TW201806624A - 吲哚啉酮化合物之用途 - Google Patents
吲哚啉酮化合物之用途 Download PDFInfo
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- TW201806624A TW201806624A TW106125399A TW106125399A TW201806624A TW 201806624 A TW201806624 A TW 201806624A TW 106125399 A TW106125399 A TW 106125399A TW 106125399 A TW106125399 A TW 106125399A TW 201806624 A TW201806624 A TW 201806624A
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Abstract
本發明提供使用維奈托克(venetoclax)與吲哚啉酮衍生物之組合治療急性骨髓白血病及瀰漫性大B細胞淋巴瘤之方法及組合物。
Description
本發明提供使用吲哚啉酮衍生物治療急性骨髓白血病及瀰漫性大B細胞淋巴瘤之方法及組合物。
十年前已表徵存在於各種尤文氏肉瘤家族腫瘤(Ewing's sarcoma family of tumors,ESFT)中之EWS-FLI轉錄因子。兒童及青少年中第二最常見骨腫瘤-尤文氏肉瘤之治療進展已改善患有局部腫瘤之患者之存活。然而,患有轉移瘤之患者仍情況不妙且療法具有短期及長期毒性。尤文氏肉瘤家族腫瘤(ESFT)之特徵在於產生EWS-FLI1之染色體易位,EWS-FLI1係一種咸信持續表現對於ESFT細胞存活而言至關重要的致癌融合轉錄因子(Balamuth, NJ, Womer, RB., Lancet Oncology 11, 184-192 (2010))。諸如FLI1及SPIB之ETS轉錄因子在人類淋巴瘤內反覆失調(Bonetti等人, Blood 2013;Lenz等人, PNAS 2008)。小分子YK-4-279抑制EWS1-FLI1融合蛋白結合於RHA,從而導致尤文氏肉瘤細胞之生長停滯及細胞凋亡(Erkizan等人, Nat Med 2009)且先前展示YK-4-279具有活體外抗淋巴瘤活性(Chung等人, AACR 2015)。 活體外及活體內研究已證明抑制癌蛋白EWS-FLI1結合於RNA解螺旋酶A (RHA)引起ESFT細胞株之增殖減少及腫瘤體積減小。EWS-FLI1缺乏酶活性,然而,RNA解螺旋酶A (RHA)與EWS-FLI1之間的蛋白質-蛋白質相互作用調節瘤形成,且因此係維持腫瘤生長所需的(Hyariye N Erkizan等人. Nature Medicine 15(7) 750-756 (2009))。破壞關鍵蛋白質相互作用之範例可用於治療包括具有類似易位之肉瘤及具有MLL易位之白血病的疾病((Helman LJ, Meltzer P. Mechanisms of sarcoma development. Nat Rev Cancer 2003;3(9):685-94);及Pui CH,等人, N Engl J Med 2004;350(15):1535-48)。此外,無序蛋白質基於其內在生物化學特性可為極佳治療標靶(Cheng Y, LeGall T, Oldfield CJ,
等人, Trends Biotechnol 2006;24(10):435-42)。
儘管多年來針對EWS-FLI1用反義及siRNA進行活體外及異種移植研究,但迄今為止,基於遞送及穩定性不足,此等研究中無一者可實際用作人類療法。因此,需要改良的治療諸如ESFT之病症之療法。 FLI-1為ETS家族轉錄因子之成員,該等轉錄因子通常在胚胎發育中具有活性,但在出生之後無活性。此家族轉錄因子存在29個成員,其中FLI-1、ETV1、ETV4及ERG四者已與廣泛癌症關聯。 目標為抑制FLI1、ETV1、ETV4或ERG或自身轉錄因子之致癌融合蛋白之結合的治療化合物將用於治療包括尤文氏肉瘤家族腫瘤、胰臟癌、前列腺癌、神經膠母細胞瘤、非小細胞肺癌之癌症及若干其他癌症。較佳實施例滿足此等需求,且亦提供其他優勢。 本文揭示之一些實施例係關於一種式(I)化合物,包括諸如其立體異構體、游離形式、醫藥學上可接受之鹽或酯、溶劑合物或此類形式之組合之形式,其中A、D、R1
、R2
、R3
、R4
、R5
、R6
及R12
如本文所定義。本文揭示之一些實施例係關於用於治療哺乳動物體內癌症之方法,該方法包含向哺乳動物投與有效量之一或多種式(I)化合物,包括諸如其立體異構體、游離形式或醫藥學上可接受之鹽之形式;或醫藥組合物,該醫藥組合物包括一或多種式(I)化合物,包括諸如其立體異構體、游離形式或醫藥學上可接受之鹽之形式。本文中所述之其他實施例係關於使用包括諸如其立體異構體、游離形式或醫藥學上可接受之鹽之形式的一或多種式(I)化合物製造供治療癌症用之藥劑。 本文描述之另外其他實施例係關於包括諸如其立體異構體、游離形式或醫藥學上可接受之鹽之形式的式(I)化合物,其用於治療癌症,其中癌症係選自由以下組成之群:尤文氏肉瘤、神經膠母細胞瘤、急性骨髓白血病、乳腺癌、頭頸癌、黑素瘤、非小細胞肺癌、卵巢癌、前列腺癌及子宮癌。下文更詳細地描述此等及其他實施例。
以下描述及實例詳細說明本發明之一較佳實施例。熟習此項技術者將認識到,存在涵蓋於本發明範疇內之本發明之大量變化及修改。因此,不應認為較佳實施例之描述限制本發明之範疇。 產生致癌轉錄因子之染色體易位為多種腫瘤(包括許多肉瘤)之標誌。尤文氏肉瘤家族腫瘤(ESFT)之特徵在於t(11;22)(q24;q12)易位,該易位產生造成此腫瘤之高度惡性表型的尤文氏肉瘤斷點區1及弗氏白血病病毒(Friend leukemia virus)整合1 (EWS-FLI1)融合轉錄因子。咸信EWS-FLI1之持續表現對於ESFT細胞存活而言至關重要。EWS-FLI1由於其惡性細胞特異性而成為有吸引力的尤文氏肉瘤治療標靶。此外,實驗證據表明EWS/FLI表現對於尤文氏肉瘤腫瘤細胞而言至關重要。用反義寡去氧核苷酸及RNA干擾(RNAi)活體外靶向EWS-FLI1抑制尤文氏肉瘤細胞生存力、生長及致癌轉型,從而支持EWS-FLI1衰減作為潛在治療模式。較佳實施例之治療劑廣泛適用於更大腫瘤群,且適用作用於治療與致癌轉錄因子相關之其他惡性疾病(諸如耐化學療法肉瘤及白血病)及難治性腫瘤(諸如尤文氏肉瘤)的治療劑。定義
除非另外定義,否則本文所用之所有技術及科學術語均具有與一般技術者通常所理解相同之含義。除非另外說明,否則本文中所提及之所有專利、申請案、公開之申請案及其他公開案均以全文引用的方式併入。除非另外說明,否則在本文中關於一個術語存在複數個定義之情況下,以此部分中之定義為準。 如本文所用,任何「R」基團,諸如(但不限於) R1
、R2
、R3
、R4
、R5
、R6
、R7
、R8
、R9
、R10
、R11
及R12
表示可連接至所指示原子之取代基。R基團可經取代或未經取代。若兩個「R」基團描述為「連在一起」,則R基團及其所連接之原子可形成環烷基、環烯基、芳基、雜芳基或雜環。舉例而言(但不限於),若指示NRa
Rb
基團之Ra
及Rb
「連在一起」,則其意謂Ra
及Rb
彼此共價鍵結以形成環:。 另外,若替代地,兩個「R」基團描述為「連同」其所連接之原子「一起」形成環,則該等R基團可不限於先前定義之變數或取代基。 如本文所用,「烷基」係指包含完全飽和(無雙鍵或參鍵)烴基之直鏈或分支鏈烴鏈。烷基可具有1至20個碳原子(每當在本文中出現時,諸如「1至20」之數值範圍係指給定範圍中之各整數;例如「1至20個碳原子」意謂烷基可由1個碳原子、2個碳原子、3個碳原子等,達至且包括20個碳原子組成,不過本定義亦涵蓋其中未規定數值範圍之術語「烷基」之出現)。烷基亦可為具有1至10個碳原子之中等尺寸烷基。烷基亦可為具有1至6個碳原子之低碳烷基。化合物中之烷基可命名為「C1
-C6
烷基」或類似名稱。僅藉助於實例,「C1
-C6
烷基」表明在烷基鏈中存在一個至六個碳原子,亦即烷基鏈係選自甲基、乙基、丙基、異丙基、正丁基、異丁基、第二丁基及第三丁基、戊基(直鏈及分支鏈)及己基(直鏈及分支鏈)。典型烷基包括(但不限於)甲基、乙基、丙基、異丙基、丁基、異丁基、第三丁基、戊基(直鏈及分支鏈)及己基(直鏈及分支鏈)。烷基可經取代或未經取代。 如本文所用,「環烷基」係指完全飽和(無雙鍵或參鍵)之單環或多環烴環系統。當由兩個或超過兩個環形成時,環可以稠合方式接合在一起。環烷基可在環中含有3個至10個原子或在環中含有3個至8個原子。環烷基可未經取代或經取代。典型環烷基包括(但絕不限於)環丙基、環丁基、環戊基、環己基、環庚基及環辛基。 如本文所用,「芳基」係指在所有環中具有完全非定域π電子系統之碳環(所有碳)單環或多環芳環系統(包括其中兩個碳環共用化學鍵之稠環系統)。芳基中之碳原子數目可變化。舉例而言,芳基可為C6
-C14
芳基、C6
-C10
芳基或C6
芳基。芳基之實例包括(但不限於)苯、萘及薁(azulene)。芳基可經取代或未經取代。 如本文所用,「雜芳基」係指含有一或多個雜原子(例如1至5個雜原子)(亦即除碳以外之元素,包括(但不限於)氮、氧及硫)之單環或多環芳環系統(具有完全非定域π電子系統之環系統)。雜芳基之環中之原子數目可變化。舉例而言,雜芳基可在環中含有4個至14個原子,在環中含有5個至10個原子或在環中含有5個至6個原子。此外,術語「雜芳基」包括其中兩個環(諸如至少一個芳基環與至少一個雜芳基環,或至少兩個雜芳基環)共用至少一個化學鍵之稠合環系統。雜芳基環之實例包括(但不限於)呋喃、呋呫、噻吩、苯并噻吩、酞嗪、吡咯、噁唑、苯并噁唑、1,2,3-噁二唑、1,2,4-噁二唑、噻唑、1,2,3-噻二唑、1,2,4-噻二唑、苯并噻唑、咪唑、苯并咪唑、吲哚、吲唑、吡唑、苯并吡唑、異噁唑、苯并異噁唑、異噻唑、三唑、苯并三唑、噻二唑、四唑、吡啶、噠嗪、嘧啶、吡嗪、嘌呤、喋啶、喹啉、異喹啉、喹唑啉、喹喏啉、㖕啉及三嗪。雜芳基可經取代或未經取代。 如本文所用,雜環烷基係指3員、4員、5員、6員、7員、8員、9員、10員,達至18員單環、雙環及三環環系統,其中碳原子連同1個至5個雜原子構成該環系統。雜環可視情況含有一或多個不飽和鍵,然而該一或多個不飽和鍵以完全非定域π電子系統不存在於所有環中之方式定位。雜原子為除碳以外之元素,包括(但不限於)氧、硫及氮。雜環可進一步含有一或多個羰基或硫羰基官能基,以便使該定義包括側氧基系統及硫基系統,諸如內醯胺、內酯、環狀醯亞胺、環狀硫醯亞胺及環狀胺基甲酸酯。當由兩個或超過兩個環形成時,環可以稠合方式接合在一起。另外,雜環烷基中之任何氮可經四級銨化。雜環烷基可未經取代或經取代。此類雜環烷基之實例包括(但不限於) 1,3-二氧雜環己烯、1,3-二噁烷、1,4-二噁烷、1,2-二氧雜環戊烷、1,3-二氧雜環戊烷、1,4-二氧雜環戊烷、1,3-氧硫雜環己烷、1,4-氧硫雜環己二烯、1,3-氧硫雜環戊烷、1,3-二硫雜環戊二烯、1,3-二硫雜環戊烷、1,4-氧硫雜環己烷、四氫-1,4-噻嗪、2H-1,2-噁嗪、順丁烯二醯亞胺、琥珀醯亞胺、巴比妥酸、硫基巴比妥酸、二側氧基哌嗪、乙內醯脲、二氫尿嘧啶、三噁烷、六氫-1,3,5-三嗪、咪唑啉、咪唑啶、異噁唑啉、異噁唑啶、噁唑啉、噁唑啶、噁唑啶酮、噻唑啉、噻唑啶、嗎啉、環氧乙烷、哌啶N-氧化物、哌啶、哌嗪、吡咯啶、吡咯啶酮、咪唑啉二酮、4-哌啶酮、吡唑啉、吡唑啶、2-側氧基吡咯啶、四氫哌喃、4H-哌喃、四氫硫哌喃、硫嗎啉、硫嗎啉亞碸、硫嗎啉碸及其苯并稠合類似物(例如苯并咪唑啉二酮、四氫喹啉及3,4-亞甲基二氧基苯基)。 術語「醫藥學上可接受之鹽」係指不會對其所投與之生物體產生顯著刺激且不會消除化合物之生物活性及性質的化合物之鹽。在一些實施例中,鹽為化合物之酸加成鹽。醫藥鹽可藉由使化合物與諸如氫鹵酸(例如氫氯酸或氫溴酸)、硫酸、硝酸及磷酸之無機酸反應而獲得。醫藥鹽亦可藉由使化合物與諸如脂族或芳族羧酸或磺酸,例如甲酸、乙酸、丁二酸、乳酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、菸鹼酸、甲磺酸、乙磺酸、對甲苯磺酸、水楊酸或萘磺酸之有機酸反應而獲得。醫藥鹽亦可藉由使化合物與鹼反應形成鹽而獲得,該鹽諸如銨鹽;鹼金屬鹽,諸如鈉鹽或鉀鹽;鹼土金屬鹽,諸如鈣鹽或鎂鹽;有機鹼(諸如二環己胺、N-甲基-D-葡糖胺、參(羥甲基)甲胺、C1
-C7
烷基胺、環己胺、三乙醇胺、乙二胺)之鹽;及與胺基酸(諸如精胺酸及離胺酸)形成之鹽。 應瞭解,在具有一或多個對掌性中心之本文中所描述之任何化合物中,若不明確指示絕對立體化學,則各中心可獨立地具有R-組態或S-組態或其混合物。因此,本文所提供之化合物可為對映異構性純、對映異構性增濃、外消旋混合物、非對映異構性純、非對映異構性增濃或立體異構體混合物。另外,應瞭解,在具有一或多個雙鍵,產生可定義為E或Z之幾何異構體之本文中所描述之任何化合物中,各雙鍵可獨立地為E或Z或其混合物。 應瞭解,當本文所揭示之化合物具有未滿價數時,則價數將以氫或其同位素(例如氫-1 (氕)及氫-2 (氘))填補。 應瞭解,本文所述之化合物可經同位素標記。用諸如氘之同位素取代可獲得某些由更大代謝穩定性產生之治療優勢,諸如增加之活體內半衰期或降低之劑量需求。化合物結構中所呈現之每一化學元素可包括該元素之任何同位素。舉例而言,在化合物結構中,氫原子可明確揭示或理解為存在於化合物中。在化合物中可存在氫原子之任何位置處,氫原子可為氫之任何同位素,包括(但不限於)氫-1 (氕)及氫-2 (氘)。因此,除非上下文另外明確指示,否則本文中提及之化合物涵蓋所有可能的同位素形式。 應瞭解,本文中所述之方法及組合包括結晶形式(亦稱為多晶型物,其包括化合物之相同元素組成之不同晶體堆積排列)、非晶相、鹽、溶劑合物及水合物。在一些實施例中,本文所述之化合物以與醫藥學上可接受之溶劑(諸如水、乙醇或其類似物)之溶劑化形式存在。在其他實施例中,本文所述之化合物以非溶劑化形式存在。溶劑合物含有化學計量或非化學計量之量的溶劑,且可在結晶過程中與醫藥學上可接受之溶劑(諸如水、乙醇或其類似物)形成。在溶劑為水時形成水合物,或在溶劑為醇時形成醇化物。另外,本文所提供之化合物可以非溶劑化以及溶劑化形式存在。一般而言,出於本文所提供之化合物及方法之目的,溶劑化形式視為等效於非溶劑化形式。 在提供值範圍的情況下,應瞭解,範圍之上限及下限以及上限與下限之間的各中間值涵蓋於實施例內。治療方法
在第一態樣中,一種用於誘導包含急性骨髓白血病中所產生之骨髓母細胞或瀰漫性大B細胞淋巴瘤中所產生之淋巴細胞之細胞的細胞凋亡之方法,其包含使細胞與有效量之維奈托克與具有式(I)之結構之化合物或其立體異構體、醫藥學上可接受之鹽或溶劑合物的組合接觸:, 其中R1
、R2
、R3
及R4
獨立地選自由H、Cl、-CN及-CF3
組成之群;其中A選自由H及C1-6
烷基組成之群;其中D選自由-OH及-O(C1-6
烷基)組成之群;其中R5
及R6
獨立地選自由H、F及C1-6
烷基組成之群,或其中R5
及R6
連在一起形成經取代或未經取代之環烷基環; 其中R12
獨立地選自由C3-8
環烷基及組成之群; 其中R7
、R8
、R9
、R10
及R11
獨立地選自由以下組成之群:H、鹵素、CN、CF3
、C1-6
烷基、芳基、雜芳基、-O(C1-6
烷基)、-O(芳基)、-O(雜芳基)、-CO2
H、-CO2
(C1-6
烷基)、-NHSO2
(C1-6
烷基)、-NHSO2
(芳基)、-NHCONH(C1-6
烷基)、-NHCON(C1-6
烷基)2
、-N(C1-6
烷基)CONH2
、-N(C1-6
烷基)CONH(C1-6
烷基)、-N(C1-6
烷基)CON(C1-6
烷基)2
、-SO2
(C1-6
烷基)、-SO2
NH2
、-SO2
NH(C1-6
烷基)、-SO2
N(C1-6
烷基)2
、C3-8
環烷基及C3-8
雜環烷基。 在第一態樣之一實施例中,R9
係選自由以下組成之群:H、鹵素、CN、CF3
、C1-6
烷基、芳基、雜芳基、-O(芳基)、-O(雜芳基)、-CO2
H、-CO2
(C1-6
烷基)、-NHSO2
(C1-6
烷基)、-NHSO2
(芳基)、-NHCONH(C1-6
烷基)、-NHCON(C1-6
烷基)2
、-N(C1-6
烷基)CONH2
、-N(C1-6
烷基)CONH(C1-6
烷基)、-N(C1-6
烷基)CON(C1-6
烷基)2
、-SO2
(C1-6
烷基)、-SO2
NH2
、-SO2
NH(C1-6
烷基)、-SO2
N(C1-6
烷基)2
、C3-8
環烷基及C3-8
雜環烷基。 在第一態樣之一實施例中,細胞為哺乳動物細胞。 在第一態樣之一實施例中,細胞為人類細胞。 在第一態樣之一實施例中,細胞為活體外細胞。 在第一態樣之一實施例中,細胞為活體內細胞。 在第二態樣中,提供治療急性骨髓白血病或瀰漫性大B細胞淋巴瘤之方法,其包含向有需要之患者投與抗增殖量之維奈托克與具有式(I)之結構之化合物或其立體異構體、醫藥學上可接受之鹽或溶劑合物的組合:, 其中R1
、R2
、R3
及R4
獨立地選自由H、Cl、-CN及-CF3
組成之群;其中A選自由H及C1-6
烷基組成之群;其中D選自由-OH及-O(C1-6
烷基)組成之群;其中R5
及R6
獨立地選自由H、F及C1-6
烷基組成之群,或其中R5
及R6
連在一起形成經取代或未經取代之環烷基環; 其中R12
獨立地選自由C3-8
環烷基及組成之群; 其中R7
、R8
、R9
、R10
及R11
獨立地選自由以下組成之群:H、鹵素、CN、CF3
、C1-6
烷基、芳基、雜芳基、-O(C1-6
烷基)、-O(芳基)、-O(雜芳基)、-CO2
H、-CO2
(C1-6
烷基)、-NHSO2
(C1-6
烷基)、-NHSO2
(芳基)、-NHCONH(C1-6
烷基)、-NHCON(C1-6
烷基)2
、-N(C1-6
烷基)CONH2
、-N(C1-6
烷基)CONH(C1-6
烷基)、-N(C1-6
烷基)CON(C1-6
烷基)2
、-SO2
(C1-6
烷基)、-SO2
NH2
、-SO2
NH(C1-6
烷基)、-SO2
N(C1-6
烷基)2
、C3-8
環烷基及C3-8
雜環烷基。 在第二態樣之一實施例中,R9
係選自由以下組成之群:H、鹵素、CN、CF3
、C1-6
烷基、芳基、雜芳基、-O(芳基)、-O(雜芳基)、-CO2
H、-CO2
(C1-6
烷基)、-NHSO2
(C1-6
烷基)、-NHSO2
(芳基)、-NHCONH(C1-6
烷基)、-NHCON(C1-6
烷基)2
、-N(C1-6
烷基)CONH2
、-N(C1-6
烷基)CONH(C1-6
烷基)、-N(C1-6
烷基)CON(C1-6
烷基)2
、-SO2
(C1-6
烷基)、-SO2
NH2
、-SO2
NH(C1-6
烷基)、-SO2
N(C1-6
烷基)2
、C3-8
環烷基及C3-8
雜環烷基。 在第三態樣中,提供維奈托克與具有式(I)之結構之化合物或其立體異構體、醫藥學上可接受之鹽或溶劑合物的組合之用途,其用於治療急性骨髓白血病或瀰漫性大B細胞淋巴瘤:, 其中R1
、R2
、R3
及R4
獨立地選自由H、Cl、-CN及-CF3
組成之群;其中A選自由H及C1-6
烷基組成之群;其中D選自由-OH及-O(C1-6
烷基)組成之群;其中R5
及R6
獨立地選自由H、F及C1-6
烷基組成之群,或其中R5
及R6
連在一起形成經取代或未經取代之環烷基環; 其中R12
獨立地選自由以下組成之群:經取代或未經取代之C3-8
環烷基、經取代或未經取代之C3-8
雜環烷基、及;其中R7
、R8
、R9
、R10
及R11
獨立地選自由以下組成之群:H、鹵素、CN、CF3
、C1-6
烷基、芳基、雜芳基、-O(C1-6
烷基)、-O(芳基)、-O(雜芳基)、-CO2
H、-CO2
(C1-6
烷基)、-NHSO2
(C1-6
烷基)、-NHSO2
(芳基)、-NHCONH(C1-6
烷基)、-NHCON(C1-6
烷基)2
、-N(C1-6
烷基)CONH2
、-N(C1-6
烷基)CONH(C1-6
烷基)、-N(C1-6
烷基)CON(C1-6
烷基)2
、-SO2
(C1-6
烷基)、-SO2
NH2
、-SO2
NH(C1-6
烷基)、-SO2
N(C1-6
烷基)2
、C3-8
環烷基及C3-8
雜環烷基;且其中R13
選自由-O(C1-6
烷基)及-N(C1-6
烷基)2
組成之群。 在第三態樣之一實施例中,R9
係選自由以下組成之群:H、鹵素、CN、CF3
、C1-6
烷基、芳基、雜芳基、-O(芳基)、-O(雜芳基)、-CO2
H、-CO2
(C1-6
烷基)、-NHSO2
(C1-6
烷基)、-NHSO2
(芳基)、-NHCONH(C1-6
烷基)、-NHCON(C1-6
烷基)2
、-N(C1-6
烷基)CONH2
、-N(C1-6
烷基)CONH(C1-6
烷基)、-N(C1-6
烷基)CON(C1-6
烷基)2
、-SO2
(C1-6
烷基)、-SO2
NH2
、-SO2
NH(C1-6
烷基)、-SO2
N(C1-6
烷基)2
、C3-8
環烷基及C3-8
雜環烷基。 在第一態樣之一實施例中,R12
未經取代或經鹵素(例如Cl或F)取代。 在第一態樣、第二態樣或第三態樣之一實施例中,R9
係選自由氮丙啶基、氮雜環丁烷基、吡咯啶基及嗎啉基組成之群。 在第一態樣、第二態樣或第三態樣之一實施例中,R9
係選自由異丙基及環丙基組成之群。 在第一態樣、第二態樣或第三態樣之一實施例中,化合物具有式(Ia)之結構:, 或其立體異構體、醫藥學上可接受之鹽或溶劑合物,其中R1
、R2
、R3
及R4
獨立地選自由H及Cl組成之群;其中R7
、R8
、R10
及R11
獨立地選自由H及鹵素組成之群;且其中R9
獨立地選自由C3-8
環烷基及C3-8
雜環烷基組成之群。 在第一態樣、第二態樣或第三態樣之一實施例中,R1
及R4
為Cl且R2
及R3
為H。 在第一態樣、第二態樣或第三態樣之一實施例中,化合物具有選自由以下組成之群之結構:
或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 在第一態樣、第二態樣或第三態樣之一實施例中,化合物係選自由以下組成之群:
或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 如技術方案1至6中任一項之方法,其中該化合物具有選自由以下組成之群之結構:
或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 在第一態樣、第二態樣或第三態樣之一實施例中,化合物具有選自由以下組成之群之結構:
或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 在第一態樣、第二態樣或第三態樣之一實施例中,化合物具有以下結構:, 或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 在第一態樣、第二態樣或第三態樣之一實施例中,化合物具有以下結構:, 或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 在第一態樣、第二態樣或第三態樣之一實施例中,化合物具有以下結構:, 或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。合成方法 本文所述之式(I)化合物可以多種方式製備。本文展示及描述式(I)化合物之通用合成途徑。本文所示及所述之途徑僅具說明性且不意欲、亦不應理解為以任何方式限制申請專利範圍之範疇。熟習此項技術者將能夠基於本文中之揭示內容而認識到所揭示之合成之修改且設計替代途徑;所有此類修改及替代途徑均屬於申請專利範圍之範疇內。 視存在之取代基而定,小分子抑制劑可呈醫藥學上可接受之鹽之形式。如本文所用之術語「醫藥學上可接受之鹽」為廣義術語,且對一般技術者具有其一般及習用含義(且並不限於特殊或自定義含義),且係指(不限於)由醫藥學上可接受之無毒酸或鹼製備之鹽。合適醫藥學上可接受之鹽包括:金屬鹽,例如鋁鹽、鋅鹽;鹼金屬鹽,諸如鋰鹽、鈉鹽及鉀鹽;鹼土金屬鹽,諸如鈣鹽及鎂鹽;有機鹽,例如離胺酸、N,N'-二苯甲基乙二胺、氯普魯卡因(chloroprocaine)、膽鹼、二乙醇胺、乙二胺、葡甲胺(N-甲基還原葡糖胺)、普魯卡因(procaine)及tris之鹽;游離酸及游離鹼之鹽;無機鹽,例如硫酸鹽、鹽酸鹽及氫溴酸鹽;及目前具有廣泛醫藥用途且列舉於熟習此項技術者熟知之來源(諸如Merck Index)中之其他鹽。可選擇任何適合之成分以製備本文所論述之治療劑之鹽,其限制條件為其無毒且實質上不干擾所需活性。 較佳實施例之化合物可包括異構體、外消旋體、光學異構體、對映異構體、非對映異構體、互變異構體及順/反構象異構體。所有此類異構體形式均包括於較佳實施例中,包括其混合物。如上文所論述,較佳實施例之化合物可具有對掌性中心,例如其可含有不對稱碳原子且可因此呈對映異構體或非對映異構體及其混合物(例如外消旋體)之形式存在。不對稱碳原子可呈(R)-組態或(S)-組態存在,或可呈(R)-形式與(S)-形式之混合物存在。以下為式(I)化合物之異構體形式: 化合物可呈非晶形式或呈結晶形式。較佳實施例之化合物之結晶形式可以多晶型物之形式存在,其包括於較佳實施例中。此外,本發明之一些化合物可與水或其他有機溶劑形成溶劑合物。此類溶劑合物類似地包括於較佳實施例之範疇內。某些醫藥組合物
一般較佳以靜脈內或皮下單位劑型投與較佳實施例之抑制劑;然而,亦涵蓋其他投與途徑。所涵蓋之投與途徑包括(但不限於)經口、非經腸、靜脈內及皮下。較佳實施例之抑制劑可調配為液體製劑以例如經口投與。合適形式包括懸浮液、糖漿、酏劑及其類似物。經口投與之尤其較佳單位劑型包括錠劑及膠囊。經組態以每日一次投與之單位劑型尤其較佳;然而,在某些實施例中,可能需要將單位劑型組態成每日兩次或更多次投與。 較佳實施例之醫藥組合物較佳與接受者之血液或其他體液等張。可使用酒石酸鈉、丙二醇或其他無機或有機溶質實現組合物之等張性。氯化鈉尤其較佳。可採用緩衝劑,諸如乙酸及鹽、檸檬酸及鹽、硼酸及鹽以及磷酸及鹽。非經腸媒劑包括氯化鈉溶液、林格氏右旋糖(Ringer's dextrose)、右旋糖及氯化鈉、乳酸化林格氏液或不揮發性油。靜脈內媒劑包括流體及營養補充劑、電解質補充劑(諸如基於林格氏右旋糖之電解質補充劑)及其類似物。 可使用醫藥學上可接受之增稠劑將醫藥組合物之黏度維持在所選程度。因為甲基纖維素可輕易地及可廉價獲得且易於處理,所以其為較佳。其他合適增稠劑包括例如三仙膠、羧甲基纖維素、羥丙基纖維素、卡波姆(carbomer)及其類似物。增稠劑之較佳濃度視所選擇之增稠劑而定。較佳係使用會實現所選擇之黏度之量。通常係從溶液藉由添加此類增稠劑來製備黏稠組合物。 可採用醫藥學上可接受之防腐劑以增加醫藥組合物之存放期。苄醇可為合適的,不過亦可採用包括例如對羥基苯甲酸酯、硫柳汞、氯丁醇或苯紮氯銨之多種防腐劑。防腐劑之合適濃度通常為按組合物之總重量計約0.02%至約2%,但視所選擇之試劑而定可能需要更大或更小之量。還原劑,如上文所述,可有利地用於維持調配物之良好存放期。 較佳實施例之抑制劑可與合適載劑、稀釋劑或賦形劑(諸如無菌水、生理鹽水、葡萄糖或其類似物)混合且可含有輔助物質,諸如潤濕劑或乳化劑、pH緩衝劑、膠凝或黏度增強添加劑、防腐劑、調味劑、顏料及其類似物,視投藥途徑及所需製劑而定。參見例如「Remington:The Science and Practice of Pharmacy」, Lippincott Williams & Wilkins; 第20版 (2003年6月1日)及「Remington's Pharmaceutical Sciences,」Mack Pub. Co.; 第18版及第19版 (分別為1985年12月及1990年6月)。此類製劑可包括錯合劑、金屬離子、聚合物(諸如聚乙酸、聚乙醇酸、水凝膠、聚葡萄糖及其類似物)、脂質體、微乳液、微胞、單層或多層囊泡、紅血球血影細胞或原生質球狀體。脂質調配物之合適脂質包括(但不限於)單酸甘油酯、二酸甘油酯、髓硫脂、溶血卵磷脂、磷脂、皂素、膽酸及其類似物。此類其他組分之存在可影響物理狀態、溶解性、穩定性、活體內釋放速率及活體內清除速率,且因此根據預期應用選擇此類其他組分,使得載劑之特徵經調整以適應所選擇之投藥途徑。 對於經口投與,醫藥組合物可呈錠劑、水性或油性懸浮液、分散性粉末或顆粒、乳液、硬膠囊或軟膠囊、糖漿或酏劑提供。意圖經口使用之組合物可根據此項技術中已知的用於製備醫藥組合物之任何方法製備且可包括一或多種以下試劑:甜味劑、調味劑、著色劑及防腐劑。水性懸浮液可含有與適合於製備水性懸浮液之賦形劑混合的活性成份。 用於經口使用之調配物亦可呈硬明膠膠囊提供,其中活性成份與諸如碳酸鈣、磷酸鈣或高嶺土之惰性固體稀釋劑混合,或呈軟明膠膠囊提供。在軟膠囊中,抑制劑可溶解或懸浮於合適液體,諸如水或油介質,諸如花生油、橄欖油、脂肪油、液體石蠟或液體聚乙二醇。亦可使用針對經口投與調配之穩定劑及微球體。膠囊可包括由明膠製成之配合插入式膠囊,以及由明膠及塑化劑(諸如甘油或山梨糖醇)製成之軟密封膠囊。配合插入式膠囊可含有與諸如乳糖之填充劑、諸如澱粉之黏合劑及/或諸如滑石或硬脂酸鎂之潤滑劑以及視情況選用之穩定劑混合的活性成份。 錠劑可未包覆包衣或藉由已知方法包覆包衣以延緩在胃腸道中之崩解及吸收,且藉此提供歷經較長時間段之持續作用。舉例而言,可使用諸如單硬脂酸甘油酯之延時物質。當以諸如錠劑形式之固體形式投與時,固體形式通常包含約0.001 wt. %或更少至約50 wt. %或更多之活性成份,較佳約0.005 wt. %、0.01 wt. %、0.02 wt. %、0.03 wt. %、0.04 wt. %、0.05 wt. %、0.06 wt. %、0.07 wt. %、0.08 wt. %、0.09 wt. %、0.1 wt. %、0.2 wt. %、0.3 wt. %、0.4 wt. %、0.5 wt. %、0.6 wt. %、0.7 wt. %、0.8 wt. %、0.9 wt. %或1 wt. %至約2 wt. %、3 wt. %、4 wt. %、5 wt. %、6 wt. %、7 wt. %、8 wt. %、9 wt. %、10 wt. %、15 wt. %、20 wt. %、25 wt. %、30 wt. %、35 wt. %、40 wt. %或45 wt. %。 錠劑可含有與包括惰性材料之醫藥學上可接受之無毒賦形劑混合的活性成份。舉例而言,錠劑可藉由壓縮或模製,視情況與一或多種其他成份一起製備。壓縮錠劑可藉由在合適機器中壓縮視情況與黏合劑、潤滑劑、惰性稀釋劑、表面活性劑或分散劑混合之呈自由流動形式(諸如粉末或顆粒)之活性成份來製備。模製錠劑可藉由在合適機器中模製用惰性液體稀釋劑濕潤之粉末狀抑制劑之混合物來製得。 較佳地,各錠劑或膠囊含有約1 mg或更少至約1,000 mg或更多之較佳實施例之抑制劑,更佳約10 mg、20 mg、30 mg、40 mg、50 mg、60 mg、70 mg、80 mg、90 mg或100 mg至約150 mg、200 mg、250 mg、300 mg、350 mg、400 mg、450 mg、500 mg、550 mg、600 mg、650 mg、700 mg、750 mg、800 mg或900 mg。最佳地,提供一定劑量範圍內之錠劑或膠囊以准許投與分次劑量。因此可便利選擇適於患者之劑量及每日待投與之劑量數目。在某些實施例中,將待投與之兩種或超過兩種治療劑合併為單一錠劑或其他劑型(例如,呈組合療法)可為較佳的;然而,在其他實施例中,以分開劑型提供治療劑可為較佳的。 合適惰性材料包括稀釋劑,諸如碳水化合物、甘露醇、乳糖、無水乳糖、纖維素、蔗糖、經改質之聚葡萄糖、澱粉及其類似物;或無機鹽,諸如三磷酸鈣、磷酸鈣、磷酸鈉、碳酸鈣、碳酸鈉、碳酸鎂及氯化鈉。崩解劑或成粒劑可包括於調配物中,例如諸如玉米澱粉之澱粉、褐藻酸、羥基乙酸澱粉鈉、安伯來特(Amberlite)、羧甲基纖維素鈉、超支鏈澱粉、褐藻酸鈉、明膠、橙皮、酸性羧甲基纖維素酸、天然海綿及膨潤土、不溶性陽離子交換樹脂、諸如瓊脂、加拉亞膠(karaya)或黃蓍膠之粉末狀膠或者褐藻酸或其鹽。 黏合劑可用於形成硬錠劑。黏合劑包括來自天然產物之材料(諸如阿拉伯膠(acacia)、黃蓍膠、澱粉及明膠)、甲基纖維素、乙基纖維素、羧甲基纖維素、聚乙烯吡咯啶酮、羥丙基甲基纖維素及其類似物。 潤滑劑可包括於錠劑調配物中,諸如硬脂酸或其鎂鹽或鈣鹽、聚四氟乙烯、液體石蠟、植物油及蠟、月桂基硫酸鈉、月桂基硫酸鎂、聚乙二醇、澱粉、滑石、熱解矽氧、水合矽鋁酸鹽及其類似物。 亦可採用界面活性劑,例如陰離子清潔劑,諸如月桂基硫酸鈉、磺琥珀酸鈉二辛酯及磺酸鈉二辛酯;陽離子清潔劑,諸如苯紮氯銨或苄索氯銨;或非離子清潔劑,諸如聚氧乙烯氫化蓖麻油、單硬脂酸甘油酯、聚山梨醇酯、蔗糖脂肪酸酯、甲基纖維素或羧甲基纖維素。 可採用控制釋放調配物,其中胺磷汀或其類似物併入准許藉由擴散或瀝濾機制釋放之惰性基質中。緩慢降解基質亦可併入調配物中。其他遞送系統可包括定時釋放、延遲釋放或持續釋放遞送系統。 可使用包衣,例如非腸衣物質,諸如甲基纖維素、乙基纖維素、羥乙基纖維素、甲基羥乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素、羧甲基纖維素鈉、聚維酮及聚乙二醇;或諸如鄰苯二甲酸酯之腸衣物質。為識別或表徵抑制劑劑量之不同組合,可添加染料或顏料。 當以液體形式經口投與時,諸如水、石油、動物或植物來源之油(諸如花生油、礦物油、大豆油或芝麻油)或合成油之液體載劑可添加至活性成份中。生理鹽水溶液、右旋糖或其他醣溶液,或諸如乙二醇、丙二醇或聚乙二醇之二醇亦為合適液體載劑。醫藥組合物亦可呈水包油乳液形式。油相可為植物油,諸如橄欖油或花生油;礦物油,諸如液體石蠟,或其混合物。合適乳化劑包括天然存在之膠,諸如阿拉伯膠及黃蓍膠;天然存在之磷脂,諸如大豆卵磷脂;來源於脂肪酸及己糖醇酐之酯或偏酯,諸如脫水山梨糖醇單油酸酯;及此等偏酯與環氧乙烷之縮合產物,諸如聚氧乙烯脫水山梨糖醇單油酸酯。乳液亦可含有甜味劑及調味劑。 亦可採用肺遞送。化合物在吸入時遞送至肺部且穿過肺上皮內層到達血流。可採用設計用於治療產品之肺遞送的多種機械裝置,包括但不限於噴霧器、定劑量吸入器及粉末吸入器,熟習此項技術者對該等裝置均熟悉。此等裝置採用適合於分配化合物之調配物。通常,各調配物特定用於所採用之裝置類型且除療法中有用之稀釋劑、佐劑及/或載劑外,亦可涉及合適推進劑物質之使用。 化合物及/或其他視情況選用之活性成份針對肺遞送呈粒子形式有利地製備,平均粒度為0.1 mm或更少至10 mm或更多,更佳約0.2 mm、0.3 mm、0.4 mm、0.5 mm、0.6 mm、0.7 mm、0.8 mm或0.9 mm至約1.0 mm、1.5 mm、2.0 mm、2.5 mm、3.0 mm、3.5 mm、4.0 mm、4.5 mm、5.0 mm、5.5 mm、6.0 mm、6.5 mm、7.0 mm、7.5 mm、8.0 mm、8.5 mm、9.0 mm或9.5 mm。對於抑制劑之肺遞送,醫藥學上可接受之載劑包括碳水化合物,諸如海藻糖、甘露醇、木糖醇、蔗糖、乳糖及山梨糖醇。用於調配物之其他成份可包括DPPC、DOPE、DSPC及DOPC。可使用天然或合成界面活性劑,包括聚乙二醇及諸如環葡聚糖之聚葡萄糖。亦可使用膽汁鹽及其他相關增強劑,以及纖維素及纖維素衍生物,及胺基酸。亦可採用脂質體、微囊、微球體、包合錯合物及其他類型之載劑。 適用於噴嘴或超音波噴霧器之醫藥調配物通常包含溶解或懸浮於水中之抑制劑,其濃度為每毫升溶液約0.01 mg或更少至100 mg或更多之抑制劑,較佳每毫升溶液約0.1 mg、1 mg、2 mg、3 mg、4 mg、5 mg、6 mg、7 mg、8 mg、9 mg或10 mg至約15 mg、20 mg、25 mg、30 mg、35 mg、40 mg、45 mg、50 mg、55 mg、60 mg、65 mg、70 mg、75 mg、80 mg、85 mg或90 mg。調配物亦可包括緩衝液及單糖(例如用於穩定蛋白質及調節滲透壓)。噴霧器調配物亦可含有界面活性劑以減少或防止在形成氣溶膠時由溶液霧化所導致之表面誘導之抑制劑聚集。 用於定劑量吸入器裝置之調配物一般包含細微粉碎之粉末,該粉末含有藉助於界面活性劑懸浮於推進劑中之活性成份。推進劑可包括習知推進劑,諸如氯氟碳化物、氫氯氟碳化物、氫氟碳化物及烴。較佳推進劑包括三氯氟甲烷、二氯二氟甲烷、二氯四氟乙醇、1,1,1,2-四氟乙烷及其組合。合適界面活性劑包括脫水山梨糖醇三油酸酯、大豆卵磷脂及油酸。 用於自粉末吸入器裝置分配之調配物通常包含含有抑制劑之細微粉碎之乾粉,其視情況包括呈促進粉末自裝置分散之量的膨化劑,諸如乳糖、山梨糖醇、蔗糖、甘露醇、海藻糖或木糖醇,該量通常為調配物之約1 wt. %或更少至99 wt. %或更多,較佳調配物之約5 wt. %、10 wt. %、15 wt. %、20 wt. %、25 wt. %、30 wt. %、35 wt. %、40 wt. %、45 wt. %或50 wt. %至約55 wt. %、60 wt. %、65 wt. %、70 wt. %、75 wt. %、80 wt. %、85 wt. %或90 wt. %。 當較佳實施例之化合物藉由靜脈內、非經腸或其他注射投與時,其較佳呈無熱原質之非經腸可接受之水溶液或油性懸浮液形式。懸浮液可根據此項技術中熟知之方法使用合適分散劑或濕潤劑及懸浮劑來調配。具有合適pH、等張性、穩定性及類似性質之可接受水溶液之製備在此項技術之技術範圍內。用於注射之較佳醫藥組合物較佳含有等張媒劑,諸如1,3-丁二醇、水、等張氯化鈉溶液、林格氏溶液、右旋糖溶液、右旋糖及氯化鈉溶液、乳酸化林格氏液或此項技術中已知之其他媒劑。另外,無菌不揮發性油習用作溶劑或懸浮介質。出於此目的,可採用任何溫和不揮發性油,包括合成單酸甘油酯或二酸甘油酯。此外,諸如油酸之脂肪酸同樣可用於形成可注射製劑。醫藥組合物亦可含有穩定劑、防腐劑、緩衝劑、抗氧化劑或熟習此項技術者已知之其他添加劑。 注射持續時間可視各種因素而調節,且可包含歷經數秒或更少時間至0.5小時、0.1小時、0.25小時、0.5小時、0.75小時、1小時、2小時、3小時、4小時、5小時、6小時、7小時、8小時、9小時、10小時、11小時、12小時、13小時、14小時、15小時、16小時、17小時、18小時、19小時、20小時、21小時、22小時、23小時或24小時或更多時間之連續靜脈內投與過程投與之單一注射。 較佳實施例之化合物可另外採用醫藥組合物中習用之呈技術確定之形式及技術確定之含量的佐劑組份。因此,舉例而言,組合物可含有用於組合療法之其他相容醫藥活性物質(諸如補充抗菌劑、止癢劑、收斂劑、局部麻醉劑、消炎劑、還原劑、化學治療劑及類似試劑),或可含有可用於物理調配較佳實施例之各種劑型之物質,諸如賦形劑、染料、增稠劑、穩定劑、防腐劑或抗氧化劑。可與較佳實施例之化合物組合使用之抗癌劑包括(但不限於):長春花生物鹼,諸如長春鹼及長春新鹼;蒽環黴素,諸如小紅莓、道諾黴素(daunorubicin)、表柔比星(epirubicin);蒽,諸如比生群(bisantrene)及米托蒽醌(mitoxantrone);表鬼臼毒素(epipodophyllo-toxin),諸如依託泊苷(etoposide)及替尼泊甙(teniposide);及其他抗癌藥物,諸如放射菌素D、絲裂黴素C、光神黴素、甲胺喋呤、多烯紫杉醇、依託泊苷(VP-16)、太平洋紫杉醇、多烯紫杉醇及阿德力黴素(adriamycin);及免疫抵制劑(例如環孢靈A、他克莫司(tacrolimus))。在一些實施例中,本文所提供之化合物、組合物及方法可與以下組合:組蛋白脫乙醯基酶抑制劑(HDAC)、極光激酶抑制劑、去甲基化劑(諸如5-氮雜胞苷)、利用自然殺手細胞之免疫療法、IGF-IR抗體、尤文氏抗原抗體、免疫抑制藥物及羥基尿素。組蛋白脫乙醯基酶抑制劑之實例包括伏立諾他(vorinostat)、羅米地辛(romidepsin)、帕比司他(panobinostat)、丙戊酸、貝林諾他(belinostat)、莫塞諾他(mocetinostat)、吉韋諾他(givinostat)及曲古黴素A (trichostatin A)。極光激酶抑制劑之實例包括ZM447439、海司帕汀(hesperadin)及VX-680。去甲基化劑之實例包括5-氮雜胞苷、5-氮雜脫氧胞苷及普魯卡因(procaine)。免疫抑制藥物之實例包括6-巰基嘌呤及硫唑嘌呤。某些套組
較佳實施例之化合物可呈套組形式提供給投藥醫師或其他健康保理專業人士。套組為一種套裝組件,其容納了一個容器及用於向個體投與醫藥組合物之說明書,該容器包含在合適醫藥組合物中之化合物。套組亦可視情況含有一或多種其他治療劑,例如目前用於治療本文所述之肉瘤之化學治療劑。舉例而言,可提供含有一或多種包含較佳實施例之化合物與一或多種其他化學治療劑之組合的組合物的套組,或可提供含有較佳實施例之抑制劑及其他治療劑的分開醫藥組合物。為了連續或依序投與,套組亦可含有分開劑量之較佳實施例之化合物。套組可視情況含有一或多個診斷工具及使用說明書。套組可含有合適遞送裝置,例如注射器及類似裝置,以及用於投與抑制劑及任何其他治療劑之說明書。套組可視情況含有用於儲存、重組(若適用)及投與所包括之任何或所有治療劑之說明書。套組可包括考慮給予個體之投藥數目的複數個容器。實例
ETS家族轉錄因子對於發育、分化、增殖而言至關重要,且在細胞凋亡及組織重塑方面起重要作用。由過度表現、基因融合及藉由RAS/MAPK及PI3K信號傳導之調節導致的ETS蛋白質失調之轉錄後果會引起正常細胞功能改變,且導致增殖增加、持續血管生成、侵入及癌轉移。在急性骨髓白血病(AML)及瀰漫性大B細胞淋巴瘤(DLBCL)中已報導過度表現之ETS蛋白質及ETS家族融合蛋白。在DLBCL中,11q24.3區已鑑別為反覆病灶及疾病發病機制之促成因子,從而導致ETS家族成員ETS1及FLI1之失調。另外,在AML中,ERG (ETS家族成員)之過度表現及易位已展示與複雜或正常核型之不良預後相關聯。 TK216為一種直接結合EWS-FLI1,抑制ETS家族轉錄因子腫瘤蛋白之生物活性之同類第一小分子且目前處於在患有尤文氏肉瘤之患者中之臨床研究下。EWS1-FLI1為已展示驅動尤文氏肉瘤(ES)之融合蛋白。在臨床前效能模型中,TK216阻斷EWS-FLI1與RNA解螺旋酶A之間的結合,展示經EWS-FLI1反應啟動子轉染之COS7細胞之顯著轉錄減少(EC50
< 100 nM),且以奈莫耳濃度抑制A4573細胞(表現EWS-FLI1之尤文氏肉瘤細胞株)之增殖(EC50
< 200 nM)。TK2164,7- 二氯 -3-(2-(4- 環丙基苯基 )-2- 側氧基乙基 ))-3- 羥基吲哚啉 -2- 酮
TK216在具有失調ETS家族成員之一組AML及DLBCL細胞株中亦具有抗增殖作用,引起細胞週期停滯且誘導細胞凋亡。在所評估之骨髓細胞株中觀察到FLI1及/或ERG ETS家族成員(HL-60、Kasumi-1、ML-2、MOLM-13、MOLM-16及THP-1)之上調。用TK216處理在48小時時展示細胞生存力降低且誘發細胞之劑量依賴性細胞凋亡。類似地,在一組DLBCL細胞株(TMD-8、HBL-1、U2932、DOHH2、WSU-DLCL2、OCI-Ly18及OCI-Ly19)中,TK216處理引起細胞增殖減少及細胞凋亡增加。DLBCL之異種移植模型中之活體內功效研究表明與活體外發現一致之抗腫瘤活性,證實TK216藉由靶向促成疾病之發病機制的ETS家族轉錄因子中之異常表現及易位來治療AML及DLBCL之效用及功效。 TK216之作用機制說明於圖1中。如圖1中所說明,TK216在瘤形成(非固著依賴性生長;小鼠體內之腫瘤)、變化之基因表現( E2G2 (染色質調節因子); VEGF-A (血管生成))及替代性拼接(細胞週期素D1b (啟動細胞週期);ARID1A-ex18L (染色質調節因子))中具有活性。TK216抑制細胞凋亡(漸進式細胞死亡;抑制腫瘤生長)、變化之基因表現(¯ E2G2;¯ VEGF-A)及變異同功異型物(細胞週期素D1a (減緩細胞週期);ARID1A-ex185 (非致癌))。 TK216處理抑制EWS-FLI1蛋白質相互作用,從而減少轉錄及增殖。在A4573中,在用TK216或DMSO對照處理後使FLI1免疫沈澱(參見圖2)。 TK216降低經含有EWS-FLI1 DNA結合位點之EWS-FLI1及NROB1報導螢光素酶質體共轉染之COS7細胞的轉錄活性,如圖3中所示。 用TK216處理引起尤文氏肉瘤A4573細胞株中增殖之劑量依賴性抑制,如圖4中所示。 TK216在AML細胞株中顯示抗增殖活性。在72小時CellTiter-Glo分析中測定各細胞株之TK216之IC50
,如圖5及表1中所示。表 1. AML 細胞株中之 TK216 IC50
TK216在DLBCL細胞株中顯示抗增殖活性。在72小時CellTiter-Glo分析中測定各細胞株之TK216之IC50
,如圖6及表2中所示。表 2. DLBCL 細胞株中之 TK216 IC50
TK216誘導DLBCL細胞株中之細胞凋亡。細胞經不同濃度之TK216處理18 h且藉由偵測裂解卡斯蛋白酶3來分析細胞凋亡。將裂解卡斯蛋白酶3之量相對於b-肌動蛋白校正且呈現為相對於對照之倍數,如圖7及圖8中所示。 在與BCL-2 (ABT199)及BTK (ACP196)抑制劑組合時,TK216顯示協同作用。中位數作用分析用於確定當與ABT199 (BCL-2i)及ACP196 (BTKi)組合時TK216之協同作用、拮抗作用或累加作用。CalcuSyn軟體用於使用周/塔拉萊方程式測定聯合指數(CI),如圖9及圖10中所示。 TK216在DLBCL異種移植模型中顯示抗腫瘤活性。在含有TMD-8腫瘤(一種DLBCL-ABC異種移植模型)之裸小鼠體內分析TK216之抗腫瘤活性。TK216呈100 mg/kg之溶液經口投與,每日兩次,為期13天。結果展示於圖11中。 用TK216處理引起腫瘤生長抑制。TK216在處理13天後與媒劑對照相比使TMD-8異種移植模型之腫瘤生長抑制77%,如圖12中所示。 如以上資料所證明,TK216為一種直接結合EWS-FLI1,抑制ETS家族轉錄因子之生物活性的同類第一小分子。在具有失調ETS家族成員之AML及DLBCL細胞株中,用TK216處理可有效抑制增殖且誘導細胞凋亡。DLBCL細胞株中之TK216與BCL-2及BTK抑制劑之組合產生協同活性且允許更有效之細胞增殖之抑制。每日經口投與TK216有效抑制具有ETS家族成員之失調表現之異種移植模型中的腫瘤生長,且耐受性良好。EWS-FLI1致癌基因之抑制為治療尤文氏肉瘤,例如復發性/難治癒之尤文氏肉瘤提供有前景之方法。 維奈托克(4-(4-{[2-(4-氯苯基)-4,4-二甲基-1-環己烯-1-基]甲基}-1-哌嗪基)-N
-({3-硝基-4-[(四氫-2H
-哌喃-4-基甲基)胺基]苯基}磺醯基)-2-1H
-吡咯并[2,3-b
]吡啶-5-基氧基)苯甲醯胺)用於治療例如已復發或難以用先前治療治癒及具有17p缺失基因突變之患者體內的慢性淋巴球性白血病。 維奈托克
測試TK216與維奈托克之組合且已證明在DLBCL細胞株中之劑量-作用中呈現協同作用。在圖13至圖15之每一者中,頂部曲線(×)對應組合療法,中間曲線(¤)對應TK216,且底部曲線(+)對應維奈托克。圖13為TMD8細胞株中TK216與維奈托克組合之劑量-作用曲線。圖14為U2932細胞株中TK216與維奈托克組合之劑量-作用曲線。圖15為HLB1細胞株中TK216與維奈托克組合之劑量-作用曲線。 劑量-作用測試在DLBLC細胞株(TMD8、HBL1、U2932)中進行,在整個給藥中指示協同效應,如圖16中所示。 諸如FLI1及SPIB之ETS轉錄因子在人類淋巴瘤中反覆失調。小分子YK-4-279 (亦稱為YK-279或YK279,為4,7-二氯-3-羥基-3-(2-(4-甲氧基苯基)-2-側氧基乙基)吲哚啉-2-酮)抑制EWS1-FLI1融合蛋白與RHA結合,伴隨尤文氏肉瘤細胞之生長停滯及細胞凋亡且展現活體外抗淋巴瘤活性。YK-4-279 4,7- 二氯 -3- 羥基 -3-(2-(4- 甲氧基苯基 )-2- 側氧基乙基 ) 吲哚啉 -2- 酮
TK-216為處於患有復發性或難治癒之尤文氏肉瘤之患者的1期中之YK-4-279臨床衍生物。已在淋巴瘤模型中針對TK-216進行臨床前測試。 使用Tecan D300e數位分配器及384孔盤使56個淋巴瘤細胞株[27個瀰漫性大B細胞淋巴瘤(DLBCL);10個套細胞淋巴瘤;6個邊緣區淋巴瘤;5個退行性大T細胞淋巴瘤;8個其他]曝露於TK-216遞增劑量,持續72 h。用MTT量測細胞增殖。在NOD-SCID小鼠中進行活體內研究;在約sc 60 mm3腫瘤體積下開始處理。研究表明TK-216極具活性,其中中位數IC50為449 nM (95% C.I.:367-506),如圖1中所示。敏感性不受起源(B對T;活化B細胞類型DLBCL對生發中心類型DLBCL)之淋巴瘤細胞或MYC及TP53狀態影響。對於攜帶BCL2染色體易位之細胞株中之較低敏感性,無統計學上顯著之趨勢(P=0.07,僅DLBCL;P=0.06,所有細胞株)。抗腫瘤活性主要為細胞毒性,如在6個DLBCL細胞株(TMD8、U2932、HBL1、OCI-LY-18、WSU-DLCL2、DOHH2;TK-216或DMSO,持續24 h、48 h、72 h)中進行細胞週期分析及磷脂結合蛋白V染色時所證實,其中G2/M停滯在時間依賴性細胞凋亡前,如圖2中所示。 隨後使用DLBCL TMD8細胞異種移植測試抗腫瘤活性,如圖3中所示。與對照組(n=10)相比,經TK-216 (100 mg/Kg,每日兩次;n=9)處理之小鼠清楚呈現腫瘤生長之減少,在第3天時已顯而易見且隨時間推移變得更加明顯(第3天、第5天、第8天、第11天:P<0.01;在第13天,因為對照組由於腫瘤體積必須停止而不可獲得P)且在第11天腫瘤體積減少四倍(P<0.01)。亦在DLBCL細胞株中測試TK-216與其他靶向試劑之組合,如圖4中所示。觀察到TK-216與免疫調節劑來那度胺(在2/2活化B細胞類型DLBCL中具協同作用),與溴結構域及額外末端蛋白質(BET)抑制劑OTX015 (MK-8628)(在2/4細胞中具協同作用及1/4細胞中具累加作用),與抗CD20單株抗體利妥昔單抗(在2/3細胞中具協同作用),及與BCL2抑制劑維奈托克(在3/4細胞中具協同作用)之組合的益處。後者之協同作用可與先前提及的TK-216 IC50值與BCL2易位之存在之間的負趨勢有關。 試驗結果證明,作為單一試劑及與其他治療劑組合兩種情況下,TK-216均呈現強臨床前抗淋巴瘤活性。 兩個主要DLBCL亞型為生發中心B細胞(GCB)及ABC類型,特徵為個體生物及臨床特徵。因為達至40% DLBCL患者仍未用標準治療治癒,所以需要新穎療法。YK-4-279為一種抑制EWS1-FLI1融合蛋白與RHA結合,從而引起尤文氏肉瘤細胞中之生長停滯及細胞凋亡之小分子。其衍生物TK-216為處於I期之ETS家族轉錄因子之同類第一抑制劑(用於復發性或難治癒之尤文氏肉瘤之NCT02657005)。兩種化合物均已展示有前景之臨床前抗淋巴瘤活性。已獲得關於其在DLBCL中之作用機制之資料。 使用Tecan D300e數位分配器及96孔盤使細胞株曝露於單獨或與其他化合物組合之YK-4-279或TK-216,持續72 h。用MTT量測細胞增殖。用周/塔拉萊聯合指數測定協同作用。用Illumina HumanHT 12 Expression BeadChips進行基因表現圖譜分析(GEP)。在NOD-SCID小鼠體內進行活體內研究且在sc 60 mm3腫瘤體積下開始處理。 TK-216展示強活體外及活體內抗淋巴瘤活性。已在與TK-216相同之ABC DLBCL模型(TMD8異種移植)中證明YK-4-279之抗腫瘤活性。與對照組(n=10)相比,經YK-4-279 (100 mg/Kg,每日兩次;n=9)處理之小鼠在第8天及第11天(P<0.01)以及第13天(因為對照組由於腫瘤體積必須停止而不可獲得P)清楚呈現腫瘤生長之減少。根據TK-216在與免疫調節藥物(IMID)來那度胺組合時在ABC DLBCL中展示特定協同作用之組合資料,在4個DLBCL細胞株(2個ABC,2個GCB)中,當YK-4-279與BTK抑制劑依魯替尼、PI3K-δ抑制劑艾代拉里斯、BET抑制劑OTX-015及來那度胺組合時,YK-4-279加來那度胺之組合實現最大益處,其中在兩個ABC DLBCL中均具有協同作用。因為來那度胺在套細胞淋巴瘤(MCL)中具活性,所以亦在兩個MCL細胞株中證實TK-216與來那度胺之組合的協同作用。 為瞭解YK-4-279及TK-216之作用機制,使不同ETS因子之基線RNA表現量與對藥物之敏感性相關。SPIB為呈現與YK-4-279及TK-216二者最顯著負相關性之基因,尤其在ABC DLBCL細胞株中(P<0.05)。SPIB為ABC DLBCL之已知致癌基因(Lenz等人, PNAS 2008)且其參與ABC DLBCL中對來那度胺之反應(Yang等人, Cancer Cell 2012)。YK-4-279抑制EWS1-FLI1與解螺旋酶RHA及DDX5結合(Selvanathan等人, PNAS 2012)。因此,評估YK-4-279及TK-216對SPIB是否具有相似作用且其是否誘導類似於來那度胺之細胞作用。蛋白質建模表明FLI1及SPIB之3D結構高度重疊。Co-IP實驗展示在兩個ABC DLBCL細胞株中SPIB結合至RHA及DDX5。在使細胞曝露於TK216或YK-4-279 (500 nM,4-10 h)時,與RHA之結合減少且在更低程度上,與DDX5之結合減少。類似於來那度胺(Yang等人, Cancer Cell 2012),TK-216使細胞中之IRF4減少且上調IRF7蛋白質。曝露於活性(S)-對映異構體或非活性(R)-對映異構體(500 nM,4-8 h)之兩個ABC DLBCL細胞株之GEP展示(S)-YK-4-279造成多個snoRNA之重大上調-與化合物對解螺旋酶及RNA編輯之干擾相容之作用。在ABC DLBCL中,ETS抑制劑YK-4-279及其臨床衍生物TK-216干擾參與RNA編輯之SPIB及解螺旋酶。此外,兩種化合物與來那度胺作用類似,抑制IRF4及上調IRF7,且在ABC DLBCL及MCL二者中與IMID協同作用。例示性方法及組合物
方法1:一種誘導包含急性骨髓白血病中所產生之骨髓母細胞或瀰漫性大B細胞淋巴瘤中所產生之淋巴細胞之細胞中的細胞凋亡之方法,其包含使細胞與有效量之以下組合接觸: 至少一種選自由以下組成之群之治療劑:免疫調節劑、溴結構域及額外末端蛋白質抑制劑、抗CD20單株抗體及BCL2抑制劑;與 具有式(I)之結構之化合物或其立體異構體、醫藥學上可接受之鹽或溶劑合物:, 其中R1
、R2
、R3
及R4
獨立地選自由H、Cl、-CN及-CF3
組成之群;其中A選自由H及C1-6
烷基組成之群;其中D選自由-OH及-O(C1-6
烷基)組成之群;其中R5
及R6
獨立地選自由H、F及C1-6
烷基組成之群,或其中R5
及R6
連在一起形成經取代或未經取代之環烷基環;其中R12
獨立地選自由以下組成之群:經取代或未經取代之C3-8
環烷基、經取代或未經取代之C3-8
雜環烷基、及;其中R7
、R8
、R9
、R10
及R11
獨立地選自由以下組成之群:H、鹵素、CN、CF3
、C1-6
烷基、芳基、雜芳基、-O(C1-6
烷基)、-O(芳基)、-O(雜芳基)、-CO2
H、-CO2
(C1-6
烷基)、-NHSO2
(C1-6
烷基)、-NHSO2
(芳基)、-NHCONH(C1-6
烷基)、-NHCON(C1-6
烷基)2
、-N(C1-6
烷基)CONH2
、-N(C1-6
烷基)CONH(C1-6
烷基)、-N(C1-6
烷基)CON(C1-6
烷基)2
、-SO2
(C1-6
烷基)、-SO2
NH2
、-SO2
NH(C1-6
烷基)、-SO2
N(C1-6
烷基)2
;且其中R13
選自由-O(C1-6
烷基)及-N(C1-6
烷基)2
組成之群。 方法2:一種治療急性骨髓白血病或瀰漫性大B細胞淋巴瘤之方法,其包含向有需要之患者投與抗增殖量之以下組合: 至少一種選自由以下組成之群之治療劑:免疫調節劑、溴結構域、額外末端蛋白質抑制劑、抗CD20單株抗體及BCL2抑制劑;與 具有式(I)之結構之化合物或其立體異構體、醫藥學上可接受之鹽或溶劑合物:, 其中R1
、R2
、R3
及R4
獨立地選自由H、Cl、-CN及-CF3
組成之群;其中A選自由H及C1-6
烷基組成之群;其中D選自由-OH及-O(C1-6
烷基)組成之群;其中R5
及R6
獨立地選自由H、F及C1-6
烷基組成之群,或其中R5
及R6
連在一起形成經取代或未經取代之環烷基環;其中R12
獨立地選自由以下組成之群:經取代或未經取代之C3-8
環烷基、經取代或未經取代之C3-8
雜環烷基、及; 其中R7
、R8
、R9
、R10
及R11
獨立地選自由以下組成之群:H、鹵素、CN、CF3
、C1-6
烷基、芳基、雜芳基、-O(C1-6
烷基)、-O(芳基)、-O(雜芳基)、-CO2
H、-CO2
(C1-6
烷基)、-NHSO2
(C1-6
烷基)、-NHSO2
(芳基)、-NHCONH(C1-6
烷基)、-NHCON(C1-6
烷基)2
、-N(C1-6
烷基)CONH2
、-N(C1-6
烷基)CONH(C1-6
烷基)、-N(C1-6
烷基)CON(C1-6
烷基)2
、-SO2
(C1-6
烷基)、-SO2
NH2
、-SO2
NH(C1-6
烷基)、-SO2
N(C1-6
烷基)2
;且其中R13
選自由-O(C1-6
烷基)及-N(C1-6
烷基)2
組成之群。 方法3:方法1至方法2中之任一者之方法,其中R9
選自由以下組成之群:H、鹵素、CN、CF3
、C1-6
烷基、芳基、雜芳基、-O(芳基)、-O(雜芳基)、-CO2
H、-CO2
(C1-6
烷基)、-NHSO2
(C1-6
烷基)、-NHSO2
(芳基)、-NHCONH(C1-6
烷基)、-NHCON(C1-6
烷基)2
、-N(C1-6
烷基)CONH2
、-N(C1-6
烷基)CONH(C1-6
烷基)、-N(C1-6
烷基)CON(C1-6
烷基)2
、-SO2
(C1-6
烷基)、-SO2
NH2
、-SO2
NH(C1-6
烷基)、-SO2
N(C1-6
烷基)2
;且其中R13
選自由-O(C1-6
烷基)及-N(C1-6
烷基)2
組成之群。 方法4:方法1至方法3中之任一者之方法,其中該細胞為哺乳動物細胞。 方法5:方法1至方法4中之任一者之方法,其中該細胞為人類細胞。 方法6:方法1至方法5中之任一者之方法,其中該細胞為活體外細胞。 方法7:方法1至方法6中之任一者之方法,其中該細胞為活體內細胞。 方法8:方法1至方法7中之任一者之方法,其中治療劑為免疫調節劑。 方法9:方法1至方法7中之任一者之方法,其中免疫調節劑為來那度胺。 方法10:方法1至方法7中之任一者之方法,其中治療劑為溴結構域及額外末端蛋白質抑制劑。 方法11:方法1至方法7中之任一者之方法,其中溴結構域及額外末端蛋白質抑制劑為OTX015。 方法12:方法1至方法7中之任一者之方法,其中治療劑為抗CD20單株抗體。 方法13:方法1至方法7中之任一者之方法,其中抗CD20單株抗體為利妥昔單抗。 方法14:方法1至方法7中之任一者之方法,其中治療劑為BCL2抑制劑。 方法15:方法1至方法7中之任一者之方法,其中BCL2抑制劑為維奈托克。 方法16:方法1至15中之任一者之方法,其中R9
係選自由氮丙啶基、氮雜環丁烷基、吡咯啶基及嗎啉基組成之群。 方法17:方法1至方法15中之任一者之方法,其中R9
係選自由異丙基及環丙基組成之群。 方法18:方法1至方法15中之任一者之方法,其中該化合物具有式(Ia)之結構或其立體異構體、醫藥學上可接受之鹽或溶劑合物:, 其中R1
、R2
、R3
及R4
獨立地選自由H及Cl組成之群;其中R7
、R8
、R10
及R11
獨立地選自由H及鹵素組成之群;且其中R9
獨立地選自由C3-8
環烷基及C3-8
雜環烷基組成之群。 方法19:方法1至方法15中之任一者之方法,其中R1
及R4
為Cl且R2
及R3
為H。 方法20:方法1至方法15中之任一者之方法,其中該化合物具有選自由以下組成之群之結構:
或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 方法21:方法1至方法15中之任一者之方法,其中該化合物具有選自由以下組成之群之結構:
或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 方法22:方法1至方法15中之任一者之方法,其中該化合物具有選自由以下組成之群之結構:
或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 方法23:方法1至方法15中之任一者之方法,其中該化合物具有選自由以下組成之群之結構:
或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 方法24:方法1至方法15中之任一者之方法,其中該化合物具有以下結構:, 或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 方法25:方法1至方法15中之任一者之方法,其中該化合物具有以下結構:, 或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 方法26:方法1至方法15中之任一者之方法,其中該化合物具有以下結構:, 或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 組合物27:一種醫藥組合物,其包含: 至少一種選自由以下組成之群之治療劑:免疫調節劑、溴結構域、額外末端蛋白質抑制劑、抗CD20單株抗體及BCL2抑制劑;及 具有式(I)之結構之化合物或其立體異構體、醫藥學上可接受之鹽或溶劑合物:, 其中R1
、R2
、R3
及R4
獨立地選自由H、Cl、-CN及-CF3
組成之群;其中A選自由H及C1-6
烷基組成之群;其中D選自由-OH及-O(C1-6
烷基)組成之群;其中R5
及R6
獨立地選自由H、F及C1-6
烷基組成之群:,或其中R5
及R6
連在一起形成經取代或未經取代之環烷基環;其中R12
獨立地選自由以下組成之群:經取代或未經取代之C3-8
環烷基、經取代或未經取代之C3-8
雜環烷基、及;其中R7
、R8
、R9
、R10
及R11
獨立地選自由以下組成之群:H、鹵素、CN、CF3
、C1-6
烷基、芳基、雜芳基、-O(C1-6
烷基)、-O(芳基)、-O(雜芳基)、-CO2
H、-CO2
(C1-6
烷基)、-NHSO2
(C1-6
烷基)、-NHSO2
(芳基)、-NHCONH(C1-6
烷基)、-NHCON(C1-6
烷基)2
、-N(C1-6
烷基)CONH2
、-N(C1-6
烷基)CONH(C1-6
烷基)、-N(C1-6
烷基)CON(C1-6
烷基)2
、-SO2
(C1-6
烷基)、-SO2
NH2
、-SO2
NH(C1-6
烷基)、-SO2
N(C1-6
烷基)2
;且其中R13
選自由-O(C1-6
烷基)及-N(C1-6
烷基)2
組成之群。 組合物28:組合物1之組合物,其中R9
選自由以下組成之群:H、鹵素、CN、CF3
、C1-6
烷基、芳基、雜芳基、-O(芳基)、-O(雜芳基)、-CO2
H、-CO2
(C1-6
烷基)、-NHSO2
(C1-6
烷基)、-NHSO2
(芳基)、-NHCONH(C1-6
烷基)、-NHCON(C1-6
烷基)2
、-N(C1-6
烷基)CONH2
、-N(C1-6
烷基)CONH(C1-6
烷基)、-N(C1-6
烷基)CON(C1-6
烷基)2
、-SO2
(C1-6
烷基)、-SO2
NH2
、-SO2
NH(C1-6
烷基)、-SO2
N(C1-6
烷基)2
;且其中R13
選自由-O(C1-6
烷基)及-N(C1-6
烷基)2
組成之群。 組合物29:組合物27至組合物28中之任一者之組合物,其中治療劑為免疫調節劑。 組合物30:組合物27至組合物28中之任一者之組合物,其中免疫調節劑為來那度胺。 組合物31:組合物27至組合物28中之任一者之組合物,其中治療劑為溴結構域及額外末端蛋白質抑制劑。 組合物32:組合物27至組合物28中之任一者之組合物,其中溴結構域及額外末端蛋白質抑制劑為OTX015。 組合物33:組合物27至組合物28中之任一者之組合物,其中治療劑為抗CD20單株抗體。 組合物34:組合物27至組合物28中之任一者之組合物,其中抗CD20單株抗體為利妥昔單抗。 組合物35:組合物27至組合物28中之任一者之組合物,其中治療劑為BCL2抑制劑。 組合物36:組合物27至組合物28中之任一者之組合物,其中BCL2抑制劑為維奈托克。 組合物37:組合物27至組合物37中之任一者之組合物,其中R9
係選自由氮丙啶基、氮雜環丁烷基、吡咯啶基及嗎啉基組成之群。 組合物38:組合物27至組合物37中之任一者之組合物,其中R9
係選自由異丙基及環丙基組成之群。 組合物39:組合物27至組合物37中之任一者之組合物,其中該化合物具有式(Ia)之結構:或其立體異構體、醫藥學上可接受之鹽或溶劑合物,其中R1
、R2
、R3
及R4
獨立地選自由H及Cl組成之群;其中R7
、R8
、R10
及R11
獨立地選自由H及鹵素組成之群;且其中R9
獨立地選自由C3-8
環烷基及C3-8
雜環烷基組成之群。 組合物40:組合物27至組合物37中之任一者之組合物,其中R1
及R4
為Cl且R2
及R3
為H。 組合物41:組合物27至組合物37中之任一者之組合物,其中該化合物具有選自由以下組成之群之結構:
或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 組合物42:組合物27至組合物37中之任一者之組合物,其中該化合物具有選自由以下組成之群之結構:
或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 組合物43:組合物27至組合物37中之任一者之組合物,其中該化合物具有選自由以下組成之群之結構:
或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 組合物44:組合物27至組合物37中之任一者之組合物,其中該化合物具有選自由以下組成之群之結構:
或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 組合物45:組合物27至組合物37中之任一者之組合物,其中該化合物具有以下結構:, 或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 組合物46:組合物27至組合物37中之任一者之組合物,其中該化合物具有以下結構:, 或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 組合物47,其中該化合物具有以下結構:, 或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。 儘管已在圖式及前述描述中詳細說明及描述本發明,但此類說明及描述應視為說明性或例示性而非限制性的。本發明不限於所揭示之實施例。熟習此項技術者在實踐所主張之揭示內容時,自圖式、揭示內容及所附申請專利範圍的研究中可理解且實現所揭示之實施例的變化形式。 所有本文中引用之參考文獻均以全文引用的方式併入本文中。若以引用的方式併入之公開案及專利或專利申請案與本說明書所含之揭示內容相矛盾,則本說明書意欲替代及/或優先於任何此類相矛盾之材料。 除非另外定義,否則所有術語(包括技術及科學術語)應指對一般技術者來說普通且慣用之含義,且除非本文中明確定義,否則不限於特殊或定製含義。應注意,當描述本發明之某些特徵或態樣時特定術語之使用不應視為係暗示該術語在本文中重新定義以限於包括與彼術語相關之本發明之特徵或態樣的任何特殊特性。 在提供值範圍的情況下,應瞭解,範圍之上限及下限以及上限與下限之間的各中間值涵蓋於實施例內。 除非另有明確規定,否則本申請案中所用、尤其隨附申請專利範圍中所用之術語及片語及其變化形式應視為開放性的,而非限制性的。作為上述內容之實例,術語『包括』應理解為意謂『包括(但不限於)(including, without limitation/including but not limited to)』或其類似表述;如本文所用之術語『包含』與『包括』、『含有』或『特徵在於』同義且為包括性或開放性的且不排除額外未列出之要素或方法步驟;術語『具有』應解釋為『至少具有』;術語『包括』應解釋為『包括(但不限於)』;術語『實例』用於提供所論述項目之例示性情況,而非其窮盡性或限制性清單;諸如『已知』、『普通』、『標準』及具有類似含義之術語之形容詞不應視為將所描述項目限制於指定時間段或指定時間可獲得之項目,而實際上應理解為涵蓋現在或在將來任何時間可獲得或已知之已知、普通或標準技術;且如『較佳地』、『較佳』、『所需』或『所需的』以及具有類似含義之詞語的術語之使用不應理解為暗示某些特徵對於本發明之結構或功能為關鍵、必需或甚至至關重要的,而實際上應理解為僅意欲突出在本發明之特定實施例中可採用或可不採用之替代或額外特徵。同樣,除非另外明確說明,否則與連接詞『及』關聯之一組項目不應理解為需要彼等項目中之每一者均存在於群組中,而應理解為『及/或』。類似地,除非另外明確說明,否則與連接詞『或』關聯之一組項目不應理解為在彼群組中需要相互排他性,而應理解為『及/或』。 關於本文中實質上任何複數及/或單數術語之使用,熟習此項技術者可在上下文及/或應用中適當時將複數轉化為單數及/或將單數轉化為複數。為清晰起見,本文中可明確闡述各種單數/複數置換。不定冠詞「一個(a或an)」不排除複數個。僅僅在彼此不同之附屬項中敍述某些措施的事實並不表明此等措施不能有利地組合使用。申請專利範圍中之任何參考記號均不應視為限制範疇。 熟習此項技術者將進一步瞭解,若意圖特定數目之所引入之技術方案敍述,則技術方案中將明確敍述此意圖,且在無此敍述的情況下不存在此意圖。舉例而言,為幫助理解,以下隨附申請專利範圍可含有介紹性片語「至少一個」及「一或多個」之使用以引入技術方案敍述。然而,此類片語之使用不應理解為暗示藉由不定冠詞「一(a/an)」引入技術方案敍述將含有此類所引入之技術方案敍述之任何特定技術方案限制於僅含一個此類敍述的實施例,即使同一技術方案包括介紹性片語「一或多個」或「至少一個」以及諸如「一」之不定冠詞時(例如,「一」通常應解釋為意謂「至少一個」或「一或多個」);此情況同樣適用於用以引入技術方案敍述之定冠詞的使用。此外,即使明確地敍述特定數目之所引入之技術方案敍述,熟習此項技術者亦將認識到,此類敍述通常應解釋為意謂至少
所敍述之數目(例如,不具有其他修飾語的「兩個敍述」之直接敍述通常意謂至少兩個
敍述或兩個或超過兩個
敍述)。此外,在使用類似於「A、B及C中之至少一者等」之慣例的彼等情況下,一般而言,意欲此類結構以熟習此項技術者將理解該慣例之意義來理解(例如,「具有A、B及C中之至少一者之系統」將包括(但不限於)具有單獨A、單獨B、單獨C、A與B一起、A與C一起、B與C一起及/或A、B與C一起之系統等)。在使用類似於「A、B或C中之至少一者等」之慣例的彼等情況下,一般而言,意欲此類結構以熟習此項技術者將理解該慣例之意義來理解(例如,「具有A、B或C中之至少一者之系統」將包括(但不限於)具有單獨A、單獨B、單獨C、A與B一起、A與C一起、B與C一起及/或A、B與C一起之系統等)。熟習此項技術者將進一步瞭解,無論在描述內容、申請專利範圍或圖式中,實際上任何呈現兩個或超過兩個替代性術語之分離性詞語及/或片語均應理解為涵蓋包括該等術語中之一者、該等術語中之任一者或兩個術語的可能性。舉例而言,片語「A或B」應理解為包括「A」或「B」或「A及B」的可能性。 本說明書中用於表示成分之量、反應條件等之所有數值均應理解為在所有情況下均由術語『約』修飾。因此,除非有相反指示,否則本文中所闡述之數值參數為近似值,可視設法實現之所需特性而變。至少且不試圖限制等同原則於主張本申請案之優先權之任何申請案中的任何申請專利範圍之範疇中的應用,各數值參數應根據有效數位之數目及一般捨入方法來理解。 此外,儘管已出於清晰及理解之目的藉助於說明及實例相當詳細地描述上述內容,但熟習此項技術者清楚可進行某些改變及修改。因此,該等描述及實例不應視為將本發明之範疇限制在本文所述之特定實施例及實例,而亦涵蓋屬於本發明之真正範疇及精神內之所有修改及替代方案。
圖1為說明TK216 (在本文中亦稱為TK-216,其為4,7-二氯-3-(2-(4-環丙基苯基)-2-側氧基乙基))-3-羥基吲哚啉-2-酮)在瘤形成中具有活性且抑制細胞凋亡之圖。 圖2展示TK216治療抑制EWS-FLI1蛋白質相互作用,從而減少轉錄及增殖。 圖3展示TK216降低經含有EWS-FLI1 DNA結合位點之EWS-FLI1及NROB1報導螢光素酶質體共轉染之COS7細胞的轉錄活性。 圖4展示利用TK216之處理引起尤文氏肉瘤A4573細胞株中之增殖之劑量依賴性抑制。 圖5展示TK216在AML細胞株中顯示抗增殖活性。 圖6展示TK216在DLBCL細胞株中顯示抗增殖活性。 圖7及圖8展示TK216誘導DLBCL細胞株中之細胞凋亡,其中裂解卡斯蛋白酶3之量相對於b-肌動蛋白校正且呈現為相對於對照之倍數。 圖9展示TK216在與BCL-2 (ABT199)抑制劑組合時顯示協同作用,其中CalcuSyn軟體用於使用周/塔拉萊方程式(Chou/Talalay equation)測定聯合指數(CI)。 圖10展示TK216在與BTK (ACP196)抑制劑組合時顯示協同作用,其中CalcuSyn軟體用於使用周/塔拉萊方程式測定聯合指數(CI)。 圖11展示TK216在TMD8異種移植模型中顯示抗腫瘤活性。 圖12展示利用TK216之處理在處理13天後與媒劑對照相比抑制TMD-8異種移植模型之腫瘤生長。 圖13為TMD8細胞株中TK216與維奈托克組合之劑量-作用曲線,其中頂部曲線(×)對應組合療法,中間曲線(¤)對應TK216,且底部曲線(+)對應維奈托克。 圖14為U2932細胞株中TK216與維奈托克組合之劑量-作用曲線,其中頂部曲線(×)對應組合療法,中間曲線(¤)對應TK216,且底部曲線(+)對應維奈托克。 圖15為HLB1細胞株中TK216與維奈托克組合之劑量-作用曲線,其中頂部曲線(×)對應組合療法,中間曲線(¤)對應TK216,且底部曲線(+)對應維奈托克。 圖16展示在DLBLC細胞株(TMD8、HBL1、U2932)中進行之劑量-作用測試之結果,其表明不同劑量之協同作用。 圖17展示在淋巴瘤細胞株中TK-216之IC50值根據個別組織學的分佈。Y軸:IC50值。在各盒鬚圖中,盒中間之線表示中位數且盒自第25百分位數延伸至第75百分位數(四分位數範圍,IQ);鬚延伸至上鄰近值及下鄰近值(亦即±1.5 IQ)。 圖18A及圖18B展示在DLBCL細胞株中TK-216之細胞凋亡及細胞週期分佈。圖18A):曝露於TK-216 (500 nM) 24 hr、48 hr或72 hr之DLBCL細胞株中之細胞凋亡的誘導。在圖中展示四個代表性(兩個ABC及兩個GCB)結果。圖18B):用500 nM TK-216處理24 hr、48 hr或72 hr之DLBCL細胞株中之細胞週期分佈。在圖中,展示兩個代表性(一個ABC及一個GCB)結果。DMSO處理用作對照。 圖19展示在ABC-DLBCL之異種移植模型中TK-216之作用。用TMD8細胞(15 × 106
)皮下接種之NOD-Scid小鼠分為兩組,分別用TK-216 (100 mg/kg,每日兩次,經口,n= 9)及對照媒劑(n=10)處理。在各盒鬚圖中,盒中間之線表示中位數且盒自第25百分位數延伸至第75百分位數(四分位數範圍,IQ);鬚延伸至上鄰近值及下鄰近值(亦即±1.5 IQ)。 圖20展示DLBCL細胞株中之TK216組合:在個別細胞株中獲得之CI值之盒鬚圖。Y軸:CI值。在各盒鬚圖中,盒中間之線表示中位數且盒自第25百分位數延伸至第75百分位數(四分位數範圍,IQ);鬚延伸至上鄰近值及下鄰近值(亦即±1.5 IQ);外部值已自圖中省略。因為CI值>3,所以未繪出TMD8中TK-216/利妥昔單抗(rituximab)之CI、Karpas422中TK-216/利妥昔單抗之CI、OCI-LY-10中TK-216/利妥昔單抗之CI。所測試之組合包括苯達莫司汀(bendamustine)、硼替佐米(bortezomib)、依魯替尼(ibrutinib)、艾代拉里斯(idelalisib)、來那度胺(lenalidomide)、OTX015 (百拉布瑞斯(birabresib),CAS編號202590-98-5)、PQR309 (比米拉里斯(bimiralisib),CAS編號1225037-39-7 (游離鹼))、賽林西爾(selinexor)、維奈托克及長春新鹼(vincristine)。觀察到TK216與硼替佐米(TMD8)、艾代拉里斯(OCI-LY-10、KARPAS422)、來那度胺(OCI-LY-10、TMD8)、OTX015 (KARPAS422)、維奈托克(OCI-LY-10、KARPAS422、TMD8)及長春新鹼(SU-DHL-4)之組合之協同作用。觀察到TK216與苯達莫司汀(KARPAS422)、依魯替尼(OCI-LY-10,TMD8)、艾代拉里斯(TMD8)、OTX015 (OCI-LY-10、TMD8)、PQR309 (KARPAS422、SU-DHL-4、TMD8)、賽林西爾(KARPAS422、TMD8)及長春新鹼(OCI-LY-10、KARPAS422)之組合之累加作用。未觀察到TK216與苯達莫司汀(OCI-LY-10、SU-DHL-4、TMD8)、硼替佐米 (OCI-LY-10)、艾代拉里斯(SU-DHL-4)、OTX015 (SU-DHL-4)、PQR309 (OCI-LY-10)、賽林西爾 (OCI-LY-10、SU-DHL-4)、維奈托克(SU-DHL-4)及長春新鹼(TMD8)之組合之有益效果。
Claims (25)
- 一種誘導細胞凋亡之方法,該細胞包含急性骨髓白血病中所產生之骨髓母細胞或瀰漫性大B細胞淋巴瘤中所產生之淋巴細胞,該方法包含使該細胞與有效量之以下組合接觸: 至少一種選自由以下組成之群之治療劑:溴結構域、額外末端蛋白質抑制劑、抗CD20單株抗體及BCL2抑制劑;與 具有式(I)結構之化合物或其立體異構體、醫藥學上可接受之鹽或溶劑合物:, 其中R1 、R2 、R3 及R4 獨立地選自由H、Cl、-CN及-CF3 組成之群;其中A選自由H及C1-6 烷基組成之群;其中D選自由-OH及-O(C1-6 烷基)組成之群;其中R5 及R6 獨立地選自由H、F及C1-6 烷基組成之群,或其中R5 及R6 連在一起形成經取代或未經取代之環烷基環;其中R12 獨立地選自由以下組成之群:經取代或未經取代之C3-8 環烷基、經取代或未經取代之C3-8 雜環烷基、及; 其中R7 、R8 、R9 、R10 及R11 獨立地選自由以下組成之群:H、鹵素、CN、CF3 、C1-6 烷基、芳基、雜芳基、-O(C1-6 烷基)、-O(芳基)、-O(雜芳基)、-CO2 H、-CO2 (C1-6 烷基)、-NHSO2 (C1-6 烷基)、-NHSO2 (芳基)、-NHCONH(C1-6 烷基)、-NHCON(C1-6 烷基)2 、-N(C1-6 烷基)CONH2 、-N(C1-6 烷基)CONH(C1-6 烷基)、-N(C1-6 烷基)CON(C1-6 烷基)2 、-SO2 (C1-6 烷基)、-SO2 NH2 、-SO2 NH(C1-6 烷基)、-SO2 N(C1-6 烷基)2 ;且其中R13 選自由-O(C1-6 烷基)及-N(C1-6 烷基)2 組成之群。
- 一種治療急性骨髓白血病或瀰漫性大B細胞淋巴瘤之方法,其包含向有需要之患者投與抗增殖量之以下組合: 至少一種選自由以下組成之群之治療劑:溴結構域、額外末端蛋白質抑制劑、抗CD20單株抗體及BCL2抑制劑;與 具有式(I)結構之化合物或其立體異構體、醫藥學上可接受之鹽或溶劑合物:, 其中R1 、R2 、R3 及R4 獨立地選自由H、Cl、-CN及-CF3 組成之群;其中A選自由H及C1-6 烷基組成之群;其中D選自由-OH及-O(C1-6 烷基)組成之群;其中R5 及R6 獨立地選自由H、F及C1-6 烷基組成之群,或其中R5 及R6 連在一起形成經取代或未經取代之環烷基環;其中R12 獨立地選自由以下組成之群:經取代或未經取代之C3-8 環烷基、經取代或未經取代之C3-8 雜環烷基、及; 其中R7 、R8 、R9 、R10 及R11 獨立地選自由以下組成之群:H、鹵素、CN、CF3 、C1-6 烷基、芳基、雜芳基、-O(C1-6 烷基)、-O(芳基)、-O(雜芳基)、-CO2 H、-CO2 (C1-6 烷基)、-NHSO2 (C1-6 烷基)、-NHSO2 (芳基)、-NHCONH(C1-6 烷基)、-NHCON(C1-6 烷基)2 、-N(C1-6 烷基)CONH2 、-N(C1-6 烷基)CONH(C1-6 烷基)、-N(C1-6 烷基)CON(C1-6 烷基)2 、-SO2 (C1-6 烷基)、-SO2 NH2 、-SO2 NH(C1-6 烷基)、-SO2 N(C1-6 烷基)2 ;且其中R13 選自由-O(C1-6 烷基)及-N(C1-6 烷基)2 組成之群。
- 如請求項1至2中任一項之方法,其中R9 選自由以下組成之群:H、鹵素、CN、CF3 、C1-6 烷基、芳基、雜芳基、-O(芳基)、-O(雜芳基)、-CO2 H、-CO2 (C1-6 烷基)、-NHSO2 (C1-6 烷基)、-NHSO2 (芳基)、-NHCONH(C1-6 烷基)、-NHCON(C1-6 烷基)2 、-N(C1-6 烷基)CONH2 、-N(C1-6 烷基)CONH(C1-6 烷基)、-N(C1-6 烷基)CON(C1-6 烷基)2 、-SO2 (C1-6 烷基)、-SO2 NH2 、-SO2 NH(C1-6 烷基)、-SO2 N(C1-6 烷基)2 ;且其中R13 選自由-O(C1-6 烷基)及-N(C1-6 烷基)2 組成之群。
- 如請求項1至3中任一項之方法,其中該細胞為哺乳動物細胞。
- 如請求項1至4中任一項之方法,其中該細胞為人類細胞。
- 如請求項1至5中任一項之方法,其中該細胞為活體外細胞。
- 如請求項1至6中任一項之方法,其中該細胞為活體內細胞。
- 如請求項1至7中任一項之方法,其中該治療劑為溴結構域及額外末端蛋白質抑制劑。
- 如請求項1至7中任一項之方法,其中該溴結構域及額外末端蛋白質抑制劑為OTX015。
- 如請求項1至7中任一項之方法,其中該治療劑為抗CD20單株抗體。
- 如請求項1至7中任一項之方法,其中該抗CD20單株抗體為利妥昔單抗(rituximab)。
- 如請求項1至7中任一項之方法,其中該治療劑為BCL2抑制劑。
- 如請求項1至7中任一項之方法,其中該BCL2抑制劑為維奈托克(venetoclax)。
- 如請求項1至13中任一項之方法,其中R9 係選自由氮丙啶基、氮雜環丁烷基、吡咯啶基及嗎啉基組成之群。
- 如請求項1至13中任一項之方法,其中R9 係選自由異丙基及環丙基組成之群。
- 如請求項1至13中任一項之方法,其中該化合物具有式(Ia)之結構:, 或其立體異構體、醫藥學上可接受之鹽或溶劑合物,其中R1 、R2 、R3 及R4 獨立地選自由H及Cl組成之群;其中R7 、R8 、R10 及R11 獨立地選自由H及鹵素組成之群;且其中R9 獨立地選自由C3-8 環烷基及C3-8 雜環烷基組成之群。
- 如請求項1至13中任一項之方法,其中R1 及R4 為Cl,且R2 及R3 為H。
- 如請求項1至13中任一項之方法,其中該化合物具有選自由以下組成之群之結構:
- 如請求項1至13中任一項之方法,其中該化合物具有選自由以下組成之群之結構:
- 如請求項1至13中任一項之方法,其中該化合物具有選自由以下組成之群之結構:
- 如請求項1至13中任一項之方法,其中該化合物具有選自由以下組成之群之結構:
- 如請求項1至13中任一項之方法,其中該化合物具有以下結構:, 或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。
- 如請求項1至13中任一項之方法,其中該化合物具有以下結構:, 或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。
- 如請求項1至13中任一項之方法,其中該化合物具有以下結構:, 或其立體異構體、醫藥學上可接受之鹽、酯或溶劑合物。
- 一種醫藥組合物,其包含: 至少一種選自由以下組成之群之治療劑:溴結構域、額外末端蛋白質抑制劑、抗CD20單株抗體及BCL2抑制劑;及 具有式(I)結構之化合物或其立體異構體、醫藥學上可接受之鹽或溶劑合物:, 其中R1 、R2 、R3 及R4 獨立地選自由H、Cl、-CN及-CF3 組成之群;其中A選自由H及C1-6 烷基組成之群;其中D選自由-OH及-O(C1-6 烷基)組成之群;其中R5 及R6 獨立地選自由H、F及C1-6 烷基組成之群,或其中R5 及R6 連在一起形成經取代或未經取代之環烷基環;其中R12 獨立地選自由以下組成之群:經取代或未經取代之C3-8 環烷基、經取代或未經取代之C3-8 雜環烷基、及;其中R7 、R8 、R9 、R10 及R11 獨立地選自由以下組成之群:H、鹵素、CN、CF3 、C1-6 烷基、芳基、雜芳基、-O(C1-6 烷基)、-O(芳基)、-O(雜芳基)、-CO2 H、-CO2 (C1-6 烷基)、-NHSO2 (C1-6 烷基)、-NHSO2 (芳基)、-NHCONH(C1-6 烷基)、-NHCON(C1-6 烷基)2 、-N(C1-6 烷基)CONH2 、-N(C1-6 烷基)CONH(C1-6 烷基)、-N(C1-6 烷基)CON(C1-6 烷基)2 、-SO2 (C1-6 烷基)、-SO2 NH2 、-SO2 NH(C1-6 烷基)、-SO2 N(C1-6 烷基)2 ;且其中R13 選自由-O(C1-6 烷基)及-N(C1-6 烷基)2 組成之群。
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KR102282794B1 (ko) * | 2016-07-29 | 2021-07-27 | 온크터널 테라퓨틱스, 인코포레이티드. | 인돌리논 화합물의 용도 |
CN110818611B (zh) * | 2018-08-13 | 2023-01-24 | 中国科学院上海药物研究所 | 一类吲哚酮类化合物、其制备方法、药物组合物和用途 |
JP2022509257A (ja) * | 2018-11-30 | 2022-01-20 | アプトース バイオサイエンシズ インコーポレイテッド | 2,3-ジヒドロ-イソインドール-1-オン化合物を用いた組合せ療法及び様々な変異を有する患者を治療するための方法 |
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PH12019500070A1 (en) | 2019-10-14 |
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CN114569606B (zh) | 2024-04-19 |
JP2021107456A (ja) | 2021-07-29 |
KR20190025043A (ko) | 2019-03-08 |
JP2019522037A (ja) | 2019-08-08 |
JP7208659B2 (ja) | 2023-01-19 |
US20220362211A1 (en) | 2022-11-17 |
CN109789127A (zh) | 2019-05-21 |
JP7182304B2 (ja) | 2022-12-02 |
JP6885629B2 (ja) | 2021-06-16 |
US10646470B2 (en) | 2020-05-12 |
EP3490553A1 (en) | 2019-06-05 |
JP2021050227A (ja) | 2021-04-01 |
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US10159660B2 (en) | 2018-12-25 |
US20190022062A1 (en) | 2019-01-24 |
US11285132B2 (en) | 2022-03-29 |
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