TW202100162A - 包含碳環核苷酸之3’3’-環二核苷酸 - Google Patents
包含碳環核苷酸之3’3’-環二核苷酸 Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本發明係關於包含碳環核苷酸之3'3'-環二核苷酸及其衍生物,其可調節STING接附蛋白之活性。
Description
本發明係關於包含碳環核苷酸之新穎3'3'-環二核苷酸、包含此類化合物之組合物、用於其合成之方法及其在各種病狀之療法中之用途。
免疫系統已進化出消除病原體及維持宿主之內穩定的機制。其可主要分為兩個分支:先天性免疫及適應性免疫。先天性免疫系統藉由一連串模式識別受體(PRR)識別病原體之存在或宿主之內穩定破壞,該等受體偵測與病原體或損壞相關聯之小型配位體集合。此等配位體一般被稱作病原體相關分子模式(PAMP)或損害相關分子模式(DAMP) (Takeuchi O等人,Cell, 2010:140, 805-820)。在過去的二十年,已鑑別多種PRR,包括鐸樣受體、視黃酸誘導性基因(RIG-I)樣受體、核苷酸結合寡聚域樣(NOD)受體、C型凝集素受體及胞溶質DNA感測子(Brubaker SW等人,Annu Rev Immunol, 2015:33,257-290)。藉由PRR識別PAMP及DAMP最終引起細胞介素及趨化介素(包括干擾素)之上調,及免疫細胞募集至感染位點。所有此等過程減緩病原體複製且促進適應性免疫性之產生。
細胞DNA通常限於健康細胞之細胞核及粒線體。因此,存在於胞溶質中之DNA代表指示存在病原體或宿主內穩定破壞之信號。宿主細胞之胞溶質中外源性DNA之感測引發兩種不同先天性免疫信號傳導級聯。第一種包括AIM2 (在黑素瘤2中不存在)及干擾素誘導之蛋白16 (IFI16)且誘導炎性體複合物形成,其繼而將原介白素(IL) 1β及原-IL-18處理成活性細胞介素(Wang Q等人.Expert Opin . Ther . Targets
, 2015: 19, 113)。第二路徑涉及IRF之DNA依賴性活化因子(DAI)、DEAD盒多肽41 (DDX41)及環狀GMP-AMP合酶(cGAS,亦稱為MB21D1),且經由接附蛋白STING (干擾素基因刺激因子,亦稱為TMEM173、MITA、ERIS)觸發轉錄因子NFκ-B (核因子κ B)及IRF-3 (干擾素調節因子3)之活化(Unterholzner L,Immunology
, 2013: 218, 1312-1321)。
可替代地,STING接附蛋白可藉由第二信使環二核苷酸(CDN)活化(Burdette等人,Nature 2011: 478,515-518)。具有針對STING之親和力之CDN含有與兩個3'-5'(3'3'-CDN)、兩個2'-5'(2'2'-CDN)或2'-5'及3'-5'磷酸二酯鍵(2'3'-CDN)連接之兩個嘌呤核苷酸單磷酸。原型2'3'-cGAMP (c[G(2',5')pA(3',5')p])為在病原體或自身dsDNA之存在下活化宿主cGAS蛋白的產物(Zhang等人, Molecular Cell 2013:51,226-235)。STING之活化最終引起釋放第I型及第III型干擾素及多種細胞介素及趨化介素,諸如IL-6、TNF-α及INF-γ。
第I型干擾素(IFN)為免疫調節細胞介素,其在病毒免疫中起關鍵作用。其可誘導樹突狀細胞(DC)及巨噬細胞成熟及活化(Galluci等人, Nat Med, 1999:5, 1249-1255)且可促進T細胞及B細胞存活、活化及分化。此外,干擾素能夠活化抑制病毒複製之許多胞內路徑。第I型干擾素之臨床效用已由其在治療慢性B型及C型肝炎中之有效性證明(Lin及Young, Cytokine Growth Factor Rev, 2014:25,369-376)。
另外,干擾素在治療人類癌症中展示效用(Cohen等人, N Engl J Med, 2005:353,2477-2490,Tsao等人, N Engl J Med, 2004:351,998-1012)。其可抑制腫瘤細胞增殖且可與許多經批准之抗癌劑發揮協同作用。此外,第I型IFN可對免疫細胞起作用以誘導抗腫瘤反應(Musella等人, Oncoimmunology 2017:6:e1314424)。第I型IFN信號傳導經展示為在小鼠中之腫瘤起始T細胞預致敏(priming)中至關重要。缺乏樹突狀細胞中IFN-α/β受體之動物無法抑制免疫原性腫瘤,且在向CD8+ T細胞的抗原交叉呈遞中有缺陷(Fuertes等人, J Exp Med, 2011:208, 2005-2016, Diamond等人, J Exp Med, 2011:208:1989-2003)。與此等觀測結果一致,已展示STING蛋白促效劑之瘤內注射會誘導小鼠中之已形成腫瘤之消退,且產生能夠抑制遠端癌轉移及提供長期存活之免疫記憶之實質性全身免疫反應(Corrales等人, Cell Rep, 2015:11,1018-1030)。
據信CDN可促進細胞及體液免疫之預致敏。舉例而言,在動物模型中展示CDN為有效佐劑(Dubensky等人, Ther Adv Vaccines, 2013:1,131-143)。
專利公開案WO 2014/093936、WO 2014/189805、WO 2013/185052、US 2014/03441976、WO 2015/077354、WO 2015/185565、WO 2016/145102、WO 2017/093933、WO 2017/027646、WO 2017/027645、WO 2017/175156、WO 2017/175147、WO 2017/123657、WO 2018/013908、WO 2018/013887、WO2018/009652、WO 2018/009648及WO 2018/009466揭示某些化合物及其在誘導免疫反應中之用途。
投與STING之小分子促效劑可引起先天免疫系統反應之刺激,包括誘導干擾素及其他細胞介素。此類促效劑可具有作為抗病毒劑及抗癌劑之效用,用作疫苗中之佐劑,或可用於治療過敏性或其他發炎性疾病,諸如鼻炎或哮喘。本發明之目標為描述可具有治療此等疾病之效用的新穎環二核苷酸及其衍生物。
在一個態樣中,本文中提供一種式(I)化合物:,
或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽,
其中
X1
及X3
各自獨立地係OH、OR3
、SH或SR3
;
X2
及X4
各自獨立地係O或S;
Y係O或CH2
;
R1a
、R1b
、R2a
及R2b
各自獨立地係H、OR5
、NH2
或鹵素;
各R5
獨立地係H或C1
-C6
烷基;
各R3
獨立地係C1
-C6
烷基或-L-R4
;
各R4
獨立地係-O(C=O)-N(R4a
)2
、-O(C=O)-NHR4a
、-O(C=O)-R4a
或-O(C=O)-O-R4a
;
各R4a
獨立地係C1
-C20
烷基、C2
-C20
烯基、C2
-C20
炔基、-(C1
-C6
伸烷基)-(C3
-C14
環烷基)或C3
-C20
環烷基,其各自視情況經1、2或3個R4b
取代;
各R4b
獨立地係-OH、-SH、-NH2
、=O、=NH、=S、鹵素、-N3
、-CN、C1
-C6
烷氧基、C1
-C6
烷硫基、C1
-C6
烷胺基或C1
-C6
二烷胺基;
L係L1
、L1
-O(C=O)-L2
、L1
-(C=O)O-L2
、L1
-O-L2
、L1
-S(O)n
-L2
、L1
-O(C=O)O-L2
、L1
-O(C=O)NR6
-L2
、L1
-NR6
(C=O)O-L2
或L1
-O(C=O)-L2
-O-L3
;
L1
係C1
-C6
伸烷基、C2
-C6
伸烯基、C2
-C6
伸炔基或C7
-C13
烷基伸芳基;
L2
係C1
-C6
伸烷基、C2
-C6
伸烯基、C2
-C6
伸炔基、C6
-C10
伸芳基或5員至10員伸雜芳基;
L3
係C1
-C6
伸烷基、C2
-C6
伸烯基或C2
-C6
伸炔基;
R6
係H或C1
-C6
烷基;
n係0、1或2;
鹼基1
及鹼基2
各自獨立地係
其中
A、A1
、A2
、A3
及A4
各自獨立地係H、OH、SH、F、Cl、Br、I、NH2
、OR15
、SR15
、NHR15
、N(R15
)2
或R16
;
各Z獨立地係O、S或NR15
;
各R15
獨立地係H、-C(=Z1
)R16
、-C(=Z1
)OR16
、-C(=Z1
)SR16
、-C(=Z1
)N(R16
)2
、C1
-C6
烷基、C2
-C6
烯基、C2
-C6
炔基、C3
-C7
環烷基、C2
-C10
雜環烷基、C6
-C10
芳基或C2
-C10
雜芳基;
各Z1
獨立地係O或S;且
各R16
獨立地係H、C1
-C6
烷基、C2
-C6
烯基、C2
-C6
炔基、C3
-C7
環烷基、C2
-C10
雜環烷基、C6
-C10
芳基或C2
-C10
雜芳基。
本發明包括一種醫藥組合物,其包含式(I)化合物或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽,及醫藥學上可接受之載劑、賦形劑及/或稀釋劑。
本文中亦描述一種治療疾病或病症之方法,例如一種治療或預防感染性疾病、癌症或發炎性疾病之方法,該方法包含向有需要之人類或動物投與有效量之式(I)化合物或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽,或前述任一者之醫藥組合物。
本文中進一步描述一種增強疫苗之功效之方法,其包含投與有效量之式(I)化合物或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽,或前述任一者之醫藥組合物。
本文中進一步描述一種調節人類或動物中STING接附蛋白誘導第I型干擾素、細胞介素及/或趨化介素(取決於STING接附蛋白)產生(例如,誘導STING接附蛋白依賴性第I型干擾素、細胞介素或趨化介素)之活性之方法,該方法包含投與有效量之式(I)化合物或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽,或前述任一者之醫藥組合物。
對相關申請案的交叉參考
本申請案主張2019年3月7日申請之美國臨時申請案第62/815,169號之優先權,其出於所有目的以全文引用的方式併入本文中。I . 綜述
本發明提供新穎碳環核苷酸,其結合至STING接附蛋白且調節(例如:活化) STING接附蛋白之活性。II . 定義
除非另外定義,否則本文中所用的所有技術及科學術語均具有如一般熟習此項技術者通常所理解的相同含義。在化學基團之前或末端的破折號為方便起見指示與母基團之連接點;化學基團可在具有或不具有一或多個破折號之情況下描繪而不失去其一般含義。字首,諸如「Cu - v
」或「Cu
-Cv
」指示後繼基團具有u至v個碳原子,其中u及v為整數。舉例而言,「C1 - 6
烷基」或「C1
-C6
烷基」指示烷基具有1至6個碳原子。
「烷基」為直鏈或分支鏈飽和單價烴。舉例而言,烷基可具有1至10個碳原子(亦即,C1 - 10
烷基)或1至8個碳原子(亦即,C1 - 8
烷基)或1至6個碳原子(亦即,C1 - 6
烷基)或1至4個碳原子(亦即,C1 - 4
烷基)。烷基之實例包括但不限於甲基(Me,-CH3
)、乙基(Et,-CH2
CH3
)、1-丙基(n
-Pr,正丙基,-CH2
CH2
CH3
)、2-丙基(i
-Pr,異丙基,-CH(CH3
)2
)、1-丁基(n
-Bu,正丁基,-CH2
CH2
CH2
CH3
)、2-甲基-1-丙基(i
-Bu,異丁基,-CH2
CH(CH3
)2
)、2-丁基(s
-Bu,第二丁基,-CH(CH3
)CH2
CH3
)、2-甲基-2-丙基(t
-Bu,第三丁基,-C(CH3
)3
)、1-戊基(正戊基,-CH2
CH2
CH2
CH2
CH3
)、2-戊基(-CH(CH3
)CH2
CH2
CH3
),3-戊基(-CH(CH2
CH3
)2
)、2-甲基-2-丁基(-C(CH3
)2
CH2
CH3
)、3-甲基-2-丁基(-CH(CH3
)CH(CH3
)2
)、3-甲基-1-丁基(-CH2
CH2
CH(CH3
)2
)、2-甲基-1-丁基(-CH2
CH(CH3
)CH2
CH3
)、1-己基(-CH2
CH2
CH2
CH2
CH2
CH3
)、2-己基(-CH(CH3
)CH2
CH2
CH2
CH3
)、3-己基(-CH(CH2
CH3
)(CH2
CH2
CH3
))、2-甲基-2-戊基(-C(CH3
)2
CH2
CH2
CH3
)、3-甲基-2-戊基(-CH(CH3
)CH(CH3
)CH2
CH3
)、4-甲基-2-戊基(-CH(CH3
)CH2
CH(CH3
)2
)、3-甲基-3-戊基(-C(CH3
)(CH2
CH3
)2
)、2-甲基-3-戊基(-CH(CH2
CH3
)CH(CH3
)2
)、2,3-二甲基-2-丁基(-C(CH3
)2
CH(CH3
)2
)、3,3-二甲基-2-丁基(-CH(CH3
)C(CH3
)3
及辛基(-(CH2
)7
CH3
)。
如本文所用之「伸烷基」係指二價直鏈或分支鏈飽和單價烴基,其藉由自不同碳原子移除兩個氫原子而衍生自烷烴。
「烷氧基」係指基團-O-烷基,其中烷基如上文所定義。舉例而言,C1 - 4
烷氧基係指具有1至4個碳之-O-烷基。
「烯基」為具有至少一個碳-碳雙鍵之直鏈或分支鏈單價烴基。舉例而言,烯基可具有2至8個碳原子(亦即,C2 - 8
烯基)或2至6個碳原子(亦即,C2 - 6
烯基)或2至4個碳原子(亦即,C2 - 4
烯基)。烯基之實例包括但不限於乙烯基(-CH=CH2
)、烯丙基(-CH2
CH=CH2
)及-CH2
-CH=CH-CH3
。
如本文所用之「伸烯基」係指具有至少一個碳-碳雙鍵之二價直鏈或分支鏈單價烴基,其藉由自不同碳原子移除兩個氫原子而衍生自烯烴。
「炔基」為具有至少一個碳-碳參鍵之直鏈或分支鏈單價烴基。舉例而言,炔基可具有2至8個碳原子(亦即,C2 - 8
炔基)或2至6個碳原子(亦即,C2 - 6
炔基)或2至4個碳原子(亦即,C2 - 4
炔基)。炔基之實例包括但不限於乙炔基(-C≡CH)、炔丙基(-CH2
C≡CH)及-CH2
-C≡C-CH3
。
如本文所用之「伸炔基」係指具有至少一個碳-碳參鍵之二價直鏈或分支鏈單價烴基,其藉由自不同碳原子移除兩個氫原子而衍生自炔烴。
如本文所用之「鹵基」或「鹵素」係指氟(-F)、氯(-Cl)、溴(-Br)及碘(-I)。
如本文所用之「芳基」係指單全碳芳環或多縮合全碳環系統,其中至少一個環為芳族。舉例而言,在某些實施例中,芳基具有6至20個碳原子、6至14個碳原子或6至12個碳原子。芳基包括苯基。芳基亦包括具有約9至20個碳原子之多縮合環系統(例如,包含2、3或4個環之環系統),其中至少一個環為芳族且其中其他環可為芳族或可不為芳族(亦即,碳環)。此類多縮合環系統視情況在多縮合環系統之任何碳環部分上經一或多個(例如,1、2或3個)側氧基取代。多縮合環系統之環在價數要求允許時可經由稠合、螺及橋鍵彼此連接。亦應理解,當參考某一原子範圍員芳基(例如,6員至10員芳基)時,原子範圍係針對芳基之總環原子。舉例而言,6員芳基將包括苯基且10員芳基將包括萘基及1,2,3,4-四氫萘基。芳基之非限制性實例包括但不限於苯基、茚基、萘基、1,2,3,4-四氫萘基、蒽基及其類似基團。
如本文所用之「伸芳基」係指單芳環或多縮合全碳環系統(其中至少一個環為芳族)上之二價基團,其藉由自環或環系統上之不同碳原子移除兩個氫原子而形成。
如本文所用之「烷芳基」係指如本文所定義之烷基,其中烷基之一或多個氫原子獨立地經可相同或不同的芳基取代基置換。烷基及芳基可為上文所描述之烷基及芳基中之任一者。在某些實施例中,烷芳基具有7至24個碳原子、7至16個碳原子、7至13個碳原子或7至11個碳原子。由碳原子數界定之烷芳基係指組成性烷基及芳基之組合中存在的碳原子總數。舉例而言,C7
烷芳基係指苯甲基,而C11
烷芳基包括1-甲基萘基及正戊基苯基。烷芳基之非限制性實例包括但不限於苯甲基、2,2-二甲基苯基、正戊基苯基、1-甲基萘基、2-乙基萘基及其類似基團。烷芳基可未經取代或經取代。
如本文所用之「烷基伸芳基」係指由烷烴與芳環連接形成之基團上的二價基團,其中該基團藉由自烷烴及芳環中之各者移除兩個氫原子而形成。
如本文所用之術語「雜芳基」係指環中具有至少一個除碳以外的原子之單芳環,其中該原子選自由氧、氮及硫組成之群;「雜芳基」亦包括具有至少一個此類芳環之多縮合環系統,該等多縮合環系統進一步描述於下文中。因此,「雜芳基」包括具有約1至6個碳原子及約1至4個選自由氧、氮及硫組成之群的雜原子之單芳環。硫及氮原子亦可以氧化形式存在,其限制條件為環為芳族。例示性雜芳基環系統包括但不限於吡啶基、嘧啶基、噁唑基或呋喃基。「雜芳基」亦包括多縮合環系統(例如,包含2個環之環系統),其中如上文所定義之雜芳基與選自以下之一或多個環縮合以形成多縮合環系統:雜芳基(以形成例如1,8-萘啶基)、雜環(以形成例如1,2,3,4-四氫-1,8-萘啶基)、碳環(以形成例如5,6,7,8-四氫喹啉基)及芳基(以形成例如吲唑基)。因此,雜芳基(單芳環或多縮合環系統)在雜芳基環內具有約1至9個碳原子及約1至6個雜原子。此類多縮合環系統可視情況在縮合環之碳環或雜環部分上經一或多個(例如,1、2、3或4個)側氧基取代。多縮合環系統之環在價數要求允許時可經由稠合、螺及橋鍵彼此連接。應理解,多縮合環系統之個別環可相對於彼此以任何順序連接。應理解,雜芳基或雜芳基多縮合環系統之連接點可在雜芳基或雜芳基多縮合環系統之任何適合原子處,包括碳原子及雜原子(例如,氮)。亦應理解,當參考某一原子範圍員雜芳基(例如,5員至10員雜芳基)時,原子範圍係針對雜芳基之總環原子且包括碳原子及雜原子。舉例而言,5員雜芳基將包括噻唑基且10員雜芳基將包括喹啉基。雜芳基環亦可由環內碳數描述,例如5員至10員雜芳基亦可描述為C2
-C8
雜芳基。例示性雜芳基包括但不限於吡啶基、吡咯基、吡嗪基、嘧啶基、噠嗪基、吡唑基、噻吩基、吲哚基、咪唑基、噁唑基、異噁唑基、噻唑基、呋喃基、噁二唑基、噻二唑基、喹啉基、異喹啉基、苯并噻唑基、苯并噁唑基、吲唑基、喹喔啉基、喹唑啉基、5,6,7,8-四氫異喹啉基、苯并呋喃基、苯并咪唑基、硫茚基、吡咯并[2,3-b]吡啶基、喹唑啉基-4(3H)-酮及三唑基。
如本文所用之「伸雜芳基」係指雜芳環或環系統上之二價基團,其中該基團藉由自不同碳移除兩個氫原子而形成。
「環烷基」係指具有3至20個環碳原子(亦即,C3 - 20
環烷基),例如3至12個環原子,例如3至10個環原子,或3至8個環原子,或3至6個環原子,或3至5個環原子,或3至4個環原子之單飽和或部分不飽和全碳環。術語「環烷基」亦包括多縮合之飽和及部分不飽和全碳環系統(例如,包含2、3或4個碳環之環系統)。因此,環烷基包括多環碳環,諸如雙環碳環(例如,具有約6至12個環碳原子之雙環碳環,諸如雙環[3.1.0]己烷及雙環[2.1.1]己烷),及多環碳環(例如具有至多約20個環碳原子之三環及四環碳環)。多縮合環系統之環在價數要求允許時可經由稠合、螺及橋鍵彼此連接。單環環烷基之非限制性實例包括環丙基、環丁基、環戊基、1-環戊-1-烯基、1-環戊-2-烯基、1-環戊-3-烯基、環己基、1-環己-1-烯基、1-環己-2-烯基及1-環己-3-烯基。
如本文所用之「雜環基」或「雜環」或「雜環烷基」係指環中具有至少一個雜原子(亦即,至少一個選自氧、氮及硫之環雜原子)之單飽和或部分不飽和非芳環或非芳族多環系統。除非另外說明,否則雜環基具有3至約20個環原子,例如3至12個環原子,例如3至10個環原子,或3至8個環原子,或3至6個環原子,或3至5個環原子,或4至6個環原子,或4至5個環原子。因此,術語包括環中具有約1至6個環碳原子及約1至3個選自由氧、氮及硫組成之群之環雜原子的單飽和或部分不飽和環(例如,3、4、5、6或7員環)。多縮合環(例如雙環雜環基)系統之環在價數要求允許時可經由稠合、螺及橋鍵彼此連接。雜環包括但不限於氮雜環丁烷、氮雜環丙烷、咪唑啶、嗎啉、環氧乙烷(環氧化物)、氧雜環丁烷、硫雜環丁烷、哌嗪、哌啶、吡唑啶、哌啶、吡咯啶、吡咯啶酮、四氫呋喃、四氫噻吩、二氫吡啶、四氫吡啶、奎寧環、2-氧雜-6-氮雜螺[3.3]庚-6-基、6-噁-1-氮雜螺[3.3]庚-1-基、2-硫雜-6-氮雜螺[3.3]庚-6-基、2,6-二氮雜螺[3.3]庚-2-基、2-氮雜雙環[3.1.0]己-2-基、3-氮雜雙環[3.1.0]己基、2-氮雜雙環[2.1.1]己基、2-氮雜雙環[2.2.1]庚-2-基、4-氮雜螺[2.4]庚基、5-氮雜螺[2.4]庚基及其類似物。
如本文所用之「側氧基」係指=O。
如本文所用之「經取代」係指其中基團之一或多個氫原子獨立地經如所指示之一或多個取代基(例如,1、2、3或4個或更多)置換。
「本發明化合物」包括本文所揭示之化合物,例如本發明化合物包括式(I)、(II)、(III)及(IV)之化合物,包括實例之化合物。
如本文所用之「治療(treatment/treat/treating)」係指用於獲得有益或所需結果之方法。出於本發明之目的,有益或所需結果包括但不限於症狀緩解及/或症狀程度減輕及/或預防與疾病或病狀相關之症狀的惡化。在一個實施例中,「治療」包括以下中之一或多者:a)抑制疾病或病狀(例如,減少由疾病或病狀引起之一或多種症狀,及/或減輕疾病或病狀之程度);b)減緩或遏制與疾病或病狀相關之一或多種症狀的發展(例如,使疾病或病狀穩定、延緩疾病或病狀之惡化或進展);及c)緩解疾病或病狀,例如使臨床症狀消退、改善疾病病況、延緩疾病進展、提高生活品質及/或延長存活期。
如本文所用之「延緩」疾病或病狀之發展意謂推遲、阻礙、減緩、扼止、穩定及/或延遲疾病或病狀之發展。此延緩可具有不同時間長度,視所治療之疾病及/或個體之病史而定。如熟習此項技術者顯而易見,足夠或顯著延緩可實際上涵蓋預防,從而使個體不罹患疾病或病狀。
如本文所用之「預防(prevent/prevention/preventing)」係指防止疾病或病症發作以使得疾病之臨床症狀不發展的療法。因此,「預防」係關於在個體中可偵測到疾病病徵之前向個體投與療法(例如,投與治療物質)(例如,在個體中不存在可偵測感染物(例如,病毒)下向個體投與治療物質)。個體可為具有罹患疾病或病症之風險的個體,諸如具有已知與疾病或病症之罹患或發作相關之一或多個風險因素之個體。因此,在某些實施例中,術語「預防HBV感染」係指向不具有可偵測之HBV感染的個體投與抗HBV治療物質。應理解,抗HBV預防性療法之個體可為具有感染HBV病毒之風險的個體。亦應理解,預防不需要100%成功率。在一些情況下,預防可理解為降低感染風險,而非完全消除感染發生。
如本文所用,「調節(modulation/modulating)」蛋白質(例如,STING接附蛋白)之活性係指改變活性以使得活性提高或降低。在一些實施例中,調節提高活性。
「病毒感染」描述一種患病病況,其中病毒侵入健康細胞,使用細胞之繁殖機制以倍增或複製且最終溶解細胞,從而導致細胞死亡,釋放病毒顆粒且藉由新產生之後代病毒感染其他細胞。某些病毒之潛伏感染亦為病毒感染之可能結果。
「增強」係指由於向動物或人類投與治療有效劑量之本發明化合物,例如式(I)化合物,有效劑量之疫苗之免疫原性活性的任何形式提高,其中該化合物在向同一動物或人類投與有效劑量之疫苗之前、同時或緊接之後的任何時間投與。
如本文所用之「動物」係指哺乳動物,例如家畜,諸如豬、牛、馬、狗、貓、大鼠或小鼠,或非人類靈長類動物,諸如食蟹獼猴或黑猩猩。
如本文所使用之「具有風險之個體」係指具有罹患待治療病狀之風險的個體。「具有風險」之個體可患有或可不患有可偵測之疾病或病狀,且在本文所描述之方法治療之前可顯示或可不顯示可偵測之疾病。「具有風險」指示個體具有一或多種所謂的風險因素,其為與罹患疾病或病狀相關的可量測參數且為此項技術中已知的。具有此等風險因素中之一或多者的個體比不具有此等風險因素的個體具有更高的罹患疾病或病狀之機率。
如本文所用之「治療有效量」或「有效量」係指可有效地引發所需生物學或醫學反應之量,包括在向個體投與以用於治療疾病時足以實現此類疾病治療之化合物的量。有效量將視化合物、待治療之個體之疾病及其嚴重程度及年齡、體重等而變化。有效量可包括一系列量。如此項技術中所理解,有效量可呈一或多次劑量形式,亦即,單次劑量或多次劑量可為達成所需治療終點所需的。在投與一或多種治療劑之情形下可考慮有效量,且若與一或多種其他藥劑結合可達成或已達成所需或有益的結果,則單一藥劑可視為以有效量給予。任何共投與化合物之適合劑量可視情況因化合物之組合作用(例如,累加或協同效應)而減少。
「醫藥學上可接受之賦形劑」包括但不限於任何佐劑、載劑、賦形劑、助滑劑、甜味劑、稀釋劑、防腐劑、染料/著色劑、風味增強劑、界面活性劑、濕潤劑、分散劑、懸浮劑、穩定劑、等張劑、溶劑或乳化劑,其已經美國食品與藥物管理局(the United States Food and Drug Administration)批准為可接受用於人類或家畜。
如本文所用之「共投與」係指在投與單位劑量之一或多種額外治療劑之前或之後投與單位劑量之本文所揭示之化合物,例如,在投與一或多種額外治療劑之數秒、數分鐘或數小時內投與本文所揭示之化合物。舉例而言,在一些實施例中,首先投與單位劑量之本發明化合物,接著在數秒或數分鐘內投與單位劑量之一或多種額外治療劑。可替代地,在其他實施例中,首先投與單位劑量之一或多種額外治療劑,接著在數秒或數分鐘內投與單位劑量之本發明化合物。在一些實施例中,首先投與單位劑量之本發明化合物,接著在數小時(例如,1至12小時)之時段後投與單位劑量之一或多種額外治療劑。在其他實施例中,首先投與單位劑量之一或多種額外治療劑,接著在數小時(例如,1至12小時)之時段後投與單位劑量之本發明化合物。共投與本文所揭示之化合物與一或多種額外治療劑一般係指同時或依序投與本文所揭示之化合物及一或多種額外治療劑,使得治療有效量之各藥劑存在於患者體內。
亦提供本文所描述之化合物之醫藥學上可接受之鹽、水合物、溶劑合物、互變異構形式、多晶型物及前藥。「醫藥學上可接受」或「生理學上可接受」係指化合物、鹽、組合物、劑型及其他物質適用於製備適用於獸醫學或人類醫藥用途之醫藥組合物。
本文所描述之化合物可製備及/或調配為醫藥學上可接受之鹽或在適當時製備及/或調配為自由鹼。醫藥學上可接受之鹽為擁有所需的自由鹼之藥理學活性的化合物之自由鹼形式之無毒鹽。此等鹽可衍生自無機或有機酸或鹼。舉例而言,含有鹼性氮之化合物可藉由使該化合物與無機或有機酸接觸而製備為醫藥學上可接受之鹽。醫藥學上可接受之鹽之非限制性實例包括硫酸鹽、焦硫酸鹽、硫酸氫鹽、亞硫酸鹽、亞硫酸氫鹽、磷酸鹽、磷酸單氫鹽、磷酸二氫鹽、偏磷酸鹽、焦磷酸鹽、氯化物、溴化物、碘化物、乙酸鹽、丙酸鹽、癸酸鹽、辛酸鹽、丙烯酸鹽、甲酸鹽、異丁酸鹽、己酸鹽、庚酸鹽、丙炔酸鹽、乙二酸鹽、丙二酸鹽、丁二酸鹽、辛二酸鹽、癸二酸鹽、反丁烯二酸鹽、順丁烯二酸鹽、丁炔-1,4-二酸鹽、己炔-1,6-二酸鹽、苯甲酸鹽、氯苯甲酸鹽、甲基苯甲酸鹽、二硝基苯甲酸鹽、羥基苯甲酸鹽、甲氧基苯甲酸鹽、鄰苯二甲酸鹽、磺酸鹽、甲基磺酸鹽、丙基磺酸鹽、苯磺酸鹽、二甲苯磺酸鹽、萘-1-磺酸鹽、萘-2-磺酸鹽、苯乙酸鹽、苯丙酸鹽、苯丁酸鹽、檸檬酸鹽、乳酸鹽、γ-羥丁酸鹽、乙醇酸鹽、酒石酸鹽及杏仁酸鹽。其他適合之醫藥學上可接受之鹽的清單見於Remington: The Science and Practice of Pharmacy, 第21版, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006中。
本文所揭示之化合物之「醫藥學上可接受之鹽」的實例亦包括衍生自適當鹼之鹽,該鹼諸如鹼金屬(例如,鈉、鉀)、鹼土金屬(例如,鎂)、銨及N(C1
-C4
烷基)4 +
。亦包括鹼加成鹽,諸如鈉鹽或鉀鹽。
亦提供本文中所描述之化合物或其醫藥學上可接受之鹽、異構體或混合物,其中連接至碳原子之1至n個氫原子可經氘原子或D置換,其中n為分子中之氫原子的數目。如此項技術中已知,氘原子為氫原子之非放射性同位素。此類化合物可增加代謝抗性,且因此當向哺乳動物投與時,可適用於延長本文所描述之化合物或其醫藥學上可接受之鹽、異構體或混合物之半衰期。參見例如Foster, 「Deuterium Isotope Effects in Studies of Drug Metabolism」, Trends Pharmacol. Sci., 5(12):524-527 (1984)。藉由此項技術中熟知之手段,例如藉由採用其中一或多個氫原子已經氘置換之起始物質合成此類化合物。
可併入所揭示之化合物中之同位素之實例亦包括氫、碳、氮、氧、磷、氟、氯及碘之同位素,諸如分別為2
H、3
H、11
C、13
C、14
C、13
N、15
N、15
O、17
O、18
O、31
P、32
P、35
S、18
F、36
Cl、123
I及125
I。經正電子發射同位素(諸如11
C、18
F、15
O及13
N)取代可適用於正電子發射斷層攝影術(PET)研究,以檢查受質受體佔用率。經同位素標記之式(I)化合物一般可藉由熟習此項技術者已知之習知技術或藉由類似於如以下所陳述之實例中所描述之方法的方法,使用適當的經同位素標記之試劑替代先前所採用的未經標記之試劑來製備。
本文所揭示之實施例之化合物或其醫藥學上可接受之鹽可含有一或多個不對稱中心,且可因此產生對映異構體、非對映異構體及其他立體異構形式,該等立體異構形式可在絕對立體化學方面針對胺基酸定義為(R
)-或(S
)-或(D)-或(L)-。本發明意欲包括所有此類可能的異構體,以及其外消旋及光學純形式。具光學活性之(+)及(-)、(R
)-及(S
)-或(D)-及(L)-異構體可使用對掌性合成子或對掌性試劑來製備,或使用習知技術(例如層析及分步結晶)來解析。用於製備/分離個別對映異構體之習知技術包括自適合之光學純前驅體進行對掌性合成或使用例如對掌性高壓液相層析(HPLC)對外消旋體(或鹽或衍生物之外消旋體)進行解析。當本文所描述之化合物含有烯系雙鍵或其他幾何不對稱中心時,且除非另外規定,否則意欲化合物包括E及Z幾何異構體。同樣,亦意欲包括所有互變異構形式。在化合物以其對掌性形式表示時,應理解,實施例涵蓋但不限於特定非對映異構性或對映異構性增濃形式。在未指定但存在對掌性時,應理解,實施例係針對特定非對映異構性或對映異構性增濃形式;或此類化合物之外消旋或非外消旋混合物。如本文所用,「非外消旋混合物」係比率不為1:1的立體異構體之混合物。
如本文所用之「立體異構體」係指由相同鍵所鍵結之相同原子構成但具有不可互換的不同三維結構之化合物。本發明涵蓋各種立體異構體及其混合物且包括「對映異構體」,對映異構體係指分子彼此間為不可重疊之鏡像的兩種立體異構體。
如本文所用之「互變異構體」係指質子自分子之一個原子轉移至同一分子之另一原子。本發明包括任何該等化合物之互變異構體。
如本文所用之「溶劑合物」係指溶劑與化合物之相互相用之產物。亦提供本文所描述之化合物之鹽的溶劑合物。亦提供本文所描述之化合物之水合物。
如本文所用之「水合物」係指與一或多個水分子以化學方式締合之本發明化合物。
如本文所用之「前藥」係指藥物之衍生物,其在向人體投與時根據一些化學或酶促路徑轉化成母體藥物。III . 化合物
本文提供一種式(J)化合物:,
或其醫藥學上可接受之鹽,
其中
X1
及X3
各自獨立地係OH、OR3
、SH或SR3
;
X2
及X4
各自獨立地係O或S;
Y係O或CH2
;
R1a
、R1b
、R2a
及R2b
各自獨立地係H、OR5
、NH2
或鹵素;
各R5
獨立地係H或C1
-C6
烷基;
各R3
獨立地係C1
-C6
烷基或-L-R4
;
各R4
獨立地係-O(C=O)-N(R4a
)2
、-O(C=O)-NHR4a
、-O(C=O)-R4a
或-O(C=O)-O-R4a
;
各R4a
獨立地係C1
-C20
烷基、C2
-C20
烯基、C2
-C20
炔基、-(C1
-C6
伸烷基)-(C3
-C14
環烷基)或C3
-C20
環烷基,其中各R4a
獨立地視情況經1、2或3個R4b
取代;
各R4b
獨立地係-OH、-SH、-NH2
、=O、=NH、=S、鹵素、-N3
、-CN、C1
-C6
烷基、C1
-C6
烷氧基、C1
-C6
烷硫基、C1
-C6
烷胺基或C1
-C6
二烷胺基;
L係L1
、L1
-O(C=O)-L2
、L1
-(C=O)O-L2
、L1
-O-L2
、L1
-S(O)n
-L2
、L1
-O(C=O)O-L2
、L1
-O(C=O)NR6
-L2
、L1
-NR6
(C=O)O-L2
或L1
-O(C=O)-L2
-O-L3
;
L1
係C1
-C6
伸烷基、C2
-C6
伸烯基、C2
-C6
伸炔基或C7
-C13
烷基伸芳基;
L2
係C1
-C6
伸烷基、C2
-C6
伸烯基、C2
-C6
伸炔基、C6
-C10
伸芳基或5員至10員伸雜芳基;
L3
係C1
-C6
伸烷基、C2
-C6
伸烯基或C2
-C6
伸炔基;
R6
係H或C1
-C6
烷基;
n係0、1或2;
鹼基1
及鹼基2
各自獨立地係
其中
A、A1
、A2
、A3
及A4
各自獨立地係H、OH、SH、F、Cl、Br、I、NH2
、OR15
、SR15
、NHR15
、N(R15
)2
或R16
;
各Z獨立地係O、S或NR15
;
各R15
獨立地係H、-C(=Z1
)R16
、-C(=Z1
)OR16
、-C(=Z1
)SR16
、-C(=Z1
)N(R16
)2
、C1
-C6
烷基、C2
-C6
烯基、C2
-C6
炔基、C3
-C7
環烷基、C2
-C10
雜環烷基、C6
-C10
芳基或C2
-C10
雜芳基;
各Z1
獨立地係O或S;且
各R16
獨立地係H、C1
-C6
烷基、C2
-C6
烯基、C2
-C6
炔基、C3
-C7
環烷基、C2
-C10
雜環烷基、C6
-C10
芳基或C2
-C10
雜芳基。
本文提供一種式(I)化合物,,
或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽,
其中
X1
及X3
各自獨立地係OH、OR3
、SH或SR3
;
X2
及X4
各自獨立地係O或S;
Y係O或CH2
;
R1a
、R1b
、R2a
及R2b
各自獨立地係H、OR5
、NH2
或鹵素;
各R5
獨立地係H或C1
-C6
烷基;
各R3
獨立地係C1
-C6
烷基或-L-R4
;
各R4
獨立地係-O(C=O)-N(R4a
)2
、-O(C=O)-NHR4a
、-O(C=O)-R4a
或-O(C=O)-O-R4a
;
各R4a
獨立地係C1
-C20
烷基、C2
-C20
烯基、C2
-C20
炔基、-(C1
-C6
伸烷基)-(C3
-C14
環烷基)或C3
-C20
環烷基,其各自視情況經1、2或3個R4b
取代;
各R4b
獨立地係-OH、-SH、-NH2
、=O、=NH、=S、鹵素、-N3
、-CN、C1
-C6
烷氧基、C1
-C6
烷硫基、C1
-C6
烷胺基或C1
-C6
二烷胺基;
L係L1
、L1
-O(C=O)-L2
、L1
-(C=O)O-L2
、L1
-O-L2
、L1
-S(O)n
-L2
、L1
-O(C=O)O-L2
、L1
-O(C=O)NR6
-L2
、L1
-NR6
(C=O)O-L2
或L1
-O(C=O)-L2
-O-L3
;
L1
係C1
-C6
伸烷基、C2
-C6
伸烯基、C2
-C6
伸炔基或C7
-C13
烷基伸芳基;
L2
係C1
-C6
伸烷基、C2
-C6
伸烯基、C2
-C6
伸炔基、C6
-C10
伸芳基或5員至10員伸雜芳基;
L3
係C1
-C6
伸烷基、C2
-C6
伸烯基或C2
-C6
伸炔基;
R6
係H或C1
-C6
烷基;
n係0、1或2;
鹼基1
及鹼基2
各自獨立地係
其中
A、A1
、A2
、A3
及A4
各自獨立地係H、OH、SH、F、Cl、Br、I、NH2
、OR15
、SR15
、NHR15
、N(R15
)2
或R16
;
各Z獨立地係O、S或NR15
;
各R15
獨立地係H、-C(=Z1
)R16
、-C(=Z1
)OR16
、-C(=Z1
)SR16
、-C(=Z1
)N(R16
)2
、C1
-C6
烷基、C2
-C6
烯基、C2
-C6
炔基、C3
-C7
環烷基、C2
-C10
雜環烷基、C6
-C10
芳基或C2
-C10
雜芳基;
各Z1
獨立地係O或S;且
各R16
獨立地係H、C1
-C6
烷基、C2
-C6
烯基、C2
-C6
炔基、C3
-C7
環烷基、C2
-C10
雜環烷基、C6
-C10
芳基或C2
-C10
雜芳基。
在式(I)及/或(II)化合物之一些實施例中,Y係CH2
。在一些實施例中,Y係O。
在式(I)及/或(II)之化合物之一些實施例中,X2
及X4
各自係O。
在式(I)、(II)及/或(III)化合物之一些實施例中,鹼基1
及鹼基2
各自獨立地係:
其中
A、A1
、A2
、A3
及A4
各自獨立地係H、OH、SH、F、Cl、Br、I、NH2
、OR15
、SR15
、NHR15
或N(R15
)2
。
在一些實施例中,鹼基1
及鹼基2
各自獨立地係:
其中
A、A1
、A2
、A3
及A4
各自獨立地係H、OH、SH、F、Cl、Br、I、NH2
、OR15
、SR15
、NHR15
、N(R15
)2
或R16
。
在一些實施例中,鹼基1
及鹼基2
各自獨立地係:。
在一些實施例中,鹼基1
及鹼基2
各自獨立地係:。
在一些實施例中,鹼基1
及鹼基2
各自獨立地係: 。
在一些實施例中,鹼基1
及鹼基2
各自獨立地係:。
在一些實施例中,鹼基1
係,
且鹼基2
係。
在一些實施例中,鹼基1
係,
且鹼基2
係。
在一些實施例中,鹼基1
係,
且鹼基2
係。
在一些實施例中,鹼基1
係,
且鹼基2
係。
在一些實施例中,鹼基1
及鹼基2
各自係。
在式(I)、(II)及/或(III)化合物之一些實施例中,A1
係OH。在一些實施例中,A1
係NH2
。
在式(I)、(II)及/或(III)化合物之一些實施例中,A2
係H且A1
係NH2
。在一些實施例中,A2
係NH2
且A1
係OH。
在式(I)、(II)及/或(III)化合物之一些實施例中,A1
、A2
、A3
及A4
各自獨立地係H、OH或NH2
。在一些實施例中,A1
係OH或NH2
。在一些實施例中,A2
係H或NH2
。在一些實施例中,A3
係H或NH2
。在一些實施例中,A4
係NH2
。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,A1
、A2
及A3
各自獨立地係H、OH或NH2
。在一些實施例中,A1
係OH或NH2
。在一些實施例中,A2
係H或NH2
。在一些實施例中,A3
係H或NH2
。在一些實施例中,A1
係OH或NH2
;A2
係H或NH2
;且A3
係H。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,X1
及X3
各自獨立地係OH或SH。在一些實施例中,X1
及X3
各自係OH。在一些實施例中,X1
及X3
各自係SH。在一些實施例中,X1
係SH;且X3
係OH。在一些實施例中,X1
係OH;且X3
係SH。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,X1
係OH;且X3
係OR3
。在一些實施例中,X1
係OR3
;且X3
係OH。在一些實施例中,X1
及X3
各自獨立地係OR3
。在一些實施例中,X1
係SR3
;且X3
係OH。在一些實施例中,X1
係OH;且X3
係SR3
。在一些實施例中,X1
係SR3
;且X3
係SH。在一些實施例中,X1
係SH;且X3
係SR3
。在一些實施例中,X1
及X3
各自獨立地係SR3
。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,各R3
獨立地係-L-R4
。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,L係L1
、L1
-O(C=O)-L2
、L1
-(C=O)O-L2
、L1
-O-L2
、L1
-O(C=O)O-L2
、L1
-O(C=O)NR6
-L2
或L1
-NR6
(C=O)O-L2
。在一些實施例中,L係L1
、L1
-O(C=O)-L2
、L1
-(C=O)O-L2
、L1
-O-L2
或L1
-O(C=O)O-L2
。在一些實施例中,L係L1
、L1
-O(C=O)-L2
或L1
-O-L2
。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,L1
係C1
-C6
伸烷基或C7
-C13
烷基伸芳基。在一些實施例中,L1
係C1
-C6
伸烷基,諸如-CH2
-。在一些實施例中,L1
係C7
-C13
烷基伸芳基,諸如-CH2
-Ph-。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,L2
係C1
-C6
伸烷基、C6
-C10
伸芳基或5員至10員伸雜芳基。在一些實施例中,L2
係C1
-C6
伸烷基或C6
-C10
伸芳基。在一些實施例中,L2
係C1
-C6
伸烷基,諸如-CH2
-。在一些實施例中,L2
係C6
-C10
伸芳基,諸如伸苯基。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,L係L1
、L1
-O(C=O)-L2
或L1
-O-L2
;L1
係C1
-C6
伸烷基或C7
-C13
烷基伸芳基;L2
係C1
-C6
伸烷基或C6
-C10
伸芳基。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,R4
係-O(C=O)-R4a
或-O(C=O)-O-R4a
。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,R4a
係C1
-C20
烷基、C2
-C20
烯基、C2
-C20
炔基或-(C1
-C6
伸烷基)-(C3
-C14
環烷基)。在一些實施例中,R4a
係C3
-C20
環烷基,例如C3
-C16
環烷基、C3
-C10
環烷基、C3
-C8
環烷基、C3
-C7
環烷基、C5
-C8
環烷基或C4
-C7
環烷基。在一些實施例中,R4a
係C1
-C20
烷基或-(C1
-C6
伸烷基)-(C3
-C14
環烷基)。在一些實施例中,R4a
係C1
-C20
烷基或-CH2
-(C3
-C14
環烷基)。在一些實施例中,R4a
係-CH2
-(C3
-C14
環烷基),例如-CH2
-(C3
-C10
環烷基)、-CH2
-(C3
-C8
環烷基)、-CH2
-(C3
-C7
環烷基)或-CH2
-(C5
-C8
環烷基)。在一些實施例中,R4a
係C1
-C20
烷基,諸如C1
-C16
烷基、C3
-C20
烷基、C3
-C18
烷基、C3
-C16
烷基、C3
-C14
烷基、C3
-C12
烷基、C3
-C10
烷基、C3
-C8
烷基、C2
-C8
烷基、C1
-C8
烷基、C1
-C6
烷基、C2
-C6
烷基或C3
-C6
烷基。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,X1
係。
在一些實施例中,X1
係;且R4a
係C3
-C20
烷基。
在一些實施例中,X1
係 ;且R4a
係C3
-C20
烷基。
在一些實施例中,X1
係。
在一些實施例中,X1
係。
在一些實施例中,X1
係。
在一些實施例中,X1
係。
在一些實施例中,X1
係。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,X3
係。
在一些實施例中,X3
係;且R4a
係C3
-C20
烷基。
在一些實施例中,X3
係 ;且R4a
係C3
-C20
烷基。
在一些實施例中,X3
係。
在一些實施例中,X3
係。
在一些實施例中,X3
係。
在一些實施例中,X3
係。
在一些實施例中,X3
係。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,R2a
經1或2個R2b
取代。在一些實施例中,R2a
經一個R2b
取代。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,R2b
係-OH、鹵素、-CN、C1
-C6
烷氧基或C1
-C6
烷硫基。在一些實施例中,R2b
係鹵素,例如F或Cl。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,X1
係OR3
或SR3
;R3
係-L-R4
;L係L1
;L1
係C1
-C6
伸烷基;R4
係-O(C=O)-R4a
或-O(C=O)-O-R4a
;且R4a
係C1
-C20
烷基。在一些實施例中,X1
係OR3
或SR3
;R3
係-L-R4
;L係L1
;L1
係-CH2
-;R4
係-O(C=O)-R4a
或-O(C=O)-O-R4a
;且R4a
係C3
-C20
烷基。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,X3
係OR3
或SR3
;R3
係-L-R4
;L係L1
;L1
係C1
-C6
伸烷基;R4
係-O(C=O)-R4a
或-O(C=O)-O-R4a
;且R4a
係C1
-C20
烷基。在一些實施例中,X3
係OR3
或SR3
;R3
係-L-R4
;L係L1
;L1
係-CH2
-;R4
係-O(C=O)-R4a
或-O(C=O)-O-R4a
;且R4a
係C3
-C20
烷基。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,X1
係OR3
或SR3
;R3
係-L-R4
;L係L1
;L1
係C7
-C13
烷基伸芳基;R4
係-O(C=O)-R4a
或-O(C=O)-O-R4a
;且R4a
係C1
-C20
烷基。在一些實施例中,X1
係OR3
或SR3
;R3
係-L-R4
;L係L1
;L1
係-CH2
-Ph-;R4
係-O(C=O)-R4a
或-O(C=O)-O-R4a
;且R4a
係C3
-C20
烷基。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,X3
係OR3
或SR3
;R3
係-L-R4
;L係L1
;L1
係C7
-C13
烷基伸芳基;R4
係-O(C=O)-R4a
或-O(C=O)-O-R4a
;且R4a
係C1
-C20
烷基。在一些實施例中,X3
係OR3
或SR3
;R3
係-L-R4
;L係L1
;L1
係-CH2
-Ph-;R4
係-O(C=O)-R4a
或-O(C=O)-O-R4a
;且R4a
係C3
-C20
烷基。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,R5
係H或Me。在一些實施例中,R5
係H。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,R1a
與R1b
不同。在一些實施例中,R1a
及R1b
中之至少一者係H。在一些實施例中,R1a
係H、OH、OMe或F,且R1b
係H。在一些實施例中,R1a
係H、OH或F,且R1b
係H。在一些實施例中,R1a
係OH或F,且R1b
係H。在一些實施例中,R1a
係OH,且R1b
係H。在一些實施例中,R1a
係OMe,且R1b
係H。在一些實施例中,R1a
係F,且R1b
係H。在一些實施例中,R1a
係H,且R1b
係H、OH、OMe或F。在一些實施例中,R1a
係H,且R1b
係H、OH或F。在一些實施例中,R1a
係H,且R1b
係OH或F。在一些實施例中,R1a
係H,且R1b
係OH。在一些實施例中,R1a
係H,且R1b
係OMe。在一些實施例中,R1a
係H,且R1b
係F。在一些實施例中,R1a
係F,且R1b
係H。在一些實施例中,R1a
及R1b
各自係H。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,R2a
與R2b
不同。在一些實施例中,R2a
及R2b
中之至少一者係H。在一些實施例中,R2a
係H、OH、NH2
或F,且R2b
係H。在一些實施例中,R2a
係H、OH或F,且R2b
係H。在一些實施例中,R2a
係OH或F,且R2b
係H。在一些實施例中,R2a
係OH,且R2b
係H。在一些實施例中,R2a
係NH2
,且R2b
係H。在一些實施例中,R2a
係F,且R2b
係H。在一些實施例中,R2a
及R2b
各自係H。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,R1a
、R1b
、R2a
及R2b
各自獨立地係H、OH、OMe或F。在一些實施例中,R1a
、R1b
、R2a
及R2b
各自獨立地係H、OH或F。在一些實施例中,R1a
及R1b
中之至少一者係H,且R2a
及R2b
中之至少一者係H。在一些實施例中,R2a
係OH,R2b
係H,R1a
係F且R1b
係H。在一些實施例中,R2a
係OH,R2b
係H,R1a
係OH且R1b
係H。在一些實施例中,R2a
係OH,R2b
係H,R1a
係H且R1b
係OH。在一些實施例中,R2a
係OH,R2b
係H,R1a
係H且R1b
係F。在一些實施例中,R2a
係OH,R2b
係H,R1a
係OMe且R1b
係H。在一些實施例中,R2a
及R2b
各自係H,R1a
係OH且R1b
係H。在一些實施例中,R1a
及R2a
各自係F,且R1b
及R2b
各自係H。
在式(I)、(II)、(III)及/或(IV)化合物之一些實施例中,R1b
及R2b
各自係H。
在一些實施例中,化合物係式(I)、(II)、(III)及/或(IV)化合物,或其醫藥學上可接受之鹽。
在一些實施例中,式(I)、(II)、(III)及/或(IV)化合物具有如所描繪之結構,或為其互變異構體、對映異構體或醫藥學上可接受之鹽。
本發明化合物,例如式(I)、(II)、(III)及/或(IV)化合物可在數個等效描繪中展示。舉例而言,式(II)化合物通常如上文所示在本文中描繪,其中各核苷之3'-取代基面向彼此:。
以上式(II)化合物等效於如以下所描繪之式(II)化合物:。
此外,先前繪圖中之各者等效於以下對式(Ib)化合物之描繪:。
先前描繪中之各者等效於以下對式(II)化合物之描繪:。IV . 組合物
在某些實施例中,本發明提供一種醫藥組合物,其包含本發明化合物(例如式(I)、(II)、(III)及/或(IV)化合物)或其醫藥學上可接受之鹽,及醫藥學上可接受之賦形劑。
在某些實施例中,醫藥組合物包含一或多種額外治療劑,如下文更充分闡述。
包含本文所揭示之化合物或其醫藥學上可接受之鹽的醫藥組合物可用可根據常規實踐選擇的一或多種醫藥學上可接受之賦形劑製備。錠劑可含有包括助滑劑、填充劑、黏合劑及其類似物之賦形劑。水性組合物可以無菌形式製備,且在意欲用於藉由除經口投與以外的途徑進行遞送時一般可為等張的。所有組合物均可視情況含有賦形劑,諸如Rowe等人, Handbook of Pharmaceutical Excipients, 第6版, American Pharmacists Association, 2009中所闡述之賦形劑。賦形劑可包括抗壞血酸及其他抗氧化劑、螯合劑(諸如EDTA)、碳水化合物(諸如糊精)、羥烷基纖維素、羥烷基甲基纖維素、硬脂酸及其類似物。在某些實施例中,組合物以固體劑型提供,包括固體口服劑型。
組合物包括適用於各種投與途徑,包括經口投與之組合物。組合物可以單位劑型呈現,且可藉由藥劑學技術中熟知之任何方法製備。此類方法包括使活性成分(例如,本發明化合物或其醫藥鹽)與一或多種醫藥學上可接受之賦形劑締合的步驟。組合物可藉由使活性成分與液體賦形劑或細粉狀固體賦形劑或兩者均勻且緊密地締合,且隨後視需要使產物成形來製備。技術及調配物一般見於Remington: The Science and Practice of Pharmacy, 第21版, Lippincott Williams and Wilkins, Philadelphia, Pa., 2006中。
本文所描述之適用於經口投與之組合物可以離散單元(單位劑型)呈現,包括但不限於膠囊、扁囊劑或錠劑,各自含有預定量之活性成分。在一個實施例中,醫藥組合物為錠劑。
本文所揭示之醫藥組合物包含一或多種本文所揭示之化合物,或其醫藥學上可接受之鹽,以及醫藥學上可接受之賦形劑及視情況選用之其他治療劑。含有活性成分之醫藥組合物可呈適用於預期投與方法之任何形式。當用於例如口服使用時,可製備錠劑、糖衣錠、口含錠、水性或油性懸浮液、可分散散劑或顆粒、乳液、硬或軟膠囊、糖漿或酏劑。可根據製造醫藥組合物之技術中已知的任何方法製備意欲用於口服使用的組合物,且該等組合物可含有一或多種賦形劑,包括甜味劑、調味劑、著色劑及防腐劑以便提供可口製劑。含有與醫藥學上可接受之無毒賦形劑摻合之活性成分之錠劑為可接受的,該等賦形劑適用於製造錠劑。此等賦形劑可為例如惰性稀釋劑,諸如碳酸鈣或碳酸鈉、乳糖、單水合乳糖、交聯羧甲纖維素鈉、聚維酮、磷酸鈣或磷酸鈉;粒化劑及崩解劑,諸如玉米澱粉或褐藻酸;黏合劑,諸如纖維素、微晶纖維素、澱粉、明膠或阿拉伯膠;及潤滑劑,諸如硬脂酸鎂、硬脂酸或滑石。錠劑可未經包覆或可利用已知技術(包括微囊封裝)包覆以延緩在胃腸道中之崩解及吸附,且因此提供較長時段的持續作用。舉例而言,可單獨或與蠟一起使用諸如單硬脂酸甘油酯或二硬脂酸甘油酯之時間延遲材料。
可與非活性成分組合產生劑型之活性成分的量可視預期治療個體及特定投與模式而變化。舉例而言,在一些實施例中,向人類經口投與之劑型可含有約1至1000 mg活性物質,該活性物質與適當且適宜量之醫藥學上可接受之賦形劑一起調配。在某些實施例中,醫藥學上可接受之賦形劑的範圍為總組合物之約5至約95% (重量:重量)。
在某些實施例中,包含本發明化合物(例如式(I)、(II)、(III)及/或(IV)化合物)或其醫藥學上可接受之鹽的組合物在一個變化形式中不含有影響活性成分代謝速率的試劑。因此,應理解,包含本發明化合物之組合物在一個態樣中不包含將影響(例如減緩、阻礙或扼止)本發明化合物或與本發明化合物分開、依序或同時投與的任何其他活性成分之代謝的試劑。亦應理解,本文所詳述之方法、套組、製品及其類似者中之任一者在一個態樣中不包含將影響(例如減緩、阻礙或扼止)本發明化合物或與本發明化合物分開、依序或同時投與的任何其他活性成分之代謝的試劑。
本發明亦包括如上文所描述之醫藥組合物,其用於調節STING接附蛋白活性,以誘導第I型干擾素、細胞介素或趨化介素之STING依賴性產生。
本發明進一步包括如上文所描述之醫藥組合物,其用於治療或預防感染性疾病,諸如病毒感染,例如由B型肝炎或C型肝炎病毒引起之感染;癌症;或發炎性疾病,例如過敏、鼻炎或哮喘。
本發明進一步包括以醫藥學上可接受之組合物之單一活性成分投與之本發明化合物,其可藉由此項技術中已知之習知方法製備,例如藉由使活性成分與醫藥學上可接受之治療惰性有機及/或無機載劑或賦形劑結合,或藉由與其混合。
另一可能性為使用本發明化合物作為與已知藥物中之其他活性成分具有協同效應之第二或其他活性成分,或與此類藥物一起投與本發明化合物。
本發明化合物亦可以在活體內釋放活性成分的前藥形式或其他經適當改質之形式使用。V . 方法
在一些實施例中,治療疾病或病症之方法包含向有需要之人類或動物投與治療有效量之本發明化合物,或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽。
在一些實施例中,調節(例如:提高) STING接附蛋白之活性之方法包含投與有效量之本發明化合物,或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽。可藉由使細胞與有效量之本發明化合物,或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽接觸,在細胞中進行STING接附蛋白之調節,例如活化。接觸細胞可發生在活體外或活體內。調節STING接附蛋白之活性可藉由量測受該蛋白影響之多個下游生物化學信號中之任一者來確定。
干擾素基因刺激因子(STING)接附蛋白,亦稱為STING、STING蛋白、跨膜蛋白173 (TMEM173)、MPYS、IRF3活化之介體(MITA)或內質網干擾素刺激子(ERIS),為人類中由TMEM173基因(UniProt碼Q86WV6;NCBI參考序列:NP_938023.1 (同功異型物1)及NP_001288667 (同功異型物2))編碼之蛋白質。咸信STING接附蛋白經由不同分子機制充當直接胞溶質DNA感測子(CDS)及第I型干擾素信號傳導之接附蛋白。已證實STING接附蛋白可經由TBK1活化下游轉錄因子STAT6及IRF3,且經由IKKβ活化NF-κB,其可實現針對胞內病原體之抗病毒反應或先天性免疫反應。當細胞經胞內病原體(諸如病毒、分枝桿菌及胞內寄生蟲)感染時,STING接附蛋白藉由誘導第I型干擾素產生而在先天性免疫中起作用。由STING接附蛋白介導之第I型干擾素藉由自分泌及旁分泌信號傳導保護經感染細胞及鄰近細胞免受局部感染。
STING接附蛋白之活化又活化蛋白激酶TBK1,其隨後活化下游轉錄因子NF-κB及IRF-3。咸信STING接附蛋白之活化最終會引起釋放第I型及第III型干擾素以及多種細胞介素及趨化介素,諸如IL-6、TNF-α及INF-γ。因此,在人類或動物中誘導STING接附蛋白依賴性第I型干擾素、細胞介素或趨化介素會引起該人類或動物中NF-κB、IRF-3、第I型干擾素、第III型干擾素、IL-6、TNF-α及INF-γ中之一或多者之活化。
進一步提供一種預防或治療對STING接附蛋白之調節(例如,活化)有反應之疾病或病狀之方法,其包含向有需要之人類或動物投與治療有效量之本發明化合物,或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽。
進一步提供一種在人類或動物中誘導STING接附蛋白依賴性第I型干擾素、細胞介素或趨化介素之方法,其包含投與治療有效量之本發明化合物,或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽。
進一步提供一種治療或預防感染性疾病(例如,病毒感染)之方法,其包含向有需要之人類或動物投與治療有效量之本發明化合物,或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽。
感染性疾病涵蓋由體內存在外來微生物引起之疾病。其包括病毒感染、細菌感染(諸如由革蘭氏(gram)陽性及革蘭氏陰性細菌引起之細菌感染)、真菌感染及由其他微生物(諸如原蟲)引起之感染。在一些實施例中,感染性疾病為病毒感染。
可藉由本發明之方法治療或預防之病毒感染可為由病毒引起之任何感染,例如來自以下病毒家族中之任一者之病毒:腺病毒科(Adenoviridae
),諸如腺病毒(adenoviruse);杯狀病毒科(Calciviridae
);絲狀病毒科(Filoviridae
),諸如埃博拉(ebola);黃病毒科(Flaviviridae
),例如登革熱(dengue)發燒、西尼羅河病毒(West Nile virus)、茲卡病毒(Zika virus)、腦炎(encephalitis)、C型肝炎及黃熱病;肝去氧核糖核酸病毒科(Hepadnaviridae
),例如B型肝炎;疱疹病毒科(Herpesviridae
),例如單純疱疹病毒(herpes simplex virus;HSV) 1及2、水痘帶狀疱疹病毒(varicella zoster virus)、巨細胞病毒(cytomegalovirus;CMV)及疱疹病毒(herpes virus);細小病毒科(Parvoviridae
) (細小病毒(parvoviruse));副黏液病毒科(Paramyxoviridae
),例如副流感(parainfluenza)、流行性腮腺炎(mump)及麻疹(measle);乳頭多瘤空泡病毒科(Papovaviridae
) (乳頭瘤病毒(papilloma virus)、多瘤病毒(polyoma virus));小核糖核酸病毒科(Picornaviridae
),例如脊髓灰質炎(polio)、A型肝炎病毒;腸病毒(enterovirus)、人類柯沙奇病毒(human Coxsackie virus)、鼻病毒(rhinovirus)及埃可病毒(echovirus);痘病毒科(Poxviridae
),例如痘瘡病毒(variola virus)、痘苗病毒(vaccinia virus)及痘病毒(pox virus);逆轉錄病毒科(Retroviridae
),例如人類免疫缺乏病毒,諸如HIV-1;彈狀病毒科(Rhabdoviradae
),例如狂犬病(rabies);及披膜病毒科(Togaviridae
),例如馬腦炎病毒(equine encephalitis virus)及風疹病毒(rubella virus)。在一些實施例中,病毒感染為B型肝炎或C型肝炎感染。
本文進一步描述一種治療或預防發炎性疾病之方法,其包含向有需要之人類或動物投與治療有效量之本發明化合物,或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽。
發炎性疾病包括但不限於過敏、鼻炎及哮喘。
本文進一步描述一種治療或預防癌症之方法,其包含向有需要之人類或動物投與治療有效量之本發明化合物,或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽。
可藉由本發明之方法治療或預防之癌症包括實體腫瘤、白血病及淋巴瘤,包括但不限於腎上腺癌、膀胱癌、骨癌、腦癌、乳癌、結腸癌、結腸直腸癌、眼癌、胃癌、頭頸癌、諸如腎細胞癌之腎癌、肝癌、諸如非小細胞肺癌之肺癌、卵巢癌、胰臟癌、前列腺癌、諸如鱗狀細胞癌及黑素瘤之皮膚癌、甲狀腺癌、子宮癌、陰道癌、諸如骨髓白血病及淋巴母細胞白血病之白血病及諸如多發性骨髓瘤之骨髓瘤。癌症可為未經治療的,或復發性及/或難治性的。
本文進一步描述一種增強疫苗之功效之方法,其包含向有需要之人類或動物投與治療有效量之本發明化合物,或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽。
本發明包括本發明化合物或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽,其用作人類或動物中之藥劑。
本發明進一步包括本發明化合物或其互變異構體、對映異構體或醫藥學上可接受之鹽,其用於調節(例如,提高) STING接附蛋白之活性。
本發明進一步包括本發明化合物或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽,其用於預防或治療對STING接附蛋白之調節(例如,活化)有反應的人類或動物之疾病或病狀。
本發明進一步包括本發明化合物或其互變異構體、對映異構體或醫藥學上可接受之鹽,其單獨或與一或多種治療活性物質組合用於人類或動物中之第I型干擾素、細胞介素或趨化介素之STING依賴性誘導。
本發明進一步包括本發明化合物或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽,其單獨或與一或多種治療活性劑組合用於治療或預防人類或動物之感染性疾病。
本發明進一步包括本發明化合物或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽,其單獨或與一或多種治療活性物質組合用於治療或預防人類或動物之感染性疾病,例如病毒感染,例如由B型肝炎病毒或HIV引起之感染。
本發明進一步包括本發明化合物或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽,其單獨或與一或多種治療活性劑組合用於治療或預防人類或動物之癌症。
本發明進一步包括本發明化合物或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽,其用於在人類或動物中增強疫苗功效。
本發明進一步包括一種醫藥組合物,其用於調節STING接附蛋白活性以在人類或動物中誘導第I型干擾素、細胞介素或趨化介素之STING依賴性產生。
本發明進一步包括一種醫藥組合物,其用於治療或預防人類或動物之病毒感染、癌症或發炎性疾病。
本發明進一步包括本發明化合物或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽用於產生治療或預防病毒感染、癌症或發炎性疾病之藥劑之用途。VI . 投藥
本發明化合物(在本文中亦稱為活性成分)可藉由適於待治療病狀之任何途徑投與。適合途徑包括經口、經直腸、經鼻、局部(包括頰內及舌下)、經皮、經陰道及非經腸(包括皮下、肌肉內、靜脈內、瘤內、皮內、鞘內及硬膜外)及其類似途徑。應瞭解,較佳途徑可隨例如接受者之病狀而變化。本文所揭示之某些化合物之優點為其為經口生物可用且可經口給藥。
本發明化合物可根據有效給藥方案向個體投與持續所需時間段或持續時間,諸如至少約一個月、至少約2個月、至少約3個月、至少約6個月或至少約12個月或更長時間。在一個變化形式中,化合物按每日或間歇性時程投與個體生命之持續時間。
本發明化合物之劑量或給藥頻率可在治療療程內基於投藥醫師之判斷來調節。
化合物可以有效量向個體(例如,人類)投與。在某些實施例中,化合物每日投與一次。
化合物可藉由任何適用途徑及手段,諸如藉由經口或非經腸(例如,靜脈內)投與來投與。化合物之治療有效量可包括每日每公斤體重約0.00001 mg至每日每公斤體重約10 mg,諸如每日每公斤體重約0.0001 mg至每日每公斤體重約10 mg,或諸如每日每公斤體重約0.001 mg至每日每公斤體重約1 mg,或諸如每日每公斤體重約0.01 mg至每日每公斤體重約1 mg,或諸如每日每公斤體重約0.05 mg至每日每公斤體重約0.5 mg,或諸如每日約0.3 mg至約30 mg,或諸如每日約30 mg至約300 mg。
本發明化合物可以任何劑量之本發明化合物(例如,1 mg至1000 mg化合物)與一或多種額外治療劑組合。治療有效量可包括每劑量約1 mg至每劑量約1000 mg,諸如每劑量約50 mg至每劑量約500 mg,或諸如每劑量約100 mg至每劑量約400 mg,或諸如每劑量約150 mg至每劑量約350 mg,或諸如每劑量約200 mg至每劑量約300 mg。本發明化合物之其他治療有效量係每劑量約100、125、150、175、200、225、250、275、300、325、350、375、400、425、450、475或約500 mg。本發明化合物之其他治療有效量係每劑量約100 mg,或每劑量約125、150、175、200、225、250、275、300、350、400、450或約500 mg。可每小時、每日或每週投與單次劑量。舉例而言,單次劑量可每隔1小時、2小時、3小時、4小時、6小時、8小時、12小時、16小時投與一次或每隔24小時投與一次。單次劑量亦可每隔1天、2天、3天、4天、5天、6天投與一次或每隔7天投與一次。單次劑量亦可每隔1週、2週、3週投與一次,或每隔4週投與一次。在某些實施例中,單次劑量可每隔一週投與一次。單次劑量亦可每月投與一次。
本發明化合物之給藥頻率將由個別患者之需求確定,且可為例如每日一次或每日兩次或更多次。化合物之投與持續治療或預防疾病所必需的時長。舉例而言,可將化合物向感染病毒(例如,B型肝炎病毒)之人類投與持續20天至180天之時段,或例如持續20天至90天之時段,或例如持續30天至60天之時段。
投與可為間歇性的,其中在數天或更多天之時段期間患者接受日劑量之本發明化合物,接著在數天或更多天之時段期間患者不接受日劑量之化合物。舉例而言,患者可每隔一天或每週三次接受一劑量之化合物。同樣藉助於實例,患者可每天接受一劑量之化合物持續1至14天之時段,接著在7至21天之時段期間患者不接受一劑量之化合物,接著在後續時段(例如,1至14天)期間患者再次接受日劑量之化合物。在臨床上需要治療患者時,可重複投與化合物隨後不投與化合物之交替的時段。
在一個實施例中,提供醫藥組合物,其包含本發明化合物或其醫藥學上可接受之鹽與一或多種(例如,一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑之組合,及醫藥學上可接受之賦形劑。
在一個實施例中,提供套組,其包含本發明化合物或其醫藥學上可接受之鹽與一或多種(例如,一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑之組合。
在某些實施例中,本發明化合物或其醫藥學上可接受之鹽與一種、兩種、三種、四種或更多種額外治療劑組合。在某些實施例中,本發明化合物或其醫藥學上可接受之鹽與兩種額外治療劑組合。在其他實施例中,本發明化合物或其醫藥學上可接受之鹽與三種額外治療劑組合。在其他實施例中,本發明化合物或其醫藥學上可接受之鹽與四種額外治療劑組合。一種、兩種、三種、四種或更多種額外治療劑可為選自相同類別之治療劑的不同治療劑,及/或其可選自不同類別之治療劑。
在某些實施例中,當本發明化合物與如本文所描述之一或多種額外治療劑組合時,組合物之組分按同時或依序方案投與。當依序投與時,該組合可以兩次或更多次投與形式投與。
在某些實施例中,本發明化合物與一或多種額外治療劑以單一劑型組合用於同時向患者投與,例如呈用於經口投與之固體劑型。
在某些實施例中,本發明化合物與一或多種額外治療劑共投與。VII . 組合療法
在某些實施例中,提高一種用於治療或預防患有感染性疾病、癌症或發炎性疾病或具有罹患該疾病之風險之人類的該疾病之方法,其包含向人類投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑之組合。在一個實施例中,提供一種用於治療或預防患有感染性疾病、癌症或發炎性疾病或具有罹患該疾病之風險之人類的該疾病之方法,其包含向人類投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑之組合。
在某些實施例中,本發明提供一種用於治療病毒感染之方法,其包含向有需要之個體投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑之組合,該等額外治療劑適用於治療病毒感染。在一些實施例中,病毒感染為B型肝炎感染。在一些實施例中,病毒感染為HIV感染。
在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與一種、兩種、三種、四種或更多種額外治療劑組合。在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與兩種額外治療劑組合。在其他實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與三種額外治療劑組合。在其他實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與四種額外治療劑組合。一種、兩種、三種、四種或更多種額外治療劑可為選自相同類別之治療劑的不同治療劑,及/或其可選自不同類別之治療劑。組合療法之投與
在某些實施例中,本文所揭示之化合物與一或多種額外治療劑一起投與。本文所揭示之化合物與一或多種額外治療劑之共投與通常係指同時或依序投與本文所揭示之化合物及一或多種額外治療劑,使得個體體內存在治療有效量之本文所揭示之化合物及一或多種額外治療劑。當依序投與時,該組合可以兩次或更多次投與形式投與。
共投與本文所揭示之化合物與一或多種額外治療劑一般係指同時或依序投與本文所揭示之化合物及一或多種額外治療劑,使得治療有效量之各藥劑存在於患者體內。
在某些實施例中,如本文所揭示之化合物(例如,任何式I化合物)可以任何劑量之式I化合物(例如,10 mg至1000 mg之化合物)與一或多種(例如,一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑組合。
共投與包括在投與單位劑量之一或多種額外治療劑之前或之後投與單位劑量之本文所揭示之化合物。本文所揭示之化合物可在投與一或多種額外治療劑之數秒、數分鐘或數小時內投與。舉例而言,在一些實施例中,首先投與單位劑量之本文所揭示之化合物,接著在數秒或數分鐘內投與單位劑量之一或多種額外治療劑。可替代地,在其他實施例中,首先投與單位劑量之一或多種額外治療劑,接著在數秒或數分鐘內投與單位劑量之本文所揭示之化合物。在一些實施例中,首先投與單位劑量之本文所揭示之化合物,接著在數小時(例如,1至12小時)之時段後投與單位劑量之一或多種額外治療劑。在其他實施例中,首先投與單位劑量之一或多種額外治療劑,接著在數小時(例如,1至12小時)之時段後投與單位劑量之本文所揭示之化合物。
在某些實施例中,本發明化合物與一或多種額外治療劑以單一劑型組合用於同時向個體投與,例如呈用於經口投與之固體劑型。
在某些實施例中,將本發明之化合物調配為錠劑,其可視情況含有一或多種適用於治療所治療之疾病之其他化合物。在某些實施例中,錠劑可含有用於治療病毒性疾病,例如B型肝炎病毒或HIV之另一活性成分。
在某些實施例中,此類錠劑適用於每日一次給藥。
在一個實施例中,提供醫藥組合物,其包含本文所揭示之化合物或其醫藥學上可接受之鹽與一或多種(例如,一種、兩種、三種、一或兩種或一至三種)額外治療劑之組合,及醫藥學上可接受之載劑、稀釋劑或賦形劑。
在一個實施例中,提供套組,其包含本文所揭示之化合物或其醫藥學上可接受之鹽與一或多種(例如,一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑之組合。病毒組合療法
本文中所描述之化合物可與一或多種抗病毒劑一起使用或組合,該等抗病毒劑包括阿巴卡韋(abacavir)、阿昔洛韋(aciclovir)、阿德福韋(adefovir)、金剛胺(amantadine)、安普那韋(amprenavir)、阿比朵爾(arbidol)、阿紮那韋(atazanavir)、立普妥(artipla)、溴夫定(brivudine)、西多福韋(cidofovir)、可比韋(combivir)、依度尿苷(edoxudine)、依法韋侖(efavirenz)、安卓西他賓(emtricitabine)、恩夫韋地(enfuvirtide)、因提弗(entecavir)、弗維森(fomvirsen)、夫沙那韋(fosamprenavir)、膦甲酸(foscarnet)、膦乙醇(fosfonet)、更昔洛韋(ganciclovir)、加德西(gardasil)、伊巴他濱(ibacitabine)、英木洛韋(immunovir)、碘苷(idoxuridine)、咪喹莫特(imiquimod)、茚地那韋(indinavir)、肌苷、整合酶抑制劑、干擾素(包括第III型干擾素、第II型干擾素、第I型干擾素)、拉米夫定(lamivudine)、洛匹那韋(lopinavir)、洛韋胺(loviride)、MK-0518、馬拉維若(maraviroc)、嗎啉脒胍(moroxydine)、奈非那韋(nelfinavir)、奈韋拉平(nevirapine)、多吉美(nexavir)、核苷類似物、奧司他韋(oseltamivir)、噴昔洛韋(penciclovir)、帕拉米韋(peramivir)、普可那利(pleconaril)、鬼臼毒素(podophyllotoxin)、蛋白酶抑制劑、逆轉錄酶抑制劑、利巴韋林(ribavirin)、金剛乙胺(rimantadine)、利托那韋(ritonavir)、沙奎那韋(saquinavir)、司他夫定(stavudine)、替諾福韋(tenofovir)、替諾福韋雙索酯(tenofovir disoproxil)、替拉那韋(tipranavir)、曲氟尿苷(trifluridine)、曲利志韋(trizivir)、曲金剛胺(tromantadine)、特魯瓦達(truvada)、纈更昔洛韋(valganciclovir)、維克維若(vicriviroc)、阿糖腺苷(vidarabine)、偉拉咪定(viramidine)、紮西他濱(zalcitabine)、紮那米韋(zanamivir)、齊多夫定(zidovudine)及其組合。
在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與5-30 mg反丁烯二酸替諾福韋艾拉酚胺(tenofovir alafenamide fumarate)、半反丁烯二酸替諾福韋艾拉酚胺(tenofovir alafenamide hemifumarate)或替諾福韋艾拉酚胺(tenofovir alafenamide)組合。在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與5-10;5-15;5-20;5-25;25-30;20-30;15-30;或10-30 mg之反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺組合。在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與10 mg反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺組合。在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與25 mg反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺組合。如本文所揭示之化合物(例如,式I化合物)可以任何劑量之化合物(例如,50 mg至500 mg之化合物)與本文所提供之試劑組合,如同劑量之各組合具體且分別地列出一般。
在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與100-400 mg反丁烯二酸替諾福韋雙索酯、半反丁烯二酸替諾福韋雙索酯或替諾福韋雙索酯組合。在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與100-150、100-200、100-250、100-300、100-350、150-200、150-250、150-300、150-350、150-400、200-250、200-300、200-350、200-400、250-350、250-400、350-400或300-400 mg之反丁烯二酸替諾福韋雙索酯、半反丁烯二酸替諾福韋雙索酯或替諾福韋雙索酯組合。在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與300 mg反丁烯二酸替諾福韋雙索酯、半反丁烯二酸替諾福韋雙索酯或替諾福韋雙索酯組合。在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與250 mg反丁烯二酸替諾福韋雙索酯、半反丁烯二酸替諾福韋雙索酯或替諾福韋雙索酯組合。在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與150 mg反丁烯二酸替諾福韋雙索酯、半反丁烯二酸替諾福韋雙索酯或替諾福韋雙索酯組合。如本文所揭示之化合物(例如,式I化合物)可以任何劑量之化合物(例如,50 mg至500 mg之化合物)與本文所提供之試劑組合,如同劑量之各組合具體且分別地列出一般。HIV 組合療法
在某些實施例中,提供一種用於治療或預防患有HIV感染或具有罹患HIV感染之風險之人類或動物的HBV感染之方法,其包含向人類或動物投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、一或兩種或一至三種)額外治療劑之組合。在一個實施例中,提供一種用於治療患有HIV感染或具有罹患HIV感染之風險之人類或動物的HBV感染之方法,其包含向人類或動物投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、一或兩種或一至三種)額外治療劑之組合。
在某些實施例中,本發明提供一種用於治療HIV感染之方法,其包含向有需要之個體投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種適用於治療HIV感染的額外治療劑之組合。
在某些實施例中,本文所揭示之化合物調配為錠劑,其可視情況含有一或多種適用於治療HIV之其他化合物。在某些實施例中,錠劑可含有用於治療HIV之另一活性成分,諸如HIV蛋白酶抑制劑、HIV非核苷或非核苷酸逆轉錄酶抑制劑、HIV核苷或核苷酸逆轉錄酶抑制劑、HIV整合酶抑制劑、HIV非催化位點(或異位)整合酶抑制劑、藥物動力學增強劑及其組合。
在某些實施例中,此類錠劑適用於每日一次給藥。
在上述實施例中,額外治療劑可為抗HIV劑。在一些實施例中,額外治療劑選自由以下組成之群:HIV組合藥物、HIV蛋白酶抑制劑、HIV非核苷或非核苷酸逆轉錄酶抑制劑、HIV核苷或核苷酸逆轉錄酶抑制劑、HIV整合酶抑制劑、HIV非催化位點(或異位)整合酶抑制劑、HIV進入抑制劑、HIV成熟抑制劑、免疫調節劑、免疫治療劑、抗體-藥物接合物、基因修飾劑、基因編輯劑(諸如CRISPR/Cas9、鋅指核酸酶、歸巢核酸酶、合成核酸酶、TALEN)、細胞療法(諸如嵌合抗原受體T細胞,CAR-T及經工程改造之T細胞受體,TCR-T)、潛時逆轉劑、靶向HIV衣殼之化合物(包括衣殼抑制劑)、基於免疫之療法、磷脂醯肌醇3-激酶(PI3K)抑制劑、α-4/β-7拮抗劑、HIV抗體、雙特異性抗體及「抗體樣」醫療性蛋白質、HIV p17基質蛋白抑制劑、IL-13拮抗劑、肽基-脯胺醯基順式-反式異構酶A調節劑、二硫化蛋白質異構酶抑制劑、補體C5a受體拮抗劑、DNA甲基轉移酶抑制劑、HIV vif基因調節劑、Vif二聚拮抗劑、HIV-1病毒感染性因子抑制劑、TAT蛋白抑制劑、HIV-1 Nef調節劑、Hck酪胺酸激酶調節劑、混合譜系激酶-3 (MLK-3)抑制劑、HIV-1剪接抑制劑、Rev蛋白抑制劑、整合素拮抗劑、核蛋白抑制劑、剪接因子調節劑、含有COMM域之蛋白1調節劑、HIV核糖核酸酶H抑制劑、逆細胞週期素調節劑、CDK-9抑制劑、樹突狀ICAM-3捕獲非整合素1抑制劑、HIV GAG蛋白抑制劑、HIV POL蛋白抑制劑、補體因子H調節劑、泛素連接酶抑制劑、脫氧胞苷激酶抑制劑、細胞週期素依賴性激酶抑制劑、前蛋白轉化酶PC9刺激劑、ATP依賴性RNA解螺旋酶DDX3X抑制劑、逆轉錄酶激活複合抑制劑、G6PD及NADH-氧化酶抑制劑、藥物動力學增強劑、HIV基因療法、HIV疫苗及其他HIV治療劑及其組合。
在一些實施例中,額外治療劑選自由以下組成之群:用於HIV之組合藥物、用於治療HIV之其他藥物、HIV蛋白酶抑制劑、HIV逆轉錄酶抑制劑、HIV整合酶抑制劑、HIV非催化位點(或異位)整合酶抑制劑、HIV進入(融合)抑制劑、HIV成熟抑制劑、潛伏逆轉劑、衣殼抑制劑、基於免疫之療法、PI3K抑制劑、HIV抗體,及雙特異性抗體,及「抗體樣」醫療性蛋白質,及其組合。 HIV 組合藥物
組合藥物之實例包括ATRIPLA®
(依法韋侖、反丁烯二酸替諾福韋雙索酯及安卓西他賓);COMPLERA®
(EVIPLERA®
;利匹韋林(rilpivirine)、反丁烯二酸替諾福韋雙索酯及安卓西他賓);STRIBILD®
(埃替格韋(elvitegravir)、考比西他(cobicistat)、反丁烯二酸替諾福韋雙索酯及安卓西他賓);TRUVADA®
(反丁烯二酸替諾福韋雙索酯及安卓西他賓;TDF+FTC);DESCOVY® (替諾福韋艾拉酚胺及安卓西他賓);ODEFSEY® (替諾福韋艾拉酚胺、安卓西他賓及利匹韋林)、GENVOYA® (替諾福韋艾拉酚胺、安卓西他賓、考比西他及埃替格韋);BIKTARVY® (比替拉韋(bictegravir)、安卓西他賓、替諾福韋艾拉酚胺);地瑞那韋(darunavir)、半反丁烯二酸替諾福韋艾拉酚胺、安卓西他賓及考比西他;依法韋侖、拉米夫定(lamivudine)及反丁烯二酸替諾福韋雙索酯;拉米夫定及反丁烯二酸替諾福韋雙索酯;替諾福韋及拉米夫定;替諾福韋艾拉酚胺及安卓西他賓;半反丁烯二酸替諾福韋艾拉酚胺及安卓西他賓;半反丁烯二酸替諾福韋艾拉酚胺、安卓西他賓及利匹韋林;半反丁烯二酸替諾福韋艾拉酚胺、安卓西他賓、考比西他及埃替格韋;COMBIVIR®
(齊多夫定及拉米夫定;AZT+3TC);EPZICOM®
(LIVEXA®
;硫酸阿巴卡韋及拉米夫定;ABC+3TC);KALETRA®
(ALUVIA®
;洛匹那韋及利托那韋);TRIUMEQ®
(都魯拉韋(dolutegravir)、阿巴卡韋及拉米夫定);TRIZIVIR®
(硫酸阿巴卡韋、齊多夫定及拉米夫定;ABC+AZT+3TC);阿紮那韋及考比西他;硫酸阿紮那韋及考比西他;硫酸阿紮那韋及利托那韋;地瑞那韋(darunavir)及考比西他;都魯拉韋及利匹韋林;都魯拉韋及鹽酸利匹韋林;都魯拉韋、硫酸阿巴卡韋及拉米夫定;拉米夫定、奈韋拉平及齊多夫定;雷特格韋(raltegravir)及拉米夫定;多拉韋林(doravirine)、拉米夫定及反丁烯二酸替諾福韋雙索酯;多拉韋林、拉米夫定及替諾福韋雙索酯;都魯拉韋+拉米夫定、拉米夫定+阿巴卡韋+齊多夫定、拉米夫定+阿巴卡韋、拉米夫定+反丁烯二酸替諾福韋雙索酯、拉米夫定+齊多夫定+奈韋拉平、洛匹那韋+利托那韋、洛匹那韋+利托那韋+阿巴卡韋+拉米夫定、洛匹那韋+利托那韋+齊多夫定+拉米夫定、替諾福韋+拉米夫定,及反丁烯二酸替諾福韋雙索酯+安卓西他賓+鹽酸利匹韋林、咯匹那韋、利托那韋、齊多夫定及拉米夫定;Vacc-4x及羅米地辛(romidepsin);及APH-0812。HIV 蛋白酶抑制劑
HIV蛋白酶抑制劑之實例包括安普那韋、阿紮那韋、貝卡那韋(brecanavir)、地瑞那韋、夫沙那韋、夫沙那韋鈣、茚地那韋、硫酸茚地那韋、洛匹那韋、奈非那韋、甲磺酸奈非那韋、利托那韋、沙奎那韋、甲磺酸沙奎那韋、替拉那韋、DG-17、TMB-657 (PPL-100)、T-169、BL-008及TMC-310911。HIV 逆轉錄酶抑制劑
HIV非核苷或非核苷酸逆轉錄酶抑制劑之實例包括達匹韋林(dapivirine)、地拉韋定(delavirdine)、甲磺酸地拉韋定、多拉韋林、依法韋侖、依曲韋林(etravirine)、香菇多醣(lentinan)、奈韋拉平、利匹韋林、ACC-007、AIC-292、KM-023、PC-1005及VM-1500。
HIV核苷或核苷酸逆轉錄酶抑制劑之實例包括阿德福韋、阿德福韋酯、阿茲夫定(azvudine)、安卓西他賓、替諾福韋、替諾福韋艾拉酚胺、反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺、替諾福韋雙索酯、反丁烯二酸替諾福韋雙索酯、半反丁烯二酸替諾福韋雙索酯、VIDEX®
及VIDEXEC®
(地達諾新(didanosine),ddl)、阿巴卡韋、硫酸阿巴卡韋、阿洛夫定(alovudine)、阿普瑞西他濱(apricitabine)、森沙戊定(censavudine)、地達諾新、艾夫他濱(elvucitabine)、非替那韋(festinavir)、氟沙定替酯(fosalvudine tidoxil)、CMX-157、達匹韋林、多拉韋林、依曲韋林、OCR-5753、乳清酸替諾福韋雙索酯、福齊夫定替酯(fozivudine tidoxil)、拉米夫定、福斯非茲(phosphazid)、司他夫定(stavudine)、紮西他濱(zalcitabine)、齊多夫定、GS-9131、GS-9148、MK-8504及KP-1461。HIV 整合酶抑制劑
HIV整合酶抑制劑之實例包括埃替格韋、薑黃素、薑黃素之衍生物、菊苣酸、菊苣酸之衍生物、3,5-二咖啡醯奎寧酸、3,5-二咖啡醯奎寧酸之衍生物、金黃三羧酸、金黃三羧酸之衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯之衍生物、酪胺酸磷酸化抑制劑、酪胺酸磷酸化抑制劑之衍生物、槲皮素、槲皮素之衍生物、雷特格韋、都魯拉韋、JTK-351、比替拉韋(bictegravir)、AVX-15567、卡伯拉韋(cabotegravir) (長效可注射)、二酮喹啉-4-1衍生物、整合酶-LEDGF抑制劑、萊德金(ledgin)、M-522、M-532、NSC-310217、NSC-371056、NSC-48240、NSC-642710、NSC-699171、NSC-699172、NSC-699173、NSC-699174、芪二磺酸、T-169及卡伯拉韋。
HIV非催化位點或異位整合酶抑制劑(NCINI)之實例包括CX-05045、CX-05168及CX-14442。HIV 進入抑制劑
HIV進入(融合)抑制劑之實例包括森尼韋若(cenicriviroc)、CCR5抑制劑、gp41抑制劑、CD4連接抑制劑、gp120抑制劑及CXCR4抑制劑。
CCR5抑制劑之實例包括阿普納維(aplaviroc)、維克維若、馬拉維若、森尼韋若、PRO-140、艾達他韋(adaptavir) (RAP-101)、尼非韋羅(nifeviroc) (TD-0232)、抗GP120/CD4或CCR5雙特異性抗體、B-07、MB-66、多肽C25P、TD-0680及vMIP (海米普(Haimipu))。
gp41抑制劑之實例包括艾博韋他(albuvirtide)、恩夫韋地、BMS-986197、恩夫韋地生物更佳藥、恩夫韋地生物類似藥、HIV-1融合抑制劑(P26-Bapc)、ITV-1、ITV-2、ITV-3、ITV-4、PIE-12三聚體及西夫韋他(sifuvirtide)。
CD4連接抑制劑之實例包括伊利祖單抗(ibalizumab)及CADA類似物。
gp120抑制劑之實例包括Radha-108 (瑞西普托(receptol)) 3B3-PE38、BanLec、基於膨潤土之奈米醫藥、福斯薩維緩血酸胺(fostemsavir tromethamine)、IQP-0831及BMS-663068。
CXCR4抑制劑之實例包括普樂沙福(plerixafor)、ALT-1188、N15肽及vMIP (海米普)。HIV 成熟抑制劑
HIV成熟抑制劑之實例包括BMS-955176及GSK-2838232。潛伏逆轉劑
潛伏逆轉劑之實例包括組蛋白去乙醯基酶(HDAC)抑制劑、諸如萬珂(velcade)之蛋白酶體抑制劑、蛋白激酶C (PKC)活化劑、Smyd2抑制劑、BET-溴域4 (BRD4)抑制劑、離子黴素(ionomycin)、PMA、SAHA (辛二醯苯胺異羥肟酸或辛二醯基、苯胺及異羥肟酸)、AM-0015、ALT-803、NIZ-985、NKTR-255、IL-15調節抗體、JQ1、二硫龍、兩性黴素B及諸如拉格唑拉(largazole)類似物之泛素抑制劑以及GSK-343。
HDAC抑制劑之實例包括羅米地辛、伏立諾他(vorinostat)及帕比諾他(panobinostat)。
PKC活化劑之實例包括吲哚拉坦(indolactam)、普羅斯坦(prostratin)、巨大戟醇B,及DAG-內酯。衣殼抑制劑
衣殼抑制劑之實例包括衣殼聚合抑制劑或衣殼分裂化合物、諸如偶氮二甲醯胺之HIV核衣殼p7 (NCp7)抑制劑、HIV p24衣殼蛋白質抑制劑、AVI-621、AVI-101、AVI-201、AVI-301及AVI-CAN1-15系列。基於免疫之療法
基於免疫之療法之實例包括鐸樣受體調節劑,諸如TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TLR12及TLR13;計劃性細胞死亡蛋白1 (Pd-1)調節劑;計劃性死亡配位體1 (Pd-L1)調節劑;IL-15調節劑;德瑪韋(DermaVir);介白素-7;氯奎寧(plaquenil) (羥基氯奎);普留淨(proleukin) (阿地介白素(aldesleukin),IL-2);干擾素α;干擾素α-2b;干擾素α-n3;聚乙二醇化干擾素α;干擾素γ;羥基脲;黴酚酸嗎啉乙酯(MPA)及其酯衍生物黴酚酸嗎啉乙酯(MMF);利巴韋林;瑞他立德(rintatolimod)、聚合物聚乙二亞胺(PEI);吉朋(gepon);瑞他立德;IL-12;WF-10;VGV-1;MOR-22;BMS-936559;CYT-107、介白素-15/Fc融合蛋白、諾姆福隆(normferon)、聚乙二醇化干擾素(peginterferon) α-2a、聚乙二醇化干擾素α-2b、重組型介白素-15、RPI-MN、GS-9620、STING調節劑、RIG-I調節劑、NOD2調節劑及IR-103。
TLR8調節劑之實例包括莫托莫特(motolimod)、雷西莫特(resiquimod)、3M-051、3M-052、MCT-465、IMO-4200、VTX-763、VTX-1463及以下文獻中所揭示之調節劑:US20140045849 (Janssen)、US20140073642 (Janssen)、WO2014/056953 (Janssen)、WO2014/076221 (Janssen)、WO2014/128189 (Janssen)、US20140350031 (Janssen)、WO2014/023813 (Janssen)、US20080234251 (Array Biopharma)、US20080306050 (Array Biopharma)、US20100029585 (Ventirx Pharma)、US20110092485 (Ventirx Pharma)、US20110118235 (Ventirx Pharma)、US20120082658 (Ventirx Pharma)、US20120219615 (Ventirx Pharma)、US20140066432 (Ventirx Pharma)、US20140088085 (VentirxPharma)、US20140275167 (Novira therapeutics)、US20130251673 (Novira therapeutics)、美國專利第9670205號(Gilead Sciences Inc.)、US20160289229 (Gilead Sciences Inc.)、美國專利申請案第15/692161號(Gilead Sciences Inc.)及美國專利申請案第15/692093號(Gilead Sciences Inc.)。磷脂醯肌醇 3 - 激酶 ( PI3K ) 抑制劑
PI3K抑制劑之實例包括艾德斯布(idelalisib)、艾培昔布(alpelisib)、布帕昔布(buparlisib)、CAI乳清酸鹽、考班昔布(copanlisib)、杜維力絲(duvelisib)、吉達力絲(gedatolisib)、來那替尼(neratinib)、帕努昔布(panulisib)、哌立福新(perifosine)、皮克立西(pictilisib)、皮拉力絲(pilaralisib)、甲磺酸普喹替尼(puquitinib mesylate)、瑞戈替布(rigosertib)、瑞戈替布鈉、索諾昔布(sonolisib)、泰尼西布(taselisib)、AMG-319、AZD-8186、BAY-1082439、CLR-1401、CLR-457、CUDC-907、DS-7423、EN-3342、GSK-2126458、GSK-2269577、GSK-2636771、INCB-040093、LY-3023414、MLN-1117、PQR-309、RG-7666、RP-6530、RV-1729、SAR-245409、SAR-260301、SF-1126、TGR-1202、UCB-5857、VS-5584、XL-765及ZSTK-474。α - 4 / β - 7 拮抗劑
整合素α-4/β-7拮抗劑之實例包括PTG-100、TRK-170、阿布里單抗(abrilumab)、艾托珠單抗(etrolizumab)、卡洛斯特甲基(carotegrast methyl)及維多珠單抗(vedolizumab)。HIV 抗體、雙特異性抗體及「抗體樣」醫療性蛋白質
HIV抗體、雙特異性抗體及「抗體樣」醫療性蛋白質之實例包括DARTs®
、DUOBODIES®
、BITES®
、XmAbs®
、TandAbs®
、Fab衍生物、bnAB (廣譜中和HIV-1抗體)、BMS-936559、TMB-360及靶向HIV gp120或gp41之抗體、靶向HIV之抗體募集分子、抗CD63單株抗體、抗GB病毒C抗體、抗GP120/CD4、CCR5雙特異性抗體、抗nef單域抗體、抗Rev抗體、駱駝衍生之抗CD18抗體、駱駝衍生之抗ICAM-1抗體、DCVax-001、靶向gp140之抗體、基於gp41之HIV治療性抗體、人類重組型mAb (PGT-121)、伊利祖單抗、Immuglo及MB-66。
以此方式靶向HIV之抗體之實例包括巴維昔單抗(bavituximab)、UB-421、C2F5、2G12、C4E10、C2F5+C2G12+C4E10、8ANC195、3BNC117、3BNC60、10-1074、PGT145、PGT121、PGT-151、PGT-133、MDX010 (伊派利單抗(ipilimumab))、DH511、N6、VRC01 PGDM1400、A32、7B2、10E8、10E8v4、CAP256-VRC26.25、DRVIA7、VRC-07-523、VRC-HIVMAB080-00-AB、VRC-HIVMAB060-00-AB、MGD-014及VRC07。HIV雙特異性抗體之實例包括MGD014。藥物動力學增強劑
藥物動力學增強劑之實例包括考比西他及利托那韋。HIV 疫苗
HIV疫苗之實例包括肽疫苗、重組型子單元蛋白疫苗、活載體疫苗、DNA疫苗、CD4衍生之肽疫苗、疫苗組合、rgp120 (AIDSVAX)、ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144)、單體gp120 HIV-1次型C疫苗、Remune、ITV-1、Contre Vir、Ad5-ENVA-48、DCVax-001 (CDX-2401)、Vacc-4x、Vacc-C5、VAC-3S、多進化枝DNA重組型腺病毒-5 (rAd5)、Pennvax-G、Pennvax-GP、HIV-TriMix-mRNA疫苗、HIV-LAMP-vax、Ad35、Ad35-GRIN、NAcGM3/VSSP ISA-51、聚-ICLC輔佐疫苗、TatImmune、GTU-multiHIV (FIT-06)、gp140[δ]V2.TV1+MF-59、rVSVIN HIV-1 gag疫苗、SeV-Gag疫苗、AT-20、DNK-4、ad35-Grin/ENV、TBC-M4、HIVAX、HIVAX-2、NYVAC-HIV-PT1、NYVAC-HIV-PT4、DNA-HIV-PT123、rAAV1-PG9DP、GOVX-B11、GOVX-B21、TVI-HIV-1、Ad-4 (Ad4-env進化枝C+Ad4-mGag)、EN41-UGR7C、EN41-FPA2、PreVaxTat、AE-H、MYM-V101、CombiHIVvac、ADVAX、MYM-V201、MVA-CMDR、DNA-Ad5 gag/pol/nef/nev (HVTN505)、MVATG-17401、ETV-01、CDX-1401、rcAD26.MOS1.HIV-Env、Ad26.Mod.HIV疫苗、AGS-004、AVX-101、AVX-201、PEP-6409、SAV-001、ThV-01、TL-01、TUTI-16、VGX-3300、IHV-001及病毒樣顆粒疫苗(諸如假病毒顆粒疫苗)、CombiVICHvac、LFn-p24 B/C融合疫苗、基於GTU之DNA疫苗、HIV gag/pol/nef/env DNA疫苗、抗TAT HIV疫苗、綴合多肽疫苗、樹突狀細胞疫苗、基於gag之DNA疫苗、GI-2010、gp41 HIV-1疫苗、HIV疫苗(PIKA佐劑)、I i-key/MHC II類抗原決定基雜交肽疫苗、ITV-2、ITV-3、ITV-4、LIPO-5、多進化枝Env疫苗、MVA疫苗、Pennvax-GP、pp71缺失型HCMV載體HIV gag疫苗、重組型肽疫苗(HIV感染)、NCI、rgp160 HIV疫苗、RNActive HIV疫苗、SCB-703、Tat Oyi疫苗、TBC-M4、治療性HIV疫苗、UBI HIV gp120、Vacc-4x+羅米地辛、變異型gp120多肽疫苗、rAd5 gag-pol env A/B/C疫苗、DNA.HTI及MVA.HTI。額外 HIV 治療劑
額外HIV治療劑之實例包括揭示於以下中之化合物:WO 2004/096286 (Gilead Sciences)、WO 2006/015261 (Gilead Sciences)、WO 2006/110157 (Gilead Sciences)、WO 2012/003497 (Gilead Sciences)、WO 2012/003498 (Gilead Sciences)、WO 2012/145728 (Gilead Sciences)、WO 2013/006738 (Gilead Sciences)、WO 2013/159064 (Gilead Sciences)、WO 2014/100323 (Gilead Sciences)、US 2013/0165489 (University of Pennsylvania)、US 2014/0221378 (Japan Tobacco)、US 2014/0221380 (Japan Tobacco)、WO 2009/062285 (Boehringer Ingelheim)、WO 2010/130034 (Boehringer Ingelheim)、WO 2013/006792 (Pharma Resources)、US 20140221356 (Gilead Sciences)、US 20100143301 (Gilead Sciences)及WO 2013/091096 (Boehringer Ingelheim)。
用於治療HIV之其他藥物之實例包括乙醯嗎喃(acemannan)、阿拉泊韋(alisporivir)、BanLec、去鐵酮、格瑪木因(Gamimune)、米特法林(metenkefalin)、納曲酮(naltrexone)、普拉斯汀(Prolastin)、REP 9、RPI-MN、VSSP、H1viral、SB-728-T、1,5-二咖啡醯奎寧酸、rHIV7-shl-TAR-CCR5RZ、AAV-eCD4-Ig基因療法、MazF基因療法、BlockAide、ABX-464、AG-1105、APH-0812、BIT-225、CYT-107、HGTV-43、HPH-116、HS-10234、IMO-3100、IND-02、MK-1376、MK-8507、MK-8591、NOV-205、PA-1050040 (PA-040)、PGN-007、SCY-635、SB-9200、SCB-719、TR-452、TEV-90110、TEV-90112、TEV-90111、TEV-90113、RN-18、Immuglo,及VIR-576。基因療法及細胞療法
基因療法及細胞療法包括用於使基因沉默之基因修飾;用於直接殺死經感染細胞之基因方法;經設計以將個體之大部分自身免疫系統替換以增強對經感染細胞之免疫反應或使個體之自身免疫系統活化以殺死經感染細胞或尋找且殺死經感染細胞之免疫細胞輸注;用於修飾細胞活性以進一步改變針對感染之內源性免疫反應性之基因方法。
樹突狀細胞療法之實例包括AGS-004。基因編輯劑
基因編輯系統之實例包括CRISPR/Cas9系統、鋅指核酸酶系統、TALEN系統、歸巢核酸內切酶系統及大範圍核酸酶系統。
靶向HIV之CRISPR/Cas9系統之實例包括EBT101。CAR - T 細胞療法
CAR-T細胞療法包括工程改造以表現嵌合抗原受體(CAR)之免疫效應細胞之群體,其中CAR包含HIV抗原結合域。HIV抗原包括HIV包膜蛋白或其部分、gp120或其部分、gp120上之CD4結合位點、gp120上之CD4誘導結合位點、gp120上之N聚醣、gp120之V2、gp41上之近膜區域。免疫效應細胞為T細胞或NK細胞。在一些實施例中,T細胞為CD4+ T細胞、CD8+ T細胞或其組合。
HIV CAR-T之實例包括VC-CAR-T。TCR - T 細胞療法
TCR-T細胞療法包括經工程改造以靶向經病毒感染之細胞表面上之HIV衍生之肽的T細胞。
熟習此項技術者應瞭解,上文所列之額外治療劑可包括於上文所列之類別中之多於一者中。特定類別不欲限制彼等類別中所列之彼等化合物的功能。
在一具體實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與HIV核苷或核苷酸逆轉錄酶抑制劑及HIV非核苷逆轉錄酶抑制劑組合。在另一具體實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與HIV核苷或核苷酸逆轉錄酶抑制劑及HIV蛋白酶抑制化合物組合。在另一實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與HIV核苷或核苷酸逆轉錄酶抑制劑、HIV非核苷逆轉錄酶抑制劑及藥物動力學增強劑組合。在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與至少一種HIV核苷逆轉錄酶抑制劑、整合酶抑制劑及藥物動力學增強劑組合。在另一實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與兩種HIV核苷或核苷酸逆轉錄酶抑制劑組合。
在一特定實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與一種、兩種、三種、四種或更多種選自以下之額外治療劑組合:ATRIPLA®
(依法韋侖、反丁烯二酸替諾福韋雙索酯及安卓西他賓);COMPLERA®
(EVIPLERA®
;利匹韋林、反丁烯二酸替諾福韋雙索酯及安卓西他賓);STRIBILD®
(埃替格韋、考比西他、反丁烯二酸替諾福韋雙索酯及安卓西他賓);TRUVADA®
(反丁烯二酸替諾福韋雙索酯及安卓西他賓;TDF +FTC);DESCOVY® (替諾福韋艾拉酚胺及安卓西他賓);ODEFSEY® (替諾福韋艾拉酚胺、安卓西他賓及利匹韋林);GENVOYA® (替諾福韋艾拉酚胺、安卓西他賓、考比西他及埃替格韋);BIKTARVY® (比替拉韋、安卓西他賓、替諾福韋艾拉酚胺);阿德福韋;阿德福韋酯;考比西他;安卓西他賓;替諾福韋;替諾福韋雙索酯;反丁烯二酸替諾福韋雙索酯;替諾福韋艾拉酚胺;半反丁烯二酸替諾福韋艾拉酚胺;TRIUMEQ®
(都魯拉韋、阿巴卡韋及拉米夫定);都魯拉韋、硫酸阿巴卡韋及拉米夫定;雷特格韋;雷特格韋及拉米夫定;馬拉維若;恩夫韋地;ALUVIA®
(KALETRA®
;咯匹那韋及利托那韋);COMBIVIR®
(齊多夫定及拉米夫定;AZT+3TC);EPZICOM®
(LIVEXA®
;硫酸阿巴卡韋及拉米夫定;ABC+3TC);TRIZIVIR®
(硫酸阿巴卡韋、齊多夫定及拉米夫定;ABC+AZT+3TC);利匹韋林;鹽酸利匹韋林;硫酸阿紮那韋及考比西他;阿紮那韋及考比西他;地瑞那韋及考比西他;阿紮那韋;硫酸阿紮那韋;都魯拉韋;埃替格韋;利托那韋;硫酸阿紮那韋及利托那韋;地瑞那韋;拉米夫定;普拉斯汀;夫沙那韋;夫沙那韋鈣依法韋侖;依曲韋林;奈非那韋;甲磺酸奈非那韋;干擾素;地達諾新;司他夫定;茚地那韋;硫酸茚地那韋;替諾福韋及拉米夫定;齊多夫定;奈韋拉平;沙奎那韋;甲磺酸沙喹那韋;阿地介白素;紮西他濱;替拉那韋;安普那韋;地拉韋定;甲磺酸地拉韋定;Radha-108 (瑞西普托);拉米夫定及反丁烯二酸替諾福韋雙索酯;依法韋侖;拉米夫定及反丁烯二酸替諾福韋雙索酯;福斯非茲;拉米夫定;奈韋拉平及齊多夫定;阿巴卡韋;以及硫酸阿巴卡韋。
在一特定實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與以下組合:硫酸阿巴卡韋、替諾福韋、替諾福韋雙索酯、反丁烯二酸替諾福韋雙索酯、半反丁烯二酸替諾福韋雙索酯、替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或比替拉韋。
在一特定實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與以下組合:替諾福韋、替諾福韋雙索酯、反丁烯二酸替諾福韋雙索酯、替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或比替拉韋。
在一特定實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與以下組合:選自由以下組成之群的第一額外治療劑:硫酸阿巴卡韋、替諾福韋、替諾福韋雙索酯、反丁烯二酸替諾福韋雙索酯、替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺及比替拉韋;及選自由安卓西他賓及拉米夫定組成之群的第二額外治療劑。
在一特定實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與以下組合:選自由以下組成之群的第一額外治療劑:替諾福韋、替諾福韋雙索酯、反丁烯二酸替諾福韋雙索酯、替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺及比替拉韋;及第二額外治療劑,其中第二額外治療劑為安卓西他賓。
在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與5-30 mg反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺及200 mg安卓西他賓組合。在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與5-10 mg、5-15 mg、5-20 mg、5-25 mg、25-30 mg、20-30 mg、15-30 mg或10-30 mg反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺及200 mg安卓西他賓組合。在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與10 mg反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺及200 mg安卓西他賓組合。在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與25 mg反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺或替諾福韋艾拉酚胺及200 mg安卓西他賓組合。如本文所揭示之化合物(例如,式I化合物)可以任何劑量之化合物(例如,1 mg至500 mg之化合物)與本文所提供之試劑組合,如同劑量之各組合具體且分別地列出一般。
在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與200-400 mg反丁烯二酸替諾福韋雙索酯、半反丁烯二酸替諾福韋雙索酯或替諾福韋雙索酯及200 mg安卓西他賓組合。在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與200-250、200-300、200-350、250-350、250-400、350-400、300-400或250-400 mg反丁烯二酸替諾福韋雙索酯、半反丁烯二酸替諾福韋雙索酯或替諾福韋雙索酯及200 mg安卓西他賓組合。在某些實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與300 mg反丁烯二酸替諾福韋雙索酯、半反丁烯二酸替諾福韋雙索酯或替諾福韋雙索酯及200 mg安卓西他賓組合。如本文所揭示之化合物(例如,式I化合物)可以任何劑量之化合物(例如,1 mg至500 mg之化合物)與本文所提供之試劑組合,如同劑量之各組合具體且分別地列出一般。HBV 組合療法
在某些實施例中,提供一種用於治療或預防患有HBV感染或具有罹患HBV感染之風險之人類的HBV感染之方法,其包含向人類投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑之組合。在一個實施例中,提供一種用於治療患有HBV感染或具有罹患HBV感染之風險之人類的HBV感染之方法,其包含向人類投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑之組合。
在某些實施例中,本發明提供一種用於治療HBV感染之方法,其包含向有需要之患者投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、四種、一或兩種、一至三種或一至四種)額外治療劑之組合,該等額外治療劑適用於治療HBV感染。
本文所描述之化合物可與以下中之一或多者一起使用或組合:化學治療劑、免疫調節劑、免疫治療劑、治療性抗體、治療性疫苗、雙特異性抗體及「抗體樣」醫療性蛋白質(諸如DARTs®、Duobodies®、Bites®、XmAbs®、TandAbs®、Fab衍生物)、抗體-藥物接合物(ADC)、基因修飾劑或基因編輯劑(諸如CRISPR Cas9、鋅指核酸酶、歸巢核酸內切酶、合成核酸酶、TALEN)、細胞療法(諸如CAR-T (嵌合抗原受體T細胞)及TCR-T (經工程改造之T細胞受體)藥劑)或其任何組合。
在某些實施例中,式(I)化合物調配為錠劑,其可視情況含有一或多種適用於治療HBV之其他化合物。在某些實施例中,錠劑可含有用於治療HBV之另一活性成分,諸如3-二加氧酶(IDO)抑制劑、載脂蛋白A1調節劑、精胺酸酶抑制劑、B淋巴細胞及T淋巴細胞衰減因子抑制劑、布魯頓氏酪胺酸激酶(Bruton's tyrosine kinase;BTK)抑制劑、CCR2趨化介素拮抗劑、CD137抑制劑、CD160抑制劑、CD305抑制劑、CD4促效劑及調節劑、靶向HBcAg之化合物、靶向B型肝炎核心抗原(HBcAg)之化合物、核心蛋白異位調節劑、共價閉合環狀DNA (cccDNA)抑制劑、親環素抑制劑、細胞毒性T淋巴細胞相關蛋白質4 (ipi4)抑制劑、DNA聚合酶抑制劑、核酸內切酶調節劑、表觀遺傳調節劑、法尼醇X受體(Farnesoid X receptor)促效劑、HBsAg抑制劑、HBsAg分泌或組裝抑制劑、HBV DNA聚合酶抑制劑、HBV複製抑制劑、HBV RNAse抑制劑、HBV病毒進入抑制劑、HBx抑制劑、B型肝炎大型包膜蛋白調節劑、B型肝炎大型包膜蛋白刺激劑、B型肝炎結構蛋白調節劑、B型肝炎表面抗原(HBsAg)抑制劑、B型肝炎表面抗原(HBsAg)分泌或組裝抑制劑、B型肝炎病毒E抗原抑制劑、B型肝炎病毒複製抑制劑、肝炎病毒結構蛋白抑制劑、HIV-1逆轉錄酶抑制劑、玻尿酸酶抑制劑、IAPs抑制劑、IL-2促效劑、IL-7促效劑、免疫調節劑、吲哚胺-2抑制劑、核糖核苷酸還原酶抑制劑、介白素-2配位體、ipi4抑制劑、離胺酸去甲基酶抑制劑、組蛋白去甲基酶抑制劑、KDM1抑制劑、KDM5抑制劑、殺手細胞凝集素樣受體子族G成員1抑制劑、淋巴細胞活化基因3抑制劑、淋巴毒素β受體活化劑、Axl調節劑、B7-H3調節劑、B7-H4調節劑、CD160調節劑、CD161調節劑、CD27調節劑、CD47調節劑、CD70調節劑、GITR調節劑、HEVEM調節劑、ICOS調節劑、Mer調節劑、NKG2A調節劑、NKG2D調節劑、OX40調節劑、SIRPα調節劑、TIGIT調節劑、Tim-4調節劑、Tyro調節劑、Na+-牛膽酸酯共輸送多肽(NTCP)抑制劑、自然殺手細胞受體2B4抑制劑、NOD2基因刺激劑、核蛋白抑制劑、核蛋白調節劑、PD-1抑制劑、PD-L1抑制劑、肽基脯胺醯異構酶抑制劑、磷脂醯肌醇-3激酶(PI3K)抑制劑、視黃酸誘導性基因1刺激劑、逆轉錄酶抑制劑、核糖核酸酶抑制劑、RNA DNA聚合酶抑制劑、SLC10A1基因抑制劑、SMAC模擬物、Src酪胺酸激酶抑制劑、干擾素基因刺激因子(STING)促進劑、NOD1刺激劑、T細胞表面醣蛋白CD28抑制劑、T細胞表面醣蛋白CD8調節劑、胸腺素促效劑、胸腺素α 1配位體、Tim-3抑制劑、TLR-3促效劑、TLR-7促效劑、TLR-9促效劑、TLR9基因刺激劑、鐸樣受體(TLR)調節劑、病毒性核糖核苷酸還原酶抑制劑及其組合。HBV 組合藥物
用於治療HBV之組合藥物的實例包括TRUVADA®
(反丁烯二酸替諾福韋雙索酯及安卓西他賓);ABX-203、拉米夫定及PEG-IFN-α;ABX-203阿德福韋及PEG-IFNα;以及INO-1800 (INO-9112及RG7944)。其他 HBV 藥物
用於治療HBV之其他藥物的實例包括α-羥基環庚三烯酚酮、安多索韋(amdoxovir)、β-羥基胞嘧啶核苷、AL-034、CCC-0975、艾夫他濱(elvucitabine)、依澤替米貝(ezetimibe)、環孢素A、龍膽苦苷(gentiopicrin/gentiopicroside)、JNJ-56136379、硝唑尼特(nitazoxanide)、比林納潘特(birinapant)、NJK14047、NOV-205 (莫里克桑(molixan),BAM-205)、寡苷酸、米沃替酯(mivotilate)、菲隆(feron)、GST-HG-131、左旋咪唑(levamisole)、卡舒寧(Ka Shu Ning)、阿洛菲隆(alloferon)、WS-007、Y-101 (替芬泰(Ti Fen Tai))、rSIFN-co、PEG-IIFNm、KW-3、BP-Inter-014、齊墩果酸(oleanolic acid)、HepB-nRNA、cTP-5 (rTP-5)、HSK-II-2、HEISCO-106-1、HEISCO-106、赫普巴納(Hepbarna)、IBPB-006IA、和普印芬(Hepuyinfen)、DasKloster 0014-01、ISA-204、將安泰(Jiangantai) (肝西康(Ganxikang))、MIV-210、OB-AI-004、PF-06、胡黃連苷(picroside)、DasKloster-0039、和普蘭太(hepulantai)、IMB-2613、TCM-800B、還原麩胱甘肽、RO-6864018、RG-7834、UB-551及ZH-2N,及US20150210682 (Roche)、US 2016/0122344 (Roche)、WO2015173164、WO2016023877、US2015252057A (Roche)、WO16128335A1 (Roche)、WO16120186A1 (Roche)、US2016237090A (Roche)、WO16107833A1 (Roche)、WO16107832A1 (Roche)、US2016176899A (Roche)、WO16102438A1 (Roche)、WO16012470A1 (Roche)、US2016220586A (Roche)及US2015031687A (Roche)中所揭示之化合物。HBV 疫苗
HBV疫苗包括預防性及治療性疫苗。HBV預防性疫苗之實例包括Vaxelis、Hexaxim、Heplisav、Mosquirix、DTwP-HBV疫苗、Bio-Hep-B、D/T/P/HBV/M (LBVP-0101;LBVW-0101)、DTwP-Hepb-Hib-IPV疫苗、Heberpenta L、DTwP-HepB-Hib、V-419、CVI-HBV-001、Tetrabhay、B型肝炎預防性疫苗(Advax Super D)、Hepatrol-07、GSK-223192A、ENGERIX B®
、重組型B型肝炎疫苗(肌肉內,Kangtai Biological Products)、重組型B型肝炎疫苗(漢遜多形酵母(Hansenual polymorpha yeast),肌肉內,Hualan Biological Engineering)、重組B型肝炎表面抗原疫苗、Bimmugen、Euforavac、Eutravac、anrix-DTaP-IPV-Hep B、HBAI-20、Infanrix-DTaP-IPV-Hep B-Hib、Pentabio Vaksin DTP-HB-Hib、Comvac 4、Twinrix、Euvax-B、Tritanrix HB、Infanrix Hep B、Comvax、DTP-Hib-HBV疫苗、DTP-HBV疫苗、Yi Tai、Heberbiovac HB、Trivac HB、GerVax、DTwP-Hep B-Hib疫苗、Bilive、Hepavax-Gene、SUPERVAX、Comvac5、Shanvac-B、Hebsulin、Recombivax HB、Revac B mcf、Revac B+、Fendrix、DTwP-HepB-Hib、DNA-001、Shan5、Shan6、rhHBsAG疫苗、HBI五價疫苗、LBVD、Infanrix HeXa及DTaP-rHB-Hib疫苗。
HBV治療性疫苗之實例包括HBsAG-HBIG複合物、ARB-1598、Bio-Hep-B、NASVAC、abi-HB (靜脈內)、ABX-203、Tetrabhay、GX-110E、GS-4774、肽疫苗(εPA-44)、Hepatrol-07、NASVAC (NASTERAP)、IMP-321、BEVAC、Revac B mcf、Revac B+、MGN-1333、KW-2、CVI-HBV-002、AltraHepB、VGX-6200、FP-02、FP-02.2、TG-1050、NU-500、HBVax、im/TriGrid/抗原疫苗、Mega-CD40L佐劑化疫苗、HepB-v、RG7944 (INO-1800)、基於重組型VLP之治療性疫苗(HBV感染,VLP Biotech)、AdTG-17909、AdTG-17910、AdTG-18202、ChronVac-B、TG-1050及Lm HBV。HBV DNA 聚合酶抑制劑
HBV DNA聚合酶抑制劑之實例包括阿德福韋(HEPSERA®
)、安卓西他賓(EMTRIVA®
)、反丁烯二酸替諾福韋雙索酯(VIREAD®
)、替諾福韋艾拉酚胺、替諾福韋、替諾福韋雙索酯、反丁烯二酸替諾福韋艾拉酚胺、半反丁烯二酸替諾福韋艾拉酚胺、替諾福韋迪皮夕(tenofovir dipivoxil)、反丁烯二酸替諾福韋迪皮夕、替諾福韋十八烷氧基乙酯、CMX-157、拜斯福韋(besifovir)、因提弗(BARACLUDE®
)、順丁烯二酸因提弗、替比夫定(telbivudine) (TYZEKA®
)、非洛西韋(filocilovir)、帕拉德福韋(pradefovir)、克來夫定(clevudine)、利巴韋林、拉米夫定(EPIVIR-HBV®
)、疊氮膦(phosphazide)、泛昔洛韋(famciclovir)、弗索林(fusolin)、美他卡韋(metacavir)、SNC-019754、FMCA、AGX-1009、AR-II-04-26、HIP-1302、天冬胺酸替諾福韋雙索酯、乳清酸替諾福韋雙索酯及HS-10234。免疫調節劑
免疫調節劑之實例包括瑞他立德、鹽酸艾咪朵爾(imidol hydrochloride)、因加容(ingaron)、德瑪韋、氯奎寧(羥基氯奎)、普留淨、羥基脲、黴酚酸嗎啉乙酯(MPA)及其酯衍生物黴酚酸嗎啉乙酯(MMF)、JNJ-440、WF-10、AB-452、利巴韋林、IL-12、INO-9112、聚合物聚伸乙亞胺(PEI)、吉朋、VGV-1、MOR-22、CRV-431、JNJ-0535、TG-1050、ABI-H2158、BMS-936559、GS-9688、RO-7011785、RG-7854、AB-506、RO-6871765、AIC-649及IR-103。鐸樣受體 ( TLR ) 調節劑
TLR調節劑包括TLR1、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10、TLR11、TLR12及TLR13之調節劑。TLR3調節劑之實例包括瑞他立德、聚-ICLC、RIBOXXON®
、阿伯辛(Apoxxim)、RIBOXXIM®
、IPH-33、MCT-465、MCT-475及ND-1.1。
TLR7調節劑之實例包括GS-9620、GSK-2245035、咪喹莫特、雷西莫特、DSR-6434、DSP-3025、IMO-4200、MCT-465、MEDI-9197、3M-051、SB-9922、3M-052、林托普(Limtop)、D、特拉莫德(telratolimod))、SP-0509、TMX-30X、TMX-202、RG-7863、RG-7795、LHC-165、RG-7854及US20100143301 (Gilead Sciences)、US20110098248 (Gilead Sciences)及US20090047249 (Gilead Sciences)中所揭示之化合物。
TLR8調節劑之實例包括莫托莫特、雷西莫特、3M-051、3M-052、MCT-465、IMO-4200、VTX-763、VTX-1463、GS-9688及以下中所揭示之化合物:US20140045849 (Janssen)、US20140073642 (Janssen)、WO2014/056953 (Janssen)、WO2014/076221 (Janssen)、WO2014/128189 (Janssen)、US20140350031 (Janssen)、WO2014/023813 (Janssen)、US20080234251 (Array Biopharma)、US20080306050 (Array Biopharma)、US20100029585 (Ventirx Pharma)、US20110092485 (Ventirx Pharma)、US20110118235 (Ventirx Pharma)、US20120082658 (Ventirx Pharma)、US20120219615 (Ventirx Pharma)、US20140066432 (Ventirx Pharma)、US20140088085 (Ventirx Pharma)、US20140275167 (Novira Therapeutics)、US20130251673 (Novira Therapeutics)、美國專利案第9670205號、US20160289229、美國專利申請案第15/692161號及美國專利申請案第15/692093號。
TLR9調節劑之實例包括BB-001、BB-006、CYT-003、IMO-2055、IMO-2125、IMO-3100、IMO-8400、IR-103、IMO-9200、阿托莫特(agatolimod)、DIMS-9054、DV-1079、DV-1179、AZD-1419、利福莫特(leftolimod) (MGN-1703)、利騰莫特(litenimod)及CYT-003-QbG10。
TLR7、TLR8及TLR9調節劑之實例包括以下中所揭示之化合物:WO2017047769 (Teika Seiyaku)、WO2015014815 (Janssen)、WO2018045150(Gilead Sciences Inc)、WO2018045144 (Gilead Sciences Inc)、WO2015162075(Roche)、WO2017034986 (University of Kansas)、WO2018095426 (Jiangsu Hengrui Medicine Co Ltd)、WO2016091698(Roche)、WO2016075661 (GlaxoSmithKline Biologicals)、WO2016180743 (Roche)、WO2018089695 (Dynavax Technologies)、WO2016055553 (ROche)、WO2015168279 (Novartis)、WO2016107536 (Medshine Discovery)、WO2018086593 (Livo (Shanghai) Pharmaceutical)、WO2017106607(Merck)、WO2017061532 (Sumitomo Dainippon Pharma)、WO2016023511 (Chia Tai Tianqing Pharmaceutical)、WO2017076346 (Chia Tai Tianqing Pharmaceutical)、WO2017046112(ROche)、WO2018078149(Roche)、WO2017040233 (3M Co)、WO2016141092 (Gilead Sciences)、WO2018049089 (BristolMyers Squibb)、WO2015057655 (Eisai Co Ltd)、WO2017001307 (Roche)、WO2018005586 (BristolMyers Squibb)、WO201704023(3M Co)、WO2017163264 (Council of Scientific and Industrial Research (India))、WO2018046460 (GlaxoSmithKline Biologicals)、WO2018047081 (Novartis)、WO2016142250 (Roche)、WO2015168269 (Novartis)、WO201804163 (Roche)、WO2018038877 (3M Co)、WO2015057659 (Eisai Co Ltd)、WO2017202704 (Roche)、WO2018026620 (BristolMyers Squibb)、WO2016029077 (Janus Biotherapeutics)、WO201803143 (Merck)、WO2016096778 (Roche)、WO2017190669 (Shanghai De Novo Pharmatech)、US09884866 (University of Minnesota)、WO2017219931 (Sichuan KelunBiotech Biopharmaceutical)、WO2018002319 (Janssen Sciences)、WO2017216054(Roche)、WO2017202703 (Roche)、WO2017184735 (IFM Therapeutics)、WO2017184746 (IFM Therapeutics)、WO2015088045 (Takeda Pharmaceutical)、WO2017038909 (Takeda Pharmaceutical)、WO2015095780 (University of Kansas)、WO2015023958 (University of Kansas)。干擾素 α 受體配位體
干擾素α受體配位體之實例包括干擾素α-2b (INTRON A®
)、聚乙二醇化干擾素α-2a (PEGASYS®
)、聚乙二醇化干擾素α-1b、干擾素α 1b (HAPGEN®
)、維爾多納(Veldona)、因氟拉度(Infradure)、羅飛龍-A (Roferon-A)、YPEG-干擾素α-2a (YPEG-rhIFNα-2a)、P-1101、艾爾吉隆(Algeron)、阿爾法隆(Alfarona)、因加容(干擾素γ)、rSIFN-co (重組型超級化合物干擾素)、Y聚乙二醇化干擾素α-2b (YPEG-rhIFNα-2b)、MOR-22、聚乙二醇化干擾素α-2b (PEG-INTRON®
)、拜氟隆(Bioferon)、樂複能(Novaferon)、因木塔(Inmutag) (因氟隆(Inferon))、MULTIFERON®、干擾素α-n1 (HUMOFERON®
)、干擾素β-1a (AVONEX®
)、沙氟隆(Shaferon)、干擾素α-2b (Axxo)、阿法菲酮(Alfaferone)、干擾素α-2b (BioGeneric Pharma)、干擾素-α 2 (CJ)、拉氟隆(Laferonum)、VIPEG、BLAUFERON-A、BLAUFERON-B、因特瑪斯(Intermax) α、瑞爾迪隆(Realdiron)、蘭斯嗪(Lanstion)、匹伽氟隆(Pegaferon)、PDferon-B PDferon-B、干擾素α-2b (IFN,Laboratorios Bioprofarma)、α干擾素2b、卡爾氟隆(Kalferon)、匹格納咯(Pegnano)、氟隆雪(Feronsure)、PegiHep、干擾素α 2b (Zydus-Cadila)、干擾素α 2a、Optipeg A、Realfa 2B、瑞力氟隆(Reliferon)、干擾素α-2b (Amega)、干擾素α-2b (Virchow)、ropeg干擾素α-2b、rHSA-IFN α-2a (重組型人類血清白蛋白干擾素α 2a融合蛋白)、rHSA-IFN α 2b、重組型人類干擾素α-(1b、2a、2b)、聚乙二醇化干擾素α-2b (Amega)、聚乙二醇化干擾素α-2a、里阿非隆-EC (Reaferon-EC)、普羅喹氟(Proquiferon)、優尼氟隆(Uniferon)、優瑞福(Urifron)、干擾素α-2b (Changchun Institute of Biological Products)、安特氟隆(Anterferon)、山氟隆(Shanferon)、雷氟隆(Layfferon)、上生雷泰(Shang Sheng Lei Tai)、INTEFEN、SINOGEN、福康泰(Fukangtai)、匹格斯塔(Pegstat)、rHSA-IFN α-2b、SFR-9216及Interapo (Interapa)。玻尿酸酶抑制劑
玻尿酸酶抑制劑之實例包括阿斯君默(astodrimer)。B 型肝炎 表面抗原 ( HBsAg ) 抑制劑
HBsAg抑制劑之實例包括HBF-0259、PBHBV-001、PBHBV-2-15、PBHBV-2-1、REP-9AC、REP-9C、REP-9、REP-2139、REP-2139-Ca、REP-2165、REP-2055、REP-2163、REP-2165、REP-2053、REP-2031及REP-006及REP-9AC'。
HBsAg分泌抑制劑之實例包括BM601。細胞毒性 T 淋巴細胞相關蛋白質 4 ( ipi4 ) 抑制劑
細胞毒性T淋巴細胞相關蛋白質4 (ipi4)抑制劑之實例包括AGEN-2041、AGEN-1884、伊匹魯密單抗(ipilumimab)、貝拉西普(belatacept)、PSI-001、PRS-010、Probody mAb、曲美木單抗(tremelimumab)及JHL-1155。親環素抑制劑
親環素抑制劑之實例包括CPI-431-32、EDP-494、OCB-030、SCY-635、NVP-015、NVP-018、NVP-019、STG-175,及US8513184 (Gilead Sciences)、US20140030221 (Gilead Sciences)、US20130344030 (Gilead Sciences)及US20130344029 (Gilead Sciences)中所揭示之化合物。HBV 病毒進入抑制劑
HBV病毒進入抑制劑之實例包括米魯德西B (Myrcludex B)。靶向病毒 mRNA 之反義寡核苷酸
靶向病毒mRNA之反義寡核苷酸之實例包括ISIS-HBVRx、IONIS-HBVRx、IONIS-GSK6-LRx、GSK-3389404、RG-6004。短干擾 RNA ( siRNA ) 及 ddRNAi 。
siRNA之實例包括TKM-HBV (TKM-HepB)、ALN-HBV、SR-008、HepB-nRNA,及ARC-520、ARC-521、ARB-1740、ARB-1467。
DNA引導RNA干擾(ddRNAi)之實例包括BB-HB-331。核酸內切酶調節劑
核酸內切酶調節劑之實例包括PGN-514。核糖核苷酸還原酶抑制劑
核糖核苷酸還原酶抑制劑之實例包括曲美多斯(Trimidox)。HBV E 抗原抑制劑
HBV E抗原抑制劑之實例包括漢黃芩素(wogonin)。共價閉合環狀 DNA ( cccDNA ) 抑制劑
cccDNA抑制劑之實例包括BSBI-25及CHR-101。法尼醇 X 受體促效劑
法尼醇X受體促效劑之實例為諸如EYP-001、GS-9674、EDP-305、MET-409、曲匹氟索(Tropifexor)、AKN-083、RDX-023、BWD-100、LMB-763、INV-3、NTX-023-1、EP-024297及GS-8670。HBV 抗體
靶向B型肝炎病毒表面抗原之HBV抗體之實例包括GC-1102、XTL-17、XTL-19、KN-003、IV Hepabulin SN及完全人類單株抗體療法(B型肝炎病毒感染,Humabs BioMed)。
包括單株抗體及多株抗體之HBV抗體之實例包括祖泰特(Zutectra)、上生甘迪(Shang Sheng Gan Di)、Uman Big (B型肝炎超免疫)、Omri-Hep-B、Nabi-HB、Hepatect CP、HepaGam B、易甘替(igantibe)、硫力瓦(Niuliva)、CT-P24、B型肝炎免疫球蛋白(靜脈內,pH4,HBV感染,Shanghai RAAS Blood Products)及福韋普(Fovepta)(BT-088)。
完全人類單株抗體包括HBC-34。CCR2 趨化介素拮抗劑
CCR2趨化介素拮抗劑之實例包括丙帕鍺(propagermanium)。胸腺素促效劑
胸腺素促效劑之實例包括胸腺法新(Thymalfasin),重組型胸腺素α1 (GeneScience)。細胞介素
細胞介素之實例包括重組型IL-7、CYT-107、介白素-2 (IL-2,Immunex)、重組型人類介白素-2 (Shenzhen Neptunus)、IL-15、IL-21、IL-24及西莫介白素(celmoleukin)。核蛋白調節劑
核蛋白調節劑可為HBV核心或衣殼蛋白抑制劑。核蛋白調節劑之實例包括GS-4882、AB-423、AT-130、GLS4、NVR-1221、NVR-3778、AL-3778、BAY 41-4109、甲磺酸莫非賽定(morphothiadine mesilate)、ARB-168786、ARB-880、JNJ-379、RG-7907、HEC-72702、AB-506、ABI-H0731、JNJ-440、ABI-H2158及DVR-23。
衣殼抑制劑之實例包括以下中所揭示之化合物:US20140275167 (Novira Therapeutics)、US20130251673 (Novira Therapeutics)、US20140343032 (Roche)、WO2014037480 (Roche)、US20130267517 (Roche)、WO2014131847 (Janssen)、WO2014033176 (Janssen)、WO2014033170 (Janssen)、WO2014033167 (Janssen)、WO2015/059212 (Janssen)、WO2015118057(Janssen)、WO2015011281 (Janssen)、WO2014184365 (Janssen)、WO2014184350 (Janssen)、WO2014161888 (Janssen)、WO2013096744 (Novira)、US20150225355 (Novira)、US20140178337 (Novira)、US20150315159 (Novira)、US20150197533 (Novira)、US20150274652 (Novira)、US20150259324、(Novira)、US20150132258 (Novira)、US9181288 (Novira)、WO2014184350 (Janssen)、WO2013144129 (Roche)、WO2017198744(Roche)、US 20170334882(Novira)、US 20170334898 (Roche)、WO2017202798(Roche)、WO2017214395(Enanta)、WO2018001944 (Roche)、WO2018001952(Roche)、WO2018005881(Novira)、WO2018005883(Novira)、WO2018011100(Roche)、WO2018011160(Roche)、WO2018011162(Roche)、WO2018011163(Roche)、WO2018036941(Roche)、WO2018043747(Kyoto Univ)、US20180065929 (Janssen)、WO2016168619 (Indiana University)、WO2016195982 (The Penn State Foundation)、WO2017001655 (Janssen)、WO2017048950 (Assembly Biosciences)、WO2017048954 (Assembly Biosciences)、WO2017048962 (Assembly Biosciences)、US20170121328 (Novira)、US20170121329 (Novira)。
轉錄抑制劑之實例包括以下中所揭示之化合物:WO2017013046 (Roche)、WO2017016960 (Roche)、WO2017017042 (Roche)、WO2017017043 (Roche)、WO2017061466 (Toyoma chemicals)、WO2016177655 (Roche)、WO2016161268 (Enanta)、WO2017001853 (Redex Pharma)、WO2017211791 (Roche)、WO2017216685 (Novartis)、WO2017216686 (Novartis)、WO2018019297 (Ginkgo Pharma)、WO2018022282 (Newave Pharma)、US20180030053 (Novartis)、WO2018045911 (Zhejiang Pharma)。視黃酸誘導性基因 1 刺激劑
視黃酸誘導性基因1刺激劑之實例包括SB-9200、SB-40、SB-44、ORI-7246、ORI-9350、ORI-7537、ORI-9020、ORI-9198及ORI-7170、RGT-100。NOD2 刺激劑
NOD2刺激劑之實例包括SB-9200。磷脂醯肌醇 3 - 激酶 ( PI3K ) 抑制劑
PI3K抑制劑之實例包括艾德昔布、ACP-319、AZD-8186、AZD-8835、布帕昔布、CDZ-173、CLR-457、皮克立西、來那替尼、瑞戈替布、瑞戈替布鈉、EN-3342、TGR-1202、艾培昔布、杜維昔布、IPI-549、UCB-5857、泰尼昔布、XL-765、吉達昔布、ME-401、VS-5584、考班昔布、乳清酸CAI、哌立福新、RG-7666、GSK-2636771、DS-7423、帕努昔布、GSK-2269557、GSK-2126458、CUDC-907、PQR-309、INCB-40093、皮拉昔布、BAY-1082439、甲磺酸普喹替尼、SAR-245409、AMG-319、RP-6530、ZSTK-474、MLN-1117、SF-1126、RV-1729、索諾昔布、LY-3023414、SAR-260301、TAK-117、HMPL-689、特納昔布(tenalisib)、沃塔昔布(voxtalisib)及CLR-1401。吲哚胺 - 2 , 3 - 二加氧酶 ( IDO ) 路徑抑制劑
IDO抑制劑之實例包括艾帕斯塔(epacadostat) (INCB24360)、雷米諾他(resminostat) (4SC-201)、因多莫得(indoximod)、F-001287、SN-35837、NLG-919、GDC-0919、GBV-1028、GBV-1012、NKTR-218,及US20100015178 (Incyte)、US2016137652 (Flexus Biosciences、Inc.)、WO2014073738 (Flexus Biosciences、Inc.)及WO2015188085 (Flexus Biosciences、Inc.)中所揭示之化合物。PD - 1 抑制劑
PD-1抑制劑之實例包括賽咪單抗(cemiplimab)、納武單抗(nivolumab)、派立珠單抗(pembrolizumab)、皮立珠單抗(pidilizumab)、BGB-108、STI-A1014、SHR-1210、PDR-001、PF-06801591、IBI-308、GB-226、STI-1110、JNJ-63723283、CA-170、德瓦魯單抗(durvalumab)、阿特珠單抗(atezolizumab)及mDX-400、JS-001、坎立珠單抗(Camrelizumab)、斯迪利單抗(Sintilimab)、斯迪利單抗、緹勒珠單抗(tislelizumab)、BCD-100、BGB-A333、JNJ-63723283、GLS-010 (WBP-3055)、CX-072、AGEN-2034、GNS-1480 (表皮生長因子受體拮抗劑;計劃性細胞死亡配位體1抑制劑)、CS-1001、M-7824 (PD-L1/TGF-β雙功能融合蛋白)、傑諾珠單抗(Genolimzumab)、BMS-936559。PD - L1 抑制劑
PD-L1抑制劑之實例包括阿特珠單抗、阿維魯單抗(avelumab)、AMP-224、MEDI-0680、RG-7446、GX-P2、德瓦魯單抗、KY-1003、KD-033、MSB-0010718C、TSR-042、ALN-PDL、STI-A1014、GS-4224、CX-072及BMS-936559。
PD-1抑制劑之實例包括以下中所揭示之化合物:WO2017112730 (Incyte Corp)、WO2017087777(Incyte Corp)、WO2017017624、WO2014151634 (BristolMyers Squibb Co)、WO201317322 (BristolMyers Squibb Co)、WO2018119286 (Incyte Corp)、WO2018119266 (Incyte Corp)、WO2018119263(Incyte Corp)、WO2018119236 (Incyte Corp)、WO2018119221(Incyte Corp)、WO2018118848 (BristolMyers Squibb Co)、WO20161266460(BristolMyers Squibb Co)、WO2017087678 (BristolMyers Squibb Co)、WO2016149351 (BristolMyers Squibb Co)、WO2015033299 (Aurigene Discovery Technologies Ltd)、WO2015179615(Eisai Co Ltd;Eisai Research Institute)、WO2017066227(BristolMyers Squibb Co)、WO2016142886 (Aurigene Discovery Technologies Ltd)、WO2016142852(Aurigene Discovery Technologies Ltd)、WO2016142835 (Aurigene Discovery Technologies Ltd; Individual)、WO2016142833 (Aurigene Discovery Technologies Ltd)、WO2018085750 (BristolMyers Squibb Co)、WO2015033303 (Aurigene Discovery Technologies Ltd)、WO2017205464 (Incyte Corp)、WO2016019232 (3M Co;Individual;Texas A&M University System)、WO2015160641 (BristolMyers Squibb Co)、WO2017079669 (Incyte Corp)、WO2015033301 (Aurigene Discovery Technologies Ltd)、WO2015034820 (BristolMyers Squibb Co)、WO2018073754 (Aurigene Discovery Technologies Ltd)、WO2016077518 (BristolMyers Squibb Co)、WO2016057624 (BristolMyers Squibb Co)、WO2018044783 (Incyte Corp)、WO2016100608 (BristolMyers Squibb Co)、WO2016100285 (BristolMyers Squibb Co)、WO2016039749 (BristolMyers Squibb Co)、WO2015019284 (Cambridge Enterprise Ltd)、WO2016142894 (Aurigene Discovery Technologies Ltd)、WO2015134605 (BristolMyers Squibb Co)、WO2018051255 (Aurigene Discovery Technologies Ltd)、WO2018051254 (Aurigene Discovery Technologies Ltd)、WO2017222976 (Incyte Corp)、WO2017070089 (Incyte Corp)、WO2018044963 (BristolMyers Squibb Co)、WO2013144704 (Aurigene Discovery Technologies Ltd)、WO2018013789 (Incyte Corp)、WO2017176608 (BristolMyers Squibb Co)、WO2018009505 (BristolMyers Squibb Co)、WO2011161699 (Aurigene Discovery Technologies Ltd)、WO2015119944 (Incyte Corp; Merck Sharp & Dohme Corp)、WO2017192961 (Incyte Corp)、WO2017106634 (Incyte Corp)、WO2013132317 (Aurigene Discovery Technologies Ltd)、WO2012168944 (Aurigene Discovery Technologies Ltd)、WO2015036927 (Aurigene Discovery Technologies Ltd)、WO2015044900 (Aurigene Discovery Technologies Ltd)、WO2018026971 (Arising International)。重組型胸腺素 α - 1
重組型胸腺素α-1之實例包括NL-004及聚乙二醇化胸腺素α-1。布魯頓氏酪胺酸激酶 ( BTK ) 抑制劑
BTK抑制劑之實例包括ABBV-105、阿卡拉布魯替尼(acalabrutinib) (ACP-196)、ARQ-531、BMS-986142、達沙替尼(dasatinib)、依魯替尼(ibrutinib)、GDC-0853、PRN-1008、SNS-062、ONO-4059、BGB-3111、ML-319、MSC-2364447、RDX-022、X-022、AC-058、RG-7845、司培替尼(spebrutinib)、TAS-5315、TP-0158、TP-4207、HM-71224、KBP-7536、M-2951、TAK-020、AC-0025及在US20140330015 (Ono Pharmaceutical)、US20130079327 (Ono Pharmaceutical)及US20130217880 (Ono Pharmaceutical)中所揭示之化合物。KDM 抑制劑
KDM5抑制劑之實例包括以下中所揭示之化合物:WO2016057924 (Genentech/Constellation Pharmaceuticals)、US20140275092 (Genentech/Constellation Pharmaceuticals)、US20140371195 (Epitherapeutics)及US20140371214 (Epitherapeutics)、US20160102096 (Epitherapeutics)、US20140194469 (Quanticel)、US20140171432、US20140213591 (Quanticel)、US20160039808 (Quanticel)、US20140275084 (Quanticel)、WO2014164708 (Quanticel)。
KDM1抑制劑之實例包括US9186337B2 (Oryzon Genomics)中所揭示之化合物、GSK-2879552及RG-6016。STING 促效劑
STING促效劑之實例包括SB-11285、AdVCA0848、STINGVAX及以下中所揭示之化合物:WO 2018065360 (Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH、Germany)、WO 2018009466 (Aduro Biotech)、WO 2017186711 (InvivoGen)、WO 2017161349 (Immune Sensor)、WO 2017106740 (Aduro Biotech)、US 20170158724 (Glaxo Smithkiline)、WO 2017075477 (Aduro Biotech)、US 20170044206 (Merck)、WO 2014179760 (University of California)、WO2018098203 (Janssn)、WO2018118665 (Merck)、WO2018118664 (Merck)、WO2018100558 (Takeda)、WO2018067423 (Merck)、WO2018060323 (Boehringer)。非核苷逆轉錄酶抑制劑 ( NNRTI )
NNRTI之實例包括以下中所揭示之化合物:WO2018118826 (Merck)、WO2018080903 (Merck)、WO2018119013 (Merck)、WO2017100108 (Idenix)、WO2017027434 (Merck)、WO2017007701 (Merck)、WO2008005555 (Gilead)。HBV 複製抑制劑
B型肝炎病毒複製抑制劑之實例包括異噻氟定(isothiafludine)、IQP-HBV、RM-5038及新甘帖(Xingantie)。精胺酸酶抑制劑
精胺酸酶抑制劑之實例包括CB-1158、C-201及雷米諾他。基因療法及細胞療法
基因療法及細胞療法包括用於使基因沉默之基因修飾;用於直接殺死經感染細胞之基因方法;經設計以將患者之大部分自身免疫系統替換以增強對經感染細胞之免疫反應或使患者之自身免疫系統活化以殺死經感染細胞或尋找且殺死經感染細胞之免疫細胞輸注;用於修飾細胞活性以進一步改變針對感染之內源性免疫反應性之基因方法。基因編輯劑
基因組編輯系統之實例包括CRISPR/Cas9系統、鋅指核酸酶系統、TALEN系統、歸巢核酸內切酶系統及大範圍核酸酶系統;例如,經由靶向裂解進行之cccDNA消除,及改變B型肝炎病毒(HBV)病毒基因中之一或多者。改變(例如,基因剔除及/或阻斷基因表現)PreC
、C
、X
、PreSI
、PreS2
、S、P
或SP
基因係指(1)降低或消除PreC
、C
、X
、PreSI
、PreS2
、S、P
或SP
基因表現;(2)干擾前核心蛋白(Precore)、核心蛋白(Core)、X蛋白質、長表面蛋白質、中表面蛋白質、S蛋白質(亦稱為HBs抗原及HBsAg)、聚合酶蛋白質及/或B型肝炎剪接蛋白質功能(HBe、HBc、HBx、PreS1、PreS2、S、Pol及/或HBSP);或(3)減少或消除HBe、HBc、HBx、LHBs、MHBs、SHBs、Pol及/或HBSP蛋白質之細胞內、血清及/或腦實質內含量。PreC
、C
、X
、PreSI
、PreS2
、S、P
及/或SP
基因中之一或多個的基因表現阻斷係藉由靶向在HBV cccDNA及/或整合式HBV DNA內之基因來進行。CAR - T 細胞療法
CAR T細胞療法包括經工程改造以表現嵌合抗原受體(CAR)之免疫效應細胞之群體,其中CAR包含HBV抗原結合域。免疫效應細胞為T細胞或NK細胞。在一些實施例中,T細胞為CD4+ T細胞、CD8+ T細胞或其組合。細胞可為自體或同種異體的。TCR - T 細胞療法
TCR T細胞療法包括表現HBV特異性T細胞受體之T細胞。TCR-T細胞經工程改造以靶向經病毒感染細胞之表面上呈現的HBV衍生肽。在一些實施例中,T細胞表現HBV表面抗原(HBsAg)特異性TCR。針對HBV之治療的TCR-T療法之實例包括LTCR-H2-1。
在另一具體實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與以下組合:HBV DNA聚合酶抑制劑;一或兩種選自由以下組成之群的額外治療劑:免疫調節劑、TLR調節劑、HBsAg抑制劑、HBsAg分泌或組裝抑制劑、HBV治療性疫苗、HBV抗體(包括靶向B型肝炎病毒表面抗原之HBV抗體及雙特異性抗體)及「抗體樣」醫療性蛋白質(諸如DARTs®
、DUOBODIES®
、BITES®
、XmAbs®
、TandAbs®
、Fab衍生物或TCR樣抗體)、親環蛋白抑制劑、視黃酸誘導性基因1刺激劑、RIG-I樣受體刺激劑、PD-1抑制劑、PD-L1抑制劑、精胺酸酶抑制劑、PI3K抑制劑、IDO抑制劑及NOD2刺激劑;及一或兩種選自由以下組成之群的額外治療劑:HBV病毒進入抑制劑、NTCP抑制劑、HBx抑制劑、cccDNA抑制劑、靶向B型肝炎病毒表面抗原之HBV抗體、siRNA、miRNA基因治療劑、sshRNA、KDM5抑制劑及核蛋白調節劑(HBV核心或衣殼蛋白調節劑)。
在另一具體實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與HBV DNA聚合酶抑制劑及至少一種選自由以下組成之群的第二額外治療劑組合:免疫調節劑、TLR調節劑、HBsAg抑制劑、HBV治療性疫苗、HBV抗體(包括靶向B型肝炎病毒表面抗原之HBV抗體)以及雙特異性抗體及「抗體樣」醫療性蛋白質(諸如DARTs®
、DUOBODIES®
、BITES®
、XmAbs®
、TandAbs®
、Fab衍生物或TCR樣抗體)、親環蛋白抑制劑、視黃酸誘導性基因1刺激劑、RIG-I樣受體刺激劑、PD-1抑制劑、PD-L1抑制劑、精胺酸酶抑制劑、PI3K抑制劑、IDO抑制劑及NOD2刺激劑。
在另一具體實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與HBV DNA聚合酶抑制劑及至少一種選自由以下組成之群的第二額外治療劑組合:HBV病毒進入抑制劑、NTCP抑制劑、HBx抑制劑、cccDNA抑制劑、靶向B型肝炎病毒之表面抗原之HBV抗體、siRNA、miRNA基因治療劑、sshRNA、KDM5抑制劑及核蛋白調節劑(HBV核心或衣殼蛋白抑制劑)。
在一特定實施例中,本文所揭示之化合物或其醫藥學上可接受之鹽與以下組合:化合物,諸如以下中所揭示之化合物:美國公開案第2010/0143301號(Gilead Sciences)、美國公開案第2011/0098248號(Gilead Sciences)、美國公開案第2009/0047249號(Gilead Sciences)、美國專利第8722054號(Gilead Sciences)、美國公開案第2014/0045849號(Janssen)、美國公開案第2014/0073642號(Janssen)、WO2014/056953 (Janssen)、WO2014/076221 (Janssen)、WO2014/128189 (Janssen)、美國公開案第2014/0350031號(Janssen)、WO2014/023813 (Janssen)、美國公開案第2008/0234251號(Array Biopharma)、美國公開案第2008/0306050號(Array Biopharma)、美國公開案第2010/0029585號(Ventirx Pharma)、美國公開案第2011/0092485號(Ventirx Pharma)、US2011/0118235 (Ventirx Pharma)、美國公開案第2012/0082658號(Ventirx Pharma)、美國公開案第2012/0219615號(Ventirx Pharma)、美國公開案第2014/0066432號(Ventirx Pharma)、美國公開案第2014/0088085號(Ventirx Pharma)、美國公開案第2014/0275167號(Novira Therapeutics)、美國公開案第2013/0251673號(Novira Therapeutics)、美國專利第8513184號(Gilead Sciences)、美國公開案第2014/0030221號(Gilead Sciences)、美國公開案第2013/0344030號(Gilead Sciences)、美國公開案第2013/0344029號(Gilead Sciences)、US20140275167 (Novira Therapeutics)、US20130251673 (Novira Therapeutics),美國公開案第2014/0343032號(Roche)、WO2014037480 (Roche)、美國公開案第2013/0267517號(Roche)、WO2014131847 (Janssen)、WO2014033176 (Janssen)、WO2014033170 (Janssen)、WO2014033167 (Janssen)、WO2015/059212 (Janssen)、WO2015118057 (Janssen)、WO2015011281 (Janssen)、WO2014184365 (Janssen)、WO2014184350 (Janssen)、WO2014161888 (Janssen)、WO2013096744 (Novira)、US20150225355 (Novira)、US20140178337 (Novira)、US20150315159 (Novira)、US20150197533 (Novira)、US20150274652 (Novira)、US20150259324、(Novira)、US20150132258 (Novira)、US9181288 (Novira)、WO2014184350 (Janssen)、WO2013144129 (Roche)、US20100015178 (Incyte)、US2016137652 (Flexus Biosciences、Inc.)、WO2014073738 (Flexus Biosciences、Inc.)、WO2015188085 (Flexus Biosciences、Inc.)、美國公開案第2014/0330015號(Ono Pharmaceutical)、美國公開案第2013/0079327號(Ono Pharmaceutical)、美國公開案第2013/0217880號(Ono pharmaceutical)、WO2016057924 (Genentech/Constellation Pharmaceuticals)、US20140275092 (Genentech/Constellation Pharmaceuticals)、US20140371195 (Epitherapeutics)及US20140371214 (Epitherapeutics)、US20160102096 (Epitherapeutics)、US20140194469 (Quanticel)、US20140171432、US20140213591 (Quanticel)、US20160039808 (Quanticel)、US20140275084 (Quanticel)、WO2014164708 (Quanticel)、US9186337B2 (Oryzon Genomics),及用於治療HBV之其他藥物及其組合。癌症組合療法
在一個實施例中,本發明化合物可與癌症治療之其他治療方法一起採用。較佳地,涵蓋具有化學治療劑、激素、抗體、手術及/或輻射治療之組合療法。
在一些實施例中,其他抗癌療法為手術及/或放射線療法。
在一些實施例中,其他抗癌療法為至少一種額外癌症藥劑。
在一些實施例中,提供一種組合,其包含本發明化合物或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽及至少一種其他癌症藥劑。
在一些實施例中,提供一種組合,其包含本發明化合物或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽及至少一種其他癌症藥劑,其用於療法。
在一些實施例中,提供包含本發明化合物或其互變異構體、對映異構體、水合物、溶劑合物或醫藥學上可接受之鹽及至少一種癌症藥劑之組合的用途,其用於製造用於治療癌症之藥劑。
其他癌症藥物之實例包括嵌入物質,諸如蒽環黴素(anthracycline)、小紅莓(doxorubicin)、艾達黴素(idarubicin)、表柔比星(epirubicin)及道諾黴素(daunorubicin);拓樸異構酶抑制劑,諸如伊立替康(irinotecan)、拓朴替康(topotecan)、喜樹鹼(camptothecin)、片螺素D (lamellarin D)、依託泊苷(etoposide)、替尼泊苷(teniposide)、米托蒽醌(mitoxantrone)、安吖啶(amsacrine)、玫瑰樹鹼(ellipticines)及金黃三羧酸(aurintricarboxylic acid);亞硝基脲化合物,諸如卡莫司汀(carmustine) (BCNU)、洛莫司汀(lomustine) (CCNU)及鏈脲菌素(streptozocin);氮芥,諸如環磷醯胺、雙氯乙基甲胺(mechlorethamine)、烏拉莫司汀(uramustine)、苯達莫司汀(bendamustine)、美法侖(melphalan)、苯丁酸氮芥(chlorambucil)、馬磷醯胺(mafosfamide)、曲洛磷胺(trofosfamid)及異環磷醯胺(ifosfamide);磺酸烷基酯,諸如白消安及曲奧舒凡(treosulfan);烷基化劑,諸如普卡巴嗪(procarbazin)、達卡巴嗪(dacarbazin)、替莫唑胺(temozolomid)及噻替派(thiotepa);鉑類似物,諸如順鉑(cisplatin)、卡鉑(carboplatin)、奈達鉑(nedaplatin)、奧沙利鉑(oxaliplatin)、賽特鉑(satraplatin)及四硝酸三鉑(triplatin tetranitrate);微管破壞藥物,諸如長春鹼(vinblastine)、秋水仙醯胺(colcemid)及諾考達唑(nocodazole);抗葉酸劑,諸如甲胺喋呤(methotrexate)、胺基喋呤(aminopterin)、二氯甲胺喋呤(dichloromethotrexat)、培美曲塞(pemetrexed)、雷替曲塞(raltitrexed)及普拉曲沙(pralatrexate):嘌呤類似物,諸如硫唑嘌呤(azathioprine)、巰基嘌呤(mercaptopurine)、硫鳥嘌呤(thioguanine)、氟達拉濱(fludarabine)、磷酸氟達拉賓、噴司他汀(pentostatin)及克拉屈濱(cladribine);嘧啶類似物,諸如5-氟尿嘧啶(fluorouracil)、氟尿苷(floxuridine)、阿糖胞苷(cytarabine)、6-氮尿嘧啶、吉西他濱(gemcitabine);類固醇,諸如吉西他津(gestagene)、安德羅津(androgene)、糖皮質激素(glucocorticoids)、地塞米松(dexamethasone)、潑尼龍(prednisolone)及潑尼松(prednisone);抗癌抗體,諸如單株抗體,例如阿侖單抗(alemtuzumab)、阿泊珠單抗(apolizumab)、西妥昔單抗(cetuximab)、依帕珠單抗(epratuzumab)、加利昔單抗(galiximab)、吉妥單抗(gemtuzumab)、伊派利單抗、拉貝珠單抗(labetuzumab)、帕尼單抗(panitumumab)、利妥昔單抗(rituximab)、曲妥珠單抗(trastuzumab)、尼妥珠單抗(nimotuzumab)、馬帕木單抗(mapatumumab)、馬妥珠單抗(matuzumab)、rhMab ICR62及帕妥珠單抗(pertuzumab)、放射性標記抗體及抗體-藥物接合物;抗癌肽,諸如放射性標記肽及肽-藥物接合物;及紫杉烷(taxane)及紫杉烷類似物,諸如太平洋紫杉醇(paclitaxel)及多西他賽(docetaxel)。
在某些實施例中,提供一種用於治療或預防患有過度增殖性病症或癌症或具有罹患過度增殖性病症或癌症之風險之人類或動物的過度增殖性病症或癌症之方法,其包含向人類或動物投與治療有效量之如本文所揭示之本發明化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、一或兩種或一至三種)額外治療劑之組合。在一個實施例中,提供一種用於治療患有過度增殖性病症或癌症或具有罹患過度增殖性病症或癌症之風險之人類或動物的過度增殖性病症或癌症之方法,其包含向人類或動物投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、一或兩種或一至三種)額外治療劑之組合。
在某些實施例中,本發明提供一種治療過度增殖性病症或癌症之方法,該方法包含向有需要之個體投與治療有效量之本文所揭示之化合物或其醫藥學上可接受之鹽與治療有效量之一或多種適用於治療過度增殖性病症或癌症的額外治療劑之組合。
本文所描述之化合物可與以下中之一或多者一起使用或組合:化學治療劑、抗癌劑、抗血管生成劑、抗纖維化劑、免疫治療劑、治療性抗體、雙特異性抗體及「抗體樣」醫療性蛋白質(諸如DARTs®、Duobodies®、Bites®、XmAbs®、TandAbs®、Fab衍生物)、抗體-藥物接合物(ADC)、放射線治療劑、抗腫瘤劑、抗增殖劑、溶瘤病毒、基因修飾劑或編輯劑(諸如CRISPR/Cas9、鋅指核酸酶或合成核酸酶、TALEN)、CAR (嵌合抗原受體) T細胞免疫治療劑、經工程改造之T細胞受體(TCR-T)或其任何組合。此等治療劑可呈化合物、抗體、多肽或聚核苷酸之形式。在一個實施例中,本文提供一種產品,其包含用於同時、分開或依序用於療法的呈組合製劑形式的本文所描述之化合物及額外治療劑。
一或多種治療劑包括但不限於基因、配位體、受體、蛋白質或因子之抑制劑、促效劑、拮抗劑、配位體、調節劑、刺激劑、阻斷劑、活化劑或遏制劑。額外治療劑之非限制性實例包括:阿貝爾森(Abelson)鼠類白血病病毒致癌基因同源物1基因(ABL,諸如ABL1)、乙醯基-CoA羧化酶(諸如ACC1/2)、活化CDC激酶(ACK,諸如ACK1)、腺苷脫胺酶、腺苷受體(諸如A2B、A2a、A3)、腺苷酸環化酶、ADP核糖基環化酶-1、促腎上腺皮質激素受體(ACTH)、氣單胞菌溶素、AKT1基因、Alk-5蛋白激酶、鹼性磷酸酶、α1腎上腺素受體、α2腎上腺素受體、α-酮戊二酸去氫酶(KGDH)、胺肽酶N、AMP活化蛋白激酶、多形性淋巴瘤激酶(ALK,諸如ALK1)、雄激素受體、血管生成素(諸如配位體-1、配位體-2)、血管收縮素原(AGT)基因、鼠類胸腺瘤病毒致癌基因同源物1 (AKT)蛋白激酶(諸如AKT1、AKT2、AKT3)、載脂蛋白A-I (APOA1)基因、細胞凋亡誘導因子、細胞凋亡蛋白(諸如1、2)、細胞凋亡信號調節激酶(ASK,諸如ASK1)、精胺酸酶(I)、精胺酸脫亞胺酶、芳香酶、流星(Asteroid)同源物1 (ASTE1)基因、共濟失調毛細管擴張及Rad 3相關(ATR)絲胺酸/蘇胺酸蛋白激酶、極光(Aurora)蛋白激酶(諸如1、2)、Axl酪胺酸激酶受體、含桿狀病毒IAP重複序列5 (BIRC5)基因、基礎免疫球蛋白、B細胞淋巴瘤2 (BCL2)基因、Bcl2結合組分3、Bcl2蛋白、BCL2L11基因、BCR (斷點簇區)蛋白及基因、β腎上腺素受體、β-連環蛋白、B淋巴細胞抗原CD19、B淋巴細胞抗原CD20、B淋巴細胞細胞黏附分子、B淋巴細胞刺激劑配位體、骨形態生成蛋白-10配位體、骨形態生成蛋白-9配位體調節劑、短尾畸形蛋白、緩激肽受體、B-Raf原癌基因(BRAF)、Brc-Abl酪胺酸激酶、含溴域及外部域(BET)溴域蛋白(諸如BRD2、BRD3、BRD4)、布魯頓氏酪胺酸激酶(BTK)、調鈣蛋白、調鈣蛋白依賴性蛋白激酶(CaMK,諸如CAMKII)、癌症睪丸抗原2、癌症睪丸抗原NY-ESO-1、癌症/睪丸抗原1B (CTAG1)基因、大麻受體(諸如CB1、CB2)、碳酸酐酶、酪蛋白激酶(CK,諸如CKI、CKII)、凋亡蛋白酶(諸如凋亡蛋白酶-3、凋亡蛋白酶-7、凋亡蛋白酶-9)、凋亡蛋白酶8細胞凋亡相關半胱胺酸肽酶CASP8-FADD樣調節子、凋亡蛋白酶募集域蛋白-15、組織蛋白酶G、CCR5基因、CDK活化激酶(CAK)、檢查點激酶(諸如CHK1、CHK2)、趨化介素(C-C基元)受體(諸如CCR2、CCR4、CCR5)、趨化介素((C-X-C基元)受體(諸如CXCR4、CXCR1及CXCR2)、趨化介素CC21配位體、膽囊收縮素CCK2受體、絨膜促性腺激素、c-套組(酪胺酸-蛋白激酶套組或CD117)、緊密連接蛋白(諸如6、18)、分化簇(CD),諸如CD4、CD27、CD29、CD30、CD33、CD37、CD40、CD40配位體受體、CD40配位體、CD40LG基因、CD44、CD45、CD47、CD49b、CD51、CD52、CD55、CD58、CD66e、CD70基因、CD74、CD79、CD79b、CD79B基因、CD80、CD95、CD99、CD117、CD122、CDw123、CD134、CDw137、CD158a、CD158b1、CD158b2、CD223、CD276抗原;群集素(CLU)基因、群集素、c-Met(肝細胞生長因子受體(HGFR))、補體C3、結締組織生長因子、COP9信號體次單元5、CSF-1 (群落刺激因子1受體)、CSF2基因、CTLA-4 (細胞毒性T淋巴細胞蛋白4)受體、細胞週期素D1、細胞週期素G1、細胞週期素依賴性激酶(CDK,諸如CDK1、CDK1B、CDK2-9)、環加氧酶(諸如1、2)、CYP2B1基因、半胱胺酸棕櫚醯基轉移酶豪豬蛋白、細胞色素P450 11B2、細胞色素P450 17、細胞色素P450 17A1、細胞色素P450 2D6、細胞色素P450 3A4、細胞色素P450還原酶、細胞介素信號傳導-1、細胞介素信號傳導-3、細胞質異檸檬酸去氫酶、胞嘧啶脫胺酶、胞嘧啶DNA甲基轉移酶、細胞毒性T淋巴細胞蛋白-4、DDR2基因、δ樣蛋白配位體(諸如3、4)、去氧核糖核酸酶、Dickkopf-1配位體、二氫葉酸還原酶(DHFR)、二氫嘧啶去氫酶、二肽基肽酶IV、盤狀域受體(DDR,諸如DDR1)、DNA結合蛋白(諸如HU-β)、DNA依賴性蛋白激酶、DNA旋轉酶、DNA甲基轉移酶、DNA聚合酶(諸如α)、DNA引子酶、dUTP焦磷酸酶、L-多巴色素互變異構酶、棘皮動物微管樣蛋白4、EGFR酪胺酸激酶受體、彈性蛋白酶、延長因子1α2、延長因子2、內皮因子、核酸內切酶、內質網素、內皮唾酸蛋白、內皮生長抑素、內皮素(諸如ET-A、ET-B)、zeste基因增強子同源物2 (EZH2)、肝配蛋白(Ephrin) (EPH)酪胺酸激酶(諸如Epha3、Ephb4)、肝配蛋白B2配位體、表皮生長因子、表皮生長因子受體(EGFR)、表皮生長因子受體(EGFR)基因、後生因子、上皮細胞黏附分子(EpCAM)、Erb-b2 (v-erb-b2禽類有核紅血球白血病病毒致癌基因同源物2)酪胺酸激酶受體、Erb-b3酪胺酸激酶受體、Erb-b4酪胺酸激酶受體、E-選擇蛋白、雌二醇17β去氫酶、雌激素受體(諸如α、β)、雌激素相關受體、真核轉譯始動因子5A (EIF5A)基因、輸出蛋白1、胞外信號相關激酶(諸如1、2)、胞外信號調節激酶(ERK)、因子(諸如Xa、VIIa)、法尼醇X受體(FXR)、Fas配位體、脂肪酸合酶(FASN)、鐵蛋白、FGF-2配位體、FGF-5配位體、纖維母細胞生長因子(FGF,諸如FGF1、FGF2、FGF4)、纖維結合蛋白、Fms相關酪胺酸激酶3 (Flt3)、局部黏著斑激酶(FAK,諸如FAK2)、葉酸水解酶前列腺特異性膜抗原1 (FOLH1)、葉酸受體(諸如α)、葉酸、葉酸轉運體1、FYN酪胺酸激酶、成對鹼性胺基酸切割酶(FURIN)、β-葡糖苷酸酶、半乳糖苷基轉移酶、半乳糖凝集素-3、神經節苷脂GD2、糖皮質激素、糖皮質激素誘導之TNFR相關蛋白質GITR受體、麩胺酸羧肽酶II、麩醯胺酸酶、麩胱甘肽S-轉移酶P、肝糖合成酶激酶(GSK,諸如3-β)、磷脂肌醇蛋白聚醣3 (GPC3)、促性腺激素釋放激素(GNRH)、顆粒球巨噬細胞群落刺激因子(GM-CSF)受體、顆粒球-群落刺激因子(GCSF)配位體、生長因子受體結合蛋白2 (GRB2)、Grp78 (78 kDa葡萄糖調節蛋白)鈣結合蛋白、分子伴隨蛋白groEL2基因、熱休克蛋白(諸如27、70、90α、β)、熱休克蛋白基因、熱穩定腸毒素受體、刺蝟蛋白、肝素酶、肝細胞生長因子、HERV-H LTR相關蛋白質2、己醣激酶、組胺H2受體、組蛋白甲基轉移酶(DOT1L)、組蛋白去乙醯基酶(HDAC,諸如1、2、3、6、10、11)、組蛋白H1、組蛋白H3、HLA第I類抗原(A-2α)、HLA第II類抗原、同源盒蛋白NANOG、HSPB1基因、人類白細胞抗原(HLA)、人類乳頭狀瘤病毒(諸如E6、E7)蛋白、玻尿酸、玻尿酸酶、低氧誘導性因子-1α (HIF1α)、壓印母本表現轉錄物(H19)基因、促分裂原活化蛋白激酶激酶激酶激酶1 (MAP4K1)、酪胺酸-蛋白激酶HCK、I-κ-B激酶(IKK,諸如IKKbe)、IL-1α、IL-1β、IL-12、IL-12基因、IL-15、IL-17、IL-2基因、IL-2受體α次單元、IL-2、IL-3受體、IL-4、IL-6、IL-7、IL-8、免疫球蛋白(諸如G、G1、G2、K、M)、免疫球蛋白Fc受體、免疫球蛋白γ Fc受體(諸如I、III、IIIA)、吲哚胺2,3-二加氧酶(IDO,諸如IDO1)、吲哚胺吡咯2,3-二加氧酶1抑制劑、胰島素受體、胰島素樣生長因子(諸如1、2)、整合素α-4/β-1、整合素α-4/β-7、整合素α-5/β-1、整合素α-V/β-3、整合素α-V/β-5、整合素α-V/β-6、細胞間黏附分子1 (ICAM-1)、干擾素(諸如α、α2、β、γ)、黑素瘤中不存在之干擾素誘導性蛋白2 (AIM2)、第I型干擾素受體、介白素1配位體、介白素13受體α2、介白素2配位體、介白素-1受體相關之激酶4 (IRAK4)、介白素-2、介白素-29配位體、異檸檬酸去氫酶(諸如IDH1、IDH2)、傑納斯激酶(JAK,諸如JAK1、JAK2)、Jun N端激酶、激肽釋放酶相關肽酶3 (KLK3)基因、殺手細胞Ig樣受體、激酶插入域受體(KDR)、驅動蛋白樣蛋白KIF11、基爾斯滕(Kirsten)大鼠肉瘤病毒致癌基因同源物(KRAS)基因、吻素(KiSS-1)受體、KIT基因、v-套組哈迪-朱克曼(Hardy-Zuckerman) 4貓肉瘤病毒致癌基因同源物(KIT)酪胺酸激酶、乳鐵傳遞蛋白、羊毛固醇-14去甲基酶、LDL受體相關蛋白質-1、白三烯A4水解酶、李斯特菌溶胞素、L-選擇蛋白、促黃體生成激素受體、解離酶、淋巴細胞活化基因3蛋白(LAG-3)、淋巴細胞抗原75、淋巴細胞功能抗原-3受體、淋巴細胞特異性蛋白酪胺酸激酶(LCK)、淋巴細胞趨化介素、Lyn (Lck/Yes新穎型)酪胺酸激酶、離胺酸去甲基酶(諸如KDM1、KDM2、KDM4、KDM5、KDM6、A/B/C/D)、溶血磷脂酸-1受體、溶酶體相關膜蛋白家族(LAMP)基因、離胺醯氧化酶同源物2、離胺醯氧化酶蛋白(LOX)、離胺醯氧化酶樣蛋白(LOXL,諸如LOXL2)、造血祖細胞激酶1 (HPK1)、肝細胞生長因子受體(MET)基因、巨噬細胞群落刺激因子(MCSF)配位體、巨噬細胞遷移抑制性因子、MAGEC1基因、MAGEC2基因、主穹隆蛋白、MAPK活化蛋白激酶(諸如MK2)、Mas相關G蛋白偶合受體、基質金屬蛋白酶(MMP,諸如MMP2、MMP9)、Mcl-1分化蛋白、Mdm2 p53結合蛋白、Mdm4蛋白、Melan-A (MART-1)黑素瘤抗原、黑素細胞蛋白Pmel 17、黑素細胞刺激性激素配位體、黑素瘤抗原家族A3 (MAGEA3)基因、黑素瘤相關抗原(諸如1、2、3、6)、膜銅胺氧化酶、間皮素、MET酪胺酸激酶、代謝型麩胺酸受體1、金屬還原酶STEAP1 (前列腺六跨膜上皮抗原1)、轉移抑素、甲硫胺酸胺肽酶-2、甲基轉移酶、粒線體3酮脂醯CoA硫解酶、活化促分裂原蛋白激酶(MAPK)、促分裂原活化蛋白激酶(MEK,諸如MEK1、MEK2)、mTOR (雷帕黴素機制性目標(絲胺酸/蘇胺酸激酶)、mTOR複合物(諸如1、2)、黏蛋白(諸如1、5A、16)、mut T同源物(MTH,諸如MTH1)、Myc原癌基因蛋白、骨髓細胞白血病1 (MCL1)基因、富肉豆蔻醯基化丙胺酸蛋白激酶C受質(MARCKS)蛋白、NAD ADP核糖基轉移酶、利鈉肽受體C、神經細胞黏附分子1、神經激肽1 (NK1)受體、神經激肽受體、神經纖毛蛋白2、NFκB活化蛋白、NIMA相關激酶9 (NEK9)、氧化氮合酶、NK細胞受體、NK3受體、NKG2 A B活化NK受體、去甲腎上腺素轉運體、Notch (諸如Notch-2受體、Notch-3受體、Notch-4受體)、核紅細胞系2相關因子2、核因子(NF) κB、核仁素、核仁磷酸蛋白、核仁磷酸蛋白多形性淋巴瘤激酶(NPM-ALK)、2側氧基戊二酸酯去氫酶、2,5-寡腺苷酸合成酶、O-甲基鳥嘌呤DNA甲基轉移酶、類鴉片受體(諸如δ)、鳥胺酸去羧酶、乳清酸磷酸核糖轉移酶、孤兒核激素受體NR4A1、骨鈣化素、破骨細胞分化因子、骨橋蛋白、OX-40 (腫瘤壞死因子受體超家族成員4 TNFRSF4,或CD134)受體、P3蛋白、p38激酶、p38 MAP激酶、p53腫瘤抑制蛋白、副甲狀腺激素配位體、過氧化體增殖物活化受體(PPAR,諸如α、δ、γ)、P-醣蛋白(諸如1)、磷酸酶及張力蛋白同源物(PTEN)、磷脂醯肌醇3-激酶(PI3K)、磷酸肌醇-3激酶(PI3K,諸如α、δ、γ)、磷酸化酶激酶(PK)、PKN3基因、胎盤生長因子、血小板衍生生長因子(PDGF,諸如α、β)、血小板衍生生長因子(PDGF,諸如α、β)、多效性抗藥性轉運體、叢蛋白B1、PLK1基因、polo樣激酶(PLK)、Polo樣激酶1、聚ADP核糖聚合酶(PARP,諸如PARP1、2及3)、黑素瘤中優先表現之抗原(PRAME)基因、戊烯基結合蛋白(PrPB)、可能轉錄因子PML、孕酮受體、計劃性細胞死亡1 (PD-1)、計劃性細胞死亡配位體1抑制劑(PD-L1)、saposin前體(PSAP)基因、前列腺素受體(EP4)、前列腺特異性抗原、前列腺酸磷酸酶、蛋白酶體、蛋白E7、蛋白法尼基轉移酶、蛋白激酶(PK,諸如A、B、C)、蛋白酪胺酸激酶、蛋白酪胺酸磷酸酶β、原癌基因絲胺酸/蘇胺酸-蛋白激酶(PIM,諸如PIM-1、PIM-2、PIM-3)、P-選擇蛋白、嘌呤核苷磷酸化酶、嘌呤受體P2X配位體閘控離子通道7 (P2X7)、丙酮酸去氫酶(PDH)、丙酮酸去氫酶激酶、丙酮酸激酶(PYK)、5-α-還原酶、Raf蛋白激酶(諸如1、B)、RAF1基因、Ras基因、Ras GTP酶、RET基因、Ret酪胺酸激酶受體、視網膜母細胞瘤相關蛋白質、視黃酸受體(諸如γ)、類視黃素X受體、Rheb (大腦中富集的Ras同源物) GTP酶、Rho (Ras同源物)相關蛋白激酶2、核糖核酸酶、核糖核苷酸還原酶(諸如M2次單元)、核糖體蛋白S6激酶、RNA聚合酶(諸如I、II)、Ron (來源於南特之受體(Recepteur d'Origine Nantais))酪胺酸激酶、ROS1 (ROS原癌基因1,受體酪胺酸激酶)基因、Ros1酪胺酸激酶、Runt相關轉錄因子3、γ-分泌酶、S100鈣結合蛋白A9、肌內質網鈣ATP酶、第二粒線體衍生之凋亡蛋白酶活化子(SMAC)蛋白、分泌捲曲相關蛋白質-2、信號蛋白-4D、絲胺酸蛋白酶、絲胺酸/蘇胺酸激酶(STK)、絲胺酸/蘇胺酸-蛋白激酶(TBK,諸如TBK1)、信號轉導及轉錄(STAT,諸如STAT-1、STAT-3、STAT-5)、信號傳導淋巴細胞性活化分子(SLAM)家族成員7、前列腺六跨膜上皮抗原(STEAP)基因、SL細胞介素配位體、平滑(SMO)受體、碘化鈉共轉運體、磷酸鈉共轉運體2B、生長抑素受體(諸如1、2、3、4、5)、音蝟因子蛋白、非七激酶子(Son of sevenless;SOS)、特異蛋白1 (Sp1)轉錄因子、鞘磷脂合酶、神經鞘胺醇激酶(諸如1、2)、神經鞘胺醇-1-磷酸鹽受體-1、脾酪胺酸激酶(SYK)、SRC基因、Src酪胺酸激酶、STAT3基因、類固醇硫酸酯酶、干擾素基因刺激因子(STING)受體、干擾素基因刺激蛋白、基質細胞衍生之因子1配位體、SUMO (小泛素樣修飾因子)、超氧化物歧化酶、存活素蛋白、突觸蛋白3、多配位體蛋白聚醣-1、共核蛋白α、T細胞表面醣蛋白CD28、tank結合激酶(TBK)、TATA盒結合蛋白相關因子RNA聚合酶I次單元B (TAF1B)基因、T細胞CD3醣蛋白ζ鏈、T細胞分化抗原CD6、含T細胞免疫球蛋白及黏蛋白域3 (TIM-3)、T細胞表面醣蛋白CD8、Tec蛋白酪胺酸激酶、Tek酪胺酸激酶受體、端粒酶、端粒酶逆轉錄酶(TERT)基因、肌腱蛋白、TGFβ2配位體、血小板生成素受體、胸苷激酶、胸苷磷酸化酶、胸苷酸合酶、胸腺素(諸如α1)、甲狀腺激素受體、促甲狀腺激素受體、組織因子、TNF相關細胞凋亡誘導配位體、TNFR1相關死亡域蛋白、TNF相關細胞凋亡誘導性配位體(TRAIL)受體、TNFSF11基因、TNFSF9基因、鐸樣受體(TLR,諸如1-13)、拓樸異構酶(諸如I、II、III)、轉錄因子、轉移酶、運鐵蛋白、轉型生長因子(TGF,諸如β)激酶、轉型生長因子TGF-β受體激酶、轉麩醯胺酸酶、移位相關蛋白質、跨膜醣蛋白NMB、Trop-2鈣信號轉導蛋白、滋胚層醣蛋白(TPBG)基因、滋胚層醣蛋白、肌旋蛋白受體激酶(Trk)受體(諸如TrkA、TrkB、TrkC)、色胺酸5-羥化酶、微管蛋白、腫瘤壞死因子(TNF,諸如α、β)、腫瘤壞死因子13C受體、腫瘤進展基因座2 (TPL2)、腫瘤蛋白53 (TP53)基因、腫瘤抑制因子候選物2 (TUSC2)基因、酪胺酸酶、酪胺酸羥化酶、酪胺酸激酶(TK)、酪胺酸激酶受體、含免疫球蛋白樣及EGF樣域酪胺酸激酶(TIE)受體、酪胺酸蛋白激酶ABL1抑制劑、泛素、泛素羧基水解酶同工酶L5、泛素硫酯酶-14、泛素綴合酶E2I (UBE2I、UBC9)、尿素酶、尿激酶纖維蛋白溶酶原活化物、子宮球蛋白、香草精類VR1、血管細胞黏附蛋白1、血管內皮生長因子受體(VEGFR)、T細胞活化V域Ig抑制因子(VISTA)、VEGF-1受體、VEGF-2受體、VEGF-3受體、VEGF-A、VEGF-B、波形蛋白、維生素D3受體、原癌基因酪胺酸-蛋白激酶Yes、Wee-1蛋白激酶、威爾姆斯氏(Wilms')腫瘤抗原1、威爾姆斯氏腫瘤蛋白、X性聯細胞凋亡抑制蛋白、鋅指蛋白轉錄因子或其任何組合。
額外治療劑之非限制性實例可由其作用機制分類成例如以下各組:
- 抗代謝物/抗癌劑,諸如嘧啶類似物氟尿苷、卡培他濱(capecitabine)、阿糖胞苷、CPX-351 (脂質體阿糖胞苷、道諾黴素)及TAS-118;
- 嘌呤類似物、葉酸拮抗劑(諸如普拉曲沙)及相關抑制劑;
- 抗增殖/抗有絲分裂劑,包括天然產物,諸如長春花生物鹼(vinca alkaloid) (長春鹼、長春新鹼(vincristine))及微管瓦解劑,諸如紫杉烷(太平洋紫杉醇、多西他賽)、長春鹼、諾考達唑、埃博黴素(epothilone)、長春瑞賓(vinorelbine) (NAVELBINE®
)及表鬼臼毒素(epipodophyllotoxin) (依託泊苷、替尼泊苷);
- DNA損傷劑,諸如放射菌素、安吖啶、白消安、卡鉑、苯丁酸氮芥、順鉑、環磷醯胺(CYTOXAN®
)、放線菌素D、道諾黴素、小紅莓、表柔比星、異環磷醯胺、美法侖、二氯甲二乙胺、絲裂黴素C、米托蒽醌、亞硝基脲、丙卡巴肼、紫杉醇、克癌易(Taxotere)、替尼泊苷、依託泊苷及三伸乙基硫代磷醯胺;
- DNA低甲基化劑,諸如瓜達西汀(guadecitabine) (SGI-110)、ASTX727;
- 抗生素,諸如放線菌素D、道諾黴素、小紅莓、艾達黴素、蒽環黴素、米托蒽醌、博來黴素(bleomycin)、普卡黴素(plicamycin) (光神黴素(mithramycin));
- 酶,諸如系統地代謝L-天冬醯胺且剝奪不具有合成其自身天冬醯胺之能力的細胞之L-天冬醯胺酶;
- 抗血小板劑;
- 靶向Bcl-2之DNAi寡核苷酸,諸如PNT2258;
- 活化或再活化潛伏人類免疫缺乏病毒(HIV)之藥劑,諸如帕比諾他及羅米地辛;
- 天冬醯胺酶刺激劑,諸如克立他酶(crisantaspase) (Erwinase®)及GRASPA (ERY-001、ERY-ASP)、聚乙二醇化卡拉斯酶(calaspargase pegol);
- 泛Trk、ROS1及ALK抑制劑,諸如恩曲替尼(entrectinib)、TPX-0005;
- 多形性淋巴瘤激酶(ALK)抑制劑,諸如艾樂替尼(alectinib)、色瑞替尼(ceritinib);
- 抗增殖/抗有絲分裂烷基化劑,諸如氮芥環磷醯胺及類似物(美法侖、氯芥苯丁酸、六甲蜜胺(hexamethylmelamine)、噻替派)、烷基亞硝基脲(卡莫司汀)及類似物、鏈脲菌素及三氮烯(達卡巴嗪);
- 抗增殖/抗有絲分裂抗代謝物,諸如葉酸類似物(甲胺喋呤);
- 鉑配位錯合物(順鉑、奧沙利鉑(oxiloplatinim)及卡鉑)、丙卡巴肼、羥基脲、米托坦及胺麩精(aminoglutethimide);
- 激素、激素類似物(雌激素、他莫昔芬(tamoxifen)、戈舍瑞林(goserelin)、比卡魯胺(bicalutamide)及尼魯胺(nilutamide))及芳香酶抑制劑(來曲唑(letrozole)及阿那曲唑(anastrozole));
- 抗凝劑,諸如肝素、合成肝素鹽及其他凝血酶之抑制劑;
- 纖維蛋白溶解劑,諸如組織纖維蛋白溶酶原活化因子、鏈球菌激酶、尿激酶、阿司匹林(aspirin)、雙嘧達莫(dipyridamole)、噻氯匹定(ticlopidine)及克羅匹多(clopidogrel);
- 抗遷移劑;
- 抗分泌劑(布瑞汀(breveldin));
- 免疫抑制劑,諸如他克莫司(tacrolimus)、西羅莫司(sirolimus)、硫唑嘌呤及黴酚酸酯;
- 生長因子抑制劑及血管內皮生長因子抑制劑;
- 纖維母細胞生長因子抑制劑,諸如FPA14;
- 抗VEGFR抗體,諸如IMC-3C5、GNR-011、塔尼比單抗(tanibirumab);
- 抗VEGF/DDL4抗體,諸如ABT-165;
- 抗鈣黏素抗體,諸如HKT-288;
- 抗CD70抗體,諸如AMG-172;含有抗富含白胺酸之重複物之15號(LRRC15)抗體,諸如ABBV-085. ARGX-110;
- 血管收縮素受體阻斷劑、氧化氮供體;
- 反義寡核苷酸,諸如AEG35156、IONIS-KRAS-2.5Rx、EZN-3042、RX-0201、IONIS-AR-2.5Rx、BP-100 (普瑞博森(prexigebersen))、IONIS-STAT3-2.5Rx;
- DNA干擾寡核苷酸,諸如PNT2258、AZD-9150;
- 抗ANG-2抗體,諸如MEDI3617及LY3127804;
- 抗ANG-1/ANG-2抗體,諸如AMG-780;
- 抗MET/EGFR抗體,諸如LY3164530;
- 抗EGFR抗體,諸如ABT-414、AMG-595、萊西單抗(necitumumab)、ABBV-221、馬佛多坦德帕土西珠單抗(depatuxizumab mafodotin) (ABT-414)、托木妥昔單抗(tomuzotuximab)、ABT-806、維必施(vectibix)、莫多西單抗(modotuximab)、RM-1929;
- 抗CSF1R抗體,諸如艾瑪圖單抗(emactuzumab)、LY3022855、AMG-820、FPA-008 (卡比拉單抗(cabiralizumab));
- 抗CD40抗體,諸如RG7876、SEA-CD40、APX-005M、ABBV-428;
- 抗內皮因子抗體,諸如TRC105 (卡妥昔單抗(carotuximab));
- 抗CD45抗體,諸如131I-BC8 (洛單抗(lomab)-B);
- 抗HER3抗體,諸如LJM716、GSK2849330;
- 抗HER2抗體,諸如馬妥昔單抗(margetuximab)、MEDI4276、BAT-8001;
- 抗HLA-DR抗體,諸如IMMU-114;
- 抗IL-3抗體,諸如JNJ-56022473;
- 抗OX40抗體,諸如MEDI6469、MEDI6383、MEDI0562 (塔沃西單抗(tavolixizumab))、MOXR0916、PF-04518600、RG-7888、GSK-3174998、INCAGN1949、BMS-986178、GBR-8383、ABBV-368;
- 抗EphA3抗體,諸如KB-004;
- 抗CD20抗體,諸如奧比珠單抗(obinutuzumab)、IGN-002;
- 抗CD20/CD3抗體,諸如RG7828;
- 抗CD37抗體,諸如AGS67E、奧特勒土珠單抗(otlertuzumab) (TRU-016);
- 抗ENPP3抗體,諸如AGS-16C3F;
- 抗FGFR-3抗體,諸如LY3076226、B-701;
- 抗FGFR-2抗體,諸如GAL-F2;
- 抗C5抗體,諸如ALXN-1210;
- 抗CD27抗體,諸如瓦里木單抗(varlilumab) (CDX-1127);
- 抗TROP-2抗體,諸如IMMU-132;
- 抗NKG2a抗體,諸如莫納珠單抗(monalizumab);
- 抗VISTA抗體,諸如HMBD-002;
- 抗PVRIG抗體,諸如COM-701;
- 抗EpCAM抗體,諸如VB4-845;
- 抗BCMA抗體,諸如GSK-2857916;
- 抗CEA抗體,諸如RG-7813;
- 抗分化簇3 (CD3)抗體,諸如MGD015;
- 抗葉酸受體α抗體,諸如IMGN853;
- MCL-1抑制劑,諸如AMG-176、S-64315及AZD-5991、483-LM、A-1210477、UMI-77、JKY-5-037;
- epha2抑制劑,諸如MM-310;
- 抗LAG-3抗體,諸如瑞拉單抗(relatlimab) (ONO-4482)、LAG-525、MK-4280、REGN-3767;
- raf激酶/VEGFR抑制劑,諸如RAF-265;
- 多蜂房蛋白(EED)抑制劑,諸如MAK683;
- 抗纖維母細胞活化蛋白(FAP)/IL-2R抗體,諸如RG7461;
- 抗纖維母細胞活化蛋白(FAP)/TRAIL-R2抗體,諸如RG7386;
- 抗海藻糖基-GM1抗體,諸如BMS-986012;
- p38 MAP激酶抑制劑,諸如那力替尼(ralimetinib);
- PRMT1抑制劑,諸如MS203;
- 神經鞘胺醇激酶2 (SK2)抑制劑,諸如奧帕尼布(opaganib);
- FLT3‐ITD抑制劑,諸如BCI-332;
- 核紅細胞系2相關因子2刺激劑,諸如奧瑪韋隆(omaveloxolone) (RTA-408);
- 肌旋蛋白受體激酶(TRK)抑制劑,諸如LOXO-195、ONO-7579;
- 抗ICOS抗體,諸如JTX-2011、GSK3359609;
- 抗DR5 (TRAIL2)抗體,諸如DS-8273;
- 抗GD2抗體,諸如APN-301;
- 抗介白素-17 (IL-17)抗體,諸如CJM-112;
- 抗碳酸酐酶IX抗體,諸如TX-250;
- 抗CD38阿騰金(attenukine),諸如TAK573;
- 抗黏蛋白1抗體,諸如加迪珠單抗(gatipotuzumab);
- 黏蛋白1抑制劑,諸如GO-203-2C;
- MARCKS蛋白抑制劑,諸如BIO-11006;
- 葉酸拮抗劑,諸如阿弗地林(arfolitixorin);
- 半乳糖凝集素-3抑制劑,諸如GR-MD-02;
- 磷酸化P68抑制劑,諸如RX-5902;
- CD95/TNF調節劑,諸如奧弗沃巴(ofranergene obadenovec);
- PI3K/Akt/mTOR抑制劑,諸如ABTL-0812;
- 泛PIM激酶抑制劑,諸如INCB-053914;
- IL-12基因刺激劑,諸如EGEN-001、塔沃特德(tavokinogene telseplasmid);
- 熱休克蛋白HSP90抑制劑,諸如TAS-116、PEN-866;
- VEGF/HGF拮抗劑,諸如MP-0250;
- SYK酪胺酸激酶/FLT3酪胺酸激酶抑制劑,諸如TAK-659;
- SYK酪胺酸激酶/JAK酪胺酸激酶抑制劑,諸如ASN-002;
- FLT3酪胺酸激酶抑制劑,諸如FF-10101;
- FLT3酪胺酸激酶促效劑,諸如CDX-301;
- FLT3/MEK1抑制劑,諸如E-6201;
- IL-24拮抗劑,諸如AD-IL24;
- RIG-I促效劑,諸如RGT-100;
- 氣單胞菌溶素刺激劑,諸如托普欣(topsalysin);
- P-醣蛋白1抑制劑,諸如HM-30181A;
- CSF-1拮抗劑,諸如ARRY-382、BLZ-945;
- 抗間皮素抗體,諸如SEL-403;
- 胸苷激酶刺激劑,諸如阿格維克(aglatimagene besadenovec);
- Polo樣激酶1抑制劑,諸如PCM-075;
- TLR-7促效劑,諸如TMX-101 (咪喹莫特);
- NEDD8抑制劑,諸如佩沃塔特(pevonedistat) (MLN-4924)、TAS-4464;
- 多效性路徑調節劑,諸如阿多米德(avadomide) (CC-122);
- FoxM1抑制劑,諸如硫鏈絲菌;
- 抗MUC1抗體,諸如Mab-AR-20.5;
- 抗CD38抗體,諸如伊薩土西單抗(isatuximab)、MOR-202;
- UBA1抑制劑,諸如TAK-243;
- Src酪胺酸激酶抑制劑,諸如VAL-201;
- VDAC/HK抑制劑,諸如VDA-1102;
- BRAF/PI3K抑制劑,諸如ASN-003;
- Elf4a抑制劑,諸如羅西替布(rohinitib)、eFT226;
- TP53基因刺激劑,諸如ad-p53;
- PD-L1/EGFR抑制劑,諸如GNS-1480;
- 視黃酸受體α (RARα)抑制劑,諸如SY-1425;
- SIRT3抑制劑,諸如YC8-02;
- 基質細胞衍生之因子1配位體抑制劑,諸如聚乙二醇化奧拉希德(olaptesed pegol) (NOX-A12);
- IL-4受體調節劑,諸如MDNA-55;
- 精胺酸酶-I刺激劑,諸如佩拉酶(pegzilarginase);
- 拓樸異構酶I抑制劑/低氧誘導性因子-1α抑制劑,諸如PEG-SN38 (聚乙二醇化非特坎(firtecan pegol));
- 低氧誘導性因子-1α抑制劑,諸如PT-2977、PT-2385;
- CD122促效劑,諸如NKTR-214;
- p53腫瘤抑制蛋白刺激劑,諸如克維林(kevetrin};
- Mdm4/Mdm2 p53結合蛋白抑制劑,諸如ALRN-6924;
- 紡錘體驅動蛋白(KSP)抑制劑,諸如非那西布(filanesib) (ARRY-520);
- CD80-fc融合蛋白抑制劑,諸如FPT-155;
- 多發性內分泌腺瘤蛋白及混合系白血病(MLL)抑制劑,諸如KO-539;
- 肝x受體促效劑,諸如RGX-104;
- IL-10促效劑,諸如AM-0010;
- EGFR/ErbB-2抑制劑,諸如瓦尼替尼(varlitinib);
- VEGFR/PDGFR抑制劑,諸如沃羅拉尼(vorolanib);
- IRAK4抑制劑,諸如CA-4948;
- 抗TLR-2抗體,諸如OPN-305;
- 調鈣蛋白調節劑,諸如CBP-501;
- 糖皮質激素受體拮抗劑,諸如瑞拉蘭特(relacorilant) (CORT-125134);
- 第二粒線體衍生之凋亡蛋白酶活化子(SMAC)蛋白抑制劑,諸如BI-891065;
- 乳鐵傳遞蛋白調節劑,諸如LTX-315;
- Kit酪胺酸激酶/PDGF受體α拮抗劑,諸如DCC-2618;
- KIT抑制劑,諸如PLX-9486;
- 輸出蛋白1抑制劑,諸如艾塔尼西(eltanexor);
- EGFR/ErbB2/Ephb4抑制劑,諸如特色瓦替尼(tesevatinib);
- 抗CD33抗體,諸如IMGN-779;
- 抗KMA抗體,諸如MDX-1097;
- 抗TIM-3抗體,諸如TSR-022、LY-3321367、MBG-453;
- 抗CD55抗體,諸如PAT-SC1;
- 抗PSMA抗體,諸如ATL-101;
- 抗CD100抗體,諸如VX-15;
- 抗EPHA3抗體,諸如非巴珠單抗(fibatuzumab);
- 抗Erbb抗體,諸如CDX-3379、HLX-02、塞里班土單抗(seribantumab);
- 抗APRIL抗體,諸如BION-1301;
- 抗Tigit抗體,諸如BMS-986207、RG-6058;
- CHST15基因抑制劑,諸如STNM-01;
- RAS抑制劑,諸如NEO-100;
- 生長抑素受體拮抗劑,諸如OPS-201;
- CEBPA基因刺激劑,諸如MTL-501;
- DKK3基因調節劑,諸如MTG-201;
- p70s6k抑制劑,諸如MSC2363318A;
- 甲硫胺酸胺基肽酶2 (MetAP2)抑制劑,諸如M8891、APL-1202;
- 精胺酸N-甲基轉移酶5抑制劑,諸如GSK-3326595;
- 抗計劃性細胞死亡蛋白1 (抗PD-1)抗體,諸如納武單抗(OPDIVO®、BMS-936558、MDX-1106)、派立珠單抗(KEYTRUDA®、MK-3477、SCH-900475、拉立珠單抗(lambrolizumab),CAS登記號1374853-91-4)、皮立珠單抗、PF-06801591、BGB-A317、GLS-010 (WBP-3055)、AK-103 (HX-008)、MGA-012、BI-754091、REGN-2810 (賽咪單抗(cemiplimab))、AGEN-2034、JS-001、JNJ-63723283、傑諾珠單抗(CBT-501)、LZM-009、BCD-100、LY-3300054、SHR-1201、BAT-1306,以及抗計劃性死亡配位體1 (抗PD-L1)抗體,諸如BMS-936559、阿特珠單抗(MPDL3280A)、德瓦魯單抗(MEDI4736)、阿維魯單抗、CK-301 (MSB0010718C)、MEDI0680、CX-072、CBT-502、PDR-001 (斯帕塔利單抗(spartalizumab))、TSR-042 (多斯利單抗(dostarlimab))、JTX-4014、BGB-A333、SHR-1316、CS-1001 (WBP-3155、KN-035、IBI-308、FAZ-053及MDX1105-01);
- PD-L1/VISTA拮抗劑,諸如CA-170;
- 抗PD-L1/TGFβ抗體,諸如M7824;
- 抗運鐵蛋白抗體,諸如CX-2029;
- 抗IL-8 (介白素-8)抗體,諸如HuMax-Inflam;
- ATM (共濟失調毛細管擴張)抑制劑,諸如AZD0156;
- CHK1抑制劑,諸如GDC-0575、LY2606368 (普瑞替布(prexasertib))、SRA737、RG7741 (CHK1/2);
- CXCR4拮抗劑,諸如BL-8040、LY2510924、布利沙福(burixafor) (TG-0054)、X4P-002、X4P-001-IO;
- EXH2抑制劑,諸如GSK2816126;
- HER2抑制劑,諸如來那替尼(neratinib)、圖卡替尼(tucatinib) (ONT-380);
- KDM1抑制劑,諸如ORY-1001、IMG-7289、INCB-59872、GSK-2879552;
- CXCR2拮抗劑,諸如AZD-5069;
- GM-CSF抗體,諸如朗齊魯單抗(lenzilumab);
- DNA依賴性蛋白激酶抑制劑,諸如MSC2490484A (尼瑟替布(nedisertib))、VX-984、AsiDNA (DT-01);
- 蛋白激酶C (PKC)抑制劑,諸如LXS-196、索塔妥林(sotrastaurin);
- 選擇性雌激素受體下調劑(SERD),諸如氟維司群(fulvestrant) (Faslodex®)、RG6046、RG6047、艾拉司群(elacestrant) (RAD-1901)及AZD9496;
- 選擇性雌激素受體共價拮抗劑(SERCA),諸如H3B-6545;
- 選擇性雄激素受體調節劑(SARM),諸如GTX-024、達諾米德(darolutamide);
- 轉型生長因子-β (TGF-β)激酶拮抗劑,諸如高倫替布(galunisertib);
- 抗轉型生長因子-β (TGF-β)抗體,諸如LY3022859、NIS793、XOMA 089;
- 雙特異性抗體,諸如MM-141 (IGF-1/ErbB3)、MM-111 (Erb2/Erb3)、JNJ-64052781 (CD19/CD3)、PRS-343 (CD-137/HER2)、AFM26 (BCMA/CD16A)、JNJ-61186372 (EGFR/cMET)、AMG-211 (CEA/CD3)、RG7802 (CEA/CD3)、ERY-974 (CD3/GPC3)、范茨珠單抗(vancizumab)(血管生成素/VEGF)、PF-06671008 (鈣黏素/CD3)、AFM-13 (CD16/CD30)、APVO436 (CD123/CD3)、弗圖珠單抗(flotetuzumab)(CD123/CD3)、REGN-1979 (CD20/CD3)、MCLA-117 (CD3/CLEC12A)、MCLA-128 (HER2/HER3)、JNJ-0819、JNJ-7564 (CD3/血紅素)、AMG-757 (DLL3-CD3)、MGD-013 (PD-1/LAG-3)、AK-104 (CTLA-4/PD-1)、AMG-330 (CD33/CD3)、AMG-420 (BCMA/CD3)、BI-836880 (VEFG/ANG2)、JNJ-63709178 (CD123/CD3)、MGD-007 (CD3/gpA33)、MGD-009 (CD3/B7H3);
- 突變型選擇性EGFR抑制劑,諸如PF-06747775、EGF816 (納紮替尼(nazartinib))、ASP8273、ACEA-0010、BI-1482694;
- 抗GITR (糖皮質激素誘導之腫瘤壞死因子受體相關蛋白質)抗體,諸如MEDI1873、FPA-154、INCAGN-1876、TRX-518、BMS-986156、MK-1248、GWN-323;
- 抗δ樣蛋白配位體3 (DDL3)抗體,諸如特西諾瓦單抗(rovalpituzumab tesirine);
- 抗群集素抗體,諸如AB-16B5;
- 抗肝配蛋白-A4 (EFNA4)抗體,諸如PF-06647263;
- 抗RANKL抗體,諸如德諾單抗(denosumab);
- 抗間皮素抗體,諸如BMS-986148、抗MSLN-MMAE;
- 抗磷酸鈉共轉運體2B (NaP2B)抗體,諸如立伐土珠單抗(lifastuzumab);
- 抗c-Met抗體,諸如ABBV-399;
- 腺苷A2A受體拮抗劑,諸如CPI-444、AZD-4635、普雷迪南(preladenant)、PBF-509;
- α-酮戊二酸去氫酶(KGDH)抑制劑,諸如CPI-613;
- XPO1抑制劑,諸如西林俄(selinexor) (KPT-330);
- 異檸檬酸去氫酶2 (IDH2)抑制劑,諸如艾那尼布(enasidenib) (AG-221);
- IDH1抑制劑,諸如AG-120及AG-881 (IDH1及IDH2)、IDH-305、BAY-1436032;
- 介白素-3受體(IL-3R)調節劑,諸如SL-401;
- 精胺酸脫亞胺酶刺激劑,諸如聚乙二醇精胺酸酶(ADI-PEG-20);
- 抗體-藥物接合物,諸如MLN0264 (抗GCC、鳥苷酸環化酶C)、T-DM1 (曲妥珠單抗恩他新(trastuzumab emtansine),Kadcycla)、米拉珠單抗(milatuzumab)-小紅莓(hCD74-DOX)、貝倫妥單抗維多汀(brentuximab vedotin)、DCDT2980S、保納珠單抗維多汀(polatuzumab vedotin)、SGN-CD70A、SGN-CD19A、英妥珠單抗奧米欣(inotuzumab ozogamicin)、洛瓦土珠單抗美登素(lorvotuzumab mertansine)、SAR3419、尹薩珠單抗戈維特坎(isactuzumab govitecan)、因福土單抗維多汀(enfortumab vedotin) (ASG-22ME)、ASG-15ME、DS-8201 (曲妥珠單抗德魯特坎(trastuzumab deruxtecan))、225Ac-林妥珠單抗(lintuzumab)、U3-1402、177Lu-特特拉克斯坦-特圖瑪(tetraxetan-tetuloma)、替索圖單抗維多汀(tisotumab vedotin)、阿內圖單抗拉夫坦辛(anetumab ravtansine)、CX-2009、SAR-566658、W-0101、保納珠單抗維多汀、ABBV-085;
- 緊密連接蛋白-18抑制劑,諸如克迪西單抗(claudiximab);
- β-連環蛋白抑制劑,諸如CWP-291;
- 抗CD73抗體,諸如MEDI-9447 (奧勒魯單抗(oleclumab))、CPX-006、IPH-53、BMS-986179;
- CD73拮抗劑,諸如AB-680、PSB-12379、PSB-12441、PSB-12425;
- CD39/CD73拮抗劑,諸如PBF-1662;
- 趨化介素受體2 (CCR)抑制劑,諸如PF-04136309、CCX-872、BMS-813160 (CCR2/CCR5);
- 胸苷酸合酶抑制劑,諸如ONX-0801;
- ALK/ROS1抑制劑,諸如勞拉替尼(lorlatinib);
- 端粒酶抑制劑,諸如G007-LK;
- Mdm2 p53-結合蛋白抑制劑,諸如CMG-097、HDM-201;
- c-PIM抑制劑,諸如PIM447;
- BRAF抑制劑,諸如達拉非尼(dabrafenib)、維羅非尼(vemurafenib)、恩拉菲尼(encorafenib) (LGX818)、PLX8394;
- 神經鞘胺醇激酶-2 (SK2)抑制劑,諸如Yeliva® (ABC294640);
- 細胞週期抑制劑,諸如司美替尼(selumetinib) (MEK1/2),及沙帕他濱(sapacitabine);
- AKT抑制劑,諸如MK-2206、伊巴替布(ipatasertib)、阿弗替布(afuresertib)、AZD5363及ARQ-092、卡瓦替布(capivasertib)、曲西立濱(triciribine);
- 抗CTLA-4 (細胞毒性T淋巴細胞蛋白-4)抑制劑,諸如曲美木單抗、AGEN-1884、BMS-986218;
- c-MET抑制劑,諸如AMG-337、薩沃替尼(savolitinib)、提瓦替尼(tivantinib)(ARQ-197)、卡普尼布(capmatinib)及特潑替尼(tepotinib)、ABT-700、AG213、AMG-208、JNJ-38877618 (OMO-1)、默萊替尼(merestinib)、HQP-8361;
- c-Met/VEGFR抑制劑,諸如BMS-817378、TAS-115;
- c-Met/RON抑制劑,諸如BMS-777607;
- BRAF/EGFR抑制劑,諸如BGB-283;
- bcr/abl抑制劑,諸如瑞巴替尼(rebastinib)、阿西尼布(asciminib);
- MNK1/MNK2抑制劑,諸如eFT-508;
- mTOR抑制劑/細胞色素P450 3A4刺激劑,諸如TYME-88;
- 離胺酸特異性去甲基酶-1 (LSD1)抑制劑,諸如CC-90011;
- 泛RAF抑制劑,諸如LY3009120、LXH254、TAK-580;
- Raf/MEK抑制劑,諸如RG7304;
- CSF1R/KIT及FLT3抑制劑,諸如派西尼布(pexidartinib) (PLX3397);
- 激酶抑制劑,諸如凡德他尼(vandetanib);
- E選擇蛋白拮抗劑,諸如GMI-1271;
- 分化誘導劑,諸如維甲酸;
- 表皮生長因子受體(EGFR)抑制劑,諸如奧希替尼(osimertinib) (AZD-9291);
- 拓樸異構酶抑制劑,諸如小紅莓、道諾黴素、放線菌素D、艾尼西德(eniposide)、表柔比星、依託泊苷、艾達黴素、伊立替康、米托蒽醌、匹蒽醌(pixantrone)、索布佐生(sobuzoxane)、拓朴替康、伊立替康、MM-398 (脂質體伊立替康)、沃薩洛辛(vosaroxin)及GPX-150、阿多比欣(aldoxorubicin)、AR-67、瑪韋替尼(mavelertinib)、AST-2818、阿維替尼(avitinib) (ACEA-0010)、伊洛福芬(irofulven) (MGI-114);
- 皮質類固醇,諸如可的松(cortisone)、地塞米松、氫化可的松、甲基潑尼龍、潑尼松、潑尼龍;
- 生長因子信號轉導激酶抑制劑;
- 核苷類似物,諸如DFP-10917;
- Axl抑制劑,諸如BGB-324 (貝西替尼(bemcentinib))、SLC-0211;
- BET抑制劑,諸如INCB-054329、INCB057643、TEN-010、AZD-5153、ABT-767、BMS-986158、CC-90010、GSK525762 (莫尼西布(molibresib))、NHWD-870、ODM-207、GSK-2820151、GSK-1210151A、ZBC246、ZBC260、ZEN3694、FT-1101、RG-6146、CC-90010、米韋西布(mivebresib)、BI-894999、PLX-2853、PLX-51107、CPI-0610、GS-5829;
- PARP抑制劑,諸如奧拉帕尼(olaparib)、蘆卡帕尼(veliparib)、他拉柔帕尼(talazoparib)、ABT-767、BGB-290;
- 蛋白酶體抑制劑,諸如依薩佐米(ixazomib)、卡非佐米(carfilzomib) (Kyprolis®)、馬瑞佐米(marizomib);
- 麩醯胺酸酶抑制劑,諸如CB-839;
- 疫苗,諸如肽疫苗TG-01 (RAS)、GALE-301、GALE-302、萊尼哌嗎-s (nelipepimut-s)、SurVaxM、DSP-7888、TPIV-200、PVX-410、VXL-100、DPX-E7、ISA-101、6MHP、OSE-2101、加利哌嗎-S (galinpepimut-S)、SVN53-67/M57-KLH、IMU-131;細菌載體疫苗,諸如CRS-207/GVAX、阿利莫金非洛巴克(axalimogene filolisbac) (ADXS11-001);腺病毒載體疫苗,諸如那多拉金非拉維克(nadofaragene firadenovec);自體Gp96疫苗;樹突狀細胞疫苗,諸如CVactm、斯塔賽爾-T (stapuldencel-T)、艾他賽爾-T (eltrapuldencel-T)、SL-701、BSK01TM、洛卡賽爾-T (rocapuldencel-T) (AGS-003)、DCVAC、CVactm
、斯塔賽爾-T、艾他賽爾-T、SL-701、BSK01TM
、ADXS31-142;溶瘤疫苗,諸如塔里穆尼拉赫韋克(talimogene laherparepvec)、派替莫金德瓦維克(pexastimogene devacirepvec)、GL-ONC1、MG1-MA3、小病毒H-1、ProstAtak、恩那希瑞(enadenotucirev)、MG1MA3、ASN-002 (TG-1042);治療性疫苗,諸如CVAC-301、CMP-001、PF-06753512、VBI-1901、TG-4010、ProscaVax™;腫瘤細胞疫苗,諸如Vigil® (IND-14205)、Oncoquest-L疫苗;減毒活、重組型、血清型1脊髓灰白質炎病毒疫苗,諸如PVS-RIPO;阿達洛德西莫林(Adagloxad simolenin);MEDI-0457;DPV-001,一種腫瘤衍生之自噬小體增濃型癌症疫苗;RNA疫苗,諸如CV-9209、LV-305;DNA疫苗,諸如MEDI-0457、MVI-816、INO-5401;表現p53之經修飾之痘瘡病毒安卡拉(vaccinia virus Ankara)疫苗,諸如MVA-p53;DPX-Survivac;BriaVax™;GI-6301;GI-6207;GI-4000;
- 抗DLL4 (δ樣配位體4)抗體,諸如登西珠單抗(demcizumab);
- STAT-3抑制劑,諸如那帕布新(napabucasin) (BBI-608);
- ATP酶p97抑制劑,諸如CB-5083;
- 平滑(SMO)受體抑制劑,諸如Odomzo® (索尼得吉(sonidegib),先前LDE-225)、LEQ506、維莫德吉(vismodegib) (GDC-0449)、BMS-833923、格拉吉伯(glasdegib) (PF-04449913)、LY2940680及伊曲康唑(itraconazole);
- 干擾素α配位體調節劑,諸如干擾素α-2b、干擾素α-2a生物類似物(Biogenomics)、羅派干擾素(ropeginterferon)α-2b (AOP-2014、P-1101、PEG IFN α-2B)、穆提非隆(Multiferon)(阿法耐提(Alfanative),維拉金(Viragen))、干擾素α 1b、羅飛龍-A (Roferon-A)(坎非隆(Canferon)、Ro-25-3036)、干擾素α-2a後續生物製劑(拜斯度(Biosidus))(因木塔,Inter 2A)、干擾素α-2b後繼生物製劑(拜斯度-拜非隆、斯托非隆(Citopheron)、嘎納帕(Ganapar),Beijing Kawin Technology-卡非隆(Kaferon))、阿法菲酮、聚乙二醇化干擾素α-1b、聚乙二醇化干擾素α-2b後續生物製劑(Amega)、重組型人類干擾素α-1b、重組型人類干擾素α-2a、重組型人類干擾素α-2b、維托珠單抗(veltuzumab)-IFNα 2b結合物、Dynavax(SD-101)及干擾素α-n1 (霍莫非隆(Humoferon)、SM-10500、蘇米非隆(Sumiferon));
- 干擾素γ配位體調節劑,諸如干擾素γ (OH-6000、奧格瑪(Ogamma) 100);
- IL-6受體調節劑,諸如托西利單抗(tocilizumab)、思圖昔單抗(siltuximab)、AS-101 (CB-06-02、IVX-Q-101);
- 端粒酶調節劑,諸如特托莫肽(tertomotide) (GV-1001、HR-2802、Riavax)及伊美司他(imetelstat) (GRN-163、JNJ-63935937);
- DNA甲基轉移酶抑制劑,諸如替莫唑胺(temozolomide) (CCRG-81045)、地西他濱(decitabine)、瓜達西汀(S-110、SGI-110)、KRX-0402、RX-3117、RRx-001及阿紮胞苷(azacitidine);
- DNA旋轉酶抑制劑,諸如匹蒽醌及索布佐生;
- Bcl-2家族蛋白抑制劑,諸如ABT-263、維奈托克(venetoclax) (ABT-199)、ABT-737及AT-101;
- Notch抑制劑,諸如LY3039478 (克尼斯塔(crenigacestat))、他瑞妥單抗(tarextumab) (抗Notch2/3)、BMS-906024;
- 抗肌肉抑制素抑制劑,諸如蘭多單抗(landogrozumab);
- 玻尿酸酶刺激劑,諸如PEGPH-20;
- Wnt路徑抑制劑,諸如SM-04755、PRI-724、WNT-974;
- γ-分泌酶抑制劑,諸如PF-03084014、MK-0752、RO-4929097;
- Grb-2 (生長因子受體結合蛋白-2)抑制劑,諸如BP1001;
- TRAIL路徑誘導性化合物,諸如ONC201、ABBV-621;
- 局部黏著斑激酶抑制劑,諸如VS-4718、迪法替尼(defactinib)、GSK2256098;
- 刺蝟抑制劑,諸如薩瑞德吉(saridegib)、索尼得吉(LDE225)、格拉吉伯及維莫德吉;
- 極光激酶抑制劑,諸如阿立塞替(alisertib) (MLN-8237)及AZD-2811、AMG-900、巴塞替尼(barasertib)、ENMD-2076;
- HSPB1調節劑(熱休克蛋白27,HSP27),諸如溴夫定(brivudine)、阿帕托森(apatorsen);
- ATR抑制劑,諸如BAY-937、AZD6738、AZD6783、VX-803、VX-970 (貝佐替布(berzosertib))及VX-970;
- mTOR抑制劑,諸如賽泮替布(sapanisertib)及維塞替布(vistusertib) (AZD2014)、ME-344;
- mTOR/PI3K抑制劑,諸如吉達力絲、GSK2141795、奧米力絲(omipalisib)、RG6114;
- Hsp90抑制劑,諸如AUY922、奧那勒斯(onalespib) (AT13387)、SNX-2112、SNX5422;
- 鼠類雙重微小(mdm2)致癌基因抑制劑,諸如DS-3032b、RG7775、AMG-232、HDM201及伊達努素(idasanutlin)(RG7388);
- CD137促效劑,諸如烏瑞魯單抗(urelumab)、烏圖木單抗(utomilumab)(PF-05082566);
- STING促效劑,諸如ADU-S100 (MIW-815)、SB-11285、MK-1454、SR-8291、AdVCA0848、GSK-532、SYN-STING、MSA-1、SR-8291;
- FGFR抑制劑,諸如FGF-401、INCB-054828、BAY-1163877、AZD4547、JNJ-42756493、LY2874455、Debio-1347;
- 脂肪酸合酶(FASN)抑制劑,諸如TVB-2640;
- 抗KIR單株抗體,諸如利瑞路單抗(lirilumab) (IPH-2102)、IPH-4102;
- 抗原CD19抑制劑,諸如MOR208、MEDI-551、AFM-11、因厄比利珠單抗(inebilizumab);
- CD44結合子,諸如A6;
- 蛋白質磷酸酶2A (PP2A)抑制劑,諸如LB-100;
- CYP17抑制劑,諸如西維諾尼(seviteronel) (VT-464)、ASN-001、ODM-204、CFG920、乙酸阿比特龍(abiraterone acetate);
- RXR促效劑,諸如IRX4204;
- 刺蝟/平滑(hh/Smo)拮抗劑,諸如塔拉吉伯(taladegib)、帕替吉伯(patidegib);
- 補體C3調節劑,諸如因普拉姆PGG (Imprime PGG);
- IL-15促效劑,諸如ALT-803、NKTR-255及hetIL-15;
- EZH2 (zeste基因增強子同源物2)抑制劑,諸如塔澤斯塔(tazemetostat)、CPI-1205、GSK-2816126;
- 溶瘤病毒,諸如派拉瑞普(pelareorep)、CG-0070、MV-NIS療法、HSV-1716、DS-1647、VCN-01、ONCOS-102、TBI-1401、塔沙圖瑞(tasadenoturev) (DNX-2401)、沃西金阿米維克(vocimagene amiretrorepvec)、RP-1、CVA21、Celyvir、LOAd-703、OBP-301;
- DOT1L (組蛋白甲基轉移酶)抑制劑,諸如皮諾斯塔(pinometostat) (EPZ-5676);
- 毒素,諸如霍亂毒素(Cholera toxin)、蓖麻毒素、假單胞菌外毒素(Pseudomonas exotoxin)、百日咳博特氏菌(Bordetella pertussis)腺苷酸環化酶毒素、白喉毒素及凋亡蛋白酶活化劑;
- DNA質體,諸如BC-819;
- PLK 1、2及3之PLK抑制劑,諸如伏拉塞替(volasertib) (PLK1);
- WEE1抑制劑,諸如AZD1775 (阿達替布(adavosertib));
- Rho激酶(ROCK)抑制劑,諸如AT13148、KD025;
- ERK抑制劑,諸如GDC-0994、LY3214996、MK-8353;
- IAP抑制劑,諸如ASTX660、debio-1143、比林納潘特、APG-1387、LCL-161;
- RNA聚合酶抑制劑,諸如魯尼特丁(lurbinectedin) (PM-1183)、CX-5461;
- 微管蛋白抑制劑,諸如PM-184、BAL-101553 (利沙布林(lisavanbulin))、OXI-4503、弗拉帕欣(fluorapacin) (AC-0001)及普拉布林(plinabulin);
- 鐸樣受體4 (TL4)促效劑,諸如G100、GSK1795091及PEPA-10;
- 延長因子1α2抑制劑,諸如普替德新(plitidepsin);
- CD95抑制劑,諸如APG-101、APO-010、阿蘇賽普(asunercept);
- WT1抑制劑,諸如DSP-7888;
- 剪接因子3B次單元1 (SF3B1)抑制劑,諸如H3B-8800;
- PDGFR α/KIT突變體特異性抑制劑,諸如BLU-285;
- SHP-2抑制劑,諸如TNO155 (SHP-099)、RMC-4550;及
- 類視黃素Z受體γ (RORγ)促效劑,諸如LYC-55716。
在一些實施例中,治療或預防患有過度增殖性病症或癌症或具有罹患過度增殖性病症或癌症之風險之人類或動物的過度增殖性病症或癌症之方法包含向人類或動物投與治療有效量之如本文所揭示之本發明化合物或其醫藥學上可接受之鹽與治療有效量之一或多種(例如,一種、兩種、三種、一種或兩種或一至三種)選自由以下組成之群之額外治療劑之組合:細胞凋亡信號調節激酶(ASK)抑制劑;布魯頓氏酪胺酸激酶(BTK)抑制劑;分化簇47 (CD47)抑制劑;週期素依賴性激酶(CDK)抑制劑;盤狀域受體(DDR)抑制劑;組蛋白去乙醯基酶(HDAC)抑制劑;吲哚胺-吡咯-2,3-二加氧酶(IDO1)抑制劑;傑納斯激酶(JAK)抑制劑;離胺醯氧化酶樣蛋白(LOXL)抑制劑;基質金屬蛋白酶(MMP)抑制劑;促分裂原活化蛋白激酶(MEK)抑制劑;磷脂醯肌醇3-激酶(PI3K)抑制劑;脾酪胺酸激酶(SYK)抑制劑;鐸樣受體8 (TLR8)抑制劑;鐸樣受體9 (TLR9)抑制劑;酪胺酸激酶抑制劑(TKI)及其任何組合或其醫藥學上可接受之鹽。非限制性實例包括:
-細胞凋亡信號調節激酶 ( ASK ) 抑制劑 :
ASK抑制劑包括ASK1抑制劑。ASK1抑制劑之實例包括但不限於WO 2011/008709 (Gilead Sciences)及WO 2013/112741 (Gilead Sciences)中所描述之抑制劑;
-布魯頓氏酪胺酸激酶 ( BTK ) 抑制劑 :
BTK抑制劑之實例包括但不限於(S)-6-胺基-9-(1-(丁-2-炔醯基)吡咯啶-3-基)-7-(4-苯氧基苯基)-7H-嘌呤-8(9H)-酮、阿卡拉布魯替尼(ACP-196)、BGB-3111、CB988、HM71224、依魯替尼、M-2951 (伊沃替尼(evobrutinib))、M7583、替拉替尼(tirabrutinib) (ONO-4059)、PRN-1008、司培替尼(CC-292)、TAK-020、維卡替尼(vecabrutinib)、ARQ-531、SHR-1459、DTRMWXHS-12、TAS-5315;
-分化簇 47 ( CD47 ) 抑制劑 :
CD47抑制劑之實例包括但不限於抗CD47 mAb (Vx-1004)、抗人類CD47 mAb (CNTO-7108)、CC-90002、CC-90002-ST-001、人類化抗CD47抗體(Hu5F9-G4)、NI-1701、NI-1801、RCT-1938及TTI-621;
-細胞週期素依賴性激酶 ( CDK ) 抑制劑 :
CDK抑制劑包括CDK1、2、3、4、6、7及9之抑制劑,諸如阿貝力布(abemaciclib)、阿昔迪布(alvocidib) HMR-1275、夫拉平度(flavopiridol))、AT-7519、戴那西里(dinaciclib)、艾博蘭斯(ibrance)、FLX-925、LEE001、帕泊昔布(palbociclib)、利伯西利(ribociclib)、瑞戈替布、西林俄、UCN-01、SY1365、CT-7001、SY-1365、G1T38、米西西尼(milciclib)、曲拉西利(trilaciclib)及TG-02;
-盤狀域受體 ( DDR ) 抑制劑 :
DDR抑制劑包括DDR1及/或DDR2之抑制劑。DDR抑制劑之實例包括(但不限於) WO 2014/047624 (Gilead Sciences)、US 2009-0142345 (Takeda Pharmaceutical)、US 2011-0287011 (Oncomed Pharmaceuticals)、WO 2013/027802 (Chugai Pharmaceutical)及WO 2013/034933 (Imperial Innovations)中所揭示之抑制劑;
-組蛋白去乙醯基酶 ( HDAC ) 抑制劑 :
HDAC抑制劑之實例包括但不限於阿貝司他(abexinostat)、ACY-241、AR-42、BEBT-908、貝林諾他(belinostat)、CKD-581、CS-055 (HBI-8000)、CUDC-907 (非米斯他(fimepinostat))、恩替諾特(entinostat)、吉韋諾他(givinostat)、莫塞諾他(mocetinostat)、帕比諾他、普拉諾他(pracinostat)、奎西諾他(quisinostat) (JNJ-26481585)、雷米諾他、瑞科諾他(ricolinostat)、SHP-141、丙戊酸(VAL-001)、伏立諾他、替諾斯汀(tinostamustine)、雷米斯特(remetinostat)、恩替諾特;
-吲哚胺 - 吡咯 - 2 , 3 - 二加氧酶 ( IDO1 ) 抑制劑 :
IDO1抑制劑之實例包括但不限於BLV-0801、艾帕斯塔、F-001287、GBV-1012、GBV-1028、GDC-0919、因多莫得、NKTR-218、基於NLG-919之疫苗、PF-06840003、哌喃並萘醌衍生物(SN-35837)、雷米諾他、SBLK-200802、BMS-986205及shIDO-ST、EOS-200271、KHK-2455、LY-3381916;
-傑納斯激酶 ( JAK ) 抑制劑 :
JAK抑制劑抑制JAK1、JAK2及/或JAK3。JAK抑制劑之實例包括(但不限於)AT9283、AZD1480、巴瑞替尼(baricitinib)、BMS-911543、非達替尼(fedratinib)、非戈替尼(filgotinib) (GLPG0634)、甘多替尼(gandotinib) (LY2784544)、INCB039110、來他替尼(lestaurtinib)、莫羅替尼(momelotinib)(CYT0387)、NS-018、帕瑞替尼(pacritinib)(SB1518)、皮非替尼(peficitinib) (ASP015K)、盧佐替尼(ruxolitinib)、托法替尼(tofacitinib) (先前塔索替尼(tasocitinib))、INCB052793及XL019;
-離胺醯氧化酶樣蛋白 ( LOXL ) 抑制劑 :
LOXL抑制劑包括LOXL1、LOXL2、LOXL3、LOXL4及/或LOXL5之抑制劑。LOXL抑制劑之實例包括但不限於WO 2009/017833 (Arresto Biosciences)中所描述之抗體。LOXL2抑制劑之實例包括但不限於WO 2009/017833 (Arresto Biosciences)、WO 2009/035791 (Arresto Biosciences)及WO 2011/097513 (Gilead Biologics)中所描述之抗體;
-基質金屬蛋白酶 ( MMP ) 抑制劑 :
MMP抑制劑包括MMP1至MMP10之抑制劑。MMP9抑制劑之實例包括但不限於馬立馬司他(marimastat) (BB-2516)、西馬司他(cipemastat) (Ro 32-3555)、GS-5745 (安德西單抗(andecaliximab))及WO 2012/027721 (Gilead Biologics)中描述之抑制劑;
-促分裂原活化蛋白激酶 ( MEK ) 抑制劑 :
MEK抑制劑包括安奎諾爾(antroquinonol)、畢尼替尼(binimetinib)、考比替尼(cobimetinib) (GDC-0973、XL-518)、MT-144、司美替尼(AZD6244)、索拉非尼(sorafenib)、曲美替尼(trametinib) (GSK1120212)、阿瑟替布(uprosertib) +曲美替尼、PD-0325901、皮馬瑟替(pimasertib)、LTT462、AS703988、CC-90003、瑞法美替尼(refametinib);
-磷脂醯肌醇 3 - 激酶 ( PI3K ) 抑制劑 :
PI3K抑制劑包括PI3Kγ、PI3Kδ、PI3Kβ、PI3Kα及/或泛PI3K之抑制劑。PI3K抑制劑之實例包括但不限於ACP-319、AEZA-129、AMG-319、AS252424、AZD8186、BAY 10824391、BEZ235、布帕昔布(BKM120)、BYL719 (艾培昔布)、CH5132799、考班昔布(BAY 80-6946)、杜維昔布、GDC-0032、GDC-0077、GDC-0941、GDC-0980、GSK2636771、GSK2269557、艾德斯布(Zydelig®)、INCB50465、IPI-145、IPI-443、IPI-549、KAR4141、LY294002、LY3023414、MLN1117、OXY111A、PA799、PX-866、RG7604、瑞戈替布、RP5090、RP6530、SRX3177、泰尼西布、TG100115、TGR-1202 (溫布昔布(umbralisib))、TGX221、WX-037、X-339、X-414、XL147 (SAR245408)、XL499、XL756、渥曼青黴素(wortmannin)、ZSTK474以及WO 2005/113556 (ICOS)、WO 2013/052699 (Gilead Calistoga)、WO 2013/116562 (Gilead Calistoga)、WO 2014/100765 (Gilead Calistoga)、WO 2014/100767 (Gilead Calistoga)及WO 2014/201409 (Gilead Sciences)中所描述之化合物;
-脾酪胺酸激酶 ( SYK ) 抑制劑 :
SYK抑制劑之實例包括但不限於6-(1H-吲唑-6-基)-N-(4-N-嗎啉基苯基)咪唑并[1,2-a]吡嗪-8-胺、BAY-61-3606、瑟杜替尼(cerdulatinib) (PRT-062607)、恩妥替尼(entospletinib)、福他替尼(fostamatinib) (R788)、HMPL-523、NVP-QAB 205 AA、R112, R343、塔馬替尼(tamatinib) (R406)及US 8450321 (Gilead Connecticut)中所描述之SYK抑制劑及U.S. 2015/0175616中所描述之SYK抑制劑;
-鐸樣受體 8 ( TLR8 ) 抑制劑 :
TLR8抑制劑之實例包括但不限於E-6887、IMO-4200、IMO-8400、IMO-9200、MCT-465、MEDI-9197、莫托莫特、雷西莫特、VTX-1463及VTX-763;
-鐸樣受體 9 ( TLR9 ) 抑制劑 :
TLR9抑制劑之實例包括但不限於AST-008、IMO-2055、IMO-2125、勒菲妥莫特(lefitolimod)、利騰莫特、MGN-1601及PUL-042;及
-酪胺酸激酶抑制劑 ( TKI ) :
TKI可靶向表皮生長因子受體(EGFR)以及纖維母細胞生長因子(FGF)、血小板衍生生長因子(PDGF)及血管內皮生長因子(VEGF)之受體。TKI之實例包括但不限於阿法替尼(afatinib)、ARQ-087 (德贊替尼(derazantinib))、asp5878、AZD3759、AZD4547、伯舒替尼(bosutinib)、布加替尼(brigatinib)、卡博替尼(cabozantinib)、西地尼布(cediranib)、克諾拉尼(crenolanib)、達可替尼(dacomitinib)、達沙替尼、多韋替尼(dovitinib)、E-6201、厄達替尼(erdafitinib)、埃羅替尼(erlotinib)、吉非替尼(gefitinib)、吉列替尼(gilteritinib) (ASP-2215)、FP-1039、HM61713、埃克替尼(icotinib)、伊馬替尼(imatinib)、KX2-391 (Src)、拉帕替尼(lapatinib)、來他替尼、樂伐替尼(lenvatinib)、米哚妥林(midostaurin)、尼達尼布(nintedanib)、ODM-203、奧希替尼(AZD-9291)、普納替尼(ponatinib)、波齊奧替尼(poziotinib)、喹雜替尼(quizartinib)、拉多替尼(radotinib)、羅西替尼(rociletinib)、索凡替尼(sulfatinib) (HMPL-012)、舒尼替尼(sunitinib)、替沃尼布(tivoanib)及TH-4000、MEDI-575 (抗PDGFR抗體)。
如本文所用,術語「化學治療劑」或「化學治療」(或在用化學治療劑治療之情況下之「化學療法」)意欲涵蓋適用於治療癌症之任何非蛋白質(亦即,非肽)化合物。化學治療劑之實例包括但不限於:烷基化劑,諸如噻替派及環磷醯胺(CYTOXAN®
);磺酸烷基酯,諸如白消安、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶,諸如苯佐替派(benzodepa)、卡波醌(carboquone)、美妥替派(meturedepa)及烏瑞替派(uredepa);伸乙亞胺及甲基三聚氰胺,包括六甲蜜胺、三伸乙基蜜胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺及三米蜜胺;多聚乙醯,尤其布拉他辛(bullatacin)及布拉他辛酮(bullatacinone);喜樹鹼,包括合成類似物拓朴替康;苔蘚抑素(bryostatin)、海洋抑素(callystatin);CC-1065,包括其阿多來新(adozelesin)、卡折來新(carzelesin)及比折來新(bizelesin)合成類似物;念珠藻素(cryptophycin),尤其念珠藻素1及念珠藻素8;海兔毒素(dolastatin);多卡黴素(duocarmycin),包括合成類似物KW-2189及CBI-TMI;艾榴塞洛素(eleutherobin);5-氮雜胞苷;水鬼蕉鹼(pancratistatin);匍枝珊瑚醇(sarcodictyin);海綿抑素(spongistatin);氮芥,諸如苯丁酸氮芥、萘氮芥、環磷醯胺、葡磷醯胺(glufosfamide)、伊沃醯胺(evofosfamide)、苯達莫司汀、雌莫司汀(estramustine)、異環磷醯胺、甲基二(氯乙基)胺、甲基二(氯乙基)胺氧化物鹽酸鹽、美法侖、新氮芥(novembichin)、苯芥膽甾醇(phenesterine)、潑尼莫司汀(prednimustine)、曲磷胺(trofosfamide)及尿嘧啶氮芥;亞硝基脲,諸如卡莫司汀、氯脲菌素(chlorozotocin)、福莫司汀(foremustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)及雷莫司汀(ranimustine);抗生素,諸如烯二炔抗生素(例如,卡奇黴素(calicheamicin),尤其卡奇黴素γII及卡奇黴素φI1)、包括達內黴素(dynemicin) A之達內黴素,諸如氯屈膦酸鹽(clodronate)之雙膦酸鹽、埃斯培拉黴素(esperamicin)、新制癌菌素(neocarzinostatin)發色團及相關色蛋白烯二炔抗生素色素體、阿克拉黴素(aclacinomycin)、放線菌素、安麯黴素(authramycin)、偶氮絲胺酸、博來黴素、放線菌素C、卡拉比辛(carabicin)、卡尼米辛(carrninomycin)、嗜癌菌素(carzinophilin)、色黴素(chromomycin)、放線菌素D、道諾黴素、地托比星(detorubicin)、6-重氮-5-側氧基-L-正白胺酸、小紅莓(包括N-嗎啉基-小紅莓、氰基-N-嗎啉基-小紅莓、2-吡咯啉基-小紅莓及去氧小紅莓)、表柔比星、依索比星(esorubicin)、艾達黴素、麻西羅黴素(marcellomycin)、諸如絲裂黴素C之絲裂黴素、黴酚酸、諾加黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、泊非羅黴素(porfiromycin)、嘌呤黴素(puromycin)、奎那黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑菌素(streptonigrin)、鏈脲菌素、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)及左柔比星(zorubicin);抗代謝物,諸如甲胺喋呤及5-氟尿嘧啶(5-FU);葉酸類似物,諸如迪莫林(demopterin)、甲胺喋呤、蝶羅呤(pteropterin)及曲美沙特(trimetrexate);嘌呤類似物,諸如氟達拉濱、6-巰基嘌呤、硫咪嘌呤、及硫鳥嘌呤;嘧啶類似物,諸如安西他濱(ancitabine)、阿紮胞苷、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷、二去氧尿苷、去氧氟尿苷、依諾他濱(enocitabine)及氟尿苷;雄激素,諸如卡魯睪酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)及睪內酯(testolactone);抗腎上腺,諸如胺麩精、米托坦及曲洛司坦(trilostane);葉酸補充劑,諸如亞葉酸;放射性治療劑,諸如鐳-223;單端孢黴烯(trichothecene),尤其T-2毒素、黏液黴素(verracurin) A、桿孢菌素(roridin) A及胺癸叮(anguidine);類紫杉醇,諸如太平洋紫杉醇(TAXOL®
)、白蛋白結合型紫杉醇(abraxane)、多西他賽(TAXOTERE®
)、卡巴他賽(cabazitaxel)、BIND-014、替司他賽(tesetaxel);鉑類似物,諸如順鉑及卡鉑、NC-6004奈鉑(nanoplatin);乙醯葡醛酯;醛磷醯胺醣苷;胺基乙醯丙酸;恩尿嘧啶;安吖啶;赫布西爾(hestrabucil);比山群(bisantrene);艾達曲克(edatraxate);得弗伐胺(defofamine);秋水仙鹼;地吖醌(diaziquone);艾弗欣(elformthine);依利醋銨(elliptinium acetate);埃博黴素;依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多醣;甲醯四氫葉酸;氯尼達明(lonidamine);類美登素(maytansinoid),諸如美登素及安絲菌素(ansamitocin);丙脒腙(mitoguazone);米托蒽醌;莫哌達醇(mopidamol);二胺硝吖啶(nitracrine);噴司他汀;苯來美特(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);氟嘧啶;醛葉酸;鬼臼酸;2-乙基醯肼;丙卡巴肼;多醣-K (PSK);雷佐生(razoxane);根瘤菌素(rhizoxin);西索菲蘭(sizofiran);螺旋鍺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);曲貝替定(trabectedin)、三亞胺醌(triaziquone);2,2',2''-特洛米安(tricUorotriemylamine);胺基甲酸酯;長春地辛(vindesine);達卡巴嗪;甘露醇氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);哌泊溴烷(pipobroman);加西托星(gacytosine);阿拉伯糖苷(「Ara-C」);環磷醯胺;賽派塔(thiopeta);苯丁酸氮芥;吉西他濱(GEMZAR®
);6-硫鳥嘌呤;巰基嘌呤;甲胺喋呤;長春鹼;鉑;依託泊苷(VP-16);異環磷醯胺;米托蒽醌;長春新鹼(vancristine);長春瑞賓(NAVELBINE®
);諾凡特龍(novantrone);替尼泊苷;依達曲沙(edatrexate);道諾黴素;胺基喋呤;希羅達(xeoloda);伊班膦酸鹽(ibandronate);CPT-11;拓樸異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(DFMO);類視黃素,諸如視黃酸;卡培他濱;NUC-1031;FOLFIRI (氟尿嘧啶、甲醯四氫葉酸及伊立替康);及以上中之任一者之醫藥學上可接受之鹽、酸或衍生物。
「化學治療劑」之定義亦包括抗激素劑,諸如用於調節或抑制腫瘤上之激素作用的抗雌激素及選擇性雌激素受體調節劑(SERM)、芳香酶抑制劑、抗雄激素及以上中之任一者之醫藥學上可接受之鹽、酸或衍生物。抗激素劑
抗雌激素及SERM之實例包括例如他莫昔芬(包括NOLVADEXTM
)、雷諾昔芬(raloxifene)、曲洛昔芬(droloxifene)、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、雷洛昔芬(keoxifene)、LY117018、奧那司酮(onapristone)及托瑞米芬(toremifene) (FARESTON®
)。
芳香酶抑制劑調節腎上腺中之雌激素產生。實例包括4(5)-咪唑、胺麩精、乙酸甲地孕酮(MEGACE®
)、依西美坦(exemestane)、福美司坦(formestane)、法屈唑(fadrozole)、伏羅唑(vorozole) (RIVISOR®
)、來曲唑(FEMARA®
)及阿那曲唑(ARIMIDEX®
)。
抗雄激素之實例包括阿帕魯胺(apalutamide)、阿比特龍、恩雜魯胺(enzalutamide)、氟他胺(flutamide)、加利特隆(galeterone)、尼魯胺、比卡魯胺、亮丙立德(leuprolide)、戈舍瑞林、ODM-201、APC-100、ODM-204。
孕酮受體拮抗劑之實例包括奧那司酮。抗血管生成劑
抗血管生成劑包括但不限於類視黃素酸及其衍生物、2-甲氧雌二醇、ANGIOSTATIN®
、ENDOSTATIN®
、瑞戈非尼(regorafenib)、尼庫拉布(necuparanib)、蘇拉明(suramin)、角鯊胺(squalamine)、金屬蛋白酶-1之組織抑制劑、金屬蛋白酶-2之組織抑制劑、纖維蛋白溶酶原活化物抑制劑-1、纖維蛋白溶酶原活化物抑制劑-2、軟骨衍生之抑制劑、太平洋紫杉醇(白蛋白結合型太平洋紫杉醇)、血小板因子4、硫酸魚精蛋白(鯡精蛋白)、硫酸鹽化幾丁質衍生物(由雪蟹殼製備)、硫酸鹽化多醣肽聚醣複合物(sp-pg)、星形孢菌素、基質代謝調節劑(包括脯胺酸類似物,諸如l-氮雜環丁烷-2-甲酸(LACA)、順羥基脯胺酸、d,I-3,4-去氫脯胺酸、硫脯胺酸)、α,α'-二吡啶基、β-胺基丙腈反丁烯二酸鹽、4-丙基-5-(4-吡啶基)-2(3h)-噁唑酮、甲胺喋呤、米托蒽醌、肝素、干擾素、2巨球蛋白-血清、金屬蛋白酶-3之雞抑制劑(ChIMP-3)、胰凝乳蛋白酶抑制劑(chymostatin)、十四硫酸β-環糊精、艾尼米欣(eponemycin)、煙黴素(fumagillin)、硫代蘋果酸金鈉、d-青黴胺、β-1-抗膠原酶-血清、α-2-抗纖維蛋白溶酶、比山群、氯苯紮利二鈉(lobenzarit disodium)、n-2-羧基苯基-4-氯胺基苯甲酸二鈉或「CCA」、沙力度胺(thalidomide)、血管生成抑制性類固醇、羧基胺基咪唑、金屬蛋白酶抑制劑(諸如BB-94)、S100A9之抑制劑(諸如他喹莫德(tasquinimod))。其他抗血管生成劑包括抗體,較佳針對以下此等血管生成生長因子之單株抗體:β-FGF、α-FGF、FGF-5、VEGF同功異型物、VEGF-C、HGF/SF及Ang-1/Ang-2。抗纖維化劑
抗纖維化劑包括但不限於諸如β-胺基丙腈(BAPN)之類化合物,以及關於離胺醯氧化酶抑制劑及其在治療與膠原蛋白異常沈積相關之疾病及病狀中之用途的US 4965288及關於抑制LOX以治療各種病理性纖維化狀態之化合物的US 4997854中所揭示之化合物,該等申請案以引用之方式併入本文中。其他例示性抑制劑描述於與諸如2-異丁基-3-氟-烯丙胺、2-異丁基-3-氯-烯丙胺或2-異丁基-3-溴-烯丙胺之化合物相關的US 4943593中;US 5021456、US 5059714、US 5120764、US 5182297、與2-(1-萘基氧基甲基)-3-氟烯丙胺相關之US 5252608中;及US 2004-0248871中,該等申請案以引用之方式併入本文中。
例示性抗纖維化劑亦包括與離胺醯氧化酶之活性位點之羰基反應的一級胺,且更尤其在結合羰基之後生成共振穩定化產物的一級胺,諸如以下一級胺:乙二胺(emylenemamine)、肼、苯肼及其衍生物;胺脲及脲衍生物;胺基腈,諸如BAPN或2-硝基乙胺;不飽和或飽和鹵胺,諸如2-溴基-乙胺、2-氯乙胺、2-三氟乙胺、3-溴丙胺及對鹵基苯甲基胺;及硒基高半胱胺酸內酯。
其他抗纖維化劑為滲透或不滲透細胞之銅螯合劑。例示性化合物包括阻斷來源於藉由離胺醯氧化酶使離胺醯殘基及羥離胺醯殘基氧化去胺之醛衍生物的間接抑制劑。實例包括硫醇胺(尤其D-青黴胺)及其類似物,諸如2-胺基-5-巰基-5-甲基己酸、D-2-胺基-3-甲基-3-((2-乙醯胺基乙基)二硫基)丁酸、對2-胺基-3-甲基-3-((2-胺基乙基)二硫基)丁酸、硫化鈉-4-((對1-二甲基-2-胺基-2-羧基乙基)二硫基)丁烷、2-乙醯胺基乙基-2-乙醯胺基乙硫醇磺酸鹽及三水合鈉-4-巰基丁烷亞磺酸鹽。免疫治療劑
免疫治療劑包括且不限於適用於治療個體之治療性抗體。治療性抗體之一些實例包括阿巴伏單抗(abagovomab)、ABP-980、阿達木單抗(adecatumumab)、阿夫妥珠單抗(afutuzumab)、阿侖單抗、阿妥莫單抗(altumomab)、阿瑪西單抗(amatuximab)、麻安莫單抗(anatumomab)、阿西莫單抗(arcitumomab)、巴維昔單抗、貝妥莫單抗(bectumomab)、貝伐珠單抗(bevacizumab)、比伐珠單抗(bivatuzumab)、布林莫單抗(blinatumomab)、貝倫妥單抗、坎妥珠單抗(cantuzumab)、卡托莫西單抗(catumaxomab)、CC49、西妥昔單抗、西他土珠單抗(citatuzumab)、西妥木單抗(cixutumumab)、昔瓦土單抗(clivatuzumab)、康納木單抗(conatumumab)、達西珠單抗(dacetuzumab)、達洛圖單抗(dalotuzumab)、達雷木單抗(daratumumab)、地莫單抗(detumomab)、迪奴圖單抗(dinutuximab)、德珠單抗(drozitumab)、杜里土單抗(duligotumab)、杜西吉土單抗(dusigitumab)、依美昔單抗(ecromeximab)、埃羅妥珠單抗(elotuzumab)、艾米貝珠單抗(emibetuzumab)、恩斯土昔單抗(ensituximab)、鄂托默單抗(ertumaxomab)、埃達珠單抗(etaracizumab)、伐吐珠單抗(farletuzumab)、費拉妥珠單抗(ficlatuzumab)、非吉單抗(figitumumab)、法蘭土單抗(flanvotumab)、浮土西單抗(futuximab)、加尼圖單抗(ganitumab)、吉妥珠單抗、吉瑞昔單抗(girentuximab)、格雷巴土木單抗(glembatumumab)、異貝莫單抗(ibritumomab)、伊戈伏單抗(igovomab)、伊姆加土珠單抗(imgatuzumab)、因達西單抗(indatuximab)、英妥珠單抗(inotuzumab)、英妥木單抗(intetumumab)、伊派利單抗(YERVOY®、MDX-010、BMS-734016及MDX-101)、伊妥木單抗(iratumumab)、拉貝珠單抗、來沙木單抗(lexatumumab)、林妥珠單抗、洛瓦土珠單抗、魯卡木單抗(lucatumumab)、馬帕木單抗、馬妥珠單抗、米拉珠單抗、明瑞莫單抗(minretumomab)、米妥莫單抗(mitumomab)、莫格利珠單抗(mogamulizumab)、莫昔土莫單抗(moxetumomab)、那莫單抗(naptumomab)、納納土單抗(narnatumab)、萊西單抗、尼妥珠單抗、諾非單抗(nofetumomab)、OBI-833、奧比珠單抗、奧卡拉珠單抗(ocaratuzumab)、奧伐木單抗(ofatumumab)、奧拉單抗(olaratumab)、奧那組單抗(onartuzumab)、奧普珠單抗(oportuzumab)、奧戈伏單抗(oregovomab)、帕尼單抗、帕薩珠單抗(parsatuzumab)、帕蘇多托克斯(pasudotox)、帕特里土單抗(patritumab)、潘妥莫單抗(pemtumomab)、帕妥珠單抗、平妥單抗(pintumomab)、普托木單抗(pritumumab)、拉克莫單抗(racotumomab)、拉德瑞單抗(radretumab)、雷莫蘆單抗(ramucirumab) (Cyramza®)、里樂木單抗(rilotumumab)、利妥昔單抗、羅妥木單抗(robatumumab)、薩馬里珠單抗(samalizumab)、沙妥莫單抗(satumomab)、西羅珠單抗(sibrotuzumab)、思圖昔單抗、索利托單抗(solitomab)、辛圖珠單抗(simtuzumab)、他卡珠單抗(tacatuzumab)、他普莫單抗(taplitumomab)、泰納莫單抗(tenatumomab)、泰普洛單抗(teprotumumab)、替加珠單抗(tigatuzumab)、托西莫單抗(tositumomab)、曲妥珠單抗、土庫珠單抗(tucotuzumab)、烏妥昔單抗(ublituximab)、維托珠單抗、沃爾希珠單抗(vorsetuzumab)、伏妥莫單抗(votumumab)、紮魯姆單抗(zalutumumab)及3F8。利妥昔單抗可用於治療惰性B細胞癌症,其包括邊緣區淋巴瘤、WM、CLL及小淋巴細胞性淋巴瘤。利妥昔單抗與化學療法劑之組合尤其有效。
例示性治療性抗體可進一步用放射性同位素粒子,諸如銦-111、釔-90 (90Y-昔瓦土單抗)或碘-131標記或與其組合。癌症基因療法及細胞療法
癌症基因療法及細胞療法包括將正常基因插入至癌細胞中以置換突變或改變基因;使突變基因沉默之基因修飾;直接殺死癌細胞之遺傳學方法;包括經設計以置換個體自身免疫系統之大部分的免疫細胞輸注,以增強對癌細胞之免疫反應,或活化個體自身免疫系統(T細胞或自然殺手細胞)以殺死癌細胞,或發現且殺死癌細胞;修改細胞活性以進一步改變針對癌症之內源性免疫反應性的遺傳學方法。基因編輯劑
基因組編輯系統之實例包括CRISPR/Cas9系統、鋅指核酸酶系統、TALEN系統、歸巢核酸內切酶系統及大範圍核酸酶系統。CAR - T 細胞療法 及 TCR - T 細胞 療法
CAR-T細胞療法包括經工程改造以表現嵌合抗原受體(CAR)之免疫效應細胞群體,其中CAR包含腫瘤抗原結合域。免疫效應細胞為T細胞或NK細胞。TCR-T細胞療法包括經工程改造以靶向腫瘤細胞表面上之腫瘤衍生肽之TCR-T細胞。細胞可為自體或同種異體的。
在一些實施例中,CAR包含抗原結合域、跨膜域及胞內信號傳導域。
在一些實施例中,胞內域包含初級信號傳導域、共刺激域或初級信號傳導域及共刺激域兩者。
在一些實施例中,初級信號傳導域包含一或多種選自由以下組成之群的蛋白質之功能信號傳導域:CD3ζ、CD3γ、CD3δ、CD3ε、共同FcRγ (FCERIG)、FcRβ (FcεRlb)、CD79a、CD79b、FcγRIIa、DAP10及DAP12。
在一些實施例中,共刺激域包含一或多種選自由以下組成之群的蛋白質之功能域:CD27、CD28、4-1BB (CD137)、OX40、CD30、CD40、PD-1、ICOS、淋巴細胞功能相關抗原-1 (LFA-I)、CD2、CD7、LIGHT、NKG2C、B7-H3、與CD83特異性結合之配位體、CDS、ICAM-1、GITR、BAFFR、HVEM (LIGHTR)、SLAMF7、NKp80 (KLRFI)、CD160、CD19、CD4、CD8α、CD8β、IL2Rβ、IL2Rγ、IL7Rα、ITGA4、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD 1 ld、ITGAE、CD103、ITGAL、CD 1 la、LFA-1、ITGAM、CD1 lb、ITGAX、CD1 lc、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、TNFR2、TRANCE/RANKL、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRTAM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、CD69、SLAMF6 (NTB-A、Ly108)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、LAT、GADS、SLP-76、PAG/Cbp、NKp44、NKp30、NKp46及NKG2D。
在一些實施例中,跨膜域包含選自由以下組成之群之蛋白質的跨膜域:T細胞受體之α、β或ζ鏈、CD28、CD3ε、CD45、CD4、CD5、CD8、CD9、CD16、CD22、CD33、CD37、CD64、CD80、CD86、CD134、CD137、CD154、KIRDS2、OX40、CD2、CD27、LFA-1 (CD1 la、CD18)、ICOS (CD278)、4-1BB (CD137)、GITR、CD40、BAFFR、HVEM (LIGHTR)、SLAMF7、NKp80 (KLRF1)、CD160、CD19、IL2Rβ、IL2Rγ、IL7R u、ITGA1、VLA1、CD49a、ITGA4、IA4、CD49D、ITGA6、VLA-6、CD49f、ITGAD、CD1 ld、ITGAE、CD103、ITGAL、CD1 la、LFA-1、ITGAM、CD1 lb、ITGAX、CD1 lc、ITGB1、CD29、ITGB2、CD18、LFA-1、ITGB7、TNFR2、DNAM1 (CD226)、SLAMF4 (CD244、2B4)、CD84、CD96 (Tactile)、CEACAM1、CRTAM、Ly9 (CD229)、CD160 (BY55)、PSGL1、CD100 (SEMA4D)、SLAMF6 (NTB-A、Ly108)、SLAM (SLAMF1、CD150、IPO-3)、BLAME (SLAMF8)、SELPLG (CD162)、LTBR、PAG/Cbp、NKp44、NKp30、NKp46、NKG2D及NKG2C。
在一些實施例中,抗原結合域結合腫瘤抗原。
在一些實施例中,腫瘤抗原選自由以下組成之群:CD19;CD123;CD22;CD30;CD171;CS-1 (亦稱為CD2亞類1、CRACC、SLAMF7、CD319及19A24);C型凝集素樣分子-1 (CLL-1或CLECLI);CD33;表皮生長因子受體變異體III (EGFRvlll);神經節苷脂G2 (GD2);神經節苷脂GD3 (aNeuSAc(2-8)aNeuSAc(2-3)bDGaip(1-4)bDGIcp(1-1)Cer);TNF受體家族成員B細胞成熟(BCMA);Tn抗原((Tn Ag)或(GaINAcu-Ser/Thr));前列腺特異性膜抗原(PSMA);受體酪胺酸激酶樣孤兒受體1 (RORI);Fms樣酪胺酸激酶3 (FLT3);腫瘤相關醣蛋白72 (TAG72);CD38;CD44v6;癌胚抗原(CEA);上皮細胞黏附分子(EPCAM);B7H3 (CD276);KIT (CD117);介白素-13受體次單元α-2 (IL-13Ra2或CD213A2);間皮素;介白素11受體α (IL-11Ra);前列腺幹細胞抗原(PSCA);蛋白酶絲胺酸21 (睪蛋白或PRSS21);血管內皮生長因子受體2 (VEGFR2);路易斯(Lewis) (Y)抗原;CD24;血小板衍生生長因子受體β (PDGFR-β);階段特異性胚胎抗原-4 (SSEA-4);CD20;δ樣3 (DLL3);葉酸受體α;受體酪胺酸蛋白激酶,ERBB2 (Her2/neu);黏蛋白1,細胞表面相關(MUC1);表皮生長因子受體(EGFR);神經細胞黏附分子(NCAM);前列腺酶;前列腺酸磷酸酶(PAP);突變型延長因子2 (ELF2M);肝配蛋白B2;纖維母細胞活化蛋白α (FAP);胰島素樣生長因子1受體(IGF-I受體),碳酸酐酶IX (CAIX);蛋白酶體(前體,巨蛋白因子)次單元,β型,9 (LMP2);醣蛋白100 (gp100);由斷點簇區(BCR)及阿貝爾森鼠類白血病病毒致癌基因同源物1 (Abl)組成之致癌基因融合蛋白(bcr-abl);酪胺酸酶;肝配蛋白A型受體2 (EphA2);海藻糖基GM1;唾液酸基路易斯黏附分子(sLe);神經節苷脂GM3 (aNeuSAc(2-3)bDGalp(1-4)bDGlcp(1-1)Cer);轉麩醯胺酸酶5 (TGS5);高分子量黑素瘤相關抗原(HMWMAA);o-乙醯基-GD2神經節苷脂(OAcGD2);葉酸受體β;腫瘤內皮細胞標記物1 (TEM1/CD248);腫瘤內皮細胞標記物7相關(TEM7R);前列腺六跨膜上皮抗原I (STEAP1);緊密連接蛋白6 (CLDN6);促甲狀腺激素受體(TSHR);G蛋白偶合受體類別C第5組,成員D (GPRCSD);X染色體開讀框61 (CXORF61);CD97;CD179a;多形性淋巴瘤激酶(ALK);聚唾液酸;胎盤特異性1 (PLAC1);globoH醣基神經醯胺六醣部分(GloboH);乳腺分化抗原(NY-BR-1);尿溶蛋白2 (UPK2);A型肝炎病毒細胞受體1 (HAVCR1);腎上腺素受體β3 (ADRB3);泛連接蛋白3 (PANX3);G蛋白偶合受體20 (GPR20);淋巴細胞抗原6複合物,基因座K 9 (LY6K);嗅覺受體51E2 (ORS IE2);TCRγ替代讀框蛋白(TARP);威爾姆斯氏腫瘤蛋白(WT1);癌症/睪丸抗原1 (NY-ESO-1);癌症/睪丸抗原2 (LAGE-la);黑素瘤相關抗原1 (MAGE-A1);定位於染色體12p上之ETS移位變異體基因6 (ETV6-AML);精子蛋白17 (SPA17);X抗原家族成員1A (XAGE1);血管生成素結合細胞表面受體2 (Tie 2);黑素瘤癌症睪丸抗原-1 (MADCT-1);黑素瘤癌症睪丸抗原-2 (MAD-CT-2);Fos相關抗原1;腫瘤蛋白p53 (p53);p53突變體;前列腺蛋白;存活素;端粒酶;前列腺癌腫瘤抗原-1 (PCTA-1或半乳糖凝集素8),由T細胞識別之黑素瘤抗原1 (MelanA或MARTI);大鼠肉瘤(Ras)突變體;人類端粒酶逆轉錄酶(hTERT);肉瘤移位斷點;黑素瘤細胞凋亡抑制劑(ML-IAP);ERG (跨膜蛋白酶,絲胺酸2 (TMPRSS2) ETS融合基因);N-乙醯基葡糖胺基-轉移酶V (NA17);成對盒蛋白Pax-3 (PAX3);雄激素受體;細胞週期素B1;v-myc禽類髓細胞瘤病病毒致癌基因神經母細胞瘤衍生同源物(MYCN);Ras同源物家族成員C (RhoC);酪胺酸酶相關蛋白質2 (TRP-2);細胞色素P450 1B1(CYP IBI);CCCTC結合因子(鋅指蛋白)樣(BORIS或壓印位點調節子兄弟蛋白),由T細胞識別之鱗狀細胞癌抗原3 (SART3);成對盒蛋白Pax-5 (PAX5);前頂體素結合蛋白sp32 (OY-TES I);淋巴細胞特異性蛋白酪胺酸激酶(LCK);激酶錨蛋白4 (AKAP-4);滑膜肉瘤,X斷點2 (SSX2);晚期醣化最終產物受體(RAGE-I);腎普遍存在蛋白1 (RUI);腎普遍存在蛋白2 (RU2);豆莢蛋白;人類乳頭狀瘤病毒E6 (HPV E6);人類乳頭狀瘤病毒E7 (HPV E7);腸羧基酯酶;突變型熱休克蛋白70-2 (mut hsp70-2);CD79a;CD79b;CD72;白細胞相關免疫球蛋白樣受體1 (LAIRI);IgA Fc片段受體(FCAR或CD89);白細胞免疫球蛋白樣受體子族A成員2 (LILRA2);CD300分子樣家族成員f (CD300LF);C型凝集素域家族12成員A (CLEC12A);骨髓基質細胞抗原2 (BST2);含EGF樣模組黏蛋白樣激素受體樣2 (EMR2);淋巴細胞抗原75 (LY75);磷脂肌醇蛋白聚醣-3 (GPC3);Fc受體樣5 (FCRL5);及免疫球蛋白λ樣多肽1 (IGLL1)。
在一些實施例中,腫瘤抗原選自CD150、5T4、ActRIIA、B7、BMCA、CA-125、CCNA1、CD123、CD126、CD138、CD14、CD148、CD15、CD19、CD20、CD200、CD21、CD22、CD23、CD24、CD25、CD26、CD261、CD262、CD30、CD33、CD362、CD37、CD38、CD4、CD40、CD40L、CD44、CD46、CD5、CD52、CD53、CD54、CD56、CD66a-d、CD74、CD8、CD80、CD92、CE7、CS-1、CSPG4、ED-B纖維結合蛋白、EGFR、EGFRvIII、EGP-2、EGP-4、EPHa2、ErbB2、ErbB3、ErbB4、FBP、GD2、GD3、HER1-HER2組合、HER2-HER3組合、HERV-K、HIV-1包膜醣蛋白gp120、HIV-1包膜醣蛋白gp41、HLA-DR、HM1.24、HMW-MAA、Her2、Her2/neu、IGF-1R、IL-11Rα、IL-13R-α2、IL-2、IL-22R-α、IL-6、IL-6R、Ia、Ii、L1-CAM、L1細胞黏附分子、路易斯Y、Ll-CAM、MAGE A3、MAGE-A1、MART-1、MUC1、NKG2C配位體、NKG2D配位體、NYESO-1、OEPHa2、PIGF、PSCA、PSMA、ROR1、T101、TAC、TAG72、TIM-3、TRAIL-R1、TRAIL-Rl (DR4)、TRAIL-R2 (DR5)、VEGF、VEGFR2、WT-I、G蛋白偶合受體、α胎蛋白(AFP)、血管生成因子、外源性同源結合分子(ExoCBM)、致癌基因產物、抗葉酸受體、c-Met、癌胚抗原(CEA)、細胞週期素(D1)、肝配蛋白B2、上皮腫瘤抗原、雌激素受體、胚胎乙醯膽鹼e受體、葉酸結合蛋白、gp100、B型肝炎表面抗原、κ鏈、κ輕鏈、kdr、λ鏈、活素(livin)、黑素瘤相關抗原、間皮素、小鼠雙微小2同源物(MDM2)、黏蛋白16 (MUC16)、突變型p53、突變型ras、壞死抗原、癌胚抗原、ROR2、孕酮受體、前列腺特異性抗原、tEGFR、肌腱蛋白、P2-微球蛋白、Fc受體樣5 (FcRL5)。
細胞療法之非限制性實例包括艾普塞爾-L (Algenpantucel-L)、西普亮塞-T (Sipuleucel-T)、(BPX-501)瑞沃賽爾(rivogenlecleucel) US9089520、WO2016100236、AU-105、ACTR-087、活化之同種異體自然殺手細胞CNDO-109-AANK、MG-4101、AU-101、BPX-601、FATE-NK100、LFU-835造血幹細胞、艾米亮塞-T (Imilecleucel-T)、巴塔賽爾-T (baltaleucel-T)、PNK-007、UCARTCS1、ET-1504、ET-1501、ET-1502、ET-190、CD19-ARTEMIS、ProHema、經FT-1050處理之骨髓幹細胞療法、CD4CARNK-92細胞、CryoStim、AlloStim、慢病毒轉導之huCART-meso細胞、CART-22細胞、EGFRt/19-28z/4-1BBL CAR T細胞、自體4H11-28z/fIL-12/EFGRt T細胞、CCR5-SBC-728-HSPC、CAR4-1BBZ、CH-296、dnTGFbRII-NY-ESOc259T、Ad-RTS-IL-12、IMA-101、IMA-201、CARMA-0508、TT-18、CMD-501、CMD-503、CMD-504、CMD-502、CMD-601、CMD-602、CSG-005。
在一些實施例中,腫瘤靶向抗原包括:α-胎蛋白,諸如ET-1402及AFP-TCR;炭疽毒素受體1,諸如抗TEM8 CAR T細胞療法;B細胞成熟抗原(BCMA),諸如bb-2121、UCART-BCMA、ET-140、KITE-585、MCM-998、LCAR-B38M、CART-BCMA、SEA-BCMA、BB212、UCART-BCMA、ET-140、P-BCMA-101、AUTO-2 (APRIL-CAR);抗CLL-1抗體,諸如KITE-796;B7同源物6,諸如CAR-NKp30及CAR-B7H6;B淋巴細胞抗原CD19,諸如TBI-1501、CTL-119 huCART-19 T細胞、JCAR-015 US7446190、JCAR-014、JCAR-017、WO2016196388、WO2016033570、WO2015157386)、西卡思羅(axicabtagene ciloleucel) (KTE-C19)、US7741465、US6319494、UCART-19、EBV-CTL、T替沙津魯-T (T tisagenlecleucel-T) (CTL019)、WO2012079000、WO2017049166、表現CD19CAR-CD28-CD3ζ-EGFRt之T細胞、CD19/4-1BBL鎧裝CAR T細胞療法、C-CAR-011、CIK-CAR.CD19、CD19CAR-28-ζ T細胞、PCAR-019、MatchCART、DSCAR-01、IM19 CAR-T;B淋巴細胞抗原CD20,諸如ATTCK-20;B淋巴細胞細胞黏附物,諸如UCART-22、JCAR-018 WO2016090190;NY-ESO-1,諸如GSK-3377794、TBI-1301;碳酸酐酶,諸如DC-Ad-GMCAIX;凋亡蛋白酶9自殺基因,諸如CaspaCIDe DLI、BPX-501;CCR5,諸如SB-728;CDw123,諸如MB-102、UCART-123;CD20m,諸如CBM-C20.1;CD4,諸如ICG-122;CD30,諸如CART30 (CBM-C30.1;CD33,諸如CIK-CAR.CD33;CD38,諸如T-007、UCART-38;CD40配位體,諸如BPX-201;CEACAM蛋白4調節劑,諸如MG7-CART;緊密連接蛋白6,諸如CSG-002;靶向EBV,諸如CMD-003;EGFR,諸如自體4H11-28z/fIL-12/EFGRt T細胞;核酸內切酶,諸如PGN-514、PGN-201;埃-巴二氏病毒(Epstein-Barr virus)特異性T淋巴細胞,諸如TT-10;Erbb2,諸如CST-102、CIDeCAR;神經節苷脂(GD2),諸如4SCAR-GD2;麩胺酸羧肽酶II,諸如CIK-CAR.PSMA、CART-PSMA-TGFßRDN、P-PSMA-101;磷脂醯肌醇蛋白聚醣-3 (GPC3),諸如TT-16、GLYCAR;血紅素,諸如PGN-236;肝細胞生長因子受體,諸如抗cMet RNA CAR T;人類乳頭狀瘤病毒E7蛋白,諸如KITE-439;免疫球蛋白γ Fc受體III,諸如ACTR087;IL-12,諸如DC-RTS-IL-12;IL-12促效劑/黏蛋白16,諸如JCAR-020;IL-13 α 2,諸如MB-101;IL-2,諸如CST-101;K-Ras GTPase,諸如抗KRAS G12V mTCR細胞療法;神經細胞黏附分子L1 L1CAM (CD171),諸如JCAR-023;潛伏性膜蛋白1/潛伏性膜蛋白2,諸如Ad5f35-LMPd1-2轉導之自體樹突狀細胞;黑素瘤相關抗原10,諸如MAGE-A10C796T MAGE-A10 TCR;黑素瘤相關抗原3/黑素瘤相關抗原6 (MAGE A3/A6),諸如KITE-718;間皮素,諸如CSG-MESO、TC-210;NKG2D,諸如NKR-2;Ntrkr1酪胺酸激酶受體,諸如JCAR-024;T細胞受體,諸如BPX-701、IMCgp100;T淋巴細胞,諸如TT-12;腫瘤浸潤性淋巴細胞,諸如LN-144、LN-145;及威爾姆斯氏腫瘤蛋白,諸如JTCR-016、WT1-CTL。淋巴瘤或白血病組合療法
在一些實施例中,額外治療劑適用於治療淋巴瘤或白血病。此等藥劑包括阿地介白素、阿昔迪布、三水合阿米福汀(amifostine trihydrate)、胺基喜樹鹼(aminocamptothecin)、抗新普拉通(antineoplaston) A10、抗新普拉通AS2-1、抗胸腺細胞球蛋白、三氧化二砷、Bcl-2家族蛋白抑制劑ABT-263、β阿立辛(beta alethine)、BMS-345541、硼替佐米(bortezomib) (VELCADE®
)、硼替佐米(VELCADE®
,PS-341)、苔蘚抑素1、布舒凡(bulsulfan)、坎帕斯(campath)-1H、卡鉑、卡非佐米(Kyprolis®)、卡莫司汀、乙酸卡泊芬淨(caspofungin acetate)、CC-5103、苯丁酸氮芥、CHOP (環磷醯胺、小紅莓、長春新鹼及潑尼松)、順鉑、克拉屈濱、氯法拉濱、薑黃素、CVP (環磷醯胺、長春新鹼及潑尼松)、環磷醯胺、環孢靈(cyclosporine)、阿糖胞苷、地尼介白素迪夫托斯(denileukin diftitox)、地塞米松、多西他賽、海兔毒素10、小紅莓、鹽酸小紅莓、DT-PACE (地塞米松、沙力度胺、順鉑、小紅莓、環磷醯胺及依託泊苷)、恩紮妥林(enzastaurin)、阿法依泊汀(epoetin alfa)、依託泊苷、依維莫司(everolimus)(RAD001)、FCM (氟達拉濱、環磷醯胺及米托蒽醌)、FCR (氟達拉濱、環磷醯胺及利妥昔單抗)、非瑞替尼(fenretinide)、非格司亭(filgrastim)、夫拉平度、氟達拉濱、FR (氟達拉濱及利妥昔單抗)、格爾德黴素(geldanamycin) (17-AAG)、hyperCVAD (超分割環磷醯胺、長春新鹼、小紅莓、地塞米松、甲胺喋呤及阿糖胞苷)、ICE (異環磷醯胺、卡鉑及依託泊苷)、異環磷醯胺、鹽酸伊立替康、干擾素α-2b、伊沙匹隆、來那度胺(REVLIMID®
,CC-5013)、淋巴介質活化之殺手細胞、MCP (米托蒽醌、苯丁酸氮芥及潑尼龍)、美法侖、美司鈉(mesna)、甲胺喋呤、鹽酸米托蒽醌、莫特沙芬釓(motexafin gadolinium)、黴酚酸嗎啉乙酯(mycophenolate mofetil)、奈拉濱(nelarabine)、奧巴克拉(obatoclax) (GX15-070)、奧利默森(oblimersen)、乙酸奧曲肽(octreotide acetate)、Ω-3脂肪酸、Omr-IgG-am (WNIG,Omrix)、奧沙利鉑、太平洋紫杉醇、帕泊昔布(PD0332991)、派非格司亭(pegfilgrastim)、聚乙二醇化脂質體鹽酸小紅莓、派瑞弗辛(perifosin)、潑尼龍、潑尼松、重組型flt3配位體、重組型人類血小板生成素、重組型干擾素α、重組型介白素-11、重組型介白素-12、利妥昔單抗、R-CHOP (利妥昔單抗及CHOP)、R-CVP (利妥昔單抗及CVP)、R-FCM (利妥昔單抗及FCM)、R-ICE (利妥昔單抗及ICE)及R-MCP (利妥昔單抗及MCP)、R-羅斯維汀(R-roscovitine) (塞利希布(seliciclib)、CYC202)、沙格司亭(sargramostim)、檸檬酸西地那非(sildenafil citrate)、辛伐他汀(simvastatin)、西羅莫司、苯乙烯基碸、他克莫司、坦螺旋黴素(tanespimycin)、坦羅莫司(temsirolimus)(CCl-779)、沙力度胺、治療性同種異體淋巴細胞、噻替派、替吡法尼(tipifarnib)、長春新鹼、硫酸長春新鹼、酒石酸氫長春瑞賓、SAHA (辛二醯苯胺異羥肟酸,或辛二醯基、苯胺及氧肟酸)、維羅非尼(Zelboraf®)、維奈托克(ABT-199)。
一種改良方法為放射免疫療法,其中單株抗體與放射性同位素粒子,諸如銦-111、釔-90及碘-131組合。組合療法之實例包括但不限於碘-131托西莫單抗(BEXXAR®
)、釔-90替伊莫單抗(ibritumomab tiuxetan) (ZEVALIN®
)以及BEXXAR®
及CHOP。
上文所提及之療法可補充有幹細胞移植或治療或與其組合。治療性程序包括周邊血液幹細胞移植、自體造血幹細胞移植、自體骨髓移植、抗體療法、生物療法、酶抑制劑療法、全身照射、幹細胞輸注、在幹細胞支持下之骨髓消融、經活體外處理之周邊血液幹細胞移植、臍帶血移植、免疫酶技術、低LET鈷-60 γ射線療法、博萊黴素、習知手術、輻射療法及非清髓性同種異體造血幹細胞移植。非霍奇金氏淋巴瘤 ( Non - Hodgkin ' s Lymphoma ) 組合療法
在一些實施例中,額外治療劑適用於治療非霍奇金氏淋巴瘤(NHL),尤其B細胞起源之非霍奇金氏淋巴瘤,該等治療劑包括單株抗體、標準化學療法方法(例如CHOP、CVP、FCM、MCP及其類似物)、放射免疫療法及其組合,尤其抗體療法與化學療法之整合。
用於治療NHL/B細胞癌症的非綴合的單株抗體之實例包括利妥昔單抗、阿侖單抗、人類或人類化抗CD20抗體、盧米西單抗(lumiliximab)、抗TNF相關細胞凋亡誘導配位體(抗TRAIL)、貝伐珠單抗、加利昔單抗、依帕珠單抗、SGN-40及抗CD74。
用於NHL/B細胞癌症之治療的實驗抗體藥劑之實例包括奧伐木單抗、ha20、PRO131921、阿侖單抗、加利昔單抗、SGN-40、CHIR-12.12、依帕珠單抗、盧米西單抗、阿泊珠單抗、米拉珠單抗及貝伐珠單抗。
用於NHL/B細胞癌症之化學療法的標準方案之實例包括CHOP、FCM、CVP、MCP、R-CHOP、R-FCM、R-CVP及R-MCP。
用於NHL/B細胞癌症之放射免疫療法之實例包括釔-90替伊莫單抗(ZEVALIN®
)及碘-131托西莫單抗(BEXXAR®
)。套細胞淋巴瘤組合療法
在一些實施例中,額外治療劑適用於治療套細胞淋巴瘤(MCL),其包括組合化學療法,諸如CHOP、hyperCVAD及FCM。此等方案亦可補充有單株抗體利妥昔單抗以形成組合療法R-CHOP、hyperCVAD-R及R-FCM。上文所提及之療法中之任一者可與幹細胞移植或ICE組合以治療MCL。
適用於治療MCL之治療劑之其他實例包括:
- 免疫療法,諸如單株抗體(如利妥昔單抗)及癌症疫苗,諸如GTOP-99,其係基於個別個體之腫瘤之基因組成;
- 放射免疫療法,其中單株抗體與放射性同位素粒子組合,諸如碘-131托西莫單抗(BEXXAR®
)、釔-90替伊莫單抗(ZEVALIN®
)及BEXXAR®
依序與CHOP一起用於治療;
- 與高劑量化學療法偶合之自體幹細胞移植,投與蛋白酶體抑制劑,諸如硼替佐米(VELCADE®
或PS-341),或投與抗血管生成劑,諸如沙力度胺,尤其與利妥昔單抗組合;
- 引起Bcl-2蛋白分解且提高癌細胞對化學療法之敏感性之藥物,諸如奧利默森,與其他化學治療劑組合;
- mTOR抑制劑,其可引起細胞生長之抑制及甚至細胞死亡。非限制性實例為西羅莫司、坦羅莫司(TORISEL®
,CCI-779)、CC-115、CC-223、SF-1126、PQR-309 (必米昔布(bimiralisib))、沃塔昔布(voxtalisib)、GSK-2126458以及坦羅莫司與RITUXAN®
、VELCADE®
或其他化學治療劑組合;
- 其他藥劑,諸如夫拉平度、帕泊昔布(PD0332991)、R-羅斯維汀(塞利希布,CYC202)、苯乙烯基碸、奧巴克拉(GX15-070)、TRAIL、抗TRAIL死亡受體DR4及DR5抗體、坦羅莫司(TORISEL®
,CCl-779)、依維莫司(RAD001)、BMS-345541、薑黃素、SAHA、沙力度胺、來那度胺(REVLIMID®
,CC-5013)及格爾德黴素(17-AAG)。瓦爾登斯特倫氏巨球蛋白血症 ( Waldenstrom ' s Macroglobulinemia ) 組合療法
在一些實施例中,額外治療劑適用於治療瓦爾登斯特倫氏巨球蛋白血症(WM),其包括阿地介白素、阿侖單抗、阿昔迪布、三水合阿米福汀、胺基喜樹鹼、抗新普拉通A10、抗新普拉通AS2-1、抗胸腺細胞球蛋白、三氧化二砷、自體人類腫瘤衍生之HSPPC-96、Bcl-2家族蛋白抑制劑ABT-263、β阿立辛、硼替佐米(VELCADE®
)、苔蘚抑素1、白消安、坎帕斯-1H、卡鉑、卡莫司汀、乙酸卡泊芬淨、CC-5103、順鉑、氯法拉濱、環磷醯胺、環孢靈、阿糖胞苷、地尼介白素迪夫托斯、地塞米松、多西他賽、海兔毒素10、鹽酸小紅莓、DT-PACE、恩紮妥林、阿法依泊汀、依帕珠單抗(hLL2-抗CD22人類化抗體)、依託泊苷、依維莫司、非瑞替尼、非格司亭、氟達拉濱、異環磷醯胺、銦-111單株抗體MN-14、碘-131托西莫單抗、鹽酸伊立替康、伊沙匹隆、淋巴激素活化之殺手細胞、美法侖、美司鈉、甲胺喋呤、鹽酸米托蒽醌、單株抗體CD19 (諸如替沙津魯-T、CART-19、CTL-019)、單株抗體CD20、莫特沙芬釓、黴酚酸嗎啉乙酯、奈拉濱、奧利默森、乙酸奧曲肽、ω-3脂肪酸、奧沙利鉑、太平洋紫杉醇、派非格司亭、聚乙二醇化脂質體鹽酸小紅莓、噴司他汀、哌立福新、潑尼松、重組型flt3配位體、重組型人類血小板生成素、重組型干擾素α、重組型介白素-11、重組型介白素-12、利妥昔單抗、沙格司亭、檸檬酸西地那非(VIAGRA®
)、辛伐他汀、西羅莫司、他克莫司、坦螺旋黴素、沙力度胺、治療性同種異體淋巴細胞、噻替派、替吡法尼、托西莫單抗、維托珠單抗、硫酸長春新鹼、酒石酸氫長春瑞賓、伏立諾他、WT1 126-134肽疫苗、WT-1類似物肽疫苗、釔-90替伊莫單抗、釔-90人類化依帕珠單抗及其任何組合。
用於治療WM之治療性程序之其他實例包括周邊血液幹細胞移植、自體造血幹細胞移植、自體骨髓移植、抗體療法、生物療法、酶抑制劑療法、全身照射、幹細胞輸注、在幹細胞支持下之骨髓消融、經活體外處理之周邊血液幹細胞移植、臍帶血移植、免疫酶技術、低LET鈷-60 γ射線療法、博萊黴素、習知手術、輻射療法及非清髓性同種異體造血幹細胞移植。彌漫性大 B 細胞淋巴瘤組合療法
在一些實施例中,額外治療劑適用於治療彌漫性大B細胞淋巴瘤(DLBCL),其包括環磷醯胺、小紅莓、長春新鹼、潑尼松、抗CD20單株抗體、依託泊苷、博萊黴素、關於WM所列出之許多藥劑及其任何組合,諸如ICE及R-ICE。慢性淋巴細胞性白血病組合療法
在一些實施例中,額外治療劑適用於治療慢性淋巴細胞性白血病(CLL),其包括苯丁酸氮芥、環磷醯胺、氟達拉濱、噴司他汀、克拉屈濱、小紅莓、長春新鹼、潑尼松、潑尼龍、阿侖單抗、關於WM所列出之許多藥劑以及組合化學療法及化學免疫療法,包括以下常用組合方案:CVP、R-CVP、ICE、R-ICE、FCR及FR。骨髓纖維化組合療法
在一些實施例中,額外治療劑適合於治療骨髓纖維化,其包括刺蝟抑制劑、組蛋白去乙醯基酶(HDAC)抑制劑及酪胺酸激酶抑制劑。刺蝟抑制劑之非限制性實例為薩瑞德吉及維莫德吉。
HDAC抑制劑之實例包括但不限於普拉諾他及帕比諾他。
酪胺酸激酶抑制劑之非限制性實例為來他替尼、伯舒替尼、伊馬替尼、吉列替尼、拉多替尼及卡博替尼。過度增殖性疾病組合療法
在一些實施例中,額外治療劑適用於治療過度增殖性疾病,其包括吉西他濱、白蛋白結合型太平洋紫杉醇及吉西他濱/白蛋白結合型太平洋紫杉醇與JAK抑制劑及/或PI3Kδ抑制劑。膀胱癌組合療法
在一些實施例中,額外治療劑適合於治療膀胱癌,其包括阿特珠單抗、卡鉑、順鉑、多西他賽、小紅莓、氟尿嘧啶(5-FU)、吉西他濱、伊多米德(idosfamide)、干擾素α-2b、甲胺喋呤、絲裂黴素、白蛋白結合型太平洋紫杉醇、太平洋紫杉醇、培美曲塞、噻替派、長春鹼及其任何組合。乳癌組合療法
在一些實施例中,額外治療劑適合於治療乳癌,其包括白蛋白結合型太平洋紫杉醇、阿那曲唑、卡培他濱、卡鉑、順鉑、環磷醯胺、多西他賽、小紅莓、表阿黴素、依維莫司、依西美坦、氟尿嘧啶、氟維司群、吉西他濱、伊沙匹隆、拉帕替尼、來曲唑、甲胺喋呤、米托蒽醌、太平洋紫杉醇、聚乙二醇化脂質體小紅莓、帕妥珠單抗、他莫昔芬、托瑞米芬、曲妥珠單抗、長春瑞賓及其任何組合。三陰性乳癌組合療法
在一些實施例中,額外治療劑適用於治療三陰性乳癌,其包括環磷醯胺、多西他賽、小紅莓、表柔比星、氟尿嘧啶、太平洋紫杉醇及其組合。結腸直腸癌組合療法
在一些實施例中,額外治療劑適用於治療結腸直腸癌,其包括貝伐珠單抗、卡培他濱、西妥昔單抗、氟尿嘧啶、伊立替康、甲醯四氫葉酸、奧沙利鉑、帕尼單抗、ziv-阿柏西普及其任何組合。去勢抵抗性前列腺癌組合療法
在一些實施例中,額外治療劑適用於治療去勢抵抗性前列腺癌,其包括阿比特龍、卡巴他賽、多西他賽、恩雜魯胺、潑尼松、西普亮塞-T及其任何組合。食道及食道胃接合處癌症組合療法
在一些實施例中,額外治療劑適用於治療食道及食道胃接合處癌症,其包括卡培他濱、卡鉑、順鉑、多西他賽、表柔比星、氟嘧啶、氟尿嘧啶、伊立替康、甲醯四氫葉酸、奧沙利鉑、太平洋紫杉醇、雷莫蘆單抗、曲妥珠單抗及其任何組合。胃癌組合療法
在一些實施例中,額外治療劑適用於治療胃癌,其包括卡培他濱、卡鉑、順鉑、多西他賽、表柔比星、氟嘧啶、氟尿嘧啶、伊立替康、甲醯四氫葉酸、絲裂黴素、奧沙利鉑、太平洋紫杉醇、雷莫蘆單抗、曲妥珠單抗及其任何組合。頭頸癌組合療法
在一些實施例中,額外治療劑適用於治療頭頸癌,其包括阿法替尼、博萊黴素、卡培他濱、卡鉑、西妥昔單抗、順鉑、多西他賽、氟尿嘧啶、吉西他濱、羥基脲、甲胺喋呤、納武單抗、太平洋紫杉醇、派立珠單抗、長春瑞賓及其任何組合。肝膽癌組合療法
在一些實施例中,額外治療劑適用於治療肝膽癌,其包括卡培他濱、順鉑、氟嘧啶、5-氟尿嘧啶、吉米他賓(gemecitabine)、奧沙利鉑、索拉非尼及其任何組合。肝細胞癌組合療法
在一些實施例中,額外治療劑適用於治療肝細胞癌,其包括卡培他濱、小紅莓、吉西他濱、索拉非尼及其任何組合。非小細胞肺癌組合療法
在一些實施例中,額外治療劑適用於治療非小細胞肺癌(NSCLC),其包括阿法替尼、白蛋白結合型太平洋紫杉醇、艾樂替尼、貝伐珠單抗、貝伐珠單抗、卡博替尼、卡鉑、順鉑、克卓替尼、達拉非尼、多西他賽、埃羅替尼、依託泊苷、吉西他濱、納武單抗、太平洋紫杉醇、派立珠單抗、培美曲塞、雷莫蘆單抗、曲美替尼、曲妥珠單抗、凡德他尼、維羅非尼、長春鹼、長春瑞賓及其任何組合。小細胞肺癌組合療法
在一些實施例中,額外治療劑適用於治療小細胞肺癌(SCLC),其包括本達斯米(bendamustime)、卡鉑、順鉑、環磷醯胺、多西他賽、小紅莓、依託泊苷、吉西他濱、伊皮利單抗(ipillimumab)、伊立替康、納武單抗、太平洋紫杉醇、替莫唑胺、拓朴替康、長春新鹼、長春瑞賓及其任何組合。黑素瘤組合療法
在一些實施例中,額外治療劑適用於治療黑素瘤,其包括白蛋白結合型太平洋紫杉醇、卡鉑、順鉑、克比替尼(cobiemtinib)、達拉非尼、達拉巴嗪(dacrabazine)、IL-2、伊馬替尼、干擾素α-2b、伊派利單抗、亞硝基脲、納武單抗、太平洋紫杉醇、派立珠單抗、皮利木單抗(pilimumab)、替莫唑胺、曲美替尼、維羅非尼、長春鹼及其任何組合。卵巢癌組合療法
在一些實施例中,額外治療劑適用於治療卵巢癌,其包括5-氟尿嘧啶、白蛋白結合型太平洋紫杉醇、六甲蜜胺、阿那曲唑、貝伐珠單抗、卡培他濱、卡鉑、順鉑、環磷醯胺、多西他賽、小紅莓、依託泊苷、依西美坦、吉西巴賓(gemcibabine)、異環磷醯胺、伊立替康、來曲唑、乙酸亮丙立德、脂質體小紅莓、乙酸甲地孕酮、美法侖、奧拉帕尼、奧沙利鉑、太平洋紫杉醇、帕佐泮尼、培美曲塞、他莫昔芬、拓朴替康、長春瑞賓及其任何組合。胰臟癌組合療法
在一些實施例中,額外治療劑適用於治療胰臟癌,其包括5-氟尿嘧啶、白蛋白結合型太平洋紫杉醇、卡培他濱、順鉑、多西他賽、埃羅替尼、氟嘧啶、吉西他濱、伊立替康、甲醯四氫葉酸、奧沙利鉑、太平洋紫杉醇及其任何組合。腎細胞癌組合療法
在一些實施例中,額外治療劑適用於治療腎細胞癌,其包括阿西替尼、貝伐珠單抗、卡博替尼、埃羅替尼、依維莫司、樂瓦替尼(levantinib)、納武單抗、帕佐泮尼、索拉非尼、舒尼替尼、坦羅莫司及其任何組合。VII . 套組
本發明提供一種套組,其包含本發明化合物或其醫藥學上可接受之鹽。該套組可進一步包含例如用於治療病毒感染之使用說明書。使用說明書一般為書面說明書,但含有說明書之電子儲存媒體(例如,磁碟或光碟)亦為可接受的。
本發明亦提供一種醫藥套組,其包含有包含本發明化合物或其醫藥學上可接受之鹽的一或多個容器。與此類容器視情況相關聯的可為由管理醫藥產物之製造、使用或銷售之政府機構所規定形式的注意事項,該注意事項反映由用於人類投與之製造、使用或銷售機構的批准。各種組分(若存在超過一種組分)可封裝於獨立容器中,或在交叉反應性及存放期允許的情況下,可以將一些組分合併於一個容器中。套組可呈單位劑型、散裝封裝(例如,多劑量封裝)或次單位劑量。套組亦可包括多個單位劑量之化合物及使用說明書,且以足以供藥房(例如,醫院藥房及混配藥房)儲存及使用之量封裝。
亦提供製品,其包含單位劑量之本發明化合物或其醫藥學上可接受之鹽,以適合封裝用於本文所描述之方法。適合封裝為此項技術中已知,且包括例如小瓶、容器、安瓿、瓶子、罐、可撓性封裝及其類似物。製品可進一步經滅菌及/或密封。 IX . 實例
實施例亦關於適用於製備目標化合物或其醫藥學上可接受之鹽的方法及中間物。
提供適用於合成所揭示之化合物的通常已知之化學合成流程及條件的許多一般參考文獻為可用的(參見例如Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 第7版, Wiley-Interscience, 2013)。
如本文所描述之化合物可藉由此項技術中已知之任何方法純化,包括層析法,諸如高效液相層析(HPLC)、製備型薄層層析、急驟管柱層析及離子交換層析。可使用任何適合之固定相,包括正相及逆相以及離子樹脂。所揭示之化合物最通常經由矽膠及/或氧化鋁層析法來純化。參見例如Introduction to Modern Liquid Chromatography, 第2版, L. R. Snyder及J. J. Kirkland編, John Wiley and Sons, 1979;及Thin Layer Chromatography, E. Stahl (編), Springer-Verlag, New York, 1969。
化合物係使用標準儀器法表徵。除非另外說明,否則1
H、19
F及31
P NMR譜在Bruker AvanceTM III HD 400 MHz NMR上獲得。在Waters Q-Tof Micro上獲得電灑離子化法(ESI)模式下之質譜。
在用於製備目標化合物之任何製程期間,可能必要及/或需要保護所涉及之任何分子上的敏感性或反應性基團。此可藉助於習知保護基達成,如描述於標準著作中,諸如T. W. Greene及P. G. M. Wuts, 「Protective Groups in Organic Synthesis」, 第4版, Wiley, New York 2006。可在適宜後續階段使用此項技術已知之方法移除保護基。
適用於實施例之方法的例示性化學實體現將參考說明性合成流程關於本文中其通用製備及隨後具體實例來描述。業內人士應認識到,為獲得本文之各種化合物,起始物質可經適當選擇,以使得按需要在存在或不存在保護措施下經由反應流程帶有最終所需取代基,得到所需產物。可替代地,可能需要或希望在最終所需取代基之位置利用可經由反應流程攜帶且適當時經所需取代基置換的適合基團。此外,熟習此項技術者應認識到,以下流程中所展示之轉化可按與特定側基之官能性相容之任何次序執行。一般流程中所描繪之各反應較佳在約0℃至所用有機溶劑之回流溫度的溫度下運作。
本文所提供之實例描述本文所揭示之化合物的合成以及用於製備該等化合物之中間物。應理解,可組合本文所描述之個別步驟。亦應理解,獨立批次之化合物可組合且隨後繼續用於下一合成步驟中。
在以下實例描述中,描述具體實施例。足夠詳細地描述此等實施例以使熟習此項技術者能夠實踐本發明之某些實施例。可利用其他實施例,且可在不脫離本發明之範疇的情況下作出邏輯及其他改變。因此,以下描述並不意欲限制本發明之範疇。
本發明之方法一般提供特定對映異構體或非對映異構體作為所需產物,但在所有情況下均未確定對映異構體或非對映異構體之立體化學。當未確定對映異構體或非對映異構體中特定立體中心之立體化學時,在不展示彼特定立體中心處的任何立體化學之情況下繪製化合物,儘管該化合物可為實質上對映異構性或非對映異構性純。
本發明化合物之代表性合成描述於以下流程及隨後特定實例中。除非另外指示,否則化合物使用MarvinSketch (ChemAxon, Budapest, Hungary)命名。
實例中詳細描述之特定3'3'-環二核苷酸係根據下文所描述之通用合成方法合成。
分析型HPLC、質譜、化合物之UV吸光度及純度用Waters UPLC-MS系統量測,該系統由Waters UPLC H級核心系統、UPLC PDA偵測器及質譜儀Waters SQD2組成。所用MS方法為ESI+及/或ESI-,錐孔電壓= 30 V,質量偵測器範圍為100 - 1000 Da或500 - 1600 Da。如所指示使用兩組HPLC條件:(a) C18 (管柱:ProntoSIL,Prontopearl C18 SH 2.2 μm,100×2.0 mm;LC方法:H2
O/CH3
CN,0.1%甲酸作為改質劑,梯度0 - 100%,運作長度7分鐘,流量0.5毫升/分鐘)及(b) HILIC (管柱:SeQuant ZIC-pHILIC,5 μm,聚合,50×2.1 mm;LC方法:CH3
CN/0.01 M乙酸銨水溶液梯度10 - 60%,運作長度7分鐘,流量0.3毫升/分鐘)。
下文展示之實例中使用之縮寫包括以下。縮寫清單:
實例 1 . 環戊烷核苷酸單體之合成
縮寫 | |
ACN | 乙腈 |
BSA | 牛血清白蛋白 |
Bn | 苯甲基 |
Bz | 苯甲醯基 |
Cbz | 苯甲氧基羰基 |
DABCO | 1,4-二氮雜雙環[2.2.2]辛烷 |
DAST | (二乙胺基)三氟化硫 |
dba | 二苯亞甲基丙酮 |
DCA | 二氯乙酸 |
DCE | 1,2-二氯乙烷 |
DCM | 二氯甲烷 |
dppf | 1,1'-二茂鐵二基-雙(二苯基膦) |
DIPEA | N ,N -二異丙基乙胺 |
DMF | 二甲基甲醯胺 |
DMOCP | 2-氯-5,5-二甲基-1,3,2-二氧磷雜環己烷-2-氧化物 |
DMEM | 達爾伯克氏改良伊格爾氏培養基(Dulbecco's Modified Eagle's Medium) |
DMSO | 二甲亞碸 |
DMTr | 4,4'-二甲氧基三苯基甲基 |
DMTrCl | 4,4'-二甲氧基三苯基甲基氯 |
DSF | 差示掃描螢光測定法 |
ESI | 電灑離子化法 |
FBS | 胎牛血清 |
FCC | 急驟管柱層析 |
HILIC | 疏水相互作用層析 |
HPLC | 高解析度質譜 |
iBu | 異丁基 |
iPr | 異丙基 |
LiHMDS | 雙(三甲基矽烷基)胺基鋰 |
NMMO | N-甲基嗎啉N-氧化物 |
PBMC | 周邊血液單核細胞 |
TBAF | 四丁基氟化銨 |
TBDMS | 第三丁基二甲基矽烷基 |
TBDMSCl | 第三丁基二甲基氯矽烷 |
TBHP | 第三丁基過氧化氫 |
TEA | 三乙胺 |
TEAB | 三乙基碳酸氫銨 |
TES | 三乙基矽烷 |
TFA | 三氟乙酸 |
THF | 四氫呋喃 |
TMSCl | 氯三甲基矽烷 |
XantPhos | 4,5-雙(二苯基膦基)-9,9-二甲基二苯并哌喃 |
( 1R , 4S , 5R , 6S )- 5 , 6 - 二羥基 - 2 - 氮雜雙環 [ 2 . 2 . 1 ] 庚 - 3 - 酮 ( 1 ) :
向(1R
)-(-)-2-氮雜雙環[2.2.1]庚-5-烯-3-酮(21.8 g,0,2 mol)於二噁烷(400 mL)中之冰冷溶液中添加4-甲基嗎啉N-氧化物單水合物(40.5 g,0.3 mol),接著緩慢添加OsO4
(0.15 M水溶液,2 mL) (流程1)。NMMO之緩慢溶解指示反應進程,反應混合物在0℃下攪拌1小時且在室溫下攪拌2小時。藉由添加亞硫酸氫鈉(30%水溶液,5 mL)淬滅反應物,蒸發揮發物,將粗產物吸附於二氧化矽上,施加於二氧化矽塞上且用MeOH/CHCl3
梯度(0-20%)溶離純化合物,得到標題化合物。NMR譜匹配文獻資料(J. Org. Chem. 1981, 46(16), 3268)。
流程1
(1R
,4S
,5R
,6S
)-5,6-雙((第三丁基二甲基矽烷基)氧基)-2-氮雜雙環[2.2.1]庚-3-酮(2
):將中間物1
(28.16 g,0.2 mol)與DMF (2×100 mL)共蒸餾,溶解於無水DMF (400 mL)中,且向此溶液中添加咪唑(53.6 g,0.79 mol),接著緩慢添加TBDMSCl (118.6 g,0.79 mol)。在3小時之後,藉由添加MeOH (50 mL)淬滅反應物,蒸發所有揮發物,使蜂蜜狀殘餘物溶解於AcOEt (1.5 L)中且用飽和NaHCO3
溶液(2×300 mL)及水(300 mL)洗滌。有機相經硫酸鈉乾燥且蒸發。進行管柱層析(乙酸乙酯/石油醚-20-100%),得到標題化合物。NMR譜匹配文獻資料(J. Med. Chem., 2005, 48(24), 7675)。
( 1R , 4S , 5R , 6S )- 5 , 6 - 雙 (( 第三丁基二甲基矽烷基 ) 氧基 )- 3 - 側氧基 - 2 - 氮雜雙環 [ 2 . 2 . 1 ] 庚烷 - 2 - 羧酸 苯甲酯 ( 3 ) :
使2
(38.84 g,104.5 mmol)於無水THF (500 mL)中之溶液在氬氣氛圍下於乾冰-丙酮浴中冷卻至-78℃。經10分鐘向此溶液中逐滴添加LiHMDS (1 M THF溶液,105 mL)。再過10分鐘之後,經10分鐘逐滴添加氯甲酸苯甲酯(22.4 mL,156.8 mmol)且再攪拌反應混合物10分鐘。仍在-78℃下,反應物藉由添加飽和NH4
Cl溶液(50 mL)淬滅,用AcOEt (1.5 L)稀釋且用飽和NaHCO3
溶液(300 mL)及水(300 mL)洗滌。有機相經硫酸鈉乾燥且蒸發。進行管柱層析(AcOEt/石油醚10-30%),得到標題化合物:1
H NMR (401 MHz, CDCl3
) δ 7.43 - 7.32 (m, 5H), 5.25及5.21 (d,J =
12.2 Hz, 1H), 4.22 (dt,J =
2.2, 1.2 Hz, 1H), 4.15 (dd,J =
5.6, 1.8 Hz, 1H), 3.99 (dd,J =
5.5, 1.7 Hz, 1H), 2.63 (dt,J =
2.3, 1.1 Hz, 1H), 2.28 (dt,J =
10.3, 1.5 Hz, 1H), 1.93 (dp,J =
10.1, 1.7 Hz, 1H), 0.89 (s, 9H), 0.88 (s, 9H), 0.10 (s, 3H), 0.07 (s, 6H), 0.05 (s, 3H);13
C NMR (101 MHz, CDCl3
) δ 173.01, 150.55, 135.16, 128.76, 128.66, 128.59, 72.98, 70.78, 68.32, 63.49, 54.78, 32.36, 26.02, 25.98, 18.33, 18.24, -4.30, -4.40, -4.83, -4.91; ESI MSm/z
(%): 506.3 (19) [M+H], 528.3 (100) [M+Na]; HRMS ESI (C26
H44
O5
NSi2
)計算值:506.27525,實驗值:506.27532。
(( 1R , 2S , 3R , 4R )- 2 , 3 - 雙 (( 第三丁基二甲基矽烷基 ) 氧基 )- 4 -( 羥甲基 ) 環戊基 ) 胺基甲酸苯甲酯 ( 4 ) :
使3
(49.7 g,98 mmol)於THF-MeOH混合物(5:1,600 mL)中之溶液冷卻至0℃,且經30分鐘以10份添加NaBH4
(7.4 g,196 mmol)。將反應物在室溫下攪拌2小時,用AcOEt (1 L)稀釋且用水(2×300 mL)洗滌。有機相經硫酸鈉乾燥且蒸發。進行管柱層析(AcOEt/甲苯0-25%),得到標題化合物:1
H NMR (401 MHz, DMSO-d 6
) δ 7.40 - 7.27 (m, 5H), 7.13 (d,J
= 8.5 Hz, 1H), 4.99 (d,J
= 2.8 Hz, 2H), 4.56 (bs, 1H), 3.81 (t,J
= 4.1 Hz, 1H), 3.77 (m, 1H), 3.70 (dd,J
= 6.1, 3.9 Hz, 1H), 3.46 - 3.22 (m, 2H), 2.06 (dt,J
= 13.3, 9.2 Hz, 1H), 1.94 (m, 1H), 1.09 (dt,J
= 13.2, 6.6 Hz, 1H), 0.87 (s, 9H), 0.84 (s, 9H), 0.05 (s, 3H), 0.04 (s, 3H), 0.03 (s, 3H), 0.02 (s, 3H);13
C NMR (101 MHz, DMSO-d 6
) δ 155.62, 137.43, 128.46, 127.90, 127.87, 77.71, 74.35, 65.25, 63.11, 54.58, 44.72, 29.61, 25.99, 25.95, 17.95, 17.94, -4.26, -4.38, -4.43, -4.49; ESI MSm/z
(%): 510.3 (27) [M+H], 532.3 (100) [M+Na]; HRMS ESI (C26
H47
O5
NNaSi2
)計算值:532.28850,實驗值:532.28828。
((1R
,2R
,3S
,4R
)-4-胺基-2,3-雙((第三丁基二甲基矽烷基)氧基)環戊基)甲醇(5
):向4
(47.6 g,93 mmol)於THF (250 mL)中之溶液中添加Pd/C (10%,2 g),且將此反應混合物在鋼製巴氏高壓容器(parr bomb)中在10巴H2
下氫化12小時。在矽藻土墊上濾出催化劑,用甲醇充分洗滌過濾器。蒸發揮發物,得到標題化合物:1
H NMR (401 MHz, DMSO-d 6
) δ 3.89 (t,J
= 4.5 Hz, 1H), 3.44 (t,J 2
= 4.9 Hz, 1H), 3.37 (dd,J
= 10.4, 5.6 Hz, 1H), 3.29 (dd,J
= 10.5, 6.0 Hz, 1H), 3.06 - 2.95 (m, 1H), 2.07 - 1.95 (m, 1H), 1.95 - 1.86 (m, 1H), 0.94 - 0.89 (m, 1H), 0.87 (s, 9H), 0.86 (s, 9H), 0.07 (s, 3H), 0.04 (s, 3H), 0.04 (s, 3H), 0.02 (s, 3H);13
C NMR (101 MHz, DMSO-d 6
) δ 81.14, 74.73, 63.11, 55.40, 45.00, 32.67, 26.06, 26.02, 18.05, 17.95, -4.18, -4.22, -4.39; ESI MSm/z
(%): 376.3 (100) [M+H], 398.3 (7) [M+Na]; HRMS ESI (C18
H42
O3
NSi2
)計算值:376.26977,實驗值:376.26999。
((1R
,2R
,3S
,4R
)-4-(6-氯-9H
-嘌呤-9-基)-2,3-雙((第三丁基二甲基矽烷基)氧基)環戊基)甲醇(6
):向5
(20 g,53 mmol)於n
-BuOH (300 mL)中之溶液中添加DIPEA (28 mL)及4,6-二氯-5-甲醯胺基嘧啶(12.3 g,64 mmol)。將所得混合物在密封容器中在130℃下加熱24小時。蒸發揮發物,進行管柱層析(AcOEt/甲苯0-60%),得到標題化合物:1
H NMR (401 MHz, DMSO-d 6
) δ 8.87 (s, 1H), 8.78 (s, 1H), 5.01 (q,J
= 9.5 Hz, 1H), 4.92 (t,J
= 5.2 Hz, 1H), 4.51 (dd,J
= 9.6, 4.1 Hz, 1H), 4.04 (d,J
= 4.1 Hz, 1H), 3.60 (ddd,J
= 10.8, 7.9, 5.0 Hz, 1H), 3.51 (dt,J
= 11.0, 5.5 Hz, 1H), 2.35 (dt,J
= 13.4, 9.6 Hz, 1H), 2.17 - 2.05 (m, 1H), 1.92 (ddd,J
= 13.5, 9.7, 5.4 Hz, 1H), 0.91及0.56 (s, 9H), 0.11, 0.07, -0.19, -0.67 (s, 3H);13
C NMR (101 MHz, DMSO) δ 152.24, 151.40, 149.33, 147.24, 131.61, 76.34, 74.16, 63.14, 59.68, 46.05, 27.48, 25.97, 25.48, 17.93, 17.43, -4.30, -4.45, -4.54, -5.81; HRMS ESI (C23
H42
O3
N4
ClSi2
)計算值:513.24785,實驗值:513.24790。
((1R
,2R
,3S
,4R
)-4-(2-胺基-6-氯-9H
-嘌呤-9-基)-2,3-雙((第三丁基二甲基矽烷基)氧基)環戊基)甲醇(7
):向5
(20 g, 53 mmol)於n
-BuOH (300 mL)中之溶液中添加DIPEA (28 mL)及2-胺基-4,6-二氯-5-甲醯胺基嘧啶(13.2 g,64 mmol)。將所得混合物在密封容器中在160℃下加熱24小時。蒸發揮發物,進行管柱層析(AcOEt/甲苯20-100%),得到標題化合物:1
H NMR (401 MHz, DMSO-d 6
) δ 8.25 (s, 1H), 6.81 (s, 2H), 4.87 (t,J
= 5.3 Hz, 1H), 4.74 (q,J
= 9.5 Hz, 1H), 4.49 (dd,J
= 9.6, 4.2 Hz, 1H), 4.01 (d,J
= 4.1 Hz, 1H), 3.57 (ddd,J
= 11.0, 8.0, 5.2 Hz, 1H), 3.49 (dt,J
= 11.0, 5.6 Hz, 1H), 2.27 (dt,J
= 13.4, 9.7 Hz, 1H), 2.11 - 2.01 (m, 1H), 1.76 (ddd,J
= 14.0, 9.5, 5.2 Hz, 1H), 0.91 (s, 9H), 0.65 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H), -0.16 (s, 3H), -0.51 (s, 3H);13
C NMR (101 MHz, DMSO-d 6
) δ 159.56, 154.42, 149.50, 142.87, 124.09, 75.99, 74.55, 63.22, 58.88, 46.12, 27.71, 26.05, 25.66, 18.01, 17.61, -4.31, -4.42, -5.54; ESI MSm/z
(%): 528.3 (100) [M+H], 550.2 (49) [M+Na]; HRMS ESI (C23
H43
O3
N5
ClSi2
)計算值:528.25875,實驗值:528.25868。
9-((1R
,2S
,3R
,4R
)-2,3-雙((第三丁基二甲基矽烷基)氧基)-4-(羥甲基)環戊基)-1,9-二氫-6H
-嘌呤-6-酮(8
):將6
(3 g,5.8 mmol)、DABCO (721 mg,6.4 mmol)及K2
CO3
(1.62 g,11.7 mmol)於水-二噁烷混合物(1:1,80 mL)中之溶液在90℃下攪拌30分鐘。向混合物中添加水(50 mL),蒸發二噁烷,用紙過濾器收集沈澱產物且用水充分洗滌。在乾燥器中經P2
O5
乾燥隔夜後,獲得標題化合物:1
H NMR (401 MHz, DMSO-d 6
) δ 12.25 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 4.89 (t,J
= 5.3 Hz, 1H), 4.83 (q,J
= 9.5 Hz, 1H), 4.42 (dd,J
= 9.6, 4.1 Hz, 1H), 4.01 (d,J
= 4.1 Hz, 1H), 3.59 - 3.51 (m, 1H), 3.51 - 3.42 (m, 1H), 2.31 (dt,J
= 13.3, 9.6 Hz, 1H), 2.11 - 2.01 (m, 1H), 1.77 (ddd,J
= 13.2, 9.5, 5.3 Hz, 1H), 0.91 (s, 9H), 0.64 (s, 9H), 0.11(s, 3H), 0.07(s, 3H), -0.16(s, 3H), -0.52 (s, 3H);13
C NMR (101 MHz, DMSO) δ 156.81, 148.80, 145.24, 139.92, 124.75, 76.80, 74.45, 63.18, 58.96, 46.02, 28.30, 26.01, 25.63, 17.97, 17.56, -4.28, -4.40, -4.50, -5.71; HRMS ESI (C23
H42
O4
N4
NaSi2
)計算值:517.26368,實驗值:517.26370。
2-胺基-9-((1R
,2S
,3R
,4R
)-2,3-雙((第三丁基二甲基矽烷基)氧基)-4-(羥甲基)環戊基)-1,9-二氫-6H
-嘌呤-6-酮(9
):將7
(8 g,15 mmol)、DABCO (1.87 g,17 mmol)及K2
CO3
(4.19 g,30 mmol)於水-二噁烷混合物(1:1,200 mL)中之溶液在90℃下攪拌1小時。向混合物中添加水(150 mL),蒸發二噁烷,用紙過濾器收集沈澱產物且用水充分洗滌。在乾燥器中經P2
O5
乾燥隔夜後,獲得標題化合物:1
H NMR (401 MHz, DMSO-d 6
) δ 10.51 (s, 1H), 7.77 (s, 1H), 6.29 (s, 2H), 4.85 (t,J
= 5.3 Hz, 1H), 4.63 (q,J
= 9.4 Hz, 1H), 4.43 (dd,J
= 9.5, 4.2 Hz, 1H), 3.98 (d,J
= 4.3 Hz, 1H), 3.54 (ddd,J
= 11.0, 7.8, 5.3 Hz, 1H), 3.47 (dt,J
= 11.1, 5.6 Hz, 1H), 2.24 (dt,J
= 13.4, 10.0 Hz, 1H), 2.11 - 2.01 (m, 1H), 1.67 (ddd,J
= 13.9, 9.3, 5.2 Hz, 1H), 0.90 (s, 9H), 0.69 (s, 9H), 0.10 (s, 3H), 0.07 (s, 3H), -0.13 (s, 3H), -0.42 (s, 3H);13
C NMR (101 MHz, DMSO) δ 156.99, 153.14, 151.61, 136.93, 117.34, 76.48, 74.82, 63.19, 58.35, 46.08, 28.45, 26.07, 25.76, 18.04, 17.69, -4.28, -4.33, -4.43, -5.49; ESI MSm/z
(%): 510.3 (100) [M+H], 532.3 (89) [M+Na]; HRMS ESI (C23
H44
O4
N5
Si2
)計算值:510.29263,實驗值:510.29263。
N
-(9-((1R
,2S
,3R
,4R
)-2,3-雙((第三丁基二甲基矽烷基)氧基)-4-(羥甲基)環戊基)-6-側氧基-6,9-二氫-1H
-嘌呤-2-基)異丁醯胺(10
):使中間物9
(7.7 g,15.2 mmol)與吡啶(2×30 mL)共沸,溶解於吡啶(70 mL)中,且逐滴添加TMSCl (4.8 mL,38 mmol)。在環境溫度下攪拌反應混合物1小時後,逐滴添加異丁醯氯(2.3 mL,23 mmol),且再繼續攪拌3小時。添加水(30 mL)且繼續攪拌5分鐘,之後添加氨水(32%,45 mL)且再繼續攪拌15分鐘。蒸發揮發物且使殘餘物分配於DCM與水之間。用另外一部分DCM萃取水層,將有機層合併,經硫酸鈉乾燥且蒸發。進行FCC (MeOH/DCM,2-10%),得到產物:1
H NMR (401 MHz, DMSO-d 6
) δ 12.09 (s, 1H), 11.45 (s, 1H), 8.17 (s, 1H), 5.39 (t,J
= 5.2 Hz, 1H), 4.76 (q,J
= 9.6 Hz, 1H), 4.46 (dd,J
= 9.7, 4.3 Hz, 1H), 4.01 (d,J
= 4.3 Hz, 1H), 3.56 (ddd,J
= 10.9, 7.6, 5.0 Hz, 1H), 3.49 (dt,J
= 10.9, 5.4 Hz, 1H), 2.83 (hept,J
= 6.8 Hz, 1H), 2.33 (dt,J
= 13.5, 9.7 Hz, 1H), 2.12 - 2.01 (m, 1H), 1.62 (ddd,J
= 13.5, 9.6, 5.3 Hz, 1H), 1.13 (d,J
= 6.7 Hz, 6H), 0.92及0.67 (s, 9H), 0.13 (s, 3H), 0.09 (s, 3H), -0.12 (s, 3H), -0.44 (s, 3H);13
C NMR (101 MHz, DMSO) δ 180.35, 155.05, 149.20, 147.59, 138.82, 120.52, 77.19, 74.93, 63.18, 58.56, 46.22, 34.78, 29.22, 26.10, 25.65, 19.14, 19.06, 18.07, 17.62, -4.21, -4.32, -4.35, -5.55; ESI MSm/z
(%): 580.3 (100) [M+H], 602.3 (44) [M+Na]; HRMS ESI (C27
H50
O5
N5
Si2
)計算值:580.33450,實驗值:580.33472。
9-((1R
,2S
,3R
,4R
)-4-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-2,3-雙((第三丁基二甲基矽烷基)氧基)環戊基)-1,9-二氫-6H
-嘌呤-6-酮(11
):使中間物8
(2.6 g,mmol)與吡啶(2×20 mL)共沸,溶解於吡啶(50 mL)中且一次添加全量DMTrCl (2.1 g,6.3 mmol)。在環境溫度下攪拌反應混合物3小時後,將其用AcOEt (250 mL)稀釋,用飽和NaHCO3
水溶液及水洗滌。有機相經硫酸鈉乾燥且蒸發,得到粗中間物11
,其不經進一步純化即用於下一反應。藉由逆相FCC (ACN之水溶液,50-100%)純化樣品:1
H NMR (401 MHz, DMSO-d 6
) δ 12.24 (s, 1H), 8.08 (s, 1H), 7.80 (s, 1H), 7.49 - 7.44 (m, 2H), 7.34 - 7.29 (m, 6H), 7.26 - 7.20 (m, 1H), 6.93 - 6.87 (m, 4H), 4.75 (q,J
= 9.5 Hz, 1H), 4.32 (dd,J
= 9.7, 4.1 Hz, 1H), 3.96 (d,J
= 4.1 Hz, 1H), 3.73 (m, 6H), 3.25 - 3.19 (m, 1H), 3.16 - 3.10 (m, 1H), 2.38 - 2.27 (m, 1H), 2.27 - 2.19 (m, 1H), 1.97 (ddd,J
= 13.6, 9.6, 4.9 Hz, 1H), 0.90 (s, 9H), 0.63 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H), -0.25 (s, 3H), -0.63 (s, 3H);13
C NMR (101 MHz, DMSO) δ 158.24, 158.23, 156.74, 148.47, 145.33, 144.63, 140.76, 135.94, 135.71, 129.93, 129.90, 127.96, 127.77, 126.80, 125.28, 113.34, 113.29, 85.60, 76.00, 74.45, 64.25, 59.70, 55.21, 43.60, 27.51, 25.96, 25.63, 17.97, 17.52, -4.37, -4.43, -4.60, -5.98; ESI MSm/z
(%): 797.4 (11) [M+H], 819.4 (100) [M+Na]; HRMS ESI (C44
H60
O6
N4
NaSi2
)計算值:819.39436,實驗值:819.39472。
N
-(9-((1R
,2S
,3R
,4R
)-4-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-2,3-雙((第三丁基二甲基矽烷基)氧基)環戊基)-6-側氧基-6,9-二氫-1H
-嘌呤-2-基)異丁醯胺(12
):使中間物10
(2 g,3.4 mmol)與吡啶(2×10 mL)共沸,溶解於吡啶(40 mL)中且一次添加全量DMTrCl (1.75 g,5.2 mmol)。在環境溫度下攪拌反應混合物3小時後,將其用AcOEt (200 mL)稀釋,用飽和NaHCO3
水溶液及水洗滌。有機相經硫酸鈉乾燥且蒸發。藉由TEA-滅活矽膠管柱上之FCC (AcOEt/環己烷0-80%)純化,得到12
:1
H NMR (401 MHz, DMSO-d 6
) δ 12.06 (s, 1H), 11.37 (s, 1H), 8.01 (s, 1H), 7.47 - 7.39 (m, 2H), 7.36 - 7.26 (m, 6H), 7.26 - 7.19 (m, 1H), 6.93 - 6.86 (m, 4H), 4.76 (q,J
= 9.5 Hz, 1H), 4.16 (dd,J
= 9.5, 4.4 Hz, 1H), 3.90 (d,J
= 4.4 Hz, 1H), 3.73 (s, 6H), 3.25 - 3.14 (m, 2H), 2.77 (hept,J
= 6.8 Hz, 1H), 2.39 (dt,J
= 13.3, 9.4 Hz, 1H), 2.24 - 2.16 (m, 1H), 1.65 (ddd,J
= 13.3, 9.9, 6.1 Hz, 1H), 1.09 (d,J
= 6.8 Hz, 6H), 0.87及0.63 (s, 9H), 0.04 (s, 6H), -0.17及-0.47 (s, 3H);13
C NMR (101 MHz, DMSO) δ 180.18, 158.28, 155.05, 149.36, 147.70, 145.16, 137.87, 135.73, 135.63, 129.96, 127.96, 127.83, 126.86, 120.34, 113.30, 85.81, 77.63, 74.65, 64.55, 57.83, 55.22, 55.16, 34.79, 29.52, 26.03, 25.57, 19.03, 18.02, 17.53, -4.21, -4.37, -4.46, -5.69; ESI MSm/z
(%): 882.5 (100) [M+H]; HRMS ESI (C48
H67
N5
O7
Si2
)計算值:882.46573,實驗值:882.46581。
9-((1R
,2S
,3R
,4R
)-4-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-2,3-二羥基環戊基)-1,9-二氫-6H
-嘌呤-6-酮(13
):向粗11
(3 g,3.8 mmol)於THF (60 mL)中之溶液中添加TBAF (1 M THF溶液,15 mL),且將反應混合物在環境溫度下攪拌12小時。蒸發揮發物,且進行逆相FCC (ACN之水溶液,10-70%),得到13
:1
H NMR (401 MHz, DMSO-d 6
) δ 8.09 (s, 1H), 7.94 (s, 1H), 7.43 - 7.38 (m, 2H), 7.35 - 7.29 (m, 2H), 7.29 - 7.24 (m, 4H), 7.24 - 7.19 (m, 1H), 6.92 - 6.87 (m, 4H), 4.71 - 4.62 (m, 1H), 4.28 (dd,J
= 8.6, 5.6 Hz, 1H), 3.85 (dd,J
= 5.7, 3.7 Hz, 1H), 3.74 (s, 6H), 3.15 (dd,J
= 9.0, 5.8 Hz, 1H), 3.03 (dd,J
= 9.0, 6.2 Hz, 1H), 2.32 - 2.24 (m, 1H), 2.24 - 2.14 (m, 1H), 1.84 - 1.73 (m, 1H);13
C NMR (101 MHz, DMSO) δ 158.19, 157.03, 148.68, 145.37, 145.26, 139.67, 136.02, 129.90, 128.01, 127.88, 126.79, 124.81, 113.35, 85.39, 74.73, 71.86, 64.73, 60.14, 55.21, 43.74, 30.08; ESI MSm/z
(%): 569.3 (7) [M+H], 591.3 (100) [M+Na]; HRMS ESI (C32
H32
O6
N4
Na)計算值:591.22141,實驗值:591.22144。
N
-(9-((1R
,2S
,3R
,4R
)-4-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-2,3-二羥基環戊基)-6-側氧基-6,9-二氫-1H
-嘌呤-2-基)異丁醯胺(14
):向12
(2.6 g, 2.9 mmol)於THF (40 mL)中之溶液中添加TBAF (1 M THF溶液,12 mL),且將反應混合物在環境溫度下攪拌12小時。蒸發揮發物,且進行逆相FCC (ACN之水溶液,10-70%),得到14
:1
H NMR (401 MHz, DMSO-d 6
) δ 11.97 (bs, 2H), 7.99 (s, 1H), 7.43 - 7.36 (m, 2H), 7.36 - 7.29 (m, 6H), 7.29 - 7.24 (m, 4H), 7.24 - 7.19 (m, 1H), 6.95 - 6.84 (m, 4H), 4.62 (dt,J
= 10.9, 8.2 Hz, 1H), 4.20 (dd,J
= 8.6, 5.7 Hz, 1H), 3.83 (dd,J
= 5.7, 3.8 Hz, 1H), 3.73 (s, 6H), 3.16 (dd,J
= 9.1, 5.2 Hz), 3.03 (dd,J
= 9.1, 6.6 Hz), 2.72 (七重峰,J
= 6.8 Hz, 1H), 2.30 (dt,J
= 12.4, 7.9 Hz, 1H), 2.22 - 2.11 (m, 1H), 1.56 - 1.45 (m, 1H), 1.10 (d,J
= 6.8 Hz, 6H);13
C NMR (101 MHz, DMSO) δ 180.78, 158.19, 156.09, 149.76, 145.32, 137.49, 135.98, 129.88, 128.01, 127.87, 126.79, 120.06, 113.35, 85.43, 74.88, 71.86, 64.96, 58.75, 55.20, 35.36, 30.92, 19.33; ESI MSm/z
(%): 654.3 (100) [M+H]; HRMS ESI (C36
H39
N5
O7
)計算值:654.29277,實驗值:654.29265。
9-((1R
,2S
,3R
,4R
)-4-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-2-((第三丁基二甲基矽烷基)氧基)-3-羥基環戊基)-1,9-二氫-6H
-嘌呤-6-酮(15
):使13
(2 g,3.5 mmol)與吡啶(2×10 mL)共沸,溶解於吡啶(40 mL)中,一次添加全量及咪唑(479 mg,7 mmol),接著一次添加全量TBDMSCl (530 mg,3.5 mmol)。在環境溫度下攪拌反應混合物12小時後,將其用AcOEt (200 mL)稀釋,用飽和NaHCO3
水溶液及水洗滌。進行逆相FCC (ACN之水溶液40-90%),得到15
:1
H NMR (401 MHz, CDCl3
) δ 13.19 (bs, 1H), 8.04 (s, 1H), 7.79 (s, 1H), 7.53 - 7.47 (m, 2H), 7.41 - 7.35 (m, 4H), 7.32 - 7.27 (m, 2H), 7.25 - 7.20 (m, 1H), 6.87 - 6.81 (m, 4H), 4.82 - 4.74 (m, 1H), 4.72 (dd,J
= 8.9, 4.9 Hz, 1H), 4.01 (dd,J
= 4.6, 1.7 Hz, 1H), 3.79 (s, 3H), 3.79 (s, 3H), 3.31 (dd,J
= 9.1, 3.7 Hz, 1H), 3.24 (dd,J
= 9.1, 3.7 Hz, 1H), 2.62 (d,J
= 1.6 Hz, 1H), 2.44 - 2.29 (m, 3H), 0.77 (s, 9H), -0.14 (s, 3H), -0.38 (s, 3H);13
C NMR (101 MHz, CDCl3
) δ 159.58, 158.59, 149.46, 145.23, 144.30, 144.27, 140.29, 136.16, 130.24, 128.27, 127.95, 126.94, 125.61, 113.27, 113.21, 86.28, 77.07, 73.67, 73.56, 64.22, 61.65, 55.41, 55.32, 42.66, 28.71, 25.68, 25.64, 17.90, -5.14, -5.26; ESI MSm/z
(%): 683.4 (10) [M+H], 705.4 (100) [M+Na]; HRMS ESI (C38
H46
O6
N4
NaSi)計算值:705.30788,實驗值:705.30818。
N
-(9-((1R
,2S
,3R
,4R
)-4-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-2-((第三丁基二甲基矽烷基)氧基)-3-羥基環戊基)-6-側氧基-6,9-二氫-1H
-嘌呤-2-基)異丁醯胺(16
):使中間物14
(2.14 g,3.2 mmol)與吡啶(2×10 mL)共沸,溶解於吡啶(20 mL)中,且一次添加全量咪唑(565 mg,9.6 mmol),接著一次添加全量TBDMSCl (581 mg,3.9 mmol)。在環境溫度下攪拌反應混合物12小時後,將其用AcOEt (200 mL)稀釋,用飽和NaHCO3
水溶液及水洗滌。進行逆相FCC (ACN之水溶液40-90%),得到中間物16
:1
H NMR (401 MHz, DMSO-d 6
) δ 12.02 (s, 1H), 11.66 (s, 1H), 8.11 (s, 1H), 7.45 - 7.38 (m, 2H), 7.35 - 7.30 (m, 2H), 7.30 - 7.26 (m, 4H), 7.26 - 7.20 (m, 1H), 6.93 - 6.87 (m, 4H), 4.86 - 4.76 (m, 1H), 4.51 (d,J
= 4.6 Hz, 1H), 4.19 (dd,J
= 9.3, = 5.3 Hz, 1H), 3.83 (td,J
= 5.0, 2.1 Hz, 1H), 3.74 (s, 6H), 3.17 (dd,J
= 9.1, 6.2 Hz, 1H), 3.07 (dd,J
= 9.1, 5.1 Hz, 1H), 2.75 (七重峰,J
= 6.8 Hz, 1H), 2.29 - 2.16 (m, 2H), 1.68 (dt,J
= 11.3, 5.8 Hz, 1H), 1.10 (d,J
= 6.9 Hz, 1H), 0.65 (s, 9H), -0.13 (s, 3H), -0.33 (s, 3H);13
C NMR (101 MHz, DMSO) δ 180.10, 158.05, 158.04, 154.88, 149.25, 147.68, 145.12, 137.53, 135.70, 135.67, 129.77, 129.74, 127.82, 127.67, 126.66, 119.95, 113.16, 85.31, 77.89, 71.74, 64.62, 57.77, 55.03, 43.63, 34.69, 28.87, 25.39, 18.89, 18.80, 17.61, -5.01, -5.66; ESI MSm/z
(%): 768.4 (100) [M+H]; HRMS ESI (C42
H53
N5
O7
Si)計算值:768.37925,實驗值:768.37931。
氫膦酸(1R
,2S
,3R
,5R
)-2-((第三丁基二甲基矽烷基)氧基)-5-(羥甲基)-3-(6-側氧基-1,6-二氫-9H
-嘌呤-9-基)環戊酯,三乙銨鹽(17
):使中間物15
(300 mg,0.44 mmol)與吡啶(2×5 mL)共沸,溶解於吡啶(5 mL)中,且一次添加全量亞磷酸二苯酯(85%, 198 μL, 0.88 mmol)。在環境溫度下攪拌20分鐘後,添加TEA (1 mL),接著添加水(1 mL),且再攪拌反應物20分鐘。將所得溶液用DCM (70 mL)稀釋,且用飽和NaHCO3
水溶液洗滌且用水洗滌。有機層經硫酸鈉乾燥且蒸發。向所獲得之中間物於DCM (5 mL)中之溶液中添加水(79 μL, 4.4 mmol)、DCA (327 μL,4 mmol)於DCM (5 mL)中之溶液,且將反應混合物在環境溫度下攪拌30分鐘,之後將其用吡啶(2 ml)淬滅。在逆相FCC (ACN之水溶液,0-50%)上純化,得到呈三乙銨鹽形式之17
:1
H NMR (401 MHz, DMSO-d 6
) δ 12.37 (bs, 1H), 8.21 (s, 1H), 8.03 (s, 1H), 6.71 (d,J
= 593.1 Hz, 1H), 4.83 - 4.73 (m, 1H), 4.37 (dd,J
= 9.2, 5.3 Hz, 1H), 4.27 (ddd,J
= 10.7, 5.4, 2.3 Hz, 1H), 3.50 (d,J
= 6.1 Hz, 2H), 3.02 (q,J
= 7.2 Hz, 6H), 2.34 - 2.24 (m, 1H), 2.20 (dt,J
= 12.6, 8.6 Hz, 1H), 1.86 (ddd,J
= 12.6, 10.7, 7.8 Hz, 1H), 1.19 (t,J
= 7.3 Hz, 9H), 0.62 (s, 9H), -0.15及-0.38 (s, 3H);13
C NMR (101 MHz, DMSO) δ 156.85, 148.87, 145.32, 139.47, 124.62, 76.69 (d,J
= 4.5 Hz), 74.38, 63.23, 59.37, 45.51, 28.12, 25.54, 17.74, 8.76, -4.77, -5.57;31
P NMR (162 MHz, DMSO) δ 4.60; ESI MSm/z
(%): 443.2 (100) [M-H]; HRMS ESI (C17
H29
N4
O6
PSi)計算值:443.15158,實驗值:443.15170。
氫膦酸(1R
,2S
,3R
,5R
)-2-((第三丁基二甲基矽烷基)氧基)-5-(羥甲基)-3-(2-異丁醯胺-6-側氧基-1,6-二氫-9H
-嘌呤-9-基)環戊酯,三乙銨鹽(18
):使中間物16
(1.3 g,1.7 mmol)與吡啶(2×5 mL)共沸,溶解於吡啶(10 mL)中,且一次添加全量亞磷酸二苯酯(85%,1.14 mL,5.08 mmol)。在環境溫度下攪拌20分鐘後,添加TEA (2 mL),接著添加水(2 mL),且再攪拌反應物20分鐘。將所得溶液用DCM (200 mL)稀釋,且用飽和NaHCO3
水溶液洗滌且用水洗滌。有機層經硫酸鈉乾燥且蒸發。向所獲得之中間物於DCM (25 mL)中之溶液中添加水(306 μL,17.1 mmol)、DCA (1.3 mL,15 mmol)於DCM (10 mL)中之溶液,且將反應混合物在環境溫度下攪拌30分鐘,之後將其用吡啶(4 ml)淬滅。在逆相FCC (ACN/50 mM NH4
HCO水溶液,0-50%)上純化,得到呈銨鹽形式之18
:1
H NMR (401 MHz, DMSO-d 6
) δ 11.98 (bs, 1H), 8.22 (s, 1H), 6.69 (d,J
= 590.6 Hz, 1H), 4.89 (ddd,J
= 11.2, 9.5, 7.9, 1H), 4.25 - 4.16 (m, 2H), 3.48 (d,J
= 6.2 Hz, 2H), 3.04 (q,J
= 7.3 Hz, 6H), 2.74 (七重峰,J
= 6.8 Hz, 1H), 2.37 - 2.27 (m, 1H), 2.26 - 2.15 (m, 1H), 1.70 (td,J
= 11.9, 7.6 Hz, 1H), 1.18 (t,J
= 7.3 Hz, 9H), 1.10 (d,J
= 6.8 Hz, 1H), 0.61 (s, 9H), -0.14及-0.38 (s, 3H);13
C NMR (101 MHz, DMSO) δ 180.34, 155.09, 149.61, 147.99, 137.62, 119.93, 77.57, 74.62, 63.39, 57.37, 45.56, 45.40, 34.95, 28.33, 25.42, 19.04, 17.69, 8.69, -4.88, -5.60;31
P NMR (162 MHz, DMSO) δ 4.67; ESI MSm/z
(%): 528.2 (100) [M-H]; HRMS ESI (C21
H36
N5
O7
PSi)計算值:528.20434,實驗值:528.20437。
(2-氰基乙基)二異丙基胺基磷酸(1R,2S,3R,5R)-3-(2-胺基-6-側氧基-1,6-二氫-9H-嘌呤-9-基)-5-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-2-((第三丁基二甲基矽烷基)氧基)環戊酯(19
):在氬氣氛圍下向16
(700 mg,0.91 mmol)於無水DCE (9 mL)中之溶液中添加雙(二異丙胺基)(2-氰基乙氧基)膦(578 μL,1.82 mmol),接著添加四唑溶液(0.45 M MeCN溶液,5 mL,2.28 mmol),且將反應混合物在環境溫度下攪拌3小時。將所得混濁溶液用DCM (50 mL)稀釋,用飽和NaHCO3
水溶液(2×20 mL)洗滌,經硫酸鈉乾燥且蒸發。藉由二氧化矽上之急驟層析(丙酮/環己烷,0-70%)純化產物,在自苯凍乾之後得到呈非對映異構體之混合物形式之19
:31
P NMR (162 MHz, C6
D6
) δ 152.30, 150.10。
N
-(9-((1R
,2S
,3R
,4R
)-2,3-雙((第三丁基二甲基矽烷基)氧基)-4-(羥甲基)環戊基)-9H
-嘌呤-6-基)苯甲醯胺(20
):在氬氣氛圍下將Pd2
(dba)3
(443 mg,0.48 mmol)及XantPhos (560 mg,0.97 mmol)於無水脫氧甲苯(100 mL)中之混合物加熱至45℃持續15分鐘,形成淺綠色溶液(流程2)。向所形成之催化劑溶液中添加Cs2
CO3
(3.5 g,10.7 mmol)及苯甲醯胺(1.4 g,11.6 mmol)及6
(5 g,9.7 mmol)於無水二噁烷(100 mL)中之溶液。將反應混合物在密封容器中在100℃下加熱4小時,用AcOEt (400 mL)稀釋且用水洗滌。有機層經硫酸鈉乾燥且蒸發。在TEA-滅活矽膠管柱FCC (AcOEt/環己烷50-100%)上純化,得到20
:1
H NMR (401 MHz, CDCl3
) δ 9.14 (s, 1H), 8.79 (s, 1H), 8.06 - 8.01 (m, 2H), 7.98 (s, 1H), 7.63 - 7.57 (m, 1H), 7.55 - 7.49 (m, 2H), 4.87 - 4.76 (m, 2H), 4.55 - 4.47 (m, 1H), 4.08 (d,J
= 3.4 Hz, 1H), 3.87 - 3.81 (m, 2H), 2.62 (dt,J
= 14.3, 10.5 Hz, 1H), 2.38 (ddd,J
= 14.1, 7.4, 3.7 Hz, 1H), 2.28 - 2.22 (m, 1H), 0.94 (s, 9H), 0.72 (s, 9H), 0.11 (s, 5H), -0.17 (s, 3H), -0.74 (s, 3H);13
C NMR (101 MHz, CDCl3
) δ 164.57, 151.88, 151.04, 150.16, 144.48, 133.79, 132.97, 129.02, 127.96, 124.33, 76.89, 64.97, 63.23, 46.51, 27.17, 25.99, 25.88, 18.21, 17.86, -4.35, -4.44, -4.48, -5.82; ESI MSm/z
(%): 598.3 (100) [M+H]; HRMS ESI (C30
H47
N5
O4
Si2
)計算值:598.32449,實驗值:598.32418。
N
-(9-((1R
,2S
,3R
,4R
)-4-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-2,3-雙((第三丁基二甲基矽烷基)氧基)環戊基)-9H
-嘌呤-6-基)苯甲醯胺(21
):使中間物20
(6 g,10 mmol)與吡啶(2×20 mL)共沸,溶解於吡啶(50 mL)中,且一次添加全量DMTrCl (5.1 g,15 mmol)。在環境溫度下攪拌反應混合物3小時後,將其用AcOEt (250 mL)稀釋,用飽和NaHCO3
水溶液及水洗滌。有機相經硫酸鈉乾燥且蒸發,得到中間物21
,其不經進一步純化即用於下一步驟:ESI MSm
/z
(%): 900.5 (100) [M+H]; HRMS ESI (C51
H65
N5
O6
Si2
)計算值:900.45517;實驗值:900.45521。
N
-(9-((1R
,2S
,3R
,4R
)-4-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-2,3-二羥基環戊基)-9H
-嘌呤-6-基)苯甲醯胺(22
):向21
(7.9 g,8.7 mmol)於THF (100 mL)中之溶液中添加TBAF (1 M THF溶液,35 mL),且將反應混合物在環境溫度下攪拌12小時。蒸發揮發物,且進行TEA-滅活矽膠管柱上之FCC (MeOH/DCM 0-10%),得到中間物22
:1
H NMR (401 MHz, DMSO-d 6
) δ 11.18 (s, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 8.08 - 8.02 (m, 2H), 7.65 - 7.59 (m, 1H), 7.57 - 7.50 (m, 2H), 7.46 - 7.41 (m, 2H), 7.36 - 7.26 (m, 6H), 7.26 - 7.20 (m, 1H), 6.94 - 6.87 (m, 4H), 5.07 (s, 1H), 4.88 - 4.75 (m, 2H), 4.48 - 4.39 (m, 1H), 3.91 (dd,J
= 5.9, 3.3 Hz, 1H), 3.74 (s, 6H), 3.19 (dd,J
= 9.1, 5.9 Hz, 1H), 3.08 (dd,J
= 9.0, 6.1 Hz, 1H), 2.37 - 2.28 (m, 1H), 2.28 - 2.19 (m, 1H), 1.97 (td,J
= 11.5, 8.3 Hz, 1H);13
C NMR (101 MHz, DMSO) δ 166.00, 158.19, 152.53, 151.10, 145.41, 144.05, 136.04, 134.18, 132.31, 129.92, 128.63, 128.54, 128.02, 127.89, 126.79, 126.38, 113.36, 85.40, 74.37, 71.90, 64.73, 60.28, 55.21, 43.74, 29.36; ESI MSm/z
(%): 672.3 (100) [M+H]; HRMS ESI (C39
H37
N5
O6
)計算值:672.28221;實驗值:672.28200。
N
-(9-((1R
,2S
,3R
,4R
)-4-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-2-((第三丁基二甲基矽烷基)氧基)-3-羥基環戊基)-9H
-嘌呤-6-基)苯甲醯胺(23
):使中間物22
(5 g,7.4 mmol)與吡啶(2×40 mL)共沸,溶解於吡啶(80 mL)中,接著一次添加全量咪唑(1 g,15 mmol),接著一次添加全量TBDMSCl (1.12 g,7.4 mmol)。在環境溫度下攪拌反應混合物12小時後,將其用AcOEt (400 mL)稀釋,用飽和NaHCO3
水溶液及水洗滌。進行逆相FCC (ACN之水溶液40-90%),得到呈異構體與3-矽烷基化產物之1:1混合物形式的23
:ESI MSm
/z
(%): 786.4 (100) [M+H]; HRMS ESI (C45
H51
N5
O6
Si)計算值:786.36869;實驗值:786.36852。
氫膦酸(1R
,2S
,3R
,5R
)-3-(6-苯甲醯胺基-9H
-嘌呤-9-基)-2-((第三丁基二甲基矽烷基)氧基)-5-(羥甲基)環戊酯,三乙銨鹽(24
):使23
與對應3'-TBDMS異構體之混合物(1:1,1 g,1.27 mmol)與吡啶(2×10 mL)共沸,溶解於吡啶(10 mL)中,且一次添加全量亞磷酸二苯酯(85%,860 μL,3.82 mmol)。在環境溫度下攪拌20分鐘後,添加TEA (1.5 mL),接著添加水(1.5 mL),且再攪拌反應物20分鐘。將所得溶液用DCM稀釋,且用飽和NaHCO3
水溶液洗滌且用水洗滌。有機層經硫酸鈉乾燥且蒸發。向所獲得之中間物於DCM (15 mL)中之溶液中添加水(229 μL, 12.7 mmol)及DCA (0.94 mL,11.4 mmol)於DCM (10 mL)中之溶液,且將反應混合物在環境溫度下攪拌30分鐘,之後將其用吡啶(2 ml)淬滅。在逆相FCC (ACN之水溶液,0-50%)上純化且分離異構體,得到呈三乙銨鹽形式之24
:1
H NMR (401 MHz, DMSO-d 6
) δ 11.12 (bs, 1H), 8.71 (s, 1H), 8.62 (s, 1H), 8.08 - 8.02 (m, 2H), 7.67 - 7.61 (m, 1H), 7.58 - 7.51 (m, 2H), 6.73 (d,J
= 591.3 Hz, 1H), 4.94 (dt,J
= 10.6, 8.5 Hz, 1H), 4.50 (dd,J
= 9.1, 5.4 Hz, 1H), 4.32 (ddd,J
= 10.7, 5.4, 2.6 Hz, 1H), 3.54 (d,J
= 6.1 Hz, 2H), 3.04 (q,J
= 7.3 Hz, 6H), 2.39 - 2.30 (m, 1H), 2.30 - 2.19 (m, 1H), 2.05 - 1.93 (m, 1H), 1.20 (t,J
= 7.3 Hz, 9H), 0.60 (s, 9H), -0.15及-0.43 (s, 3H);13
C NMR (101 MHz, DMSO) δ 165.69, 152.78, 151.25, 150.34, 144.02, 133.65, 132.52, 128.61, 126.10, 76.12, 74.17, 63.26, 59.66, 45.60, 45.45, 27.73, 25.55, 17.71, 8.67, -4.72, -5.50;31
P NMR (162 MHz, DMSO) δ 4.57; ESI MSm/z
(%): 546.2 (100) [M-H]; HRMS ESI (C24
H34
N5
O6
PSi)計算值:546.19378;實驗值:546.19360。
N
-(9-((1R
,3R
,4S
)-3-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-4-羥基環戊基)-6-側氧基-6,9-二氫-1H
-嘌呤-2-基)異丁醯胺(26
):使中間物25
(493 mg,1.47 mmol, J. Am. Chem. Soc., 2003, 125 (44), 13519-13524)與吡啶(2×15 mL)共沸,溶解於吡啶(10 mL)中,且在0℃下一次添加全量DMTrCl (600 mg,1.76 mmol)(流程3)。在0℃下攪拌16小時後,再添加一份DMTrCl (150 mg,0.44 mmol)。將反應混合物在0℃下再攪拌16小時,且用飽和NaHCO3
水溶液(2 mL)淬滅且蒸發。使殘餘物溶解於AcOEt (200 mL)中,且將有機相用飽和NaHCO3
水溶液及水洗滌。有機相經硫酸鈉乾燥且蒸發。藉由在TEA-滅活矽膠上層析(DCM-丙酮1:2)純化產物,得到26
:1
H NMR (401 MHz, DMSO-d 6
) δ 12.04 (s, 1H), 11.61 (s, 1H), 8.05 (s, 1H), 7.44 - 7.36 (m, 2H), 7.31 (dd,J
= 8.5, 6.9 Hz, 2H), 7.27 - 7.18 (m, 5H), 6.94 - 6.81 (m, 4H), 4.99 - 4.84 (m, 2H), 4.07 (dq,J
= 8.4, 4.5 Hz, 1H), 3.73 (2 x s, 6H), 3.18 (dd,J
= 8.9, 5.8 Hz, 1H), 3.01 (dd,J
= 9.0, 7.3 Hz, 1H), 2.77 (p,J
= 6.8 Hz, 1H), 2.48 - 2.39 (m, 2H), 2.23 - 2.11 (m, 2H), 2.08 - 1.98 (m, 1H), 1.64 (dt,J
= 12.3, 10.1 Hz, 1H), 1.12 (dd,J
= 6.8, 0.9 Hz, 6H);13
C NMR (101 MHz, DMSO) 180.23, 158.17, 155.08, 148.72, 147.79, 145.31, 137.73, 136.02, 135.99, 129.87, 129.86, 127.96, 126.75, 120.39, 113.32, 85.38, 71.72, 64.90, 55.19, 52.48, 47.51, 40.83, 35.37, 34.88, 29.76, 19.02; ESI MSm/z
(%): 660.6 (100) [M+Na]; HRMS ESI (C36
H39
N5
O6
PNa)計算值:660.27926;實驗值:660.27893。
氫膦酸(1S
,2R
,4R
)-2-(羥甲基)-4-(2-異丁醯胺-6-側氧基-1,6-二氫-9H
-嘌呤-9-基)環戊酯,三乙銨鹽(27
):使中間物26
(680 mg,1.07 mmol)與吡啶(2×15 mL)共沸,溶解於吡啶(10 mL)中,且一次添加全量亞磷酸二苯酯(85%,721 μL,3.21 mol)。在環境溫度下攪拌20分鐘後,添加TEA (1.1 mL),隨後添加水(1.1 mL),且再攪拌反應物20分鐘。將所得溶液用DCM稀釋,且用飽和NaHCO3
水溶液洗滌及用水洗滌。有機層經硫酸鈉乾燥且蒸發。在FCC (DCM/1% Et3
N-MeOH 0至20%)上純化殘餘物。向所獲得之中間物於DCM (10 mL)中之溶液中添加水(200 μL, 11.1 mmol)及DCA (0.795 mL, 9.6 mmol)於DCM (1 mL)中之溶液,且將反應混合物在環境溫度下攪拌30分鐘,之後將其用三乙基矽烷(8.5 mL)淬滅。攪拌反應混合物1小時,且隨後添加吡啶(2 ml),且蒸發揮發物。在逆相FCC (ACN之水溶液,0-50%)上純化,得到呈三乙銨鹽形式之27
:1
H NMR (401 MHz, DMSO-d 6
) δ 12.00及11.90 (2 x brs, 2H), 8.12 (s, 1H), 6.64 (d,J
= 583.0 Hz, 1H), 4.91 (tt,J
= 10.9, 6.8 Hz, 1H), 4.47 (ddt,J
= 9.0, 5.6, 2.6 Hz, 1H), 3.04 (q,J
= 7.3 Hz, 2H), 2.87 - 2.66 (m, 1H), 2.43 - 2.03 (m, 4H), 1.65 (td,J
= 11.1, 10.5, 8.1 Hz, 1H), 1.18 (t,J
= 7.3 Hz, 3H), 1.11 (d,J
= 6.9 Hz, 6H);13
C NMR (101 MHz, DMSO) δ 180.28, 155.10, 148.81, 147.96, 137.64, 120.22, 74.47, 74.42, 63.24, 52.68, 48.66, 48.64, 45.59, 34.94, 33.88, 19.08, 19.01, 8.70;31
P NMR (162 MHz, DMSO) δ 3.13; ESI MSm/z
(%): 422.2 (100) [M+Na]; HRMS ESI (C15
H22
N5
O6
PNa)計算值:422.11999;實驗值:422.11991。
(1S
,2R
,4R
)-4-(6-胺基-9H
-嘌呤-9-基)-2-(羥甲基)環戊-1-醇(29
):將(1S
,2R
,4R
)-4-胺基-2-(羥甲基)環戊-1-醇(28
) (472 mg,3.6 mmol,根據J . Am . Chem . Soc . 2005
,127
, 18143合成)、N
-(4,6-二氯嘧啶-5-基)甲醯胺(847 mg,4.4 mmol)及DIPEA (1.27 mL,7.3 mmol)於正丁醇(17 mL)中之溶液在壓力容器中加熱至140℃(浴)持續16小時(流程4)。蒸發反應混合物,且將殘餘物在矽膠管柱上層析(200 g,乙酸乙酯→乙酸乙酯:丙酮:乙醇:水20:3:1.2:0.8,0-100%)。將所獲得之中間物溶解於氨水(25%)/二噁烷(21 mL,2:1)中,且將溶液在壓力容器中加熱至60℃持續15小時。蒸發揮發物,使殘餘物與乙醇(2×30 mL)共同蒸發,且在矽膠管柱上層析(200 g,乙酸乙酯→乙酸乙酯:丙酮:乙醇:水17:3:3:3, 0-100%),得到中間物29
:1
H NMR (400 MHz, DMSO-d6
) δ 8.21 (s, 1H), 8.12 (s, 1H), 7.16 (s, 2H), 5.01 (tt, J = 9.8, 7.7 Hz, 1H), 4.78 (d, J = 4.0 Hz, 1H), 4.69 - 4.60 (m, 1H), 4.10 (dq, J = 7.1, 3.5 Hz, 1H), 3.54 (dt, J = 10.4, 4.5 Hz, 1H), 3.49 - 3.39 (m, 1H), 2.41 - 2.30 (m, 1H), 2.30 - 2.21 (m, 1H), 2.10 - 1.92 (m, 2H), 1.74 (dt, J = 12.7, 9.4 Hz, 1H);13
C NMR (101 MHz, DMSO-d6
) δ 156.15, 152.30, 149.60, 139.54, 119.38, 71.76, 62.99, 53.08, 49.58, 40.57, 34.04; ESI MS m/z (%): 272.1 (100) [M+Na]; HRMS ESI (C11
H15
N5
O2
Na)計算值272.11180,實驗值:272.11149。
N
-(9-((1R
,3S
,4R
)-3-羥基-4-(羥甲基)環戊基)-9H
-嘌呤-6-基)苯甲醯胺(30
):使中間物29
(576 mg,2.31 mmol)與吡啶(2×15 mL)共同蒸發,溶解於吡啶(15 mL)中,冷卻至0℃且隨後在2分鐘期間逐滴添加TMSCl (2.2 mL,17.3 mmol)。將反應混合物在0℃下攪拌15分鐘,且隨後在環境溫度下攪拌1小時。使其冷卻至0℃後,緩慢添加苯甲醯氯(0.5 mL,4.3 mmol),且將所得溶液在0℃下靜置1小時且再在環境溫度下靜置12小時。隨後使反應混合物再冷卻至0℃,用水(1.85 mL)淬滅,且15分鐘後添加氨水(4.6 mL,25%)。0℃下另外15分鐘後,將反應混合物自冷卻浴移除,在r.t.下攪拌20分鐘且隨後蒸發至乾。用乙酸乙酯-乙醇混合物(50 ml,2:1)萃取所得殘餘物,且在矽藻土墊上濾出固體。藉由逆相層析(100 g,H2
O:乙腈0 → 50%)純化濃縮萃取物,得到30
:1
H NMR (400 MHz, DMSO-d6
) δ 11.11 (s, 1H), 8.72 (s, 1H), 8.58 (s, 1H), 8.07 - 8.00 (m, 2H), 7.69 - 7.60 (m, 1H), 7.59 - 7.49 (m, 2H), 5.16 (tt, J = 9.7, 7.7 Hz, 1H), 4.84 (d, J = 4.3 Hz, 1H), 4.66 (t, J = 5.2 Hz, 1H), 4.14 (dq, J = 7.5, 3.9 Hz, 1H), 3.63 - 3.53 (m, 1H), 3.54 - 3.42 (m, 1H), 2.47 - 2.38 (m, 1H), 2.33 (ddd, J = 12.9, 9.8, 6.4 Hz, 1H), 2.19 - 1.96 (m, 2H), 1.82 (dt, J = 12.6, 9.4 Hz, 1H);13
C NMR (101 MHz, DMSO-d6
) δ 165.76, 152.49, 151.32, 150.28, 143.49, 133.64, 132.54, 128.62, 128.60, 126.05, 71.69, 62.91, 53.51, 49.58, 40.47, 33.92; ESI MS m/z (%): 354.2 (100) [M+H]; HRMS ESI (C18
H20
N5
O3
)計算值354.15607,實驗值:354.15551。
N
-(9-((1R
,3R
,4S
)-3-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-4-羥基環戊基)-9H
-嘌呤-6-基)苯甲醯胺(31
):使中間物30
(634 mg,1.79 mmol)與吡啶(2×25 mL)共沸,溶解於吡啶(20 mL)中,且在0℃下一次添加全量DMTrCl (634 mg,1.97 mmol)。使反應混合物升溫至r.t.且攪拌15小時,之後使其再冷卻至0℃,且添加第二部分DMTrCl (115 mg,0.36 mmol)。將反應混合物在r.t.下再攪拌16小時,冷卻至0℃,且在0℃下添加第三部分DMTrCl (115 mg,0.36 mmol)。將反應混合物在r.t.下再攪拌16小時,且隨後用飽和NaHCO3
水溶液(6 mL)淬滅且蒸發。使殘餘物溶解於乙酸乙酯(400 mL)中,且用飽和NaHCO3
水溶液(150 mL)及鹽水(150 mL)洗滌。有機相經硫酸鈉乾燥且蒸發。藉由TEA-滅活矽膠上之層析(甲苯:丙酮1:1 → 1:2)純化產物,得到31
:1
H NMR (400 MHz, DMSO-d 6
) δ 11.12 (s, 1H), 8.69 (s, 1H), 8.52 (s, 1H), 8.15 - 7.94 (m, 2H), 7.75 - 7.60 (m, 1H), 7.55 (dd,J
= 8.2, 6.8 Hz, 2H), 7.34 - 7.19 (m, 7H), 6.89 (dd,J
= 9.0, 1.0 Hz, 3H), 5.17 (p,J
= 8.7 Hz, 1H), 4.92 (d,J
= 4.7 Hz, 1H), 4.17 (td,J
= 8.5, 7.1, 4.7 Hz, 1H), 3.73 (s, 5H), 3.23 (dd,J
= 8.9, 5.6 Hz, 1H), 3.05 (dd,J
= 9.0, 7.0 Hz, 1H), 2.43 - 2.32 (m, 1H), 2.27 - 2.16 (m, 1H), 2.17 - 2.07 (m, 1H), 1.93 (dt,J
= 12.3, 10.1 Hz, 1H);13
C NMR (101 MHz, DMSO) δ 158.16, 152.37, 150.31, 145.38, 143.73, 136.07, 133.63, 132.53, 129.87, 128.61, 127.97, 127.88, 126.74, 126.19, 113.32, 85.33, 71.86, 64.66, 55.19, 53.38, 47.58, 40.28, 34.51; ESI MS m/z (%): 656.3 (100) [M+H]; HRMS ESI (C39
H36
N5
O5
)計算值656.28675,實驗值:656.28619。
氫膦酸(1S
,2R
,4R
)-4-(6-苯甲醯胺基-9H
-嘌呤-9-基)-2-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)環戊酯,三乙銨鹽(32
):使中間物31
(500 mg,0.76 mmol)與吡啶(2×15 mL)共沸,溶解於吡啶(10 mL)中,且一次添加全量亞磷酸二苯酯(85%,516 µL,2.3 mmol)。在環境溫度下攪拌20分鐘後,添加TEA (1.13 mL),接著添加水(1.13 mL),且再攪拌反應物20分鐘。將所得溶液用DCM (200 mL)稀釋且用飽和NaHCO3
水溶液(2×100 mL)洗滌。有機層經硫酸鈉乾燥且蒸發。用FCC (DCM/1% Et3
N-MeOH 0至20%)純化所得中間物。
向以上中間物於DCM (10 mL)中之溶液中添加水(200 µL,11.1 mmol),接著添加DCA (568 µL,6.9 mmol)於DCM (6.3 mL)中之溶液。在環境溫度下攪拌反應混合物30分鐘,之後將其用三乙基矽烷(4.8 mL)淬滅。隨後攪拌反應混合物1小時,且隨後添加吡啶(5 ml),且蒸發揮發物。在逆相FCC (ACN之水溶液,0-50%)上純化,得到呈三乙銨鹽形式之32
:1
H NMR (400 MHz, DMSO-d 6
) δ 11.12 (s, 1H), 8.72 (s, 1H), 8.59 (s, 1H), 8.15 - 7.91 (m, 2H), 7.73 - 7.59 (m, 1H), 7.60 - 7.31 (m, 2H), 6.65 (d,J
= 562.7 Hz, 1H), 5.30 (s, 1H), 5.21 - 5.10 (m, 1H), 4.77 - 4.67 (m, 1H), 3.56 - 3.47 (m, 3H), 3.36 (q,J
= 7.2 Hz, 3H), 2.47 - 2.22 (m, 4H), 1.98 - 1.82 (m, 1H), 1.23 (t,J
= 7.2 Hz, 4H);31
P NMR (162 MHz, DMSO-d 6
) δ 4.69;negESI MS m/z (%): 416.1 (100) [M-H]; negHRMS ESI (C18
H19
N5
O5
P)計算值416.11293,實驗值:416.11263。
(2-氰基乙基)二異丙基胺基磷酸(1S,2R,4R)-4-(6-苯甲醯胺基-9H-嘌呤-9-基)-2-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)環戊酯(33
):在氬氣氛圍下向中間物32
(469 mg,0,72 mmol)於無水DCE (7 mL)中之溶液中添加雙(二異丙胺基)(2-氰基乙氧基)膦(454 μL,1.43 mmol),接著添加四唑(0.45 M MeCN溶液,4 mL,1.79 mmol),且將反應混合物在環境溫度下攪拌3小時。將所得混濁溶液用DCM (50 mL)稀釋,用飽和NaHCO3
水溶液(2×20 mL)洗滌,經硫酸鈉乾燥且蒸發。藉由二氧化矽上之急驟層析(丙酮/環己烷,0-70%)純化產物,在自苯凍乾之後得到呈非對映異構體之混合物形式之33
:31
P NMR (162 MHz, C6
D6
) δ 150.73, 150.56。
(1R
,2R
,3R
,5R
)-3-(6-氯-9H
-嘌呤-9-基)-5-(羥甲基)環戊烷-1,2-二醇(35
):將(1R
,2R
,3R
,5R
)-3-胺基-5-(羥甲基)環戊烷-1,2-二醇34
(1.27 g,8.6 mmol,根據Tetrahedron Lett .
,1999
,40
, 5783合成)、N
-(4, 6-二氯嘧啶-5-基)甲醯胺(1.98 g,10.3 mmol)及DIPEA (3 mL,17.2 mmol)於正丁醇(40 mL)中之溶液在壓力容器中加熱至140℃(浴)持續16小時(流程5)。蒸發揮發物,且將殘餘物在矽膠管柱上層析(500 g,乙酸乙酯→乙酸乙酯:丙酮:乙醇:水20:3:1.2:0.8,0-100%),得到35
:1
H NMR (400 MHz, DMSO-d6
) δ 8.77 (s, 1H), 8.69 (s, 1H), 5.13 (d,J
= 4.8 Hz, 1H), 5.11 - 5.03 (m, 2H), 4.71 (t,J
= 5.1 Hz, 1H), 3.93 (td,J
= 4.9, 2.5 Hz, 1H), 3.76 (td,J
= 4.6, 2.6 Hz, 1H), 3.61 (dt,J
= 10.7, 5.4 Hz, 1H), 3.49 (ddd,J
= 10.3, 6.9, 5.1 Hz, 1H), 2.33 (dt,J
= 12.4, 7.8 Hz, 1H), 2.12 (ddd,J
= 12.5, 11.1, 9.5 Hz, 1H), 2.03 - 1.93 (m, 1H);13
C NMR (101 MHz, DMSO-d6
) δ 152.45, 151.36, 148.84, 147.21, 130.95, 78.03, 76.59, 63.28, 56.04, 46.61, 30.16; ESI MS m/z (%): 307.0 (100) [M+Na]; HRMS ESI (C11
H13
N4
O3
ClNa)計算值307.05684,實驗值:307.05634。
(6aR
,8R
,9R
,9aR
)-8-(6-氯-9H
-嘌呤-9-基)-2,2,4,4-四異丙基六氫環戊[f] [1,3,5,2,4]三氧雜二矽雜環辛烷-9-醇(36
):使中間物35
(1.14 g,4.01 mmol)與吡啶(2×60 mL)共同蒸發,且溶解於無水吡啶(65 mL)中。向此溶液中逐滴添加(在15分鐘內) 1,3-二氯-1,1,3,3-四異丙基二矽氧烷(1.38 mL, 4.41 mmol)。將反應混合物在r.t.下攪拌18小時且蒸發。使殘餘物分配於乙酸乙酯(400 mL)與鹽水(150 mL)之間。將水相用乙酸乙酯(2×400 mL)萃取,合併之有機相經硫酸鈉乾燥且蒸發。進行急驟層析(120 g,環己烷-乙酸乙酯0→50%),得到36
:1
H NMR (400 MHz, DMSO-d 6
) δ 8.74 (s, 1H), 8.59 (s, 1H), 5.32 (d,J
= 5.0 Hz, 1H), 5.05 (ddd,J
= 10.9, 7.4, 6.0 Hz, 1H), 4.21 (dd,J
= 6.0, 3.7 Hz, 1H), 4.08 (td,J
= 5.7, 4.0 Hz, 1H), 3.99 (dd,J
= 11.5, 3.6 Hz, 1H), 3.75 (dd,J
= 11.5, 7.6 Hz, 1H), 2.38 - 2.03 (m, 3H), 1.19 - 0.91 (m, 28H);13
C NMR (101 MHz, DMSO) δ 152.49, 151.28, 148.92, 147.31, 131.02, 79.79, 75.99, 64.11, 55.00, 46.12, 29.17, 17.65, 17.51, 17.49, 17.43, 17.20, 17.19, 17.13, 13.10, 13.00, 12.62, 12.15; ESI MS m/z (%): 527.2 (100) [M+H]。
6-氯-9-((6aR
,8R
,9S
,9aR
)-9-氟-2,2,4,4-四異丙基六氫環戊[f] [1,3,5,2,4]三氧雜二矽雜環辛烷-8-基)-9H
-嘌呤(37
):使中間物36
(1.334 g,2.53 mmol)與甲苯(2×60 mL)共同蒸發,且溶解於無水二氯甲烷(66 mL)及吡啶(1.23 mL,15.2 mmol)中。將反應混合物用氬氣回填,且冷卻至-78℃。在10分鐘期間逐滴添加DAST (1.02 mL,7.59 mmol),且使反應混合物緩慢溫熱至r.t.隔夜。將反應混合物傾倒於冰-飽和NaHCO3
水溶液混合物(300 mL)上,且用二氯甲烷(3×150 mL)萃取水相。合併之有機相經硫酸鈉乾燥且蒸發。進行急驟層析(80 g,環己烷-乙酸乙酯0→40%),得到37
:1
H NMR (400 MHz, DMSO-d 6
) δ 8.75 (s, 1H), 8.59 (s, 1H), 5.30 (ddd,J
= 53.3, 5.1, 1.9 Hz, 1H), 5.21 - 5.07 (m, 1H), 4.72 (ddd,J
= 25.3, 9.9, 5.0 Hz, 1H), 3.96 (dd,J
= 11.8, 2.6 Hz, 1H), 3.85 (dd,J
= 11.8, 2.3 Hz, 1H), 2.29 - 2.16 (m, 2H), 2.10 - 1.97 (m, 1H), 1.15 - 0.99 (m, 28H);13
C NMR (101 MHz, DMSO) δ 151.63, 150.92, 149.42, 147.30, 131.85, 95.06 (d,J
= 188.2 Hz), 70.80 (d,J
= 18.0 Hz), 59.28, 59.11 (d,J
= 28.7 Hz), 43.84, 27.72 (d,J
= 3.5 Hz), 17.51, 17.41, 17.34, 17.26, 17.16, 17.13, 17.09, 12.89, 12.88, 12.42, 12.23;19
F NMR (376 MHz, DMSO-d 6
) δ -188.67 (ddd,J
= 54.3, 30.1, 25.3 Hz); ESI MS m/z (%): 529.2 (100) [M+H]; HRMS ESI (C23
H39
N4
O3
ClFSi2
)計算值529.22278,實驗值:529.22211。
N
-(9-((6aR
,8R
,9S
,9aR
)-9-氟-2,2,4,4-四異丙基六氫環戊[f][1,3,5,2,4]三氧雜二矽雜環辛烷-8-基)-9H
-嘌呤-6-基)苯甲醯胺(38
):向乾燥圓底燒瓶中置放Pd2
(dba)3
(37.7 mg,0.074 mmol)及dppf (60.5 mg,0.111 mmol),且將燒瓶用氬氣回填。向此混合物中添加37
(390 mg,0.74 mmol,與20 mL甲苯共同蒸發2次)於甲苯(18 mL)中之溶液,接著添加苯甲醯胺(100 mg,0.83 mmol)及碳酸銫(333 mg,1.02 mmol)。將燒瓶用氬氣回填且將反應混合物加熱至100℃(浴)持續24小時。用鹽水(120 mL)稀釋殘餘物,且用乙酸乙酯(4×150 mL)萃取產物。合併之有機相經硫酸鈉乾燥且蒸發。進行矽膠層析(200 g,甲苯-乙酸乙酯3:1 →甲苯-丙酮3:1),得到38
:1
H NMR (400 MHz, DMSO-d 6
) δ 11.18 (s, 1H), 8.56 (s, 1H), 8.54 (s, 1H), 8.19 - 7.90 (m, 2H), 7.72 - 7.62 (m, 1H), 7.60 - 7.51 (m, 2H), 5.31 (ddd,J
= 53.6, 5.1, 2.0 Hz, 1H), 5.14 (dt,J
= 30.1, 9.1 Hz, 1H), 4.80 (ddd,J
= 24.9, 9.7, 5.0 Hz, 1H), 3.99 (dd,J
= 11.9, 2.6 Hz, 1H), 3.88 (dd,J
= 11.8, 2.5 Hz, 1H), 2.25 (dq,J
= 12.9, 5.8 Hz, 2H), 2.11 - 1.95 (m, 1H), 1.39 - 0.75 (m, 28H);13
C NMR (101 MHz, DMSO) δ 165.74, 152.01, 151.01, 150.59, 144.45, 133.52, 132.59, 128.63, 128.55, 126.23, δ 95.30 (d,J
= 188.5 Hz), 70.81 (d,J
= 17.9 Hz), 59.45, 58.64 (d,J
= 28.2 Hz), 43.98, 27.92 (d,J
= 3.1 Hz), 17.54, 17.46, 17.43, 17.38, 17.28, 17.18, 17.15, 17.11, 12.92, 12.90, 12.47, 12.26;19
F NMR (376 MHz, DMSO-d 6
) δ -188.76 (ddd,J
= 54.1, 29.9, 24.8 Hz); ESI MS m/z (%): 613.4 (100) [M+H]。
N
-(9-((1R
,2S
,3R
,4R
)-2-氟-3-羥基-4-(羥甲基)環戊基)-9H
-嘌呤-6-基)苯甲醯胺(39
):使中間物38
(253 mg,0.41 mmol)與乙腈(2×15 mL)共同蒸發,溶解於無水乙腈(11 mL)中,且將燒瓶用氬氣回填。在3分鐘期間逐滴添加Et3
N.3HF (166 µL,1.02 mmol)於無水乙腈(1.5 mL)中之溶液。將反應混合物攪拌14小時,蒸發,與甲苯(15 mL)共同蒸發,且藉由逆相層析(50 g,H2
O:乙腈0 → 50%)純化產物,得到中間物39
:1
H NMR (400 MHz, DMSO-d6
) δ 11.17 (br s, 1H), 8.74 (s, 1H), 8.65 (s, 1H), 8.13 - 8.00 (m, 2H), 7.61 - 7.42 (m, 2H), 5.60 - 5.12 (m, 3H), 4.81 (t,J
= 5.2 Hz, 1H), 4.12 (dq,J
= 9.6, 4.9 Hz, 1H), 3.71 - 3.44 (m, 2H), 2.40 (dtd,J
= 12.9, 8.7, 2.1 Hz, 1H), 2.24 - 2.09 (m, 1H), 1.96 - 1.82 (m, 1H);13
C NMR (101 MHz, DMSO) δ 165.76, 152.51, 151.59, 150.50, 143.67, 133.55, 132.58, 128.62, 125.98, 95.13 (d,J
= 191.0 Hz), 70.12 (d,J
= 15.6 Hz), 62.10, 57.40 (d,J
= 23.4 Hz), 44.98 (d,J
= 2.1 Hz), 28.33 (d,J
= 6.7 Hz);19
F NMR (376 MHz, DMSO-d 6
) δ -200.08 (ddd,J
= 52.3, 19.4, 8.8 Hz); ESI MS m/z (%): 394.1 (100) [M+Na]; HRMS ESI (C18
H19
N5
O3
F)計算值:372.14664,實驗值:372.14644。
N
-(9-((1R
,2S
,3R
,4R
)-4-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-2-氟-3-羥基環戊基)-9H
-嘌呤-6-基)苯甲醯胺(40
):使中間物39
(267 mg,0.72 mmol)與吡啶(3×15 mL)共沸,溶解於吡啶(15 mL)中,且在0℃下一次添加全量DMTrCl (268 mg,0.79 mmol)。使反應混合物升溫至r.t.且再攪拌15小時。使反應混合物冷卻至0℃,且在0℃下一次添加全量第二部分DMTrCl (268 mg,0.79 mmol)。將反應混合物在r.t.下再攪拌4小時,隨後用飽和NaHCO3
水溶液(3 mL)淬滅且蒸發。使殘餘物溶解於乙酸乙酯(200 mL)中,且將有機相用飽和NaHCO3
水溶液(100 mL)及鹽水(100 mL)洗滌。有機相經硫酸鈉乾燥且蒸發。藉由TEA-滅活矽膠上之層析(甲苯:丙酮1:1)純化產物,得到40
:1
H NMR (400 MHz, DMSO-d 6
) δ 11.20 (br s, 1H), 8.70 (s, 1H), 8.59 (s, 1H), 8.22 - 7.96 (m, 2H), 7.75 - 7.60 (m, 1H), 7.61 - 7.49 (m, 2H), 7.49 - 7.40 (m, 2H), 7.37 - 7.20 (m, 6H), 6.90 (d,J
= 8.9 Hz, 3H), 5.32 (d,J
= 5.9 Hz, 1H), 4.26 (dq,J
= 12.0, 5.9 Hz, 1H), 3.74 (s, 6H), 3.23 (dd,J
= 9.1, 5.0 Hz, 1H), 3.14 (dd,J
= 9.1, 6.1 Hz, 1H), 2.48 - 2.39 (m, 1H), 2.38 - 2.30 (m, 1H), 2.09 - 1.99 (m, 1H);13
C NMR (101 MHz, DMSO) δ 158.20, 152.27, 151.37, 150.58, 145.34, 144.21, 135.97, 133.59, 132.59, 129.90, 128.63, 128.00, 127.87, 126.78, 126.18, 113.36, 94.98 (d,J
= 189.7 Hz), 85.43, 70.55 (d,J
= 16.6 Hz), 63.54, 58.24 (d,J
= 25.1 Hz), 55.20, 43.18, 28.95 (d,J
= 5.9 Hz);19
F NMR (376 MHz, DMSO-d 6
) δ -196.32 (ddd,J
= 52.7, 23.0, 12.9 Hz); ESI MS m/z (%): 674.3 (100) [M+H]; HRMS ESI (C39
H37
N5
O5
F)計算值:674.27732,實驗值:674.27606。
氫膦酸(1R
,2S
,3R
,5R
)-3-(6-苯甲醯胺基-9H
-嘌呤-9-基)-2-氟-5-(羥甲基)環戊酯,三乙銨鹽(41
):使中間物40
(408 mg,0.61 mmol)與吡啶(2×10 mL)共沸,溶解於吡啶(10 mL)中,且一次添加全量亞磷酸二苯酯(85,410 µL,1.83 mmol)。在環境溫度下攪拌20分鐘後,添加TEA (0.9 mL),接著添加水(0.9 mL),且再攪拌反應物20分鐘。將所得溶液用DCM (200 mL)稀釋且用飽和NaHCO3
水溶液(2×100 mL)洗滌。有機層經硫酸鈉乾燥且蒸發。在FCC (DCM/1% Et3
N-MeOH 0至20%)上純化殘餘物。向所獲得之中間物於DCM (10 mL)中之溶液中添加水(200 μL, 11.1 mmol)及DCA (452 µL,5.5 mmol)於DCM (5 mL)中之溶液,且將反應混合物在環境溫度下攪拌30分鐘,之後將其用三乙基矽烷(4.8 mL)淬滅。攪拌反應混合物1小時,且隨後添加吡啶(2 ml),且蒸發揮發物。在逆相FCC (ACN之水溶液,0-50%)上純化,得到呈三乙銨鹽形式之41
:1
H NMR (400 MHz, DMSO-d 6
) δ 11.18 (s, 1H), 8.74 (s, 1H), 8.65 (s, 1H), 8.25 - 7.93 (m, 2H), 7.73 - 7.62 (m, 1H), 7.55 (dd,J
= 8.2, 6.9 Hz, 2H), 6.73 (dd,J
= 601.5, 1.4 Hz, 1H), 5.35 (dt,J
= 52.4, 5.7 Hz, 1H), 5.26 - 5.13 (m, 1H), 4.64 (tt,J
= 11.3, 5.5 Hz, 1H), 3.57 (qd,J
= 11.1, 4.6 Hz, 2H), 3.10 - 3.00 (m, 4H), 2.44 - 2.21 (m, 2H), 2.02 - 1.88 (m, 1H), 1.18 (t,J
= 7.3 Hz, 6H);31
P NMR (162 MHz, DMSO-d 6
) δ 3.72;19
F NMR (376 MHz, DMSO-d 6
) δ -195.36; ESI MS m/z (%): 436.1 (100) [M+H]; HRMS ESI (C18
H20
N5
O5
FP)計算值:436.11806,實驗值:436.11748。
(2-氰基乙基)二異丙基胺基磷酸(1R,2S,3R,5R)-3-(6-苯甲醯胺基-9H-嘌呤-9-基)-5-((雙(4-甲氧基苯基)(苯基)甲氧基)甲基)-2-氟環戊酯(42
):在氬氣氛圍下向中間物40
(335 mg,0,5 mmol)於無水DCE (5 mL)中之溶液中添加雙(二異丙胺基)(2-氰基乙氧基)膦(315 μL,1 mmol),接著添加四唑溶液(0.45 M MeCN溶液,2.76 mL,1.24 mmol),且將反應混合物在環境溫度下攪拌3小時。將所得混濁溶液用DCM (50 mL)稀釋,用飽和NaHCO3
水溶液(2×20 mL)洗滌,經硫酸鈉乾燥且蒸發。藉由二氧化矽上之急驟層析純化(丙酮/環己烷,0-70%)產物,在自苯凍乾之後得到呈非對映異構體之混合物形式之42
:31
P NMR (162 MHz, 苯-d 6
) δ 152.92 (d,J
= 10.5 Hz), 152.67 (d,J
= 16.6 Hz)。實例 2 . 化合物 101 之製備
將18
(55 mg, 0.1 mmol)及三氟乙酸吡錠(29 mg,0.15 mmol)之混合物與無水ACN (3×3 mL)共蒸餾,懸浮於無水ACN (1 mL)中且在密封容器中經活化分子篩攪拌隔夜(流程6)。在單獨的燒瓶中,將N-苯甲醯基-5'-O-[雙(4-甲氧基苯基)苯基甲基]-2'-O-[(1,1-二甲基乙基)二甲基矽烷基]-腺苷, 3'-[2-氰基乙基N,N-雙(1-甲基乙基)亞胺基磷酸酯(107 mg,0.125 mmol,CAS號104992-55-4,購自Sigma-Aldrich)與無水ACN (3×3 mL)共蒸餾,懸浮於無水ACN (1 mL)中且在密封容器中經活化分子篩攪拌隔夜。將亞胺基磷酸酯之溶液經由針筒轉移至具有18
與py-TFA之懸浮液之燒瓶中,且將所得溶液在環境溫度下攪拌1小時。添加TBHP (5.5 M癸烷溶液,55 μL,0.3 mmol)且將反應混合物再攪拌30分鐘。將反應混合物用NaHSO3
(39%水溶液,54 μL,0.27 mmol)淬滅,過濾且蒸發,得到粗直鏈二聚體43
,其不經進一步純化即用於下一反應。
向粗43
於DCM (3 mL)中之溶液中逐滴添加水(18 μL,1 mmol)及DCA (74 mL,0.9 mmol)於DCM (3 mL)中之溶液。攪拌反應混合物30分鐘後,添加TES (1.5 mL),且再攪拌反應混合物90分鐘,之後將其藉由添加吡啶(1.5 mL)淬滅。蒸發揮發物,且將粗44
與無水吡啶(3×3 mL)共蒸餾且不經進一步純化即用於下一反應。
向粗44
於吡啶(2 mL)中之溶液中添加DMOCP (65 mg,0.35 mmol),且將反應混合物在環境溫度下攪拌1小時。添加水(59 μL,0.35 mmol),接著添加碘(34 mg,0.13 mmol),且將反應混合物攪拌10分鐘,之後使其冷卻至0℃,且藉由添加NaHSO3
(39%水溶液,49 μL,0.25 mmol)淬滅。在逆相FCC (ACN/50 mM NH4
HCO3
水溶液0-70%)上純化,得到45
。
將45
(20 mg)於CH3
NH2
(33%乙醇溶液,1 mL)中之溶液在環境溫度下攪拌3小時。蒸發揮發物,且將殘餘物與吡啶(3×2 mL)共蒸餾,溶解於吡啶-TEA (1:1,v
/v
, 1 mL)中,且逐滴添加HF-TEA (160 mL,1 mmol)。將反應混合物在50℃下攪拌1小時,用1 M乙酸銨(2 mL)淬滅且在製備型HPLC (ACN/0.1 M TEAB,0-30%)上純化。將適當溶離份合併,蒸發,與水(3×20 mL)及甲醇(3×20 mL)共蒸餾,溶解於水(10 mL)中,且緩慢通過10 mL Dowex 50 (Na+循環)管柱。冷凍乾燥溶離液,得到2-胺基-9-((2R,3R,3aS,7aR,9R,10S,10aR,14aR)-2-(6-胺基-9H-嘌呤-9-基)-3,5,10,12-四羥基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3, 2-j][1,3,7,9]四氧雜[2,8]二磷雜環-十二烯-9-基)-1,9-二氫-6H-嘌呤-6-酮(101
)之鈉鹽:HPLC滯留時間(HILIC, min): 4.80;1
H NMR (600 MHz, D2
O) δ 8.46 (s, 1H), 8.21 (s, 1H), 7.90 (s, 1H), 6.19 (d,J
= 1.1 Hz, 1H), 4.91 (td,J
= 8.7, 4.7 Hz, 1H), 4.72 (dd,J
= 4.7, 1.1 Hz, 1H), 4.68 (td,J
= 8.6, 4.8 Hz, 1H), 4.64 (td,J
= 8.1, 5.5 Hz, 1H), 4.53 (ddd,J
= 9.3, 2.5, 1.3 Hz, 1H), 4.47 (dd,J
= 5.5, 4.8 Hz, 1H), 4.47 (m, 1H), 4.40 (dt,J
= 12.0, 1.6 Hz, 1H), 4.20 (ddd,J
= 12.0, 3.7, 1.5 Hz, 1H), 4.08 (dt,J
= 10.4, 3.0 Hz, 1H), 4.02 (ddd,J
= 10.4, 4.8, 3.0 Hz, 1H), 2.57 (m, 1H), 2.44 (dt,J
= 13.8, 8.7 Hz, 1H), 2.14 (ddd,J
= 13.8, 9.8, 8.5 Hz, 1H);31
P NMR (202 MHz, D2
O) δ 0.40, 0.07; MS (M-H)-
671.1。實例 3 . 3 ' 3 ' CDN 硫代磷酸酯化合物 102a - 102d 之製備
將41
(55 mg,0.1 mmol)及三氟乙酸吡錠(29 mg,0.15 mmol)之混合物與無水MeCN (3×3 mL)共蒸餾,懸浮於無水MeCN (1 mL)中且在密封容器中經活化分子篩攪拌隔夜。在單獨的燒瓶中,將N-苯甲醯基-5'-O-[雙(4-甲氧基苯基)苯基甲基]-2'-去氧-2'-氟腺苷, 3'-[2-氰基乙基N,N-雙(1-甲基乙基)亞胺基磷酸酯(110 mg,0.125 mmol,CAS號136834-22-5,購自Sigma-Aldrich))與無水MeCN (3×3 mL)共蒸餾,懸浮於無水MeCN (1 mL)中且在密封容器中經活化分子篩攪拌隔夜。將來自商品之亞胺基磷酸酯之溶液經由針筒轉移至具有41
與py-TFA之懸浮液之燒瓶中,且將所得溶液在環境溫度下攪拌1小時。添加3-((N,N-二甲胺基亞甲基)胺基)-3H-1,2,4-二噻唑-5-硫酮(23 mg,0.11 mmol),且再攪拌反應混合物30分鐘。蒸發揮發物,得到粗直鏈二聚體46,其不經進一步純化即用於下一反應。
向粗46
於DCM (3 mL)中之溶液中逐滴添加水(18 μL,1 mmol)及DCA (74 μL,0.9 mmol)於DCM (3 mL)中之溶液。攪拌反應混合物30分鐘後,添加TES (1.5 mL),且再攪拌反應混合物90分鐘,之後將其藉由添加吡啶(1.5 mL)淬滅。蒸發揮發物,且將粗47
與無水吡啶(3×3 mL)共蒸餾且不經進一步純化即用於下一反應。
向粗47
於吡啶(2 mL)中之溶液中添加DMOCP (65 mg,0.35 mmol),且在環境溫度下攪拌反應混合物1小時。添加水(18 μL,1 mmol),接著添加3H-1,2-苯并二硫醇-3-酮(25 mg,0.15 mmol),且攪拌反應混合物10分鐘。蒸發揮發物,且在逆相FCC (MeCN/50 mM NH4
HCO3
水溶液0-70%)上分離產物,得到呈非對映異構體之混合物形式之48
。
將48
(23 mg)於CH3
NH2
(33%乙醇溶液,1 mL)中之溶液在環境溫度下攪拌3小時。蒸發揮發物,且在製備型HPLC (MeCN/0.1M TEAB,0-30%)上純化產物。重複冷凍乾燥合併適當溶離份以移除TEAB後,化合物102a - 102d
按其自HPLC管柱溶離順序以三乙胺鹽形式以10:9:37:44比率分別分離為四種非對映異構體:102a - 102d
:HPLC滯留時間(C18, min): 分別2.23, 2.37, 2.49, 2.62。
根據上文所描述之合成方法合成以下化合物。以下實例中之化合物使用MarvinSketch (ChemAxon, Budapest, Hungary)命名。實例 4 . 例示性式 ( I ) 化合物之合成及表徵
以下展示之化合物根據上文所描述之合成方法合成。在25℃下收集NMR譜。
實例 5 . 5 ' - 三磷酸碳腺苷之合成及表徵
實例 | 結構 / 名稱 / 表徵 | 質譜 [M-H]- |
102a | (2R,3R,3aR,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3,10-二氟-5,12-二巰基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯5,12-二氧化物 | 691.1 |
102a :HPLC滯留時間(C18, min): 2.23 | ||
102b | (2R,3R,3aR,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3,10-二氟-5,12-二巰基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯5,12-二氧化物 | 691.1 |
102b :HPLC滯留時間(C18, min): 2.37 | ||
102c | (2R,3R,3aR,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3,10-二氟-5,12-二巰基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯5,12-二氧化物 | 691.1 |
102c :HPLC滯留時間(C18, min): 2.49;1 H NMR (600 MHz, D2 O) δ 8.23 (s, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 6.54 (d,J = 14.3 Hz, 1H), 5.83 (dd,J = 50.7, 3.2 Hz, 1H), 5.16 (d,J = 51.5 Hz, 1H), 5.14 (m, 1H), 4.75 (m, 1H), 4.58 (m, 1H), 4.56 (m, 1H), 4.54 (m, 1H), 4.21 (m, 1H), 4.08 (m, 1H), 4.06 (m, 1H), 2.86 (m, 1H), 2.70 (m, 1H), 2.28 (m, 1H);31 P NMR (202 MHz, D2 O) δ 55.29, 54.68;19 F NMR (470 MHz, D2 O) δ -199.94, -195.80。 | ||
102d | (2R,3R,3aR,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3,10-二氟-5,12-二巰基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯5,12-二氧化物 | 691.1 |
102d :HPLC滯留時間(C18, min): 2.62;1 H NMR (600 MHz, D2 O) δ 8.41 (s, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 8.03 (s, 1H), 6.52 (d,J = 14.2 Hz, 1H), 5.53 (dd,J = 51.4, 3.4 Hz, 1H), 5.30 (ddd,J = 51.1, 3.0, 1.5 Hz, 1H), 5.18 (dddd,J = 16.5, 9.6, 4.2, 1.5 Hz, 1H), 5.00 (dtd,J = 24.4, 9.5, 9.5, 3.4 Hz, 1H), 4.76 (m, 1H), 4.65 (dt,J = 11.8, 1.8, 1.8 Hz, 1H), 4.59 (m, 1H), 4.34 (dt,J = 10.5, 2.6, 2.6 Hz, 1H), 4.14 (dd,J = 11.8, 4.3 Hz, 1H), 4.07 (ddd,J = 10.5, 2.5, 1.8 Hz, 1H), 2.89 (ddd,J = 15.5, 10.4, 9.6 Hz, 1H), 2.76 (m, 1H), 2.34 (ddd,J = 15.5, 8.9, 4.2 Hz, 1H);31 P NMR (202 MHz, D2 O) δ 56.39, 55.17;19 F NMR (470 MHz, D2 O) δ -198.60, -195.30。 | ||
103 | 由中間物18 及來自商品之亞胺基磷酸酯製備之2-胺基-9-((2R,3R,3aR,7aR,9R,10S,10aR,14aR)-2-(6-胺基-9H-嘌呤-9-基)-3-氟-5,10,12-三羥基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-9-基)-1,9-二氫-6H-嘌呤-6-酮 | 673.1 |
103 :HPLC滯留時間(HILIC, min): 4.69;1 H NMR (600 MHz, D2 O) δ 8.43 (s, 1H), 8.22 (s, 1H), 7.92 (s, 1H), 6.48 (d,J = 16.7 Hz, 1H), 5.49 (dd,J = 51.9, 4.0 Hz, 1H), 5.01 (dddd,J = 24.4, 9.3, 8.5, 4.0 Hz, 1H), 4.69 (td,J = 8.6, 4.6 Hz, 1H), 4.63 (td,J = 8.1, 5.5 Hz, 1H), 4.53 (ddd,J = 9.3, 2.5, 1.3 Hz, 1H), 4.47 (dd,J = 5.5, 4.6 Hz, 1H), 4.43 (dd,J = 12.2, 2.5 Hz, 1H), 4.21 (ddd,J = 12.2, 3.8, 1.3 Hz, 1H), 4.09 (dt,J = 10.5, 3.1 Hz, 1H), 4.04 (ddd,J = 10.5, 4.5, 3.1 Hz, 1H), 2.56 (m, 1H), 2.45 (dt,J = 13.8, 8.7 Hz, 1H), 2.20 (ddd,J = 13.8, 10.5, 8.6 Hz, 1H);31 P NMR (202 MHz, D2 O) δ 0.14, -0.12;19 F NMR (470 MHz, D2 O) δ -198.2。 | ||
104 | 9-((2R,3R,3aS,7aR,9R,10S,10aR,14aR)-2-(6-胺基-9H-嘌呤-9-基)-3,5,10,12-四羥基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-9-基)-1,9-二氫-6H-嘌呤-6-酮 | 656.1 |
104 :HPLC滯留時間(HILIC, min): 4.60;1 H NMR (600 MHz, D2 O) δ 8.45 (s, 1H), 8.26 (s, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 6.20 (d,J = 1.2 Hz, 1H), 4.93 (td,J = 8.7, 4.7 Hz, 1H), 4.89 (td,J = 8.6, 5.4 Hz, 1H), 4.73 (dd,J = 4.7, 1.2 Hz, 1H), 4.64 (ddd,J = 8.6, 7.4, 5.8 Hz, 1H), 4.54 (dd,J = 5.8, 5.4 Hz, 1H), 4.47 (m, 1H), 4.39 (dt,J = 12.0, 2.0 Hz, 1H), 4.20 (ddd,J = 12.0, 3.6, 1.7 Hz, 1H), 4.09 (dt,J = 10.4, 3.0 Hz, 1H), 4.03 (ddd,J = 10.4, 5.1, 3.1 Hz, 1H), 2.61 (m, 1H), 2.54 (dt,J = 13.6, 8.5 Hz, 1H), 2.08 (ddd,J = 13.6, 10.0, 8.7 Hz, 1H);31 P NMR (202 MHz, D2 O) δ 0.41, 0.20。 | ||
105 | 2-胺基-9-((2R,3S,3aR,7aR,9R,10S,10aR,14aR)-2-(6-胺基-9H-嘌呤-9-基)-3-氟-5,10,12-三羥基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-9-基)-1,9-二氫-6H-嘌呤-6-酮 | 673.1 |
105 :HPLC滯留時間(HILIC, min): 4.62;1 H NMR (600 MHz, D2 O) δ 8.46 (s, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 6.59 (dd,J = 13.3, 4.7 Hz, 1H), 5.59 (ddd,J = 51.4, 4.7, 3.7 Hz, 1H), 5.11 (dddd,J = 20.5, 9.2, 6.5, 3.7 Hz, 1H), 4.72 (ddd,J = 10.2, 8.3, 6.2 Hz, 1H), 4.70 (dd,J = 8.5, 6.3 Hz, 1H), 4.53 (t,J = 6.2 Hz, 1H), 4.36 (m, 1H), 4.26 (dt,J = 11.5, 3.4 Hz, 1H), 4.23 (dt,J = 11.5, 4.0 Hz, 1H), 4.09 (dt,J = 10.3, 3.0 Hz, 1H), 4.01 (ddd,J = 10.3, 6.1, 3.8 Hz, 1H), 2.59 (m, 1H), 2.44 (dt,J = 13.5, 8.3 Hz, 1H), 2.01 (dt,J = 13.5, 10.2 Hz, 1H);31 P NMR (202 MHz, D2 O) δ 0.64, 0.55;19 F NMR (470 MHz, D2 O) δ -193.3。 | ||
106 | 由中間物18 及來自商品之亞胺基磷酸酯製備之2-胺基-9-((2R,3aS,7aR,9R,10S,10aR,14aR)-2-(6-胺基-9H-嘌呤-9-基)-5,10,12-三羥基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-9-基)-1,9-二氫-6H-嘌呤-6-酮 | 655.1 |
106 :HPLC滯留時間(HILIC, min): 4.67;1 H NMR (600 MHz, D2 O) δ 8.44 (s, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 6.51 (dd,J = 7.3, 3.5 Hz, 1H), 5.09 (五重峰,J = 7.5 Hz, 1H), 4.72 (ddd,J = 9.3, 8.5, 5.4 Hz, 1H), 4.66 (td,J = 7.8, 5.8 Hz, 1H), 4.50 (t,J = 5.6 Hz, 1H), 4.31 (m, 1H), 4.18 (m, 2H), 4.07 (dt,J = 10.3, 3.0 Hz, 1H), 4.00 (ddd,J = 10.3, 5.0, 3.4 Hz, 1H), 2.97 (ddd,J = 14.1, 7.4, 3.5 Hz, 1H), 2.81 (dt,J = 14.1, 7.5 Hz, 1H), 2.57 (m, 1H), 2.45 (dt,J = 13.6, 8.5 Hz, 1H), 2.11 (ddd,J = 13.6, 10.3, 9.3 Hz, 1H);31 P NMR (202 MHz, D2 O) δ 0.75, 0.43。 | ||
107 | 9-((2R,3R,3aR,7aR,9R,10S,10aR,14aR)-2-(6-胺基-9H-嘌呤-9-基)-3-氟-5,10,12-三羥基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-9-基)-1,9-二氫-6H-嘌呤-6-酮 | 658.1 |
107 :HPLC滯留時間(HILIC, min): 4.43;1 H NMR (600 MHz, D2 O) δ 8.41 (s, 1H), 8.25 (s, 1H), 8.23 (s, 1H), 8.13 (s, 1H), 6.49 (d,J = 17.2 Hz, 1H), 5.50 (dd,J = 51.9, 4.1 Hz, 1H), 5.04 (dtd,J = 23.8, 9.0, 4.1 Hz, 1H), 4.89 (td,J = 8.5, 5.2 Hz, 1H), 4.63 (td,J = 8.0, 5.7 Hz, 1H), 4.55 (t,J = 5.5 Hz, 1H), 4.53 (m, 1H), 4.43 (m, 1H), 4.23 (ddd,J = 12.1, 3.6, 1.4 Hz, 1H), 4.10 (dt,J = 10.5, 3.1 Hz, 1H), 4.05 (ddd,J = 10.5, 4.7, 3.4 Hz, 1H), 2.60 (m, 1H);31 P NMR (202 MHz, D2 O) δ 0.15, -0.03;19 F NMR (470 MHz, D2 O) δ -197.8。 | ||
108 | 2-胺基-9-((2R,3R,3aS,7aR,9R,10S,10aR,14aR)-9-(6-胺基-9H-嘌呤-9-基)-3,5,10,12-四羥基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-2-基)-1,9-二氫-6H-嘌呤-6-酮 | 671.1 |
108 :HPLC滯留時間(HILIC, min): 4.79;1 H NMR (600 MHz, D2 O) δ 8.31 (s, 1H), 8.18 (s, 1H), 8.05 (s, 1H), 5.98 (d,J = 1.6 Hz, 1H), 4.94 (td,J = 8.5, 4.9 Hz, 1H), 4.86 (td,J = 8.2, 5.1 Hz, 1H), 4.73 (dd,J = 4.9, 1.6 Hz, 1H), 4.62 (ddd,J = 8.3, 7.5, 5.5 Hz, 1H), 4.53 (t,J = 5.3 Hz, 1H), 4.41 (dt,J = 8.5, 2.1 Hz, 1H), 4.35 (dt,J = 11.9, 2.3 Hz, 1H), 4.18 (ddd,J = 11.9, 3.7, 1.8 Hz, 1H), 4.10 (dt,J = 10.3, 3.0 Hz, 1H), 4.06 (ddd,J = 10.3, 4.8, 3.0 Hz, 1H), 2.63 (m, 1H), 2.58 (dt,J = 13.4, 8.8 Hz, 1H), 2.07 (ddd,J = 13.4, 9.1, 7.9 Hz, 1H);31 P NMR (202 MHz, D2 O) δ 0.38, 0.23。 | ||
109 | 2-胺基-9-((2R,3R,3aR,7aR,9R,10S,10aR,14aR)-9-(6-胺基-9H-嘌呤-9-基)-3-氟-5,10,12-三羥基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-2-基)-1,9-二氫-6H-嘌呤-6-酮 | 673.1 |
109 :HPLC滯留時間(HILIC, min): 4.71;1 H NMR (600 MHz, D2 O) δ 8.34 (s, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 6.28 (d,J = 19.1 Hz, 1H), 5.51 (dd,J = 52.0, 4.4 Hz, 1H), 5.07 (m, 1H), 4.88 (td,J = 8.1, 4.7 Hz, 1H), 4.60 (td,J = 8.0, 4.7 Hz, 1H), 4.52 (t,J = 5.1 Hz, 1H), 4.45 (dq,J = 9.2, 2.0 Hz, 1H), 4.38 (m, 1H), 4.19 (ddd,J = 12.1, 3.8, 1.7 Hz, 1H), 4.11 (dt,J = 10.5, 2.7 Hz, 1H), 4.08 (dt,J = 10.5, 3.5 Hz, 1H), 2.61 (m, 1H), 2.59 (m, 1H), 2.12 (m, 1H);31 P NMR (202 MHz, D2 O) δ 0.08, 0.01;19 F NMR (470 MHz, D2 O) δ -196.6。 | ||
110 | 2-胺基-9-((2R,3aS,7aR,9R,10S,10aR,14aR)-9-(6-胺基-9H-嘌呤-9-基)-5,10,12-三羥基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-2-基)-1,9-二氫-6H-嘌呤-6-酮 | 655.1 |
110 :HPLC滯留時間(HILIC, min): 4.74;1 H NMR (600 MHz, D2 O) δ 8.36 (s, 1H), 8.23 (s, 1H), 8.03 (s, 1H), 6.32 (dd,J = 7.5, 3.0 Hz, 1H), 5.10 (m, 1H), 4.89 (td,J = 8.3, 5.5 Hz, 1H), 4.65 (ddd,J = 8.4, 7.2, 5.5 Hz, 1H), 4.53 (t,J = 5.5 Hz, 1H), 4.28 (m, 1H), 4.18 (ddd,J = 11.5, 4.3, 3.4 Hz, 1H), 4.14 (ddd,J = 11.5, 4.2, 2.8 Hz, 1H), 4.09 (dt,J = 10.4, 3.1 Hz, 1H), 4.03 (ddd,J = 10.4, 4.8, 3.2 Hz, 1H), 2.96 (ddd,J = 14.0, 7.5, 4.3 Hz, 1H), 2.75 (ddd,J = 14.0, 7.5, 6.9 Hz, 1H), 2.63 (m, 1H), 2.57 (dt,J = 13.6, 8.6 Hz, 1H), 2.09 (ddd,J = 13.6, 9.2, 8.0 Hz, 1H);31 P NMR (202 MHz, D2 O) δ 0.62, 0.58。 | ||
111 | 2-胺基-9-((2R,3S,3aR,7aR,9R,10S,10aR,14aR)-9-(6-胺基-9H-嘌呤-9-基)-3-氟-5,10,12-三羥基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-2-基)-1,9-二氫-6H-嘌呤-6-酮 | 673.1 |
111 :HPLC滯留時間(HILIC, min): 4.76;1 H NMR (600 MHz, D2 O) δ 8.34 (s, 1H), 8.23 (s, 1H), 8.05 (d,J = 2.4 Hz, 1H), 6.39 (dd,J = 14.0, 4.8 Hz, 1H), 5.53 (ddd,J = 51.5, 4.8, 3.6 Hz, 1H), 5.08 (dddd,J = 20.7, 8.3, 6.4, 3.6 Hz, 1H), 4.90 (td,J = 8.6, 5.9 Hz, 1H), 4.68 (ddd,J = 8.7, 6.5, 5.7 Hz, 1H), 4.55 (t,J = 5.8 Hz, 1H), 4.30 (m, 1H), 4.22 (m, 2H), 4.10 (dt,J = 10.3, 2.8 Hz, 1H), 4.04 (ddd,J = 10.3, 5.5, 3.3 Hz, 1H), 2.64 (m, 1H), 2.56 (dt,J = 13.6, 8.6 Hz, 1H), 2.06 (ddd,J = 13.6, 10.1, 8.6 Hz, 1H);31 P NMR (202 MHz, D2 O) δ 0.59, 0.34;19 F NMR (470 MHz, D2 O) δ -192.6。 | ||
112 | 2-胺基-9-((2R,3S,3aS,7aR,9R,10S,10aR,14aR)-9-(6-胺基-9H-嘌呤-9-基)-3,5,10,12-四羥基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-2-基)-1,9-二氫-6H-嘌呤-6-酮 | 671.1 |
112 :HPLC滯留時間(HILIC, min): 4.87;1 H NMR (600 MHz, D2 O) δ 8.35 (s, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 6.30 (d,J = 6.3 Hz, 1H), 4.90 (td,J = 8.5, 5.7 Hz, 1H), 4.89 (m, 1H), 4.77 (m, 1H), 4.66 (ddd,J = 8.3, 6.7, 5.4 Hz, 1H), 4.55 (t,J = 5.5 Hz, 1H), 4.28 (m, 2H), 4.21 (dt,J = 12.7, 4.0 Hz, 1H), 4.10 (dt,J = 10.4, 3.2 Hz, 1H), 4.04 (ddd,J = 10.4, 5.7, 3.3 Hz, 1H), 2.64 (m, 1H), 2.59 (ddd,J = 13.6, 9.2, 7.9 Hz, 1H), 2.08 (ddd,J = 13.6, 9.2, 8.0 Hz, 1H);31 P NMR (202 MHz, D2 O) δ 1.39, 0.51。 | ||
113 | 2-胺基-9-((2R,3S,3aS,7aR,9R,10S,10aR,14aR)-2-(6-胺基-9H-嘌呤-9-基)-3,5,10,12-四羥基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-9-基)-1,9-二氫-6H-嘌呤-6-酮 | 671.1 |
113 :HPLC滯留時間(HILIC, min): 4.84;1 H NMR (600 MHz, D2 O) δ 8.49 (s, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 6.49 (d,J = 6.2 Hz, 1H), 4.89 (ddd,J = 7.9, 7.5, 6.4 Hz, 1H), 4.83 (t,J = 6.3 Hz, 1H), 4.72 (ddd,J = 9.8, 8.2, 6.7 Hz, 1H), 4.67 (dt,J = 8.6, 6.0 Hz, 1H), 4.55 (dd,J = 6.7, 5.7 Hz, 1H), 4.33 (m, 1H), 4.26 (dt,J = 11.6, 2.9 Hz, 1H), 4.24 (ddd,J = 11.6, 3.6, 2.5 Hz, 1H), 4.08 (dt,J = 10.3, 3.3 Hz, 1H), 3.99 (ddd,J = 10.3, 6.3, 4.0 Hz, 1H), 2.59 (m, 1H), 2.45 (dt,J = 13.5, 8.5 Hz, 1H), 1.98 (dt,J = 13.5, 10.1 Hz, 1H);31 P NMR (202 MHz, D2 O) δ 1.40, 0.54。 | ||
114 | 2-胺基-9-((2R,3R,3aR,7aR,9R,10S,10aR,14aR)-9-(6-胺基-9H-嘌呤-9-基)-5,10,12-三羥基-3-甲氧基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-2-基)-1,9-二氫-6H-嘌呤-6-酮 | 685.1 |
114 :HPLC滯留時間(HILIC, min): 4.56;1 H NMR (600 MHz, D2 O) δ 8.31 (s, 1H), 8.19 (s, 1H), 8.03 (s, 1H), 6.06 (d,J = 1.4 Hz, 1H), 4.98 (td,J = 8.6, 5.1 Hz, 1H), 4.86 (td,J = 8.3, 5.1 Hz, 1H), 4.61 (ddd,J = 8.4, 7.4, 5.5 Hz, 1H), 4.52 (t,J = 5.3 Hz, 1H), 4.41 (dd,J = 5.1, 1.4 Hz, 1H), 4.36 (m, 1H), 4.34 (dt,J = 11.7, 2.3 Hz, 1H), 4.17 (ddd,J = 11.7, 3.7, 1.5 Hz, 1H), 4.09 (dt,J = 10.4, 3.0 Hz, 1H), 4.04 (ddd,J = 10.4, 4.1, 3.0 Hz, 1H), 2.62 (m, 1H), 2.57 (dt,J = 13.5, 8.7 Hz, 1H), 2.06 (ddd,J = 13.5, 9.2, 8.0 Hz, 1H);31 P NMR (202 MHz, D2 O) δ 0.21, 0.12。 | ||
115 | (6R,8R,15R,17R)-17-(2-胺基-6-側氧基-6,9-二氫-1H-嘌呤-9-基)-8-(6-胺基-9H-嘌呤-9-基)-3,9,12-三羥基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 655.1 |
115 :HPLC滯留時間(HILIC, min): 4.68;1 H NMR (600 MHz, D2 O) δ 8.50 (s, 1H), 8.24 (s, 1H), 7.92 (s, 1H), 6.21 (d,J = 1.0 Hz, 1H), 4.95 (m, 1H), 4.90 (td,J = 8.8, 4.7 Hz, 1H), 4.78 (m, 1H), 4.71 (dd,J = 4.7, 1.0 Hz, 1H), 4.46 (m, 1H), 4.38 (m, 1H), 4.17 (ddd,J = 12.0, 3.9, 1.5 Hz, 1H), 4.08 (dt,J = 10.3, 2.8 Hz, 1H), 3.94 (ddd,J = 10.3, 4.8, 2.6 Hz, 1H), 2.49 (m, 1H), 2.45 (m, 1H), 2.44 (m, 2H), 2.07 (m, 1H);31 P NMR (202 MHz, D2 O) δ 0.57, 0.08。 | ||
116 | 使用實例2中所描述之方法,由中間物27 及N-苯甲醯基-5'-O-[雙(4-甲氧基苯基)苯基甲基]-2'-去氧-2'-氟腺苷, 3'-[2-氰基乙基N,N-雙(1-甲基乙基)胺基磷酸酯合成之(6R,8R,15R,17R)-17-(2-胺基-6-側氧基-6,9-二氫-1H-嘌呤-9-基)-8-(6-胺基-9H-嘌呤-9-基)-9-氟-3,12-二羥基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 657.1 |
116 :HPLC滯留時間(HILIC, min): 4.57;1 H NMR (600 MHz, D2 O) δ 8.44 (s, 1H), 8.22 (s, 1H), 7.90 (s, 1H), 6.47 (d,J = 16.8 Hz, 1H), 5.48 (dd,J = 51.8, 4.0 Hz, 1H), 5.01 (dddd,J = 23.8, 6.8, 6.0, 4.0 Hz, 1H), 4.95 (m, 1H), 4.77 (m, 1H), 4.52 (m, 1H), 4.41 (dd,J = 12.2, 2.1 Hz, 1H), 4.18 (ddd,J = 12.2, 4.1, 1.3 Hz, 1H), 4.09 (dt,J = 10.4, 2.9 Hz, 1H), 3.96 (ddd,J = 10.4, 4.3, 2.7 Hz, 1H), 2.49 (m, 1H), 2.43 (m, 3H), 2.10 (m, 1H);31 P NMR (202 MHz, D2 O) δ 0.27, 0.01;19 F NMR (470 MHz, D2 O) δ -198.1。 | ||
117 | (6R,8R,15R,17R)-17-(2-胺基-6-側氧基-6,9-二氫-1H-嘌呤-9-基)-8-(6-胺基-9H-嘌呤-9-基)-3,12-二羥基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 639.1 |
117 :HPLC滯留時間(HILIC, min): 4.59;1 H NMR (600 MHz, D2 O) δ 8.45 (s, 1H), 8.21 (s, 1H), 7.93 (s, 1H), 6.49 (dd,J =7.4, 3.2 Hz, 1H), 5.09 (m, 1H), 4.94 (m, 1H), 4.78 (m, 1H), 4.30 (dddd,J = 7.1, 2.9, 2.5, 2.2 Hz, 1H), 4.17 (dt,J = 11.8, 2.9 Hz, 1H), 4.14 (ddd,J = 11.8, 4.3, 2.2 Hz, 1H), 4.07 (dt,J = 10.2, 2.8 Hz, 1H), 3.93 (ddd,J = 10.2, 4.4, 3.2 Hz, 1H), 2.97 (ddd,J = 14.0, 7.5, 3.2 Hz, 1H), 2.82 (dt,J = 14.0, 8.0, 7.4 Hz, 1H), 2.47 (m, 2H), 2.45 (m, 2H), 2.03 (m, 1H);31 P NMR (202 MHz, D2 O) δ 0.85, 0.22。 | ||
118 | (6R,8R,15R,17R)-17-(2-胺基-6-側氧基-6,9-二氫-1H-嘌呤-9-基)-8-(6-胺基-9H-嘌呤-9-基)-3,12,18-三羥基-9-甲氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 685.1 |
118 :HPLC滯留時間(HILIC, min): 4.53;1 H NMR (600 MHz, D2 O) δ 8.46 (s, 1H), 8.24 (s, 1H), 7.93 (s, 1H), 6.28 (d,J =1.0 Hz, 1H), 4.95 (td,J = 8.8, 4.8 Hz, 1H), 4.70 (td,J = 8.7, 4.8 Hz, 1H), 4.47 (dd,J = 5.6, 4.8 Hz, 1H), 4.42 (m, 1H), 4.38 (m, 1H), 4.36 (dd,J = 4.8, 1.0 Hz, 1H), 4.19 (ddd,J = 11.5, 3.7, 1.5 Hz, 1H), 4.07 (dt,J = 10.5, 3.0 Hz, 1H), 4.02 (ddd,J = 10.5, 4.7, 3.0 Hz, 1H), 3.71 (s, 3H), 2.56 (m, 1H), 2.44 (dt,J = 13.8, 8.7 Hz, 1H), 2.16 (ddd,J = 13.8, 10.5, 8.6 Hz, 1H);31 P NMR (202 MHz, D2 O) δ 0.21, 0.08。 | ||
119 | 使用實例2中所描述之方法,由中間物32 及N-苯甲醯基-5'-O-[雙(4-甲氧基苯基)苯基甲基]-2'-去氧-2'-氟腺苷, 3'-[2-氰基乙基N,N-雙(1-甲基乙基)胺基磷酸酯合成之(2R, 3R, 3aR, 7aR, 9R, 10aS, 14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3-氟-5,12-二羥基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯5,12-二氧化物 | 641.1 |
119 :HPLC滯留時間(HILIC, min): 4.08;1 H NMR (600 MHz, D2 O) δ 8.50 (s, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 8.07 (s, 1H), 6.51 (d,J =15.2 Hz, 1H), 5.57 (dd,J = 51.7, 3.6 Hz, 1H), 5.13 (dddd,J = 8.6, 8.0, 5.4, 3.9 Hz, 1H), 4.99 (dddd,J = 24.2, 9.6, 8.3, 3.6 Hz, 1H), 4.74 (m, 1H), 4.58 (d,J = 9.6 Hz, 1H), 4.49 (dd,J = 12.1, 2.2 Hz, 1H), 4.23 (ddd,J = 12.1, 3.6, 0.9 Hz, 1H), 4.17 (dt,J = 10.3, 2.5 Hz, 1H), 4.10 (ddd,J = 10.3, 3.3, 1.6 Hz, 1H), 2.72 (ddd,J = 14.5, 9.9, 8.6 Hz, 1H), 2.62 (ddd,J = 14.0, 6.7, 3.9 Hz, 1H), 2.51 (m, 1H), 2.43 (ddd,J = 14.0, 8.6, 8.0 Hz, 1H), 2.19 (ddd,J = 14.5, 9.7, 5.4 Hz, 1H);31 P NMR (202.4 MHz, D2 O) δ 0.08, -0.12;19 F NMR (470.4 MHz, D2 O) δ -198.73。 | ||
120 | 使用實例2中所描述之方法,由中間物41 及N-苯甲醯基-5'-O-[雙(4-甲氧基苯基)苯基甲基]-2'-去氧-2'-氟腺苷, 3'-[2-氰基乙基N,N-雙(1-甲基乙基)胺基磷酸酯合成之(2R,3R,3aR,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3,10-二氟-5,12-二羥基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯5,12-二氧化物 | 659.1 |
120 : HPLC滯留時間(HILIC, min): 4.06;1 H NMR (600 MHz, D2 O) δ 8.46 (s, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 8.08 (s, 1H), 6.50 (d,J =15.0 Hz, 1H), 5.56 (dd,J = 51.7, 3.6 Hz, 1H), 5.34 (ddd,J = 51.2, 3.8, 1.7 Hz, 1H), 5.17 (dddd,J = 19.0, 9.4, 5.1, 1.7 Hz, 1H), 4.94 (dddd,J = 24.3, 9.5, 8.2, 3.6 Hz, 1H), 4.68 (dddd,J = 24.7, 10.4, 8.0, 3.8 Hz, 1H), 4.59 (ddd,J = 9.5, 2.0, 1.0 Hz, 1H), 4.52 (bdd,J = 12.1, 2.0 Hz, 1H), 4.25 (ddd,J = 12.1, 3.7, 1.0 Hz, 1H), 4.22 (bdt,J = 10.5, 2.0 Hz, 1H), 4.17 (dt,J = 10.5, 2.2 Hz, 1H), 2.83 (dt,J = 15.0, 10.2 Hz, 1H), 2.74 (m, 1H), 2.36 (ddd,J = 15.0, 9.2, 5.1 Hz, 1H);31 P NMR (202.4 MHz, D2 O) δ -0.16, -0.74;19 F NMR (470.4 MHz, D2 O) δ -198.92, -194.37。 | ||
121 | 使用實例2中所描述之方法,由中間物41 及中間物42 合成之(2R,3S,3aR,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3,10-二氟-5,12-二羥基十二氫二環戊[d,j][1,3,7,9]四氧雜[2,8]-二磷雜環十二烯5,12-二氧化物 | 657.1 |
121 :HPLC滯留時間(HILIC, min): 3.99;1 H NMR (600 MHz, D2 O) δ 8.37 (s, 1H), 8.03 (s, 1H), 5.36 (ddd,J = 51.0, 3.4, 1.3 Hz, 1H), 5.20 (dddd,J = 16.1, 9.6, 3.5, 1.3 Hz, 1H), 4.74 (m, 1H), 4.27 (m, 2H), 2.95 (ddd,J = 15.8, 11.0, 9.6 Hz, 1H), 2.37 (ddd,J = 15.8, 8.6, 3.5 Hz, 1H), 2.79 (m, 1H);31 P NMR (202.4 MHz, D2 O) δ -0.16;19 F NMR (470.4 MHz, D2 O) δ -196.00。 | ||
122 | 9,9'-((2R,3R,3aR,7aR,9R,10S,10aR,14aR)-3-氟-5,10,12-三羥基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-2,9-二基)雙(2-胺基-1,9-二氫-6H-嘌呤-6-酮) | 689.1 |
122 :HPLC滯留時間(HILIC, min): 5.18;1 H NMR (600 MHz, D2 O) δ 8.02 (s, 1H), 7.94 (s, 1H), 6.27 (d,J = 19.0 Hz, 1H), 5.53 (dd,J = 52.0, 4.4 Hz, 1H), 5.10 (dddd,J = 22.8, 9.1, 8.5, 4.4 Hz, 1H), 4.69 (ddd,J = 9.1, 8.8, 5.5 Hz, 1H), 4.63 (td,J = 8.1, 5.7 Hz, 1H), 4.49 (t,J = 5.6 Hz, 1H), 4.44 (d,J = 9.1 Hz, 1H), 4.36 (dt,J = 12.2, 1.6 Hz, 1H), 4.18 (ddd,J = 12.2, 3.8, 1.8 Hz, 1H), 4.09 (dt,J = 10.5, 3.6 Hz, 1H), 4.03 (dt,J = 10.5, 3.6 Hz, 1H), 2.45 (dt,J = 13.6, 8.5 Hz, 1H), 2.09 (ddd,J = 13.6, 10.4, 9.1 Hz, 1H);31 P NMR (202.4 MHz, D2 O) δ 0.19, 0.15;19 F NMR (470.4 MHz, D2 O) δ -196.75。 | ||
123 | 9,9'-((2R,3S,3aR,7aR,9R,10aS,14aR)-3,5,12-三羥基-5,12-二氧離子基十二氫二環戊[d,j][1,3,7,9]四氧雜[2,8]-二磷雜-環十二烯-2,9-二基)雙(2-胺基-1,9-二氫-6H-嘌呤-6-酮):HPLC滯留時間(HILIC, min): 5.14。 | 669.1 |
124 | (2R,3aS,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-10-氟-5,12-二羥基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯5,12-二氧化物 | 641.1 |
124 :HPLC滯留時間(HILIC, min): 4.13;1 H NMR (600 MHz, D2 O) δ 8.47 (s, 1H), 8.35 (s, 1H), 8.12 (s, 1H), 8.09 (s, 1H), 6.95 (dd,J = 7.3, 2.0 Hz, 1H), 5.17 (dddd,J = 20.2, 9.0, 5.8, 2.0 Hz, 1H), 5.33 (ddd,J = 51.2, 4.1, 2.0 Hz, 1H), 5.02 (m,J = 9.3, 7.8, 7.8, 7.0 Hz, 1H), 4.72 (dddd,J = 23.4, 7.9, 5.9, 4.1 Hz, 1H), 4.33 (m, 1H), 4.31 (m, 1H), 4.27 (dt,J = 10.3, 2.3, 2.2 Hz, 1H), 4.22 (m, 1H), 4.17 (ddd,J = 10.3, 4.1, 1.8 Hz, 1H), 3.01 (ddd,J = 13.8, 9.3, 7.3 Hz, 1H), 2.86 (ddd,J = 13.8, 9.3, 7.3 Hz, 1H), 2.78 (ddd,J = 14.4, 10.0, 9.0 Hz, 1H), 2.72 (m,J = 10.0, 9.4, 7.9, 2.2, 1.8 Hz, 1H), 2.35 (ddd,J = 14.4, 9.4, 5.8 Hz, 1H)。31 P NMR (202.4 MHz, D2 O) δ -0.57, 0.42;19 F NMR (470.4 MHz, D2 O) δ -193.57。 | ||
125 | (2R,3aS,7aR,9R,10aS,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-5,12-二羥基十二氫二環戊[d,j][1,3,7,9]-四氧雜[2,8]二磷雜環十二烯5,12-二氧化物 | 621.1 |
125 :HPLC滯留時間(HILIC, min): 4.05;1 H NMR (600 MHz, D2 O) δ 8.37 (s, 2H), 8.04 (s, 2H), 5.12 (dddd,J = 9.0, 8.1, 5.5, 4.1 Hz, 2H), 4.81 (m, 2H), 4.22 (dt,J = 10.2, 2.5, 2.4 Hz, 2H), 4.07 (ddd,J = 10.2, 3.3, 1.5 Hz, 2H), 2.72 (ddd,J = 14.7, 9.5, 9.0 Hz, 2H), 2.63 (ddd,J = 13.7, 6.7, 4.1 Hz, 2H), 2.51 (m, 2H), 2.44 (dt,J = 13.7, 8.1, 8.1 Hz, 2H), 2.18 (ddd,J = 14.7, 9.7, 5.5 Hz, 2H)。31 P NMR (202.4 MHz, D2 O) δ 0.58。 | ||
126 | (2R,3aS,7aR,9R,10aS,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-5,12-二羥基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯5,12-二氧化物 | 623.1 |
126 :HPLC滯留時間(HILIC, min): 4.06;1 H NMR (600 MHz, D2 O) δ 8.49 (s, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 8.12 (s, 1H), 6.49 (dd,J = 7.2, 2.5 Hz, 1H), 5.12 (dddd,J = 8.6, 7.6, 7.0, 5.7 Hz, 1H), 5.07 (ddt,J = 8.8, 7.7, 7.7, 7.2 Hz, 1H), 4.78 (m, 1H), 4.32 (m, 1H), 4.27 (ddd,J = 11.8, 2.9, 1.8 Hz, 1H), 4.19 (ddd,J = 11.8, 4.2, 1.7 Hz, 1H), 4.12 (dt,J = 10.3, 2.8, 2.7 Hz, 1H), 4.02 (ddd,J = 10.3, 4.2, 2.1 Hz, 1H), 3.00 (ddd,J = 14.0, 7.2, 2.5 Hz, 1H), 2.85 (ddd,J = 14.0, 8.8, 7.2 Hz, 1H), 2.65 (dt,J = 14.0, 8.6, 8.6 Hz, 1H), 2.61 (ddd,J = 13.8, 6.8, 5.7 Hz, 1H), 2.51 (m, 1H), 2.47 (dt,J = 13.8, 7.6, 7.6 Hz, 1H), 2.13 (ddd,J = 14.0, 10.2, 7.0 Hz, 1H)。31 P NMR (202.4 MHz, D2 O) δ 0.06, 0.68。 | ||
127 | (1R,6R,8R,9R,10R,15R,17R,18R)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-3,12-二羥基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 659.1 |
127 :HPLC滯留時間(HILIC, min): 4.00;1 H NMR (600 MHz, D2 O) δ 8.42 (s, 1H), 8.32 (s, 1H), 8.23 (s, 1H), 8.23 (s, 1H), 6.49 (d,J =17.5 Hz, 1H), 5.50 (dd,J = 51.9, 4.2 Hz, 1H), 5.27 (ddd,J = 51.1, 5.0, 2.1 Hz, 1H), 5.18 (dddd,J = 25.0, 11.9, 7.1, 5.0 Hz, 1H), 5.08 (dtd,J = 27.7, 9.2, 4.2 Hz, 1H), 4.68 (dddd,J = 22.6, 8.8, 6.4, 2.1 Hz, 1H), 4.53 (d,J = 9.2 Hz, 1H), 4.42 (d,J = 12.1 Hz, 1H), 4.20 (ddd,J = 12.1, 3.4, 1.3 Hz, 1H), 4.15 (dt,J = 10.3, 3.1 Hz, 1H), 4.02 (ddd,J = 10.3, 5.2, 2.5 Hz, 1H), 2.55 (m, 1H), 2.52 (dt,J = 12.2, 10.2 Hz, 1H), 2.41 (q,J = 11.9 Hz, 1H);31 P NMR (202.4 MHz, D2 O) δ 0.29, -0.54;19 F NMR (470.4 MHz, D2 O) δ -197.30, -187.86。 | ||
128a | (1R,6R,8R,9S,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-3,12-二硫基-2,4,11,13-四氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 689.1 |
128a :HPLC滯留時間(C18, min): 2.35。 | ||
128b | (1R,6R,8R,9S,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-3,12-二硫基-2,4,11,13-四氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 689.1 |
128b :HPLC滯留時間(C18, min): 2.50;1 H NMR (600 MHz, D2 O) δ 8.38 (s, 2H), 8.06 (s, 2H), 5.34 (ddd,J = 51.0, 3.5, 1.6 Hz, 2H), 5.20 (dddd,J = 16.6, 9.5, 4.0, 1.6 Hz, 2H), 4.86 (dtd,J = 25.5, 10.1, 10.1, 3.5 Hz, 2H), 4.36 (dt,J = 10.5, 2.8, 2.8 Hz, 2H), 4.17 (ddd,J = 10.5, 2.8, 2.5 Hz, 2H), 2.91 (ddd,J = 15.6, 10.9, 9.5 Hz, 2H), 2.79 (m, 2H), 2.33 (ddd,J = 15.6, 8.6, 4.0 Hz, 2H)。31 P NMR (202.4 MHz, D2 O) δ 55.71;19 F NMR (470.4 MHz, D2 O) δ -195.07。 | ||
129a | 根據上文針對化合物102a -102d 描述之方案合成之(1S,6R,8R,9R,10R,15R,17R)-17-(2-胺基-6-側氧基-6,9-二氫-1H-嘌呤-9-基)-8-(6-胺基-9H-嘌呤-9-基)-9-氟-3,12-二硫基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮。四種非對映異構體129a -129d 以8:9:41:42比率自HPLC分離:129a :滯留時間(C18, min): 2.26。 | 689.1 |
129b | 根據上文針對化合物102a -102d 描述之方案合成之(1S,6R,8R,9R,10R,15R,17R)-17-(2-胺基-6-側氧基-6,9-二氫-1H-嘌呤-9-基)-8-(6-胺基-9H-嘌呤-9-基)-9-氟-3,12-二硫基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮。四種非對映異構體129a -129d 以8:9:41:42比率自HPLC分離:129b :滯留時間(C18, min): 2.36。 | 689.1 |
129c | (1S,6R,8R,9R,10R,15R,17R)-17-(2-胺基-6-側氧基-6,9-二氫-1H-嘌呤-9-基)-8-(6-胺基-9H-嘌呤-9-基)-9-氟-3,12-二硫基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 689.1 |
129c :HPLC滯留時間(C18, min): 2.44;1 H NMR (600 MHz, D2 O) δ 8.43 (s, 1H), 8.21 (s, 1H), 7.98 (s, 1H), 6.45 (d,J = 16.9 Hz, 1H), 5.65 (dd,J = 51.6, 4.1 Hz, 1H), 5.18 (dddd,J = 26.2, 12.8, 9.4, 4.1 Hz, 1H), 4.90 (m, 1H), 4.84 (m, 1H), 4.58 (d,J = 9.4 Hz, 1H), 4.54 (dt, 11.9, 2.5, 2.5 Hz, 1H), 4.14 (ddd,J = 11.9, 3.9, 1.2 Hz, 1H), 4.03 (dt,J = 10.0, 3.2, 3.2 Hz, 1H), 3.98 (ddd,J = 10.0, 7.0, 4.6 Hz, 1H), 2.52 (m, 2H), 2.47 (m, 2H), 1.87 (m, 1H);31 P NMR (202.4 MHz, D2 O) δ 56.99, 54.72;19 F NMR (470.4 MHz, D2 O) δ -197.88。 | ||
129d | (1S,6R,8R,9R,10R,15R,17R)-17-(2-胺基-6-側氧基-6,9-二氫-1H-嘌呤-9-基)-8-(6-胺基-9H-嘌呤-9-基)-9-氟-3,12-二硫基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 689.1 |
129d :HPLC滯留時間(C18, min): 2.58;1 H NMR (600 MHz, D2 O) δ 8.43 (s, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 6.45 (d,J = 16.9 Hz, 1H), 5.47 (dd,J = 51.6, 4.1 Hz, 1H), 5.17 (dtd,J = 23.6, 9.5, 9.5, 4.1 Hz, 1H), 4.91 (m, 2H), 4.54 (d,J = 9.5 Hz, 1H), 4.52 (dt,J = 12.5, 2.3, 2.3 Hz, 1H), 4.12 (ddd,J = 12.5, 4.7, 1.5 Hz, 1H), 4.06 (ddd,J = 10.3, 4.2, 2.7 Hz, 1H), 3.99 (ddd,J = 10.3, 5.0, 4.0 Hz, 1H), 2.51 (m, 1H), 2.46 (m, 3H), 2.02 (m, 1H)。31 P NMR (202.4 MHz, D2 O) δ 56.23, 54.74;19 F NMR (470.4 MHz, D2 O) δ -197.19。 | ||
130a | (1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-12-羥基-3-硫基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 675.1 |
130a :HPLC滯留時間(C18, min): 2.38。1 H NMR (501 MHz, DMSO-d 6 ) δ 8.40 (s, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 6.50 (d,J = 14.3 Hz, 1H), 5.55 (dd,J = 51.7, 3.3 Hz, 1H), 5.32 (ddd,J = 51.2, 3.5, 1.5 Hz, 1H), 5.15 (dddd,J = 16.6, 9.7, 4.0, 1.5, Hz, 1H), 4.89 (dtd,J = 24.4, 8.9, 3.3, Hz, 1H), 4.78 (m, 1H), 4.66 (dt,J = 12.0, 1.9 Hz, 1H), 4.62 (dt,J = 8.9, 1.9, 1.0, Hz, 1H), 4.24 (bd,J = 10.3 Hz, 1H), 4.18 (bdd,J = 12.0, 4.5 Hz, 1H), 4.15 (dt,J = 10.3, 2.0 Hz, 1H), 2.90 (ddd,J = 15.6, 10.7, 9.7 Hz, 1H), 2.75 (bq,J = 10.7, 8.9, 8.7 Hz, 1H), 2.37 (ddd,J = 15.6, 8.7, 4.0 Hz, 1H)。31 P NMR (202.4 MHz, DMSO-d 6 ) δ 55.30, -0.29。19 F NMR (470.4 MHz, DMSO-d 6 ) δ -195.13, -199.19。 | ||
130b | (1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-12-羥基-3-硫基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 675.1 |
130b :HPLC滯留時間(C18, min): 2.40。1 H NMR (501 MHz, DMSO-d 6 ) δ 8.37 (s, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 8.03 (s, 1H), 6.52 (d,J = 14.3 Hz, 1H), 5.53 (dd,J = 51.5, 3.4 Hz, 1H), 5.30 (ddd,J = 51.0, 3.1, 1.6 Hz, 1H), 5.15 (dddd,J = 16.9, 9.6, 4.1, 1.6, Hz, 1H), 4.85 (m, 1H), 4.75 (m, 1H), 4.64 (dt,J = 11.6, 1.9 Hz, 1H), 4.62 (dt,J = 9.5, 1.9 Hz, 1H), 4.23 (bd,J = 10.3 Hz, 1H), 4.16 (bdd,J = 11.6, 4.6 Hz, 1H), 4.13 (dt,J = 10.3, 2.0 Hz, 1H), 2.88 (ddd,J = 15.5, 10.8, 9.6 Hz, 1H), 2.73 (bq,J = 10.8, 8.9, 8.8 Hz, 1H), 2.36 (ddd,J = 15.5, 8.8, 4.1 Hz, 1H)。31 P NMR (202.4 MHz, DMSO-d 6 ) δ 55.16, -0.30。19 F NMR (470.4 MHz, DMSO-d 6 ) δ -194.65, -199.10。 | ||
131 | (1R,6R,8R,9R,10R,15R,17R,18S)-8-(2-胺基-6-側氧基-6,9-二氫-1H-嘌呤-9-基)-17-(6-胺基-9H-嘌呤-9-基)-9,18-二氟-3,12-二羥基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮:HPLC滯留時間(C18, min): 1.97。 | 675.1 |
132a | (1R,6R,8R,9R,10R,15R,17R,18S)-8-(2-胺基-6-側氧基-6,9-二氫-1H-嘌呤-9-基)-17-(6-胺基-9H-嘌呤-9-基)-9,18-二氟-3,12-二硫基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 707.1 |
132a :HPLC滯留時間(C18, min): 2.41。非對映異構體3:1之混合物。 | ||
132b | (1R,6R,8R,9R,10R,15R,17R,18S)-8-(2-胺基-6-側氧基-6,9-二氫-1H-嘌呤-9-基)-17-(6-胺基-9H-嘌呤-9-基)-9,18-二氟-3,12-二硫基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮HPLC滯留時間(C18, min): 2.56。 | 707.1 |
141a | (1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-12-羥基-3-硫基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 675.1 |
141a :HPLC滯留時間(C18, min): 2.49;1 H NMR (600 MHz, D2 O) δ 8.41 (s, 1H), 8.33 (d,J = 1.6 Hz, 1H), 8.15 (s, 1H), 8.13 (s, 1H), 6.46 (d,J = 16.6 Hz, 1H), 5.52 (dd,J = 51.9, 4.0 Hz, 1H), 5.30 (ddd,J = 51.0, 5.2, 3.4 Hz, 1H), 5.16 (dddd,J = 22.6, 9.7, 7.4, 5.2 Hz, 1H), 5.05 (dtd,J = 23.8, 9.0, 4.0 Hz, 1H), 4.81 (tdd,J = 10.3, 7.0, 3.4 Hz, 1H), 4.59 (dt,J = 11.6, 2.5 Hz, 1H), 4.56 (ddd,J = 9.0, 2.5, 1.0 Hz, 1H), 4.15 (ddd,J = 11.6, 3.9, 1.0 Hz, 1H), 4.14 (dt,J = 10.5, 2.8 Hz, 1H), 4.05 (d,J = 10.5 Hz, 1H), 2.60 (ddd,J = 12.8, 8.6, 7.4 Hz, 1H), 2.54 (m, 1H), 2.41 (dt,J = 12.8, 9.8 Hz, 1H)。31 P NMR (202.4 MHz, D2 O) δ 54.90, 0.12;19 F NMR (470.4 MHz, D2 O) δ -189.36, -198.10。 | ||
141b | (1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-12-羥基-3-硫基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 675.1 |
141b :HPLC滯留時間(C18, min): 2.51;1 H NMR (600 MHz, D2 O) δ 8.59 (s, 1H), 8.31 (d,J = 1.9 Hz, 1H), 8.21 (s, 1H), 8.20 (s, 1H), 6.46 (d,J = 16.6 Hz, 1H), 5.51 (dd,J = 51.9, 4.0 Hz, 1H), 5.47 (ddd,J = 50.5, 4.4, 4.0 Hz, 1H), 5.14 (dtd,J = 23.4, 9.0, 9.0, 4.0 Hz, 1H), 5.12 (dddd,J = 23.6, 11.5, 7.3, 4.4 Hz, 1H), 4.78 (m, 1H), 4.54 (ddd,J = 9.0, 2.3, 1.2 Hz, 1H), 4.45 (dt,J = 11.8, 2.3 Hz, 1H), 4.22 (ddd,J = 11.8, 3.7, 1.2 Hz, 1H), 4.15 (dt,J = 10.3, 3.3 Hz, 1H), 4.01 (ddd,J = 10.3, 6.2, 3.2 Hz, 1H), 2.61 (m, 1H), 2.54 (dt,J = 12.5, 7.3 Hz, 1H), 2.37 (q,J = 11.5 Hz, 1H)。31 P NMR (202.4 MHz, D2 O) δ 55.75, 0.44;19 F NMR (470.4 MHz, D2 O) δ -187.65, -198.14。 | ||
142a | (1R,6R,8R,10S,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-18-氟-3,12-二硫基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 707.1 |
132b :HPLC滯留時間(C18, min): 2.56。1 H NMR (501 MHz, DMSO-d 6 ) δ 8.44 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 8.07 (s, 1H), 6.48 (dd,J = 7.1, 2.0 Hz, 1H), 5.29 (ddd,J = 51.0, 3.9, 2.5 Hz, 1H), 5.17 (dddd,J = 18.0, 9.5, 5.5, 2.5 Hz, 1H), 5.05 (dddd,J = 10.9, 9.3, 8.0, 6.8, Hz, 1H), 4.81 (m, 1H), 4.42 (dt,J = 11.7, 3.0 Hz, 1H), 4.35 (dddd,J = 8.0, 3.0, 2.6, 1.5 Hz, 1H), 4.21 (dt,J = 10.2, 3.1 Hz, 1H), 4.15 (ddd,J = 11.7, 4.8, 1.5 Hz, 1H), 4.13 (ddd,J = 10.2, 2.9, 2.0 Hz, 1H), 3.18 (ddd,J = 13.8, 6.8, 2.0 Hz, 1H), 2.83 (ddd,J = 13.8, 9.3, 7.1 Hz, 1H), 2.80 (dt,J = 14.5, 9.5 Hz, 1H), 2.73 (bq,J = 9.0 Hz, 1H), 2.31 (ddd,J = 14.5, 9.0, 5.5 Hz, 1H)。31 P NMR (202.4 MHz, DMSO-d 6 ) δ 55.79, 55.25。19 F NMR (470.4 MHz, DMSO-d 6 ) δ -194.55。 | ||
142b | (1R,6R,8R,10S,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-18-氟-3,12-二硫基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 707.1 |
132b :HPLC滯留時間(C18, min): 2.56。1 H NMR (501 MHz, DMSO-d 6 ) δ 8.47 (s, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 8.01 (s, 1H), 6.48 (dd,J = 7.0, 1.6 Hz, 1H), 5.33 (ddd,J = 51.1, 3.5, 2.0 Hz, 1H), 5.17 (dddd,J = 17.5, 9.3, 4.7, 2.0, Hz, 1H), 5.11 (ddt,J = 9.8, 8.3, 6.5, Hz, 1H), 4.85 (ddd,J = 19.5, 9.5, 3.5, Hz, 1H), 4.46 (dt,J = 11.8, 2.6 Hz, 1H), 4.33 (dtd,J = 8.3, 2.6, 1.3 Hz, 1H), 4.30 (dt,J = 10.3, 2.8 Hz, 1H), 4.15 (ddd,J = 11.8, 4.9, 1.3 Hz, 1H), 4.07 (ddd,J = 10.3, 3.0, 1.8 Hz, 1H), 3.00 (ddd,J = 13.3, 6.5, 1.6 Hz, 1H), 2.87 (ddd,J = 13.6, 9.8, 7.0 Hz, 1H), 2.85 (dt,J = 15.0, 9.5 Hz, 1H), 2.76 (bq,J = 9.5 Hz, 1H), 2.34 (ddd,J = 15.0, 8.8, 4.7 Hz, 1H)。31 P NMR (202.4 MHz, DMSO-d 6 ) δ 55.95, 55.25。19 F NMR (470.4 MHz, DMSO-d 6 ) δ -194.77。 |
((1R
,2R
,3S
,4R
)-4-(6-胺基-9H
-嘌呤-9-基)-2,3-雙((第三丁基二甲基矽烷基)氧基)環戊基)甲醇(1001
):將6
(1.03 g,2 mmol)於乙醇氨(3.5 M,10 mL)中之溶液在微波反應器中在140℃下加熱1小時。蒸發揮發物,且進行FCC (MeOH/DCM,5-2°%),得到1001
(0.81 g,81 %):694.81 [M+H]+
(ESI);1
H NMR (401 MHz, DMSO-d 6
) δ 8.20 (s, 1H), 8.11 (s, 1H), 7.15 (bs, 2H), 4.92 (t,J
= 5.2 Hz, 1H), 4.81 (q,J
= 9.4 Hz, 1H), 4.56 (dd,J
= 9.4, 4.1 Hz, 1H), 4.03 (d,J
= 4.5 Hz, 1H), 3.59 (ddd,J
= 10.7, 7.8, 4.8 Hz, 1H), 3.51 (dt,J
= 11.0, 5.6 Hz, 1H), 2.28 (dt,J
= 13.4, 9.5 Hz, 1H), 2.12 - 2.01 (m, 1H), 1.89 (ddd,J
= 14.0, 9.4, 5.2 Hz, 1H), 0.92及0.64 (s, 9H), 0.11, 0.08, -0.19, -0.60 (s, 3H);13
C NMR (101 MHz, DMSO) δ 156.17, 152.12, 149.77, 140.94, 119.81, 76.03, 74.56, 63.33, 59.25, 46.04, 27.78, 26.03, 25.70, 18.00, 17.60, -4.28, -4.36, -4.54, -5.68。
芒黴素(Aristeromycin) (1002
):向1001
(0.81 g,1.6 mmol)於THF (10 mL)中之溶液中添加TBAF (1 M THF溶液,5 mL),且將所得溶液在環境溫度下攪拌24小時。蒸發揮發物,且進行FCC (親水相互作用液相層析(HILIC)模式,SiO2
,水/ACN,10-50%),得到1002
。NMR譜匹配文獻資料(Tetrahedron 58 (2002) 9889-9895)。
((1R
,2R
,3S
,4R
)-4-(6-胺基-9H
-嘌呤-9-基)-2,3-二羥基環戊基)甲基三磷酸氫三鈉(1003
):在0℃下,在氬氣氛圍下向1002
(50 mg,0.19 mmol)於無水磷酸三甲酯(0.7 mL)中之溶液中添加新蒸餾POCl3
(0.023 mL),且將所得溶液在此溫度下攪拌2小時。添加焦磷酸三丁銨(517 mg,0.94 mmol)及Bu3
N (0.211 mL)於DMF (2 mL)中之溶液,且在-5℃下繼續攪拌2小時。添加TEAB (2 M水溶液,4 mL)以淬滅反應物,且進行製備型HPLC (0.1 M TEAB水溶液對ACN,0-30%),得到呈三乙銨鹽形式之1003
,隨後使用DOWEX 50W (Na+
循環)將其變成鈉鹽,得到所需化合物:HRMS ESI (C11
H19
O12
N5
P3
)計算值:506.0243;實驗值:506.0252;1
H NMR (401 MHz, D2
O) δ 8.33 (s, 1H), 8.12 (s, 1H), 4.89 - 4.80 (m, 1H), 4.50 (dd,J
= 9.4, 5.6 Hz, 1H), 4.24 (dd,J
= 5.8, 3.1 Hz, 1H), 4.19 - 4.10 (m, 1H), 4.09 - 4.00 (m, 1H), 2.60 - 2.49 (m, 1H), 2.49 - 2.38 (m, 1H), 1.97 - 1.74 (m, 1H);13
C NMR (101 MHz, D2
O) δ 155.03, 151.87, 149.18, 140.46, 118.36, 75.42, 71.13, 66.98 (d,J
= 5.9 Hz, 1C), 58.56, 43.21 (d,J
= 8.3 Hz, 1C), 28.47;31
P NMR (162 MHz, D2
O) δ -6.63 (d,J
= 18.3 Hz, 1P), -8.08 (d,J
= 19.4 Hz, 1P), -19.78 (t,J
= 18.8 Hz, 1P)。實例 6 . 3 ' 3 ' CDN 之 酶促製備
2'-氟-2'-去氧腺苷-5'-三磷酸(目錄號N-1007)係購自TriLink Biotechnologies (San Diego, USA)。
將1 µmol 2'-氟-2'-去氧腺苷-5'-三磷酸及1 µmol如上文所描述之5'-三磷酸碳腺苷(1003
)或2 µmol 5'-三磷酸碳腺苷溶解於含pH 8.0,10 mM MgCl2
、100 mM NaCl、1 mM DTT、20 μM BMB171二腺苷酸環化酶之500 µl 50 mM HEPES K緩衝液中,且在振盪器上在50℃下培育隔夜。反應混合物在25,000 g下旋轉20分鐘且上清液通過3,000 Da過濾器濃縮器(目錄號88512,ThermoFisher, Waltham, USA)。向經過溶離份之流量添加碳酸氫三乙銨緩衝液(TEAB,目錄號T7408,Sigma Aldrich, Czech Republic)達至0.1 M最終濃度。接著,使用含0-10% ACN之0.1 M TEAB之50分鐘梯度(3 mL/min)在半製備型C18管柱(Luna 5 μm C18 250×10 mm)上純化樣品。藉由在50%甲醇中之3次蒸發/溶解循環自所收集之溶離份移除TEAB且使蒸發物溶解於不含內毒素之水(目錄號TMS-011-A,Merck Millipore, Prague, Czech Republic)中。使用SeQuant ZIC-pHILIC管柱(目錄號150461,150×4.6 mm,5 µm聚合物,Merck Millipore, Prague, Czech Republic)及具有乙腈之線性梯度(20分鐘內90%至50%;流動速率為0.6毫升/分鐘)之10 mM乙酸銨緩衝液pH 7.0,用Alliance HT層析系統(2795分離模組,2996 PDA偵測器,Micromass ZQ質量偵測器,Waters, Milford, USA)進行CDN之鑑別。使用陰性ESI方法進行電離;偵測CDN之帶負電及帶雙重負電的離子。
實例 7 . 3 ' 3 ' CDN 前藥之合成及表徵
化合物 | 結構/ 名稱 | 質譜 [M-H]- |
133 | (2R,3S,3aR,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3,5,10,12-四羥基十二氫二環戊[d,j][1,3,7,9]四氧雜[2,8]-二磷雜環十二烯5,12-二氧化物 | 653.1 |
134 | (1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9-氟-3,12,18-三羥基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八烷-3,12-二酮 | 657.4 |
方法A:將於無水MeOH (1000 uL)中之CDN (1 umol,TEA鹽)在RT下用氫氧化四丁銨(2 umol,1 M MeOH溶液,2 uL)處理,且攪拌30分鐘。減壓移除溶劑且將殘餘物與無水甲苯(1×500 uL)及無水ACN (2×500 uL)共蒸餾。在RT下在氬氣氛圍下將於無水ACN (700 uL)中之殘餘物用特戊醯氧甲基碘(10 umol,2.64 uL,J.E.Coughlin等人;Bioorg. Med. Chem. Lett. 20 (2010) 1783-1786)處理9小時。將反應混合物用1 ml 50% H2
O/ACN淬滅,且進一步用3 ml水稀釋,且直接施加至HPLC管柱(HPLC方法1)。將含產物之溶離份合併,蒸發且自二噁烷冷凍乾燥。
HPLC方法1
時間 ( 分鐘 ) | 流量 ( 毫升 / 分鐘 ) | H2 O (%) | 1:1 H2 O/ACN (%) | ACN (%) |
0 | 1 | 100 | - | - |
3 | 1 | 100 | - | - |
10 | 3 | 100 | - | - |
40 | 3 | - | 100 | - |
55 | 3 | - | - | 100 |
60 | 3 | - | - | 100 |
製備型HPLC純化在具有裝填有C18逆相樹脂之管柱(XTerra®製備型RP18管柱,5 μm,10×100 mm)之Waters Delta 600層析系統上進行。在所有方法中使用線性梯度。
方法B:在室溫下將於50% ACN水溶液(800 μL)中之環二核苷酸(1 μmol,Et3
NH+
Na+Na+
鹽)用特戊醯氧甲基碘(10 umol,2.64 uL,J.E.Coughlin等人;Bioorg. Med. Chem. Lett. 20 (2010) 1783-1786)處理隔夜,形成對應前藥。將反應混合物用水(3 mL)稀釋,且直接施加至HPLC管柱,且使用HPLC方法2純化。將含產物之溶離份冷凍乾燥。
HPLC方法2
時間( 分鐘) | 流量( 毫升 / 分鐘 ) | H2 O (%) | 1:1 H2 O/ACN (%) | ACN (%) |
0 | 3 | 80 | 20 | - |
10 | 3 | 80 | 20 | - |
30 | 3 | - | 100 | - |
50 | 3 | - | 50 | 50 |
60 | 3 | - | - | 100 |
製備型HPLC純化在具有裝填有C18逆相樹脂之管柱(XTerra®製備型RP18管柱,5 μm,10×100 mm)之Waters Delta 600層析系統上進行。在所有方法中使用線性梯度。
上文所描述之C18分析型HPLC方法用於標準分析。
以下化合物使用前述方法使用上文所描述之化合物合成。
前驅化合物 | 前藥化合物 |
102d | 140 |
106 | 139a 及139b |
119 | 137a 及137b |
120 | 135a 、136b-d 、 143a-b 、 144a-c 145a-c 及 146a-c |
121 | 138a 及138b |
128 | 147 |
129d | 148 |
130a | 149a |
130b | 149b |
132a | 150a |
132b | 150b |
142b | 151 |
表1:例示性化合物及表徵資料
實例 8 . 生物評估
化合物 | 結構/ 資料 | (M+H)+ 計算值 / 實驗值 | |
135a | 774.2 | ||
135a :特戊酸(((2R,3R,3aR,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3,10-二氟-12-羥基-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-5-基)氧基)甲酯:HPLC滯留時間(C18, min): 3.23, 3.26。 | |||
136b | 888.3 | ||
136b :(((2R,3R,3aR,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3,10-二氟-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-5,12-二基)雙(氧基))雙(亞甲基)雙(2,2-二甲基丙酸酯):HPLC滯留時間(C18, min): 3.67。 | |||
136c | 888.3 | ||
136c :(((2R,3R,3aR,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3,10-二氟-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-5,12-二基)雙(氧基))雙(亞甲基)雙(2,2-二甲基丙酸酯):HPLC滯留時間(C18, min): 3.80。 | |||
136d | 888.3 | ||
136d :(((2R,3R,3aR,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3,10-二氟-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]-二磷雜環十二烯-5,12-二基)雙(氧基))雙(亞甲基)雙(2,2-二甲基丙酸酯):HPLC滯留時間(C18, min): 3.85;1 H NMR (DMSO-d6 ) δ 8.31 (s, 2H), 8.19 (s, 1H), 8.17 (s, 1H), 7.39 (br s, 2H), 7.31 (br s, 2H), 6.40 (dd,J = 19.6,J = 2.2, 1H), 5.92 (m, 2H), 5.78 (m, 2H), 5.60-5.71 (m, 4H), 5.49 (dt,J = 51.3, 5.6 Hz, 1H), 5.12-5.24 (m, 2H), 4.24-4.43 (m, 5H), 3.43 (m, 1H), 2.72 (m, 1H), 1.95 (m, 1H) 1.18 (s, 9H), 1.11 (s, 9H);31 P NMR (DMSO-d6 ) δ -1.93 (s, 1P); -2.66 (s, 1P);19 F NMR (DMSO-d6 ) δ -191.17 (ddd,J = 51.2, 23.1, 11.4 Hz, 1F), -197.71 (dt,J = 51.0, 18.6 Hz, 1F)。 | |||
137a | 871.6 | ||
137a :(((2R,3R,3aR,7aR,9R,10aS,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3-氟-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-5,12-二基)雙(氧基))雙(亞甲基)雙(2,2-二甲基丙酸酯):HPLC滯留時間(C18, min): 3.93。 | |||
137b | 871.5 | ||
137b :(((2R,3R,3aR,7aR,9R,10aS,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3-氟-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-5,12-二基)雙(氧基))雙(亞甲基)雙(2,2-二甲基丙酸酯):HPLC滯留時間(C18, min): 4.14;1 H NMR (DMSO-d6 ) δ 8.30 (s, 1H), 8.27 (s, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.41 (bs, 2H), 7.26 (bs, 2H), 6.39 (dd,J = 19.7, 1.9 Hz, 1H), 5.77-5.91 (m, 2H), 5.58-5.71 (m, 4H), 5.11 (m, 1H), 5.05 (m, 1H), 4.31-4.41 (m, 2H), 4.17-4.22 (m, 3H), 2.35-2.70 (m, 4H), 1.88 (m, 1H), 1.18 (s, 9H), 1.11 (s, 9H);31 P NMR (DMSO-d6 ) δ -1.40 (s, 1P), -2.73 (s, 1P);19 F NMR (DMSO-d6 ) δ -197.42 (dt,J = 51.7, 18.8 Hz, 1F)。 | |||
138a | 887.6 | ||
138a :(((2R,3S,3aR,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3,10-二氟-5,12-二氧離子基十二氫二環戊[d,j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-5,12-二基)雙(氧基))雙(亞甲基)雙(2,2-二甲基丙酸酯):HPLC滯留時間(C18, min): 3.82。 | |||
138b | 887.6 | ||
138b :(((2R,3S,3aR,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3,10-二氟-5,12-二氧離子基十二氫二環戊[d,j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-5,12-二基)雙(氧基))雙(亞甲基)雙(2,2-二甲基丙酸酯):HPLC滯留時間(C18, min): 4.12;1 H NMR (DMSO-d6 ) δ 8.34 (s, 2H); 8.15 (s, 2H); 7.34 (bs, 4H), 5.50-5.68 (m, 6H), 5.11-5.23 (m, 4H); 4.25 (m, 2H), 4.18 (m, 2H), 2.70 (m, 2H); 2.44 (m, 2H), 1.88 (m, 2H), 1.17 (s, 18H);31 P NMR (DMSO-d6 ) δ -1.43 (s, 2P);19 F NMR (DMSO-d6 ) δ -194.89 (m, 2F)。 | |||
139a | 871.6 | ||
139a :(((2R,3aS,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-10-氟-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-5,12-二基)雙(氧基))雙(亞甲基)雙(2,2-二甲基丙酸酯)異構體混合物:HPLC滯留時間(C18, min): 3.77;31 P NMR (DMSO-d6 ): -0.98 (s, 1P), -1.68 (s, 1P), -4.45 (s, 1P), -4.92 (s, 1P)。 | |||
139b | 871.6 | ||
139b :(((2R,3aS,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-10-氟-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-5,12-二基)雙(氧基))雙(亞甲基)雙(2,2-二甲基丙酸酯):HPLC滯留時間(C18, min): 4.06;1 H NMR (DMSO-d6 ) δ 8.39 (s, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 8.15 (s, 1H), 7.35 (br s, 2H), 7.34 (br s, 2H), 6.41 (dd,J = 8.0, 6.2 Hz, 1H), 5.54-5.70 (m, 5H), 5.51 (m, 1H), 5.12-5.24 (m, 2H), 4.14 (m, 1H), 4.33 (m, 1H), 4.26 (m, 1H), 4.15 (m, 1H), 4.09 (m, 1H), 3.32 (m, 1H), 2.64-2.73 (m, 2H), 2.42 (m, 1H), 1.85 (m, 1H), 1.20 (s, 9H), 1.12 (s, 9H);31 P NMR (DMSO-d6 ) δ -0.92 (s, 1P), -1.78 (s, 1P);19 F NMR (DMSO-d6 ) δ -196.35 (m, 1F)。 | |||
140 | 921.2 | ||
140 :(((2R,3R,3aR,7aR,9R,10S,10aR,14aR)-2,9-雙(6-胺基-9H-嘌呤-9-基)-3,10-二氟-5,12-二氧離子基十氫-2H-環戊[d]呋喃并[3,2-j][1,3,7,9]四氧雜[2,8]二磷雜環十二烯-5,12-二基)雙(硫烷二基))雙(亞甲基)雙(2,2-二甲基丙酸酯):HPLC滯留時間(C18, min): 4.28;1 H NMR (501 MHz, DMSO-d 6 ) δ 8.37 (s, 1H), 8.35 (s, 1H), 8.18 (s, 1H), 8.15 (s, 1H), 7.44 (bs, 2H), 7.34 (bs, 2H), 6.40 (dd,J = 16.8, 3.4 Hz, 1H), 6.06-5.92 (m, 2H), 5.63-5.37 (m, 6H), 5.17 (m, 1H), 4.51-4.45 (m, 2H), 4.37-4.19 (m, 3H), 2.77 (m, 1H), 2.45 (m, 1H), 1.90 (m, 1H), 1.17 (s, 9H), 1.06 (s, 9H);31 P NMR (202.4 MHz, DMSO-d 6 ) δ 28.48, 27.25;19 F NMR (470.4 MHz, DMSO-d 6 ) δ -193.71, -201.32。 | |||
143a | 丙-2-基碳酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-3,12-二側氧基-3-({[(丙-2-基氧基)羰基]氧基}甲氧基)-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]氧基}甲酯 | 893.4 | |
143a :HPLC滯留時間(C18, min): 3.60; | |||
143b | 丙-2-基碳酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-3,12-二側氧基-3-({[(丙-2-基氧基)羰基]氧基}甲氧基)-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]氧基}甲酯 | 893.4 | |
143b :HPLC滯留時間(C18, min): 3.83;1 H NMR (501 MHz, DMSO-d 6 ) δ 8.33 (s, 2H), 8.19 (s, 1H), 8.17 (s, 1H), 7.43 (bs, 2H), 7.47 (bs, 2H), 6.41 (dd,J = 18.9, 2.5 Hz, 1H), 5.77 - 5.95 (m, 2H), 5.58 - 5.70 (m, 2H), 5.49 (dt,J = 51.2, 5.8 Hz, 1H), 5.11 - 5.26 (m, 2H), 4.85 (七重峰,J = 6.2 Hz, 2H), 4.78 (七重峰,J = 6.2 Hz, 2H), 4.38 - 4.44 (m, 2H), 4.23 - 4.33 (m, 3H), 2.73 (m, 1H), 2.41 (m, 2H), 1.93 (m, 2H), 1.16 - 1.25 (m, 12H)。31 P NMR (202.4 MHz, DMSO-d 6 ) δ -2.31 (s), -2.84 (s)。19 F NMR (470.4 MHz, DMSO-d 6 ) δ -191.72 (ddd,J = 51.6, 22.7, 10.7 Hz), -198.66 (dt,J = 51.4, 17.6 Hz) | |||
144a | 2,2-二甲基丁酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-3-{[(2,2-二甲基丁醯基)氧基]甲氧基}-9,18-二氟-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]氧基}甲酯 | 917.4 | |
144a :HPLC滯留時間(C18, min): 3.30; | |||
144b | 2,2-二甲基丁酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-3-{[(2,2-二甲基丁醯基)氧基]甲氧基}-9,18-二氟-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]氧基}甲酯 | 917.4 | |
144b :HPLC滯留時間(C18, min): 3.47; | |||
144c | 2,2-二甲基丁酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-3-{[(2,2-二甲基丁醯基)氧基]甲氧基}-9,18-二氟-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]氧基}甲酯 | 917.4 | |
144c :HPLC滯留時間(C18, min): 3.73;1 H NMR (501 MHz, CD3 CN) δ 8.21 (s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 6.20 - 6.32 (m, 5H), 5.58 - 5.91 (m, 6H), 5.47 (dm,J = 51.4 Hz, 1H), 5.27 (m, 1H), 5.06 (dtd,J = 25.4, 8.9, 3.1 Hz, 1H), 4.39 - 4.45 (m, 2H), 4.26 - 4.34 (m, 3H), 2.73 (m, 1H), 2.51 (m, 2H), 2.10 (m, 2H), 1.52 - 1.62 (m, 4H), 1.17 (s, 6H), 1.12 (s, 3H), 1.12 (s, 3H), 0.84 (t,J = 7.5 Hz, 3H), 0.79 (t,J = 7.5 Hz, 3H)。31 P NMR (202.4 MHz, CD3 CN) δ -2.58, -3.11。19 F NMR (470.4 MHz, CD3 CN) δ -189.05 (m), -196.35 (m)。 | |||
145a | 1-甲基環己烷-1-羧酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-3-[(1-甲基環己烷羰基氧基)甲氧基]-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]氧基}甲酯 | 969.2 | |
145a :HPLC滯留時間(C18, min): 3.56; | |||
145b | 1-甲基環己烷-1-羧酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-3-[(1-甲基環己烷羰基氧基)甲氧基]-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]氧基}甲酯 | 969.0 | |
145b :HPLC滯留時間(C18, min): 3.75; | |||
145c | 1-甲基環己烷-1-羧酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-3-[(1-甲基環己烷羰基氧基)甲氧基]-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]氧基}甲酯 | 969.0 | |
145c :HPLC滯留時間(C18, min): 4.04;1 H NMR (501 MHz, CD3 CN) δ 8.22 (s, 1H), 8.17 (s, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 6.29 (d,J = 20.0 Hz, 1H), 6.15 - 6.28 (m, 4H), 5.59 - 5.91 (m, 6H), 5.46 (dm,J = 51.6 Hz, 1H), 5.28 (m, 1H), 5.06 (dtd,J = 25.2, 8.9, 3.0 Hz, 1H) 4.39 - 4.45 (m, 2H), 4.26 - 4.35 (m, 3H), 2.73 (m, 1H), 2.50 (m, 2H), 2.10 (m, 2H), 1.96 (m, 4H), 1.19 - 1.62 (m, 16H), 1.18及1.12 (s, 6H)。31 P NMR (202.4 MHz, CD3 CN) δ -2.53, -3.04。19 F NMR (470.4 MHz, CD3 CN) δ -188.94 (m), -196.35 (m)。 | |||
146a | 辛酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-3-[(辛醯氧基)甲氧基]-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]氧基}甲酯 | 973.5 | |
146a :HPLC滯留時間(C18, min): 4.02; | |||
146b | 辛酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-3-[(辛醯氧基)甲氧基]-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]氧基}甲酯 | 973.1 | |
144b :HPLC滯留時間(C18, min): 4.14; | |||
146c | 辛酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-3-[(辛醯氧基)甲氧基]-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]氧基}甲酯 | 973.0 | |
144c :HPLC滯留時間(C18, min): 4.39;1 H NMR (501 MHz, CD3 CN) δ 8.23 (s, 1H), 8.19 (s, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 6.29 (d,J = 19.7 Hz, 1H), 6.19 (bs, 2H), 6.15 (bs, 2H), 5.85 (m, 1H), 5.59 - 5.81 (m, 5H), 5.44 (dm,J = 51.3 Hz, 1H),5.27 (m, 1H), 5.06 (dtd,J = 25.1, 9.1 Hz, 3.5 Hz, 1H), 4.39 - 4.45 (m, 2H), 4.24 - 4.34 (m, 3H), 2.73 (m, 1H), 2.49 (m, 2H), 2.10 (m, 2H), 2.40 (t,J = 7.5 Hz, 4H), 2.33 (t,J = 7.5 Hz, 4H), 1.51 - 1.62 (m, 4H), 1.19 - 1.32 (m, 16H), 0.83 - 0.87 (m, 6H)。31 P NMR (202.4 MHz, CD3 CN) δ -2.50 (s), -2.96 (s)。19 F NMR (470.4 MHz, CD3 CN) δ -189.31 (m), -196.64 (m)。 | |||
147 | 2,2-二甲基丙酸{[(1R,6R,8R,9S,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-12-({[(2,2-二甲基丙醯基)氧基]甲基}硫基)-9,18-二氟-3,12-二側氧基-2,4,11,13-四氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-3-基]硫基}甲酯 | 918.4 | |
147:HPLC滯留時間(C18, min): 4.18。1 H NMR (501 MHz, DMSO-d 6 ) δ 8.38 (s, 2H), 8.15 (s, 2H), 7.33 (bs, 4H), 5.66 (ddd,J = 50.4, 8.5, 5.3 Hz, 2H), 5.38 - 5.47 (m, 6H), 5.18 (m, 2H), 4.29及4.14 (m, 2H), 2.75 (m, 2H), 2.45及1.85 (m, 2H), 1.15 (s, 18H)。31 P NMR (202.4 MHz, DMSO-d 6 ) δ 27.86。19 F NMR (470.4 MHz, DMSO-d 6 ) δ -197.97。 | |||
148 | 2,2-二甲基丙酸{[(1S,6R,8R,9R,10R,15R,17R)-17-(2-胺基-6-側氧基-6,9-二氫-1H-嘌呤-9-基)-8-(6-胺基-9H-嘌呤-9-基)-3-({[(2,2-二甲基丙醯基)氧基]甲基}硫基)-9-氟-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]硫基}甲酯 | 918.4 | |
148 :HPLC滯留時間(C18, min): 4.13。1 H NMR (501 MHz, DMSO-d 6 ) δ 10.62 (bs, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.85 (s, 1H), 7.40 (bs, 2H), 6.44 (bs, 2H), 6.39 (dd,J = 17.7, 2.8 Hz, 2H), 5.90 - 6.00 (m, 2H), 5.31 - 5.48 (m, 5H), 4.85 (m, 1H), 4.46 (m, 1H), 4.40 (m, 1H), 4.28 (m, 1H), 4.16 - 4.22 (m, 2H), 2.55 - 2.64 (m, 3H), 2.35及1.74 (m, 1H), 1.16及1.05 (s, 9H)。31 P NMR (202.4 MHz, DMSO-d 6 ) δ 28.81, 26.32。19 F NMR (470.4 MHz, DMSO-d 6 ) δ -199.90 (dt,J F,2 ' = 51.7,J F,1 ' =J F,3 ' = 16.1 Hz)。 | |||
149a | 2,2-二甲基丙酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-12-羥基-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-3-基]硫基}甲酯 | 790.9 | |
149a : HPLC滯留時間(C18, min): 3.21,1 H NMR (501 MHz, DMSO-d 6 ) δ 8.36 (s, 1H), 8.27 (s, 1H), 8.19及8.19 (s, 1H), 7.51 (bs, 4H), 6.33 (dd,J = 17.7, 1.6 Hz, 1H), 5.65 (dm,J = 52.4 Hz, 1H), 5.37 - 5.55 (m, 3H), 5.26 (m, 1H), 5.02 - 5.17 (m, 2H), 4.43 (m, 1H), 4.38 (m, 1H), 4.26 (m, 1H), 3.88 - 3.97 (m, 2H), 2.56 (m, 1H), 2.37及1.94 (m, 1H), 1.06 (s, 9H)。31 P NMR (202.4 MHz, DMSO-d 6 ) δ 26.97, -1.28。19 F NMR (470.4 MHz, DMSO-d 6 ) δ -190.41, -197.48。 | |||
149b | 2,2-二甲基丙酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-9,18-二氟-12-羥基-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-3-基]硫基}甲酯 | 790.9 | |
149b : HPLC滯留時間(C18, min): 3.22。 | |||
150a | 2,2-二甲基丙酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8-(2-胺基-6-側氧基-6,9-二氫-1H-嘌呤-9-基)-17-(6-胺基-9H-嘌呤-9-基)-3-({[(2,2-二甲基丙醯基)氧基]甲基}硫基)-9,18-二氟-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]硫基}甲酯 | 936.8 | |
150a : HPLC滯留時間(C18, min): 3.87。 | |||
150b | 2,2-二甲基丙酸{[(1R,6R,8R,9R,10R,15R,17R,18S)-8-(2-胺基-6-側氧基-6,9-二氫-1H-嘌呤-9-基)-17-(6-胺基-9H-嘌呤-9-基)-3-({[(2,2-二甲基丙醯基)氧基]甲基}硫基)-9,18-二氟-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]硫基}甲酯 | 936.5 | |
150b : HPLC滯留時間(C18, min): 4.17。1 H NMR (501 MHz, DMSO-d 6 ) δ 10.83 (bs, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 7.92 (s, 1H), 7.34 (bs, 2H), 6.53 (bs, 2H), 6.20 (dd,J = 17.2, 3.3 Hz, 2H), 5.89 (m, 1H), 5.76 (ddd,J = 50.9, 5.1, 3.4 Hz, 1H), 5.37 - 5.59 (m, 6H), 5.16 (m, 1H), 4.56 (m, 1H), 4.44 (m, 1H), 4.20 - 4.35 (m, 3H), 2.76 (m, 1H), 2.42及1.90 (m, 1H), 1.15及1.05 (s, 9H)。31 P NMR (202.4 MHz, DMSO-d 6 ) δ 28.42, 28.11。19 F NMR (470.4 MHz, DMSO-d 6 ) δ -192.25, -199.28。 | |||
151 | 2,2-二甲基丙酸{[(1R,6R,8R,10S,15R,17R,18S)-8,17-雙(6-胺基-9H-嘌呤-9-基)-3-({[(2,2-二甲基丙醯基)氧基]甲基}硫基)-18-氟-3,12-二側氧基-2,4,7,11,13-五氧雜-3λ5 ,12λ5 -二磷雜三環[13.3.0.06 ,10 ]十八-12-基]硫基}甲酯 | 903.8 | |
151 : HPLC滯留時間(C18, min): 3.44。1 H NMR (501 MHz, CD3 CN) δ 8.23 (s, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.95 (s, 1H), 6.40 (t,J = 6.9 Hz, 1H), 6.00 (bs, 4H), 5.81 (m, 1H), 5.36 - 5.64 (m, 6H), 5.12 (m, 1H), 4.43 - 4.52 (m, 2H), 4.14 - 4.29 (m, 3H), 3.34 (m, 1H), 2.81 (m, 1H), 2.72 (ddd,J = 14.6, 6.4, 3.0 Hz, 1H), 2.52及1.99 (m, 2H), 1.21 (s, 9H), 1.11 (s, 9H)。31 P NMR (202.4 MHz, CD3 CN) δ 29.11, 28.02。19 F NMR (470.4 MHz, CD3 CN) δ -196.02 (dm,J F,2 ' =50.8 Hz)。 |
環二核苷酸判定為STING促效劑:(A)若在STING差示掃描螢光測定檢測法(DSF)中證明其在熱偏移> 0.5℃之情況下結合於人類STING蛋白之AQ對偶基因形式,及(B)若其在EC50
<100 µmol.l- 1
之情況下證明經由螢火蟲螢光素酶報導子之IRF-3依賴性表現之STING活化。ISRE 報導子質體 ( pGL64 . 27 - 4xISRE )
藉由Sigma Aldrich (Czech Republic, Prague)合成含有四個干擾素敏感性反應元件(ISRE)之序列AAAGATCTTGGAAAGTGAAACCTTGGAAAACGAAACTGGACAAAGGGAAACTGCAGAAACTGAAACAAAGCTTAA (SEQ ID NO:1)及TTAAGCTTTGTTTCAGTTTCTGCAGTTTCCCTTTGTCCAGTTTCGTTTTCCAAGGTTTCACTTTCCAAGATCTTT (SEQ ID NO:2)之兩個互補寡核苷酸。寡核苷酸以等莫耳量混合,雜交且藉由限制性核酸內切酶HindIII (目錄號R0104S,NEB, Ipswich, USA)及BglII (目錄號R0144S,NEB, Ipswich, USA)裂解。最終,其接合至由相同酶線性化之質體pGL4.27 (目錄號E6651,Promega, Madison, USA)。因此,具有四個ISRE位點之序列置放於螢火蟲螢光素酶報導基因之最小啟動子之上游。293T wtSTING - FL 報導細胞
在轉染之前一天,293T細胞(目錄號CRL-3216,ATCC, Manassas, USA))在具有高葡萄糖(目錄號D5796,Sigma Aldrich, Czech Republic)之補充有10%熱滅活FBS (目錄號S1520,Biowest, Riverside, USA)之不含抗生素之DMEM中,以125,000個細胞/公分2
之密度接種至經聚-D-離胺酸(目錄號P6407,Sigma Aldrich, Czech Republic)塗佈之六孔盤上。在轉染之日,將編碼人類野生型STING (WT STING)之2.5 μg質體pUNO1-hSTING-WT (目錄號puno1-hstingwt,InvivoGen, San Diego, USA,)在125 μL OptiMEM培養基(目錄號31985062,ThermoFisher, Waltham, USA)中稀釋且與相同的含有12.5 μL脂染胺2000之125 μL培養基(目錄號11668019,ThermoFisher, Waltham, USA)混合。在室溫(RT)下培育5分鐘後,將250 μL混合物逐滴添加至一個孔中之細胞。細胞在37℃,5% CO2
下培育36小時,且隨後用0.05%胰蛋白酶及0.22 g/L EDTA (目錄號皆為L0941,Biowest, Riverside, USA)剝離。
經轉染之細胞在具有高葡萄糖之含有10%熱滅活FBS、30 μg/mL之殺稻瘟菌素(blasticidin) (目錄號ant-bl-05,InvivoGen, San Diego, USA)、0.06 mg/ml之青黴素G及0.1 mg/ml之硫酸鏈黴素(目錄號皆為L0018,Biowest, Riverside, USA)之DMEM培養基中,以50,000個細胞/1公分2
之密度接種至經聚-D-離胺酸塗佈之六孔盤上。每3-4天補充培養基一次,直至形成對殺稻瘟菌素具有抗性之可見細胞群落。
根據如上文所描述之相同程序,穩定表現WT STING之殺稻瘟菌素抗性細胞用pGL64.27-4xISRE質體進一步轉染。在具有高葡萄糖之含有10%熱滅活FBS、30 μg/mL之殺稻瘟菌素、0.06 mg/ml之青黴素G及0.1 mg/ml之硫酸鏈黴素之DMEM中,關於對300 μg/mL之潮黴素(hygromycin) (目錄號10687010,ThermoFisher, Waltham, USA)之抗性選擇經轉染之細胞。由細胞在96孔盤中經過限數稀釋法來製備經穩定地雙重轉染的細胞之均質培養物,且選擇具有來源於單一細胞之細胞之孔。擴增此等細胞,且使用單株小鼠抗STING抗體(目錄號MAB7169,1:1000稀釋;2o
抗體目錄號HAF007,1:2000稀釋,皆來自R&D Systems, Minneapolis, USA)藉由西方墨點法(western blot)及藉由在50 µM STING促效劑2'3'cGAMP (目錄號tlrl-nacga23,InvivoGen, San Diego, USA)存在下誘導螢火蟲螢光素酶表現來確認WT STING之表現。用與pUNO1質體互補之引子pUNO1_Seq_F (TGCTTGCTCAACTCTACGTC) (SEQ ID NO:3)及pUNO1_Seq_R (GTGGTTTGTCCAAACTCATC) (SEQ ID NO:4)擴增來自經轉染的細胞之基因組DNA,且藉由DNA測序來確認經轉染的細胞中存在WT STING基因。使用 293T wtSTING - FL 報導細胞之毛地黃皂苷 ( Digitonin ) 檢測法
293T wtSTING-FL細胞在具有高葡萄糖之補充有10%熱滅活FBS之100 μl DMEM中,以250,000個細胞/公分2
之密度接種至經聚-D-離胺酸塗佈之96孔盤上。次日,移除培養基且向細胞中添加含於毛地黃皂苷緩衝液中之化合物之三倍連續稀釋液,該緩衝液包含:50 mmol.l- 1
HEPES (目錄號H3375,Sigma Aldrich, Czech Republic) pH 7.0、100 mmol.l- 1
KCl、3 mmol.l- 1
MgCl2
、0.1 mmol.l- 1
DTT (目錄號D0632,Sigma Aldrich, Czech Republic)、85 mmol.l- 1
蔗糖(目錄號S7903,Sigma Aldrich, Czech Republic)、0.2% BSA (目錄號A2153,Sigma Aldrich, Czech Republic)、1 mmol.l- 1
ATP (目錄號A1852, Sigma Aldrich, Czech Republic)、0.1 mmol.l- 1
GTP (目錄號G8877,Sigma Aldrich, Czech Republic)及10 µg/mL之毛地黃皂苷A (目錄號D141,Sigma Aldrich, Czech Republic)。在37℃,5% CO2
下培育30分鐘後移除緩衝液,細胞用100 µl培養基洗滌一次,且將100 µl培養基添加至各孔中。具有細胞之盤在37℃,5% CO2
下培育5小時,移除50 μl培養基且向各孔中添加30 μl ONE-Glo™螢光素酶檢測系統試劑(目錄號E6120,Promega, Madison, USA)。用Synergy H1 (Biotek, Winooski, USA)讀取發光度。使用GraphPad Prism (La Jolla, USA)由8點劑量-反應曲線計算50%有效濃度(EC50
)。對照化合物3'3'-c-二-GMP (目錄號tlrl-nacdg)、3'3'-c-二-AMP (目錄號tlrl-nacda)、3'3'-cGAMP (目錄號tlrl-nacga)、2'3'-cGAMP (目錄號tlrl-nacga23)及2'2'-cGAMP (目錄號tlrl-nacga22)購自Invivogen (San Diego, USA)。WT STING 及 AQ STING 蛋白質
使用PCR (Phusion® High-Fidelity DNA Polymerase,目錄號M0530S,NEB, Ipswich, USA),使用來自pUNO1-hSTING-WT (目錄號puno1-hstingwt,InvivoGen, San Diego, USA)及pUNO1-hSTING-HAQ質體(puno1-hsting-haq,InvivoGen, San Diego, USA)之寡核苷酸hSTING140-BamH-For (GTGGGATCCGCCCCAGCTGAGATCTCTGCAG) (SEQ ID NO:5)及hSTING379-Not-Rev3 (TATGCGGCCGCCTATTACACAGTAACCTCTTCCTTTTC) (SEQ ID NO:6)擴增WT及AQ人類STING (G230A-R293Q)cDNA。經純化之PCR產物用限制酶BamHI (目錄號R0136S,NEB, Ipswich, USA)及NotI (目錄號R0189S,NEB, Ipswich, USA)裂解且選殖至經相同酶線性化之pSUMO載體中。藉由在pHis-parallel2質體(Clontech, Moutain View, USA)之NdeI與BamHI位點之間引入8-His-SUMO序列來產生質體pSUMO。因此,pSUMO-STING WT或pSUMO-STING AQ質體編碼具有N端8×His及SUMO標籤之經截短之人類WT STING或AQ STING (胺基酸殘基140-343)。
重組型WT STING及AQ STING蛋白在Rosetta-gami B (DE3)勝任細胞(目錄號71136-3,Merck Millipore, Billerica, USA)中過表現。使用Dounce均質器,使細菌集結粒再懸浮於含有50 mmol.l- 1
TrisCl (目錄號T1503,Sigma Aldrich, Czech Republic) pH 8.0、300 mmol.l- 1
NaCl、3 mmol.l- 1
β-巰基乙醇(目錄號M6250,Sigma Aldrich, Czech Republic)、10%甘油(目錄號G5516,Sigma Aldrich, Czech Republic)及20 mmol.l- 1
咪唑(目錄號I5513,Sigma Aldrich, Czech Republic)之冰冷的溶解緩衝液中。向均質物中添加DNase I (目錄號D5025,Sigma Aldrich, Czech Republic)及RNase A (目錄號R6513,Sigma Aldrich, Czech Republic) (最終濃度50 μg/ml)以及MgCl2
(最終濃度5 mmol.l- 1
)且使用French Press G-M™ High-Pressure Cell Press Homogenizer (1500 psi,3個循環)使細菌裂解。溶解物在30,000 g下旋轉20分鐘且上清液與Ni-NTA樹脂(目錄號745400.25,Macherey-Nagel, Düren, Germany)一起溫和攪拌30分鐘。將樹脂倒入層析管柱中,用50 ml緩衝液A (50 mmol.l- 1
TrisCl (pH 8.0)、800 mmol.l- 1
NaCl、3 mmol.l- 1
β-巰基乙醇;10%甘油;20 mmol.l- 1
咪唑)洗滌且用含有300 mmol.l- 1
咪唑之15 ml緩衝液A溶離經8-His-SUMO標記之STING蛋白。用重組型SUMO蛋白酶(80 µg/ml之蛋白質溶液,目錄號12588018,ThermoFisher, Waltham, USA)使經溶離之蛋白質裂解。在含有150 mmol.l- 1
NaCl及10%甘油之50 mmol.l- 1
Tris Cl緩衝液pH 7.4中,使用HiLoad 16/60 Superdex 75 (目錄號28989333,GE Healthcare Bio-Sciences, Pittsburgh, USA)藉由尺寸排阻層析進一步純化蛋白質。蛋白質用Amicon® Ultra-15 10 K裝置(目錄號UFC901008,Merck Millipore, Billerica, USA)濃縮且在液態N2
中急驟冷凍。
STING蛋白之WT及AQ對偶基因形式在含有150 mmol.l- 1
NaCl、1:500 SYPRO Orange (目錄號S6650,ThermoFisher, Waltham, USA)及150 μM CDN或水之100 mmol.l- 1
TrisCl緩衝液pH 7.4中稀釋至0.1 mg/ml之最終濃度。將反應混合物之20 μL溶液一式三份地抽吸至96孔光學反應盤中且用即時PCR循環器(LightCycler ® 480 Instrument II - Roche, Basel, Switzerland)進行樣品之熱變性。進行熱變性曲線之一階導數以計算STING-CDN複合物及STING去輔基蛋白質之變性溫度。藉由自STING CDN複合物之平均變性溫度減去STING去輔基蛋白之平均變性溫度來計算各CDN之熱偏移。BMB171 二腺苷酸環化酶
以化學方式合成經重組型密碼子最佳化之編碼來自芽孢桿菌屬(Bacillus sp.)之二腺苷酸環化酶BMB171之cDNA且藉由GenScript (Piscataway, NJ)在載體pET-28b(+)之NcoI與XhoI位點之間選殖。蛋白質在大腸桿菌(E. coli) BL21 (DE3) (ThermoFisher, Waltham, USA)中過表現。使用Dounce均質器,使細菌集結粒再懸浮於含有20 mM磷酸鈉緩衝液(pH 7.4)、500 mM NaCl、10%甘油及20 mM咪唑之冰冷的溶解緩衝液中。向均質物中添加DNase I及RNase A (最終濃度50 µg/ml)以及MgCl2
(最終濃度5 mM),且使用MSE Soniprep 150 (3 mm Tip Solid鈦指數探針,2 min,50%功率,振幅12微米)使細菌溶解。溶解物在30,000×g下旋轉20分鐘且將上清液裝載至5 mL HisTrap管柱(GE Healthcare BioSciences, Pittsburgh, USA)上。樹脂用50 ml溶解緩衝液及50 ml洗滌緩衝液(20 mM磷酸鈉緩衝液(pH 7.4)、500 mM NaCl、10%甘油及125 mM咪唑)洗滌,且BMB171用含有500 mM NaCl、10%甘油及300 mM咪唑之15 ml 20 mM磷酸鈉緩衝液(pH 7.4)緩衝液溶離。蛋白質在含有150 mM NaCl、50 mM Tris (pH 7.4)及10%甘油之緩衝液中,使用HiLoad 16/60 Superdex 75藉由尺寸排阻層析進一步純化。藉由Amicon® Ultra-15 10 K裝置(Merck Millipore Ltd.),用50%甘油、50 mM Tris (pH 7.6)、100 mM NaCl、1 mM DTT、1 mM EDTA更換蛋白質緩衝液,且BMB171在液態N2
中急驟冷凍。
表2. STING結合及293T WT STING毛地黃皂苷細胞資料
293T WT STING 標準 報導子檢測
化合物 | DSF ∆Tm ( ℃ ) | 293T WT STING 毛地黃皂苷 EC50 (µM) | |
WT STING | AQ STING | ||
101 | 3.6 | 11.3 | 0.8 |
102a | 6.7 | 11.2 | 0.11 |
102b | 11.9 | 16.9 | 0.005 |
102c | - | - | 0.01 |
102d | - | - | 0.01 |
103 | 7.6 | 16.6 | 0.01 |
104 | 3.4 | 11.4 | 0.2 |
105 | 0.8 | 7.0 | 1.6 |
106 | 1.9 | 9.0 | 0.4 |
107 | 7.6 | 16.7 | 0.01 |
108 | 5.2 | 14.3 | 0.04 |
109 | 8.9 | 18.5 | 0.01 |
110 | 5.8 | 15.7 | 0.05 |
111 | 4.1 | 13.7 | 0.07 |
112 | 5.2 | 13.2 | 0.12 |
113 | 2.1 | 7.9 | 3.6 |
114 | 0.4 | 4.6 | 21.8 |
115 | 3.8 | 10.5 | 0.07 |
116 | 8.5 | 13.1 | 0.007 |
117 | 2.2 | 7.1 | 0.2 |
118 | 0.5 | 1.5 | >15 |
119 | 5.7 | 16.6 | 0.05 |
120 | 10.3 | 17.0 | 0.01 |
121 | 7.6 | 13.9 | 0.05 |
122 | 3.5 | 9.5 | 1.6 |
123 | 1.1 | 4.6 | 1.2 |
124 | 6.2 | 12.8 | 0.05 |
125 | 0.7 | 5.1 | 13.2 |
126 | 1.1 | 7.5 | 1.8 |
127 | 2.6 | 7.9 | 0.1 |
128a | 9.6 | 14.8 | 0.01 |
128b | 12.2 | 17.5 | 0.01 |
129a | 6.4 | 14.0 | 0.1 |
129b | 7.0 | 13.2 | 0.2 |
129c | 6.4 | 13.2 | 0.4 |
129d | 13.7 | 20.8 | 0.007 |
130a | 14.7 | 20.7 | 0.01 |
130b | 13.6 | 20.3 | 0.01 |
131 | 13.4 | 21.4 | 0.01 |
132a | 12.9 | 19.9 | 0.008 |
132b | 18.6 | 26.1 | 0.01 |
133 | 0.6 | 4.4 | 1.2 |
134 | 6.4 | 13.2 | 0.02 |
141a | 0.3 | 3.9 | 3.0 |
141b | 5.3 | 11.6 | 0.05 |
142a | - | - | 0.03 |
142b | - | - | 0.02 |
3'3'c- 二 -GMP | 2.6 | 7.7 | 5.8 |
3'3'c- 二 -AMP | 2.6 | 9.3 | 0.3 |
3'3'-cGAMP | 5.1 | 13.3 | 0.16 |
2'2'-cGAMP | 11.5 | 19.4 | 0.03 |
2'3'-cGAMP | 15.2 | 22.7 | 0.03 |
293T wtSTING-FL細胞在具有高葡萄糖之補充有10%熱滅活FBS之100 μl DMEM培養基中,以250,000個細胞/公分2
之密度接種至經聚-D-離胺酸塗佈之白色96孔微盤上。次日,移除培養基且向細胞中添加化合物於100 μl培養基中之三倍連續稀釋物。將含細胞之盤在37℃與5% CO2
下培育7小時。移除50 μl培養基後,向各孔中添加30 μl ONE-Glo™螢光素酶檢測系統試劑(目錄號E6120,Promega, Madison, USA),且用Synergy H1 (Biotek, Winooski, USA)讀取發光度。使用GraphPad Prism (La Jolla, USA)由8點劑量-反應曲線計算50%有效濃度(EC50
)。對照化合物3'3'-cGAMP (目錄號tlrl-nacga)、2'3'-cGAMP (目錄號tlrl-nacga23)及2'2'-cGAMP (目錄號tlrl-nacga22)購自Invivogen (San Diego, USA)。
表3:293T WT STING標準報導子檢測資料
周邊血液單核細胞檢測
化合物 | 293T WT STING EC50 ( μ M) |
102a | 1.8 |
102b | 0.7 |
102d | 0.4 |
119 | 11.7 |
120 | 1.9 |
121 | 2.6 |
124 | 4.9 |
128b | 0.4 |
129d | 0.3 |
130a | 1.0 |
130b | 1.2 |
132b | 0.2 |
135a | 0.3 |
136b | 0.06 |
136c | 0.05 |
136d | 0.01 |
137a | 0.2 |
137b | 0.09 |
138a | 0.07 |
138b | 0.02 |
139a | 0.003 |
139b | 0.001 |
140 | 0.001 |
142b | 0.5 |
143a | 0.1 |
143b | 0.005 |
144a | 0.02 |
144b | 0.001 |
144c | 0.001 |
145a | 0.12 |
145b | 0.001 |
145c | 0.006 |
146a | 0.0001 |
146b | 0.0003 |
146c | 0.001 |
147 | 0.007 |
148 | 0.02 |
149a | 0.2 |
149b | 0.2 |
150a | 0.04 |
150b | 0.2 |
151 | 0.008 |
3'3'-cGAMP | 68.4 |
2'2'-cGAMP | 10.2 |
2'3'-cGAMP | 36.9 |
在活體外周邊血液單核細胞(PBMC)檢測中測試所選化合物。將新分離之PBMC以500,000個細胞/孔之密度在50 μl補充有10%熱滅活FBS之RPMI 1640培養基中接種於U形96孔盤中。連續稀釋測試化合物在50 μl培養基中添加至孔中,且細胞與化合物一起在37℃與5% CO2
下培育1小時。隨後含有細胞之盤在500 g下旋轉5分鐘,且移除培養基。將細胞藉由使用離心用細胞培養基洗滌兩次,且溫和地再懸浮於100 μl不含化合物之培養基中。在37℃與5% CO2
下培育15小時後,收集細胞培養基且用ProcartaPlex Assays (ThermoFisher, Waltham, USA)及MAGPIX System (Merck KGaA, Darmstadt, Germany)測定干擾素-α (INF-α)、干擾素-γ (INF-γ)及腫瘤壞死因子-α (TNF-α)之含量。使用GraphPad Prism (San Diego, CA, USA)由6點劑量-反應曲線計算50%有效濃度(EC50
)。報告值為一至四個供體運作之平均值。
表4:周邊血液單核細胞資料
化合物 | PBMC EC50 (μM) | ||
IFN-γ | TNF-α | IFN-α | |
119 | 169 | 146 | 265 |
120 | 36.6 | 72.6 | 64 |
121 | 200 | 254 | 254 |
124 | 43 | 223 | 290 |
128b | 6.5 | 19 | 27 |
129d | 23 | 25 | 27 |
136d | 2.4 | 0.8 | 0.9 |
138a | 1.5 | 1.9 | 3.2 |
138b | 2.6 | 1.3 | 1.0 |
139a | 0.1 | 0.1 | 0.1 |
139b | 0.1 | 0.1 | 0.3 |
143b | 0.15 | 0.3 | 0.3 |
144b | 0.05 | 0.02 | 0.04 |
144c | 0.003 | 0.002 | 0.004 |
145b | 0.002 | 0.006 | 0.007 |
145c | 0.01 | 0.02 | 0.04 |
146a | 0.04 | 0.04 | 0.04 |
146b | 0.01 | 0.01 | 0.02 |
146c | 0.02 | 0.01 | 0.02 |
147 | 0.02 | 0.05 | 0.07 |
148 | 0.6 | 0.3 | 0.8 |
150a | 0.7 | 0.7 | 1 |
儘管出於清楚理解之目的已藉助於說明及實例相當詳細地描述了前述發明,但熟習此項技術者應瞭解,可在所附申請專利範圍之範疇內實踐某些改變及修改。另外,本文中所提供之各參考文獻係以全文引用之方式併入本文中,其併入程度如同與各參考文獻單獨以引用的方式併入之程度相同。當本申請案與本文所提供之參考文獻之間存在衝突時,應以本申請案為準。
Claims (52)
- 一種式(I)化合物:, 或其醫藥學上可接受之鹽, 其中 X1 及X3 各自獨立地係OH、OR3 、SH或SR3 ; X2 及X4 各自獨立地係O或S; Y係O或CH2 ; R1a 、R1b 、R2a 及R2b 各自獨立地係H、OR5 、NH2 或鹵素; 各R5 獨立地係H或C1 -C6 烷基; 各R3 獨立地係C1 -C6 烷基或-L-R4 ; 各R4 獨立地係-O(C=O)-N(R4a )2 、-O(C=O)-NHR4a 、-O(C=O)-R4a 或-O(C=O)-O-R4a ; 各R4a 獨立地係C1 -C20 烷基、C2 -C20 烯基、C2 -C20 炔基、-(C1 -C6 伸烷基)-(C3 -C14 環烷基)或C3 -C20 環烷基,其中各R4a 獨立地視情況經1、2或3個R4b 取代; 各R4b 獨立地係-OH、-SH、-NH2 、=O、=NH、=S、鹵素、-N3 、-CN、C1 -C6 烷氧基、C1 -C6 烷硫基、C1 -C6 烷胺基或C1 -C6 二烷胺基; L係L1 、L1 -O(C=O)-L2 、L1 -(C=O)O-L2 、L1 -O-L2 、L1 -S(O)n -L2 、L1 -O(C=O)O-L2 、L1 -O(C=O)NR6 -L2 、L1 -NR6 (C=O)O-L2 或L1 -O(C=O)-L2 -O-L3 ; L1 係C1 -C6 伸烷基、C2 -C6 伸烯基、C2 -C6 伸炔基或C7 -C13 烷基伸芳基; L2 係C1 -C6 伸烷基、C2 -C6 伸烯基、C2 -C6 伸炔基、C6 -C10 伸芳基或5員至10員伸雜芳基; L3 係C1 -C6 伸烷基、C2 -C6 伸烯基或C2 -C6 伸炔基; R6 係H或C1 -C6 烷基; n係0、1或2; 鹼基1 及鹼基2 各自獨立地係 其中 A、A1 、A2 、A3 及A4 各自獨立地係H、OH、SH、F、Cl、Br、I、NH2 、OR15 、SR15 、NHR15 、N(R15 )2 或R16 ; 各Z獨立地係O、S或NR15 ; 各R15 獨立地係H、-C(=Z1 )R16 、-C(=Z1 )OR16 、-C(=Z1 )SR16 、-C(=Z1 )N(R16 )2 、C1 -C6 烷基、C2 -C6 烯基、C2 -C6 炔基、C3 -C7 環烷基、C2 -C10 雜環烷基、C6 -C10 芳基或C2 -C10 雜芳基; 各Z1 獨立地係O或S;且 各R16 獨立地係H、C1 -C6 烷基、C2 -C6 烯基、C2 -C6 炔基、C3 -C7 環烷基、C2 -C10 雜環烷基、C6 -C10 芳基或C2 -C10 雜芳基。
- 如請求項1至2中任一項之化合物,其中 X1 及X3 各自獨立地係OR3 。
- 如請求項1至2中任一項之化合物,其中 X1 係OR3 ;且 X3 係SR3 。
- 如請求項1至2中任一項之化合物,其中 X1 係SR3 ;且 X3 係OR3 。
- 如請求項1至2中任一項之化合物,其中 X1 係OH;且 X3 係SR3 。
- 如請求項1至2中任一項之化合物,其中 X1 係SR3 ;且 X3 係OH。
- 如請求項1至2中任一項之化合物,其中 X1 係OR3 ;且 X3 係SR3 。
- 如請求項1至2中任一項之化合物,其中 X1 係SR3 ;且 X3 係OR3 。
- 如請求項1至2中任一項之化合物,其中 X1 及X3 各自獨立地係SR3 。
- 如請求項1至2中任一項之化合物,其中 各R3 獨立地係-L-R4 。
- 如請求項1至2中任一項之化合物,其中 各R4 獨立地係-O(C=O)-R4a 或-O(C=O)-O-R4a 。
- 如請求項1至2中任一項之化合物,其中 各R4a 獨立地係C1 -C20 烷基或-(C1 -C6 伸烷基)-(C3 -C14 環烷基)。
- 如請求項1至2中任一項之化合物,其中 L係L1 、L1 -O(C=O)-L2 或L1 -O-L2 ; L1 係C1 -C6 伸烷基或C7 -C13 烷基伸芳基; L2 係C1 -C6 伸烷基或C6 -C10 伸芳基。
- 如請求項1至2中任一項之化合物,其中 X1 係OR3 或SR3 ; R3 係-L-R4 ; L係L1 ; L1 係C1 -C6 伸烷基; R4 係-O(C=O)-R4a 或-O(C=O)-O-R4a ;且 R4a 係C1 -C20 烷基。
- 如請求項1至2中任一項之化合物,其中 X1 係OR3 或SR3 ; R3 係-L-R4 ; L係L1 ; L1 係C7 -C13 烷基伸芳基; R4 係-O(C=O)-R4a 或-O(C=O)-O-R4a ;且 R4a 係C1 -C20 烷基。
- 如請求項1至2中任一項之化合物,其中 X3 係OR3 或SR3 ; R3 係-L-R4 ; L係L1 ; L1 係C1 -C6 伸烷基; R4 係-O(C=O)-R4a 或-O(C=O)-O-R4a ;且 R4a 係C1 -C20 烷基。
- 如請求項1至2中任一項之化合物,其中 X3 係OR3 或SR3 ; R3 係-L-R4 ; L係L1 ; L1 係C7 -C13 烷基伸芳基; R4 係-O(C=O)-R4a 或-O(C=O)-O-R4a ;且 R4a 係C1 -C20 烷基。
- 如請求項1至2中任一項之化合物,其中 R4a 係C3 -C16 烷基。
- 如請求項1至2中任一項之化合物,其中 X1 及X3 各自獨立地係OH或SH。
- 如請求項1至2中任一項之化合物,其中 X2 及X4 各自係O。
- 2及28中任一項之化合物,其中 A1 、A2 、A3 及A4 各自獨立地係H、OH或NH2 。
- 2及28中任一項之化合物,其中 A1 、A2 及A3 各自獨立地係H、OH或NH2 。
- 2、28及32中任一項之化合物,其中 R5 係H或Me。
- 2、28及32中任一項之化合物,其中 R1a 與R1b 不同。
- 2、28及32中任一項之化合物,其中 R2a 與R2b 不同。
- 2、28及32中任一項之化合物,其中 R1a 及R1b 中之至少一者係H。
- 2、28及32中任一項之化合物,其中 R2a 及R2b 中之至少一者係H。
- 2、28及32中任一項之化合物,其中 R1a 、R1b 、R2a 及R2b 各自獨立地係H、OH、OMe或F。
- 2、28及32中任一項之化合物,其中 R1b 及R2b 各自係H。
- 2、28及32中任一項之化合物,其中 R1a 係F,且 R1b 係H。
- 2、28及32中任一項之化合物,其中 R2a 係F,且 R2b 係H。
- 一種醫藥組合物,其包含如請求項1至45中任一項之化合物或其醫藥學上可接受之鹽,及醫藥學上可接受之載劑、賦形劑及/或稀釋劑。
- 一種在細胞中活化STING接附蛋白之活體外方法,該方法包含使該細胞與有效量之如請求項1至45中任一項之化合物或其醫藥學上可接受之鹽,或如請求項46之醫藥組合物接觸。
- 一種如請求項1至45中任一項之化合物或其醫藥學上可接受之鹽或如請求項46之醫藥組合物之用途,其用於製造用於治療或預防人類或動物之對STING接附蛋白之活化作用有反應的疾病或病症之藥劑。
- 一種如請求項1至45中任一項之化合物或其醫藥學上可接受之鹽或如請求項46之醫藥組合物之用途,其用於製造在人類或動物中增強疫苗之功效之藥劑。
- 一種如請求項1至45中任一項之化合物或其醫藥學上可接受之鹽或如請求項46之醫藥組合物之用途,其用於製備用於治療或預防人類或動物之病毒感染、癌症或發炎性疾病之藥劑。
- 如請求項50之用途,其中該病毒感染係B型肝炎感染或HIV感染。
- 如請求項48至51中任一項之用途,其中該藥劑進一步包含另一治療活性劑或係與另一治療活性劑一起投與。
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