TWI712605B - 含有cti藥效基團之雙功能性細胞毒性劑 - Google Patents
含有cti藥效基團之雙功能性細胞毒性劑 Download PDFInfo
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- TWI712605B TWI712605B TW105107952A TW105107952A TWI712605B TW I712605 B TWI712605 B TW I712605B TW 105107952 A TW105107952 A TW 105107952A TW 105107952 A TW105107952 A TW 105107952A TW I712605 B TWI712605 B TW I712605B
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Abstract
本發明關於新穎的下式之雙官能性CTI-CTI及CBI-CTI二聚物:F1-L1-T-L2-F2其中F1、L1、T、L2和F2係如本文所定義,該等二聚物有用於治療增生性疾病,其中本發明的二聚物可功能作為獨立藥物、抗體藥物共軛體(ADC)的酬載及有用於與此等ADC之製造及投予有關的連接子-酬載化合物;且關於包括前述二聚物、連接子-酬載及ADC之組成物以及使用該等二聚物、連接子-酬載及ADC以治療病理性病狀(包括癌症)之方法。
Description
本發明關於用於治療增生性疾病之新穎的雙官能性CTI-CTI及CBI-CTI二聚物。本發明的二聚物可功能作為獨立藥物、抗體藥物共軛體(ADC)的酬載及用於與此等ADC之製造及投予有關的連接子-酬載化合物。本發明進一步關於包括前述二聚物、連接子-酬載及ADC之組成物以及使用該等二聚物、連接子-酬載及ADC以治療病理性病狀(包括癌症)之方法。
含有兩個活性DNA烷基化結構組元(亦即CBI或CPI)之雙官能性類似物含有稠合在一起的兩個烷基化結構組元(例如兩個CPI結構組元)。由於兩個反應性烷基化結構組元的存在而使該等化合物為活性DNA交聯劑,而僅具有一個烷基化結構組元之化合物(例如倍癌黴素(duocarmycin))為DNA單烷基化劑。
上文所示之化合物為來自文獻的代表性實例且經報導為有效力的細胞毒素:A(“Glycosidic Prodrugs of Highly Potent Bifunctional Duocarmycin Derivatives for Selective Treatment of Cancer”,Angew.Chem.Int.Ed.2010,49,7336-7339;“Duocarmycin Analogues Target Aldehyde Dehydrogenase 1 in LungCancer Cells”,Angew.Chem.Int.Ed.2012,51,2874-2877;“Bifunctional prodrugs and drugs”,WO 2011/054837,DE 10 2009 051 799;“The Two Faces of Potent Antitumor Duocarmycin-Based Drugs:A Structural Dissection Reveals Disparate Motifs for DNA versus Aldehyde Dehydrogenase 1 Affinity”,Angew.Chem.Int.Ed.2013,52,1-6);B(“Interstrand DNA Cross-linking with Dimers of the Spirocyclopropyl Alkylating Moiety of CC-1065”,J.Am.Chem.SOC.1989,11 1,6428-6429;“CC-1065 analogs having two CPI subunits useful as antitumor agents and ultraviolet light absorbers”,Eur.Pat.Appl.(1990),EP 359454),亦為化合物C及D;C
(“Synthesis and DNA Cross-Linking by a Rigid CPI Dimer”,J.Am.Chem.SOC.1991,113,8994-8995;“Nucleotide Preferences for DNA Interstrand Cross-Linking Induced by the Cyclopropylpyrroloindole Analogue U-77,779”,Biochemistry 1993,32,2592-2600;“Determination of the Structural Role of the Internal Guanine-Cytosine Base Pair in Recognition of a Seven-Base-Pair Sequence Cross-Linked by Bizelesin”,Biochemistry 1995,34,11005-11016;“Analysis of the Monoalkylation and Cross-Linking Sequence Specificity of Bizelesin,a Bifunctional Alkylation AgentRelated to(+)-CC-1065”,J.Am.Chem.SOC.1993,115,5925-5933;“Mapping of DNA Alkylation Sites Induced by Adozelesin and Bizelesin in Human Cells by Ligation-Mediated Polymerase Chain Reaction”,Biochemistry 1994,33,6024-6030;“DNA Interstrand Cross-Links Induced by the Cyclopropylpyrroloindole Antitumor Agent Bizelesin Are Reversible upon Exposure to Alkali”,Biochemistry 1993,32,9108-9114;“Replacement of the Bizelesin Ureadiyl Linkage by a Guanidinium Moiety Retards Translocation from Monoalkylation to Cross-Linking Sites on DNA”,J.Am.Chem.Soc.1997,119,3434-3442;“DNA interstrand cross-linking,DNA sequence specificity,and induced conformational changes produced by a dimeric analog of
(+)-CC-1065”,Anti-Cancer Drug Design(1991),6,427-452;“A phase I study of bizelesin,a highly potent and selective DNAinteractive agent,in patients with advanced solid malignancies”,Ann Oncol.2003 May;14(5):775-782;“A Phase I study of bizelesin(NSC 615291)in patients with advanced solid tumors”,Clin Cancer Res.2002,3,712-717;“Solution conformation of a bizelesin A-tract duplex adduct:DNA-DNA cross-linking of an A-tract straightens out bent DNA”,J Mol Biol.1995,252,86-101;“Preclinical pharmacology of bizelesin,a potent bifunctional analog of the DNA-binding antibiotic CC-1065”,Cancer Chemother Pharmacol.1994,34,317-322);及D(“CC-1065 analogs having two CPI subunits useful as antitumor agents and ultraviolet light absorbers”,Eur.Pat.Appl.(1990),EP 359454)。活性DNA烷基化結構組元原則上可以其前藥形式存在,其於生物介質中轉化成活性藥物,或者以其活性狀態存在,其不需進一步轉化。雙官能性交聯劑的前藥至活性藥物之轉化係以下列所示之CBI二聚物為範例:
對應之轉化係發生在以其前藥狀態存在之所有的雙官能性交聯劑。
已報導其他相關的雙官能性交聯劑。(“Chemical and Biological Explorations of the Family of CC-1065 and the Duocarmycin Natural Products”,Current Topics in Medicinal Chemistry,2009,9,1494-1524;“DNA interstrand cross-linking agents and their chemotherapeutic potential”,Curr Med Chem.2012,19,364-385;“Design and Synthesis of a Novel DNA-DNA Interstrand Adenine-Guanine Cross-Linking Agent”,J.Am.Chem.Soc.2001,123,4865-4866;“Effect of base sequence on the DNA cross-linking properties of pyrrolobenzodiazepine(PBD)dimers”,Nucleic Acids Res.2011,39,5800-5812;“Sequence-selective recognition of duplex DNA through covalent interstrand cross-linking:kinetic and molecular modeling studies with pyrrolobenzodiazepine dimers”,Biochemistry.2003,42,8232-8239;“Bifunctional alkylating agents derived from duocarmycin SA:potent antitumor activity with altered sequence selectivity”,Bioorg Med Chem Lett.2000,10,495-498;“Design,Synthesis and Cytotoxicity Evaluation of 1-Chloromethyl-5-hydroxy-1,2-dihydro-3H-benz[e]indole(seco-CBI)Dimers”,Bioorganic & Medicinal Chemistry 2000,8,1607-1617)。
有關含單體二級-CBI之細胞毒素的磷酸鹽前藥策略已由Zhao等人(“Synthesis and biological evaluation of
antibody conjugates of phosphate prodrugs of cytotoxic DNA alkylators for the targeted treatment of cancer”,J.Med.Chem.2012,55,766-782)及Zhang等人(“Immunoconjugates containing phosphate-prodrugged DNA minor groove binding agents,compositions containing them,and methods of making them and their use for treating cancer”,WO 2012/162482)說明。
已於最近說明將某些CBI二聚物用作為ADC酬載(“I-(Chloromethyl)-2,3-Dihydro-IH-Benzo[e]indole Dimer Antibody-Drug Conjugate Compounds,and Methods of Use and Treatment”,WO2015/023355)。
藥物與抗體共軛(直接或經由連接子)包含各種因素之考量,包括用於藥物共軛之化學基團的識別和位置、藥物釋出機制、提供藥物釋出之結構元素及對釋出之游離藥物的結構修飾。另外,若藥物係於抗體內化後釋出,則藥物釋出機制必須與共軛體之細胞內運輸一致。
雖然已嘗試以抗體遞送一些不同的藥物類別,但僅少數藥物類別經證實有效作為抗體藥物共軛體,同時維持適合的毒性輪廓。一種此類別為奧里斯他汀(auristatin),天然產物尾海兔素10(dolastatin 10)的衍生物。代表性奧里斯他汀包括(N-甲基纈胺酸-纈胺酸-尾海兔異白胺酸-尾海兔洛因-降麻黃鹼)及(N-甲基纈胺酸-纈胺酸-尾海兔異白胺酸-尾海兔洛因-苯基丙胺酸)。其他相關的微管蛋白結合劑包括美坦素(maytansine)(例如參見如WO 2005/037992所
公開的“Cell-binding agent-maytansinoid conjugates linked via a noncleavable linker,preparation methods,and methods using them for targeting specific cell populations”)。用於與抗體鍵聯的其他細胞毒性藥物包括DNA-結合藥物,諸如卡其黴素(calicheamicin),其引起序列特異性雙股DNA裂解。用於ADC之另一類別的DNA結合細胞毒性藥物包括二聚合吡咯並苯並二氮雜環庚三烯(例如參見如WO2013/041606所公開的“Preparation of unsymmetrical pyrrolobenzodiazepines dimers for inclusion in targeted conjugates”)。已嘗試抗體遞送的另一此類別之藥物為DNA結合烷基化劑,諸如倍癌黴素類似物CC-1065(參見如WO2010/062171所公開的“Preparation of CC-1065 analogs and their conjugates for treatment of cancer”)及相關的化合物(參見如WO 2007/038658所公開的“Antibody-drug peptide conjugates for use as cytotoxins in cancer treatment”及如WO2012/162482所公開的“Immunoconjugates containing phosphate-prodrugged DNA minor groove binding agents,compositions containing them,and methods of making them and their use for treating cancer”)。然而,該等藥物全部皆具有關於疾病適應症及治療輪廓的限制,且因此對具有改進經由抗體共軛可遞送之性質的額外藥物仍有需求。因此,本發明提供具有二聚物作為酬載之新穎的ADC。
已知為有效力的DNA烷基化結構組元的另一雜環係
以〝CTI〞基團代表(CTI:1,2,8,8a-四氫-4H-環丙[c]噻吩並[3,2-e]吲哚-4-酮,“Fundamental relationships between structure,reactivity,and biological activity for the duocarmycins and CC-1065”,J.Med.Chem.2009,52(19),5771-5780,“Rational Design,Synthesis,and Evaluation of Key Analogues of CC-1065 and the Duocarmycins”,J.AM.CHEM.SOC.2007,129,14092-14099)。已說明含CTI之倍癌黴素單體作為ADC酬載(“Synthesis of functionalized thieno-indole derivs.optionally containing a peptidic residue for the treatment of cancer and their use in the preparation of conjugates”,WO 2013/149946;“Preparation of new functionalized alkylating agents containing a thieno-indole moiety linked to a DNA-binding moiety for treating cancers and their use in the prepn.of conjugates”,WO 2013/149948)。在〝CBI〞、〝CPI〞與〝CTI〞之間的結構差異描述於下圖中:
CBI、CPI及CTI分別係在第一芳族環上以CBI具有苯基,CPI具有吡咯及CTI具有噻吩雜環而有差異。圖形亦顯示氯化物前藥。該等前藥係在生物介質中以損失氯化氫而轉化成活性藥物。因此,氯化物前藥及活性環丙基種類二者就彼等的生物活性而言應被視為等效物。CBI、CPI及相關基團之氯化物前藥的概念已完整記載於文獻中(“Design,Synthesis,and Evaluation of Duocarmycin O-Amino Phenol Prodrugs Subject”,J.Med.Chem.2010,53,7731-7738,及其中的參考8。)
Me-CTI及iso-Me-CTI基團二者已於倍癌黴素的背景
下說明(“Chemical and biological explorations of the family of CC-1065 and the duocarmycin natural products”,Curr Top Med Chem.2009,9(16),1494-1524)。
本發明說明以CTI結構組元為基礎之新型結構的二聚物類似物。本發明亦說明對應之CTI二聚物及CBI-CTI混合型結構之間隔元素。術語CBI及CTI係用於氯化物前藥變型以及活性環丙基種類二者。另外,亦說明該等二聚物種類之連接子取代以及抗體藥物共軛體之製備。
已知沒有含CTI結構組元之二聚物,且使用本發明的CTI二聚物與先前所述之二聚物種類相比而導致顯著改變的化學反應性及生物性質。由此以CTI種類製備之二聚物代表獨特的藥物實體。在本發明中,吾等說明含有兩個CTI基團或攜有一個CBI及一個CTI基團的混種之新型二聚物。此外,吾等揭示如何使該等二聚物種類連接至用於附著至抗體之適合的連接子分子。
更特定言之,本發明指向包含以CTI/CTI及/或以CTI/CBI為基礎(包括如本文詳述之CBI及CTI的二級形式)之二聚物的細胞毒性二聚物、包含此等二聚物之抗體藥物共軛體及使用彼等以治療癌症和其他適應症之方法。CBI及CPI結構二者可以其二級形式表示且可如本文詳述方式取代及衍生。另外,二級形式的酚官能性可以乙酸酯基團衍生。當乙酸酯基團可於生物介質中輕易地水解以給
出游離酚時,則酚系乙酸酯官能性在功能上與酚等效。
因此,本發明關於化合物與含有彼等之醫藥組成物、彼等之製備及化合物之用途,主要地但非專有地用於抗癌劑。根據一個態樣,本發明關於式I之〝酬載〞化合物:F1-L1-T-L2-F2 (式I)或其醫藥上可接受之鹽或溶劑合物,其中:F1和F2各自獨立地選自環系統A、B、C、D、E、F、G和H:
在本發明的實施態樣中,變數n為0至50,較佳為0至25,較佳為0至10,且較佳為1至5。變數n可較佳為0、1、2、3、4或5。
在本發明其他的實施態樣中,變型-Y-為C(O)N(RA)2或C(S)N(RA)2,其中一個RA為氫或-C1-C20烷基,及另一個RA為-C1-C20烷基-N(R)2,使得形成以下結構:
其中A為氧或硫。
其他形式的立方烷(例如如本文所概述之經取代形式)及非立方烷亦有可能且包括在本發明內。
根據本發明的另一態樣,其係提供式IIA之〝連接子-酬載〞化合物:L-P (式IIA)或其醫藥上可接受之鹽或溶劑合物,其中:P為:F1-L1-T-L2-F2其中:F1和F2各自獨立地選自環系統A、B、C、D、E、F、G和H:
在本發明其他的實施態樣中,變型-Y-為C(O)N(RA)2
或C(S)N(RA)2,其中一個RA為氫或-C1-C20烷基及另一個RA為-C1-C20烷基-N(R)-,使得形成以下結構:
其中各A獨立為氧或硫。
根據本發明的又另一態樣,其係提供式IIIA之抗體藥物共軛化合物:AB-(L-P)1-20 (式IIIA)或其醫藥上可接受之鹽或溶劑合物,其中:AB為抗體;P為:F1-L1-T-L2-F2其中:F1和F2各自獨立地選自環系統A、B、C、D、E、F、G和H:
本發明的額外態樣包括諸如那些本文述及之化合物,
其中各R獨立地選自由下列所組成之群組:H、氘、-C1-C20烷基和-NH2;關於各環系統中出現的V1,各V1獨立為O或N(R);關於各環系統中出現的V2,各V2獨立為O或N(R);關於各環系統中出現的W1和W2,W1和W2各自獨立為H、-C1-C5烷基、-C(O)OR或-C(O)NR2;關於各環系統中出現的X,各X獨立為鹵基;關於各環系統中出現的Y,各Y獨立地選自由下列所組成之群組:H、-C(O)RA、-C(O)N(RA)2、碳水化合物(諸如糖基)、-NO2、-PO(ORA)2、胺基酸和肽(特別為以蛋白酶(諸如組織蛋白酶和基質金屬蛋白酶)裂解之肽),其中各RA獨立地選自由下列所組成之群組:H、-C1-C20烷基、-C1-C8雜烷基、-C3-C8碳環基和-C1-C20烷基N(R)2,其中該-C1-C20烷基、-C1-C8雜烷基、-C3-C8碳環基和-C1-C20烷基N(R)2隨意地經1至3個獨立地選自R的取代基取代;L1和L2各自獨立地選自直接鍵和羰基;且T係選自:-NRB-T1-NRC-,其中RB和RC各自獨立為H或-C1-C8烷基,-C(O)hetC(O)-,其中het為含有1或2個獨立地選自O、N和S的雜原子之5至12員的單環雜芳基,其中het隨意地經1至8個各自獨立地選自由下列所組成之群組的取
代基取代:-C1-C8烷基、-NH2和-NH2,且在het上之該等隨意的取代基隨意地經-C1-C8烷基取代,及-C(A1)X1-T2-X1C(B1)-,其中T2為:
其中各X1為鍵,其中A1和B1各自獨立為=O,其中R1、R2、R3和R4各自獨立為H或R1和R2形成環系統,或R3和R4形成環系統,或R1和R2及R3和R4二者各自獨立地形成環系統,或R1和R3形成環系統,或R2和R4形成環系統,或R1和R3及R2和R4二者各自獨立地形成環系統,其中該等環系統獨立地選自-C1-C10雜環基或-C3-C8碳環基,且其中D為鍵或選自由下列所組成之群組:-S-、-C1-C8伸烷基-、-C6-C14伸芳基-、-C6-C14伸雜芳基-、-C1-C10雜環基和-C3-C8碳環基,其中該-C1-C8伸烷基-、-C6-C14伸芳基-、-C6-C14伸雜芳基-、-C1-C10雜環基和-C3-C8碳環基隨意地經下列者取代:-NH2、-N(R)C(O)H或-N(R)C(O)OH。
本發明的額外態樣包括諸如那些本文述及之化合物,其中二或多個R隨意地連結以形成一或多個環。
本發明的額外態樣包括諸如那些本文述及之化合物,其中各R獨立地選自由下列所組成之群組:H、氘、-C1-C20烷基和-NH2;
關於V1出現的各環系統中,各V1獨立為O或N(R);關於V2出現的各環系統中,各V2獨立為O或N(R);關於W1和W2出現的各環系統中,W1和W2各自獨立為H、-C1-C5烷基、-C(O)OR或-C(O)NR2;關於X出現的各環系統中,各X獨立為鹵基;關於Y出現的各環系統中,各Y獨立地選自鍵、H、-C(O)RA、-C(S)RA、-C(O)ORA、-S(O)2ORA、-C(O)N(RA)2、-C(S)N(RA)2、碳水化合物(諸如糖基)、-NO2、-P(O)(ORA)2、胺基酸和肽(特別為以蛋白酶(諸如組織蛋白酶和基質金屬蛋白酶)裂解之肽),其中各RA獨立地選自H、-C1-C20烷基、-C1-C8雜烷基、-C6-C14芳基、芳烷基、-C1-C10雜環基、-C3-C8碳環基、-C1-C20烷基N(R)2、-C1-C20伸烷基、-C1-C8伸雜烷基、-C6-C14伸芳基、伸芳烷基、-C1-C10雜環基、-C3-C8碳環基和-C1-C20烷基N(R)-及RF,其中該RA隨意地經1至3個獨立地選自R的取代基取代,且其中一個Y為二價且與L鍵結,RF為-N(R6)QN(R5)C(O)-且在鄰接N(R5)之羰基與L鍵結,其中R5和R6各自獨立地選自由下列所組成之群組:H、-C1-C8烷基和-C1-C8雜烷基,或R5或R6與Q上經取代之碳連結以形成-C1-C10雜環基或-C6-C14雜芳基環,或R5與R6一起連結以形成-C1-C10雜環基或-C6-C14雜芳基環系統,且其中Q為-C1-C8伸烷基-、-C6-C14伸芳基-或-C3-C8碳環基-,其中Q、R5和R6各自獨立且隨意地
經1至3個獨立地選自R的取代基取代;L1和L2各自獨立地選自直接鍵和羰基;及T係選自:-NRB-T1-NRC-,其中RB和RC各自獨立為H或-C1-C8烷基,-C(O)hetC(O)-,其中het為含有1或2個獨立地選自O、N和S的雜原子之5至12員的單環雜芳基,其中het隨意地經1至8個各自獨立地選自由下列所組成之群組的取代基取代:-C1-C8烷基、-NH2和-NH2,且在het上之該等隨意的取代基隨意地經-C1-C8烷基取代,及-C(A1)X1-T2-X1C(B1)-,其中T2為:
其中各X1為鍵,其中A1和B1各自獨立為=O,其中R1、R2、R3和R4各自獨立為H,或R1和R2形成環系統,或R3和R4形成環系統,或R1和R2及R3和R4二者各自獨立地形成環系統,或R1和R3形成環系統,或R2和R4形成環系統,或R1和R3及R2和R4二者各自獨立地形成環系統,其中該等環系統獨立地選自-C1-C10雜環基或-C3-C8碳環基,且其中D為鍵或選自由下列所組成之群組:-S-、-C1-C8伸烷基-、-C6-C14伸芳基-、-C6-C14伸雜芳基-、-C1-C10雜環基和-C3-C8碳環基,其中該-C1-C8伸烷基-、-C6-C14伸芳基-、-C6-C14伸雜芳基-、-C1-C10雜環基
和-C3-C8碳環基隨意地經下列者取代:-NH2、-N(R)C(O)H或-N(R)C(O)OH。
本發明的額外態樣包括諸如那些本文述及之化合物,其中各R獨立地選自由下列所組成之群組:H、氘、-C1-C20烷基和-NH2;關於V1出現的各環系統中,各V1獨立為O或N(R);關於V2出現的各環系統中,各V2獨立為O或N(R);關於W1和W2出現的各環系統中,W1和W2各自獨立為H、-C1-C5烷基、-C(O)OR或-C(O)NR2;關於X出現的各環系統中,各X獨立為鹵基;關於Y出現的各環系統中,各Y獨立地選自由下列所組成之群組:H、-C(O)RA、-C(O)N(RA)2、碳水化合物(諸如糖基)、-NO2、-PO(ORA)2、胺基酸和肽(特別為以蛋白酶(諸如組織蛋白酶和基質金屬蛋白酶)裂解之肽),其中各RA獨立地選自由下列所組成之群組:H、-C1-C20烷基、-C1-C8雜烷基、-C3-C8碳環基和-C1-C20烷基N(R)2,其中該-C1-C20烷基、-C1-C8雜烷基、-C3-C8碳環基和-C1-C20烷基N(R)2隨意地經1至3個獨立地選自R的取代基取代;L1和L2各自獨立地選自直接鍵和羰基;且T為-C(A1)X1-T2-X1C(B1)-,其中T2為:
其中各X1為鍵,其中A1和B1各自獨立為=O,其中R1、R2、R3和R4各自獨立為H,或R1和R2形成環系統,或R3和R4形成環系統,或R1和R2及R3和R4二者各自獨立地形成環系統,或R1和R3形成環系統,或R2和R4形成環系統,或R1和R3及R2和R4二者各自獨立地形成環系統,其中該等環系統獨立地選自-C1-C10雜環基或-C3-C8碳環基,且其中D為鍵或選自由下列所組成之群組:-S-、-C1-C8伸烷基-、-C6-C14伸芳基-、-C6-C14伸雜芳基-、-C1-C10雜環基和-C3-C8碳環基,其中該-C1-C8伸烷基-、-C6-C14伸芳基-、-C6-C14伸雜芳基-、-C1-C10雜環基和-C3-C8碳環基隨意地經下列者取代:-NH2、-N(R)C(O)H或-N(R)C(O)OH。
本發明的額外態樣包括諸如那些本文述及之化合物,其中LA係選自由下列所組成之群組:-鹵基、-N(R)2、-CON(R)2、隨意地經-NO2或-CON(R)2取代之-S-芳基、隨意地經-NO2取代之-S-雜芳基、烷基-SO2-雜芳基、芳基-SO2-雜芳基-和
LB為LB1-LB2-LB3,其中LB1不存在或為一或多個選自由下列所組成之群組的組份:-C(O)-、-C(S)-、-C(O)NR-、-C(O)C1-C6烷基-、-C(O)NRC1-C6烷基-、-C1-C6烷基(OCH2CH2)1-6-、-C(O)C1-C6烷基NRC(O)-、-C(O)C1-C6烷基(OCH2CH2)1-6-、-C1-C6烷基(OCH2CH2)1-6-C(O)-、-C1-C6烷基-S-S-C1-C6烷基NRC(O)CH2-、-C1-C6烷基(OCH2CH2)1-6NRC(O)CH2-、-C(O)C1-C6烷基-NRC(O)C1-6烷基-、-C(O)-C1-C6烷基(OCH2CH2)1-6NRC(O)-、-C(O)C1-C6烷基-苯基(NR-C(O)C1-C6烷基)1-4-、-C(O)C1-C6烷基(OCH2CH2)1-6-NRC(O)C1-C6烷基-、-C1-C6烷基-、-S-、-C(O)-CH(NR-C(O)C1-C6烷基)-C1-C6烷基-和(-CH2-CH2-O-)1-20,其中LB2為AA0-12,其中AA為天然胺基酸、非天然胺基酸或-(CR15)o-S-S-(CR15)p,其中o和p各自獨立為1至20的整數,且LB3為-PABA-、-PABC-、-C(O)(CH2)nC(O)-或不存在;且LC不存在。
本發明的額外態樣包括諸如那些本文述及之抗體藥物共軛體,其中LA係選自:至AB的鍵,-NR-(至AB的鍵),-雜芳基-(至AB的鍵)、
LB為LB1-LB2-LB3,其中LB1不存在或為一或多個選自由下列所組成之群組的組份:-C(O)-、-C(S)-
、-C(O)NR-、-C(O)C1-C6烷基-、-C(O)NRC1-C6烷基-、-C1-C6烷基(OCH2CH2)1-6-、-C(O)C1-C6烷基NRC(O)-、-C(O)C1-C6烷基(OCH2CH2)1-6-、-C1-C6烷基(OCH2CH2)1-6-C(O)-、-C1-C6烷基-S-S-C1-C6烷基NRC(O)CH2-、-C1-C6烷基(OCH2CH2)1-6NRC(O)CH2-、-C(O)C1-C6烷基-NRC(O)C1-6烷基-、-C(O)-C1-C6烷基(OCH2CH2)1-6NRC(O)-、-C(O)C1-C6烷基-苯基(NR-C(O)C1-C6烷基)1-4-、-C(O)C1-C6烷基(OCH2CH2)1-6-NRC(O)C1-C6烷基-、-C1-C6烷基-、-S-、-C(O)-CH(NR-C(O)C1-C6烷基)-C1-C6烷基-和(-CH2-CH2-O-)1-20,其中LB2為AA0-12,其中AA為天然胺基酸、非天然胺基酸或-(CR15)o-S-S-(CR15)p,其中o和p各自獨立為1至20的整數,且LB3為-PABA-、-PABC-、-C(O)(CH2)nC(O)-或不存在。
本發明的額外態樣包括諸如那些本文述及之化合物,其中一或多個W為C1-C3烷基。
本發明的額外態樣包括諸如那些本文述及之化合物,其中X為氯。
本發明的額外態樣包括諸如那些本文述及之化合物,其中一個Y為H或-C(O)C1-C10烷基。
本發明的額外態樣包括諸如那些本文述及之化合物,其中一或多個Z為H。
本發明的額外態樣包括諸如那些本文述及之化合物,其中T係選自醯胺或式-NH-C(O)-NH-或-NH-C(O)-het-C(O)-NH-之胺基-繫鏈-胺基。
本發明的額外態樣包括諸如那些本文述及之化合物,其中 醯胺為-C(O)NH-或-NHC(O)-。
本發明的額外態樣包括諸如那些本文述及之化合物,其中het為選自下列的雜芳基:吡咯-2-,5-二基-、呋喃-2,5-二基-、吲哚-2,5-二基、苯並呋喃-2,5-二基和3,6-二氫苯並[1,2-b:4,3-b]二吡咯-2,7-二基。
本發明的額外態樣包括諸如那些本文述及之化合物,其中L1和L2係選自羰基、2-羰基吲哚-5-基、2-羰基-6-羥基-7-甲氧基吲哚-5-基、2-羰基-1,2,3,6-四氫苯並[1,2-b:4,3-b]二吡咯-7-基、2-羰基-4-羥基-5-甲氧基-1,2,3,6-四氫苯並[1,2-b:4,3-b’]二吡咯-7-基和2-羰基-4-羥基-5-甲氧基-1,2,3,6-四氫苯並[1,2-b:4,3-b’]二吡咯-7-基。
本發明的額外態樣包括諸如那些本文引述之化合物,其中下列中之一或多者適用:W為甲基;X為鹵素;Y為氫或-COR,其中R為C1-C10烷基;及Z為氫。
本發明亦包括如本文所述之化合物,其中T係選自醯
胺(亦即-C(O)NH-或-NHC(O)-);或式-NH-T’-NH之胺基-繫鏈-胺基,其中T’為羰基或-C-(O)-het-C(O)-,其中T為式NH-T’-NH之胺基-繫鏈-胺基,T’可為羰基(亦即-C-(O)-)或-C(O)-het-C(O)-,其中het為選自下列的雜芳基:吡咯-2-,5-二基-、呋喃-2,5-二基-、吲哚-2,5-二基、苯並呋喃-2,5-二基或3,6-二氫苯並[1,2-b:4,3-b]二吡咯-2,7-二基。
本發明的實施態樣亦包括那些如本文所述之化合物,其中L1和L2係選自2-羰基吲哚-5-基、2-羰基-6-羥基-7-甲氧基吲哚-5-基、2-羰基-1,2,3,6-四氫苯並[1,2-b:4,3-b]二吡咯-7-基、2-羰基-4-羥基-5-甲氧基-1,2,3,6-四氫苯並[1,2-b:4,3-b’]二吡咯-7-基和2-羰基-4-羥基-5-甲氧基-1,2,3,6-四氫苯並[1,2-b:4,3-b’]二吡咯-7-基。
本發明亦包括連接子-酬載或包含本文所述之酬載化合物之基團的抗體藥物共軛體。
本發明重要地包括本文所述之化合物及其任何醫藥上可接受之鹽或溶劑合物的醫藥組成物,其中醫藥組成物包括醫藥上可接受之賦形劑。
本發明進一步關於治療癌症之方法,其包含將治療有效量的一或多種本文所述之化合物或包含該等化合物中之一或多者的醫藥組成物或組成物類投予需要其之病患。
一些化合物(包括本文所描述之酬載、連接子-酬載及ADC)係以特定的立體異構物形式顯示。然而,本發明意味著包括該等化合物的所有立體異構物形式。例如,可將具有兩個立體異構物中心的化合物描述成化合物的R,S形式,但本發明表達所有的立體異構物形式,例如R,R、R,S、S,R和S,S。
本發明指向細胞毒性雙官能性化合物、包含該等細胞毒性雙官能性化合物之抗體藥物共軛體(ADC)及使用彼等治療癌症和其他病理性病狀之方法。本發明亦關於使用此等化合物及/或共軛體於試管內、原位及活體內偵測、診斷或治療哺乳動物細胞或相關聯的病理性病狀之方法。
除非另有其他陳述,否則如本文所使用的下列術語及詞組意欲具有下列意義。當本文使用商標名稱時,該商標名稱包括商標名稱產品的產品配方、學名藥及活性醫藥成分,除非上下文另有其他指示。
本文的術語〝抗體〞(或〝Ab〞)係最廣義地使用且尤其涵蓋完整單株抗體、多株抗體、單特異性抗體、多重特
異性抗體(例如雙特異性抗體)及展現所欲生物活性之抗體片段。完整抗體主要地具有兩個區域:可變區和恆定區。可變區結合至目標抗原且與其交互作用。可變區包括互補決定區(CDR),其可辨識且結合至特定抗原上的特定結合位置。恆定區可由免疫系統辨識且與其交互作用(例如參見Janeway等人之2001,Immuno.Biology,5th Ed.,Garland Publishing,New York)。抗體可具有任何型式或類別(例如IgG、IgE、IgM、IgD和IgA)或亞類別(例如IgG1、IgG2、IgG3、IgG4、IgA1和IgA2)。抗體可衍生自任何適當物種。在一些實施態樣中,抗體具有人類或鼠類來源。抗體可為例如人類、人源化或嵌合抗體。
術語〝特異性地結合〞及〝特異性結合〞係指結合至預定抗原的抗體。抗體典型地以至少約1x107M-1之親和性結合,且以大於其結合至除了預定抗原或密切相關之抗原以外的非特異性抗原(例如BSA、酪蛋白)至少兩倍的親和性結合至預定抗原。
如本文所使用的術語〝單株抗體〞係指自實質上同質性抗體族群所獲得的抗體,亦即包含族群之個別抗體是相同的,除了可以少量存在的可能天然發生的突變。單株抗體具有直接導向單一抗原位置的高特異性。修飾字〝單株〞表明由於自實質上同質性抗體族群所獲得的抗體特質,且不應解釋成需要以任何特定的方法製造抗體。
術語〝單株抗體〞尤其包括〝嵌合〞抗體,其中一部分的重及/或輕鏈與自特定物種或屬於特定抗體類別或亞
類別所衍生之抗體的相應序列相同或同質性,而其餘的鏈與自其他物種或屬於其他抗體類別或亞類別所衍生之抗體以及此等抗體之片段的相應序列相同或同質性,只要彼等展現所欲生物活性。
作為適合於抗體類別的〝完整抗體〞為包含抗原結合之可變區以及輕鏈恆定區(C L)與重鏈恆定區CH1、CH2、CH3和CH4之抗體。恆定區可為原態序列恆定區(例如人類原態序列恆定區)或其胺基酸序列變型。
完整抗體可具有一或多個〝效應子功能〞,其係指那些可歸屬於抗體之Fc區(例如原態序列Fc區或胺基酸序列變型Fc區)的生物活性。抗體效應子功能的實例包括補體依賴性細胞毒性、抗體依賴性細胞媒介之細胞毒性(ADCC)及抗體依賴性細胞媒介之吞噬作用。
〝抗體片段〞包含完整抗體的一部分,較佳地包含其抗原結合或其可變區。抗體片段的實例包括Fab、Fab’、F(ab')2和Fv片段、雙功能抗體、三功能抗體、四功能抗體、線性抗體、單鏈抗體分子、scFv、scFv-Fc、由抗體片段形成之多重特異性抗體片段、由Fab表現基因庫所產生之片段或經免疫特異性地結合至目標抗原(例如癌細胞抗原、病毒抗原或微生物抗原)的任一上述者之抗原決定位結合片段。
在抗體的上下文中,術語〝可變〞係指抗體的可變區之特定部位,其有廣泛不同的序列且用於每一特定抗體對其特定抗原之結合及特異性。此可變性集中在輕鏈及重鏈
可變區中稱為〝高度可變區〞的三個片段。可變區的更高度保守部位稱為框架區(FR)。原態重和輕鏈的可變區分別包含四個以三個高度可變區連接之框架區。
術語〝高度可變區〞在本文使用時係指抗體之胺基酸殘基,其負責抗原結合。高度可變區通常包含來自〝互補決定區〞或〝CDR〞之胺基酸殘基(例如在輕鏈可變區中的殘基24-34(L1)、50-56(L2)和89-97(L3)及重鏈可變區中的31-35(H1),50-65(H2)和95-102(L3);Kabat等人(Sequences of Proteins of Immunological Interest,5th Ed.Public Health Service,National Institutes of Health,Bethesda,Md.(1991))及/或來自〝高度可變環圈〞之殘基(例如在輕鏈可變區中的殘基26-32(L1)、50-52(L2)和91-96(L3)及重鏈可變區中的殘基26-32(H1)、53-55(142)和96-101(H3);Chothia和Lesk之1987,J.Mol.Biol.196:901-917)。FR殘基為那些除了如本文所定義之高度可變區殘基以外的可變區殘基。
〝單鏈Fv〞或〝scFv〞抗體片段包含抗體之V.sub.H和V.sub.L區,其中該等區係以單一多肽鏈存在。Fv多肽典型地進一步地包含介於V.sub.H與V.sub.L區之間的多肽連接子,其能使scFv形成用於抗原結合之所欲結構。有關scFv之檢視,參見Pluckthun in The Pharmacology of Monoclonal Antibodies,vol.113,Rosenburg and Moore eds.,Springer-Verlag,New York,pp.269-315(1994)。
術語〝雙功能抗體〞係指具有兩個抗原結合位置的小
抗體片段,該片段包含連接至相同的多肽鏈中的輕鏈可變區(VL)之重鏈可變區(VH)。藉由使用連接子(其太短而不容許在相同的鏈上的兩個區之間配對)迫使區與另一鏈的互補區配對且產生兩個抗原結合位置。雙功能抗體更完整地說明於例如EP 0 404 097、WO 93/11161和Hollinger等人之1993,Proc.Natl.Acad.Sci.USA 90:6444-6448中。
非人類(例如囓齒類)抗體之〝人源化〞形式為嵌合抗體,其含有自非人類免疫球蛋白所衍生之最小序列。最大部分的人源化抗體為人類免疫球蛋白(接受者抗體),其中來自接受者的高度可變區之殘基以來自具有所欲特異性、親和性及容量的非人類物種(施予者抗體,諸如小鼠、大鼠、兔或非人類靈長類)的高度可變區之殘基置換。在一些情況中,人類免疫球蛋白之框架區(FR)殘基以相應之非人類殘基置換。此外,人源化抗體可包含未於接受者抗體或施予者抗體中發現的殘基。進行該等修飾以進一步提升抗體性能。人源化抗體通常包含實質上全部至少一種及典型為兩種可變區,其中全部或實質上全部的高度可變環圈相應於非人類免疫球蛋白的那些高度可變環圈且全部或實質上全部的FR為人類免疫球蛋白序列的那些FR。人源化抗體亦隨意地包含至少一部分的免疫球蛋白恆定區(Fc),典型為人類免疫球蛋白恆定區。關於進一步之細節,參見Jones等人之1986,Nature 321:522-525;Riechmann等人之1988,Nature 332:323-329;及Presta之1992,Curr.Op.Struct.Biol.2:593-596。
本文所使用的〝經分離〞意指自(a)天然來源,諸如植物或動物細胞或細胞培養物,或(b)合成有機化學反應混合物的其他組份分離。如本文所使用的〝純化〞意指當分離時,該分離物含有至少分離物重量的95%,及在另一態樣中為至少98%之化合物(例如共軛物)。
〝經分離〞之抗體為已鑑別且自其天然環境的組份分離及/或回收之抗體。其天然環境之污染組份為可能干擾抗體之診斷或醫療用途之材料且可包括酵素、激素和其他蛋白質或非蛋白質溶質。在較佳的實施態樣中,將抗體純化至(1)如以勞里(Lowry)方法所測定之大於95重量%之抗體,且最佳為大於99重量%,(2)使用旋轉杯定序儀(spinning cup sequenator)足以獲得至少15個N端或內部胺基酸序列殘基的程度,或(3)在還原或非還原條件下使用Coomassie藍或較佳為銀染色的SDS-PAGE而為同質性。經分離之抗體包括在重組細胞內的原位抗體,因為抗體的天然環境中之至少一組份不存在。然而,經分離之抗體一般係以至少一個純化步驟製得。
〝誘發細胞凋亡〞之抗體為誘發計畫性細胞死亡之抗體,如藉由膜聯蛋白(annexin)V之結合、DNA之片段化、細胞縮減、內質網之擴張、細胞片段化及/或膜囊(稱為細胞凋亡體)之形成所測定。細胞為腫瘤細胞,例如乳房、卵巢、胃、子宮內膜、唾液腺、肺、腎、結腸、甲狀腺、胰臟或膀胱細胞。各種方法可用於評估與細胞凋亡相關聯的細胞事件。例如,磷脂醯絲胺酸(PS)移位可藉由膜
聯蛋白結合來測量;DNA片段化可通過DNA梯度化來評估;且核/染色質凝聚連同DNA片段化可藉由任何增加的亞二倍體細胞來評估。
術語〝治療有效量〞係指有效治療哺乳動物之疾病或病症的藥物量。在癌症的例子中,藥物的治療有效量可降低癌細胞數;降低腫瘤大小;抑制(亦即減緩至某種程度且較佳地停止)癌細胞浸潤至周邊器官;抑制(亦即減緩至某種程度且較佳地停止)腫瘤轉移;抑制腫瘤生長至某種程度;及/或緩解與癌症相關聯的症候中之一或多者至某種程度。藥物可抑制現有癌細胞的生長及/或殺死現有癌細胞到達一定的程度,其可為細胞抑制性及/或細胞毒性。關於癌症療法的功效可例如藉由評估疾病進展時間(TTP)及/或測定反應率(RR)來測量。
術語〝實質量〞係指大多數,亦即大於50%之族群、混合物或樣品。
術語〝細胞內代謝物〞係指在細胞內部對抗體藥物共軛體(ADC)之代謝過程或反應所生成之化合物。代謝過程或反應可為酵素過程,諸如ADC的肽連接子之蛋白溶解性裂解。細胞內代謝物包括但不限於在進入、擴散、吸收或運送至細胞中之後經歷細胞內裂解的抗體及游離藥物。
術語〝經細胞內裂解〞及〝細胞內裂解〞係指細胞內部對ADC或類似者之代謝過程或反應,由此破壞在藥物部分與抗體之間的共價附著(例如連接子),導致在細胞內部自抗體解離之游離藥物或共軛物的其他代謝物。ADC
之裂解部分因此為細胞內代謝物。
術語〝生物利用性〞係指投予病患之藥物給出的全身性利用性(亦即血液/血漿濃度)。生物利用性為絕對術語,其表明自投予之劑型達到藥物的全身循環之時間(速率)及總量(程度)二者的測量。
術語〝細胞毒性活性〞係指ADC或該ADC的細胞內代謝物殺死細胞、抑制細胞或抗增生之效應。細胞毒性活性可以IC50值表示,該值為使一半細胞存活的每單位體積之濃度(莫耳或質量)。
〝病症〞為可自藥物或抗體藥物共軛物之治療而得利的任何病狀。此包括慢性及急性病症或疾病,其包括那些易使哺乳動物患有討論中的病症之病理性病狀。欲以本文治療之病症的非限制性實例包括良性和惡性癌症;白血病和淋巴系統惡性病;神經元、神經膠質細胞、星狀膠質細胞、下視丘與其他腺體、巨噬細胞、上皮、基質和囊胚腔病症;及發炎、血管生成和免疫性病症。
術語〝癌症〞及〝癌性〞係指或說明哺乳動物之生理病狀或病症,其典型地以失調之細胞生長為特徵。〝腫瘤〞包含一或多種癌性細胞。
〝病患〞的實例包括但不限於人類、大鼠、小鼠、天竺鼠、猴、豬、山羊、母牛、馬、狗、貓、鳥和家禽。在範例的實施態樣中,病患為人類。
除非在上下文另有其他指示,否則術語〝治療〞係指醫療性治療及預防性措施以防止復發,其中目標為抑制或
減慢(減輕)非所欲生理變化或病症,諸如癌症之發展或擴散。就本發明的目的而言,有利或所欲的臨床結果包括但不限於無論是否可偵測或不可偵測的症候緩解、疾病程度的縮減、疾病的穩定化(亦即不惡化)狀態、疾病進展的延緩或減慢、疾病狀態的改善或緩和及免除(無論是部分或全部)。〝治療〞亦可意指與若未接受治療之預期的存活率相比而延長存活率。那些需要治療者包括已具有病狀或病症者以及那些具有病狀或病症傾向者。
在癌症的上下文中,術語〝治療〞包括任何或所有的抑制腫瘤細胞、癌細胞或腫瘤之生長;抑制腫瘤細胞或癌細胞之複製;減輕整體腫瘤負荷或降低癌性細胞數目;及改善與疾病相關聯的一或多種症候。
在自體免疫疾病的上下文中,術語〝治療〞包括任何或所有的抑制與自體免疫疾病狀態相關聯的細胞(包括但不限於產生自體免疫抗體的細胞)之複製、減輕自體免疫抗體負荷及改善自體免疫疾病的一或多種症候。
在感染性疾病的上下文中,術語〝治療〞包括任何或所有:抑制可引起感染性疾病之病原的生長、增殖或複製,以及改善感染性疾病的一或多種症候。
術語〝包裝插頁〞用於指習慣上包括在市售醫療產品包裝中的使用說明書,其含有關於使用此等醫療產品的適應症、用法、劑量、投藥、禁忌及/或警告的訊息。
如本文所使用的術語〝細胞〞、〝細胞株〞及〝細胞培養物〞可交換使用且所有此等名稱包括後代。字語〝轉
型體〞及〝轉型細胞〞包括初代目標細胞及培養物或由其所衍生的後代而無關於轉移數目。亦應瞭解所有的後代由於蓄意或無意的突變而使DNA內容可能不完全相同。包括具有與原始轉型細胞中篩選而相同功能或生物學活性的突變後代。自上下文清楚預期的不同名稱。
如本文所使用的CBI係指1,2,9,9a-四氫-4H-苯並[e]環丙[c]吲哚-4-酮或其經取代或衍生之形式。CBI亦可指CBI之二級形式或二級-CBI,其亦稱為1-(氯甲基)-2,3-二氫-1H-苯並[e]吲哚-5-醇或其經取代或衍生之形式(或形式類)。
如本文所使用的CPI係指1,2,8,8a-四氫環丙[c]吡咯並[3,2-e]吲哚-4(5H)-酮或其經取代或衍生之形式。CPI亦可指CPI之二級形式或二級-CPI,其亦稱為8-(氯甲基)-1-甲基-3,6,7,8-四氫吡咯並[3,2-e]吲哚-4-醇或其經取代或衍生之形式(或形式類)。
除非另有其他指示,否則術語〝烷基〞(其本身或作為另一術語的一部分)係指具有指定的碳原子數之直鏈或支鏈飽和烴(例如〝C1-C8〞烷基係指具有從1至8個碳原子之烷基)。烷基典型地包含從1至20個碳原子,較佳為從1至8個碳原子,且更佳為從1至4個碳原子。當未指定碳原子數時,則烷基具有從1至8個碳原子。代表性直鏈C1-C8烷基包括但不限於甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基和正辛基;且支鏈C1-C8烷基包括但不限於-異丙基、-二級丁基、-異丁基、-三級丁
基、-異戊基和-2-甲基丁基;不飽和C2-C8烷基烷基包括但不限於乙烯基、烯丙基、1-丁烯基、2-丁烯基、異丁烯基、1-戊烯基、2-戊烯基、3-甲基-1-丁烯基、2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基、1-己烯基、2-己烯基、3-己烯基、乙炔基、丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基和3-甲基-1-丁炔基。本文所述及之〝烷基〞係指如上述的未經取代及經取代之部分。
除非另有其他指示,否則術語〝伸烷基〞(其本身或作為另一術語的一部分)係指具有陳述的碳原子數(典型為1-18個碳原子)且具有兩個藉由自母體烷烴之相同或兩個不同的碳原子移除兩個氫原子所衍生之單價基團中心的飽和、支鏈或直鏈或環狀烴基。伸烷基典型地包含從1至18個碳原子,較佳為從1至10個碳原子,更佳為從1至8個碳原子,且最佳為從1至4個碳原子。典型的伸烷基包括但不限於:伸甲基(-CH2-)、1,2-伸乙基(-CH2CH2-)、1,3-伸丙基(-CH2CH2CH2-)、1,4-伸丁基(-CH2CH2CH2CH2-)及類似者。〝C1-C10〞直鏈伸烷基為式-(CH2)1-10-之直鏈飽和烴基。C1-C10伸烷基的實例包括伸甲基、伸乙基、伸丙基、伸丁基、伸戊基、伸己基、伸庚基、伸辛基、伸壬基和伸癸基。本文所述及之〝伸烷基〞係指如上述的未經取代及經取代之部分。
除非另有其他指示,否則術語〝雜烷基〞(其本身或與另一術語之組合)意指(除非另有其他陳述)穩定的直鏈或支鏈烴或其組合,完全飽和或含1至3之不飽和度,由陳
述的碳原子數及從1至3個選自由O、N、Si和S所組成之群組的雜原子所組成,且其中氮和硫原子可隨意地氧化且氮雜原子可隨意地四級化。雜原子O、N和S可位於雜烷基的任何內部位置上。雜原子Si可位於雜烷基的任何位置上,包括使烷基附著至分子剩餘部分的位置上。可使至多兩個雜原子連續。雜烷基典型地包含從1至15個碳原子,較佳為從1至12個碳原子,更佳為從1至8個碳原子,且最佳為從1至4個碳原子。本文所述及之〝雜烷基〞係指如上述的未經取代及經取代之部分。
除非另有其他指示,否則術語〝伸雜烷基〞(其本身或作為另一取代基的一部分)意指自雜烷基(如上文所討論)所衍生之二價基。伸雜烷基的雜原子亦可佔據鏈端之任一端或兩端。本文所述及之〝伸雜烷基〞係指如上述的未經取代及經取代之部分。
本文的術語H或氫典型地係指包含單一質子及不含中子之氫原子,但亦包括已知為氘之氫同位素,其包含單一質子及單一中子。
除非另有其他指示,否則〝芳基〞(其本身或作為另一術語的一部分)意指藉由自母體芳族環系統的單一碳原子中移除一個氫原子所衍生之具有5-20個,較佳為5-14個或6-14個碳原子的經取代或未經取代之單價碳環芳族烴基。典型的芳基包括但不限於自苯、經取代苯、萘、蒽、聯苯及類似者所衍生之基團。經取代之碳環芳族基團(例如芳基)可經一或多個,較佳為1至5個下列基團取
代:C1-C8烷基、-O-(C1-C8烷基)、-C(O)R9、-OC(O)R9、-C(O)OR9、-C(O)NH2、-C(O)NHR'、-C(O)N(R')2、-NHC(O)R'、-S(O)2R'、-S(O)R'、-OH、鹵素、-N3、-NH2、-NH(R9)、-N(R9)2和-CN;其中各R9獨立地選自-H、C1-C8烷基和未經取代之芳基。在一些實施態樣中,經取代之碳環芳族基團可進一步包括下列中之一或多者:-NHC(=NH)NH2、-NHCONH2、-S(=O)2R9和-SR9。〝伸芳基〞為相應之二價部分。
〝經取代之烷基〞(或〝經取代之伸烷基〞、〝經取代之雜烷基〞或〝經取代之伸雜烷基〞)意指如上文所討論之相關的含烷基基團,其中一或多個氫各自獨立地經取代基置換。典型的取代基包括但不限於-X、-R10、-O-、-OR10、-SR10、-S-、-NR10 2、-NR10 3、=NR10、-CX3、-CN、-OCN、-SCN、-N=C=O、-NCS、-NO、-NO2、=N2、-N3、-NR10C(=O)R10R10、-C(=O)NR10 2、-SO3 -、-SO3H、-S(=O)2R10、-OS(=O)2OR10、-S(=O)2NR10、-S(=O)R10、-OP(=O)(OR10)2、-P(=O)(OR10)2、-PO3 2-、PO3H2、-AsO2H2、-C(=O)R10、-C(=O)X、-C(=S)R10、-CO2R10、-CO2 -、-C(=S)OR10、-C(=O)SR10、-C(=S)SR10、-C(=O)NR10 2、-C(=S)NR10 2或-C(=N R10)N R10 2,其中各X獨立為鹵素:-F,-Cl,-Br或-I;且各R10獨立為-H、C1-C20烷基、C1-C20雜烷基、C6-C20芳基、C1-C10雜環基、保護基或前藥部分。如上述之芳基、伸烷基和伸雜烷基亦可經類似地取代。
除非另有其他指示,否則〝芳烷基〞(其本身或另一術語的一部分)意指經如上文定義之芳基取代之如經如上文定義之烷基。
除非另有其他指示,否則〝C3-C10雜環基〞(其本身或作為另一術語的一部分)係指具有從2至10個,2至14個,或2至20個碳原子,較佳為3至8個碳原子(亦稱為環員)及一至四個獨立地選自N、O、P或S之雜原子環員且藉自母體環系統的環原子移除一個氫原子所衍生之單價經取代或未經取代之芳族或非芳族單環、雙環或三環系統。可將雜環基中的一或多個N、C或S原子氧化。包括雜原子的環可為芳族或非芳族。芳族雜環在本文有時稱為雜芳基。除非另有其他註明,否則雜環基係在任何雜原子或碳原子上附著至其側基以導致穩定的結構。C2-C10雜環基的代表性實例包括但不限於四氫呋喃基、氧雜環丁烷基、吡喃基、吡咯啶基、哌啶基、哌基、苯並呋喃基、苯並噻吩、苯並噻唑基、吲哚基、苯並吡唑基、吡咯基、噻吩基(噻吩(thiopene))、呋喃基、噻唑基、咪唑基、吡唑基、三唑基、喹啉基(包括諸如1,2,3,4-四氫喹啉基之部分)、嘧啶基、吡啶基、吡啶酮基、吡基、嗒基、異噻唑基、異噁唑基、四唑基、環氧化物、氧雜環丁烷和BODIPY(經取代或未經取代)。C2-C10雜環基可經至多七個基團取代,包括但不限於C1-C8烷基、C1-C8雜烷基、-OR11、芳基、-C(O)R11、-OC(O)R11、-C(O)OR11
、-C(O)NH2、-C(O)NHR11、-C(O)N(R11)2、-NHC(O)R11、-S(=O)2R11、-S(O)R11、鹵素、-N3、-NH2、-NH(R11)、-N(R11)2和-CN;其中各R11獨立地選自-H、C1-C8烷基、C1-C8雜烷基和芳基。在一些實施態樣中,經取代之雜環基亦可包括一或多個:-NHC(=NH)NH2、-NHCONH2、-S(=O)2R11和-SR11。雜環基或C2-C10雜環基為相應之二價部分。二價芳族雜環在本文有時稱為伸雜芳基或C2-C10伸雜芳基。
如上文所註明的芳族雜環有時稱為雜芳基,且除了雜原子以外,較佳地含有5-14個、6-14個或6-20個碳原子。雜芳基可為單環、雙環或三環狀環系統。代表性雜芳基包括但不限於三唑基、四唑基、噁二唑基、吡啶基、呋喃基、苯並呋喃基、噻吩基、苯並噻吩基、喹啉基、吡咯基、吲哚基、噁唑基、苯並噁唑基、咪唑基、苯並咪唑基、噻唑基、苯並噻唑基、異噁唑基、吡唑基、異噻唑基、嗒基、嘧啶基、吡基、三基、噌啉基、酞基、喹唑啉基、嘧啶基、氮雜環庚三烯基、氧雜環庚三烯基和喹噁啉基。雜芳基隨意地經取代。典型的取代基包括但不限於-X、-Rh、-O-、-ORh、-SRh、-S-、-NRh 2、-NRh 3、=NRh、-CX3、-CN、-OCN、-SCN、-N=C=O、-NCS、-NO、-NO2、=N2、-N3、-NRhC(=O)Rh、-C(=O)NRh 2、-SO3 -、-SO3H、-S(=O)2Rh、-OS(=O)2ORh、-S(=O)2NRh、-S(=O)Rh、-OP(=O)(ORh)2、-P(=O)(ORh)2、-PO3 2-、PO3H2、-AsO2H2、-C(=O)Rh、-C(=O)X、-C(=S)Rh
、-CO2Rh、-CO2 -、-C(=S)ORh、-C(=O)SRh、-C(=S)SRh、-C(=O)NRh 2、-C(=S)NRh 2、-C(=NR)NRh 2、C1-C20雜烷基、C6-C20芳基、C3-C8雜環基、保護基或前藥部分,其中各X獨立為鹵素、-F、-Cl、-Br或-I;且各Rh獨立為-H或C1-C6烷基。二價芳族雜環在本文有時稱為伸雜芳基或C1-C10伸雜芳基。
除非另有其他指示,否則〝雜芳烷基〞(其本身或另一術語的一部分)意指經如上文定義之芳族雜環基取代之如上文定義之烷基。雜芳烷基(Heteroaralklo)為相應之二價部分。
除非另有其他指示,否則〝C3-C8碳環基〞(其本身或如另一術語的一部分)為藉由自母體環系統的環原子移除一個碳原子所衍生之3-、4-、5-、6-、7-或8-員單價、經取代或未經取代、飽和或不飽和非芳族單環或雙環狀碳環。C3-C8碳環基包括但不限於環丙基、環丁基、環戊基、環戊二烯基、環己基、環己烯基、1,3-環己二烯基、1,4-環己二烯基、環庚基、1,3-環庚二烯基、1,3,5-環庚三烯基、環辛基、環辛二烯基、雙環(1.1.1.)戊烷和雙環(2.2.2.)辛烷。C3-C8碳環基可未經取代或經至多七個包括但不限於下列之基團取代:C1-C8烷基、C1-C8雜烷基、-OR11,芳基、-C(O)R11、-OC(O)R11、-C(O)OR11、-C(O)NH2、-C(O)NHR11、-C(O)N(R11)2、-NHC(O)R11、-S(=O)2R11、-S(=O)R11、-OH、-鹵素、-N3、-NH2、-NH(R11)、-N(R11)2和-CN;其中各R11獨立地選自-H、
C1-C8烷基、C1-C8雜烷基和芳基。〝C3-C8碳環基〞為相應之二價部分。
如本文所使用的疊氮基取代基係指-N=N=N;氰酸根取代基係指-O-CN;硫氰酸根取代基係指-S-CN;異氰酸根取代基係指-N=C=O;且硫異氰酸根取代基意指-S-N=C=O。
術語〝手性〞係指具有與鏡像夥伴不可重疊的性質之分子,且術語〝非手性〞係指可與其鏡像夥伴重疊之分子。
術語〝立體異構物〞係指具有完全相同的化學構成,但關於原子或基團在空間中之排列不同的化合物。
〝非鏡像異構物〞係指具有二或多個手性中心之立體異構物且彼等的分子彼此不為鏡像。非鏡像異構物具有不同的物理性質,例如熔點、沸點、光譜性質及反應性。非鏡像異構物之混合物可在高解析分析程序下分離,諸如電泳和層析術。
本文所使用的立體化學定義及慣例通常遵循;S.P.Parker編輯之McGraw-Hill Dictionary of Chemical Terms,McGraw-Hill Book Company,New York(1984);及Eliel和Wilen之Stereochemistry of Organic化合物,John Wiley & Sons,Inc.,New York(1994)。許多有機化合物係以光學活性形式存在,亦即彼等具有使平面偏振光的平面旋轉之能力。在說明光學活性化合物時,使用字首D及L或R及S代表分子在其手性中心周圍的絕對組態。使用字首d及l或(+)及(-)標示以化合物使平面偏極光旋轉的標誌,以(-)或l意指化合物為左旋。以(+)或d為字首的化合物為右旋。該等立體異構物給出相同的化學結構,除了彼等互為鏡像以外。特異性立體異構物亦可稱為鏡像異構物,且此等異構物之混合物常稱為鏡像異構物混合物。以50:50之鏡像異構物混合物稱為消旋性混合物或消旋物,其可在化學反應或過程中沒有立體選擇或立體特異性時發生。術語〝消旋性混合物〞及〝消旋物〞係指兩種鏡像異構種類之等莫耳混合物,沒有光學活性。
胺基酸〝衍生物〞包括具有藉由母體胺基酸之共價附著(諸如藉由烷基化、糖化、乙醯化、磷酸化及類似者)而取代或修飾之胺基酸。在〝衍生物〞的定義範圍內進一步包括例如具有經取代之鍵聯以及本技術中已知的其他修飾之一或多種胺基酸類似物。
〝天然胺基酸〞係指精胺酸、麩醯胺酸、苯基丙胺酸、酪胺酸、色胺酸、離胺酸、甘胺酸、丙胺酸、組胺酸、絲胺酸、脯胺酸、麩胺酸、天冬胺酸、蘇胺酸、半胱胺酸、蛋胺酸、白胺酸、天冬醯胺、異白胺酸和纈胺酸,除非在上下文另有其他指示。
〝保護基〞係指當附著至分子中的反應性基團時遮蔽、降低或阻止反應性的部分。保護基的實例可見於T.W.Greene與P.G.M.Wuts之Protective Groups in Organic Synthesis,3rd edition,John Wiley & Sons,New
York,1999,及Harrison與Harrison等人之Compendium of Synthetic Organic Methods,Vols.1-8(John Wiley and Sons,1971-1996),將該等以其完整內容併入本文以供參考。代表性羥基保護基包括醯基、苯甲基和三苯甲基醚、四氫吡喃基醚、三烷基矽基醚及烯丙基醚。代表性胺基保護基包括甲醯基、乙醯基、三氟乙醯基、苯甲基、苯甲氧基羰基(CBZ)、三級丁氧基羰基(Boc)、三甲基矽基(TMS)、2-三甲基矽基乙磺醯基(SES)、三苯甲基和經取代之三苯甲基、烯丙氧基羰基、9-茀基甲氧基羰基(FMOC)、硝基-藜蘆氧基羰基(NVOC)及類似者。
〝羥基保護基〞包括但不限於甲氧基甲基醚、2-甲氧基乙氧基甲基醚、四氫吡喃基醚、苯甲基醚、對-甲氧基苯甲基醚、三甲基矽基醚、三乙基矽基醚、三異丙基矽基醚、三級丁基二甲基矽基醚、三苯基甲基矽基醚、乙酸酯、經取代之乙酸酯、三甲基乙酸酯、苯甲酸酯、甲磺酸酯和對-甲苯磺酸酯。
〝脫離基〞係指可經另一官能基取代之官能基。此等脫離基為本技術中所孰知,且實例包括但不限於鹵化物(例如氯化物、溴化物、碘化物)、甲磺醯基(methanesulfonyl)(甲磺醯基(mesyl))、對-甲苯磺醯基(甲苯磺醯基(tosyl))、三氟甲磺醯基(trifluoromethylsulfonyl)(三氟甲磺醯基(triflate))和三氟甲磺酸酯。
如本文所使用的詞組〝醫藥上可接受之鹽〞係指化合物的醫藥上可接受之有機或無機鹽。化合物典型地含有至
少一個胺基,且因此酸加成鹽可以此胺基形成。範例的鹽類包括但不限於硫酸鹽、檸檬酸鹽、乙酸鹽、草酸鹽、氯化物、溴化物、碘化物、硝酸鹽、硫酸氫鹽、磷酸鹽、酸性磷酸鹽、異菸鹼酸鹽、乳酸鹽、水楊酸鹽、酸性檸檬酸鹽、酒石酸鹽、油酸鹽、鞣酸鹽、泛酸鹽、酒石酸氫鹽、抗壞血酸鹽、琥珀酸鹽、丁烯二酸酸鹽、蘋果酸鹽、龍膽酸鹽、反丁烯二酸酸鹽、葡萄糖酸鹽、葡萄糖醛酸鹽、糖質酸鹽、甲酸鹽、苯甲酸鹽、麩胺酸鹽、甲磺酸鹽、乙磺酸鹽、苯磺酸鹽、對-甲苯磺酸鹽和雙羥萘酸鹽(亦即1,1’-亞甲基-雙-(2-羥基-3-萘甲酸鹽))。醫藥上可接受之鹽可包含納入的另一分子,諸如乙酸鹽離子、琥珀酸鹽離子或其他抗衡離子。抗衡離子可為使母體化合物上的電荷穩定之任何有機或無機部分。此外,醫藥上可接受之鹽可在其結構中具有一個以上的荷電原子。在多重荷電原子為醫藥上可接受之鹽的一部分的情況可具有多重抗衡離子。因此,醫藥上可接受之鹽可具有一或多個荷電原子及/或一或多個抗衡離子。
〝醫藥上可接受之溶劑合物〞或〝溶劑合物〞係指一或多種溶劑分子與本發明化合物或共軛物之締合。形成醫藥上可接受之溶劑合物的溶劑實例包括但不限於水、異丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。
術語〝負載力〞或〝藥物負載力〞或〝酬載負載力〞表示或係指ADC分子中的每份抗體之酬載平均數(〝酬載〞及〝酬載類〞可在本文與〝藥物〞及〝藥物類〞交換
使用)。藥物負載力可在每份抗體從1至20份藥物的範圍內。這有時稱為DAR或藥物對抗體比例。本文所述之ADC的組成物典型地具有從1-20之DAR,且在特定的實施態樣中從1-8、從2-8、從2-6、從2-5和從2-4。典型的DAR值為2、4、6和8。每份抗體之藥物平均數或DAR值可以慣例方式特徵化,諸如UV/可見光光譜術、質譜術、ELISA分析法和HPLC。亦可測定量化之DAR值。在一些情況中,具有特定的DAR值之同質性ADC的分離、純化及特徵化可藉由諸如反相HPLC或電泳之方式達成。DAR可受到抗體上的附著位置數量之限制。例如,其中附著點為半胱胺酸硫醇時,抗體可能僅具有一個或數個半胱胺酸硫醇基或可能僅具有一個或數個足夠可經由其附著連接子的反應性硫醇基。在一些實施態樣中,半胱胺酸硫醇為形成鏈間的二硫鍵之半胱胺酸殘基的硫醇基。在一些實施態樣中,半胱胺酸硫醇為不形成鏈間的二硫鍵之半胱胺酸殘基的硫醇基。典型地以少於藥物部分的理論最大值在共軛反應期間與抗體共軛。抗體可含有例如許多不與連接子或連接子中間物反應的離胺酸殘基。僅以最大的反應性離胺酸基可與反應性連接子試劑反應。
抗體通常不含有許多(若有的話)可經由連接子連結至藥物的游離及反應性半胱胺酸硫醇基。抗體中大多數的半胱胺酸硫醇殘基係以二硫橋形式存在且必須以還原劑(諸如二硫蘇糖醇(DTT))還原。抗體可接受變性條件以顯露反應性親核性基團,諸如離胺酸或半胱胺酸。ADC之負載
力(藥物/抗體比例)可以數種不同的方式控制,包括:(i)限制藥物-連接子相對於抗體的莫耳過量,(ii)限制共軛反應時間或溫度,及(iii)部分或限制用於半胱胺酸硫醇修飾的還原條件。在一個以上的親核性基團與藥物連接子反應時,則所得產物為每份抗體具有一或多個藥物部分分佈的ADC之混合物。每份抗體的藥物平均數可藉由例如對抗體具特異性及對藥物具特異性之雙重ELISA抗體檢定法而自混合物計算。在混合物中的個別ADC可藉由質譜術鑑別及藉由HPLC(例如疏水性交互作用層析術)分離。
下列為可能不以另外的方式於本申請案中定義及說明之縮寫及定義列表:DMSO(係指二甲亞碸),HRMS(係指高解析質譜術),DAD(係指二極體陣列偵測),TFA(係指2,2,2-三氟乙酸或三氟乙酸),TFF(係指切向流過濾),EtOH(係指乙醇),MW(係指分子量),HPLC(係指高性能液相層析術),prep HPLC(係指製備性高性能液相層析術),etc.(係指等等),trityl(係指1,1’,1”-乙-1,1,1-三基三苯),THF(係指四氫呋喃),NHS(係指1-羥基-2,5-吡咯啶二酮),Cbz(係指羧基苯甲基),eq.(係指當量),n-BuLi(係指正丁基鋰),OAc(係指乙酸鹽),MeOH(係指甲醇),i-Pr(係指異丙基或丙-2-基),NMM(係指4-甲基嗎啉),及〝-〞(在表中係指此時無有效數據)。
本文所使用的二價部分及取代基意謂著該部分或取代基係於任一方向或兩個方向上結合或連結。例如,-C(O)NR-部分(在LB1及別處之定義中)意指表達-C(O)NR-
以及-NRC(O)-;-C(O)C1-C6烷基部分意謂著表達-C(O)C1-C6烷基-以及-C1-C6烷基C(O)-等等。在其〝左〞及〝右〞側連結的不對稱二價部分之說明更概括地意謂著表達如呈示之部分(該部分之左側連結在所書寫之左側上,該部分之右側連結在所書寫之右側上)及如呈示之部分的反向(該部分之左側連結在所書寫之右側上,該部分之右側連結在所書寫之左側上)二者。
本文使用術語〝鍵〞及〝不存在〞說明不包括原子或原子類的變型。因此在二價變型〝不存在〞時,則應瞭解其意指鄰接的部分彼此結合。例如,若LB2不存在,則應瞭解LB1可結合至LB3;或者若LB1和LB2二者皆不存在,則應瞭解LA可結合至LB3。同樣地,若二價變型經定義為〝鍵〞,則應瞭解其意指沒有原子存在且鄰接的部分彼此結合。因此,例如在變型〝D〞經定義為鍵時,則應意識鄰接D的碳(在定義T2之結構中)彼此結合。應瞭解不存在的單價變型為氫或能進一步共價鍵結之電子對。
如上所註明,本文的術語〝抗體〞(或〝A〞、〝Ab〞或〝AB〞)係最廣義地使用且尤其涵蓋完整單株抗體、多株抗體、單特異性抗體、多重特異性抗體(例如雙特異性抗體)及展現所欲生物活性之抗體片段。另外,雖然本文所述之本發明的特定態樣係指抗體藥物共軛體,但是進一步設想共軛體的抗體部分可能經與受體、抗原或與
給出的目標細胞族群締合之其他的易接受部分特異性地結合或反應性地締合或複合之任何事物置換。例如,代替含有抗體的本發明之共軛體可含有與受體、抗原或其他尋求醫療或其他生物修飾的細胞族群之其他的易接受部分結合、複合或反應之靶定分子。此等分子的實例包括較小分子量的蛋白質、多肽或肽、凝集素、醣蛋白、非肽、維生素、營養物運送分子(諸如但不限於運鐵蛋白)或任何其他細胞結合分子或物質。在特定的態樣中,抗體或其他此種靶定分子係見效於遞送藥物至與抗體或其他靶定分子交互作用之特定的目標細胞族群。
在另一態樣中,本發明關於式IIIA或IIIB之抗體藥物共軛體,其中抗體AB係選自:曲妥珠美(trastuzumab)、曲妥珠美突變型(例如本文或國際專利申請案PCT/IB2012/056234中所揭示之曲妥珠美突變型)、奧戈伏馬(oregovomab)、依決洛馬(edrecolomab)、西妥昔馬(cetuximab)、抗玻璃黏連蛋白受體(αvβ3)之人源化單株抗體、阿來珠馬(alemtuzumab)、用於治療非霍奇金(Hodgkin)氏淋巴瘤之包括人源化抗-HLA-DR抗體的抗-HLA-DR抗體、131I Lym-1、用於治療非霍奇金氏淋巴瘤之包括鼠類抗-HLA-Dr10抗體的抗-HLA-Dr10抗體、抗-cd33抗體、用於治療霍奇金氏病或非霍奇金氏淋巴瘤之包括人源化抗-CD22 mAb的抗-cd22抗體、拉貝珠馬(labetuzumab)、畢法珠馬(bevacizumab)、替伊莫馬(ibritumomab tiuxetan)、奧法沐馬(ofatumumab)、帕尼沐
馬(panitumumab)、利妥昔馬(rituximab)、托西莫馬(tositumomab)、易普利沐馬(ipilimumab)和吉妥珠馬(Gemtuzumab)。
可存在於抗體單元上的雜原子包括硫(在一個實施態樣中,來自抗體的氫硫基)、氧(在一個實施態樣中,來自抗體的羰基、羧基或羥基)及氮(在一個實施態樣中,來自抗體的一級或二級胺基)。這些雜原子可存在於抗體天然狀態的抗體上,例如天然發生的抗體上,或可經由化學修飾而引入抗體中。
在一個實施態樣中,抗體單元具有氫硫基及抗體單元係經由氫硫基的硫原子鍵結。
在另一實施態樣中,抗體具有可與活化酯(此等酯包括但不限於N-羥基琥珀醯亞胺、五氟苯酯和對-硝苯酯)反應的離胺酸殘基,且因此形成由抗體單元之氮原子與羰基所組成之醯胺鍵。
在又另一態樣中,抗體單元具有可經化學修飾以引入一或多個氫硫基的一或多個離胺酸殘基。可用於修飾離胺酸的試劑包括但不限於N-琥珀醯亞胺基S-乙醯基硫乙酸酯(SATA)和2-亞胺基四氫噻吩鹽酸鹽(托特氏試劑(Traut's Reagent))。
在又另一實施態樣中,抗體單元可具有可經化學修飾以具有一或多個氫硫基的一或多個碳水化合物基團。
在又另一實施態樣中,抗體單元可具有可經氧化以提供醛基的一或多個碳水化合物基團(參見例如Laguzza等
人之1989,J.Med.Chem.32(3):548-55)。相應之醛可與反應位置(諸如肼和羥胺)形成鍵。其他用於蛋白質修飾以附著或締合藥物之方案說明於Current Protocols in Protein Science,vol.2,John Wiley & Sons(2002)中(併入本文以供參考)。
當共軛體包含代替抗體的非免疫反應性蛋白質、多肽或肽單元時,則有用的非免疫反應性蛋白質、多肽或肽單元包括但不限於運鐵蛋白、表皮生長因子(〝EGF〞)、鈴蟾素、胃泌素、胃泌素釋放肽、血小板衍生性生長因子、IL-2、IL-6、轉化生長因子(〝TOP〞)(諸如TGF-α和TGF-β),牛痘生長因子(〝VGF〞)、胰島素和類胰島素生長因子I與II、體抑素、凝集素及來自低密度脂蛋白的脫輔基蛋白。
有用的多株抗體為自免疫動物之血清所衍出之異質性抗體分子族群。有用的單株抗體為抗特定的抗原決定子(例如癌細胞抗原、病毒抗原、微生物抗原、蛋白質、肽、碳水化合物、化學品、核酸或其片段)之同質性抗體族群。抗關注之抗原的單株抗體(mAb)可藉由使用本技術中已知的任何技術製得,該技術提供以培養物中連續的細胞株來製造抗體分子。
有用的單株抗體包括但不限於人類單株抗體、人源化單株抗體、抗體片段或嵌合單株抗體。人類單株抗體可藉由本技術中已知的許多技術中之任一者製得(例如Teng等人之1983,Proc.Natl.Acad.Sci.USA.80:7308-7312;
Kozbor等人之1983,Immunology Today 4:72-79;及Olsson等人之1982,Meth.Enzymol.92:3-16)。
抗體亦可為雙特異性抗體。製造雙特異性抗體之方法為本技術中已知且於下文討論。
抗體可為可免疫特異性地結合至目標細胞(例如癌細胞抗原、病毒抗原或微生物抗原)的抗體或結合至腫瘤細胞或基質的其他抗體之功能活性片段、衍生物或類似物。關於此點,〝功能活性〞意指片段、衍生物或類似物能夠引出抗-抗-個體遺傳型抗體,其辨識與衍生出片段、衍生物或類似物的抗體辨識之相同抗原。在範例的實施例中,免疫球蛋白分子之個體遺傳型的抗原性尤其可藉由刪除框架及CDR序列(其為特異性地辨識抗原之CDR序列的C端)而增強。為了測定結合抗原之CDR序列,可將含CDR序列之合成肽藉由本技術中已知的任何結合檢定法(例如BIA核心檢定法)與抗原用於結合檢定法中(CDR序列的位置,參見例如Kabat等人之1991,Sequences of Proteins of Immunological Interest,Fifth Edition,National Institute of Health,Bethesda,Md.;Kabat E等人之1980,J.Immunology 125(3):961-969)。
其他有用的抗體包括抗體片段,諸如但不限於F(ab')2片段、Fab片段、Fvs、單鏈抗體、雙功能抗體、三功能抗體、四功能抗體、scFv、scFv-FV或具有與抗體相同的特異性之任何其他分子。
另外,可使用標準重組DNA技術製得的包含人類和
非人類部分二者的重組抗體(諸如嵌合和人源化單株抗體)為有用的抗體。嵌合抗體為其中不同的部分係自不同的動物種類所衍生之分子,諸如那些具有自鼠類單株所衍生之可變區及人類免疫球蛋白恆定區的部分(參見例如美國專利案號4,816,567;及美國專利案號4,816,397,將其完整內容併入本文以供參考)。人源化抗體為來自非人類種類之抗體分子,其具有一或多個來自非人類種類之互補決定區(CDR)及具有來自人類免疫球蛋白之框架區(參見例如美國專利案號5,585,089,將其完整內容併入本文以供參考)。此等嵌合及人源化單株抗體可藉由本技術中已知的重組DNA技術製得,例如使用下列中所述之方法:國際公開案號WO 87/02671;歐州專利公開案號0 184 187;歐州專利公開案號0 171 496;歐州專利公開案號0 173 494;國際公開案號WO 86/01533;美國專利案號4,816,567;歐州專利公開案號012 023;Berter等人之1988,Science 240:1041-1043;Liu等人之1987,Proc.Natl.Acad.Sci.USA 84:3439-3443;Liu等人之1987,J.Immunol.139:3521-3526;Sun等人之1987,Proc.Natl.Acad.Sci.USA 84:214-218;Nishimura等人之1987,Cancer.Res.47:999-1005;Wood等人之1985,Nature 314:446-449;及Shaw等人之1988,J.Natl.Cancer Inst.80:1553-1559;Morrison,1985,Science 229:1202-1207;Oi等人之1986,BioTechniques 4:214;美國專利案號5,225,539;Jones等人之1986,Nature 321:552-525;
Verhoeyan等人之1988,Science 239:1534;及Beidler等人之1988,J.Immunol.141:4053-4060;將每一該等以其完整內容併入本文以供參考。
完全人類抗體特別合意且可使用不能夠表現內源性免疫球蛋白重鏈和輕鏈基因,但是可表現人類重鏈和輕鏈基因的轉殖基因小鼠製得。轉殖基因小鼠係以正常方式經選定之抗原免疫,例如以本發明的所有或一部分多肽。導向對抗抗原之單株抗體可使用慣例的融合瘤技術獲得。由轉殖基因小鼠所藏匿之人類免疫球蛋白轉殖基因在B細胞分化期間重新排列且繼而進行類別轉換及體細胞突變。因此,使用此技術有可能製得治療上有用的IgG、IgA、IgM和IgE抗體。關於檢視此製造人類抗體之技術,參見Lonberg和Huszar之1995,Int.Rev.Immunol.13:65-93。關於製造人類抗體和人類單株抗體之技術及製造此等抗體之方案的詳細討論,參見例如美國專利案號5,625,126;5,633,425;5,569,825;5,661,016;5,545,806;將每一該等以其完整內容併入本文以供參考。其他的人類抗體可於市場上自例如Abgenix,Inc.(現為Amgen,Freemont,Calif.)及Medarex(Princeton,N.J.)獲得。
辨識所選定之抗原決定位的完全人類抗體可使用稱為〝引導選擇〞之技術產生。此方法中使用所選定之非人類單株抗體(例如小鼠抗體)引導用於辨識相同的表面決定位之完全人類抗體的選擇。(參見例如Jespers等人之1994,Biotechnology 12:899-903)。人類抗體亦可使用本
技術中已知的各種技術製得,包括噬菌體表現庫(phage display library)(參見例如Hoogenboom和Winter之1991,J.Mol.Biol.227:381;Marks等人之1991,J.Mol.Biol.222:581;Quan和Carter之2002,The rise of monoclonal antibodies as therapeutics,In Anti-IgE and Allergic Disease,Jardieu和Fick編輯之Marcel Dekker,New York,N.Y.,Chapter 20,pp.427-469)。
在其他的實施態樣中,抗體為抗體之融合蛋白或其功能活性片段,例如其中抗體係在N端或C端經由共價鍵(例如肽鍵)融合至非來自抗體的另一蛋白質之胺基酸序列(或其部分,較佳為蛋白質之至少10、20或50個胺基酸部分)。抗體或其片段較佳地於恆定區的N端共價連結至其他的蛋白質。
抗體包括經任一修飾之類似物及衍生物,亦即藉由任何類型的分子之共價附著,只要此共價附著容許抗體保留其抗原結合免疫特異性即可。例如但非限制方式,抗體之衍生物及類似物包括那些已進一步例如藉由醣化、乙醯化、聚乙二醇化、磷酸化、醯胺化、以已知的保護/阻斷基團衍化、蛋白溶解性裂解、鍵聯至細胞抗體單元或其他蛋白質等等而修飾者。許多化學修飾中之任一者可藉由已知的技術進行,包括但不限於特異性化學裂解、乙醯化、甲醯化、在衣黴素(tunicamycin)存在下的代謝合成法等等。另外,類似物或衍生物可含有一或多種非天然胺基酸。
抗體可在與Fc受體交互作用之胺基酸殘基中進行修飾(例如取代、刪除或添加)。抗體可特別在經鑑別涉及抗-Fc區與FcRn受體之間的交互作用之胺基酸殘基中進行修飾(參見例如國際公開案號WO 97/34631,將其完整內容併入本文以供參考)。
癌細胞抗原的免疫特異性抗體可於市場上獲得或可藉由熟習本技術領域者已知的任何方法製得,諸如化學合成法或重組表現技術。編碼癌細胞抗原的免疫特異性抗體之核苷酸序列可自例如GenBank資料庫或與其類似的資料庫、文獻發表或藉由常規的選殖及定序而獲得。
在特定的實施態樣中,可使用治療癌症的已知抗體。癌細胞抗原的免疫特異性抗體可於市場上獲得或可藉由熟悉本技術領域者已知的任何方法製得,諸如重組表現技術獲得。編碼癌細胞抗原的免疫特異性抗體之核苷酸序列可自例如GenBank資料庫或與其類似的資料庫、文獻發表或藉由常規的選殖及定序而獲得。有效治療癌症之抗體的實例包括但不限於OVAREX,其為治療卵巢癌之鼠類抗體;PANOREX(Glaxo Wellcome,NC),其為治療大腸直腸癌之鼠類IgG2a抗體;西妥昔馬ERBITUX(Imclone Systems Inc.,NY),其為治療表皮生長因子陽性癌症(諸如頭頸部癌症)之抗-EGFR IgG嵌合抗體;Vitaxin(MedImmune,Inc.,MD),其為治療肉瘤之人源化抗體;CAMPATH I/H(Leukosite,MA),其為治療慢性淋巴球性白血病(CLL)之人源化IgG1抗體;SMART ID10(Protein
Design Labs,Inc.,CA),其為治療非霍奇金氏淋巴瘤之人源化抗-HLA-DR抗體;ONCOLYM(Techniclone,Inc.,CA),其為治療非霍奇金氏淋巴瘤的放射標記之鼠類抗-HLA-Dr10抗體;ALLOMUNE(BioTransplant,CA),其為治療霍奇金氏病或非霍奇金氏淋巴瘤之人源化抗-CD2 mAb;及CEACIDE(Immunomedics,NJ),其為治療大腸直腸癌之人源化抗-CEA抗體。
在發現對癌症診斷及醫療有效的細胞目標之嘗試中,研究者已尋求鑑別出與跨膜或其他腫瘤相關聯的多肽,與在一或多種正常的非癌性細胞上相比,該等多肽可特異性地表現在一或多種特定類型的癌細胞表面上。與在非癌性細胞表面上相比,此等與腫瘤相關聯的多肽時常更豐富地表現在癌細胞表面上。此等與腫瘤相關聯的細胞表面抗原多肽之鑑別造就以特異性地靶定癌細胞之能力,經由以抗體為基準的治療法進行破壞。
連接子(本文有時稱為〝[連接子]〞)為雙官能性化合物,其可用於連接藥物及抗體以形成抗體藥物共軛體(ADC)。此等共軛體有用於例如形成導向對抗與腫瘤相關聯的抗原之免疫共軛體。此等共軛體容許細胞毒性藥物選擇性遞送至腫瘤細胞。
在ADC中,連接子的作用在於使酬載附著至抗體。
在一個態樣中,引入具有第二反應位置的連接子單元
之第二區段,例如親電子基團,其與抗體單元(例如抗體)上存在的親核性基團反應。在抗體上有用的親核性基團包括但不限於氫硫基、羥基和胺基。抗體之親核性基團的雜原子與連接子單元上的親電子基團反應且形成至連接子單元的共價鍵。有用的親電子基團包括但不限於馬來醯亞胺和鹵乙醯胺基團。親電子基團提供用於抗體附著的適宜位置。
在另一實施態樣中,連接子單元具有反應位置,其具有與抗體上存在的親電子基團反應之親核性基團。在抗體上有用的親電子基團包括但不限於醛和酮羰基。連接子單元之親核性基團的雜原子可與抗體上的親電子基團反應且形成至抗體的共價鍵。連接子單元上有用的親核性基團包括但不限於醯肼、肟、胺基、肼、縮胺基硫脲(thiosemicarbazone)、肼羧酸酯和芳醯肼。在抗體上的親電子基團提供用於附著至連接子單元的適宜位置。
胺基官能基亦為對連接子單元有用的反應位置,因為彼等可與化合物的羧酸或活化酯反應以形成醯胺鍵聯。本發明以肽為基準之化合物典型地可藉由在二或多個胺基酸及/或肽片段之間形成肽鍵而製得。此等肽鍵可例如根據在肽化學領域中熟知的液相合成法製得(參見例如Schroder和Lubke之"The Peptides",volume 1,pp 76-136,1965,Academic Press)。
本發明的上下文中,特別但不限於連接子組份,諸如L1、L2(包L2 A、L2 B和L2 C)及L3,表達方式〝選自...中之
一或多者〞或〝...中之一或多者〞表明可相同或不同,為或可為接續排列的多重組份。因此,例如,L3可為-C1-6烷基-、-NR-或其他個別列示之組份,但亦可為-C1-6烷基-NR-,或2或多個列示之組份的任何其他組合。
在另一實施態樣中,連接子單元具有可與抗體親核物(諸如半胱胺酸)反應之反應位置。反應位置係由經碸取代之雜環所組成。碸接著經抗體親核物(亦即半胱胺酸)置換且在抗體與雜環之間新形成的鍵連接抗體至連接子。參見WO 2014/144878。
本發明化合物及共軛體可使用下列實施例中概述之合成程序來製造。如下文更詳細地說明,本發明化合物及共軛體可使用具有用於結合至化合物的反應位置之連接子單元區段來製備。在一個態樣中,引入具有第二反應位置的連接子單元之第二區段,例如親電子基團,其與抗體單元(例如抗體)上存在的親核性基團反應。在抗體上有用的親核性基團包括但不限於氫硫基、羥基和胺基。抗體之親核性基團的雜原子與連接子單元上的親電子基團反應且形成至連接子單元的共價鍵。有用的親電子基團包括但不限於馬來醯亞胺和鹵乙醯胺基團。親電子基團提供用於抗體附著的適宜位置。
在另一實施態樣中,連接子單元具有反應位置,其具有與抗體上存在的親電子基團反應之親核性基團。在抗體
上有用的親電子基團包括但不限於醛和酮羰基。連接子單元之親核性基團的雜原子可與抗體上的親電子基團反應且形成至抗體的共價鍵。連接子單元上有用的親核性基團包括但不限於醯肼、肟、胺基、肼、縮胺基硫脲、肼羧酸酯和芳醯肼。在抗體上的親電子基團提供用於附著至連接子單元的適宜位置。
胺基官能基亦為對連接子單元有用的反應位置,因為彼等可與化合物的羧酸或活化酯反應以形成醯胺鍵聯。本發明以肽為基準之化合物典型地可藉由在二或多個胺基酸及/或肽片段之間形成肽鍵而製得。此等肽鍵可例如根據在肽化學領域中熟知的液相合成法製得(參見例如Schroder和Lubke之"The Peptides",volume 1,pp 76-136,1965,Academic Press)。
如以下更詳細地說明,共軛體可使用具有用於結合至本發明化合物之反應位置的連接子區段及引入具有用於抗體之反應位置的連接子另一區段來製備。在一個態樣中,連接子單元具有反應位置,其具有與抗體單元(諸如抗體)上存在的親核性基團反應之親電子基團。親電子基團提供用於抗體附著的適宜位置。在抗體上有用的親核性基團包括但不限於氫硫基、羥基及胺基。抗體之親核性基團的雜原子與連接子單元上的親電子基團反應且形成至連接子單元的共價鍵。有用的親電子基團包括但不限於馬來醯亞胺和鹵乙醯胺基團。
在另一實施態樣中,連接子單元具有反應位置,其具
有與抗體單元上存在的親電子基團反應之親核性基團。在抗體上的親電子基團提供用於附著至連接子單元的適宜位置。在抗體上有用的親電子基團包括但不限於醛和酮羰基。連接子單元之親核性基團的雜原子可與抗體上的親電子基團反應且形成至抗體的共價鍵。連接子單元上有用的親核性基團包括但不限於醯肼、肟、胺基、肼、縮胺基硫脲、肼羧酸酯和芳醯肼。
在本發明的另一實施態樣中,本發明的鍵聯係使用工程化抗體恆定區多肽或其部分,其中工程化恆定區包含至少一個胺基酸取代以引入有用於共軛的半胱胺酸殘基,且其中恆定區多肽為工程化人類IgG重鏈恆定區(Cy)多肽或其部分,其包含至少一個選自由下列所組成之群組的胺基酸取代:根據Kabat的EU索引之K246、D249、D265、S267、D270、N276、Y278、E283、R292、E293、E294、Y300、V302、V303、L314、N315、E318、K320、I332、E333、K334、1336、E345、Q347、S354、R355、M358、K360、Q362、K370、Y373、D376、A378、E380、E382、Q386、E388、N390、K392、T393、D401、F404、T411、D413、K414、R416、Q418、Q419、N421、M428、A431、L432、T437、Q438、K439、L443和S444。
在本發明的另一實施態樣中,本發明的鍵聯係使用工程化抗體恆定區多肽或其部分,其中工程化恆定區包含至少一個胺基酸取代以引入有用於共軛的半胱胺酸殘基,且
其中恆定區多肽為工程化人類λ輕鏈恆定區(CA)多肽或其部分,其包含至少一個選自由下列所組成之群組的胺基酸取代:根據Kabat編號之K110、A111、L125、K149C、V155、G158、T161、Q185、S188、H189、S191、T197、V205、E206、K207、T208和A210。
在本發明的又另一實施態樣中,本發明的鍵聯係使用工程化抗體恆定區多肽或其部分,其中工程化恆定區包含至少一個胺基酸取代以引入有用於共軛的半胱胺酸殘基,且其中恆定區多肽為工程化人類κ輕鏈恆定區(CK)多肽或其部分,其包含至少一個選自由下列所組成之群組的胺基酸取代:根據Kabat編號之A111、K183和N210。
在本發明的又另一實施態樣中,本發明的鍵聯係使用工程化抗體恆定區多肽或其部分,其中工程化恆定區包含至少一個胺基酸取代以引入有用於共軛的半胱胺酸殘基,且其中恆定區多肽為工程化Cy多肽或其部分,其包含至少一個選自由下列所組成之群組的胺基酸序列:SEQ ID編號:97-100、102、104、107-127和129-163,如WO2013/093809中所揭示,將其完整內容併入本文以供參考。
在本發明的又另一實施態樣中,本發明的鍵聯係使用工程化抗體恆定區多肽或其部分,其中工程化恆定區包含至少一個胺基酸取代以引入有用於共軛的半胱胺酸殘基,且其中恆定區多肽為工程化CK多肽或其部分,其包含至少一個選自由下列所組成之群組的胺基酸序列:SEQ ID
編號:90、92、95、164、166和169,如WO2013/093809中所揭示,將其完整內容併入本文以供參考。
在本發明的又另一實施態樣中,本發明的鍵聯係使用工程化抗體恆定區多肽或其部分,其中工程化恆定區包含至少一個胺基酸取代以引入有用於共軛的半胱胺酸殘基,且其中恆定區多肽為工程化CA多肽或其部分,其包含至少一個選自由下列所組成之群組的胺基酸序列:SEQ ID編號:172-186,如WO2013/093809中所揭示,將其完整內容併入本文以供參考。
在本發明的另一實施態樣中,上述工程化Cy多肽進一步包含至少一種選自由下列所組成之群組的突變:在根據Kabat的EU索引之胺基酸位置284、287、A327、N384、L398和V422上的突變。
在特定的實施態樣中,本發明化合物可在轉麩醯胺酸酶的存在下共價交聯至含Fc或含Fab之多肽,該多肽係以醯基施予者的含麩醯胺酸標籤(例如含Gln之肽標籤或Q-標籤)或藉由多肽工程化(例如經由在多肽上的胺基酸刪除、插入、取代、突變或其任何組合)來達成反應性的內源性麩醯胺酸(亦即在胺及轉麩醯胺酸酶的存在下形成作為醯基施予者的共價鍵之能力)而工程化,先決條件為本發明化合物包含胺施予劑(例如包含或附著至反應胺的小分子),由此形成以胺施予劑工程化的含Fc之多肽共軛體
的穩定及同質性族群,此胺施予劑係經由醯基施予者的含麩醯胺酸標籤或經由暴露/易接近/反應性之內源性麩醯胺酸而以位置特異性地共軛至含Fc或含Fab之多肽。例如,本發明化合物可如國際專利申請序號PCT/IB2011/054899所述方式共軛,將其完整內容併入本文以供參考。在特定的實施態樣中,為了促進本發明化合物在轉麩醯胺酸酶的存在下共軛至以醯基施予者的含麩醯胺酸標籤或藉由多肽工程化來達成反應性的內源性麩醯胺酸而工程化的含Fc或含Fab之多肽,使Z為NH2。
在特定的實施態樣中,本發明化合物可共價附著至人類輕鏈κ區恆定區(CLκ)(根據Kabat之全輕鏈編號)之K188側鏈。例如,本發明化合物可如美國專利申請序號13/180,204中所述方式共軛,將其完整內容併入本文以供參考。在特定的實施態樣中,為了促進與K188 CLκ共軛,使Z為;R7於每次出現時獨立地選自由下列所組成之群組:F、Cl、I、Br、NO2、CN和CF3;且h為1、2、3、4或5。
在特定的實施態樣中,本發明提供包含經共價共軛至抗體(或其抗原結合部分)的本發明化合物之組成物,其中在組成物中的至少約50%,或至少約60%,或至少約70%,或至少約80%,或至少約90%之本發明化合物共軛
至K188 CLκ上的抗體或其抗原結合部分。
在特定的實施態樣中,本發明化合物可共軛至催化性抗體(諸如醛縮酶抗體或其抗原結合部分)之組合位置。醛縮酶抗體含有組合位置部分,當未受阻礙時(例如藉由共軛),其可催化脂族酮施予者與醛受體之間的醛醇加成反應。將美國專利申請公開案號US 2006/205670的內容併入本文以供參考,特別為說明連接子的第78-118頁及說明抗體、其有用的片段、其變型和其修飾、h38C2、組合位置和互補決定區(CDR)及有關的抗體技術的段落[0153]-[0233]。術語〝組合位置〞包括涉入抗原結合之CDR及鄰接的框架殘基。
在其他的實施態樣中,本發明的另一態樣關於包括有效量的本發明化合物及/或其抗體藥物共軛體及醫藥上可接受之載劑或媒劑的醫藥組成物。在特定的實施態樣中,組成物適合於獸醫學或人類投予。
本發明的醫藥組成物可呈容許組成物投予病患的任何形式。例如,組成物可呈固體或液體形式。典型的投予路徑包括但不限於非經腸、經眼及腫瘤內。非經腸投予包括皮下注射、靜脈內、肌肉內或胸骨內注射或輸注技術。在一個態樣中,組成物係非經腸投予。在特定的實施態樣中,組成物係經靜脈內投予。
醫藥組成物可經調配以容許本發明化合物及/或其抗
體藥物共軛體在組成物投予病患時具有生物利用性。組成物可採用一或多種劑量單位形式,例如錠劑可為單一劑量單位,且含有液體形式的本發明化合物及/或其抗體藥物共軛體的容器可容納複數個單位劑量。
用於製備醫藥組成物的材料以所使用的量可為無毒性。那些一般熟習本技術領域者明白在醫藥組成物中的活性成分之最優化劑量將取決於各種因素而定。相關的因素包括但不限於動物類型(例如人類)、本發明化合物及/或其抗體藥物共軛體的特定形式、投予方式及所使用的組成物。
醫藥上可接受之載劑或媒劑可為固體或微粒,使得組成物為例如錠劑或粉末形式。載劑可為液體。另外,載劑可為微粒。
組成物可呈液體形式,例如溶液、乳液或懸浮液。在以注射投予之組成物中亦可包括界面活性劑、保存劑、濕潤劑、分散劑、懸浮劑、緩衝劑、穩定劑及等張劑中之一或多者。
無論是否為溶液、懸浮液或其他類似形式,液體組成物亦可包括下列中之一或多者:無菌稀釋劑,諸如注射用水、食鹽水溶液(較佳為生理食鹽水)、林格(Ringer)氏溶液、等張氯化鈉;固定油,諸如合成單或二酸甘油酯(其可充作為溶劑或懸浮介質)、聚乙二醇、甘油、環糊精、丙二醇或其他溶劑;抗細菌劑,諸如苯甲醇或對羥基苯甲酸酯;抗氧化劑,諸如抗壞血酸或亞硫酸氫鈉;螯合劑,
諸如乙二胺四乙酸;緩衝劑,諸如乙酸鹽、檸檬酸鹽、磷酸鹽或胺基酸;及用於調整張力之劑,諸如氯化鈉或右旋糖。非經腸組成物可密封在玻璃、塑膠或其他材質所製成的安瓿、可丟棄式注射管或多重劑量小瓶中。生理食鹽水為範例的佐劑。注射用組成物較佳為無菌的。
有效治療特定病症或病狀之本發明化合物及/或其抗體藥物共軛體的量將取決於病症或病狀的本性而定,且可藉由標準的臨床技術決定。另外,試管內或活體內檢定法可隨意地用於協助鑑別出最優化劑量範圍。在組成物中所使用的精確劑量亦將取決於投予路徑及疾病或病症的嚴重性而定,且應根據醫師的判斷及每位病患的情況來決定。
組成物包含有效量的本發明化合物及/或其抗體藥物共軛體,得以獲得適合的劑量。此量典型地佔組成物重量的至少約0.01%之本發明化合物及/或其抗體藥物共軛體。在範例的實施態樣中,醫藥組成物經製備而使得非經腸的劑量單位含有約0.01重量%至約2重量%之量的本發明化合物及/或其抗體藥物共軛體。
用於靜脈內投予之組成物可包含以每公斤病患體重計約0.01至約100毫克本發明化合物及/或其抗體藥物共軛體。在一個態樣中,組成物可包括以每公斤病患體重計約1至約100毫克本發明化合物及/或其抗體藥物共軛體。在另一態樣中,所投予之量係在約0.1至約25毫克/公斤體重之本發明化合物及/或其抗體藥物共軛體的範圍內。
通常投予病患的本發明化合物及/或其抗體藥物共軛
體之劑量典型為約0.01毫克/公斤至約20毫克/公斤病患體重。在一個態樣中,投予病患之劑量係介於約0.01毫克/公斤至約10毫克/公斤患病體重之間。在另一態樣中,投予病患之劑量係介於約0.1毫克/公斤至約10毫克/公斤患病體重之間。在另一態樣中,投予病患之劑量係介於約0.1毫克/公斤至約5毫克/公斤患病體重之間。在另一態樣中,投予之劑量係介於約0.1毫克/公斤至約3毫克/公斤患病體重之間。在另一態樣中,投予之劑量係介於約1毫克/公斤至約3毫克/公斤患病體重之間。
本發明化合物及/或其抗體藥物共軛體可以任何適宜的路徑投予,例如以輸注或快速注射。投予可為全身性或局部。已知各種遞送系統,例如包封在微脂粒、微粒子、微膠囊、膠囊等等中,且可用於投予本發明化合物及/或其抗體藥物共軛體。在特定的實施態樣中,將一種以上的本發明化合物及/或其抗體藥物共軛體投予病患。
在特定的實施態樣中,希望以一或多種本發明化合物及/或其抗體藥物共軛體局部投予需要治療的區域。這可以例如而不以限制方式於手術期間以局部輸注;在手術後例如連同傷口敷料一起以局部塗敷;以射法;藉助於導管;或藉助於植入物(植入物為多孔性、無孔性或凝膠狀材料,包括膜,諸如矽橡膠膜或纖維)而達成。在一個實施態樣中,投予可藉由在癌症、腫瘤或贅瘤或贅瘤前組織之位置(或較早位置)上直接注射。在另一實施態樣中,投予可藉由在自體免疫疾病表徵位置(或較早位置)上直接注
射。
在又另一實施態樣中,本發明化合物及/或其抗體藥物共軛體可以控制釋出型系統遞送,可使用諸如但不限於泵或各種聚合物材料。在又另一實施態樣中,控制釋出型系統可放置在本發明化合物及/或其抗體藥物共軛體的目標附近,例如肝,因此僅需要全身劑量的一小部分(參見例如Goodson之in Medical Applications of Controlled Release,supra,vol.2,pp.115-138(1984))。可使用在以Langer(Science 249:1527-1533(1990))之檢視中所討論的其他控制釋出型系統。
術語〝載劑〞係指可與化合物或其抗體藥物共軛體投予之稀釋劑、佐劑或賦形劑。此等醫藥載劑可為液體,諸如水及油類,包括那些石油醚、動物、植物或合成來源。載劑可為食鹽水及類似者。另外,可使用輔助劑、穩定劑及其他劑。在一個實施態樣中,當投予患病時,化合物或共軛體及醫藥上可接受之載劑為無菌的。當化合物或共軛體係經靜脈內投予時,則以水為範例的載劑。食鹽水溶液及水性右旋糖和甘油溶液亦可用作為液體載劑,特別用於注射溶液。若有要求時,本發明組成物亦可含有少量濕潤劑或乳化劑或pH緩衝劑。
本發明組成物可採用溶液、丸劑、粉末、持續釋出型調配物形式或任何其他適合於使用的形式。適合的醫藥載劑之其他實例說明於E.W.Martin之“Remington’s Pharmaceutical Sciences”中。
在一實施態樣中,本發明化合物及/或其抗體藥物共軛體係依照常規程序調配成適合於靜脈內投予動物(特別為人類)之醫藥組成物。用於靜脈內投予之載劑或媒劑典型為無菌等張水性緩衝溶液。在必要時,組成物亦可包括增溶劑。用於靜脈內投予之組成物可隨意地包含局部麻醉劑以緩和注射位置的疼痛,諸如利多卡因(lignocaine)。成分通常係單獨供應或一起混合於單位劑型中,例如成為在指示活性劑的量之密封容器中的無水凍乾粉末或不含水的濃縮物,諸如在安瓶或小袋中。在本發明化合物及/或其抗體藥物共軛體欲以輸注投予時,其可以例如含無菌醫藥級之水或食鹽水的輸注瓶分配。在本發明化合物及/或其抗體藥物共軛體以注射投予時,可提供注射用無菌水或食鹽水的安瓶,使得成分可在投予前混合。
組成物可包括各種修改固體或液體劑量單位之物理形式的材料。例如,組成物可包括形成圍繞活性成分之包膜殼的材料。形成包膜殼的材料典型為惰性且可選自例如糖、蟲膠和其他腸溶性包膜劑。另一選擇地,可將活性成分裝入明膠膠囊中。
無論是呈固體或液體形式,本發明組成物可包括用於治療癌症之藥理劑。
本發明的另一態樣關於使用本發明化合物及其抗體藥物共軛體治療癌症之方法。
本發明化合物及/或其抗體藥物共軛體有用於抑制腫瘤細胞或癌細胞之增殖、引起腫瘤或癌細胞凋亡、或治療病患之癌症。本發明化合物及/或其抗體藥物共軛體可據此用於治療動物癌症的各種設定中。該共軛體可用於遞送本發明化合物至腫瘤細胞或癌細胞。不受到理論的束縛,在一個實施態樣中,共軛體之抗體結合至與癌細胞或腫瘤細胞相關聯的抗原或與其締合,且共軛體可通過受體媒介之細胞吞噬作用或其他內化機制而置入(內化)腫瘤細胞或癌細胞內部。抗原可附著至腫瘤細胞或癌細胞或可為與腫瘤細胞或癌細胞相關聯的細胞外基質蛋白質。在特定的實施態樣中,一旦在細胞內部時,一或多種特異性肽序列經一或多種與腫瘤細胞或癌細胞相關聯的蛋白酶而以酵素或水解方式裂解,導致本發明化合物自共軛體釋出。經釋出之本發明化合物接著自由地在細胞內遷移且誘發細胞毒性或細胞抑制活性。共軛體亦可經細胞內蛋白酶裂解而釋出本發明化合物。在可替代的實施態樣中,本發明化合物係在腫瘤細胞或癌細胞外部自共軛物裂解且本發明化合物隨後穿透細胞。
在特定的實施態樣中,共軛體提供共軛-特異性腫瘤或癌症藥物靶定,因此降低本發明化合物的一般毒性。
在另一實施態樣中,抗體單元結合至腫瘤細胞或癌細胞。
在另一實施態樣中,抗體單元結合至腫瘤細胞或癌細胞抗原,其係在腫瘤細胞或癌細胞表面上。
在另一實施態樣中,抗體單元結合至腫瘤細胞或癌細胞抗原,其為與腫瘤細胞或癌細胞相關聯的細胞外基質蛋白質。
抗體單元對特定的腫瘤細胞或癌細胞之特異性可具有決定該等腫瘤或癌症受到最有效治療的重要性。
可以本發明化合物及/或其抗體藥物共軛體治療之特定類型的癌症包括但不限於膀胱、乳房、子宮頸、結腸、子宮內膜、腎、肺、食道、卵巢、攝護腺、胰臟、皮膚、胃和睪丸的惡性腫瘤;及血源性癌症,包括但不限於白血病和淋巴瘤。
癌症之多模式療法:包括但不限於腫瘤、轉移或以不受控制之細胞生長為特徵的其他疾病或病症之癌症可藉由投予本發明化合物及/或其抗體藥物共軛體而治療或抑制。
在其他的實施態樣中提供治療癌症之方法,其包括將有效量的本發明化合物及/或其抗體藥物共軛體及化療劑投予對其有需求的病患。在一個實施態樣中,化療劑為以其治療之癌症經發現不為頑抗型。在另一實施態樣中,化療劑為以其治療之癌症經發現為頑抗型。可將本發明化合物及/或其抗體藥物共軛體投予亦接受手術作為癌症治療的病患。
在一些實施態樣中,病患亦接受另外的治療,諸如放射療法。在特定的實施態樣中,本發明化合物及/或其抗體藥物共軛體係與化療劑或與放射療法同時投予。在另一
特定的實施態樣中,化療劑或放射療法係在投予本發明化合物及/或其抗體藥物共軛體之前或之後投予。
化療劑可經一系列時期投予。可投予任一種或組合之化療劑,諸如標準的照護化療劑。
另外,在經證實或可證實化療或放射療法太毒時,例如導致欲治療之病患不可接受或不能忍受的副作用,則可提供以本發明化合物及/或其抗體藥物共軛體之治療癌症方法作為化療或放射療法之替代法。欲治療之病患可隨意地以另一癌症治療法治療,諸如手術、放射療法或化療法,其係取決於該治療經發現為可接受或可忍受的。
本發明化合物及/或其抗體藥物共軛體亦可以試管內或活體外方式使用,諸如用於治療特定的癌症,包括但不限於白血病和淋巴瘤,此治療包含自體幹細胞移植。其可包含多步驟過程,其包括採集動物的自體造血幹細胞且清除所有的癌細胞,接著經由投予高劑量的本發明化合物及/或其抗體藥物共軛體與或不與伴隨的高劑量放射療法以根絕動物餘留之骨髓細胞群,且將幹細胞移植物輸注回動物。接著提供支持性照護,同時恢復骨髓功能及病患復原。
本發明進一步以下列的實施例說明,不意欲以其限制本發明的範疇。
實驗通常係在惰性氛圍下(但氮氣或氬氣)進行,特別在其中使用氧或水分敏感性試劑或中間物的例子中。通常使用市售溶劑及試劑而不進一步純化,包括在適當時的無水溶劑(通常為來自Aldrich Chemical Company,Milwaukee,Wisconsin之Sure-SealTM產品)。質譜數據係來自液相層析術-質譜(LCMS)或大氣壓化學離子化(APCI)S)的報告。核磁共振(NMR)數據的化學位移係參考所使用的氘化溶劑之殘留波峰而以百萬分之份(ppm,δ)表示。
可參考在其他實施例或方法中的程序之合成法來改變反應方案(反應長度與溫度)。薄層層析術、LC-MS或HPLC LC-MS或HPLC通常係接續在反應之後且在適當時進行整理。純化可能隨實驗而改變:通常選擇用於洗提液/梯度的溶劑與溶劑比以提供適當的滯留時間。除非另有其他指定,否則反相HPLC流份係經由低壓凍乾/冷凍乾燥而濃縮。中間物及最終化合物係在密封的小瓶或燒瓶中於氮氣下貯存在(0℃)或室溫下。化合物名稱係以ACD Labs軟體產生。
溶劑及/或試劑的縮寫係以美國化學學會(American Chemical Society)指導方針為基準且標註於下文:Ac=乙醯基
Boc=N-三級丁氧基羰基
CDI=N,N'-羰基二咪唑
DCC=1,3-二環己基碳二醯亞胺
DCE=二氯乙烷
DCM=二氯甲烷
DEA=N,N-二乙胺
DEAD=偶氮二羧酸二乙酯
DIAD=偶氮二羧酸二異丙酯
DIBAL-H=氫化二異丁基鋁
DIPEA(或)胡尼格(Hunig)氏鹼=N,N-二異丙基乙胺
DMA=二甲基乙醯胺
DMAP=4-二甲基胺基吡啶
DME=二甲氧基乙烷
DMF=N,N-二甲基甲醯胺
DMSO=二甲亞碸
DPPA=疊氮磷酸二苯酯
EDCI=1-乙基-3-(3-二甲基胺基丙基)碳二醯亞胺
EtOAc=乙酸乙酯
Fmoc=茀基甲氧基羰基
h=小時
HATU=o-(7-氮雜苯並三唑-1-基)-N,N,N',N'-四甲脲六氟磷酸鹽
HBTU=N,N,N',N'-四甲基-O-(1H-苯並三唑-1-基)脲六氟磷酸鹽
HOAc=乙酸
HOAt=1-羥基-7-氮雜苯並三唑
HOBt=氫化1-羥基苯並三唑
LDA=二異丙基醯胺鋰
Me=甲基
MS=分子篩
MTBE=甲基三級丁醚
n-BuLi=正丁基鋰
NBS=N-溴琥珀醯亞胺
NMM=N-甲基嗎啉
Ph=苯基
PPTS=對-甲苯磺酸吡錠
p-TsOH=對-甲苯磺酸
rt=室溫
TBAI=碘化四丁基銨
TEA=三乙胺
Tf=三氟甲烷磺酸鹽
TFA=TFA
THF=四氫呋喃
TPTU=O-(2-氧代-1(2H)吡啶基)-N,N,N,’N’-四甲脲四氟硼酸鹽
方案A:管柱:Waters Acquity UPLC HSS T3,2.1毫米x 50毫米,C18,1.7微米;移動相A:在水中的0.1%甲酸(v/v);移動相B:在乙腈中的0.1%甲酸(v/v);梯度:
5% B經0.1分鐘,5%至95% B經2.5分鐘,95% B經0.35分鐘;流速:1.25毫升/分鐘。溫度:60℃;偵測:200-450奈米;MS(+)範圍100-2000道耳頓;注射體積:5微升;儀器:Waters Acquity。
方案B:管柱:Waters Acquity UPLC HSS T3,C18,2.1 x 50毫米,1.7微米;移動相A:在水中的0.1%甲酸(v/v);移動相B:在乙腈中的0.1%甲酸(v/v);梯度:5% B經0.1分鐘,5%至95% B經1.5分鐘,95% B經0.35分鐘;流速:1.25毫升/分鐘。溫度:60℃;偵測:200-450奈米;MS(+)範圍100-2000道耳頓;注射體積:5微升;儀器:Waters Acquity。
方法A:管柱:Phenomenex Luna phenylhexyl 150 x 21.2毫米,5微米;移動相A:在水中的0.02% TFA(v/v);移動相B:在乙腈中的0.02% TFA(v/v);梯度:20% B經1.5分鐘,20% B至100% B經8.5分鐘,接著100% B經2.0分鐘;流速:27毫升/分鐘。溫度:未經控制;偵測:DAD 210-360奈米;MS(+)範圍150-2000道耳頓;儀器:305 RP Waters Fractional Lynx LCMS
方法B:管柱:Phenomenex Luna C18,100 x 30毫米,5微米;移動相A:在水中的0.02% TFA(v/v);移動相B:在乙腈中的0.02% TFA(v/v);梯度:20% B經1.5分鐘,20% B至100% B經8.5分鐘,接著95% B經2.0分鐘;
流速:30毫升/分鐘。溫度:未經控制;偵測:UV 215奈米;儀器:Gilson
方法C:Phenomenex Luna C18,100 x 30毫米,5微米;移動相A:在水中的0.02% TFA(v/v);移動相B:在乙腈中的0.02% TFA(v/v);梯度:可變式,經10至20分鐘增加在A中的B之梯度。流速:27至30毫升/分鐘。溫度:未經控制;偵測:UV 215奈米;儀器:Gilson
通用程序A:將草醯氯(1-2.5當量)添加至0℃下在THF、二氯甲烷或二者之混合物中的單或二酸之攪拌溶液中,接著添加催化量的DMF。容許反應在0℃下攪拌數分鐘,然後容許溫熱至室溫且接著在室溫下攪拌30分鐘至數小時。接著將反應在真空中濃縮。在一些例子中,接著將粗製材料與庚烷或其他相關溶劑或溶劑類共沸一至數次。接著將粗製材料經高壓乾燥,然後用於下一步驟中。
通用程序B:將醯氯或二醯氯添加至0℃下在THF、二氯甲烷或二者之混合物中(或在一些例子中以其他相關溶劑或溶劑類)的胺(2-2.5當量)之攪拌溶液中,接著添加吡啶(3-6當量)、三乙胺(3-6當量)或其他相關鹼(3-6當量)。容許反應在0℃下攪拌幾秒鐘至數分鐘,然後容許溫熱至室溫且接著在室溫下攪拌10分鐘至數小時。接著將反應在真空中濃縮。在一些例子中,接著將粗製材料與庚烷或其他相關溶劑或溶劑類共沸一至數次。在一些例子
中,接著將粗製材料以所述方法純化,諸如二氧化矽層析術或中壓反相C18層析術。
步驟1:(S)-8-(氯甲基)-4-羥基-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-羧酸三級丁酯(2)之合成:將10% Pd/C(33毫克)添加至THF(1.5毫升)中的(8S)-4-(苯甲氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-羧酸三級丁酯(1)[如J.Am.Chem.Soc.,2007,129,14092-14099中所述而製得](100毫克,0.225毫莫耳)之攪拌溶液中,接著添加25%甲酸銨水溶液(0.15毫升)。將溶液攪拌2小時。將溶液以醚(6毫升)稀釋且添加硫酸鈉。將混合物經由矽藻土過濾且在真空中移除溶劑,以提供成為白色固體的所欲產物2(79毫克,100%)。
步驟2:(S)-4-乙醯氧基-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-羧酸三級丁酯(3)之合成:將(S)-8-(氯甲基)-4-羥基-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-羧酸三級丁酯(2.69毫克,0.19毫莫耳)溶解在CH2Cl2
(2毫升)中。添加吡啶(46毫克,0.585毫莫耳)。添加乙醯氯(16毫升,0.234毫莫耳)且將反應攪拌2小時。在真空中移除溶劑。將粗製殘餘物以快速層析術(0-100% EtOAc/庚烷)純化,以提供所欲產物(45毫克,58%)。
步驟3:乙酸(S)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-酯(4)之合成:將(S)-4-乙醯氧基-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-羧酸三級丁酯(3)(45毫克,0.11毫莫耳)溶解在二噁烷(1毫升)中。添加在二噁烷中的4N HCl(1毫升)且將溶液攪拌2小時。移除溶液以提供定量產率之粗製標的材料且立即使用原樣子的該材料。
將雙環[1.1.1]庚烷-1,3-二羧酸(50毫克)放入小瓶中且溶解在THF(1毫升)且添加1滴DMF。緩慢地添加草二醯氯(122毫克,0.961毫莫耳,0.0825毫升)且使溶液快速起泡。在2小時之後,移除溶劑且以二醯氯6的原樣子用於後續反應中。
步驟1:二乙酸(8S,8'S)-(雙環[1.1.1]庚烷-1,3-二羰基)雙(8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6,4-二基)酯(7):標題化合物係依照通用程序B使用4(20.0毫克,0.060毫莫耳)、6(5.81毫克,0.0301毫莫耳,0.0301毫升,在THF中的1M)、吡啶(14.3毫克,0.181毫莫耳)及THF(1.0毫升)而製得,且將材料以中壓反相C18層析術(梯度:在水中的0%至80%乙腈,在各相中具有0.02% TFA)純化,以提供所欲產物7(8.0毫克,20%)。LC-MS(方案B):m/z 711.3[M+H]+,滯留時間=1.12分鐘。
步驟1:(R)-8-(氯甲基)-4-羥基-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-羧酸三級丁酯(9)之合成:將10% Pd/C(33毫克)添加至THF(1.5毫升)中的(8R)-4-(苯甲氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-
羧酸三級丁酯(8)[如J.Am.Chem.Soc.,2007,129,14092-14099中所述而製得](100毫克,0.225毫莫耳)之攪拌溶液中,接著添加25%甲酸銨水溶液(0.15毫升)。將溶液攪拌2小時。將溶液以醚(6毫升)稀釋且添加硫酸鈉。將混合物經由矽藻土過濾且在真空中移除溶劑,以提供成為白色固體的所欲產物9(79毫克,100%)。
步驟2:(R)-4-乙醯氧基-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-羧酸三級丁酯(10)之合成:將(R)-8-(氯甲基)-4-羥基-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-羧酸三級丁酯(2)(69毫克,0.19毫莫耳)溶解在CH2Cl2(2毫升)中。添加吡啶(46毫克,0.585毫莫耳)。添加乙醯氯(16毫升,0.234毫莫耳)且將反應攪拌2小時。在真空中移除溶劑。將粗製殘餘物以快速層析術(0-100% EtOAc/庚烷)純化,以提供所欲產物10(53毫克,69%)。
步驟3:乙酸(R)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-酯(11)之合成:將(R)-4-乙醯氧基-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-羧酸三級丁酯(10)(53毫克,0.13毫莫耳)溶解在二噁烷(1毫升)中。添加在二噁烷中的4N HCl(1毫升)且將溶液攪拌2小時。移除溶液以提供定量產率之粗製標的產物且立即以其原樣子用於二乙酸(8R,8'R)-(雙環[1.1.1]庚烷-1,3-二羰基)雙(8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6,4-二基)酯(11)之製備。
步驟1:二乙酸(8R,8'R)-(雙環[1.1.1]庚烷-1,3-二羰基)雙(8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6,4-二基)酯(12)之合成:標題化合物係依照通用程序B使用11(20.0毫克,0.060毫莫耳)、6(5.81毫克,0.0301毫莫耳,0.0301毫升,在THF中的1M)、吡啶(14.3毫克,0.181毫莫耳)及THF(1.0毫升)而製得,且使用中壓反相C18層析術(梯度:在水中的0%至80%乙腈,在各相中具有0.02% TFA)純化,以提供所欲產物12(5.9毫克,14%)。LC-MS(方案B):m/z 711.2[M+H]+,滯留時間=1.12分鐘。
步驟1:(S)-8-(氯甲基)-4-羥基-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-6-羧酸三級丁酯(14)之合成:將(S)-4-(苯甲氧基)-8-(氯甲基)-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-6-羧酸三級丁酯(13)[如J.Am.Chem.Soc.,2007,129,14092-14099中所述而製得](250毫克,0.563毫莫耳)溶解在THF(5.63毫升)中。添加10% Pd/C(80毫克)。添加新鮮製得的25%水性甲酸銨鹽(500毫克,2毫莫耳,0.5毫升)且將反應攪拌30分鐘。將反應混合物以醚(15毫升)稀釋且添加Na2SO4。將溶液經由矽藻土過濾且在真空中移除溶劑,以提供標題化合物14(191毫克,95%)。
步驟2:(S)-4-乙醯氧基-8-(氯甲基)-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-6-羧酸三級丁酯(15)之合成:將(S)-8-(氯甲基)-4-羥基-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-6-羧酸三級丁酯(14,171毫克,0.483毫莫耳)溶解在CH2Cl2(5.0毫升)中。添加吡啶(213毫克,2.69毫莫耳),接著添加乙醯氯(114毫克,1.45毫莫耳)。將反應攪拌隔夜且溶液轉變成橘/棕色。在真空中移除溶劑以留下橘色粗製固體。將粗製殘餘物以快速層析術(0-100% EtOAc/庚烷)純化,在移除溶劑之後提供所欲產物15(171.0毫克,89.4%)。
步驟3:乙酸(S)-8-(氯甲基)-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-4-酯(16)之合成:將(S)-4-乙醯氧基-8-(氯甲基)-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-6-羧酸三級丁酯(15,20毫克,0.051毫莫耳)溶解在二噁烷中的4N
HCl(1毫升)中。容許反應放置隔夜且移除溶劑,以提供定量產率之粗製標的材料16且立即使用該材料。
步驟1:二乙酸雙環[1.1.1]庚-1,3-二基雙[羰基(8S)-8-(氯甲基)-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-6,4-二基]酯(17)之合成:標題化合物係依照通用程序B使用16(17毫克,0.051)、6(4.94毫克,0.026毫莫耳,0.0301毫升,在THF中的1M)、吡啶(14.3毫克,0.181毫莫耳)及THF(1.0毫升)而製得,且使用中壓反相C18層析術(梯度:在水中的0%至80%乙腈,在各相中具有0.02% TFA)純化,以提供所欲產物17(10.0毫克,27%)LC-MS(方案B):m/z 711.1[M+H]+,滯留時間=1.12分鐘。
步驟1:(R)-8-(氯甲基)-4-羥基-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-6-羧酸三級丁酯(19)之合成:將(R)-4-(苯甲氧基)-8-(氯甲基)-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-6-羧酸三級丁酯(18)[如J.Am.Chem.Soc.,2007,129,14092-14099中所述而製得](250毫克,0.563毫莫耳)溶解在THF(5.63毫升)中。添加10% Pd/C(80毫克)。添加新鮮製得的25%水性甲酸銨鹽(500毫克,2毫莫耳,0.5毫升)且將反應攪拌30分鐘。將反應混合物以醚(15毫升)稀釋且添加Na2SO4。將溶液經由矽藻土過濾且在真空中移除溶劑,以留下白色粗製固體19(156毫克,78%)。
步驟2:(R)-4-乙醯氧基-8-(氯甲基)-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-6-羧酸三級丁酯(20)之合成:將(R)-8-(氯甲基)-4-羥基-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-6-羧酸三級丁酯(19,136毫克,0.384毫莫耳)溶解在DCM(5.0毫升)中。添加吡啶(213毫克,2.69毫莫耳),接著添加乙醯氯(114毫克,1.45毫莫耳)。將反應攪拌隔夜且溶液轉變成橘/棕色。在真空中移除溶劑以留下橘色粗製固體。將粗製殘餘物以快速層析術(0-100% EtOAc/庚烷)純化,在移除溶劑之後提供所欲產物20(113.0毫克,
74%)。
步驟3:乙酸(R)-8-(氯甲基)-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-4-酯(21)之合成:將(R)-4-乙醯氧基-8-(氯甲基)-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-6-羧酸三級丁酯(20,25毫克,0.051毫莫耳)溶解在二噁烷中的4N HCl(1毫升)中。容許反應放置隔夜且移除溶劑,以提供定量產率之粗製標的材料21且立即使用該材料。
步驟1:二乙酸雙環[1.1.1]庚-1,3-二基雙[羰基(8R)-8-(氯甲基)-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-6,4-二基]酯(22)之合成:標題化合物係依照通用程序B使用21(17毫克,0.051毫莫耳)、6(4.94毫克,0.026毫莫耳,0.0301毫升,在THF中的1M)、吡啶(14.3毫克,0.181毫莫耳)及THF(1.0毫升)而製得,且使用中壓反相C18層析術(梯度:在水中的0%至80%乙腈,在各相中具有0.02% TFA)純化,以提供所欲產物22(8.6毫克,19%)LC-MS(方案B):m/z 711.1[M+H]+,滯留時間=1.12分
鐘。
步驟1:二乙酸(8S,8'S)-戊二醯基雙(8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6,4-二基)酯(24)之合成:將3(10毫克,0.025毫莫耳)之溶液在室溫下以4M HCl(二噁烷中0.5毫升)處理1小時且在真空中濃縮。將殘餘物溶解在THF(2毫升)中且添加戊二醯氯(2.13毫克,0.0125毫莫耳),接著添加DIPEA(13微升,0.074毫莫耳)。將所得混合物在室溫下攪拌30分鐘。將反應混合物濃縮且將殘餘物以使用MeOH/DCM(0-10%)之矽膠層析術純化,以給出成為灰白色固體的產物,將其以MeOH處理,過濾,以給出成為灰白色固體的6毫克(70%)產物24。LC-MS(方案B):m/z 687.1[M+H]+,滯留時間=1.11分鐘。
1H NMR(400MHz,CDCl3)δ=8.24(s,2H),7.13(s,2H),4.36(d,J=10.5Hz,2H),4.17(m,2H),4.06(m,2H),3.74(d,J=10.9Hz,2H),3.39(t,J=10.9Hz,2H),2.80
(m,2H),2.66(m,2H),2.55(s,6H),2.37(s,6H),2.22(m,2H)。
步驟1:二乙酸(8R,8'R)-戊二醯基雙(8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6,4-二基)酯(25)之合成:將10(10毫克,0.025毫莫耳)之溶液在室溫下以4M HCl(二噁烷中的0.5毫升)處理1小時且在真空中濃縮。將殘餘物溶解在THF(2毫升)中且添加戊二醯氯(2.13毫克,0.0125毫莫耳),接著添加吡啶(12毫克,0.15毫莫耳)。將所得混合物在室溫下攪拌4小時,在真空中濃縮且將殘餘物以反相HPLC純化(方法C),以給出成為灰白色固體的1.5毫克(17%)產物25。LC-MS(方案B):m/z 687.1[M+H]+,,滯留時間=1.11。
1H NMR(400MHz,CDCl3)δ=8.24(s,2H),7.13(s,2H),4.37(d,J=10.5Hz,2H),4.18(m,2H),4.06(m,2H),3.73(d,J=10.9Hz,2H),3.39(t,J=10.9Hz,2H),2.77(m,2H),2.66(m,2H),2.55(s,6H),2.37(s,6H),2.22(m,
2H)。
步驟1:二乙酸(8S,8'S)-戊二醯基雙(8-(氯甲基)-2-甲基-7,8-二氫-6H-噻吩並[2,3-e]吲哚-6,4-二基)酯(26):將15(12毫克,0.03毫莫耳)之溶液在室溫下以4M HCl(二噁烷中的0.5毫升)處理1小時且在真空中濃縮。將殘餘物溶解在THF(2毫升)中且添加戊二醯氯(2.5毫克,0.015毫莫耳),接著添加DIPEA(16微升,0.09毫莫耳)。將所得混合物在室溫下攪拌30分鐘,在真空中濃縮且將殘餘物以使用MeOH/DCM(0-10%)之ISCO純化,以給出成為灰白色固體的6毫克(60%)產物26:LC-MS(方案B):m/z 687.1[M+H]+,滯留時間=1.11。
1H NMR(400MHz,CDCl3)δ=8.12(s,2H),6.84(s,2H),4.32(m,2H),4.2(m,2H),4.05(d,J=10.9Hz,2H),3.93(m,2H),3.62(m,2H),2.68(br.s.,4H),2.56(s,6H),2.37(s,6H),2.19(br.s.,2H)。
步驟1:(8S)-8-(氯甲基)-4-羥基-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-羧酸三級丁酯(2)之合成:將10重量%之鈀/碳(250毫克)添加至0℃下在18毫升THF中的(8S)-4-(苯甲氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-羧酸三級丁酯1[如J.Am.Chem.Soc.,2007,129,14092-14099中所述而製得](575毫克,1.30毫莫耳)之攪拌溶液中,接著緩慢地逐滴添加2.0毫升在水中的25%甲酸銨。容許反應在0℃下攪拌~90分鐘。將反應以醚稀釋,接著添加硫酸鈉。將反應經由矽藻土薄墊過
濾,接著將其以醚清洗兩次。將有機物合併且接著濃縮,然後放置在真空下,得到成為灰白色固體的2(458毫克,定量)。LC-MS(方案A):m/z 352.2[M-H],滯留時間=1.96分鐘。
步驟2:乙酸(8S)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-酯(4)之合成:將乙醯氯(0.0462毫升,0.650毫莫耳)添加至0℃下在8毫升二氯甲烷的2(209毫克,0.591毫莫耳)之攪拌溶液中,接著立即添加吡啶(0.0714毫升,0.886毫莫耳)。容許反應在0℃下攪拌~10分鐘。將反應在二氧化矽上濃縮。接著進行二氧化矽層析術(梯度:在庚烷中的0%-15%丙酮)。在適當的試驗管中濃縮且放置在真空下以產生白色固體。將二噁烷中的4M HCl(10毫升,40毫莫耳)添加至此白色固體中且容許反應在室溫下攪拌~90分鐘。將反應以庚烷稀釋,在真空中濃縮且接著放置在真空下以產生成為淺橘色固體的4(170毫克,80%產率,2個步驟)。LC-MS(方案A):m/z 296.1[M+H]+,滯留時間=1.56分鐘。1H NMR(400MHz,DMSO-d 6 ):δ 7.53(s,1H),7.05(s,1H),4.27-4.19(m,1H),3.93-3.86(m,1H),3.80-3.75(m,1H),3.72-3.64(m,2H),2.54(s,3H),2.37(s,3H)。
步驟3:3-(氯羰基)雙環[1.1.1]庚烷-1-羧酸甲酯(28)之合成:依照通用程序A使用3-(甲氧基羰基)雙環[1.1.1]庚烷-1-羧酸27(86.8毫克,0.510毫莫耳)、草醯氯(0.0525毫升,0.612毫莫耳)、THF(6毫升)及1滴DMF製得成為
白色固體的28(97毫克,定量)。使用未進一步純化的粗製物28原樣子。
步驟4:(8S)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基磷酸二苯甲酯(29)之合成:將四氯化碳(0.997毫升,10.3毫莫耳)添加至8毫升THF及8毫升乙腈中的2(4.5克,13.4毫莫耳)之攪拌溶液中,接著添加胡尼格氏鹼(0.512毫升,2.94毫莫耳)、亞磷酸二苯甲酯(0.974毫升,4.41毫莫耳)及DMAP(18毫克,0.147毫莫耳)。容許反應在室溫下攪拌~10分鐘。將反應在二氧化矽上濃縮。接著進行二氧化矽層析術(梯度:在庚烷中的0%-25%丙酮)。在適當的試驗管中濃縮且放置在真空下以產生白色固體。將粗製材料溶解在5毫升二氯甲烷中,接著添加三氟乙酸(5毫升,70毫莫耳)。容許反應在室溫下攪拌60秒,立即在真空中濃縮且接著放置在高真空下以產生成為白色且透明的油與固體混合物29(321毫克,70%產率,2個步驟)。LC-MS(方案A):m/z 514.1[M+H]+,滯留時間=2.14分鐘。
步驟5:3-{[(8S)-4-{[雙(苯甲氧基)磷醯基]氧基}-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基]羰基}雙環[1.1.1]庚烷-1-羧酸(30)之合成:依照通用程序B使用29(315毫克,0.502毫莫耳)、28(94.6毫克,0.502毫莫耳)、三乙胺(0.210毫升,1.50毫莫耳)及THF(20毫升),且使用矽膠層析術(梯度:在庚烷中的0%至35%丙酮)純化。在適當的試驗管中組合且在真空中濃縮以產生
白色固體。將材料溶解在THF(10毫升)中,接著添加溶解在2.5毫升水中的氫氧化鋰。容許反應在室溫下攪拌~45分鐘。將反應以二氯甲烷稀釋且經由添加1N HCl(水性)而淬滅。將反應轉移至分液漏斗中。將有機層分離且將水層以二氯甲烷清洗兩次。將有機層合併,以食鹽水清洗一次,以水清洗一次,經硫酸鈉乾燥,過濾,在真空中濃縮且接著放置在高真空下以產生30(178毫克,57%產率,2個步驟)。LC-MS(方案A):m/z 652.2[M+H]+,滯留時間=1.97分鐘。
步驟6:(8S)-6-{[3-(氯羰基)雙環[1.1.1]戊-1-基]羰基}-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基磷酸二苯甲酯(31)之合成:依照通用程序A使用30(174毫克,0.267毫莫耳)、草醯氯(0.0298毫升,0.347毫莫耳)、THF(5毫升)、二氯甲烷(1毫升)及1滴DMF製得成為白色固體的31(182毫克,定量)。使用未進一步純化的粗製物31原樣子。
步驟7:乙酸(8S)-6-[(3-{[(8S)-4-{[雙(苯甲氧基)磷醯基]氧基}-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基]羰基}雙環[1.1.1]戊-1-基)羰基]-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-酯(32)之合成:依照通用程序B使用31(167毫克,0.249毫莫耳)、4(99.3毫克,0.299毫莫耳)、三乙胺(0.104毫升,0.747毫莫耳)及THF(20毫升),且使用矽膠層析術(梯度:在庚烷中的0%至50%丙酮)純化。在適當的試驗管中組合且在真空中濃
縮以產生白色固體的32(103毫克,45%)。LC-MS(方案A):m/z 929.3[M+H]+,滯留時間=2.44分鐘。1H NMR(400MHz,DMSO-d6):δ 8.37(s,1H),8.09(s,1H),7.54-7.50(m,2H),7.39-7.33(m,10H),5.23-5.14(m,4H),4.53-4.46(m,2H),4.38-4.25(m,4H),4.02-3.95(m,2H),3.78-3.69(m,2H),2.63(s,6H),2.57-2.53(m,6H),2.39(s,3H)。
步驟8:4-硝苯基碳酸(8S)-8-(氯甲基)-6-[(3-{[(8S)-8-(氯甲基)-1-甲基-4-(膦醯氧基)-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基]羰基}雙環[1.1.1]戊-1-基)羰基]-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-酯(33)之合成:將二噁烷中的4M HCl(6.0毫升,20毫莫耳)添加至6毫升甲醇中的32(99毫克,0.11毫莫耳)之攪拌溶液中。容許反應在室溫下攪拌~15分鐘。將反應濃縮且接著放置在高真空下。將6毫升二氯甲烷及6毫升THF中的粗製材料在0℃下添加至粗製材料之攪拌溶液中,添加氯甲酸對-硝苯酯(38.6毫克,0.192毫莫耳),接著立即添加三乙胺(0.0742毫升,0.532毫莫耳)。容許反應在0℃下攪拌~5分鐘且接著容許溫熱至室溫,同時攪拌。容許反應在室溫下攪拌~10分鐘。將反應濃縮。將3毫升二氯甲烷中的TFA(3,0毫升,39毫莫耳)之溶液添加至3毫升二氯甲烷中的粗製材料之攪拌溶液中,接著添加噻吩(0.109毫升,1.06毫莫耳)。容許反應在室溫下攪拌~6小時。將反應濃縮。將粗製材料以幾毫升DMSO稀釋且接著注射在25克C18前置
管柱上(其事先以乙腈及接著以水平衡,在各相中具有0.02% TFA)。將材料以中壓反相C18層析術(梯度:在水中的20%至65%乙腈,在各相中具有0.02% TFA)純化,以適當的試驗管使用genevac濃縮以產生成為白色固體的33(37毫克,40%,3個步驟)。LC-MS(方案A):m/z 872.3[M+H]+,滯留時間=1.86分鐘。1H NMR(400MHz,DMSO-d6):δ 8.44(s,1H),8.40-8.33(m,3H),7.78-7.72(m,2H),7.59(m,1H),7.47(m,1H),4.53-4.44(m,2H),4.38-4.22(m,4H),4.04-3.94(m,2H),3.81-3.75(m,1H),3.72-3.65(m,1H),2.62(s,6H),2.58(s,3H),2.54(s,3H)。
步驟1:N-[1-(2,5-二氧代-2,5-二氫-1H-吡咯-1-基)-21-氧代-3,6,9,12,15,18-六氧雜二十一烷-21-基]-L-纈胺醯基-N~5~-胺甲醯基-N-[4-(羥基甲基)苯基]-L-鳥胺酸醯胺(36)之合成:將1-(2,5-二氧代-2,5-二氫-1H-吡咯-1-基)-3,6,9,12,15,18-六氧雜二十一-21-酸,34(628毫克,1.45毫莫耳)、20毫升二氯甲烷、2毫升DMF、HATU(501毫克,1.32毫莫耳)及胡尼格氏鹼(0.92毫升,5.3毫莫耳)添加至圓底燒瓶中。容許反應在室溫下攪拌2分鐘,然後添加L-纈胺醯基-N~5~-胺甲醯基-N-[4-(羥基甲
基)苯基]-L-鳥胺酸醯胺,35(500毫克,1.32毫莫耳)。容許反應在室溫下攪拌~90分鐘,然後經由添加TFA而淬滅。將反應濃縮至較少的體積,以幾毫升DMSO稀釋且接著注射在25克C18前置管柱上(其事先以乙腈及接著以水平衡,在各相中具有0.02% TFA)。將材料以中壓反相C18層析術(梯度:在水中的5%至40%乙腈,在各相中具有0.02% TFA)純化,以適當的試驗管使用genevac濃縮以產生成為透明固體的36(514毫克,49%)。LC-MS(方案A):m/z 795.5[M+H]+,滯留時間=1.01分鐘。
步驟2:N-[1-(2,5-二氧代-2,5-二氫-1H-吡咯-1-基)-21-氧代-3,6,9,12,15,18-六氧雜二十一烷-21-基]-L-纈胺醯基-N~5~-胺甲醯基-N-[4-({[(4-硝基苯氧基)羰基]氧基}甲基)苯基]-L-鳥胺酸醯胺(37)之合成:將胡尼格氏鹼(0.096毫升,0.554毫莫耳)添加至4毫升DMF中的36(210毫克,0.264毫莫耳)及碳酸雙(4-硝苯基)酯(161毫克,0.528毫莫耳)之攪拌溶液中。容許反應在室溫下攪拌~2小時。將反應注射在25克C18前置管柱上(其事先以乙腈及接著以水平衡,在各相中具有0.02% TFA)。將材料以中壓反相C18層析術(梯度:在水中的5%至55%乙腈,在各相中具有0.02% TFA)純化,以適當的試驗管使用genevac濃縮以產生成為固體的37(180毫克,71%)。LC-MS(方案A):m/z 960.5[M+H]+,滯留時間=1.48分鐘。
步驟3:N-[1-(2,5-二氧代-2,5-二氫-1H-吡咯-1-基)-21-氧代-3,6,9,12,15,18-六氧雜二十一烷-21-基]-L-纈胺醯
基-N~5~-胺甲醯基-N-[4-(4,7,10,10-四甲基-3,8-二氧代-2,9-二氧雜-4,7-二氮雜十一烷-1-基)苯基]-L-鳥胺酸醯胺(39)之合成:將2,6-二甲基吡啶(0.154毫升,1.33毫莫耳)添加至6毫升DMA中的37(640毫克,0.667毫莫耳)及38[如J.Med.Chem.1992,33,559-567中所述而製得](127毫克,0.674毫莫耳)之攪拌溶液中,接著添加胡尼格氏鹼(0.232毫升,1.33毫莫耳)及HOAT(9.1毫克,0.67毫莫耳)。容許反應在室溫下攪拌~15分鐘。將反應注射在25克C18前置管柱上(其事先以乙腈及接著以水平衡,在各相中具有0.02% TFA)。將材料以中壓反相C18層析術(梯度:在水中的5%至40%乙腈,在各相中具有0.02% TFA)純化,以適當的試驗管使用genevac濃縮以產生成為似臘的白色固體39(564毫克,84%)。LC-MS(方案A):m/z 1009.7[M+H]+,滯留時間=1.43分鐘。
步驟4:N-[1-(2,5-二氧代-2,5-二氫-1H-吡咯-1-基)-21-氧代-3,6,9,12,15,18-六氧雜二十一烷-21-基]-L-纈胺醯基-N~5~-胺甲醯基-N-{4-[({甲基[2-(甲基胺基)乙基]胺甲醯基}氧基)甲基]苯基}-L-鳥胺酸醯胺(40)之合成:將TFA(3.0毫升,40毫莫耳)添加至6毫升二氯甲烷中的39(470毫克,0.466毫莫耳)之攪拌混合物中。容許反應在室溫下攪拌~10分鐘。將反應濃縮。將殘餘物以中壓反相C18層析術(梯度:在水中的5%至30%乙腈,在各相中具有0.02% TFA)純化,以適當的試驗管使用genevac濃縮以產生成為白色油/固體混合物的40(326毫克,68%)。LC-MS
(方案A):m/z 909.8[M+H]+,滯留時間=0.91分鐘。
步驟1:N-[1-(2,5-二氧代-2,5-二氫-1H-吡咯-1-基)-21-氧代-3,6,9,12,15,18-六氧雜二十一烷-21-基]-L-纈胺醯基-N~5~-胺甲醯基-N-[4-({[(2-{[({(8S)-8-(氯甲基)-6-[(3-{[(8S)-8-(氯甲基)-1-甲基-4-(膦醯氧基)-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基]羰基}雙環[1.1.1]戊-1-基)羰基]-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基}氧基)羰基](甲基)胺基}乙基)(甲基)胺甲醯基]氧基}甲基)苯基]-L-鳥胺酸醯胺
(41)之合成:將1.0毫升DMA添加至含有33(8.0毫克,0.0092毫莫耳)及40(10.3毫克,0.0101毫莫耳)之2打蘭(dram)小瓶中,接著添加胡尼格氏鹼(0.00639毫升,0.0367毫莫耳)、2,6-二甲基吡啶(0.00425毫升,0.0367毫莫耳)及HOAT(1.25毫克,0.0367毫莫耳)。容許反應在室溫下攪拌~5分鐘。將反應粗製物注射在4克C18前置管柱上(其事先以乙腈及接著以水平衡,在各相中具有0.02% TFA)。將材料以中壓反相C18層析術(梯度:在水中的15%至50%乙腈,在各相中具有0.02% TFA)純化,接著以方法A二次純化,以適當的試驗管使用genevac濃縮以產生成為白色固體的41(8.9毫克,59%)。LC-MS(方案A):m/z 1642.9[M+2H]+,滯留時間=1.61分鐘。
步驟1:5-氯-5-氧代戊酸三級丁酯(44)之製備:將草醯氯(0.58毫升,1.2毫莫耳,在DCM中的2M)在0℃下添加至THF(3毫升)中的5-(三級丁氧基)-5-氧代戊酸(110毫克,0.58毫莫耳)之溶液中,接著添加1滴DMF。將混合物在0℃下攪拌30分鐘且在真空中濃縮,以給出成為白色固體的對應之醯氯44。
步驟2:三乙酸(2S,3R,4S,5S,6S)-2-(((S)-6-(三級丁氧基羰基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)-6-(甲氧基羰基)四氫-2H-吡喃-3,4,5-三酯(43)之合成:將4A MS(1.17克,粉末,<5微米,經活化)添加至DCM(23毫升)中的2(226毫克,0.64毫莫耳)之溶液中且將混合物在室溫下攪拌30分鐘。將α-D-葡萄糖醛酸苷甲酯2,3,4-三乙酸酯1-2,2,2-三氯乙烷亞胺酸酯
(42,367毫克,0.77毫莫耳)添加至反應混合物中且將混合物冷卻至-25℃。緩慢地添加在DCM(10毫升)中的BF3.Et2O(0.13毫升,0.32毫莫耳)之溶液且將混合物在低於-20℃下攪拌1小時。將反應混合物過濾且將溶液在真空中濃縮。將殘餘物以使用在庚烷中的0-60% EtOAc梯度之矽膠層析術純化,以給出成為黃色固體的261毫克(61%)產物43。
LC-MS(方案B):m/z 692.1(M+Na),滯留時間=1.09分鐘。1H NMR(400MHz,氯仿-d)δ=7.29(s,1H),7.13(s,1H),5.40(br.s.,3H),4.30(d,J=7.4Hz,2H),4.06-3.92(m,2H),3.85-3.73(m,4H),3.69(d,J=10.5Hz,1H),3.36(t,J=10.5Hz,1H),2.56(s,3H),2.10(s,6H),2.08(s,3H),1.62(s,9H)。
步驟2:三乙酸(2S,3R,4S,5S,6S)-2-(((S)-6-(5-(三級丁氧基)-5-氧代戊醯基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)-6-(甲氧基羰基)四氫-2H-吡喃-3,4,5-三酯(45)之合成:將43(261毫克,0.39毫莫耳)之溶液以二噁烷中的4M HCl(3毫升)處理1小時。在真空中濃縮且將殘餘物溶解在THF(3.0毫升)中,添加在THF(3.0毫升)中的醯氯44(0.58毫莫耳)之溶液,接著添加TEA(0.163毫升,1.2毫莫耳)。將混合物在0℃下攪拌30分鐘。將混合物濃縮且將殘餘物以使用在庚烷中的EtOAc(0-70%)梯度之矽膠層析術純化,以給出成為灰白色固體的產物224毫克(78%)。LC-MS(方案B):m/z 740.2
[M+H]+,滯留時間=1.07分鐘。1H NMR(400MHz,氯仿-d)δ=8.26(br.s.,1H),7.13(s,1H),5.45-5.25(m,4H),4.32(d,J=9.0Hz,2H),4.12(t,J=8.8Hz,1H),4.05(d,J=8.6Hz,1H),3.79-3.66(m,5H),3.33(t,J=10.9Hz,1H),2.63(d,J=7.0Hz,1H),2.58-2.47(m,4H),2.45-2.35(m,2H),2.06(m,11H),1.47(s,9H)。
步驟3:三乙酸(2S,3R,4S,5S,6S)-2-(((S)-8-(氯甲基)-6-(5-((S)-8-(氯甲基)-4-羥基-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)-6-(甲氧基羰基)四氫-2H-吡喃-3,4,5-三酯(46)之合成:將45(116毫克,0.16毫莫耳)之溶液在室溫下以DCM(1.5毫升)及TFA(1毫升)處理1小時,在真空中濃縮且將殘餘物在0℃下溶解在THF中且添加草醯氯(0.16毫升,0.32毫莫耳,在DCM中的2M)及DMF(1滴)。將混合物在0℃下攪拌30分鐘且在真空中濃縮,以給出對應之醯氯。
在分液漏斗中,將化合物2(83毫克,0.24毫莫耳)在室溫下以二噁烷中的4M HCl(2毫升)處理1小時且在真空中濃縮,將殘餘物在0℃下溶解在THF(5毫升)中且添加Et3N(100微升,0.78毫莫耳),接著添加在THF(5毫升)中的上述醯氯之溶液。將混合物在0℃下攪拌20分鐘。將混合物濃縮且將殘餘物以使用在庚烷中的EtOAc(0-100%)梯度之矽膠層析術純化,以給出成為灰白色固體的114毫克(79%)產物46。LC-MS(方案B):m/z 919.1
[M+H]+,滯留時間=1.05分鐘,1H NMR(400MHz,DMSO-d6)δ=10.41(s,1H),8.22(s,1H),7.93(s,1H),7.47(s,1H),7.38(s,1H),5.81-5.70(m,4H),5.63-5.52(m,1H),5.19(t,J=8.6Hz,1H),5.12(t,J=9.8Hz,1H),4.76(d,J=9.8Hz,1H),4.30-4.16(m,3H),3.86(m,2H),3.68(s,3H),3.64-3.51(m,2H),2.73(br.s.,1H),2.62(m,2H),2.50(s,6H),2.10-2.02(m,12H)。
步驟4:三乙酸(2S,3R,4S,5S,6S)-2-(((S)-6-(5-((S)-4-(((2-((三級丁氧基羰基)(甲基)胺基)乙基)(甲基)胺甲醯基)氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)-6-(甲氧基羰基)四氫-2H-吡喃-3,4,5-三酯(47)之合成:將DCM(0.5毫升)中的氯甲酸4-硝苯酯(22毫克,0.10毫莫耳)之溶液添加至0℃下在THF(3毫升)中的46(50毫克,0.054毫莫耳)之溶液中,接著添加DIPEA(57微升,0.33毫莫耳),且將混合物在0℃下攪拌1小時。將THF(0.5毫升)中的38T[如J.Med.Chem.1992,33,559-567所述而製得](31毫克,0.16毫莫耳)之溶液添加至上述混合物中,將混合物在0℃下攪拌30分鐘且在真空中濃縮,且將殘餘物以使用在庚烷中的EtOAc(0-100%)梯度之矽膠層析術純化,以給出成為白色固體的56毫克(91%)產物47。LC-MS(方案B):m/z 1150.2[M+NH4],滯留時間=1.14分鐘。
步驟5:(2S,3S,4S,5R,6S)-6-(((S)-6-(5-((S)-4-(((2-
((三級丁氧基羰基)(甲基)胺基)乙基)(甲基)胺甲醯基)氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)-3,4,5-三羥基四氫-2H-吡喃-2-羧酸(48)之合成:將水(0.5毫升)中的LiOH.H2O(21毫克,0.49毫莫耳)之溶液添加至0℃下在THF/MeOH(1/1,6毫升)中的47(56毫克,0.049毫莫耳)之溶液中。將混合物在0℃下攪拌1小時。添加乙酸(50毫克)且將反應在真空中濃縮,以給出成為白色固體的45毫克(90%)粗製產物48。LC-MS(方案B):m/z 1014.9[M+Na],滯留時間=1.0分鐘。
步驟6:(2S,3S,4S,5R,6S)-6-(((S)-8-(氯甲基)-6-(5-((S)-8-(氯甲基)-4-(((2-((((4-((23S,26S)-1-(2,5-二氧代-2,5-二氫-1H-吡咯-1-基)-23-異丙基-21,24-二氧代-26-(3-脲丙基)-3,6,9,12,15,18-六氧雜-22,25-二氮雜二十七烷27-醯胺基)苯甲基)氧基)羰基)(甲基)胺基)乙基)(甲基)胺甲醯基)氧基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)-3,4,5-三羥基四氫-2H-吡喃-2-羧酸(49)及(8S)-8-(氯甲基)-6-{5-[(8S)-8-(氯甲基)-4-羥基-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基]-5-氧代戊醯基}-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基β-D-吡喃葡萄糖醛酸(57)之合成:將化合物48(23毫克,0.02毫莫耳)在0℃下以預冷卻之TFA(1毫升)處理5分鐘且在真空中濃縮。將殘餘物
溶解在DMF(2毫升)中且添加化合物37(19毫克,0.02毫莫耳)、二甲基吡啶(14微升,0.12毫莫耳)、DIPEA(21微升,0.12毫莫耳)及HOAt(2.7毫克,0.02毫莫耳),將混合物在30℃下攪拌1小時。將混合物以反相HPLC純化(方法C),以給出成為灰白色固體的8毫克(20%)化合物49:LC-MS(方案B):m/z 1714.6[M+H]+,滯留時間=0.89分鐘,及成為膠的7毫克(50%)化合物57:LC-MS(方案B):m/z 779.1[M+H]+,滯留時間=0.90分鐘。
步驟1:5-氯-5-氧代戊酸甲酯(51)之製備:將5-甲氧基-5-氧代戊酸(128毫克,0.88毫莫耳)在0℃下溶解在THF(5毫升)中且添加草醯氯(0.9毫升,1.8毫莫耳,在DCM中的2M)及DMF(1滴),且將混合物在0℃下攪拌30分鐘。在真空中濃縮,以給出成為白色固體的對應之醯氯51,其以未進一步純化而使用。
步驟2:(S)-4-((雙(苯甲氧基)磷醯基)氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-羧酸三級丁酯(50)之合成:將CCl4(1毫升)、DIPEA(0.52毫升,2.94
毫莫耳)、亞磷酸二苯酯(1.03毫升,4.41毫莫耳)及DMAP(18毫克)添加至ACN(8毫升)及THF(8毫升)中的2(260毫克,0.74毫莫耳)之溶液中。將混合物在室溫下攪拌15分鐘,在真空中濃縮。將殘餘物以使用在庚烷中的EtOAc(0-60%)梯度之矽膠層析術純化,以給出成為無色油的365毫克(81%)產物50。LC-MS(方案B):m/z 631.2[M+H]+,滯留時間=1.18分鐘。
步驟3:(S)-5-(4-((雙(苯甲氧基)磷醯基)氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊酸甲酯(52)之合成:將TFA(3毫升)添加至DCM(3毫升)中的50(365毫克,0.58毫莫耳)之溶液中,將混合物在室溫下攪拌2分鐘且在真空中濃縮。將殘餘物溶解在THF(5.0毫升)中,添加在THF(5.0毫升)中的醯氯51(0.88毫莫耳)之溶液中,接著添加Et3N(0.37毫升,0.24毫莫耳)且將混合物在0℃下攪拌30分鐘。將反應濃縮且將殘餘物以使用在庚烷中的EtOAc(0-80%)梯度之矽膠層析術純化,以給出成為無色油的240毫克(64%)產物52。LC-MS(方案B):m/z 642.1[M+H]+,滯留時間=1.09分鐘。
步驟4:(S)-5-(4-((雙(苯甲氧基)磷醯基)氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊酸(53)之合成:將水(2.5毫升)中的LiOH/H2O(155毫克,3.7毫莫耳)之溶液添加至0℃下T在HF(10毫升)中的52(235毫克,0.37毫莫耳)之溶液中且將混合物在0℃
下攪拌1.5小時。將混合物以DCM稀釋,以1M HCl酸化,將有機層分離且將水相以DCM萃取兩次。將合併的有機相經MgSO4乾燥。將混合物在真空中濃縮且將殘餘物以反相HPLC純化(方法C),以給出成為灰白色泡沫的27毫克(12%)產物53。LC-MS(方案B):m/z 628.1[M+H]+,滯留時間=1.01分鐘。
步驟5:((S)-8-(氯甲基)-6-(5-((S)-8-(氯甲基)-4-羥基-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)磷酸二苯甲酯(54)之合成:將草醯氯(0.043毫升,0.086毫莫耳,在DCM中的2M)及DMF(1滴)添加至0℃下在THF(5毫升)中的53(27毫克,0.043毫莫耳)之溶液中。將混合物在0℃下攪拌30分鐘且在真空中濃縮,以給出成為黃色泡沫的對應之醯氯。
在單獨的小瓶中,將化合物2(23毫克,0.064毫莫耳)在室溫下以4M HCl(1毫升)處理1小時且在真空中濃縮。將殘餘物溶解在THF(5毫升)中,冷卻至0℃且添加至THF(5毫升)中的上述醯氯之溶液及Et3N(0.018毫升,0.13毫莫耳)中。將混合物在真空中濃縮且將殘餘物以反相HPLC純化(方法C),以給出成為灰白色固體的28毫克(75%)產物54。LC-MS(方案B):m/z 863.2[M+H]+,滯留時間=1.16分鐘。
步驟6:(4-硝苯基)碳酸(S)-8-(氯甲基)-6-(5-((S)-8-(氯甲基)-1-甲基-4-(膦醯氧基)-7,8-二氫-6H-噻吩並[3,2-e]
吲哚-6-基)-5-氧代戊醯基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-酯(55)及磷酸二氫(8S)-8-(氯甲基)-6-{5-[(8S)-8-(氯甲基)-4-羥基-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基]-5-氧代戊醯基}-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-酯(61)之合成:將DCM(0.5毫升)中的氯甲酸4-硝苯酯(19.4毫克,0.092毫莫耳)之溶液及DIPEA(0.049毫升,0.28毫莫耳)添加至0℃下在THF(5毫升)中的54(40毫克,0.046毫莫耳)之溶液中。將混合物在0℃下攪拌30分鐘。將反應在真空中濃縮且將殘餘物以使用在庚烷中的丙酮(0-60%)梯度之矽膠層析術純化,以給出成為白色固體的48毫克中間物PNP碳酸酯。將其溶解在DCM(2毫升)中,添加TFA(2毫升)及噻吩(0.047毫升,0.46毫莫耳)且將混合物在室溫下攪拌3小時。將反應在真空中濃縮且將殘餘物以反相HPLC純化(方法C),以給出成為白色固體的17.8毫克(46%)之產物55(17.8毫克,46%):LC-MS(方案B):m/z 848.2[M+H]+,滯留時間=1.09分鐘,及成為膠的5.2毫克(17%)產物61:LC-MS(方案B):m/z 683.2[M+H]+,滯留時間=0.93分鐘。
步驟7:(4-((23S,26S)-1-(2,5-二氧代-2,5-二氫-1H-吡咯-1-基)-23-異丙基-21,24-二氧代-26-(3-脲丙基)-3,6,9,12,15,18-六氧雜-22,25-二氮雜二十七-27-醯胺基)苯甲基)乙-1,2-二基雙(甲基胺甲酸)(S)-8-(氯甲基)-6-(5-((S)-8-(氯甲基)-1-甲基-4-(膦醯氧基)-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-甲基-7,8-二氫-6H-噻吩並
[3,2-e]吲哚-4-酯(56)之合成:將40(13.9毫克,0.014毫莫耳)、二甲基吡啶(0.009毫升,0.074毫莫耳)、DIPEA(0.013毫升,0.074毫莫耳)及HOAt(1.7毫克,0.012毫莫耳)添加至DMF(1毫升)中的55(10.5毫克,0.012毫莫耳)之溶液中。將混合物在室溫下攪拌20分鐘,在真空中濃縮且將殘餘物以反相HPLC純化(方法C),以給出成為白色泡沫的12毫克(60%)產物56。LC-MS(方案B):m/z 1619.6[M+2H]+,滯留時間=0.95分鐘。
步驟1:二乙酸五環[4.2.0.0~2,5~.0~3,8~.0~4,7~]辛-1,4-二基雙[羰基(8S)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6,4-二基]酯(60)之合成:將3(47毫克,0.12毫莫耳)之溶液在室溫下以4M HCl(在二噁烷中的1.5毫升)處理90分鐘且在真空中濃縮,將殘餘物溶解在DCM(4毫升)及TEA(0.025毫升)中且添加至溶解在1毫
升無水二氯甲烷中的1,4-立方烷二羧酸(11.5毫克,0.06毫莫耳,72)之溶液中,接著添加HATU(47毫克,0.12毫莫耳)。將反應在室溫下攪拌16小時。將混合物以反相HPLC管柱純化:(Phenomenex Column Luna C18 5u 150 x 21.5毫米,梯度20%-90% AcCN/水(各者中具有0.02% AcOH)經20分鐘(加上以20% AcCN/水的最初6分鐘等位洗提時間),以供給3.1毫克60(白色固體,7%)。LC-MS(方案A):m/z:747.1(M+H)+,滯留時間=2.39分鐘。
步驟1:(S)-4-(苯甲氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚(63)之合成:將EtOAc中的4.0M HCl(5毫升)在0℃下逐滴添加無水DCM(5毫升)中的化合物1(300毫克,0.676毫莫耳)之攪拌溶液中。在添加之後,將混合物在室溫下攪拌1.5小時。將混合物在真空中濃縮,接著與DCM共蒸發一次,以給出產物63(260毫克,100%)且以其原樣子用於下一步驟。
步驟2:(S)-5-(4-(苯甲氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊酸三級丁酯
(63)之合成:將DCM中的25% TFA(10毫升)添加至含有(S)-4-(苯甲氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-羧酸三級丁酯(1)(500毫克,1.13毫莫耳)的圓底燒瓶中。將反應攪拌30分鐘。將反應濃縮且放置在真空下30分鐘,以給出去boc之殘餘物63,將其溶解在5毫升DCM中且用於以下步驟中。
將草醯氯(0.101毫升,1.13毫莫耳)添加至含有在5毫升無水DCM中的5-(三級丁氧基)-5-氧代戊酸(212毫克,1.13毫莫耳)之以N2吹洗的圓底燒瓶中。將1滴DMF添加至此溶液中且將系統攪拌3小時。注意立即形成的氣體。將反應以真空濃縮,以給出粗製醯氯44,將其溶解在DCM中且添加至含有上述去保護之殘餘物63及TEA(0.144毫升)之圓底燒瓶中。將反應在室溫下攪拌2小時。將粗製反應混合物以真空濃縮,溶解在25毫升DCM中且轉移至分液漏斗中。以1M HCl(3x)、水(3x)及食鹽水(2x)清洗有機層。將有機層經硫酸鈉乾燥,過濾且將過濾物濃縮至粗製固體。將粗製產物以矽膠層析術(梯度:在DCM中的0%至10% MeOH)純化,以給出成為黃色固體的64(525毫克,90%)。LC-MS(方案A):m/z 514[M+H]+,滯留時間=2.43分鐘。
步驟3:(S)-5-((S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)丙醯胺基)-1-(氯甲基)-1,2-二氫-3H-苯並[e]吲哚-3-羧酸三級丁酯(66)之合成:將(S)-(1-氯-1-代氧丙-2-基)胺甲酸(9H-茀-9-基)甲酯(991毫克,3.0毫莫耳)添加至圓底燒瓶
中的15毫升DCM中的(S)-5-胺基-1-(氯甲基)-1,2-二氫-3H-苯並[e]吲哚-3-羧酸三級丁酯(1000毫克,3.0毫莫耳,65)(如WO 2015023355中所述而製得)中,接著添加1.2毫升胡尼格氏鹼。將反應攪拌1小時且濃縮成粗製玻璃物。將粗製反應混合物以矽膠層析術(梯度:在DCM中的0%至10% MeOH)純化,以給出成為白色固體的66(1529毫克,80%)。LC-MS(方案A):m/z 626[M+H]+,滯留時間=2.32分鐘。
步驟4:((S)-1-(((S)-3-(5-((S)-4-(苯甲氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-(氯甲基)-2,3-二氫-1H-苯並[e]吲哚-5-基)胺基)-1-代氧丙-2-基)胺甲酸(9H-茀-9-基)甲酯(67)之合成:將2.5毫升TFA添加至10毫升DCM中的(S)-5-(4-(苯甲氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊酸三級丁酯(500毫克,0.973毫莫耳,64)之攪拌溶液中且將反應攪拌3小時。在完成時,將反應在真空下濃縮成淡白色固體。接著將固體溶解在5毫升無水DCM及草醯氯(0.32毫升,0.93毫莫耳)中。將反應攪拌3小時且在真空下濃縮成白色固體。將(S)-5-((S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)丙醯胺基)-1-(氯甲基)-1,2-二氫-3H-苯並[e]吲哚-3-羧酸三級丁酯(0.973毫莫耳,66)溶解在DCM中的25% TFA(5毫升)且攪拌30分鐘。將反應在真空下濃縮且再溶解至5毫升DCM中。添加胡尼格氏鹼(0.32毫升),接著添加先前所述之醯氯。將反應攪拌2小
時。在完成時,將反應混合物在真空下濃縮。將粗製產物以矽膠層析術(梯度:在DCM中的0%至10% MeOH)純化,以給出成為白色固體的67(510毫克,54%)。LC-MS(方案A):m/z 965[M+H]+,滯留時間=2.61分鐘。
步驟5:((S)-1-(((S)-1-(((S)-3-(5-((S)-4-(苯甲氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-(氯甲基)-2,3-二氫-1H-苯並[e]吲哚-5-基)胺基)-1-氧代丙-2-基)胺基)-3-甲基-1-氧代丁-2-基)胺甲酸三級丁酯(68)之合成:將5毫升二乙胺添加至5毫升DCM中的((S)-1-(((S)-3-(5-((S)-4-(苯甲氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-(氯甲基)-2,3-二氫-1H-苯並[e]吲哚-5-基)胺基)-1-氧代丙-2-基)胺甲酸(9H-茀-9-基)甲酯(500毫克,0.518毫莫耳,67)之攪拌溶液中。將反應攪拌3小時且在真空下濃縮成黃色固體。將黃色粗製固體溶解在10毫升無水THF中,接著添加(三級丁氧基羰基)-L-纈胺酸2,5-二氧代吡咯啶-1-酯(163毫克,0.518毫莫耳),接著添加TEA(0.2毫升)。將反應在70℃下攪拌4小時。在完成時,將反應混合物在真空下濃縮。將粗製產物以矽膠層析術(梯度:在DCM中的0%至10% MeOH)純化,以給出成為白色固體的68(198毫克,40%)。LC-MS(方案A):m/z 942[M+H]+,滯留時間=2.49分鐘。
步驟6:((S)-1-(((S)-1-(((S)-1-(氯甲基)-3-(5-((S)-8-(氯甲基)-4-羥基-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-
6-基)-5-氧代戊醯基)-2,3-二氫-1H-苯並[e]吲哚-5-基)胺基)-1-氧代丙-2-基)胺基)-3-甲基-1-氧代丁-2-基)胺甲酸三級丁酯(69)之合成:將7毫升THF中的((S)-1-(((S)-1-(((S)-3-(5-((S)-4-(苯甲氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-(氯甲基)-2,3-二氫-1H-苯並[e]吲哚-5-基)胺基)-1-氧代丙-2-基)胺基)-3-甲基-1-氧代丁-2-基)胺甲酸三級丁酯(325毫克,0.345毫莫耳,68)之攪拌溶液在氮氣下使用冰浴冷卻至0℃。接著添加10重量%之鈀/活性碳(10毫克),接著緩慢地添加0.5毫升在水中的25%甲酸銨。容許反應攪拌在0℃下攪拌1小時。在完成時,將反應混合物經由矽藻土墊過濾且將過濾物在真空下濃縮。將粗製產物以矽膠層析術(梯度:在DCM中的0%至10% MeOH)純化,以給出成為黃色固體的69(181毫克,61%)。LC-MS(方案A):m/z 852[M+H]+,滯留時間=2.18分鐘。
步驟7:((S)-1-(((S)-1-(((S)-3-(5-((S)-4-((雙(苯甲氧基)磷醯基)氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-(氯甲基)-2,3-二氫-1H-苯並[e]吲哚-5-基)胺基)-1-氧代丙-2-基)胺基)-3-甲基-1-氧代丁-2-基)胺甲酸三級丁酯(70)之合成:將四氯化碳(2.04毫升,21.0毫莫耳)添加至10毫升THF及10毫升AcCN中的((S)-1-(((S)-1-(((S)-1-(氯甲基)-3-(5-((S)-8-(氯甲基)-4-羥基-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-2,3-二氫-1H-苯並[e]吲哚-5-基)胺基)-1-氧代丙-
2-基)胺基)-3-甲基-1-氧代丁-2-基)胺甲酸三級丁酯(165毫克,0.193毫莫耳,69)之攪拌溶液中,接著添加胡尼格氏鹼(1.12毫升,6.45毫莫耳)、亞磷酸二苯甲酯(320毫克,1.16毫莫耳)及DMAP(催化量)。容許反應在室溫下攪拌20分鐘。將反應濃縮成粗製玻璃物。將粗製反應混合物以矽膠層析術(梯度:在DCM中的0%至10% MeOH)純化,以給出成為白色玻璃物的70(51毫克,24%)。LC-MS(方案A):m/z 1113[M-H]-,滯留時間=2.50分鐘。
步驟8:磷酸二氫(S)-8-(氯甲基)-6-(5-((S)-1-(氯甲基)-5-((S)-2-((S)-2-(6-(2,5-二氧代-2,5-二氫-1H-吡咯-1-基)己醯胺基)-3-甲基丁醯胺基)丙醯胺基)-1,2-二氫-3H-苯並[e]吲哚-3-基)-5-氧代戊醯基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-酯(62)之合成:在配備有攪拌棒的圓底燒瓶中,將((S)-1-(((S)-1-(((S)-3-(5-((S)-4-((雙(苯甲氧基)磷醯基)氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-(氯甲基)-2,3-二氫-1H-苯並[e]吲哚-5-基)胺基)-1-氧代丙-2-基)胺基)-3-甲基-1-氧代丁-2-基)胺甲酸三級丁酯(40毫克,0.036毫莫耳,70)溶解在5毫升DCM中。添加TFA(2.5毫升)及2滴噻吩且將反應攪拌6小時。將粗製材料在真空下濃縮。將粗製殘餘物溶解在3毫升DMF中且添加6-(2,5-二氧代-2,5-二氫-1H-吡咯-1-基)己酸五氟苯酯(71)(13.6毫克,0.036毫莫耳),接著添加TEA(0.036毫莫耳)。將反應攪拌1小時。將反應在真空下濃縮且以HPLC方法純化,以給出成為白色固體
的62(25毫克,68%),滯留時間=7.115分鐘。LC-MS(方案A):m/z 1025[M+H]+,滯留時間=2.01分鐘。
步驟1:N~2~-乙醯基-N~6~-[(9H-茀-9-基甲氧基)羰基]-L-離胺醯基-L-纈胺醯基-N~5~-胺甲醯基-N-[4-(4,7,10,10-四甲基-3,8-二氧代-2,9-二氧雜-4,7-二氮雜十一烷-1-基)苯基]-L-鳥胺酸醯胺(72A)之合成:將38[如J.Med.Chem.1992,33,559-567中所述而製得](241毫克,1.28毫莫耳)在0℃下於N2氣球下添加至DMF(20毫升)中的N~2~-乙醯基-N~6~-[(9H-茀-9-基甲氧基)羰基]-L-離胺醯基-L-纈胺醯基-N~5~-胺甲醯基-N-[4-({[(4-硝基苯氧基)羰基]氧基}甲基)苯基]-L-鳥胺酸醯胺(72)(如US 9169264中所述)(1.00克,1.07毫莫耳)之攪拌溶液中。將所得混合物在0℃下攪拌30分鐘。將混合物倒入TBME(200毫升)中。將所得白色懸浮液過濾且以TBME(200毫升)清洗,以供給成為黃色固體的標題化合物72A(750毫克,71.3%)。
步驟2:N~2~-乙醯基-N~6~-[(9H-茀-9-基甲氧基)羰
基]-L-離胺醯基-L-纈胺醯基-N~5~-胺甲醯基-N-{4-[({甲基[2-(甲基胺基)乙基]胺甲醯基}氧基)甲基]苯基}-L-鳥胺酸醯胺(74)之合成:將TFA(50.0毫升)在0℃下添加至DCM(60.0毫升)中的化合物72A(10.00克,10.1毫莫耳)之攪拌懸浮液中。將所得溶液在0℃下攪拌40分鐘。將所得懸浮液過濾。將濾餅以TBME(200毫升)清洗且在真空中乾燥至無水,以供給粗製產物。將粗製產物以製備性HPLC(管柱:Phenomenex Synergi Max-RP 250X50毫米,10微米,梯度:在水中的25%至55%乙腈,在各相中具有0.1% TFA,經17.5分鐘,且以含有0.1% TFA之水中的100%乙腈固定8分鐘,流速:80毫升/分鐘)純化,以給出成為白色固體的標題化合物74(5.2克,51.3%產率)。
1H NMR(400MHz,DMSO-d6)10.03(s,1H),8.47(br.s.,2H),8.10(d,J=7.0Hz,1H),8.03(d,J=7.8Hz,1H),7.89(d,J=7.5Hz,2H),7.69(d,J=7.3Hz,3H),7.60(d,J=8.5Hz,2H),7.45-7.38(m,2H),7.36-7.29(m,4H),7.26(t,J=5.4Hz,1H),6.02(br.s.,1H),5.01(s,2H),4.43-4.33(m,1H),4.32-4.16(m,5H),3.49(t,J=6.0Hz,2H),3.06-2.92(m.,6H)2.86(s,3H),2.62-2.53(m,3H),1.99(dd,J=6.5,13.3Hz,1H),1.85(s,3H),1.76-1.27(m,10H),0.83(d,J=6.8Hz,3H),0.86(d,J=6.8Hz,3H)。
步驟1:三乙酸(2S,3R,4S,5S,6S)-2-(((S)-8-(氯甲基)-6-(5-((S)-8-(氯甲基)-1-甲基-4-(((4-硝基苯氧基)羰基)氧基)-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)-6-(甲氧基羰基)四氫-2H-吡喃-3,4,5-三酯(73)之合成:
將DCM(0.5毫升)中的氯甲酸4-硝苯酯(55毫克,0.26毫莫耳)之溶液添加至0℃下在THF(5毫升)中的46
(120毫克,0.13毫莫耳)之溶液中,接著添加Et3N(109微升,0.78毫莫耳),且將混合物在0℃下攪拌30分鐘。將混合物在真空中濃縮且將殘餘物以反相HPLC純化(方法C),以給出成為白色固體的109毫克(77%)產物73。LC-MS(方案B):m/z 1086.5(m+H),滯留時間=1.24分鐘。
步驟2:三乙酸(2S,3R,4S,5S,6S)-2-(((S)-6-(5-((S)-4-(((2-((((4-((9S,12S,15S)-9-乙醯胺基-1-(9H-茀-9-基)-12-異丙基-3,10,13-三氧代-15-(3-脲丙基)-2-氧雜-4,11,14-三氮雜十六-16-醯胺基)苯甲基)氧基)羰基)(甲基)胺基)乙基)(甲基)胺甲醯基)氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)-6-(甲氧基羰基)四氫-2H-吡喃-3,4,5-三酯(75)之合成:將化合物73(50毫克,0.046毫莫耳)溶解在DMF(2毫升)中且將(2-(甲基胺基)乙基)胺甲酸4-((9S,12S,15S)-9-乙醯胺基-1-(9H-茀-9-基)-12-異丙基-3,10,13-三氧代-15-(3-脲丙基)-2-氧雜-4,11,14-三氮雜十六-16-醯胺基)苯甲基甲酯(74,55毫克,0.055毫莫耳)、二甲基吡啶(0.021毫升,0.18毫莫耳)、DIPEA(0.032毫升,0.18毫莫耳)及HOAt(6毫克,0.046毫莫耳)添加至其中。將混合物在室溫下攪拌1小時。將混合物在真空中濃縮且將殘餘物以反相HPLC純化(方法C),在冷凍乾燥之後給出成為白色粉末的72毫克(85%)產物75。LC-MS(方案B):m/z 1833.3(M+H),滯留時間=1.17分鐘。1H NMR(400MHz,DMSO-d6)δ=
10.02(br.s.,1H),8.22(s,1H),8.19-8.13(m,1H),8.10(d,J=6.6Hz,1H),8.02(d,J=7.8Hz,1H),7.89(d,J=7.4Hz,2H),7.69(d,J=7.0Hz,3H),7.57(d,J=7.0Hz,2H),7.54-7.38(m,5H),7.37-7.30(m,3H),7.26(br.s.,3H),5.99(br.s.,1H),5.74(d,J=7.0Hz,1H),5.64-5.49(m,1H),5.20(t,J=8.8Hz,1H),5.13(t,J=9.6Hz,1H),5.04(br.s.,1H),5.00(br.s.,1H),4.81-4.70(m,1H),4.39(br.s.,2H),4.32-4.11(m,14H),3.95-3.80(m,3H),3.62(br.s.,1H),3.56(br.s.,1H),3.48(br.s.,2H),3.12(br.s.,1H),3.03(br.s.,2H),3.00-2.91(m,6H),2.88(br.s.,3H),2.82-2.67(m,4H),2.67-2.55(m,7H),2.10(s,1H),2.08-1.91(m,14H),1.85(s,3H),1.79-1.64(m,2H),1.61(br.s.,2H),1.54-1.32(m,5H),1.31-1.23(m,2H),1.23-1.12(m,2H),0.84(d,J=6.6Hz,3H),0.87(d,J=6.6Hz,3H)。
步驟3:LP:(2S,3S,4S,5R,6S)-6-(((S)-6-(5-((S)-4-(((2-((((4-((S)-2-((S)-2-((S)-2-乙醯胺基-6-胺基己醯胺基)-3-甲基丁醯胺基)-5-脲戊醯胺基)苯甲基)氧基)羰基)(甲基)胺基)乙基)(甲基)胺甲醯基)氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)-3,4,5-三羥基四氫-2H-吡喃-2-羧酸(76)之製備:將化合物75(44毫克,0.024毫莫耳)溶解在DMF(1毫升)、THF(5毫升)及MeOH(1毫升)中,冷卻至0℃,添加LiOH.H2O
(10毫克,0.24毫莫耳)且將混合物在0℃下攪拌60分鐘。將混合物以添加HOAc(30微升)而酸化且在真空中濃縮。將殘餘物以反相HPLC純化(方法C),以給出成為白色粉末的25.0毫克(66%)產物76。
LC-MS(方案B):m/z 1471.1(M+2H)+,滯留時間=0.75分鐘。1H NMR(500MHz,DMSO-d6)δ=8.09(br.s.,2H),7.97(d,J=8.1Hz,1H),7.68(br.s.,2H),7.48(d,J=7.6Hz,1H),7.44-7.39(m,1H),7.39-7.31(m,2H),7.22-7.12(m,1H),5.97(br.s.,1H),5.45-5.32(m,2H),5.18(br.s.,1H),5.06(d,J=5.6Hz,1H),4.98(br.s.,1H),4.92(br.s.,1H),4.31(br.s.,1H),4.26-4.05(m,8H),3.82(d,J=10.0Hz,1H),3.76(d,J=10.5Hz,1H),3.70(d,J=7.6Hz,1H),3.66-3.57(m,1H),3.57-3.44(m,5H),3.43-3.36(m,2H),3.36-3.28(m,3H),3.12-3.07(m,2H),3.05(br.s.,1H),3.00-2.91(m,2H),2.88(d,J=9.8Hz,3H),2.80(s,2H),2.72-2.59(m,4H),2.59-2.37(m,22H),2.02(s,2H),1.97-1.83(m,3H),1.78(s,3H),1.69(td,J=3.2,6.4Hz,2H),1.66-1.48(m,3H),1.47-1.32(m,4H),1.32-1.14(m,4H),0.76(d,J=6.4Hz,3H),0.79(d,J=5.9Hz,3H)。
步驟1:三乙酸(2R,3S,4S,5R,6S)-2-(乙醯氧基甲基)-6-(((S)-6-(三級丁氧基羰基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)四氫-2H-吡喃-3,4,5-三酯
(78)之合成:將化合物2(300毫克,0.85毫莫耳)溶解在DCM(30毫升)中且添加4A MS(1.5克,粉末狀,<5微米,經活化),且將混合物在室溫下攪拌30分鐘。將α-D-半乳吡喃糖2,3,4,6-四乙酸酯1-2,2,2-三氯乙烷亞胺酸酯(449毫克,93%,0.85毫莫耳)添加至反應混合物中且將混合物冷卻至-15℃,且緩慢地添加在DCM(5毫升)中的BF3.Et2O(0.052毫升,0.42毫莫耳)之溶液且將反應混合物在-15℃--20℃下攪拌1小時。將反應混合物經由矽藻土墊濾出,以丙酮清洗,濃縮,以給出殘餘物。將殘餘物以MeOH處理且在真空中濃縮,以給出成為灰白色固體的580毫克(100%)產物78。
LC-MS(方案B):m/z:706.4(M+Na),滯留時間=1.09分鐘。
步驟2:三乙酸(2R,3S,4S,5R,6S)-2-(乙醯氧基甲基)-6-(((S)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)四氫-2H-吡喃-3,4,5-三酯(79)之合成:將化合物78(580毫克,0.85毫莫耳)以二噁烷中的4M HCl溶液(5毫升)處理30分鐘且將混合物在真空中濃縮,以給出成為綠色固體的粗製產物79,其以未進一步純化而使用。
LC-MS(方案B):m/z 584.3(M+H),滯留時間=0.94分鐘。1H NMR(400MHz,甲醇-d4)δ=7.53(s,1H),7.22(s,1H),5.57-5.46(m,3H),5.34(dd,J=2.0,9.0Hz,1H),4.53(d,J=6.6Hz,2H),4.42(t,J=6.4Hz,1H),4.25(dt,J=6.4,11.2Hz,2H),4.18-4.01(m,5H),3.74(dd,J=8.6,
11.7Hz,2H),3.69(s,14H),2.68-2.58(m,4H),2.23(s,3H),2.19-2.14(m,2H),2.14-2.07(m,7H),2.07-1.94(m,6H),1.33(s,3H)。
步驟3:三乙酸(2R,3S,4S,5R,6S)-2-(乙醯氧基甲基)-6-(((S)-6-(5-(三級丁氧基)-5-氧代戊醯基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)四氫-2H-吡喃-3,4,5-三酯(80)之合成:將THF(10毫升)中的5-(三級丁氧基)-5-氧代戊酸(44,191毫克,1.02毫莫耳)之溶液冷卻至0℃且添加草醯氯(1.02毫升,在DCM中的2M),接著添加1滴DMF。將混合物在0℃下攪拌30分鐘且在真空中濃縮,以給出成為蠟的對應之醯氯。將其溶解在THF(10毫升)中且添加至THF(10毫升)中的79(526毫克,0.85毫莫耳)之溶液中,接著添加Et3N(0.354毫升,2.54毫莫耳)。將混合物在0℃下攪拌30分鐘。將混合物濃縮且將殘餘物以使用在庚烷中的0%至70%乙酸乙酯梯度之矽膠層析術純化,以給出成為灰白色固體的448毫克(70%)產物80。
LC-MS(方案B):m/z 754.4(M+H),滯留時間=1.06分鐘。
步驟4:三乙酸(2R,3S,4S,5R,6S)-2-(乙醯氧基甲基)-6-(((S)-8-(氯甲基)-6-(5-((S)-8-(氯甲基)-4-羥基-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)四氫-2H-吡喃-3,4,5-三酯(84)之合成:將化合物80(448毫克,0.59
毫莫耳)之溶液在室溫下以DCM(3毫升)及TFA(2毫升)處理1小時且將混合物在真空中濃縮,以給出成綠色固體的212毫克游離酸。將酸81(167毫克,0.24毫莫耳)溶解在THF(5毫升)中且將溶液冷卻至0℃,且添加草醯氯(0.24毫升,在DCM中的2M),接著添加DMF(1滴)。將混合物在0℃下攪拌30分鐘且在真空中濃縮,以給出對應之醯氯82,其以未進一步純化而用於下一步驟中。
將在二噁烷中的4M HCl(2毫升)中的化合物2(102毫克,0.28毫莫耳)之溶液在室溫下攪拌1小時且將混合物在真空中濃縮,以給出成為綠色固體的化合物83,將其溶解在THF(5毫升)中且冷卻至0℃。添加TEA(0.2毫升,1.44毫莫耳),接著添加在THF(5毫升)中的粗製醯氯82之溶液且將混合物在0℃下攪拌20分鐘。將混合物濃縮且將殘餘物以使用在庚烷中的0%至70%丙酮梯度之矽膠層析術純化,以給出成為黃色固體的196毫克(88%)產物84。
LC-MS(方案B):m/z 933.5(M+H),滯留時間=1.05分鐘。1H NMR(400MHz,DMSO-d6)δ=8.26(s,1H),7.94(s,1H),7.46(s,1H),7.39(s,1H),5.51(d,J=7.8Hz,1H),5.42-5.26(m,3H),4.59-4.46(m,1H),4.33-4.23(m,2H),4.23-4.15(m,4H),4.15-4.07(m,2H),4.04(s,4H),3.87(dd,J=10.5,18.0Hz,2H),3.67(t,J=9.8Hz,1H),3.57(t,J=10.1Hz,1H),3.33(s,1H),3.31(s,1H),2.83-2.67(m,2H),2.60(dd,J=6.4,16.2Hz,3H),2.19(s,
3H),2.15-2.09(m,4H),2.07(s,4H),1.97(S,6H)。
步驟5:三乙酸(2R,3S,4S,5R,6S)-2-(乙醯氧基甲基)-6-(((S)-8-(氯甲基)-6-(5-((S)-8-(氯甲基)-1-甲基-4-(((4-硝基苯氧基)羰基)氧基)-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)四氫-2H-吡喃-3,4,5-三酯(85)之合成:將氯甲酸4-硝苯酯(45毫克,0.21毫莫耳)添加在0℃下在THF(5毫升)中的84(100毫克,0.107毫莫耳)之溶液中,接著添加Et3N(0.060毫升,0.43毫莫耳)。將混合物在0℃下攪拌60分鐘。將混合物在真空中濃縮,以給出成為黃色泡沫的142毫克粗製產物,將其以反相HPLC純化(方法C),以給出成為灰白色固體的50毫克(43%)產物85。(方案B):m/z 1098.5(M+H),滯留時間=1.05分鐘。
步驟6:三乙酸(2S,3R,4S,5S,6R)-2-(((S)-6-(5-((S)-4-(((2-((((4-((9S,12S,15S)-9-乙醯胺基-1-(9H-茀-9-基)-12-異丙基-3,10,13-三氧代-15-(3-脲丙基)-2-氧雜-4,11,14-三氮雜十六-16-醯胺基)苯甲基)氧基)羰基)(甲基)胺基)乙基)(甲基)胺甲醯基)氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)-6-(乙醯氧基甲基)四氫-2H-吡喃-3,4,5-三酯(86)之合成:將(2-(甲基胺基)乙基)胺甲酸4-((9S,12S,15S)-9-乙醯胺基-1-(9H-茀-9-基)-12-異丙基-3,10,13-三氧代-15-(3-脲丙基)-2-氧雜-4,11,14-三氮雜十六-16-醯胺基)苯甲基甲酯(7445毫克,0.045毫
莫耳)及DIPEA(0.024毫升,0.136毫莫耳)添加至DMF(2毫升)中的85(50毫克,0.045毫莫耳)之溶液中。將混合物在室溫下攪拌60分鐘且使用反相HPLC純化(方法C),以給出成為白色固體的26毫克(31%)產物86:LC-MS(方案B):m/z 1847.1(M+H),滯留時間=1.06分鐘。1H NMR(400MHz,DMSO-d6)δ=10.01(br.s.,1H),8.25(s,1H),8.20-8.12(m,1H),8.09(d,J=6.6Hz,1H),8.02(d,J=8.2Hz,1H),7.89(d,J=7.8Hz,2H),7.69(d,J=7.0Hz,3H),7.57(d,J=7.4Hz,2H),7.47-7.37(m,4H),7.37-7.30(m,3H),7.26(br.s.,3H),5.98(br.s.,1H),5.50(d,J=7.0Hz,1H),5.46-5.27(m,5H),5.02(d,J=19.1Hz,2H),4.52(br.s.,1H),4.39(br.s.,1H),4.32-4.14(m,13H),4.14-4.03(m,1H),3.95-3.81(m,2H),3.75-3.59(m,6H),3.56(br.s.,2H),3.48(br.s.,2H),3.12(br.s.,1H),3.03(br.s.,2H),2.94(s,3H),2.97(s,2H),2.87(br.s.,2H),2.83-2.67(m,3H),2.66-2.54(m,7H),2.19(s,4H),2.12(s,3H),2.09-2.03(m,4H),2.03-1.90(m,7H),1.85(s,3H),1.78(t,J=6.4Hz,1H),1.68(d,J=7.8Hz,1H),1.61(br.s.,2H),1.53-1.33(m,5H),1.32-1.18(m,2H),0.84(d,J=7.0Hz,3H),0.87(d,J=6.6Hz,3H)。
步驟7:LP:((S)-8-(氯甲基)-6-(5-((S)-8-(氯甲基)-1-甲基-4-(((2S,3R,4S,5R,6R)-3,4,5-三羥基-6-(羥基甲基)四氫-2H-吡喃-2-基)氧基)-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚
-4-基)乙-1,2-二基雙(甲基胺甲酸)4-((S)-2-((S)-2-((S)-2-乙醯胺基-6-胺基己醯胺基)-3-甲基丁醯胺基)-5-脲戊醯胺基)苯甲酯(77)之合成:將水中的LiOH(1M,0.26毫升,0.26毫莫耳)之溶液添加至0℃下在THF(2毫升)和MeOH(2毫升)中的86(24毫克,0.013毫莫耳)之溶液中且將混合物在0℃至室溫下攪拌2小時。添加乙酸(20微升),將混合物濃縮且將殘餘物以反相HPLC純化(方法C),以給出成為白色泡沫的14毫克(69%)產物77:LC-MS(方案B):m/z 1456.9(M+2H)+,滯留時間=0.75分鐘。1H NMR(500MHz,DMSO-d6)δ=10.07-9.96(m,1H),8.29-8.18(m,1H),8.18-8.09(m,2H),8.06(d,J=8.1Hz,1H),7.73(d,J=8.6Hz,1H),7.66(br.s.,3H),7.56(d,J=7.8Hz,2H),7.50(d,J=9.3Hz,1H),7.47-7.39(m,2H),7.35(d,J=7.6Hz,1H),7.32-7.25(m,2H),6.04(br.s.,1H),5.11(d,J=6.4Hz,1H),5.05(br.s.,1H),5.01(br.s.,1H),4.40(br.s.,1H),4.36-4.16(m,10H),4.10(d,J=11.7Hz,3H),4.00(br.s.,3H),3.96-3.80(m,10H),3.77(br.s.,4H),3.73-3.55(m,11H),3.52(br.s.,1H),3.48(br.s.,3H),3.12(br.s.,1H),3.05(br.s.,2H),3.01-2.91(m,4H),2.88(br.s.,2H),2.86-2.72(m,4H),2.72-2.53(m,13H),2.45(t,J=7.5Hz,1H),2.06-1.92(m,3H),1.86(s,4H),1.71-1.56(m,3H),1.56-1.42(m,4H),1.42-1.23(m,4H),0.85(dd,J=6.6,14.7Hz,6H)。
步驟1:(((9H-茀-9-基)甲氧基)羰基)-L-纈胺酸2,5-二氧代吡咯啶-1-酯(88)之合成:將DCC(100克,0.487莫耳)在冰浴下分批添加至THF(1800毫升)中的化合物87(150克,0.442莫耳)及HOSu(56克,0.487莫耳)之溶液中。在添加之後,將反應在室溫下攪拌隔夜。將反應冷卻至-5℃,過濾且以冷THF清洗,將過濾物在真空中濃縮且將殘餘物自MTBE再結晶,以給出成為白色固體的175克(91%)化合物88。
步驟2:(S)-2-((S)-2-((((9H-茀-9-基)甲氧基)羰基)胺
基)-3-甲基丁醯胺基)-5-脲戊酸(90)之合成:將DME(750毫升)中的化合物88(100克,0.229莫耳)之溶液在冰浴下逐滴添加至水(750毫升)中的化合物89(40.14克,0.229莫耳)及NaHCO3(19.23克,0.229莫耳)之溶液中。在添加期間形成白色懸浮液。添加額外的THF(400毫升)以改進溶解度。在添加之後,將溶液在25-30℃下攪拌2天。將飽和水性K2CO3添加至反應中,以調整pH至8-9,接著以EtOAc(500毫升×5)萃取。將水層以水性檸檬酸調整pH至3-4。形成膠狀材料且過濾。將濕濾餅溶解在THF(1.5公升)中。添加甲醇,直到固體溶解為止。將溶液在真空中濃縮以移除30%溶劑且接著冷卻至室溫。將TBME(2公升)添加至溶液中且將混合物在室溫下攪拌隔夜。將混合物過濾且將濕濾餅在真空中乾燥,以給出成為白色固體的60克(53%)化合物90。
步驟3:((S)-1-(((S)-1-((4-(羥基甲基)苯基)胺基)-1-氧代-5-脲戊-2-基)胺基)-3-甲基-1-氧代丁-2-基)胺甲酸(9H-茀-9-基)甲酯(92)之合成:將化合物91(34.7克,0.282莫耳)添加至DCM/MeOH(1公升/500毫升)中的化合物90(70克,0.141莫耳)之懸浮液中,接著添加EEDQ(69.7克,0.282莫耳)。將混合物在40℃下攪拌隔夜。將反應混合物過濾且將濕濾餅懸浮在EtOAc/TBME(500毫升/200毫升)中且攪拌30分鐘,接著過濾。將固體以EtOAc/TBME清洗,以提供成為灰白色固體65克(77%)的化合物92。1H NMR(400MHz,DMSO-d6)δ=9.98(s,
1H),8.11(d,1H),7.87(d,2H),7.77(m,2H),7.52(d,2H),7.39(m,3H),7.30(m,2H),7.21(d,2H),5.97(m,1H),5.41(s,2H),5.10(m,1H),4.42(m,3H),4.22(m,3H),3.90(m,1H),2.93(m,2H),1.98(m,1H),1.50(m,2H),1.30(m,2H),0.84(m,6H)。
步驟4:((S)-3-甲基-1-(((S)-1-((4-((((4-硝基苯氧基)羰基)氧基)甲基)苯基)胺基)-1-氧代-5-脲戊-2-基)胺基)-1-氧代丁-2-基)胺甲酸(9H-茀-9-基)甲酯(94)之合成:將碳酸雙(4-硝苯基)酯(3.78克,12.4毫莫耳,93)分批添加至添加至無水DMF(120毫升)中的((S)-1-(((S)-1-((4-(羥基甲基)苯基)胺基)-1-氧代-5-脲戊-2-基)胺基)-3-甲基-1-氧代丁-2-基)胺甲酸(9H-茀-9-基)甲酯(3.74克,8.31毫莫耳,92)之溶液中,接著在0℃下逐滴添加DIPEA(1.21克,9.32毫莫耳)。將反應混合物在室溫下攪拌隔夜。TLC(MeOH:CH2Cl2=1:10)顯示反應完成。將反應混合物逐滴添加至攪拌的MTBE(2.5公升)中。以過濾收集粗製產物。將濾餅以MTBE清洗且在高真空下乾燥,以供給成為棕色固體的2.7克(57%)化合物94。
步驟5:乙-1,2-二基雙(甲基胺甲酸)4-((S)-2-((S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-甲基丁醯胺基)-5-脲戊醯胺基)苯甲基三級丁酯(95)之合成:將HOAT(332毫克,2.44毫莫耳)、2,6-二甲基吡啶(950毫克,8.87毫莫耳)在0℃下添加至DMA(15毫升)中的化合物94(1.7克,2.217毫莫耳)之溶液中。將混合物在0℃下攪拌5分
鐘。接著將(2-(甲基胺基)乙基)胺甲酸三級丁基甲酯(38,459毫克,2.44毫莫耳)添加至0℃下的混合物中,接著在0℃下添加DIPEA(860毫克,6.65毫莫耳)。將混合物在室溫下攪拌1小時,倒入TBME(800毫升)中,攪拌30分鐘,過濾且將濾餅在真空中濃縮,以給出成為黃色固體的粗製產物(1.06克)。將粗製產物以矽膠層析術(梯度:DCM:MeOH=100:1-10:1)純化,以給出成為白色固體的600毫克(33%)產物95。
步驟6:(2-(甲基胺基)乙基)胺甲酸4-((S)-2-((S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-甲基丁醯胺基)-5-脲戊醯胺基)苯甲基甲酯(96)之合成:將TFA(5毫升)在0℃下添加至無水DCM(10毫升)中的化合物95(600毫克,0.735毫莫耳)之攪拌溶液中且在0℃下攪拌1小時。將混合物在真空中濃縮,以給出成為白色固體的550毫克(100%)標題化合物96。1H NMR(400MHz,DMSO-d6)δ=10.09(br,1H),8.40(s,2H),8.14(d,1H),7.90(d,2H),7.74(m,2H),7.61(d,2H),7.43(m,3H),7.33(m,4H),6.00(s,1H),5.43(s,2H),5.02(s,2H),4.42-4.23(m,4H),3.93(m,1H),3.50(m,2H),3.08-2.94(m,4H),2.88(s,3H),2.59(m,3H),1.99(m,1H),1.69-1.59(m,2H),1.46-1.39(m,2H),0.90-0.85(m,6H)。
步驟1:三乙酸(2S,3R,4S,5S,6S)-2-(((S)-6-(5-((S)-4-(((2-((((4-((S)-2-((S)-2-((((9H-茀-9-基)甲氧基)羰基)胺基)-3-甲基丁醯胺基)-5-脲戊醯胺基)苯甲基)氧基)羰基)(甲基)胺基)乙基)(甲基)胺甲醯基)氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)-6-(甲氧基羰基)四氫-2H-吡喃-3,4,5-三酯(97)之合成:將Fmoc-VCPABC-DMEA連接子96(24毫克,0.029毫莫耳)、2,6-二甲基吡啶(0.0167毫升,0.14毫莫耳)、DIPEA(0.0253毫升,0.14毫莫耳)及HOAt(3.3毫克,0.024毫莫耳)添加至DMF(1.5毫升)中的化合物73(26毫克,0.024毫莫耳)之溶液中。將混合物在室溫下攪拌30
分鐘且在真空中濃縮,以給出殘餘物。將粗製物進行HPLC純化(方法C),以給出成為白色固體的33毫克(83%)產物97。LC-MS(方案B):m/z 1660.9(M+H),滯留時間=1.11分鐘。
步驟2:(2S,3S,4S,5R,6S)-6-(((S)-6-(5-((S)-4-(((2-((((4-((S)-2-((S)-2-胺基-3-甲基丁醯胺基)-5-脲戊醯胺基)苯甲基)氧基)羰基)(甲基)胺基)-乙基)(甲基)胺甲醯基)氧基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-8-(氯甲基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)-3,4,5-三羥基四氫-2H-吡喃-2-羧酸(98)之合成:將水(0.5毫升)中的LiOH.H2O(12毫克,0.28毫莫耳)之溶液添加至冷卻至0℃的THF(3毫升)及MeOH(3毫升)中的97(46毫克,0.028毫莫耳)之溶液中。將混合物在0℃下攪拌1小時。添加AcOH(0.03毫升)以中和混合物且在真空中濃縮,以給出白色固體殘餘物。將其以HPLC純化(方法C),以給出成為灰白色固體的28毫克(72%)產物98。LC-MS(方案B):m/z 1300.6(M+H),滯留時間=0.78分鐘。1H NMR(400MHz,DMF)δ=10.33-10.21(m,1H),8.84(d,J=7.4Hz,1H),8.63(br.s.,3H),8.41-8.28(m,2H),8.05(s,1H),7.81-7.63(m,2H),7.57-7.41(m,3H),7.38(br.s.,2H),6.52(br.s.,1H),5.39(d,J=6.6Hz,1H),5.17(br.s.,1H),5.12(br.s.,1H),4.74(br.s.,1H),4.48-4.28(m,5H),4.24(br.s.,1H),4.09(s,4H),4.04-3.89(m,2H),3.84-3.67(m,6H),
3.67-3.52(m,4H),3.32(s,9H),3.26(br.s.,2H),3.19(br.s.,1H),3.14-3.04(m,4H),3.00(s,2H),2.94(br.s.,2H),2.85(br.s.,2H),2.79-2.68(m,5H),2.62(s,4H),2.64(s,3H),2.42-2.29(m,1H),2.23-2.05(m,11H),1.92(br.s.,1H),1.78(br.s.,1H),1.60(br.s.,2H),1.15(br.S.,6H)。
步驟3:(2S,3S,4S,5R,6S)-6-(((S)-8-(氯甲基)-6-(5-((S)-8-(氯甲基)-4-(((2-((((4-((23S,26S)-1-(2,5-二氧代-2,5-二氫-1H-吡咯-1-基)-23-異丙基-21,24-二氧代-26-(3-脲丙基)-3,6,9,12,15,18-六氧雜-22,25-二氮雜二十七-27-醯胺基)苯甲基)氧基)羰基)(甲基)胺基)乙基)(甲基)胺甲醯基)氧基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)氧基)-3,4,5-三羥基四氫-2H-吡喃-2-羧酸(49)之合成:將1-(2,5-二氧代-2,5-二氫-1H-吡咯-1-基)-3,6,9,12,15,18-六氧雜二十一-21-酸全氟苯酯(5.6毫克,0.009毫莫耳,99)及DIPEA(0.007毫升,0.042毫莫耳)添加至溶解在DMF(1毫升)中的98(10毫克,0.007毫莫耳)之溶液中。將混合物在室溫下攪拌30分鐘。將混合物以HPLC純化(方法C),以給出成為白色泡沫的10毫克(82%)產物49。LC-MS(方案B):m/z 1715.7(M+H),滯留時間=0.89分鐘。1H NMR(400MHz,乙腈-d3)δ=8.21(br.s.,2H),7.56(d,J=7.4Hz,1H),7.31-7.10(m,4H),6.78(s,2H),5.25(br.S.,1H),5.11(br.s.,1H),5.02(br.s.,1H),4.50(br.S.,
1H),4.18(br.s.,2H),3.77(br.s.,2H),3.71(br.s.,3H),3.66-3.42(m),3.37-3.24(m,4H),3.16(br.s.,1H),3.12-2.95(m,4H),2.93(s,2H),2.77-2.47(m,H),2.22-2.02(m,4H),1.51(br.s.,2H),0.95(br.S.,6H)。
步驟1:乙-1,2-二基雙(甲基胺甲酸)4-((S)-2-((S)-2-((S)-2-乙醯胺基-6-胺基己醯胺基)-3-甲基丁醯胺基)-5-脲戊醯胺基)苯甲基((S)-8-(氯甲基)-6-(5-((S)-8-(氯甲基)-1-甲基-4-(膦醯氧基)-7,8-二氫-6H-噻吩並[3,2-e]吲哚-6-基)-5-氧代戊醯基)-1-甲基-7,8-二氫-6H-噻吩並[3,2-e]吲哚-4-基)酯(100)之合成:將74(45毫克,0.045毫莫耳)、二甲基吡啶(0.019毫升,0.16毫莫耳)、DIPEA(0.029毫升,0.16毫莫耳)及HOAt(5.6毫克,0.041毫莫耳)添加至DMF(3毫升)中的55(35毫克,0.041毫莫耳)之溶液中。
將混合物在室溫下攪拌3小時。將哌啶(0.3毫升,3毫莫耳)添加至所得混合物中,在室溫下攪拌20分鐘。將混合物在真空中濃縮且將殘餘物以HPLC(方法C)純化,在冷凍乾燥之後給出成為白色粉末的35毫克(62%)產物100。LC-MS(方案B):m/z 1374.8(M+H),滯留時間=0.92分鐘。1H NMR(400MHz,DMSO-d6)δ=8.45(d,J=13.7Hz,1H),8.14(s,1H),8.17(s,1H),8.05(d,J=7.4Hz,1H),7.76(br.s.,3H),7.58(d,J=8.2Hz,1H),7.52-7.39(m,2H),7.30-7.16(m,1H),6.09(br.s.,1H),5.15-4.94(m,2H),4.40(br.s.,1H),4.35-4.08(m,8H),3.95-3.79(m,2H),3.69(br.s.,1H),3.60(d,J=10.5Hz,3H),3.49(br.s.,3H),3.13(br.s.,1H),3.06(br.s.,1H),3.03-2.91(m,4H),2.88(s,2H),2.76(br.s.,4H),2.61(d,J=6.6Hz,2H),2.56(s,6H),1.98(m,3H),1.86(s,3H),1.65(m,3H),1.58-1.49(m,3H),1.46(m,2H),1.40-1.20(m,3H),0.85(m,6H)。
如本文所註明,在表1和2中的所述化合物可以彼等的乙酸鹽或酚前藥階段存在,兩者迅速轉化成雙環丙基活性藥物種類。此相互轉化在檢定介質中迅速發生。於是所有三種化合物形式在功能上等效且在癌細胞增生檢定中得到相同的生長抑制值。因此,說明為〝雙乙酸鹽〞之化合物亦需要說明彼等功能上等效的酚及雙環丙基種類。
製備下列的酬載。所有的酬載係使用通用程序A和B或指示之方法而製得。
在上列的實例中,變型Pg為H、醯基、磷酸根PO3H2、碳水化合物、胺基酸或肽(且特別為以蛋白酶(諸如組織蛋白酶和基質金屬蛋白酶)裂解之肽)。
表4:下列的連接子/酬載係使用上述用於製備表3中所示之連接子/酬載類似物之程序而製得。
在表4中,Pg為H、醯基、磷酸根PO3H2、碳水化合物、胺基酸或肽(特別為以蛋白酶(諸如組織蛋白酶和基質金屬蛋白酶)裂解之肽)。
在表5中,Pg為H、醯基、磷酸根PO3H2、碳水化合物、胺基酸或肽(特別為以蛋白酶(諸如組織蛋白酶和基質金屬蛋白酶)裂解之肽)。
癌細胞株係自ATCC(Manassas,VA)獲得。N87(源自於轉移性肝位置的人類胃癌)。HL60(白血病)及MDA-MB-361 DYT2(人類乳癌MDA-MB-361)係在RPMI 1640培養基中生長。所有的培養基係10%胎牛血清、1%丙酮酸鈉及1% L-麩醯胺酸(Invitrogen,Grand Island,NY)補充。人類臍帶靜脈內皮細胞(HUVEC)係自Lonza
(Allendale,NJ)獲得且維持在以EGM-2 SingleQuots(Lonza # CC-4176)補充之EGM2培養基中。將所有的細胞維持在加濕的保溫器中(37℃,5% CO2)。
將100微升培養基中的細胞在96槽孔盤中培養。將癌細胞株以添加兩組重複的50微升3X儲液之指定化合物的10種濃度處理。將細胞與化合物培育四天,接著將30微升CellTiter® 96 AQueous One MTS溶液(Promega Cat # G3582)添加至細胞中,在37℃培育1.5小時,接著在Victor讀盤儀(Perkin Elmer,Waltham,MA)上以490奈米測量吸光度。相對細胞存活率係以未經處理之對照槽孔之百分比測定。IC50值係使用四參數邏輯模式#203與XLfit v4.2(IDBS,Guildford,Surry,UK)計算。
所使用的細胞株:A375(黑色素瘤)、PC3MM2(攝護腺)、PC3(攝護腺)。
將細胞接種於96槽孔盤中隔夜,然後暴露於濃度增加的抗IL13Rα2 ADC或對照組ADC。在4天之後,相對於對照組細胞評定各培養物的存活率。IC50值係以邏輯非線性回歸法計算而來。
人類AML細胞株(HL60、NB4、HEL92.1.7和Raji)係自美國典型培養物保藏中心(American Type Culture Collection)(Manassas,VA)獲得。細胞係在以10% FBS、1% Pen/Strep和L-麩醯胺酸混合物、1mM丙酮酸鈉、10mM HEPES及0.27%葡萄糖(Life Technology,Carlsbad,CA)補充之RPMI培養基中生長。測試細胞株的P-醣蛋白之內源活性水平,多重藥物抗性蛋白質及乳癌抗性蛋白質係使用市售流式細胞儀套組(eFLUXX-ID;ENZO Life Sciences,Plymouth Meeting,PA)測定。
將用於細胞毒性檢定之細胞覆蓋在96槽孔透明盤(Corning)中且以不同濃度的化合物處理4天。存活率係使用CellTiter Glo發光細胞存活率檢定套組(Promega,Madison,WI)測定且使用Victor X3讀盤儀(Perkin Elmer Waltham,MA)測量。數據係相對於對照組(DMSO或PBS)而標準化。IC50值經定義為引起50%之生長抑制的濃度。IC50值係使用邏輯非線性回歸法模式編號203與XL fit v4.2(IDBS,Guildford,Surry,UK)計算而來。所有的實驗點係設置在兩組重複的槽孔中且獨立地重複進行。
在處理前24小時將目標表現N87(胃癌)、MDA-MB-361-DYT2(乳癌)或不表現(HT-29)細胞接種於96槽孔細胞培養盤中。將細胞以三倍連續稀釋的抗體藥物共軛體處理。細胞存活率係在處理後96小時以CellTiter 96®
AQueousOne Solution Cell Proliferation MTS檢定法(Promega,Madison WI)測定。相對細胞存活率係以未經處理之對照組之百分比測定。IC50值係使用四參數邏輯模式#203與XLfit v4.2(IDBS,Guildford,Surry,UK)計算而來。
將酬載及ADC之細胞毒性的結果顯示於表6和10中。
將杜貝可(Dulbecco)氏磷酸鹽緩衝之食鹽水(PBS,Lonza,pH 7.4)中的醫療抗體之溶液以添加的3.0-3.5當量
參(2-羧乙基)膦鹽酸鹽(TCEP,在PBS中的5mM溶液)還原。將反應在37℃下培育1-2小時且接著容許冷卻至周圍溫度。共軛係藉由添加7當量連接子-酬載[在N,N-二甲基乙醯胺(DMA)中的10mM溶液]來進行。將額外的DMA添加至反應混合物中,在最終反應混合物中達成15%(v/v)之總有機溶劑組份。將反應在周圍溫度下培育1小時。在周圍溫度下1小時之後,將粗製反應經由GE Sephadex脫鹽管柱進行PBS的緩衝液交換或將過量連接子-酬載經由添加10當量半胱胺酸(在PBS中的20mM溶液)而淬滅。在任一例子中,接著將粗製材料以粒徑排除層析術(SEC,方案C)純化。將單體流份匯聚且若必要時濃縮,以給出ADC。
含有工程化半胱胺酸殘基(Kabat numbering,參見WO2013093809)的醫療抗體之溶液係在50毫米磷酸鹽緩衝液pH 7.4中製備。添加PBS、EDTA(0.5M儲液)及TCEP(0.5M儲液),使得最終蛋白質濃度為~10毫克/毫升,最終EDTA濃度為~20mM及最終TCEP濃度為約~6.6mM(100莫耳當量)。容許反應放置在室溫下2-48小時且接著將緩衝液使用GE PD-10 Sephadex G25管柱依照製造商的指示交換成PBS。替代方法(諸如滲濾或透析)亦可用於特殊的情況中。將所得溶液以約50當量脫氫抗壞
血酸鹽(在1:1之EtOH/水中的50毫米儲液)處理。容許抗體放置在4℃下隔夜且接著將緩衝液使用GE PD-10 Sephadex G25管柱依照製造商的指示交換成PBS。再者,替代方法(諸如滲濾或透析)亦可用於特殊的情況中。
與因此製備之抗體的共軛係藉由添加10當量連接子-酬載[在N,N-二甲基乙醯胺(DMA)中的10mM溶液]來進行。將額外的DMA添加至反應混合物中,在最終反應混合物中達成15%(v/v)之總有機溶劑組份。在一些情況中添加額外的PBS,在反應中達成5-10毫克/毫升之最終總抗體濃度。在室溫下1-2小時之後,將反應混合物緩衝液交換成PBS(如上述)且以粒徑排除層析術(SEC,方案D)純化。將單體流份匯聚且若必要時濃縮,以給出ADC。在一些情況中,接著將ADC在23-37℃下以0.5-1.0克Bio-Beads SM-2吸附劑(Bio-Rad)經4-18小時SEC純化之後進行後續培育,過濾且若必要時接著濃縮。
將攜有轉麩醯胺酸酵素反應性麩醯胺酸殘基之醫療抗體透析至無菌水(Lonza)中。經轉麩醯胺酸酶媒介之共軛係藉由將5.0-15毫克/毫升之水中的含抗體之轉麩醯胺酸酶反應性麩醯胺酸與30mM磷酸鉀pH7.4 DILUT-IT Dissolution Media Concentrate(J.T.Baker)、150mM氯化鈉(NaCl)、15.0-20.0倍莫耳過量的攜有酬載之胺基烷基連
接子(在DMSO中的10-30mM溶液)及30-60毫克/毫升之轉麩醯胺酸酶酵素粉末(Ajinomoto Activa TI)混合來進行。另外,將DMSO添加至反應混合物中,在最終反應混合物中達成5-10%(v/v)之總有機溶劑組份。在一些情況中添加額外的水,在反應中達成5-10毫克/毫升之最終總抗體濃度。將所得混合物在周圍溫度下培育5-6小時。接著添加另一30-60毫克/毫升之轉麩醯胺酸酶固體且將混合物進一步在周圍溫度下另外培育18小時。在隔夜之後,將粗製反應的緩衝液使用GE Healthcare Sephadex緩衝液交換管柱依照製造商的指示交換成杜貝可氏磷酸鹽緩衝之食鹽水(PBS,pH7.4,Lonza)。將粗製材料以粒徑排除層析術(SEC,方案D)或疏水性交互作用層析術(HIC,方案G)純化。在純化之後,將單體流份匯聚且若必要時濃縮,以給出ADC。在其中ADC係以HIC純化的實施例中,接著將匯聚之流份的緩衝液使用GE Healthcare Sephadex緩衝液交換管柱依照製造商的指示交換成杜貝可氏磷酸鹽緩衝之食鹽水(PBS,pH7.4,Lonza)。在一些情況中,接著將ADC在23-37℃下以0.5-1.0克Bio-Beads SM-2吸附劑(Bio-Rad)經4-18小時純化之後進行後續培育,過濾且若必要時接著濃縮。
ADC係經由關於純度的粒徑排除層析術(SEC)和疏水性交互作用層析術(HIC)及計算藥物-抗體比例(DAR,負載力)的串聯之液相層析術電噴霧離子化法與質譜法而特徵化。
方案C:管柱:Agilent Poroshell 300SB-C8,75 x 2.1毫米,2.6微米;移動相A:在水中的0.1%甲酸(v/v);移動相B:在乙腈中的0.1%甲酸(v/v);梯度:最初條件:20% B至45% B經4分鐘;流速:1.0毫升/分鐘。溫度:60℃;偵測:220奈米;MS(+)範圍400-2000Da;注射體積:10微升;儀器:Agilent 1100 LC,Waters MicromassZQ MS。反摺積係使用MaxEnt1進行。
方案D:管柱:GE Superdex 200(10/300GL);移動相:經磷酸鹽緩衝之食鹽水(PBS,1X,pH 7.4);等位洗提;流速:1.0毫升/分鐘。溫度:周圍溫度;儀器:GE Akta Explorer。
方案E:管柱=Waters BEH300-C4,1.1 x 100毫米(P/N=186004496);儀器=具有SQD2質譜偵測器之Acquity UPLC;流速=0.7毫升/分鐘;溫度=80℃;緩衝液A=水+0.1%甲酸;緩衝液B=乙腈+0.1%甲酸。梯度操作係從3% B至95% B經2分鐘,在95% B保持0.75分鐘及接著在3% B再平衡。樣品在注射前立即以TCEP或DTT還原。洗提液係以LCMS(400-2000道耳頓)監控且蛋白質波峰係使用MaxEnt1反摺積。DAR係以如先前所述之重量平均負載力記述。
方案F:管柱:TSKGel Butyl NPR,4.6毫米x 3.5公分(P/N=S0557-835);緩衝液A=含有10mM磷酸鹽的1.5M硫酸銨,pH 7;緩衝液B=10mM磷酸鹽,pH 7+20%異丙醇;流速=0.8毫升/分鐘;溫度=周圍溫度;梯
度=0% B至100% B經12分鐘,在100% B保持2分鐘,接著在100% A再平衡,儀器:Agilent 1100 HPLC。
方案G:管柱:GE HiTrap Butyl HP,5毫升;移動相:1M磷酸鉀、50mM Tris-HCl,pH7(緩衝液A);50mM Tris-HCl,pH7(緩衝液B);梯度洗提:0-100%緩衝液B經10-20個管柱體積;流速:5.0毫升/分鐘。溫度:周圍溫度;儀器:GE Akta Explorer。
Claims (10)
- 一種式(I)化合物:F1-L1-T-L2-F2 (I)或其醫藥上可接受之鹽,其中:F1和F2各自獨立地選自環系統A和C:
- 根據申請專利範圍第5至6項中任一項之化合物或其醫藥上可接受之鹽,其中該抗體AB係選自曲妥珠美(trastuzumab)、曲妥珠美突變體、奧戈伏馬(oregovomab)、依決洛馬(edreeolomab)、西妥昔馬(cetuximab)、抗玻璃黏連蛋白受體(αvβ3)之人源化單株抗體、阿來珠馬(alemtuzumab)、抗-HLA-DR抗體、131I Lym 1、抗-HLA-Dr10抗體、抗-cd33抗體、抗-cd22抗體、拉貝珠馬(labetuzumab)、畢法珠馬(bevacizumab)、替伊莫馬(ibritumomab tiuxetan)、奧法沐馬(ofatumumab)、帕尼沐馬(panitumumab)、利妥昔馬(rituximab)、托西莫馬(tositumomab)、易普利沐馬(ipilimumab)及吉妥珠馬(gemtuzumab)。
- 一種醫藥組成物,其包含根據申請專利範圍第1至7項中任一項之化合物或其醫藥上可接受之鹽及醫藥上可接受之賦形劑。
- 一種根據申請專利範圍第1至7項中任一項之化合物或根據申請專利範圍第8項之醫藥組成物於製造藥劑之用途,該藥劑係用於治療病患的癌症。
- 根據申請專利範圍第9項之用途,其中該癌症為膀胱癌、乳癌、子宮頸癌、結腸癌、子宮內膜癌、腎癌、肺癌、食道癌、卵巢癌、攝護腺癌、胰臟癌、皮膚癌、胃癌(stomaeh(gastric)cancer)、睪丸癌、白血病和淋巴瘤。
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US20210061923A1 (en) | 2021-03-04 |
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BR112017018706A2 (pt) | 2018-04-17 |
KR20170129828A (ko) | 2017-11-27 |
CA2923862A1 (en) | 2016-09-20 |
AU2016238551B2 (en) | 2020-01-02 |
CA2923862C (en) | 2024-02-13 |
BR112017018706B1 (pt) | 2023-01-24 |
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