CN114437078A - 一种降解btk的氘代物及其在医药上的应用 - Google Patents
一种降解btk的氘代物及其在医药上的应用 Download PDFInfo
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- CN114437078A CN114437078A CN202111260386.6A CN202111260386A CN114437078A CN 114437078 A CN114437078 A CN 114437078A CN 202111260386 A CN202111260386 A CN 202111260386A CN 114437078 A CN114437078 A CN 114437078A
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Abstract
本发明涉及一种通式(I)所述的化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,及其中间体和制备方法,以及在制备治疗与抑制或降解BTK相关疾病的药物中的应用
Description
技术领域
本发明涉及一种通式(I)所述的化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,及其中间体和制备方法,以及在制备治疗与抑制或降解BTK相关疾病的药物中的应用。
背景技术
布鲁顿酪氨酸蛋白激酶(BTK,Bruton’s tyrosine kinase)是非受体蛋白酪氨酸激酶Tec家族的成员,是B细胞抗原受体(BCR)信号通路中的关键调节因子,分布在淋巴系统、造血及血液系统中。BTK突变会引起下游肿瘤细胞的增殖、分化以及血管生成等信号通路的激活,会导致X连锁无丙种球蛋白血症、非霍奇金淋巴瘤(NHL)与许多B细胞恶性肿瘤,包括慢性淋巴细胞性白血病(CLL)、套细胞淋巴瘤以及弥漫大B细胞淋巴瘤。由于主要在B细胞和髓细胞中表达,BTK是一种靶向性和安全性较好的靶点。
PROTAC(proteolysis targeting chimera)分子是一类能够同时结合靶向蛋白和E3泛素连接酶的双功能化合物,此类化合物能够被细胞的蛋白酶体识别,引起靶向蛋白的降解,能够有效地降低靶向蛋白在细胞中的含量。通过在PROTAC分子引入能结合不同靶向蛋白的配体,使PROTAC技术应用于各种疾病的治疗成为可能,该技术近年来同时得到了广泛的关注。
因此,有必要开发新型的BTK抑制剂和E3泛素连接酶的PROTAC药物,用于治疗与BTK相关的肿瘤疾病。
发明内容
本发明的目的就是提供一种能够抑制并降解Btk(Bruton's tyrosine kinase)即布鲁顿酪氨酸蛋白激酶的化合物及其制备和应用。
本发明提供一种化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,化合物选自通式(I)所示的化合物,其中
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31、R32、R33、R34、R35、R36、R37、R38、R39、R40各自独立的选自H或D,条件是至少有1个选自D。
本发明通式(I)的一些实施方案中,R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31、R32、R33、R34、R35、R36、R37各自独立的选自H或D,条件是至少有1个选自D;
R38、R39、R40选自H。
本发明提供一种如下所示化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
本发明实施方案中,其中,药学上可接受的盐选自马来酸、富马酸、氢卤酸(优选为氢溴酸和盐酸)、硫酸、磷酸、L-酒石酸、柠檬酸、L-苹果酸、马尿酸、D-葡萄糖醛酸、乙醇酸、粘酸、琥珀酸、乳酸、乳清酸、帕莫酸、丙二酸、龙胆酸、水杨酸、草酸或戊二酸。
本发明涉及一种药物组合物,包括上述化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,以及药学上可接受的载体。
本发明涉及上述的化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶用于制备治疗与抑制或降解BTK相关疾病的药物中的应用,优选制备治疗肿瘤或自身免疫疾病药物中的应用,所述的肿瘤优选非霍奇金淋巴瘤、慢性淋巴细胞性白血病、套细胞淋巴瘤、B细胞淋巴瘤,所述自身免疫疾病优选内风湿关节炎或银屑病。
本领域的参考书和专著,详细介绍了可用于制备本文所述化合物的反应物的合成,或提供了描述该制备方法的文章以供参考。这些参考书和专著包括:“SyntheticOrganic Chemistry”,John Wiley&Sons,Inc.,New York;S.R.Sandler et al.,“OrganicFunctional Group Preparations,”2nd Ed.,Academic Press,New York,1983;H.O.House,“Modern Synthetic Reactions”,2nd Ed.,W.A.Benjamin,Inc.Menlo Park,Calif.1972;T.L.Gilchrist,“Heterocyclic Chemistry”,2nd Ed.,John Wiley&Sons,NewYork,1992;J.March,“Advanced Organic Chemistry:Reactions,Mechanisms andStructure”,4th Ed.,Wiley Interscience,New York,1992;Fuhrhop,J.and Penzlin G.“Organic Synthesis:Concepts,Methods,Starting Materials”,Second,Revised andEnlarged Edition(1994)John Wiley&Sons ISBN:3 527-29074-5;Hoffman,R.V.“OrganicChemistry,An Intermediate Text”(1996)Oxford University Press,ISBN 0-19-509618-5;Larock,R.C.“Comprehensive Organic Transformations:A Guide toFunctional Group Preparations”2nd Edition(1999)Wiley-VCH,ISBN:0-471-19031-4;March,J.“Advanced Organic Chemistry:Reactions,Mechanisms,and Structure”4thEdition(1992)John Wiley&Sons,ISBN:0-471-60180-2;Otera,J.(editor)“ModernCarbonyl Chemistry”(2000)Wiley-VCH,ISBN:3-527-29871-1;Patai,S.“Patai’s1992Guide to the Chemistry of Functional Groups”(1992)Interscience ISBN:0-471-93022-9;Solomons,T.W.G.“Organic Chemistry”7th Edition(2000)John Wiley&Sons,ISBN:0-471-19095-0;Stowell,J.C.,“Intermediate Organic Chemistry”2ndEdition(1993)Wiley-Interscience,ISBN:0-471-57456-2;“Industrial OrganicChemicals:Starting Materials and Intermediates:An Ullmann’s Encyclopedia”(1999)John Wiley&Sons,ISBN:3-527-29645-X,in 8volumes;“Organic Reactions”(1942-2000)John Wiley&Sons,in over 55volumes;and“Chemistry of FunctionalGroups”John Wiley&Sons,in 73volumes.
通过美国化学会化学文摘社制备的已知化学物质的索引,可以选择性地识别特定和类似的反应物,这些索引可在大多数公共图书馆和大学图书馆以及在线获得。已知但在目录中不可商购的化学品可选地由定制化学合成工厂制备,其中许多标准化学供应工厂(例如,上面列出的那些)提供定制合成服务。制备和选择本文所述化合物的药用盐的参考文献是P.H.Stahl&C.G.Wermuth“Handbook of Pharmaceutical Salts”,VerlagHelvetica Chimica Acta,Zurich,2002.
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素包括17F和19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或者有机碱,所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备,该修饰可以通过常规的操作或者在体内被除去,而得到母体化合物。当本发明的前药被施予哺乳动物个体时,前药被割裂形成游离的氨基或者羧基。
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。
“动物”是指包括哺乳动物,例如人、陪伴动物、动物园动物和家畜,优选人、马或者犬。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“互变异构体”是指分子中某一原子在两个位置迅速移动而产生的官能团异构体,如酮式-烯醇式异构和酰胺-亚胺醇式异构等。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
“IC50”是对指定的生物过程(或该过程中的某个组分比如酶、受体、细胞等)抑制一半时所需的药物或者抑制剂的浓度。
具体实施方式
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。本文所述反应中使用的化合物是根据本领域技术人员已知的有机合成技术制备的,起始于市售化学品和(或)化学文献中所述的化合物。“市售化学品”是从正规商业来源获得的,供应商包括:泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、南京药石、药明康德和百灵威科技等公司。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm,薄层层析分离纯化产品采用的规格是0.4mm-0.5mm;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体。
实施例1:
5-[3-(3-{4-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基](3,3,4,5,5-D5)哌啶-1-基}氮杂环丁-1-基)氮杂环丁-1-基]-2-(2,6-二氧代哌啶-3-基)-2,3-二氢-1H-异吲哚-1,3-二酮(化合物1)
5-[3-(3-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl](3,3,4,5,5-D5)piperidin-1-yl}azetidin-1-yl)azetidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione
第一步:4-氧代(3,3,5,5-D4)哌啶-1-甲酸叔丁酯(1b)
tert-butyl 4-oxo(3,3,5,5-D4)piperidine-1-carboxylate
将金属钠(332.4mg,14.5mmol)分批次室温加入到盛有重水(270mL)的单口反应瓶中,然后立即将N-叔丁氧羰基-4-哌啶酮(1a)(7.25g,36.4mmol)的D3-氘代乙腈(135mL)溶液加入到反应瓶中,氮气氛围下升温至90℃下搅拌。LC-MS监测反应完成后,将反应体系冷却至室温,用D3-氘代氯仿萃取反应液(80mL×2),合并有机相,无水硫酸钠干燥,减压浓缩,得到粗品4-氧代(3,3,5,5-D4)哌啶-1-甲酸叔丁酯(1b)(7.3g)。
LCMS m/z=148.2[M-55]+.
第二步:4-羟基(3,3,4,5,5-D5)哌啶-1-甲酸叔丁酯(1c)
tert-butyl 4-hydroxy(3,3,4,5,5-D5)piperidine-1-carboxylate
将粗品4-氧代(3,3,5,5-D4)哌啶-1-甲酸叔丁酯(1b)(7.3g)溶于D1-氘代甲醇(60mL)中,置换为氮气氛围,冰水浴冷却下分批次加入D4-氘代硼氢化钠(3.0g,71.7mmol),加完后撤去冰水浴,自然升温至室温反应。TLC监测反应结束后,冰水浴冷却下加入重水(10mL)淬灭反应,减压浓缩除去大部分甲醇,加入饱和氯化铵水溶液(100mL),用二氯甲烷萃取(100mL×2),合并有机相,有机相依次用饱和氯化铵水溶液(100mL)和水(100mL)洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)=3:1),得到4-羟基(3,3,4,5,5-D5)哌啶-1-甲酸叔丁酯(1c)(7.2g,从化合物1a算两步收率:96%)。
1H NMR(400MHz,CDCl3)δ5.79(d,2H),4.98(d,2H),3.88(s,1H),3.42(s,9H).
LCMS m/z=151.2[M-55]+.
第三步:4-(甲磺酰氧基)(3,3,4,5,5-D5)哌啶-1-甲酸叔丁酯(1d)
tert-butyl 4-(methanesulfonyloxy)(3,3,4,5,5-D5)piperidine-1-carboxylate
将4-羟基(3,3,4,5,5-D5)哌啶-1-甲酸叔丁酯(1c)(2.00g,9.69mmol)溶解在20mL二氯甲烷中,加入三乙胺(1.96g,19.4mmol),冰浴冷却下慢慢滴加甲磺酰氯(1.66g,14.5mmol),加完后继续冰浴下反应30min。向反应体系中加入20mL水,分液,有机层用水(20mL x 3)洗涤,无水硫酸钠干燥,减压浓缩,得粗品4-(甲磺酰氧基)(3,3,4,5,5-D5)哌啶-1-甲酸(1d)(2.7g)。
第四步:4-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基](3,3,4,5,5-D5)哌啶-1-甲酸叔丁酯(1e)
tert-butyl4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl](3,3,4,5,5-D5)piperidine-1-carboxylate
将3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(2.90g,9.56mmol)悬浮在20mL DMF中,依次加入上述粗品4-(甲磺酰氧基)(3,3,4,5,5-D5)哌啶-1-甲酸(1d)(2.70g)和碳酸铯(9.30g,28.5mmol),加完后升温至100℃反应1h。将反应体系冷却至室温,加入30mL水和60mL乙酸乙酯,分液,水层再用30mL乙酸乙酯萃取,合并有机层,有机相用30mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)=100:0-19:1),得4-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基](3,3,4,5,5-D5)哌啶-1-甲酸叔丁酯(1e)(2.30g,从化合物1c算两步收率:48%)。
1H NMR(400MHz,CDCl3)δ8.37(s,1H),7.68–7.61(m,2H),7.42–7.33(m,2H),7.20–7.12(m,3H),7.11–7.05(m,2H),5.61(br.s,2H),4.41–4.17(m,2H),3.02–2.88(m,2H),1.48(s,9H).
LCMS m/z=492.3[M+1]+.
第五步:3-(4-苯氧基苯基)-1-[(3,3,4,5,5-D5)哌啶-4-基]-1H-吡唑并[3,4-d]嘧啶-4-胺(1f)
3-(4-phenoxyphenyl)-1-[(3,3,4,5,5-D5)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将4-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基](3,3,4,5,5-D5)哌啶-1-甲酸叔丁酯(1e)(6.99g,14.2mmol)溶解在30mL二氯甲烷中,加入15mL三氟乙酸,加完后室温反应2h。将反应液减压浓缩,向残留物中加入70mL甲基叔丁基醚打浆1h,抽滤,收集滤饼,将滤饼悬浮在200mL甲醇/二氯甲烷(v/v=1:9)的混合溶剂中,滴加4mol/L氢氧化钠水溶液调pH至10,分液,有机层用无水硫酸钠干燥,减压浓缩,得粗品3-(4-苯氧基苯基)-1-[(3,3,4,5,5-D5)哌啶-4-基]-1H-吡唑并[3,4-d]嘧啶-4-胺(1f)(5.28g)。
第六步:3-{4-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基](3,3,4,5,5-D5)哌啶-1-基}氮杂环丁-1-甲酸叔丁酯(1g)
tert-butyl3-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl](3,3,4,5,5-D5)piperidin-1-yl}azetidine-1-carboxylate
将上述粗品3-(4-苯氧基苯基)-1-[(3,3,4,5,5-D5)哌啶-4-基]-1H-吡唑并[3,4-d]嘧啶-4-胺(1f)(5.28g)溶解在50mL 1,2-二氯乙烷中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(4.62g,27.0mmol)和冰醋酸(1.60g,27.0mmol),再加入三乙酰氧基硼氢化钠(5.71g,27.0mmol),加完后室温搅拌16h。向反应体系中加入50mL二氯甲烷和20mL水,滴加4mol/L氢氧化钠水溶液调pH至8,分液,有机层用30mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)=100:0-19:1),得3-{4-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基](3,3,4,5,5-D5)哌啶-1-基}氮杂环丁-1-甲酸叔丁酯(1g)(5.40g,从化合物1e算两步收率:70%)。
第七步:1-[1-(氮杂环丁-3-基)(3,3,4,5,5-D5)哌啶-4-基]-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1h)
1-[1-(azetidin-3-yl)(3,3,4,5,5-D5)piperidin-4-yl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-{4-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基](3,3,4,5,5-D5)哌啶-1-基}氮杂环丁-1-甲酸叔丁酯(1g)(5.40g,9.88mmol)溶解在25mL二氯甲烷中,加入10mL三氟乙酸,加完后室温反应2h。将反应液减压浓缩,向残留物中加入50mL甲基叔丁基醚打浆1h,抽滤,收集滤饼,将滤饼悬浮在200mL甲醇/二氯甲烷(v/v)=1:9)的混合溶剂中,滴加4mol/L氢氧化钠水溶液调pH至10,分液,有机层用无水硫酸钠干燥,减压浓缩,得粗品1-[1-(氮杂环丁-3-基)(3,3,4,5,5-D5)哌啶-4-基]-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1h)(4.40g)。
第八步:3-(3-{4-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基](3,3,4,5,5-D5)哌啶-1-基}氮杂环丁-1-基)氮杂环丁-1-甲酸叔丁酯(1i)
tert-butyl3-(3-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl](3,3,4,5,5-D5)piperidin-1-yl}azetidin-1-yl)azetidine-1-carboxylate
将上述粗品1-[1-(氮杂环丁-3-基)(3,3,4,5,5-D5)哌啶-4-基]-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1h)(4.40g)溶解在45mL 1,2-二氯乙烷中,加入3-氧代氮杂环丁-1-甲酸叔丁酯(3.37g,19.7mmol)和冰醋酸(1.48g,24.7mmol),再加入三乙酰氧基硼氢化钠(4.17g,19.7mmol),加完后室温搅拌16h。向反应体系中加入50mL二氯甲烷和20mL水,滴加4mol/L氢氧化钠水溶液调pH至8,分液,有机层用30mL饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)=100:0-19:1),得3-(3-{4-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基](3,3,4,5,5-D5)哌啶-1-基}氮杂环丁-1-基)氮杂环丁-1-甲酸叔丁酯(1i)(5.90g,从化合物1g算两步收率:99%)。
第九步:1-{1-[1-(氮杂环丁-3-基)氮杂环丁-3-基](3,3,4,5,5-D5)哌啶-4-基}-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1j)
1-{1-[1-(azetidin-3-yl)azetidin-3-yl](3,3,4,5,5-D5)piperidin-4-yl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
将3-(3-{4-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基](3,3,4,5,5-D5)哌啶-1-基}氮杂环丁-1-基)氮杂环丁-1-甲酸叔丁酯(1i)(5.90g,9.80mmol)溶解在30mL二氯甲烷中,加入15mL三氟乙酸,加完后室温反应2h。将反应液减压浓缩,向残留物加入60mL甲基叔丁基醚打浆1h,抽滤,收集滤饼,将滤饼悬浮在200mL甲醇/二氯甲烷(v/v)=1:9的混合溶剂中,滴加4mol/L氢氧化钠水溶液调pH至10,分液,有机层用无水硫酸钠干燥,减压浓缩,得粗品1-{1-[1-(氮杂环丁-3-基)氮杂环丁-3-基](3,3,4,5,5-D5)哌啶-4-基}-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1j)(4.40g)。
第十步:5-[3-(3-{4-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基](3,3,4,5,5-D5)哌啶-1-基}氮杂环丁-1-基)氮杂环丁-1-基]-2-(2,6-二氧代哌啶-3-基)-2,3-二氢-1H-异吲哚-1,3-二酮(化合物1)
5-[3-(3-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl](3,3,4,5,5-D5)piperidin-1-yl}azetidin-1-yl)azetidin-1-yl]-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione
将上述粗品1-{1-[1-(氮杂环丁-3-基)氮杂环丁-3-基](3,3,4,5,5-D5)哌啶-4-基}-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-4-胺(1j)(4.40g)溶解在20mL DMSO中,依次加入二异丙基乙胺(6.18g,47.8mmol)和2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(合成方法见WO2017197056)(2.90g,10.5mmol),加完后升温至90℃反应4h。将反应液冷却至室温,慢慢滴加40mL水,继续搅拌10min,过滤,滤饼用20mL水洗涤,收集滤饼,滤饼用100mL甲醇/二氯甲烷(v/v)=1:9的混合溶剂溶解,无水硫酸钠干燥,减压浓缩后粗品用硅胶柱色谱分离纯化(二氯甲烷/甲醇(v/v)=100:0-19:1),得5-[3-(3-{4-[4-氨基-3-(4-苯氧基苯基)-1H-吡唑并[3,4-d]嘧啶-1-基](3,3,4,5,5-D5)哌啶-1-基}氮杂环丁-1-基)氮杂环丁-1-基]-2-(2,6-二氧代哌啶-3-基)-2,3-二氢-1H-异吲哚-1,3-二酮(化合物1)(5.30g,从化合物1i算两步收率:71%)。
1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),8.23(s,1H),7.73–7.58(m,3H),7.50–7.36(m,2H),7.26–7.06(m,5H),6.83–6.75(m,1H),6.70–6.61(m,1H),5.05(dd,1H),4.10–3.99(m,2H),3.86–3.76(m,2H),3.69–3.56(m,1H),3.49–3.36(m,2H),3.04–2.76(m,6H),2.65–2.46(m,2H),2.07–1.92(m,3H).
LCMS m/z=758.2[M+1]+.
生物测试例
1.细胞增殖抑制实验
Mino培养基为RPMI1640+10%FBS,培养于37℃、5%CO2孵箱中。细胞铺板96孔板。其中Mino细胞5000个/孔,每孔90μL。每孔加入10μL不同浓度的化合物。每个浓度设3复孔,最后一列为DMSO溶媒对照组,在37℃、5%CO2条件下继续培养72小时。72小时后,每孔加入100μL检测试剂(Cell Viability Assay,Promega,G7573),混匀2分钟,室温孵育10分钟,用酶标仪(PHERAstar FSX)测定荧光信号值。使用origin9.2软件,计算化合物抑制细胞增殖的IC50值,并根据式(1)计算在化合物最高浓度下的抑制率Max inhi.%。
Max inhi.%=(1-T72给药/T72溶媒)×100式(1)。
抑制Mino细胞增殖的IC50值结果见表1.
表1抑制Mino细胞增殖的IC50值
序号 | 化合物编号 | IC<sub>50</sub>(nM) |
1 | 化合物1 | <200 |
结论:运用本发明技术所合成的化合物对Mino细胞(套细胞淋巴瘤细胞)增殖有一定的抑制作用。
2.大鼠药代动力学测试
实验目的:本试验通过单剂量静脉和灌胃给予受试物于SD大鼠,测定大鼠血浆中受试物的浓度,评价受试物在大鼠体内药代特征和生物利用度。
试验动物:雄性SD大鼠,200~250g,6~8周龄,6只/化合物。购于成都达硕实验动物有限公司。
试验方法:试验当天,6只SD大鼠按体重随机分组。给药前1天禁食不禁水12~14h,给药后4h给食。
表2
*剂量以游离碱计。
取样:于给药前及给药后异氟烷麻醉经眼眶取血0.1mL,置于EDTAK2离心管中。5000rpm,4℃离心10min,收集血浆。
G1组采集血浆时间点:0,5min,15min,30min,1,2,4,6,8,24h。
G2组采集血浆时间点:0,15min,30min,1,2,4,6,8,24h。
分析检测前,所有样品存于-80℃。用LC-MS/MS对样品进行定量分析。
表3化合物在大鼠血浆中药代动力学参数
受试化合物 | 给药方式* | AUC<sub>0-t</sub>(ng/ml·h) | F(%) |
化合物1 | i.g.(20mg/kg) | 10354±1938 | 21.9±4.1 |
*注:i.g.(灌胃)给予化合物;
结论:运用本发明技术所合成的化合物在大鼠体内具有一定的口服生物利用度。
3.Mino细胞中BTK降解检测
Mino人套细胞淋巴瘤细胞株,购自于ATCC,培养条件:RPMI-1640+15%FBS+1%双抗,培养于37℃,5%CO2孵箱中。细胞铺板6孔板,5×105个/孔。铺板后,加入不同浓度化合物,37℃,5%CO2孵箱中培养48小时。培养结束后,收集细胞,加入RIPA裂解液(beyotime,Cat.P0013B)于冰上裂解15分钟后,12000rpm,4℃离心10分钟,收集上清蛋白样品,用BCA试剂盒(Beyotime,Cat.P0009)进行蛋白定量后,将蛋白稀释为0.25mg/mL,使用全自动蛋白质印迹定量分析仪(Proteinsimple)运用试剂盒(Protein simple,Cat.SM-W004)检测BTK(CST,Cat.8547S)和内参β-actin(CST,Cat.3700S)的表达。使用compass软件计算BTK相对于内参的表达量并使用Origen9.2软件根据式(2)计算DC50值。其中BTK给药为不同剂量给药组BTK表达量,BTK溶媒为溶媒对照组BTK表达量。
BTK%=BTK给药/BTK溶媒×100 式(2)
表4 Mino细胞中BTK降解的DC50值
序号 | 化合物编号 | DC<sub>50</sub>(nM) |
1 | 化合物1 | 2.3 |
结论:运用本发明技术所合成的化合物对Mino细胞中的BTK有显著的降解作用。
4、体外激酶检测
激酶BTK wt(Carna,Cat.No 08-180)和BTK C481S(Carna,Cat.No 08-547)配制成2.5×的激酶溶液,底物FAM-P2(GL Biochem,Cat.No.112394)与ATP((Sigma,Cat.No.A7699-1G)配制成2.5×的底物溶液。在384孔板中加入5μL不同浓度的化合物,加入10μL 2.5×的激酶溶液,室温孵育10分钟。加入10μL 2.5×的底物溶液,于28℃孵育适当时间后,加入30μL终止液终止反应,使用Caliper EZ reader2仪器检测。运用XLFit exceladd-in version 5.4.0.8软件计算IC50值。抑制率计算公式见式(3),其中max为DMSO对照读数,min为阴性对照读数,conversion为化合物读数
抑制率%=(max-conversion)/(max-min)*100. 式(3)
其结果见表5:
表5抑制BTK wt/C481S激酶的IC50值
序号 | 化合物编号 | BTK C481S IC<sub>50</sub>(nM) | BTK wt IC<sub>50</sub>(nM) |
1 | 化合物1 | 7.5 | 11 |
结论:运用本发明技术所合成的化合物对BTKwt/C481S激酶有显著的抑制作用。
Claims (8)
2.根据权利要求1所述的化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24、R25、R26、R27、R28、R29、R30、R31、R32、R33、R34、R35、R36、R37各自独立的选自H或D,条件是至少有1个选自D;
R38、R39、R40选自H。
4.根据权利要求1-3任一项所述的化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,药学上可接受的盐选自马来酸、富马酸、氢卤酸(优选为氢溴酸和盐酸)、硫酸、磷酸、L-酒石酸、柠檬酸、L-苹果酸、马尿酸、D-葡萄糖醛酸、乙醇酸、粘酸、琥珀酸、乳酸、乳清酸、帕莫酸、丙二酸、龙胆酸、水杨酸、草酸或戊二酸。
5.一种药物组合物,包括权利要求1-4任意一项所述的化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶,以及药学上可接受的载体。
6.根据权利要求1-4任意一项所述的化合物或者其氘代物、立体异构体、互变异构体、水合物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶用于制备治疗与抑制或降解BTK相关疾病的药物中的应用。
7.根据权利要求6所述应用,所述的疾病选自肿瘤或自身免疫疾病。
8.根据权利要求7所述应用,所述的肿瘤选自非霍奇金淋巴瘤、慢性淋巴细胞性白血病、套细胞淋巴瘤、B细胞淋巴瘤,自身免疫疾病选自内风湿关节炎或银屑病。
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