CN103483338A - 作为p38map激酶抑制剂的三唑并吡啶衍生物 - Google Patents
作为p38map激酶抑制剂的三唑并吡啶衍生物 Download PDFInfo
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- CN103483338A CN103483338A CN201310309129.6A CN201310309129A CN103483338A CN 103483338 A CN103483338 A CN 103483338A CN 201310309129 A CN201310309129 A CN 201310309129A CN 103483338 A CN103483338 A CN 103483338A
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Abstract
式(I)的化合物是p38MAP激酶的抑制剂,其可用作抗炎药,用于治疗呼吸道疾病以及其它疾病,其中:R1是C1-C6烷基、C3-C6环烷基、任选地被取代的苯基、任选地被取代的5或6元单环杂芳基、或式(II)的基团,其中n是1或2,且R3和R4独立地是H或C1-C6烷基,或R3和R4与它们连接的氮一起形成6元杂环,所述杂环任选地含有选自N和O的其它杂原子;Y是-O-或-S(O)p-,其中p是0、1或2;A是任选地取代的二价亚芳基、或单环或双环亚杂芳基、或具有5或6个环原子的C3-C6二价亚环烷基、或亚哌啶基,其中环氮连接至R2NHC(=O)W-;W是键、-NH-或-C(RA)(RB)-,其中RA和RB独立地是H、甲基、乙基、氨基、羟基或卤素;且R2是在权利要求书中定义的基团,
Description
本申请是申请日为2010年2月16日、申请号为201080007822.2、发明名称为“作为P38MAP激酶抑制剂的三唑并吡啶衍生物”的中国发明专利申请的分案申请。
技术领域
本发明涉及作为p38MAPK抑制剂的化合物和组合物,它们可在呼吸道疾病以及其它疾病的治疗中用作抗炎剂。
背景技术
促分裂原活化蛋白激酶(MAPK)构成针对脯氨酸的丝氨酸/苏氨酸激酶家族,它们通过双重磷酸化来活化它们的底物。p38MAP激酶存在4种已知的人类同种型:p38α、p38β、p38γ和p38δ。p38激酶(它们也称作细胞因子抑制性的抗炎药物结合蛋白(CSBP)、应激活化蛋白激酶(SAPK)和RK)负责磷酸化(Stein等人,Ann.Rep.Med Chem.,1996,31,289-298)和活化转录因子(诸如ATF-2、MAX、CHOP和C/ERPb)以及其它激酶(诸如MAPKAP-K2/3或MK2/3),且它们自身被物理和化学应激(例如紫外线、渗透性应激)、促炎细胞因子和细菌脂多糖(LPS)活化(Herlaar E.&Brown Z.,Molecular Medicine Today,1999,5,439-447)。已经证实,p38磷酸化的产物会介导炎性细胞因子(包括肿瘤坏死因子α(TNFα)、白介素-(IL-)-1和环加氧酶-2(COX-2))的生成。还已知IL-1和TNFα会刺激其它促炎细胞因子(诸如IL-6和IL-8)的生成。
IL-1和TNFα是由多种细胞(诸如单核细胞或巨噬细胞)生成的生物物质。已经证实,IL-1会介导多种被认为对于免疫调节和其它生理状态(诸如炎症)而言重要的生物活性(例如Dinarello等人,Rev.Infect.Disease,1984,6,51)。过度的或失调的TNF生成(尤其是TNFα)已经牵涉介导或加重许多疾病,且认为,TNF可以造成或促成一般的炎症效应。IL-8是由几种细胞类型(包括单核细胞、成纤维细胞、内皮细胞和角质化细胞)生成的趋化因子。它从内皮细胞的生成是由IL-1、TNF或脂多糖(LPS)诱导。IL-8在体外会刺激许多功能。已经证实,它对于嗜中性粒细胞、T-淋巴细胞和嗜碱性粒细胞具有化学引诱物性质。IL-8生成的增加也会引起嗜中性粒细胞向体内炎症部位的趋化性。
几种其它促炎蛋白(例如,IL-6、GM-CSF、COX-2、胶原酶和溶基质蛋白酶)的合成和/或作用也需要通过p38(以及上述的IL-1、TNF和IL-8)来抑制信号转导,预期是用于调节免疫系统的过度和破坏性活化的高度有效的机制。该预期得到了关于p38激酶抑制剂所描述的有效且不同的抗炎活性的支持(Badger等人,J.Pharm.Exp.Thera.,1996,279,1453-1461;Griswold等人,Pharmacol.Comm.,1996,7,323-229)。具体地,已经将p38激酶抑制剂描述为类风湿性关节炎的潜在治疗剂。除了p38活化与慢性炎症和关节炎之间的联系以外,也有数据提示p38在气道疾病(尤其是COPD和哮喘)的发病机制中的作用。应激刺激(包括烟草烟雾、感染或氧化产物)可以造成肺环境内的炎症。已经证实,p38的抑制剂会抑制LPS和卵白蛋白诱导的气道TNF-α、IL-1β、IL-6、IL-4、IL-5和IL-13(Haddad等人,Br.J.Pharmacol.,2001,132(8),1715-1724;Underwood等人,Am.J.Physiol.Lung Cell.Mol.2000,279,895-902;Duan等人,2005Am.J.Respir.Crit.Care Med.,171,571-578;Escott等人Br.J.Pharmacol.,2000,131,173-176;Underwood等人,J.Pharmacol.Exp.Ther.2000,293,281-288)。此外,它们在LPS、臭氧或香烟烟雾动物模型中显著抑制嗜中性粒细胞增多症和MMP-9的释放。还有大量临床前数据证实了与肺有关的抑制p38激酶的潜在益处(Lee等人,Immunopharmacology,2000,47,185-200)。因而,p38活化的治疗性抑制可能在气道炎症的调节中是重要的。
P.Chopra等人已经综述了p38MAPK途径在不同疾病中的牵涉(Expert Opinion on Investigational Drugs,2008,17(10),1411-1425)。据信,本发明的化合物可用于治疗p38介导的疾病,诸如:哮喘、慢性或急性支气管收缩、支气管炎、急性肺损伤及支气管扩张、肺动脉高压(pulmonary artery hypertension)、肺结核、肺癌、一般性炎症(例如炎性肠病)、关节炎、神经炎症、疼痛、发热、纤维变性疾病、肺障碍及疾病(例如,氧过多肺泡损伤)、心血管疾病、缺血后再灌注损伤及充血性心脏衰竭、心肌病、中风、缺血、再灌注损伤、肾再灌注损伤、脑水肿、神经创伤以及脑创伤、神经变性障碍、中枢神经系统障碍、肝疾病及肾炎、胃肠病症、溃疡疾病、局限性回肠炎、眼疾病、眼科病症、青光眼、眼睛组织的急性损伤以及眼创伤、糖尿病、糖尿病性肾病、皮肤有关的病症、因为感染引起的肌痛、流行性感冒、内毒素性休克、中毒性休克综合征、自身免疫疾病、移植物排斥、骨吸收疾病、多发性硬化、银屑病、湿疹、女性生殖系统的障碍、病理(但非恶性)病症(诸如,血管瘤、鼻咽的血管纤维瘤及骨缺血性坏死)、良性及恶性肿瘤/瘤形成(包括癌症、白血病、淋巴瘤)、系统性红斑性狼疮(SLE)、血管生成(包括瘤形成)、出血、凝固、辐射损伤和/或转移。活性TNF的慢性释放可造成恶病质及厌食,并且TNF可以致命。TNF也已经牵涉感染性疾病。这些疾病包括,例如,疟疾、分枝杆菌感染及脑膜炎。这些也包括病毒感染,例如HIV、流行性感冒病毒和疱疹病毒(包括1型单纯疱疹病毒(HSV-1)、2型单纯疱疹病毒(HSV-2)、巨细胞病毒(CMV)、水痘-带状疱疹病毒(VZV)、非洲淋巴细胞瘤病毒、人类疱疹病毒6(HHV-6)、人类疱疹病毒7(HHV-7)、人类疱疹病毒8(HHV-8));假性狂犬病及鼻气管炎等。
G.J.Hanson(Expert Opinions on Therapeutic Patents,1997,7,729-733)、J Hynes等人(Current Topics in Medicinal Chemistry,2005,5,967-985)、C.Dominguez等人(Expert Opinions on Therapeutics Patents,2005,15,801-816)以及L.H.Pettus和R.P.Wurtz(Current Topics inMedicinal Chemistry,2008,8,1452-1467)已经综述了已知的P38激酶抑制剂。含有三唑并吡啶基序的P38激酶抑制剂是本领域已知的,例如WO07/091152、WO04/072072、WO06/018727。
发明内容
本发明的化合物是包括p38α激酶在内的p38促分裂原活化蛋白激酶(“p38MAPK”、“p38激酶”或“p38”)的抑制剂,且是细胞因子和趋化因子生成(包括TNFα和IL-8生成)的抑制剂。它们具有许多治疗用途,用于治疗炎性疾病、尤其是变应性和非变应性气道疾病、更特别是阻塞性或炎性气道疾病诸如慢性阻塞性肺疾病(“COPD”)和哮喘。它们因此特别适合肺递送(通过鼻或嘴吸入)。
根据本发明,提供了式(I)的化合物或其药学上可接受的盐:
其中:
R1是C1-C6烷基、C3-C6环烷基、任选地被取代的苯基、任选地被取代的5或6元单环杂芳基、或式(II)的基团
其中n是1或2;且R3和R4独立地是H或C1-C6烷基,或R3和R4与它们连接的氮一起形成6元杂环,所述杂环任选地含有选自N和O的其它杂原子;
Y是-O-或-S(O)p-,其中p是0、1或2;
A是任选地取代的二价亚芳基、或单环或双环亚杂芳基、或具有5或6个环原子的C3-C6二价亚环烷基、或亚哌啶基,其中环氮连接至R2NHC(=O)W-;
W是键、-NH-或-C(RA)(RB)-,其中RA和RB独立地是H、甲基、乙基、氨基、羟基或卤素;且
R2是式(IIIA)、(IIIB)或(IIIC)的基团:
其中
m是0或1;
q是0、1、2或3;
T是-N=或-CH=;
R5是H或F;
R7是-CH3、-C2H5、-CH2OH、-CH2SCH3、-SCH3或-SC2H5;
R8是-CH3或-C2H5;且
每次出现的R6独立地是H、C1-C6烷基、羟基或卤素;或单次出现的R6是式(IVA)、(IVB)或(IVC)的基团
同时任何其它出现的R6独立地是H、C1-C6烷基、羟基或卤素;
其中n和p如上面所定义;
且,其中在R6中
R61a和R61b是H、烷基,或R61a和R61b可以与它们连接的氮一起结合形成杂环,所述杂环任选地含有选自N和O的其它杂原子。
在另一个方面,本发明包括药物组合物,其含有本发明化合物以及一种或多种药学上可接受的载体和/或赋形剂。特别优选的是适合吸入进行肺给药的组合物。
在另一个方面,本发明包括本发明化合物用于治疗从p38MAP激酶活性的抑制中获益的疾病或病症的用途。优选的用途为阻塞性或炎性气道疾病的治疗。使用本发明的化合物可潜在地治疗所有形式的阻塞性或炎性气道疾病,尤其是选自下列的阻塞性或炎性气道疾病:慢性嗜酸粒细胞性肺炎,哮喘,COPD,包括慢性支气管炎、肺气肿或与COPD有关或无关的呼吸困难的COPD,以不可逆的进行性气道阻塞为特征的COPD,成人呼吸窘迫综合征(ARDS),因其它药物治疗所发生的气道反应过度的恶化,以及与肺动脉高血压(pulmonary hypertension)有关的气道疾病,包括囊性纤维化病在内的慢性炎性疾病,支气管扩张和肺纤维化(特发性的)。当局部地向肺(例如通过吸入和鼻内递送)或通过全身途径(例如,口服、静脉内和皮下递送)施用p38激酶抑制剂时,预见到效力。
发明详述
科学术语
本文使用的术语“(Ca-Cb)烷基”(其中a和b是整数)表示具有a至b个碳原子的直链或支链烷基。因而,例如,当a是1且b是6时,该术语包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基和正己基。
本文使用的术语“碳环的”表示具有最多16个环原子(它们都是碳)的单环、二环或三环基团,包括芳基和环烷基。
本文使用的术语“环烷基”表示具有3-8个碳原子的单环饱和碳环基团,包括例如,环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
术语“二价亚环烷基”表示具有2个不饱和价的环烷基,诸如下述的1,3-亚环戊基和1,4-亚环己基:
本文使用的无限制的术语“芳基”表示单环或双环碳环芳族基团,且包括具有2个通过共价键直接相连的单环碳环芳族环的基团。这样的基团的实例是苯基、联苯基和萘基。
术语“二价亚芳基”表示具有2个不饱和价的单环或双环芳基,诸如下述的1,3-亚苯基或1,4-亚苯基:
或下述的1,4-萘基(1,4-naphthalenyl):
本文使用的无限制的术语“杂芳基”表示含有一个或多个选自S、N和O的杂原子的单环或双环芳族基团,且包括具有2个这样的单环、或一个这样的单环和一个单环芳环(它们通过共价键直接相连)的基团。这样的基团的代表性实例是噻吩基、苯并噻吩基、呋喃基、苯并呋喃基、吡咯基、咪唑基、苯并咪唑基、噻唑基、苯并噻唑基、异噻唑基、苯并异噻唑基、吡唑基、唑基、苯并唑基、异唑基、苯并异唑基、异噻唑基、三唑基、苯并三唑基、噻二唑基、二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吲哚基和吲唑基。
本文使用的无限制的术语“杂环基”或“杂环的”包括上面定义的“杂芳基”,且在它的非芳族含义中,是指含有一个或多个选自S、N和O的杂原子的单环、二环或三环非芳族基团,以及由含有一个或多个这样的杂原子的单环非芳族基团(其共价地连接到另一个这样的基团上或单环碳环基团上)组成的基团。这样的基团的实例是吡咯基、呋喃基、噻吩基、哌啶基、咪唑基、唑基、异唑基、噻唑基、噻二唑基、吡唑基、吡啶基、吡咯烷基、嘧啶基、吗啉基、哌嗪基、吲哚基、吗啉基、苯并呋喃基、吡喃基、异唑基、苯并咪唑基、亚甲二氧基苯基、亚乙二氧基苯基、马来酰亚氨基和琥珀酰亚氨基。
术语“二价亚杂芳基”表示具有2个不饱和价的单环或双环杂芳基,诸如下述的:
下面是目前优选的
除非在它出现的上下文中另外指出,在本文中应用于任意芳基或杂芳基部分的术语“取代的”是指被至少一个取代基取代,所述取代基例如选自:(C1-C6)烷基、(C1-C6)氟代烷基、(C1-C6)烷氧基(包括在芳族环的邻近碳原子上的亚甲二氧基和亚乙二氧基取代)、(C1-C6)氟代烷氧基、(C1-C6)烷氧基-(C1-C6)烷基、苄氧基-(C1-C6)烷基、(C1-C6)烷氧基-(C1-C6)烷氧基、苄氧基-(C1-C6)烷氧基、羟基、羟基(C1-C6)烷基、羟基(C1-C6)烷氧基、巯基、巯基(C1-C6)烷基、(C1-C6)烷硫基、环丙基、卤素(包括氟和氯)、O-苄基、硝基、腈(氰基)、-COOH、四唑基、-COORA、-CORA、-SO2RA、-CONH2、-SO2NH2、-CONHRA、-SO2NHRA、-CONRARB、-SO2NRARB、-NH2、-NHRA、-NRARB、-OCONH2、-OCONHRA、-OCONRARB、-NHCORA、-NHCOORA、-NRBCOORA、-NHSO2ORA、-NRBSO2ORA、-NHCONH2、-NRACONH2、-NHCONHRB、-NRACONHRB、-NHCONRARB或-NRACONRARB,其中RA和RB独立地是(C1-C4)烷基,或RA和RB当连接到同一个氮上时,可以与该氮一起形成环状氨基,诸如吗啉基、哌啶基或哌嗪基。“任选的取代基”可以是在上面的描述中包括的取代基之一。
本发明的化合物可能以一种或多种几何异构、光学异构、对映异构、非对映异构和互变异构的形式存在,包括但不限于顺式和反式形式、E-和Z-形式、R-、S-和内消旋形式、酮-和烯醇-形式。除非另有说明,提及的特定化合物包括所有这样的异构形式,包括其外消旋形式和其它混合物。在适当时,通过应用或采用已知的方法(例如色谱技术和重结晶技术),可以从它们的混合物中分离出这样的异构体。在适当时,通过应用或采用已知的方法(例如不对称合成),可以制备这样的异构体。
本文使用的术语“盐”包括碱加成盐、酸加成盐和铵盐。如上面简单提及的,本发明的酸性化合物可与碱形成盐,包括药学上可接受的盐,所述碱例如:碱金属氢氧化物,例如氢氧化钠和氢氧化钾;碱土金属氢氧化物,例如氢氧化钙、氢氧化钡和氢氧化镁;有机碱,例如N-甲基-D-葡糖胺、胆碱三(羟甲基)氨基-甲烷、L-精氨酸、L-赖氨酸、N-乙基哌啶、二苄胺等。本发明的那些碱性化合物可与无机酸和有机酸形成盐,包括药学上可接受的盐,所述无机酸例如氢卤酸,例如氢氯酸或氢溴酸、硫酸、硝酸或磷酸等,所述有机酸例如乙酸、三氟乙酸、酒石酸、琥珀酸、富马酸、马来酸、苹果酸、水杨酸、柠檬酸、甲磺酸、对甲苯磺酸、苯甲酸、苯磺酸、谷氨酸、乳酸和扁桃酸等。具有碱性氮的那些化合物(I)也可以与药学上可接受的反荷离子形成季铵盐,诸如氯化铵、溴化铵、乙酸铵、甲酸铵、对甲苯磺酸铵、琥珀酸铵、半-琥珀酸铵、萘-二磺酸铵、甲磺酸铵、三氟乙酸铵、昔萘酸铵等。关于盐的综述,参见Stahl和Wermuth的Handbook of Pharmaceutical Salts:Properties,Selection,and Use(Wiley-VCH,Weinheim,Germany,2002)。
预见到,本发明的化合物可以以水合物和溶剂化物的形式制备。在本文中,包括在本文的权利要求中提及的任意“本发明有关的化合物”或“本发明的化合物”或“本发明化合物”等,都包括这样的化合物的盐、水合物和溶剂化物。术语‘溶剂化物’在本文中用于描述这样的分子复合物,其包含本发明的化合物和化学计量量的一种或多种药学上可接受的溶剂分子,例如乙醇。当所述溶剂是水时,使用术语‘水合物’。
本发明的个别化合物可以以几种多晶型存在,且可以以不同的晶体习性得到。
所述化合物也可以以其前药的形式施用。因此,可能自身是有活性的或可能本身几乎不具有或根本不具有药理学活性的某些化合物衍生物在施用进体内或到体表上时,可以转化为具有希望的活性的本发明的化合物,例如,通过水解裂解。这类衍生物称作为‘前药’。关于前药的应用的进一步信息,参见:Pro-drugs as Novel Delivery Systems,Vol.14,ACSSymposium Series(T.Higuchi和V.J.Stella)和Bioreversible Carriers inDrug Design,Pergamon Press,1987(E.B.Roche编,AmericanPharmaceutical Association;C.S.Larsen和J.stergaard,Design andapplication of prodrugs,见Textbook of Drug Design and Discovery,第3版,2002,Taylor and Francis)。
例如,通过用本领域技术人员已知的称作为‘前部分(pro-moieties)’的某些部分(例如,在H.Bundgaard的Design of Prodrugs(Elsevier,1985)中所描述的)替换在式(I)化合物中存在的适当官能团,可以制备根据本发明的前药。这样的实例可以是羧基(诸如在氨苄西林的匹氨西林前药中使用的-CO-O-CH2-O-CO-tBu)、酰胺(-CO-NH-CH2-NAlk2)或脒(-C(=N-O-CH3)-NH2)的前药。
在本发明的化合物中,二价基团–W-[A]-Y-可以是,例如,下面的具体实施例化合物中的任意对应基团。例如,该基团可以是下面的式(B)-(J)之一:
本发明化合物的一个亚类具有式(IA):
其中V、V’、X和X’独立地是-CH=或-N=;且R1、R2、Y和W如关于式(I)所定义。在该亚类中,化合物可以具有式(IA1):
其中Y是O或S,且R1和R2如关于式(I)所定义。
本发明化合物的另一个亚类具有式(IB):
其中U是CH或N,且R1、R2、Y和W如关于式(I)所定义,条件是,当U是N时,则W不是NH。在该亚类中,化合物可以具有式(IB1):
其中Y是O或S,且R1和R2如关于式(I)所定义。
本发明化合物的另一个亚类具有式(IC):
其中Y是O或S,R2如在权利要求1中所定义,且R1是关于上面式(I)所定义的苯基、5或6元单环杂芳基、或式(II)的基团。
在本发明的化合物中,包括上面的式(IA)、(IA1)、(IB)、(IB1)和(IC)的亚类,具体的目前优选的结构特征包括下述:
R1可以是关于上面式(I)所定义的式(II)的基团,其中基团-NR3R4是吗啉基。
R1可以是异丙基或2,6-二氯苯基。
R2可以是关于上面式(I)所定义的式(IIIC)的基团,其中R7和R8各自是甲基。
R2可以具有式(IIID)、(IIIE)、(IIIF)或(IIIG):
R2可以是关于上面式(I)所定义的式(IIIA)的基团,其中m是0。
R2可以是关于上面式(I)所定义的式(IIIB)的基团,其中(a)T是-CH=,且R5=H;或(b)T是-N=,且R5=H;或(c)T是-CH=,且R5=F。
在二价基团A中的任选的取代基包括:-CN、-F、-Cl、-Br、-NO2、-OH、-SO2C1-C2烷基、-SO2C1-C2完全或部分氟化的烷基、C1-C4烷基、完全或部分氟化的C1-C4烷基、C1-C4烷氧基、完全或部分氟化的C1-C4烷氧基和-SCF3。
二价基团A可以是6元环(诸如亚苯基或亚吡啶基),其以1,3(间)或1,4(对)方向连接到Y和W上。
二价基团A可以是以反式-1,4方向连接到W和Y上的亚环己基。
W可以是-CH2-。
实用性
如上所述,本发明的化合物是p38MAPK抑制剂,因而可以用于治疗从p38酶的抑制中获益的疾病或病症。这样的疾病和病症可从文献中获知,且在上面已经提到几种。但是,所述化合物通常用作抗炎剂,尤其是用于治疗呼吸性疾病。具体地,所述化合物可以用于治疗慢性阻塞性肺疾病(COPD)、慢性支气管炎、肺纤维化、肺炎、急性呼吸窘迫综合征(ARDS)、肺气肿或吸烟诱发的肺气肿、固有的(非变应性的哮喘)和非固有的(变应性的)哮喘、轻度哮喘、中度哮喘、严重哮喘、类固醇抵抗型哮喘、嗜中性粒细胞性哮喘、支气管炎性哮喘、运动诱发的哮喘、职业性哮喘和细菌感染后诱发的哮喘、囊性纤维化病、肺纤维化和支气管扩张。
组合物
如上所述,本发明涉及的化合物是p38激酶抑制剂,且可用于治疗几种疾病,例如呼吸道的炎性疾病。这样的疾病的实例在上面有所提及,包括哮喘、鼻炎、变应性气道综合征、支气管炎和慢性阻塞性肺疾病。
应当理解,任意特定患者的具体剂量水平取决于多种因素,包括使用的具体化合物的活性、年龄、体重、一般健康、性别、饮食、给药时间、给药途径、排泄速率、药物联合以及正在治疗的特定疾病的严重性。如药学领域所要求的,通过临床试验确定给药的最佳剂量水平和频率。一般而言,对于口服给药,按照单次或分份剂量,日剂量范围是在约0.001mg至约100mg/kg人体重、经常0.01mg至约50mg/kg,例如0.1至10mg/kg的范围内。一般而言,对于吸入给药,按照单次或分份剂量,日剂量范围是在约0.1μg至约1mg/kg人体重、优选0.1μg至50μg/kg的范围内。另一方面,在有些情况下,可能必须使用在这些限度以外的剂量。对于本发明的目的,吸入给药是优选的。
可以制备本发明涉及的化合物,用于通过与它们的药代动力学性质相一致的任意途径进行给药。可口服给药的组合物可以是片剂、胶囊、散剂、颗粒剂、锭剂、液体或凝胶制剂的形式,例如口服的、局部的或无菌的肠胃外溶液或悬浮液。用于口服给药的片剂和胶囊可以是单位剂量呈现形式,并且可含有常规赋形剂,例如:粘合剂,例如糖浆、阿拉伯胶、明胶、山梨醇、黄蓍胶或聚乙烯吡咯烷酮;填充剂,例如乳糖、糖、玉米淀粉、磷酸钙、山梨醇或甘氨酸;压片润滑剂,例如硬脂酸镁、滑石、聚乙二醇或二氧化硅;崩解剂,例如马铃薯淀粉,或可接受的湿润剂,例如月桂基硫酸钠。根据普通医药实践中公知的方法,可以将片剂包衣。口服的液体制剂可以是例如水性或油性悬浮液、溶液、乳剂、糖浆剂或酏剂的形式,或可以作为在使用前用水或其它合适的媒介物重配的干燥产品。这种液体制剂可含有常规的添加剂,例如:助悬剂,例如山梨醇、糖浆剂、甲基纤维素、葡萄糖糖浆剂、明胶、氢化的可食用脂肪;乳化剂,例如卵磷脂、脱水山梨糖醇单油酸酯或阿拉伯胶;非水性媒介物(可包括食用油),例如杏仁油、分馏的椰子油、油性酯(如甘油)、丙二醇或乙醇;防腐剂,例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或山梨酸,以及在需要时的常规调味剂或着色剂。
为了局部施用于皮肤,可以将所述药物制成乳膏剂、洗剂或软膏剂。可用于所述药物的乳膏剂或软膏剂制剂是本领域公知的常规制剂,例如如在药剂学的标准教科书(如英国药典)中所述。
活性成分还可在无菌介质中肠胃外地给药。根椐所使用的媒介物和浓度,所述药物可以悬浮或溶解在媒介物中。有利地,还可将佐剂(如局部麻醉剂、防腐剂和缓冲剂)溶解在媒介物中。
但是,对于呼吸道的炎性疾病的治疗,本发明的化合物也可以配制成用于吸入,例如作为鼻喷雾剂、或干粉或气溶胶吸入器。对于吸入递送,活性化合物优选地为微粒形式。通过包括喷雾干燥、冷冻干燥和微粉化在内的多种技术,可以制备这些微粒。使用例如压力驱动的喷射雾化器或超声雾化器,可以产生气溶胶,优选地使用推进剂驱动的定量气溶胶或微粉化的活性化合物的不含推进剂的给药(来自例如吸入式胶囊或其它“干粉”递送系统)。
例如,本发明的组合物可制备为悬浮液用于从喷雾器递送,或制备为液体推进剂中的气溶胶而用于例如加压定量吸入器(PMDI)中。适用于PMDI的推进剂为熟练技术人员所已知,包括CFC-12、HFA-134a、HFA-227、HCFC-22(CCl2F2)和HFA-152(CH4F2和异丁烷)。
在本发明的一个优选实施方案中,本发明的组合物为干粉形式,用于使用干粉吸入器(DPI)的递送。很多类型的DPI是已知的。
可以用辅助递送和释放的赋形剂配制用于给药递送的微粒。例如,在干粉制剂中,可以用有助于从DPI流向肺的大载体颗粒来配制微粒。合适的载体颗粒是已知的,包括乳糖颗粒;它们可具有大于90μm的质量中值直径(mass median aerodynamic diameter)。
在基于气溶胶的制剂的情况下,一个实施例是:
本发明的化合物 24mg/罐
卵磷脂,NF Liq.Conc. 1.2mg/罐
三氯氟甲烷,NF 4.025g/罐
二氯二氟甲烷,NF 12.15g/罐。
可根据所用的吸入器系统,如前所述地给予活性化合物。除了活性化合物之外,给药形式可以额外含有赋形剂,例如,推进剂(例如对于定量气溶胶,可使用氟利昂)、表面活性物质、乳化剂、稳定剂、防腐剂、调味剂、填充剂(例如对于粉末吸入器,可使用乳糖),或者如果合适时,还含有其它活性化合物。
对于吸入目的,可以得到很多种产生和施用具有最合适粒度的气溶胶的系统,其中使用适合患者的吸入技术。除了使用接合管( adaptor)(间隔器(spacer)、扩张器(expander))和梨形容器(例如 )和发射吹气(puffer)喷雾的自动装置()之外,对于定量气溶胶,特别是对于粉末吸入器的情况,可以得到很多种技术方案(例如 或例如EP-A-0505321所述的吸入器)。另外,本发明的化合物可以在多室装置中递送,从而允许递送联合药剂。
组合
其它化合物可以与本发明涉及的化合物相组合,用于预防和治疗炎性疾病,尤其是呼吸系统疾病。因而,本发明也涉及药物组合物,其包含治疗有效量的本发明化合物和一种或多种其它治疗剂。适用于与本发明化合物联合治疗的治疗剂包括、但不限于:(1)皮质甾类,例如丙酸氟替卡松、糠酸氟替卡松、糠酸莫米松、二丙酸倍氯米松、环索奈德、布地奈德、GSK685698、GSK870086、QAE397、QMF149、TPI-1020;(2)β2-肾上腺素能受体激动剂诸如沙丁胺醇(salbutamol)、沙丁胺醇(albuterol)、特布他林、非诺特罗,和长效β2-肾上腺素能受体激动剂诸如沙美特罗、茚达特罗、福莫特罗(包括富马酸福莫特罗)、阿福特罗、卡莫特罗、GSK642444、GSK159797、GSK159802、GSK597501、GSK678007、AZD3199;(3)皮质甾类/长效β2激动剂组合产品,诸如沙美特罗/丙酸氟替卡松(Advair/Seretide)、福莫特罗/布地奈德(Symbicort)、福莫特罗/丙酸氟替卡松(Flutiform)、福莫特罗/环索奈德、福莫特罗/糠酸莫米松、茚达特罗/糠酸莫米松、茚达特罗/QAE397、GSK159797/GSK685698、GSK159802/GSK685698、GSK642444/GSK685698、GSK159797/GSK870086、GSK159802/GSK870086、GSK642444/GSK870086、阿福特罗/环索奈德;(4)抗胆碱能药,例如毒蕈碱-3(M3)受体拮抗剂诸如异丙托溴铵、噻托溴铵、Aclidinium(LAS-34273)、NVA-237、GSK233705、Darotropium、GSK573719、GSK961081、QAT370、QAX028;(5)双重药理学M3-抗胆碱能/β2-肾上腺素能受体激动剂诸如GSK961081;(6)白三烯调节剂,例如白三烯拮抗剂诸如孟鲁司特、扎鲁司特或普仑司特,或白三烯生物合成抑制剂诸如齐留通或BAY-1005,或LTB4拮抗剂诸如阿美卢班,或FLAP抑制剂诸如GSK2190914、AM-103;(7)磷酸二酯酶-IV(PDE-IV)抑制剂(口服或吸入),例如罗氟司特、西洛司特、奥米司特、ONO-6126、Tetomilast、妥非司特、UK500,001、GSK256066;(8)抗组胺剂,例如选择性的组胺-1(H1)受体拮抗剂,例如非索非那定、citirizine、氯雷他定或阿司咪唑,或双重H1/H3受体拮抗剂诸如GSK835726、GSK1004723;(9)镇咳药,例如可待因或右美沙芬(dextramorphan);(10)粘液溶解剂,例如N乙酰基半胱氨酸或弗多司坦;(11)祛痰药/粘液动力学(mucokinetic)调节剂,例如氨溴素、高渗溶液(例如盐水或甘露醇)或表面活性剂;(12)肽粘液溶解剂,例如重组人脱氧核糖核酶I(阿法链道酶和rhDNA酶)或螺杀菌素;(13)抗生素,例如阿奇霉素、妥布霉素和氨曲南;(14)非选择性的COX-1/COX-2抑制剂,例如布洛芬或酮洛芬;(15)COX-2抑制剂,例如塞来考昔和罗非昔布;(16)VLA-4拮抗剂,例如在WO97/03094和WO97/02289中所述的那些;(17)TACE抑制剂和TNF-α抑制剂,例如抗-TNF单克隆抗体,例如注射用英利昔单抗和CDP-870和TNF受体免疫球蛋白分子,例如Enbrel;(18)基质金属蛋白酶抑制剂,例如MMP-12;(19)人嗜中性粒细胞弹性酶抑制剂,例如ONO-6818或在WO2005/026124、WO2003/053930和WO06/082412中所述的那些;(20)A2b拮抗剂诸如在WO2002/42298中所述的那些;(21)趋化因子受体功能调节剂,例如CCR3和CCR8的拮抗剂;(22)调节其它类前列腺素受体的作用的化合物,例如血栓烷A2拮抗剂;DP1拮抗剂诸如MK-0524,CRTH2拮抗剂诸如ODC9101和AZD1981,和混合的DP1/CRTH2拮抗剂诸如AMG009;(23)PPAR激动剂,包括PPARα激动剂(诸如非诺贝特)、PPARδ激动剂、PPARγ激动剂,例如吡格列酮、罗格列酮和巴格列酮;(24)甲基黄嘌呤诸如茶碱或氨茶碱,和甲基黄嘌呤/皮质甾类组合诸如茶碱/布地奈德、茶碱/丙酸氟替卡松、茶碱/环索奈德、茶碱/糠酸莫米松和茶碱/二丙酸倍氯米松;(25)A2a激动剂诸如在EP1052264和EP1241176中所述的那些;(26)CXCR2或IL-8拮抗剂诸如SCH527123或GSK656933;(27)IL-R信号传递调节剂诸如kineret和ACZ885;(28)MCP-1拮抗剂诸如ABN-912。
合成方法
根据在方案1-6中说明的途径,可以制备本发明的化合物。
方案1
可以如下从通式(IX)的化合物制备通式(I-a)的化合物:
其中r是0或1,Y是S或O,且Ra是如在通式(I)中关于R1所定义。
通过与通式(X)的胺反应:
RbNH2(X),
其中Rb是如在通式(I)中关于R2所定义。
在有诸如二异丙基乙胺或三乙胺等碱存在下,使用合适的偶联剂诸如2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐、1-乙基-3-(3’-二甲氨基丙基)碳二亚胺或二环己基碳二亚胺。该反应可以在合适的溶剂(诸如二氯甲烷、N,N-二甲基甲酰胺或四氢呋喃)中在一定温度范围内(优选地在室温)进行。
或者,可以如下从通式(IX)的化合物制备式(I-a)的化合物:在有或没有溶剂(诸如二氯甲烷或N,N-二甲基甲酰胺)存在下,在一定温度范围内(优选室温至100℃),与合适的卤化剂(如草酰氯或亚硫酰氯)反应,随后在合适的溶剂(诸如四氢呋喃)中,使用合适的碱(诸如二异丙基乙胺),在一定温度范围内(优选室温至80℃),与通式(X)的胺反应。
可以如下从通式(V)的化合物制备通式(IX)的化合物:
其中X是合适的离去基团(诸如氟化物、溴化物或碘化物)
通过与通式(VIII)的化合物反应:
其中R是H或烷基,使用合适的催化剂诸如碘化亚铜(I)、氯化亚铜(I)、乙酸钯、四(三苯基膦)钯(0)或二氯(1,1’-二(二苯基膦基)二茂铁)钯(II),在有或没有合适的配体(诸如(2,9-二甲基)-1,10-菲咯啉、脯氨酸、1,2-环己基二胺或膦)存在下,使用诸如碳酸铯、氢氧化钾、碳酸钾或叔丁醇钠等碱。可以在合适的溶剂(诸如甲苯、N-甲基吡咯烷酮或N,N-二甲基甲酰胺)中,在一定温度范围内(优选40至150℃),进行该反应;如果R是烷基,然后根据本领域技术人员已知的方法进行水解。
可以如下从通式(IV)的化合物制备通式(V)的化合物:
使用合适的氧化剂(诸如氯胺T、四乙酸铅或二乙酸碘苯(III)),在合适的溶剂(诸如二氯甲烷或乙醇)中,在一定温度范围内(优选室温至100℃)。
可以如下从通式(II)的化合物制备通式(IV)的化合物:
通过在合适的溶剂(诸如乙醇或四氢呋喃)中,在一定温度范围内(优选室温至80℃),与通式(III)的醛反应:
RaCHO(III)。
或者,可以如下从式(II)的化合物制备式(IV)的化合物:
在有碱(诸如二异丙基乙胺)存在下,在合适的溶剂(诸如二氯甲烷或乙腈)中,在一定温度范围内(优选室温至150℃),使用合适的酰化剂/脱水剂(诸如三苯基膦/三氯乙腈),与通式(VI)的化合物反应:
RaCO2H(VI)。
或者,可以如下从式(VII)的化合物制备式(IV)的化合物:
使用合适的脱水剂(诸如Burgess试剂、三苯基膦和六氯乙烷、磷酰氯、醋酸)或Mitsunobu条件(偶氮二羧酸二乙酯/三苯基膦/三甲基叠氮基硅烷),在有或没有合适的溶剂(诸如四氢呋喃、甲苯或NMP)存在下,在一定温度范围内(优选室温至120℃)。
如关于从式(IX)的化合物制备式(I-a)的化合物所述,通过与通式(VI)的羧酸反应,可以从通式(II)的化合物制备通式(VII)的化合物。
方案2
可以如下从通式(XII)的化合物制备通式(I-b)的化合物:
(XII),其中Ra是如在通式(I)中关于R1所定义,
其中Rb是如在通式(I)中关于R2所定义。
根据已知的文献方法(例如WO2006/009741、EP1609789),可以从通式(X)的胺制备通式(XIII)的化合物。
或者,可以如下从通式(XII)的化合物制备通式(I-b)的化合物:使用合适的偶联剂(诸如光气、二光气或三光气),在合适的溶剂(诸如二氯甲烷、甲苯、四氢呋喃或乙腈)中,使用合适的碱(诸如三乙胺、吡啶或二异丙基乙胺),在一定温度范围内(优选0-100℃),与通式(X)的胺反应。
可以如下从通式(V)的化合物制备通式(XII)的化合物:
使用合适的碱(诸如碳酸铯、氢氧化钾、碳酸钾或叔丁醇钠),在有或没有合适的催化剂(诸如碘化亚铜(I)或溴化亚铜(I))和合适的配体(诸如(2,9-二甲基)-1,10-菲咯啉、脯氨酸或1,2-环己基二胺)存在下,与通式(XI)的化合物反应:
可以在合适的溶剂(诸如甲苯、N-甲基吡咯烷酮、甲醇或N,N-二甲基甲酰胺)中,在一定温度范围内(优选40-150℃),进行该反应。
方案3
可以如下从通式(XVI)的化合物制备通式(I-c)的化合物:
如关于从式(XII)的化合物制备式(I-b)的化合物所述,与通式(XIII)或(X)的化合物反应。
根据本领域技术人员已知的方法,通过去保护,可以从通式(XV)的化合物制备通式(XVI)的化合物:
其中Rc可以是合适的保护基或H。
可以如下从通式(V)的化合物制备通式(XV)的化合物:
如关于从式(XI)的化合物制备式(XII)的化合物所述,与通式(XIV)的化合物反应:
方案4
可以如下从通式(XIX)的化合物制备通式(I-d)的化合物:
如关于从式(XII)的化合物制备式(I-b)的化合物所述,与通式(XIII)或(X)的化合物反应。
可以如下从通式(XVIII)的化合物制备通式(XIX)的化合物:
在有催化剂(诸如炭载钯、氧化铂或阮内镍)存在下,在有或没有酸(诸如盐酸或醋酸)存在下,在合适的溶剂(诸如甲醇、乙醇或乙酸乙酯),在一定温度范围内(优选室温至80℃),与合适的还原剂(诸如氯化锡(II)、铁或氢气)反应。
或者,可以如下从通式(V)的化合物制备通式(XIX)的化合物:
在合适的溶剂(诸如四氢呋喃或二乙醚)中,在一定温度范围内(优选-78℃至室温),使通式(XVII)的化合物与合适的金属化的物质(诸如丁基锂、氯化镁或异丙基氯化镁)反应:
其中Rd是H。
如关于从通式(V)的化合物制备通式(XIX)的化合物所述,通过与通式(XVII)的化合物(其中Rd是O)反应,可以从通式(V)的化合物制备通式(XVIII)的化合物。
方案5
可以如下从通式(XXII)的化合物制备通式(I-e)的化合物:
在有或没有合适的催化剂(诸如碘化钾或碘化钠)存在下,在合适的溶剂(诸如二氯甲烷、四氢呋喃或乙腈)中,在一定温度范围内(优选室温至80℃),使用合适的碱(诸如二异丙基乙胺、碳酸钾、碳酸钠或氢化钠),与通式(XXIII)的化合物反应:
根据已知的文献方法(例如Migliara等人Farmaco(1992),47(1),111-19),可以从通式(X)的胺制备通式(XXIII)的化合物。
根据本领域技术人员已知的方法,通过去保护,可以从通式(XXI)的化合物制备通式(XXII)的化合物:
其中Rc是合适的保护基。
如关于从式(XI)的化合物制备式(XII)的化合物所述,通过与通式(XX)的化合物反应,
可以从通式(V)的化合物制备通式(XXI)的化合物:
方案6
如关于从通式(IX)的化合物制备通式(I-a)的化合物所述,通过与式(X)的胺反应,可以从通式(XXVI)的化合物制备通式(I-f)的化合物:
根据本领域技术人员已知的方法,通过去保护,可以从通式(XXV)的化合物制备通式(XXVI)的化合物:
其中R是烷基。
如关于从通式(XI)的化合物制备通式(XII)的化合物所述,通过与通式(V)的化合物反应,可以从通式(XXIV)的化合物制备通式(XXV)的化合物:
方案7
可以如在Chem.Soc.Jpn.,1980,53,2007-11中所述,制备通式(V)的化合物。
方案8
通过与通式(X)的胺反应:
RbNH2(X),
其中Rb是如在上述通式(I)中关于R2所定义,
可以从通式(XXIX)的化合物制备通式(I-g)的化合物:
根据本领域技术人员已知的方法,通过去保护,可以从通式(XXVIII)的化合物制备通式(XXIX)的化合物:
其中Rc是烷基。
可以如下从通式(XXVII)的化合物制备通式(XXVIII)的化合物:
在合适的溶剂(诸如四氢呋喃、DMF或二乙醚)中,在一定温度范围内(优选室温至80℃),使用合适的碱(诸如六甲基二硅胺烷基锂(lithium hexamethyldisilazide)或氢化钠),与合适的化合物RdX(XXXI)反应。
根据本领域技术人员已知的方法,通过与通式(XXX)的醇反应,
RcOH(XXX)
可以从通式(IX)的化合物制备通式(XXVII)的化合物:
其中r是1,Y是S或O,且Ra是如在通式(I)中关于R1所定义。
一般实验细节
在实验部分中使用的缩写:
aq.=含水的;
DCM=二氯甲烷;
DIPEA=二异丙基乙胺;
DMF=N,N-二甲基甲酰胺;
DMSO=二甲亚砜;
EDCI HCl=1-乙基-3-(3'-二甲氨基丙基)碳二亚胺盐酸盐;
EtOAc=乙酸乙酯;
EtOH=乙醇;
FCC=快速柱色谱法;
h=小时;
HOBt=1-羟基-苯并三唑;
HPLC=高效液相色谱法;
LCMS=液相色谱法质谱法;
MeCN=乙腈;
MeOH=甲醇;
min=分钟;
NMR=核磁共振;
RT=室温;
Rt=保留时间;
sat.=饱和的;
SCX-2=强阳离子交换色谱法;
TFA=三氟乙酸;
THF=四氢呋喃。
使用来自MDL Inc的Autonom2000命名软件,指定结构的命名。
除非另有说明,所有反应都在氮气氛下进行。
在Varian Unity Inova400波谱仪(具有运行在400MHz的5mm倒置检测三共振探头)上,或在Bruker Avance DRX400波谱仪(具有运行在400MHz的5mm倒置检测三共振TXI探头)上,或在BrukerAvance DPX300波谱仪(具有运行在300MHz的标准5mm双频率探头)上,得到NMR谱。按照相对于四甲基硅烷的ppm,给出迁移。使用DataChord Spectrum Analyst4.0.b21版,指定NMR谱。
在通过快速柱色谱法纯化产物的情况下,‘快速二氧化硅’表示用于色谱法的硅胶,0.035-0.070mm(220-440目)(例如Fluka硅胶60),并施加高达10p.s.i的氮压力来加速柱洗脱,或使用伴侣(Companion)纯化系统或使用Biotage SP1纯化系统。所有溶剂和商业试剂按照接收时的状态使用。
使用C18-反相柱(100×22.5mm内径,Genesis柱,7μm粒度)、或苯基-己基柱(250x21.2mm内径,Gemini柱,5μm粒度),纯化通过制备型HPLC纯化的化合物,在230或254nm紫外检测,流速5-20mL/min,用100-0至0-100%水/乙腈(含有0.1%TFA或0.1%甲酸)或水/MeOH(含有0.1%TFA或0.1%甲酸)进行梯度洗脱。合并含有目标产物的级分(通过LCMS分析鉴别),通过蒸发,去除有机级分,将剩余的水性级分低压冻干,得到终产物。将通过制备型HPLC纯化的产物分离为甲酸盐或TFA盐,除非另有说明。
使用的液相色谱法质谱法(LCMS)和HPLC系统是:
方法1
具有C18-反相柱(30×4.6mm Phenomenex Luna3μm粒度)的Waters ZMD四极质谱仪,洗脱液为A:水+0.1%甲酸;B:乙腈+0.1%甲酸。梯度:
检测-MS、ELS、UV(200μL分流至具有线内(in-line)紫外检测器的MS)。MS电离方法-电喷雾(正离子和负离子)。
方法2
具有C18-反相柱(30×4.6mm Phenomenex Luna3μm粒度)的Waters Platform LC四极质谱仪,洗脱液为A:水+0.1%甲酸;B:乙腈+0.1%甲酸。梯度:
检测-MS、ELS、UV(200μL分流至具有线内紫外检测器的MS)。MS电离方法-电喷雾(正离子和负离子)。
方法3
Phenomenex Gemini C18-反相柱(250×21.20mm5μm粒度),洗脱液为A:水+0.1%甲酸;B:乙腈+0.1%甲酸。梯度–在15min内95%A/5%B至5%A/95%B,流速18mL/min。检测-设定在220nM波长的线内紫外检测器。
方法4
具有C18-反相柱(100×3.0mm Higgins Clipeus,5μm粒度)的Waters Micromass ZQ2000,洗脱液为A:水+0.1%甲酸;B:乙腈+0.1%甲酸。梯度:
检测-MS、ELS、UV(100μL分流至具有线内紫外检测器的MS)。MS电离方法-电喷雾(正离子)。
方法5
具有C18-反相柱(30×4.6mm Phenomenex Luna3μm粒度)的Waters Platform LC四极质谱仪,洗脱液为A:水+0.1%甲酸;B:甲醇+0.1%甲酸。梯度:
检测-MS、ELS、UV(200μL分流至具有线内HP1100DAD检测器的MS)。MS电离方法-电喷雾(正离子和负离子)。
方法6
Phenomenex Gemini C18-反相柱(250×21.20mm5μm粒度),洗脱液为A:水+0.1%甲酸;B:甲醇+0.1%甲酸。梯度–在15min内95%A/5%B至5%A/95%B,流速18mL/min。检测–设定在254nM波长的线内紫外检测器。
方法7
具有C18-反相柱(100×3.0mm Higgins Clipeus,5μm粒度)的Waters Micromass ZQ2000,洗脱液为A:水+0.1%甲酸;B:甲醇+0.1%甲酸。梯度:
检测-MS、ELS、UV(100μL分流至具有线内紫外检测器的MS)。MS电离方法-电喷雾(正离子)。
方法8
具有C18-反相柱(30×4.6mm Phenomenex Luna3μm粒度)的Waters ZMD四极质谱仪,洗脱液为A:水+0.1%甲酸;B:甲醇+0.1%甲酸。梯度:
检测-MS、ELS、UV(200μL分流至具有线内Waters996DAD检测器的MS)。MS电离方法-电喷雾(正离子和负离子)。
方法9
具有Acquity BEH C18柱(50×2.1mm,1.7μm粒度)的WatersMicromass ZQ2000,洗脱液为A:水+0.1%甲酸;B:甲醇+0.1%甲酸。梯度:
检测-MS、UV PDA。MS电离方法-电喷雾(正离子/负离子)。
方法10
具有C18-反相柱(100×3.0mm Higgins Clipeus,5μm粒度)的Waters Quatro Microtriple四极质谱仪,洗脱液为A:水+0.1%甲酸;B:甲醇+0.1%甲酸。梯度:
检测-MS、ELS、UV(100μL分流至具有线内紫外检测器的MS)。MS电离方法-电喷雾(正离子/负离子)。
方法11
具有C18-反相柱(Acquity BEH C18反相柱,1.7um,100x2.1mm)的Waters ZMD四极质谱仪,洗脱液为A:水+0.1%甲酸;B:乙腈+0.1%甲酸。梯度:
检测-MS、UV PDA。MS电离方法-电喷雾(正离子/负离子)。
实施例1
N-环丙基甲基-3-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基}-苯甲酰胺
a.N-(5-碘-吡啶-2-基)-N'-[1-[3-(2-吗啉-4-基-乙氧基)-苯基]-亚甲-(E)-基]-肼
向5-碘-2-肼基吡啶(6.62g,0.028mmol)在EtOH(90mL)中的悬浮液中,加入3-(2-吗啉-4-基-乙氧基)-苯甲醛(6.63g,0.028mmol)。将反应物在氮下在回流下加热2h,然后冷却至室温。通过过滤,收集得到的沉淀,并用EtOH洗涤,得到标题化合物(10.93g,86%),为白色固体。LCMS(方法1):Rt2.37min,m/z453[MH+]。1H NMR(300MHz,CD3OD):δ8.24(1H,d,J2.2),7.90-7.84(2H,m),7.36-7.18(3H,m),7.12(1H,d,J8.8),6.94-6.89(1H,m),4.19(2H,t,J5.4),3.72(4H,t,J4.6),2.83(2H,t,J5.4),2.62(4H,t,J4.6)。
b.6-碘-3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶
向实施例1步骤a(10.93g,24.16mmol)在DCM(100mL)/EtOH(15mL)中的溶液中,加入PhI(OAc)2(10.74g,33.35mmol)。将反应物在室温搅拌72h,用DCM(25mL)稀释,然后用氢氧化钠水溶液(1M,25mL)和盐水(25mL)洗涤。干燥(MgSO4)有机层,过滤,并在真空中浓缩滤液。与Et2O(10mL)一起研磨残余物,通过过滤,收集得到的固体,得到标题化合物(9.98g,92%),为灰白色固体。LCMS(方法1):Rt2.11min,m/z451[MH+]。1H NMR(400MHz,DMSO-d6):δ8.69(1H,s),7.71(1H,d,J9.5),7.60(1H,d,J9.5),7.53(1H,t,J7.9),7.47-7.41(2H,m),7.18(1H,d,J8.1),4.21(2H,t,J5.7),3.59(4H,t,J4.5),2.75(2H,t,J5.7),2.45(4H,m)。
c.3-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基}-苯甲酸
给反应器装入实施例1步骤b(400mg,0.888mmol)、3-巯基苯甲酸(205mg,1.24mmol)、[1,1'-二(二苯基膦基)二茂铁]二氯钯(II)与DCM的1:1络合物(138mg,0.168mmol)、碳酸铯(578mg,1.777mmol)和DMF(3mL)。在氩下将反应物脱气(x3)。将反应物在90℃加热24h,然后冷却至室温,过滤,在真空中浓缩滤液,得到标题化合物(422mg,定量)。LCMS(方法2):Rt2.20min,m/z477[MH+]。
d.N-环丙基甲基-3-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基}-苯甲酰胺
给反应器装入实施例1步骤c(213mg,0.447mmol)、环丙烷甲胺(32mg,0.447mmol)、HATU(212mg,0.558mmol)和DMF(3mL)。加入DIPEA(225μL,1.34mmol),将反应物在室温搅拌24h然后在真空中浓缩,并通过反相制备型HPLC(方法3)直接地纯化粗残余物,得到标题化合物(92mg,39%),为灰白色固体。LCMS(方法4):Rt6.55min,m/z530[MH+]。1HNMR(400MHz,CDCl3):δ8.39(1H,s),7.89(1H,s),7.75-7.65(2H,m),7.51-7.30(5H,m),7.17(1H,d,J9.6),7.08(1H,d,J8.4),6.85(1H,m),4.25(2H,t,J5.2),3.79(4H,t,J4.4),3.26(2H,t,J6.2),3.00(2H,t,J5.2),2.77(4H,m),1.07-0.95(1H,m),0.52-0.44(2H,m),0.24-0.18(2H,m)。
使用与在实施例1中使用的方法类似的方法,制备下面的实施例。
实施例10
1-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-3-(4-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基}-苯基)-脲
a.3-(6-溴-[1,2,4]三唑并[4,3-a]吡啶-3-基)-苯酚
将三溴化硼(1M在DCM中,13.1mL,13.1mmol)缓慢地加入在-78℃的搅拌的3-(3-苄氧基-苯基)-6-溴-[1,2,4]三唑并[4,3-a]吡啶(1g,2.63mmol)在DCM(5mL)中的溶液中。使反应物温热至室温,搅拌24h,并用饱和NaHCO3溶液处理,直到pH>7。用DCM:MeOH9:1(mL)萃取产物,干燥(MgSO4),并在真空中浓缩。通过FCC(DCM:MeOH,1:0至9:1)纯化粗残余物,得到标题化合物(350mg,46%),为黄色固体。LCMS(方法2):Rt2.65min,m/z290和292[MH+]。
b.6-溴-3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶
将实施例10步骤a(250mg,1.21mmol)、N-(2-溴乙基)吗啉盐酸盐(306mg,1.32mmol)和K2CO3(500mg,3.62mmol)在DMF(20mL)中的混合物在50℃加热24h。然后将反应物冷却至室温,并在真空中浓缩。通过FCC(DCM:MeOH,1:0至9:1)纯化残余物,得到标题化合物(479mg,98%),为黄色油。1HNMR(300MHz,CDCl3):δ8.44(1H,dd,J1.7,1),7.74-7.69(1H,m),7.50(1H,t,J7.9),7.39-7.35(2H,m),7.35-7.30(1H,m),7.14-7.08(1H,m),4.21(2H,t,J5.6),3.74(4H,t,J4.6),2.85(2H,t,J5.6),2.63-2.56(4H,m)。
c.4-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基}-苯胺
以与实施例1步骤c类似的方式,使用实施例10步骤b和4-氨基-苯-硫醇,制备标题化合物。LCMS(方法2):Rt2.14min,m/z448[MH+]。
d.1-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-3-(4-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基}-苯基)-脲
将实施例10步骤c(315mg,0.703mmol)、5-(2,2,2-三氯乙氧基羰基)氨基-3-叔丁基-1-对甲苯基-1H-吡唑(299mg,0.703mmol)和DIPEA(116μL,0.675mmol)在DMSO(3mL)中的混合物在55℃加热24h。在真空中浓缩反应物,并通过反相制备型HPLC(方法3)纯化残余物,得到标题化合物(202mg,41%),为灰白色固体。LCMS(方法4):Rt8.46min,m/z703[MH+]。1H NMR(400MHz,CDCl3):δ9.30(1H,br s),8.34(1H,br s),8.16(1H,s),7.49-7.41(3H,m),7.37(1H,d,J9.6),7.29(2H,d,J8.4),7.25-7.20(2H,m),7.18(2H,d,J8),7.09-7.04(2H,m),6.90(2H,d,J8),6.44(1H,s),4.15(2H,t,J5.4),3.72(4H,t,J4.5),2.88(2H,t,J5.4),2.64(4H,t,J4.4),2.11(3H,s),1.30(9H,s)。
使用与在实施例10(步骤c-d)中使用的方法类似的方法,制备下述实施例:
实施例12
1-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-3-(6-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基}-吡啶-3-基)-脲
a.3-[3-(2-吗啉-4-基-乙氧基)-苯基]-6-(5-硝基-吡啶-2-基硫烷基)-[1,2,4]三唑并[4,3-a]吡啶
向在0℃的实施例1步骤b(300mg,0.67mmol)在THF(5mL)中的溶液中,逐滴加入在Et2O(335μL,0.67mmol)中的2M异丙基氯化镁。将反应物在0℃搅拌1h,然后加入2,2’-二硫二(5-硝基-吡啶)(227mg,0.73mmol)。使反应物温热至室温,并搅拌另外1h,然后用EtOAc(10mL)稀释。用1M NaOH(10mL)、盐水(10mL)洗涤有机层,干燥(MgSO4),并在真空中浓缩。通过反相制备型HPLC(方法3)进行纯化,得到标题化合物(50mg,16%),为黄色固体。LCMS(方法1):Rt2.33min,m/z479[MH+]。1H NMR(400MHz,CD3OD):δ9.16(1H,d,J2.6),8.80(1H,t,J1.2),8.41(1H,dd,J8.9,2.7),7.90(1H,dd,J9.6,1),7.60-7.53(2H,m),7.50-7.45(3H,m),7.25-7.20(1H,m),4.27(2H,t,J5.4),3.73(4H,t,J4.7),2.94(2H,t,J5.4),2.70(4H,t,J4.5)。
b.6-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基}-吡啶-3-基胺
将实施例12步骤a(50mg,0.11mmol)溶解于EtOH(10mL)中,并用Pd/C(10%)(10mg)处理。在氢气氛下在室温搅拌反应物72h。在氮下过滤催化剂,在真空中浓缩滤液,得到标题化合物(31mg,66%)。LCMS(方法1):Rt1.94min,m/z449[MH+]。
c.1-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-3-(6-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基}-吡啶-3-基)-脲
以与实施例10步骤d类似的方式,使用实施例12步骤b,制备标题化合物。LCMS(方法4):Rt8.06min,m/z704[MH+]。1H NMR(400MHz,CDCl3):δ8.70(1H,br s),8.57(1H,s),8.25(1H,dd,J8.7,2.7),7.99(1H,d,J2.7),7.73(1H,br s),7.63(1H,d,J9.5),7.47(1H,t,J8),7.35-7.23(6H,m),7.09(1H,dd,J8.4,2.5),7.04(2H,d,J8),6.45(1H,s),4.20(2H,t,J5.4),3.73(4H,t,J4.6),2.91(2H,t,J5.4),2.67(4H,s),2.22(3H,s),1.34(9H,s)。
实施例13
1-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-3-(5-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基}-吡啶-2-基)-脲
a.5-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基}-吡啶-2-基胺
以与实施例1步骤c类似的方式,使用2-氨基-5-巯基吡啶二盐酸盐,制备标题化合物。LCMS(方法1):Rt1.77min,m/z449[MH+]。
b.1-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-3-(5-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基}-吡啶-2-基)-脲
以与实施例10步骤d类似的方式,使用实施例13步骤a,制备标题化合物。LCMS(方法4):Rt8.25min,m/z704[MH+]。1H NMR(400MHz,CD3OD):δ8.31(1H,s),7.84(1H,dd,J8.7,2.4),7.81-7.77(1H,m),7.74(1H,d,J2.4),7.55(1H,t,J7.9),7.41-7.33(5H,m),7.30(2H,d,J8.1),7.22(1H,dd,J8.4,2.4),7.03(1H,d,J8.6),6.51(1H,s),4.26(2H,t,J5.4),3.75(4H,t,J4.6),2.97(2H,t,J5.4),2.74(4H,t,J4.6),2.26(3H,s),1.34(9H,s)。
实施例14
1-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-3-(反式-4-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基}-环己基)-脲
a.(反式-4-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基}-环己基)-氨基甲酸叔丁酯
在氩气氛下,将实施例1步骤b(234mg,0.52mmol)、碘化亚铜(I)(9mg,0.052mmol)、1,10-菲咯啉(19mg,0.104mmol)、碳酸铯(335mg,1.04mmol)和反式-4-boc-氨基环己醇(560mg,2.6mmol)在甲苯(3mL)中的混合物在110℃加热72h。将悬浮液冷却至室温,用EtOAc(10mL)稀释,并通过HiFlo进行过滤。在真空中浓缩滤液,通过反相制备型HPLC(方法3)纯化残余物,得到标题化合物(205mg,39%),为灰白色固体。LCMS(方法2):Rt2.53min,m/z538[MH+]。
b.反式-4-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基}-环己基胺三氟乙酸盐
将实施例14步骤a(196mg,0.178mmol)在TFA(2mL)和DCM(10mL)中的溶液在室温搅拌0.5h,然后在真空中浓缩,得到标题化合物(定量产率)。LCMS(方法2):Rt0.38min,m/z438[M-CF3CO2 +]。
c.1-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-3-(反式-4-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基}-环己基)-脲
以与实施例10步骤d类似的方式,使用实施例14步骤b,制备标题化合物。LCMS(方法4):Rt7.84min,m/z693[MH+]。1H NMR(400MHz,CDCl3):δ7.76(1H,d,J2),7.61(1H,d,J9.9),7.47(1H,t,J8.1),7.34-7.27(4H,m),7.13(2H,d,J8.1),7.10-7.03(2H,m),6.86(1H,s),6.28(1H,s),5.49(1H,d,J7.6),4.19(2H,t,J5.4),4.06-3.97(1H,m),3.76-3.67(5H,m),2.88(2H,t,J5.4),2.62(4H,t,J4.4),2.29(3H,s),2.07(4H,d,J11.4),1.65-1.53(2H,m),1.33(9H,s),1.29-1.16(2H,m)。
使用与在实施例14中使用的方法类似的方法,制备下面的实施例。
实施例17
N-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-2-(4-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基}-哌啶-1-基)-乙酰胺
a.3-[3-(2-吗啉-4-基-乙氧基)-苯基]-6-(哌啶-4-基氧基)-[1,2,4]三唑并[4,3-a]吡啶
以与实施例14步骤a-b类似的方式,使用N-Boc-4-羟基哌啶,制备标题化合物,随后在SCX-2柱上纯化。LCMS(方法5):Rt0.38,1.87min,m/z424[MH+]。
b.N-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-2-氯-乙酰胺
将5-叔丁基-2-对甲苯基-2H-吡唑-3-基胺(886mg,3.86mmol)、吡啶(465μL,5.80mmol)和氯乙酰氯(462μL,5.80mmol)在DCM(5mL)中的溶液在室温搅拌2h。用饱和碳酸氢钠水溶液和DCM稀释反应混合物,并用DCM萃取得到的水层2次。干燥(MgSO4)合并的有机层,并在真空中浓缩,得到标题化合物(1.17g,100%),为黄色固体。LCMS(方法5):Rt4.41min,m/z306[MH+]。
c.N-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-2-(4-{3-[3-(2-吗啉-4-基-乙氧基)-苯基]-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基}-哌啶-1-基)-乙酰胺
将实施例17步骤a(32mg,0.076mmol)、实施例17步骤b(23mg,0.076mmol)、碘化钾(4mg,0.002mmol)和碳酸钾(13mg,0.091mmol)在乙腈(5mL)中的溶液加热至回流2.5h。使反应混合物冷却至室温,在真空中浓缩,并通过反相制备型HPLC(方法6)纯化2次,得到标题化合物(5mg,9%),为白色固体。LCMS(方法4):δRt6.21min,m/z693[MH+]。1H NMR(400MHz,CD3OD):7.92(1H,d,J2.0),7.76(1H,d,J9.9),7.58(1H,t,J8.1),7.43-7.32(7H,m),7.22(1H,dd,J8.4,2.3),6.51(1H,s),4.36-4.29(1H,m),4.26(2H,t,J5.4),3.72(4H,t,J4.6),3.10(2H,s),2.89(2H,t,J5.4),2.72-2.62(6H,m),2.44-2.32(5H,m),1.85(2H,m),1.61-1.53(2H,m),1.33(9H,s)。
实施例18
N-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-2-{4-[3-(3-羟基-苯基)-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基]-苯基}-乙酰胺
以与实施例10步骤a类似的方式,使用实施例8,制备标题化合物。LCMS(方法7):Rt12.01min,m/z589[MH+]。1H NMR(400MHz,CD3OD):δ8.35(1H,t,J1.2),7.74(1H,dd,J9.6,1.0),7.45-7.36(1H,m),7.37-7.32(3H,m),7.24-7.20(4H,m),7.25-7.07(4H,m),6.99(1H,ddd,J8.2,2.4,1.1),6.32(1H,s),3.58(2H,s),2.31(3H,s),1.31(9H,s)。
实施例19
N-{5-叔丁基-2-[4-(2-吗啉-4-基-乙氧基)-苯基]-2H-吡唑-3-基}-2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基)-苯基]-乙酰胺
a.5-叔丁基-2-[4-(2-吗啉-4-基-乙氧基)-苯基]-2H-吡唑-3-基胺
在氮气氛下,用偶氮二羧酸二异丙酯(0.808mg,4mmol)处理4-(5-氨基-3-叔丁基-吡唑-1-基)-苯酚(WO2005/110994,0.462g,2mmol)、2-吗啉-4-基-乙醇(0.327g,2.5mmol)和三苯基膦(1.05g,4mmol)在THF(5mL)中的溶液。将反应混合物在室温搅拌16h,然后用二乙醚稀释。用水洗涤有机层。用碳酸钾碱化得到的水层,并用EtOAc萃取。用柠檬酸水溶液洗涤得到的有机层,并用碳酸钾碱化得到的水层,用EtOAc萃取(3次)。干燥得到的有机层(Na2SO4),蒸发至干燥,然后与二乙醚(10mL)一起声处理,并过滤,得到标题化合物(0.297g,43%),为白色固体。LCMS(方法5):Rt0.41,2.16min,m/z345[MH+]。1H NMR(400MHz,CDCl3):δ7.46-7.39(2H,m),6.98-6.93(2H,m),5.50(1H,s),4.15-4.08(2H,m),3.75(4H,t,J4.5),3.63(2H,bs),2.83-2.78(2H,m),2.59(4H,t,J4.3),1.34-1.26(9H,m)。
b.N-{5-叔丁基-2-[4-(2-吗啉-4-基-乙氧基)-苯基]-2H-吡唑-3-基}-2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基)-苯基]-乙酰胺
以与实施例1步骤c-d类似的方式,使用3-巯基乙酸和实施例19步骤a,制备标题化合物。LCMS(方法7):Rt9.09min,m/z654[MH+]。1HNMR(400MHz,CDCl3):8.12(1H,s),7.70(1H,d,J9.6),7.22(2H,d,J8.0),7.20-7.09(5H,m),7.12-7.05(1H,m),6.93-6.86(2H,m),6.57(1H,s),4.17(2H,t,J5.7),3.73(4H,t,J4.5),3.64(2H,s),3.41-3.32(1H,m),2.84(2H,t,J5.7),2.59(4H,t,J4.4),1.56(3H,s),1.54(3H,s),1.32(9H,s)。
实施例20
N-[5-叔丁基-2-(4-羟基-苯基)-2H-吡唑-3-基]-2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基)-苯基]-乙酰胺
a.N-{5-叔丁基-2-[4-(叔丁基-二甲基-硅烷氧基)-苯基]-2H-吡唑-3-基}-2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基)-苯基]-乙酰胺
以与实施例19步骤b类似的方式,使用5-叔丁基-2-[4-(叔丁基-二甲基-硅烷氧基)-苯基]-2H-吡唑-3-基胺(US2006/035922),制备标题化合物。LCMS(方法5):Rt4.96min,m/z655[MH+]。1H NMR(300MHz,CD3OD):δ8.47(1H,s),7.65(1H,dd,J=9.60,1.01Hz),7.35-7.24(3H,m),7.22-7.17(4H,m),6.89-6.84(2H,m),6.30(1H,s),3.59(2H,s),2.99(1H,m),1.48(3H,s),1.45(3H,s),1.30(9H,s),0.99(9H,s),0.20(6H,s)。
b.N-[5-叔丁基-2-(4-羟基-苯基)-2H-吡唑-3-基]-2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基)-苯基]-乙酰胺
将实施例20步骤a(80mg,0.12mmol)和三乙胺三氢氟化物(40mg,0.24mmol)在THF(2mL)中的溶液在室温搅拌24h,然后用EtOAc稀释,用饱和碳酸氢钠水溶液洗涤,干燥(Na2SO4),并蒸发。通过FCC(DCM/MeOH100/0至95/5)纯化残余物,溶解于EtOAc中,用柠檬酸水溶液和盐水洗涤,干燥(Na2SO4),在40℃在真空中蒸发和干燥,得到标题化合物(45mg,68%),为粉红色的固体。LCMS(方法7):Rt11.15min,m/z541[MH+]。1H NMR(400MHz,CDCl3):δ8.23(1H,s),7.91(1H,s),7.74(1H,d,J9.5),7.25-7.14(5H,m),7.05(2H,d,J8.4),6.85(2H,t,J8.6),6.51(1H,s),3.64(2H,s),3.47-3.38(1H,m),1.55(3H,s),1.53(3H,s),1.31(9H,s)。
实施例21
1-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-3-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基)-环己基]-脲
a.异丁酸N'-(5-氟-吡啶-2-基)-酰肼
用EDCI HCl(1.15g,6mmol)处理5-氟-2-肼基-吡啶(0.59g,4.65mmol)、异丁酸(528mg,6mmol)和HOBt水合物(153mg,1mmol)在DCM(10mL)中的溶液。将反应混合物在室温搅拌40min,倒到饱和碳酸氢钠水溶液(40mL)上,用4份DCM萃取,干燥(Na2SO4),蒸发,并通过FCC(DCM/EtOAc9/1至3/7)进行纯化,得到标题化合物(0.42g,46%)。LCMS(方法8):Rt2.46min,m/z198[MH+]。
b.6-氟-3-异丙基-[1,2,4]三唑并[4,3-a]吡啶
用1,2-六氯乙烷(690mg,2.91mmol)处理在0℃的实施例21步骤a(0.41g,2.08mmol)、三苯基膦(763mg,2.91mmol)和三乙胺(0.87mL,6.24mmol)在THF(5mL)中的溶液。将反应混合物在0℃搅拌40min,然后在室温搅拌20min,用水淬灭,用EtOAc萃取2次,干燥(Na2SO4),蒸发,并通过FCC(环己烷/EtOAc1/0至1/1)纯化2次,得到标题化合物(274mg,含有20%PPh3O,58%),为白色固体。LCMS(方法5):Rt2.58min,m/z180[MH+]。
c.4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基)-环己基胺
在氩下在80℃加热反式-4-氨基-环己醇(402mg,3.6mmol)和叔丁醇钾(395mg,3.6mmol)在甲苯(1mL)和1,3-二甲基-3,4,5,6-四氢-2(1H)-嘧啶酮(0.5mL)中的溶液20min,然后用实施例21步骤b(274mg,含有20%PPh3O,1.2mmol)处理。将反应混合物搅拌1h,用水淬灭,并用3份EtOAc萃取。在SCX柱(MeOH至在MeOH中的1N NH3)上纯化水层和合并的有机层,并通过FCC(DCM/含有0.1%NH3的MeOH100/0至85/15)纯化得到的残余物,得到标题化合物(235mg,71%)。LCMS(方法5):Rt1.86min,m/z275[MH+]。
d.1-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-3-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基)-环己基]-脲
以与实施例10步骤d类似的方式,从实施例21步骤c开始,并使用二烷替代DMSO,制备标题化合物。LCMS(方法7):Rt11.66min,m/z530[MH+]。1H NMR(400MHz,CDCl3):δ7.60(1H,d,J9.9),7.37(1H,s),7.34(2H,d,J8.2),7.19(2H,d,J8.1),7.03(1H,dd,J9.9,2.0),6.37(1H,s),6.23(1H,s),5.12(1H,d,J7.5),4.07(1H,m),3.73(1H,m),3.31-3.22(1H,m),2.34(3H,s),2.12-2.05(4H,m),1.68-1.56(2H,m),1.51(3H,s),1.49(3H,s),1.54-1.31(2H,m),1.34(9H,s)。
实施例22
N-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基)-环己基]-乙酰胺
a.[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基)-环己基]-乙酸乙酯
以与实施例21步骤c类似的方式,从反式-(4-羟基-环己基)-乙酸乙酯开始,制备标题化合物(Krieg等人,Journal fuer Praktische Chemie1987,329(6),1123-30))。LCMS(方法5):Rt4.16-4.23min,m/z346[MH+]。
b.[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基)-环己基]-乙酸
将实施例22步骤a(50mg,0.145mmol)和1N氢氧化钠(0.5mL,0.5mmol)在MeOH(2mL)中的溶液在室温搅拌16h。用饱和碳酸氢钠水溶液处理反应混合物,蒸发至干燥,并在反相FCC(水/MeOH100/0至0/100)上纯化,得到2个级分。用1N HCl溶液,将第一个洗脱级分酸化至pH5,并用EtOAc萃取。干燥(MgSO4)有机层,过滤,与来自色谱法的第二个洗脱级分组合,并在真空中浓缩。将得到的残余物溶解于MeOH/EtOAc(1:1,10mL)中,过滤,并蒸发至干燥,得到标题化合物,为淡褐色固体(27mg,59%)。LCMS(方法5):Rt3.58-3.65min,m/z318[MH+]。
c.N-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基)-环己基]-乙酰胺
以与实施例1步骤d类似的方式,从实施例22步骤b开始,制备标题化合物。LCMS(方法10):Rt11.59min,m/z529[MH+]。1H NMR(400MHz,CDCl3):δ7.67(1H,d,J9.9),7.38(1H,s),7.36-7.25(4H,m),7.20(1H,m),7.04(1H,dd,J9.8,2.0),6.60(1H,s),4.10-3.98(1H,m),3.3.28(1H,m),2.41(3H,s),2.21(2H,d,J6.5),2.16(3H,m),1.93(4H,m),1.52(3H,s),1.51(3H,s),1.34(9H,s),1.23-1.07(2H,m)。
实施例23
N-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基)-苯基]-乙酰胺
a.6-碘-3-异丙基-[1,2,4]三唑并[4,3-a]吡啶
以与实施例1步骤a-b类似的方式,使用2-甲基-丙醛,制备标题化合物。LCMS(方法5):Rt3.43min,m/z288[MH+]。1H NMR(300MHz,CD3OD):8.75(1H,s),7.58(1H,dd,J9.6,1.5),7.52(1H,dd,J9.6,1.1),3.68-3.49(1H,m),1.50(3H,s),1.47(3H,s)。
b.2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基)-苯基]-乙酰胺
将实施例23步骤a(430mg,1.5mmol)、2-(4-羟基苯基)乙酸叔丁酯(WO2008/024746,621mg,3mmol)、碳酸铯(978mg,3mmol)、氯化亚铜(I)(74mg,0.75mmol)和2,2,6,6-四甲基庚二酮(28mg,0.15mmol)在N-甲基吡咯烷酮(2mL)中的溶液在115℃加热1h。将反应混合物冷却至室温,用二乙醚稀释,并用水洗涤。用EtOAc和DCM萃取水层,干燥(Na2SO4)合并的有机层,过滤,并在真空中浓缩。在SCX-2柱上纯化得到的油,用EtOAc、MeOH、然后用在MeOH中的1N氨洗脱。在真空中浓缩氨级分,通过FCC(DCM/含有NH3的MeOH10/0至9/1,然后使用EtOAc)纯化2次,得到标题化合物,为橙色胶(44mg,8%)。LCMS(方法8):Rt4.30min,m/z368[MH+]。
c.[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基)-苯基]-乙酸
将实施例23步骤b(44mg,0.12mmol)、TFA(1mL)和茴香醚(1mL)在DCM(1mL)中的溶液在室温搅拌1h,然后在真空中蒸发。将得到的残余物悬浮于二乙醚(3mL)中,过滤,并在真空中干燥,得到标题化合物(38mg,定量)。LCMS(方法5):Rt3.65min,m/z312[MH+]。
d.N-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基)-苯基]-乙酰胺
以与实施例1步骤d类似的方式,从实施例23步骤c开始,制备标题化合物。LCMS(方法10):Rt11.60min,m/z523[MH+]。1H NMR(400MHz,CDCl3):7.77(1H,d,J9.9),7.66(1H,s),7.29(1H,s),7.26-7.15(4H,m),7.14(2H,d,J8.1),7.05(1H,dd,J9.9,2.0),6.98(2H,d,J8.1),6.60(1H,s),3.67(2H,s),3.27(1H,m),2.39(3H,s),1.52(3H,s),1.50(3H,s),1.33(9H,s)。
实施例24
N-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基)-苯基]-丙酰胺
a.[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基)-苯基]-乙酸甲酯
向4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基)-苯基]-乙酸(以与实施例1步骤c类似的方式制备)(209mg,0.639mmol)在MeOH(20mL)中的溶液中,加入浓缩HCl(25μL),将反应物回流搅拌5h。将反应物冷却至室温,在真空中浓缩,在DCM(5mL)和饱和NaHCO3(5mL)之间分配,分离有机层,干燥(MgSO4),并在真空中浓缩,得到标题化合物(218mg)。LCMS(方法1):Rt3.04min,m/z342[MH+]。
b.2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基)-苯基]-丙酸甲酯
将来自实施例24步骤b的产物(218mg,0.637mmol)在THF(5mL)中的溶液冷却至0℃,加入LiHMDS(1M在己烷中,702μL,0.702mmol)。10min后,加入碘代甲烷(43μL,0.702mmol),并在0℃继续搅拌0.5h,然后缓慢地温热至室温,同时搅拌过夜。用饱和NH4Cl溶液(5mL)淬灭反应物,用Et2O(2x10mL)萃取,干燥(MgSO4),并在真空中浓缩。使用0-10%DCM/MeOH,通过色谱法进行纯化,得到标题化合物(69.2mg,30%)。LCMS(方法1):Rt3.25min,m/z356[MH+]。
c.2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基)-苯基]-丙酸
将来自实施例24步骤c的产物(69.2mg,0.194mmol)在1M NaOH(1mL)和MeOH(2mL)中的溶液在室温搅拌3.5h。用醋酸(1mL)淬灭反应物,并在真空中浓缩,得到标题化合物。LCMS(方法1):Rt3.11min,m/z342[MH+]。
d.N-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基)-苯基]-丙酰胺
以与实施例1步骤d类似的方式,从实施例24步骤c开始,制备标题化合物。LCMS(方法4):Rt5.25min,m/z553[MH+]。1H NMR(400MHz,MeOD):δ8.53(1H,dd,J1.6,1.0Hz),7.66(1H,dd,J9.5,1.0Hz),7.34(2H,m),7.31(1H,dd,J9.5,1.6Hz),7.23(2H,m),7.09(4H,s),6.27(1H,s),3.72(1H,q,J7.1Hz),3.55(1H,m),2.31(3H,s),1.47(6H,2x d,J6.9Hz),1.40(3H,d,J7.1Hz),1.30(9H,s)。
实施例25
1-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-3-[4-(3-环戊基-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基)-环己基]-脲
以与实施例21类似的方式,制备标题化合物。LCMS(方法11):Rt4.59min,m/z555[M+]。1H NMR(400MHz,MeOD):δ7.88(1H,dd,J2.1,0.8),7.60(1H,dd,J9.9,0.8),7.30(4H,m),7.25(1H,dd,9.9,2.1),6.27(1H,s),4.32(1H,m),3.57(2H,m),2.38(3H,s),2.20(2H,m),2.10(2H,m),1.87(9H,m),1.56(2H,m),1.35(1H,m),1.28(9H,s)。
实施例26
1-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基)-环己基]-3-[5-(1-甲基-1-甲基硫烷基-乙基)-2-对甲苯基-2H-吡唑-3-基]-脲
以与实施例1步骤d类似的方式,从实施例21步骤c开始,制备标题化合物。LCMS(方法11):Rt4.59min,m/z561[M+]。1H NMR(400MHz,MeOD):δ7.85(1H,dd,J2.1,0.8),7.57(1H,dd,J9.9,0.8),7.30(4H,m),7.21(1H,dd,9.9,2.1),6.41(1H,s),4.32(1H,m),3.56(1H,m),(1H,sept.,J6.9),2.38(3H,s),2.11(2H,m),1.98(2H,m),1.91(3H,s),1.61(6H,s),1.56(2H,m),1.42(6H,d,J6.9),1.35(3H,m)。
实施例27
N-{5-叔丁基-2-[3-(2-吡啶-4-基-乙氧基)-苯基]-2H-吡唑-3-基}-2-[4-(3-异丙基-[1,2,4]三唑并[4,3-a]吡啶-6-基硫烷基)-苯基]-乙酰胺
以与实施例1步骤d类似的方式,制备标题化合物。LCMS(方法11):Rt3.81min,m/z646[MH+]。1H NMR(400MHz,CDCl3):δ8.53-8.49(2H,m),8.04(1H,s),7.64(1H,d,J9.6),7.26(1H,s NH),7.24-7.10(7H,m),7.02(1H,dd,J9.6,1.6),6.87(1H,t,J2.4),6.82(1H,ddd,J8.4,2.4,1.0),6.63(1H,d,J7.9),6.57(1H,s),4.19(2H,t,J6.4),3.62(2H,s),2.36-3.28(1H,m),3.08(2H,t,J6.4),1.51(6H,d,6.9),1.29(9H,s)。
实施例28
使用与在实施例1中使用的方法类似的方法,制备实施例28。LCMS(方法11):Rt5.12min,m/z525[MH+]。1H NMR(400MHz,CDCl3):δ1.36(9H,s),1.54(6H,d,J8Hz),2.41(3H,s),3.37(1H,q,J8Hz),6.71(1H,s),7.12-7.16(1H,m),7.28-7.33(2H,m),7.35-7.46(5H,m),6.68-7.73(1H,m),7.78(1H,s),7.91(1H,s),8.12(1H,s)。
实施例29
1-(5-叔丁基-2-对甲苯基-2H-吡唑-3-基)-3-[4-(3-吡啶-2-基-[1,2,4]三唑并[4,3-a]吡啶-6-基氧基)-环己基]-脲
以与实施例10步骤d类似的方式,使用二烷替代DMSO,并在80℃加热,制备标题化合物。LCMS(方法7):Rt4.95min,m/z565[MH+]。1H NMR(400MHz,DMSO):δ.9.36(1H,dd,J2.3,0.8),8.74(1H,ddd,J4.9,1.8,1.1),8.34(1H,dt,J8.1,1.1,1.1),8.03-7.97(1H,m),7.91(1H,s,NH),7.86(1H,dd,J9.8,0.8),7.48(1H,ddd,J7.5,4.9,1.1),7.37(1H,dd,J9.8,2.3),7.31-7.24(4H,m),6.52(1H,d,J7.4NH),6.21(1H,s),4.34-4.24(1H,m),3.52-3.40(1H,m),2.32(3H,s),2.12-2.00(2H,m),1.92-1.84(2H,m),1.56-1.44(2H,m),1.34-1.22(2H,m),1.20(9H,s)。
生物学试验
p38激酶试验
将人重组p38酶(在大肠杆菌中表达,并通过与MKK6酶(Calbiochem#559324)一起温育进行活化)用作酶活性的来源。
在已经用重组ATF-2(Biosource#PHF0043)包被的高结合的、澄清的、平底96孔试验板中进行试验。与p38激酶一起温育实验化合物2h,然后如下开始激酶试验:加入ATP,以得到250μM的试验浓度。使用ELISA,检测和定量ATF-2的磷酸化。这包括,在有抗-磷酸-ATF2、生物素化的抗-IgG和链霉抗生物素-HRP存在下的连续温育。与HRP生色底物(TMB)一起温育,带来与产生的磷酸化的底物的量成比例的吸光度。使用多孔板读数器,检测吸光度。
在DMSO中稀释化合物,然后加入到试验缓冲液中,试验中的最终DMSO浓度是1%。
将IC50定义为特定化合物实现对照的50%抑制时的浓度。
结果如表1所示:
表1
实施例 | p38α抑制 |
实施例1 | + |
实施例2 | ++ |
实施例3 | ++ |
实施例4 | ++++ |
实施例5 | ++ |
实施例6 | ++++ |
实施例7 | ++++ |
实施例8 | +++ |
实施例9 | +++ |
实施例10 | +++ |
实施例11 | + |
实施例12 | +++ |
实施例13 | ++ |
实施例14 | +++ |
实施例15 | ++ |
实施例16 | +++ |
实施例17 | + |
实施例18 | ++++ |
实施例19 | + |
实施例20 | +++ |
实施例21 | +++ |
实施例22 | + |
实施例23 | ++++ |
实施例24 | ++ |
实施例25 | ++++ |
实施例26 | +++ |
实施例27 | +++ |
实施例28 | +++ |
实施例29 | +++ |
在上面的表1中,如下指示p38α结合效力(IC50值):<2000-500nM‘+’;<500-100nM‘++’;10-<100nM‘+++’;<10nM‘++++’。测试的所有化合物表现出<2000nM的IC50值;NT:未测试。
p38功能试验
细胞p38的抑制减少TNFα的释放,该功能响应可以通过测量LPS活化的THP-1细胞(一种无限增殖化的单核细胞的细胞系)或从新鲜抽取的人血分离的外周血单核细胞(PBMC)的上清液中TNFα的量来定量。
如下预处理接种在96孔平板中的细胞:加入p38抑制剂1h,随后加入脂多糖(LPS),以活化细胞因子生产和释放。按照生产商的说明书,使用R&D Systems酶联免疫吸附测定(ELISA)试剂盒(产品DY210),定量释放进细胞上清液中的TNFα的量。
在加入之前,在DMSO中稀释化合物,试验中最终的DMSO浓度是0.3%。将EC50定义为给定的化合物达到对照的50%抑制时的浓度。
结果如表2所示:
表2
实施例 | EC50 |
实施例1 | + |
实施例2 | ++ |
实施例3 | +++ |
实施例4 | +++ |
实施例5 | ++ |
实施例6 | +++ |
实施例7 | ++++ |
实施例8 | ++ |
实施例9 | + |
实施例10 | +++ |
实施例11 | ++ |
实施例12 | +++ |
实施例13 | +++ |
实施例14 | +++ |
实施例15 | + |
实施例16 | + |
实施例17 | + |
实施例18 | +++ |
实施例19 | + |
实施例20 | +++ |
实施例21 | +++ |
实施例22 | + |
实施例23 | ++++ |
实施例24 | NT |
实施例25 | NT |
实施例26 | NT |
实施例27 | NT |
实施例28 | NT |
实施例29 | NT |
在上面的表2中,如下指示EC50值:<7000-500nM‘+’;<500-100nM‘++’;10-<100nM‘+++’;<10nM‘++++’。测试的所有化合物表现出<2000nM的EC50值;NT:未测试。
生物学试验
COPD炎症(烟草烟雾诱导的肺炎)的临床前小鼠模型。
以前的研究已经确定,在连续4或11天每天进行TS暴露的最终烟草烟雾(TS)暴露后24h(在本文报道的研究中使用该时间点),在支气管肺泡灌洗(BAL)中回收的炎症细胞的数目显著升高。
将小鼠暴露于TS的方案、得到支气管肺泡灌洗(BAL)的方案、制备用于细胞分类计数的细胞离心涂片器载玻片的方案如下所述。
连续4或11天每天将小鼠暴露于TS
在该暴露方案中,在单个透明的聚碳酸酯室(27cm x16cm x12cm)中,将小鼠分成5组进行暴露。使来自香烟的TS进入暴露室,流速为100ml/min。为了使重复暴露于高水平的TS(6只香烟)造成的任何潜在问题最小化,在暴露期内逐渐增加小鼠向TS的暴露至最多6只香烟。对于4天暴露,使用的暴露计划如下:
第1天:4只香烟 (大约32min暴露)
第2天:4只香烟 (大约32min暴露)
第3天:6只香烟 (大约48min暴露)
第4天:6只香烟 (大约48min暴露)
对于11天暴露,使用的暴露计划如下:
第1天:2只香烟 (大约16min暴露)
第2天:3只香烟 (大约24min暴露)
第3天:4只香烟 (大约32min暴露)
第4天:5只香烟 (大约40min暴露)
第5-11天:6只香烟 (大约48min暴露)
将另一组小鼠基于每天相同的时间长度暴露于空气,作为对照(没有TS暴露)。
支气管肺泡灌洗(BAL)分析
如下进行支气管肺泡灌洗:使用缩短至大约8mm的Portex尼龙静脉内插管(粉红色路厄头),将导管插入气管。使用磷酸盐缓冲盐水(PBS)作为灌洗液。轻轻滴入0.4ml的体积,并使用1ml注射器抽吸3次,然后放入埃彭道夫管中,并在以后测定之前保持在冰上。
细胞计数:
通过离心,使灌洗液与细胞分离,并倾析和冷冻上清液,用于以后的分析。将细胞沉淀物重新悬浮于已知体积的PBS中,并通过使用血球计数器在显微镜下计数染色的(Turks染色)等分试样,计算总细胞数目。
如下进行细胞分类计数:
将残余的细胞沉淀物稀释至大约105细胞/ml。将500μl的体积放入细胞离心涂片器载玻片的漏斗中,并在800rpm离心8min。风干载玻片,并按照专有说明书,使用‘Kwik-Diff’溶液(Shandon)进行染色。当干燥并盖上盖玻片以后,使用光学显微术,计数差别细胞。使用光学显微术,由无偏见操作人员计数多达400个细胞。使用标准的形态测定技术,鉴别细胞。
药物治疗
给啮齿类动物(诸如小鼠和大鼠)强制安装鼻呼吸装置,因而经口递送用于吸入的实验材料(诸如治疗剂)将不会产生良好的肺暴露。结果,一般通过在室内的鼻内、气管内或全身气溶胶暴露吸入,实现治疗剂向啮齿类动物的肺的递送。
所述室方法使用大量实验材料,且通常预定用于吸入毒理学研究,而不是药理学效力研究。由于几乎所有的实验材料是递送给肺,气管内给药是一种非常有效的递送方法,但是这完全是一项侵入性的技术。具体地,对于在小鼠中的研究,它的技术要求也非常高,因为气管的直径非常小。鼻内途径的侵入性低于气管内途径,所以特别适合重复给药研究,诸如下述的4-11天小鼠模型。在鼻内给药后,约50%的给药剂量被递送给肺(Eyles JE,Williamson ED和Alpar HO.1999,Int J Pharm,189(1):75-9)。
作为经口吸入的替代途径,给小鼠鼻内施用媒介物(0.2%吐温80在盐水中)、实施例10(30μg/kg)、实施例10(100μg/kg)或实施例10(300μg/kg)。每天在暴露于空气(每天最多50分钟)之前1小时,对照组的小鼠接受媒介物。进行TS暴露4天。在最终的TS暴露之后24h,进行BAL。
数据管理和统计分析
将所有结果表示为每只动物的单个数据点,并计算每个组的平均值。由于正态性检验是正值,对数据进行单因素方差分析法检验(ANOVA),随后进行多重比较的Bonferroni校正,以便检验治疗组之间的显著性。<0.05的“p”值被认为是统计上显著的。使用下式,在Excel表格程序内自动地计算细胞数据的抑制百分比:
使用上式,手工地计算其它参数的抑制数据。
附图说明
图1的条形图说明了最终暴露后24小时给实验小鼠鼻内施用媒介物(0.2%吐温80在盐水中)、实施例10(30μg/kg)、实施例10(100μg/kg)或实施例10(300μg/kg)对烟草烟雾诱导的BAL细胞的数目的影响。
图2的条形图解释了最终暴露后24小时给实验小鼠鼻内施用媒介物(0.2%吐温80在盐水中)、实施例10(30μg/kg)、实施例10(100μg/kg)或实施例10(300μg/kg)对烟草烟雾诱导的BAL嗜中性粒细胞的数目的影响。
如图1所示,当通过鼻内途径施用时,30、100或300μg/kg的实施例10显著抑制TS诱导的BAL细胞流入。对于BAL嗜中性粒细胞,观察到类似的结果(图2)。结果证实了在暴露于TS的小鼠的肺中的清楚的抗炎作用。
具体实施方式:
1.式(I)的化合物或其药学上可接受的盐:
其中:
R1是C1-C6烷基、C3-C6环烷基、任选地被取代的苯基、任选地被取代的5或6元单环杂芳基、或式(II)的基团
其中n是1或2,且R3和R4独立地是H或C1-C6烷基,或R3和R4与它们连接的氮一起形成6元杂环,所述杂环任选地含有选自N和O的其它杂原子;
Y是-O-或-S(O)p-,其中p是0、1或2;
A是任选地取代的二价亚芳基、或单环或双环亚杂芳基、或具有5或6个环原子的C3-C6二价亚环烷基、或亚哌啶基,其中环氮连接至R2NHC(=O)W-;
W是键、-NH-或-C(RA)(RB)-,其中RA和RB独立地是H、甲基、乙基、氨基、羟基或卤素;且
R2是式(IIIA)、(IIIB)或(IIIC)的基团:
其中
m是0或1;
q是0、1、2或3;
T是-N=或-CH=;
R5是H或F;
R7是-CH3;-C2H5;-CH2OH、-CH2SCH3;-SCH3或-SC2H5;
R8是-CH3或-C2H5;且
每次出现的R6独立地是H、C1-C6烷基、羟基或卤素;或单次出现的R6是式(IVA)、(IVB)或(IVC)的基团
同时任何其它出现的R6独立地是H、C1-C6烷基、羟基或卤素;
其中n和p如上面所定义;
且,其中在R6中
R61a和R61b是H、烷基,或R61a和R61b可以与它们连接的氮一起结合形成杂环,所述杂环任选地含有选自N和O的其它杂原子。
2.如实施方式1要求保护的化合物,其中二价基团-W-[A]-Y-具有下式(B)-(J)之一:
3.如实施方式1要求保护的化合物,其具有式(IA):
其中:
V、V’、X和X’独立地是-CH=或-N=;且
R1、R2、Y和W如在实施方式1中所定义。
4.如实施方式1要求保护的化合物,其具有式(IA1):
其中Y是O或S,且R1和R2如在实施方式1中所定义。
5.如实施方式1要求保护的化合物,其具有式(IB):
其中:
U是CH或N,且;
R1、R2、Y和W如在实施方式1中所定义,条件是,当U是N时,则W不是NH。
6.如实施方式1要求保护的化合物,其具有式(IB1):
其中Y是O或S,且R1和R2如在实施方式1中所定义。
7.如实施方式1要求保护的化合物,其具有式(IC):
其中Y是O或S,R2如在实施方式1中所定义,且R1是苯基、或6元单环杂芳基或如在实施方式1中所定义的式(II)的基团。
8.如前述实施方式中任一项要求保护的化合物,其中R1是如在实施方式1中所定义的式(II)的基团,其中基团-NR3R4是吗啉基。
9.如实施方式1-7中任一项要求保护的化合物,其中R1是异丙基或2,6-二氯苯基。
10.如前述实施方式中任一项要求保护的化合物,其中R2是如在实施方式1中所定义的式(IIIC)的基团,其中R7和R8各自是甲基。
11.如实施方式1-9中任一项要求保护的化合物,其中R2具有式(IIID)、(IIIE)、(IIIF)或(IIIG):
12.如实施方式1-9中任一项要求保护的化合物,其中R2是如在实施方式1中所定义的式(IIIA)的基团,其中m是0。
13.如实施方式1-9中任一项要求保护的化合物,其中R2是如在实施方式1中所定义的式(IIIB)的基团,其中(a)T是-CH=,且R5=H;或(b)T是-N=,且R5=H;或(c)T是-CH=,且R5=F。
14.药物组合物,其包含在前述实施方式任一项中要求保护的化合物以及一种或多种药学上可接受的载体和/或赋形剂。
15.如实施方式14要求保护的组合物,其适合吸入进行肺给药。
16.如实施方式1-13中任一项要求保护的化合物用于治疗从p38MAP激酶活性的抑制中获益的疾病或病症的用途。
17.如实施方式16要求保护的用途,其中所述疾病或病症是慢性嗜酸粒细胞性肺炎、哮喘、COPD、成人呼吸窘迫综合征(ARDS)、因其它药物治疗所发生的气道反应过度的恶化或与肺动脉高血压有关的气道疾病。
Claims (10)
1.式(I)的化合物或其药学上可接受的盐:
其中:
R1是C1-C6烷基、C3-C6环烷基、任选地被取代的苯基、任选地被取代的5或6元单环杂芳基、或式(II)的基团
其中n是1或2,且R3和R4独立地是H或C1-C6烷基,或R3和R4与它们连接的氮一起形成6元杂环,所述杂环任选地含有选自N和O的其它杂原子;
Y是-O-或-S(O)p-,其中p是0、1或2;
A是任选地取代的二价亚芳基、或单环或双环亚杂芳基、或具有5或6个环原子的C3-C6二价亚环烷基、或亚哌啶基,其中环氮连接至R2NHC(=O)W-;
W是键、-NH-或-C(RA)(RB)-,其中RA和RB独立地是H、甲基、乙基、氨基、羟基或卤素;且
R2是式(IIIA)、(IIIB)或(IIIC)的基团:
其中
m是0或1;
q是0、1、2或3;
T是-N=或-CH=;
R5是H或F;
R7是-CH3;-C2H5;-CH2OH、-CH2SCH3;-SCH3或-SC2H5;
R8是-CH3或-C2H5;且
每次出现的R6独立地是H、C1-C6烷基、羟基或卤素;或单次出现的R6是式(IVA)、(IVB)或(IVC)的基团
同时任何其它出现的R6独立地是H、C1-C6烷基、羟基或卤素;
其中n和p如上面所定义;
且,其中在R6中
R61a和R61b是H、烷基,或R61a和R61b可以与它们连接的氮一起结合形成杂环,所述杂环任选地含有选自N和O的其它杂原子。
5.如权利要求1要求保护的化合物,其具有式(IB):
其中:
U是CH或N,且;
R1、R2、Y和W如在权利要求1中所定义,条件是,当U是N时,则W不是NH。
7.如权利要求1要求保护的化合物,其具有式(IC):
其中Y是O或S,R2如在权利要求1中所定义,且R1是苯基、5或6元单环杂芳基或如在权利要求1中所定义的式(II)的基团。
8.如前述权利要求中任一项要求保护的化合物,其中R1是如在权利要求1中所定义的式(II)的基团,其中基团-NR3R4是吗啉基。
9.如权利要求1-7中任一项要求保护的化合物,其中R1是异丙基或2,6-二氯苯基。
10.如前述权利要求中任一项要求保护的化合物,其中R2是如在权利要求1中所定义的式(IIIC)的基团,其中R7和R8各自是甲基。
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GB201009731D0 (en) | 2010-06-10 | 2010-07-21 | Pulmagen Therapeutics Inflamma | Kinase inhibitors |
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RU2623734C9 (ru) * | 2011-12-09 | 2017-09-18 | КЬЕЗИ ФАРМАЧЕУТИЧИ С.п.А. | Ингибиторы киназы |
JP6128449B2 (ja) * | 2011-12-09 | 2017-05-17 | チエシ ファルマスーティシ エス.ピー.エー. | キナーゼ阻害剤 |
CA2879431A1 (en) | 2012-07-17 | 2014-01-23 | Washington University | Anti-mucus drugs and uses therefor |
US9181242B2 (en) | 2013-06-06 | 2015-11-10 | Chiesi Farmaceutici S.P.A. | Kinase inhibitors |
WO2014195400A1 (en) * | 2013-06-06 | 2014-12-11 | Chiesi Farmaceutici S.P.A. | Kinase inhibitors |
KR20160016973A (ko) * | 2013-06-06 | 2016-02-15 | 키에시 파르마슈티시 엣스. 피. 에이. | P38 - map 키나아제 억제제로서 [1, 2, 4] 트리아졸로 [4, 3 - a] 피리딘의 유도체 |
GB201321742D0 (en) * | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
US11242319B2 (en) | 2014-11-05 | 2022-02-08 | Flexus Biosciences, Inc. | Immunoregulatory agents |
UY36390A (es) * | 2014-11-05 | 2016-06-01 | Flexus Biosciences Inc | Compuestos moduladores de la enzima indolamina 2,3-dioxigenasa (ido), sus métodos de síntesis y composiciones farmacéuticas que los contienen |
US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
AU2018346709A1 (en) | 2017-10-05 | 2020-04-16 | Fulcrum Therapeutics, Inc. | Use of p38 inhibitors to reduce expression of DUX4 |
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EA201190119A1 (ru) | 2012-05-30 |
IL214658A0 (en) | 2011-09-27 |
KR20110116030A (ko) | 2011-10-24 |
EP2398798A1 (en) | 2011-12-28 |
TN2011000380A1 (en) | 2013-03-27 |
PE20120655A1 (es) | 2012-06-07 |
WO2010094956A1 (en) | 2010-08-26 |
SG174134A1 (en) | 2011-10-28 |
MX2011008496A (es) | 2011-11-18 |
US8557797B2 (en) | 2013-10-15 |
ZA201105993B (en) | 2012-10-31 |
CO6420344A2 (es) | 2012-04-16 |
JP2012517992A (ja) | 2012-08-09 |
CN102395586A (zh) | 2012-03-28 |
BRPI1005327A2 (pt) | 2019-09-24 |
US20120088763A1 (en) | 2012-04-12 |
AU2010215261A1 (en) | 2011-09-08 |
MA33128B1 (fr) | 2012-03-01 |
CA2752693A1 (en) | 2010-08-26 |
CL2011001977A1 (es) | 2011-11-18 |
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