TW201920177A - 具有雜雙芳基部分之類鐸受體7(tlr7)促效劑,其結合物及其等之方法及用途 - Google Patents
具有雜雙芳基部分之類鐸受體7(tlr7)促效劑,其結合物及其等之方法及用途 Download PDFInfo
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- TW201920177A TW201920177A TW107128400A TW107128400A TW201920177A TW 201920177 A TW201920177 A TW 201920177A TW 107128400 A TW107128400 A TW 107128400A TW 107128400 A TW107128400 A TW 107128400A TW 201920177 A TW201920177 A TW 201920177A
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- JJAHTWIKCUJRDK-UHFFFAOYSA-N succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate Chemical compound C1CC(CN2C(C=CC2=O)=O)CCC1C(=O)ON1C(=O)CCC1=O JJAHTWIKCUJRDK-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000006092 tetrahydro-1,1-dioxothienyl group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical class C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- 238000006177 thiolation reaction Methods 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 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
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229960003732 tyramine Drugs 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 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
- 150000003751 zinc Chemical class 0.000 description 1
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- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A—HUMAN NECESSITIES
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Abstract
Description
本發明係關於類鐸受體7 (「TLR7」)促效劑及其結合物,以及此類促效劑及其結合物之製備及使用方法。
類鐸受體(「TLR」)為識別病原體相關分子模式(「PAMP」)之細胞表面受體。TLR由於結合相應PAMP而活化,其用信號發送病原體之可能感染且刺激免疫系統以對抗該感染。人類具有11種TLR,稱為TLR1至TLR11。
藉由促效劑活化TLR (主要研究TLR7)可藉由刺激免疫反應而對疫苗及免疫療法劑在治療除真正病原體感染外之各種病狀中之作用具有輔助作用。
TLR7識別與單股RNA病毒相關之PAMP。其活化誘導諸如IFNα及IFNβ之I型干擾素分泌(Lund等人 2004)。TLR7具有兩個結合位點,一個用於諸如ssRNA40之單股RNA配體(Berghöfer等人 2007)且一個用於鳥苷(Zhang等人 2016)。
TLR7可結合至類鳥苷合成促效劑且由其活化,該等促效劑諸如基於1H
-咪唑并[4,5-c]喹啉架構之咪喹莫特(imiquimod)、雷西莫特(resiquimod)及嘎德莫特(gardiquimod)。
亦已知基於喋啶酮分子架構之合成TLR7促效劑,實例如已處於2期臨床試驗之威沙立德(vesatolimod) (Desai等人 2015)。據報導,威沙立德之效能比相應的嘌呤-8-酮化合物之效能小100倍,如藉由IFN-α誘導所量測(Roethle等人 2013)。
其他合成TLR7促效劑係基於通常根據式(A)之類嘌呤架構:其中R、R'及R''為結構式變數,其中R''通常含有未經取代或經取代之芳環或雜芳環。
具有類嘌呤之生物活性分子及其用於治療諸如纖維化、發炎性病症、癌症或致病性感染之病狀之用途的揭示案包括: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;Peterson 2014;Pryde 2010;及Seifert 2015。
基團R''可為吡啶基: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揭示TLR7調節劑,其中一個巨環跨越嘌呤部分之兩個環:
TLR7促效劑可與搭配物分子結合,該搭配物分子可為例如磷脂、聚(乙二醇) (「PEG」)或另一TLR (通常為TLR2)。例示性揭示案包括: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。亦已揭示與抗體之結合:Akinbobuyi等人 2013及2015a,及Gadd等人 2015。常見結合位點位於式(A)之基團R''處。
亦已揭示基於5H
-吡咯并[3,2-d
]嘧啶架構之TLR7促效劑。參見Cortez等人 2017a及2017b;McGowan等人 2017;及Li等人 2018。
Jensen等人 2015揭示陽離子脂質媒劑用於遞送TLR7促效劑之用途。
一些TLR7促效劑(包括雷西莫特)為雙TLR7/TLR8促效劑。參見例如Beesu等人 2017;Lioux等人 2016;及Vernejoul等人 2014。
亦已揭示基於5H
-吡咯并[3,2-d
]嘧啶架構之TLR7促效劑。參見Cortez等人 2017a及2017b;McGowan等人 2017;及Li等人 2018。
本文所引用之第一作者或發明者之文獻的完整引用及年份列於本說明書末尾。
在一個態樣中,本說明書提供一種具有式(I)或式(II)結構之化合物其中 R1
為(C1
-C5
烷基)O、(C1
-C2
烷基)O(CH2
)2 - 3
O、(C1
-C5
烷基)C(=O)O、(C1
-C5
烷基)NH、(C1
-C2
烷基)O(CH2
)2 - 3
NH或(C1
-C5
烷基)C(=O)NH; R2
在每次出現時獨立地為H、C1
-C3
烷基、鹵基、O(C1
-C3
烷基)、CN或NO2
; X在每次出現時獨立地為CR2
或N;且 Ar為選自以下之5員雜芳香族部分:吡咯基、呋喃基、苯硫基、吡唑基、咪唑基、噁唑基、異噁唑基、1,2,3-***基、1,2,4-***基、四唑基、1,2,4-噁二唑基、1,2,4-噻二唑基、1,3,4-噁二唑基、1,3,4-噻二唑基、1,2,5-噁二唑基、1,2,5-噻二唑基、1,2,3,4-噁***基及1,2,3,4-噻***基。
式(I)及式(II)化合物具有作為TLR7促效劑之活性,且其中一些可經結合以靶向遞送至預期作用之標靶組織或器官。
相關申請案之交叉引用
本申請案根據35 U.S.C. §119(e)主張2017年8月16申請之US臨時申請案第62/546,211號之權益;該申請案之揭示內容以引用之方式併入本文中。 定義
「抗體」意謂完整抗體及其任何抗原結合片段(亦即「抗原結合部分」)或單鏈變體。完整抗體為包含由二硫鍵相互連接之至少兩條重(H)鏈及兩條輕(L)鏈的蛋白質。各重鏈包含重鏈可變區(VH
)及包含三個域CH1
、CH2
及CH3
之重鏈恆定區。各輕鏈包含輕鏈可變區(VL
或Vk
)及包含單一域CL
之輕鏈恆定區。VH
及VL
區可進一步再分成高變區,稱為互補決定區(CDR),穿插有較保守構架區(FR)。各VH
及VL
包含三個CDR及四個FR,其自胺基至羧基端以如下次序排列:FR1、CDR1、FR2、CDR2、FR3、CDR3及FR4。可變區含有與抗原相互作用之結合域。恆定區可介導抗體與宿主組織或因子之結合,包括免疫系統之各種細胞(例如效應細胞)及經典補體系統之第一組分(Clq)。抗體在抗體以5 × 10- 8
M或更小、更佳1 × 10- 8
M或更小、更佳6 × 10- 9
M或更小、更佳3 × 10- 9
M或更小、甚至更佳2 × 10- 9
M或更小之KD
結合於抗原X時稱為「特異性結合」於抗原X。抗體可為嵌合、人類化或較佳人類抗體。重鏈恆定區可經工程改造以影響糖基化類型或程度,延長抗體半衰期,增強或減少與效應細胞或補體系統之相互作用,或調節一些其他特性。工程改造可藉由置換、添加或刪除一或多個胺基酸或藉由用來自另一免疫球蛋白類型之域置換域或前述方法之組合來完成。
抗體之「抗原結合片段」及「抗原結合部分」(或簡單地「抗體部分」或「抗體片段」)意謂抗體之保留特異性結合於抗原之能力的一或多個片段。已證實抗體之抗原結合功能可藉由全長抗體之片段執行,該等片段諸如(i) Fab片段,其為由VL
、VH
、CL
及CH1
域組成之單價片段;(ii) F(ab')2
片段,其為包含由鉸鏈區處之二硫橋鍵連接之兩個Fab片段的二價片段;(iii) Fab'片段,其基本上為具有鉸鏈區部分之Fab (參見例如Abbas等人,Cellular and Molecular Immunology
, 第6版, Saunders Elsevier 2007);(iv) Fd片段,其由VH
及CH1
域組成;(v) Fv片段,其由抗體之單臂的VL
及VH
域組成;(vi) dAb片段(Ward等人, (1989)Nature 341
:544-546),其由VH
域組成;(vii)經分離之互補決定區(CDR);以及(viii)奈米抗體,其為含有單一可變域及兩個恆定域之重鏈可變區。較佳抗原結合片段為Fab、F(ab')2
、Fab'、Fv及Fd片段。此外,儘管Fv片段之兩個域VL
及VH
由不同基因編碼,但該等域可使用重組方法藉由合成連接子接合,該合成連接子使得該等域能夠形成為其中VL
區與VH
區配對形成單價分子之單一蛋白質鏈(稱為單鏈Fv或scFv);參見例如Bird等人(1988)Science 242
:423-426;及Huston等人(1988)Proc . Natl . Acad . Sci . USA 85
:5879-5883)
。此類單鏈抗體亦涵蓋於術語抗體之「抗原結合部分」內。
除非另外規定,否則根據Kabat系統(Kabat等人, 「Sequences of proteins of immunological interest」, 第5版, 公開案第91-3242號, 美國衛生與公眾服務部(U.S. Dept. Health & Human Services), NIH, Bethesda, Md., 1991, 以下簡稱「Kabat」)提及抗體重鏈或輕鏈可變區(VH
或VL
)中胺基酸位置之編號(例如提及SEQ ID NO:清單中之直鏈編號),且根據如Kabat中所列之EU索引提及抗體重鏈或輕鏈恆定區(CH1
、CH2
、CH3
或CL
)中胺基酸位置之編號。參見Lazar等人之US 2008/0248028 A1,該文獻之例如此類使用之揭示內容以引用之方式併入本文中。此外,免疫遺傳學資訊系統(ImMunoGeneTics Information System;IMGT)在其網站提供了名稱為「IMGT Scientific Chart: Correspondence between C Numberings」之表,其展示其用於重鏈恆定區之編號系統、EU編號及Kabat編號之間的對應關係。
「經分離抗體」意謂實質上不含具有不同抗原特異性之其他抗體的抗體(例如特異性結合抗原X之經分離抗體實質上不含特異性結合除抗原X以外之抗原的抗體)。然而,特異性結合抗原X之經分離抗體可與諸如來自其他物種之抗原X分子之其他抗原具有交叉反應性。在某些實施例中,經分離抗體特異性結合於人類抗原X且不與其他(非人類)抗原X抗原交叉反應。此外,經分離抗體可實質上不含其他細胞物質及/或化學物質。
「單株抗體」或「單株抗體組合物」意謂具有單一分子組成之抗體分子的製劑,其對特定抗原決定基展現單一結合特異性及親和力。
「人類抗體」意謂具有如下可變區之抗體,其中構架區與CDR區(及恆定區(若存在))均衍生自人類生殖系免疫球蛋白序列。人類抗體可包括後續修飾,包括天然或合成修飾。人類抗體可包括並非由人類生殖系免疫球蛋白序列編碼之胺基酸殘基(例如,藉由活體外隨機或定點突變誘發或藉由活體內體細胞突變引入之突變)。然而,「人類抗體」不包括源自另一哺乳動物物種(諸如小鼠)之生殖系的CDR序列已經移植至人類構架序列上之抗體。
「人類單株抗體」意謂呈現單一結合特異性之抗體,其具有如下可變區,其中構架區與CDR區均衍生自人類生殖系免疫球蛋白序列。在一個實施例中,人類單株抗體由融合瘤產生,該融合瘤包括與永生化細胞融合之獲自轉殖基因非人類動物(例如轉殖基因小鼠)的B細胞,該轉殖基因非人類動物具有包含人類重鏈轉殖基因及輕鏈轉殖基因之基因組。
「脂族基」意謂直鏈或分支鏈、飽和或不飽和的非芳香族烴部分,其具有指定數目個碳原子(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,後面三個片語為具有1至5個碳原子之脂族部分的同義詞),或在未明確指定碳原子數目時具有1至4個碳原子(在不飽和脂族部分之實例中具有2至4個碳原子)。類似理解適用於其他類型中之碳數目,如在C2-4
烯烴、C4
-C7
環脂族基等中。以類似方式,諸如「(CH2
)1-3
」之術語應理解為下標為1、2或3之簡寫,因而此類術語表示CH2
、CH2
CH2
及CH2
CH2
CH2
。
「烷基」意謂飽和脂族部分,其中指定碳原子數之相同慣例適用。以說明之方式,C1
-C4
烷基部分包括(但不限於)甲基、乙基、丙基、異丙基、異丁基、第三丁基、1-丁基、2-丁基及其類似物。「伸烷基」意謂烷基之二價對應物,諸如CH2
CH2
、CH2
CH2
CH2
及CH2
CH2
CH2
CH2
。
「烯基」意謂具有至少一個碳-碳雙鍵之脂族部分,其中指定碳原子數之相同慣例適用。以說明之方式,C2
-C4
烯基部分包括(但不限於)乙烯基(ethenyl/vinyl)、2-丙烯基(烯丙基或丙-2-烯基)、順-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)及其類似基團。
「炔基」意謂具有至少一個碳-碳參鍵之脂族部分,其中指定碳原子數之相同慣例適用。以說明之方式,C2
-C4
炔基包括乙炔基(ethynyl/acetylenyl)、炔丙基(丙-2-炔基)、1-丙炔基、丁-2-炔基及其類似基團。
「環脂族基」意謂具有1至3個環之飽和或不飽和、非芳香族烴部分,各環具有3至8個(較佳3至6個)碳原子。「環烷基」意謂其中各環飽和之環脂族部分。「環烯基」意謂其中至少一個環具有至少一個碳-碳雙鍵之環脂族部分。「環炔基」意謂其中至少一個環具有至少一個碳-碳參鍵之環脂族部分。以說明之方式,環脂族部分包括(但不限於)環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環庚基、環辛基及金剛烷基。較佳環脂族部分為環烷基部分,尤其環丙基、環丁基、環戊基及環己基。「伸環烷基」意謂環烷基之二價對應物。
「雜環脂族基」意謂如下環脂族部分,其中在其至少一個環中,至多三個(較佳1至2個)碳經獨立地選自N、O或S之雜原子置換,其中N及S可視情況經氧化且N可視情況經四級銨化。較佳環脂族部分由大小為5員至6員之一個環組成。類似地,「雜環烷基」、「雜環烯基」及「雜環炔基」分別意謂環烷基、環烯基或環炔基部分,其中其至少一個環經如此修飾。例示性雜環脂族部分包括氮丙啶基、氮雜環丁烷基、1,3-二氧雜環己烷基、氧雜環丁烷基、四氫呋喃基、吡咯啶基、哌啶基、哌基、四氫哌喃基、四氫硫哌喃基、四氫硫哌喃基碸、嗎啉基、硫代嗎啉基、硫代嗎啉基亞碸、硫代嗎啉基碸、1,3-二氧戊環基、四氫-1,1-二側氧基噻吩基、1,4-二氧雜環己烷基、硫雜環丁烷基及其類似基團。「伸雜環烷基」意謂雜環烷基之二價對應物。
「烷氧基」、「芳基氧基」、「烷基硫基」及「芳基硫基」分別意謂-O(烷基)、-O(芳基)、-S(烷基)及-S(芳基)。實例分別為甲氧基、苯氧基、甲基硫基及苯基硫基。
除非指示較窄含義,否則「鹵素」或「鹵基」意謂氟、氯、溴或碘。
「芳基」意謂具有單環、雙環或三環環系統(較佳單環)之烴部分,其中各環具有3至7個碳原子且至少一個環為芳香族。環系統中之環可彼此稠合(如在萘基中)或彼此鍵結(如在聯苯中)且可與非芳香族環稠合或鍵結(如在茚滿基或環己基苯基中)。以進一步說明之方式,芳基部分包括(但不限於)苯基、萘基、四氫萘基、茚滿基、聯苯、菲基、蒽基及苊基。「伸芳基」意謂芳基之二價對應物,例如1,2-伸苯基、1,3-伸苯基或1,4-伸苯基。
「雜芳基」意謂具有單環、雙環或三環環系統(較佳5員至7員單環)之部分,其中各環具有3至7個碳原子,且至少一個環為含有1至4個獨立地選自N、O或S之雜原子的芳環,其中N及S可視情況經氧化且N可視情況經四級銨化。此類至少一個含雜原子芳環可與其他類型之環稠合(如在苯并呋喃基或四氫異喹啉基中)或與其他類型之環直接鍵結(如在苯基吡啶基或2-環戊基吡啶基中)。以進一步說明之方式,雜芳基部分包括吡咯基、呋喃基、苯硫基(噻吩基)、咪唑基、吡唑基、噁唑基、異噁唑基、噻唑基、異噻唑基、***基、四唑基、吡啶基、N-側氧基吡啶基、嗒基、嘧啶基、吡基、喹啉基、異喹啉炔基、喹唑啉基、㖕啉基、喹喏啉基、㖠啶基、苯并呋喃基、吲哚基、苯并苯硫基、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、二苯并苯硫基、吖啶基及其類似基團。「伸雜芳基」意謂雜芳基之二價對應物。
若據指示部分可經取代,諸如如在「未經取代或經取代之C1
-C5
烷基」或「視情況經取代之雜芳基」中藉由使用「未經取代或經取代」或「視情況經取代」措辭,則此類部分可具有一或多個獨立選擇之取代基,較佳數目為一至五個,更佳數目為一個或兩個。取代基及取代模式可由一般熟習此項技術者考慮取代基所連接之部分而選擇,以提供化學上穩定且可藉由此項技術中已知之技術以及本文所闡述之方法合成的化合物。若一個部分鑑別為「未經取代或經取代」或「視情況經取代」,則在一較佳實施例中,此類部分未經取代。
「芳基烷基」、「(雜環脂族基)烷基」、「芳基烯基」、「芳基炔基」、「聯芳基烷基」及其類似基團意謂烷基、烯基或炔基部分,視情況可經芳基、雜環脂族基、聯芳基等部分取代,視情況可在烷基、烯基或炔基部分上具有開放(不飽和)價態,例如如在苯甲基、苯乙基、N-咪唑基乙基、N-嗎啉基乙基及其類似基團中。相反地,「烷基芳基」、「烯基環烷基」及其類似基團意謂芳基、環烷基等部分,視情況可經烷基、烯基等部分取代,視情況可例如如在甲基苯基(甲苯基)或烯丙基環己基中。「羥烷基」、「鹵烷基」、「烷基芳基」、「氰基芳基」及其類似基團意謂烷基、芳基等部分,視情況可經一或多個所鑑別取代基(視情況可為羥基、鹵基等)取代。
舉例而言,可容許的取代基包括(但不限於)烷基(尤其甲基或乙基)、烯基(尤其烯丙基)、炔基、芳基、雜芳基、環脂族基、雜環脂族基、鹵基(尤其氟基)、鹵烷基(尤其三氟甲基)、羥基、羥烷基(尤其羥乙基)、氰基、硝基、烷氧基、-O(羥烷基)、-O(鹵烷基) (尤其-OCF3
)、-O(環烷基)、-O(雜環烷基)、-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、-CO2
H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羥烷基)、-C(=O)NH2
、-C(=O)NH(烷基)、-C(=O)N(烷基)2
、-OC(=O)(烷基)、-OC(=O)(羥烷基)、-OC(=O)O(烷基)、-OC(=O)O(羥烷基)、-OC(=O)NH2
、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2
、疊氮基、-NH2
、-NH(烷基)、-N(烷基)2
、-NH(芳基)、-NH(羥烷基)、-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(環烷基)、-S(=O)烷基、-SO2
(烷基)、-SO2
NH2
、-SO2
NH(烷基)、-SO2
N(烷基)2
以及其類似基團。
若經取代之部分為脂族部分,則較佳取代基為芳基、雜芳基、環脂族基、雜環脂族基、鹵基、羥基、氰基、硝基、烷氧基、-O(羥烷基)、-O(鹵烷基)、-O(環烷基)、-O(雜環烷基)、-O(芳基)、烷基硫基、芳基硫基、=O、=NH、=N(烷基)、=NOH、=NO(烷基)、-CO2
H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羥烷基)、-C(=O)NH2
、-C(=O)NH(烷基)、-C(=O)N(烷基)2
、-OC(=O)(烷基)、-OC(=O)(羥烷基)、-OC(=O)O(烷基)、-OC(=O)O(羥烷基)、-OC(=O)NH2
、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2
、疊氮基、-NH2
、-NH(烷基)、-N(烷基)2
、-NH(芳基)、-NH(羥烷基)、-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(環烷基)、-SO2
(烷基)、-SO2
NH2
、-SO2
NH(烷基)及-SO2
N(烷基)2
。更佳取代基為鹵基、羥基、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
、疊氮基、-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
。尤其較佳的為苯基、氰基、鹵基、羥基、硝基、C1
-C4
烷氧基、O(C2
-C4
伸烷基)OH及O(C2
-C4
伸烷基)鹵基。
若經取代之部分為環脂族、雜環脂族、芳基或雜芳基部分,則較佳取代基為烷基、烯基、炔基、鹵基、鹵烷基、羥基、羥烷基、氰基、硝基、烷氧基、-O(羥烷基)、-O(鹵烷基)、-O(芳基)、-O(環烷基)、-O(雜環烷基)、烷基硫基、芳基硫基、-C(=O)(烷基)、-C(=O)H、-CO2
H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羥烷基)、-C(=O)NH2
、-C(=O)NH(烷基)、-C(=O)N(烷基)2
、-OC(=O)(烷基)、-OC(=O)(羥烷基)、-OC(=O)O(烷基)、-OC(=O)O(羥烷基)、-OC(=O)NH2
、-OC(=O)NH(烷基)、-OC(=O)N(烷基)2
、疊氮基、-NH2
、-NH(烷基)、-N(烷基)2
、-NH(芳基)、-NH(羥烷基)、-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(環烷基)、-S(=O)烷基、-SO2
(烷基)、-SO2
NH2
、-SO2
NH(烷基)及-SO2
N(烷基)2
。更佳取代基為烷基、烯基、鹵基、鹵烷基、羥基、羥烷基、氰基、硝基、烷氧基、-O(羥烷基)、-C(=O)(烷基)、-C(=O)H、-CO2
H、-C(=O)NHOH、-C(=O)O(烷基)、-C(=O)O(羥烷基)、-C(=O)NH2
、-C(=O)NH(烷基)、-C(=O)N(烷基)2
、-OC(=O)(烷基)、-OC(=O)(羥烷基)、-OC(=O)O(烷基)、-OC(=O)O(羥烷基)、-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
。尤其較佳的為C1
-C4
烷基、氰基、硝基、鹵基及C1
-C4
烷氧基。
若陳述一範圍,如同「C1
-C5
烷基」或「5至10%」,則此類範圍包括範圍之端點,如同第一實例中之C1
及C5
及第二實例中之5%及10%。
除非特別指示特定立體異構體(例如藉由結構式中相關立構中心之加粗或短劃鍵,藉由將結構式中之雙鍵描述為具有E或Z構型或藉由使用指明立體化學之命名法),否則所有立體異構體均以純化合物以及其混合物之形式包括在本發明之範疇內。除非另外指明,否則個別對映異構體、非對映異構體、幾何異構體及其組合及混合物均由本發明涵蓋。
熟習此項技術者將瞭解化合物可具有互變異構形式(例如酮及烯醇形式)、共振形式及兩性離子形式,其等效於本文所用之結構式中所描繪之形式,且該等結構式涵蓋此類互變異構、共振或兩性離子形式。
「醫藥學上可接受之酯」意謂活體內(例如在人體中)水解產生母化合物或其鹽或自身活性類似於母化合物的酯。適合酯包括C1
-C5
烷酯、C2
-C5
烯酯或C2
-C5
炔酯,尤其甲酯、乙酯或正丙酯。
「醫藥學上可接受之鹽」意謂適用於醫藥調配物之化合物之鹽。若化合物具有一或多個鹼性基團,則鹽可為酸加成鹽,諸如硫酸鹽、氫溴酸鹽、酒石酸鹽、甲磺酸鹽、順丁烯二酸鹽、檸檬酸鹽、磷酸鹽、乙酸鹽、雙羥萘酸鹽(恩波酸鹽(embonate))、氫碘酸鹽、硝酸鹽、鹽酸鹽、乳酸鹽、甲基硫酸鹽、反丁烯二酸鹽、苯甲酸鹽、丁二酸鹽、甲磺酸鹽、乳糖酸鹽、辛二酸鹽、甲苯磺酸鹽及其類似鹽。若化合物具有一或多個酸性基團,則鹽可為如下鹽,諸如鈣鹽、鉀鹽、鎂鹽、葡甲胺鹽、銨鹽、鋅鹽、哌鹽、緩血酸胺鹽、鋰鹽、膽鹼鹽、二乙胺鹽、4-苯基環己胺鹽、苄星青黴素(benzathine)鹽、鈉鹽、四甲銨鹽及其類似鹽。多晶型結晶形式及溶劑合物亦涵蓋在本發明之範疇內。
在本說明書之式中,橫向於鍵之波浪線()或鍵末尾之星號(*)表示共價連接位點。舉例而言,對式中R為或R為之陳述意謂。
在本說明書之該等式中,穿過芳環在其兩個碳之間的鍵意謂連接至該鍵之基團可位於該芳環中藉由移除隱含存在之氫而變得可用的任何位置處。以說明之方式,式表示 。在另一說明中,表示。
一般而言,出於一致性及便利性,在本文中以烯醇形式呈現互變異構結構。熟習此項技術者將瞭解,該等互變異構結構亦可以等效酮形式呈現,且兩種互變異構體等效。 TLR7促效劑
在式(I)/(II)中,部分Ar視情況可經取代。取代基可例如為C1
-C3
烷基、C3
-C3
環烷基(CH2
)1 - 3
R3
、(CH2
)1 - 3
C(=O)(CH2
)0 - 3
R3
,其中R3
為鹵基OH、CN、NH2
、NH(C1
-C5
烷基)、N(C1
-C5
烷基)2
、NH(C3
-C6
環烷基)、NH(C4
-C8
雙環烷基)、NH(C6
-C10
螺環烷基)、N(C3
-C6
環烷基)2
、NH(CH2
)1 - 3
(芳基)、N((CH2
)1 - 3
(芳基))2
、具有結構之環胺部分、6員芳香族或雜芳香族部分或者5員雜芳香族部分; 其中 烷基、環烷基、雙環烷基、螺環烷基、環胺、6員芳香族或雜芳香族部分或者5員雜芳香族部分視情況經一或多個選自以下之取代基取代:OH、鹵基、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
及N(C1
-C3
烷基)2
;且 環烷基、雙環烷基、螺環烷基或環胺部分可具有經O、S、NH、N(C1
-C3
烷基)或N(Boc)置換之CH2
基團。
熟習此項技術者將瞭解,取決於取代基連接至Ar之碳抑或氮,
式(I)中之R1
較佳為n
-BuO、n
-BuNH、EtO、MeO或MeOCH2
CH2
O;更佳為n
-BuO或MeOCH2
CH2
O;且最佳為n
-BuO。
在式(I)中,各R2
較佳為H。
在一個實施例中,式(I)化合物由式(I')表示,其中各X'獨立地為CH或N,且R1
及Ar如上文關於式(I)所定義:
在一個實施例中,式(II)化合物由式(II')表示,其中各X'獨立地為CH或N,且R1
及Ar如上文關於式(II)所定義
在一個實施例中,式(I)化合物由式(Ia)表示其中R1
如上文關於式(I)所定義,各X'獨立地為CH或N,且R4
如下文所定義。
在一個實施例中,式(I)化合物由式(Ib)表示其中R1
如上文關於式(I)所定義,各X'獨立地為CH或N,且R4
如下文所定義。
在一個實施例中,式(I)化合物由式(Ic)表示其中R1
如上文關於式(I)所定義,各X'獨立地為CH或N,且R4
如下文所定義。
在式(Ia)、式(Ib)及式(Ic)中,R4
為H、C1
-C3
烷基、C3
-C3
環烷基(CH2
)1 - 3
R3
、(CH2
)1 - 3
C(=O)(CH2
)0 - 3
R3
,其中R3
為鹵基、OH、CN、NH2
、NH(C1
-C5
烷基)、N(C1
-C5
烷基)2
、NH(C3
-C6
環烷基)、NH(C4
-C8
雙環烷基)、NH(C6
-C10
螺環烷基)、N(C3
-C6
環烷基)2
、NH(CH2
)1 - 3
(芳基)、N((CH2
)1 - 3
(芳基))2
、具有結構之環胺部分、6員芳香族或雜芳香族部分或者5員雜芳香族部分; 其中 烷基、環烷基、雙環烷基、螺環烷基、環胺、6員芳香族或雜芳香族部分或者5員雜芳香族部分視情況經一或多個選自以下之取代基取代:OH、鹵基、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
及N(C1
-C3
烷基)2
;且 環烷基、雙環烷基、螺環烷基或環胺部分可具有經O、S、NH、N(C1
-C3
烷基)或N(Boc)置換之CH2
基團。
在式(Ia)、式(Ib)及式(Ic)中,R1
較佳為n-BuO。
在式(Ia)、式(Ib)及式(Ic)中,R4
較佳為。
式(Ia)化合物之實例包括: 。
式(Ib)化合物之實例包括:。
式(Ic)化合物之實例為:。
表A呈現本文中所揭示之化合物之生物活性資料。一組資料係關於使用HEK-Blue™ TLR7報導分析之TLR7促效作用活性,如下文中所描述。另一組資料係關於介白素6 (IL-6)之誘導,介白素6係在TLR7路徑中起重要作用的細胞介素。出於比較,亦呈現雷西莫特、威沙立德、嘎德莫特及化合物B (CAS登記號226906-84-9)之活性。
結合物綜述
本文中所揭示之TLR7促效劑可藉由局部投與或藉由以與靶向部分之結合物形式靶向遞送而遞送至預期作用位點。較佳地,靶向部分為抗體或其抗原結合部分,且其抗原位於預期作用位置,例如若預期作用位點位於腫瘤(癌症)則其抗原為腫瘤相關抗原。較佳地,相比於正常細胞,癌細胞唯一表現或過度表現腫瘤相關抗原。腫瘤相關抗原可位於癌細胞表面上或由癌細胞分泌至其環境中。
在一個態樣中,提供一種包含本發明化合物及配體之結合物,其由式( I V )
表示 [D(XD
)a
(C)c
(XZ
)b
]m
Z (IV) 其中Z為靶向部分,D為本發明之促效劑,且-(XD
)a
C(XZ
)b
-由於連接Z與D而統稱為「連接部分」或「連接子」。在連接子內,C為經設計以在D之預期生物學作用位點處或附近裂解之可裂解基團;XD
及XZ
分別為間隔開D與C及C與Z之間隔部分(或「間隔基」);下標a、b及c獨立地為0或1 (亦即,XD
、XZ
及C視情況存在)。下標m為1、2、3、4、5、6、7、8、9或10 (較佳1、2、3或4)。D、XD
、C、XZ
及Z更充分描述於下文中。
藉由結合於安置有其抗原或受體之標靶組織或細胞,Z將結合物引導至此處。基團C在標靶組織或細胞處之裂解釋放D,從而局部地發揮其效應。以此方式,達成D在預期作用位點之精確遞送,從而降低所需劑量。另外,D在處於其結合狀態時通常沒有生物活性(或活性明顯更低),從而減少脫靶效應。
如由下標m所反映,視可供用於結合之位點Z之數目及所用實驗條件而定,各Z可與多於一個D結合。熟習此項技術者將瞭解,雖然各個別Z與整數數目個D結合,但是結合物之製備可分析D與Z之非整數比率,其反映統計平均值。此比率稱為取代比率(「SR」)或藥物-抗體比率(「DAR」)。 靶向部分Z
較佳地,靶向部分Z為抗體。為方便及簡潔起見且以非限制方式,本說明書中關於Z及其結合物之詳細論述以其為抗體之情形書寫,但熟習此項技術者將理解,其他類型之Z亦可在細節上作必要修改後結合。舉例而言,帶有作為靶向部分之葉酸之結合物可靶向表面上具有葉酸受體之標靶細胞(Leamon等人, Cancer Res.2008
, 68 (23), 9839)。出於相同原因,本說明書中之詳細論述主要關於1:1比率之Z與D (m = 1)書寫。
可用於本發明結合物中之抗體包括識別以下抗原之抗體:間皮素、***特異性膜抗原(PSMA)、CD19、CD22、CD30、CD70、B7H3、B7H4 (亦稱為O8E)、蛋白質酪胺酸激酶7 (PTK7)、磷脂醯肌醇蛋白聚糖-3、RG1、岩藻糖基-GM1、CTLA-4及CD44。抗體可為動物(例如鼠類)、嵌合、人類化或較佳人類抗體。抗體較佳為單株抗體,尤其單株人類抗體。針對前述抗原中之一些的人類單株抗體之製備揭示於以下文獻中:Korman等人, US 8,609,816 B2 (2013;B7H4,亦稱為08E;特定言之抗體2A7、1G11及2F9); Rao-Naik等人, 8,097,703 B2 (2012;CD19;特定言之抗體5G7、13F1、46E8、21D4、21D4a、47G4、27F3及3C10);King等人, US 8,481,683 B2 (2013;CD22;特定言之抗體12C5、19A3、16F7及23C6);Keler等人, US 7,387,776 B2 (2008;CD30;特定言之抗體5F11、2H9及17G1);Terrett等人, US 8,124,738 B2 (2012;CD70;特定言之抗體2H5、10B4、8B5、18E7及69A7);Korman等人, US 6,984,720 B1 (2006;CTLA-4;特定言之抗體10D1、4B6及1E2);Korman等人, US 8,008,449 B2 (2011;PD-1;特定言之抗體17D8、2D3、4H1、5C4、4A11、7D3及5F4);Huang等人, US 2009/0297438 A1 (2009;PSMA;特定言之抗體1C3、2A10、2F5、2C6);Cardarelli等人, US 7,875,278 B2 (2011;PSMA;特定言之抗體4A3、7F12、8C12、8A11、16F9、2A10、2C6、2F5及1C3);Terrett等人, US 8,222,375 B2 (2012;PTK7;特定言之抗體3G8、4D5、12C6、12C6a及7C8);Harkins等人, US 7,335,748 B2 (2008;RG1;特定言之抗體A、B、C及D);Terrett等人, US 8,268,970 B2 (2012;間皮素;特定言之抗體3C10、6A4及7B1);Xu等人, US 2010/0092484 A1 (2010;CD44;特定言之抗體14G9.B8.B4、2D1.A3.D12及1A9.A6.B9);Deshpande等人, US 8,258,266 B2 (2012;IP10;特定言之抗體1D4、1E1、2G1、3C4、6A5、6A8、7C10、8F6、10A12、10A12S及13C4);Kuhne等人, US 8,450,464 B2 (2013;CXCR4;特定言之抗體F7、F9、D1及E2);以及Korman等人, US 7,943,743 B2 (2011;PD-L1;特定言之抗體3G10、12A4、10A5、5F8、10H10、1B12、7H1、11E6、12B7及13G4);該等文獻之揭示內容以引用之方式併入本文中。較佳地,抗體為抗間皮素抗體。
除為抗體外,Z亦可為抗體片段(諸如Fab、Fab'、F(ab')2
、Fd或Fv)或抗體模擬物,諸如親和抗體(affibody)、單域抗體(dAb)、奈米抗體、單抗體、DARPin、抗運載蛋白(anticalin)、萬能抗體(versabody)、雙運載蛋白(duocalin)、脂質運載蛋白(lipocalin)或高親和性多聚體(avimer)。
Z上若干不同反應性基團中之任一者可為結合位點,包括離胺酸殘基中之ε-胺基、側鏈碳水化合物部分、天冬胺酸或麩胺酸側鏈上之羧酸基、半胱胺酸-半胱胺酸二硫基及半胱胺酸硫醇基。適用於結合之抗體反應性基團之論述參見例如Garnett,Adv. Drug Delivery Rev. 2001
, 53, 171-216以及Dubowchik及Walker,Pharmacology & Therapeutics 1999
, 83, 67-123,其揭示內容以引用之方式併入本文中。
大部分抗體具有多個離胺酸殘基,該等殘基可經由其ε-胺基藉由醯胺、脲、硫脲或胺基甲酸酯鍵而結合。
可藉由若干方法使用半胱胺酸之側鏈中之硫醇(-SH)基來形成結合物。該硫醇基可用於在其與連接子上之硫醇基之間形成雙硫鍵。另一方法係經由與連接子上之順丁烯二醯亞胺基之邁克爾加成反應(Michael addition)。
通常,儘管抗體具有半胱胺酸殘基,但其沒有游離的硫醇基,因為其所有半胱胺酸都形成了鏈內或鏈間二硫鍵。為了產生游離的硫醇基,可減少天然二硫基。參見例如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,可藉由使抗體突變、用半胱胺酸取代另一胺基酸或將半胱胺酸***多肽鏈中而引入具有游離-SH基團之半胱胺酸。參見例如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日申請之US臨時申請案第62/270245號。在另一方法中,將半胱胺酸添加至重鏈或輕鏈的C端。參見例如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,Bioconjugate Chem. 2002
, 13, 985;Yang等人,Protein Engineering 2003
, 16, 761;及Olafson等人,Protein Engineering Design & Selection 2004
, 17, 21。此段落中引用之文獻的揭示內容以引用之方式併入本文中。 連接子及其組分
如上文所提及,連接子包含多達三個元件:可裂解基團C及視情況存在之間隔基XZ
及XD
。
基團C在生理條件下可裂解。較佳地,基團C在結合物處於血液循環中時相對穩定,但在結合物到達其預期作用位點後容易裂解。
較佳基團C為肽,相對於由血清中之蛋白酶裂解,其由標靶細胞內之蛋白酶選擇性裂解。通常,肽包含1至20個胺基酸,較佳1至6個胺基酸,更佳2至3個胺基酸。胺基酸可為天然及/或非天然α-胺基酸。天然胺基酸為由遺傳密碼編碼之胺基酸以及衍生自其之胺基酸,例如羥基脯胺酸、γ-羧基麩胺酸、瓜胺酸及O-磷絲胺酸。在本說明書中,術語「胺基酸」亦包括胺基酸類似物及模擬物。類似物為如下化合物,其具有天然胺基酸之相同通用H2
N(R)CHCO2
H結構,但R基團不為天然胺基酸中存在之基團。類似物之實例包括高絲胺酸、正白胺酸、甲硫胺酸-亞碸及甲硫胺酸甲基鋶。胺基酸模擬物為如下化合物,其具有不同於α-胺基酸之通用化學結構的結構,但以類似於α-胺基酸之方式起作用。胺基酸可具有遺傳編碼胺基酸之「L」立體化學以及對映異構「D」立體化學。
較佳地,C含有為蛋白酶之裂解識別序列的胺基酸序列。許多裂解識別序列為此項技術中已知的。參見例如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);其揭示內容以引用之方式併入本文中。
基團C可經選擇以使得其由癌症附近之細胞外基質中所存在的蛋白酶裂解,該蛋白酶例如附近死亡癌細胞所釋放之蛋白酶或癌細胞所分泌之腫瘤相關蛋白酶。例示性細胞外腫瘤相關蛋白酶為纖維蛋白溶酶、基質金屬蛋白酶(MMP)、甲拌磷寡肽酶(TOP)及CD10。參見例如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)。通常為存在於細胞內部之溶酶體酶的組織蛋白酶D有時存在於腫瘤環境中,有可能由死亡癌細胞所釋放。
對於經設計以藉由酶裂解之結合物而言,C較佳包含經選擇以藉由諸如組織蛋白酶B、C、D、H、L及S (尤其組織蛋白酶B)之蛋白酶裂解的胺基酸序列。例示性組織蛋白酶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,除非上下文明確指示,否則胺基酸序列以N至C方向書寫,如同H2
N-AA2
-AA1
-CO2
H。)參見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;其揭示內容以引用之方式併入。
可用於裂解肽基連接子之另一酶為豆莢蛋白,一種較佳在Ala-Ala-Asn處裂解之溶酶體半胱胺酸蛋白酶。
在一個實施例中,基團C為包含兩個胺基酸序列-AA2
-AA1
-之肽,其中AA1
為離胺酸、精胺酸或瓜胺酸,且AA2
為***酸、纈胺酸、丙胺酸、白胺酸或異白胺酸。在另一實施例中,C由具有一至三個胺基酸之序列組成,其選自由以下組成之群: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。更佳地,C為前述群中之兩個至三個胺基酸肽。
由單個胺基酸組成之可裂解基團C之製備及設計揭示於Chen等人, US 8,664,407 B2 (2014)中,其揭示內容以引用之方式併入本文中。
基團C可直接結合於Z或D;亦即,間隔基XZ
或XD
視情況可不存在。
在存在時,間隔基XZ
提供C與Z之間的空間分隔,以免前者空間干擾後者之抗原結合或後者空間干擾前者之裂解。此外,間隔基XZ
可用於賦予結合物增加之溶解性或降低之凝集特性。間隔基XZ
可包含一或多個模組區段,其可組裝於任何數目之組合中。間隔基XZ
之適合區段之實例為: ,及其組合,其中下標g為0或1,且下標h為1至24,較佳2至4。此等區段可組合,諸如如下所說明:。
若存在,間隔基XD
提供C與D之間的空間分隔,以免後者空間上或電子學上干擾前者之裂解。間隔基XD
亦可用於將其他分子量及化學官能基引入結合物中。一般而言,其他質量及官能基將影響結合物之血清半衰期及其他特性。因此,經由明智選擇間隔基,可調節結合物之血清半衰期。間隔基XD
亦可類似於上文關於間隔基XZ
之描述由模組區段組裝。
間隔基XZ
及/或XD
在存在時較佳在Z與C或D與C之間分別提供4至25個原子、更佳4至20個原子之線性分隔。
除共價連接抗體與藥物以外,連接子可執行其他功能。舉例而言,連接子可含有聚(乙二醇) (「PEG」)基團。由於結合步驟通常涉及在水性介質中將藥物-連接子偶合至抗體,因此PEG基團可增加藥物-連接子之水溶解度。另外,PEG基團可增加所得ADC之溶解度或降低其凝集。若存在PEG基團,則可將其併入間隔基XZ
或XD
或兩者中。PEG基團中重複單元之數目可為2至20,較佳4至10。
間隔基XZ
或XD
或兩者可包含自分解部分。自分解部分為如下部分,其(1)結合至C以及Z或D中之一者,且(2)具有使得基團C之裂解起始反應序次之結構,從而使自分解部分自身視情況與Z或D脫離。換言之,遠離Z或D之位點處之反應(基團C之裂解)使得XZ
-Z或XD
-D鍵亦斷裂。自分解部分之存在在間隔基XD
之情形下為適宜的,因為若在結合物裂解後間隔基XD
或其一部分保持連接於D,則D之生物活性可能受損。在可裂解基團C為多肽的情形下使用自分解部分為尤其適宜的,在該實例中自分解部分通常鄰近於該多肽定位,以便防止D在空間上或在電子學上干擾肽裂解。
結合至D之羥基或胺基的例示性自分解部分(i)至(v)如下所示:
自分解部分為點線a與b (或點線b與c)之間的結構,其中展示相鄰結構特徵以提供背景。自分解部分(i)及(v)結合至D-NH2
(亦即經由胺基結合),而自分解部分(ii)、(iii)及(iv)結合至D-OH (亦即經由羥基或羧基結合)。點線b處之鍵由於酶(在結構(i)至(v)之實例中為肽酶且在結構(vi)之實例中為β-葡糖醛酸酶)而發生之裂解起始自分解反應序次,其引起點線a處之鍵裂解以及視情況D-OH或D-NH2
之隨後釋放。以說明之方式,結構(i)及(iv)之自分解機制如下所示:
換言之,自分解基團之一個部分處之第一化學鍵的裂解起始一連串步驟,其引起自分解基團之另一部分處之第二化學鍵(將自分解基團連接至藥物之化學鍵)裂解,從而釋放藥物。
在一些情況下,自分解基團可串聯使用,如結構(vii)所示。在此情況下,點線c處之裂解觸發點線b與c之間的部分藉由1,6-消除反應而自我分解,接著點線a與b之間的部分藉由環化-消除反應而自我分解。關於自分解部分之其他揭示案參見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 (勘誤表第941頁);Boyd等人, US 7,691,962 B2;Boyd等人, US 2008/0279868 A1;Sufi等人, WO 2008/083312 A2;Feng, US 7,375,078 B2;Jeffrey等人, US 8,039,273;及Senter等人, US 2003/0096743 A1;其揭示內容以引用之方式併入。
在另一實施例中,Z與D藉由不可裂解連接子連接,亦即不存在C。D之代謝最終將連接子減小成不會干擾D之生物活性的較小附接部分。 結合技術
本文中所揭示之TLR7促效劑之結合物較佳藉由以下方式製得:首先製備包含D及連接子(XD
)a
(C)c
(XZ
)b
(其中XD
、C、XZ
、a、b及c如針對式(II)所定義)之化合物,以形成由式(V)表示之藥物-連接子化合物: D-(XD
)a
(C)c
(XZ
)b
-R31
(V) 其中R31
為適用於與Z上之補體官能基反應形成結合物之官能基。適合基團R31
之實例包括胺基、疊氮基、硫醇、環辛炔、其中R32
為Cl、Br、F、甲磺酸酯或甲苯磺酸酯,且R33
為Cl、Br、I、F、OH、-O-N-丁二醯亞胺基、-O-(4-硝基苯基)、-O-五氟苯基或-O-四氟苯基。通常可用於製備適合部分D-(XD
)a
C(XZ
)b
-R31
之化學方法揭示於以下中: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, US 7,691,962 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);其揭示內容以引用之方式併入本文中。
較佳反應性官能基-R31
為-NH2
、-OH、-CO2
H、-SH、順丁烯二醯亞胺基、環辛炔、疊氮基(-N3
)、羥基胺基(-ONH2
)或N-羥基丁二醯亞胺基。尤其較佳的官能基-R31
為:。
-OH基團可用抗體上(例如天冬胺酸或麩胺酸側鏈上)之羧基酯化。
-CO2
H基團可用抗體上之-OH基團酯化或用抗體上(例如離胺酸側鏈上)之胺基醯胺化。
N-羥基丁二醯亞胺基為功能上活化之羧基且可便利地藉由與胺基(例如離胺酸之胺基)反應醯胺化。
順丁烯二醯亞胺基可與抗體上之-SH基團(例如來自半胱胺酸或來自引入硫氫基官能基之抗體之化學修飾)在邁克爾加成反應中結合。
若抗體不具有用於結合之半胱胺酸-SH,則離胺酸殘基之側鏈中之ε-胺基可與2-亞胺基硫雜環戊烷或N-丁二醯亞胺基-3-(2-吡啶基二硫基)丙酸酯(「SPDP」)反應以引入游離的硫醇(-SH)基,從而實際上產生半胱胺酸替代物。硫醇基可與順丁烯二醯亞胺或其他親核試劑受體基團反應以實現結合。下方示出2-亞胺基硫雜環戊烷情形下之機制。
通常,達成每個抗體二至三個硫醇的硫醇化水準。代表性過程參見Cong等人, US 8,980,824 B2 (2015),其揭示內容以引用之方式併入本文中。
在相反配置中,可以用4-(順丁烯二醯亞胺基甲基)-環己甲酸N-丁二醯亞胺基酯(「SMCC」)或其磺化變體磺基-SMCC (該兩者可購自Sigma-Aldrich)修飾抗體Z,以向其中引入順丁烯二醯亞胺基。隨後,可使用連接子上具有-SH基團之藥物-連接子化合物來實現結合。
替代結合方法使用無銅「點擊化學法(click chemistry)」,其中將疊氮基添加在應變環辛炔上以形成1,2,3-***環。參見例如Agard等人,J. Amer. Chem. Soc. 2004
,126
, 15046;Best,Biochemistry 2009
,48
, 6571,其揭示內容以引用之方式併入本文中。疊氮基可位於抗體上且環辛炔位於藥物-連接子部分上或反之亦然。較佳環辛炔基為二苯并環辛炔(DIBO)。具有DIBO基團之各種試劑可獲自Invitrogen/Molecular Probes, Eugene, Oregon。以下反應說明DIBO基團連接於抗體(Ab)之情況下的點擊化學法結合:
另一結合技術涉及將非天然胺基酸引入抗體中,其中非天然胺基酸提供用於與藥物部分中之反應性官能基結合的官能基。舉例而言,非天然胺基酸對乙醯基***酸可併入抗體或其他多肽中,如Tian等人, WO 2008/030612 A2 (2008)中所教示。對乙醯基***酸中之酮基可經由與連接子-藥物部分上之羥基胺基形成肟而成為結合位點。替代地,可將非天然胺基酸對疊氮基***酸併入抗體中,得到疊氮基官能基以如上所述經由點擊化學法結合。非天然胺基酸亦可使用無細胞方法而併入抗體或其他多肽中,如Goerke等人, US 2010/0093024 A1 (2010)及Goerke等人,Biotechnol . Bioeng . 2009
, 102 (2), 400-416中所教示。前述揭示內容以引用之方式併入本文中。因此,在一個實施例中,用於製備結合物之抗體具有一或多個經非天然胺基酸置換之胺基酸,該非天然胺基酸較佳為對乙醯基***酸或對疊氮基***酸,更佳為對乙醯基***酸。
根據Jeger等人,Angew . Chem . Int . Ed . 2010
,49
, 9995,另一結合技術使用轉麩醯胺酸酶(較佳為來自茂源鏈黴菌(Streptomyces mobaraensis
)之細菌性轉麩醯胺酸酶或BTG)。BTG在麩醯胺酸之側鏈甲醯胺(胺受體)與伸烷基胺基(胺供體) (其可為例如離胺酸之ε-胺基或5-胺基-正戊基)之間形成醯胺鍵。在典型結合反應中,如下所示,麩醯胺酸殘基位於抗體上,而伸烷基胺基位於連接子-藥物部分上:
麩醯胺酸殘基位於多肽鏈上對其對BTG介導之轉醯胺作用之敏感性具有很大影響。抗體上之麩醯胺酸殘基通常均不為BTG受質。然而,若抗體去糖基化,糖基化位點為重鏈之天冬醯胺297 (N297;根據如Kabat等人, 「Sequences of proteins of immunological interest」, 第5版, 公開案第91-3242號, 美國健康與人類服務部(U.S. Dept. Health & Human Services), NIH, Bethesda, Md., 1991;下文簡稱「Kabat」中所闡述之EU索引編號),則鄰近的麩醯胺酸295 (Q295)表現為BTG敏感的。抗體可藉由用PNGase F (肽-N-糖苷酶F)處理而以酶方式去糖基化。替代地,抗體可藉由在恆定區中引入N297A突變而以無糖苷之形式合成,從而去除N297糖基化位點。此外,已證實N297Q取代不僅去除糖基化,且亦引入同樣為胺受體之第二麩醯胺酸殘基(在位置297處)。由此,在一個實施例中,抗體去糖基化。在另一實施例中,抗體具有N297Q取代。熟習此項技術者將瞭解,藉由合成後修飾或藉由引入N297A突變進行之去糖基化使每個抗體產生二個BTG反應性麩醯胺酸殘基(每條重鏈一個,在位置295處),而具有N297Q取代之抗體將具有四個BTG反應性麩醯胺酸殘基(每條重鏈兩個,在位置295及297處)。
藉由向抗體中引入含有麩醯胺酸之肽或「標記物」,抗體亦可表現為對BTG介導之結合敏感,例如Pons等人, US 2013/0230543 A1 (2013)及Rao-Naik等人, WO 2016/144608 A1中所教示。
在補充方法中,可藉由改變BTG之胺基酸序列而改變其受質特異性,使得其變得能夠與未經修飾抗體中之麩醯胺酸295反應,如Rao-Naik等人, WO 2017/059158 A1 (2017)中所教示。
雖然最常用的細菌性轉麩醯胺酸酶為來自茂源鏈黴菌之細菌性轉麩醯胺酸酶,但亦可考慮來自受質特異性略微不同的其他細菌之轉麩醯胺酸酶,諸如來自拉達卡鏈輪絲菌(Streptoverticillium ladakanum
)之轉麩醯胺酸酶(Hu等人, US 2009/0318349 A1 (2009)、US 2010/0099610 A1 (2010)及US 2010/0087371 A1 (2010))。
具有一級或二級烷基胺之本發明TLR7促效劑尤其適合於以結合物形式使用,因為二級胺提供用於連接連接子之官能基。此類TLR7促效劑-連接子化合物之實例為化合物11
,其含有酶促可裂解連接子。圖 4
示出可據其製備化合物11
之流程。
含有非酶促可裂解連接子之TLR7促效劑-連接子化合物之實例為化合物13
。圖 5
示出用於合成化合物13
之流程。
化合物11
及13
均含有一級烷基胺基,使得其能夠與轉麩醯胺酸酶結合。下文實例中描述適合的結合過程。
亦可使用分選酶A (Sortase A)來實現結合,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。分選酶A識別基元(通常LPXTG,其中X為任何天然胺基酸)可位於配體Z上,且親核性受體基元(通常GGG)可為式(III)
中之基團R31
,或反之亦然。 TLR7促效劑結合物
應用前述技術,可製備TLR7促效劑結合物,諸如下方所示之結合物: 其中m為1、2、3或4,且Ab為抗體。 聚乙二醇化
將聚(乙二醇) (PEG)鏈連接至藥物(「聚乙二醇化」)可改良藥物之藥物動力學特性。藥物之循環半衰期增加,有時增加超過一個數量級,同時降低了達成所要治療效果所需要的劑量。聚乙二醇化亦可減少藥物之代謝降解且降低其免疫原性。論述參見Kolate等人, J. Controlled Release 2014, 192, 167。
聚乙二醇化最初應用於生物藥物。截至2016年,已批准超過十種聚乙二醇化生物製劑。Turecek等人, J. Pharmaceutical Sci. 2016, 105, 460。最近,受該理論於生物製劑中之成功應用的刺激,人們注意力已轉向其於小分子藥物中之應用。除前述益處外,聚乙二醇化小分子藥物可具有增加的溶解度且引起較少毒性作用。Li等人 Prog. Polymer Sci. 2013, 38, 421。
本文所揭示之化合物可經聚乙二醇化。在化合物具有脂族羥基或脂族一級或二級胺時,諸如化合物Ia-01或Ia-02 (箭頭)之情形,該化合物可利用習知技術(諸如二環己基碳化二亞胺(DCC)、HATU、N-羥基丁二醯亞胺酯以及其類似技術)藉由含有羧基之PEG分子經由酯基、醯胺基、碳酸酯基或胺基甲酸酯基而聚乙二醇化。用於對醫藥分子進行聚乙二醇化之各種其他方法揭示於Alconcel等人, Polymer Chem. 2011, 2, 1442中,其揭示內容以引用之方式併入本文中。
視需要,本文中所揭示之TLR7促效劑可經由包含自分解部分之酶促可裂解連接子聚乙二醇化,從而允許未經聚乙二醇化之促效劑以設計方式釋放。此外,若含有PEG之分子具有用於連接至蛋白質之適合官能基(諸如胺),則聚乙二醇化可與同蛋白質(諸如抗體)之結合組合。蛋白質可提供額外治療功能,或在抗體的情況下可提供靶向功能。在下方反應序次中示出此等理論,其中TLR7-NH-R通常表示TLR7促效劑:
在上述反應序次中,纈胺酸-瓜胺酸(Val-Cit)二肽可藉由組織蛋白酶B裂解,其中對胺基苯甲基氧基羰基(PABC)充當自分解間隔基。用於結合之官能基為胺基,其暫時受Fmoc基團保護。結合由轉麩醯胺酸酶實現,其中麩醯胺酸(Gln)側鏈充當醯基受體。視聚乙二醇化之目的而定,表示PEG重複單元之數目的下標x可廣泛變化,如下文所論述。出於一些目的,x可相對較小,諸如2、4、8、12或24。出於其他目的,x較大,例如介於約45與約910之間。
熟習此項技術者將理解,該序次為說明性的,且可使用如此項技術中所熟知的其他要素(肽、自分解基團、結合方法、PEG長度等)。熟習此項技術者亦將理解,雖然上述序次組合聚乙二醇化與結合,但聚乙二醇化不需要結合。且反之亦然。
在化合物沒有脂族羥基或脂族一級或二級胺時,如在化合物3 (圖1)之情形中,仍然可在芳胺(箭頭)處聚乙二醇化。在該位置處進行聚乙二醇化之方法由Zarraga, US 2017/0166384 A1 (2007)揭示,其揭示內容以引入之方式併入。
在一些實施例中,可能需要單個分子中連接有多個聚乙二醇化促效劑。舉例而言,可在季戊四醇(C(CH2
OH)4
)上構築四個聚乙二醇化臂,且TLR7促效劑可連接至各聚乙二醇化臂。參見Gao等人, US 2013/0028857 A1 (2013),其揭示內容以引用之方式併入。
為了調節藥物動力學,通常較佳的係PEG部分之分子量介於約2 kDa (對應於約45個-(CH2
CH2
O)-重複單元)與約40 kDa (對應於約910個-(CH2
CH2
O)-重複單元)之間,更佳介於約5 kDa與約20 kDa之間。亦即,上式中下標x之範圍為約45至約910。應理解,PEG組合物並非100%均質的,而是實際上呈現分子量分佈。因此,例如對「20 kDa PEG」之提及意謂具有20 kDa之平均分子量的PEG。
聚乙二醇化亦可用於改良促效劑之溶解度。在此等情況下,可使用較短PEG鏈,例如包含2、4、8、12或24個重複單元。 實例
可參考以下實例進一步理解本發明之實踐,其係以說明方式提供且不意謂具有限制性。 實例1-式(Ia)化合物之合成
此實例及圖 1
及圖
7係關於式(Ia)化合物之合成。
首先參看圖 1
:使氮氣鼓泡通過含有以下之可密封試管2分鐘:含9-(4-溴苯甲基)-2-丁氧基-8-甲氧基-9H-嘌呤-6-胺1
(根據WO 2011/049815 A1製備,400 mg,0.985 mmol)、2-(3-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1H-吡唑-1-基)乙酸乙酯2
(359 mg,1.280 mmol)及K2
CO3
(476 mg,3.45 mmol)之二噁烷(12 ml)及水(3 ml)。添加肆(三苯基膦)鈀(0) (114 mg,0.098 mmol),且使N2
鼓泡通過該試管另外1分鐘。隨後密封試管,且在80℃下攪拌2.5小時後,反應完成。冷卻後,添加EtOAc (20 m),且經由CELITE™墊濾出固體。分離濾液之兩個層。用EtOAc萃取水層兩次。經合併之有機萃取物經Na2
SO4
乾燥,過濾且濃縮。粗產物經12 g矽膠管柱純化,用20% MeOH/二氯甲烷(DCM,0-30%梯度)溶離。濃縮所要溶離份,得到酯3
(168 mg,0.350 mmol,35.6%產率)。LCMS ESI:C24
H29
N7
O4
之計算值= 480.2 (M+H+
),實驗值480.1 (M+H+
)。
用1.0 N HCl將濾液之水層酸化至pH 4,且用20% MeOH/DCM (3×15 mL)萃取。經合併之有機萃取物經Na2
SO4
乾燥,過濾且濃縮,得到酸4
(97 mg,0.215 mmol,21.82%產率)。LCMS ESI:C22
H25
N7
O4
之計算值= 452.2 (M+H+
),實驗值452.1 (M+H+
)。
用(2-胺基乙基)胺基甲酸第三丁酯(26.6 mg,0.166 mmol)、三甲胺(TEA,0.046 mL,0.332 mmol)及-(3H-[1,2,3]***并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基異六氟磷酸酯(V) (HATU,54.7 mg,0.144 mmol)處理酸4
(50 mg,0.111 mmol)於N,N-二甲基甲醯胺(1.5 mL)中之經攪拌溶液。2小時後,用水淬滅反應混合物,且在室溫(RT)下攪拌隔夜。藉由過濾收集所得固體,並風乾。將粗製固體溶解於0.5 mL THF中且用1.0 N HCl (0.5 mL)處理。在60℃下攪拌6小時後,反應完成。粗產物經15.5 g C18 Aq管柱純化,且用0.05% TFA/ACN:0.05% TFA/H2
O (0-50%梯度)溶離,得到化合物( Ia - 02 )
(三氟乙酸鹽,10.1 mg,0.017 mmol,15.06%產率)。LCMS ESI:C23
H29
N9
O3
之計算值= 480.2 (M+H+
),實驗值480.1 (M+H+
)。1
H NMR (400 MHz, 甲醇-d4
) δ 7.93 (s, 1H), 7.82 (s, 1H), 7.43 (d,J
=8.4 Hz, 2H), 7.32 (s, 2H), 4.89 (s, 2H), 4.81 (s, 2H), 4.29 - 4.10 (m, 2H), 3.41 (t,J
=5.7 Hz, 2H), 2.98 (t,J
=5.7 Hz, 2H), 1.72 - 1.54 (m, 2H), 1.38 (d,J
=7.7 Hz, 2H), 0.87 (t,J
=7.4 Hz, 3H)。
現參看圖 7
:向2-丁氧基-8-甲氧基-9H-嘌呤-6-胺14
(CAS登記號866268-31-7,TFA鹽,500 mg,1.423 mmol)及碳酸銫(1,484 mg,4.55 mmol)於DMF (10 mL)中之懸浮液中添加2-(4-(溴甲基)苯基)-4,4,5,5-四甲基-1,3,2-二氧硼㖦15
(CAS登記號138500-85-3,507 mg,1.708 mmol)。將反應混合物在環境溫度下攪拌3小時後,反應完成,得到兩種主要產物。反應物用飽和NH4
Cl淬滅。藉由過濾收集所得固體並乾燥,得到混合物17
(600 mg,0.242 mmol,17.03%產率)與化合物16
(600 mg,0.926 mmol,65.1%產率)之混合物。LCMS ESI (化合物17
):C17
H23
BN5
O4
之計算值= 372.2 (M+H+),實驗值372.2 (M+H+)。LCMS ESI (化合物16
):C23
H33
BN5
O4
之計算值= 454.3 (M+H+),實驗值454.2 (M+H+)。
向化合物17
(600 mg,0.242 mmol)與化合物16
(600 mg,0.926 mmol)之混合物中添加含2-(4-溴-1H-吡唑-1-基)乙-1-醇18
(CAS登記號214614-81-0,336 mg,1.757 mmol)及K2
CO3
(607 mg,4.39 mmol)之二噁烷(8 mL)及水(2.000 mL)。使氮氣鼓泡通過反應混合物2分鐘。隨後添加PdCl2
(dppf)-CH2
Cl2
加合物(154 mg,0.188 mmol)。將氮氣鼓泡至該反應混合物中另外1分鐘。密封反應容器,且將其內含物在80℃下攪拌5小時。冷卻反應混合物,用乙酸乙酯稀釋且過濾。濾液經Na2
SO4
乾燥,且濃縮。粗產物藉由ISCO矽膠管柱(40 g)純化,用20% MeOH/DCM (DCM梯度0-40%)溶離。濃縮所要溶離份,得到化合物19
(247 mg,0.565 mmol,45.0%產率)。LCMS ESI:C23
H27
N7
O3
之計算值= 438.2 (M+H+),實驗值438.1(M+H+)。1
H NMR (400 MHz, 甲醇-d4) δ 8.00 (s, 1H), 7.84 (s, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 5.13 (s, 2H), 4.34 (t, J=6.6 Hz, 2H), 4.26 (s, 2H), 4.14 (s, 3H), 3.92 (t, J=5.4 Hz, 2H), 1.84 - 1.65 (m, 2H), 1.59 - 1.37 (m, 2H), 1.00 (t, J=7.5 Hz, 3H)。
向化合物19
(57 mg,0.130 mmol)於THF (0.5 mL)中之經攪拌懸浮液中添加HCl (1.0 N於水中,1 mL,0.130 mmol)。將反應混合物在60℃下攪拌3小時後反應完成。冷卻後,藉由過濾收集白色固體沈澱並用水沖洗,且風乾,得到化合物Ia - 01
(37 mg,0.086 mmol,65.7%產率)。LCMS ESI:C22
H25
N7
O3
之計算值= 424.2 (M+H+),實驗值423.9(M+H+)。1
H NMR (400 MHz, 甲醇-d4) δ 8.20 - 7.94 (m, 1H), 7.89 (br s, 1H), 7.55 (br d, J=7.7 Hz, 2H), 7.43 (br d, J=7.9 Hz, 2H), 5.05 (s, 2H), 4.55 (t, J=6.3 Hz, 2H), 4.25 (br d, J=1.8 Hz, 2H), 4.08 - 3.59 (m, 2H), 1.87 - 1.69 (m, 2H), 1.57 - 1.41 (m, 2H), 1.00 (t, J=7.4 Hz, 3H)。
用亞硫醯氯(1.175 mL,16.10 mmol)處理化合物Ia - 01
(341 mg,0.805 mmol)於THF (10 mL)中之經攪拌懸浮液,且隨後在RT下攪拌4小時。用DCM (3×)共沸去除亞硫醯氯。殘餘物隨後經ISCO矽膠管柱(24 g)純化,用20% MeOH/DCM (DCM梯度0-45%)溶離。濃縮所要溶離份,得到化合物Ia - 07
(200 mg,0.453 mmol,56.2%產率)。LCMS ESI:C22
H24
ClN7
O2
之計算值= 442.2 (M+H+),實驗值442.2 (M+H+)。1
H NMR (500 MHz, DMSO-d6) δ 9.99 (br s, 1H), 8.21 (s, 1H), 7.91 (s, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.30 (br d, J=8.1 Hz, 2H), 6.46 (br s, 2H), 4.85 (s, 2H), 4.51 - 4.39 (m, 2H), 4.20 - 4.10 (m, 2H), 4.02 (br t, J=5.8 Hz, 2H), 1.68 - 1.58 (m, 2H), 1.44 - 1.31 (m, 2H), 0.92 (t, J=7.4 Hz, 3H)。
向化合物Ia - 07
(87 mg,0.1969 mmol)於DMF (5 mL)中之懸浮液中添加環丁胺(0.5 mL,5.9 mmol)。將反應混合物在60℃下攪拌18小時。冷卻後,用旋轉式蒸發器去除多餘胺。用DMSO (15 ml)稀釋反應混合物。濾出不可溶物質。藉由C18 (Accu製備型)層析進行純化,用0.05% TFA/乙腈:0.05% TFA/水(0-40%梯度)溶離。將所要溶離份濃縮至1/3體積,冷凍且凍乾,得到化合物Ia - 04
(47 mg,0.079 mmol,40.1%產率)。LCMS ESI:C26
H32
N8
O2
之計算值= 477.3 (M+H+),實驗值477.2 (M+H+)。1
H NMR (400 MHz, 甲醇-d4) δ 7.87 (s, 1H), 7.72 (s, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 4.88 (s, 2H), 4.19 (t, J=6.6 Hz, 2H), 4.13 (t, J=6.5 Hz, 2H), 3.14 (br t, J=7.7 Hz, 1H), 2.87 (t, J=6.4 Hz, 2H), 2.18 - 2.06 (m, 2H), 1.71 - 1.56 (m, 6H), 1.46 - 1.30 (m, 2H), 0.86 (t, J=7.4 Hz, 3H)。
以類似方式製備其他式(Ia)化合物。其分析性資料提供於表B中。
在聚乙二醇化之圖示中,DCC介導的化合物( Ia - 01 )
與HO2
C(CH2
CH2
O)37
CH3
之酯化得到實例2-式(Ib)化合物之合成
此實例及圖 2
係關於式(Ib)化合物之合成。
使用與針對化合物3所描述類似的過程,由化合物1及化合物5 (CAS登記號1266480-56-1)製備化合物6。LCMS ESI:C27H34N6O4S之計算值= 539.2 (M+H+),實驗值539.1 (M+H+)。1H NMR (400 MHz, 甲醇-d4) δ 7.59 (d, J=8.4 Hz, 2H), 7.47 (s, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.28 (s, 1H), 5.14 (s, 2H), 4.41 (s, 2H), 4.34 (t, J=6.6 Hz, 2H), 4.14 (s, 3H), 1.84 - 1.65 (m, 2H), 1.56 - 1.40 (m, 11H), 1.00 (t, J=7.4 Hz, 3H)。
用HCl (1.0 N於水中,1.0 mL)處理化合物6 (45 mg,0.084 mmol)於THF (1 mL)中之經攪拌溶液。在70℃下攪拌5小時後,反應完成。濃縮反應混合物。粗產物經15.5 g C18 Aq管柱純化,且用0.05% TFA/乙腈:0.05% TFA/H2O (0-50%梯度)溶離,得到為三氟乙酸鹽之化合物(Ib-01) (31.1 mg,0.057 mmol,67.7%產率)。LCMS ESI:C27H34N6O4S之計算值= 425.2 (M+H+),實驗值425.1 (M+H+)。1H NMR (400 MHz, 甲醇-d4) δ 7.58 (d, J=1.3 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.45 (s, 1H), 7.32 (d, J=8.1 Hz, 2H), 4.89 (s, 2H), 4.23 (s, 2H), 4.18 (t, J=6.6 Hz, 2H), 1.71 - 1.47 (m, 2H), 1.43 - 1.16 (m, 2H), 0.85 (t, J=7.4 Hz, 3H)。
以類似方式製備化合物(Ib-02)。LCMS ESI:計算值= 426.2 (M+H+),實驗值426.2 (M+H+)。 實例3-式(Ic)化合物之合成
此實例及圖 3
係關於式(Ic)化合物之合成。
使用與針對化合物3
所描述類似的過程,由化合物7
(根據WO 2011/049815 A1製備)及化合物8
(CAS登記號1092351-92-2)製備化合物9
。LCMS ESI:C23
H32
BN5O4
之計算值= 452.3 (M-H+
),實驗值452.1 (M-H+
)。
使用與針對化合物( Ib - 01 )
所描述類似的過程,由化合物9
製備化合物( Ic - 01 )
。LCMS ESI:C20
H22
N6
O4
之計算值= 411.2 (M+H+
),實驗值411.2 (M+H+
)。1
H NMR (500 MHz, DMSO-d6
) δ 7.98 - 7.79 (m, 3H), 7.43 (br d,J
=8.2 Hz, 2H), 6.35 (s, 2H), 4.93 (s, 2H), 4.43 (br s, 2H), 4.15 (t,J
=6.6 Hz, 2H), 1.67 - 1.49 (m, 2H), 1.42 - 1.28 (m, 2H), 0.87 (t,J
=7.4 Hz, 3H)。 實例4-TLR7促效活性分析
此實例描述一種用於分析本說明書中所揭示之化合物之TLR7促效活性的方法。
將經工程改造之具有人類TLR7分泌之胚胎鹼性磷酸酶(SEAP)報導轉殖基因的人類胚胎腎藍色細胞(HEK-Blue™ TLR細胞;Invivogen)懸浮於非選擇性培養基(DMEM高葡萄糖(Invitrogen),其補充有10%胎牛血清(Sigma))中。將HEK-Blue™ TLR7細胞添加至384孔組織培養盤中之各孔(每孔15,000個細胞),且在37℃、5% CO2
下培育16至18小時。將化合物(100 nl)施配至含有HEK-Blue™ TLR細胞之孔中,且將經處理細胞在37℃、5% CO2
下進行培育。處理18小時後,將十微升新製的Quanti-Blue™試劑(Invivogen)添加至各孔,培育30分鐘(37℃,5% CO2
),且使用Envision盤式讀取器(OD = 620 nm)來量測SEAP含量。計算半數最大有效濃度值(EC50
;誘導分析基線與最大值之間一半反應的化合物濃度)。
圖 6
為展示由此獲得的化合物( Ib - 02 )
之資料的代表性曲線圖。 實例5-轉麩醯胺酸酶介導之結合
以下過程可用於轉麩醯胺酸酶介導之促效劑-連接子化合物結合,其中連接子具有可充當胺供體之胺基。抗體可為具有轉麩醯胺酸酶反應性麩醯胺酸的抗體,例如具有N297A或N297Q取代之抗體。結合係藉由重組細菌性轉麩醯胺酸酶進行,其中抗體:酶之莫耳比為5:1。結合係使用標準方案於50 mM Tris緩衝液(pH 8.0)中在37℃下培育隔夜而進行。在用50 mM Tris (pH 8.0)預平衡之蛋白A管柱上純化所得結合物。將結合物用0.1 M檸檬酸鈉緩衝液(pH 3.5)溶離。用1 M Tris (pH 9.0)中和溶離之溶離份。可在20 mg/mL山梨糖醇、10 mg/mL甘胺酸(pH 5.0)中調配結合物。 實例6-介白素6誘導分析
此實例描述一種用於分析本說明書中所揭示之化合物之介白素6誘導的方法。
使用ECHO聲學液體操作技術將於DMSO中稀釋之化合物轉移至Matrix Technologies透明V底384孔盤之個別孔中(每孔25 nL)。使用CyBio FeliX液體操作儀將人類全血樣品(25 μL)添加至各孔。將培養盤在培養盤震盪器上震盪三分鐘,之後在37℃下培育反應混合物20小時。隨後向各孔中添加Basel RPMI 1640培養基(補充有L-麩醯胺酸) (每孔25 μL),之後藉由離心(450 × g,5分鐘,環境溫度)自各樣品釋放出血漿。隨後使用FeliX液體操作儀將處理後之血漿樣品(3 μL)轉移至白色、較淺的384孔ProxiPlate (Perkin Elmer)之個別孔中,且使用如製造商PerkinElmer所描述之AlphaLISA技術來量測其介白素6含量。使用資料分析軟體來確定化合物EC50
值,其中使用平均DMSO值確定基線,且使用最高所測試濃度下之參考化合物值確定100%誘導。可使用諸如Graphpad Prism™之軟體來確定EC50
。
熟習此項技術者將理解,此實例中之條件及方法為說明性且非限制性的,並且其變化形式或其他結合方法為此項技術中已知的且可用於本發明中。
本發明之前述詳細描述包括主要或僅涉及本發明之特定部分或態樣的段落。應瞭解,出於明晰及便利之目的,特定特徵可不僅在揭示該特徵之段落中相關,且本文之揭示內容包括不同段落中存在之資訊的所有適當組合。類似地,儘管本文之各種圖式及描述係關於本發明之特定實施例,但應瞭解,若特定特徵揭示於特定圖式或實施例之情形下,則此類特徵亦可以適當程度與另一特徵組合用於另一圖式或實施例之情形下或通常本發明中。
此外,儘管本發明尤其關於某些較佳實施例進行描述,但本發明並不限於此類較佳實施例。確切而言,本發明之範疇藉由所附申請專利範圍界定。 參考文獻
下文提供以下參考文獻的完整引用,之前在本說明書中該等參考文獻以簡化方式以第一作者(或發明者)及日期形式引用。此等參考文獻各自以引用的方式併入本文中以用於所有目的。
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圖 1
、圖 2
、圖 3
及圖 7
示出用於製備本發明化合物之流程。
圖 4
及圖 5
示出用於製備促效劑-連接子化合物之流程。
圖 6
為示出本發明化合物之TLR7促效作用活性的代表性曲線圖。
Claims (16)
- 一種化合物,其具有式(I)或式(II)之結構其中 R1 為(C1 -C5 烷基)O、(C1 -C2 烷基)O(CH2 )2 - 3 O、(C1 -C5 烷基)C(=O)O、(C1 -C5 烷基)NH、(C1 -C2 烷基)O(CH2 )2 - 3 NH或(C1 -C5 烷基)C(=O)NH; R2 在每次出現時獨立地為H、C1 -C3 烷基、鹵基、O(C1 -C3 烷基)、CN或NO2 ; X在每次出現時獨立地為CR2 或N;且 Ar為選自以下之5員雜芳香族部分:吡咯基、呋喃基、苯硫基、吡唑基、咪唑基、噁唑基、異噁唑基、1,2,3-***基、1,2,4-***基、四唑基、1,2,4-噁二唑基、1,2,4-噻二唑基、1,3,4-噁二唑基、1,3,4-噻二唑基、1,2,5-噁二唑基、1,2,5-噻二唑基、1,2,3,4-噁***基及1,2,3,4-噻***基。
- 如請求項1之化合物,其具有由式(I')表示之結構其中各X'獨立地為CH或N,且Ar及R1 如請求項1中所定義。
- 如請求項1之化合物,其具有由式(II')表示之結構其中各X'獨立地為CH或N,且Ar及R1 如請求項1中所定義。
- 如請求項1之化合物,其具有由式(Ia)、式(Ib)或式(Ic)表示之結構 其中R1 如請求項1中所定義,各X'獨立地為CH或N,且R4 為H、C1 -C3 烷基、C3 -C3 環烷基(CH2 )1 - 3 R3 、(CH2 )1 - 3 C(=O)(CH2 )0 - 3 R3 ,其中R3 為鹵基OH、CN、NH2 、NH(C1 -C5 烷基)、N(C1 -C5 烷基)2 、NH(C3 -C6 環烷基)、NH(C4 -C8 雙環烷基)、NH(C6 -C10 螺環烷基)、N(C3 -C6 環烷基)2 、NH(CH2 )1 - 3 (芳基)、N((CH2 )1 - 3 (芳基))2 、具有結構之環胺部分、6員芳香族或雜芳香族部分或者5員雜芳香族部分; 其中 烷基、環烷基、雙環烷基、螺環烷基、環胺、6員芳香族或雜芳香族部分或者5員雜芳香族部分視情況經一或多個選自以下之取代基取代:OH、鹵基、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 及N(C1 -C3 烷基)2 ;且 環烷基、雙環烷基、螺環烷基或環胺部分可具有經O、S、NH、N(C1 -C3 烷基)或N(Boc)置換之CH2 基團。
- 如請求項4之化合物,其具有由式(Ia)表示之結構:。
- 如請求項4之化合物,其具有由式(Ib)表示之結構:。
- 如請求項4之化合物,其具有由式(Ic)表示之結構:。
- 如請求項4之化合物,其中R4 為 。
- 如請求項1之化合物,其與抗體結合。
- 如請求項1之化合物,其與大小介於2 kDa與40 kDa之間的聚(乙二醇)部分共價結合。
- 如請求項1之化合物,其用於治療能夠藉由活化類鐸受體7而治療之病狀。
- 如請求項4之化合物,其與抗體結合。
- 如請求項4之化合物,其與大小介於2 kDa與40 kDa之間的聚(乙二醇)部分共價結合。
- 如請求項4之化合物,其用於治療能夠藉由活化類鐸受體7而治療之病狀。
- 一種醫藥組合物,其包含如請求項1至14中任一項之化合物及醫藥學上可接受之賦形劑。
- 一種如請求項1至14中任一項之化合物的用途,其係用於製造用以治療能夠藉由活化類鐸受體7而治療之病狀的藥劑。
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WO2019035970A1 (en) | 2019-02-21 |
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JP2020531468A (ja) | 2020-11-05 |
AR112593A1 (es) | 2019-11-13 |
CA3072754A1 (en) | 2019-02-21 |
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PE20200701A1 (es) | 2020-06-23 |
US10927114B2 (en) | 2021-02-23 |
JP7228571B2 (ja) | 2023-02-24 |
EP3668870A1 (en) | 2020-06-24 |
CN111295385A (zh) | 2020-06-16 |
US20200048254A1 (en) | 2020-02-13 |
BR112020002953A2 (pt) | 2020-08-11 |
US10487084B2 (en) | 2019-11-26 |
US20200317672A1 (en) | 2020-10-08 |
KR102628855B1 (ko) | 2024-01-25 |
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