TW201700482A - 蛋白酶體抑制劑 - Google Patents
蛋白酶體抑制劑 Download PDFInfo
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- TW201700482A TW201700482A TW105111120A TW105111120A TW201700482A TW 201700482 A TW201700482 A TW 201700482A TW 105111120 A TW105111120 A TW 105111120A TW 105111120 A TW105111120 A TW 105111120A TW 201700482 A TW201700482 A TW 201700482A
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- Prior art keywords
- amino
- acid
- methylbutyl
- ethinyl
- compound
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Abstract
本發明提供適用作蛋白酶體抑制劑之新穎化合物。本發明亦提供含有本發明之化合物的醫藥組合物以及使用該等組合物用於治療各種疾病之方法。
Description
本發明係關於適用作蛋白酶體抑制劑之酸及酸酯化合物。本發明亦提供含有本發明之化合物的醫藥組合物以及使用該等組合物用於治療各種疾病之方法。
酸及酸酯化合物展現各種醫藥學上適用之生物活性。Shenvi等人在美國專利第4,499,082號(1985年)中揭示:肽酸(peptide boronic acid)為某些蛋白水解酶之抑制劑。Kettner及Shenvi在美國專利第5,187,157號(1993年)、美國專利第5,242,904號(1993年)及美國專利第5,250,720號(1993年)中描述了一類抑制胰蛋白酶樣蛋白酶之肽酸。Kleeman等人在美國專利第5,169,841號(1992年)中揭示了抑制腎素之作用的N-末端經修飾之肽酸。Kinder等人在美國專利第5,106,948號(1992年)中揭示了抑制癌細胞生長之某些酸化合物。Bachovchin等人在WO 07/0005991中揭示了抑制纖維母細胞活化蛋白之肽酸化合物。
酸及酸酯化合物特別有希望成為蛋白酶體(亦即一種負責大部分細胞內蛋白質周轉之多催化蛋白酶)之抑制劑。Adams等人在美國專利第5,780,454號(1998年)中描述了適用作蛋白酶體抑制劑之肽酸酯及酸化合物。此文獻還描述了酸酯及酸化合物減少肌肉蛋白降解率、降低細胞中NF-κB之活性、降低細胞中p53蛋白之降解
率、抑制細胞中之細胞週期蛋白(cyclin)降解、抑制癌細胞生長及抑制NF-κB依賴性細胞黏附的用途。Furet等人之WO 02/096933、Chatterjee等人之WO 05/016859以及Bernadini等人之WO 05/021558及WO 06/08660中揭示了據報導具有蛋白酶體抑制劑活性之其他酸酯及酸化合物。
Ciechanover,Cell,79:13-21(1994)揭示:蛋白酶體為泛素-蛋白酶體途徑之蛋白水解組分,在此途徑中蛋白質藉由與多個泛素分子結合而被靶向降解。Ciechanover還揭示:泛素-蛋白酶體途徑在各種重要生理過程中起關鍵作用。Rivett等人,Biochem.J.291:1(1993)揭示蛋白酶體展現出胰蛋白酶、胰凝乳蛋白酶及肽基麩胺醯基肽酶活性。構成26S蛋白酶體催化核心的為20S蛋白酶體。McCormack等人,Biochemistry 37:7792(1998)教示了各種肽受質被20S蛋白酶體所分解,該等受質包括Suc-Leu-Leu-Val-Tyr-AMC、Z-Leu-Leu-Arg-AMC及Z-Leu-Leu-Glu-2NA,其中Suc為N-琥珀醯基,AMC為7-胺基-4-甲基香豆素,且2NA為2-萘胺。
蛋白酶體抑制體現了癌症治療之一種重要新策略。King等人,Science 274:1652-1659(1996)描述了泛素-蛋白酶體途徑在調控細胞週期、腫瘤生長及轉移方面之重要作用。作者教示:在細胞週期期間許多關鍵調控蛋白質(包括細胞週期蛋白及細胞週期蛋白依賴性激酶p21及p27KIP1)藉由泛素-蛋白酶體途徑而暫時性地被降解。細胞需要此等蛋白質之有序降解以加快細胞週期且進行有絲分裂。
此外,轉錄調控也需要泛素-蛋白酶體途徑。Palombella等人,Cell,78:773(1994)教示:轉錄因子NF-κB之活化受到蛋白酶體介導之抑制蛋白IκB之降解的調控。NF-κB又對調控涉及免疫及炎症反應之基因起重要作用。Read等人,Immunity 2:493-506(1995)教示:細胞黏附分子(例如E-選擇蛋白、ICAM-1及VCAM-1)之表現需要泛素-蛋白
酶體途徑。Zetter,Seminars in Cancer Biology 4:219-229(1993)教示:細胞黏附分子係藉由引導腫瘤細胞向體內遠處組織位點黏附及外滲以及自脈管系統向體內遠處組織位點黏附及外滲而涉及於活體內之腫瘤轉移及血管生成。此外,Beg及Baltimore,Science 274:782(1996)教示:NF-κB為一種抗細胞凋亡控制因子,且NF-κB活化之抑制使細胞對環境壓力及細胞毒性劑更加敏感。
蛋白酶體抑制劑VELCADE®(硼替佐米(bortezomib);N-2-吡嗪羰基-L-苯丙胺酸-L-白胺酸酸)為首個得到監管機構批准之蛋白酶體抑制劑。Mitsiades等人,Current Drug Targets,7:1341(2006)綜述了使得硼替佐米獲准用於治療已接受至少一種先前療法之多發性骨髓瘤患者的臨床研究。Fisher等人,J.Clin.Oncol.,30:4867描述了一種確認硼替佐米在復發或難治性套細胞淋巴瘤患者中之活性的國際多中心II期研究。Ishii等人,Anti-Cancer Agents in Medicinal Chemistry,7:359(2007)及Roccaro等人,Curr.Pharm.Biotech.,7:1341(2006)討論了多種可促成硼替佐米抗腫瘤活性之分子機制。
由以上參考文獻所證明,蛋白酶體為治療性干預之重要靶點。因此,不斷需要新穎及/或改良之蛋白酶體抑制劑。
本發明提供作為有效蛋白酶體抑制劑之化合物。此等化合物適用於活體外及活體內抑制蛋白酶體活性,且尤其適用於治療各種細胞增殖性疾病。
本發明之化合物具有通式(I):
或其醫藥學上可接受之鹽或酸酐,其中:Z1及Z2各自獨立地為羥基、烷氧基、芳氧基或芳烷氧基;或Z1及Z2一起形成源自酸錯合劑之部分;且環A係選自由以下者組成之群:
式(I)之酸化合物(其中Z1及Z2各自為羥基)係以下列化學名稱來提及。
單獨使用或作為較大部分之一部分使用的術語"烷基"係指具有1至12個碳原子之直鏈或支鏈或環狀脂族基團。術語"烷氧基"係指-O-烷基。
單獨使用或作為較大部分之一部分使用的術語"芳基"及"芳-"(例如"芳烷基"、"芳烷氧基"或"芳氧基烷基")係指含有1至3個環之C6-C14芳族烴,該等環中之每一者視情況經取代。較佳地,芳基為C6-10芳基。芳基包括(但不限於)苯基、萘基及蒽基。"芳烷基"或"芳基烷基"含有與烷基共價連接之芳基,該烷基或該芳基各自獨立地視情況經取代。較佳地,芳烷基為C6-10芳基(C1-6)烷基、C6-10芳基(C1-4)烷基或C6-10芳基(C1-3)烷基,包括(但不限於)苯甲基、苯乙基及萘甲基。
本文中所用之術語"經取代"意謂指定部分之氫基被特定取代基之基團置換,其限制條件為取代作用導致穩定或化學上可行之化合物。合適取代基之非限制性實例包括C1-6烷基、C3-8環烷基、C1-6烷基(C3-8)環烷基、C2-8烯基、C2-8炔基、氰基、胺基、C1-6烷基胺基、二(C1-6)烷基胺基、苯甲基胺基、二苯甲基胺基、硝基、羧基、羰基(C1-6)烷氧基、三氟甲基、鹵素、C1-6烷氧基、C6-10芳基、C6-10芳基(C1-6)烷基、C6-10芳基(C1-6)烷氧基、羥基、C1-6烷基硫基、C1-6烷基亞磺醯基、C1-6烷基磺醯基、C6-10芳基硫基、C6-10芳基亞磺醯基、C6-10芳基磺醯基、C6-10芳基、C1-6烷基(C6-10)芳基及鹵代(C6-10)芳基。
本文中所使用之短語"一或多個取代基"係指多個取代基,其等於基於可利用之成鍵位點的數目有可能的一個至最大數目之取代基,其限制條件為滿足上述穩定性及化學可行性之條件。除非另有說明,否則視情況經取代之基團可在該基團之各個可取代位置處具有取代基,
且取代基可相同或者不同。本文中所使用之術語"獨立地選定"意謂可針對單一化合物中之指定變數之多種情形選擇相同或不同之值。
術語"約"在本文中係用於意謂近似、大約、大致或左右。當術語"約"與數值範圍聯合使用時,其係藉由將界限擴展至所述數值以上及以下來修飾彼範圍。一般而言,術語"約"在本文中係用於修飾高於或低於所述值10%之數值。
本文中所使用之術語"包含"意謂"包括(但不限於)"。
除非另有說明,否則本文中所示之結構意謂包括區別僅在於存在一或多個同位素富集原子之化合物。例如,除了以氘或氚置換氫原子或以13C或14C富集碳置換碳原子之外具有本發明之結構的化合物在本發明之範圍之內。
本文中所用之術語"酸"係指含有-B(OH)2部分之化合物。在一些實施例中,酸化合物可藉由使酸部分脫水而形成寡聚酸酐。舉例而言,Snyder等人,J.Am.Chem.Soc.80:3611(1958)報導了寡聚芳基酸。
本文中所使用之術語"酸酐"係指由兩個或兩個以上酸化合物分子結合同時失去一或多個水分子所形成的化合物。當與水混合時,酸酐化合物被水化以釋放游離酸化合物。在各種實施例中,酸酐可含有兩個、三個、四個或四個以上酸單位,且可具有環狀或線性構型。本發明之肽酸化合物之寡聚酸酐的非限制性實例如下所示。
在式(1)及(2)中,變數n為0至約10之整數,較佳為0、1、2、3或4。在一些實施例中,酸酐化合物含有式(2)之環狀三聚體("硼氧烴三聚物(boroxine)"),其中n為1。變數W具有式(3):
其中環A具有上文關於式(I)所述之值。
在一些實施例中,酸酐化合物中所存在之至少80%酸以單寡聚酸酐形式存在。在一些實施例中,酸酐化合物中所存在之至少85%、90%、95%或99%酸以單寡聚酸酐形式存在。在某些較佳實施例中,酸酐化合物由具有式(3)之硼氧烴三聚物組成,或基本上由該後者組成。
較佳可由相應酸藉由暴露於脫水條件(包括(但不限於)再結晶、凍乾、暴露於熱及/或暴露於乾燥劑)下來製備酸酐化合物。合適再結晶溶劑之非限制性實例包括乙酸乙酯、二氯甲烷、己烷、乙醚、乙腈、乙醇及其混合物。
在一些實施例中,Z1及Z2一起形成源自酸錯合劑之部分。為了本發明之目的,術語"酸錯合劑"係指任何具有至少兩個官能基之化合物,該至少兩個官能基中之每一者可與硼形成共價鍵。合適官能基之非限制性實例包括胺基及羥基。在一些實施例中,至少一個官能基為羥基。術語"源自酸錯合劑之部分"係指藉由自酸錯合劑之兩個
官能基移除氫原子所形成的部分。
本文中所使用之術語"酸酯"係指含有-B(Z1)(Z2)部分之化合物,其中Z1或Z2中至少一個為烷氧基、芳烷氧基或芳氧基;或Z1及Z2一起形成源自具有至少一個羥基之酸錯合劑的部分。
在一些實施例中,Z1及Z2一起形成源自具有至少兩個被鏈或環中之至少兩個相連原子所隔開的羥基之化合物的部分,該鏈或該環含有碳原子及(視情況)可為N、S或O之一或多個雜原子,其中在各情況下與硼相連之原子為氧原子。
本文中所使用之術語"具有至少兩個羥基之化合物"係指任何具有兩個或兩個以上羥基之化合物。為了本發明之目的,兩個羥基較佳被至少兩個相連原子、較佳約2至約5個相連原子、更佳2或3個相連原子所隔開。為了方便起見,術語"二羥基化合物"可用於指代上述定義的具有至少兩個羥基之化合物。因此,本文中所使用之術語"二羥基化合物"並不意欲受限於僅具有兩個羥基之化合物。源自具有至少兩個羥基之化合物的部分可藉由其羥基中之任意兩個的氧原子與硼相連。較佳地,硼原子、與硼相連之氧原子及連接兩個氧原子之原子一起形成5或6員環。
為了本發明之目的,酸錯合劑較佳為醫藥學上可接受的,即適合於投與人類。在一些較佳實施例中,酸錯合劑為糖。術語"糖"包括任何多羥基碳水化合物部分,包括單醣、雙醣、多醣、糖醇及胺基糖。在一些實施例中,糖為單醣、雙醣、糖醇或胺基糖。合適糖之非限制性實例包括葡萄糖、蔗糖、果糖、海藻糖、甘露醇、山梨醇、葡糖胺及N-甲基葡糖胺。在某些實施例中,糖為甘露醇或山梨醇。因此,在糖為甘露醇或山梨醇之實施例中,Z1及Z2一起形成式C6H12O6之部分,其中兩個脫質子化羥基之氧原子與硼形成共價連接以形成酸酯化合物。在某些特定實施例中,Z1及Z2一起形成源自D-甘露醇之
部分。
在一些實施例中,式(I)之化合物係如Plamondon等人在WO 02/059131中所描述製備成凍乾粉,該案之全文據此以引用之方式併入本文中。在一些實施例中,凍乾粉亦包含游離二羥基化合物。較佳地,游離二羥基化合物與式(I)之化合物係以在約0.5:1至約100:1、更佳為約5:1至約100:1之範圍內的莫耳比例存在於混合物中。在二羥基化合物為甘露醇之各種實施例中,凍乾粉包含莫耳比例在約10:1至約100:1、約20:1至約100:1或約40:1至約100:1範圍內的游離甘露醇與甘露醇酸酯。
在一些實施例中,凍乾粉包含甘露醇及式(I)之化合物,大體上不含其他組份。然而,組合物可進一步含有一或多種其他醫藥學上可接受之賦形劑、載劑、稀釋劑、填充劑、鹽、緩衝劑、穩定劑、增溶劑及此項技術中熟知之其他物質。含有此等物質之醫藥學上可接受之調配物的製備係描述於(例如)Remington:The Science and Practice of Pharmacy,第20版,A.Gennaro編,Lippincott Williams & Wilkins,2000或最新版本中。
較佳根據Plamondon等人在WO 02/059131中描述之程序製備包含式(I)之化合物的凍乾粉。因此,在一些實施例中,用以製備凍乾粉之方法包含:(a)製備包含肽酸及二羥基化合物之水性混合物;及(b)凍乾該混合物。
一般合成方法
式(I)之化合物可藉由熟習此項技術者已知之方法來製備。參見,例如Adams等人之美國專利第5,780,454號;Pickersgill等人之國際專利公開案WO 2005/097809。例示性合成途徑如以下流程1中所示。
化合物i與N-端保護之甘胺酸(ii)偶合,隨後進行N-端脫保護,從而提供化合物iii。適合之保護基(PG)的實例包括(但不限於)醯基保護基,例如甲醯基、乙醯基(Ac)、琥珀醯基(Suc)及甲氧基琥珀醯基;及胺基甲酸酯保護基,例如第三丁氧羰基(Boc)、苄氧羰基(Cbz)及茀基甲氧羰基(Fmoc)。肽偶合反應可藉由預先使化合物ii之羧酸部分轉化成活化酯(例如,O-(N-羥基琥珀醯亞胺)酯),隨後用化合物i處理來進行。或者,可藉由使羧酸與肽偶合試劑相接觸而在原位產生活化酯。適合之肽偶合試劑的實例包括(但不限於)碳化二亞胺試劑,例如二環己基碳化二亞胺(DCC)或1-(3-二甲胺基丙基)-3-乙基碳化二亞胺(EDC);鏻試劑,例如苯并三唑-1-基氧基參(二甲基胺基)鏻六氟磷酸鹽(BOP);及試劑,例如,O-(1H-苯并三唑-1-基)-N,N,N',N'-四甲基四氟硼酸酯(TBTU)。
隨後,使化合物iii與經取代之苯甲酸(ArCO2H)偶合以提供化合物iv。上述用於化合物i及ii之偶合的肽偶合條件亦適合於使化合物iii與ArCO2H偶合。隨後,將酸部分脫保護以獲得化合物v。較佳在包含酸酯化合物iv、有機酸接受體、低碳烷醇、C5-8烴溶劑及水性
無機酸之兩相混合物中藉由轉酯作用來達成脫保護步驟。
或者,如流程2所示,可顛倒偶合反應之順序。因而,首先使O-端保護之甘胺酸(vi)與經取代之苯甲酸(ArCO2H)偶合,然後發生酯水解反應,從而形成化合物vii。隨後,如上文關於流程1所描述,達成與化合物i之偶合及酸脫保護以獲得化合物v。
用途、調配及投藥
本發明提供作為有效蛋白酶體抑制劑之化合物。可在活體外或活體內檢定該等化合物抑制蛋白酶體介導之肽水解或蛋白質降解的能力。
因此,在另一態樣中,本發明提供一種用於抑制細胞中蛋白酶體之一或多種肽酶活性的方法,其包括使需要蛋白酶體抑制之細胞與本文所述之化合物或其醫藥學上可接收之鹽、酸酯或酸酐相接觸。
本發明亦提供一種用於抑制細胞增殖之方法,其包含使需要該抑制之細胞與本文所述之化合物相接觸。短語"抑制細胞增殖"係用來
表示與未接觸抑制劑之細胞相比本發明之化合物在所接觸之細胞中抑制細胞數目或細胞生長的能力。可藉由使用細胞計數器來計數細胞或藉由細胞存活力檢定(例如,MTT或WST檢定)來評估細胞增殖。在細胞呈實體生長(例如,實體腫瘤或器官)之狀況下,可藉由例如使用測徑器量測生長且比較被接觸細胞與未經接觸之細胞的生長之尺寸來評估細胞增殖。
較佳地,與未經接觸之細胞的生長相比,與抑制劑相接觸之細胞的生長被延遲至少約50%。在各種實施例中,與未經接觸之細胞相比,被接觸細胞之細胞增殖被抑制了至少約75%,至少約90%,或至少約95%。在一些實施例中,短語"抑制細胞增殖"包括與未經接觸之細胞相比被接觸細胞之數目減少。因此,在被接觸細胞中抑制細胞增殖之蛋白酶體抑制劑可促使被接觸細胞經歷生長延遲、生長停滯、程式化細胞死亡(即細胞凋亡)或細胞壞死。
在另一態樣中,本發明提供一種醫藥組合物,其包含式(I)之化合物或其醫藥學上可接受之鹽或酸酐,及醫藥學上可接受之載劑。
若在此等組合物中使用本發明之化合物的醫藥學上可接受之鹽,則該鹽較佳係源自無機或有機酸或鹼。關於適合之鹽的綜述可參見(例如)Berge等人,J.Pharm.Sci.66:1-19(1977)及Remington:The Science and Practice of Pharmacy,第20版,A.Gennaro編,Lippincott Williams & Wilkins,2000。
適合之酸加成鹽之非限制性實例包括以下各者:乙酸鹽、己二酸鹽、海藻酸鹽、天門冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、丁酸鹽、檸檬酸鹽、樟腦酸鹽、樟腦磺酸鹽、環戊烷丙酸鹽、二葡糖酸鹽、十二烷基硫酸鹽、乙烷磺酸鹽、反丁烯二酸鹽、葡庚糖酸鹽(lucoheptanoate)、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、2-羥基乙烷磺酸鹽、乳酸鹽、順丁烯二酸
鹽、甲烷磺酸鹽、2-萘磺酸鹽、煙酸鹽、草酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、3-苯基-丙酸鹽、苦味酸鹽、特戊酸鹽、丙酸鹽、琥珀酸鹽、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽及十一酸鹽。
適合之鹼加成鹽包括(但不限於):銨鹽;鹼金屬鹽,例如鋰鹽、鈉鹽及鉀鹽;鹼土金屬鹽,例如鈣鹽及鎂鹽;其他多價金屬鹽,例如鋅鹽;與有機鹼形成之鹽,該等有機鹼例如有二環己胺、N-甲基-D-葡糖胺、第三丁胺、乙二胺、乙醇胺及膽鹼;以及與胺基酸形成之鹽,該等胺基酸例如有精胺酸、離胺酸及類似物。在一些實施例中,醫藥學上可接受之鹽為式(I)之酸化合物的鹼加成鹽,其中Z1及Z2均為羥基。
術語"醫藥學上可接受之載劑"在本文中係用於指與接受個體(較佳為哺乳動物,更佳為人類)相容且適合於向目標位置傳遞活性劑但不會使試劑活性終止的物質,所述受試物件。為達成活性劑之所欲用途,與載劑相關之毒性或不良效應(若存在時)較佳與合理之風險/益處比相當。
術語"載劑"、"佐劑"或"媒劑"在本文中可互換使用且包括適合於所要特定劑型之任意及所有溶劑、稀釋劑及其他液體媒劑、分散或懸浮助劑、表面活性劑、pH調節劑、等張劑、增稠劑或乳化劑、防腐劑、固體黏合劑、潤滑劑及類似物。Remington:The Science and Practice of Pharmacy,第20版,A.Gennaro編,Lippincott Williams & Wilkins,2000揭示了用於調配醫藥學上可接受之組合物的各種載劑及用於其製備之已知技術。除非任何習知載劑介質例如由於產生任何不良之生物學效應或不然以有害方式與醫藥學上可接受之組合物的任何其他組份發生相互作用而與本發明之化合物不相容,否則其之使用涵蓋在本發明之範圍內。可充當醫藥學上可接受之載劑的物質之一些實例包括(但不限於)離子交換劑、氧化鋁、硬脂酸鋁、卵磷脂、血清蛋
白(例如人血清白蛋白);緩衝物質,例如磷酸鹽、碳酸鹽、氫氧化鎂及氫氧化鋁、甘胺酸、山梨酸或山梨酸鉀;飽和植物脂肪酸之偏甘油酯混合物;水、無熱原質水、鹽或電解質,例如硫酸魚精蛋白、磷酸氫二鈉、磷酸氫鉀、氯化鈉及鋅鹽;矽膠、三矽酸鎂、聚乙烯吡咯啶酮、聚丙烯酸酯、蠟、聚乙烯-聚氧丙烯嵌段聚合物、羊毛脂;糖,例如乳糖、葡萄糖、蔗糖及甘露醇;澱粉,例如玉米澱粉及馬鈴薯澱粉;纖維素及其衍生物,例如羧甲基纖維素鈉、乙基纖維素及醋酸纖維素;粉狀黃蓍膠、麥芽、明膠、滑石、賦形劑,例如可可脂及栓劑蠟;油類,例如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油;二醇類,例如丙二醇及聚乙二醇;酯類,例如油酸乙酯及月桂酸乙酯;瓊脂、褐藻酸、等張鹽水、林格氏溶液(Ringer's solution);醇類,例如乙醇、異丙醇、十六醇及甘油;環糊精,例如羥丙基β-環糊精及磺丁基醚β-環糊精;潤滑劑,例如十二烷基硫酸鈉及硬脂酸鎂;石油烴,例如礦物油及礦脂(petrolatum)。依照調配者之判斷,著色劑、釋放劑、包衣劑、甜味劑、調味劑及加香劑、防腐劑及抗氧化劑亦可存在於組合物中。
本發明之醫藥組合物可藉由此項技術中熟知之方法製造,例如習知粒化、混合、溶解、膠囊化、凍乾或乳化製程等。組合物可以各種形式來製得,包括顆粒劑、沈澱物或微粒、粉末(包括凍乾粉末、旋轉乾燥粉末或噴霧乾燥粉末、非晶形粉末)、錠劑、膠囊、糖漿、栓劑、注射劑、乳液、酏劑、懸浮液或溶液。
根據一較佳實施例,為向哺乳動物(較佳人類)投藥對本發明之組合物進行調配。本發明之此等醫藥組合物可以口服、非經腸方式、藉由吸入噴霧劑、以局部、經直腸、經鼻、經口腔、經陰道方式或經由植入式儲集器投與。本文中所使用之術語"非經腸"包括皮下、靜脈內、肌肉內、關節內、滑膜內、胸骨內、鞘內、肝內、病灶內及顱內
注射或輸注技術。較佳地,組合物係口服、靜脈內或皮下投與。本發明之調配物可被設計為短效、速釋或長效的。更進一步地,化合物可以局部而非全身性方式投與,例如在腫瘤位點處(例如藉由注射)投與。
用於口服之液體劑型包括(但不限於)醫藥學上可接受之乳液、微乳液、溶液、懸浮液、糖漿及酏劑。除活性化合物之外,液體劑型還可含有此項技術中通常使用之惰性稀釋劑,例如水或其他溶劑、增溶劑及乳化劑,例如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、環糊精、二甲基甲醯胺、油類(尤其為棉籽油、落花生油、玉米油、胚芽油、橄欖油、蓖麻油及芝麻油)、甘油、四氫糠醇、聚乙二醇及脫水山梨糖醇脂肪酸酯,以及其混合物。除了惰性稀釋劑外,口服組合物亦可包括佐劑,例如,潤濕劑、乳化劑及懸浮劑、甜味劑、調味劑及加香劑。
可根據已知技術使用適合之分散劑或潤濕劑及懸浮劑來調配可注射製劑,例如無菌可注射之水性或油質懸浮液。無菌可注射製劑亦可為於無毒、非經腸可接受之稀釋劑或溶劑中的無菌可注射溶液、懸浮液或乳液,例如於1,3-丁二醇中之溶液。在可接受之媒劑及溶劑中,可使用的有水、林格氏溶液、U.S.P.及等張氯化鈉溶液。此外,習知使用無菌固定油作為溶劑或懸浮介質。為此目的,可使用任何溫和的固定油,包括合成單甘油酯及二甘油酯。此外,在注射劑之製備中使用脂肪酸,例如油酸。可對可注射調配物進行滅菌,例如,藉由經由濾菌器過濾,或藉由在無菌固體組合物形式中併入殺菌劑,所述組合物可在使用前溶解於或分散於無菌水或其他無菌可注射介質中。經調配用於非經腸投藥之組合物可藉由團注或藉由定時推注來注射,或可藉由連續輸注來投與。
用於口服之固體劑型包括膠囊、錠劑、丸劑、粉末及顆粒劑。
在此等固體劑型中,將活性化合物與至少一種惰性、醫藥學上可接受之賦形劑或載劑(諸如檸檬酸鈉或磷酸二鈣)及/或a)填充劑或擴充劑(諸如澱粉、乳糖、蔗糖、葡萄糖、甘露醇及矽酸)、b)黏合劑(諸如羧甲基纖維素、海藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖及阿拉伯膠)、c)保濕劑(諸如甘油)、d)崩解劑(諸如瓊脂-瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、海藻酸、某些矽酸鹽及碳酸鈉)、e)阻溶劑(諸如石蠟)、f)吸收促進劑(諸如四級銨化合物)、g)潤濕劑(諸如十六醇及單硬脂酸甘油酯)、h)吸收劑(諸如高嶺土及膨潤土)及i)潤滑劑(諸如滑石、硬脂酸鈣、硬脂酸鎂、固態聚乙二醇、十二烷基硫酸鈉及其混合物。在膠囊、錠劑及丸劑之情況下,所述劑型亦可包含緩衝劑,例如磷酸鹽或碳酸鹽。
使用賦形劑(例如,乳糖或奶糖以及高分子量聚乙二醇及類似物)亦可將相似類型之固體組合物用作軟填充及硬填充明膠膠囊中之填充物。可利用包衣及外殼(例如腸溶衣及醫藥調配技術中熟知之其他包衣來製備錠劑、糖衣藥丸、膠囊、丸劑及顆粒劑之固體劑型。其可視情況含有遮光劑,且亦可為僅在或優先在腸道某特定部分視情況以延遲方式釋放活性成分之組合物。可使用之包埋組合物的實例包括聚合物質及蠟。使用賦形劑(例如,乳糖或奶糖以及高分子量聚乙二醇及類似物)亦可將相似類型之固體組合物用作軟填充及硬填充明膠膠囊中之填充物。
活性化合物亦可與一或多種上述賦形劑一起呈微膠囊形式。可利用包衣及外殼(例如腸溶衣、控釋包衣及醫藥調配技術中熟知之其他包衣來製備錠劑、糖衣药丸、膠囊、丸劑及顆粒劑之固體劑型。在此等固體劑型中,可將活性化合物與至少一種惰性稀釋劑(例如蔗糖、乳糖或澱粉)混合。如在正常作業中,此等劑型亦可包含除惰性稀釋劑之外的其他物質,例如壓片潤滑劑及其他壓片助劑,諸如硬脂
酸鎂及微晶纖維素。在膠囊、錠劑及丸劑之情況下,該等劑型亦可包含緩衝劑。其可視情況含有遮光劑,且亦可為僅在或優先在腸道某特定部分視情況以延遲方式釋放活性成分之組合物。可使用之包埋組合物的實例包括聚合物質及蠟。
用於局部或經皮投與本發明之化合物的劑型包括軟膏、糊劑、乳膏、洗劑、凝膠、粉末、溶液、噴劑、吸入劑或貼片。在無菌條件下,將活性組份與醫藥學上可接受之載劑及任何所需之防腐劑或緩衝劑按要求混合。眼用調配物、滴耳劑及滴眼劑亦涵蓋於本發明之範圍之內。另外,本發明還涵蓋經皮貼片之用途,該等經皮貼片具有提供化合物於體內之受控傳遞的額外益處。此等劑型可藉由使化合物溶解或分散於適合之介質中而製得。亦可使用吸收增強劑來增加化合物穿過皮膚之通量。可藉由提供速率控制膜或藉由將化合物分散於聚合物基質或凝膠中來控制速率。
在一些實施例中,式(I)之化合物係靜脈內投與。在此等實施例中,式(I)之化合物(其中Z1及Z2一起形成源自酸錯合劑之部分)可製備成上述凍乾粉之形式。較佳藉由添加適合於醫藥投藥之水性溶劑來複配凍乾粉。適合之複配溶劑的實例包括(但不限於)水、鹽水及磷酸鹽緩衝鹽水(PBS)。較佳地,使用標準(0.9%)鹽水來複配凍乾粉。在複配後,在酸酯化合物與相應游離酸化合物之間建立平衡。在一些實施例中,在添加水性介質後很快達到平衡,例如在10-15分鐘之內。平衡時所存在之酸酯與酸的相對濃度取決於以下參數,例如溶液pH值、溫度、酸錯合劑之性質以及存在於凍乾粉中之酸錯合劑與酸酯化合物的比例。
本發明之醫藥組合物較佳係為了投與患有蛋白酶體介導性病症或處於患上蛋白酶體介導性病症或經歷蛋白酶體介導性病症復發之風險之中的患者而調配。本文中所使用之術語"患者"意謂動物,較佳為
哺乳動物,更佳為人類。本發明之較佳醫藥組合物為經調配用於口服投藥、靜脈內投藥或皮下投藥之彼等組合物。然而,含有治療有效量之本發明之化合物的上述劑型中之任一者完全在常規試驗之範圍之內,且因此,完全在本發明之範圍之內。在一些實施例中,本發明之醫藥組合物可進一步含有另一治療劑。在一些實施例中,該另一治療劑為通常向患有所治療疾病或病狀之患者投與的治療劑。
"治療有效量"意謂足以引起可偵測到之蛋白酶體活性或蛋白酶體介導性病症嚴重性之降低的量。所需蛋白酶體抑制劑之量應取決於抑制劑對給定細胞種類之有效性以及治療該病症所需之時間長度。亦應瞭解,對於任何特殊患者而言,特定劑量及治療方案應取決於各種因素,包括所使用之特定化合物的活性、患者之年齡、體重、總體健康情況、性別及飲食、投藥時間、排泄率、藥物組合、治療醫師之判斷以及所治療之特定疾病的嚴重性。本發明之組合物中所存在的其他治療劑之量通常應不超過就含有彼治療劑作為唯一活性劑之組合物而言通常將投與的量。較佳地,其他治療劑之量的範圍可為含有彼治療劑作為唯一治療活性劑之組合物中通常所存在之量的約50%至約100%。
在另一態樣中,本發明提供一種用於治療患有蛋白酶體介導性病症或處於患上蛋白酶體介導性病症或經歷蛋白酶體介導性病症復發之風險之中的患者之方法。本文中所使用之術語"蛋白酶體介導性病症"包括由蛋白酶體表現或活性之增加所引起或特徵在於蛋白酶體表現或活性之增加或需要蛋白酶體活性的任何病症、疾病或病狀。術語"蛋白酶體介導性病症"還包括蛋白酶體活性之抑制有益處之任何病症、疾病或病狀。
舉例而言,本發明之化合物及醫藥組合物適用於治療經由受蛋白酶體活性調控之蛋白質(例如,NFκB、p27Kip、p21WAF/CIP1、p53)所介導的病症。相關病症包括炎性病症(例如,類風濕性關節炎、炎症
性腸病、哮喘、慢性阻塞性肺病(COPD)、骨關節炎、皮膚病(例如,異位性皮炎、牛皮癬))、血管增殖性病症(例如,動脈粥樣硬化症、再狹窄)、眼部增殖性病症(例如,糖尿病性視網膜病變)、良性增殖性病症(例如,血管瘤)、自體免疫疾病(例如,多發性硬化、組織及器官排斥反應),以及與感染相關之炎症(例如,免疫反應)、神經退行性疾病(例如,阿茲海默氏病(Alzheimer's disease)、帕金森氏病(Parkinson's disease)、運動神經元疾病、神經病理性疼痛、三聯體重複病(triplet repeat disorder)、星形細胞瘤及由酒精性肝病導致之神經退化)、缺血性損傷(例如,中風)及惡病質(例如,伴隨各種生理病理狀態之加速肌肉蛋白降解(例如,神經損傷、絕食、發燒、酸中毒、HIV感染、癌症及某些內分泌病))。
本發明之化合物及醫藥組合物特別適用於治療癌症。本文中所使用之術語"癌症"係指一種細胞病症,其特徵為不受控制或失調之細胞增殖、降低之細胞分化、不適當地侵襲周圍組織之能力及/或在異位位點形成新的生長之能力。術語"癌症"包括(但不限於)實體腫瘤及血液腫瘤。術語"癌症"涵蓋皮膚、組織、器官、骨、軟骨、血液及血管之疾病。術語"癌症"還包括原發癌及轉移癌。
可用所揭示之蛋白酶體抑制劑治療的實體腫瘤之非限制性實例包括胰腺癌;膀胱癌;結腸直腸癌;乳腺癌,包括轉移性乳腺癌;前列腺癌,包括雄激素依賴性前列腺癌及雄激素非依賴性前列腺癌;腎癌,包括(例如)轉移性腎細胞癌;肝細胞癌;肺癌,包括(例如)非小細胞肺癌(NSCLC)、細支氣管肺泡癌(BAC)及肺腺癌;卵巢癌,包括(例如)進行性上皮癌或原發性腹膜癌;子宮頸癌;胃癌;食道癌;頭頸部癌,包括(例如)頭頸部鱗狀細胞癌;黑色素瘤;神經內分泌癌,包括轉移性神經內分泌腫瘤;腦部腫瘤,包括(例如)神經膠質瘤、退行性少突神經膠質瘤、成人多形性膠質母細胞瘤及成人退行性星形細
胞瘤;骨癌;及軟組織肉瘤。
可用所揭示之蛋白酶體抑制劑治療的血液惡性腫瘤之非限制性實例包括急性骨髓白血病(AML);慢性骨髓性白血病(CML),包括加速期CML及急變期CML(CML-BP);急性淋巴母細胞白血病(ALL);慢性淋巴細胞白血病(CLL);霍奇金病(Hodgkin's disease,HD);非霍奇金淋巴瘤(NHL),包括濾泡性淋巴瘤及套細胞淋巴瘤;B細胞淋巴瘤;T細胞淋巴瘤;多發性骨髓瘤(MM);瓦爾登斯特倫巨球蛋白血症(Waldenstrom's macroglobulinemia);骨髓發育不良症候群(MDS),包括難治性貧血(RA)、難治性貧血伴有環形鐵粒幼細胞(RARS)、難治性貧血伴有原始細胞過多(RAEB)及轉變中之RAEB(RAEB-T);及骨髓增殖性症候群。
在一些實施例中,本發明之化合物或組合物用於治療患有癌症或處於患上癌症或經歷癌症復發之風險之中的患者,該癌症係選自由多發性骨髓瘤及套細胞淋巴瘤組成之群。
在一些實施例中,本發明之蛋白酶體抑制劑與另一治療劑聯合投與。該另一治療劑亦可抑制蛋白酶體,或可以不同機制起作用。在一些實施例中,該另一治療劑為通常向患有所治療疾病或病狀之患者投與的治療劑。本發明之蛋白酶體抑制劑可與另一治療劑一起以單一劑型或以獨立劑型投與。當以獨立劑型投與時,該另一治療劑可在投與本發明之蛋白酶體抑制劑之前、同時或之後投與。
在一些實施例中,式(I)之蛋白酶體抑制劑與抗癌劑聯合投與。本文中所使用之術語"抗癌劑"係指出於治療癌症之目的向癌症個體投與的任何藥劑。
DNA損傷化療劑之非限制性實例包括拓撲異構酶I抑制劑(例如,伊立替康(irinotecan)、拓撲替康(topotecan)、喜樹鹼(camptothecin)及其類似物或代謝物及阿黴素(doxorubicin));拓撲異構酶II抑制劑(例
如,足葉乙甙(etoposide)、替尼泊甙(teniposide)及柔紅黴素(daunorubicin));烷基化劑(例如,美法侖(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulfan)、噻替派(thiotepa)、異環磷醯胺(ifosfamide)、卡氮芥(carmustine)、洛莫司汀(lomustine)、司莫司汀(semustine)、鏈脲佐菌素(streptozocin)、氮烯咪胺(decarbazine)、甲胺蝶呤(methotrexate)、絲裂黴素C(mitomycin C)及環磷醯胺(cyclophosphamide));DNA嵌入劑(例如,順鉑(cisplatin)、奧沙利鉑(oxaliplatin)及卡鉑(carboplatin));DNA嵌入劑及自由基產生劑,例如博萊黴素(bleomycin);以及核苷模擬物(例如,5-氟尿嘧啶(5-fluorouracil)、卡培他濱(capecitibine)、吉西他濱(gemcitabine)、氟達拉濱(fludarabine)、阿糖胞苷(cytarabine)、巰基嘌呤(mercaptopurine)、硫鳥嘌呤(thioguanine)、噴妥司汀(pentostatin)及羥基脲(hydroxyurea))。
破壞細胞複製之化療劑包括:紫杉醇(paclitaxel)、多西紫杉醇(docetaxel)及相關類似物;長春新鹼(vincristine)、長春鹼(vinblastin)及相關類似物;沙利度胺(thalidomide)、來那度胺(lenalidomide)及相關類似物(例如,CC-5013及CC-4047);蛋白酪胺酸激酶抑制劑(例如甲磺酸伊馬替尼(imatinib mesylate)及吉非替尼(gefitinib));蛋白酶體抑制劑(例如,硼替佐米);NF-κB抑制劑,包括IκB激酶抑制劑;與過表現於癌症中之蛋白質結合且進而下調細胞複製的抗體(例如,曲妥珠單抗(trastuzumab)、利妥昔單抗(rituximab)、西妥昔單抗(cetuximab)及貝伐單抗(bevacizumab));及已知在癌症中被上調、過表現或活化之蛋白質或酶的其他抑制劑,該抑制會下調細胞複製。
為了更充分地理解本發明,陳述以下製備實例及測試實例。此等實施例說明如何製備或測試特定化合物,但不應視為以任何方式限制本發明之範圍。
縮寫
分析型LC-MS方法
使用下列梯度在Symmetry C18-3.5μm-4.6×50mm柱上進行光譜量測:
溶劑A:2%異丙醇、98%水、10mM NH4OAc
溶劑B:75%乙腈、25%甲醇、10mM NH4OAc
實例1:[(1R)-1-({[(2,3-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁
基]
酸.20 D-甘露醇(I-1)之合成
步驟1:[(2,3-二氟苯甲醯基)胺基]乙酸甲酯
向2,3-二氟苯甲酸(0.190g,1.2mmol)之四氫呋喃(5mL)溶液中添加甘胺酸甲酯鹽酸鹽(0.150g,1.2mmol)、HOBt(0.162g,1.2mmol)、DIEA(0.209mL,1.2mmol)及EDCI(0.252g,1.3mmol)。使反應混合物攪拌隔夜。用飽和碳酸氫鈉溶液中止反應混合物反應,且使產物分溶於DCM中。分離有機層,繼而移除溶劑,得到[(2,3-二氟苯甲醯基)胺基]乙酸甲酯,其不經純化即用於下一步驟。
步驟2:[(2,3-二氟苯甲醯基)胺基]乙酸
向[(2,3-二氟苯甲醯基)胺基]乙酸甲酯(0.250g,1.1mmol)之甲醇(7mL)溶液中添加氫氧化鋰(0.053g,2.2mmol)及水(3mL)。使反應混合物攪拌隔夜。將混合物用水(20mL)稀釋且用1N HCl(5mL)酸化。使產物於DCM/甲醇(4:1)中分溶。用硫酸鈉乾燥有機層,且移除溶劑,得到[(2,3-二氟苯甲醯基)胺基]乙酸,其不經純化即用於下一步驟。
步驟3:2,3-二氟-N-[2-({(1R)-3-甲基-1-[(3aR,4R,6R,7aS)-3a,5,5-三甲基六氫-4,6-亞甲基-1,3,2-苯并二氧硼-2-基]丁基}胺基)-2-側氧基乙基]苯甲醯胺
向[(2,3-二氟苯甲醯基)胺基]乙酸(0.205g,0.95mmol)之二甲基甲醯胺(10mL)溶液中添加TBTU(0.337g,1.0mmol)及(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-亞甲基-1,3,2-苯并二氧硼-2-基]丁-1-胺之三氟乙酸鹽(0.362g,0.95mmol)。使混合物冷取至0℃,且逐滴添加DIEA(0.498mL,2.9mmol)。使反應混合物溫熱至室溫且攪拌隔夜。用100mL水中止反應,且使產物分溶於DCM中。用硫酸鈉乾燥有機層,且移除溶劑,得到2,3-二氟-N-[2-({(1R)-3-甲基-1-[(3aR,4R,6R,7aS)-3a,5,5-三甲基六氫-4,6-亞甲基-1,3,2-苯并二氧硼-2-基]丁基}胺基)-2-側氧基乙基]苯甲醯胺。
步驟4:[(1R)-1-({[(2,3-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]
酸
向2,3-二氟-N-[2-({(1R)-3-甲基-1-[(3aR,4R,6R,7aS)-3a,5,5-三甲基六氫-4,6-亞甲基-1,3,2-苯并二氧硼-2-基]丁基}胺基)-2-側氧基乙基]苯甲醯胺(0.536g,1.2mmol)之甲醇/1N HCl(1:1)(1.5mL)溶液中添加庚醇(1mL)及酸異丁酯(0.207g,2.0mmol)。使反應混合物攪拌隔夜。將庚醇層分離且濃縮甲醇/HCl層。藉由逆相HPLC純化粗產物,得到[(1R)-1-({[(2,3-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸。
步驟5:[(1R)-1-({[(2,3-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]
酸.20 D-甘露醇(I-1)
向[(1R)-1-({[(2,3-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸(0.085g,0.26mmol)於第三丁醇(2mL)及水(5mL)中之溶液中添加D-甘露醇(0.943g,5.2mmol)。溫熱溶液且使之攪拌直至全部溶解。接著將溶液冷凍且藉由凍乾法移除溶劑,得到[(1R)-1-({[(2,3-二
氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸.20 D-甘露醇(I-1)(0.98g,97%)。
實例2:[(1R)-1-({[(2-溴苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]
酸.20 D-甘露醇(I-5)之合成
步驟1:[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-亞甲基-1,3,2-苯并二氧硼-2-基]丁基}胺基)-2-側氧基乙基]胺基甲酸第三丁酯
經15分鐘向(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-亞甲基-1,3,2-苯并二氧硼-2-基]丁-1-胺之三氟乙酸鹽(4.9g,10.8mmol)、N-α-(第三丁氧羰基)甘胺酸(1.98g,11.3mmol)及TBTU(3.81g,11.9mmol)於DCM(100mL)中之混合物中逐滴添加DIEA(5.64mL,32.4mmol)之DCM(25mL)溶液。使反應混合物攪拌隔夜且加以濃縮。藉由柱層析純化粗產物,得到[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-亞甲基-1,3,2-苯并二氧硼-2-基]丁基}胺基)-2-側氧基乙基]胺基甲酸第三丁酯(2.5g,55%)。
步驟2:2-胺基-N-{(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫
-4,6-亞甲基-1,3,2-苯并二氧硼-2-基]丁基}乙醯胺
向[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-亞甲基-1,3,2-苯并二氧硼-2-基]丁基}胺基)-2-側氧基乙基]胺基甲酸第三丁酯(2.5g,5.9mmol)之DCM(15mL)溶液中添加二噁烷(5.9mL)中之4M HCl。使反應混合物攪拌2小時且加以濃縮,得到2-胺基-N-{(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-亞甲基-1,3,2-苯并二氧硼-2-基]丁基}乙醯胺,其不經純化即用於下一步驟。
步驟3:2-溴-N-[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-亞甲基-1,3,2-苯并二氧硼-2-基]丁基}胺基)-2-側氧基乙基]苯甲醯胺
向2-溴苯甲酸(0.124g,0.62mmol)之DCM(2.25mL)溶液中添加EDCI(0.119g,0.62mmol)、HOBt(0.084g,0.62mmol)、N-甲基嗎啉(0.185mL,1.68mmol)及2-胺基-N-{(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-亞甲基-1,3,2-苯并二氧硼-2-基]丁基}乙醯胺(0.2g,0.56mmol)。使反應混合物攪拌2小時且加以濃縮。將殘餘物用水稀釋且用EtOAc萃取。將有機溶液合併,用鹽水洗滌,經MgSO4乾燥,過濾且加以濃縮。藉由柱層析純化粗產物,得到2-溴-N-[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-亞甲基-1,3,2-苯并二氧硼-2-基]丁基}胺基)-2-側氧基乙基]苯甲醯胺(0.22g,78%)。
步驟4:[(1R)-1-({[(2-溴苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]
酸
向2-溴-N-[2-({(1R)-3-甲基-1-[(3aS,4S,6S,7aR)-3a,5,5-三甲基六氫-4,6-亞甲基-1,3,2-苯并二氧硼-2-基]丁基}胺基)-2-側氧基乙基]苯甲醯胺(0.220g,0.44mmol)於甲醇/己烷(1:1)(2.2mL)中之溶液中添加1N HCl(1mL,1.0mmol)及酸異丁酯(0.078g,0.76mmol)。將反應混合
物攪拌隔夜。濃縮反應混合物且藉由逆相HPLC純化,得到[(1R)-1-({[(2-溴苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸(0.119g,73%)。
步驟5:[(1R)-1-({[(2-溴苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]
酸.20 D-甘露醇(I-5)
向[(1R)-1-({[(2-溴苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸(0.103g,0.28mmol)於第三丁醇(9mL)及水(15mL)中之溶液中添加D-甘露醇(1.01g,5.5mmol)。溫熱溶液且使之攪拌直至全部溶解。接著將溶液冷凍且藉由凍乾法移除溶劑,得到[(1R)-1-({[(2-溴苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸.20 D-甘露醇(I-5)(0.92g,84%)。
以與實例1或2類似之方法由適當之起始物質製備下表中之化合物。
實例2:20S蛋白酶體分析
於37℃下向384孔黑色微量滴定板中溶於DMSO之1μL測試化合物中添加25μL含有人類PA28活化子(Boston Biochem,終濃度12nM)與Ac-WLA-AMC(β5選擇性受質)(終濃度15μM)之檢定緩衝液,隨後於37℃下再添加25μL含有人類20S蛋白酶體(Boston Biochem,終濃度0.25nM)之檢定緩衝液。檢定緩衝液係由20mM HEPES、0.5mM EDTA及0.01% BSA組成,pH值為7.4。用BMG Galaxy板讀數器(37℃,380nm激發,460nm發射,20增益)跟蹤反應。相對於0%抑制(DMSO)及100%抑制(10μM硼替佐米)對照組計算抑制百分比。
當以此檢定測試時,化合物I-1至I-21均展現IC50值小於50nM。
實例3:抗增殖檢定
將100μL補充有10%胎牛血清(Invitrogen)之適當細胞培養基(McCoy's 5A for HCT-116,Invitrogen)中的HCT-116(1000)或其他腫瘤細胞接種於96孔細胞培養板之孔中,且於37℃下培育隔夜。將測試化合物加入到孔內且將板於37℃下培育96小時。向各孔中添加MTT或WST試劑(10μL,Roche),且按製造商所述於37℃下培育4小時。針對MTT,根據製造商說明書(Roche)使所代謝之染料增溶隔夜。對於MTT使用分光光度計(Molecular Devices)在595nm(主波長)及690nm(參比波長)下讀取各孔之光密度,對於WST則在450nm下讀取各孔之光密度。對於MTT,自主波長之光密度值減去參比光密度值。使用設為100%之DMSO對照組的值來計算抑制百分比。
實例4:活體內腫瘤功效模型
使用1mL 26 3/8-ga針(Becton Dickinson Ref#309625)將100μL RPMI-1640培養基(Sigma-Aldrich)中之新鮮分離的HCT-116(2-5×106
個)或其他腫瘤細胞無菌注射至雌性CD-1裸小鼠(5-8週齡,Charles River)右背側之皮下間隙內。或者,一些異種移植模型需要腫瘤片段之連續傳代。在此等情況中,經由13-ga套管針(Popper & Sons 7927)將腫瘤組織之小片段(約1mm3)經皮下植入至經麻醉(3-5%異氟烷/氧混合物)之C.B-17/SCID小鼠(5-8週齡,Charles River)的右背側。自接種後第7天開始,使用游標卡尺每週2次量測腫瘤。使用標準程序(0.5×(長度×寬度2))計算腫瘤體積。當腫瘤體積達到約200mm3時,將小鼠隨機分為若干治療組且開始接受藥物治療。基於先前自藥物動力學/藥效學及最大耐受劑量研究中獲得之結果確定各實驗之給藥劑量及時程。對照組將接受不含任何藥物之媒劑。通常,以不同劑量及時程將測試化合物(100-200μL)經由靜脈(27-ga針)、口服(20-ga管飼針)或皮下(27-ga針)途徑投與。每週兩次量測腫瘤尺寸及體重,且當對照腫瘤達到約2000mm3時終止研究。
儘管前文已出於清晰性及理解之目的相當詳細地描述了本發明,但此等特定實施例應被視為說明性的而非具限制性。此項技術者在閱讀本揭示案後應瞭解,在不脫離本發明之真實範圍的情況下可對形式及細節作出各種改變,本發明之真實範圍應由隨附申請專利範圍而非具體實施例所界定。
本文中所提及之專利及科技文獻為此項技術者提供了可利用之知識。除非另有定義,否則本文中所用之所有技術及科學術語具有與熟習本發明所屬技術之普通人員之通常理解相同的含義。本文中所引用之已授權專利、申請案及參考文獻係以引用之方式併入本文中,其引用程度就如同特定地及個別地指示將各個已授權專利、申請案及參考文獻以引用之方式併入一般。在矛盾之情況下,應以本揭示案(包括定義)為準。
Claims (5)
- 一種式(I)之化合物,
- 如請求項1之化合物,其係選自由以下所組成之群:[(1R)-1-({[(2,3-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(5-氯-2-氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(3,5-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸; [(1R)-1-({[(2,5-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2-溴苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2-氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2-氯-5-氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(4-氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(3,4-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(3-氯苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2,5-二氯苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(3,4-二氯苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(3-氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2-氯-4-氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2,3-二氯苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2-氯苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸; [(1R)-1-({[(2,4-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(4-氯-2-氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(4-氯苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2,4-二氯苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;及[(1R)-1-({[(3,5-二氯苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;或其醫藥學上可接受之鹽或酸酐。
- 如請求項1之化合物,其為選自由以下所組成之群的酸化合物之甘露醇酯:[(1R)-1-({[(2,3-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(5-氯-2-氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(3,5-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2,5-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2-溴苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2-氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2-氯-5-氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁 基]酸;[(1R)-1-({[(4-氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(3,4-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(3-氯苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2,5-二氯苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(3,4-二氯苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(3-氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2-氯-4-氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2,3-二氯苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2-氯苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2,4-二氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(4-氯-2-氟苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(4-氯苯甲醯基)胺基]乙醯基}胺基)-3-甲基丁基]酸;[(1R)-1-({[(2,4-二氯苯甲醯基)胺基]乙醯基}胺基]-3-甲基丁 基]酸;及[(1R)-1-({[(3,5-二氯苯甲醯基)胺基]乙醯基}胺基]-3-甲基丁基]酸。
- 一種醫藥組合物,其包含如請求項1之化合物及醫藥學上可接受之載劑。
- 一種如請求項4之醫藥組合物的用途,其係用於製備用以治療癌症之藥物。
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US11/890,412 US7442830B1 (en) | 2007-08-06 | 2007-08-06 | Proteasome inhibitors |
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US (11) | US20180099984A1 (zh) |
TW (1) | TW201700482A (zh) |
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2008
- 2008-08-05 TW TW105111120A patent/TW201700482A/zh unknown
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2017
- 2017-12-07 US US15/834,394 patent/US20180099984A1/en not_active Abandoned
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2018
- 2018-06-29 US US16/022,977 patent/US20180305380A1/en not_active Abandoned
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2019
- 2019-01-17 US US16/250,149 patent/US20190144470A1/en not_active Abandoned
- 2019-08-07 US US16/533,900 patent/US20190359636A1/en not_active Abandoned
-
2020
- 2020-02-20 US US16/795,749 patent/US20200190118A1/en not_active Abandoned
- 2020-09-09 US US17/015,156 patent/US20200407376A1/en not_active Abandoned
-
2021
- 2021-03-19 US US17/206,392 patent/US20210206784A1/en not_active Abandoned
- 2021-09-29 US US17/489,663 patent/US20220017542A1/en not_active Abandoned
-
2022
- 2022-04-14 US US17/720,621 patent/US20220251117A1/en not_active Abandoned
-
2023
- 2023-05-02 US US18/310,771 patent/US20230265110A1/en not_active Abandoned
- 2023-11-17 US US18/512,431 patent/US20240083922A1/en active Pending
Also Published As
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US20200407376A1 (en) | 2020-12-31 |
US20220251117A1 (en) | 2022-08-11 |
US20190359636A1 (en) | 2019-11-28 |
US20190144470A1 (en) | 2019-05-16 |
US20180099984A1 (en) | 2018-04-12 |
US20210206784A1 (en) | 2021-07-08 |
US20240083922A1 (en) | 2024-03-14 |
US20230265110A1 (en) | 2023-08-24 |
US20200190118A1 (en) | 2020-06-18 |
US20180305380A1 (en) | 2018-10-25 |
US20220017542A1 (en) | 2022-01-20 |
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