CN111918871A - 基于环戊烷的sting(干扰素基因刺激物)调节剂 - Google Patents
基于环戊烷的sting(干扰素基因刺激物)调节剂 Download PDFInfo
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- CN111918871A CN111918871A CN201980019494.9A CN201980019494A CN111918871A CN 111918871 A CN111918871 A CN 111918871A CN 201980019494 A CN201980019494 A CN 201980019494A CN 111918871 A CN111918871 A CN 111918871A
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
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Abstract
通式(I)的化合物,或其药学上可接受的盐,用于制备这些化合物的方法,它包括这些化合物的组合物,以及这些化合物的用途。
Description
发明领域
本发明涉及新的基于环戊烷的STING(干扰素基因刺激物)活化剂,其可用于治疗哺乳动物中的异常细胞生长,例如癌症。本发明还涉及使用这类化合物治疗哺乳动物,尤其是人中的异常细胞生长的方法,并且涉及作为抗癌药的药物组合物。
发明背景
先天免疫系统是第一道防线,它由模式识别受体(PRR)在检测到来自病原体的配体以及与损伤相关的分子模式后引发。已经鉴定了日益增多的这些受体,目前包括双链DNA和被称作环状二核苷酸(CDN)的独特核酸的传感器。PRR的活化导致参与炎性应答的基因上调,包括抑制病原体复制和促进适应性免疫的1型干扰素(IFN)、促炎细胞因子和趋化因子。
转接蛋白STING,也称为TMEM 173,已被鉴定为应答胞质核酸先天性免疫传感途径中的中心信号传导分子。STING的活化导致IRF3和NFκB途径的上调,从而导致干扰素-β和其它细胞因子的诱导。STING对应答病原体或宿主来源的胞质DNA以及应答有时被称作第二信使的CDN的是至关重要的。G.N.Barber,“Sting:infection,inflammation and cancer,”Nat.Rev.Immun.,2015,15,pp760。
CDN首先被鉴定为负责控制原核细胞中众多反应的细菌信使。细菌CDN(例如c-di-GMP)为对称分子,其特征在于两个3’,5’磷酸二酯键。最近已通过X-射线晶体学证实了细菌CDN可以直接活化STING。因此,细菌CDN作为潜在的疫苗佐剂引起了人们的兴趣。
更最近,已证明对胞质DNA的响应包括通过被称作环鸟嘌呤腺嘌呤合酶(cGAS)的酶产生内源性CDN,从而产生一种新的哺乳动物CDN信号传导分子,该分子被鉴定为环鸟嘌呤腺嘌呤一磷酸(cGAMP),其与STING结合且激活STING。cGAMP与STING的相互作用也已通过X-射线晶体学得到了证实。与细菌CDN不同,cGAMP是一种不对称分子,其特征在于其混合的2’,5’和3’,5’磷酸二酯键。如细菌CDN,cGAMP激活STING,导致1型INF的诱导:
1型INF响应入侵病原体的作用已得到充分确立。重组IFNα为第一种被批准的生物治疗剂并且已成为病毒感染和癌症中的重要疗法。还已知INF为免疫应答的有效调节剂,作用于免疫系统的细胞。
鉴于其在调节各种生物过程中的作用,STING为用小分子调节的富有吸引力的靶标。尽管如此,迄今为止,很少有效的STING活化剂被开发或进入临床。
发明概述
施用可刺激先天性免疫应答(包括活化1型INF和其它细胞因子)的小分子化合物可成为治疗和预防包括病毒感染和癌症在内的人类疾病的重要策略。这种类型的免疫调节策略具有鉴定化合物的潜能,所述化合物不仅可用于感染性疾病而且可用于癌症、过敏性疾病和作为疫苗佐剂。
已显示本发明的某些化合物与STING结合并在与人树突细胞(DC)和外周血单核细胞(PBMC)温育时诱导1型INF和其它细胞因子和共同刺激因子。诱导人INF的化合物可用于治疗不同的病症,例如治疗过敏性疾病和其它炎性病况。本发明的某些化合物可以结合STING,但作为拮抗剂起作用,并且这些可用于治疗各种自自身免疫性疾病。
设想用活化剂或抑制剂靶向STING可能是治疗其中1型INF途径的调节是有益的疾病和病症和作为疫苗佐剂的有希望的方法,所述疾病和病症包括炎性疾病、过敏性和自身免疫性疾病、感染性疾病、癌症。
下文所述的本发明的非CDN化合物的每个实施方案可以与本说明书中所述的与其组合的实施方案非不一致的本发明的化合物的任何其他实施方案组合。此外,以下描述本发明的每个实施方案在其范围内设想了本发明化合物的药学上可接受的盐。因此,在本说明书描述的所有化合物的描述中隐含短语“或其药学上可接受的盐”。
本发明包括实施方案,其中提供式(I)的化合物:
或其药学上可接受的盐,其中
各J独立地为氧(O)或(S);
R1选自:
R2选自:
W为OH、SH、O-M+或S-M+,其中M+表示阳离子抗衡离子;
X为OH、SH、O-M+或S-M+,其中M+表示阳离子抗衡离子;
各Y独立地选自氢、卤素、C1-C6烷基、取代的C1–C6烷基、N(R3)2和OR4,或两个Y取代基结合形成一个包含0-1个杂原子的3-5元螺环环系;
各Z独立地选自氢、卤素、C1-C6烷基、取代的C1–C6烷基、N(R3)2和OR4,或两个Z取代基结合形成一个包含0-1个杂原子的3-5元螺环环系;且
R3和R4各自独立地为氢或C1-C6烷基。
本发明还包括实施方案,其中提供式(II)的化合物(其为式(I)的子集):
或其药学上可接受的盐,其中R1选自:
R2选自:
W为OH、SH、O-M+或S-M+,其中M+表示阳离子抗衡离子;
X为OH、SH、O-M+或S-M+,其中M+表示阳离子抗衡离子;
各Y独立地选自氢、卤素、C1-C6烷基、取代的C1–C6烷基、N(R3)2和OR4,或两个Y取代基结合形成一个包含0-1个杂原子的3-5元螺环环系;
各Z独立地选自氢、卤素、C1-C6烷基、取代的C1–C6烷基、N(R3)2和OR4,或两个Z取代基结合形成一个包含0-1个杂原子的3-5元螺环环系;且
R3和R4各自独立地为氢或C1-C6烷基。
本发明的其他实施方案包括式(I)和/或式(II)的化合物,其中M+选自钠、钾、钙、铵、三乙铵、三甲铵和镁。其他抗衡离子也是有用的,并且包括在本发明的范围内。注意,每个抗衡离子M+可以相同,或者在一些实施方式中可以彼此不同。
本发明实施了碱基R1和R2的不同组合。因此,在某些实施方案中,R1为且R2为R1为且R2为其中R1为且R2为R1为且R2为R1为且R2为R1为且R2为R1为且R2为R1为且R2为R1为且R2为R1为且R2为R1为且R2为R1为且R2为或R1为且R2为
其他碱基(R1和R2)和碱基的其他组合也包括在本发明的范围内。
本发明的另外实施方案包括其中一个或两个Y为卤素的实施方案。这包括其中一个Y为氢而另一个Y为卤素的实施方案。在这些实施方案的某些实施方案中,卤素为氟。
本发明的另外实施方案包括其中一个Z为氢而另一个Z为OR4的实施方案。在这些实施方案的某些实施方案中,一个或多个R4为H(氢),因此至少一个Z为OH。
本发明的另外实施方案包括其中W为-SH且X为–SH的实施方案。
本发明的另外实施方案包括其中W为-OH且X为–OH实施方案。
本发明的其他实施方案包括化合物,其选自:
或其药学上可接受的盐。
本发明的另外实施方案包括化合物,其选自:
或其药学上可接受的盐。
本发明的另外实施方案包括化合物,其选自:
或其药学上可接受的盐。
本发明的其他实施方案包括药物组合物,其包含本说明书中所述的化合物或盐或其药学上可接受的盐和药学上可接受的载体。任选地,这类组合物可以包含本说明书中所述的化合物或盐,化合物或盐为抗体-药物缀合物的组分;以及/或可以包含本说明书中所述的化合物,化合物为基于颗粒的递送系统的组分。
本发明中还实施了一种治疗哺乳动物中异常细胞生长的方法,该方法包括向哺乳动物施用治疗有效量的本说明书中所述的化合物或盐。该方法可以(也可以不)采用本说明书中所述的化合物或盐作为抗体-药物缀合物的组分,或作为基于颗粒的递送系统的组分。在这样的实施方案中,所述异常细胞生长可以为癌症。如果细胞生长异常为癌症,则被治疗的癌症可以为肺癌、骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、脊椎轴肿瘤、脑干神经胶质瘤或垂体腺瘤。
本发明中还实施了本说明书中所述的化合物或盐在制备用于治疗哺乳动物异常细胞生长的药物中的用途。在这样的实施方案中,所述异常细胞生长可以为癌症。如果异常细胞生长为癌症,则被治疗的癌症可以为肺癌、骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、脊椎轴肿瘤、脑干神经胶质瘤或垂体腺瘤。
更进一步,本发明的实施方案包括那些实施方案,其中提供了在哺乳动物中上调STING活性的方法,它包括向所述哺乳动物施用有效量的本说明书中所述的化合物或盐的步骤;以及/或提供在哺乳动物中增加干扰素-β水平的方法,它包括向所述哺乳动物施用有效量的本说明书中所述的化合物或盐的步骤。
定义
除非另有说明,否则本说明书和权利要求书中使用的以下术语具有以下所讨论的含义。在本节中定义的变量,例如R、X、n等,仅在本节中提供参考,并且并不意味着具有与在本定义节之外可使用的含义相同的含义。此外,本说明书定义的许多基团可以任选地被取代。在该定义部分中列出的典型取代基为示例性的,而无意限制本说明书和权利要求书中其他地方定义的取代基。
“烯基”是指由至少两个碳原子和至少一个碳-碳双键组成的如本说明书中所定义的烃基。有代表性的实例包括,但不限于乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丙烯基等。“亚烯基”是指烯基的二价形式。
“烷氧基”是指–O-烷基,其中烷基优选为C1-C8、C1-C7、C1-C6、C1-C5、C1-C4、C1-C3、C1-C2或C1烷基。
“烷基”是指饱和脂族烃基,包括1-20个碳原子(“(C1-C20)烷基”),优选1-12个碳原子(“(C1-C12)烷基”),更优选1-8个碳原子(“(C1-C8)烷基”),或1-6个碳原子(“(C1-C6)烷基”),或1-4个碳原子(“(C1-C4)烷基”)的直链和支链基团。烷基的实例包括甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基、新戊基等。烷基可以被取代或未被取代。典型的取代基包括环烷基、芳基、杂芳基、杂脂环族基团、羟基、烷氧基、芳氧基、巯基、烷硫基、芳硫基、氰基、卤素、羰基、硫代羰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、C-羧基、O-羧基、硝基、甲硅烷基、氨基和–NRxRy,其中Rx和Ry是例如氢、烷基、环烷基、芳基、羰基、乙酰基、磺酰基、三氟甲磺酰基和合并的5元或6元杂脂环族环。“卤代烷基”例如(C1-C8)卤代烷基是指具有一个或多个卤素取代基的烷基。“亚烷基”是指烷基的二价形式。
“炔基”是指由至少两个碳原子和至少一个碳-碳三键组成的如本说明书中所定义的烃基。有代表性的实例包括,但不限于乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基或3-丁炔基等。“亚炔基”是指炔基的二价形式。
“氨基”是指–NRxRy基团,其中Rx和Ry均为氢。
“氰基”是指-C≡N基团。氰基可以表示为CN。
“(C3-C5)环烷基”是指3-5元全碳单环。环烷基的实例为环丙烷、环丁烷、环戊烷和环戊烯,但不限于此。典型的取代基包括烷基、烷氧基、氰基、卤素、羰基C羧基、O-羧基、O-氨基甲酰基、N-氨基甲酰基、氨基和–NRxRy,其中Rx和Ry如上文所定义。环烷基的示例性实例衍生自但不限于如下基团:
“卤素”或前缀“卤代”是指氟、氯、溴和碘。优选地,卤素是指氟或氯。
“杂原子”是指选自O、N、Si、S和/或P的原子,且其中氮和硫原子可以任选地被氧化。
“杂环基”是指具有3-12个环原子的单环环系或稠合环系,所述环原子中包含1、2、3或4个选自N、O和S(O)n(其中n为0、1或2)的环杂原子和1-9个碳原子。所述的环还可以具有一个或多个双键。然而,所述的环不具有完全共轭的π-电子系统。优选的杂环包括根据如上定义的(C2-C6)杂环。适合的饱和杂脂环族基团的实例包括,但不限于:
杂环基任选地被一个或两个取代基取代,所述取代基独立地选自卤素、低级烷基。
“羟基”或“羟基”是指-OH基团。
“体外”是指在人工环境中,例如,但不限于在试管或培养基中进行的操作。
“体内”是指在例如,但不限于小鼠、大鼠、兔和/或人等活生物体内进行的操作。
“任选的”或”任选地”是指随后描述的事件或情况可能,但不一定发生,并且该描述包括事件或情况发生的实例以及事件或情况没有发生的实例。例如,“任选地被烷基取代的杂环基”是指烷基可以但不一定存在,并且该描述包括其中杂环基被烷基取代的情况以及杂环基未被烷基取代的情况。
“生物”是指由至少一个细胞组成的任何生物实体。活生物可以像单个真核细胞一样简单,也可以像哺乳动物包括人一样复杂。
“药学上可接受的赋形剂”是指将惰性物质添加到药物组合物中以进一步促进化合物的施用。赋形剂的实例包括,但不限于碳酸钙,磷酸钙,各种糖和各种类型的淀粉,纤维素衍生物,明胶,植物油和聚乙二醇。
如本说明书中所用,术语“药学上可接受的盐”是指那些保留母体化合物的生物有效性和特性的盐。这些盐包括:
(i)酸加成盐,其可以通过母体化合物的游离碱与无机酸或与有机酸反应得到,所述无机酸例如盐酸,氢溴酸,硝酸,磷酸,硫酸和高氯酸等,所述有机酸例如乙酸,草酸,(D)或(L)苹果酸,马来酸,甲磺酸,乙磺酸,对甲苯磺酸,水杨酸,酒石酸,柠檬酸,琥珀酸或丙二酸等;或
(ii)当母体化合物中存在的酸性质子被金属离子(例如碱金属离子,碱土金属离子或铝离子)替代时形成的盐;或者与有机碱(例如乙醇胺,二乙醇胺,三乙醇胺,氨基丁三醇,N-甲基葡糖胺,三烷基铵等)配位时形成的盐。
“药物组合物”是指本说明书中所述化合物或其生理学/药学上可接受的盐、溶剂化物、水合物或前药的一种或多种与其他化学成分例如生理学/药学上可接受的载体和赋形剂的混合物。药物组合物的目的在于有利于化合物向生物的施用。
如本说明书中所用,“生理学/药学上可接受的载体”是指不会对生物造成明显刺激并且不会消除所施用化合物的生物学活性和特性的载体或稀释剂。
“治疗有效量”是指所施用的化合物的量,该量将在某种程度上减轻所治疗疾病的一种或多种症状。关于癌症的治疗,治疗有效量是指具有以下作用中的至少一种的量:
(1)减小肿瘤的大小;
(2)抑制(即一定程度上减缓,优选停止)肿瘤转移;
(3)一定程度上抑制(即一定程度上减缓,优选停止)肿瘤生长;以及
(4)一定程度上缓解(或优选消除)与癌症相关的一种或多种症状。
“治疗”是指减轻或消除细胞疾病和/或其伴随症状的方法。特别是关于癌症,这些术语仅表示受癌症影响的个体的预期寿命将会增加,或者疾病症状的一种或多种将会减少。
详细描述
用于合成本发明化合物的通用方案可以在本说明书实施例部分中找到。
除非另有说明,否则本说明书中对本发明化合物的所有提及均包括对其盐、溶剂化物、水合物和配合物的提及,以及对其盐的溶剂化物、水合物和络合物的提及,包括对其多晶型物、立体异构体和同位素标记的形式的提及。
药学上可接受的盐包括酸加成和碱盐(包括二盐)。
适合的酸加成盐可以由形成无毒性盐的酸形成。实例包括乙酸盐,天冬氨酸盐,苯甲酸盐,苯磺酸盐,碳酸氢盐/碳酸盐,硫酸氢盐/硫酸盐,硼酸盐,右旋樟脑磺酸盐,柠檬酸盐,乙二磺酸盐,乙磺酸盐,甲酸盐,富马酸盐,葡庚糖酸盐,葡糖酸盐,葡糖醛酸盐,六氟磷酸盐,海苯酸盐,盐酸盐/氯化物,氢溴酸盐/溴化物,氢碘酸盐/碘化物,羟乙基磺酸盐,乳酸盐,苹果酸盐,马来酸盐,丙二酸盐,甲磺酸盐,甲基硫酸盐,萘甲酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,乳清酸盐,草酸盐,棕榈酸盐,双羟萘酸盐,磷酸盐/磷酸氢盐/磷酸二氢盐,糖二酸盐,硬脂酸盐,琥珀酸盐,酒石酸盐,甲苯磺酸盐和三氟乙酸盐。
合适的碱盐由形成无毒性盐的碱形成。实例包括铝,精氨酸,二苄基乙二胺,钙,胆碱,二乙胺,二乙醇胺,甘氨酸,赖氨酸,镁,葡甲胺,乙醇胺,钾,钠,氨基丁三醇和锌盐。有关适合盐的综述,参见Stahl and Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,Weinheim,德国,2002),其全部内容通过引用整体并入本说明书。
通过适当地将化合物和期望的酸或碱的溶液混合在一起,可以容易地制备本发明化合物的药学上可接受的盐。该盐可以从溶液中沉淀出来并通过过滤收集,或者可以通过蒸发溶剂来回收。盐中的电离度可以从完全电离到几乎未电离变化之间改变。
本发明的化合物可以以溶剂化和非溶剂化形式存在。如本说明书中所用,术语“溶剂化物”描述包含本发明化合物和一种或多种药学上可接受的溶剂分子例如乙醇的分子复合物。术语“水合物”在溶剂为水时使用。本发明药学上可接受的溶剂化物包括水合物和溶剂化物,其中结晶溶剂可以被同位素取代,例如D2O、d6-丙酮、d6-DMSO。
配合物例如笼形包合物、药物-主体包合配合物也包括在本发明的范围内,其中与上述溶剂合物相反,药物和主体以化学计量或非化学计量的量存在。还包括包含两种或更多种可以是化学计量的或非化学计量的有机和/或无机成分的药物配合物。所得的配合物可以被电离、部分被电离或未被电离。有关此类配合物的综述,参见Haleblian的J PharmSci,64(8),1269-1288(1975年8月),其公开内容通过引用整体并入本说明书。
本发明化合物的多晶型物、前药和异构体(包括光学异构体、几何异构体和互变异构体)也在本发明的范围内。
本发明化合物的衍生物本身可能几乎没有或没有药理活性,但是当施用于患者时,可以例如通过水解裂解转化为本发明化合物。此类衍生物称作“前药”。有关使用前药的更多信息可以在‘Pro-drugs as Novel Delivery Systems,第14卷,ACS SymposiumSeries(T Higuchi和W Stella)和‘Bioreversible Carriers in Drug Design’,PergamonPress,1987(ed.E B Roche,American Pharmaceutical Association)中找到,其公开内容通过引用整体并入本说明书。
本发明的前药可以例如通过用本领域技术人员已知为“前部分”的某些部分代替本发明化合物中存在的适当官能团来制备,例如在H Bundgaard的"Design of Prodrugs"(Elsevier,1985)中描述的,其公开内容通过引用整体并入本说明书。
根据本发明前药的一些实例包括:
(i)如果所述化合物包含羧酸官能团-(COOH),则前药为其酯,例如,用(C1-C8)烷基替代氢;
(ii)如果所述化合物包含醇官能团(-OH),则前药为其醚,例如,用(C1-C6)烷酰氧基甲基替代氢;以及
(iii)如果所述化合物包含伯或仲氨基官能团(-NH2或-NHR,其中R≠H),则前药为其酰胺,例如,用(C1-C10)烷酰基替代一个或两个氢。
根据上述实例和其他前药类型实例的替代基团的另外实例可以在上述参考文献中找到。
最后,某些发明化合物本身可以充当其他本发明化合物的前药。
包含一个或多个不对称碳和/或磷原子的本发明化合物可以作为两种或更多种立体异构体存在。如果根据本发明的化合物具有至少一个手性中心时,它们可以相应地以对映异构体的形式存在。如果所述化合物具有两个或更多个手性中心,它们可以另外以非对映体形式存在。类似地,如果本发明的化合物包含环丙基或其中手性存在的其他环状基团,以及烯基或亚烯基,则几何顺式/反式(或Z/E)异构体是可能的。如果化合物包含,例如,可能会发生酮基或肟基或芳族部分,则互变同分异构现象(“互变异构现象”)可以出现。单一化合物可以表现出多于一种类型的同分异构现象。
本发明的范围内包括本发明化合物的所有立体异构体、几何异构体和互变异构形式,包括表现出多于一种类型的同分异构现象的化合物及其一种或多种的混合物。还包括酸加成盐或碱式盐,其中抗衡离子为旋光性的,例如D-乳酸盐或L-赖氨酸,或外消旋体,例如DL-酒石酸盐或DL-精氨酸。
顺式/反式异构体可以通过本领域技术人员众所周知的常规技术,例如色谱法和分级结晶分离。
用于制备/分离单个对映异构体的常规技术包括由适合的光学纯前体进行手性合成或使用例如手性高压液相色谱(HPLC)或超临界流体色谱法(SFC)拆分外消旋体(或盐或衍生物的外消旋体)。
或者,可将外消旋体(或外消旋前体)与适合的光学活性化合物(例如,醇)反应,或者在化合物包含酸性或碱性部分的情况下,与酸或碱例如酒石酸或1-苯乙胺反应。可以通过色谱法和/或分级结晶分离得到的非对映异构体混合物,并且通过本领域技术人员众所周知的方式将非对映异构体的一种或两种转化为相应的纯对映体。
立体异构体混合体可以通过本领域技术人员已知的常规技术分离;参见,例如E LEliel的“Stereochemistry of Organic Compounds”(Wiley,New York,1994),其公开内容通过引用整体并入本说明书。
本发明还包括本发明的同位素标记的化合物,其中一个或多个原子被具有相同原子序数但原子量或原子数不同于自然界通常发现的原子量或原子数的原子替代。适用于包含在本发明化合物中的同位素的例子包括如下的同位素:氢,例如2H和3H,碳,例如11C、13C和14C,氯,例如36Cl,氟,例如18F,碘,例如123I和125I的同位素,氮,例如13N和15N,氧,例如15O、17O和18O,磷,例如32P,和硫,例如35S。本发明的某些同位素标记的化合物,例如掺入放射性同位素的那些可用于药物和/或底物组织分布研究。考虑到它们的易于掺入和易于检测的方式,放射性同位素为氚3H和碳-14 14C对此目的特别有用。用重氢同位素(例如氘2H)取代由于代谢稳定性更高而可以提供某些治疗优势,例如,体内半衰期延长或剂量需求降低,因此在某些情况下可能是优选的。用正电子发射同位素例如11C、18F、15O和13N取代可用于正电子发射断层摄影术(PET)研究中,以检查底物受体的占有率。
本发明的同位素标记的化合物通常可以通过本领域技术人员已知的常规技术或通过与本说明书中所述的那些类似的方法,使用适合的同位素标记的试剂替代非标记试剂来制。
根据本发明的药学上可接受的溶剂化物包括其中结晶溶剂可以被同位素取代,例如D2O、d6-丙酮、d6-DMSO的溶剂化物,。
预期用于制药用途的本发明化合物可以以结晶产物或无定形产物或其混合物形式施用。它们可以例如通过沉淀,结晶,冷冻干燥,喷雾干燥或蒸发干燥的方法作为例如固体塞、粉末或膜得到。为此目的可以使用微波或射频干燥。
所述化合物可以单独施用或与一种或多种本发明的其他化合物组合施用。通常,它们将与一种或多种药学上可接受的赋形剂一起作为制剂施用。术语“赋形剂”在本说明书中用于描述除本发明的化合物以外的任何成分。赋形剂的选择在很大程度上取决于例如特定的施用方式、赋形剂对溶解性和稳定性的作用以及剂型的性质等因素。
本说明书中所述的组合物可以单独地或与药学上可接受的赋形剂组合以足以诱导、改变或刺激适当的免疫应答的量施用于宿主。免疫应答可以包含,但不限于特异性免疫应答、非特异性免疫应答、特异性和非特异性应答、先天应答、初级免疫应答、适应性免疫、继发性免疫应答、记忆免疫应答、免疫细胞活化、免疫细胞增殖、免疫细胞分化和细胞因子表达。在某些实施方案中,将组合物与一种或多种其他组合物联合施用,所述其他组合物包括旨在刺激对一种或多种预定抗原的免疫应答的疫苗;佐剂;CTLA-4和PD-1途径拮抗剂,脂质,脂质体,化疗剂,免疫调节细胞系等。
在本发明的一些方面,本说明书中所述的方法进一步包括用另外的疗法形式治疗受试者的步骤。在一些方面,另外的疗法形式为另外的抗癌疗法,包括,但不限于化疗,放疗,手术,激素疗法和/或另外的免疫疗法。
所公开的STING调节性化合物可以作为初始治疗或用于对常规疗法无反应的癌症的治疗而施用。另外,所公开的STING调节化合物可以与其他疗法(例如手术切除,放射线,其他抗癌药等)组合使用,从而引起累加和或增强的治疗效果和/或降低某些抗癌药的细胞毒性。本发明的STING调节化合物可以与另外的药剂共同施用或共同配制,或者配制为以任何顺序与另外的药剂连续施用。
本发明的STING调节性化合物可以与其他治疗剂组合使用,其他治疗剂包括,但不限于治疗抗体,ADC,免疫调节剂,细胞毒性剂和细胞生长抑制剂。细胞毒性作用是指靶细胞(即肿瘤细胞)的消耗、消除和/或杀伤。细胞毒性剂是指对细胞具有细胞毒性和/或细胞抑制作用的活性剂。抑制细胞作用是指抑制细胞增殖。细胞生长抑制剂是指对细胞具有细胞生长抑制作用的试剂,从而抑制细胞的特定亚群(即肿瘤细胞)的生长和/或扩增。免疫调节剂是指通过细胞因子和/或抗体的产生和/或调节T细胞功能,因此通过使另一种活性剂更为有效而直接或间接抑制或减少细胞亚群(即肿瘤细胞)生长来刺激免疫应答的活性剂。
对于联合疗法,应在适合进行预期疗法的任何时间范围内施用STING调节化合物。因此,可以基本上同时(即,作为单一制剂或在数分钟或数小时内)或以任何顺序连续施用单一药剂。例如,单一药剂治疗可在彼此约一年内,例如在约10、8、6、4或2个月内,或在4、3、2或1周内,或在约5、4、3、2或1天内施用。
所公开的联合疗法可引起协同治疗作用,即大于其各自作用或治疗结果之和的作用。例如,协同治疗作用可以是比单一药剂引起的治疗作用或者给定组合的单一药剂引起的治疗作用的总和大至少约两倍,或者至少约五倍,或至少约十倍,或至少约二十倍,或至少约五十倍,或至少约一百倍。也可以将协同治疗作用测定为与单一药剂引起的治疗作用或者给定组合的单一药剂引起的治疗作用的总和相比增加至少10%,或至少20%或至少30%或至少40%或至少50%或至少60%或至少70%或至少80%或至少90%或至少100%或更多。协同作用也是一种当组合使用治疗剂时允许减少它们的给药的作用。
所述组合物可以在另外的治疗或预防组合物或模式之前、之后施用和/或与之一起施用。这些包括,但不限于B7共刺激分子,白细胞介素-2,干扰素7,GM-CSF,CTLA-4拮抗剂,OX-40/OX-40配体,CD40/CD40配体,沙格司亭,左旋咪唑,痘苗病毒,卡介苗(BCG),脂质体,明矾,弗氏完全或不完全佐剂,解毒的内毒素,矿物油,表面活性物质,例如脂卵磷脂,普卢兰尼克多元醇,聚阴离子,肽和油或烃乳液。优选诱导T细胞免疫应答的载体,相对于抗体应答其优选刺激溶细胞性T细胞应答,不过,也可以使用刺激两种类型应答的载体。在活性剂为多肽的情况下,可以施用多肽本身或编码该多肽的多核苷酸。载体可以是细胞,例如抗原呈递细胞(APC)或树突细胞。抗原呈递细胞包括例如巨噬细胞、树突细胞和B细胞这样的细胞类型。其他专业的抗原呈递细胞包括单核细胞,边缘区枯否细胞,小神经胶质细胞,朗格汉斯细胞,指状突细胞,滤泡树突细胞和T细胞。也可以使用兼性抗原呈递细胞。兼性抗原呈递细胞的实例包括星形细胞,滤泡细胞,内皮和成纤维细胞。载体可以是细菌细胞,其被转化以表达多肽或递送多核苷酸,其随后在接种个体的细胞中表达。可以添加佐剂,例如氢氧化铝或磷酸铝,以增加疫苗触发、增强或延长免疫应答的能力。其他物质也是潜在的佐剂,例如细胞因子、趋化因子和细菌核酸序列,例如CpG、toll样受体(TLR)9激动剂,以及TLR2、TLR 4、TLR 5、TLR 7、TLR 8、TLR9的其他激动剂,包括脂蛋白、LPS、单磷酰脂质A,脂磷壁酸,咪喹莫特,瑞喹莫德和此外视黄酸诱导型基因I(RIG-I)激动剂,例如I:C,它们可以单独使用或与所述组合物组合使用。佐剂的其他代表性实例包括合成的佐剂QS-21,其包含从皂树(Quillaja saponaria)皮和Colynebacterium parvum纯化的均质皂苷(McCune等人,Cancer,1979;43:1619)。应当理解,将所述佐剂进行优化。换句话说,本领域技术人员可以进行常规实验以确定要使用的最佳佐剂。
适合于递送本发明化合物的药物组合物及其制备方法对于本领域技术人员而言将是非常明显的。这样的组合物及其制备方法可以在例如‘Remington’s PharmaceuticalSciences’,第19版(Mack出版公司,1995)中找到,其公开内容通过引用整体并入本说明书。
本发明的化合物可以直接施用到血流,肌肉或内部器官中。肠胃外施用的适合方式包括静脉内,动脉内,腹膜内,鞘内,心室内,尿道内,胸骨内,颅内,肌内,皮下和肿瘤内。用于肠胃外施用的适合装置包括针头(包括微型针头)注射器、无针头注射器和输注技术。
肠胃外制剂典型地为水溶液,其可以包含赋形剂例如盐、碳水化合物和缓冲剂(优选至pH为3-9),但是对于某些应用,可以将它们更适当地配制成无菌的非水溶液或作为干燥形式,与适合的介质例如无菌、无热原的水一起使用。
在无菌条件下,例如通过冻干,使用本领域技术人员众所周知的标准制药技术,可以容易地完成肠胃外制剂的制备。
可以通过使用适当的配制技术来增加用于肠胃外溶液制备的本发明化合物的溶解度,例如掺入溶解度增强剂。肠胃外施用的制剂可以配制成立即释放和/或改进释放。改进释放制剂包括延迟释放,持续释放,脉冲释放,受控释放,靶向释放和程序释放。因此,可以将本发明的化合物配制成固体、半固体或触变液体,以作为植入的贮库施用,从而提供活性化合物的改进释放。这种制剂的例子包括涂布药物的支架和PLGA微球。
纳米粒还代表适用于大多数施用途径的药物递送系统。多年来,已经探索了各种天然和合成聚合物来制备纳米粒,其中对聚乳酸(PLA)、聚乙醇酸(PGA)及其共聚物(PLGA)进行了广泛的研究,这归因于它们的生物相容性和生物降解性。纳米粒和其他纳米载体可作为多种药物的潜在载体,例如抗癌药、抗高血压药、免疫调节剂和激素;以及大分子,例如核酸、蛋白质、肽和抗体。参见,例如,Crit.Rev.Ther.Drug Carrier Syst.21:387-422,2004;Nanomedicine:Nanotechnology,Biology and Medicine I:22-30,2005。
本发明的组合物可以包含一种或多种另外的药物活性成分,或与一种或多种另外的药物活性成分一起施用,例如佐剂,脂质,双层间交联的多层脂质体,可生物降解的聚(D,L-乳酸-乙醇酸)基于[PLGA]的或基于聚酸酐的纳米粒和纳米多孔支持的脂双层,例如脂质体,CTLA-4和PD-1途径的拮抗剂,PD-1途径阻断剂,诱导先天性免疫的灭活细菌(例如,灭活或减毒的李斯特菌单核细胞增生李斯特菌(listeria monocytogenes)),通过Toll样受体(TLR)、(NOD)样受体(NLR)、基于视黄酸诱导型基因的(RIG)-I样受体(RLR)、C型凝集素受体(CLR)、病原体相关分子模式(“PAMPs”)、化疗剂等介导先天性免疫活化的组合物。
本发明的化合物和组合物可以作为抗体-药物缀合物或其他靶向递送方式的组分施用。
局部施用
本发明的化合物可以与可溶性大分子实体,例如环糊精及其适合的衍生物或含聚乙二醇的聚合物组合,以改善其溶解性、溶出速率、掩味、生物利用度和/或稳定性,以用于上述任何一种施用方式。
例如,发现药物-环糊精复合物通常可用于大多数剂型和施用途径。包合物和非包合物都可以使用。作为与药物直接复合的替代选择,环糊精可以用作辅助添加剂,即用作载体、稀释剂或增溶剂。最常用于这些目的是α-环糊精、β-环糊精和γ-环糊精,其实例可以在PCT公开号WO 91/11172、WO 94/02518和WO 98/55148中找到,其公开内容通过引用整体并入本说明书。
剂量:活性化合物的施用量取决于所治疗的受试者,疾病或病症的严重程度,施用速率,化合物的处置以及开处方医师的判断力。一种可能的剂量范围为约0.001至约100毫克/千克体重,以每天,每隔一天,每三天,每四天,每五天,每六天,每周,每两周,每月一次施用,或按其他给药方案施用。在某些情况下,低于上述范围下限的剂量水平可能足够,而在其他情况下,仍可以使用较大剂量而不会引起任何有害副作用,这种较大剂量典型地分成几个较小的剂量进行在一整天内施用。
部件套装产品:由于可能需要施用活性化合物的组合,例如出于治疗特定疾病或病症的目的,在本发明的范围内,可以将两种或更多种药物组合物便利地合并在适合于共同施用所述组合物的套装产品小时中,所述药物组合物中的至少一种包含本发明的化合物。因此,本发明的套装产品包括两种或更多种分开的药物组合物,其中至少一种包含本发明的化合物和用于分开保存所述组合物的装置,例如容器,分开的瓶子或分开的箔包装。这类套装产品的实例为用于包装片剂、胶囊等的常见的泡罩包装。
本发明的套装产品特别适合于施用不同的剂型,例如口服和肠胃外的剂型,其用于以不同的剂量间隔施用分离的组合物,或使所述分离的组合物彼此递增。为有助于一次性,该套装产品典型地包括施用说明书,并可能附带记忆辅助工具。
实施例
通用方法
合成实验方法:
一般而言在惰性气氛(氮气或氩气)下进行实验,特别是在使用对氧气或湿气敏感的试剂或中间体的情况下。商品溶剂和试剂通常没有进一步纯化即使用,并用分子筛干燥(通常为来自Aldrich化学公司,Milwaukee,Wisconsin的Sure-SealTM产品)。质谱数据根据液相色谱-质谱法(LC-MS)、大气压化学电离(APCI)、电喷雾电离(ESI)或液相色谱-飞行时间(LC-TOF)方法报道。核磁共振(NMR)数据的化学位移以参比所用氘代溶剂的残留峰的百万分之份数(ppm)表示。
对于其他实施例或方法中的合成参比方法,反应方案(反应时长和温度)可以改变。通常,通过薄层色谱法、LC-MS或HPLC跟踪反应,并在适当时进行后处理。实验之间的纯化可以改变:通常选择用于洗脱剂/梯度的溶剂和溶剂比例,得到了适当的保留时间。除非另有说明,否则反相HPLC级分通过冻干/冷冻干燥进行浓缩。将中间体和最终化合物在氮气气氛中于(0℃)或室温下保存在封闭的小瓶或烧瓶中。化合物名称使用Chemdraw或ACDLabs软件生成。
溶剂和/或试剂的缩写基于美国化学学会(American Chemical Society)指南,并突出显示如下:
Ac=乙酰基;Boc=N-叔丁氧基羰基;BTT=苄硫基四唑;CDI=N,N'-羰基二咪唑;DCA=二氯乙酸;DCC=1,3-二环己基碳二亚胺;DCE=二氯乙烷;DCM=二氯甲烷;DDTT=(E)-N,N-二甲基-N'-(3-亚硫基-3H-1,2,4-二噻唑-5-基)甲酰亚胺;DEA=N,N-二乙胺;DIBAL-H=氢化二异丁基铝;DIPEA=N,N-二异丙基乙胺;DMA=二甲基乙酰胺;DMAP=4-二甲基氨基吡啶;DME=二甲氧基乙烷;DMF=N,N-二甲基甲酰胺;DMOCP=2-氯-5,5-二甲基-1,3,2-二氧杂磷杂环己烷2-氧化物;DMSO=二甲亚砜;DMT=二甲氧基三苯甲基;DMTCl=二甲氧基三苯甲基氯;DPPA=二苯基磷酰基叠氮化物;EDCI=1-乙基-3-(3-二甲基氨基丙基)碳二亚胺;EtOAc=乙酸乙酯;ETT=乙硫基四唑;Fmoc=芴基甲氧基羰基;h=小时;HATU=o-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐;HBTU=N,N,N′,N′-四甲基-O-(1H-苯并三唑-1-基)脲鎓六氟磷酸盐;HOAc=乙酸;HOAt=1-羟基-7-氮杂苯并三唑;HOBt=1-羟基苯并三唑水合物;LDA=二异丙基氨基锂;Me=甲基;MTBE=甲基叔丁基醚;n-BuLi=正丁基锂;NBS=N-溴琥珀酰亚胺;NMM=N-甲基吗啉;NMO=N-甲基吗啉N-氧化物;Ph=苯基;PivCl=新戊酰氯;PPTS=对甲苯磺酸吡啶鎓;p-TsOH=对-甲苯磺酸;rt=室温;TEAB=溴化四乙基铵;TBAI=碘化四丁基铵;TBS=叔丁基二甲基甲硅烷基;TBSCl=叔丁基二甲基甲硅烷基氯;TEA=三乙胺;Tf=三氟甲磺酸酯;TFA=三氟乙酸;THF=四氢呋喃;以及TPTU=O-(2-氧代-1(2H)吡啶基)-N,N,N,’N’-四甲基脲鎓四氟硼酸盐。
通用方案
方案1:
一般而言,基于环戊烷的STING活化剂的合成可以类似于用于制备环状二核苷酸合成中发现的适合大环化合物的路径(Gaffney B.L.等人;Organic Letters 2010 12(14)3269-3271)。
如方案1中示例的,手性烯丙型乙酸酯1a可以商购或合成(Deardorff D.等人;Tetrahedron Letters 1986 27(11)1255-1256)。烯丙型烷基化可以使用含氮杂环或核碱基进行,形成化合物例如1b(Trost,B.等人;Angew.Chem.Int.Ed.1996,35 1569-1572)。这些反应典型地使用钯催化剂、膦配体和碱性条件进行。其他金属催化剂和配体组合也可以用于实现相同的转化。典型地,使用二甲氧基三苯甲基氯(DMTCl)和碱实现用二甲氧基三苯甲基(DMT)保护烯丙型醇1b,得到了化合物,例如1c。用催化剂四氧化锇和N-甲基哌啶N-氧化物使1c的双键典型地二羟基化,得到了合物,例如1d。其他二羟基化试剂,例如高锰酸盐或四氧化钌可以用于相同的转化。典型地,可以使用四丁基二甲基甲硅烷基氯(TBSCl)与四唑或三氟甲磺酸四丁基二甲基甲硅烷基酯(TBSOTf)和碱对化合物例如1d进行单保护,得到了化合物,例如1e。当用3-((氯(二异丙基氨基)磷)氧基)丙腈和碱处理时,亚磷酰胺类化合物,例如化合物1f典型地由化合物例如1e制备。H-膦酸酯和硫代-H-膦酸酯,例如化合物1g通常由适当保护的核苷和膦酸的混合酸酐制备,然后如果必要,使其硫化。除去保护基,以揭示出伯醇1g。在用酸性活化剂处理亚磷酰胺类化合物例如1f后通常发生化合物例如1g和1f的偶联。然后用硫化剂例如DDTT、3H-苯并二硫杂环戊-3-酮或类似试剂使得到的偶联物质硫化,产生硫代膦酸酯,例如1h。否则,可以用试剂例如叔丁基过氧化物或类似氧化剂氧化偶联的物质,产生磷酸酯,例如1h。可以用弱酸例如二氯乙酸处理化合物,例如1h,以揭示出化合物,例如1i。可以用试剂例如DMOCP活化H-膦酸酯化合物,例如1i,以影响大环化,然后用试剂例如3H-苯并二硫杂环戊-3-酮将其硫化,生成环状硫代膦酸酯,例如1j,或用试剂例如叔丁基过氧化物氧化,生成环状磷酸酯,例如1j。在适当脱保护条件后,可以生成环状二硫代膦酸酯、二磷酸酯或混合的硫代膦酸酯-磷酸酯化合物,例如1k。可以通过标准技术例如柱色谱法、结晶、反相HPLC或SFC纯化每个步骤的化合物。如果必要,1k的非对映异构体的分离可以在本领域已知的标准方法例如手性SFC或HPLC下进行,得到了单一非对映异构体。注意:“A”表示碳(也结合氢或取代基)或氮。
实施例1
(4S,6R,7S,11aR,13R,14R,14aR,15R)-6,13-双(6-氨基-9H-嘌呤-9-基)-14-氟-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-15-醇2,9-二氧化物的合成
方案A
步骤1:N-(9-((1R,4S)-4-羟基环戊-2-烯-1-基)-9H-嘌呤-6-基)苯甲酰胺(A-3)的合成
向配备磁力搅拌棒并且用N2吹扫的烘干的圆底烧瓶(烧瓶A)中加入A-1(8330mg,34.8mmol)和DMF(50mL)。在N2气氛中向该溶液中加入NaH(60wt%的矿物油分散体,1530mg,38.3mmol)。向配备磁力搅拌棒并且用N2吹扫的第二个圆底烧瓶(烧瓶B)中加入A-2(4950mg,34.8mmol)、Pd(PPh3)4(2490mg,2.16mmol)、PPh3(913mg,3.48mmol)和THF(50mL)。30min后,将烧瓶A中的溶液转入烧瓶B。然后将烧瓶B放入油浴,在50℃在N2气氛中加热12小时。用H2O(100mL)使该反应混合物淬灭,用EtOAc转入分液漏斗。分离各相,用EtOAc(100mLx 2)和DCM/MeOH(5:1,100mL x 5)萃取合并的有机相。真空浓缩合并的有机萃取物。通过急骤柱色谱法纯化由此得到的粗残余物(240g SiO2,Isco,9%MeOH/DCM,得到了A-3(19.7g,88%),为黄色固体。LCMS[M+H]=322测定值;1H NMR(400MHz,DMSO-d6)δppm=11.18(s,1H),8.79-8.73(m,1H),8.45-8.38(m,1H),8.05(br d,J=7.5Hz,2H),7.73-7.51(m,4H),6.30-6.20(m,1H),6.07(br d,J=5.4Hz,1H),5.61(br dd,J=3.9,5.2Hz,1H),5.38(d,J=6.2Hz,1H),4.81-4.72(m,1H),3.02-2.91(m,1H),1.79(td,J=4.5,13.8Hz,1H)。
步骤2:N-(9-((1R,4S)-4-(双(4-甲氧基苯基)(苯基)甲氧基)环戊-2-烯-1-基)-9H-嘌呤-6-基)苯甲酰胺(A-4)的合成
向配备磁力搅拌棒的圆底烧瓶中加入A-3(19.7g,61.3mmol)和无水吡啶(50mL)。真空浓缩该溶液至干,再高度真空干燥1h。用N2吹扫烧瓶,然后添加无水吡啶(150mL)和DMTCl(23.9g,70.5mmol)。将该反应体系在9℃在N2气氛中搅拌12小时。用H2O使该反应体系淬灭,用EtOAc转入分液漏斗。分离各相,用EtOAc(200mL X 2)萃取水相。用盐水(100mL x2)洗涤有机萃取物,干燥(Na2SO4),过滤,真空浓缩。通过急骤柱色谱法纯化由此得到的粗残余物(240g SiO2,Isco,100%EtOAc),得到了A-4(29.2g,76%),为黄色固体。LCMS[M+H]=624测定值;1H NMR(400MHz,氯仿-d)δppm=8.94(br s,1H),8.79(s,1H),8.26(s,1H),8.03(br d,J=7.5Hz,2H),7.64-7.59(m,1H),7.57-7.47(m,4H),7.44-7.36(m,4H),7.35-7.28(m,2H),7.26-7.20(m,1H),6.87-6.81(m,4H),5.90(dd,J=1.5,5.5Hz,1H),5.65(td,J=1.8,5.5Hz,1H),5.56-5.48(m,1H),4.78-4.71(m,1H),3.80(d,J=1.0Hz,6H),2.58-2.47(m,1H),1.56(td,J=3.6,14.7Hz,1H)。
步骤3:N-(9-((1R,2S,3S,4S)-4-(双(4-甲氧基苯基)(苯基)甲氧基)-2,3-二羟基环戊基)-9H-嘌呤-6-基)苯甲酰胺(A-5)的合成
向配备磁力搅拌棒的圆底烧瓶中加入A-4(29.2g,46.8mmol)、DCM(300mL)和H2O(18mL)。向该黄色溶液中加入NMO(16.5g,140mmol)和OsO4(4%的t-BuOH溶液,20.8g,3.28mmol)。将该反应体系在16℃搅拌5小时。然后用DCM(50mL)将该反应体系转入分液漏斗,用饱和Na2SO3(100mL)淬灭。分离各相,用(100mL)洗涤有机相,干燥(Na2SO4),过滤,真空浓缩。通过急骤柱色谱法纯化由此得到的粗残余物(120g SiO2,Isco,3%MeOH/DCM-5%MeOH/DCM),得到了A-5(24.9g,80%),为黄色固体。LCMS[M+H]=658测定值;1H NMR(400MHz,氯仿-d)δppm=9.09(br s,1H),8.78-8.59(m,1H),8.02(br d,J=7.3Hz,2H),7.93-7.85(m,1H),7.60(br dd,J=4.8,6.3Hz,1H),7.56-7.39(m,5H),7.39-7.27(m,6H),7.25-7.19(m,1H),6.84(br d,J=8.8Hz,4H),5.69(br s,1H),4.65(br d,J=7.0Hz,2H),4.16(br d,J=1.3Hz,1H),3.92(br s,1H),3.78(d,J=2.0Hz,6H),3.72(t,J=4.5Hz,2H),2.95(br s,1H),2.45-2.33(m,2H),1.94-1.75(m,1H)。
步骤4:N-(9-((1R,2S,3S,4S)-4-(双(4-甲氧基苯基)(苯基)甲氧基)-3-((叔丁基二甲基甲硅烷基)氧基)-2-羟基环戊基)-9H-嘌呤-6-基)苯甲酰胺(A-6)的合成
在0℃向配备磁力搅拌棒并且在N2气氛中冷却的烘干的圆底烧瓶中滴加A-5(4.12g,6.264mmol),DCM(200mL)、Et3N(3170mg,31.3mmol)和TBSOTf(2.49mg,9.4mmol)。除去冰浴,将该反应体系在N2气氛中在20℃搅拌12小时。在该阶段,通过LCMS仍然检测到原料,在0℃再向该混合物中滴加等分的TBSOTf(2485mg,9.4mmol)。除去冰浴,将该反应混合物在N2气氛中在20℃搅拌12小时。用MeOH(15mL)使该反应体系淬灭。用DCM将该溶液转入分液漏斗,再用H2O稀释。分离各相,用1部分H2O、1部分盐水洗涤有机相,干燥(Na2SO4),过滤,真空浓缩。通过急骤柱色谱法纯化粗残余物(40g SiO2,Isco,40%EtOAc/石油醚至50%EtOAc/石油醚),得到了A-6(1.29g,26%),为白色固体。LCMS[M+H]=772测定值;1H NMR(400MHz,氯仿-d)δppm=8.95(s,1H),8.78(s,1H),8.09(s,1H),8.05-7.98(m,2H),7.64-7.57(m,1H),7.56-7.47(m,3H),7.56-7.47(m,1H),7.44-7.34(m,4H),7.33-7.28(m,2H),7.26-7.19(m,1H),6.88-6.79(m,4H),4.76(dd,J=5.6,11.7Hz,1H),4.70-4.62(m,1H),4.38(br s,1H),4.10-4.06(m,1H),3.78(d,J=1.3Hz,6H),2.98(d,J=8.8Hz,1H),2.17(s,1H),0.99(br dd,J=4.6,15.2Hz,1H),0.93-0.85(m,9H),0.14(s,3H),0.03(s,3H)。
步骤5:(1S,2R,3S,5R)-5-(6-苯甲酰氨基-9H-嘌呤-9-基)-3-(双(4-甲氧基苯基)(苯基)甲氧基)-2-((叔丁基二甲基甲硅烷基)氧基)环戊基(2-氰基乙基)二异丙基亚磷酰胺(A-7)的合成
向配备磁力搅拌棒并且用N2吹扫的烘干圆底烧瓶中加入A-6(8.80g,11.4mmol)、DIPEA(14.7g,114mmol)和无水DCM(320mL)。向该溶液中加入3-((氯(二异丙基氨基)磷基)氧基)丙腈(13.5g,57.0mmol)。将该反应体系在15℃搅拌4小时。用NaHCO3(120mL)饱和使该反应体系淬灭,用DCM(50mL)转入分液漏斗。分离各相,用(100mL)洗涤有机相,干燥(Na2SO4),真空浓缩。通过急骤柱色谱法纯化由此得到的粗残余物(120g SiO2,Isco,40%EtOAc/石油醚-60%EtOAc/石油醚)2次,得到了A-7(8.57g,77%),为淡黄色固体。LCMS[M+H]=972测定值;1H NMR(400MHz,氯仿-d)δppm=8.91(d,J=11.3Hz,1H),8.79(d,J=4.0Hz,1H),8.22-8.13(m,1H),8.08-7.98(m,2H),7.65-7.58(m,1H),7.52(q,J=7.2Hz,4H),7.44-7.35(m,4H),7.31(dt,J=1.4,7.5Hz,2H),7.25-7.21(m,1H),6.84(td,J=2.0,9.0Hz,4H),5.15-5.00(m,1H),4.99-4.79(m,1H),4.31-3.98(m,2H),3.78(s,6H),3.76-3.57(m,2H),3.50-3.34(m,2H),2.60(t,J=6.3Hz,1H),2.52-2.25(m,2H),1.33-1.14(m,1H),1.11(d,J=6.8Hz,3H),1.02(t,J=7.4Hz,6H),0.85(s,9H),0.79(d,J=6.8Hz,3H),0.11(d,J=11.8Hz,3H),-0.06(d,J=0.8Hz,3H);31P NMR(162MHz,氯仿-d)δppm=149.67(s,1P),147.94(s,1P)。
方案B
步骤1:N-(9-((2R,3R,4R,5R)-5-((双(4-甲氧基苯基)(苯基)甲氧基)甲基)-3-氟-4-羟基四氢呋喃-2-基)-9H-嘌呤-6-基)苯甲酰胺(B-2)的合成
向配备磁力搅拌棒的圆底烧瓶中加入商购的N-(9-((2R,3R,4R,5R)-3-氟-4-羟基-5-(羟基甲基)四氢呋喃-2-基)-9H-嘌呤-6-基)苯甲酰胺B-1(42.00g,37.50mmol),与无水吡啶共蒸发3次。将残余物再溶于吡啶(70mL),然后在0℃添加DMTCl(13.98g,41.25mmol)。将该混合物在25℃搅拌12h。减压浓缩该反应混合物。用DCM(200mL)稀释残余物,部分饱和NaHCO3溶液洗涤3次(200mL)。用Na2SO4(25.00g)干燥有机层,过滤,减压浓缩。通过急骤柱色谱法纯化粗残余物(SiO2,85%石油醚/EtOAc-100%EtOAc),得到了B-2(68.7g,85%),为白色固体,未经进一步纯化它被用于下一步。LCMS[M+H]=676测定值。
步骤2:(2R,3R,4R,5R)-5-(6-苯甲酰氨基-9H-嘌呤-9-基)-2-((双(4-甲氧基苯基)(苯基)甲氧基)甲基)-4-氟四氢呋喃-3-基氢膦酸酯(B-3)的合成
注意:平行进行6次反应。向配备磁力搅拌棒的圆底烧瓶中加入膦酸(21.8g,266mmol),与无水吡啶(60mL)共蒸发3次。将残余物溶于无水吡啶(180mL),同时适度加热(30℃)。在30℃向该溶液中加入B-2(12.0g,17.8mmol),此后,将由此得到的溶液冷却至0℃。在0℃向该混合物中滴加2,2-二甲基丙酰氯(21.4g,177mmol)。将该混合物温热至30℃,搅拌12h。合并6次反应。用1M TEAB(1200mL)使该反应混合物淬灭,转入分液漏斗。用3(1000mL)部分EtOAc萃取该溶液。用0.5M TEAB(500mL)、盐水(500mL)洗涤合并的有机萃取物,用Na2SO4(35.0g)干燥,过滤,真空浓缩。通过急骤柱色谱法纯化粗残余物(SiO2,2%MeOH/DCM-5%MeOH/DCM,1%TEA),以除去主要杂质,得到了B-3(100.0g,粗),为白色固体,未经进一步纯化它被用于下一步。LCMS[M-H]=738测定值。
步骤3:(2R,3R,4R,5R)-5-(6-苯甲酰氨基-9H-嘌呤-9-基)-4-氟-2-(羟基甲基)四氢呋喃-3-基氢膦酸酯(B-4)的合成
注意:平行进行5次反应。向配备磁力搅拌棒的圆底烧瓶中加入B-3(20.0g,27.0mmol),加入DCA(17.4g,135mmol)在DCM(200mL)中的溶液。将该混合物在25℃搅拌0.5h。合并5次反应。过滤反应混合物中的固体产物,与DCM(300mL)一起研磨,得到了B-4(40.0g,63%),为白色固体。LCMS[M+H]=438测定值;1H NMR(400MHz,DMSO-d6)δppm=11.95-10.65(m,1H),8.78(s,1H),8.73(s,1H),8.05(d,J=7.3Hz,2H),7.71-7.61(m,1H),7.61-7.49(m,2H),6.69(s,1H),6.46(dd,J=3.1,16.6Hz,1H),5.82(td,J=3.4,51.7Hz,1H),5.30-5.16(m,1H),4.31-4.20(m,1H),3.80(dd,J=2.8,12.2Hz,1H),3.67(dd,J=3.7,12.5Hz,1H);19F NMR(377MHz,DMSO-d6)δppm=-203.02(s,1F);31P NMR(162MHz,DMSO-d6)δppm=4.20(s,1P)。
方案C
步骤1:(2R,3R,4R,5R)-5-(6-苯甲酰氨基-9H-嘌呤-9-基)-2-((((((1S,2R,3S,5R)-5-(6-苯甲酰氨基-9H-嘌呤-9-基)-2-((叔丁基二甲基甲硅烷基)氧基)-3-羟基环戊基)氧基)(2-氰基乙氧基)硫代磷酰基)氧基)甲基)-4-氟四氢呋喃-3-基氢膦酸酯(C-1)的合成
向配备磁力搅拌棒的圆底烧瓶中加入H-膦酸酯B-4(1.0g,2.29mmol)和三氟乙酸吡啶鎓(1.77g,9.15mmol)。将固体溶于无水MeCN(10mL x 2),真空浓缩。将残余物再溶于无水MeCN(30mL),加入3A分子筛(4.0g)。将该溶液搅拌30分钟,此时加入亚磷酰胺A-7(2.67g,2.74mmol)。将该反应体系在rt搅拌1.5小时,在此期间得到均匀溶液。向该反应体系中加入DDTT(493mg,2.40mmol),将该反应体系在rt搅拌过夜。过滤该反应体系,用MeOH/DCM(1:1)洗涤固体。真空浓缩滤液,然后与正己烷/TBME(1:1)一起研磨。通过制备型高效液相色谱法纯化由此得到的粗残余物(Phenomenex Synergi Max-RP 150x50mmx10μm,含有10mMNH4HCO3的20%MeCN/H2O-含有10mM NH4HCO3的50%MeCN/H2O,120mL/min),得到了C-1(390mg,13%),为白色固体。LCMS[M+H]=1038测定值;31P NMR(162MHz,甲醇-d4)δppm=68.24(s,1P),67.74(s,1P),2.95(s,1P),2.71(s,1P)。
步骤2:N,N'-{[(4S,6R,7S,11aR,13R,14R,14aR,15R)-15-{[叔丁基(二甲基)甲硅烷基]氧基}-9-(2-氰基乙氧基)-14-氟-2-氧化-2-硫基-9-硫八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6,13-二基]双(9H-嘌呤-9,6-二基)}二苯甲酰胺(C-2)的合成
向配备磁力搅拌棒并且在N2气氛中冷却的烘干的圆底烧瓶中加入C-1(320mg,0.308mmol)和无水吡啶(10mL)。在rt在N2气氛中向该溶液中加入DMOCP(1.02g,5.55mmol)。将该反应体系在N2气氛中搅拌1小时,此时原料耗尽。在rt在N2气氛中向该反应体系中加入H2O(333mg,18.5mmol)和3H-1,2-苯并二硫杂环戊-3-酮(130mg,0.770mmol)。将该反应体系在N2气氛中在rt搅拌30分钟。用饱和NaHCO3使该反应体系淬灭,用EtOAc转入分液漏斗。分离各相,用2部分EtOAc(60mL)萃取水相。用盐水洗涤合并的有机相,干燥(Na2SO4),过滤,真空浓缩。通过急骤柱色谱法纯化粗残余物(SiO2,Isco,9%MeOH/DCM-11%MeOH/DCM)。再通过制备型薄层色谱法进一步纯化得到的物质(SiO2,11%MeOH/DCM),得到了C-2(135mg,41%),为白色固体。LCMS[M+H]=1052测定值;31P NMR(162MHz,甲醇-d4)δppm=68.90(s,1P),68.33(s,1P),64.75(s,1P),64.68(s,1P),55.42(s,1P),53.26(s,1P),52.98(s,1P)。
步骤3:N,N'-{[(4S,6R,7S,11aR,13R,14R,14aR,15R)-15-{[叔丁基(二甲基)甲硅烷基]氧基}-14-氟-2,9-二氧化-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6,13-二基]双(9H-嘌呤-9,6-二基)}二苯甲酰胺(C-3)的合成
向包含C-2(130mg,0.124mmol)的烧瓶中加入乙腈(9mL)。向得到的混悬液中加入4.5mL叔丁基胺。该反应混合物变成溶液,在室温搅拌20min。浓缩该反应体系,得到了粗C-3,为白色固体,用于下一步。
LCMS[M+H]=999.21
31P NMR(162MHz,甲醇-d4)δppm 57.61(s,1P)57.20(s,1P)55.15(s,1P)54.77(s,1P)54.00(s,1P)53.94(s,1P)52.30(s,1P)52.04(s,1P)
步骤4:9,9'-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-15-{[叔丁基(二甲基)甲硅烷基]氧基}-14-氟-2,9-二氧化-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6,13-二基]双(9H-嘌呤-6-胺)(C-4)的合成
将粗物质C-3(123mg,0.123mmol)加到6mL 33%甲胺的EtOH溶液(0.02M)中。将该溶液在室温搅拌过夜。浓缩该反应混合物,得到了粗C-4,用于下一步。
LCMS[M+H]=791.15
31P NMR(162MHz,甲醇-d4)δppm 58.63(br.s.,1P)55.08(br.s.,1P)54.57(br.s.,1P)52.50(s,1P)52.26(s,1P)
19F NMR(376MHz,甲醇-d4)δppm-200.04(s,1F)-200.59(s,1F)-201.31(br.s.,1F)
步骤5:(4S,6R,7S,11aR,13R,14R,14aR,15R)-6,13-双(6-氨基-9H-嘌呤-9-基)-14-氟-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-15-醇2,9-二氧化物(C-5)的合成
将物质C-4(97.4mg,0.123mmol)与4mL吡啶/Et3N(v/v,3/1)共蒸发3次。将该物质溶于1.13mL吡啶(0.1M),添加N2,加入三乙胺(0.102mL,c=0.1M)和三氢氟化三乙胺(993mg,6.16mmol)。将得到的反应混合物在50℃加热过夜。用NaHCO3溶液使该反应混合物淬灭至pH 6。真空除去挥发性成分。通过反相制备型-HPLC纯化残余物(Phenomenex GeminiC18 21.2x 150mm 5u柱),用10-40%MeCN的NH4HCO3水溶液(10mM)洗脱,得到了2种非对映异构体化合物,为白色固体;以及另外的非对映异构体混合物。用Phenomenex Luna Omega 5uPolar C18 21.2 x 150mm柱分离另外的2种非对映异构体,用8-40%MeCN的NH4HCO3水溶液(10mM)洗脱。
峰1,13.76mg,15.8%;
LCMS[M+H]=677.00
1H NMR(400MHz,氧化氘)δppm 8.42(s,1H)8.34(s,1H)8.30(s,1H)7.90(s,1H)6.49(d,J=16.51Hz,1H)6.27(dd,J=49.34,4.28Hz,1H)5.36-5.46(m,1H)5.10-5.24(m,2H)4.65-4.69(m,1H)4.62(br.s.,1H)4.54(d,J=8.93Hz,1H)4.34(d,J=12.84Hz,1H)4.15(dd,J=12.29,5.69Hz,1H)2.99-3.11(m,1H)2.28(dd,J=15.96,6.05Hz,1H)
31P NMR(162MHz,氧化氘)δppm 56.18(br.s.,1P)50.55(s,1P)
19F NMR(376MHz,氧化氘)δppm-200.13(s,1F)
峰2,9.97mg,9%;
LCMS[M+H]=677.00
1H NMR(400MHz,氧化氘)δppm 8.39(s,1H)8.27(s,1H)8.27(s,1H)7.85(s,1H)6.47(d,J=16.63Hz,1H)5.74(m,1H)5.32-5.42(m,1H)5.11-5.27(m,2H)4.68-4.73(m,1H)4.60(br.s.,1H)4.51(d,J=9.05Hz,1H)4.31(d,J=11.98Hz,1H)4.07-4.15(m,1H)3.02-3.11(m,1H)2.31(dd,J=15.96,6.42Hz,1H)
31P NMR(162MHz,氧化氘)δppm 57.60(s,1P)53.47(s,1P)
19F NMR(376MHz,氧化氘)δppm-199.70(s,1F)
峰3,15.25mg,17.5%;
LCMS[M+H]=677.00
1H NMR(400MHz,氧化氘)δppm 8.27(s,1H)8.26(s,1H)8.22(s,1H)7.73(s,1H)6.45(d,J=16.75Hz,1H)6.27(dd,J=50.25,3.79Hz,1H)5.46-5.53(m,1H)5.04-5.18(m,2H)4.93-5.09(m,1H)4.61-4.67(m,2H)4.55(d,J=9.66Hz,1H)4.41(d,J=12.23Hz,1H)4.06-4.14(m,1H)2.94-3.09(m,1H)2.20(dd,J=15.47,6.30Hz,1H)
31P NMR(162MHz,氧化氘)δppm 51.67(br.s.,1P)50.40(s,1P)
19F NMR(376MHz,氧化氘)δppm-200.23(s,1F)
峰4,5.73mg,6.6%;
LCMS(ES,m/z):677.00[M+H]
1H NMR(400MHz,氧化氘)δppm 8.26(s,1H)8.24(s,1H)8.21(s,1H)7.74(s,1H)6.44(d,J=17.24Hz,1H)5.73(m.,1H)5.41-5.51(m,1H)5.05-5.20(m,2H)4.70(m,1H)4.61(br.s.,1H)4.51(d,J=8.19Hz,1H)4.38(d,J=11.86Hz,1H)4.01-4.16(m,1H)3.02(m,1H)2.15-2.29(m,1H)
31P NMR(162MHz,氧化氘)δppm 51.91(s,1P)51.56(s,1P)
19F NMR(376MHz,氧化氘)δppm-199.85(s,1F)
实施例2
9-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-15-羟基-2,9-二氧化-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-
6-基]-1-甲基-1,9-二氢-6H-嘌呤-6-酮
方案D
步骤1:(1S,4R)-4-(6-氯-9H-嘌呤-9-基)环戊-2-烯-1-醇(D-2)的合成
用N2使A-1(1500mg,11mmol)、Pd(PPh3)4(610mg,0.53mmol)和PPh3(277mg,1.06mmol)在THF(6mL)中的混合物起泡15min(烧瓶A)。在单独的烧瓶(烧瓶B)中,用N2使D-1在THF(30mL)和DMA(5mL)混合物中的混悬液起泡15min,然后加入NaH(60wt%的矿物油分散体,506mg,12.7mmol)。1.5hr后,将烧瓶A的内容物转入烧瓶B(用4mL THF冲洗),将该反应体系在50℃加热过夜。浓缩该反应混合物;将残余物溶于EtOAc,用柠檬酸水溶液和盐水洗涤。用EtOAc(2x)萃取合并的水相。用MgSO4干燥合并的有机相,过滤,浓缩。通过急骤色谱法纯化粗残余物(40g SiO2,Isco,0-5%MeOH/DCM),得到了D-2(1.45g,58%),为泡沫状黄色固体。LCMS[M+H]=237测定值;1H NMR(400MHz,DMSO-d6)δppm=8.79(s,1H)8.60(s,1H)6.24(dt,J=5.53,1.94Hz,1H)6.00-6.11(m,1H)5.60(td,J=5.14,1.96Hz,1H)5.30(d,J=6.24Hz,1H)4.65-4.81(m,1H)2.94(ddd,J=14.00,8.13,7.34Hz,1H)1.80(dt,J=14.03,4.48Hz,1H)。
步骤2:9-[(1R,4S)-4-羟基环戊-2-烯-1-基]-1,9-二氢-6H-嘌呤-6-酮(D-3)的合成
向D-2(1.45g,7.03mmol)在MeOH(50mL)中的溶液中加入巯基乙醇(1.97mL,28.1mmol),然后加入甲醇钠(1.52g,28.1mmol)。回流8hr后,关闭加热,将该反应体系静置过夜。浓缩该反应体系且将其直接用于下一步。LCMS[M+H]=219测定值。
步骤3:9-[(1R,4S)-4-羟基环戊-2-烯-1-基]-1-甲基-1,9-二氢-6H-嘌呤-6-酮(D-4)的合成
向D-3(使用来自前一步骤的粗产物)在DMF(47mL)中的溶液中加入K2CO3(3.39g,24.5mmol),然后加入碘甲烷(0.655mL,10.5mmol)。搅拌过夜后,再加入2eq碘甲烷(0.873mL,14.0mmol)。1hr后,浓缩该反应体系。将残余物在DCM中搅拌成浆液,过滤以除去固体。浓缩母液,通过急骤色谱法纯化(40g SiO2,Isco,0-10%7N NH3的MeOH/DCM溶液),得到了D-4(1.17g,72%),为白色固体。LCMS[M+H]=233测定值;1H NMR(400MHz,DMSO-d6)δppm=8.39(s,1H),8.00(s,1H),6.19(td,J=2.0,5.5Hz,1H),6.05-5.90(m,1H),5.41(dt,J=2.0,5.2Hz,1H),5.26(d,J=6.4Hz,1H),4.76-4.66(m,1H),3.50(s,3H),2.89(ddd,J=7.3,8.2,13.9Hz,1H),1.68(td,J=4.5,13.9Hz,1H)。
步骤4:9-{(1R,4S)-4-[双(4-甲氧基苯基)(苯基)甲氧基]环戊-2-烯-1-基}-1-甲基-1,9-二氢-6H-嘌呤-6-酮(D-5)的合成
将化合物D-4(1.17g,5.04mmol)与无水吡啶(3x)共蒸发。残余物最后时间溶于无水吡啶(34mL),加入DMTCl(1.96g,1.15mmol),搅拌过夜。真空除去吡啶,然后将残余物溶于EtOAc,用水和盐水洗涤。用MgSO4干燥有机层,过滤,浓缩。通过急骤色谱法纯化粗残余物(80g SiO2,Isco,0-5%MeOH/DCM),得到了D-5(2.50g,93%),为黄色固体。LCMS[M+H]=535测定值;1H NMR(400MHz,DMSO-d6)δppm=8.36(s,1H)7.98(s,1H)7.44(d,J=8.07Hz,2H)7.28-7.36(m,6H)7.19-7.29(m,1H)6.91(d,J=8.31Hz,4H)5.97(d,J=5.62Hz,1H)5.46(d,J=5.50Hz,1H)5.24(br.s.,1H)4.60(br.s.,1H)3.74(s,6H)3.50(s,3H)2.34-2.45(m,1H)1.54(dt,J=13.72,4.69Hz,1H)。
步骤5:9-{(1R,2S,3S,4S)-4-[双(4-甲氧基苯基)(苯基)甲氧基]-2,3-二羟基环戊基}-1-甲基-1,9-二氢-6H-嘌呤-6-酮(D-6)的合成
向D-5(2.50g,4.68mmol)在DCM(31.2mL)中的溶液中加入水(3.12mL)、NMMO(1.64g,14.0mml)和OsO4(2.5wt%的tBuOH溶液,3.33mL,0.327mmol)。搅拌过夜后,用EtOAc稀释该反应体系,然后用饱和Na2SO3和盐水洗涤。用MgSO4干燥有机层,过滤,浓缩。通过急骤色谱法纯化粗残余物(80g SiO2,Isco,0-8%MeOH/DCM),得到了D-6(2.37g,89%)。LCMS[M+H]=569测定值;1H NMR(400MHz,DMSO-d6)δppm=8.34(s,1H)8.06(s,1H)7.38-7.49(m,2H)7.27-7.36(m,6H)7.19-7.26(m,1H)6.89(dd,J=9.05,2.32Hz,4H)5.01(d,J=6.11Hz,1H)4.74(d,J=3.79Hz,1H)4.41-4.58(m,2H)3.80-3.87(m,1H)3.73(d,J=2.20Hz,6H)3.56-3.62(m,1H)3.50(s,3H)1.84-1.97(m,1H)1.36-1.55(m,1H)。
步骤6:9-[(1R,2S,3S,4S)-4-[双(4-甲氧基苯基)(苯基)甲氧基]-3-{[叔丁基(二甲基)甲硅烷基]氧基}-2-羟基环戊基]-1-甲基-1,9-二氢-6H-嘌呤-6-酮(D-7)的合成
将化合物D-6(1.88g,3.31mmol)与无水吡啶(3x)共蒸发。将残余物溶于DMF(33mL),加入咪唑(682mg,9.92mmol),然后加入TBSCl(747mg,4.96mmol),搅拌过夜。真空除去DMF,然后将残余物溶于EtOAc,用水和盐水洗涤。用MgSO4干燥有机层,过滤,浓缩。通过急骤色谱法纯化粗残余物(80g SiO2,Isco,0-100%EtOAc/庚烷),得到了D-7(793mg,35%),为白色固体。LCMS[M+H]=683测定值;1H NMR(400MHz,DMSO-d6)δppm=8.34(s,1H)8.01(s,1H)7.42-7.49(m,2H)7.28-7.37(m,6H)7.20-7.27(m,1H)6.85-6.93(m,4H)5.12(d,J=5.62Hz,1H)4.63-4.71(m,1H)4.46-4.56(m,1H)3.78-3.84(m,2H)3.73(d,J=1.71Hz,6H)3.51(s,3H)2.08(ddd,J=14.58,10.30,6.05Hz,1H)1.29(dd,J=14.37,6.79Hz,1H)0.82(s,9H)0.04(s,3H)-0.06(s,3H)
步骤7:(1S,2R,3S,5R)-3-[双(4-甲氧基苯基)(苯基)甲氧基]-2-{[叔丁基(二甲基)甲硅烷基]氧基}-5-(1-甲基-6-氧代-1,6-二氢-9H-嘌呤-9-基)环戊基2-氰基乙基二丙-2-基亚磷酰胺(D-8)的合成
向D-7(785g,1.15mmol)在DCM(23mL)中的溶液中加入DIEA(601mL,3.45mmol),然后滴加3-((氯(二异丙基氨基)磷基)氧基)丙腈(385uL,1.72mmol)。1小时后,再滴加0.75eq3-((氯(二异丙基氨基)磷基)氧基)丙腈。再经过1小时,用EtOAc稀释该反应体系,用饱和NaHCO3和盐水洗涤。用MgSO4干燥有机层,过滤,浓缩。通过急骤色谱法纯化粗残余物(40gSiO2,Isco,0-100%EtOAc/庚烷),得到了D-8(779mg,77%),为白色固体。LCMS[M+H]=800测定值;1H NMR(400MHz,DMSO-d6)δppm=8.36(d,J=1.83Hz,1H)7.95(d,J=14.18Hz,1H)7.48(d,J=7.95Hz,2H)7.33(td,J=5.84,2.51Hz,6H)7.22-7.29(m,1H)6.87-6.95(m,4H)4.69-4.92(m,2H)3.85(d,J=6.36Hz,1H)3.74(s,6H)3.70(br.s.,1H)3.56-3.67(m,1H)3.51(d,J=6.24Hz,3H)3.33-3.48(m,3H)2.54-2.76(m,2H)2.09-2.48(m,1H)1.21-1.53(m,1H)0.95-1.08(m,9H)0.71-0.85(m,12H)0.06(d,J=19.32Hz,3H)-0.11(d,J=10.51Hz,3H);31P NMR(162MHz,DMSO-d6,内部参比H3PO4)δppm=148.32(s,1P),146.67(s,1P)。
方案E
步骤1:N-苯甲酰基-5'-O-[{[(1S,2R,3S,5R)-2-{[叔丁基(二甲基)甲硅烷基]氧基}-3-羟基-5-(1-甲基-6-氧代-1,6-二氢-9H-嘌呤-9-基)环戊基]氧基}(2-氰基乙氧基)硫代磷酰基]-2'-脱氧-2'-氟-3'-O-[羟基(氧化)-l5-磷基]腺苷(E-1)的合成
将化合物D-8(709mg,0.803mmol)与THF(3x)共蒸发。加入粉状分子筛,最后时间溶于THF(20mL),搅拌1小时(烧瓶A)。将B-4(351mg,0.803mmol)和pyTFA(930mg,4.82mol)的混合物与THF(3x)共蒸发。加入粉状分子筛,最后时间溶于THF(20mL),搅拌1小时(烧瓶B)。然后将烧瓶B的内容物加到烧瓶A中。30min后,加入DDTT(330mg,1.61mmol)。再经过30min后,浓缩该反应混合物,将残余物在DCM中搅拌成浆液。过滤出分子筛,浓缩母液。将残余物溶于加入几滴水,然后加入DCA(662uL,8.03mmol)在DCM(4mL)中的溶液的DCM(4mL)。产生鲜橙色溶液。30min后,加入吡啶,直至橙色消散。浓缩该反应混合物,通过急骤色谱法纯化(40gSiO2,Isco,0-40%MeOH/DCM,然后12g SiO2,Isco,0-40%MeOH/DCM),得到了E-1(227mg,30%)。LCMS[M+H]=950测定值;31P NMR(162MHz,DMSO-d6)δppm=67.93(s.,1P),65.55(s,1P),-0.34(s,1P),-0.68(s,1P);19F NMR(376MHz,DMSO-d6)δppm=-200.59(s,1F),-201.37(s,1F)。
步骤2:N-{9-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-15-{[叔丁基(二甲基)甲硅烷基]氧基}-9-(2-氰基乙氧基)-14-氟-6-(1-甲基-6-氧代-1,6-二氢-9H-嘌呤-9-基)-2-氧化-2-硫基-9-硫八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-13-基]-9H-嘌呤-6-基}苯甲酰胺(E-2)的合成
将化合物E-1(227mg,0.239mmol)与无水吡啶(3x)共蒸发。将残余物最后时间溶于无水吡啶(12mL),然后加入DMOCP(221mg,1.20mmol)。1小时后,再加入5eq DMOCP。4小时后,加入水(1.0mL),然后加入3H-1,2-苯并二硫杂环戊-3-酮(81mg,0.48mmol)。30min后,用饱和NaHCO3使反应淬灭,浓缩,通过急骤色谱法纯化(24g SiO2,Isco,0-40%MeOH/DCM),得到了E-2(155mg,67%)。LCMS 4峰,具有[M+H]=964测定值;31P NMR(162MHz,DMSO-d6)δppm=67.40(s,1P),67.02(s,1P),63.92(s,1P),63.80(s,1P),49.90(s,1P),49.83(s,1P),49.38(s,1P);19F NMR(376MHz,DMSO-d6)δppm=-195.70(s,1F),-196.27(s,1F),-196.54(s,1F),-196.55(s,1F)
步骤3:9-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-15-羟基-2,9-二氧化-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6-基]-1-甲基-1,9-二氢-6H-嘌呤-6-酮(E-3)的合成
向E-2(260mg,0.270mmol)在ACN(6mL)中的溶液中加入tBuNH2。15min后,浓缩该反应体系,将残余物溶于33%MeNH2的EtOH溶液(6mL)。2hr后,浓缩该反应体系,将残余物与3:1吡啶:TEA(2x)共蒸发。将残余物溶于吡啶(3mL),加入TEA(300uL),然后加入三氢氟化三乙胺(2.2mL,13.5mmol),加热至50℃过夜。浓缩,然后用饱和NaHCO3调整pH至~6。浓缩,将残余物在DCM中搅拌成浆液,过滤出固体,然后浓缩母液。通过反相制备型-HPLC纯化残余物(Phenomenex Gemini C18 21.2x 150mm 5u柱),用5-10%MeCN的NH4HCO3水溶液的溶液(10mM)洗脱,得到了4种非对映异构体。使用相同条件再纯化峰3和4。
峰1:
25mg,13%;
1H NMR(400MHz,DMSO-d6)δppm=8.44(s,1H)8.21(s,1H)8.20(s,1H)8.10(s,1H)7.40(br.s.,2H)6.29(d,J=17.85Hz,2H)5.43-5.60(m,1H)5.07-5.16(m,1H)4.97(td,J=9.93,5.93Hz,2H)4.51-4.61(m,2H)4.23(d,J=8.56Hz,1H)4.00(br.s.,2H)3.50(s,3H)2.83(br.s.,1H)1.66(dd,J=14.49,5.81Hz,1H);
31P NMR(162MHz,DMSO-d6,内部参比H3PO4)δppm=53.68(s,1P),50.53(s,1P);
19F NMR(376MHz,DMSO-d6)δppm=-197.42(s,1F)。
峰2:
32mg,16%;
1H NMR(400MHz,DMSO-d6)δppm=8.44(s,1H)8.22(s,1H)8.18(s,1H)8.13(s,1H)7.40(br.s.,2H)6.28(d,J=17.24Hz,1H)6.02-6.20(m,1H)5.06-5.15(m,1H)4.95(td,J=9.90,5.50Hz,2H)4.56(br.s.,1H)4.43(t,J=5.26Hz,1H)4.24(d,J=8.44Hz,1H)3.96-4.12(m,2H)3.49(s,3H)2.80(br.s.,1H)1.61(dd,J=14.92,5.50Hz,1H);
31P NMR(162MHz,DMSO-d6,内部参比H3PO4)δppm=53.33(s,1P),48.21(s,1P);
19F NMR(376MHz,DMSO-d6)δppm=-198.33(s,1F)。
峰3:
34mg,16%;
1H NMR(400MHz,DMSO-d6)δppm=8.41(s,1H)8.36(br.s.,1H)8.23(s,1H)8.18(s,1H)7.40(br.s.,2H)6.29(d,J=16.38Hz,1H)6.04-6.22(m,1H)5.12-5.26(m,1H)4.77-4.96(m,2H)4.37-4.48(m,2H)4.28(d,J=8.80Hz,1H)4.18(d,J=11.98Hz,1H)4.02(dd,J=11.74,5.50Hz,1H)3.50(s,3H)2.86(br.s.,1H)1.52(dd,J=15.22,5.81Hz,1H);
31P NMR(162MHz,DMSO-d6,内部参比H3PO4)δppm=49.42(s,1P),48.13(s,1P);
19F NMR(376MHz,DMSO-d6)δppm=-199.27(s,1F)。
峰4:
7mg,3.5%;
1H NMR(400MHz,DMSO-d6)δppm=8.40(s,1H)8.27(s,1H)8.20(s,1H)8.19(s,1H)7.38(br.s.,2H)6.27(d,J=16.63Hz,1H)5.40-5.60(m,1H)5.24(d,J=3.42Hz,1H)5.15-5.23(m,1H)4.82-4.99(m,2H)4.52(t,J=6.36Hz,1H)4.45(br.s.,1H)4.26(d,J=9.29Hz,1H)4.09-4.18(m,1H)3.97-4.06(m,1H)3.49(s,3H)2.85(t,J=16.08Hz,1H)1.56(dd,J=14.67,5.99Hz,1H);
31P NMR(162MHz,DMSO-d6,内部参比H3PO4)δppm=50.54(s,1P),48.91(s,1P);
19F NMR(376MHz,DMSO-d6)δppm=-198.50(s,1F)。
实施例3
9-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-15-羟基-2,9-二氧化-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6-基]-1,9-二氢-6H-嘌呤-6-酮
方案F
步骤1:(1S,4R)-4-(6-(苄氧基)-9H-嘌呤-9-基)环戊-2-烯-1-醇(F-2)的合成
按照与A-3类似的方式,在方案A步骤1中使用6-(苄氧基)-9H-嘌呤(F-1)替代A-2制备了化合物F-2,67%收率。
1H NMR(400MHz,DMSO-d6)δ=8.56(s,1H),8.32(s,1H),7.55-7.48(m,2H),7.45-7.31(m,3H),6.21(td,J=2.0,5.5Hz,1H),6.09-5.99(m,1H),5.63(s,2H),5.55(dt,J=2.0,5.2Hz,1H),5.36(d,J=6.4Hz,1H),4.74(td,J=1.5,3.1Hz,1H),3.00-2.84(m,1H),1.75(td,J=4.4,13.9Hz,1H);LCMS[M+H]=309.0.
步骤2:6-(苄氧基)-9-((1R,4S)-4-(双(4-甲氧基苯基)(苯基)-l4-oxidaneyl)环戊-2-烯-1-基)-9H-嘌呤(F-3)的合成
按照与方案A步骤2中A-4类似的方式制备了化合物F-3,82%收率。
1H NMR(400MHz,DMSO-d6)δ=8.54(s,1H),8.29(s,1H),7.51(d,J=7.0Hz,2H),7.47-7.35(m,5H),7.35-7.28(m,6H),7.26-7.20(m,1H),6.90(dd,J=2.1,9.0Hz,4H),6.00(d,J=6.0Hz,1H),5.63(s,2H),5.48-5.42(m,1H),5.38(t,J=6.1Hz,1H),4.61(t,J=5.0Hz,1H),3.73(d,J=1.3Hz,6H),2.48-2.39(m,1H),1.61(td,J=4.8,13.8Hz,1H);LCMS[M+H]=610.8.
步骤3:(1S,2S,3R,5S)-3-(6-(苄氧基)-9H-嘌呤-9-基)-5-(双(4-甲氧基苯基)(苯基)-l4-oxidaneyl)环戊-1,2-二醇(F-4)的合成
按照与方案A步骤3中A-5类似的方式制备了化合物F-4,76%收率。
1H NMR(400MHz,DMSO-d6)δ=8.55(s,1H),8.37(s,1H),7.53-7.44(m,4H),7.40(d,J=7.3Hz,3H),7.36-7.27(m,6H),7.26-7.18(m,1H),6.88(dd,J=3.1,8.9Hz,4H),5.63(s,2H),5.04(d,J=6.1Hz,1H),4.77(d,J=3.7Hz,1H),4.68-4.55(m,2H),3.86(td,J=2.4,4.6Hz,1H),3.72(d,J=2.8Hz,6H),3.59(br.s.,1H),2.01-1.90(m,1H),1.66-1.55(m,1H);LCMS[M+H]=645.8.
步骤4:(1S,2S,3S,5R)-5-(6-(苄氧基)-9H-嘌呤-9-基)-3-(双(4-甲氧基苯基)(苯基)-l4-oxidaneyl)-2-((叔丁基二甲基甲硅烷基)氧基)环戊-1-醇(F-5)的合成
按照与方案A步骤3中A-6类似的方式制备了化合物F-5,35%收率。
1H NMR(400MHz,DMSO-d6)δ=8.56(s,1H),8.32(s,1H),7.49(dd,J=7.2,14.1Hz,4H),7.40(d,J=7.3Hz,3H),7.36-7.28(m,6H),7.26-7.19(m,1H),6.88(dd,J=3.2,8.9Hz,4H),5.64(s,2H),5.14(d,J=5.5Hz,1H),4.86-4.76(m,1H),4.71-4.57(m,1H),3.87-3.75(m,2H),3.72(d,J=2.3Hz,6H),2.13(ddd,J=6.4,10.3,14.7Hz,1H),1.44(dd,J=6.9,14.4Hz,1H),0.82(s,9H),0.04(s,3H),-0.07(s,3H);LCMS[M+H]=758.8.
步骤5:(1S,2R,3S,5R)-5-(6-(苄氧基)-9H-嘌呤-9-基)-3-(双(4-甲氧基苯基)(苯基)-l4-oxidaneyl)-2-((叔丁基二甲基甲硅烷基)氧基)环戊基(2-氰基乙基)二异丙基亚磷酰胺(F-6)的合成
按照与方案A步骤3中A-7类似的方式制备了化合物F-6,73%收率。31P NMR(162MHz,DMSO-d6)δ=149.11(br.s.,1P),147.26(s,1P);LCMS[M+H]=959.0.
方案G
步骤1:(2R,3R,4R,5R)-5-(6-苯甲酰氨基-9H-嘌呤-9-基)-2-((((((1S,2R,3S,5R)-5-(6-(苄氧基)-9H-嘌呤-9-基)-2-((叔丁基二甲基甲硅烷基)氧基)-3-羟基环戊基)氧基)(2-氰基乙氧基)硫代磷酰基)氧基)甲基)-4-氟四氢呋喃-3-基氢膦酸酯(G-1)的合成
按照与方案E的步骤1中E-1类似的方式制备了化合物G-1,42%收率。
19F NMR(376MHz,DMSO-d6)δ=-201.22(s,1F),-201.70(s,1F);31P NMR(162MHz,DMSO-d6)δ=68.34(s,1P),65.79(s,1P),-0.03(s,1P),-0.15(s,1P);LCMS[M+H]=1025.
步骤2:N-{9-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-6-[6-(苄氧基)-9H-嘌呤-9-基]-15-{[叔丁基(二甲基)甲硅烷基]氧基}-9-(2-氰基乙氧基)-14-氟-2-氧化-2-硫基-9-硫八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-13-基]-9H-嘌呤-6-基}苯甲酰胺(G-2)的合成
按照与方案E步骤2中E-2类似的方式制备了化合物G-2,29%收率。
19F NMR(376MHz,DMSO-d6)δ=-194.72(s,1F),-196.58(s,1F),-196.67(s,1F),-196.96(s,1F);31P NMR(162MHz,DMSO-d6)δ=67.91(s,1P),67.60(br.s.,1P),63.96(br.s.,1P),63.78(br.s.,1P),51.01(s,2P),49.48(s,1P),48.94(s,1P);LCMS[M+H]=1039.
步骤3:9-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-15-羟基-2,9-二氧化-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6-基]-1,9-二氢-6H-嘌呤-6-酮(G-5)的合成
按照与方案E步骤3中化合物E-2类似的方式处理化合物G-2,得到了G-3,然后得到G-4。最终,向G-4(156mg,0.18mmol)在MeOH(3.00mL,c=0.06M)中的溶液中加入3N HCl(300mg,9mmol,3.00mL,3M)。在添加HCl时,形成白色沉淀。将该混悬液加热至50℃。在加热期间,该反应体系变成均匀的黄色溶液。在50℃持续搅拌4.5h。将该反应体系冷却至rt,然后用NaHCO3(饱和)中和至pH6。冻干含水混合物,然后通过制备型HPLC纯化,得到了4种非对映异构体。
峰1:41mgs,28%收率,95%de,1H NMR(400MHz,氧化氘)δ=8.43(s,1H),8.26(s,1H),8.21(s,1H),7.68(s,1H),6.49(d,J=16.1Hz,1H),5.73-5.57(m,1H),5.52-5.42(m,1H),5.24-5.09(m,2H),4.60(br.s.,1H),4.52(d,J=8.8Hz,1H),4.33(d,J=11.6Hz,1H),4.12(dd,J=6.4,11.7Hz,1H),3.13-2.99(m,1H),2.30(dd,J=5.6,16.1Hz,1H),一个不可交换的质子被溶剂峰掩蔽且未表中体现。19F NMR(376MHz,氧化氘)δ=-199.99(s,1F);31PNMR(162MHz,氧化氘)δ=55.96(br.s.,1P),51.76(s,1P)(内标H3PO4);LCMS[M+H]=678.
峰2:30mgs,19%收率,95%de,1H NMR(400MHz,氧化氘)δ=8.45(s,1H),8.27(s,1H),8.21(s,1H),7.68(s,1H),6.49(d,J=15.9Hz,1H),6.33-6.14(m,1H),5.55-5.43(m,1H),5.13(dd,J=10.9,14.9Hz,2H),4.64(d,J=5.3Hz,1H),4.61(br.s.,1H),4.55(d,J=8.9Hz,1H),4.36(d,J=10.6Hz,1H),4.16(dd,J=5.9,12.0Hz,1H),3.10-2.97(m,1H),2.25(dd,J=5.8,15.8Hz,1H);19F NMR(376MHz,氧化氘)δ=-200.31(s,1F);31P NMR(162MHz,氧化氘)δ=55.98(s,1P),50.38(s,1P)(H3PO4内标);LCMS[M+H]=678.
峰3:8mgs,7%收率,93%de,1H NMR(400MHz,氧化氘)δ=8.30(s,1H),8.27(s,1H),8.20(s,1H),7.64(s,1H),6.47(d,J=16.5Hz,1H),6.33-6.15(m,1H),5.60-5.50(m,1H),5.18-5.06(m,2H),4.63(d,J=2.6Hz,2H),4.55(d,J=9.7Hz,1H),4.43(d,J=12.3Hz,1H),4.13-4.03(m,1H),3.07-2.94(m,1H),2.19(dd,J=5.5,15.8Hz,1H);19F NMR(376MHz,氧化氘)δ=-200.30(s,1F);31P NMR(162MHz,氧化氘)δ=51.72(br.s.,1P),50.31(s,1P)(H3PO4内标);LCMS[M+H]=678.
峰4:8mgs,6%收率,93%de,1H NMR(400MHz,氧化氘)δ=8.29(br.s.,1H),8.27(br.s.,1H),8.19(s,1H),7.65(br.s.,1H),6.47(d,J=16.0Hz,1H),5.75-5.46(m,2H),5.13(br.s.,2H),4.69(br.s.,1H),4.62(br.s.,1H),4.53(d,J=7.8Hz,1H),4.40(d,J=10.8Hz,1H),4.11-4.02(m,1H),3.04(br.s.,1H),2.23(d,J=15.4Hz,1H);19F NMR(376MHz,氧化氘)δ=-199.96(br.s.,1F);31P NMR(162MHz,氧化氘)δ=53.04(br.s.,1P)(仅观察到一个峰,H3PO4内标);LCMS[M+H]=678.
实施例4
(4S,6R,7S,11aR,13R,14R,14aR,15R)-6-(4-氨基-7-甲基-1H-咪唑并[4,5-c]吡啶-1-基)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-15-醇2,9-二氧化物
按照与实施例1类似的方式,在方案A的步骤1中使用N-(7-甲基-1H-咪唑并[4,5-c]吡啶-4-基)苯甲酰胺替代A-2,制备了实施例4。
实施例5
9-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-15-羟基-2,9-二氧化-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6-基]-3-甲基-3,9-二氢-6H-嘌呤-6-酮
按照与实施例1类似的方式,在方案A的步骤1使用3-甲基-3,9-二氢-6H-嘌呤-6-酮替代A-2,制备了实施例5。
实施例6
3-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-15-羟基-2,9-二氧化-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6-基]-4-甲基-3,4-二氢-7H-咪唑并[4,5-b]吡啶-7-酮
按照与实施例1类似的方式,在方案A的步骤1中使用4-甲基-3,4-二氢-7H-咪唑并[4,5-b]吡啶-7-酮替代A-2,制备了实施例6。
实施例7
9-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-15-羟基-2,9-二氧化-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6-基]-2-甲基-1,9-二氢-6H-嘌呤-6-酮
按照与实施例3类似的方式,在方案F的步骤1中使用6-(苄氧基)-2-甲基-9H-嘌呤替代F-1,制备了实施例7。
峰1-1H NMR(400MHz,甲醇-d4)δ8.72(s,1H),8.26(s,1H),8.25(s,2H),6.42(d,J=15.8Hz,1H),5.62(dd,J=50.8,3.7Hz,1H),5.46(ddd,J=13.1,9.1,2.8Hz,1H),5.28–5.14(m,2H),4.80(t,J=6.2Hz,1H),4.68(s,1H),4.46(d,J=9.0Hz,1H),4.43–4.35(m,1H),4.18(dd,J=11.8,5.7Hz,1H),3.09–2.96(m,1H),2.25(s,3H),2.11(dd,J=15.1,6.0Hz,1H);19F NMR(376MHz,MeOD)δ-200.3;31P NMR(162MHz,MeOD)δ59.20,55.02;LCMS[M+H]=692.
峰2-1H NMR(400MHz,甲醇-d4)δ8.73(s,1H),8.25(s,1H),8.24(s,1H),6.41(d,J=15.5Hz,1H),6.22(dd,J=50.3,3.6Hz,1H),5.57–5.48(m,1H),5.23–5.09(m,2H),4.70(s,1H),4.71–4.63(m,1H),4.45(dd,J=16.5,10.9Hz,2H),4.23(dd,J=11.7,5.6Hz,1H),2.95(ddd,J=11.8,8.3,4.7Hz,1H),2.14(dd,J=15.1,6.0Hz,1H);19F NMR(376MHz,MeOD)δ-201.4;31P NMR(162MHz,MeOD)δ59.33,53.25;LCMS[M+H]=692.
峰3-1H NMR(400MHz,甲醇-d4)δ8.38(s,1H),8.15(s,1H),8.13(s,1H),6.29(d,J=16.2Hz,1H),6.12(dd,J=50.3,3.4Hz,
1H),5.36(t,J=9.4Hz,1H),5.13–4.88(m,2H),4.59(d,J=5.8Hz,2H),4.34(t,J=10.5Hz,2H),4.18(dd,J=12.4,6.4Hz,1H),2.93–2.77(m,1H),2.13(s,3H),1.98(d,J=15.0Hz,1H);19F NMR(376MHz,MeOD)δ-201.2;31P NMR(162MHz,MeOD)δ54.06,52.75;LCMS[M+H]=692.
峰4-1H NMR(400MHz,甲醇-d4)δ8.35(s,1H),8.13(s,1H),8.11(s,1H),6.28(d,J=16.5Hz,1H),5.49(dd,J=51.1,3.6Hz,1H),5.25(td,J=9.2,2.8Hz,1H),5.11(td,J=10.3,9.8,5.7Hz,1H),4.96(ddt,J=23.4,9.3,4.8Hz,1H),4.70(t,J=6.2Hz,1H),4.58(s,1H),4.37–4.27(m,2H),4.17(dd,J=12.3,6.8Hz,1H),2.92(dddd,J=14.8,10.4,6.1,3.3Hz,1H),2.19(s,3H),1.92–1.86(m,1H);19F NMR(376MHz,MeOD)δ-200.8;31P NMR(162MHz,MeOD)δ55.16,53.92;LCMS[M+H]=692.
实施例8
2-氨基-9-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-15-羟基-2,9-二氧化-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6-基]-1,9-二氢-6H-嘌呤-6-酮
按照与实施例1类似的方式,在方案A的步骤1中使用N-(6-(苄氧基)-9H-嘌呤-2-基)苯甲酰胺替代A-2,制备了实施例8。
实施例9
5-氨基-3-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-15-羟基-2,9-二氧化-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6-基]咪唑并[4,5-d][1,3]噁嗪-7(3H)-酮
按照与实施例1类似的方式,在方案A的步骤1中使用N-(7-氧代-3,7-二氢咪唑并[4,5-d][1,3]噁嗪-5-基)苯甲酰胺替代A-2,制备了实施例9。
实施例10
3-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-15-羟基-2,9-二氧化-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6-基]-3,5-二氢-9H-咪唑并[1,2-a]嘌呤-9-酮
按照与实施例1类似的方式,在方案A的步骤1中使用N-(6-(苄氧基)-9H-嘌呤-2-基)苯甲酰胺替代A-2,制备了实施例10。
实施例11
(4S,6R,7S,11aR,13R,14R,14aR,15R)-6-(4-氨基-3-甲氧基-1H-吡唑并[3,4-d]嘧啶-1-基)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-15-醇2,9-二氧化物
按照与实施例1类似的方式,在方案A的步骤1中使用N-(3-甲氧基-1H-吡唑并[3,4-d]嘧啶-4-基)苯甲酰胺替代A-2,制备了实施例11。
实施例12
4-氨基-1-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-15-羟基-2,9-二氧化-2,9-二硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6-基]-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮
按照与实施例11类似的方式,在方案C的步骤5之后使用额外的脱保护步骤,制备了实施例12。
实施例13
(4S,6R,7S,11aS,13R,14R,14aR,15R)-6,13-双(6-氨基-9H-嘌呤-9-基)-14-氟-2-硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,9,7,2,8]三氧杂硫杂二磷杂环十三烷-9,15-二醇2,9-二氧化物
按照与实施例1类似的方式,在方案C的步骤1中使用(2S,3R,4R,5R)-5-(6-苯甲酰氨基-9H-嘌呤-9-基)-4-氟-2-(巯基甲基)四氢呋喃-3-基氢膦酸酯(H-2,方案H)替代B-4,四唑替代三氟甲磺酸吡啶鎓(pyTFA)和tBuOOH替代DDT,制备了实施例13。
峰1:30mg,24%;1H NMR(400MHz,DMSO-d6)δppm 8.33(s,1H)8.23(s,1H)8.15(s,1H)8.13(s,1H)6.15-6.26(m,1H)5.66-5.85(m,1H)5.08-5.24(m,2H)4.98-5.07(m,1H)4.77(t,J=7.40Hz,1H)4.35(br.s.,2H)3.42(d,J=14.31Hz,1H)3.16-3.20(m,1H)2.84(br.s.,1H)2.57(q,J=7.25Hz,1H)1.79(br.s.,1H);31P NMR(162MHz,DMSO-d6,内部参比H3PO4)δppm 51.14(s,1P)9.89(s,1P);19F NMR(376MHz,DMSO-d6)δppm-194.39(s,1F)。
峰2:18mg,15%;1H NMR(400MHz,DMSO-d6)δppm 8.39(s,1H)8.21(s,1H)8.16(s,1H)8.13(s,1H)6.05-6.26(m,2H)5.12-5.27(m,2H)4.93-5.03(m,1H)4.62(t,J=6.30Hz,1H)4.31-4.42(m,2H)3.41(d,J=15.04Hz,1H)3.10(t,J=11.68Hz,1H)2.85(br.s.,1H)1.68(d,J=5.99Hz,1H);31P NMR(162MHz,DMSO-d6,内部参比H3PO4)δppm 48.59(s,1P)10.51(s,1P);19F NMR(376MHz,DMSO-d6)δppm-195.78(s,1F)。
方案H
步骤1:N-苯甲酰基-5'-S-苯甲酰基-2'-脱氧-2'-氟-5'-硫代腺苷(H-1)的合成
向B-1(2.00g,5.36mmol)和硫代苯甲酸(1.11g,8.04mmol)在THF(50mL)中的混悬液中加入DIAD(1.48mL,7.50mmol)和PPh3(1.97g,7.50mmol)在THF(5mL)中的溶液。搅拌过夜后,用EtOAc稀释该反应体系,用水和盐水洗涤。用MgSO4干燥有机层,过滤,浓缩。通过急骤色谱法纯化粗残余物(80g SiO2,Isco,0-100%EtOAc/庚烷),得到了H-1(2.1g,79%)。LCMS[M+H]=494测定值;1H NMR(400MHz,DMSO-d6)δppm=11.21(br.s.,1H)8.74(s,1H)8.65(s,1H)7.98-8.10(m,2H)7.83-7.93(m,2H)7.62-7.72(m,2H)7.50-7.61(m,4H)6.39(dd,J=19.20,2.20Hz,1H)5.97(d,J=6.24Hz,1H)5.61-5.79(m,1H)4.61-4.76(m,1H)4.11-4.22(m,1H)3.67(dd,J=14.06,4.28Hz,1H)3.44(dd,J=13.94,7.21Hz,1H)
步骤2:(2S,3R,4R,5R)-5-(6-苯甲酰氨基-9H-嘌呤-9-基)-4-氟-2-(巯基甲基)四氢呋喃-3-基氢膦酸酯(H-2)的合成
将H-1(1.00g,2.03mmol)与无水吡啶(3x)共蒸发,然后将残余物最后时间溶于无水吡啶(20.0mL)。用冰-水浴冷却该溶液,然后添加膦酸二苯酯(770uL,4.05mmol)。去除冰浴,将该反应体系搅拌2.5小时。再加入1eq膦酸二苯酯,1小时后,用1M TEAB使该反应体系淬灭(气体放出)。用DCM(4x)萃取,用MgSO4干燥有机相,过滤,浓缩。将残余物溶于33%MeNH2的EtOH溶液(10mL)。30min后,浓缩该反应体系,通过急骤色谱法纯化粗残余物(40g SiO2,Isco,0-100%MeOH/DCM),得到了H-2(2.1g,79%)。LCMS[M+H]=350测定值;1H NMR(400MHz,DMSO-d6)δppm=8.35(s,1H),8.16(s,1H),7.36(s,2H),6.24(dd,J=2.6,18.2Hz,1H),5.68-5.49(m,1H),4.95-4.81(m,1H),4.16-4.09(m,1H),3.01-2.93(m,1H),2.86(dd,J=6.1,14.1Hz,1H);31P NMR(162MHz,DMSO-d6)δppm=0.28(s,1P);19F NMR(376MHz,DMSO-d6)δppm=-201.15(s,1F)。
实施例14
9-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-2,9,15-三羟基-2,9-二氧化八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6-基]-1-甲基-1,9-二氢-6H-嘌呤-6-酮
按照与实施例2类似的方式,在方案E的步骤1中使用ETT替代pyTFA,DCM替代THF和tBuOOH替代DDTT,并且在步骤2中用碘替代3H-苯并二硫杂环戊-3-酮,制备了实施例14。通过反相色谱法纯化粗物质(Phenomenex Luna Omega 5um Polar柱,流动相A:H2O w/10mMNH4OAc流动相B:MeCN),得到了期望的产物。(11mg,13.8%收率)
1H NMR(400MHz,DMSO-d6)δppm 8.32(s,1H),8.21(s,1H),8.16(s,1H),8.04(s,1H),6.27(d,J=18.5Hz,1H),5.59-5.39(m,1H),5.15-5.07(m,1H),4.96-4.80(m,2H),4.51-4.48(m,1H),4.31-4.25(m,1H),4.23-4.17(m,1H),4.11-4.05(m,2H),3.46(s,3H),2.90-2.76(m,1H),1.75-1.67(m,1H);31P NMR(162MHz,DMSO-d6,内部参比H3PO4)δppm-3.42(s,1P)-6.58(s,1P);19F NMR(376MHz,DMSO-d6)δppm-198.30(s,1F)
实施例15
9-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-2,15-二羟基-2,9-二氧化-9-硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6-基]-1-甲基-1,9-二氢-6H-嘌呤-6-酮
按照与实施例2类似的方式,在方案E的步骤1中使用ETT替代pyTFA和DCM替代THF,并且在步骤2中用碘替代3H-苯并二硫杂环戊-3-酮,制备了实施例15。通过反相色谱法纯化粗物质(Phenomenex Gemini NX-C18 3um柱,流动相A:H2O w/10mM NH4OAc流动相B:MeCN),得到了两种非对映异构体产物。
峰1
15mg,20%收率
1H NMR(400MHz,D2O)δppm 8.49(s,1H),8.33(s,1H),8.21(s,1H),7.80(s,1H),6.55(d,J=16.0Hz,1H),5.78-5.66(m,1H),5.66-5.60(m,2H),5.18-5.11(m,2H),4.70-4.59(m,1H),4.59-4.54(m,1H),4.43-4.37(m,1H),4.25-4.17(m,1H),3.56(s,3H),3.13-3.03(m,1H),2.31-2.23(m,1H);31P NMR(162MHz,DMSO-d6,内部参比H3PO4)δppm 53.77(s,1P)-6.21(s,1P);19F NMR(376MHz,DMSO-d6)δppm-198.24(s,1F)
峰2
27mg,29%收率
1H NMR(400MHz,DMSO-d6)δppm 8.33(s,1H),8.18(s,1H),8.18(s,1H),8.02(s,1H),6.28(d,J=18.1Hz,1H),5.55-5.38(m,1H),5.35-5.24(m,1H),4.95-4.86(m,2H),4.86-4.79(m,1H),4.51-4.47(m,1H),4.29-4.22(m,2H),4.12-4.08(m,1H),3.46(s,3H),2.87-2.76(m,1H),1.75-1.71(m,1H);31P NMR(162MHz,DMSO-d6,内部参比H3PO4)δppm49.60(s,1P)-6.27(s,1P);19F NMR(376MHz,DMSO-d6)δppm-199.37(s,1F)
实施例16
9-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-9,15-二羟基-2,9-二氧化-2-硫基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6-基]-1-甲基-1,9-二氢-6H-嘌呤-6-酮
按照与实施例2类似的方式,在方案E的步骤1中使用ETT替代pyTFA,DCM替代THF和tBuOOH替代DDTT,制备了实施例16。通过反相色谱法纯化粗物质(Phenomenex GeminiNX-C18 3um柱,流动相A:H2O w/10mM NH4OAc流动相B:MeCN),得到了两种非对映异构体产物。
峰1
11mg,8.5%收率
1H NMR(400MHz,D2O)δppm 8.36(s,1H),8.33(s,1H),8.19(s,1H),7.71(s,1H),6.53(d,J=16.4Hz,1H),5.80-5.60(m,3H),5.25-5.11(m,2H),4.68(m,1H),4.59-4.53(m,1H),4.43(m,1H),4.20-4.13(m,1H),3.55(s,3H),3.14-3.02(m,1H),2.26-2.18(m,1H);31PNMR(162MHz,DMSO-d6,内部参比H3PO4)δppm 50.40(s,1P)-3.59(s,1P);19F NMR(376MHz,DMSO-d6)ppm-197.41(s,1F)
峰2
32mg,24.3%收率
1H NMR(400MHz,DMSO-d6)δppm 8.35(s,1H),8.28(s,1H),8.15(s,1H),8.13(s,1H),6.27(d,J=17.4Hz,1H),6.20-6.01(m,1H),5.07-4.99(m,1H),4.98-4.83(m,2H),4.48-4.37(m,2H),4.26-4.19(m,1H),4.17-4.09(m,1H),4.08-3.99(m,1H),3.47(s,3H),2.90-2.79(m,1H),1.68-1.60(m,1H);31P NMR(162MHz,DMSO-d6,内部参比H3PO4)δ48.53(s,1P)-3.30(s,1P);19F NMR(376MHz,DMSO-d6)-198.19(s,1F)
实施例17
9-[(4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-15-羟基-9-氧化-2,9-二硫基-2-硫八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9,2,8]四氧杂二磷杂环十三烷-6-基]-1-甲基-1,9-二氢-6H-嘌呤-6-酮
按照与实施例1类似的方式,在方案C的步骤1中使用化合物I-1(N-苯甲酰基-2'-脱氧-2'-氟-3'-O-[羟基(硫化)-l5-磷基]腺苷)替代B-4,ETT替代pyTFA,DCM替代THF并且在步骤2中用DPPCl替代DMOCP,制备了实施例17。
纯化:Phenomenex Gemini NX-C18 3um柱,流动相A:H2O w/10mM NH4OAc流动相B:MeCN
峰1
7.4mg,7.7%收率
1H NMR(400MHz,D2O)δppm 8.51(s,1H),8.33(s,1H),8.21(s,1H),7.74(s,1H),6.56(d,J=15.6Hz,1H),6.47-6.28(m,1H),5.80-5.69(m,1H),5.40-5.26(m,1H),5.22-5.10(m,2H),4.65-4.62(m,1H),4.62-4.56(m,1H),4.46-4.39(m,1H),4.24-4.16(m,1H),3.52(s,3H),3.17-3.03(m,1H),2.33-2.22(m,1H);31P NMR(162MHz,D2O,内部参比H3PO4)δ108.39(s,1P)56.07(s,1P);19F NMR(376MHz,D2O)-199.57(s,1F)
峰2
9.4mg,8.5%收率
1H NMR(400MHz,D2O)δppm 8.36(s,1H),8.32(s,1H),8.20(s,1H),7.69(s,1H),6.54(d,J=16.0Hz,1H),6.46-6.30(m,1H),5.86-5.75(m,1H),5.34-5.20(m,2H),5.16-5.10(m,1H),4.68-4.64(m,1H),4.63-4.58(m,1H),4.53-4.45(m,1H),4.17-4.08(m,1H),3.52(s,3H),3.16-2.99(m,1H),2.27-2.17(m,1H);31P NMR(162MHz,D2O,内部参比H3PO4)δ108.06(s,1P)51.78(s,1P);19F NMR(376MHz,D2O)-199.73(s,1F)
化合物I-1
N-苯甲酰基-2'-脱氧-2'-氟-3'-O-[羟基(硫化)-l5-磷基]腺苷
按照与实施例B-4类似的方式,根据文献方法(Jones等人Nucleosides,Nucleotides and Nucleic Acids 2009,28,352-378),在方案B的步骤2中使用膦酸二苯酯替代膦酸二丁酯且使用Li2S替代水,制备了化合物I-1。
实施例18
9-((4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-15-羟基-2,9-二巯基-2,9-二硫化八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9]四氧杂[2,8]二磷杂环十三烷-6-基)-1-甲基-1,9-二氢-6H-嘌呤-6-酮(J-5)
方案J
步骤1:O-[(1S,2R,3S,5R)-3-[双(4-甲氧基苯基)(苯基)甲氧基]-2-{[叔丁基(二甲基)甲硅烷基]氧基}-5-(1-甲基-6-氧代-1,6-二氢-9H-嘌呤-9-基)环戊基]S-[(2,4-二氯苯基)甲基]N,N-二甲基氨基硫代磷酸酯(J-1)的合成
全部溶液包含粉状分子筛。向冷却的N,N-二甲磷酰胺二氯(0.34mL,2.9mmol)在DCM(10mL)中的(冰-水浴)溶液中加入A-8(1.0g,1.5mmol)和DIEA(2.0mL,12mmol)在DCM(10mL)中的溶液。1hr后,加入(2,4-二氯苯基)甲硫醇(0.83mL,5.9mmol)在DCM(5mL)中的溶液,去除冰浴。1hr后,通过过滤除去分子筛,浓缩滤液,然后通过急骤色谱法纯化(40gSiO2,Isco,0-100%EtOAc/庚烷),得到了J-1(790mg,57%),为白色固体。31P NMR(162MHz,DMSO-d6)δppm=174.1 2,169.6
步骤2:N-苯甲酰基-5'-O-([({[(1S,2R,3S,5R)-3-[双(4-甲氧基苯基)(苯基)甲氧基]-2-{[叔丁基(二甲基)甲硅烷基]氧基}-5-(1-甲基-6-氧代-1,6-二氢-9H-嘌呤-9-基)环戊基]氧基}{[(2,4-二氯苯基)甲基]硫基}硫代磷酰基)氧基]{[(2,4-二氯苯基)甲基]硫基}硫代磷酰基)-2'-脱氧-2'-氟腺苷(J-2)的合成
将J-1(1.3g,1.3mmol)和粉状分子筛在DCM(13mL)中的混合物搅拌20min(烧瓶A)。在单独的烧瓶中,将B-1(540mg,1.5mmol)、ETT(1.3g,9.9mmol)和粉状分子筛在DMF(13mL)中的混合物搅拌20min(烧瓶B)。然后将烧瓶B的内容物加到烧瓶A中。30min后,加入DDTT(310mg,1.5mmol)。15min后,通过过滤除去分子筛,浓缩滤液,然后通过急骤色谱法纯化(40g SiO2,Isco,0-100%EtOAc/庚烷),得到了J-2(436mg,不纯)。LCMS[M+H]=1308测定值;31P NMR(162MHz,DMSO-d6)δppm=95.8,94.3;19F NMR(376MHz,DMSO-d6)δppm=201.49,201.51
步骤3:O-((2R,3R,4R,5R)-5-(6-苯甲酰氨基-9H-嘌呤-9-基)-2-((((((1S,2R,3S,5R)-2-((叔丁基二甲基甲硅烷基)氧基)-3-羟基-5-(1-甲基-6-氧代-1,6-二氢-9H-嘌呤-9-基)环戊基)氧基)((2,4-二氯苄基)硫代)磷酰基)氧基)甲基)-4-氟四氢呋喃-3-基)S-氢硫代磷酸酯(J-3)的合成
将J-2(180mg,0.14mmol,不纯)硫(13mg,0.42mmol)和次磷酸N,N-二乙基乙铵(0.120mL,0.83mmol)的混合物与吡啶一起共蒸发。将残余物溶于吡啶(1.4mL),然后加入DMOCP(77mg,0.42mmol)。~1hr后,用EtOAc稀释该反应体系,用水和盐水洗涤,浓缩。向残余物中加入DCM(2mL),然后加入二氯乙酸(120uL),得到了鲜橙色溶液。15min后,用吡啶淬灭,直至橙色消散,浓缩,通过急骤色谱法纯化(12g SiO2,Isco,0-30%MeOH/DCM),得到了J-3(64mg)。LCMS[M+H]=1086测定值;31P NMR(162MHz,DMSO-d6)δppm=96.9,94.2,49.4;48.7;19F NMR(376MHz,DMSO-d6)δppm=199.6,199.7,199.8,200.1
步骤4:N-(9-((4S,6R,7S,11aR,13R,14R,14aR,15R)-15-((叔丁基二甲基甲硅烷基)氧基)-9-((2,4-二氯苄基)硫代)-14-氟-2-巯基-6-(1-甲基-6-氧代-1,6-二氢-9H-嘌呤-9-基)-2,9-二硫化八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9]四氧杂[2,8]二磷杂环十三烷-13-基)-9H-嘌呤-6-基)苯甲酰胺(J-4)的合成
按照与C-2类似的方式,使用DPPCl替代DMOCP,制备了J-4。LCMS[M+H]=1100测定值;31P NMR(162MHz,DMSO-d6)δppm=110.4,110.3,97.1,95.5;19F NMR(376MHz,DMSO-d6)δppm=196.0,196.5
步骤5:9-((4S,6R,7S,11aR,13R,14R,14aR,15R)-13-(6-氨基-9H-嘌呤-9-基)-14-氟-15-羟基-2,9-二巯基-2,9-二硫化八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9]四氧杂[2,8]二磷杂环十三烷-6-基)-1-甲基-1,9-二氢-6H-嘌呤-6-酮(J-5)的合成
向包含J-4(24mg,0.022mmol)的烧瓶中加入ACN和33%甲胺在EtOH中的1:1溶液(0.5mL)。3hr后,蒸发该反应体系,将残余物溶于苯硫酚、TEA和二噁烷的1:1:2溶液(0.2mL)。5hr后,浓缩该反应体系。向残余物中加入TEA:吡啶的1:1溶液(0.4mL),然后加入三氢氟化三乙胺(150uL)。将该反应体系加热至70℃12hr,然后用饱和碳酸氢钠溶液淬灭,浓缩。将残余物与10%MeOH/DCM,然后与Et2O(2x)一起研磨,然后通过反相制备型-HPLC纯化[Phenomenex Gemini NX-C18 5um 21 x 150mm柱,用包含NH4HCO3(10mM)的0-80%MeCN/H2O洗脱],得到了5mg J-5。
1H NMR(400MHz,DMSO-d6)δppm 8.54(s,1H)8.19(s,1H)8.17(s,1H)8.04(s,1H)6.30(d,J=16.02Hz,1H)6.03-6.20(m,1H)5.24-5.35(m,1H)4.94-5.10(m,2H)4.75-4.81(m,1H)4.36-4.40(m,1H)4.29-4.35(m,1H)4.17-4.25(m,1H)3.88-3.95(m,1H)3.49(s,3H)2.80-2.91(m,1H)1.61-1.68(m,1H);31P NMR(162MHz,DMSO-d6)δppm 113.20,110.74;19FNMR(376MHz,DMSO-d6)δppm-198.74LCMS[M+H]=724测定值
实施例19
9,9'-((4S,6R,7S,11aR,13R,14R,14aR,15R)-14-氟-15-羟基-2,9-二巯基-2,9-二氧化八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9]四氧杂[2,8]二磷杂环十三烷-6,13-二基)双(1-甲基-1,9-二氢-6H-嘌呤-6-酮
按照与实施例17类似的方式,使用(2R,3R,4R,5R)-4-氟-2-(羟基甲基)-5-(1-甲基-6-氧代-1,6-二氢-9H-嘌呤-9-基)四氢呋喃-3-基氢膦酸酯K-4替代B-4,制备了实施例19。通过反相色谱法纯化粗物质(Phenomenex Luna Omega 5um Polar C18 4.6 x 50mm柱;流动相A:H2O w/10mM NH4OAc,流动相B:MeCN;用2.0分钟内0-10%B梯度洗脱,然后在5.5min变速10-80%,保持80%0.5分钟,然后再平衡;流速2.25mL/min),得到了4种非对映异构体产物。
峰1:38mg,10.6%;1H NMR(400MHz,DMSO-d6)δppm 8.45(s,1H)8.26(s,1H)8.18(s,1H)8.16(s,1H)6.27(d,J=18.58Hz,1H)5.51-5.68(m,1H)5.48(d,J=2.57Hz,1H)5.01-5.10(m,1H)4.95(td,J=9.75,5.69Hz,2H)4.60(br.s.,1H)4.55(t,J=5.62Hz,1H)4.20(br.s.,1H)3.95-4.02(m,1H)3.86-3.94(m,1H)3.52(s,3H)3.51(s,3H)2.82(d,J=11.62Hz,1H)1.69-1.75(m,1H);31P NMR(162MHz,DMSO-d6)δppm 53.70(s,1P)49.98(s,1P);19F NMR(376MHz,DMSO-d6)δppm-196.72(s.,1F);LCMS[M+H]=707.0.
峰2:35mg,9.3%;1H NMR(400MHz,DMSO-d6)δppm 8.44(s,1H)8.27(s,1H)8.22(s,1H)8.21(s,1H)6.10-6.26(m,2H)4.89-5.06(m,3H)4.61(br.s.,1H)4.44(t,J=5.32Hz,1H)4.20(d,J=8.80Hz,1H)3.97(d,J=2.32Hz,2H)3.52(s,3H)3.51(s,3H)2.75-2.84(m,1H)1.67(dd,J=14.73,5.07Hz,1H);31P NMR(162MHz,DMSO-d6)δppm 53.60(br.s.,1P)48.19(br.s.,1P);19F NMR(376MHz,DMSO-d6)δppm-197.17(s.,1F);LCMS[M+H]=707.0.
峰3:8mg,2%;1H NMR(400MHz,DMSO-d6)δppm 8.47(s,1H)8.24(s,1H)8.21(s,1H)8.10(s,1H)6.52(s,1H)6.26(d,J=17.61Hz,1H)5.45-5.65(m,1H)5.12-5.25(m,2H)4.81-4.97(m,2H)4.51(t,J=6.30Hz,1H)4.45(br.s.,1H)4.23(d,J=8.56Hz,1H)3.98-4.13(m,2H)3.53(s,3H)3.50(s,3H)2.74-2.87(m,1H)1.67(dd,J=14.67,6.11Hz,1H);31P NMR(162MHz,DMSO-d6)δppm 50.04(s,1P)48.32(br.s.,1P);19F NMR(376MHz,DMSO-d6)δppm-198.02(s.,1F);LCMS[M+H]=707.0.
峰4:40mg,10.9%;1H NMR(400MHz,DMSO-d6)δppm 8.46(s,1H)8.32(s,1H)8.24(s,1H)8.16(s,1H)6.27(d,J=17.48Hz,1H)6.07-6.23(m,1H)5.19(td,J=9.51,2.63Hz,1H)4.81-4.96(m,3H)4.45(br.s.,1H)4.40(t,J=5.62Hz,1H)4.24(d,J=9.41Hz,1H)4.12(d,J=11.98Hz,1H)4.01(dd,J=11.68,5.32Hz,1H)3.53(s,3H)3.50(s,3H)2.81(d,J=7.46Hz,1H)1.61(dd,J=14.55,6.24Hz,2H);31P NMR(162MHz,DMSO-d6)δppm 49.20(br.s.,1P)48.19(br.s.,1P);19F NMR(376MHz,DMSO-d6)δppm-198.36(s.,1F);LCMS[M+H]=707.0.
方案K
步骤1:2'-脱氧-2'-氟-1-甲基肌苷(K-2)的合成
按照与D-4类似的方式,在方案D的步骤3中使用2'-脱氧-2'-氟肌苷(K-1)替代D-3,制备了化合物K-2,98%收率。
1H NMR(400MHz,DMSO-d6)δppm 8.44(s,1H)8.35(s,1H)6.21(dd,J=16.75,2.69Hz,1H)5.73(d,J=6.11Hz,1H)5.25-5.47(m,1H)5.14(t,J=5.44Hz,1H)4.36-4.52(m,1H)3.93-4.04(m,1H)3.75(ddd,J=12.32,5.17,2.81Hz,1H)3.59(ddd,J=12.32,5.65,4.03Hz,1H)3.52(s,3H);19F NMR(376MHz,DMSO-d6)δppm-204.63(s,1F);LCMS[M+H]=285.1.
步骤2:5'-O-[双(4-甲氧基苯基)(苯基)甲基]-2'-脱氧-2'-氟-1-甲基肌苷(K-3)的合成
按照与B-2类似的方式,在方案B的步骤1中使用微波在100℃10min替代25℃12h,制备了化合物K-3,60%收率。
1H NMR(400MHz,DMSO-d6)δppm 8.39(s,1H)8.24(s,1H)7.29-7.36(m,2H)7.15-7.28(m,7H)6.81(dd,J=8.86,7.64Hz,4H)6.27(dd,J=19.44,1.47Hz,1H)5.72(d,J=6.85Hz,1H)5.38-5.59(m,1H)4.55-4.72(m,1H)4.10(dt,J=7.76,3.94Hz,1H)3.72(d,J=1.71Hz,6H)3.51(s,3H)3.20-3.28(m,2H);19F NMR(376MHz,DMSO-d6)δppm-199.30(s,1F);LCMS[M+H]=587.2.
步骤3:(2R,3R,4R,5R)-4-氟-2-(羟基甲基)-5-(1-甲基-6-氧代-1,6-二氢-9H-嘌呤-9-基)四氢呋喃-3-基氢膦酸酯(K-4)的合成
将K-3(1.28g,2.19mmol)与无水吡啶(3x)共蒸发,然后将残余物最后时间溶于无水吡啶(22.0mL)。在烘干的烧瓶中将该溶液滴加到膦酸二苯酯(3.6g,15.4mmol)在无水吡啶(22.0mL)中的溶液中。将该反应体系在rt在N2气氛中搅拌15min,加入三乙胺-水(12mL,1:1,v/v),持续在rt搅拌15min。真空浓缩该反应混合物,溶于DCM(22.0mL),加入DCA(5.66g,43.9mmol),在rt搅拌15min,然后用吡啶(22.0mL)淬灭。浓缩该反应体系,通过急骤色谱法纯化(40g SiO2,Isco,50%MeOH/DCM),得到了K-4(0.71g,93%),为0.8eq.Et3N盐。
1H NMR(400MHz,DMSO-d6)δppm 8.60(br.s.,1H)8.44(s,1H)8.34(s,1H)7.84(t,J=7.58Hz,0.36H)7.61(s,0.5H)7.38-7.49(m,0.75H)6.25(d,J=15.89Hz,1H)6.01(s,0.5H)5.75(s,0.2H)5.43-5.66(m,1H)4.92-5.09(m,1H)4.14(br.s.,1H)3.75(d,J=11.13Hz,1H)3.64(d,J=12.72Hz,1H)3.51(br.s.,3H)3.04-3.13(m,1.7H)1.17(t,J=7.15Hz,2.5H);31P NMR(162MHz,DMSO-d6)δppm 1.88(br.s.,1P);19F NMR(376MHz,DMSO-d6)δppm-200.26(br.s.,1F)。LCMS[M+H]=350测定值;LCMS[M+H]=349.0.
实施例20
9,9'-((4S,6R,7S,11aR,13R,14R,14aR,15R)-14-氟-2,15-二羟基-9-巯基-2,9-二氧化八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9]四氧杂[2,8]二磷杂环十三烷-6,13-二基)双(1-甲基-1,9-二氢-6H-嘌呤-6-酮)
按照与实施例15类似的方式,制备了实施例20。通过反相色谱法纯化粗物质(Phenomenex Gemini NX-C18 4.6 x 50mm 5um柱;流动相A:H2O w/10mM NH4OAc,流动相B:MeCN;用5.0分钟内0-80%B梯度洗脱,保持80%0.5分钟,然后再平衡;流速2.25mL/min),得到了两种非对映异构体产物。
峰1:33mg,23%;1H NMR(400MHz,DMSO-d6)δppm 8.44(s,1H)8.27(s,1H)8.21(s,1H)8.15(s,1H)6.25(d,J=18.58Hz,1H)5.43-5.67(m,2H)4.99-5.07(m,1H)4.89-4.98(m,1H)4.76-4.88(m,1H)4.68(br.s.,1H)4.26(br.s.,1H)4.17(br.s.,1H)3.95-4.03(m,1H)3.87-3.95(m,1H)3.52(s,3H)3.52(s,3H)2.76(br.s.,1H)1.67(dd,J=14.79,5.38Hz,1H);31P NMR(162MHz,DMSO-d6)δppm 53.57(s,1P)-5.78(br.s.,1P);19F NMR(376MHz,DMSO-d6)δppm-197.49(br.s.,1F);LCMS[M+H]=691.0.
峰2:33mg,23%;1H NMR(400MHz,DMSO-d6)δppm 8.47(s,1H)8.25(s,1H)8.24(s,1H)8.15(s,1H)7.11(br.s.,2H)6.52(s,3H)6.25(d,J=17.36Hz,1H)5.42-5.62(m,1H)5.19(d,J=3.42Hz,2H)4.88(td,J=9.96,6.36Hz,1H)4.68-4.81(m,1H)4.52(br.s.,1H)4.17-4.27(m,2H)3.97-4.14(m,2H)3.53(s,3H)3.51(s,3H)2.72-2.84(m,1H)1.61(dd,J=14.49,6.05Hz,1H);31P NMR(162MHz,DMSO-d6)δppm 48.70(br.s.,1P)-5.56(br.s.,1P);19F NMR(376MHz,DMSO-d6)δppm-196.64(br.s.,1F);LCMS[M+H]=691.0.
实施例21
9,9'-((4S,6R,7S,11aR,13R,14R,14aR,15R)-14-氟-9,15-二羟基-2-巯基-2,9-二氧化八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9]四氧杂[2,8]二磷杂环十三烷-6,13-二基)双(1-甲基-1,9-二氢-6H-嘌呤-6-酮
按照与实施例16类似的方式,制备了实施例21。通过反相色谱法纯化粗物质(Phenomenex Gemini NX-C18 3um 4.6 x 50mm柱;流动相A:H2O w/10mM NH4OAc,流动相B:MeCN;用5.0分钟内0-80%B梯度洗脱,保持80%0.5分钟,然后再平衡;流速2.25mL/min),得到了两种非对映异构体产物。
峰1:7.8mg,20%;1H NMR(400MHz,DMSO-d6)δppm 8.38(s,1H)8.31(s,1H)8.21(s,2H)6.10-6.30(m,2H)5.83(br.s.,1H)4.88(br.s.,3H)4.47(d,J=9.54Hz,2H)4.16(d,J=9.17Hz,1H)3.96-4.11(m,2H)3.52(s.,3H)3.51(s.,3H)2.80(m,1H)1.67(m,1H);31P NMR(162MHz,DMSO-d6)δppm 47.81(s,1P)-3.08(br.s.,1P);19F NMR(376MHz,DMSO-d6)δppm-200.26(br.s.,1F);LCMS[M+H]=691.0.
峰2:4mg;10%;1H NMR(400MHz,DMSO-d6)δppm 8.38(s,1H)8.19(s,2H)8.15(s,1H)6.24(d,J=18.22Hz,1H)5.78(d,J=2.69Hz,1H)5.49-5.65(m,1H)4.80-4.92(m,3H)4.55(s,1H)4.48(br.s.,1H)4.15(d,J=8.44Hz,1H)4.08(d,J=12.35Hz,1H)3.97(d,J=8.68Hz,1H)3.52(s,3H)3.51(s,3H)2.78(m,1H)1.72(d,J=11.13Hz,1H);31P NMR(162MHz,DMSO-d6)δppm 49.78(s,1P)-3.06(s,1P);19F NMR(376MHz,DMSO-d6)δppm-195.17(s,1F);LCMS[M+H]=691.0.
实施例22
9,9'-((4S,6R,7S,11aR,13R,14R,14aR,15R)-14-氟-2,9,15-三羟基-2,9-二氧化八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9]四氧杂[2,8]二磷杂环十三烷-6,13-二基)双(1-甲基-1,9-二氢-6H-嘌呤-6-酮)
按照与实施例14类似的方式,使用H-膦酸酯K-4替代B-4,制备了实施例22。通过反相色谱法纯化粗物质(Phenomenex Gemini NX-C18 3um 4.6 x 50mm柱;流动相A:H2O w/10mM NH4OAc,流动相B:MeCN;用5.0分钟内0-80%B梯度洗脱,保持80%0.5分钟,然后再平衡;流速2.25mL/min),得到了期望的产物。
1H NMR(400MHz,DMSO-d6)δppm 8.40(s,1H)8.21(s,1H)8.21(s,1H)8.19(s,1H)6.24(d,J=17.97Hz,1H)5.74(br.s.,1H)5.44-5.64(m,1H)4.83-4.96(m,2H)4.66-4.81(m,1H)4.57(br.s.,1H)4.27(d,J=4.77Hz,1H)4.06-4.18(m,2H)3.96-4.04(m,1H)3.52(s,3H)3.52(s,3H)2.71-2.82(m,1H)1.67(dd,J=13.94,5.26Hz,1H);31P NMR(162MHz,DMSO-d6)δppm-3.03(s,1P)-5.74(br.s.,1P);19F NMR(376MHz,DMSO-d6)δppm-196.01(br.s.,1F);LCMS[M+H]=675.0.
实施例23
(4S,6R,7S,11aR,13R,14R,14aR,15R)-6,13-双(6-氨基-9H-嘌呤-9-基)-14-氟-2,9,15-三羟基八氢-11H-4,7-桥亚甲基呋喃并[3,2-d][1,3,7,9]四氧杂[2,8]二磷杂环十三烷2,9-二氧化物
按照与实施例14类似的方式,使用亚磷酰胺A-7替代D-8,制备了实施例23。通过反相色谱法、使用Agela Durashell C18 25x150mm柱,用包含NH4CO3(10mM)的0-10%MeCN/H2O洗脱,纯化了粗物质。
LCMS TOF(ESI+)[M+H]+=645测定值;1H NMR(400MHz,D2O)δppm=8.31-8.24(m,3H),7.86(s,1H),6.47(d,J=16.8Hz,1H),5.76-5.55(m,1H),5.42-5.29(m,1H),5.22-5.12(m,1H),5.10-4.97(m,1H),4.68(d,J=0.8Hz,1H),4.52(d,J=7.0Hz,2H),4.37(d,J=12.3Hz,1H),4.13(dd,J=5.5,12.3Hz,1H),3.12-2.98(m,1H),2.21(dd,J=4.9,15.4Hz,1H);31P NMR(162MHz,D2O)δppm=-4.21(s,2P);19F NMR(376MHz,D2O)δppm=-200.68(br s,1F)。
生物学实施例
生化测定方法
表面等离子共振(SPR)结合
使用Biacore T200仪器(GE Healthcare)在4℃在150mM KCl、25mM Hepes(pH7.5)、1mM TCEP、2.5mM MgCl2、5%(v/v)甘油、0.005%(v/v)P20、1%(v/v)DMSO运行缓冲液中进行了表面等离子共振(SPR)STING激动剂结合研究。固定在抗生蛋白链菌素芯片上的重组蛋白为人WT或H232R STING。在所有研究中均使用了截短的STING构建体。STING构建体由具有N-末端和C-末端截短的残基155-341组成;除去了N-末端跨膜结构域(1-154)以及C末端尾(342-379)。通过大肠杆菌(E.coli)生物素连接酶(BirA)酶促实现高度特异性的N-末端生物素化,并包含了高亲和力的生物素化肽AviTagTM。用抗生蛋白链菌素预先固定的羧甲基化葡聚糖(S系列抗生蛋白链菌素CM5传感器芯片)用于捕获生物素化的STING蛋白。以每分钟100μl的流速、60秒的缔合时间和可变的解离时间,进行测试化合物注射。所有测试化合物均使用10μM起始浓度的三倍稀释系列。使用BiacoreT200数据评估软件包(GEHealthcare)进行了数据分析。将化合物注射参比空白表面和缓冲液空白。将处理后的数据拟合至平衡或动力学模型,以获得测定的解离常数KD。表1中提供了SPR结合数据。
临近闪烁测定(SPA)竞争性结合
开发了放射性配体结合测定法来确定化合物相互作用是与氚标记形式的天然STING配体3H-环鸟嘌呤(2',5')一磷酸腺嘌呤(3',5')一磷酸(3H-cGAMP)竞争。STING构建体(WT和H232R)由N-和C-末端截短的残基155-341组成;除去了N端跨膜结构域(1-154),以及C-末端尾(342-379)。通过大肠杆菌(E.coli)生物素连接酶(BirA)酶促实现了高度特异性的N-末端生物素化,并包含了高亲和力的生物素化肽AviTagTM。将100nM STING蛋白固定在150mM NaCl、25mM Hepes(pH 7.5)、0.1mM EDTA、1mM DTT、0.005%(v/v)吐温-20、1%(v/v)DMSO中的20μg抗生蛋白链菌素聚乙烯基甲苯(SA-PVT)珠上。添加100nM 3H-cGAMP和化合物,并使其在室温下平衡(20min)。以从100μM起始浓度开始的三倍稀释系列测试了化合物,然后将其归一化为完全阻断3H-cGAMP结合的阳性对照化合物和阴性对照DMSO。竞争性结合的KI由IC50用Cheng-Prusoff方程确定(Cheng&Prusoff,Biochemical Pharmacology,22(1973),pp.3099-3108)。根据经验,将在Cheng-Prusoff方程中使用的3H-cGAMP的KD值确定为1nM(对于WT STING)和750nM(R232H STING)。表2中提供了SPA竞争性结合数据。
干扰素-β诱导:THP-1ISG报告细胞系
THP-1 LuciaTM ISG细胞(InvivoGen)在由5种干扰素应答元件组成的IRF诱导型复合启动子的控制下表达分泌的萤光素酶“Lucia”报告基因。在RPMI培养基+2mM L-谷氨酰胺、10%胎牛血清和0.5%Pen-Strep中培养THP-1 LuciaTM ISG细胞。存在潮霉素B和Zeocin以维持稳定的转染。将104个细胞接种在96-孔板中,并在37℃、5%CO2下温育过夜。在培养基(最终0.5%DMSO)中稀释50μL系列稀释化合物,再温育24小时。温育后,将板以2000rpm离心10min。将每个孔的50μl细胞培养上清液转移至白色不透明96-孔板中。在25mL无内毒素的水中制备一袋QUANTI-LucTM(InvivoGen)粉末,并将100μL制备的温QUANTI-Luc溶液添加到每个包含上清液的孔中。使用Perkin-Elmer Envision微量滴定板读出器测量发光信号。使用已知最大化萤光素酶信号的阳性对照STING激动剂和阴性对照DMSO,将数据归一化为“%效应”。表3中提供了干扰素-β诱导数据。
使用不同人STING多态性测定I型干扰素活性的THP-1细胞报告基因测定法
据报道野生型(WT)STING等位基因在人群中具有可能会影响其反应的另外4种不同的单核苷酸多态性(SNP)。这些SNP称作R71H-G230A-R293Q(HAQ)、R232H、G230A-R293Q(AQ)和R293Q。为了测试所示的化合物能否激活代表人群>98%的所有五个人类STING等位基因,用包含人STING等位基因之一(Genecopoeia)的慢病毒属(lentivirus)单独转导THP-1-双KO-STING细胞(InvivoGen)。选择转导的细胞,并通过蛋白质印迹证实STING的表达(数据未显示)。将选择的细胞在50mL锥形管中培养并收获,用BC Vi-flow计数并稀释至7.4 x105细胞/ml的浓度。将135μl稀释的细胞转移至96孔板(100,000个细胞/孔)中,并在37℃和CO2培养箱中温育3-4小时。接下来,向每个孔中加入15uL的系列稀释测试化合物进行刺激,将包含细胞和化合物的平板在37℃和5%CO2下进一步温育24小时。温育后,将平板以2000rpm离心10min。将每个孔的50μl细胞培养上清液转移至白色、不透明96孔板中。在25mL无内毒素的水中制备QUANTI-LucTM(InvivoGen)粉末,并向包含培养上清液的每个孔中加入100uL制备的温QUANTI-Luc溶液,并使用Perkin Elmer Enspire微量滴定板读出器立即测量发光信号(0.2秒)。根据原始值得到RLU。表4中提供了THP-1细胞报告测定日期。
IRF3的磷酸化:THP-1或OVCAR4细胞ELISA
STING活化导致在诱导I型干扰素之前TBK1募集和IRF3转录因子磷酸化。THP-1细胞(InvivoGen)或OVCAR4细胞(Pfizer Cell Bank)生长在RPMI培养基+2mM L-谷氨酰胺、10%胎牛血清和0.5%Pen-Strep中。将104个细胞接种在96-孔板中,并且温育过夜37℃、5%CO2。将用培养基顺序稀释的化合物(最终0.5%DMSO)加到细胞中,并且再温育3小时。温育后,将板以2000rpm离心5min。然后用100μl RIPA缓冲液裂解细胞,并且在室温涡旋30分钟。然后将25μl裂解液转入澄清聚苯乙烯高结合平板,其预先已经用小鼠抗-人IRF-3俘获抗体(BD Pharmigen)包被,并且允许在4℃温育16小时。然后洗涤板,并且在室温与兔抗-磷酸-IRF3检测抗体(Cell Signaling Technologies)一起温育1.5小时。最终,将HRP-连接的二抗(Cell Signaling Technologies)加入30min,然拟合使用Glo底物试剂(R&D Systems)生成发光信号。使用Perkin-Elmer Envision微量滴定板读出器测定信号。使用已知最大化磷酸化IRF3信号的阳性对照STING激动剂将数据归一化为“%效应”且阴性对照为DMSO。表5和表6中提供了IRF3磷酸化数据。
Claims (42)
3.权利要求1和2任一项的化合物或盐,其中M+选自钠、钾、钙、铵、三乙铵、三甲铵和镁。
4.权利要求1和2任一项的化合物或盐,其中每个抗衡离子M+相同。
18.权利要求1和2任一项的化合物或盐,其中一个或两个Y为卤素。
19.权利要求1和2任一项的化合物或盐,其中一个Y为氢,而另一个Y为卤素。
20.权利要求19的化合物或盐,其中所述的卤素为氟。
21.权利要求1和2任一项的化合物或盐,其中一个Z为氢,而另一个Z为OR4。
22.权利要求1和2任一项的化合物或盐,其中W为-SH,且X为–SH。
23.权利要求1和2任一项的化合物或盐,其中W为-OH,且X为–OH。
24.权利要求1和2任一项的化合物或盐,其中W为–SH,且X为–OH。
25.权利要求1和2任一项的化合物或盐,其中W为–OH,且X为–SH。
29.根据权利要求1-28任一项的化合物或盐的单一非对映异构体。
30.药物组合物,它包含根据权利要求1-27任一项的化合物或盐或其药学上可接受的盐和药学上可接受的载体。
31.药物组合物,它包含根据权利要求1-29任一项的化合物或盐,其中所述的化合物为抗体-药物缀合物的组分。
32.药物组合物,它包含根据权利要求1-29任一项的化合物或盐,其中所述的化合物为基于颗粒的递送系统的组分。
33.治疗哺乳动物中异常细胞生长的方法,该方法包括对所述哺乳动物施用治疗有效量的根据权利要求1-29任一项的化合物或盐。
34.权利要求33的方法,其中所述的化合物或盐为抗体-药物缀合物的组分。
35.权利要求33的方法,其中所述的化合物或盐为基于颗粒的递送系统的组分。
36.权利要求33的方法,其中所述的异常细胞生长为癌症。
37.权利要求36的方法,其中所述的癌症为肺癌、骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、脊椎轴肿瘤、脑干神经胶质瘤或垂体腺瘤。
38.根据权利要求1-29任一项的化合物或盐在制备用于治疗哺乳动物中异常细胞生长的药剂中的用途。
39.权利要求38的用途,其中所述的异常细胞生长为癌症。
40.权利要求39的用途,其中所述的癌症为肺癌、骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌、胃癌、结肠癌、乳腺癌、子宫癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、外阴癌、霍奇金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾细胞癌、肾盂癌、中枢神经系统(CNS)肿瘤、原发性CNS淋巴瘤、脊椎轴肿瘤、脑干神经胶质瘤或垂体腺瘤。
41.上调哺乳动物中STING活性的方法,它包括对该哺乳动物施用有效量的根据权利1-29要求任一项的化合物或盐的步骤。
42.增加哺乳动物中干扰素-β水平的方法,它包括对该哺乳动物施用有效量的根据权利要求1-29任一项的化合物或盐的步骤。
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US11203610B2 (en) | 2017-12-20 | 2021-12-21 | Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. | 2′3′ cyclic dinucleotides with phosphonate bond activating the sting adaptor protein |
JP7037667B2 (ja) | 2017-12-20 | 2022-03-16 | インスティチュート オブ オーガニック ケミストリー アンド バイオケミストリー エーエスシーアール,ヴイ.ヴイ.アイ. | Stingアダプタータンパク質を活性化するホスホン酸結合を有する3’3’環状ジヌクレオチド |
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TW202200136A (zh) | 2020-04-10 | 2022-01-01 | 日商小野藥品工業股份有限公司 | 癌治療方法 |
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