产物7,其无需进一步纯化而在下一步中使用。
1H NMR(200MHz,CDCl3)ppm 8.14(s,2H),7.18-7.09(d,1H),7.07-7.02(d,1H),6.92-6.83(dd,1H),7.01-6.22(t,1H,CHF2),5.10-4.96(m,1H),3.96-3.84(d,2H),3.45-3.29(m,1H),3.23-3.07(m,1H),3.24-3.17(d,1H,OH),1.41-1.67(m,1H),0.75-0.53(m,2H),0.50-0.29(m,2H)。
MS/ESI+420,422[MH]+。
[α]D=+65.0°(c=0.5,MeOH)。
实施例14
通过氧化醇(12)制备醇(9)
可以按照实施例13中描述的操作,使用醇(12)代替醇(14)作为起始物质获得醇(9)。
MS/ESI+420,422[MH]+。
[α]D=-60.6°(c=0.5,MeOH)。
实施例15
制备(-)-3-环丙基甲氧基-4-甲磺酰基氨基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-吡啶-4-基)-乙酯(C1)
步骤1:3-环丙基甲氧基-4-(N-叔-丁氧羰基-N-甲磺酰基)-氨基苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)-乙酯
于室温在氮气气氛下,将1-乙基-3-[3-二甲基氨基丙基]碳二亚胺盐酸盐(2.85g)加入到醇(14)(2.0g)、4-二甲基氨基吡啶(0.3g)、3-环丙基甲氧基-4-(N-叔-丁氧羰基-N-甲磺酰基)-氨基-苯甲酸(2.0g)的干燥CH2Cl2(180ml)溶液中。
室温搅拌过夜后,用5%含水HCl洗涤混合物(2x 100ml);分离有机相并用饱和NaHCO3水溶液洗涤(2x 100ml),在Na2SO4上干燥并蒸发至干。用快速色谱法在硅胶上以梯度洗脱(己烷/EtOAc 10/1到6/4)纯化粗产物获得1.4g标题化合物。
步骤2:制备C1
将3-环丙基甲氧基-4-(N-叔-丁氧羰基-N-甲磺酰基)-氨基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)-乙酯(1.4g)溶解在CH2Cl2(140ml)中。加入4M的HCl二烷溶液(40ml)并将得到的混合物于室温搅拌24小时。然后将反应混合物蒸发至干并将残余物在iPrOH(50ml)中研磨,随后在EtOH(50ml)中研磨,再在Et2O(70ml)中研磨获得0.880g化合物(C1)。
C1的分析性表征在表1中报道。
表1
类似地,可以制备下述化合物:
●(-)-4-环丙基甲氧基-3-甲磺酰基氨基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)-乙酯,
●(-)-3,4-双-甲磺酰基氨基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)-乙酯,
●(-)-3-甲磺酰基氨基-4-甲基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-吡啶-4-基)-乙酯和
●(-)-4-甲磺酰基氨基-3-甲基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)-乙酯。
实施例16
制备(-)-3-环丙基甲氧基-4-甲磺酰基氨基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)-乙酯(C2)
根据与实施例15相同的合成操作,从醇中间体(7)起始制备化合物(C2)。可供选择地,可以从如下述实施例17中描述的化合物(C1)起始制备化合物(C2)。
实施例17
从化合物(C1)起始制备(-)-3-环丙基甲氧基-4-甲磺酰基氨基-苯甲酸1-(3-环丙基甲氧基-4-二氟甲氧基-苯基)-2-(3,5-二氯-1-氧基-吡啶-4-基)-乙酯(C2)
将化合物(C1)(0.69g)溶解在CH2Cl2(20ml)中。加入70%间氯过苯甲酸(0.355g)并将得到的溶液于室温搅拌18小时。然后加入固体Na2S2O3(0.244g)并将混合物于室温剧烈搅拌30min。滤除固体残余物;用额外的20ml CH2Cl2稀释有机溶液并用饱和的NaHCO3水溶液洗涤(3x20ml)。将有机相在Na2SO4上干燥并将溶剂蒸发掉。将残余物在EtOH(20ml)中研磨得到0.710g白色固体的希望化合物(C2)。
按照同样的路线使用适当的试剂制备下列化合物:
表2
(继续)
在合成描述的最终化合物的羧酸中间体可商购得到或是已知的或根据已知方法合成。
实施例18
合成3-环丙基甲氧基-4-(N-叔-丁氧羰基-N-甲烷-磺酰基)-氨基-苯甲酸
方案2
步骤1:3-羟基-4-硝基-苯甲酸甲酯
将3-羟基-4-硝基-苯甲酸(10g)溶解在MeOH(500ml)中。加入96%H2SO4(2ml)并将混合物加热至60℃达18小时。将反应混合物浓缩至约200ml,用EtOAc(200ml)稀释并用饱和的NaHCO3(2x 20ml)水溶液洗涤。将有机层在Na2SO4上干燥并将溶剂蒸干得到10.5g希望的中间体。
步骤2:3-环丙基甲氧基-4-硝基-苯甲酸甲酯
在N2气氛下将3-羟基-4-硝基-苯甲酸甲酯(10.5g)溶解在干燥的DMF(150ml)中。加入K2CO3(24.3g)、KI(2.6g)和溴甲基环丙烷(10.3ml)并将混合物于50℃搅拌6小时。用水(300ml)稀释反应混合物并用Et2O(2x 200ml)提取;将合并的有机层在Na2SO4上干燥并将溶剂蒸发掉得到12.7g希望的中间体。
步骤3:4-氨基-3-环丙基甲氧基-苯甲酸甲酯
将3-环丙基甲氧基-4-硝基-苯甲酸甲酯(12.7g)溶解在MeOH(100ml)和EtOAc(100ml)中;加入10%Pd/C(1.0g,悬浮在20ml水中)并将混合物在Parr仪器(H2:20psi)中氢化5小时。加入37%HCl(10ml)并使氢化持续另外的2小时以获得完全转化。使催化剂经硅藻土垫过滤,用EtOAc(200ml)稀释混合物并用NaHCO3(2x 100ml)饱和水溶液洗涤。将有机层在Na2SO4上干燥并将溶剂蒸发掉得到10.7g希望的中间体。
步骤4:3-环丙基甲氧基-4-甲磺酰基氨基-苯甲酸甲酯
于室温在N2气氛下将3-(环丙基甲氧基)-4-氨基苯甲酸甲酯(8.86g)溶解在吡啶(80mL)中。加入甲磺酰氯(4.04mL)并将混合物于室温搅拌18小时。将反应混合物蒸发至干,用1N HCl(500mL)处理粗产物并用CH2Cl2(3x 200mL)提取。将有机层在Na2SO4上干燥并将溶剂蒸发掉得到11.7g希望的中间体。
MS/ESI+300[MH]+。
步骤5:3-环丙基甲氧基-4-(N-叔-丁氧羰基-N-甲磺酰基)-氨基-苯甲酸甲酯
将3-环丙基甲氧基-4-甲磺酰基氨基-苯甲酸甲酯(3.0g)溶解在CH2Cl2(150ml)中。加入二甲基氨基吡啶(DMAP,1.22g)和Boc2O(2.18g)并将混合物于室温搅拌1小时。用5%含水HCl(2x 50ml)洗涤反应混合物,将有机层在Na2SO4上干燥并将溶剂蒸发掉。在Et2O中研磨残余物并过滤得到4.0g希望的中间体,其无需进一步纯化而在下一步中使用。
步骤6:3-环丙基甲氧基-4-(N-叔-丁氧羰基-N-甲磺酰基)-氨基-苯甲酸
将环丙基甲氧基-4-(N-叔-丁氧羰基-N-甲磺酰基)-氨基-苯甲酸甲酯(4.0g)溶解在MeOH(100ml)中。加入1N NaOH(15ml)并将得到的混合物于室温搅拌1小时,然后加热至50℃达2小时。然后用EtOAc(250ml)稀释反应混合物并用1N HCl(2x 100ml)洗涤。将有机层在Na2SO4上干燥并将溶剂蒸发掉得到3.5g希望的酸衍生物。
MS/ESI+386[MH]+。
图例
*NMR
s=单峰
d=双重峰
t=三重峰
q=四重峰
dd=双重双重峰
m=多重峰
br=宽
ESI=电喷雾
本发明化合物的药理学活性
实施例19
在外周血单核细胞(PBMCs)试验中体外测定PDE4抑制活性
本试验基于已知的由PDE4抑制剂显示出的在外周血单核细胞(PBMCs)中对脂多糖(LPS)诱导的肿瘤坏死因子-α(TNF-α)释放的抑制活性,按照之前描述的方法进行(Hatzelmann A et al J.Pharmacol.Exp.Ther.2001;297:267-279;Draheim R et al J.Pharmacol.Exp.Ther.2004;308:555-563)。
将冷冻保存的人PBMCs(100μl/well)在存在或不存在(50microl)浓度范围为10-12M到10-6M的受试化合物的情况下在96-孔板(105细胞/孔)中孵育30min。然后加入LPS(3ng/ml)。
在95%空气和5%CO2气氛的潮湿的孵箱中于37℃孵育18h后,收集培养介质并用ELISA测定TNF-α。
关于化合物C1到C6的结果以产生对LPS诱导的TNF-α释放的50%抑制作用时的受试化合物的摩尔浓度(IC50)平均值±95%置信限表示,包括在0.06到4.4nM之间。假设不存在抑制剂化合物时LPS诱导的TNF-α生成为100%并且不存在LPS时PBMCs的TNF-α的基础生成为0%,以TNF-α释放的抑制作用的百分比计算受试化合物的效果。
实施例20
评价与高亲和力HPDE4的竞争能力相比抑制低亲和力LPDE4的能力
分别按照之前Cortijo J et al Br J Pharmacol 1993,108:562-568和Duplantier AJ et al JMed Chem 1996;39:120-125的描述评价针对LPDE4和HPDE4的亲和力。
受试化合物的浓度范围在10-12M到10-5M之间。测定的化合物C1到C6针对LPDE4和HPDE4的亲和力数值在82到477之间。
对于LPDE4而言,IC50是产生cAMP消失的50%抑制时受试化合物的摩尔浓度,而对于HPDE4而言,IC50是产生[H3]咯利普兰结合的50%抑制时受试化合物的摩尔浓度。
结果表明本发明的化合物以亚纳摩尔的亲和力抑制LPDE4并且与HPDE4相比针对LPDE4有更高的选择性。
实施例21
固定剂量的卡莫特罗/C1组合对卡巴胆碱诱导的豚鼠气管收缩的协同活性。
从雄性卵白蛋白(OA)致敏的豚鼠中获得锯齿形气管片段并从一个气管中获得两份制备物。将每份制备物置于20-ml充满氧合(O2 95%和CO2 5%)的常规Krebs-Henseleit溶液的器官浴槽中并维持于37℃。在1g的静息张力下将气管制备物连接于等长收缩力(isometricforce)传感器。平衡60min后,分别以C1(10-7M)、卡莫特罗(3*10-10M)、C1和卡莫特罗的组合或媒介物对气管制备物预处理30min,之后累积给予OA(10-10-10-5g/ml)。给予OA结束时,加入最大浓度的卡巴胆碱(10-5M)获得每份制备物的最大收缩。以卡巴胆碱诱导的最大响应百分比值表示效果(100%)。
用C1(10-7M)进行制备物30-min预处理引起OA诱导的收缩的23%抑制。相似地卡莫特罗(3*10-10M)产生的抑制作用是18%。
C1(10-7M)和卡莫特罗(3*10-10M)-组合引起OA诱导的收缩减少93%。
本研究显示卡莫特罗和C1都在拮抗卡巴胆碱诱导的豚鼠气道收缩中有效。此外,与它们互补的分子作用机制相符,在功能性激动-拮抗作用的框架下,固定的组合显示出在控制豚鼠气管胆碱能收缩方面的协同效应。
Claims (19)
1.作为(-)对映异构体的通式(I)化合物
其中:
n是0或1;
R1和R2可以相同或不同,并且选自:
-直链或支链C1-C6烷基,其任选被一个或多个卤素原子取代;
-OR3,其中R3是任选被一个或多个卤素原子或C3-C7环烷基取代的直链或支链C1-C6烷基;和
-HNSO2R4,其中R4是任选被一个或多个卤素原子取代的直链或支链C1-C4烷基,
其中R1和R2中的至少一个是HNSO2R4,
其药学上可接受的无机或有机盐。
2.根据权利要求1所述的化合物,其中R1是HNSO2R4,其中R4是甲基,R2是OR3,其中R3是环丙基甲基并且n是0。
3.根据权利要求1所述的化合物,其中R1是HNSO2R4,其中R4是甲基,R2是OR3,其中R3是环丙基甲基并且n是1。
4.根据权利要求1所述的化合物,其中R1是OR3,R2是HNSO2R4,其中R4是甲基并且n是1。
5.根据权利要求1所述的化合物,其中R1是甲基,R2是HNSO2R4,其中R4是甲基并且n是1。
6.根据权利要求1所述的化合物,其中R1和R2均为HNSO2R4,其中R4是甲基并且n是0。
7.根据权利要求1所述的化合物,其中R1和R2均为HNSO2R4,其中R4是甲基并且n是1。
8.制备权利要求1所定义的化合物的方法,包括如下步骤:使醛(1)
与甲基二氯吡啶(2)反应
得到外消旋的醇(3),任选将其氧化为相应的N-氧化物衍生物(4)
用选自(S)-甲氧萘丙酸或(S)-乙酰基扁桃酸的手性酸分别缩合(3)或(4),得到非对映异构体混合物(10)
或(5)
通过色谱法或结晶,将非对映异构体混合物(10)或(5)分别分离成两个单独的非对映异构体(11)
和(13)
或(6)
和(8)
,裂解后得到醇(14)
或(+)(7)
和(-)(9)
并且然后使化合物(+)(14)或(+)(7)与合适的苯甲酸(15)反应
得到通式(I)化合物,其中R1和R2如权利要求1所定义。
9.通式(II)的化合物
其中n是如权利要求1所定义的,并且下方以星号表示的碳原子显示(S)构型。
10.权利要求1-7中任一项所定义的式(I)化合物与选自β2激动剂、M3拮抗剂和皮质类固醇的第二药物活性组分的组合。
11.根据权利要求10所述的组合,其中第二活性组分是福莫特罗或卡莫特罗。
12.药物组合物,包含权利要求1-7中任一项所定义的式(I)化合物,或根据权利要求10或11所述的组合以及一种或多种药学上可接受的载体。
13.药物组合物,包含权利要求1-7中任一项所定义的式(I)化合物,或根据权利要求10或11所述的组合以及一种或多种药学上可接受的赋形剂。
14.权利要求1-7中任一项所定义的式(I)化合物在制备药物中的用途所述药物用于预防和/或治疗以气道阻塞为特征的呼吸道疾病。
15.权利要求14的用途,其中所述以气道阻塞为特征的呼吸道疾病是哮喘和慢性阻塞性肺病。
16.装置,包含根据权利要求12-13中任一项所述的药物组合物。
17.试剂盒,包含权利要求12-13中任一项的药物组合物以及装置,该装置是单-或多-剂量干燥粉末吸入器、计量吸入器或软雾喷雾器。
18.权利要求1-7中任一项所定义的式(I)化合物在制备药物中的用途,所述药物用于预防和/或治疗变应性鼻炎。
19.权利要求1-7中任一项所定义的式(I)化合物在制备药物中的用途,所述药物用于预防和/或治疗特应性皮炎。
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