CN111032657B - 用作免疫刺激剂Toll样受体7(TLR7)激动剂的6-氨基-7,9-二氢-8H-嘌呤-8-酮衍生物 - Google Patents
用作免疫刺激剂Toll样受体7(TLR7)激动剂的6-氨基-7,9-二氢-8H-嘌呤-8-酮衍生物 Download PDFInfo
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- 230000002588 toxic effect Effects 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000007056 transamidation reaction Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229950003036 vesatolimod Drugs 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
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- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
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- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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Abstract
本发明涉及具有式(I)结构的化合物,其中R1、R2及R3如本文中所定义,所述化合物为Toll样受体7(TLR7)的激动剂,且可用作用于刺激免疫***的佐剂。一些此类化合物可以结合物形式使用以靶向递送至预期作用的器官或组织。
Description
相关申请案的交叉引用
本申请案根据35U.S.C.§119(e)主张2017年8月16申请的US临时申请案第62/546,095号的权益;该申请案的公开内容以引用的方式并入本文中。
发明背景
本发明涉及Toll样受体7(“TLR7”)激动剂及其结合物,以及此类激动剂及其结合物的制备及使用方法。
Toll样受体(“TLR”)为识别病原体相关分子模式(“PAMP”)的细胞表面受体。TLR由于结合相应PAMP而活化,其发送可能由于病原体造成感染的信号并刺激免疫***以对抗该感染。人类具有11种TLR,称为TLR1至TLR11。
通过激动剂活化TLR(主要研究TLR7)可通过刺激免疫反应而对疫苗及免疫治疗剂在治疗除实际病原体感染外的各种病状中的作用具有辅助作用。
TLR7识别与单股RNA病毒相关的PAMP。其活化诱导诸如IFNα及IFNβ的I型干扰素分泌(Lund等人,2004)。TLR7具有两个结合位点,一个用于诸如ssRNA40的单股RNA配体(等人,2007)且一个用于鸟苷(Zhang等人,2016)。
TLR7可结合至类鸟苷合成激动剂且由其活化,所述激动剂诸如基于1H-咪唑并[4,5-c]喹啉架构的咪喹莫特(imiquimod)、雷西莫特(resiquimod)及嘎德莫特(gardiquimod)。
亦已知基于喋啶酮分子架构的合成TLR7激动剂,例如已处于2期临床试验的威沙立德(vesatolimod)(Desai等人,2015)。据报导,威沙立德的效能比相应的嘌呤-8-酮化合物的效能小100倍,如通过IFN-α诱导所测量(Roethle等人,2013)。
其他合成TLR7激动剂基于通常根据式(A)的类嘌呤架构:
其中R、R'及R”为结构变量,其中R”通常含有未经取代或经取代的芳环或杂芳环。
具有类嘌呤的生物活性分子及其用于治疗诸如纤维化、炎性病症、癌症或致病性感染的病状的用途的公开案包括:Akinbobuyi等人,2015b及2016;Barberis等人,2012;Carson等人,2014;Ding等人,2016、2017a及2017b;Graupe等人,2015;Hashimoto等人,2009;Holldack等人,2012;Isobe等人,2009a及2012;Jin等人,2017a及2017b;Peterson2014;Pryde 2010;及Seifert 2015。
基团R”可为吡啶基:Bonfanti等人,2015a及2015b;Halcomb等人,2015;Hirota等人,2000;Isobe等人,2000、2002、2004、2006、2009a、2011及2012;Kasibhatla等人,2007;Koga-Yamakawa等人,2013;Musmuca等人,2009;Nakamura 2012;Ogita等人,2007;及Yu等人,2013。
Bonfanti等人,2015b公开TLR7调节剂,其中一个巨环跨越嘌呤部分的两个环:
TLR7激动剂可与搭配物分子结合,该搭配物分子可为例如磷脂、聚(乙二醇)(“PEG”)或另一TLR(通常为TLR2)。例示性公开文献包括:Carson等人,2013、2015及2016;Chan等人,2009及2011;Lioux等人,2016;Maj等人,2015;Ban等人,2017;Vernejoul等人,2014;及Zurawski等人,2012。亦已公开与抗体的结合:Akinbobuyi等人,2013及2015a,及Gadd等人,2015。常见结合位点位于式(A)的基团R”处。
亦已公开基于5H-吡咯并[3,2-d]嘧啶架构的TLR7激动剂。参见Cortez等人,2017a及2017b;McGowan等人,2017;及Li等人,2018。
Jensen等人,2015公开阳离子脂质媒剂用于递送TLR7激动剂的用途。
一些TLR7激动剂(包括雷西莫特)为TLR7/TLR8双重激动剂。参见例如Beesu等人,2017;Lioux等人,2016;及Vernejoul等人,2014。
亦已公开基于5H-吡咯并[3,2-d]嘧啶架构的TLR7激动剂。参见Cortez等人,2017a及2017b;McGowan等人,2017;及Li等人,2018。
本文所引用的第一作者或发明者的文献的完整引用及年份列于本说明书末尾。
发明内容
在一个方面中,本说明书提供一种具有式(I)结构的化合物
其中
R1为(C1-C5烷基)O、(C1-C2烷基)O(CH2)2-3O、(C1-C5烷基)C(=O)O、(C1-C5烷基)NH、(C1-C2烷基)O(CH2)2-3NH或(C1-C5烷基)C(=O)NH;
R2在每次出现时独立地为H、C1-C3烷基、卤素、O(C1-C3烷基)、CN或NO2;
R3为H、Me或(CH2)xR4,其中所述下标x为2、3或4;和
R4为H、卤素、OH、CN、NH2、NH(C1-C5烷基)、N(C1-C5烷基)2、NH(C3-C6环烷基)、NH(C4-C8双环烷基)、NH(C6-C10螺环烷基)、N(C3-C6环烷基)2、NH(CH2)1-3(芳基)、N((CH2)1-3(芳基))2,具有以下结构的环胺部分
6元芳族或杂芳族部分或5元杂芳族部分;
其中
烷基、环烷基、双环烷基、螺环烷基、环胺、6元芳族或杂芳族,或5元杂芳族部分任选地取代有一个或多个取代基,所述取代基选自OH、卤素、CN、(C1-C3烷基)、O(C1-C3烷基)、C(=O)(Me)、SO2(C1-C3烷基)、C(=O)(Et)、NH2、NH(Me)、N(Me)2、NH(Et)、N(Et)2和N(C1-C3烷基)2;和
环烷基、双环烷基、螺环烷基,或环胺部分的CH2基团可被O、S、NH、N(C1-C3烷基)或N(Boc)替代。
根据式(I)的化合物具有作为TLR7激动剂的活性,且随后其中一些可经结合以靶向递送至预期作用的标靶组织或器官。因此,它们可用于治疗通过免疫***激活而适合治疗的病况。
附图简述
图1示出制备本公开化合物的代表性流程。
图2和图3示出用于制备激动剂-连接子化合物的流程。
图4为示出本发明化合物的TLR7激动作用活性的代表性曲线图。
发明详述
定义
“抗体”是指完整抗体及其任何抗原结合片段(亦即“抗原结合部分”)或单链变体。完整抗体为包含由二硫键相互连接的至少两条重(H)链及两条轻(L)链的蛋白质。各重链包含重链可变区(VH)及包含三个域CH1、CH2及CH3的重链恒定区。各轻链包含轻链可变区(VL或Vk)及包含单一域CL的轻链恒定区。VH及VL区可进一步再分成高变区,称为互补决定区(CDR),穿插有较保守框架区(FR)。各VH及VL包含三个CDR及四个FR,其自氨基至羧基端以如下次序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3及FR4。可变区含有与抗原相互作用的结合域。恒定区可介导抗体与宿主组织或因子的结合,包括免疫***的各种细胞(例如效应细胞)及经典补体***的第一组分(Clq)。抗体在抗体以5×10-8M或更小、更优选1×10-8M或更小、更优选6×10-9M或更小、更优选3×10-9M或更小、甚至更优选2×10-9M或更小的KD结合于抗原X时称为“特异性结合”于抗原X。抗体可为嵌合、人类化或优选人类抗体。重链恒定区可经工程改造以影响糖基化类型或程度,延长抗体半衰期,增强或减少与效应细胞或补体***的相互作用,或调节一些其他特性。工程改造可通过置换、添加或删除一或多个氨基酸或通过用来自另一免疫球蛋白类型的域置换域或前述方法的组合来完成。
抗体的“抗原结合片段”及“抗原结合部分”(或简单地“抗体部分”或“抗体片段”)是指抗体的保留特异性结合于抗原的能力的一或多个片段。已证实抗体的抗原结合功能可通过全长抗体的片段执行,所述片段诸如(i)Fab片段,其为由VL、VH、CL及CH1域组成的单价片段;(ii)F(ab')2片段,其为包含由铰链区处的二硫桥键连接的两个Fab片段的二价片段;(iii)Fab'片段,其基本上为具有铰链区部分的Fab(参见例如Abbas等人,Cellular andMolecular Immunology,第6版,Saunders Elsevier 2007);(iv)Fd片段,其由VH及CH1域组成;(v)Fv片段,其由抗体的单臂的VL及VH域组成;(vi)dAb片段(Ward等人,(1989)Nature341:544-546),其由VH域组成;(vii)经分离的互补决定区(CDR);以及(viii)纳米抗体,其为含有单一可变域及两个恒定域的重链可变区。优选抗原结合片段为Fab、F(ab')2、Fab'、Fv及Fd片段。此外,尽管Fv片段的两个域VL及VH由不同基因编码,但所述域可使用重组方法通过合成连接子接合,该合成连接子使得所述域能够形成为其中VL区与VH区配对形成单价分子的单一蛋白质链(称为单链Fv或scFv);参见例如Bird等人(1988)Science242:423-426;及Huston等人(1988)Proc.Natl.Acad.Sci.USA 85:5879-5883)。此类单链抗体亦涵盖于术语抗体的“抗原结合部分”内。
除非另外规定,否则根据Kabat***(Kabat等人,“Sequences of proteins ofimmunological interest”,第5版,公开文献第91-3242号,美国卫生与公众服务部(U.S.Dept.Health&Human Services),NIH,Bethesda,Md.,1991,以下简称“Kabat”)提及抗体重链或轻链可变区(VH或VL)中氨基酸位置的编号(例如提及SEQ ID NO:清单中的直链编号),且根据如Kabat中所列的EU索引提及抗体重链或轻链恒定区(CH1、CH2、CH3或CL)中氨基酸位置的编号。参见Lazar等人的US 2008/0248028A1,该文献的例如此类使用的公开内容以引用的方式并入本文中。此外,免疫遗传学信息***(ImMunoGeneTics InformationSystem;IMGT)在其网站提供了名称为“IMGT Scientific Chart:Correspondence betweenC Numberings”的表,其展示其用于重链恒定区的编号***、EU编号及Kabat编号之间的对应关系。
“经分离抗体”是指实质上不含具有不同抗原特异性的其他抗体的抗体(例如特异性结合抗原X的经分离抗体实质上不含特异性结合除抗原X以外的抗原的抗体)。然而,特异性结合抗原X的经分离抗体可与诸如来自其他物种的抗原X分子的其他抗原具有交叉反应性。在某些实施方案中,经分离抗体特异性结合于人类抗原X且不与其他(非人类)抗原X抗原交叉反应。此外,经分离抗体可实质上不含其他细胞物质及/或化学物质。
“单克隆抗体”或“单克隆抗体组合物”是指具有单一分子组成的抗体分子的制剂,其对特定抗原决定基展现单一结合特异性及亲和力。
“人类抗体”是指具有如下可变区的抗体,其中框架区与CDR区(及恒定区(若存在))均衍生自人类生殖系免疫球蛋白序列。人类抗体可包括后续修饰,包括天然或合成修饰。人类抗体可包括并非由人类生殖系免疫球蛋白序列编码的氨基酸残基(例如,通过活体外随机或定点突变诱发或通过活体内体细胞突变引入的突变)。然而,“人类抗体”不包括源自另一哺乳动物物种(诸如小鼠)的生殖系的CDR序列已经移植至人类构架序列上的抗体。
“人类单克隆抗体”是指呈现单一结合特异性的抗体,其具有如下可变区,其中框架区与CDR区均衍生自人类生殖系免疫球蛋白序列。在一个实施方案中,人类单克隆抗体由杂交瘤产生,该杂交瘤包括与永生化细胞融合的获自转基因非人类动物(例如转基因小鼠)的B细胞,该转基因非人类动物具有包含人类重链转基因及轻链转基因的基因组。
脂族基”是指直链或支链、饱和或不饱和的非芳香族烃部分,其具有指定数目个碳原子(例如,如在“C3脂族基”、“C1-5脂族基”、“C1-C5脂族基”或“C1至C5脂族基”中,后面三个词组为具有1至5个碳原子的脂族部分的同义词),或在未明确指定碳原子数目时具有1至4个碳原子(在不饱和脂族部分的实例中具有2至4个碳原子)。类似理解适用于其他类型中的碳数目,如在C2-4烯烃、C4-C7环脂族基等中。以类似方式,诸如“(CH2)1-3”的术语应理解为下标为1、2或3的简写,因而此类术语表示CH2、CH2CH2及CH2CH2CH2。
“烷基”是指饱和脂族部分,其中指定碳原子数的相同惯例适用。以说明的方式,C1-C4烷基部分包括(但不限于)甲基、乙基、丙基、异丙基、异丁基、叔丁基、1-丁基、2-丁基等。“亚烷基”是指烷基的二价对应物,诸如CH2CH2、CH2CH2CH2及CH2CH2CH2CH2。
“烯基”是指具有至少一个碳-碳双键的脂族部分,其中指定碳原子数的相同惯例适用。以说明的方式,C2-C4烯基部分包括(但不限于)乙烯基(ethenyl/vinyl)、2-丙烯基(烯丙基或丙-2-烯基)、顺-1-丙烯基、反-1-丙烯基、E-(或Z-)2-丁烯基、3-丁烯基、1,3-丁二烯基(丁-1,3-二烯基)等。
“炔基”是指具有至少一个碳-碳叁键的脂族部分,其中指定碳原子数的相同惯例适用。以说明的方式,C2-C4炔基包括乙炔基(ethynyl/acetylenyl)、炔丙基(丙-2-炔基)、1-丙炔基、丁-2-炔基等。
“环脂族基”是指具有1至3个环的饱和或不饱和、非芳香族烃部分,各环具有3至8个(优选3至6个)碳原子。“环烷基”是指其中各环饱和的环脂族部分。“环烯基”是指其中至少一个环具有至少一个碳-碳双键的环脂族部分。“环炔基”是指其中至少一个环具有至少一个碳-碳叁键的环脂族部分。以说明的方式,环脂族部分包括(但不限于)环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环辛基及金刚烷基。优选环脂族部分为环烷基部分,尤其环丙基、环丁基、环戊基及环己基。“亚环烷基”是指环烷基的二价对应物。
“杂环脂族基”是指如下环脂族部分,其中在其至少一个环中,至多三个(优选1至2个)碳经独立地选自N、O或S的杂原子置换,其中N及S可任选经氧化且N可任选经季铵化。优选环脂族部分由大小为5元至6元的一个环组成。类似地,“杂环烷基”、“杂环烯基”及“杂环炔基”分别是指环烷基、环烯基或环炔基部分,其中其至少一个环经如此修饰。例示性杂环脂族部分包括氮丙啶基、氮杂环丁烷基、1,3-二氧杂环己烷基、氧杂环丁烷基、四氢呋喃基、吡咯烷基、哌啶基、哌嗪基、四氢吡喃基、四氢硫吡喃基、四氢硫吡喃基砜、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜、1,3-二氧戊环基、四氢-1,1-二氧代基噻吩基、1,4-二氧杂环己烷基、硫杂环丁烷基等。“亚杂环烷基”是指杂环烷基的二价对应物。
“烷氧基”、“芳基氧基”、“烷基硫基”及“芳基硫基”分别是指-O(烷基)、-O(芳基)、-S(烷基)及-S(芳基)。实例分别为甲氧基、苯氧基、甲基硫基及苯基硫基。
除非指示较窄含义,否则“卤素”或“卤基”是指氟、氯、溴或碘。
“芳基”是指具有单环、双环或三环环***(优选单环)的烃部分,其中各环具有3至7个碳原子且至少一个环为芳香族。环***中的环可彼此稠合(如在萘基中)或彼此键结(如在联苯中)且可与非芳香族环稠合或键结(如在茚满基或环己基苯基中)。以进一步说明的方式,芳基部分包括(但不限于)苯基、萘基、四氢萘基、茚满基、联苯、菲基、蒽基及苊基。“亚芳基”是指芳基的二价对应物,例如1,2-亚苯基、1,3-亚苯基或1,4-亚苯基。
“杂芳基”是指具有单环、双环或三环环***(优选5元至7元单环)的部分,其中各环具有3至7个碳原子,且至少一个环为含有1至4个独立地选自N、O或S的杂原子的芳环,其中N及S可任选经氧化且N可任选经季铵化。此类至少一个含杂原子芳环可与其他类型的环稠合(如在苯并呋喃基或四氢异喹啉基中)或与其他类型的环直接键结(如在苯基吡啶基或2-环戊基吡啶基中)。以进一步说明的方式,杂芳基部分包括吡咯基、呋喃基、噻吩基(thiophenyl或thienyl)、咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、***基、四唑基、吡啶基、N-氧代基吡啶基、哒嗪基、嘧啶基、吡嗪基、喹啉基、异喹啉炔基、喹唑啉基、噌啉基、喹噁啉基、萘啶基、苯并呋喃基、吲哚基、苯并噻吩基、噁二唑基、噻二唑基、苯并噻唑基、苯并咪唑基、苯并***基、二苯并呋喃基、咔唑基、二苯并噻吩基、吖啶基等。“亚杂芳基”是指杂芳基的二价对应物。
若所指示部分可经取代,诸如如在“未经取代或经取代的C1-C5烷基”或“任选经取代的杂芳基”中通过使用“未经取代或经取代”或“任选经取代”措辞,则此类部分可具有一或多个独立选择的取代基,优选数目为一至五个,更优选数目为一个或两个。取代基及取代模式可由本领域普通技术人员考虑取代基所连接的部分而选择,以提供化学上稳定且可通过本领域中已知的技术以及本文所阐述的方法合成的化合物。若一个部分认定为“未经取代或经取代”或“任选经取代”,则在一个优选实施方案中,此类部分未经取代。
“芳基烷基”、“(杂环脂族基)烷基”、“芳基烯基”、“芳基炔基”、“联芳基烷基”等是指烷基、烯基或炔基部分,任选可经芳基、杂环脂族基、联芳基等部分取代,任选可在烷基、烯基或炔基部分上具有开放(不饱和)价态,例如如在苯甲基、苯乙基、N-咪唑基乙基、N-吗啉基乙基等中。相反地,“烷基芳基”、“烯基环烷基”等是指芳基、环烷基等部分,任选可经烷基、烯基等部分取代,任选可例如如在甲基苯基(甲苯基)或烯丙基环己基中。“羟烷基”、“卤烷基”、“烷基芳基”、“氰基芳基”等是指烷基、芳基等部分,任选可经一或多个所述取代基(任选可为羟基、卤基等)取代。
举例而言,可容许的取代基包括(但不限于)烷基(尤其甲基或乙基)、烯基(尤其烯丙基)、炔基、芳基、杂芳基、环脂族基、杂环脂族基、卤基(尤其氟基)、卤烷基(尤其三氟甲基)、羟基、羟烷基(尤其羟乙基)、氰基、硝基、烷氧基、-O(羟烷基)、-O(卤烷基)(尤其-OCF3)、-O(环烷基)、-O(杂环烷基)、-O(芳基)、烷基硫基、芳基硫基、=O、=NH、=N(烷基)、=NOH、=NO(烷基)、-C(=O)(烷基)、-C(=O)H、-CO2H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羟烷基)、-C(=O)NH2、-C(=O)NH(烷基)、-C(=O)N(烷基)2、-OC(=O)(烷基)、-OC(=O)(羟烷基)、-OC(=O)O(烷基)、-OC(=O)O(羟烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、叠氮基、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NH(羟烷基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2、-NHC(=NH)NH2、-OSO2(烷基)、-SH、-S(烷基)、-S(芳基)、-S(环烷基)、-S(=O)烷基、-SO2(烷基)、-SO2NH2、-SO2NH(烷基)、-SO2N(烷基)2等。
若经取代的部分为脂族部分,则优选取代基为芳基、杂芳基、环脂族基、杂环脂族基、卤基、羟基、氰基、硝基、烷氧基、-O(羟烷基)、-O(卤烷基)、-O(环烷基)、-O(杂环烷基)、-O(芳基)、烷基硫基、芳基硫基、=O、=NH、=N(烷基)、=NOH、=NO(烷基)、-CO2H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羟烷基)、-C(=O)NH2、-C(=O)NH(烷基)、-C(=O)N(烷基)2、-OC(=O)(烷基)、-OC(=O)(羟烷基)、-OC(=O)O(烷基)、-OC(=O)O(羟烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、叠氮基、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NH(羟烷基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2、-NHC(=NH)NH2、-OSO2(烷基)、-SH、-S(烷基)、-S(芳基)、-S(=O)烷基、-S(环烷基)、-SO2(烷基)、-SO2NH2、-SO2NH(烷基)及-SO2N(烷基)2。更优选取代基为卤基、羟基、氰基、硝基、烷氧基、-O(芳基)、=O、=NOH、=NO(烷基)、-OC(=O)(烷基)、-OC(=O)O(烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、叠氮基、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2及-NHC(=NH)NH2。尤其优选的为苯基、氰基、卤基、羟基、硝基、C1-C4烷氧基、O(C2-C4亚烷基)OH及O(C2-C4亚烷基)卤基。
若经取代的部分为环脂族、杂环脂族、芳基或杂芳基部分,则优选取代基为烷基、烯基、炔基、卤基、卤烷基、羟基、羟烷基、氰基、硝基、烷氧基、-O(羟烷基)、-O(卤烷基)、-O(芳基)、-O(环烷基)、-O(杂环烷基)、烷基硫基、芳基硫基、-C(=O)(烷基)、-C(=O)H、-CO2H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羟烷基)、-C(=O)NH2、-C(=O)NH(烷基)、-C(=O)N(烷基)2、-OC(=O)(烷基)、-OC(=O)(羟烷基)、-OC(=O)O(烷基)、-OC(=O)O(羟烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、叠氮基、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NH(羟烷基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2、-NHC(=NH)NH2、-OSO2(烷基)、-SH、-S(烷基)、-S(芳基)、-S(环烷基)、-S(=O)烷基、-SO2(烷基)、-SO2NH2、-SO2NH(烷基)及-SO2N(烷基)2。更优选取代基为烷基、烯基、卤基、卤烷基、羟基、羟烷基、氰基、硝基、烷氧基、-O(羟烷基)、-C(=O)(烷基)、-C(=O)H、-CO2H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羟烷基)、-C(=O)NH2、-C(=O)NH(烷基)、-C(=O)N(烷基)2、-OC(=O)(烷基)、-OC(=O)(羟烷基)、-OC(=O)O(烷基)、-OC(=O)O(羟烷基)、-OC(=O)NH2、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2、-NH2、-NH(烷基)、-N(烷基)2、-NH(芳基)、-NHC(=O)(烷基)、-NHC(=O)H、-NHC(=O)NH2、-NHC(=O)NH(烷基)、-NHC(=O)N(烷基)2及-NHC(=NH)NH2。尤其优选的为C1-C4烷基、氰基、硝基、卤基及C1-C4烷氧基。
若陈述一范围,如同“C1-C5烷基”或“5至10%”,则此类范围包括范围的端点,如同第一个实例中的C1及C5及第二个实例中的5%及10%。
除非特别指示特定立体异构体(例如通过结构式中相关立构中心的加粗或短划键,通过将结构式中的双键描述为具有E或Z构型或通过使用指明立体化学的命名法),否则所有立体异构体均以纯化合物以及其混合物的形式包括在本发明的范畴内。除非另外指明,否则个别对映异构体、非对映异构体、几何异构体及其组合及混合物均由本发明涵盖。
本领域技术人员将了解化合物可具有互变异构形式(例如酮及烯醇形式)、共振形式及两性离子形式,其等效于本文所用的结构式中所描绘的形式,且所述结构式涵盖此类互变异构、共振或两性离子形式。
“药学上可接受的酯”是指活体内(例如在人体中)水解产生母化合物或其盐或自身活性类似于母化合物的酯。适合酯包括C1-C5烷酯、C2-C5烯酯或C2-C5炔酯,尤其甲酯、乙酯或正丙酯。
“药学上可接受的盐”是指适用于医药调配物的化合物的盐。若化合物具有一或多个碱性基团,则盐可为酸加成盐,诸如硫酸盐、氢溴酸盐、酒石酸盐、甲磺酸盐、马来酸盐、柠檬酸盐、磷酸盐、乙酸盐、双羟萘酸盐(恩波酸盐(embonate))、氢碘酸盐、硝酸盐、盐酸盐、乳酸盐、甲基硫酸盐、富马酸盐、苯甲酸盐、琥珀酸盐、甲磺酸盐、乳糖酸盐、辛二酸盐、甲苯磺酸盐等。若化合物具有一或多个酸性基团,则盐可为如下盐,诸如钙盐、钾盐、镁盐、葡甲胺盐、铵盐、锌盐、哌嗪盐、氨丁三醇盐、锂盐、胆碱盐、二乙胺盐、4-苯基环己胺盐、苄星青霉素(benzathine)盐、钠盐、四甲铵盐等。多晶型结晶形式及溶剂合物亦涵盖在本发明的范畴内。
在本说明书的式中,横向于键的波浪线或键末尾的星号(*)表示共价连接位点。举例而言,对式/>中R为/>或R为/>的陈述是指/>
在本说明书的所述式中,穿过芳环在其两个碳之间的键是指连接至该键的基团可位于该芳环中通过移除隐含存在的氢而变得可用的任何位置处。以说明的方式,式表示/> 在另一说明中,/>表示/>
一般而言,出于一致性及便利性,在本文中以烯醇形式呈现互变异构结构。
本领域技术人员将了解,所述互变异构结构亦可以等效酮形式呈现,且两种互变异构体等效。
化合物
式(I)中的R1优选地为n-BuO、n-BuNH、EtO、MeO或MeOCH2CH2O;更优选地为n-BuO或MeOCH2CH2O;且最优选地为n-BuO。
式(I)的(CH2)xR4的下标x优选地为2。
在式(I)和(Ia)中,R4优选地为OH、Cl、
以下示出基团R4的适合的实例,其包括双环烷基和和螺环烷基:
在一个实施方案中,根据式I所述的化合物表示为式(Ia),其中R1为n-BuO或MeOCH2CH2O,优选地为n-BuO:
根据式(Ia)所述的化合物的实例包括:
表A呈现本文中所公开的化合物的生物活性数据。一组数据涉及使用HEK-BlueTMTLR7报导分析的TLR7激动作用活性,如下文中所描述。另一组数据涉及白介素6(IL-6)的诱导,白介素6是在TLR7路径中起重要作用的细胞介素。出于比较,亦呈现雷西莫特、威沙立德、嘎德莫特及化合物B(CAS登记号226906-84-9)的活性。
结合物
综述
本文中所公开的TLR7激动剂可通过局部投与或通过以与靶向部分的结合物形式靶向递送而递送至预期作用位点。优选地,靶向部分为抗体或其抗原结合部分,且其抗原位于预期作用位置,例如若预期作用位点位于肿瘤(癌症)则其抗原为肿瘤相关抗原。优选地,相比于正常细胞,癌细胞唯一表达或过度表达肿瘤相关抗原。肿瘤相关抗原可位于癌细胞表面上或由癌细胞分泌至其环境中。
在一个方面中,提供一种包含本发明化合物及配体的结合物,其由式(II)表示
[D(XD)a(C)c(XZ)b]mZ (II)
其中Z为靶向部分,D为本发明的激动剂,且-(XD)aC(XZ)b-由于连接Z与D而统称为“连接部分”或“连接子”。在连接子内,C为经设计以在D的预期生物学作用位点处或附近裂解的可裂解基团;XD及XZ分别为间隔开D与C及C与Z的间隔部分(或“间隔基”);下标a、b及c独立地为0或1(亦即,XD、XZ及C任选存在)。下标m为1、2、3、4、5、6、7、8、9或10(优选1、2、3或4)。D、XD、C、XZ及Z更充分描述于下文中。
通过结合于安置有其抗原或受体的标靶组织或细胞,Z将结合物引导至此处。基团C在标靶组织或细胞处的裂解释放D,从而局部地发挥其效应。以此方式,达成D在预期作用位点的精确递送,从而降低所需剂量。另外,D在处于其结合状态时通常没有生物活性(或活性明显更低),从而减少脱靶效应。
如由下标m所反映,视可供用于结合的位点Z的数目及所用实验条件而定,各Z可与多于一个D结合。本领域技术人员将了解,虽然各个别Z与整数数目个D结合,但是结合物的制备可分析D与Z的非整数比率,其反映统计平均值。此比率称为取代比率(“SR”)或药物-抗体比率(“DAR”)。
靶向部分Z
优选地,靶向部分Z为抗体。为方便及简洁起见且以非限制方式,本说明书中关于Z及其结合物的详细论述以其为抗体的情形书写,但本领域技术人员将理解,其他类型的Z亦可在细节上作必要修改后结合。举例而言,带有作为靶向部分的叶酸的结合物可靶向表面上具有叶酸受体的标靶细胞(Leamon等人,Cancer Res.2008,68(23),9839)。出于相同原因,本说明书中的详细论述主要关于1:1比率的Z与D(m=1)书写。
可用于本发明结合物中的抗体包括识别以下抗原的抗体:间皮素、***特异性膜抗原(PSMA)、CD19、CD22、CD30、CD70、B7H3、B7H4(亦称为O8E)、蛋白质酪氨酸激酶7(PTK7)、磷脂酰肌醇蛋白聚糖-3、RG1、岩藻糖基-GM1、CTLA-4及CD44。抗体可为动物(例如鼠类)、嵌合、人类化或优选人类抗体。抗体优选为单克隆抗体,尤其单克隆人类抗体。针对前述抗原中的一些的人类单克隆抗体的制备公开于以下文献中:Korman等人,US 8,609,816B2(2013;B7H4,亦称为08E;特别是抗体2A7、1G11及2F9);Rao-Naik等人,8,097,703 B2(2012;CD19;特别是抗体5G7、13F1、46E8、21D4、21D4a、47G4、27F3及3C10);King等人,US 8,481,683 B2(2013;CD22;特别是抗体12C5、19A3、16F7及23C6);Keler等人,US 7,387,776B2(2008;CD30;特别是抗体5F11、2H9及17G1);Terrett等人,US 8,124,738 B2(2012;CD70;特别是抗体2H5、10B4、8B5、18E7及69A7);Korman等人,US 6,984,720 B1(2006;CTLA-4;特别是抗体10D1、4B6及1E2);Korman等人,US 8,008,449 B2(2011;PD-1;特别是抗体17D8、2D3、4H1、5C4、4A11、7D3及5F4);Huang等人,US 2009/0297438 A1(2009;PSMA;特别是抗体1C3、2A10、2F5、2C6);Cardarelli等人,US 7,875,278 B2(2011;PSMA;特别是抗体4A3、7F12、8C12、8A11、16F9、2A10、2C6、2F5及1C3);Terrett等人,US 8,222,375 B2(2012;PTK7;特别是抗体3G8、4D5、12C6、12C6a及7C8);Harkins等人,US 7,335,748 B2(2008;RG1;特别是抗体A、B、C及D);Terrett等人,US 8,268,970 B2(2012;间皮素;特别是抗体3C10、6A4及7B1);Xu等人,US 2010/0092484 A1(2010;CD44;特别是抗体14G9.B8.B4、2D1.A3.D12及1A9.A6.B9);Deshpande等人,US 8,258,266 B2(2012;IP10;特别是抗体1D4、1E1、2G1、3C4、6A5、6A8、7C10、8F6、10A12、10A12S及13C4);Kuhne等人,US 8,450,464 B2(2013;CXCR4;特别是抗体F7、F9、D1及E2);以及Korman等人,US 7,943,743 B2(2011;PD-L1;特别是抗体3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7及13G4);所述文献的公开内容以引用的方式并入本文中。优选地,抗体为抗间皮素抗体。
除为抗体外,Z亦可为抗体片段(诸如Fab、Fab'、F(ab')2、Fd或Fv)或抗体模拟物,诸如亲和抗体(affibody)、单域抗体(dAb)、纳米抗体、单抗体、DARPin、抗运载蛋白(anticalin)、万能抗体(versabody)、双运载蛋白(duocalin)、脂质运载蛋白(lipocalin)或高亲和性多聚体(avimer)。
Z上若干不同反应性基团中的任一者可为结合位点,包括赖氨酸残基中的ε-氨基、侧链碳水化合物部分、天冬氨酸或谷氨酸侧链上的羧酸基、半胱氨酸-半胱氨酸二硫基及半胱氨酸硫醇基。适用于结合的抗体反应性基团的论述参见例如Garnett,Adv.DrugDelivery Rev.2001,53,171-216以及Dubowchik及Walker,Pharmacology&Therapeutics1999,83,67-123,其公开内容以引用的方式并入本文中。
大部分抗体具有多个赖氨酸残基,所述残基可经由其ε-氨基通过酰胺、脲、硫脲或氨基甲酸酯键而结合。
可通过若干方法使用半胱氨酸的侧链中的硫醇(-SH)基来形成结合物。该硫醇基可用于在其与连接子上的硫醇基之间形成双硫键。另一方法系经由与连接子上的马来酰亚氨基的迈克尔加成(Michael addition)反应。
通常,尽管抗体具有半胱氨酸残基,但其没有游离的硫醇基,因为其所有半胱氨酸都形成了链内或链间二硫键。为了产生游离的硫醇基,可减少天然二硫基。参见例如Packard等人,Biochemistry 1986,25,3548;King等人,Cancer Res.1994,54,6176;及Doronina等人,Nature Biotechnol.2003,21,778。可替代地,可通过使抗体突变、用半胱氨酸取代另一氨基酸或将半胱氨酸***多肽链中而引入具有游离-SH基团的半胱氨酸。参见例如Eigenbrot等人,US 7,521,541 B2(2009);Chilkoti等人,Bioconjugate Chem.1994,5,504;Urnovitz等人,US 4,698,420(1987);Stimmel等人,J.Biol.Chem.2000,275,30445;Bam等人,US 7,311,902 B2(2007);Kuan等人,J.Biol.Chem.1994,269,7610;Poon等人,J.Biol.Chem.1995,270,8571;Junutula等人,Nature Biotechnology 2008,26,925;及Rajpal等人2015年12月21日申请的US临时申请案第62/270245号。在另一方法中,将半胱氨酸添加至重链或轻链的C端。参见例如Liu等人,US 8,865,875 B2(2014);Cumber等人,J.Immunol.1992,149,120;King等人,Cancer Res.1994,54,6176;Li等人,BioconjugateChem.2002,13,985;Yang等人,Protein Engineering 2003,16,761;及Olafson等人,Protein Engineering Design&Selection 2004,17,21。此段落中引用的文献的公开内容以引用的方式并入本文中。
连接子及其组分
如上文所提及,连接子包含多达三个组件:可裂解基团C及任选存在的间隔基XZ及XD。
基团C在生理条件下可裂解。优选地,基团C在结合物处于血液循环中时相对稳定,但在结合物到达其预期作用位点后容易裂解。
优选基团C为肽,其并非由血清中的蛋白酶裂解,而是由标靶细胞内的蛋白酶选择性裂解。通常,肽包含1至20个氨基酸,优选1至6个氨基酸,更优选2至3个氨基酸。氨基酸可为天然及/或非天然α-氨基酸。天然氨基酸为由遗传密码编码的氨基酸以及衍生自其的氨基酸,例如羟基脯氨酸、γ-羧基谷氨酸、瓜氨酸及O-磷丝氨酸。在本说明书中,术语“氨基酸”亦包括氨基酸类似物及模拟物。类似物为如下化合物,其具有天然氨基酸的相同通用H2N(R)CHCO2H结构,但R基团不为天然氨基酸中存在的基团。类似物的实例包括高丝氨酸、正亮氨酸、甲硫氨酸-亚砜及甲硫氨酸甲基锍。氨基酸模拟物为如下化合物,其具有不同于α-氨基酸的通用化学结构的结构,但以类似于α-氨基酸的方式起作用。氨基酸可具有遗传编码氨基酸的“L”立体化学以及对映异构“D”立体化学。
优选地,C含有作为蛋白酶的裂解识别序列的氨基酸序列。许多裂解识别序列为本领域中已知的。参见例如Matayoshi等人,Science 247:954(1990);Dunn等人,Meth.Enzymol.241:254(1994);Seidah等人,Meth.Enzymol.244:175(1994);Thornberry,Meth.Enzymol.244:615(1994);Weber等人,Meth.Enzymol.244:595(1994);Smith等人,Meth.Enzymol.244:412(1994);及Bouvier等人,Meth.Enzymol.248:614(1995);其公开内容以引用的方式并入本文中。
基团C可经选择以使得其由癌症附近的细胞外基质中所存在的蛋白酶裂解,该蛋白酶例如附近死亡癌细胞所释放的蛋白酶或癌细胞所分泌的肿瘤相关蛋白酶。例示性细胞外肿瘤相关蛋白酶为纤维蛋白溶酶、基质金属蛋白酶(MMP)、甲拌磷寡肽酶(TOP)及CD10。参见例如Trouet等人,US 7,402,556 B2(2008);Dubois等人,US 7,425,541 B2(2008);及Bebbington等人,US 6,897,034 B2(2005)。通常作为存在于细胞内部的溶酶体酶的组织蛋白酶D有时存在于肿瘤环境中,有可能由死亡癌细胞所释放。
对于经设计以通过酶裂解的结合物而言,C优选包含经选择以通过诸如组织蛋白酶B、C、D、H、L及S(尤其组织蛋白酶B)的蛋白酶裂解的氨基酸序列。例示性组织蛋白酶B可裂解肽包括Val-Ala、Val-Cit、Val-Lys、Lys-Val-Ala、Asp-Val-Ala、Val-Ala、Lys-Val-Cit、Ala-Val-Cit、Val-Gly、Val-Gln及Asp-Val-Cit。(在本文中,除非上下文明确指示,否则氨基酸序列以N至C方向书写,如同H2N-AA2-AA1-CO2H。)参见Dubowchik等人,Biorg.Med.Chem.Lett.1998,8,3341;Dubowchik等人,Bioorg.Med.Chem.Lett.1998,8,3347;及Dubowchik等人,Bioconjugate Chem.2002,13,855;其公开内容以引用的方式并入。
可用于裂解肽基连接子的另一酶为豆荚蛋白,一种优选在Ala-Ala-Asn处裂解的溶酶体半胱氨酸蛋白酶。
在一个实施方案中,基团C为包含两个氨基酸序列-AA2-AA1-的肽,其中AA1为赖氨酸、精氨酸或瓜氨酸,且AA2为苯丙氨酸、缬氨酸、丙氨酸、亮氨酸或异亮氨酸。在另一个实施方案中,C由具有一至三个氨基酸的序列组成,其选自由以下组成的群:Val-Cit、Ala-Val、Val-Ala-Val、Lys-Lys、Ala-Asn-Val、Val-Leu-Lys、Cit-Cit、Val-Lys、Ala-Ala-Asn、Lys、Cit、Ser及Glu。更优选地,C为前述群中的两个至三个氨基酸肽。
由单个氨基酸组成的可裂解基团C的制备及设计公开于Chen等人,US 8,664,407B2(2014)中,其公开内容以引用的方式并入本文中。
基团C可直接结合于Z或D;亦即,间隔基XZ或XD任选可不存在。
在存在时,间隔基XZ提供C与Z之间的空间分隔,以免前者空间干扰后者的抗原结合或后者空间干扰前者的裂解。此外,间隔基XZ可用于赋予结合物增加的溶解性或降低的凝集特性。间隔基XZ可包含一或多个模块区段,其可组装于任何数目的组合中。间隔基XZ的适合区段的实例为:
及其组合,其中下标g为0或1,且下标h为1至24,优选2至4。这些区段可组合,诸如如下所说明:
若存在,间隔基XD提供C与D之间的空间分隔,以免后者空间上或电子学上干扰前者的裂解。间隔基XD亦可用于将其他分子量及化学官能基引入结合物中。一般而言,其他质量及官能基将影响结合物的血清半衰期及其他特性。因此,经由明智选择间隔基,可调节结合物的血清半衰期。间隔基XD亦可类似于上文关于间隔基XZ的描述由模块区段组装。
间隔基XZ及/或XD在存在时优选在Z与C或D与C之间分别提供4至25个原子、更优选4至20个原子的线性分隔。
除共价连接抗体与药物以外,连接子可执行其他功能。举例而言,连接子可含有聚(乙二醇)(“PEG”)基团。由于结合步骤通常涉及在水性介质中将药物-连接子偶合至抗体,因此PEG基团可增加药物-连接子的水溶解度。另外,PEG基团可增加所得ADC的溶解度或降低其凝集。若存在PEG基团,则可将其并入间隔基XZ或XD或两者中。PEG基团中重复单元的数目可为2至20,优选4至10。
间隔基XZ或XD或两者可包含自分解部分。自分解部分为如下部分,其(1)结合至C以及Z或D中之一者,且(2)具有使得基团C的裂解起始反应序次的结构,从而使自分解部分自身任选与Z或D脱离。换言之,远离Z或D的位点处的反应(基团C的裂解)使得XZ-Z或XD-D键亦断裂。自分解部分的存在在间隔基XD的情形下为适宜的,因为若在结合物裂解后间隔基XD或其一部分保持连接于D,则D的生物活性可能受损。在可裂解基团C为多肽的情形下使用自分解部分为尤其适宜的,在该实施例中自分解部分通常邻近于该多肽定位,以便防止D在空间上或在电子学上干扰肽裂解。
结合至D的羟基或氨基的例示性自分解部分(i)至(v)如下所示:
自分解部分为点线a与b(或点线b与c)之间的结构,其中展示相邻结构特征以提供背景。自分解部分(i)及(v)结合至D-NH2(亦即经由氨基结合),而自分解部分(ii)、(iii)及(iv)结合至D-OH(亦即经由羟基或羧基结合)。点线b处的键由于酶(在结构(i)至(v)的实例中为肽酶且在结构(vi)的实例中为β-葡糖醛酸酶)而发生的裂解起始自分解反应序次,其引起点线a处的键裂解以及任选D-OH或D-NH2的随后释放。以说明的方式,结构(i)及(iv)的自分解机制如下所示:
换言之,自分解基团的一个部分处的第一化学键的裂解起始一连串步骤,其引起自分解基团的另一部分处的第二化学键(将自分解基团连接至药物的化学键)裂解,从而释放药物。
在一些情况下,自分解基团可串联使用,如结构(vii)所示。在此情况下,点线c处的裂解触发点线b与c之间的部分通过1,6-消除反应而自我分解,接着点线a与b之间的部分通过环化-消除反应而自我分解。关于自分解部分的其他公开文献参见Carl等人,J.Med.Chem.1981,24,479;Carl等人,WO 81/01145(1981);Dubowchik等人,Pharmacology&Therapeutics 1999,83,67;Firestone等人,US 6,214,345 B1(2001);Toki等人,J.Org.Chem.2002,67,1866;Doronina等人,Nature Biotechnology 2003,21,778(勘误表第941页);Boyd等人,US 7,691,962 B2;Boyd等人,US 2008/0279868 A1;Sufi等人,WO2008/083312 A2;Feng,US 7,375,078 B2;Jeffrey等人,US 8,039,273;及Senter等人,US2003/0096743 A1;其公开内容以引用的方式并入。
在另一个实施方案中,Z与D通过不可裂解连接子连接,亦即不存在C。D的代谢最终将连接子减小成不会干扰D的生物活性的较小附接部分。
结合技术
本文中所公开的TLR7激动剂的结合物优选通过以下方式制得:首先制备包含D及连接子(XD)a(C)c(XZ)b(其中XD、C、XZ、a、b及c如针对式(II)所定义)的化合物,以形成由式(III)表示的药物-连接子化合物:
D-(XD)a(C)c(XZ)b-R31 (III)
其中R31为适用于与Z上的补体官能基反应形成结合物的官能基。适合基团R31的实例包括氨基、叠氮基、硫醇、环辛炔、
及/>
其中R32为Cl、Br、F、甲磺酸酯或甲苯磺酸酯,且R33为Cl、Br、I、F、OH、-O-N-琥珀酰亚氨基、-O-(4-硝基苯基)、-O-五氟苯基或-O-四氟苯基。通常可用于制备适合部分D-(XD)aC(XZ)b-R31的化学方法公开于以下中:Ng等人,US 7,087,600 B2(2006);Ng等人,US 6,989,452 B2(2006);Ng等人,US 7,129,261 B2(2006);Ng等人,WO 02/096910 A1;Boyd等人,US7,691,962 B2;Chen等人,US 7,517,903 B2(2009);Gangwar等人,US 7,714,016 B2(2010);Boyd等人,US 2008/0279868 A1;Gangwar等人,US 7,847,105 B2(2010);Gangwar等人,US 7,968,586 B2(2011);Sufi等人,US 8,461,117 B2(2013);及Chen等人,US 8,664,407 B2(2014);其公开内容以引用的方式并入本文中。
优选反应性官能基-R31为-NH2、-OH、-CO2H、-SH、马来酰亚氨基、环辛炔、叠氮基(-N3)、羟基氨基(-ONH2)或N-羟基琥珀酰亚氨基。尤其优选的官能基-R31为:
-OH基团可用抗体上(例如天冬氨酸或谷氨酸侧链上)的羧基酯化。
-CO2H基团可用抗体上的-OH基团酯化或用抗体上(例如赖氨酸侧链上)的氨基酰胺化。
N-羟基琥珀酰亚氨基为功能上活化的羧基且可便利地通过与氨基(例如赖氨酸的氨基)反应酰胺化。
马来酰亚氨基可与抗体上的-SH基团(例如来自半胱氨酸或来自引入硫氢基官能基的抗体的化学修饰)在迈克尔加成反应中结合。
若抗体不具有用于结合的半胱氨酸-SH,则赖氨酸残基的侧链中的ε-氨基可与2-亚氨基硫杂环戊烷或N-琥珀酰亚氨基-3-(2-吡啶基二硫基)丙酸酯(“SPDP”)反应以引入游离的硫醇(-SH)基,从而实际上产生半胱氨酸替代物。硫醇基可与马来酰亚胺或其他亲核试剂受体基团反应以实现结合。下方示出2-亚氨基硫杂环戊烷情形下的机制。
通常,达成每个抗体二至三个硫醇的硫醇化水平。代表性过程参见Cong等人,US8,980,824 B2(2015),其公开内容以引用的方式并入本文中。
在相反配置中,可以用4-(马来酰亚氨基甲基)-环己甲酸N-琥珀酰亚氨基酯(“SMCC”)或其磺化变体磺基-SMCC(该两者可购自Sigma-Aldrich)修饰抗体Z,以向其中引入马来酰亚氨基。随后,可使用连接子上具有-SH基团的药物-连接子化合物来实现结合。
替代结合方法使用无铜“点击化学法(click chemistry)”,其中将叠氮基添加在应变环辛炔上以形成1,2,3-***环。参见例如Agard等人,J.Amer.Chem.Soc.2004,126,15046;Best,Biochemistry 2009,48,6571,其公开内容以引用的方式并入本文中。叠氮基可位于抗体上且环辛炔位于药物-连接子部分上或反之亦然。优选环辛炔基为二苯并环辛炔(DIBO)。具有DIBO基团的各种试剂可获自Invitrogen/Molecular Probes,Eugene,Oregon。以下反应说明DIBO基团连接于抗体(Ab)的情况下的点击化学法结合:
另一结合技术涉及将非天然氨基酸引入抗体中,其中非天然氨基酸提供用于与药物部分中的反应性官能基结合的官能基。举例而言,非天然氨基酸对乙酰基苯丙氨酸可并入抗体或其他多肽中,如Tian等人,WO 2008/030612 A2(2008)中所教示。对乙酰基苯丙氨酸中的酮基可经由与连接子-药物部分上的羟基氨基形成肟而成为结合位点。替代地,可将非天然氨基酸对叠氮基苯丙氨酸并入抗体中,得到叠氮基官能基以如上所述经由点击化学法结合。非天然氨基酸亦可使用无细胞方法而并入抗体或其他多肽中,如Goerke等人,US2010/0093024 A1(2010)及Goerke等人,Biotechnol.Bioeng.2009,102(2),400-416中所教示。前述公开内容以引用的方式并入本文中。因此,在一个实施方案中,用于制备结合物的抗体具有一或多个经非天然氨基酸置换的氨基酸,该非天然氨基酸优选为对乙酰基苯丙氨酸或对叠氮基苯丙氨酸,更优选为对乙酰基苯丙氨酸。
根据Jeger等人,Angew.Chem.Int.Ed.2010,49,9995,另一结合技术使用转谷氨酰胺酶(优选为来自茂源链霉菌(Streptomyces mobaraensis)的细菌性转谷氨酰胺酶或BTG)。BTG在谷氨酰胺的侧链甲酰胺(胺受体)与亚烷基氨基(胺供体)(其可为例如赖氨酸的ε-氨基或5-氨基-正戊基)之间形成酰胺键。在典型结合反应中,如下所示,谷氨酰胺残基位于抗体上,而亚烷基氨基位于连接子-药物部分上:
谷氨酰胺残基位于多肽链上对其对BTG介导的转酰胺作用的敏感性具有很大影响。抗体上的谷氨酰胺残基通常均不为BTG底物。然而,若抗体去糖基化,糖基化位点为重链的天冬酰胺297(N297;根据如Kabat等人,“Sequences of proteins of immunologicalinterest”,第5版,公开文献第91-3242号,美国健康与人类服务部(U.S.Dept.Health&Human Services),NIH,Bethesda,Md.,1991;下文简称“Kabat”中所阐述的EU索引编号),则邻近的谷氨酰胺295(Q295)表达为BTG敏感的。抗体可通过用PNGase F(肽-N-糖苷酶F)处理而以酶方式去糖基化。替代地,抗体可通过在恒定区中引入N297A突变而以无糖苷的形式合成,从而去除N297糖基化位点。此外,已证实N297Q取代不仅去除糖基化,且亦引入同样为胺受体的第二谷氨酰胺残基(在位置297处)。由此,在一个实施方案中,抗体去糖基化。在另一个实施方案中,抗体具有N297Q取代。本领域技术人员将了解,通过合成后修饰或通过引入N297A突变进行的去糖基化使每个抗体产生二个BTG反应性谷氨酰胺残基(每条重链一个,在位置295处),而具有N297Q取代的抗体将具有四个BTG反应性谷氨酰胺残基(每条重链两个,在位置295及297处)。
通过向抗体中引入含有谷氨酰胺的肽或“标记物”,抗体亦可表达为对BTG介导的结合敏感,例如Pons等人,US 2013/0230543 A1(2013)及Rao-Naik等人,WO 2016/144608A1中所教示。
在补充方法中,可通过改变BTG的氨基酸序列而改变其底物特异性,使得其变得能够与未经修饰抗体中的谷氨酰胺295反应,如Rao-Naik等人,WO 2017/059158 A1(2017)中所教示。
虽然最常用的细菌性转谷氨酰胺酶为来自茂源链霉菌的细菌性转谷氨酰胺酶,但亦可考虑来自底物特异性略微不同的其他细菌的转谷氨酰胺酶,诸如来自拉达卡链轮丝菌(Streptoverticillium ladakanum)的转谷氨酰胺酶(Hu等人,US 2009/0318349 A1(2009)、US 2010/0099610 A1(2010)及US 2010/0087371 A1(2010))。
具有一级或二级烷基胺的本发明激动剂尤其适合于以结合物形式使用,因为所述胺提供用于连接连接子的官能基。此类TLR7激动剂-连接子化合物的实例为化合物12,其含有酶促可裂解连接子。图2示出可据其制备化合物12的流程。
含有非酶促可裂解连接子的TLR7激动剂-连接子化合物的实例为化合物14。图3示出用于合成化合物14的流程。
化合物12及14均含有一级烷基氨基,使得其能够与转谷氨酰胺酶结合。下文实施例中描述适合的结合过程。
亦可使用分选酶A(Sortase A)来实现结合,如Levary等人,PLoS One 2011,6(4),e18342;Proft,Biotechnol.Lett.2010,32,1-10;Ploegh等人,WO 2010/087994 A2(2010);及Mao等人,WO 2005/051976 A2(2005)中所教示。分选酶A识别基序(通常LPXTG,其中X为任何天然氨基酸)可位于配体Z上,且亲核性受体基序(通常GGG)可为式(III)中的基团R31,或反之亦然。
TLR7激动剂结合物
应用前述技术,可制备TLR7激动剂结合物,诸如下方所示的结合物:
其中m为1、2、3或4,且Ab为抗体。
聚乙二醇化
将聚(乙二醇)(PEG)链连接至药物(“聚乙二醇化”)可改良药物的药物动力学特性。药物的循环半衰期增加,有时增加超过一个数量级,同时降低了达成所要治疗效果所需要的剂量。聚乙二醇化亦可减少药物的代谢降解且降低其免疫原性。论述参见Kolate等人,J.Controlled Release 2014,192,167。
聚乙二醇化最初应用于生物药物。截至2016年,已批准超过十种聚乙二醇化生物制剂。Turecek等人,J.Pharmaceutical Sci.2016,105,460。最近,受该理论于生物制剂中的成功应用的刺激,人们注意力已转向其于小分子药物中的应用。除前述益处外,聚乙二醇化小分子药物可具有增加的溶解度且引起较少毒性作用。Li等人,Prog.PolymerSci.2013,38,421。
本文所公开的化合物可经聚乙二醇化,即具有共价键合在其上的聚(乙二醇)部分。在化合物具有脂族羟基或脂族一级或二级胺时,诸如化合物Ia-01或Ia-04(箭头)的情形,该化合物可利用常规技术(诸如二环己基碳化二亚胺、HATU、N-羟基琥珀酰亚胺酯以及其类似技术)通过含有羧基的PEG分子经由酯基、酰氨基、碳酸酯基或氨基甲酸酯基而聚乙二醇化。用于对医药分子进行聚乙二醇化的各种其他方法公开于Alconcel等人,PolymerChem.2011,2,1442中,其公开内容以引用的方式并入本文中。
视需要,本文中所公开的TLR7激动剂可经由包含自分解部分的酶促可裂解连接子聚乙二醇化,从而允许未经聚乙二醇化的激动剂以设计方式释放。此外,若含有PEG的分子具有用于连接至蛋白质的适合官能基(诸如胺),则聚乙二醇化可与同蛋白质(诸如抗体)的结合组合。蛋白质可提供额外治疗功能,或在抗体的情况下可提供靶向功能。在下方反应序次中示出这些理论,其中TLR7-NH-R通常表示TLR7激动剂:
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在上述反应序次中,缬氨酸-瓜氨酸(Val-Cit)二肽可通过组织蛋白酶B裂解,其中对氨基苯甲基氧基羰基(PABC)充当自分解间隔基。用于结合的官能基为氨基,其暂时受Fmoc基团保护。结合由转谷氨酰胺酶实现,其中谷氨酰胺(Gln)侧链充当酰基受体。视聚乙二醇化的目的而定,表示PEG重复单元的数目的下标x可广泛变化,如下文所论述。出于一些目的,x可相对较小,诸如2、4、8、12或24。出于其他目的,x较大,例如介于约45与约910之间。
本领域技术人员将理解,该序次为说明性的,且可使用如本领域中所熟知的其他要素(肽、自分解基团、结合方法、PEG长度等)。本领域技术人员亦将理解,虽然上述序次组合聚乙二醇化与结合,但聚乙二醇化不需要结合。且反之亦然。
在化合物没有脂族羟基或脂族一级或二级胺时,如在化合物Ia-02的情形中,仍然可在芳胺(箭头)处聚乙二醇化。在该位置处进行聚乙二醇化的方法由Zarraga,US 2017/0166384 A1(2007)公开,其公开内容以引入的方式并入。
在一些实施方案中,可能需要单个分子中连接有多个聚乙二醇化激动剂。举例而言,可在季戊四醇(C(CH2OH)4)上构筑四个聚乙二醇化臂,且TLR7激动剂可连接至各聚乙二醇化臂。参见Gao等人,US 2013/0028857 A1(2013),其公开内容以引用的方式并入。
为了调节药物动力学,通常优选PEG部分的分子量介于约2kDa(对应于约45个-(CH2CH2O)-重复单元)与约40kDa(对应于约910个-(CH2CH2O)-重复单元)之间,更优选介于约5kDa与约20kDa之间。亦即,上式中下标x的范围为约45至约910。应理解,PEG组合物并非100%均质的,而是实际上呈现分子量分布。因此,例如对“20kDa PEG”的提及是指具有20kDa的平均分子量的PEG。
聚乙二醇化亦可用于改良激动剂的溶解度。在这些情况下,可使用较短PEG链,例如包含2、4、8、12或24个重复单元。
实施例
可参考以下实施例进一步理解本发明的实践,其以说明方式提供且不具有限制性。
实施例1–合成TLR7激动剂
本实施例和图1涉及本发明的化合物的合成。
将化合物1(CAS登记号23814-12-2;1.8g,11.03mmol)在MeOH(20mL)中的悬浮液用亚硫酰(二)氯(2.416mL,33.1mmol)处理,在0℃逐滴添加。在60℃加热反应混合物1小时,其后LCMS显示反应完成。用旋蒸仪蒸发溶剂,将粗酯2带入下一步中。LCMS ESI:计算值C8H7N3O2=178.05(M+H+);测量值:178.0(M+H+)。
将酯2(1.954g,11.03mmol)、2-溴乙-1-醇(2.76g,22.06mmol)和碳酸钾(2.287g,16.55mmol)在N,N-二甲基甲酰胺(DMF)中的混合物在60℃加热过夜。LCMS显示形成了两种产物,区域异构体3和4。将固体混合物过滤并将DMF在V-10蒸发器中蒸发以提供粗产物混合物,其无需进一步提纯即可用于下一步。
将区域异构体3和4(2.440g,11.03mmol)在DMF(10mL)中的混合物先后用叔丁基二甲基甲硅烷基氯(TBSCl,1.995g,13.24mmol)和咪唑(1.502g,22.06mmol)处理并搅拌2小时。LCMS显示反应完成。反应用EtOAc/NaHCO3饱和水溶液处理。粗产物在COMBIFLASHTM仪器上使用80g硅胶柱提纯,并用0-50%EtOAc/己烷洗脱,得到区域异构体5(0.9g,2.68mmol,24.32%产率)和6(1.0g,2.98mmol,27.0%产率)。使用NOE在芳族环上的苄基亚甲基和附近的质子之间确定区域化学。LCMS ESI:计算值C16H25N3O2Si=336.16(M+H+);测量值:336.1(M+H+)。
使用ISCO设备分离后,将区域异构体5(0.9g,2.68mmol)在THF(10mL)中的溶液在0℃用红铝(2.181mL,6.71mmol)处理并搅拌30分钟。LCMS显示反应完成。通过缓慢加入MeOH淬灭反应,并用EtOAc/盐水后处理。原样将粗产物7移至下一步。
用三苯基膦(2.78g,10.59mmol)处理产物7(2.96g,9.63mmol)的二氯甲烷(DCM,20mL)溶液,并冷却至0℃。缓慢加入N-溴琥珀酰亚胺(NBS,1.885g,10.59mmol),移去冷浴并搅拌30分钟,其后LCMS显示反应完成。蒸发溶剂并在ISCO柱上使用80g硅胶金柱提纯粗产物,用0-50%EtOAc/己烷洗脱,得到所需化合物8作为无色糊状物。LCMS ESI:计算值C15H24BrN3OSi=371.08(M+H+);测量值:372.0(M+H+)。
将化合物9(CAS登记号473930-51-7,1.577g,7.61mmol)的溶液用碳酸铯(2.73g,8.37mmol)处理,然后用化合物8(3.1g,8.37mmol)处理,并在60℃加热1小时,其后LCMS显示反应完成。滤出碳酸铯,并将反应混合物用50mL EtOAc稀释,并用水洗涤3次,浓缩产物,并在ISCO柱上使用120g硅胶金柱提纯,用0-50%EtOAc/己烷洗脱,得到所需化合物10,为白色固体。LCMS ESI:计算值C24H36N8OSi=495.6(M-H+);测量值:495.2(M-H+)。
将化合物10(1.27g,2.56mmol)和乙酸钠(1.049g,12.78mmol)的CHCl3(10mL)/THF(5ml)溶液冷却至0℃,并用溴(0.263mL,5.11mmol)缓慢处理直到反应完成。用10%亚硫酸氢钠溶液中的水溶液将反应淬灭,并用EtOAc萃取。干燥的溴化粗产物无需进一步提纯即可用于下一步。
将溴化粗产物(1474mg,2.56mmol)和甲醇锂(972mg,25.6mmol)在MeOH(10mL)中的溶液在60℃加热过夜,其后LCMS显示溴置换。蒸发MeOH,并将所得浆液用HCl(4.27mL,25.6mmol)水溶液处理并在60℃加热2小时,其后LCMS显示反应完成。通过缓慢添加水性NaOH中和反应混合物且用水洗涤所得滤液。干燥固体,获得粗产物Ia-01作为黄色固体。粗产物在有xBridge PrepC18 5m 19x150 mm柱的Shimadzu制备型HPLC上提纯并用0-50%MeOH/H2O(0.1%甲酸)洗脱,并收集含产物的级分且使用V-10蒸发器将溶剂蒸发,得到所需化合物Ia-01作为无色糊状物。LCMS ESI:计算值C18H22N8O3=397.4(M-H+),测量值:397.2(M-H+)。
用亚硫酰(二)氯(10.99μL,0.151mmol)处理化合物Ia-01(30mg,0.075mmol)的溶液并超声处理1小时,其后LCMS显示反应完成。使用V-10蒸发器蒸发溶剂且粗产物在有xBridge PrepC18 5m 19x150 mm柱的Shimadzu制备型HPLC上提纯,并用0-50%MeOH/H2O(0.1%甲酸)洗脱,并收集含产物的级分,且使用V-10蒸发器将溶剂蒸发,得到所需化合物Ia-02作为无色糊状物。LCMS ESI:计算值C18H21ClN8O2=415.8(M-H+),测量值:415.2(M-H+)。
用环丁胺(0.027g,0.375mmol)处理化合物Ia-02(0.031g,0.075mmol)的DMF(0.5mL)溶液并在70℃加热2小时。LCMS显示反应完成。粗产物在有xBridge PrepC18 5m19x150 mm柱的Shimadzu制备型HPLC上提纯并用0-50%MeOH/H2O(0.1%甲酸)洗脱,并收集含产物的级分,且使用V-10蒸发器将溶剂蒸发,得到所需产物Ia-05作为无色糊状物。1HNMR(400MHz,DMSO-d6)δ7.84–7.73(m,1H),7.45(dd,J=8.7,1.5Hz,1H),6.44–6.38(m,2H),4.96(d,J=7.4Hz,2H),4.59(q,J=5.9Hz,2H),4.08(q,J=6.9Hz,2H),3.12–2.97(m,1H),2.87(td,J=6.3,2.1Hz,2H),1.98–1.87(m,2H),1.54(dt,J=8.1,6.3Hz,2H),1.51–1.35(m,4H),1.29(qd,J=7.4,4.5Hz,2H),0.82(td,J=7.3,5.3Hz,3H)。LCMS ESI:计算值C22H2N9O2=450.5(M-H+);测量值:450.2(M-H+)。
通常按照上述步骤,但使用不同的胺代替环丁胺,制备了进一步的根据式(I)的化合物,如下表B所示:
其中R3为H或Me的式(I)的化合物可通过化合物9分别与以下化合物的烷基化制备
应用上述技术,必要时作必要修改。
实施例2–TLR7激动活性分析
此实施例描述一种用于分析本说明书中所公开的化合物的TLR7激动活性的方法。
将经工程改造的具有人类TLR7分泌的胚胎碱性磷酸酶(SEAP)报导转基因的人类胚胎肾蓝色细胞(HEK-BlueTM TLR细胞;Invivogen)悬浮于非选择性培养基(DMEM高葡萄糖(Invitrogen),其补充有10%胎牛血清(Sigma))中。将HEK-BlueTM TLR7细胞添加至384孔组织培养盘中的各孔(每孔15,000个细胞),且在37℃、5%CO2下培育16至18小时。将化合物(100nl)施配至含有HEK-BlueTM TLR细胞的孔中,且将经处理细胞在37℃、5%CO2下进行培育。处理18小时后,将十微升新制的Quanti-BlueTM试剂(Invivogen)添加至各孔,培育30分钟(37℃,5%CO2),且使用Envision盘式读取器(OD=620nm)来测量SEAP含量。计算半数最大有效浓度值(EC50;诱导分析基线与最大值之间一半反应的化合物浓度)。
图4为说明性图表,其示出了如此获得的本发明化合物(Ia-01)的数据。
实施例3–IL-6诱导
此实施例描述一种用于分析本说明书中所公开的化合物的白介素6诱导的方法。
使用ECHO声学液体操作技术将于DMSO中稀释的化合物转移至MatrixTechnologies透明V底384孔盘的个别孔中(每孔25nL)。使用CyBio FeliX液体操作仪将人类全血样品(25μL)添加至各孔。将培养盘在培养盘震荡器上震荡三分钟,之后在37℃下培育反应混合物20小时。随后向各孔中添加Basel RPMI 1640培养基(补充有L-谷氨酰胺)(每孔25μL),之后通过离心(450×g,5分钟,环境温度)自各样品释放出血浆。随后使用FeliX液体操作仪将处理后的血浆样品(3μL)转移至白色、较浅的384孔ProxiPlate(Perkin Elmer)的个别孔中,且使用如制造商PerkinElmer所描述的AlphaLISA技术来测量其白介素6含量。使用数据分析软件来确定化合物EC50值,其中使用平均DMSO值确定基线,且使用最高所测试浓度下的参考化合物值确定100%诱导。可使用诸如Graphpad PrismTM的软件来确定EC50。
实施例4–转谷氨酰胺酶介导的结合
以下过程可用于转谷氨酰胺酶介导的激动剂-连接子化合物结合,其中连接子具有可充当胺供体的氨基。抗体可为具有转谷氨酰胺酶反应性谷氨酰胺的抗体,例如具有N297A或N297Q取代的抗体。结合通过重组细菌性转谷氨酰胺酶进行,其中抗体:酶的摩尔比为5:1。结合使用标准方案于50mM Tris缓冲液(pH 8.0)中在37℃下培育隔夜而进行。在用50mM Tris(pH 8.0)预平衡的蛋白A管柱上纯化所得结合物。将结合物用0.1M柠檬酸钠缓冲液(pH 3.5)洗脱。用1M Tris(pH 9.0)中和洗脱的洗脱份。可在20mg/mL山梨糖醇、10mg/mL甘氨酸(pH 5.0)中调配结合物。
本领域技术人员将理解,此实施例中的条件及方法为说明性且非限制性的,并且其变化形式或其他结合方法为本领域中已知的且可用于本发明中。
本发明的前述详细描述包括主要或仅涉及本发明的特定部分或方面的段落。应了解,出于明晰及便利的目的,特定特征可不仅在公开该特征的段落中相关,且本文的公开内容包括不同段落中存在的信息的所有适当组合。类似地,尽管本文的各种图式及描述涉及本发明的特定实施方案,但应了解,若特定特征公开于特定图式或实施方案的情形下,则此类特征亦可以适当程度与另一特征组合用于另一图式或实施方案的情形下或一般的本发明中。
此外,尽管本发明尤其关于某些优选实施方案进行描述,但本发明并不限于此类优选实施方案。确切而言,本发明的范畴通过所附权利要求书界定。
参考文献
下文提供以下参考文献的完整引用,之前在本说明书中所述参考文献以简化方式以第一作者(或发明者)及日期形式引用。这些参考文献各自以引用的方式并入本文中以用于所有目的。
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Claims (4)
1.一种具有式(Ia)表示的结构的化合物
其中
R1为(C1-C5烷基)O;和
R4为卤素、OH、NH(C1-C5烷基)、NH(C3-C6环烷基)、NH(CH2)1-3(芳基)、
其中环烷基的CH2基团可被O、S或N(Boc)替代,
其中术语“芳基”指的是苯基。
2.根据权利要求1所述的化合物,其中R1为n-BuO且R4为OH、Cl、
3.根据权利要求1所述的化合物,其中R4为OH、Cl、
4.一种化合物,其选自
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US10472361B2 (en) | 2019-11-12 |
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