CN112625028A - 用于抑制shp2活性的化合物和组合物 - Google Patents
用于抑制shp2活性的化合物和组合物 Download PDFInfo
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- CN112625028A CN112625028A CN202011428718.2A CN202011428718A CN112625028A CN 112625028 A CN112625028 A CN 112625028A CN 202011428718 A CN202011428718 A CN 202011428718A CN 112625028 A CN112625028 A CN 112625028A
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- Prior art keywords
- methyl
- amino
- hydrogen
- hydroxy
- alkyl
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 12
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明涉及式I化合物。所述化合物是Scr Homolgy‑2磷酸酶(SHP2)的抑制剂,因而可用于治疗努南综合征、豹斑综合征和癌症。
Description
本申请是申请日为2016年6月15日、优先权日为2015年6月19日的中国专利申请201680035707.3的分案申请。
背景
发明领域
本发明涉及能够抑制SHP2活性的化合物。本发明还提供了本发明的化合物的制备方法、包含该化合物的药物制剂以及在与SHP2异常活性相关的疾病或障碍的管理中使用该化合物和组合物的方法。
发明背景
Src Homolgy-2磷酸酶(SHP2)是PTPN11基因所编码的非受体蛋白酪氨酸磷酸酶,其促进多种细胞功能,包括增殖、分化、细胞周期维持和迁移。SHP2牵涉在经由Ras-有丝分裂原-激活的蛋白激酶、JAK–STAT或磷酸肌醇3-激酶-AKT途径的信号传导中。
SHP2具有两个N-末端Src homolgy2结构域(N-SH2和C-SH2)、催化结构域(PTP)和C-末端尾。所述两个SH2结构域控制SHP2的亚细胞定位和功能调控。该分子以无活性的自身抑制构象存在,所述构象通过牵涉来自N-SH2和PTP结构域的残基的结合网络所稳定。通过例如细胞因子或生长因子的刺激导致催化位点的暴露,从而导致SHP2催化活化。
已经在多种人类疾病中识别到了PTPN11基因中的突变和随后在SHP2中的突变,所述疾病例如有努南(Noonan)综合征、豹斑综合征(Leopard Syndrome)、幼年型粒-单核细胞白血病、成神经细胞瘤、黑素瘤、急性髓样白血病以及乳房、肺和结肠的癌症。因此,SHP2代表了开发用于治疗各种疾病的新疗法的具有高度吸引力的靶标。本发明的化合物满足了对抑制SHP2活性的小分子的需求。
发明简述
在一个方面,本发明提供了式I化合物:
其中:
Y1选自N和CR7;其中R7选自氢、卤素和氨基;Y2选自N和CR8;其中R8选自氢、卤素、C1-4烷基、卤素取代的C1-2烷基、卤素取代的C1-2烷氧基和氨基;Y3选自N、CR9和C(O);其中R9选自氢、氨基、氰基、卤素、C1-2烷氧基、卤素取代的C1-2烷基、卤素取代的硫烷基、C1-3烷基、环丙基、环丙基-羰基-氨基、C1-2烷基-羰基-氨基、吗啉代基-甲基和羟基;其中,如果Y3是C(O),则Y2选自NH和-N-C1-4烷基且含有Y1、Y2和Y3的环具有不多于两条双键;R1选自氢、卤素、卤素取代的C1-2烷基、卤素取代的C1-2烷氧基、羟基取代的C1-2烷基、C1-4烷基、C1-4烷氧基、氨基和氰基;或者R1和R9与R1和R9所连接的碳原子一起形成环戊烯或1,3-二氧杂环戊烯、2,3-二氢呋喃;R2选自氢、C1-4烷基和氟;R4a和R4b各自独立地选自氢、羟基和氟;条件是,R4a和R4b不能均为OH;条件是,R4a和R4b不能同时地是OH和F;R5a选自氨基和氨基-甲基;R5b选自OH、氨基、氟、C1-6烷基、甲氧基-羰基、C3-6环烷基-C1-3烷基、羟基取代的C1-3烷基、C1-2烷氧基取代的C1-3烷基和含有1至4个选自O、S和N的杂原子的5-6元杂芳基环;其中R5b的所述C1-6烷基或C1-2烷氧基取代的C1-3烷基是未取代的或被1-3个氟取代;条件是,如果R5a是氨基,则R5b不能是OH、氨基或氟;或者R5a和R5b连同R5a和R5b所连接的碳原子一起形成选自如下的基团:
其中*C表示R5a和R5b所连接的碳原子;R10是氨基;R11a选自氢、羟基、氟、C1-3烷基、卤素取代的C1-2烷基和羟基-甲基;R11b选自氟、甲基和氢;条件是,当R11a是羟基时,R11b不是氟;R11c选自氢、C1-3烷基和羟基-甲基;R12选自氢、卤素、羟基、C1-3烷基、卤素取代的C1-3烷基、卤素取代的C1-3烷氧基和C1-3烷氧基;R13选自氢、卤素和C1-2烷基;条件是,当R12是羟基时,R13不是氟;R14选自氢和氟;R15选自氢和氟;且R6a和R6b各自独立地选自氢、羟基和氟;条件是,R6a和R6b不能同时均为OH和氟;或其可药用盐;条件是,式I化合物不包括选自如下的化合物:(R)-8-(5-((2-(叔丁基)苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺;(R)-8-(5-((2-(三氟甲基)苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺;(R)-8-(5-((2-氨基苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺;(R)-8-(5-((2,3,5,6-四氟苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺;(R)-8-(5-(吡啶-3-基硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺;(R)-8-(5-((3-(三氟甲氧基)苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺;(1-(5-((3-乙氧基苯基)硫基)吡嗪-2-基)哌啶-4-基)甲胺;(1-(5-((2-乙基苯基)硫基)吡嗪-2-基)哌啶-4-基)甲胺;(1-(5-((2-异丙基苯基)硫基)吡嗪-2-基)哌啶-4-基)甲胺;(1-(5-((2-(三氟甲氧基)苯基)硫基)吡嗪-2-基)哌啶-4-基)甲胺;(1-(5-((3-(三氟甲氧基)苯基)硫基)吡嗪-2-基)哌啶-4-基)甲胺;(1-(5-((3-溴苯基)硫基)吡嗪-2-基)哌啶-4-基)甲胺;(S)-8-(5-((2-(叔丁基)苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺;和(S)-8-(5-((4-(叔丁基)苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺。
在第二个方面,本发明提供了药物组合物,其含有与一种或多种适宜的赋形剂混合的式I化合物或其N-氧化物衍生物、互变异构体、单个异构体和异构体混合物;或其可药用盐。
在第三个方面,本发明提供了在动物中治疗疾病的方法,其中SHP2活性的调控可以阻止、抑制或改善该疾病的病状和/或症状,该方法包括给动物施用治疗有效量的式I化合物或其N-氧化物衍生物、单个异构体和异构体混合物或其可药用盐。
在第四个方面,本发明提供了在动物中治疗疾病的方法,其中SHP2活性的调控可以阻止、抑制或改善该疾病的病状和/或症状,该方法包括给动物与抗癌治疗同时或依次组合地施用治疗有效量的式I化合物或其N-氧化物衍生物、单个异构体和异构体混合物或其可药用盐。
在第五个方面,本发明提供了式I化合物在制备药剂中的用途,所述药剂用于在动物中治疗其中SHP2活性促进疾病的病状和/或症状的疾病。
在第六个方面,本发明提供了式I化合物及其N-氧化物衍生物、前药衍生物、被保护的衍生物、单个异构体和异构体混合物及其可药用盐的制备方法。
定义
本文和下文所用的通用术语在本公开内容的范围内优选具有下述含有,另有指示除外,其中更通用的术语无论在何处使用时相互独立地被更具体的术语替换或被保留,因而定义了更详细的本发明的实施方案。
“烷基”指具有至多20个碳原子的完全饱和的支链或非支链烃部分。除非另有指出,否则烷基指具有1-7个碳原子(C1-7烷基)或1-4个碳原子(C1-4烷基)的烃部分。烷基的代表性实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基等。取代的烷基是含有一个或多个、例如一个、两个或三个选自卤素、羟基或烷氧基基团的取代基的烷基基团。卤素取代的烷基和卤素取代的烷氧基可以是直链或分支的,包括甲氧基、乙氧基、二氟甲基、三氟甲基、五氟乙基、二氟甲氧基、三氟甲氧基等。
“芳基”指含有6-10个环碳原子的单环或稠合双环芳香族环体系。例如,芳基可以是苯基或萘基,优选苯基。“亚芳基”指由芳基基团衍生的二价基团。
“杂芳基”如上文对芳基所定义,其中一个或多个环成员是杂原子。例如,C5-10杂芳基是如碳原子所指示的最少5个成员,但是这些碳原子可以被杂原子所替换。因此,C5-10杂芳基包括吡啶基、吲哚基、吲哚基、喹喔啉基、喹啉基、苯并呋喃基、苯并吡喃基、苯并噻喃基、苯并[1,3]二氧杂环戊烯、咪唑基、苯并咪唑基、嘧啶基、呋喃基、噁唑基、异噁唑基、三唑基、四唑基、吡唑基、噻吩基等。
“环烷基”指含有所指示环原子数的饱和或部分不饱和的单环、稠合双环或桥连多环体系。例如,C3-10环烷基包括环丙基、环丁基、环戊基、环己基、环己烯基等。
“杂环烷基”指如本申请中定义的环烷基,条件是一个或多个所指示的环碳被选自-O-、-N=、-NR-、-C(O)-、-S-、-S(O)-或-S(O)2-的部分所替换,其中R是氢、C1-4烷基或氮保护基。例如,如本申请中用于描述本发明的化合物的C3-8杂环烷基包括吗啉代基、吡咯烷基、吡咯烷基-2-酮、哌嗪基、哌啶基、哌啶基酮、1,4-二氧杂-8-氮杂-螺[4.5]癸-8-基、硫吗啉代基、sulfanomorpholino、sulfonomorpholino等。
“卤素”(或卤代基)优选表示氯或氟,但是还可以是溴或碘。
“SHP2”指“Src Homolgy-2磷酸酶”,还称为SH-PTP2、SH-PTP3、Syp、PTP1D、PTP2C、SAP-2或PTPN11。
包含有“PTPN11突变”的癌症包括但不限于:N58Y;D61Y,V;E69K;A72V,T,D;E76G,Q,K(ALL);G60A;D61Y;E69V;F71K;A72V;T73I;E76G,K;R289G;G503V(AML);G60R,D61Y,V,N;Y62D;E69K;A72T,V;T73I;E76K,V,G,A,Q;E139D;G503A,R;Q506P(JMML);G60V;D61V;E69K;F71L;A72V;E76A(MDS);Y63C(CMML);Y62C;E69K;T507K(成神经细胞瘤);V46L;N58S;E76V(肺癌);R138Q(黑素瘤);E76G(结肠癌)。
对于本申请,上述结构表示(S)-4-((R)-1,1-二甲基乙基亚磺酰胺基)-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(chemdraw所产生的命名)和(S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(chemdraw所识别的命名)。
式I化合物可以具有不同的异构形式。例如,任意不对称碳原子可以以(R)-、(S)-或(R,S)-构型、优选以(R)-或(S)-构型存在。双键或尤其是环处的取代基可以以顺式-(=Z-)或反式(=E-)形式存在。因此,化合物可以作为异构体的混合物存在,或者优选作为纯异构体、优选作为纯的非对映异构体或纯的对映异构体存在。
当使用复数形式(例如多种化合物、多种盐)时,这包括单数形式(例如单种化合物、单种盐)。“化合物”或“该化合物”不排除存在多于一种式I化合物(或其盐)(例如在药物制剂中),“该”仅仅表示不定冠词。因此,“该”优选表示为“一种/个或多种/个”、较不优选替代地表示“一种/个”。
无论在何处提及一种或多种式I化合物,这还意欲包括该化合物的N-氧化物和/或其互变异构体。
术语“和/或其N-氧化物、其互变异构体和/或其(优选可药用)盐”尤其指式I化合物可以原样或在与其N-氧化物的混合物中存在、作为互变异构体(例如归因于酮-烯醇、内酰胺-内酰亚胺、酰胺-亚胺酸或烯胺-亚胺互变异构现象)或在与其互变异构体的混合物(例如产生的相等反应物)中存在或者作为式I化合物的盐和/或任意这些形式或两种或更多种这类形式的混合物存在。
本发明还包括本发明的化合物或其可药用盐的所有适宜的同位素变体。本发明的化合物或其可药用盐的同位素变体被定义为其中至少一个原子被具有相同原子数、但是原子质量与自然界经常发现的原子质量不同的原子所替换的那些。可以掺入到本发明的化合物及其可药用盐中的同位素的实例包括但不限于氢、碳、氮和氧的同位素,例如2H、3H、11C、13C、14C、15N、17O、18O、35S、18F、36Cl和125I。本发明的化合物及其可药用盐的某些同位素变体、例如其中掺入有放射性同位素如3H或14C的那些可用于药物和/或底物组织分布研究中。在特定的实例中,可以使用3H或14C同位素,因为它们易于制备和检测。在其它实例中,用同位素2H取代可以提供产生于较高的代谢稳定性如增加的体内半衰期或降低的剂量需求的某些治疗益处。本发明的化合物或其可药用盐的同位素变体通常可以通过常规技术、采用适宜试剂的适当同位素变体来制备。例如,本发明的化合物可以以如下所示的氚化形式存在:
优选实施方案的描述
本发明涉及能够抑制SHP2活性的化合物。在本发明的一个方面,就式I化合物而言,是式Ia化合物:
其中:
R1选自氢、卤素、卤素取代的C1-2烷基、卤素取代的C1-2烷氧基、C1-4烷基、C1-4烷氧基、氨基和氰基;R4选自氢、羟基和氟;R7选自氢、卤素和氨基;R9选自氢、甲基、甲氧基、乙氧基、羟基、羟基-甲基、三氟甲基、环丙基、吗啉代基-甲基、氰基、甲基-羰基-氨基、环丙基-羰基-氨基、五氟-λ6-硫烷基、氨基和卤素;或者R1和R9与R1和R9所连接的碳原子一起形成环戊烯;R10是氨基;R11a选自氢、氟、甲基、乙基、异丙基、三氟甲基、羟基和羟基-甲基;R11b选自氟和氢;条件是,当R11a是羟基时,R11b不是氟;R12选自氢、卤素、羟基、C1-3烷基、卤素取代的C1-3烷基、卤素取代的C1-3烷氧基和C1-3烷氧基;R13选自氢、氟和C1-2烷基;条件是,当R12是羟基时,R13不是氟;R14选自氢和氟;R15选自氢和氟;且Y2选自N和CR8;其中R8选自氢、卤素、C1-4烷基、卤素取代的C1-2烷基、卤素取代的C1-2烷氧基和氨基;或其可药用盐。
在进一步的实施方案中,R1选自氢、溴、氯、氟、甲基、异丙基、叔丁基、氟取代的甲基、甲氧基、三氟甲基、三氟甲氧基、氨基和氰基;R2是氢;R4选自氢和羟基;R7选自氢、氟、氯和氨基;R9选自氢、甲基、甲氧基、乙氧基、羟基、羟基-甲基、环丙基、氨基、三氟甲基、吗啉代基-甲基、环丙基-羰基-氨基、甲基-羰基-氨基、五氟-λ6-硫烷基、氰基、溴、氯和氟;或者R1和R9与R1和R9所连接的碳原子一起形成环戊烯;R10是氨基;R11a选自氢、羟基、甲基和羟基-甲基;R11b选自氟和氢;条件是,当R11a是羟基时,R11b不是氟;R12选自氢、氟、羟基、甲基和甲氧基;和R13选自氢、氟和甲基;条件是,当R12是羟基时,R13不是氟;和Y2选自CR8和N;其中R8选自氢、溴、氯、氟、乙基、三氟甲基、三氟甲氧基和叔丁基;或其可药用盐。
在进一步的实施方案中,R1选自氯、氟、甲基、氟取代的甲基和氰基;R2是氢;R4选自氢、氟和羟基;R7选自氢、氟、氯和氨基;R9选自氢、氨基、氯和氟;R10是氨基;R11a选自氢、羟基和甲基;R11b选自氟和氢;条件是,当R11a是羟基时,R11b不是氟;R12选自氢、氟、羟基、甲基和甲氧基;和R13选自氢、氟和甲基;条件是,当R12是羟基时,R13不是氟;或其可药用盐。
在进一步的实施方案中,是选自如下的化合物或其可药用盐:
在另一项实施方案中,是式Ib化合物:
其中:R1选自氢、卤素、卤素取代的C1-2烷基、C1-2烷基和氰基;R2是氢;R4选自氢、氟和羟基;R7选自氢、卤素和氨基;R9选自氢、甲基、甲氧基、乙氧基、羟基、羟基-甲基、三氟甲基、环丙基、吗啉代基-甲基、氰基、甲基-羰基-氨基、环丙基-羰基-氨基、五氟-λ6-硫烷基、氨基和卤素;R10是氨基;R11c选自氢、乙基、异丙基、羟基-甲基和甲基;Y2选自CR8和N;其中R8选自氢、溴、氯、氟、乙基、三氟甲基、三氟甲氧基和叔丁基;或其可药用盐。
在进一步的实施方案中,R1选自氢、氯、氟、甲基、氟取代的甲基和氰基;R4选自氢;R7选自氢、氟、氯和氨基;R9选自氢、氨基、溴、羟基、三氟甲基、甲基-羰基、羟基-甲基、氯和氟;R10是氨基;R11c选自氢、乙基、异丙基、羟基-甲基和甲基;Y2选自CR8和N;其中R8选自氢、溴、氯、氟、乙基、三氟甲基、三氟甲氧基和叔丁基;或其可药用盐。
在进一步的实施方案中,是选自如下的化合物或其可药用盐:
在另一项实施方案中,是选自如下的化合物或其可药用盐:
在另一项实施方案中,是式Ic化合物:
其中:Y2选自N和CR8;其中R8选自氢和氨基;Y3选自N和CR9;其中R9选自氢、甲基、甲氧基、乙氧基、羟基、羟基-甲基、三氟甲基、环丙基、吗啉代基-甲基、氰基、甲基-羰基-氨基、环丙基-羰基-氨基、五氟-λ6-硫烷基、氨基和卤素;R2是氢;R4选自氢、羟基和氟;R5a选自氨基和氨基-甲基;R5b选自OH、氨基、氟、C1-6烷基、甲氧基-羰基、C3-6环烷基-C1-3烷基、羟基取代的C1-3烷基、C1-2烷氧基取代的C1-3烷基和含有1至4个选自O、S和N的杂原子的5-6元杂芳基环;其中R5b的所述C1-6烷基或C1-2烷氧基取代的C1-3烷基是未取代的或被1-3个氟取代;条件是,如果R5a是氨基,则R5b不能同时是OH、氨基或氟;R7选自氢、卤素和氨基;或其可药用盐。
在进一步的实施方案中,Y2选自N和CR8;其中R8选自氢和氨基;Y3选自N和CR9;其中R9选自氢、氨基、卤素和羟基;R1选自卤素、卤素取代的C1-2烷基和氰基;R2选自氢和卤素;R4选自氢和羟基;R5a选自氨基和氨基-甲基;R5b选自OH、甲基、乙基、丙基、异丙基、异丁基、氨基、氨基-甲基、甲氧基-羰基、吡啶基和羟基-甲基;条件是,如果R5a是氨基,则R5b不能是OH、氨基或氟;R7选自氢、卤素和氨基;或其可药用盐。
在进一步的实施方案中,是选自如下的化合物或其可药用盐:
药理学和功用
Src Homolgy-2磷酸酶(SHP2)是PTPN11基因所编码的蛋白酪氨酸磷酸酶,其促进多种细胞功能,包括增殖、分化、细胞周期维持和迁移。SHP2牵涉在经由Ras-有丝分裂原-激活的蛋白激酶、JAK–STAT或磷酸肌醇3-激酶-AKT途径的信号传导中。SHP2介导受体酪氨酸激酶如ErbBl、ErbB2和c-Met的Erkl和Erk2(Erkl/2,Erk)MAP激酶的激活。
SHP2具有两个N-末端Src homolgy2结构域(N-SH2和C-SH2)、催化结构域(PTP)和C-末端尾。所述两个SH2结构域控制SHP2的亚细胞定位和功能调控。该分子以无活性构象存在,经由牵涉来自N-SH2和PTP结构域的残基的结合网络来抑制其自身活性。响应于生长因子的刺激,SHP2经由其SH2结构域结合停靠蛋白上的特定酪氨酸-磷酸化位点如Gab1和Gab2。这引起了构象变化,导致SHP2激活。
已经在多种人类疾病中识别到了PTPN11中的突变,所述疾病例如有努南综合征、豹斑综合征、幼年型粒-单核细胞白血病、成神经细胞瘤、黑素瘤、急性髓样白血病以及乳房、肺和结肠的癌症。SHP2是多种受体酪氨酸激酶、包括血小板衍生生长因子(PDGF-R)、成纤维细胞生长因子(FGF-R)和表皮生长因子(EGF-R)的受体的重要下游信号分子。SHP2还是激活促分裂原活化蛋白(MAP)激酶途径的重要下游信号分子,其可导致细胞转化(癌发展的必要条件)。SHP2的敲减显著抑制了具有SHP2突变或EML4/ALK易位的肺癌细胞系以及EGFR扩增乳癌和食管癌的细胞生长。SHP2还是胃癌、间变型大细胞淋巴癌和成胶质细胞瘤的癌基因的激活下游。
努南综合征(NS)和豹斑综合征(LS)—PTPN11突变引起LS(多发性色素斑样痣综合征,心电图传导异常,两眼距离过远,肺动脉瓣狭窄,异常生殖器,生长迟缓,感音神经性耳聋)和NS(包括心脏缺陷、颅面骨畸形和身材矮小的先天异常)。这两种障碍是RAS/RAF/MEK/ERK有丝分裂原活化蛋白激酶途径(正常细胞生长和分化所需)的组分中的种系突变引起的常染色体显性综合征家族的一部分。该途径的异常调控具有深远的影响,特别是对心脏发育具有深远的影响,导致多种异常,包括瓣膜中隔缺陷(valvuloseptal defects)和/或肥厚型心肌病(HCM)。已经确定MAPK信号传导途径的的扰动对于这些障碍而言是重要的,已经在人中识别出沿循该途径的一些候选基因,包括KRAS、NRAS、SOS1、RAF1、BRAF、MEK1、MEK2、SHOC2和CBL中的突变。在NS和LS中最常突变的基因是PTPN11。在~50%的NS病例中和几乎所有的具有NS的某些特征的LS患者中发现了PTPN11(SHP2)的种系突变。对于NS,蛋白质中的Y62D和Y63C置换是大量不变的,处于最常见的突变中。这两种突变影响SHP2的无催化活性的构象,而不干扰磷酸酶与其磷酸化信号配偶体的结合。
幼年型粒-单核细胞白血病(JMML)—在约35%的JMML(一种儿童期骨髓增生病(MPD))患者中发生PTPN11(SHP2)中的体细胞突变。这些功能获得性突变通常是N-SH2结构域或磷酸酶结构域中的点突变,其阻止催化结构域和N-SH2结构域之间的自我抑制,产生SHP2活性。
急性髓样白血病—已经在~10%的儿科急性白血病如骨髓发育不良综合征(MDS)、~7%的B细胞急性淋巴母细胞白血病(B-ALL)和~4%的急性髓样白血病(AML)中识别出PTPN11突变。
NS和白血病突变引起位于由自身抑制SHP2构象中的N-SH2和PTP结构域所形成的界面处的氨基酸的变化,破坏抑制性分子内相互作用,导致催化结构域活动过度。
SHP2在受体酪氨酸激酶(RTK)信号传导中充当正调节剂。含有RTK改变(EGFRamp,Her2amp,FGFRamp,Metamp,易位/活化的RTK,即ALK,BCR/ABL)的癌症包括食管癌、乳癌、肺癌、结肠癌、胃癌、神经胶质瘤、头颈癌。
食管癌(或食道癌)是食管的恶性病。存在多种亚型,主要是鳞状细胞癌(<50%)和腺癌。在食管腺癌和鳞状细胞癌中有高比率的RTK表达。因此,本发明的SHP2抑制剂可用于创新的治疗策略。
乳癌是一种重要类型的癌症,并且是女性的主要死因,其中患者对现有药物出现抗性。存在四种主要的乳癌亚型,包括luminal A、luminal B、Her2 lik和三阴/Basal-like。三阴乳癌(TNBC)是缺少特定靶向治疗的侵袭性乳癌。表皮生长因子受体I(EGFR)已经显现为TNBC中的有前景的靶标。Her2以及EGFR经由SHP2的抑制可以是乳癌的有前景的治疗。
肺癌—NSCLC目前是癌症相关死亡率的重要原因。占约85%的肺癌(主要是腺癌和鳞状细胞癌)。虽然细胞毒性化学治疗仍然是治疗的重要部分,但是基于肿瘤中遗传改变如EGFR和ALK的靶向治疗更可能得益于靶向治疗。
结肠癌—已知约30%至50%的结肠直肠肿瘤具有突变(异常)的KRAS,BRAF突变发生在10至15%的结肠直肠癌中。对于其结肠直肠肿瘤已经被证明过表达EGFR的患者亚群而言,这些患者呈现出对抗-EGFR疗法的有利的临床响应。
胃癌是最流行的癌症类型之一。酪氨酸激酶的异常表达(如通过胃癌细胞中的异常酪氨酸磷酸化所反映的那样)是本领域已知的。在胃癌中经常扩增三种受体酪氨酸激酶,即c-met(HGF受体)、FGF受体2和erbB2/neu。因此,不同信号途径的破坏可促进不同胃癌类型的进程。
成神经细胞瘤是发育中的交感神经系统的儿科肿瘤,占约8%的儿童癌症。间变性淋巴瘤激酶(ALK)基因的基因组改变已经被提出促进成神经细胞瘤发病机制。
头和颈鳞状细胞癌(SCCHN).高水平的EGFR表达与多种癌症、最常见是头和颈鳞状细胞癌(SCCHN)中的预后不良和对放射治疗的抗性相关。EGFR信号阻断导致抑制受体刺激、细胞增殖、侵袭和转移下降。因此,在SCCHN中,EGFR是新抗癌疗法的最佳靶标。
本发明涉及能够抑制SHP2活性的化合物。本发明还提供了本发明的化合物的制备方法和包含该化合物的药物制剂。本发明的另一方面涉及治疗SHP2-介导的障碍的方法,该方法包括给需要其的患者施用治疗有效量的如发明简述中所定义的式I化合物的步骤。
在一些实施方案中,本发明涉及如上所述的方法,其中所述SHP2-介导的障碍是选自如下、但不限于此的癌症:JMML;AML;MDS;B-ALL;成神经细胞瘤;食管癌;乳癌;肺癌;结肠癌;胃癌,头颈癌。
本发明的化合物还可用于治疗与SHP2异常活性相关的其它疾病或病症。因此,作为进一步的方面,本发明涉及治疗选自如下的障碍的方法:NS;LS;JMML;AML;MDS;B-ALL;成神经细胞瘤;食管癌;乳癌;肺癌;结肠癌;胃癌;头颈癌。
本发明的SHP2抑制剂可以有用地与其它具有药理活性的化合物或与两种或更多种其它具有药理活性的化合物组合,特别是在治疗癌症中。例如,如上定义的式(I)化合物或其可药用盐可以与一种或多种选自如下的物质组合地同时、依次或分别施用:化疗剂,例如有丝分裂抑制剂,如紫杉烷、长春花生物碱、紫杉醇、多西他赛、长春花新碱、长春花碱、长春瑞滨或长春氟宁,其它抗癌剂如顺铂、5-氟尿嘧啶或5-氟-2-4(1H,3H)-嘧啶二酮(5FU)、氟他胺或吉西他滨。
一些组合在疗法中可以提供显著的优点,包括协同活性。
在一些实施方案中,本发明涉及如上所述的方法,其中所述化合物经胃肠外施用。
在一些实施方案中,本发明涉及如上所述的方法,其中所述化合物经肌内、静脉内、皮下、口服、经肺、鞘内、局部或经鼻内施用。
在一些实施方案中,本发明涉及如上所述的方法,其中所述化合物经全身施用。
在一些实施方案中,本发明涉及如上所述的方法,其中所述患者是哺乳动物。
在一些实施方案中,本发明涉及如上所述的方法,其中所述患者是灵长类动物。
在一些实施方案中,本发明涉及如上所述的方法,其中所述患者是人。
在另一方面,本发明涉及治疗SHP2-介导的障碍的方法,该方法包括如下步骤:给需要其的患者施用治疗有效量的化疗剂与如治疗有效量的如发明概述中定义的式I化合物的组合。
药物组合物
在另一方面,本发明提供了可药用组合物,其包含与一种或多种可药用载体(添加物)和/或稀释剂一起配制的治疗有效量的一种或多种如上所述的化合物。如下文详述的那样,本发明的药物组合物可以被特别配制成用于以固体或液体形式进行施用,包括适于下述的那些:(1)口服施用,例如顿服药(水性或非水性溶液或混悬液),片剂如靶向于颊、舌下和全身吸收的那些,大丸剂,粉末,颗粒剂,应用于舌的糊剂;(2)胃肠道外施用,例如作为例如无菌溶液或混悬液或缓释制剂通过皮下、肌内、静脉内或硬膜外注射;(3)局部应用,例如作为霜剂、软膏剂或控释贴剂或应用于皮肤的喷雾;(4)阴道内或直肠内,例如作为阴道栓、霜剂或泡沫;(5)舌下给药;(6)眼睛;(7)透皮;(8)经鼻;(9)经肺;或(10)鞘内。
如本文所用的短语"治疗有效量"指化合物、材料或包含本发明的化合物的组合物的如下量:其在动物的至少细胞亚群中以可用于任何医学治疗的合理的利弊比率有效地产生一些预期治疗作用。
短语"可药用"在本文中用于指这样的化合物、材料、组合物和/或剂量形式:它们在合理的医学判断范围内适用于与人和动物的组织接触而没有过度毒性、刺激性、过敏反应或其它问题或并发症,与合理的利弊比率相称。
如本文所用的短语"可药用载体"指药学上可接受的材料、组合物或佐剂,例如液体或固体填充剂、稀释剂、赋形剂、制备助剂(例如润滑剂、滑石粉、硬脂酸镁、钙或锌或者硬脂酸)或溶剂包囊材料,它们牵涉在将主题化合物从身体的一个器官或部分运载或转运至身体的另一个器官或部分。每种载体在与制剂的其它成分相容和对患者无害的意义上必须是"可接受的"。看额用作可药用载体的材料的一些实例包括:(1)糖,例如乳糖、葡萄糖和蔗糖;(2)淀粉,例如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;(4)粉末西黄耆胶;(5)麦芽;(6)明胶;(7)滑石粉;(8)赋形剂,例如可可脂和栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、谷物油和大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨醇、甘露醇和聚乙二醇;(12)酯,例如油酸乙酯和月桂酸乙基酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁和氢氧化铝;(15)海藻酸;(16)无热原的水;(17)等张盐水;(18)Ringer's溶液;(19)乙醇;(20)pH缓冲液;(21)多元酯、聚碳酸酯和/或聚酐;和(22)药物制剂中采用的其它无毒可相容物质。
如上指出,本发明的化合物的一些实施方案可以含有碱性官能团如氨基或烷基氨基,因此能够与可药用酸形成可药用盐。在此方面的术语"可药用盐"指本发明的化合物的相对无毒的无机和有机酸加成盐。这些盐可以在施用载体或剂型生产过程中原位制备,或者通过使纯化的游离碱形式的本发明的化合物与适宜的有机或无机酸反应和在随后的纯化中分离由此形成的盐来分开地制备。代表性的盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、磷酸盐、硝酸盐、乙酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐和月桂基磺酸盐等。(参见例如Berge等人,(1977)"Pharmaceutical Salts",J.Pharm.Sci.66:1-19)。
主题化合物的可药用盐包括化合物的常规的无毒盐或季铵盐,例如来自无毒的有机或无机酸。例如,这类常规的无毒盐包括衍生自无机酸如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的那些;和由有机酸如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯基乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸、羟乙基磺酸(isothionic acid)等制备的盐。
在其它例子中,本发明的化合物可以含有一个或多个酸性官能团,因此能够与可药用碱形成可药用盐。在这些实例中的术语"可药用盐"指本发明的化合物的相对无毒的无机和有机碱加成盐。同样,这些盐可以在施用载体或剂型生产过程中原位制备,或者通过使纯化的游离酸形式的本发明的化合物与适宜的碱如可药用金属离子的氢氧化物、碳酸盐或碳酸氢盐、与氨或与可药用有机伯胺、仲胺或叔胺反应来分开地制备。代表性的盐包括碱金属或碱土金属盐包括锂、钠、钾、钙、镁和铝盐等。可用于形成碱加成盐的代表性有机胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等。(参见例如Berge等人,出处同上)
在组合物中还可以存在湿润剂、乳化剂和润滑剂如月桂硫酸钠和硬脂酸镁以及着色剂、释放及、包衣剂、甜味剂、矫味剂和香味剂、防腐剂和抗氧化剂。
可药用抗氧化剂的实例包括:(1)水溶性抗氧化剂,例如抗坏血酸、半胱氨酸盐酸盐、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠等;(2)油溶性抗氧化剂,例如抗坏血酸棕榈酸酯、丁羟茴醚(BHA)、丁羟甲苯(BHT)、卵磷脂、棓酸丙基酯、α-生育酚等;和(3)金属螯合剂,例如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
本发明的制剂包括适于口服、经鼻、局部(包括经颊和舌下)、直肠、阴道和/或胃肠道外施用的那些。制剂可以常规地以单位剂型存在,并且可以通过药学领域熟知的任意方法来制备。可以与载体材料组合以产生单个剂型的活性成分的量通常将根据所治疗的宿主、具体施用模式而异。可以与载体材料组合以产生单个剂型的活性成分的量通常是化合物产生治疗作用的量。通常,对于100%而言,该量将为约0.1%至约99%的活性成分,优选5%至约70%,最优选约10%至约30%。
在一些实施方案中,本发明的制剂包含选自环糊精、纤维素、脂质体、胶束形成剂如胆酸和聚合载体如聚酯和聚酐的赋形剂和本发明的化合物。在一些实施方案中,上述制剂使得本发明的化合物是口服可利用的。
制备这些制剂或组合物的方法包括将本发明的化合物和载体以及任选的一种或多种辅助成分联合的步骤。通常,通过将本发明的化合物和液体载体或细分散的固体载体或两者均匀和紧密地联合和然后酌情将产品成形来制备制剂。
适于口服施用的本发明的制剂可以是胶囊剂、扁囊剂、丸剂、片剂、锭剂(采用矫味基质,通常是蔗糖和阿拉伯胶或西黄耆胶)、粉末、颗粒的形式或者作为在水性或非水性液体中的溶液或混悬液或者作为水包油或油包水液体乳剂或者作为酏剂或糖浆剂或者作为软锭剂(采用惰性基质,例如明胶和甘油或者蔗糖和阿拉伯胶)和/或作为口腔清洗剂等,各自含有预定量的本发明的化合物作为活性成分。本发明的化合物还可以作为大丸剂、药糖剂或糊剂进行施用。
在用于口服施用的本发明的固体剂型(胶囊剂、片剂、丸剂、锭剂、粉末、颗粒、trouches等)中,活性成分与一种或多种可药用载体混合,例如柠檬酸钠或磷酸二钙,和/或下述任一种:(1)填充剂或増充剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸;(2)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶;(3)湿润剂,例如甘油;(4)崩解剂,例如gar-agar、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;(5)溶解延迟剂,例如石蜡;(6)吸收促进剂如季铵化合物和表面活性剂如泊洛沙姆和月桂硫酸钠;(7)润湿剂,例如鲸蜡醇、单硬脂酸甘油酯和非离子表面活性剂;(8)吸收剂,例如白陶土和膨润土;(9)润滑剂,例如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂硫酸钠、硬脂酸锌、硬脂酸钠、硬脂酸及其混合物;(10)着色剂;和(11)控释剂如交聚维酮或乙基纤维素。在胶囊、片剂和丸剂的情况中,药物组合物还可以包含缓冲剂。
相似类型的固体组合物还可以采用诸如或奶糖(milk sugars)以及高分子量聚乙二醇等的赋形剂用作软和硬壳明胶胶囊的填充物。
片剂可以通过压制或模制、任选地与一种或多种辅助成分一起制备。压制片可以采用粘合剂(例如明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如淀粉羟乙酸钠或交联羧甲基纤维素钠)、表面活性剂或分散剂来制备。模制片可以通过在适宜的机器中将用惰性液体稀释剂润湿的粉末化合物的混合物进行模制来制备。
本发明的药物组合物的片剂和其它固体剂型如锭剂、胶囊剂、丸剂和颗粒可以任选地带有刻痕或者制备有包衣和壳,例如药物制剂领域熟知的肠包衣和其它包衣。还可以采用例如羟丙基甲基纤维素(不同比例以提供预期的释放性质)、其它聚合物材料、脂质体和/或微球将它们配制成提供其中的活性成分的缓慢或控制释放。它们可以被配制成用于快速释放,例如冷冻干燥。它们可以通过例如经细菌截留滤器或通过在临用前掺入可溶于无菌水或一些其它无菌注射用介质的灭菌固体组合物形式的灭菌剂来进行灭菌。这些组合物还可以任选地含有遮光剂,并且可以具有仅在或优选在胃肠道的某些部分以延迟方式释放活性成分的组合物。可以使用的包埋组合物的实例包括聚合物质和蜡。活性成分还可以是微囊形式,酌情含有一种或多种上述赋形剂。
用于口服施用本发明的化合物的液体剂型包括可药用乳剂、微乳剂、溶液、混悬液、糖浆剂和酏剂。除了活性成分外,液体剂型还可以含有本领域常用的惰性稀释剂如水或其它溶剂、增溶剂和乳化剂如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄基醇、苯甲酸苄基酯、丙二醇、1,3-丁二醇、油(特别是棉籽油、花生油、玉米油、胚油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃基甲醇、聚乙二醇和山梨坦脂肪酸酯及其混合物。
除了惰性稀释剂,口服组合物还可以包括佐剂如湿润剂、乳化剂和助悬剂、甜味剂、矫味剂、着色剂、香味剂和防腐剂。
除了活性化合物外,混悬液还可以含有助悬剂如乙氧基化异硬脂醇、聚氧乙烯山梨醇和山梨坦酯、微晶纤维素、偏氢氧化铝(aluminum metahydroxide)、膨润土、琼脂和西黄蓍胶及其混合物。
用于直肠或阴道施用的本发明的药物组合物的制剂可以作为栓剂给出,其可以通过将一种或多种本发明的化合物与一种或多种适宜的非刺激性赋形剂或载体混合来制备,所述赋形剂或载体包含例如可可脂、聚乙二醇、栓剂蜡或水杨酸酯,其在室温是固体,但是在体温时为液体,因此在直肠或阴道腔内将熔化并释放活性化合物。
适于阴道施用的本发明的制剂还包括含有本领域已知适当的载体的子宫托、棉栓、霜剂、凝胶、糊剂、泡沫或喷雾制剂。
用于局部或透皮施用本发明的化合物的剂型包括粉末、喷雾剂、软膏剂、糊剂、霜剂、乳液剂、凝胶、溶液、贴剂和吸入剂。活性化合物可以在无菌条件下与可药用载体和与可能需要的任意防腐剂、缓冲剂或抛射剂混合。
除了本发明的活性化合物外,软膏剂、糊剂、霜剂和凝胶可以含有赋形剂如动物和植物脂肪、油、蜡、石蜡、淀粉、西黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石粉和氧化锌或其混合物。
除了本发明的化合物外,粉末和糖浆剂可以含有赋形剂如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末或这些物质的混合物。喷雾剂可以另外地含有惯用抛射剂如氯氟烃和挥发性的未取代的烃如丁烷和丙烷。
透皮贴剂可以具有提供本发明的化合物向身体的控制释放的附加优点。这类剂型可以通过将化合物溶于或分散于合适的介质中来制备。还可以使用吸收促进剂来增加化合物穿过皮肤的流量。该流量的速率可以通过提供控速膜或将化合物分散在聚合基质或凝胶中来进行控制。
眼用制剂、眼睛软膏剂、粉末、溶液等也被视为在本发明的范围内。
适于胃肠外使用的本发明的药物组合物包含一种或多种本发明的化合物以及一种或多种可药用无菌等张水性或非水性溶液、分散液、混悬液或乳液或者可以在临用前重构入无菌可注射溶液或分散液的无菌粉末,其可以含有糖、醇、抗氧化剂、缓冲剂、抑菌剂、使制剂与预期接受者的血液等张的溶质或者助悬或增稠剂。
可用于本发明的药物组合物的适宜的水性和非水性载体的实例包括水、乙醇、多元醇(如甘油、丙二醇、聚乙二醇等)及其适宜的混合物、植物油如橄榄油和可注射有机酯如油酸乙基酯。适当的流动性可以例如通过使用包衣材料如卵磷脂、通过维持所需的粒度(在分散液的情况下)和通过使用表面活性剂来维持。
这些组合物还可以含有佐剂如防腐剂、湿润剂、乳化剂和分散剂。阻止微生物对主题化合物的作用可以通过引入各种抗细菌剂和抗真菌剂如对羟苯甲酸酯、氯代丁醇、苯酚、山梨酸等来确保。还可以期望在组合物中包括等张剂如糖、氯化钠等。另外,通过引入延迟吸收的物质如单硬脂酸铝和明胶可以使注射用药物形式的吸收延长。
在一些情况中,为了延长药物的作用,期望减缓来自皮下或肌内注射的药物的吸收。这可以通过使用具有差的水溶性的结晶或无定形材料的液体混悬液来完成。从而,药物的吸收速率取决于其溶出速率,溶出速率转而又取决于结晶尺寸和结晶形式。或者,通过将药物溶解或混悬于油溶媒中来完成胃肠外施用的药物形式的延迟吸收。
可注射贮库形式通过在生物可降解聚合物如聚丙交酯-聚乙醇酸交酯中形成主题化合物的微囊基质来制备。根据药物与聚合物的比例以及所用具体聚合物的性质,可以控制药物释放速率。其它生物可降解的聚合物的实例包括聚(原酸酯)和聚(酐)。可注射贮库制剂还可以通过将药物包藏在与身体组织相容的脂质体或微乳中来制备。
当本发明的化合物作为药物施用于人和动物时,它们可以原样给予或者作为含有例如0.1-99%(更优选10至30%)的活性成分和可药用载体的联合的药物组合物给予。
本发明的制剂可以经口服、胃肠道外、局部或直肠给予。当然,它们以适于每种施用途径的形式给予。例如,它们如下进行施用:以片剂或胶囊剂形式、通过注射、吸入、眼用乳液、软膏剂、栓剂等通过注射、输注或吸收的施用;通过乳液或软膏剂的局部施用;和通过栓剂的直肠施用。
口服施用是优选的。
如本文所用的短语"胃肠道外施用"和"经胃肠道外施用"指除肠内和局部施用以外的释放模式,通常通过注射,包括但不限于静脉内、肌内、动脉内、鞘内、囊内、眼眶内、心内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内和胸骨内注射和输注。
如本文所用的短语"全身施用"、"经全身施用"、"外周施用"和"经外周施用"指不是直接进入中枢神经系统的化合物、药物或其它物质的施用,从而其进入患者的全身和因此进行代谢和其它相似过程,例如皮下施用。
这些化合物可以通过任意适宜的施用途径施用于人和其它动物用于疗法,包括口服、经鼻如通过喷雾剂、经直肠、阴道内、胃肠道外、脑池内和局部如通过粉末、软膏剂或滴剂、包括经颊和舌下。
不管所选的施用途径,本发明的化合物(其可以以适宜的水合形式使用)和/或本发明的药物组合物可以通过本领域技术人员已知的常规技术配制成可药用剂型。
本发明的药物组合物中的活性成分的实际剂量水平可以改变,以得到对于特定患者、组合物和施用模式而言有效达到预期治疗响应并且对患者无毒的活性成分的量。
所选的剂量水平将取决于多种因素,包括所用的具体的本发明的化合物或其酯、盐或酰胺的活性、施用途径、施用时间、所用具体化合物的排泄率或代谢率、吸收速率和程度、治疗持续时间、与所用具体药物组合使用的其它药物、化合物和/或材料、所治疗患者的年龄、性别、体重、状况、一般健康和在先医疗史等医学领域熟知的因素。
具有本领域普通技术的医生或兽医可容易地确定和开据出所需的药物组合物的有效量。例如,医生或兽医可以从比获得预期治疗效果所需的水平低的水平开始药物组合物中所用的本发明的化合物的剂量并且逐渐增加剂量直至获得预期效果。
通常,本发明的化合物的适宜日剂量是化合物的如下量:其有效地产生治疗效果的最低剂量。这种有效剂量通常将取决于上述因素。通常,当用于所指示的镇痛作用时,本发明的化合物的口服、静脉内、脑室内的和皮下剂量将为约0.0001至约100mg/千克体重/天。
如果希望的话,活性化合物的有效日剂量可以作为在一天中以适当间隔施用的两个、三个、四个、五个、六个或更多个亚剂量进行施用。优选的剂量是每天一次施用。
当对于本发明的化合物单独施用是可能的时,优选以药物制剂(组合物)施用该化合物。
本发明的化合物可以类似于其它药物被配制用于以任何对于人或兽医学施用而言方便的方式进行的施用。
在另一方面,本发明提供了可药用组合物,其包含与一种或多种可药用载体(添加物)和/或稀释剂一起配制的治疗有效量的一种或多种如上所述的主题化合物。如下文详述,本发明的药物组合物可以被特别配制成用于以固体或液体形式施用,包括适于如下的那些:(1)口服施用,例如顿服剂(水性或非水性溶液或混悬液)、片剂、大丸剂、粉末、颗粒、应用于舌的糊剂;(2)胃肠道外施用,例如通过皮下、肌内或静脉注射,作为例如无菌溶液或混悬液;(3)局部应用,例如作为霜剂、软膏剂或应用于皮肤、肺或粘膜的喷雾剂;或(4)阴道内或直肠内,例如作为子宫托、霜剂或泡沫剂;(5)舌下或经颊;(6)经眼;(7)透皮;或(8)经鼻。
术语"治疗"意欲还包括预防、治疗和治愈。
接受该治疗的患者是有需要的任意动物,包括灵长类动物、特别是人以及其它哺乳动物如马科动物、牛、猪和羊;和家禽和宠物(通常)。
本发明的化合物可以原样施用或者与可药用载体混合施用,并且可以与抗微生物剂如青霉素、头孢菌素、氨基糖苷和糖肽组合施用。因此,联合疗法包括以首先施用的药物的治疗效果在施用随后的药物时没有完全消失的方式依次、同时和分别施用活性化合物
微乳技术可以改善一些疏水性(水不溶性)药用物质的生物利用度。其实例包括Trimetrine(Dordunoo,S.K.,等人,Drug Development and Industrial Pharmacy,17(12),1685-1713,1991和REV 5901(Sheen,P.C.,等人,J Pharm Sci 80(7),712-714,1991)。其中,微乳通过优先将吸收指向淋巴系统而不是循环系统、由此绕过了肝脏和阻止了化合物在肝胆循环中的破坏而提供了改善的生物利用度。
虽然关注了所有适宜的两亲性载体,但是目前优选的载体通常是具有公认安全(GRAS)状态并且可以增溶本发明的化合物和当溶液与复杂水相(例如在人胃肠道中发现的那些)接触时在稍后阶段使其微乳化的那些。通常,满足这些要求的两亲性成分具有2-20的HLB(亲水亲油平衡)值,它们的结构含有C-6至C-20范围的直链脂肪族基团。其实例有聚乙烯-glycolized脂肪酸甘油酯和聚乙二醇。
特别关注了可购买获得的两亲性载体,包括Gelucire-系列、Labrafil、Labrasol或Lauroglycol(均由Gattefosse Corporation,Saint Priest,法国生产和分配)、PEG-单油酸酯、PEG-二油酸酯、PEG-单月桂酸酯和二月桂酸酯、Lecithin、聚山梨酯80等(由USA和全世界的很多公司生产和分配)。
适用于本发明的亲水性聚合物是易溶于水、可与囊形成脂质共价连接、体内可耐受并且没有毒性作用的那些(即,生物相容性的)。适宜的聚合物包括聚乙二醇(PEG)、聚乳酸(还称为聚丙交酯)、聚乙醇酸(还称为聚乙醇酸交酯)、聚乳酸-聚乙醇酸共聚物和聚乙烯醇。优选的聚合物是具有约100或120道尔顿至约5,000或10,000道尔顿、更优选约300道尔顿至约5,000道尔顿的分子量的那些。在特别优选的实施方案中,聚合物是具有约100至约5,000道尔顿的分子量、更优选约300至约5,000道尔顿的分子量的聚乙二醇。在特别优选的实施方案中,聚合物是750道尔顿的聚乙二醇(PEG(750))。聚合物还可以通过其中的单体数目来定义;本发明的优选实施方案采用具有至少3个单体的聚合物,这样的PEG聚合物由3个单体组成(约150道尔顿)。
可以适用于本发明的其它亲水性聚合物包括聚乙烯吡咯烷酮、聚甲基噁唑啉(polymethoxazoline)、聚乙基噁唑啉、聚羟丙基甲基丙烯酰胺、聚甲基丙烯酰胺、聚二甲基丙烯酰胺和衍生化纤维素如羟甲基纤维素或羟乙基纤维素。
在一些实施方案中,本发明的制剂包含选自如下的生物相容性聚合物:聚酰胺、聚碳酸酯、聚亚烷基、丙烯酸酯和甲基丙烯酸酯的聚合物、聚乙烯基聚合物、聚乙醇酸交酯、聚硅氧烷、聚氨酯及其共聚物、纤维素、聚丙烯、聚乙烯、聚苯乙烯、乳酸和乙醇酸的聚合物、聚酐、聚(原酸)酯、聚丁酸(poly(butic acid))、聚(戊酸)、聚(丙交酯-共-己内酯)、多糖、蛋白质、聚透明质酸、聚氰基丙烯酸酯及其掺合物、混合物或共聚物。
环糊精是由6、7或8个葡萄糖单元组成的环状低聚糖,分别用希腊字母α、β或γ表示。未发现存在具有少于6个葡萄糖单元的环糊精。葡萄糖单元通过α-1,4-糖苷键连接。由于糖单元的椅式构象,所有仲羟基基团(在C-2、C-3处)位于环的一侧,而所有在C-6处的伯羟基基团位于另一侧。结果,外侧面是亲水性的,使环糊精是水溶性的。与之不同,环糊精的腔是疏水性的,因为它们排列有原子C-3和C-5的氢和醚样氧。这些构造允许了多种相对疏水性化合物、包括例如类固醇化合物如17.β.-雌二醇的复合(参见例如van Uden等人,Plant Cell Tiss.Org.Cult.38:1-3-113(1994))。复合通过范德华相互作用和通过氢键形成来发生。对于环糊精化学的综述,参见Wenz,Agnew.Chem.Int.Ed.Engl.,33:803-822(1994)。
环糊精衍生物的理化性质高度取决于取代的程度。例如,它们的水溶性的范围为不溶(例如三乙酰基-β-环糊精)至147%溶解(w/v)(G-2-β-环糊精)。另外,它们可溶于多种有机溶剂中。环糊精的性质使得能够通过增加或降低它们的溶解性来控制各种制剂组分的溶解性。
已经记载了多种环糊精及其制备方法。例如,Parmeter(I)等人(US专利号3,453,259)和Gramera等人(US专利号3,459,731)描述了电中性的环糊精。其它衍生物包括具有阳离子性质的环糊精[Parmeter(II),US专利号3,453,257]、不溶性交联环糊精(Solms,US专利号3,420,788)和具有阴离子性质的环糊精[Parmeter(III),US专利号3,426,011]。在具有阴离子性质的环糊精衍生物中,已经将甲酸、亚磷酸、亚膦酸、膦酸、磷酸、硫代膦酸、硫代亚磺酸和磺酸附加在环糊精母体上[参见Parmeter(III),出处同上]而且,Stella等人还已经记载了磺烷基醚环糊精衍生物(US专利号5,134,127)。
脂质体由至少一层包封水性内室的脂双层膜组成。脂质体可以通过膜类型和通过尺寸来进行表征。小单层脂质体(SUV)具有单个膜,并且直径通常为0.02至0.05μm;大单层脂质体(LUVS)通常大于0.05μm;寡层大脂质体(Oligolamellar large vesicles)和多层脂质体具有多层、常常是向心性的膜层,并且通常大于0.1μm。具有多层非向心性的膜的脂质体,即在较大囊泡中含有多个较小的囊泡,被称为多囊脂质体。
本发明的一个方面涉及包含含有本发明的化合物的脂质体的制剂,其中脂质体膜被配制成提供具有增加的容纳量的脂质体。或者或另外地,本发明的化合物可以被包含在脂质体的脂质体双层内或吸收在其上。本发明的化合物可以用脂质表面活性剂聚集并容纳在脂质体的内部空间内;在这些情况中,脂质体膜被配制成抵抗活性剂-表面活性剂聚集物的破坏作用。
根据本发明的一项实施方案,脂质体的脂双层含有用聚乙二醇(PEG)衍生化的脂质,从而PEG链从脂双层的内面伸出进入脂质体所包封的内部空间和从脂双层的外面伸出进入周围环境。
本发明的脂质体中所含的活性剂是溶解形式。表面活性剂和活性剂的聚集物(例如含有目标活性剂的乳剂或胶束)可以被捕获在本发明的脂质体的内部空间。表面活性剂发挥分散和增溶活性剂的作用,可以选自任何事宜的脂肪族、环脂肪族或芳香族表面活性剂,包括但不限于具有不同链长度的生物相容性溶血磷脂酰胆碱(LPC)(例如约C.sub.14至约C.sub.20)。聚合物衍生的脂质如PEG-脂质也可以用于形成胶束,因为它们将发挥抑制胶束/膜融合的作用,并且因为将聚合物添加至表面活性剂分子降低了表面活性剂的CMC和帮助胶束形成。优选的是CMC在微摩尔范围的表面活性剂;可以使用较高CMC的表面活性剂来制备本发明的脂质体内捕获的胶束,但是,胶束表面活性剂单体将影响脂质体双层的稳定性并且将成为设计具有预期稳定性的脂质体中的因素。
本发明的脂质体可以通过本领域已知的多种方法中的任一种来制备。参见例如US专利号4,235,871;公开PCT申请WO 96/14057;New RRC,Liposomes:A practicalapproach,IRL Press,Oxford(1990),第33-104页;Lasic DD,Liposomes from physics toapplications,Elsevier Science Publishers BV,Amsterdam,1993。
例如,本发明的脂质体可以通过将用亲水性聚合物衍生化的脂质分散入已形成的脂质体中来制备,例如通过在相应于脂质体中预期的衍生化脂质的最终摩尔百分比的脂质浓度下使已形成的脂质体接触由脂质-接枝聚合物组成的胶束。含有亲水性聚合物的脂质体还可以通过匀化、脂质-field水合或挤出技术来制备,如本领域已知的那样。
在本发明的一个方面,脂质体被制备成具有基本均匀的在选定尺寸范围内的尺寸。一种有效的控制尺寸方法包括将脂质体的水性混悬液挤出穿过一系列具有所选均一孔径的聚碳酸酯膜;膜的孔径将大致相当于通过挤出穿过该膜所产生的脂质体的最大尺寸。参见例如US专利号4,737,323(1988年4月12日)。
本发明的制剂的释放性质取决于包囊材料、被包囊药物的浓度和释放改性剂的存在。例如,释放可以被处置成pH依赖性的,例如采用仅在低pH(如在胃中)或较高pH(如在肠中)释放的pH敏感性包衣。肠包衣可用于阻止释放发生直至通过胃。在不同材料中包封的氨腈的多重包衣或混合物可用于获得在胃中的初始释放、继之以在肠中的稍后释放。释放可以通过纳入盐或孔形成剂(其可通过从囊中扩散而增加水吸取或药物释放)来进行处置。还可以使用改变药物溶解性的赋形剂来控制释放速率。还可以掺入增加基质的降解或从基质释放的物质。根据化合物,它们可以被加入药物中,作为单独相(例如作为粒子)被加入,或者可以共同溶解在聚合物相中。在所有情况中,量应当为0.1-30%(w/w聚合物)。降解促进剂的类型包括无机盐如硫酸铵和氯化铵,有机酸如柠檬酸、苯甲酸和抗坏血酸,无机碱如碳酸钠、碳酸钾、碳酸钙、碳酸锌和氢氧化锌,有机碱如硫酸鱼精蛋白、精胺、胆碱、乙醇胺、二乙醇胺和三乙醇胺,和表面活性剂如和加入颗粒形式的为基质增加微结构的孔形成剂(即水溶性化合物如无机盐和糖)。范围应当是1-30%(w/w聚合物)。
吸收可以通过改变粒子在肠中的停留时间来进行处置。这可以例如通过给粒子包涂粘膜粘附聚合物或选择粘膜粘附聚合物作为包封材料来达到。其实例包括大多数具有游离羧基基团的聚合物,例如壳聚糖、纤维素且尤其是聚丙烯酸酯(如本文所用,聚丙烯酸酯指包括丙烯酸酯基团和经修饰的丙烯酸酯基团如氰基丙烯酸酯和甲基丙烯酸酯的聚合物)。
药物组合
本发明尤其涉及式I化合物(或包含式I化合物的药物组合物)在治疗一种或多种本文提及的疾病中的用途;其中对治疗的响应是有利的,如例如通过部分或完全除去一种或多种疾病症状至完全治愈或消除疾病所证明的那样。
式(I)化合物还可以与如下化合物和抗体-药物结合物组合进行使用:
BCR-ABL抑制剂:伊马替尼Inilotinib盐酸盐;尼洛替尼达沙替尼(BMS-345825);波舒替尼(SKI-606);Ponatinib(AP24534);Bafetinib(INNO406);Danusertib(PHA-739358),AT9283(CAS1133385-83-7);Saracatinib(AZD0530);和N-[2-[(1S,4R)-6-[[4-(环丁基氨基)-5-(三氟甲基)-2-嘧啶基]氨基]-1,2,3,4-四氢萘-1,4-亚胺-9-基]-2-氧代乙基]-乙酰胺(PF-03814735,CAS 942487-16-3)。
ALK抑制剂:PF-2341066(克唑替尼(crizotinib));5-氯-N4-(2-(异丙基磺酰基)苯基)-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌啶-1-基)苯基)嘧啶-2,4-二胺;GSK1838705A;和CH5424802。
BRAF抑制剂:Vemurafanib(PLX4032);和Dabrafenib。
FLT3抑制剂——舒尼替尼苹果酸盐(由Pfizer以商标出售);PKC412(米哚妥林);tanutinib、索拉非尼、舒尼替尼、米哚妥林、lestaurtinib、KW-2449、quizartinib(AC220)和crenolanib。
MEK抑制剂——曲美替尼(trametinib)。
血管内皮生长因子(VEGF)受体抑制剂:贝伐单抗(由Genentech/Roche以商标出售)、阿昔替尼、(N-甲基-2-[[3-[(E)-2-吡啶-2-基乙烯基]-1H-吲唑-6-基]硫基]苯甲酰胺,还称为AG013736,并且在PCT公开号WO 01/002369中记载)、BrivanibAlaninate((S)-((R)-2-氨基丙酸1-(4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基氧基)丙烷-2-基)酯,还称为BMS-582664)、莫特沙芬(motesanib)(N-(2,3-二氢-3,3-二甲基-1H-吲哚-6-基)-2-[(4-吡啶基甲基)氨基]-3-吡啶甲酰胺,在PCT公开号WO 02/066470中记载)、帕瑞肽(pasireotide)(还称为SOM230,在PCT公开号WO 02/010192中记载)、索拉非尼(以商标出售);
HER2受体抑制剂:曲妥单抗(由Genentech/Roche以商标出售)、来那替尼(neratinib)(还称为HKI-272,(2E)-N-[4-[[3-氯-4-[(吡啶-2-基)甲氧基]苯基]氨基]-3-氰基-7-乙氧基喹啉-6-基]-4-(二甲基氨基)丁-2-烯酰胺,在PCT公开号WO 05/028443中记载)、拉帕替尼或二甲苯磺酸拉帕替尼(由GlaxoSmithKline以商标出售);曲妥单抗-emtansine(i在美国,ado-曲妥单抗-emtansine,商品名Kadcyla)——由单克隆抗体曲妥单抗(Herceptin)与细胞毒性剂mertansine(DM1)连接组成的抗体-药物结合物;
CD20抗体:利妥昔单抗(由Genentech/Roche以商标和出售)、托西莫单抗(由GlaxoSmithKline以商标出售)、奥法木单抗(ofatumumab)(由GlaxoSmithKline以商标出售);
酪氨酸激酶抑制剂:厄洛替尼盐酸盐(由Genentech/Roche以商标出售)、Linifanib(N-[4-(3-氨基-1H-吲唑-4-基)苯基]-N'-(2-氟-5-甲基苯基)脲,还称为ABT 869,可获自Genentech)、舒尼替尼苹果酸盐(由Pfizer以商标出售)、波舒替尼(4-[(2,4-二氯-5-甲氧基苯基)氨基]-6-甲氧基-7-[3-(4-甲基哌嗪-1-基)丙氧基]喹啉-3-甲腈,还称为SKI-606,在US专利号6,780,996中记载)、达沙替尼(由Bristol-MyersSquibb以商标出售)、armala(还称为帕唑帕尼,由GlaxoSmithKline以商标出售)、伊马替尼和甲磺酸伊马替尼(由Novartis以商标和出售);
DNA合成抑制剂:卡培他滨(由Roche以商标Xeloda)、吉西他滨盐酸盐(由Eli Lilly and Company以商标出售)、奈拉滨((2R,3S,4R,5R)-2-(2-氨基-6-甲氧基-嘌呤-9-基)-5-(羟基甲基)氧杂环戊烷-3,4-二醇,由GlaxoSmithKline以商标和出售);
表皮生长因子受体(EGFR)抑制剂:Gefitnib(以商标出售)、N-[4-[(3-氯-4-氟苯基)氨基]-7-[[(3”S”)-四氢-3-呋喃基]氧基]-6-喹唑啉基]-4(二甲基氨基)-2-丁烯酰胺,由Boehringer Ingelheim以商标出售)、西妥昔单抗(由Bristol-Myers Squibb以商标出售)、帕尼单抗(由Amgen以商标出售);
CD40抑制剂:Dacetuzumab(还称为SGN-40或huS2C6,可获自Seattle Genetics,Inc);
促细胞凋亡受体激动剂(PARAs):Dulanermin(还称为MG-951,可获自Amgen/Genentech);
Hedgehog拮抗剂:2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲基磺酰基)-苯甲酰胺(还称为GDC-0449,在PCT公开号WO 06/028958中记载);
PI3K抑制剂:4-[2-(1H-吲唑-4-基)-6-[[4-(甲基磺酰基)哌嗪-1-基]甲基]噻吩并[3,2-d]嘧啶-4-基]吗啉(还称为GDC 0941,在PCT公开号WO09/036082和WO 09/055730中记载)、2-甲基-2-[4-[3-甲基-2-氧代-8-(喹啉-3-基)-2,3-二氢咪唑并[4,5-c]喹啉-1-基]苯基]丙腈(还称为BEZ 235或NVP-BEZ 235,在PCT公开号WO 06/122806中记载);
BCL-2抑制剂:4-[4-[[2-(4-氯苯基)-5,5-二甲基-1-环己烯-1-基]甲基]-1-哌嗪基]-N-[[4-[[(1R)-3-(4-吗啉基)-1-[(苯基硫基)甲基]丙基]氨基]-3-[(三氟甲基)磺酰基]苯基]磺酰基]苯甲酰胺(还称为BT-263,在PCT公开号WO09/155386中记载);
促分裂原活化蛋白激酶激酶(MEK)抑制剂:XL-518(Cas号1029872-29-4,可获自ACC Corp.);
mTOR抑制剂:坦罗莫司(由Pfizer以商标出售)、ridaforolimus(以前称为deferolimus,二甲基亚膦酸(1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-二羟基-19,30-二甲氧基-15,17,21,23,29,35-六甲基-2,3,10,14,20-五氧代-11,36-二氧杂-4-氮杂三环[30.3.1.04,9]三十六碳-16,24,26,28-四烯-12-基]丙基]-2-甲氧基环己基酯,还称为P23573和MK8669,在PCT公开号WO 03/064383中记载)、依维莫司(由Novartis以商标出售);
CD22抗体药物结合物:伊珠单抗奥佐米星(还称为CMC-544和WAY-207294,可获自Hangzhou Sage Chemical Co.,Ltd.);
抗胰岛素样生长因子-1受体(IGF-1R)抗体:Figitumumab(还称为CP-751,871,可获自ACC Corp)、robatumumab(CAS号934235-44-6);
抗CS1抗体:Elotuzumab(HuLuc63,CAS号915296-00-3);
CTLA-4抑制剂:Tremelimumab(IgG2单克隆抗体,可获自Pfizer,以前称为ticilimumab、CP-675,206)、伊匹木单抗(CTLA-4抗体,还称为MDX-010,CAS号477202-00-9);
烷化剂:替莫唑胺(由Schering-Plough/Merck以商标和出售)、放线菌素(还称为放线菌素D,以商标出售)、美法仑(还称为L-PAM、L-沙可来新和苯丙胺氮芥,以商标出售)、六甲蜜胺(还称为六甲基蜜胺(HMM),以商标出售)、卡莫司汀(以商标出售)、苯达莫司汀(以商标出售)、白消安(以商标和出售)、卡铂(以商标出售)、洛莫司汀(还称为CCNU,以商标出售)、顺铂(还称为CDDP,以商标和-AQ出售)、苯丁酸氮芥(以商标出售)、环玲酰胺(以商标和出售)、达卡巴嗪(还称为DTIC、DIC和咪唑甲酰胺,以商标出售)、六甲蜜胺(还称为六甲基蜜胺(HMM)以商标出售)、异环磷酰胺(以商标出售)、丙卡巴肼(以商标出售)、氮芥(还称为nitrogen mustard、mustine和盐酸氮芥,以商标出售)、链佐星(以商标出售)、塞替派(还称为硫代磷酰胺、TESPA和TSPA,以商标出售;
抗肿瘤抗生素:多柔比星(以商标和出售)、博来霉素(以商标出售)、柔红霉素(还称为柔红霉素盐酸盐、道诺霉素和红比霉素盐酸盐,以商标出售)、柔红霉素脂质体(柠檬酸柔红霉素脂质体,以商标出售)、米托蒽醌(还称为DHAD,以商标出售)、表柔比星(以商标EllenceTM出售)、依达比星(以商标Idamycin出售)、丝裂霉素C(以商标出售);
组织蛋白酶K抑制剂:Odanacatib(还称为MK-0822,N-(1-氰基环丙基)-4-氟-N2-{(1S)-2,2,2-三氟-1-[4'-(甲基磺酰基)联苯-4-基]乙基}-L-亮氨酸酰胺,可获自LanzhouChon Chemicals,ACC Corp.,和ChemieTek,在PCT公开号WO 03/075836中记载);
热激蛋白(HSP)抑制剂:Tanespimycin(17-烯丙基氨基-17-去甲氧基格尔德霉素,还称为KOS-953和17-AAG,可获自SIGMA,在US专利号4,261,989中记载);
CDK1抑制剂:阿伏西地(还称为flovopirdol或HMR-1275,2-(2-氯苯基)-5,7-二羟基-8-[(3S,4R)-3-羟基-1-甲基-4-哌啶基]-4-chromenone,在US专利号5,621,002中记载);
紫杉烷抗肿瘤药:Cabazitaxel(1-羟基-7β,10β-二甲氧基-9-氧代-5β,20-环氧紫衫烷-11-烯-2α,4,13α-三基-4-乙酸酯-2-苯甲酸酯-13-[(2R,3S)-3-{[(叔丁氧基)羰基]氨基}-2-羟基-3-苯基丙酸酯)、larotaxel((2α,3ξ,4α,5β,7α,10β,13α)-4,10-双(乙酰基氧基)-13-({(2R,3S)-3-[(叔丁氧基羰基)氨基]-2-羟基-3-苯基丙酰基}氧基)-1-羟基-9-氧代-5,20-环氧-7,19-环紫杉烷-11-烯-2-基苯甲酸酯);
5HT1a受体激动剂:扎利罗登(还称为SR57746、1-[2-(2-萘基)乙基]-4-[3-(三氟甲基)苯基]-1,2,3,6-四氢吡啶,在US专利号5,266,573中记载);
抗代谢物:Claribine(2-氯脱氧腺苷,以商标出售)、5-氟尿嘧啶(以商标出售)、6-硫代鸟嘌呤(以商标出售)、培美曲塞(以商标出售)、阿糖胞苷(还称为阿糖胞嘧啶(Ara-C),以商标出售)、阿糖胞苷脂质体(还称为Liposomal Ara-C,以商标DepoCytTM出售)、地西他滨(以商标出售)、羟基脲(以商标DroxiaTM和MylocelTM出售)、氟达拉滨(以商标出售)、氟尿苷(以商标出售)、克拉屈滨(还称为2-氯脱氧腺苷(2-CdA),以商标LeustatinTM出售)、甲氨蝶呤(还称为甲蝶呤、甲氨蝶呤钠(MTX),以商标和TrexallTM出售)、喷司他丁(以商标出售);
植物生物碱:蛋白质-结合的紫杉醇(以商标出售)、长春花碱(还称为硫酸长春花碱、长春碱和VLB,以商标和出售)、长春花新碱(还称为硫酸长春花新碱、LCR和VCR,以商标和Vincasar出售)、长春瑞滨(以商标出售)、紫杉醇(以商标Taxol和OnxalTM出售);
糖皮质激素:氢化可的松(还称为可的松、氢化可的松钠琥珀酸盐、氢化可的松钠磷酸盐,以商标Hydrocortisone Phosphate、Hydrocort和出售)、dexamethazone((8S,9R,10S,11S,13S,14S,16R,17R)-9-氟-11,17-二羟基-17-(2-羟基乙酰基)-10,13,16-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氢-3H-环戊二烯并[a]菲-3-酮)、泼尼松龙(以商标和出售)、泼尼松(以商标和出售)、甲基泼尼松龙(还称为6-甲基泼尼松龙、甲基泼尼松龙乙酸盐、甲基泼尼松龙钠琥珀酸盐,以商标 和出售);
式(I)化合物还可以与如下附加疗法组合使用:
本公开内容内的参考文献的引用无一被理解为承认所引用的文献是将不利地影响本发明的可专利性的现有技术。
本发明的化合物的制备方法
本发明还包括本发明的化合物的制备方法。在所述反应中,当终产物中需要存在反应活性官能团如羟基、氨基、亚氨基、硫代或羧基时,有必要保护这些反应活性官能团以避免它们参与不希望的反应。可以按照标准实践使用常规的保护基,例如参见T.W.Greene和P.G.M.Wuts的“有机合成中的保护基(Protective Groups in Organic Synthesis)”,John Wiley and Sons,1991。
式I化合物可以通过按照如下反应流程I进行来制备:
反应流程I:
其中Y1、Y2、Y3、R1、R2、R4a、R4b、R5a、R5b、R6a和R6b如发明简述中所定义。式I化合物可以通过使式2化合物与式3化合物在适宜的碱(例如DIPEA等)和适宜的溶剂(例如DMSO、NMP等)的存在下反应来制备。反应在约80℃至约140℃的温度范围进行,可以进行约1小时至约24小时以反应完全。
下文实施例中给出了式I化合物的合成的详细实例。
本发明的化合物的另外的制备方法
本发明的化合物可以通过将化合物的游离碱形式与可药用无机或有机酸反应来制备成可药用酸加成盐。或者,本发明的化合物的可药用碱加成盐可以通过将化合物的游离酸形式与可药用无机或有机碱反应来制备。
式I化合物还可以通过附加适当的官能团进行修饰以增强所选的生物学性质。这类修饰是本领域已知的,包括增加进入给定生物学系统(例如血液、淋巴系统、中枢神经系统、睾丸)的渗透、增加生物利用度、增加溶解性以允许胃肠道外施用(例如注射、输注)、改变代谢和/或改变分泌速率的那些。该类型修饰的实例包括但不限于酯化、例如用聚乙二醇进行酯化、用新戊酰氧基或脂肪酸取代基进行衍生化、转化为氨甲酸酯、芳环的羟基化和芳环中的杂原子取代。当提及式I化合物和/或其N-氧化物、互变异构体和/或(优选可药用)盐时,这包括这类经修饰的式子,虽然优选指式I的分子、它们的N-氧化物、它们的互变异构体和/或它们的盐。
或者,本发明的化合物的盐形式可以采用原料或中间体的盐来制备。鉴于游离形式的式I化合物和盐形式的式I化合物、包括可用作中间体的那些盐(例如在新化合物的纯化和鉴定中)之间的密切关系,上下文中对式I化合物的任何称谓将被理解为指游离形式的化合物和/或其一种或多种盐(当适当和方便时)以及一种或多种溶剂合物如水合物。
由具有碱性氮原子的式I化合物优选用有机或无机酸形成盐、例如酸加成盐,尤其是可药用盐。适宜的无机酸例如有氢卤酸如氢氯酸、硫酸或磷酸。适宜的有机酸例如有羧酸、膦酸、磺酸或氨磺酸,例如乙酸、丙酸、辛酸、癸酸、十二烷酸、乙醇酸、乳酸、富马酸、琥珀酸、丙二酸、己二酸、庚二酸、辛二酸、壬二酸、苹果酸、酒石酸、柠檬酸、氨基酸如谷氨酸或天冬氨酸、马来酸、羟基马来酸、甲基马来酸、环己烷甲酸、马来酸甲酸、苯甲酸、水杨酸、4-氨基水杨酸、酞酸、苯乙酸、扁桃酸、肉桂酸、甲烷-或乙烷-磺酸、2-羟基乙烷磺酸、乙烷-1,2-二磺酸、苯磺酸、4-甲苯磺酸、2-萘磺酸、1,5-萘-二磺酸、2-或3-甲基苯磺酸、甲基硫酸、乙基硫酸、十二烷基硫酸、N-环己基氨磺酸、N-甲基-、N-乙基-或N-丙基-氨磺酸或其它有机质子酸如抗坏血酸。
对于分离和纯化目的,还能够使用非可药用盐,例如苦味酸盐或高氯酸盐。对于治疗用途,仅可以应用可药用盐或游离化合物(当可以以药物制剂的形式使用时),因此这些是优选的。
本发明的化合物的游离酸或游离碱形式可以分别由相应的碱加成盐或酸加成盐形式来制备。例如,酸加成盐形式的本发明的化合物可以通过用适宜的碱(例如氢氧化铵溶液、氢氧化钠等)处理而转化为相应的游离碱。碱加成盐形式的本发明的化合物可以通过用适宜的酸(例如盐酸等)处理而转化为相应的游离酸。
非氧化形式的本发明的化合物可以由本发明的化合物的N-氧化物通过用还原剂(例如硫磺、二氧化硫、三苯膦、硼氢化锂、硼氢化钠、三氯化磷、三溴化物等)在适宜的惰性有机溶剂(例如乙腈、乙醇、二噁烷水溶液等)中于0至80℃进行处理来制备。
本发明的化合物的前药衍生物可以通过本领域普通技术人员已知的方法来制备(例如,进一步的细节参见Saulnier等人,(1994),Bioorganic and Medicinal ChemistryLetters,第4卷,第1985页)。例如,适当的前药可以通过使非衍生化的本发明的化合物与适宜的氨甲酰化剂(如1,1-酰氧基烷基羰基氯(carbanochloridate)、对硝基苯基碳酸酯等)反应来制备。
本发明的化合物的被保护的衍生物可以通过本领域普通技术人员已知的方法来制备。可用于建立保护基以及除去它们的技术的详细描述可参见T.W.Greene,“ProtectingGroups in Organic Chemistry”,第三版,John Wiley and Sons,Inc.,1999。
在本发明的方法中可以方便地制备或形成本发明的化合物的溶剂合物(如水合物)。本发明的化合物的水合物可通过采用有机溶剂如二氧芑(dioxin)、四氢呋喃或甲醇在水/有机溶剂混合物中重结晶来方便地制备。
还可如下制备本发明的化合物的单一立体异构体:使化合物的外消旋混合物与旋光活性的拆分试剂反应,形成一对非对映异构化合物,分离非对映异构体并回收旋光纯的对映异构体。当对映异构体的拆分可采用本发明的化合物的共价非对映异构衍生物进行时,优选可解离的复合物(如非对映异构的盐结晶)。非对映异构体具有不同的物理性质(如熔点、沸点、溶解性、反应活性等),可以利用这些不同点来容易地加以分离。非对映异构体可以通过色谱法来分离,或优选通过基于溶解性差异的分离/拆分技术来分离。然后通过任何不会导致外消旋化的实用方法回收旋光纯的对映异构体和拆分试剂。可用于从化合物的外消旋混合物中拆分其立体异构体的技术在Jean Jacques、Andre Collet,SamuelH.Wilen,“Enantiomers,Racemates and Resolutions”,John Wiley and Sons,Inc.,1981中有更详细的描述。
总之,式I化合物可以通过包括如下的方法来制备:
(a)反应流程I的那些;和
(b)任选地,将本发明的化合物转化为可药用盐;
(c)任选地,将本发明的化合物的盐形式转化为非盐形式;
(d)任选地,将本发明的化合物的非氧化形式转化为可药用N-氧化物;
(e)任选地,将本发明的化合物的N-氧化物形式转化为非氧化形式;
(f)任选地,从异构体的混合物中拆分出本发明的化合物的单独异构体;
(g)任选地,从非衍生化的本发明的化合物转化为可药用的前药衍生物;和
(h)任选地,将本发明的化合物的前药衍生物转化为其非衍生化形式。
当没有特别记载原料的生产时,该化合物是已知的或者可以类似于本领域已知的方法或如下文实施例中公开的那样来制备。
本领域技术人员将理解:上述转化仅仅是制备本发明的化合物的方法的代表,可以类似地使用其它熟知的方法。
实施例
如下实施例和中间体用于解释说明本发明而不限制其范围。实施例中所用的一些缩略语如下:乙酸(AcOH);乙腈(MeCN);三乙胺(TEA);四氢呋喃(THF);水性或含水的(aq.);气氛(atm.);2,2'-双-二苯基膦基-[1,1']联萘(BINAP);4-二甲基氨基吡啶(DMAP);叔丁氧基羰基(Boc);1,1-羰基di咪唑(CDI);焦炭酸二叔丁基酯(Boc2O);苯并三唑-1-基-氧基-三-(二甲基氨基)-磷鎓六氟磷酸盐(BOP);二氯甲烷(DCM);二乙醚(Et2O);对甲苯磺酸(PTSA);乙酸乙酯(EtOAc);乙醇(EtOH);双(三甲基甲硅烷基)氨基锂(LHMDS);偶氮二甲酸二异丙基酯(DIAD);N,N-二异丙基-乙基胺(DIEA或DIPEA);N,N-二甲基甲酰胺(DMF);二甲亚砜(DMSO);二苯基磷酰基叠氮化物(DPPA);小时(h);2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(HATU);高效液相色谱法(HPLC);异丙醇(IPA);氢化铝锂(LAH);液相色谱法质谱法联用(LCMS);二异丙基氨基锂(LDA);甲醇(MeOH);毫升(mL);分钟(min);微波(MW);双(三甲基甲硅烷基)氨基钠(NHMDS);正丁基锂(n-BuLi);1,1-双(二苯膦基)-二茂铁二氯化钯(II)(PdCl2(dppf));三(二双苯亚甲基丙酮)二钯(0)(Pd2(dba)3);双(三苯膦)二氯化钯(II)(PdCl2(PPh3)2);室温(RT);四正丁基氟化铵(TBAF);叔丁基二甲基甲硅烷基氯(TBSCl);三氟乙酸(TFA);四氢呋喃(THF);薄层色谱法(TLC);保留时间(TR);(S)-(-)-2,2'-双(二对甲苯基膦基)-1,1'-联萘((S)-TolBINAP);&4,5-双(二苯膦基)-9,9-二甲基呫吨(XantPhos)。
中间体1
5-氯吡嗪-2-硫醇钠
步骤a:将2,5-二氯吡嗪(5g,33.6mmol)、K2CO3(4.64g,33.6mmol)和3-巯基丙酸乙基酯(4.45ml,35.1mmol)在DMF(41.7ml)中的混合物于RT搅拌18小时。反应混合物用EtOAc稀释(150ml),用水洗涤(2x50ml),经Na2SO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至5%梯度的EtOAc/庚烷),得到3-((5-氯吡嗪-2-基)硫基)丙酸乙基酯(6.98g,28.3mmol)。1H NMR(400MHz,氯仿-d)δppm 8.39(d,J=1.5Hz,1H),8.23(d,J=1.5Hz,1H),4.18(q,J=7.2Hz,2H),3.42(t,J=7.0Hz,2H),2.75(t,J=7.0Hz,2H),1.27(t,J=7.1Hz,3H).MS m/z 247.1(M+H)+。
步骤b:将3-((5-氯吡嗪-2-基)硫基)丙酸乙基酯(6.98g,28.3mmol)和NaOEt溶液(21%,在乙醇中,11.92g,436.8mmol)在THF(94ml)中的混合物于0℃搅拌10分钟和于RT搅拌30分钟。反应混合物在减压下浓缩至体积的~50%,加入Et2O(400ml)。收集所得沉淀物,用Et2O冲洗,真空干燥,得到5-氯吡嗪-2-硫醇钠(4.76g,28.2mmol)。1H NMR(400MHz,DMSO-d6)δppm 7.82(d,J=1.4Hz,1H),7.77(d,J=1.4Hz,1H).MS m/z145.0/147.1(M-Na)+。
中间体S-1
2-氨基-3-氯吡啶-4-硫醇钠
步骤a:于RT和在N2气氛下,向3-氯-4-碘吡啶-2-胺(1.0g,3.93mmol)、XantPhos(136mg,0.236mmol)和Pd(OAc)2(44mg,0.196mmol)在二噁烷(13ml)中的溶液中加入3-巯基丙酸甲基酯(479μL,4.32mmol),然后加入DIPEA(1.37ml,7.86mmol)。所得溶液于100℃搅拌2小时。冷却至RT后,反应混合物用EtOAc稀释(20ml),经硅藻土垫过滤,然后用EtOAc洗涤(25ml)。合并的滤液在减压下浓缩,残余物经硅胶色谱法纯化(0至10%梯度的MeOH/DCM),得到3-((2-氨基-3-氯吡啶-4-基)硫基)丙酸甲基酯(970mg,3.93mmol).MS m/z 247.1(M+H)+。
步骤b:于RT和在N2气氛下,于RT和在N2下向3-((2-氨基-3-氯吡啶-4-基)硫基)丙酸甲基酯(1.04g,4.22mmol)在THF(14ml)中的溶液中加入乙醇钠(21%wt.在EtOH中,1.65ml,4.43mmol)。于RT剧烈搅拌40分钟后,反应混合物用DCM稀释(30ml),将其超声处理5分钟。将所得形成的固体滤出,然后用DCM洗涤(5ml),在减压下干燥,得到2-氨基-3-氯吡啶-4-硫醇钠(770mg,4.22mmol)。1H NMR(400MHz,甲醇-d4)δppm 7.23(d,J=5.56Hz,1H),6.82(d,J=5.56Hz,1H)。
采用上述操作或上述操作的变通方法,采用相应的芳基碘或芳基溴,制得表1的如下中间体。
表1
中间体S-2
2-(三氟甲氧基)吡啶-3-硫醇
步骤a:向2-(三氟甲氧基)吡啶-3-醇(0.75g,4.19mmol)和Et3N(1.17ml,8.38mmol)在DCM(15ml)中的-78℃溶液中加入三氟甲烷磺酸酐(1M,在DCM中,6.28ml,6.28mmol)。所得溶液于-78℃搅拌30分钟。反应混合物小心用饱和NaHCO3水溶液(25ml)稀释,所得混合物用DCM萃取(2x15ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。残余物经硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到三氟甲烷磺酸2-(三氟甲氧基)吡啶-3-基酯(1.25g,4.02mmol).MS m/z 312.0(M+H)+。
步骤b:于RT和在N2气氛下,向三氟甲烷磺酸2-(三氟甲氧基)吡啶-3-基酯(1.25g,4.02mmol)、XantPhos(139mg,0.241mmol)和Pd(OAc)2(45mg,0.201mmol)在二噁烷(10ml)中的溶液中加入3-巯基丙酸甲基酯(489μL,4.42mmol),然后加入DIPEA(1.4ml,8.03mmol)。所得溶液于100℃搅拌2小时。冷却至RT后,反应混合物用EtOAc稀释(20ml),经硅藻土垫过滤,然后用EtOAc洗涤(25ml)。合并的滤液在减压下浓缩,残余物经柱色谱法纯化(硅胶,0至25%梯度的EtOAc/庚烷),得到3-((2-(三氟甲氧基)吡啶-3-基)硫基)丙酸甲基酯(1.025g,3.64mmol).MS m/z 282.1(M+H)+。
步骤c:于RT和在N2下,向3-((2-(三氟甲氧基)吡啶-3-基)硫基)丙酸甲基酯(1.025g,3.64mmol)在THF(12ml)中的溶液中加入乙醇钠(21%wt.在EtOH中,1.43ml,3.83mmol)。于RT剧烈搅拌40分钟后,反应混合物用DCM稀释(40ml),超声处理5分钟。在减压下除去挥发物,残余物混悬于DCM中,倒入含有饱和NH4Cl水溶液的分液漏斗中。分离有机相,水相用DCM萃取(2x15ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。水相用1N HCl水溶液酸化,用DCM萃取(3x10ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物,得到粗的2-(三氟甲氧基)吡啶-3-硫醇(711mg,3.64mmol).MS m/z 194.1(M-H)-。
中间体S-3
3-氯-2-(吡咯烷-1-基)吡啶-4-硫醇钠
步骤a:将3-氯-2-氟-4-碘吡啶(2.0g,7.77mmol)和吡咯烷(1.93ml,23.31mmol)在DMSO(10ml)中的溶液于70℃搅拌30分钟。冷却至RT后,所得混合物倒入含有饱和NH4Cl水溶液的分液漏斗中,用Et2O萃取(5x10ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物,得到3-氯-4-碘-2-(吡咯烷-1-基)吡啶(1.66g,5.38mmol).MS m/z 309.0(M+H)+。
步骤b:于RT和在N2气氛下,向3-氯-4-碘-2-(吡咯烷-1-基)吡啶(1.66g,5.38mmol)、XantPhos(187mg,0.323mmol)和Pd(OAc)2(60mg,0.269mmol)在二噁烷(11ml)中的溶液中加入3-巯基丙酸甲基酯(655μL,5.92mmol),然后加入DIPEA(1.88ml,10.76mmol)。所得溶液于100℃搅拌2小时。冷却至RT后,反应混合物用EtOAc稀释(20ml),经硅藻土垫过滤,然后用EtOAc(25ml)洗涤。合并的滤液在减压下浓缩,残余物经柱色谱法纯化(硅胶,0至30%梯度的EtOAc/庚烷),得到3-((3-氯-2-(吡咯烷-1-基)吡啶-4-基)硫基)丙酸甲基酯(1.62g,5.38mmol).MS m/z 301.2(M+H)+。
步骤c:于RT和在N2气氛下,向3-((3-氯-2-(吡咯烷-1-基)吡啶-4-基)硫基)丙酸甲基酯(1.62g,5.38mmol)在THF(20ml)中的溶液中加入乙醇钠(21%wt.,在EtOH中,2.39ml,6.39mmol)。于RT剧烈搅拌40分钟后,反应物用DCM稀释(40ml),将其超声处理5分钟。在减压下除去挥发物,残余物未经进一步纯化进行使用。MS m/z 215.1(M-H)-。
采用上述操作或上述操作的变通方法,采用相应的芳基碘,制得表2的如下中间体。
表2
中间体S-4
3-氨基-2-(三氟甲基)苯硫醇
步骤a:将3-氟-2-(三氟甲基)苯胺(2.21g,12.35mmol)、Cs2CO3(12.08g,37.1mmol)和2-甲基丙烷-2-硫醇(4.18ml,37.1mmol)在DMF(25ml)中的混合物于130℃搅拌18小时。冷却至RT后,反应混合物倒入含有H2O(50ml)的分液漏斗中,用EtOAc萃取(100ml)。有机相用H2O(2x25ml)、盐水(2x25ml)洗涤,经MgSO4干燥,过滤,在减压下除去挥发物,得到3-(叔丁基硫基)-2-(三氟甲基)苯胺(3.08mg,12.35mmol).MS m/z 250.1(M+H)+。
步骤b:将3-(叔丁基硫基)-2-(三氟甲基)苯胺(7.19g,31.3mmol)在浓HCl(308ml)中的溶液于85℃搅拌2小时。冷却至RT后,将N2流导入溶液16小时。在减压下除去挥发物,所得固体滤出,用庚烷洗涤,在真空下干燥,得到3-氨基-2-(三氟甲基)苯硫醇(7.19g,31.3mmol).MS m/z 194.0(M+H)+。
中间体S-5
3-氯-2-环丙基吡啶-4-硫醇钠
步骤a:于RT和在N2气氛下,将2,3-二氯-4-碘吡啶(1.0g,3.65mmol)、XantPhos(127mg,0.219mmol)和Pd(OAc)2(41mg,0.183mmol)在二噁烷(7ml)中的混合物加入3-巯基丙酸甲基酯(445μL,4.02mmol),然后加入DIPEA(1.28ml,7.3mmol)。所得溶液于100℃搅拌4.5小时。冷却至RT后,反应混合物用EtOAc稀释(20ml),经硅藻土垫过滤,然后用EtOAc洗涤(25ml)。合并的滤液在减压下浓缩,残余物经硅胶色谱法纯化(10至50%梯度的EtOAc/庚烷),得到3-((2,3-二氯吡啶-4-基)硫基)丙酸甲基酯(965mg,5.38mmol).MS m/z 266.1(M+H)+。
步骤b:将3-((2,3-二氯吡啶-4-基)硫基)丙酸甲基酯(800mg,3.19mmol)、n-BuPAd2(86mg,0.240mmol)、Pd(OAc)2(36mg,0.160mmol)、Cs2CO3(3.12g,9.58mmol)和环丙基三氟硼酸钾(709mg,4.79mmol)在甲苯:H2O(10:1;13ml)中的混合物于100℃搅拌4.5小时。冷却至RT后,反应混合物倒入含有饱和NH4Cl水溶液的分液漏斗中,用EtOAc萃取(3x15ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。残余物经硅胶色谱法纯化(10至40%梯度的EtOAc/庚烷),得到3-((3-氯-2-环丙基吡啶-4-基)硫基)丙酸甲基酯(380mg,1.398mmol).MS m/z 272.1(M+H)+。
步骤c:于RT和在N2气氛下,向3-((3-氯-2-环丙基吡啶-4-基)硫基)丙酸甲基酯(380mg,1.398mmol)在THF(5ml)中的溶液中加入乙醇钠(21%wt.在EtOH中,0.548ml,1.468mmol)。于RT剧烈搅拌30分钟后,在减压下除去挥发物,得到3-氯-2-环丙基吡啶-4-硫醇钠(290mg,1.398mmol),其未经进一步纯化进行使用。MS m/z 186.1(M+H)+。
中间体S-6
6-氨基-2,3-二氯吡啶-4-硫醇
步骤a:向5,6-二氯吡啶-2-胺(2.445g,15mmol)在THF(60ml)中的0℃溶液中滴加LiHMDS(1M,在THF中,33.0ml,33.0mmol),反应混合物于0℃搅拌10分钟。加入在THF(20ml)中的Boc2O(3.60g,16.5mmol),所得混合物于该温度搅拌15分钟。使反应混合物温至RT,采用1N HCl水溶液使得pH 4。分离水层,用EtOAc萃取(2x20ml)。合并的有机相用饱和NaHCO3水溶液洗涤,经MgSO4干燥,过滤,在减压下除去挥发物。残余物经硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到(5,6-二氯吡啶-2-基)氨甲酸叔丁基酯(3.12g,11.86mmol).MSm/z 207.8(M+H-tBu)+。
步骤b:向二异丙基胺(3.25ml,22.80mmol)在THF(20ml)中的-78℃溶液中滴加n-BuLi(2.5M,在己烷中,9.12ml,22.80mmol),反应混合物于-78℃搅拌1小时。加入在THF(20ml)中的(5,6-二氯吡啶-2-基)氨甲酸叔丁基酯(3.0g,11.40mmol),所得混合物于-78℃搅拌2小时。加入在THF(20ml)中的I2(3.04g,11.97mmol),混合物于-78℃搅拌30分钟。温至RT后,反应混合物小心用H2O稀释,用EtOAc萃取(2x50ml)。合并的有机相用饱和Na2S2O3水溶液、盐水洗涤,经MgSO4干燥,过滤,在减压下除去挥发物。残余物经硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到(5,6-二氯-4-碘吡啶-2-基)氨甲酸叔丁基酯(3.33g,4.792mmol).MS m/z 332.8(M+H-tBu)+。
步骤c:向(5,6-二氯-4-碘吡啶-2-基)氨甲酸叔丁基酯(1.0g,2.57mmol)、XantPhos(89mg,0.154mmol)和Pd(OAc)2(29mg,0.129mmol)在二噁烷(10ml)中的溶液中加入3-巯基丙酸甲基酯(313μL,2.83mmol),然后于RT和在N2气氛下加入DIPEA(0.9ml,5.14mmol)。所得溶液于100℃搅拌2小时。冷却至RT后,反应混合物用EtOAc稀释(20ml),经硅藻土垫过滤,然后用EtOAc洗涤(25ml)。合并的滤液在减压下浓缩,残余物经硅胶色谱法纯化(0至25%梯度的EtOAc/庚烷),得到3-((6-((叔丁氧基羰基)氨基)-2,3-二氯吡啶-4-基)硫基)丙酸甲基酯(668mg,1.752mmol).MS m/z 325.1(M+H-tBu)+。
步骤d:将3-((6-((叔丁氧基羰基)氨基)-2,3-二氯吡啶-4-基)硫基)丙酸甲基酯(668mg,1.75mmol)和TFA(1.35ml)在DCM(10ml)中的溶液于RT搅拌1小时。此后,在减压下除去挥发物,得到6-氨基-2,3-二氯吡啶-4-硫醇(342mg,1.75mmol),其未经进一步纯化用于下一步骤。MS m/z 194.6(M+H)+。
中间体S-7
3-(三氟甲基)吡啶-4-硫醇钠
步骤a:将4-氯-3-(三氟甲基)吡啶(535mg,2.95mmol)、碳酸钾(407mg,2.95mmol)、3-巯基丙酸甲基酯(0.343ml,3.09mmol)在DMF(8ml)中的溶液于RT搅拌1小时。反应混合物用EtOAc稀释(60ml),用H2O(3x60ml)洗涤,经MgSO4干燥,过滤,在减压下浓缩,得到3-((3-(三氟甲基)吡啶-4-基)硫基)丙酸甲基酯(710mg,2.68mmol),为澄清油。MS m/z 266.1(M+H)+。
步骤b:于RT和在N2气氛下,向3-((3-(三氟甲基)吡啶-4-基)硫基)丙酸甲基酯(710mg,2.68mmol)在THF(5.4ml)中的溶液中加入乙醇钠(21%wt.在EtOH中,1.01ml,2.94mmol)。于RT剧烈搅拌1小时后,加入另外的乙醇钠(21%wt.在EtOH中,0.25ml,0.44mmol),反应混合物于RT搅拌30分钟。在减压下除去挥发物,残余物混悬于DCM(3ml)中。将混悬液过滤,在减压下干燥,得到3-(三氟甲基)吡啶-4-硫醇钠(216mg,1.074mmol),为黄褐色固体。MS m/z 180.1(M+2H-Na)+。
中间体S-8
3-氯-2-甲基吡啶-4-硫醇钠
步骤a:将3,4-二氯-2-甲基吡啶(3.05g,18.83mmol)、碳酸钾(2.73g,19.77mmol)和3-巯基丙酸甲基酯(2.19ml,19.8mmol)在DMF(25ml)中的溶液于RT搅拌4小时。反应混合物用EtOAc稀释(125ml),用H2O(3x100ml)洗涤,经MgSO4干燥,过滤,在减压下浓缩。残余物经硅胶柱色谱法纯化(0至50%梯度的EtOAc/庚烷),得到3-((3-氯-2-甲基吡啶-4-基)硫基)丙酸甲基酯(1.07g).MS m/z 246.0(M+H)+。1H NMR(400MHz,氯仿-d)δppm8.27(d,J=5.27Hz,1H),6.97(d,J=5.27Hz,1H),3.71-3.82(m,3H),3.26(t,J=7.53Hz,2H),2.78(t,J=7.53Hz,2H),2.63(s,3H)。
步骤b:于RT和在N2气氛下,向3-((3-氯-2-甲基吡啶-4-基)硫基)丙酸甲基酯(1.07g,4.35mmol)在THF(9ml)中的溶液中加入乙醇钠(21%wt.在EtOH中,1.8ml,4.82mmol)。剧烈搅拌1小时后,在减压下除去挥发物,残余物混悬于DCM(20ml)中。滤出沉淀物,在减压下干燥,得到3-氯-2-甲基吡啶-4-硫醇钠,为白色粉末(850mg),为白色固体。MSm/z 160.0(M+H-Na)+。1H NMR(400MHz,DMSO-d6)δppm 7.36(d,J=5.31Hz,1H),6.97(d,J=5.31Hz,1H),2.30(s,3H)。
中间体S-9
2-甲氧基-3-(三氟甲基)吡啶-4-硫醇钠
步骤a:向二异丙基胺(0.966ml,6.77mmol)在THF(20ml)中的-78℃溶液中滴加n-BuLi(1.6M,在己烷中,4.23ml,6.77mmol),反应混合物于-78℃搅拌5分钟。加入2-甲氧基-3-(三氟甲基)吡啶(1.2g,6.77mmol)在THF(10ml)中的溶液,所得混合物于-78℃搅拌2小时。于-78℃加入在THF(5ml)中的I2(1.72g,6.77mmol),使所得混合物在30分钟内温至RT,于该温度进一步搅拌30分钟。在减压下除去挥发物,残余物溶于Et2O(200ml)中。有机层依次用饱和Na2S2O3水溶液(200ml)、饱和NH4Cl水溶液(200ml)、饱和NaHCO3水溶液(200ml)洗涤,经MgSO4干燥,过滤,在减压下除去挥发物。残余物经硅胶色谱法纯化(0至25%梯度的EtOAc/庚烷),得到4-碘-2-甲氧基-3-(三氟甲基)吡啶(540mg,1.354mmol).MS m/z 304.0(M+H)+。
步骤b:于RT和在N2气氛下,向4-碘-2-甲氧基-3-(三氟甲基)吡啶(540mg,1.354mmol)、XantPhos(63mg,0.108mmol)和Pd(OAc)2(12mg,0.054mmol)在二噁烷(1.5ml)中的溶液中加入3-巯基丙酸甲基酯(158μL,1.422mmol),然后加入DIPEA(0.47ml,2.71mmol)。所得溶液于105℃搅拌30分钟。冷却至RT后,反应混合物用EtOAc稀释(10ml),经硅藻土垫过滤,然后用EtOAc洗涤(15ml)。合并的滤液浓缩,残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到3-((2-甲氧基-3-(三氟甲基)吡啶-4-基)硫基)丙酸甲基酯(344mg,1.165mmol).MS m/z 296.1(M+H)+。
步骤c:于RT和在N2气氛下,向3-((2-甲氧基-3-(三氟甲基)吡啶-4-基)硫基)丙酸甲基酯(340mg,1.151mmol)在THF(2.3ml)中的溶液中加入乙醇钠(21%wt.在EtOH中,0.52ml,1.382mmol)。于RT剧烈搅拌30分钟后,在减压下除去挥发物,残余物混悬于DCM(10ml)中。所得混悬液过滤,在减压下干燥,得到3-氯-2-甲基吡啶-4-硫醇盐(850mg,4.31mmol),为白色固体。MS m/z 210.0(M+H)+。
中间体S-10
2-(三氟甲基)吡啶-3-硫醇
步骤a:在氮气atm下,于RT向3-溴-2-(三氟甲基)吡啶(1.0g,4.42mmol)、XantPhos(256mg,0.442mmol)、Pd2(dba)3(203mg,0.221mmol)在二噁烷(12ml)中的溶液中加入3-巯基丙酸2-乙基己基酯(1.1ml,4.87mmol),然后加入DIPEA(1.55ml,8.85mmol)。所得混合物在微波反应器中于110℃照射1小时。冷却至RT后,反应混合物经硅藻土垫过滤,然后用EtOAc(25ml)洗涤。合并的滤液在减压下浓缩,所得残余物经硅胶色谱法纯化(0至30%梯度的EtOAc/庚烷),得到3-((2-(三氟甲基)吡啶-3-基)硫基)丙酸2-乙基己基酯(1.41g,3.88mmol).MS m/z 364.0(M+H)+。
步骤b:于-78℃和在N2 atm下,向3-((2-(三氟甲基)吡啶-3-基)硫基)丙酸2-乙基己基酯(1.0g,2.75mmol)在THF(8ml)中的溶液中加入叔丁醇钾(1M,在THF中,8.25ml,8.25mmol)。于-78℃剧烈搅拌20分钟后,反应物用K2CO3(2M,在H2O中,0.5ml)淬灭,在减压下除去挥发物。残余物倒入含有K2CO3(2M,在H2O中,30ml)的分液漏斗中。混合物用Et2O(2x20ml)萃取,水相用6N HCl酸化直至pH 4,所得混浊混悬液用CHCl3/IPA(9/1;3x20ml)萃取,得到2-(三氟甲基)吡啶-3-硫醇(380mg,2.12mmol).MS m/z180.0(M+H)+。
中间体S-11
3-氨基-2-氯苯硫醇
步骤a:将2-甲基丙烷-2-硫醇(137ml,1216mmol)、2-氯-3-氟苯胺(63.2g,437mmol)和碳酸铯(283g,868mmol)在DMF(650ml)中的混悬液于120℃搅拌16小时。冷却至RT后,反应混合物用EtOAc稀释(500ml),用H2O、盐水洗涤,经Na2SO4干燥,过滤,在减压下浓缩,得到3-(叔丁基硫基)-2-氯苯胺(111.2g,423mmol).MS m/z 216.1(M+H)+。
步骤b:将3-(叔丁基硫基)-2-氯苯胺(53g,246mmol)和浓HCl(700ml)的混悬液于45℃剧烈搅拌8小时和于RT剧烈搅拌16小时。冷却至0℃后,过滤混悬液,固体用浓HCl(100ml)和己烷(3x100ml)洗涤,在减压下干燥,得到3-氨基-2-氯苯硫醇盐酸盐(42g,214mmol).MS m/z 159.6(M+H)+。
中间体W-1
(5,6-二氯-4-碘吡啶-2-基)氨甲酸叔丁基酯
步骤a:于0℃向5,6-二氯吡啶-2-胺(590mg,3.62mmol)在THF(16.3ml)中的溶液中加入LHMDS(1M溶液,在THF中,7.96ml,7.96mmol)。反应物于0℃搅拌10分钟,然后将Boc2O(869mg,3.98mmol)在THF(5ml)中的溶液加入反应混合物中。所得混合物于0℃搅拌15分钟,然后通过添加1N HCl使pH为4。混合物用EtOAc稀释,用饱和NaHCO3水溶液和盐水洗涤,经Na2SO4干燥,过滤,在减压下浓缩。残余物经硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到(5,6-二氯吡啶-2-基)氨甲酸叔丁基酯(790mg,3.00mmol)。1H NMR(400MHz,氯仿-d)δppm 7.86(d,J=8.7Hz,1H),7.70(d,J=8.7Hz,1H),7.20(br.s,1H),1.51(s,9H).MS m/z207.0(M+H-56)+。
步骤b:于-78℃向二异丙基胺(1ml,7.07mmol)在THF(5ml)中的溶液中加入n-BuLi(2.5M,在己烷中,2.83ml,7.07mmol)。混合物于-78℃搅拌1小时,加入(5,6-二氯吡啶-2-基)氨甲酸叔丁基酯(930mg,3.53mmol)在THF(5ml)中的溶液。于-78℃搅拌2小时后,加入碘(987mg,3.89mmol)在THF(5ml)中的溶液,所得混合物于-78℃搅拌另外30分钟。使反应混合物温至RT,用水稀释,用EtOAc萃取(2x50ml)。合并的有机层用饱和Na2S2O3水溶液和盐水洗涤,经Na2SO4干燥,过滤,在减压下浓缩。残余物经硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到(5,6-二氯-4-碘吡啶-2-基)氨甲酸叔丁基酯(813mg,2.09mmol)。1H NMR(400MHz,氯仿-d)δppm 8.45(s,1H),7.12(s,1H),1.52(s,9H).MS m/z 332.9(M+H-56)+。
采用上述操作或上述操作的变通方法,采用5-氯-6-氟吡啶-2-胺作为原料,合成了(5-氯-6-氟-4-碘吡啶-2-基)氨甲酸叔丁基酯。
中间体W-2
(6-氨基-5-氯-4-碘吡啶-2-基)氨甲酸叔丁基酯)
向(5-氯-6-氟-4-碘吡啶-2-基)氨甲酸叔丁基酯(144mg,0.38mmol)在DMSO(1.8ml)中的溶液中加入NH4OH水溶液(50wt.%,1.18ml)。反应混合物于80℃搅拌16小时,然后冷却至RT。混合物用EtOAc稀释,用水和盐水洗涤,经Na2SO4干燥,过滤,在减压下浓缩。所得残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到(6-氨基-5-氯-4-碘吡啶-2-基)氨甲酸叔丁基酯).MS m/z 313.7(M+H-tertBu)+。
中间体C-1
3-氯-4-((5-氯吡嗪-2-基)硫基)吡啶-2-胺
将5-氯吡嗪-2-硫醇钠(4.75g,28.2mmol)、3-氯-4-碘吡啶-2-胺(7.88g,31.0mmol)、XantPhos(1.3g,2.25mmol)、Pd2(dba)3(1.03g,1.13mmol)和DIPEA(9.8ml,56.3mmol)在二噁烷(脱气,113ml)中的混合物于105℃搅拌14小时。冷却至RT后,反应混合物经硅藻土垫过滤,用EtOAc(50ml)冲洗。合并的滤液在减压下浓缩,残余物经硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到3-氯-4-((5-氯吡嗪-2-基)硫基)吡啶-2-胺(4.07g,14.01mmol).MS m/z 273.0(M+H)+。
采用上述操作或上述操作的变通方法,采用相应的碘-或溴-吡嗪,合成了表3的如下化合物。
表3
中间体C-2
4-氯-5-((5-氯吡嗪-2-基)硫基)哒嗪-3-醇
将4,5-二氯哒嗪-3-醇(979mg,5.93mmol)、5-氯吡嗪-2-硫醇钠(500mg,2.97mmol)和DIPEA(1.03ml,0.593mmol)在THF(29.7ml)中的溶液于RT搅拌18小时。反应混合物经硅藻土垫过滤,倒入含有饱和NH4Cl水溶液(40ml)的分液漏斗中,用EtOAc萃取(2x15ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去溶剂。所得残余物经硅胶色谱法纯化(0至100%梯度的EtOAc/庚烷),得到4-氯-5-((5-氯吡嗪-2-基)硫基)哒嗪-3-醇(210mg,0.763mmol),为白色固体。1H NMR(400MHz,DMSO-d6)δppm 13.53(s,1H),8.82(d,J=1.4Hz,1H),8.80(d,J=1.4Hz,1H),7.80(s,1H).MS m/z275.0(M+H)+。
中间体C-3
2-氯-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪
将2-(三氟甲基)吡啶-3-硫醇(100mg,0.558mmol)、2-溴-5-氯-吡嗪(195μL,0.670mmol)、Pd2(dba)3(12.8mg,0.014mmol)、XantPhos(17.8mg,0.031mmol)和DIPEA(144mg,1.12mmol)在二噁烷(脱气,2.79ml中)的混合物于120℃搅拌2.5小时。冷却至RT后,反应混合物经硅藻土垫过滤,然后用EtOAc(10ml)洗涤。合并的滤液在减压下浓缩,所得残余物经硅胶色谱法纯化(0至25%梯度的EtOAc/庚烷),得到2-氯-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪(252mg,0.864mmol),为棕色油。1H NMR(400MHz,氯仿-d)δppm 8.68(dd,J=4.7,1.5Hz,1H),8.25(d,J=1.5Hz,1H),8.18(d,J=1.5Hz,1H),7.98(dd,J=8.1,1.5Hz,1H),7.49(dd,J=8.0,4.7Hz,1H).MS m/z292.0(M+H)+。
中间体C-4
2-氯-4-((5-氯吡嗪-2-基)硫基)烟腈
将5-氯吡嗪-2-硫醇钠(31.9mg,0.189mmol)、2-氯-4-碘烟腈(50mg,0.189mmol)、XantPhos(10.9mg,0.019mmol)、二乙酰氧基钯(2.1mg,0.0095mmol)和DIPEA(0.066ml,0.378mmol)在二噁烷(脱气,1ml)中的混合物于100℃搅拌3小时。冷却至RT后,反应混合物用饱和NH4Cl水溶液稀释,用EtOAc萃取(2x)。合并的有机层经MgSO4干燥,过滤,在减压下浓缩,所得残余物经硅胶色谱法纯化(0至100%梯度的EtOAc/庚烷),得到2-氯-4-((5-氯吡嗪-2-基)硫基)烟腈(22mg,0.078mmol)。1H NMR(400MHz,DMSO-d6)δppm 8.88(d,J=1.3Hz,1H),8.84(d,J=1.3Hz,1H),8.54(d,J=5.5Hz,1H),7.59(d,J=5.5Hz,1H).MS m/z 283.1(M+H)+。
中间体C-5
2-氯-3-((5-氯吡嗪-2-基)硫基)苯胺
将3-氨基-2-氯苯硫醇(724mg,3.69mmol)、2,5-二氯吡嗪(500mg,3.36mmol)和碳酸钾(1.39g,10.07mmol)在DMF/MeCN(1/1,20ml)中的混合物于85℃搅拌4小时。冷却至RT后,反应混合物经硅藻土垫过滤,然后用MeCN(10ml)洗涤。合并的滤液在减压下浓缩,所得残余物经硅胶色谱法纯化(0至20%梯度的EtOAc/庚烷),得到2-氯-3-((5-氯吡嗪-2-基)硫基)苯胺(285mg,1.037mmol).MS m/z 272.1(M+H)+。
中间体C-6
5,6-二氯-4-((5-氯吡嗪-2-基)硫基)吡啶-2-胺
步骤a:将(5,6-二氯-4-碘吡啶-2-基)氨甲酸叔丁基酯(203mg,0.52mmol)、5-氯吡嗪-2-硫醇钠(103mg,0.55mmol)、Pd2(dba)3(24mg,0.026mmol)、XantPhos(30mg,0.052mmol)和DIPEA(0.18ml,1.04mmol)在二噁烷(脱气,2.6ml)中的混合物在N2气氛下于110℃搅拌8小时。冷却至RT后,反应物经硅藻土垫过滤,滤液在减压下浓缩。所得残余物经硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到(5,6-二氯-4-((5-氯吡嗪-2-基)硫基)吡啶-2-基)氨甲酸叔丁基酯(136mg,0.33mmol).MS m/z 352.9(M+H-tertBu)+。
步骤b:向(5,6-二氯-4-((5-氯吡嗪-2-基)硫基)吡啶-2-基)氨甲酸叔丁基酯(135mg,0.33mmol)在MeOH(1.65ml)中的溶液中加入HCl(4M,在二噁烷中的溶液,1.65ml,6.62mmol),混合物于RT搅拌2小时。反应混合物在减压下浓缩,得到粗的5,6-二氯-4-((5-氯吡嗪-2-基)硫基)吡啶-2-胺盐酸盐(113mg,0.33mmol).MS m/z 309.0(M+H)+。
采用上述操作或上述操作的变通方法,采用(6-氨基-5-氯-4-碘吡啶-2-基)氨甲酸叔丁基酯作为原料,合成了3-氯-4-((5-氯吡嗪-2-基)硫基)吡啶-2,6-二胺二盐酸盐。MSm/z 287.9(M+H)+。
中间体B-1
4-苯基哌啶-4-胺
步骤a:将N-(1-苄基-4-苯基哌啶-4-基)乙酰胺(400mg,1.3mmol)和Pd/C(10%wt.,138mg)在MeOH中的混悬液在氢气气氛下剧烈搅拌16小时。反应混合物经硅藻土垫过滤,在减压下除去挥发物。所得残余物溶于EtOAc中,将其用饱和NaHCO3水溶液、盐水洗涤,经MgSO4干燥,过滤,在减压下浓缩,得到N-(4-苯基哌啶-4-基)乙酰胺,其未经任何进一步纯化用于下一步骤。
步骤b:将N-(4-苯基哌啶-4-基)乙酰胺(150mg,0.69mmol)和4N LiOH(2.1ml,8.40mmol)在MeOH/二噁烷(1/1,4ml)中的混悬液于100℃搅拌16小时。冷却至RT后,在减压下除去挥发物,剩余水相用EtOAc萃取(3x5ml)。合并的有机相用盐水洗涤,经MgSO4干燥,过滤,在减压下浓缩,得到4-苯基哌啶-4-胺,为无色油,其未经进一步纯化进行使用。
中间体B-2
((4-(吡嗪-2-基)哌啶-4-基)甲基)氨甲酸叔丁基酯
步骤a:在10分钟内于0℃向在DMF(30ml)中的氢化钠混悬液(60%在矿物油中,1.90g,47.7mmol)中滴加在DMF(5ml)中的2-(吡嗪-2-基)乙腈(1.90g,15.90mmol)。所得混合物于0℃搅拌30分钟。于0℃加入在DMF(5ml)中的N-苄基-2-氯-N-(2-氯乙基)乙胺(4.7g,17.5mmol),所得混合物于0℃搅拌15分钟和于90℃搅拌16小时。冷却至RT后,反应混合物用饱和NaHCO3水溶液稀释,用EtOAc萃取(3x25ml)。合并的有机相经Na2SO4干燥,过滤,在减压下浓缩,所得残余物通过用己烷研制进行纯化,得到1-苄基-4-(吡嗪-2-基)哌啶-4-甲腈(1.60g,5.76mmol)。
步骤b:于RT向1-苄基-4-(吡嗪-2-基)哌啶-4-甲腈(1.50g,5.39mmol)在NH3(7N,在MeOH中,50ml)中的溶液中加入阮内镍(50%在水中,750mg)。所得混悬液在氢气atm(60psi)下于RT剧烈搅拌直至原料消耗(~16h)。反应混合物经硅藻土垫过滤,然后用MeOH(50ml)洗涤。在减压下除去挥发物,得到(1-苄基-4-(吡嗪-2-基)哌啶-4-基)甲胺(1.20g,4.25mmol),其未经进一步纯化用于下一步骤。MS m/z 319(M+H)+。
步骤c:将(1-苄基-4-(吡嗪-2-基)哌啶-4-基)甲胺(1.20g,4.25mmol)、Et3N(1.17ml,8.51mmol)和Boc2O(1.95ml,8.51mmol)在DCM(50ml)中的溶液于RT搅拌2小时。反应物用H2O稀释,将其用DCM萃取(3x25ml)。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至100%梯度的EtOAc/庚烷),得到((1-苄基-4-(吡嗪-2-基)哌啶-4-基)甲基)氨甲酸叔丁基酯(1.30g,3.40mmol).MS m/z383(M+H)+。
步骤d:将((1-苄基-4-(吡嗪-2-基)哌啶-4-基)甲基)氨甲酸叔丁基酯(1.50g,3.93mmol)和Pd(OH)2(20%在碳上,600mg,50%湿度)在MeOH(20ml)中的混悬液在氢气atm(50psi)下于RT剧烈搅拌3小时。反应混合物经硅藻土垫过滤,然后用MeOH(50ml)洗涤。在减压下除去挥发物,得到((4-(吡嗪-2-基)哌啶-4-基)甲基)氨甲酸叔丁基酯(1.10g,3.76mmol),其未经进一步纯化进行使用。MS m/z 283(M+H)+。
采用上述操作或上述操作的变通方法,采用相应的可购买获得的杂芳族乙腈,制得表4的如下中间体。
表4
中间体B-3
((4-异丁基哌啶-4-基)甲基)氨甲酸叔丁基酯
步骤a:于-78℃向LHMDS溶液(1M,在THF中,16.45ml,16.45mmol)中加入1-苄基哌啶-4-甲腈(1.50g,7.49mmol)在THF(37.4ml)中的溶液。所得黄色溶液于-78℃搅拌1小时。加入1-碘-2-甲基丙烷(5.60ml,48.7mmol),使反应混合物温至RT,继续搅拌3天。于0℃加入饱和NH4Cl水溶液(~30ml),混合物用EtOAc萃取。有机相用水(50ml)和盐水(50ml)洗涤。各水层用EtOAc萃取,合并的有机相经Na2SO4干燥,过滤,在减压下浓缩,得到粗的1-苄基-4-异丁基哌啶-4-甲腈(2.54g),为黄色油,其未经进一步纯化直接进行使用).MS m/z 257.3(M+H)+。
步骤b:将粗的1-苄基-4-异丁基哌啶-4-甲腈(2.48g)、Boc2O(6.33g,29.0mmol)和氯化镍(II)水合物(1.15g,4.84mmol)在MeOH(38.7ml)中的溶液于RT搅拌15分钟。于0℃分批加入硼氢化钠(2.56g,67.7mmol),继续于RT搅拌18小时。于0℃加入另外的硼氢化钠(2.56g,67.7mmol),所得混合物于35℃搅拌18小时。冷却至RT后,在减压下除去挥发物,所得残余物混悬于DCM(100ml)中,经硅藻土垫过滤。滤液在减压下浓缩,所得残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到((1-苄基-4-异丁基哌啶-4-基)甲基)氨甲酸叔丁基酯(482mg,1.34mmol),为无色油。MS m/z 361.4(M+H)+。
步骤c:将((1-苄基-4-异丁基哌啶-4-基)甲基)氨甲酸叔丁基酯(482mg,1.34mmol)和Pd/C(10wt.%,142mg)在MeOH(6.7ml)中的混悬液在氢气气氛下剧烈搅拌18小时。混合物经硅藻土垫过滤,然后用MeOH洗涤,在减压下除去挥发物,得到((4-异丁基哌啶-4-基)甲基)氨甲酸叔丁基酯(338mg,1.25mmol),其未经进一步纯化直接进行使用。MS m/z271.3(M+H)+。
采用上述操作或上述操作的变通方法,采用相应的碘烷烃,合成如下化合物。
表5
中间体B-4
外消旋反式-((3-羟基-4-甲基哌啶-4-基)甲基)氨甲酸叔丁基酯
步骤a:于0℃将氢化锂(0.118g,14.8mmol)在THF(20ml)中的溶液加入丙酮羟腈(1.4ml,14.8mmol)中。所得反应混合物于RT搅拌2小时。在减压下除去挥发物,得到白色固体。于RT向该固体在THF(60ml)中的溶液中滴加3-苄基-6-甲基-7-氧杂-3-氮杂双环[4.1.0]庚烷(2.0g,9.85mmol)。溶液回流加热14小时。冷却至RT后,加入水(10ml),所得混合物用EtOAc萃取(3x100ml)。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤,在减压下浓缩。所得残余物经硅胶色谱法纯化(0至20%梯度的EtOAc/庚烷),得到外消旋反式-1-苄基-3-羟基-4-甲基哌啶-4-甲腈(0.70g,3.0mmol)。1H NMR(400MHz,DMSO-d6)δppm 7.36-7.22(m,5H),5.25(d,J=6.0Hz,1H),3.70-3.67(m,1H),3.49(dd,J=13.2,10.4Hz,2H),2.37(m,3H),1.88-1.74(m,2H),1.25(s,3H).MS m/z 231.2(M+H)+。
步骤b:将外消旋反式-1-苄基-3-羟基-4-甲基哌啶-4-甲腈(1.3g,5.6mmol)和阮内镍(50%在水中,600mg)在氨(7N在EtOH中;80ml)中的混悬液在氢气atm下(气囊)于RT剧烈搅拌6小时。混合物在N2下经硅藻土过滤,用MeOH洗涤。在减压下除去挥发物,得到反式-4-(氨基甲基)-1-苄基-4-甲基哌啶-3-醇(1.6g,4.79mmol),其未经进一步纯化用于下一步骤。MS m/z 235.2(M+H)+。
步骤c:将反式-4-(氨基甲基)-1-苄基-4-甲基哌啶-3-醇(1.6g,4.79mmol)、Boc2O(2.84ml,12.4mmol)和NaHCO3(0.935g,11.1mmol)在CHCl3(70ml)中的溶液于RT搅拌14小时。混合物用DCM稀释,用冰水和盐水洗涤,经Na2SO4干燥,过滤,在减压下浓缩。所得残余物经硅胶色谱法纯化(0至5%梯度的MeOH/DCM),得到外消旋反式-(1-苄基-3-羟基-4-甲基哌啶-4-基)甲基)氨甲酸叔丁基酯(1.1g,3.3mmol).MS m/z 335.3(M+H)+。
步骤d:将外消旋反式-((1-苄基-3-羟基-4-甲基哌啶-4-基)甲基)氨甲酸叔丁基酯(1.1g,3.3mmol)和Pd(OH)2(20%在炭上;0.250g)在MeOH(60ml)中的混悬液在氢气atm下(气囊)于RT剧烈搅拌6小时。所得混合物经硅藻土过滤,用MeOH洗涤,在减压下浓缩。残余物从己烷(10ml)和二乙醚(2ml)中研制,得到外消旋反式-((3-羟基-4-甲基哌啶-4-基)甲基)氨甲酸叔丁基酯(0.70g,2.87mmol),为白色粉末。1H NMR(400MHz,甲醇-d4)δppm3.42(dd,J=9.9,4.4Hz,1H),3.12(d,J=13.9Hz,1H),2.94-2.84(m,2H),2.82-2.68(m,2H),2.62(dd,J=12.5,10.0Hz,1H),1.44(s,9H),1.41-1.30(m,2H),0.91(s,3H).MS m/z 245.1(M+H)+。
中间体B-5
外消旋顺式-((3-羟基-4-甲基哌啶-4-基)甲基)氨甲酸叔丁基酯
步骤a:将外消旋反式-1-苄基-3-羟基-4-甲基哌啶-4-甲腈(2.0g,8.70mmol)、三苯膦(3.41g,13.0mmol)和DIAD(2.63g,13.0mmol)在THF(30ml)中的溶液于0℃搅拌10分钟。逐批加入4-硝基苯甲酸(2.18g,13.0mmol),所得混合物于RT搅拌16小时。混合物用水稀释,用EtOAc萃取。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤,在减压下浓缩。所得残余物用MeOH研制,得到外消旋顺式-4-硝基苯甲酸1-苄基-4-氰基-4-甲基哌啶-3-基酯(1.5g,3.96mmol),其未经进一步纯化进行使用。MS m/z380(M+H)+。
步骤b:外消旋顺式-4-硝基苯甲酸1-苄基-4-氰基-4-甲基哌啶-3-基酯(1.5g,3.96mmol)和碳酸钾(1.07g,7.92mmol)在MeOH(20ml)中的溶液于0℃剧烈搅拌10分钟和于RT剧烈搅拌1小时。在减压下除去挥发物。所得残余物用水稀释,用EtOAc萃取(3x)。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤,在减压下浓缩。所得残余物经硅胶色谱法纯化(0至15%梯度的EtOAc/庚烷),得到外消旋顺式-1-苄基-3-羟基-4-甲基哌啶-4-甲腈(0.8g,3.5mmol)。1H NMR(400MHz,CDCl3)δppm 7.36-7.26(m,5H),3.99(d,J=12.4Hz,1H),3.67(d,J=12.8,1H),3.60-3.51(m,2H),3.11-3.07(m,2H),2.76-2.69(m,2H),2.24(dd,J=12.8,6.0Hz,1H),1.87-1.80(m,1H),1.54(s,3H).MS m/z 231(M+H)+。
步骤c:将顺式-1-苄基-3-羟基-4-甲基哌啶-4-甲腈(800mg,3.5mmol)和阮内镍(50%在水中,700mg)在氨(7N在EtOH中;20ml)中的混悬液在氢气atm下(气囊)于RT剧烈搅拌16小时。混合物在N2 atm下经硅藻土过滤,用MeOH冲洗。在减压下除去挥发物,得到外消旋顺式-4-(氨基甲基)-1-苄基-4-甲基哌啶-3-醇(700mg,3.0mmol),其未经进一步纯化用于下一步骤。MS m/z 235.2(M+H)+。
步骤d:将顺式-4-(氨基甲基)-1-苄基-4-甲基哌啶-3-醇(700mg,3.0mmol)、Boc2O(1.1ml,2.99mmol)和Et3N(860μL,5.98mmol)在DCM(10ml)中的溶液于RT搅拌2小时。混合物用DCM稀释,用冰水和盐水洗涤,经Na2SO4干燥,过滤,在减压下浓缩。所得残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到外消旋顺式-(1-苄基-3-羟基-4-甲基哌啶-4-基)甲基)氨甲酸叔丁基酯(700mg,2.10mmol),其未经进一步纯化用于下一步骤。MS m/z335(M+H)+。
步骤e:将外消旋顺式-(1-苄基-3-羟基-4-甲基哌啶-4-基)甲基)氨甲酸叔丁基酯(700mg,2.1mmol)和Pd(10%在炭上;300mg)在MeOH(20ml)中的混悬液在氢气atm下(气囊)于RT剧烈搅拌5小时。所得混合物经硅藻土过滤,用MeOH洗涤,在减压下浓缩。所得残余物经硅胶色谱法纯化(0至10%梯度的MeOH/DCM),得到外消旋顺式-((3-羟基-4-甲基哌啶-4-基)甲基)氨甲酸叔丁基酯(200mg,0.8mmol),为白色粉末。1H NMR(400MHz,甲醇-d4)δppm3.73-3.67(m,1H),3.59(dd,J=11.1,7.7Hz,1H),3.15-2.99(m,4H),1.90(m,1H),1.62(m,1H),1.47(m,1H),1.44(s,9H),0.96(s,3H).MS m/z 245(M+H)+。
中间体B-6
外消旋1-(1,1-二甲基乙基亚磺酰氨基)-2,2-二氟-8-氮杂螺[4.5]癸烷-8-甲酸
叔丁基酯
步骤a:于-78℃向NHMDS的溶液(1M,在THF中,8.68ml,8.68mmol)中加入1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(2.0g,7.89mmol)在THF(5ml)中的溶液。于该温度搅拌30分钟后,加入N-氟苯磺酰胺(2.49g,7.89mmol)在THF(10ml)中的溶液。于-78℃搅拌3小时后,混合物用饱和NaHCO3水溶液(100ml)稀释,用DCM萃取(3x100ml)。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤,在减压下浓缩。所得残余物经硅胶色谱法纯化(0至25%梯度的EtOAc/庚烷),得到外消旋2-氟-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(351mg,1.29mmol),MS m/z 272.1(M+H)+和与原料共洗脱的2,2-二氟-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯。合并的含二氟酮的级分通过硅胶色谱法纯化(0至5%梯度的MeOH/DCM),得到2,2-二氟-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(573mg,1.98mmol).MSm/z 290.1(M+H)+。
步骤b:将2,2-二氟-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(220mg,0.76mmol)、外消旋2-甲基丙烷-2-亚磺酰胺(184mg,1.52mmol)和乙醇钛(IV)(0.640ml,3.0mmol)在THF(4ml)中的溶液于90℃搅拌30分钟。冷却至0℃后,一次性加入硼氢化锂(33mg,1.5mmol)。搅拌30分钟后,反应混合物通过添加MeOH进行淬灭。在减压下除去挥发物。所得残余物用盐水稀释,用EtOAc萃取(4x10ml)。合并的有机相经Na2SO4干燥,过滤,在减压下浓缩。所得残余物经硅胶色谱法纯化(10至50%梯度的EtOAc/庚烷),得到外消旋1-(1,1-二甲基乙基亚磺酰氨基)-2,2-二氟-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯,为白色粉末(190mg,0.48mmol).MS m/z 395.2(M+H)+。
中间体B-7
1-((R)-1,1-二甲基乙基亚磺酰氨基)-2-氟-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基
酯
将外消旋2-氟-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(78mg,0.28mmol)、乙醇钛(IV)(235μL,1.1mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(68mg,0.56mmol)在THF(1.5ml)中的溶液于90℃搅拌1小时。冷却至0℃后,一次性加入硼氢化锂(12mg,0.56mmol)。搅拌30分钟后,反应混合物通过添加MeOH进行淬灭。在减压下除去挥发物。所得残余物用盐水稀释,用EtOAc萃取(4x10ml),合并的有机相经Na2SO4干燥,过滤,在减压下浓缩。所得残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到1-((R)-1,1-二甲基乙基亚磺酰氨基)-2-氟-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(异构体的混合物,64mg,0.17mmol).MS m/z 377.3(M+H)+。
中间体B-8
1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁基酯
步骤a:将4-甲酰基哌啶-1-甲酸叔丁基酯(35.0g,164mmol)、叔丁醇锂(15.77g,197mmol)和烯丙基溴(11.54ml,189mmol)在DMF(328ml)中的混合物于0℃搅拌1小时。混合物倒入含有饱和NH4Cl水溶液/H2O(1/1,500ml)的分液漏斗中,将其用Et2O萃取(5x50ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至25%梯度的EtOAc/庚烷),得到4-烯丙基-4-甲酰基哌啶-1-甲酸叔丁基酯(24g,95mmol),为无色油。1H NMR(400MHz,氯仿-d)δppm 9.52(s,1H),5.53-5.76(m,1H),4.96-5.19(m,2H),3.80(br.s,2H),2.97(t,J=11.49Hz,2H),2.26(d,J=7.33Hz,2H),1.95(dt,J=13.71,3.13Hz,2H),1.38-1.58(m,11H)。
步骤b:在N2 atm下,于-78℃向4-烯丙基-4-甲酰基哌啶-1-甲酸叔丁基酯(24g,95mmol)在THF(300ml)中的溶液中加入乙烯基溴化镁(1M,在THF中,118ml,118mmol)。在1小时内使所得混合物温至RT。混合物倒入含有饱和NH4Cl水溶液(250ml)的分液漏斗中,将其用EtOAc萃取(4x50ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物,得到4-烯丙基-4-(1-羟基烯丙基)哌啶-1-甲酸叔丁基酯(26.7g,95mmol),为无色油,其未经进一步纯化用于下一反应。1H NMR(400MHz,氯仿-d)δppm9.52(s,1H),5.56-5.75(m,1H),5.05-5.18(m,2H),3.80(br.s.,2H),2.97(t,J=11.49Hz,2H),2.26(d,J=7.33Hz,2H),1.96(dt,J=13.83,3.06Hz,2H),1.49-1.60(m,2H),1.41-1.49(m,9H)。
步骤c:将4-烯丙基-4-(1-羟基烯丙基)哌啶-1-甲酸叔丁基酯(26.7g,95mmol)和Dess-Martin过碘烷(44.3g,105mmol)在DCM(380ml)中的混合物于RT搅拌1小时。混合物倒入含有饱和NaHCO3水溶液/Na2SO3(1/1,300ml)的分液漏斗中,将其用DCM萃取(4x50ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物,得到白色固体。将该固体混悬于庚烷(250ml)中,超声处理5分钟。白色混悬液经硅藻土垫过滤,在减压下除去挥发物,得到4-丙烯酰基-4-烯丙基哌啶-1-甲酸叔丁基酯(26.5g,95mmol),为黄色油,其未经进一步纯化用于下一反应。1H NMR(400MHz,氯仿-d)δppm 6.81(dd,J=16.93,10.36Hz,1H),6.40(dd,J=16.80,1.89Hz,1H),5.71(dd,J=10.36,2.02Hz,1H),5.46-5.66(m,1H),4.91-5.14(m,2H),3.78(br.s.,2H),2.96(br.s,2H),2.25-2.39(m,2H),1.97-2.15(m,2H),1.37-1.57(m,11H)。
步骤d:向4-丙烯酰基-4-烯丙基哌啶-1-甲酸叔丁基酯(26.5g,95mmol)在甲苯(脱气,850ml)中的溶液中加入在甲苯(脱气,100ml)中的Grubbs II催化剂(2.02g,2.38mmol)。所得混合物于85℃搅拌45分钟。在减压下除去溶剂,所得残余物经硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁基酯(20.76g,83mmol),为棕色固体。将该化合物和DDQ(565mg,2.49mmol)在甲苯(540ml)中的溶液于RT搅拌15分钟。所得亮红色溶液经硅藻土垫过滤。将炭(200g)加入滤液中,所得混悬液于RT搅拌2小时。混合物经硅藻土垫过滤,滤液在减压下浓缩。所得残余物经硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁基酯(15.6g,62.3mmol),为白色固体。1H NMR(400MHz,氯仿-d)δppm 7.63-7.74(m,1H),6.20(dt,J=5.81,2.15Hz,1H),3.99-4.25(m,2H),2.92(t,J=11.62Hz,2H),2.63(s,2H),1.72-1.86(m,2H),1.49(s,9H),1.29(d,J=12.88Hz,2H)。
中间体B-9
(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-8-氮杂螺[4.5]癸烷-8-
甲酸苄基酯
步骤a:在N2 atm.下,于0℃向1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁基酯(4.2g,16.71mmol)和CuI(6.37g,33.4mmol)在Et2O(100ml)中的混悬液中加入MeLi(1.6M,在THF中,31.3ml,50.1mmol)。于0℃搅拌90分钟后,混合物倒入含有饱和NH4Cl水溶液的分液漏斗中,用EtOAc萃取(3x15ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到3-甲基-1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁基酯(4.23g,15.82mmol),为无色油。1H NMR(400MHz,氯仿-d)δppm 3.89-4.00(m,1H),3.83(d,J=13.39Hz,1H),3.11(ddd,J=13.64,10.36,3.28Hz,1H),2.99(ddd,J=13.58,10.42,3.54Hz,1H),2.47-2.59(m,1H),2.19-2.36(m,2H),1.74-1.97(m,2H),1.50-1.65(m,2H),1.48(s,9H),1.33-1.44(m,2H),1.17(d,J=6.32Hz,3H)。
步骤b:将3-甲基-1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁基酯(4.23g,15.82mmol)和TFA(17ml)在DCM(80ml)中的混合物于RT搅拌30分钟。在减压下除去挥发物。将所得残余物、DIPEA(13.82ml,79mmol)和氯甲酸苄基酯(3.39ml,23.73mmol)的混合物于RT搅拌16小时。混合物倒入含有饱和NH4Cl水溶液的分液漏斗中,将其用DCM萃取(3x25ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(4.58g,15.20mmol),为浅黄色油).MS m/z 302.2(M+H)+。
步骤c:将3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(4.58g,15.20mmol)通过如下手性SFC进一步纯化:柱:IA 21x250mm,流速:70g/分钟,流动相:45%(9/1EtOH/MeCN)在CO2中,检测:220nm UV,得到(R)-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(2.02g,6.70mmol),TR:2.0分钟;和(S)-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(2.11g,7.0mmol),TR:3.6分钟。
步骤d:将(R)-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(2.02g,6.70mmol)、乙醇钛(IV)(5.62ml,26.8mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(1.625g,13.4mmol)在THF(67ml)中的溶液于65℃搅拌16小时。混合物冷却至-78℃,加入MeOH(12ml),继之以硼氢化锂(0.438g,20.11mmol)。所得混合物于-78℃至RT搅拌16小时。缓慢加入饱和NH4Cl水溶液以萃取过量氢硼化物,然后加入EtOAc(100ml)。所得混合物剧烈搅拌15分钟,然后经硅藻土垫过滤。在减压下除去挥发物,所得残余物经硅胶色谱法纯化(5to90%梯度的EtOAc/庚烷),得到(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(1.94g,4.77mmol),为白色固体。MS m/z 407.3(M+H)+。
采用上述操作或上述操作的变通方法,采用(S)-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯作为原料,合成了(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯。
中间体B-10
(1R,3R)-3-((叔丁基二甲基甲硅烷基)氧基)-1-((R)-1,1-二甲基乙基亚磺酰氨
基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯)
步骤a:将CuCl(142mg,1.432mmol)、(S)-TolBINAP(972mg,1.432mmol)和叔丁醇钠(138mg,1.432mmol)在THF(60ml)中的混合物于RT搅拌30分钟。加入在THF(20ml)中的双(联硼酸频那醇酯)二硼烷(13.34g,52.5mmol),所得混合物于RT搅拌10分钟。加入在THF(50ml)中的1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁基酯(12.0g,47.7mmol),继之以MeOH(3.9ml,95mmol)。所得混合物于RT搅拌16小时。加入H2O(150ml),继之以过硼酸钠(36.7g,239mmol),所得混合物于RT剧烈搅拌1小时。所得绿色混悬液经硅藻土垫过滤,倒入含有饱和NaHCO3/Na2SO3水溶液(1/1,300ml)的分液漏斗中,用EtOAc萃取(4x40ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物,得到粗的(R)-3-羟基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯。对该混合物进行对映异构体测定,显示出90%ee(Rt(S):1.59分钟,Rt(R):1.80分钟;手性SFC;柱:IA 4.6x100mm,流速:70g/分钟,流动相:5-55%MeOH在CO2中,检测:220nm UV)。将(R)-3-羟基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯粗品(47.7mmol)、咪唑(4.87g,71.6mmol)和TBSCl(8.99g,59.6mmol)在DMF(120ml)中的混合物于RT搅拌16小时。反应混合物倒入含有饱和NH4Cl水溶液/H2O(1/1,250ml)的分液漏斗中,将其用Et2O(5x50ml)萃取。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至30%梯度的EtOAc/庚烷),得到(R)-3-((叔丁基二甲基甲硅烷基)氧基)-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(13.115g,34.2mmol),为无色油,静置后固化。
步骤b:将(R)-3-((叔丁基二甲基甲硅烷基)氧基)-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(8.0g,20.86mmol)、乙醇钛(IV)(17.49ml,83.0mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(5.06g,41.7mmol)在THF(100ml)中的溶液于65℃搅拌16小时。冷却至-78℃后,加入MeOH(15ml),继之以硼氢化锂(1.363g,62.6mmol)。所得混合物于-78℃搅拌16小时。缓慢加入饱和NH4Cl水溶液以萃取过量氢硼化物,然后加入EtOAc(100ml)。所得混合物剧烈搅拌15分钟,然后经硅藻土垫过滤。在减压下除去挥发物,所得残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到(1R,3R)-3-((叔丁基二甲基甲硅烷基)氧基)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(5.3g,10.84mmol),为白色固体。MS m/z 489.3(M+H)+和389.3(M+H-Boc)+。
中间体B-11
(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-
甲酸叔丁基酯
将(1R,3R)-3-((叔丁基二甲基甲硅烷基)氧基)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(3.84g,7.86mmol)和TBAF(1M,在THF中;8.64ml,8.64mmol)在THF(40ml)中的混合物于RT搅拌30分钟。在减压下除去挥发物,所得残余物经硅胶色谱法纯化(0至10%梯度的MeOH/DCM),得到(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(2.94g,7.86mmol).MS m/z375.3(M+H)+。
中间体B-12
(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-
甲酸叔丁基酯
步骤a:向(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(3.0g,8.01mmol)、三苯膦(4.2g,16.02mmol)和异喹啉-1-甲酸(4.16g,24.03mmol)在THF(80ml)中的溶液中加入DIAD(3.1ml,16.02mmol)。所得混合物于RT搅拌1小时。反应物用EtOAc稀释(50ml),经硅藻土垫过滤,倒入含有饱和NaHCO3水溶液的分液漏斗中,用EtOAc萃取(3x25ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至4%梯度的MeOH/DCM),得到(2S,4R)-异喹啉-1-甲酸8-(叔丁氧基羰基)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-2-基酯(3.65g,6.89mmol),为橙色固体。MS m/z530.3(M+H)+。
步骤b:将(2S,4R)-异喹啉-1-甲酸8-(叔丁氧基羰基)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-2-基酯(3.65g,6.89mmol)和氢氧化锂(2.95g,68.9mmol)在THF/H2O(1/1,70ml)中的混合物于RT搅拌2小时。混合物倒入含有饱和NH4Cl水溶液的分液漏斗中,将其用EtOAc萃取(3x15ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至10%梯度的MeOH/DCM),得到(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(2.35g,6.27mmol),为白色固体。MS m/z 275.2(M+H-Boc)+。
中间体B-13
(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲氧基-8-氮杂螺[4.5]癸烷-
8-
甲酸叔丁基酯
将(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(500mg,1.335mmol)、氧化银(I)(340mg,1.468mmol)和碘甲烷(0.25ml,4.0mmol)在DCM(5ml)中的混合物于RT(避光)搅拌24小时和于45℃(避光)搅拌24小时。冷却至RT后,混合物经硅藻土垫过滤,在减压下除去挥发物,所得残余物经硅胶色谱法纯化(0至5%梯度的MeOH/DCM),得到(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲氧基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(248mg,0.638mmol).MS m/z 289.2(M+H-Boc)+。
采用上述操作或上述操作的变通方法,采用(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯作为原料,合成了(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲氧基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯。
中间体B-14
外消旋1-((叔丁氧基羰基)氨基)-3,3-二氟-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基
酯
步骤a:将3-((叔丁基二甲基甲硅烷基)氧基)-1-(1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(365mg,0.746mmol)和HCl(4M,在二噁烷中,1.86ml,7.46mmol)在MeOH(4ml)中的混合物于40℃搅拌1小时。冷却至RT后,在减压下除去挥发物,得到粗的4-氨基-8-氮杂螺[4.5]癸烷-2-醇,为白色固体。MS m/z 171.1(M+H)+。
步骤b:将粗的4-氨基-8-氮杂螺[4.5]癸烷-2-醇、DIPEA(2.6ml,14.92mmol)和Boc2O(407mg,1.865mmol)在THF(15ml)中的混合物于RT搅拌16小时。混合物倒入含有饱和NH4Cl水溶液的分液漏斗中,将其用Et2O萃取(5x10ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(10至80%梯度的EtOAc/庚烷),得到1-((叔丁氧基羰基)氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(275mg,0.742mmol).MS m/z 271.3(M+H-Boc)+。
步骤c:将1-((叔丁氧基羰基)氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(275mg,0.742mmol)和Dess-Martin过碘烷(472mg,1.113mmol)在DCM(7.5ml)中的混合物于0℃搅拌2小时。混合物倒入含有饱和NaHCO3水溶液的分液漏斗中,将其用DCM萃取(3x10ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(5至75%梯度的EtOAc/庚烷),得到1-((叔丁氧基羰基)氨基)-3-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(135mg,0.366mmol)。1H NMR(400MHz,氯仿-d)δppm 4.57(d,J=9.09Hz,1H),4.16(d,J=8.08Hz,1H),3.89-4.08(m,2H),2.77-2.93(m,2H),2.71(dd,J=18.95,8.08Hz,1H),2.50(d,J=18.19Hz,1H),2.07-2.24(m,2H),1.76(td,J=12.82,4.67Hz,1H),1.58-1.70(m,1H),1.42-1.53(m,18H),1.25-1.38(m,1H)。
步骤d:将1-((叔丁氧基羰基)氨基)-3-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(95mg,0.258mmol)和DeoxoFluor(190μL,1.031mmol)在DCM(1ml)中的混合物于50℃搅拌48小时。混合物倒入含有饱和NaHCO3水溶液/冰的分液漏斗中,将其用EtOAc萃取(3x5ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至30%梯度的EtOAc/庚烷),得到1-((叔丁氧基羰基)氨基)-3,3-二氟-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(52mg,0.133mmol)。1H NMR(400MHz,氯仿-d)δppm 4.55(d,J=9.35Hz,1H),3.78-4.02(m,3H),2.64-2.86(m,2H),2.38-2.59(m,1H),2.10-2.32(m,1H),1.79-2.10(m,2H),1.58(qd,J=12.72,3.79Hz,1H),1.27-1.52(m,21H)。
采用上述操作或上述操作的变通方法,采用手性纯的(1R,3R)-3-((叔丁基二甲基甲硅烷基)氧基)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯作为原料,合成了(R)-1-((叔丁氧基羰基)氨基)-3,3-二氟-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯。
中间体B-15
(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-氟-8-氮杂螺[4.5]癸烷-8-甲
酸叔丁基酯
将(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(400mg,1.068mmol)和DAST(1M,在DCM中,1.87ml,1.87mmol)在DCM(8.5ml)中的混合物于0℃搅拌90分钟。反应混合物通过添加饱和NaHCO3水溶液(5ml)进行淬灭。于0℃搅拌10分钟后,分离各相,水层用DCM萃取(2x5ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物,得到(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-氟-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯,其未经进一步纯化用于下一步骤。MS m/z 277.2(M+H-Boc)+。
中间体B-16
(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-氟-8-氮杂螺[4.5]癸烷-8-甲
酸叔丁基酯
将(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(200mg,0.534mmol)和DAST(1M,在DCM中,934μL,0.934mmol)在DCM(5ml)中的混合物于0℃搅拌90分钟。反应混合物通过添加饱和NaHCO3水溶液(5ml)进行淬灭。于RT搅拌10分钟后,分离各相,水层用DCM萃取(2x5ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物,得到(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-氟-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯,其未经进一步纯化用于下一步骤。MS m/z 277.2(M+H-Boc)+。
中间体B-17
4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯
按照Dirat等人,WO2004/078750,2004年9月16日的操作,由哌啶-1,4-二甲酸1-叔丁基酯4-乙基酯以4个步骤制备了4-羟基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯。1H NMR(400MHz,氯仿-d)δppm 4.13(dd,J=10.1,4.6Hz,1H),4.03(dd,J=4.6,2.0Hz,1H),3.78-3.71(m,2H),3.69(d,J=8.6Hz,1H),3.67-3.58(m,2H),3.29(m,1H),3.16(m,1H),1.78(m,2H),1.58(m,1H),1.50(m,2H),1.47(s,9H).MS m/z 258.1(M-H)+。
将4-羟基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(544mg,2.11mmol)和Dess-Martin过碘烷(1.39g,3.17mmol)在DCM(10ml)中的溶液于0℃搅拌2小时。加入饱和NaHCO3/Na2S2O3水溶液(1/1,10ml),分离有机相,水溶液相用DCM萃取(3x10ml)。合并的有机相经Na2SO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(470mg,1.84mmol),为无色油,其在静置后结晶。1H NMR(400MHz,氯仿-d)δppm 4.08(s,2H),4.05(s,2H),3.88(dt,J=13.7,4.9Hz,2H),3.12(ddd,J=13.6,9.8,3.6Hz,2H),1.75(ddd,J=13.9,9.7,4.2Hz,2H),1.58-1.51(m,2H),1.48(s,9H).MS m/z 256.2(M+H)+。
中间体B-18
(S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸
叔丁基酯
将4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(220mg,0.86mmol)、乙醇钛(IV)(725μL,3.45mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(209mg,1.72mmol)在THF(4ml)中的溶液于90℃搅拌1小时。冷却至0℃后,加入硼氢化锂(23mg,1.06mmol)。搅拌30分钟后,反应混合物通过添加MeOH进行淬灭。在减压下除去挥发物。所得残余物用盐水稀释,将其用EtOAc萃取(4x10ml)。合并的有机相经Na2SO4干燥,过滤,在减压下除去挥发物,所得残余物经硅胶色谱法纯化(0至100%梯度的EtOAc/庚烷),得到(S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(170mg,0.47mmol).MS m/z 361.1(M+H)+。
采用上述操作或上述操作的变通方法,采用相应的酮和磺酰胺,合成了表6的如下化合物。
表6
中间体B-19&B-20
(3S,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]
癸烷-8-甲酸叔丁基酯&(3R,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基
-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯
步骤a:于-78℃向4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(2.47g,9.67mmol)在THF(24ml)中的溶液中加入LHMDS(1M,在THF中,9.67ml,9.67mmol)。混合物于该温度搅拌30分钟后,加入在THF(10ml)中的碘甲烷(0.605ml,9.67mmol)。使所得混合物温至RT,搅拌1小时。反应混合物用EtOAc和饱和NaHCO3水溶液稀释。有机层用盐水洗涤,经Na2SO4干燥,过滤,在减压下浓缩。所得褐色油经硅胶色谱法纯化(0至20%梯度的EtOAc/庚烷),得到3-甲基-4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(318mg,1.18mmol).MS m/z 270.2(M+H)+。
步骤b:将3-甲基-4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(318mg,1.18mmol)、乙醇钛(IV)(990μL,4.72mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(286mg,2.361mmol)在THF(4ml)中的溶液于90℃搅拌90分钟。冷却至0℃后,一次性加入硼氢化锂(65.3mg,3.00mmol),所得混合物于RT搅拌16小时。缓慢加入饱和NH4Cl水溶液以萃取过量氢硼化物,然后加入EtOAc(25ml)。所得混合物剧烈搅拌15分钟,然后经硅藻土垫过滤。有机相用饱和NaHCO3水溶液和盐水洗涤,经Na2SO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至100%梯度的EtOAc/庚烷),得到(4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(88mg,0.235mmol).MS m/z375.2(M+H)+。
步骤c:通过手性SFC进行非对映异构体分离。柱:LUXC4 30x250mm,流速:80g/分钟,流动相:20%MeOH在CO2中,检测:210nm,得到(3R,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯Rt=4.0分钟;和(3S,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯TR=4.55分钟。
(3S,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯的供选制备:
步骤a:向二异丙基胺(23.4ml,166mmol)在THF(220ml)中的-10℃溶液中滴加n-BuLi(2.5M,在己烷中,64.1ml,160mmol)。于该温度搅拌30分钟后,滴加在THF(50ml)中的哌啶-1,4-二甲酸1-叔丁基酯4-乙基酯(27.5g,107mmol),所得混合物于0℃搅拌30分钟。加入(S)-2-((叔丁基二甲基甲硅烷基)氧基)丙醛(20.47ml,102mmol),混合物于0℃搅拌1小时和于RT搅拌1小时。反应物用饱和NaHCO3水溶液/H2O(1:4,125ml)稀释,加入EtOAc(50ml),分离各相。水相进一步用EtOAc萃取(3x100ml)。合并的有机相经Na2SO4干燥,过滤,在减压下除去溶剂。所得残余物未经进一步纯化用于下一步骤。MS m/z 346.4(M+H-Boc)+。
步骤b:向粗的4-((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)哌啶-1,4-二甲酸1-叔丁基酯4-乙基酯(95g,214mmol)在THF(600ml)中的溶液中逐批加入硼氢化锂(7.0g,321mmol),所得混合物于RT搅拌16小时。冷却至0℃后,加入饱和NaHCO3水溶液/H2O(1/2,150ml),所得混合物剧烈搅拌直至不再观察到气体发生。加入EtOAc(100ml),混合物过滤,分离各相,水相进一步用EtOAc萃取(3x50ml)。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤,在减压下除去挥发物,得到4-((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)-4-(2-羟基乙基)哌啶-1-甲酸叔丁基酯(64.8g,161mmol),其未经进一步纯化用于下一步骤。
步骤c:将4-((2S)-2-((叔丁基二甲基甲硅烷基)氧基)-1-羟基丙基)-4-(2-羟基乙基)哌啶-1-甲酸叔丁基酯(64.8g,161mmol)和TBAF(1M,在THF中,242ml,242mmol)在THF(500ml)中的溶液于RT搅拌2小时。加入饱和NaHCO3水溶液/H2O(1:2,150ml),分离各相,水相进一步用EtOAc萃取(3x100ml)。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(20至100%梯度的EtOAc/庚烷),得到4-((2S)-1,2-二羟基丙基)-4-(2-羟基乙基)哌啶-1-甲酸叔丁基酯(39.25g,136mmol),为半固体无色油。
步骤d:向NaH(10.60g,424mmol)在THF(600ml)中的0℃混悬液中滴加4-((2S)-1,2-二羟基丙基)-4-(2-羟基乙基)哌啶-1-甲酸叔丁基酯(35.06g,121mmol)和4-甲苯磺酰氯(23.1g,121mmol)在THF(200ml)中的溶液。所得混合物于0℃搅拌1小时。于-20℃缓慢加入饱和NH4Cl水溶液(~5ml),反应物剧烈搅拌直至不再观察到气体发生。此时,加入饱和NH4Cl水溶液(100ml),继之以盐水(100ml),混合物用EtOAc萃取(3x100ml)。合并的有机相经Na2SO4干燥,过滤,在减压下除去溶剂,得到(3S)-4-羟基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(32.19g,119mmol),其未经进一步纯化用于下一步骤。MS m/z 171.1(M-Boc)-。
步骤e:将(3S)-4-羟基-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(32.19g,119mmol)和Dess-Martin过碘烷(67.4g,154mmol)在DCM(300ml)中的溶液于0℃搅拌2小时。混合物温至RT,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到(3S)-3-甲基-4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(27.68g,92mmol),为浅黄色油。1H NMR(400MHz,氯仿-d)δppm 4.09(d,J=9.60Hz,1H),3.66-3.86(m,4H),3.03(ddd,J=13.77,9.73,3.79Hz,1H),2.90(ddd,J=13.64,10.23,3.41Hz,1H),1.68(ddd,J=13.83,9.92,4.29Hz,1H),1.41-1.59(m,2H),1.30-1.40(m,10H),1.20-1.25(m,3H)。
步骤f:将(3S)-3-甲基-4-氧代-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(22.52gmg,84mmol)、乙醇钛(IV)(70.1ml,334mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(21g,173mmol)在THF(300ml)中的溶液于90℃搅拌21小时。冷却至-4℃后,加入MeOH(30ml),然后滴加(维持反应温度低于2℃)硼氢化锂(1.82g,84mmol),所得混合物于-4℃搅拌1小时。缓慢加入饱和NH4Cl水溶液以萃取过量氢硼化物(半固体),然后加入EtOAc(500ml)。所得混合物于RT剧烈搅拌15分钟,然后经硅藻土垫过滤,然后用EtOAc(500ml)洗涤。在减压下除去挥发物,所得残余物经硅胶色谱法纯化(0至100%梯度的EtOAc/庚烷),得到(3S,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯,为95:5非对映异构混合物(较少的非对映异构体(3R,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯)。
步骤g:通过手性SFC进行非对映异构体分离。柱:LC-4 30x250mm,流速:100g/分钟,流动相:30%MeOH在CO2中,检测:225nm,TR:0.95分钟(较少的非对映异构体TR:0.55分钟),得到(3S,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(19g,50.68mmol).MS m/z 375.2。1H NMR(400MHz,氯仿-d)δppm4.24-4.16(m,1H),4.03-3.94(m,1H),3.91-3.85(m,1H),3.84-3.78(m,1H),3.64(d,J=9.1Hz,1H),3.50-3.42(m,1H),3.32(d,J=10.1Hz,1H),2.99-2.85(m,2H),1.82(td,J=18.1,15.1,7.7Hz,2H),1.62-1.53(m,1H),1.53-1.47(m,1H),1.46(s,9H),1.22(d,J=6.4Hz,3H)。
采用上述操作或上述操作的变通方法,采用相应的碘烷烃,合成了表7的如下化合物。
表7
中间体B-21
(1R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-2-甲基-8-氮杂螺[4.5]癸烷-8-甲酸
叔丁基酯
步骤a:于0-5℃向1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(2.2g,8.68mmol)在THF(24ml)中的溶液中加入LHMDS(1M,在THF中,8.68ml,8.68mmol)。混合物于该温度搅拌30分钟后,加入碘甲烷(0.543ml,8.68mmol)。使所得混合物温至RT,搅拌另外2小时。反应混合物用EtOAc和饱和NaHCO3水溶液稀释。有机相用盐水洗涤,经Na2SO4干燥,过滤,在减压下浓缩。所得褐色油经硅胶色谱法纯化(0至25%梯度的EtOAc/庚烷),得到外消旋2-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(1.3g,4.86mmol).MS m/z 268.1。(M+H)+。
步骤b:将外消旋2-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(267mg,0.999mmol)、乙醇钛(IV)(837μL,3.99mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(242mg,1.997mmol)在THF(10ml)中的溶液于85℃搅拌24小时。冷却至-78℃后,加入MeOH(12ml),继之以硼氢化锂(65.3mg,3.00mmol)。所得混合物于-78℃至RT搅拌16小时。缓慢加入饱和NH4Cl水溶液以萃取过量氢硼化物,然后加入EtOAc(100ml)。所得混合物剧烈搅拌15分钟,然后经硅藻土垫过滤。在减压下除去挥发物,所得残余物经硅胶色谱法纯化(0至60%梯度的EtOAc/庚烷(含有0.25%of Et3N)),得到(1R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-2-甲基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(92mg,0.247mmol).MS m/z 373.1(M+H)+。
中间体B-22
外消旋(1S,2S,3S)-1-((叔丁氧基羰基)氨基)-2,3-二羟基-8-氮杂螺[4.5]癸烷-
8-甲酸叔丁基酯
步骤a:在N2气氛下,向1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁基酯(2g,7.96mmol)和氯化铯(III)七水合物(3.26g,8.75mmol)的混合物中加入MeOH(60ml)和THF(20ml)。所得混合物于RT搅拌1小时,冷却至0℃,加入硼氢化钠(0.60g,15.9mmol)。反应混合物于0℃搅拌1小时,然后倒入1N NaOH(75ml)中。混合物用Et2O(3x50ml)萃取,合并的萃取物经Na2SO4干燥,过滤,在减压下浓缩。残余物经硅胶色谱法纯化(10至60%梯度的含有0.25%NEt3的EtOAc/庚烷),得到外消旋1-羟基-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁基酯(2.01g,7.93mmol),为橙色油。1H NMR(400MHz,氯仿-d)δppm 5.99-5.94(m,1H),5.89-5.83(m,1H),4.32(s,1H),3.79-3.65(m,2H),3.29-3.12(m,2H),2.36-2.27(m,1H),2.26-2.15(m,1H),1.81-1.71(m,1H),1.55-1.50(m,2H),1.49(s,9H),1.43-1.36(m,1H).MS m/z276.2(M+Na)+。
步骤b:于0℃、在N2气氛下,向外消旋1-羟基-8-氮杂螺[4.5]癸-2-烯-8-甲酸叔丁基酯(1.63g,6.43mmol)在DCM(64ml)中的溶液中依次加入叔丁基过氧化氢(5.5M在癸烷中的溶液,1.4ml,7.72mmol)和氧钒基乙酰丙酮酯(156mg,0.643mmol)。反应混合物于0℃搅拌20分钟和于RT搅拌15小时。反应混合物倒入饱和Na2SO3水溶液(50ml)中,用DCM萃取(3x25ml)。合并的萃取物经Na2SO4干燥,过滤,在减压下浓缩。残余物经硅胶色谱法纯化(10至60%梯度的含有0.25%NEt3的EtOAc/庚烷),得到外消旋(1R,2R,5S)-2-羟基-6-氧杂螺[二环[3.1.0]己烷-3,4'-哌啶]-1'-甲酸叔丁基酯(805mg,单对映异构体)。1H NMR(400MHz,氯仿-d)δppm 3.92-3.78(m,3H),3.65(t,J=2.27Hz,1H),3.56(t,J=2.27Hz,1H),2.99-2.82(m,2H),2.22(d,J=14.65Hz,1H),1.78(br.s.,1H),1.70-1.58(m,3H),1.47-1.40(m,10H).MS m/z 170.1(M+H-Boc)+。
步骤c:在氮气气氛下,于0℃向外消旋(1R,2R,5S)-2-羟基-6-氧杂螺[双环[3.1.0]己烷-3,4'-哌啶]-1'-甲酸叔丁基酯(805mg,2.99mmol)、三苯膦(1.57g,5.98mmol)和亚氨基二甲酸二叔丁基酯(1.30g,5.98mmol)在THF(15ml)中的溶液中缓慢加入DIAD(1.16ml,5.98mmol)。所得混合物于0℃搅拌5分钟,于RT搅拌10分钟,然后加热至40℃达15小时。反应混合物用EtOAc稀释(25ml),倒入饱和NH4Cl水溶液中,用EtOAc萃取(3x10ml)。合并的萃取物经Na2SO4干燥,过滤,在减压下浓缩。残余物经硅胶色谱法纯化(0至40%梯度的含有0.25%NEt3的EtOAc/含有0.25%NEt3的庚烷),得到外消旋(1R,2S,5S)-2-((二叔丁氧基羰基)氨基)-6-氧杂螺[双环[3.1.0]己烷-3,4'-哌啶]-1'-甲酸叔丁基酯(480mg;单对映异构体。MS m/z 491.3(M+Na)+。
步骤d:向外消旋(1R,2S,5S)-2-((二叔丁氧基羰基)氨基)-6-氧杂螺[二环[3.1.0]己烷-3,4'-哌啶]-1'-甲酸叔丁基酯(346mg)在CHCl3(4ml)中的溶液中加入HOAc(0.2ml)。反应混合物于RT搅拌5小时,在减压下浓缩,得到粗的外消旋(3aS,6S,6aS)-N,N'-双-(叔丁基羰基)-6-羟基四氢螺[环戊二烯并[d]噁唑-4,4'-哌啶]-2(5H)-酮(295mg;单对映异构体),为澄清油。1H NMR(400MHz,氯仿-d)δppm 4.74(dd,J=7.45,1.39Hz,1H),4.48(br.s,1H),4.42(d,J=7.33Hz,1H),4.04(br.s,2H),2.78(br.s,2H),2.03-1.99(m,2H),1.93-1.79(m,3H),1.66-1.58(m,1H),1.56(s,9H),1.46(s,9H).MS m/z 435.2(M+Na)+。
步骤e:向粗的外消旋(3aS,6S,6aS)-N,N'-双-(叔丁基羰基)-6-羟基四氢螺[环戊二烯并[d]噁唑-4,4'-哌啶]-2(5H)-酮(125mg)在MeOH(1.5ml)中的溶液中加入Cs2CO3(20mg,0.06mmol),反应混合物于RT搅拌5小时。混合物用EtOAc(10ml)和饱和NH4Cl水溶液/水(1:1,10ml)稀释。分离水层,用EtOAc萃取(2x10ml)。合并的萃取物经MgSO4干燥,过滤,在减压下浓缩。残余物经SFC纯化(Princetone 2-EP 20x150mm 5um,CO2/MeOH 80g/min120bar),得到外消旋(1S,2S,3S)-1-((叔丁氧基羰基)氨基)-2,3-二羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(44mg,单对映异构体),为澄清油。1H NMR(400MHz,氯仿-d)δppm5.02(d,J=9.35Hz,1H),4.17-4.10(m,1H),4.04(br.s.,1H),3.96(br.s.,3H),2.83(d,J=12.13Hz,2H),2.22-2.10(m,1H),1.98(br.s.,2H),1.76(td,J=12.88,4.55Hz,1H),1.64-1.52(m,1H),1.46(s,9H),1.45(s,9H).MS m/z 409.3(M+Na)+。
中间体B-23
((1R,3R)-3-(三氟甲基)-8-氮杂螺[4.5]癸烷-1-基)氨甲酸叔丁基酯
步骤a:于0℃向1-氧代-8-氮杂螺[4.5]癸-2-烯-8-甲酸苄基酯(3.05g,10.7mmol)在THF(40ml)中的溶液加入三甲基(三氟甲基)硅烷(2M,在THF中,6.41ml)和TBAF(1M,在THF中,0.214ml),所得混合物于0℃搅拌1.5小时。反应混合物小心用2M HCl水溶液(10ml)稀释,于0℃搅拌1小时。溶液进一步用饱和NH4Cl水溶液(50ml)稀释,用EtOAc萃取(3x50ml)。合并的有机层经Na2SO4干燥,过滤,在减压下除去挥发物。残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到1-氧代-3-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯,为无色油(2.22g,6.25mmol)。1H NMR(400MHz,氯仿-d)δppm 7.45-7.31(m,5H),5.16(s,2H),3.84(dd,J=8.9,5.1Hz,1H),3.30(ddd,J=13.5,9.5,3.4Hz,1H),3.21(ddd,J=13.5,9.8,3.6Hz,1H),3.03-2.87(m,1H),2.66(ddd,J=18.8,8.4,1.5Hz,1H),2.46(dd,J=18.9,10.7Hz,1H),2.38-2.25(m,1H),1.97-1.79(m,2H),1.70-1.58(m,1H),1.54(m,3H)。19F NMR(376MHz,氯仿-d)δppm-72.08(d,J=8.0Hz)。13C NMR(101MHz,氯仿-d)δppm 215.93,155.18,136.67,128.53,128.07,127.93,125.74(q,J=263Hz),67.24,47.96,40.35,39.86,37.30,32.77(q,J=29Hz),33.77(q,J=3Hz),31.89,31.10。
步骤b:将1-氧代-3-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(2.22g,6.25mmol)、(R)-叔丁烷亚磺酰胺(1.514g,12.50mmol)和四乙氧基钛(5.70g,5.24ml,25mmol)在THF(50ml)中的混合物加热至80℃达16小时。反应混合物冷却至-78℃,然后加入MeOH(10ml)和硼氢化锂(0.408g,18.74mmol)。历经3小时使反应混合物温至RT。反应混合物小心地用饱和NH4Cl水溶液(50ml)稀释。所得杂相混合物经硅藻土过滤,用EtOAc洗涤。分离滤液层,水层用EtOAc萃取(2x25ml)。合并的有机层经Na2SO4干燥,过滤,在减压下除去挥发物,得到粗的(1R)-1-(((R)-叔丁基亚硫酰基)氨基)-3-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯,为白色固体,其未经进一步纯化用于下一步骤。MS:m/z 461.3(M+H)+。
步骤c:向粗的(1R)-1-(((R)-叔丁基亚硫酰基)氨基)-3-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(2.88g,6.25mmol)在MeOH(25ml)中的溶液中加入HCl(4M在二噁烷中,3.13ml)。所得溶液于环境温度搅拌1小时。在减压下除去挥发物,所得残余物在减压下干燥2小时。残余物溶于CH2Cl2和DIPEA(5.57ml,31.3mmol)中,加入焦碳酸二叔丁基酯(2.05g,9.4mmol)。所得混合物于环境温度搅拌72小时。反应混合物用饱和NH4Cl水溶液(50ml)稀释,用CH2Cl2(3x25ml)萃取。合并的有机层经Na2SO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至100%梯度的EtOAc/庚烷),得到(1R,3R)-1-((叔丁氧基羰基)氨基)-3-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(0.90g,1.97mmol),为白色固体,还有1.47g(1R,3R)-1-((叔丁氧基羰基)氨基)-3-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯和(1R,3S)-1-((叔丁氧基羰基)氨基)-3-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯的混合物。该混合物通过制备型SFC进一步纯化(柱:IB 21x250mm,10%IPA共溶剂),得到(1R,3R)-1-((叔丁氧基羰基)氨基)-3-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(0.60g,1.32mmol)[1H NMR(400MHz,氯仿-d)δppm 7.34-7.20(m,5H),5.06(s,2H),4.39(d,J=9.6Hz,1H),3.96-3.75(m,3H),2.99(t,J=11.0Hz,2H),2.65(dq,J=18.3,9.1Hz,1H),2.24(dt,J=15.3,8.3Hz,1H),1.77(dd,J=13.9,9.7Hz,1H),1.66(dd,J=13.9,8.4Hz,1H),1.60-1.41(m,3H),1.39(s,9H),1.31-1.16(m,2H)]和(1R,3S)-1-((叔丁氧基羰基)氨基)-3-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(0.50g,1.09mmol)[1H NMR(400MHz,氯仿-d)δppm 7.44-7.30(m,5H),5.15(s,2H),4.36(d,J=9.1Hz,1H),4.24-4.01(m,2H),3.88(q,J=8.7Hz,1H),2.91(dd,J=29.7,16.1Hz,2H),2.72(ddt,J=14.6,9.7,5.0Hz,1H),2.30-2.11(m,2H),1.77-1.60(m,2H),1.46(m,12H),1.27-1.15(m,1H)]。
步骤d:将(1R,3R)-1-((叔丁氧基羰基)氨基)-3-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(0.90g,1.97mmol)和Pd/C(10%wt.,200mg)在EtOH(40ml)中的混合物在H2气氛(气囊)下氢化2小时。混合物喷射氮气5分钟,然后经硅藻土过滤,用EtOH冲洗。滤液在减压下浓缩,在减压下干燥,得到粗的((1R,3R)-3-(三氟甲基)-8-氮杂螺[4.5]癸烷-1-基)氨甲酸叔丁基酯(625mg,1.94mmol),为白色泡沫,其未经纯化直接进行使用。1H NMR(400MHz,氯仿-d)δppm 4.54(d,J=9.7Hz,1H),3.84(q,J=8.8Hz,1H),3.00(tt,J=12.1,4.0Hz,2H),2.79-2.63(m,3H),2.28(ddd,J=13.5,8.8,6.8Hz,1H),2.19(d,J=8.5Hz,1H),1.80(qd,J=14.0,9.1Hz,2H),1.63(qd,J=9.0,3.4Hz,2H),1.47(m,12H)。19F NMR(376MHz,氯仿-d)δppm-71.42(d,J=9.6Hz)。
按照上述操作,由(1R,3S)-1-((叔丁氧基羰基)氨基)-3-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(0.50g,1.09mmol)制得((1R,3S)-3-(三氟甲基)-8-氮杂螺[4.5]癸烷-1-基)氨甲酸叔丁基酯(355mg,1.09mmol)。1H NMR(400MHz,氯仿-d)δppm 4.45(d,J=9.3Hz,1H),3.80(q,J=9.2Hz,1H),3.15-2.96(m,2H),2.79(t,J=11.9Hz,1H),2.67(tt,J=13.8,6.9Hz,2H),2.17(dd,J=13.7,9.1Hz,2H),1.73(td,J=13.2,4.3Hz,1H),1.68-1.56(m,1H),1.54-1.31(m,12H),1.26-1.13(m,1H),0.84(d,J=4.6Hz,1H)。
中间体B-24
((1S,3R)-2,2-二氟-3-甲基-8-氮杂螺[4.5]癸烷-1-基)氨甲酸叔丁基酯
步骤a:向LiHMDS(1M,在THF中,3.7ml,3.7mmol)在THF(15ml)中的-78℃溶液中滴加在THF(5ml)中的(R)-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(1.0g,3.32mmol)。于-78℃搅拌30分钟后,加入在THF(5ml)中的N-氟-N-(苯基磺酰基)苯磺酰胺(1.15g,3.65mmol),所得混合物于该温度搅拌30分钟。温至RT后,反应混合物倒入含有饱和NaHCO3水溶液(25ml)的分液漏斗中,将其用EtOAc萃取(3x30ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。残余物经硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到(3R)-2-氟-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(1.05g,3.32mmol).MSm/z 320.2(M+H)+。
步骤b:向LiHMDS(1M,在THF中,3.45ml,3.45mmol)在THF(15ml)中的-78℃溶液中加入在THF(5ml)中的(3R)-2-氟-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(1.0g,3.13mmol)。于-78℃搅拌30分钟后,加入在THF(5ml)中的N-氟-N-(苯基磺酰基)苯磺酰胺(1.086g,3.44mmol),所得混合物于该温度搅拌1小时。温至RT后,反应混合物倒入含有饱和NaHCO3水溶液(25ml)的分液漏斗中,用EtOAc萃取(3x30ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。残余物经硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到(R)-2,2-二氟-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(1.17g,3.32mmol)。1H NMR(400MHz,氯仿-d)δppm7.30-7.48(m,5H),5.16(s,2H),3.75-3.99(m,2H),3.32-3.44(m,1H),3.28(ddd,J=13.52,9.47,3.54Hz,1H),2.25-2.47(m,1H),2.17(ddd,J=13.20,7.52,2.78Hz,1H),1.72-1.92(m,2H),1.42-1.62(m,2H),1.24(dd,J=7.33,0.76Hz,3H)。19FNMR(376MHz,氯仿-d)δppm-119.79(br d,J=277.64Hz,1F),-123.89(d,J=271.90Hz,1F)。
步骤c:将(R)-2,2-二氟-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(1.17g,3.32mmol)、乙醇钛(IV)(2.91ml,13.87mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(841mg,6.94mmol)在THF(35ml)中的溶液于60℃搅拌4小时。冷却至-78℃后,加入MeOH(3.5ml),继之以硼氢化锂(0.227g,10.40mmol)。所得混合物于-78℃至RT搅拌2小时。缓慢加入饱和NH4Cl水溶液,然后加入EtOAc(100ml)。所得混合物剧烈搅拌5分钟,然后经硅藻土垫过滤。在减压下除去挥发物,残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到(1S,3R)-1-(((R)-叔丁基亚硫酰基)氨基)-2,2-二氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(700mg,1.582mmol),为单对映异构体。MS m/z443.3(M+H)+。
步骤d:向(1S,3R)-1-(((R)-叔丁基亚硫酰基)氨基)-2,2-二氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(700mg,1.582mmol)在MeOH(10ml)中的溶液中加入HCl(4M,在二噁烷中,3.95ml,15.82mmol)。所得混合物于45℃搅拌30分钟。冷却至RT后,在减压下除去挥发物。将该残余物、Boc2O(432mg,1.977mmol)和DIPEA(2.76ml,15.82mmol)在THF(20ml)中的溶液于RT搅拌16小时。混合物倒入含有饱和NH4Cl水溶液的分液漏斗中,用EtOAc萃取(3x10ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物,残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到(1S,3R)-1-((叔丁氧基羰基)氨基)-2,2-二氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(645mg,1.471mmol).MS m/z 383.3(M+H-tBu)+。
步骤e:将Pd/C(10%wt,78mg)在MeOH(10ml)中的混悬液在H2气氛(气囊)下剧烈搅拌5分钟。加入在MeOH(10ml)中的(1S,3R)-1-((叔丁氧基羰基)氨基)-2,2-二氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(645mg,1.471mmol),所得混悬液在H2气氛下剧烈搅拌16小时。反应混合物经硅藻土垫过滤,将垫用DCM洗涤,在减压下除去挥发物,得到((1S,3R)-2,2-二氟-3-甲基-8-氮杂螺[4.5]癸烷-1-基)氨甲酸叔丁基酯(448mg,1.471mmol),其未经进一步纯化进行使用。MS m/z 305.3(M+H)+。
中间体B-25
((1R,2S,3R)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-1-基)氨甲酸叔丁基酯(A)和
((1S,2R,3R)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-1-基)氨甲酸叔丁基酯(B);(A:B的混合物
=4:1)
步骤a:向LiHMDS(1M,在THF中,7.31ml,7.31mmol)在THF(30ml)中的-78℃溶液中滴加在THF(10ml)中的(R)-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(2.0g,6.64mmol)。于-78℃搅拌30分钟后,加入在THF(10ml)中的N-氟-N-(苯基磺酰基)苯磺酰胺(2.3g,7.30mmol),所得混合物于该温度搅拌30分钟。温至RT后,反应混合物倒入含有饱和NaHCO3水溶液(25ml)的分液漏斗中,用EtOAc萃取(3x30ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。残余物经硅胶色谱法纯化(0至40%梯度的EtOAc/庚烷),得到非对映异构体(2S,3R)-2-氟-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(较多)和(2R,3R)-2-氟-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(较少)的4:1混合物(1.81g,5.67mmol)。该非对映异构混合物未经进一步纯化用于下一步骤。MS m/z 320.2(M+H)+。
步骤b:将非对映异构体(2S,3R)-2-氟-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(较多)和(2R,3R)-2-氟-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(较少)的4:1混合物(1.95g,6.11mmol)、乙醇钛(IV)(5.12ml,24.42mmol)和(R)-2-甲基丙烷-2-亚磺酰胺(1.48g,12.21mmol)在THF(35ml)中的混合物于60℃搅拌4小时。冷却至-78℃后,加入MeOH(3.5ml),继之以硼氢化锂(0.399g,18.32mmol)。所得混合物于-78℃至RT搅拌2小时。缓慢加入饱和NH4Cl水溶液以萃取过量氢硼化物,然后加入EtOAc(100ml)。所得混合物剧烈搅拌5分钟,然后经硅藻土垫过滤。在减压下除去挥发物,残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到(1R,2S,3R)-1-(((R)-叔丁基亚硫酰基)氨基)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯和(1S,2R,3R)-1-(((R)-叔丁基亚硫酰基)氨基)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯的4:1混合物(2.05g,4.83mmol)。该非对映异构混合物未经进一步纯化用于下一步骤。MS m/z 443.3(M+H)+。
步骤c:向(1R,2S,3R)-1-(((R)-叔丁基亚硫酰基)氨基)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯和(1S,2R,3R)-1-(((R)-叔丁基亚硫酰基)氨基)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯的4:1混合物(2.05mg,4.83mmol)在MeOH(20ml)中的溶液中加入HCl(4M,在二噁烷中,12ml,48.0mmol)。所得混合物于45℃搅拌30分钟。冷却至RT后,在减压下除去挥发物。该残余物、Boc2O(1.32g,6.04mmol)和DIPEA(8.43ml,48.3mmol)在THF(40ml)中的混合物于RT搅拌1小时。反应混合物倒入含有饱和NH4Cl水溶液的分液漏斗中,用EtOAc萃取(3x25ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物,残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到(1R,2S,3R)-1-((叔丁氧基羰基)氨基)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯和(1S,2R,3R)-1-((叔丁氧基羰基)氨基)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯的4:1混合物(1.51g,3.59mmol)。该非对映异构混合物未经进一步纯化用于下一步骤。MS m/z 383.3(M+H-tBu)+。
步骤d:将Pd/C(10%wt.,78mg)在MeOH(10ml)中的混悬液在H2气氛(气囊)下剧烈搅拌5分钟。加入在MeOH(10ml)中的(1R,2S,3R)-1-((叔丁氧基羰基)氨基)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯和(1S,2R,3R)-1-((叔丁氧基羰基)氨基)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯的4:1混合物(1.50g,3.57mmol),所得混悬液在H2气氛下剧烈搅拌16小时。反应混合物经硅藻土垫过滤,将垫用DCM洗涤,在减压下除去挥发物,得到((1R,2S,3R)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-1-基)氨甲酸叔丁基酯和((1S,2R,3R)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-1-基)氨甲酸叔丁基酯的4:1混合物(1.07g,3.74mmol)。该非对映异构混合物未经进一步纯化用于下一步骤。MS m/z 305.3(M+H)+。
中间体B-26
2-((1S,2S,3R)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-1-基)异二氢吲哚-1,3-二酮
步骤a:于-78℃向(2S,3R)-2-氟-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(1.89g,5.92mmol;含40%的(2R,3R)-2-氟-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸酯)在THF/MeOH(9:1 20ml)中的溶液中加入LiBH4(2M,在THF中,11.84ml,23.67mmol)。所得混合物于-78℃搅拌30分钟。向溶液中缓慢加入饱和NH4Cl水溶液,使混合物温至RT。混合物用EtOAc萃取(3x),合并的有机相用盐水洗涤,经MgSO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到(1R,2S,3R)-2-氟-1-羟基-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(970mg,3.02mmol).MS m/z 322.2(M+H)+。1HNMR(400MHz,甲醇-d4)δ7.37-7.28(m,5H),5.10(s,2H),4.47(dt,J=54.4,4.7Hz,1H),3.86(d,J=12.9Hz,2H),3.65(dd,J=18.0,4.7Hz,1H),3.20-3.03(m,2H),2.39-2.21(m,1H),2.20-2.10(m,1H),1.75-1.60(m,2H),1.45(d,J=13.4Hz,1H),1.29(d,J=13.1Hz,1H),1.08(d,J=7.1Hz,3H),0.96(dd,J=13.3,8.5Hz,1H)。
步骤b:向(1R,2S,3R)-2-氟-1-羟基-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(1.03g,3.20mmol)、三苯膦(1.68g,6.41mmol)、苯邻二甲酰亚胺(0.943g,6.41mmol)在THF(20ml)中的溶液中滴加DIAD(1.25ml,6.41mmol)。所得混合物于55℃搅拌16小时。冷却至RT后,反应混合物倒入含有饱和NH4Cl水溶液的分液漏斗中,用EtOAc萃取(5x10ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到(1S,2S,3R)-1-(1,3-二氧代异二氢吲哚-2-基)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(2.3g,~50%纯,基于UV吸收)。该物质未经进一步纯化用于下一步骤。MS m/z 451.2(M+H)+。
步骤c:将Pd/C(10%wt.,170mg)在MeOH(15ml)中的混悬液在H2气氛(气囊)下剧烈搅拌5分钟。然后,加入在MeOH(15ml)中的(1S,2S,3R)-1-(1,3-二氧代异二氢吲哚-2-基)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(50%纯,基于UV吸收,3.20mmol),所得混悬液在H2气氛下剧烈搅拌2.5小时。反应混合物经硅藻土垫过滤,将垫用DCM洗涤,在减压下除去挥发物,得到2-((1S,2S,3R)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-1-基)异二氢吲哚-1,3-二酮(294mg,0.929mmol).MS m/z 317.2(M+H)+。
中间体B-27
1-((R)-1,1-二甲基乙基亚磺酰胺基)-2-(羟基甲基)-8-氮杂螺[4.5]癸烷-8-甲
酸叔丁基酯
步骤a:按照“Suna,E等人,(J.Org.Chem.2014,79,3715-3724)中的操作,将THF(8ml)、MeOH(0.811ml,20mmol)和低聚甲醛(660mg,22mmol)加入厚壁压力容器中,反应混合物于100℃加热70分钟。使反应混合物冷却至RT。在冷却至RT后,在容器底部形成沉淀物。加入另外的THF(1.2ml)调节甲氧基甲醇的浓度为在THF中的2M溶液。基于作为限定试剂的MeOH评估了定量产率。
步骤b:在N2气氛下,向含有1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(238g,939mmol)的烧瓶中加入(R)-(+)-2-甲基-2-丙烷亚磺酰胺(171g,1409mmol)。加入乙醇钛(IV)(985ml,4.70mol),然后将混合物加热至105℃达4小时。移去加热套,将混合物在N2气流下和EtOAc(6L)一起经由FEP试管套真空转移10L 4-颈烧瓶中,所述烧瓶装配有顶部机械搅拌棒和在冰水浴中冷却的具有N2入口接头的250mL加液漏斗。历经30-45分钟经由加液漏斗滴加水(288ml),产生大量浅黄色盐沉淀。除去冷浴液,使混悬液老化15分钟,然后将整个混合物经由硅藻土过滤,用EtOAc(2x1L)洗涤。然后将滤液用水洗涤(3x1L),在减压下浓缩。在浓缩和反添加庚烷(2L)后,使水共沸出,这导致在烧瓶内壁上产生盐的浑浊白色膜沉淀。将浅棕色混合物经中等烧结玻璃漏斗过滤(用EtOAc和庚烷冲洗)。滤液进一步浓缩直至大部分EtOAc被除去,加入另外的庚烷(1L)。混合物在减压下进一步浓缩以产生沉淀,加入另外的庚烷(500ml)以保持混合物流动。混合物于RT搅拌,然后用冰浴冷却,然后通过真空过滤分离固体。固体用冰冷的庚烷洗涤三次。固体在减压下干燥,得到(R,E)-1-((叔丁基亚硫酰基)亚氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯,为乳状固体(408.9g,66.7%产率)。1H NMR(400MHz,氯仿-d)δppm 3.93(m,2H),3.05(m,3H),2.71(dt,J=19.6,7.2Hz,1H),1.96-1.71(m,6H),1.49(s,9H),1.42(m,2H),1.27(s,9H)。
步骤c:在N2气氛下于,-78℃向(R,E)-1-((叔丁基亚硫酰基)亚氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(1.95g,5.47mmol)在THF(27.3ml)中的溶液中缓慢加入LiHMDS(1M,在THF中,6.02ml),反应混合物于-78℃搅拌10分钟。历经~10分钟滴加甲氧基甲醇(2M,在THF中,9.57ml),使反应混合物温至0℃,于该温度继续搅拌1小时。将反应混合物小心用饱和NH4Cl水溶液(20ml)稀释,用EtOAc萃取。合并的有机层用盐水洗涤,经MgSO4干燥,在减压下浓缩。残余物经柱色谱法纯化(硅胶,0至100%的EtOAc/庚烷),得到(E)-1-(((R)-叔丁基亚硫酰基)亚氨基)-2-(羟基甲基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(1.14g),为白色固体。1H NMR(400MHz,DMSO-d6)δppm 4.90(t,J=5.1Hz,1H),3.83(dd,J=14.1,8.5Hz,2H),3.67(dt,J=9.5,4.5Hz,1H),3.39(td,J=9.7,4.7Hz,1H),3.16(dt,J=9.0,5.8Hz,1H),2.84(d,J=60.4Hz,2H),2.08-1.85(m,2H),1.84-1.62(m,2H),1.62-1.49(m,1H),1.39(s,12H),1.13(s,9H)。
步骤d:在N2气氛下和于-78℃,向(E)-1-(((R)-叔丁基亚硫酰基)亚氨基)-2-(羟基甲基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(1.025g,2.65mmol)在THF(12ml)和MeOH(1.2ml)中的溶液中加入LiBH4(87mg,3.98mmol)。反应混合物于-78℃搅拌5分钟,然后使其温至室温。反应混合物小心用饱和NaHCO3水溶液(5ml)稀释,用EtOAc萃取。合并的有机层用盐水洗涤,经MgSO4干燥,在减压下浓缩。残余物经柱色谱法纯化(硅胶,0至20%梯度的MeOH/DCM),得到1-((R)-1,1-二甲基乙基亚磺酰胺基)-2-(羟基甲基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(778mg),为白色固体。1H NMR(400MHz,DMSO-d6)表明存在胺的诊断NH信号,处于4.98ppm(d,J=10.4Hz,1H)。
中间体B-28
(2R,3S)-3-甲基-2-(三氟甲基)-8-氮杂螺[4.5]癸烷-1-胺
步骤a:向(S)-3-甲基-1-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(2.1g,6.97mmol)在THF(30ml)中的-78℃溶液中加入LiHMDS(1M,在THF中,8.36ml,8.36mmol),反应混合物于-78℃搅拌30分钟。加入氯三乙基硅烷(1.23ml,7.32mmol),使反应混合物温至RT,于该温度搅拌18小时。反应混合物倒入含有饱和NH4Cl水溶液(125ml)的分液漏斗中,用庚烷萃取(3x125ml)。合并的有机萃取物经MgSO4干燥,过滤,在减压下浓缩。残余物经硅胶色谱法纯化(0至30%梯度的EtOAc/庚烷),得到(S)-3-甲基-1-((三乙基甲硅烷基)氧基)-8-氮杂螺[4.5]癸-1-烯-8-甲酸苄基酯(2.78g,6.69mmol),为澄清油。MS m/z 416.3(M+H)+。
步骤b:将(S)-3-甲基-1-((三乙基甲硅烷基)氧基)-8-氮杂螺[4.5]癸-1-烯-8-甲酸苄基酯(2.14g,5.15mmol)、1-三氟甲基-1,2-benziodoxol-3-(1H)-酮(60%wt.,含40%wt.FW-80作为添加剂)(Togni’s II,4.07g,7.72mmol)和Cu(I)SCN(63mg,0.515mmol)在DMF(43ml)中的混合物于50℃搅拌3天。冷却至RT后,反应混合物用Et2O稀释,过滤,将过滤垫用Et2O(150ml)洗涤。有机层用饱和NaHCO3水溶液(2x150ml)洗涤,经MgSO4干燥,过滤,在减压下除去挥发物。残余物经硅胶色谱法纯化(0至30%梯度的EtOAc/庚烷),得到(2R,3S)-3-甲基-1-氧代-2-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(1.52g,4.12mmol),为澄清油。1H NMR(400MHz,氯仿-d)δppm 7.30-7.45(m,5H),5.15(s,2H),4.00(dt,J=13.36,4.99Hz,1H),3.79(dt,J=13.49,4.93Hz,1H),3.26-3.39(m,1H),3.20(ddd,J=13.49,9.72,3.64Hz,1H),2.55-2.70(m,1H),2.42-2.55(m,1H),2.29(dd,J=13.30,6.53Hz,1H),1.81-1.92(m,1H),1.65(ddd,J=13.49,9.47,3.89Hz,1H),1.45-1.58(m,1H),1.38(br d,J=12.30Hz,2H),1.32(d,J=6.27Hz,3H)。19F NMR(376MHz)δppm-66.32(br d,J=7.76Hz).MS m/z 370.2(M+H)+。
步骤c:将O-甲基羟基胺盐酸盐(2.896g,34.7mmol)、(2R,3S)-3-甲基-1-氧代-2-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(854mg,2.312mmol)和吡啶(3.74ml,46.2mmol)在EtOH(7.5ml)中的混合物于90℃搅拌18小时。冷却至RT后,反应混合物倒入含有H2O(60ml)和饱和CuSO4水溶液(60ml)的分液漏斗中,将其用Et2O萃取(3x120ml)。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。残余物经硅胶色谱法纯化(0至30%梯度的EtOAc/庚烷),得到(2R,3S)-1-(甲氧基亚氨基)-3-甲基-2-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯的两种E/Z立体异构体的混合物(750mg,1.882mmol),为澄清油。MS m/z399.1(M+H)+。
步骤d:将Pd/C(10%wt.,68.8mg)在MeOH(2ml)中的混悬液于RT在H2气氛(气囊)下剧烈搅拌5分钟。向该混悬液中加入(2R,3S)-1-(甲氧基亚氨基)-3-甲基-2-(三氟甲基)-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯的E/Z异构体(515mg,1.293mmol)在MeOH(4ml)中的溶液,所得混合物在H2气氛下剧烈搅拌30分钟。反应混合物经硅藻土垫过滤,用DCM洗涤(70ml)。滤液在减压下浓缩,得到(2R,3S)-3-甲基-2-(三氟甲基)-8-氮杂螺[4.5]癸烷-1-酮O-甲基肟的E/Z异构体的混合物(351mg,1.275mmol),为澄清油。MS m/z265.1(M+H)+。
步骤e:将(2R,3S)-3-甲基-2-(三氟甲基)-8-氮杂螺[4.5]癸烷-1-酮O-甲基肟的E/Z异构体的混合物(210mg,0.795mmol)、Et3N(0.886ml,6.36mmol)和BnBr(0.378ml,3.18mmol)在MeCN(1.5ml)中的溶液于RT搅拌1.5小时。反应混合物倒入含有H2O(25ml)和饱和NH4Cl水溶液(25ml)的分液漏斗中,用DCM萃取(3x50ml)。合并的有机萃取物经MgSO4干燥,过滤,在减压下除去挥发物。残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到(2R,3S)-8-苄基-3-甲基-2-(三氟甲基)-8-氮杂螺[4.5]癸烷-1-酮O-甲基肟的E/Z异构体的混合物(219mg,0.618mmol),为澄清油。MS m/z355.2(M+H)+。
步骤f:向(2R,3S)-8-苄基-3-甲基-2-(三氟甲基)-8-氮杂螺[4.5]癸烷-1-酮O-甲基肟的E/Z异构体(150mg,0.423mmol)在THF(1ml)中的0℃溶液中滴加BH3-THF复合物(1M,在THF中,6.35ml,6.35mmol),使反应混合物历经10分钟温至RT,加热至80℃,于该温度搅拌24小时。冷却至0℃后,反应混合物小心用H2O(5ml)稀释。产气停止后(5分钟),使反应混合物温至RT,加入NaOH水溶液(2M,3ml,6mmol),反应混合物于80℃搅拌2小时。反应混合物倒入含有NaOH水溶液(1M,20ml)的分液漏斗中,用DCM萃取(3x20ml)。合并的有机萃取物经MgSO4干燥,过滤,在减压下除去挥发物。残余物经HPLC纯化(梯度洗脱,乙腈在水中的45-70%溶液,5mM NH4OH改性剂),得到(2R,3S)-8-苄基-3-甲基-2-(三氟甲基)-8-氮杂螺[4.5]癸烷-1-胺的差向异构体的混合物(81mg,0.248mmol),为橙色油。MS m/z 327.1(M+H)+。
步骤g:在氮气气氛下,向(2R,3S)-8-苄基-3-甲基-2-(三氟甲基)-8-氮杂螺[4.5]癸烷-1-胺的差向异构体(90.6mg,0.278mmol)在MeOH(2ml)中的溶液中加入Pd/C(10%wt.,59.1mg,0.056mmol)。反应混合物在H2气氛(气囊)下剧烈搅拌26小时。反应混合物用DCM稀释,经硅藻土过滤,将垫用DCM(100ml)洗涤。在减压下除去挥发物,得到(2R,3S)-3-甲基-2-(三氟甲基)-8-氮杂螺[4.5]癸烷-1-胺的差向异构体的混合物(68mg,0.276mmol),为棕色油。MS m/z 237.2(M+H)+。
中间体B-29
2,8-二氮杂螺[4.5]癸-1-烯-1-胺盐酸盐
步骤a:于RT向2-氧代-1,8-二氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(300mg,1.180mmol)在DCM(3ml)中的溶液中加入五硫化二磷(110mg,0.495mmol),然后加入六甲基二硅氧烷(2.26ml,10.6mmol)。反应物于RT搅拌3小时,然后用EtOAc稀释,经硅藻土过滤。滤液在减压下浓缩。粗产物经硅胶色谱法纯化(0至80%梯度的EtOAc/庚烷),得到1-硫代-2,8-二氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(0.290g,1.07mmol),为白色固体。1H NMR(400MHz,DMSO-d6)δppm 10.39(s,1H),3.66(dt,J=13.6,4.9Hz,2H),3.09(s,2H),2.78(t,J=7.8Hz,2H),1.95(t,J=7.8Hz,2H),1.57(dd,J=6.6,4.8Hz,4H),1.39(s,9H).MS m/z 271(M+H)+。
步骤b:向1-硫代-2,8-二氮杂螺[4.5]癸烷-8-甲酸酯(100mg,0.370mmol)在THF(3ml)中的溶液中滴加碘甲烷(0.231ml,3.70mmol)。所得溶液于RT搅拌16小时。反应混合物缓慢变得更黄,在搅拌规定的反应时间后产生亮黄色沉淀物。反应混合物浓缩,在真空下干燥,得到黄色固体。将黄色固体加入MeOH(2ml)中,用氨(在MeOH中的7M溶液,3ml)处理,在密闭试管中于100℃加热8小时。反应物冷却至RT,在减压下浓缩,得到固体,将其用MeCN研制,过滤。滤液在减压下浓缩,残余物经硅胶色谱法纯化(0至30%梯度的MeOH/DCM),得到1-氨基-2,8-二氮杂螺[4.5]癸-1-烯-8-甲酸叔丁基酯(87mg,0.343mmol)。1H NMR(400MHz,DMSO-d6)δppm9.38(s,1H),8.81(d,J=25.2Hz,2H),3.98(s,2H),3.55(t,J=7.0Hz,2H),2.82(s,2H),2.12(t,J=7.1Hz,2H),1.74(td,J=12.9,4.7Hz,2H),1.57(d,J=12.7Hz,2H),1.41(s,9H).MS m/z 254(M+H)+。
步骤c:于RT向1-氨基-2,8-二氮杂螺[4.5]癸-1-烯-8-甲酸叔丁基酯(86mg,0.339mmol)在DCM(3ml)中的溶液中加入HCl(4M在二噁烷中的溶液,0.5ml,2.0mmol),反应物搅拌16小时。反应混合物浓缩,残余物用MeCN研制,过滤,得到2,8-二氮杂螺[4.5]癸-1-烯-1-胺(57.7mg,0.254mmol),为褐色固体。1H NMR(400MHz,DMSO-d6)δppm 9.64(s,1H),9.39-9.23(m,1H),9.15(s,1H),9.07(s,1H),8.70(d,J=12.5Hz,1H),3.54(t,J=6.9Hz,2H),3.32(d,J=13.3Hz,2H),3.05-2.88(m,2H),2.18(t,J=6.9Hz,2H),2.01(td,J=13.7,4.3Hz,2H),1.80(d,J=13.8Hz,2H).MS m/z 154(M+H)+。
中间体B-30
(4R)-4-氨基-2-甲基-8-氮杂螺[4.5]癸烷-2-醇
步骤a:将(2R,4R)-4-氨基-8-氮杂螺[4.5]癸烷-2-醇二盐酸盐(623mg,2.56mmol)、Na2CO3(1.36g,12.80mmol)和氯甲酸苄基酯(1.05g,6.14mmol)在H2O(5ml)中的混合物于RT剧烈搅拌30分钟。加入THF(0.5ml),所得混合物于RT搅拌18小时。混合物用水和DCM稀释。分离水层,用DCM萃取(2x10ml)。合并的有机相经Na2SO4干燥,过滤,在减压下浓缩。所得残余物经硅胶色谱法纯化(0至100%梯度的EtOAc/庚烷),得到(1R,3R)-1-(((苄氧基)羰基)氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(940mg,2.14mmol),为白色泡沫。MS m/z 439.3(M+H)+。
步骤b:将(1R,3R)-1-(((苄氧基)羰基)氨基)-3-羟基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(440mg,1.003mmol)和Dess-Martin过碘烷(638mg,1.505mmol)在DCM(6ml)中的混合物于0℃搅拌1小时和于RT搅拌18小时。反应混合物用饱和NaHCO3/Na2S2O3水溶液(1:1,25ml)稀释。分离水相,用DCM萃取(3x15ml)。合并的有机相用盐水洗涤,经MgSO4干燥,过滤,在减压下浓缩。所得残余物经硅胶色谱法纯化(0至70%梯度的EtOAc/庚烷),得到(R)-1-(((苄氧基)羰基)氨基)-3-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(415mg,0.951mmol),为白色泡沫。MS m/z 437.2(M+H)+。
步骤c:于-30至-40℃,向MeLi(1.2M,在THF中,2.61ml,3.13mmol)在THF(15ml)中的溶液中滴加在THF(5ml)中的(R)-1-(((苄氧基)羰基)氨基)-3-氧代-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(415mg,0.951mmol)。所得混合物于-30至-40℃搅拌20分钟。混合物用NaHSO4(10%溶液,在H2O中)和EtOAc稀释,在剧烈搅拌下使其温至RT。混合物倒入含有饱和NaHCO3水溶液的分液漏斗中,分离各相。水相进一步用EtOAc(15ml)萃取,合并的有机相经Na2SO4干燥,过滤,在减压下浓缩。将所得残余物(313mg)、Na2CO3(498mg,4.70mmol)和氯甲酸苄基酯(295mg,1.729mmol)在水(10ml)和THF(1ml)的溶液中于RT剧烈搅拌3天。混合物用EtOAc稀释,分离水相,用EtOAc萃取(3x15ml)。合并的有机相在减压下浓缩。所得残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到两种非对映异构体:非对映异构体A(112mg,0.25mmol),为无色半固体,MS m/z 453.3(M+H)+,非对映异构体B(45mg,0.010mmol),为白色泡沫,MS m/z 453.3(M+H)+。
步骤d:将非对映异构体A(50mg,0.11mmol)和Pd/C(10wt.%;12mg,0.011mmol)在MeOH(8ml)中的混合物在氢气气氛下剧烈搅拌2小时。加入硅藻土,混合物经硅藻土垫过滤,然后用DCM洗涤。滤液在减压下浓缩,得到(4R)-4-氨基-2-甲基-8-氮杂螺[4.5]癸烷-2-醇,为无色固体,其未经进一步纯化进行使用。MS m/z 185.2(M+H)+。
采用上述操作或上述操作的变通方法,采用非对映异构体B作为原料,合成了相应的立体异构体。
中间体B-31
2-((1S,2S,3R)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-1-基)异二氢吲哚-1,3-二酮
步骤a:向(1R,2S,3R)-2-氟-1-羟基-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(760mg,2.365mmol)在THF(16.5ml)中的溶液中加入三苯膦(744mg,2.85mmol)和DIAD(0.557ml,2.84mmol)。所得混合物于0℃搅拌20分钟,加入叠氮磷酸二苯酯(0.787ml,3.55mmol)。反应混合物温至RT,于该温度搅拌18小时。反应混合物倒入含有EtOAc(30ml)的分液漏斗中,有机相用饱和NH4Cl水溶液和盐水洗涤。合并的有机相经MgSO4干燥,过滤,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至50%梯度的EtOAc/庚烷),得到(1S,2S,3R)-1-叠氮基-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(432mg,1.247mmol).MS m/z 347.2(M+H)+。1H NMR(400MHz,氯仿-d)δppm 7.43-7.31(m,5H),5.15(s,2H),4.48(dt,J=54.4,7.5Hz,1H),3.93(s,2H),3.61(dd,J=16.1,6.9Hz,1H),3.13-2.95(m,2H),2.31-2.13(m,1H),1.96(dd,J=13.1,9.3Hz,1H),1.81-1.64(m,2H),1.47(s,1H),1.32-1.19(m,2H),1.16(d,J=6.7Hz,3H)。
步骤b:将Pd/C(10%wt.,65mg)和(1S,2S,3R)-1-叠氮基-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(423mg,1.221mmol)在EtOH(12.2ml)中的混悬液在H2气氛(气囊)下剧烈搅拌16小时。反应混合物经硅藻土垫过滤,在减压下除去挥发物,得到粗的(1S,2S,3R)-2-氟-3-甲基-8-氮杂螺[4.5]癸烷-1-胺(235mg,0.966mmol),其未经进一步纯化进行使用。MS m/z 317.2(M+H)+。1H NMR(400MHz,氯仿-d)δppm 4.15(dt,J=55.5,8.1Hz,1H),2.95(dt,J=12.5,3.7Hz,2H),2.87(dd,J=16.6,8.0Hz,1H),2.74(tdd,J=12.4,7.3,2.8Hz,2H),2.19-2.02(m,1H),1.95(dd,J=13.4,8.4Hz,1H),1.71-1.48(m,4H),1.34-1.23(m,3H),1.18-1.09(m,4H)。
中间体B-32
外消旋(1S,2S,3S)-1-氨基-8-氮杂螺[4.5]癸烷-2,3-二醇三氟乙酸盐
向外消旋(1S,2S,3S)-1-((叔丁氧基羰基)氨基)-2,3-二羟基-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(21mg,0.054mmol)在DCM(1ml)中的溶液中加入三氟乙酸(0.1ml,1.298mmol),混合物于30℃搅拌30分钟。在减压下除去挥发物,得到粗的外消旋(1S,2S,3S)-1-氨基-8-氮杂螺[4.5]癸烷-2,3-二醇三氟乙酸盐(单对映异构体),为澄清油,其未经进一步纯化直接进行使用。MS m/z187.1(M+H)+。
中间体B-33
(3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺
在N2 atm.下,向在MeOH(200ml)中的(3S,4S)-4-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(9.4g,25.1mmol)中缓慢加入HCl(4M在二噁烷中的溶液,35ml,140mmol)。反应混合物于50℃加热40分钟,在N2气流下继续搅拌18小时。反应混合物在减压下浓缩。残余物用MeOH和MeCN稀释,在减压下浓缩。残余物在超声下用MeCN研制。过滤固体,在高真空中干燥,得到(3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺盐酸盐,为白色粉末。
按照对所述(3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺盐酸盐的操作,以(R)-2-((叔丁基二甲基甲硅烷基)氧基)丙醛为原料和采用(S)-叔丁基亚磺酰胺,制备了(3R,4R)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺盐酸盐。
中间体B-34
(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸烷-1-基)丙烷-2-亚磺酰胺
在冰浴冷却下,向(R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(1g,2.79mmol)在二噁烷(14ml)中的搅拌溶液中缓慢加入硫酸(0.623ml,11.2mmol)。反应混合物于RT搅拌1小时,用NaOH水溶液稀释直至pH=12。混合物用DCM萃取(3x30ml)。合并的有机层通过相分离器以除去残余的水,在减压下浓缩,得到粗的(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸烷-1-基)丙烷-2-亚磺酰胺(642mg),其未经进一步纯化直接进行使用。
中间体B-35
(1R,3R)-3-甲基-8-氮杂螺[4.5]癸烷-1-胺
在氮气atm.下,将(1R,3R)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯(182mg,0.448mmol)和HCl(4M在二噁烷中的溶液,6.7ml)在MeOH(2.5ml)中的混合物于140℃在MW中照射23小时。混合物在减压下浓缩。残余物混悬于Et2O(10ml)中。除去澄清溶液,剩余的固体在减压下干燥,得到粗的(1R,3R)-3-甲基-8-氮杂螺[4.5]癸烷-1-胺盐酸盐(126mg),为灰色乳状固体。
采用上述操作或上述操作的变通方法,采用(1R,3S)-1-((R)-1,1-二甲基乙基亚磺酰氨基)-3-甲基-8-氮杂螺[4.5]癸烷-8-甲酸苄基酯作为原料,合成了(1R,3S)-3-甲基-8-氮杂螺[4.5]癸烷-1-胺二盐酸盐。
中间体B-36
(R)-8-氮杂螺[4.5]癸烷-1-胺
向(1R)-1-(1,1-二甲基乙基亚磺酰氨基)-8-氮杂螺[4.5]癸烷-8-甲酸叔丁基酯(4.66g,13mmol)在MeOH(10ml)中的溶液中加入HCl(4M在二噁烷中的溶液,32.5ml,130mmol)。混合物于50℃搅拌1小时。在减压下除去挥发物,残余物混悬于甲苯(5ml)和Et2O(10ml)中,混合物在减压下浓缩,得到粗的(R)-8-氮杂螺[4.5]癸烷-1-胺盐酸盐,其未经进一步纯化直接进行使用。MS m/z 155.1(M+H)+。
采用上述操作或上述操作的变通方法,采用相应的被保护的胺,合成了表8的如下化合物。
表8
实施例1
(2R,4R)-4-氨基-8-(6-氨基-5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-8-
氮杂螺[4.5]癸烷-2-醇
将(2R,4R)-4-氨基-8-氮杂螺[4.5]癸烷-2-醇盐酸盐(0.305mmol)和3-氯-4-((5-氯吡嗪-2-基)硫基)吡啶-2-胺(92mg,0.336mmol)在DIPEA/NMP(2:1;3ml)中的混合物于100℃剧烈搅拌18小时。冷却至RT后,在减压下除去挥发物,所得残余物经HPLC纯化(梯度洗脱,15-40%MeCN在水中,5mM NH4OH改性剂),得到(2R,4R)-4-氨基-8-(6-氨基-5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-2-醇(55mg,0.135mmol),为白色固体。
实施例2
(R)-8-(5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-
胺
将(R)-8-氮杂螺[4.5]癸烷-1-胺盐酸盐(5.13mmol)和3-氯-4-((5-氯吡嗪-2-基)硫基)吡啶-2-胺(1.00g,3.36mmol)在DIPEA/DMSO(1:1;15ml)中的混合物于105℃剧烈搅拌18小时。冷却至RT后,在减压下除去挥发物,所得残余物在搅拌下用水(~50ml)稀释。滤出固体,用水冲洗,通过硅胶色谱法纯化(5-50%梯度的MeOH/DCM)。级分在减压下浓缩,残余物混悬于MeCN/水中,冷冻干燥,得到(R)-8-(5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺(550mg),为白色固体。
实施例3
(3S,4S)-8-(5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-3-甲基-2-氧杂-8-
氮杂螺[4.5]癸烷-4-胺
将(3S,4S)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺(75mg,0.443mmol)、3-氯-4-((5-氯吡嗪-2-基)硫基)吡啶-2-胺(117mg,0.403mmol)和DIPEA(805μL,4.63mmol)在DMSO(805μL)中的混合物于100℃搅拌18小时。冷却至RT后,在减压下除去挥发物,所得残余物经HPLC纯化(梯度洗脱,25-50%MeCN在水中,5mM NH4OH改性剂),得到(3S,4S)-8-(5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-3-甲基-2-氧杂-8-氮杂螺[4.5]癸烷-4-胺(99mg,0.243mmol)。
实施例4
8-(5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)-3-氧杂-1,8-二氮杂螺[4.5]癸-
1-烯-2-胺
步骤a:将(4-(羟基甲基)哌啶-4-基)氨甲酸叔丁基酯(300mg,1.303mmol)和HCl(4M在二噁烷中的溶液,1.2ml,4.8mmol)在MeOH(2ml)中的溶液于RT搅拌16小时。在减压下除去挥发物,得到(4-氨基哌啶-4-基)甲醇盐酸盐(238mg,1.172mmol),为灰白色固体。1HNMR(400MHz,甲醇-d4)δppm 3.76(s,2H),3.40(s,2H),3.29-3.17(m,2H),2.24-1.91(m,4H)。
步骤b:将2-氯-5-((2,3-二氯吡啶-4-基)硫基)吡嗪(70mg,0.304mmol)、(4-氨基哌啶-4-基)甲醇盐酸盐(103mg,0.336mmol)和DIPEA(1.0ml,5.73mmol)在NMP(2ml)中的溶液于90℃搅拌16小时。冷却至RT后,反应物用EtOAc稀释,分离有机相,用水和盐水洗涤,经Na2SO4干燥,在减压下除去挥发物。所得残余物经硅胶色谱法纯化(0至40%梯度的MeOH/DCM),得到(4-氨基-1-(5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)哌啶-4-基)甲醇(50mg,0.127mmol)。1H NMR(400MHz,DMSO-d6)δppm 8.49(d,J=1.4Hz,1H),8.33(d,J=1.3Hz,1H),8.11(d,J=5.3Hz,1H),6.74(d,J=5.3Hz,1H),4.69(s,1H),4.19-3.98(m,3H),3.54-3.40(m,2H),1.92(s,2H),1.61-1.48(m,2H),1.42-1.29(m,2H).MS m/z 386.1(M+H)+。
步骤c:将(4-氨基-1-(5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)哌啶-4-基)甲醇(48mg,0.124mmol)和NaHCO3(104mg,1.243mmol)在EtOH(3ml)中的溶液加入溴化氰(3M在DCM中的溶液,414μL,1.24mmol)。所得混合物于RT搅拌16小时。反应混合物用EtOAc稀释,用水和盐水洗涤,经MgSO4干燥,过滤,在减压下除去溶剂。所得残余物经HPLC纯化(梯度洗脱,15-40%MeCN在水中,0.1%TFA改性剂),得到8-(5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)-3-氧杂-1,8-二氮杂螺[4.5]癸-1-烯-2-胺,为其三氟乙酸盐(28.4mg,0.044mmol)。
实施例5
(R)-4-((5-(1-氨基-8-氮杂螺[4.5]癸烷-8-基)吡嗪-2-基)硫基)-2-氯烟腈
向2-氯-4-((5-氯吡嗪-2-基)硫基)烟腈(15mg,0.053mmol)在DMSO(1ml)中的溶液中加入2-甲基-N-((R)-8-氮杂螺[4.5]癸烷-1-基)丙烷-2-亚磺酰胺(13.7mg,0.053mmol)和DIPEA(0.018ml,0.106mmol)。所得混合物于100℃搅拌1小时。反应混合物冷却至RT。加入HCl(4M在二噁烷中的溶液,0.106ml,0.424mmol),混合物于RT搅拌1小时。通过HPLC纯化(梯度洗脱,15-40%MeCN在水中,0.1%TFA作为改性剂),得到(R)-4-((5-(1-氨基-8-氮杂螺[4.5]癸烷-8-基)吡嗪-2-基)硫基)-2-氯烟腈,为其三氟乙酸盐(101mg)。
实施例6
4-甲基-1-(5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)哌啶-4-胺
将2-氯-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪(60mg,0.206mmol)和(4-甲基哌啶-4-基)氨甲酸叔丁基酯(70.5mg,0.329mmol)在DIPEA(2ml)和NMP(0.8ml)中的混合物于95℃搅拌24小时。使反应混合物冷却至RT,在减压下除去挥发物。将所得残余物和HCl(4M在二噁烷中的溶液,0.73ml,2.92mmol)在MeOH(2ml)中的溶液于35℃搅拌2小时、于40℃搅拌1小时和于RT搅拌16小时。在减压下除去挥发物,所得残余物经HPLC纯化(梯度洗脱,25-50%MeCN在水中,5mM NH4OH改性剂),得到4-甲基-1-(5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)哌啶-4-胺(54.0mg,0.146mmol)。
实施例7
(R)-5-((5-(1-氨基-8-氮杂螺[4.5]癸烷-8-基)吡嗪-2-基)硫基)-4-氯哒嗪-3-
醇
步骤a:将4-氯-5-((5-氯吡嗪-2-基)硫基)哒嗪-3-醇(25mg,0.091mmol)、(R)-2-甲基-N-((R)-8-氮杂螺[4.5]癸烷-1-基)丙烷-2-亚磺酰胺(23.5mg,0.091mmol)和DIPEA(32μL,0.182mmol)在DMSO(1ml)中的溶液于100℃搅拌1小时。冷却至RT后,在减压下除去挥发物,所得残余物经HPLC纯化(梯度洗脱25-60%MeCN在水中,5mM NH4OH改性剂),得到(R)-N-((R)-8-(5-((5-氯-6-羟基哒嗪-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-基)-2-甲基丙烷-2-亚磺酰胺(12.6mg,0.025mmol).MS m/z 497.1(M+H)+。
步骤b:将(R)-N-((R)-8-(5-((5-氯-6-羟基哒嗪-4-基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-基)-2-甲基丙烷-2-亚磺酰胺(10.6mg,0.021mmol)和HCl(4M在二噁烷中的溶液,27μL,0.107mmol)在DCM(2ml)中的溶液于RT搅拌1小时。在减压下除去挥发物,所得残余物经HPLC纯化(梯度洗脱15-40%MeCN在水中,0.1%TFA改性剂),得到(R)-5-((5-(1-氨基-8-氮杂螺[4.5]癸烷-8-基)吡嗪-2-基)硫基)-4-氯哒嗪-3-醇,为其三氟乙酸盐(3.2mg,0.018mmol)。
实施例8
4-((5-(1,9-二氮杂螺[5.5]十一碳-9-基)吡嗪-2-基)硫基)-3-氯吡啶-2-胺
步骤a:将3-氯-4-((5-氯吡嗪-2-基)硫基)吡啶-2-胺(40mg,0.146mmol)和1,9-二氮杂螺[5.5]十一碳-1-甲酸叔丁基酯(52.7mg,0.161mmol)在DIPEA(0.5ml,2.86mmol)和DMSO(0.5ml)中的混合物于105℃搅拌18小时。冷却至RT后,混合物倒入含有盐水的分液漏斗中,将其用EtOAc萃取(3x5ml)。合并的有机层经Na2SO4干燥,过滤,在减压下浓缩,得到粗的9-(5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-1,9-二氮杂螺[5.5]十一碳-1-甲酸叔丁基酯,其未经进一步纯化直接用于下一步骤。MS m/z 491.3(M+H)+。
步骤b:将粗的9-(5-((2-氨基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-1,9-二氮杂螺[5.5]十一碳-1-甲酸叔丁基酯和HCl(4M在二噁烷中的溶液,3.0ml,12mmol)在MeOH(3ml)中的混合物于RT搅拌30分钟。在减压下除去挥发物,所得残余物经HPLC纯化(梯度洗脱15-40%MeCN在水中,5mM NH4OH改性剂),得到4-((5-(1,9-二氮杂螺[5.5]十一碳-9-基)吡嗪-2-基)硫基)-3-氯吡啶-2-胺(15mg,0.038mmol),为白色固体。
实施例9
4-((5-(4-(氨基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫基)-3-氯苯胺
步骤a:将3-氯-4-((5-氯吡嗪-2-基)硫基)苯胺(0.32g,1.18mmol)、((4-甲基哌啶-4-基)甲基)氨甲酸叔丁基酯(0.54g,2.35mmol)和DIPEA(0.9ml,5.2mmol)在NMP(10ml)中的溶液在油浴中于130℃加热16小时。冷却至RT后,反应混合物用EtOAc稀释(150ml),用水和盐水洗涤,经MgSO4干燥,过滤,在减压下浓缩。残余物溶于含有1%MeOH的DCM(3ml)中,通过硅胶色谱法纯化(20至100%梯度的EtOAc的庚烷溶液),得到((1-(5-((4-氨基-2-氯苯基)硫基)吡嗪-2-基)-4-甲基哌啶-4-基)甲基)氨甲酸叔丁基酯(0.40g,0.86mmol).MS m/z464.2(M+H)+。
步骤b:向((1-(5-((4-氨基-2-氯苯基)硫基)吡嗪-2-基)-4-甲基哌啶-4-基)甲基)氨甲酸叔丁基酯(0.1g,0.22mmol)在DCM(5ml)中的溶液中于RT滴加三氟乙酸(1ml,13mmol)。于RT搅拌2小时后,反应混合物用甲苯稀释两次(5ml),在减压下浓缩至干。残余物溶于MeOH(6ml)中,通过HPLC纯化(梯度洗脱15-40%MeCN在水中,0.1%TFA改性剂),得到4-((5-(4-(氨基甲基)-4-甲基哌啶-1-基)吡嗪-2-基)硫基)-3-氯苯胺,为其三氟乙酸盐(0.08g,0.16mmol)。
采用上述操作或上述操作的变通方法,采用相应的硫代吡嗪(tiopyrazine)衍生物和被保护的胺,制得如表9中定义的如下式I化合物。
表9
实验
评价了本发明的化合物选择性抑制SHP2活性的能力。本文所述的本发明的化合物的抑制性质可以通过在如下任一实验中测试来证明。
SHP2变构抑制实验
SHP2通过双-酪氨酰基-磷酸化肽与其Src Homology 2(SH2)结构域的激活被变构激活。稍后的激活步骤导致释放出SHP2的自身抑制界面,这转而使SHP2蛋白酪氨酸磷酸酶(PTP)活化和可用于底物识别和反应催化。SHP2的催化活性采用替代底物DiFMUP以迅速荧光实验模式进行监测。
更具体而言,磷酸酶反应在平底、低边缘、非结合表面的384-孔黑色聚苯乙烯板(Corning,Cat#3575)中采用25μL的最终反应体积和如下实验缓冲液条件于室温进行:60mMHEPES,pH 7.2,75mM NaCl,75mM KCl,1mM EDTA,0.05%P-20,5mM DTT。
采用如下实验监测了本发明的化合物(浓度为0.003-100μM不等)对SHP2的抑制:其中,将0.5nM SHP2与0.5μM肽IRS1_pY1172(dPEG8)pY1222(序列:H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-酰胺)(SEQ ID NO:1)一起温育。于25℃温育30-60分钟后,将替代底物DiFMUP(Invitrogen,cat#D6567)加入反应物中,于25℃温育30分钟。然后通过添加5μl160μM bpV(Phen)溶液(Enzo Life Sciences cat#ALX-270-204)将反应物淬灭。采用微量板读数器(Envision,Perki-Elmer),采用分别是340nm和450nm的激发波长和发射波长,监测了荧光信号。采用用基于对照的标准化进行了标准化的IC50回归曲线,分析了抑制剂剂量响应曲线。上文的实施例和表9中显示了本发明的化合物的IC50结果。
p-ERK细胞实验
采用SureFireTMPhospho-ERK 1/2试剂盒(PerkinElmer)的p-ERK细胞实验:使KYSE-520细胞(30,000个细胞/孔)在96-孔板培养基中生长过夜,用20、6.6、2.2、0.74、0.24、0.08、0.027μM浓度的Shp2抑制剂于37℃处置2小时。通过加入SureFirephospho-细胞外信号调节激酶(pERK)实验试剂盒(PerkinElmer)所提供的30μL溶解缓冲液(PerkinElmer)使温育终止。按照生产商的指导进行取样。采用2101多标记读数器(PerkinElmer Envision)一式两份测定了来自pERK的荧光信号。通过总ERK信号将抑制百分数进行了标准化,并与DMSO溶媒对照进行了比较。
集落形成实验和细胞增殖实验
将KYSE-520细胞(1500个细胞/孔)铺在24-孔板的300μL培养基(含10%FBS的RPMI-1640,Lonza)中。对于药物处置,在细胞铺板后24小时和5天加入各浓度的本发明的化合物(20、10、5、2.5、1.25μM)。在第11天,将集落用0.2%结晶紫(MP Biomedicals)染色,随后溶于20%乙酸中用于采用Spectramax读数器(Thermo Scientific)进行定量。在细胞增殖实验中,将细胞(1500个细胞/孔)铺在96-孔板的100μL培养基(含10%FBS的RPMI-1640,Lonza)中。在第6天,加入50μL Celltiter-Glo试剂(Promega),按照供应商(Promega)的指示测定发光信号。
可以理解,本文所述的实施例和实施方案仅用于解释说明的目的,并且鉴于其的各种变通和变化将被提示给本领域技术人员并包括在本申请的宗旨和范围以及所附权利要求的范围内。
序列表
<110> 诺华股份有限公司(Novartis AG)
<120> 用于抑制SHP2活性的化合物和组合物
<130> PAT056592-WO-PCT
<160> 1
<170> 专利版本3.5
<210> 1
<211> 21
<212> PRT
<213> 人工序列
<220>
<223> 衍生自胰岛素受体底物-1(IRS-1)的双磷酸化肽
<220>
<221> MOD_RES
<222> (3)..(3)
<223> 磷酸化酪氨酸
<220>
<221> MISC_FEATURE
<222> (10)..(10)
<223> dPEG8
<220>
<221> MOD_RES
<222> (14)..(14)
<223> 磷酸化酪氨酸
<220>
<221> MOD_RES
<222> (21)..(21)
<223> 酰胺化赖氨酸
<400> 1
Leu Asn Xaa Ile Asp Leu Asp Leu Val Xaa Leu Ser Thr Xaa Ala Ser
1 5 10 15
Ile Asn Phe Gln Xaa
20
Claims (14)
1.式I化合物:
其中:
Y1选自N和CR7;其中R7选自氢、卤素和氨基;
Y2选自N和CR8;其中R8选自氢、卤素、C1-4烷基、卤素取代的C1-2烷基、卤素取代的C1-2烷氧基和氨基;
Y3选自N、CR9和C(O);其中R9选自氢、氨基、氰基、卤素、C1-2烷氧基、卤素取代的C1-2烷基、卤素取代的硫烷基、C1-3烷基、环丙基、环丙基-羰基-氨基、C1-2烷基-羰基-氨基、吗啉代基-甲基和羟基;其中如果Y3是C(O),则Y2选自NH和-N-C1-4烷基且含有Y1、Y2和Y3的环具有不多于两条双键;
R1选自氢、卤素、卤素取代的C1-2烷基、卤素取代的C1-2烷氧基、羟基取代的C1-2烷基、C1-4烷基、C1-4烷氧基、氨基和氰基;或者R1和R9与R1和R9所连接的碳原子一起形成环戊烯或1,3-二氧杂环戊烯、2,3-二氢呋喃;
R2选自氢、C1-4烷基和氟;
R4a和R4b各自独立地选自氢、羟基和氟;条件是,R4a和R4b不能均为OH;条件是,R4a和R4b不能同时地是OH和F;
R5a选自氨基和氨基-甲基;
R5b选自OH、氨基、氟、C1-6烷基、甲氧基-羰基、C3-6环烷基-C1-3烷基、羟基取代的C1-3烷基、C1-2烷氧基取代的C1-3烷基和含有1至4个选自O、S和N的杂原子的5-6元杂芳基环;其中R5b的所述C1-6烷基或C1-2烷氧基取代的C1-3烷基是未取代的或被1-3个氟取代;条件是,如果R5a是氨基,则R5b不能是OH、氨基或氟;或者R5a和R5b连同R5a和R5b所连接的碳原子一起形成选自如下的基团:
其中*C表示R5a和R5b所连接的碳原子;R10是氨基;R11a选自氢、羟基、氟、C1-3烷基、卤素取代的C1-2烷基和羟基-甲基;R11b选自氟、甲基和氢;条件是,当R11a是羟基时,R11b不是氟;R11c选自氢、C1-3烷基和羟基-甲基;R12选自氢、卤素、羟基、C1-3烷基、卤素取代的C1-3烷基、卤素取代的C1-3烷氧基和C1-3烷氧基;R13选自氢、卤素和C1-2烷基;条件是,当R12是羟基时,R13不是氟;R14选自氢和氟;R15选自氢和氟;且
R6a和R6b各自独立地选自氢、羟基和氟;条件是,R6a和R6b不能同时均为OH和氟;或其可药用盐;条件是,式I化合物不包括选自如下的化合物:(R)-8-(5-((2-(叔丁基)苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺;(R)-8-(5-((2-(三氟甲基)苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺;
(R)-8-(5-((2-氨基苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺;
(R)-8-(5-((2,3,5,6-四氟苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺;
(R)-8-(5-(吡啶-3-基硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺;
(R)-8-(5-((3-(三氟甲氧基)苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺;
(S)-8-(5-((2-(叔丁基)苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺;和
(S)-8-(5-((4-(叔丁基)苯基)硫基)吡嗪-2-基)-8-氮杂螺[4.5]癸烷-1-胺。
2.权利要求1的化合物,具有式Ia:
其中:
R1选自氢、卤素、卤素取代的C1-2烷基、卤素取代的C1-2烷氧基、C1-4烷基、C1-4烷氧基、氨基和氰基;
R4选自氢、羟基和氟;
R7选自氢、卤素和氨基;
R9选自氢、甲基、甲氧基、乙氧基、羟基、羟基-甲基、三氟-甲基、环丙基、吗啉代基-甲基、氰基、甲基-羰基-氨基、环丙基-羰基-氨基、五氟-λ6-硫烷基、氨基和卤素;或者R1和R9与R1和R9所连接的碳原子一起形成环戊烯;
R10是氨基;
R11a选自氢、氟、甲基、乙基、异丙基、三氟甲基、羟基和羟基-甲基;
R11b选自氟和氢;条件是,当R11a是羟基时,R11b不是氟;
R12选自氢、卤素、羟基、C1-3烷基、卤素取代的C1-3烷基、卤素取代的C1-3烷氧基和C1-3烷氧基;
R13选自氢、氟和C1-2烷基;条件是,当R12是羟基时,R13不是氟;
R14选自氢和氟;
R15选自氢和氟;且
Y2选自N和CR8;其中R8选自氢、卤素、C1-4烷基、卤素取代的C1-2烷基、卤素取代的C1-2烷氧基和氨基;或其可药用盐。
3.权利要求2的化合物,其中:
R1选自氢、溴、氯、氟、甲基、异丙基、叔丁基、氟取代的甲基、甲氧基、三氟-甲基、三氟甲氧基、氨基和氰基;
R4选自氢和羟基;
R7选自氢、氟、氯和氨基;
R9选自氢、甲基、甲氧基、乙氧基、羟基、羟基-甲基、环丙基、氨基、三氟甲基、吗啉代基-甲基、环丙基-羰基-氨基、甲基-羰基-氨基、五氟-λ6-硫烷基、氰基、溴、氯和氟;或者R1和R9与R1和R9所连接的碳原子一起形成环戊烯;
R10是氨基;
R11a选自氢、羟基、甲基和羟基-甲基;
R11b选自氟和氢;条件是,当R11a是羟基时,R11b不是氟;
R12选自氢、氟、羟基、甲基和甲氧基;和
R13选自氢、氟和甲基;条件是,当R12是羟基时,R13不是氟;且
Y2选自CR8和N;其中R8选自氢、氯、氟、乙基、三氟甲基、三氟甲氧基和叔丁基;或其可药用盐。
6.权利要求5的化合物,其中:
R1选自氢、氯、氟、甲基、氟取代的甲基和氰基;
R4选自氢;
R7选自氢、氟、氯和氨基;
R9选自氢、氨基、羟基、三氟甲基、甲基-羰基、羟基-甲基、氯和氟;
R10是氨基;
R11c选自氢、乙基、异丙基、羟基-甲基和甲基;
Y2选自CR8和N;其中R8选自氢、氯、氟、乙基、三氟甲基、三氟甲氧基和叔丁基;或其可药用盐。
9.权利要求1的化合物,具有式Ic:
其中:
Y2选自N和CR8;其中R8选自氢和氨基;
Y3选自N和CR9;其中R9选自氢、甲基、甲氧基、乙氧基、羟基、羟基-甲基、三氟-甲基、环丙基、吗啉代基-甲基、氰基、甲基-羰基-氨基、环丙基-羰基-氨基、五氟-λ6-硫烷基、氨基和卤素;
R1选自卤素、卤素取代的C1-2烷基、C1-2烷基和氰基;
R2是氢;
R4选自氢、羟基和氟;
R5a选自氨基和氨基-甲基;
R5b选自OH、氨基、氟、C1-6烷基、甲氧基-羰基、C3-6环烷基-C1-3烷基、羟基取代的C1-3烷基、C1-2烷氧基取代的C1-3烷基和含有1至4个选自O、S和N的杂原子的5-6元杂芳基环;其中R5b的所述C1-6烷基或C1-2烷氧基取代的C1-3烷基是未取代的或被1-3个氟取代;条件是,如果R5a是氨基,则R5b不能同时地是OH、氨基或氟;
R7选自氢、卤素和氨基;或其可药用盐。
10.权利要求9的化合物,其中:
Y2选自N和CR8;其中R8选自氢和氨基;
Y3选自N和CR9;其中R9选自氢、氨基、卤素和羟基;
R1选自卤素、卤素取代的C1-2烷基和氰基;
R2选自氢和卤素;
R4选自氢和羟基;
R5a选自氨基和氨基-甲基;
R5b选自OH、甲基、乙基、丙基、异丙基、异丁基、氨基、氨基-甲基、甲氧基-羰基、吡啶基和羟基-甲基;条件是,如果R5a是氨基,则R5b不能是OH、氨基或氟;
R7选自氢、卤素和氨基;或其可药用盐。
12.药物组合物,包含权利要求1的化合物或其可药用盐以及至少一种可药用载体。
13.治疗方法,该方法包括以对于预防性或治疗性治疗受SHP2活性所介导的疾病或病症而言有效的量给需要该治疗的人施用权利要求1的化合物或其可药用盐。
14.权利要求13的方法,其中所述受SHP2活性所介导的疾病或病症选自努南综合征、豹斑综合征、幼年型粒-单核细胞白血病、成神经细胞瘤、黑素瘤、急性髓样白血病、乳癌、食管癌、肺癌、结肠癌、头部癌症、成神经细胞瘤、头和颈鳞状细胞癌、胃癌、间变性大细胞淋巴瘤和成胶质细胞瘤。
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US10287266B2 (en) | 2019-05-14 |
US20180186770A1 (en) | 2018-07-05 |
EP3310774A1 (en) | 2018-04-25 |
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