TWI574686B - 1,5-二苯基-戊-1,4-二烯-3-酮化合物 - Google Patents

1,5-二苯基-戊-1,4-二烯-3-酮化合物 Download PDF

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TWI574686B
TWI574686B TW100129846A TW100129846A TWI574686B TW I574686 B TWI574686 B TW I574686B TW 100129846 A TW100129846 A TW 100129846A TW 100129846 A TW100129846 A TW 100129846A TW I574686 B TWI574686 B TW I574686B
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aromatic ring
compound
cancer
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nmr
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石秋洋
北村俊雄
施謙
川島 敏行
王惠康
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石秋洋
北村俊雄
施謙
川島 敏行
王惠康
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Description

1,5-二苯基-戊-1,4-二烯-3-酮化合物 相關申請案之相互參照
本申請案主張2010年8月20日所提出的美國臨時專利申請案序號61/375,534之優先權。先述申請案的內容其全文藉此以參考方式併入本文。
本發明係關於具有1,5-二苯基戊-1,4-二烯-3-酮骨架的新穎化合物。這些化合物可使用來治療癌、炎性疾病或自體免疫性疾病。
信號轉導及轉錄活化子(STAT)蛋白質係調控細胞對生長因子之反應的轉錄因子。這些蛋白質藉由生長因子受體相關的酪胺酸激酶經由酪胺酸磷酸化而活化。經活化的STAT蛋白質促進細胞存活及增生。現在,已良好地建立出STAT3或STAT5的持續活化會促進實體及造血癌二者之細胞生長、侵襲及轉移。參見例如,Expert Opin. Investig. Drugs,2009,18(1):45-56。
在正常淋巴細胞中,STAT蛋白質(例如,STAT3)亦經由細胞素受體相關的Janus激酶(JAKs)調控細胞對細胞素(諸如,白細胞介素-6(IL-6))之反應。參見例如,Neoplasia 2008,10:287-297。IL-6在罹患造血癌、炎性疾病、自體免疫性疾病及停經後骨質疏鬆症之患者中經異常地提昇。IL-6的抑制細胞作用(例如,藉由引發STAT3蛋白質降解)已歸因於這些疾病之治療。
就此而論,可使用去活化STAT蛋白質的化合物來治療多種癌、炎性疾病及自體免疫性疾病。
本發明係以一群具有1,5-二苯基-戊-1,4-二烯-3-酮骨架、能去活化STAT蛋白質的化合物之發現為基礎。
本發明的一個觀點係關於一種式(I)之化合物:
其中X及Y各者各自獨立地係H、烷基或鹵基,或X與Y一起係-CH2-、-(CH2)2-、-(CH2)CRaRb(CH2)-、-(CH2)NRa(CH2)-或-(CH2)O(CH2)-,Ra及Rb各者各自獨立地係H、烷基、C(O)-烷基、C(O)-環烷基、C(O)-NH-烷基或C(O)-NH-環烷基;及R1、R2、R3、R4、R5、R1’、R2’、R3’、R4’及R5’各者各自獨立地係H、烷基(例如,經鹵基或SO2Rd取代的烷基)、鹵基、OH、Rc-O-、RdS(O)2-O-或(Rd)2P(O)-O-,Rc係未經取代的烷基或經鹵基、OH、烷氧基、胺基、環烷基、雜環烷基、芳基或雜芳基取代的烷基,及Rd係H、OH、烷基、烷氧基、胺基或芳基;其中R1係與R1’或R5’不同、R2係與R2’或R4’不同、R3係與R3’不同、R4係與R2’或R4’不同、或R5係與R1’或R5’不同。
參照式(I),該化合物的支組具有一或多個下列特徵:R2係OH,或R2係RdS(O)2-O-或(Rd)2P(O)-O-(Rd係H、OH、烷基、烷氧基、胺基或芳基,例如,Rd係乙基);R2’係Rc-O-(Rc係經胺基取代的烷基);X及Y各者係H,或X與Y一起係-(CH2)NRa(CH2)-;及Ra係C(O)-R、C(O)NRR’或經環烷基取代的烷基(R及R’各者各自獨立地係烷基或環烷基)。
本發明的另一個觀點係關於一種式(II)之化合物:
其中X及Y各者各自獨立地係H、烷基或鹵基,或X與Y一起係-CH2-、-(CH2)2-、-(CH2)CRaRb(CH2)-、-(CH2)NRa(CH2)-或-(CH2)O(CH2)-,Ra及Rb各者各自獨立地係H、烷基、C(O)-烷基、C(O)-環烷基、C(O)-NH-烷基或C(O)-NH-環烷基;及R1、R2、R3、R4、R5、R1’、R2’、R3’、R4’及R5’各者各自獨立地係H、烷基(例如,經鹵基或SO2Rd取代的烷基)、鹵基、OH、Rc-O-、RdS(O)2-O-或(Rd)2P(O)-O-,Rc係未經取代的烷基或經鹵基、OH、烷氧基、胺基、環烷基、雜環烷基、芳基或雜芳基取代的烷基,及Rd係H、OH、烷基、烷氧基、胺基或芳基;其中R1、R2、R3、R4、R5、R1’、R2’、R3’、R4’及R5’之至少一個係RdS(O)2-O-、(Rd)2P(O)-O-或(RdO)2P(O)-O-。
參照式(II),該化合物的支組具有一或多個下列特徵:X及Y各者係H;R2係RdS(O)2-O-或(Rd)2P(O)-O-(Rd係H、OH、烷基、烷氧基、胺基或芳基;例如,Rd係乙基);R2’係R-O-(R係經胺基取代的烷基),或R2’係RdS(O)2-O-或(Rd)2P(O)-O-(Rd係H、OH、烷基、烷氧基、胺基或芳基,例如,Rd係乙基);及R1’、R3’及R4’之一係RdS(O)2-O-或(Rd)2P(O)-O-(Rd係H、OH、烷基、烷氧基、胺基或芳基,例如,Rd係乙基)。
本發明的又另一個觀點係關於一種式(III)之化合物:
其中每個X係N或CH;R1、R2、R3、R4、R5、R1’、R2’、R3’、R4’及R5’各者各自獨立地係H、烷基(例如,經鹵基或SO2Rd取代的烷基)、鹵基、OH、Rc-O-、RdS(O)2-O-或(Rd)2P(O)-O-,Rc係未經取代的烷基或經鹵基、OH、烷氧基、胺基、環烷基、雜環烷基、芳基或雜芳基取代的烷基,及Rd係H、OH、烷基、烷氧基、胺基或芳基;及R6係C(O)-Re、C(O)NReRf或烷基(例如,未經取代的烷基或經環烷基取代的烷基),Re及Rf各者各自獨立地係烷基或環烷基。
參照式(III),該化合物的支組具有一或多個下列特徵:X係N;R2係OH或R-O-(R係經胺基取代的烷基,例如,R係CH2H2N(C2H5)2);及R6係環丙基羰基或環丙基甲基。
用語”烷基”指為包含1-10個碳原子的飽和線性或分枝烴部分,諸如-CH3或-CH(CH3)2。用語”環烷基”指為3-10員飽和環狀烴部分,諸如環己基。用語”雜環烷基”指為3-10員具有至少一個環雜原子(例如,N、O或S)的飽和環狀部分,諸如4-四氫哌喃基。用語”芳基”指為具有一或多個芳香環的烴部分。該芳基部分的實施例包括苯基(Ph)、伸苯基、萘基、伸萘基、芘基、蒽基及菲基。用語”雜芳基”指為具有一或多個包含至少一個雜原子(例如,N、O或S)的芳香環之一部分。該雜芳基部分的實施例包括呋喃基、伸呋喃基、茀基、吡咯基、噻吩基、唑基、咪唑基、噻唑基、吡啶基、嘧啶基、喹唑啉基、喹啉基、異喹啉基及吲哚基。
除非有詳細指明,否則於此提到的烷基、環烷基、雜環烷基、芳基及雜芳基包括經取代及未經取代的部分二者。在環烷基、雜環烷基、芳基及雜芳基上可能的取代基包括(但不限於)C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C20環烷基、C3-C20環烯基、C1-C20雜環烷基、C1-C20雜環烯基、C1-C10烷氧基、芳基、芳氧基、雜芳基、雜芳氧基、胺基、C1-C10烷基胺基、C1-C20二烷基胺基、芳基胺基、二芳基胺基、C1-C10烷基磺胺基、芳基磺胺基、C1-C10烷基亞胺基、芳基亞胺基、C1-C10烷基磺亞胺基、芳基磺亞胺基、羥基、鹵基、硫基、C1-C10烷硫基、芳硫基、C1-C10烷基碸基、芳基碸基、醯基胺基、胺醯基、胺基硫醯基、脒基、胍、脲基、氰基、硝基、亞硝基、疊氮基、醯基、硫醯基、醯氧基、羧基及羧酸酯。另一方面,在烷基上可能的取代基包括上述敘述之全部取代基,除了C1-C10烷基外。該環烷基、雜環烷基、芳基及雜芳基亦可彼此并合。
若合適的話,上述化合物包括該化合物它們本身、和其鹽、前藥體及溶劑化物。例如,可在1,5-二苯基-戊-1,4-二烯-3-酮化合物之陰離子與正電荷基團(例如,銨離子)間形成鹽。合適的陰離子包括氯化物、溴化物、碘化物、硫酸鹽、硝酸鹽、磷酸鹽、檸檬酸鹽、甲磺酸鹽、三氟醋酸鹽、醋酸鹽、琥珀酸鹽、蘋果酸鹽、甲苯磺酸鹽、酒石酸鹽、反丁烯二酸鹽、麩胺酸鹽、葡萄糖醛酸鹽、乳酸鹽、戊二酸鹽及順丁烯二酸鹽。同樣地,亦可在1,5-二苯基-戊-1,4-二烯-3-酮化合物之陽離子與負電荷基團(例如,羧酸鹽)間形成鹽。合適的陽離子包括鈉離子、鉀離子、鎂離子、鈣離子及銨陽離子。該化合物亦可呈前藥體及溶劑化物形式。該前藥體的實施例包括酯類及其它醫藥可接受的衍生物(其在給藥至患者後能提供活性化合物)。該溶劑化物指為在活性化合物與醫藥可接受的溶劑間形成之複合物。該醫藥可接受的溶劑之實施例包括水、乙醇、異丙醇、醋酸乙酯、醋酸及乙醇胺。
該化合物包括非芳香族雙鍵。因此,它們可發生如為順或反異構物形式。此異構物形式係經考慮到。
本發明的又另一個觀點係關於一種用來治療癌、炎性疾病或自體免疫性疾病的方法。該方法包括將一有效量的一或多種上述化合物給藥至需要其之患者。
在本發明之範圍內亦包括一使用來治療癌/炎性疾病/自體免疫性疾病之包含一或多種上述化合物與醫藥可接受的載劑之組合物,及一此組合物用於僅提到的治療之藥劑的製造之用途。
在下列描述中提出本發明的一或多個具體實例之細節。將從描述中及從申請專利範圍中明瞭本發明的其它特徵、目標及優點。
上述化合物可藉由在技藝中熟知的方法製備。下列反應方案1、2及3闡明使用來各別合成式(I)、(II)及(III)之化合物的一般合成途徑。
反應方案1
如顯示在上述反應方案1中,於鹼性條件下縮合苯甲醛與過量的丙酮以提供4-苯基丁-3-烯-2-酮化合物,讓其與第二苯甲醛化合物縮合以獲得式(I)之化合物。從而獲得的產物可經進一步修改以製備其它的式(I)之化合物。
反應方案2
如顯示在上述反應方案2中,讓經羥基取代的1,5-二苯基戊-1,4-二烯-3-酮化合物(其可藉由上述的方法製備)與磺醯氯或氯化膦/氯磷酸酯/三氯化磷醯或醯基氯縮合,以提供式(II)之化合物。類似地,3,5-二亞苄基哌啶-4-酮化合物可與碸基氯/氯化膦/醯基氯縮合以提供亦由式(II)涵蓋的化合物。
反應方案3
如顯示在上述反應方案3中,讓哌啶-4-酮與醯基氯或溴烷反應以提供N-經取代的哌啶-4-酮,其隨後與2當量的苯甲醛縮合以獲得由式(III)涵蓋之對稱的3,5-二亞苄基哌啶-4-酮化合物。該N-經取代的哌啶-4-酮可首先與1當量的苯甲醛,然後與1當量的第二苯甲醛反應,以製備不對稱的3,5-二亞苄基哌啶-4-酮化合物,其亦由式(III)涵蓋。
下列顯示依上述方法製備之典型的式(I)、(II)及(III)之化合物:
上述化合物會去活化STAT蛋白質。因此,本發明涵蓋一種將一有效量之一或多種化合物給藥至患有癌、炎性疾病或自體免疫性疾病的患者之方法。
用語”以...治療”或”治療”指為將一或多種化合物給藥至具有上述症狀、此症狀的徵兆或朝向此症狀的體質之患者,其目的為提供治療效應,例如以治癒、減輕、改變、影響、改善或防止上述病症、其徵兆或朝向其之體質。”有效量”指為在經治療的患者上提供治療效應所需要之活性化合物的量。如由熟習該項技術者了解,有效劑量將依所治療的疾病型式、給藥途徑、賦形劑之使用及與其它治療性治療共使用的可能性而變化。
可藉由本發明之方法治療的癌包括多種器官的實體及血液腫瘤二者。該實體腫瘤的實施例包括胰癌、膀胱癌、結腸癌、結腸直腸癌、乳房癌(例如,轉移性乳房癌)、前列腺癌(例如,雄性激素相依、雄性激素無關或閹割抗性前列腺癌)、腎臟癌(例如,轉移性腎細胞癌)、肝細胞癌、肺癌(例如,非小細胞肺癌、細支氣管肺泡癌或肺腺癌)、卵巢癌(例如,進行性上皮或原發性腹膜癌)、子宮頸癌、胃癌、食道癌、頭頸癌(例如,頭及頸的鱗狀細胞癌)、黑腫瘤、神經內分泌癌(例如,轉移性神經內分泌腫瘤)、腦腫瘤(例如,神經膠質瘤、分化不良寡樹突膠質瘤、成年多形神經膠母細胞瘤或成年分化不良星細胞瘤)、骨癌及軟組織肉瘤。該血液腫瘤的實施例包括多種白血病(例如,骨髓性白血病、慢性骨髓性白血病或CML[加速期CML及CML急性期]、急性淋巴胚細胞白血病或慢性淋巴球性白血病)、Hodgkin’s病、淋巴瘤、非Hodgkin’s淋巴瘤(例如,濾泡淋巴瘤或外套細胞淋巴瘤)、B細胞淋巴瘤、T細胞淋巴瘤、多發性骨髓瘤、Waldenstrom’s大球蛋白血症、骨髓造血分化不良症候群(例如,頑固性貧血、含有環狀含鐵胚血球的頑固性貧血、含有過量芽細胞的頑固性貧血或RAEB、或轉變中RAEB)、及骨髓增生性症候群。
可藉由本發明之方法治療的炎性疾病包括(但不限於)氣喘、動脈粥瘤硬化、類風濕性關節炎、發炎性腸道疾病、Crohn、潰瘍性結腸炎、缺血性心臟病、心肌病、腎絲球腎炎、腎症候群、肝炎B或C感染、呼吸道融合瘤病毒感染(肺)及Guillain-Barré症候群。
可藉由本發明之方法治療的自體免疫性疾病包括(但不限於)過敏性腦病、慢性阻塞性肺疾、牛皮癬、牛皮癬性關節炎、糖尿病、全身性紅斑狼瘡、多發性硬化、多肌炎、皮肌炎、混合性結締組織疾病、Sjögren’s症候群、Wegener’s肉芽腫病、結節性多動脈炎、類風濕性關節炎及自發性血小板減少性紫瘢病。
為了實行本發明之方法,可非經腸道、口服、鼻、直腸、局部或頰地給藥含有一或多種上述化合物的組合物。如於本文中所使用的用語”非經腸式”指為皮下、皮內、靜脈內、肌肉內、關節內、動脈內、滑膜內、胸骨內、鞘內、病灶內或顱內注射,和任何合適的輸液技術。
無菌可注射組合物可為在無毒非經腸道之可接受的稀釋劑或溶劑中之溶液或懸浮液,諸如在1,3-丁二醇中的溶液。在可接受的媒劑及溶劑當中,使用的有甘露醇、水、Ringer’s溶液及等滲壓氯化鈉溶液。此外,習知上使用非揮發性油作為溶劑或懸浮媒體(例如,合成的單或二甘油酯類)。在注射物質之製備中,脂肪酸(諸如油酸及其甘油酯衍生物)有用作為天然醫藥可接受的油,諸如橄欖油或蓖麻油,特別是其聚氧乙基化的形式。這些油溶液或懸浮液亦可包含長鏈醇稀釋劑或分散劑、羧甲基纖維素或類似的分散劑。為了調配的目的,亦可使用其它普通使用的界面活性劑(諸如Tweens或Spans)或其它類似的乳化劑或生物可利用率促進劑(其普通使用來製造醫藥可接受的固體、液體或其它劑型)。
用於口服給藥之組合物可為任何口服可接受的劑形,包括膠囊、錠劑、乳液及水性懸浮液、分散液及溶液。在錠劑的情況中,普通使用的載劑包括乳糖及玉黍蜀粉。典型上,亦加入潤滑劑,諸如硬脂酸鎂。對以膠囊形式口服給藥來說,有用的稀釋劑包括乳糖及乾玉黍蜀粉。當口服給藥水性懸浮液或乳液時,該活性成份可懸浮或溶解在與乳化或懸浮劑結合的油相中。若須要時,可加入某些變甜、風味或著色劑。
可根據在醫藥調配物的技藝中熟知之技術來製備鼻噴霧劑或吸入組合物。例如,此組合物可使用苄醇或其它合適的防腐劑、吸收促進劑(以提高生物可利用率)、碳氟化合物、及/或在技藝中已知的其它溶解或分散劑製備成在鹽液中之溶液。
該含有一或多種活性化合物之組合物亦可以栓劑形式給藥而用於直腸給藥。
在該醫藥組合物中的載劑必需”可接受”,在觀念上其與該組合物之活性成份相容(及以能安定該活性成份為較佳)且對欲治療的患者無害。可使用一或多種增溶劑作為醫藥賦形劑來傳遞活性1,5-二苯基-戊-1,4-二烯-3-酮化合物。其它載劑的實施例包括膠態氧化矽、硬脂酸鎂、纖維素、硫酸月桂酯鈉及D & C黃色#10。
上述的1,5-二苯基-戊-1,4-二烯-3-酮化合物可對其在去活化STAT蛋白質及治療上述疾病的效力來進行初步篩選,此藉由試管內試驗,然後藉由動物實驗及臨床試驗證實。將亦由一般熟知此技藝之人士明瞭其它方法。
下列特定實施例欲解釋僅作為闡明用,且無論如何不以任何方式限制本揭示的剩餘部分。咸信熟習該項技術者可沒有進一步詳細闡述而根據於此之描述將本發明使用至其最大程度。全部於此所引用的公告其全文藉此以參考方式併入本文。
化學合成
使用未經校正的Fisher-John熔點裝置來測量熔點。在Varian Gemini 300或Inova 400光譜儀上測量質子核磁共振(1H NMR)及13C NMR光譜,且使用四甲基矽烷作為內部標準。以d(ppm)報導化學位移。在Shimadzu LCMS-2010上獲得質譜(MS)。在Grace矽凝膠匣上進行CombiFlash層析系統,用於一般的分離及純化。亦使用一使用矽凝膠板(Kieselgel 60,F254,1.00毫米)的製備型薄層色層分析法來分離及純化。使用經預塗佈的矽凝膠板(Kieselgel 60,F254,0.25毫米)用於薄層色層分析法(TLC)分析。全部試劑及溶劑皆從Aldrich、Fisher、VWR或其它供應商購買。
化合物1-4及21之合成
如在下列反應方案4中所顯示般製備化合物1-4及21:
反應方案4
在4℃下,於冰浴中,在羥基苯甲醛於DMF中之溶液中加入K2CO3(每個羥基2當量)及甲基氯甲基醚(氯化MOM)(每個羥基1.3當量)。在室溫下攪拌該溶液並藉由TLC監視3-5小時後,加入己烷類/二氯甲烷(1:1)及允許攪拌30分鐘。過濾出固體及濃縮濾出液。以EtOAc稀釋所產生的殘餘物及以H2O清洗兩次。以EtOAc萃取水層。在Na2SO4上乾燥結合的有機層及濃縮。藉由CombiFlash色層分析系統,使用Grace矽凝膠管柱及己烷類/醋酸乙酯(作為沖提液)純化粗產物,以提供經MOM保護的羥基苯甲醛。藉由10%NaOH(1.2當量NaOH)催化,讓所產生的化合物在乙醇中進一步與過量丙酮反應。在室溫下攪拌且由TLC監視1-5小時後,以CH2Cl2稀釋該反應混合物,以H2O清洗兩次及以CH2Cl2萃取兩次。在藉由CombiFlash系統使用己烷類/醋酸乙酯作為沖提液純化後,獲得經MOM保護的羥基-苯基-丁-3-烯-2-酮。讓所產生的化合物與適當經MOM保護的羥基苯甲醛反應以獲得經MOM保護的羥基1,5-二苯基-戊-1,4-二烯-3-酮,其藉由在50%醋酸水溶液中加熱去保護,以獲得想要的產物。
化合物1:黃色結晶固體;ESI MS m/z:251.10[M+H]+1H NMR(300 MHz,CDCl3) d:7.75(d,1H,J=15.0赫茲,H-1),7.63(d,1H,J=15.0赫茲,H-5),7.64(m,2H,芳香環H),7.43-7.41(m,2H,芳香環H),7.72-7.27(m,2H,芳香環H),7.21-7.19(d,1H,J=6.0赫茲,芳香環H),7.13-7.12(m,1H,芳香環H),7.08(d,1H,J=15.0赫茲,H-2),7.06(d,1H,J=15.0赫茲,H-4),6.92-6.83(m,1H,芳香環H),5.38(br. 1H,OH)。
化合物2:黃色結晶固體;ESI MS m/z:267.29[M+H]+1H NMR(300 MHz,CD3OD3) d:8.10(d,1H,J=15.0赫茲,H-1),7.63(d,1H,J=15.0赫茲,H-5),7.75-7.62(m,1H,芳香環H),7.25(d,1H,J=15.0赫茲,H-4),7.22(d,1H,J=15.0赫茲,H-2),7.21-7.11(m,4H,芳香環H),6.91-6.84(m,3H,芳香環H),3.68(br. 2H,OH)。
化合物3:黃色結晶固體;ESI MS m/z:281.05[M-H]-1H NMR(300 MHz,CD3OD3) d:7.68(d,1H,J=15.9赫茲,H-5),7.66(d,1H,J=15.9赫茲,H-1),7.27-6.97(m,5H,芳香環H),6.99(d,1H,J=15.9赫茲,H-4),6.88-6.84(m,2H,芳香環H),6.80(d,1H,J=15.9赫茲,H-2),4.91(br. 3H,OH)。
化合物4:黃色結晶固體;ESI MS m/z:281.05[M-H]-1H NMR(300 MHz,CD3OD3) d:7.70(d,1H,J=15.9赫茲,H-5),7.65(d,1H,J=15.9赫茲,H-1),7.60-7.56(dd,2H,芳香環H),7.15-7.06(m,2H,芳香環H),7.12(d,1H,J=15.9赫茲,H-4),6.98(d,1H,J=15.9赫茲,H-2),6.81(t,3H,J=8.4赫茲,芳香環H)。
化合物21:黃色結晶固體;ESI MS m/z:281.09[M-H]-1H NMR(300 MHz,CD3OD3)d:7.63(d,1H,J=15.9赫茲,H-5),7.56(d,1H,J=15.9赫茲,H-1),7.21-7.05(m,3H,芳香環H),7.12(d,1H,J=15.9赫茲,H-4),7.03(d,1H,J=15.9赫茲,H-2),6.82-6.778(m,1H,芳香環H),6.57(d,2H,J=2.1赫茲,芳香環H),6.29(t,1H,J=2.1赫茲,芳香環H)。
化合物20、30、31、38、39、41、42、44、62-64、73及75之合成
如在下列反應方案5中所顯示出般製備化合物20、30、31、38、39、41、42、44、62-64、73及75:
反應方案5
使用與如上所述相同的方式讓經甲氧基取代的苯甲醛與丙酮反應,接著與經第二甲氧基取代的苯甲醛縮合,以獲得經甲氧基取代的1,5-二苯基-戊-1,4-二烯-3-酮化合物30及31或經甲基甲氧基取代的1,5-二苯基-戊-1,4-二烯-3-酮。在CH2Cl2中,以BBr3(每個甲氧基2當量)從-78℃至0℃至室溫去甲基化(或部分去甲基化),提供想要的酚粗產物。藉由TLC監視該反應。在完成後,將該反應混合物傾入酸性的冰/水中,然後藉由乙基醚萃取。在CombiFlash色層分析系統上純化後,獲得想要的產物(即,化合物20、62-64)。
化合物20:紅色結晶固體;ESI MS m/z:281.10[M-H]-1H NMR(300 MHz,CD3OD3) d:8.06(d,1H,J=15.9赫茲,H-5),7.63(d,1H,J=15.9赫茲,H-1),7.26-7.05(m,5H,芳香環H及H-2,4),6.86-6.62(m,4H,芳香環H)。
化合物62:非晶相,ESI MS m/z:309.0[M+H]+1H NMR(400 MHz,丙酮-d6) d:8.03-7.94(m,2H,H-1,5),7.15-7.00(m,3H,芳香環H),6.96-6.87(m,3H,芳香環H),6.68(d,J=16.0赫茲,1H,H-2),6.65(d,J=16.0赫茲,1H,H-4),3.85(s,3H,OCH3),2.12(s,3H,CH3),2.10(s,3H,CH3)。
化合物63:明黃色固體,ESI MS m/z:295.1[M+H]+1H NMR(400 MHz,CD3OD) d:8.01(d,2H,J=15.6赫茲,H-1,5),7.66-7.64(m,2H,芳香環H),6.98(d,2H,J=15.6赫茲,H-2,4),6.66-6.64(m,4H,芳香環H),2.40(s,6H,CH3)。
化合物64:非晶相,ESI MS m/z:309.1[M+H]+1H NMR(400 MHz,丙酮-d6) d:8.07-7.94(m,2H,H-1,5),7.75-7.67及7.08-7.01(m,1H,芳香環H),7.50-7.44(m,2H,芳香環H),6.83-6.73(m,1H,芳香環H),6.70-6.66(m,2H,芳香環H),6.48(d,J=16.0赫茲,1H,H-2),6.47(d,J=16.0赫茲,1H,H-4),3.81(s,3H,OCH3),1.98(s,3H,CH3),1.94(s,3H,CH3)。
如在上述反應方案5中所顯示般,藉由在室溫下,於乙醇/20%NaOH水溶液中,讓經取代的苯甲醛與(E)-4-(3-羥基苯基)丁-3-烯-2-酮反應來合成化合物38、39、41、42、44、73及75。藉由TLC監視該反應。在完成後,藉由醋酸中和該溶液,以醋酸乙酯萃取及濃縮,以獲得想要的產物。為了供應化合物44,藉由在室溫下,於乙醇溶液中,以0.1當量的對-甲苯磺酸吡錠處理來移除THP保護基團(其經引進以製得3-甲氧基-4-(四氫-哌喃-2-基氧基)-苯甲醛)。
化合物38:淡黃色針;mp 159-160℃;C19H18O4,ESI-MS:m/z 311.2[M+H]+1H NMR(300 MHz,DMSO-d6):7.75,7.65(1H每個,二者d,J=16.2赫茲,H-1,5),7.42(1H,d,J=2.1赫茲,H-2’),7.34(1H,dd,J=2.1,8.4赫茲,H-6’),7.25,7.23(1H每個,二者d,J=16.2赫茲,H-2,4),7.28-7.13(2H,m,H-4”,5”),7.14(1H,br. t,H-2”),7.04(1H,d,J=8.4赫茲,H-5’),6.86(1H,br. d,8.4赫茲,H-6”),3.84,3.82(二者s,3H每個,OCH3 X 2)。
化合物39:黃色細結晶;mp 152-153℃;C18H16O3,ESI-MS:m/z 281.2[M+H]+1H NMR(300 MHz,DMSO-d6):7.76,7.62(1H每個,二者d,J=16.2赫茲,H-1,5),7.72(2H,d,J=9.0赫茲,H-2’,6’),7.22(1H,d,8.0赫茲,H-6”),7.18,7.17(1H每個,二者d,J=16.2赫茲,H-2,4),7.17(1H,m,5”),7.09(1H,br. 3,H-2”),6.98(2H,d,J=9.0赫茲,H-3’,5’),6.81(1H,br. d,8.0赫茲,H-4”),3.77(s,3H,OCH3)。
化合物41:淡黃色針;mp 138-139℃;C18H13F3O2,ESI-MS:m/z 319.2[M+H]+1H NMR(300 MHz,DMSO-d6):8.14(1H,br.,H-2’),8.07(1H,br. d,J=7.8赫茲,H-6’),7.81,7.50(1H每個,二者d,J=15.9赫茲,H-1,2),7.78-7.62(2H,m,H-4’,5’),7.69,7.19(1H每個,二者d,J=16.2赫茲,H-4,5),7.22(2H,4”,5”),7.10(1H,br. s,H-2”),6.83(1H,br. d,J=8.7赫茲,H-6”)。
化合物42:淡黃色細結晶;mp 159-160℃;C17H13FO2,ESI-MS:m/z 269.2[M+H]+1H NMR(300 MHz,DMSO-d6):7.92(1H,dt,J=1.8,7赫茲,H-4’),7.73,7.42(1H每個,二者d,J=16.2赫茲,H-1,2),7.69,7.16(1H每個,二者d,J=16.2赫茲,H-4,5),7.47(1H,m,H-5”),7.30-7.12(3H,m,2’,5’,6’,4”),7.10(1H,br. s,H-2”),6.82(1H,dt,J=1.8,7.2赫茲,H-6”)。
化合物44:黃色細結晶;mp 144-145℃;C23H26O10S3,ESI-MS:m/z 559.1[M+H]+1H NMR(300 MHz,DMSO -d6):7.63-6.93(11H,m,芳香族H及乙烯基H),3.81(2H,s,OCH3)。
化合物73:灰白色固體,ESI MS m/z:269.5[M+H]+1H NMR(400 MHz,CDCl3)d:7.68(d,J=16.0赫茲,1H,H-1),7.67(d,J=16.0赫茲,1H,H-5),7.37-7.35(m,2H,芳香環H),7.29-7.24(m,2H,芳香環H),7.18-7.16(m,1H,芳香環H),7.11-7.08(m,2H,芳香環H),7.04(d,J=16.0赫茲,1H,H-4),7.01(d,J=16.0赫茲,1H,H-2),6.91-6.88(m,1H,芳香環H)。
化合物75:淺黃色固體,ESI MS m/z:335.5[M+H]+1H NMR(400 MHz,CDCl3)d:7.69(d,J=15.6赫茲,1H,H-1),7.67(d,J=15.6赫茲,1H,H-5),7.49-7.47(m,1H,芳香環H),7.42-7.39(m,2H,芳香環H),7.28-7.22(m,2H,芳香環H),7.16-7.14(m,2H,芳香環H),7.05(d,J=16.0赫茲,1H,H-4),7.02(d,J=16.0赫茲,1H,H-2),6.95-6.92(m,1H,芳香環H)。
化合物12、13及15-17之合成
如在反應方案6中所顯示般,藉由以在Roberta Costi等人,Bioorganic & Medicinal Chemistry 2004,12:199-215中所描述者為基準所修改的方法來合成化合物12、13及15-17。
反應方案6
在哌啶-4-酮於DMF中的溶液中,加入三乙基胺(1.5當量)及氯化N,N-二乙基乙醯胺(1.5當量)。在室溫下攪拌所產生的溶液5小時或直到完成(藉由TLC觀察)。蒸發溶劑及將殘餘物分配在H2O與EtOAc中。以EtOAc萃取水層,並在Na2SO4上乾燥結合的有機層及濃縮。藉由CombiFlash色層分析系統,使用矽凝膠匣及CH2Cl2/MeOH梯度沖提液來純化粗產物,以獲得4-側氧-哌啶-1-羧酸二乙基醯胺,其隨後在醋酸(99.7%)中且充入HCl氣體(0.5-1小時)與3-羥基苯醛(2.5當量)反應。在室溫下攪拌3小時後,蒸發溶劑及藉由CombiFlash色層分析系統與己烷類/EtOAc作為沖提液來純化粗產物,接著從MeOH結晶以獲得化合物12,如為黃色結晶固體。
化合物12:黃色結晶固體;ESI MS m/z:407.49[M+H]+1H NMR(300 MHz,CD3OD) d:7.61(s. 2H,亞苄基CH=),7.16(t,2H,J=7.5赫茲,芳香環H),6.82-6.79(m,2H,芳香環H),6.75-6.71(m,4H,芳香環H),4.36(s,4H,4-側氧-哌啶-H-2,6),2.95(q,4H,-NCH 2 CH3),0.71(t,6H,-NCH2CH 3 )。
以與如上所述相同的方式製備化合物16,除了使用環丙羰基氯(1.5當量)取代氯化N,N-二乙基乙醯胺外。
化合物16:黃色固體;ESI MS m/z:376.16[M+H]+1H NMR(300 MHz,DMSO-d6) d:7.59(s. 2H,亞苄基CH=),7.30(t,2H,J=7.5Hz,芳香環H),6.98-6.93(m,4H,芳香環H),6.87-6.85(m,2H,芳香環H),3.39(s,4H,4-側氧-哌啶-H-2,6),1.69(m,1H,環丙羰基CH),0.62-0.58(m,4H,環丙羰基CH 2 )。
藉由在DMF中,於K2CO3存在下,讓哌啶-4-酮與1-溴-丁烷(1.5當量)或溴甲基-環丙烷(1.5當量)反應來合成化合物15及17。在室溫下攪拌24小時後或藉由MS監視,藉由蒸發移除該反應溶劑。將殘餘物分配在H2O與EtOAc中,及以H2O清洗有機層兩次。然後,以EtOAc萃取水層及在Na2SO4上乾燥萃取物。藉由CombiFlash色層分析系統,使用矽凝膠匣及CH2Cl2/MeOH梯度沖提液來純化粗產物。遵循上述相同的程序,讓所獲得之N-經取代的4-側氧-哌啶化合物與3-羥基苯醛(2.5當量)縮合,以獲得想要的產物。
化合物15:黃色固體;ESI MS m/z:364.19[M+H]+1H NMR(300 MHz,CD3OD) d:7.64(s. 2H,亞苄基CH=),7.21(t,2H,J=8.1赫茲,芳香環H),6.85(d,br,2H,J=8.1赫茲,芳香環H),6.80-6.76(m,4H,芳香環H),3.80(s,4H,4-側氧-哌啶-H-2,6),2.50(t,2H,J=8.1赫茲,-NCH 2 CH2-),1.42-1.30(m,2H,-NCH2 CH 2 CH2-),1.27-1.14(m,2H,-NCH2CH2 CH 2 CH3),0.81(t,3H,-NCH2CH2CH2 CH 3 )。
化合物17:黃色固體;ESI MS m/z:362.18[M+H]+1H NMR(300 MHz,DMSO-d3) d:7.66(s.2H,亞苄基CH=),7.21(t,2H,J=7.8赫茲,芳香環H),6.86(d,br,2H,J=7.2赫茲,芳香環H),6.81-6.75(m,4H,芳香環H),3.90(s,4H,4-側氧-哌啶-H-2,6),2.40(d,2H,J=6.6赫茲,亞甲基-環丙烷-CH 2 ),0.65(m,1H,環丙烷CH),0.43-0.37(m,2H,環丙烷CH 2 ),0.11-0.07(m,2H,環丙烷CH 2 )。
從在DMF中處理側氧-(4-側氧-環己基)-醋酸與1-乙基-3-(3-二甲基胺基丙基)碳二醯亞胺(2當量)及4-二甲基胺基吡啶(催化量)開始來合成化合物13。在室溫下攪拌大約10分鐘後,在冰浴中冷卻該反應混合物及加入二乙胺(1.5當量)。在室溫下攪拌所得的混合物5小時伴隨著TLC監視。藉由蒸發移除溶劑。以EtOAc稀釋殘餘物及以H2O清洗兩次。然後,以EtOAc萃取水層及在Na2SO4上乾燥有機層。在透過CombiFlash色層分析系統使用矽凝膠匣及CH2Cl2/MeOH梯度沖提液純化後,獲得想要的中間物N,N-二乙基-2-側氧-2-(4-側氧-環己基)-乙醯胺,遵循上述相同的程序,讓其進一步與3-羥基苯醛(2.5當量)縮合,以獲得想要的產物,如為黃色固體。ESI MS m/z:406.51[M+H]+1H NMR(300 MHz,DMSO-d6) d:7.54(s. 2H,亞苄基CH=),7.25(t,2H,J=7.8赫茲,芳香環H),6.93-6.89(m,4H,芳香環H),6.81-6.78(m,2H,芳香環H),3.23(q,4H,J=7.2赫茲,-NCH 2 CH3),2.95(m,4H,4-側氧-環己基-H-2,6),2.54(m,1H,環己基-H-1),0.94(m,6H,-NCH2CH 3 )。
化合物5-11、14、18、22-29、32-34、37、40、43、53、65-66、69-70、74、77及78之合成
這些化合物之合成顯示在反應方案7中。
反應方案7
在CH2Cl2(包含小量DMF)中的1,5-雙-(3-羥基-苯基)-戊-1,4-二烯-3-酮(藉由顯示在反應方案4中的方法合成)溶液中,慢慢加入乙磺醯基氯(~10當量)及Et3N(~10當量)。在室溫下攪拌所得的混合物4-5小時。以CH2Cl2稀釋該反應混合物,以水清洗兩次及以CH2Cl2萃取。在Na2SO4上乾燥有機萃取物,過濾及濃縮以獲得粗產物,如為黃色固體。藉由快速管柱過濾來純化粗產物,然後結晶及從EtOAc再結晶,以獲得想要的產物化合物6,如為淺黃色結晶固體。產率>78%。ESI MS m/z:451.2[M+H]+1H NMR(300 MHz,CDCl3) d:7.71(d,2H,J=15.9赫茲,H-1,5),7.57-7.53(m,4H,芳香環H),7.47(t,2H,J=7.8赫茲,芳香環H),7.34-7.31(m,2H,芳香環H),7.08(d,2H,J=15.9赫茲,H-2,4),3.34(q,4H,J=7.5赫茲,-OSO2CH 2 CH3),1.58(t,6H,J=7.5赫茲,-OSO2CH2CH 3 )。
以類似於上述所描述的方式合成化合物5、7-11、22、26、27、40、43、53、65-66、69-70、74及77。
化合物5:淺黃色結晶固體;ESI MS m/z:451.2[M+H]+1H NMR(300 MHz,CDCl3)d:7.72(d,2H,J=15.9赫茲,H-1,5),7.66(d,4H,J=8.7赫茲,芳香環H),7.34(d,4H,J=8.7赫茲,芳香環H),7.04(d,2H,J=15.9赫茲,H-2,4),3.33(q,4H,J=7.5赫茲,-OSO2CH 2 CH3),1.57(t,6H,J=7.5赫茲,-OSO2CH2CH 3 )。
化合物7:黃色結晶固體;ESI MS m/z:343.4[M+H]+1H NMR(300 MHz,CDCl3) d:7.76(d,1H,J=15.9赫茲,H-5),7.70(d,1H,J=15.9赫茲,H-1),7.65-7.62(m,2H,芳香環H),7.57-7.53(m,2H,芳香環H),7.49-7.42(m,4H,芳香環H),7.34-7.30(m,1H,芳香環H),7.10(d,1H,J=15.9赫茲,H-4),7.09(d,1H,J=15.9赫茲,H-2),3.33(q,2H,J=7.5赫茲,-OSO2CH 2 CH3),1.58(t,3H,J=7.5赫茲,-OSO2CH2CH 3 )。
化合物8:灰白色結晶固體;ESI MS m/z:423.2[M+H]+1H NMR(300 MHz,CDCl3) d:7.70(d,2H,J=15.9赫茲,H-1,5),7.58-7.38(m,4H,芳香環H),7.48(t,2H,J=7.5Hz,芳香環H),7.36-7.33(m,2H,芳香環H),7.08(d,2H,J=15.9赫茲,H-2,4),3.21(s,6H,-OSO2CH 3 )。
化合物9:黃色結晶固體;ESI MS m/z:479.2[M+H]+1H NMR(300 MHz,CDCl3) d:7.71(d,2H,J=15.9赫茲,H-1,5),7.57-7.53(m,4H,芳香環H),7.47(t,2H,J=7.8赫茲,芳香環H),7.34-7.31(m,2H,芳香環H),7.08(d,2H,J=15.9赫茲,H-2,4),3.31-3.26(m,4H,-OSO2CH 2 CH2CH3),2.12-1.99(m,4H,-OSO2CH2CH 2 CH3),1.16(t,6H,J=7.5赫茲,-OSO2CH2CH 2 CH3)。
化合物10:淺黃色濃油;ESI MS m/z:547.2[M+H]+1H NMR(300 MHz,CDCl3) d:7.88-7.85(m,4H,磺酸苯酯芳香環H),7.71(t,2H,磺酸苯酯芳香環H),7.59(d,2H,J=15.9赫茲,H-1,5),7.59-7.48(m,6H,磺酸苯酯經取代的及聯苯芳香環H),7.35(t,2H,J=7.8赫茲,芳香環H),7.27-7.25(m,2H,聯苯芳香環H),7.03-7.00(m,2H,聯苯芳香環H),6.95(d,2H,J=15.9赫茲,H-2,4)。
化合物11:淺黃色結晶固體;ESI MS m/z:559.1[M+H]+1H NMR(300 MHz,CDCl3) d:7.73(d,1H,J=15.9赫茲,H-5),7.72-7.70(dd,1H,芳香環H),7.67(d,1H,J=15.9赫茲,H-1),7.67(d,2H,J=8.7赫茲,2”,6”芳香環H),7.55-7.50(m,2H,芳香環H),7.34(d,2H,J=8.7赫茲,3”,5”芳香環H),7.05(d,1H,J=15.9赫茲,H-4),7.03(d,1H,J=15.9赫茲,H-2),3.47(m,6H,-OSO2CH 2 CH3),1.58(m,9H,-OSO2CH2CH 3 )。
化合物26:非晶相;ESI MS m/z:559.1[M+H]+1H NMR(300 MHz,CDCl3) d:8.02(d,1H,J=15.9赫茲,H-1),7.72-7.70(dd,1H,芳香環H),7.73(d,1H,J=15.9赫茲,H-5),7.59-7.33(m,6H,芳香環H),7.20(d,1H,J=15.9赫茲,H-2),7.07(d,1H,J=15.9赫茲,H-4),3.58(q,2H,J=7.5赫茲,-OSO2CH 2 CH3),3.45(q,2H,J=7.5赫茲,-OSO2CH 2 CH3),3.35(q,2H,J=7.5赫茲,-OSO2CH 2 CH3),1.67(t,3H,J=7.5赫茲,-OSO2CH2CH 3 ),1.63-1.56(m,6H,-OSO2CH2CH 3 )。
化合物27:非晶相;ESI MS m/z:559.1[M+H]+1H NMR(300 MHz,CDCl3) d:7.71(d,1H,J=15.9赫茲,H-1),7.65(d,1H,J=15.9赫茲,H-5),7.54-7.39(m,5H,芳香環H),7.34-7.25(m,2H,芳香環H),7.09(d,1H,J=15.9赫茲,H-2),7.06(d,1H,J=15.9赫茲,H-4),3.40-3.01(m,6H,-OSO2CH 2 CH3),1.61-156(m,9H,-OSO2CH2CH 3 )。
化合物40:油狀糖漿;C21H22O6S,ESI-MS:m/z 403.2[M+H]+1H NMR(300 MHz,DMSO-d6):7.77-6.99(11H,m,芳香族H及乙烯基H),3.80(3H每個,s,OCH 3 ),3.77(3H每個,s,OCH 3 ),3.50(2H,m,SO2CH 2 CH3),1.34(3H,m,SO2CH2CH 3 )。
化合物43:淡黃色針,mp 102-103℃;C23H26O10S3,ESI-MS:m/z 559.1[M+H]+1H NMR(300 MHz,DMSO-d6):7.89-7.35(11H,m,芳香族H及乙烯基H),3.62(4H,m,SO2CH 2 CH3 X 2),3.53(2H,q,J=7.5赫茲,SO2CH 2 CH3),1.37(9H,m,SO2CH2CH 3 X3)。
化合物22:黃色固體;ESI MS m/z:546.19[M+H]+1H NMR(300 MHz,CDCl3) d:7.77(s. 2H,亞苄基CH=),7.50-7.28(m,8H,芳香環H),3.92(s,4H,環己基-H-3,5),3.35-3.25(m,6H,-OSO2CH 2 CH3),2.46(d,2H,J=6.6赫茲,-CH 2 ),1.59-1.50(m,9H,-OSO2CH2CH 3 ),0.86(m,1H,環丙烷基CH),0.50-0.44(m,2H,環丙烷基CH 2 ),0.15-0.08(m,2H,環丙羰基CH 2 )。
化合物53:黃色油狀,ESI MS m/z:481.0[M+H]+1H NMR(400 MHz,CD3OD) d:7.68(d,2H,J=16.2赫茲,H-1,5),7.63-7.54(m,2H,芳香環H),7.46-7.39(m,1H,芳香環H),7.33-7.01(m,4H,芳香環H;2H,H-2,4亞苄基CH=),6.84-6.81(m,1H,芳香環H),2.95(s,12H,-OSO2N(CH 3 )2)。
化合物65:非晶相,ESI MS m/z:479.6[M+H]+1H NMR(400 MHz,CDCl3) d:7.65(d,2H,J=16.0赫茲,H-1,5),7.48(br,2H,芳香環H),7.46-7.43(m,2H,芳香環H),7.31(d,2H,J=8.4赫茲,芳香環H),6.99(d,2H,J=16.0赫茲,H-2,4),3.36(q,4H,J=7.2赫茲,-OSO2CH 2 CH3),2.37(s,6H,CH3),1.57(t,6H,J=7.2赫茲,-OSO2CH2CH 3 )。
化合物66:橙色帶黃色固體,ESI MS m/z:401.6[M+H]+1H NMR(400 MHz,CDCl3) d:7.67(d,1H,J=16.0赫茲,H-1),7.63(d,1H,J=16.0赫茲,H-5),7.48-7.40(m,4H,芳香環H),7.30(d,1H,J=8.4赫茲,芳香環H),6.00(d,1H,J=16.0赫茲,H-2),5.91(d,1H,J=16.0赫茲,H-4),6.82(d,1H,J=8.4赫茲,芳香環H),3.86(s,3H,OCH3),3.36(q,2H,J=7.2赫茲,-OSO2CH 2 CH3),2.37(s,3H,CH3),2.23(s,3H,CH3),1.57(t,3H,,J=7.2赫茲,-OSO2CH2CH 3 )。
化合物69:帶褐色固體,ESI MS m/z:479.6[M+H]+1H NMR(400 MHz,CDCl3) d:7.94(d,2H,J=16.0赫茲,H-1,5),7.65(d,2H,J=8.4赫茲,芳香環H),7.14-7.12(m,4H,芳香環H),6.92(d,2H,J=16.0赫茲,H-2,4),3.28(q,4H,J=7.2赫茲,-OSO2CH 2 CH3),2.46(s,6H,-CH 3 ),1.53(t,6H,J=7.2赫茲,-OSO2CH2CH 3 )。
化合物70:淺帶褐色固體,ESI MS m/z:401.1[M+H]+1H NMR(400 MHz,CDCl3) d:7.99(d,1H,J=15.6赫茲,H-1),7.91(d,1H,J=15.6赫茲,H-5),7.65-7.61(m,2H,芳香環H),7.14-7.12(m,3H,芳香環H),6.93(d,1H,J=15.6赫茲,H-2),6.86(d,1H,J=15.6赫茲,H-4),6.77-6.74(m,1H,芳香環H),3.82(s,3H,OCH3),3.29(q,2H,J=7.2赫茲,-OSO2CH 2 CH3),2.46(s,6H,CH3),1.53(t,3H,,J=7.2赫茲,-OSO2CH2CH 3 )。
化合物74:淺帶黃色固體,ESI MS m/z:361.1[M+H]+1H NMR(400 MHz,CDCl3) d:7.66(d,2H,J=16.0赫茲,H-1,5),7.52-7.50(m,2H,芳香環H),7.45-7.41(m,1H,芳香環H),7.37-7.35(m,2H,芳香環H),7.30-7.28(m,2H,芳香環H),7.11-7.08(m,1H,芳香環H),7.04(d,1H,J=16.0赫茲,H-2),7.03(d,1H,J=16.0赫茲,H-4),3.26(q,2H,J=7.6赫茲,-OSO2CH 2 CH3),1.55(t,3H,,J=7.6赫茲,-OSO2CH2CH 3 )。
化合物77:帶黃色固體,ESI MS m/z:427.1[M+H]+1H NMR(400 MHz,CDCl3) d:7.68(d,2H,J=16.0赫茲,H-1,5),7.53-7.51(m,3H,芳香環H),7.46-7.41(m,3H,芳香環H),7.31-7.26(m,2H,芳香環H),7.05(dd,2H,J=16.0,1.6赫茲,H-2,4),3.31(q,2H,J=7.2赫茲,-OSO2CH 2 CH3),1.55(t,3H,J=7.2赫茲,-OSO2CH2CH 3 )。
以類似於合成1,5-雙-(3-羥基-苯基)-戊-1,4-二烯-3-酮之方式合成化合物78。使用乙醯氯(3當量)取代乙磺醯基氯。在室溫下攪拌3-4小時後,將該反應混合物傾入水中及以CH2Cl2萃取。以水然後鹽水清洗結合的有機層,在Na2SO4上乾燥,過濾及濃縮以提供淺黃色固體粗產物。以CombiFlash色層分析計使用正己烷/EtOAc作為沖提液純化,提供定量產率之想要的化合物。淺帶黃色結晶固體,ESI MS m/z:351.1[M+H]+1H NMR(400 MHz,CDCl3) d:7.67(d,2H,J=16.0赫茲,H-1,5),7.46-7.38(m,4H,芳香環H),7.34-7.33(m,2H,芳香環H),7.14-7.11(m,2H,芳香環H),7.02(d,2H,J=16.0,H-2,4),2.31(s,6H,-COCH 3 )。
以類似於合成1,5-雙-(3-羥基-苯基)-戊-1,4-二烯-3-酮的方式合成化合物14及24。使用氯磷酸二乙基酯(~10當量,對化合物14來說)或氯磷酸二甲基酯(~10當量,對化合物24來說)取代乙磺醯基氯。在室溫下攪拌2小時後,將該反應混合物傾入水中及以CH2Cl2萃取。以水然後鹽水清洗結合的有機層,在Na2SO4上乾燥,過濾及濃縮以提供黃色固體粗產物。以CombiFlash色層分析計使用CH2Cl2/MeOH作為沖提液純化,提供定量產率之想要的化合物。
化合物14:非晶相;ESI MS m/z:539.22[M+H]+1H NMR(300 MHz,CDCl3) d:7.69(d,2H,J=15.9赫茲,H-1,5),7.51(br. 2H,芳香環H),7.46-7.39(m,4H,芳香環H),7.32-7.28(m,2H,芳香環H),7.09(d,2H,J=15.9赫茲,H-2,4),4.32-4.22(m,8H,OCH 2 CH3),1.41(t,12H,J=7.2赫茲,OCH2CH 3 )。
化合物24:非晶相,ESI MS m/z:483.09[M+H]+1H NMR(300 MHz,CDCl3) d:7.69(d,2H,J=15.9赫茲,H-1,5),7.49-7.37(m,6H,芳香環H),7.28-7.25(m,2H,芳香環H),7.06(d,2H,J=15.9赫茲,H-2,4),3.91(s,6H,OCH 3 ),3.87(s,6H,OCH 3 )。
以類似於上述的方式合成化合物18、23、25、32-34及37。使用二乙基氯化膦(~10-15當量)來製備化合物18、35及38,使用二苯基氯化膦(~10當量)來製得化合物23,及使用二甲基氯化膦(~10當量)來製得化合物25、32及33。在室溫下攪拌2小時後,將該反應混合物傾入水中及以CH2Cl2萃取。以水及鹽水清洗有機層,在Na2SO4上乾燥,過濾及濃縮以提供粗產物化合物,如為黃色固體。以CombiFlash色層分析計使用CH2Cl2/MeOH作為沖提液純化,提供定量產率之想要的化合物。
化合物18:非晶相;ESI MS m/z:475.22[M+H]+1H NMR(300 MHz,CDCl3) d:7.70(d,2H,J=15.9赫茲,H-1,5),7.52(d,2H,J=0.9赫茲,芳香環H),7.40-7.27(m,6H,芳香環H),7.09(d,2H,J=15.9赫茲,H-2,4),1.99-1.86(m,8H,CH 2 CH3),1.30-1.16(m,12H,CH2CH 3 )。
化合物23:黃色結晶固體;ESI MS m/z:667.61[M+H]+1H NMR(300 MHz,CDCl3) d:7.95-7.88(m,8H,芳香環H),7.76-7.67(m,2H,芳香環H),7.60(d,2H,J=15.9赫茲,H-1,5),7.55-7.26(m,18H,芳香環H),6.97(d,2H,J=15.9赫茲,H-2,4)。
化合物25:黃色結晶固體;ESI MS m/z:419.07[M+H]+1H NMR(300 MHz,CDCl3) d:7.70(d,2H,J=15.9赫茲,H-1,5),7.50(d,2H,J=1.5赫茲,芳香環H),7.45-7.37(m,4H,芳香環H),7.30-7.26(m,2H,芳香環H),7.08(d,2H,J=15.9赫茲,H-2,4),1.71(s,6H,CH3),1.67(s,6H,CH3)。
化合物32:淺橙色固體;ESI MS m/z:381.14[M+Na]+1H NMR(400 MHz,CD3OD) d:8.09(d,1H,J=16.0赫茲,H-1),7.65(d,1H,J=16.0赫茲,H-5),7.26(d,1H,J=16.0赫茲,H-2),7.15(d,1H,J=16.0赫茲,H-4),7.23(t,1H,J=8.0赫茲,芳香環H),7.15-7.08(m,3H,芳香環H),6.85-6.81(m,2H,芳香環H),6.70(t,1H,J=8.0赫茲,芳香環H),1.26(s,6H,CH 3 )。
化合物33:黃色固體;ESI MS m/z:457.14[M+Na]+1H NMR(400 MHz,CD3OD) d:8.11(d,1H,J=16.0赫茲,H-1),7.70(d,1H,J=16.0赫茲,H-5),7.56-7.54(m,1H,芳香環H),7.44(t,1H,J=8.0赫茲,芳香環H),7.28(d,1H,J=16.0赫茲,H-2),7.15(d,1H,J=16.0赫茲,H-4),7.28-7.21(m,1H,芳香環H),7.15-7.08(m,3H,芳香環H),6.84-6.82(m,1H,芳香環H),6.70(t,1H,J=8.0赫茲,芳香環H),1.72(s,3H,CH 3 ),1.68(s,3H,CH 3 ),1.27-1.19(m,6H,CH 3 )。
化合物34:非晶相;ESI MS m/z:489.08[M-H]-1H NMR(400 MHz,CDCl3) d:8.14(d,1H,J=15.2赫茲,H-1),7.73(d,1H,J=15.2赫茲,H-5),7.58-7.56(m,2H,芳香環H),7.48-7.45(m,1H,芳香環H),7.33-7.28(m,3H,芳香環H),7.17-7.14(m,1H,芳香環H),6.87-6.71(m,2H,H-2,4),2.03-1.98(m,4H,CH 2 CH3),1.86-1.66(m,4H,CH 2 CH3),1.28-1.13(m,12H,CH2CH 3 )。
化合物37:非晶相;ESI MS m/z:595.08[M-H]-1H NMR(400 MHz,CDCl3) d:7.77(d,1H,J=15.6赫茲,H-5),7.69(d,1H,J=15.6赫茲,H-1),7.56-7.53(m,2H,芳香環H),7.44-7.40(m,2H,芳香環H),7.32-7.14(m,4H,芳香環H及H-2,4),7.02-6.93(m,1H,芳香環H),2.02-1.89(m,12H,CH 2 CH3),1.26-1.06(m,18H,CH2CH 3 )。
藉由下列程序合成化合物28及29。將1,5-雙-(3-羥基-苯基)-戊-1,4-二烯-3-酮(藉由在反應方案4中所闡明的方法合成)(0.16毫莫耳)在乙腈中的溶液冷卻至-78℃。在其中加入在乙腈中之Et3N(20當量)及新鮮蒸餾的POCl3(10當量)。在-78℃下攪拌所得的混合物2.5小時或藉由TLC監視。在完成後,將該反應溶液升溫至0℃及加入水(~1毫升)與吡啶(0.4毫升)。在0℃至室溫下攪拌所產生的反應混合物1.5小時及濃縮至乾燥。藉由逆相管柱色層分析計,使用C18矽凝膠及MeOH/H2O純化該粗產物(如為化合物28或29之混合物)以獲得想要的產物。
化合物28:黃色固體;ESI MS m/z:377.01[M-H+MeOH]+1H NMR(300 MHz,D2O) d:7.63(d,2H,J=15.9赫茲,H-1,5),7.45-7.38(m,6H,芳香族H),7.24-7.21(m,2H,芳香族H),7.11(d,2H,J=15.9赫茲,H-2,4)。
化合物29:黃色固體;ESI MS m/z:425.1[M-H]+1H NMR(300 MHz,D2O) d:7.47(d,2H,J=15.9赫茲,H-1,5),7.40-7.26(m,6H,芳香族H),7.21(br,2H,芳香族H),6.95(d,2H,J=15.9赫茲,H-2,4)。
化合物19、35-36、45-46、48、52、54-59及76之合成。 反應方案8
從1,5-雙-(3-羥基-苯基)-戊-1,4-二烯-3-酮或化合物20及62-64製備化合物19、35、36、67、68、71及72(反應方案8)。於K2CO3(2.5當量)存在下,使用在DMF中的(2-溴-乙基)-二乙基-胺氫溴酸(1當量)來製備化合物19。在室溫下攪拌該反應混合物24小時。過濾出固體及濃縮濾出液。以CH2Cl2稀釋所產生的殘餘物及以水清洗兩次。以CH2Cl2萃取水層兩次及在Na2SO4上乾燥。在藉由CombiFlash色層分析系統使用Grace矽凝膠匣及CH2Cl2/MeOH純化後,獲得化合物19。
化合物19:非晶相;ESI MS m/z:366.30[M+H]+1H NMR(300 MHz,CD3OD) d:7.74(d,1H,J=15.9赫茲,H-1),7.73(d,1H,J=15.9赫茲,H-5),7.39-7.12(m,7H,芳香族H),7.22(d,1H,J=15.9赫茲,H-2),7.17(d,1H,J=15.9赫茲,H-4),7.63-7.02及6.89-6.84(m,1H,芳香族H),4.25(t,2H,J=5.4赫茲,OCH 2 CH2N(CH2CH3)2),3.17(t,2H,J=5.4赫茲,OCH2CH 2 N(CH2CH3)2),2.93(q,4H,J=7.2赫茲,OCH2CH2N(CH 2 CH3)2),1.21(t,6H,J=7.2赫茲,OCH2CH2N(CH2CH 3 )2)。
化合物35:ESI MS m/z:382.75[M+H]+1H NMR(400 MHz,CD3OD)d:8.03(d,1H,J=16.0赫茲,H-1),7.34(d,1H,J=16.0赫茲,H-5),7.17(d,1H,J=16.0赫茲,H-4),7.10(d,1H,J=16.0赫茲,H-2),7.23-7.07(m,4H,芳香族H),6.98(t,1H,J=8.0赫茲,芳香族H),6.87(dd,1H,J=1.6,8.4赫茲,芳香族H),6.83(dd,1H,J=2.0,8.4赫茲,芳香族H),4.03(t,2H,J=4.8,9.6赫茲,OCH 2 CH2N(CH2CH3)2),2.85(t,2H,J=4.8,9.6赫茲,OCH2CH 2 N(CH2CH3)2),2.74(q,4H,J=7.2赫茲,OCH2CH2N(CH 2 CH3)2),1.13(t,6H,J=7.2赫茲,OCH2CH2N(CH2CH 3 )2)。
化合物36:ESI MS m/z:481.28[M+H]+1H NMR(400 MHz,CD3OD) d:8.04(d,1H,J=16.0赫茲,H-1),7.74(d,1H,J=16.0赫茲,H-5),7.25-7.15(m,6H,芳香族H,及H-4,2),7.02-6.95(m,2H,芳香族H),6.89-6.85(m,1H,芳香族H),4.20(dd,2H,J=5.2,4.8赫茲,OCH 2 CH2N(CH2CH3)2),4.05(dd,2H,J=5.2,4.8赫茲,OCH 2 CH2N(CH2CH3)2),3.10(dd,2H,J=4.8,4.4赫茲,OCH2CH 2 N(CH2CH3)2),2.92(dd,2H,J=4.8,4.4赫茲,OCH2CH 2 N(CH2CH3)2),2.66(m,8H,OCH2CH2N(CH 2 CH3)2),1.13(m,12H,OCH2CH2N(CH2CH 3 )2)。
化合物67:非晶相,ESI MS m/z:394.2[M+H]+1H NMR(400 MHz,CD3OD) d:7.67(d,2H,J=15.6赫茲,H-1,5),7.51-7.36(m,4H,芳香環H),7.08-6.70(m,4H,H-2,4及芳香環H),4.15(t,2H,J=5.2赫茲,OCH 2 CH2N(CH2CH3)2),2.99(t,2H,J=5.2赫茲,OCH2CH 2 N(CH2CH3)2),2.73-2.71(m,4H,OCH2CH2N(CH 2 CH3)2),2.23(s,3H,CH3),2.23-2.17(m,3H,CH3),1.13-1.09(m,6H,OCH2CH2N(CH2CH 3 )2)。
化合物68:非晶相,ESI MS m/z:408.1[M+H]+1H NMR(400 MHz,CD3OD) d:7.68(d,2H,J=15.2赫茲,H-1,5),7.52-7.44(m,4H,芳香環H),7.07(dd,2H,J=15.2,4.8赫茲,H-2,4),6.96-6.92(m,2H,芳香環H),4.18(t,2H,J=4.8赫茲,OCH 2 CH2N(CH2CH3)2),3.85(s,3H,OCH3),3.08(t,2H,J=5.2赫茲,OCH2CH 2 N(CH2CH3)2),2.80(m,4H,OCH2CH2N(CH 2 CH3)2),2.24(s,3H,CH3),2.20(s,3H,CH3),1.14(t,6H,J=6.8赫茲,OCH2CH2N(CH2CH 3 )2)。
化合物71:淺帶褐色固體,ESI MS m/z:408.1[M+H]+1H NMR(400 MHz,CD3OD) d:8.03(d,2H,J=16.0赫茲,H-1,5),7.74(d,2H,J=9.2赫茲,芳香環H),7.07(d,2H,J=16.0,H-2,4),6.81-6.75(m,3H,芳香環H),6.64(br,1H,芳香環H),4.11(t,2H,J=5.6赫茲,OCH 2 CH2N(CH2CH3)2),3.80(s,3H,OCH3),2.90(t,2H,J=5.6赫茲,OCH2CH 2 N(CH2CH3)2),2.66(m,4H,OCH2CH2N(CH 2 CH3)2),2.45(s,6H,CH3),1.08(t,6H,J=7.2赫茲,OCH2CH2N(CH2CH 3 )2)。
化合物72:帶黃色固體,ESI MS m/z:394.1[M+H]+1H NMR(400 MHz,CD3OD) d:8.02(dd,2H,J=15.6,4.8赫茲,H-1,5),7.74-7.65(m,2H,芳香環H),7.03(d,1H,J=15.6赫茲,H-2),7.99(d,1H,J=15.6赫茲,H-4),6.81(br,2H,芳香環H),6.66-6.65(m,2H,芳香環H),4.13(t,2H,J=5.6赫茲,OCH 2 CH2N(CH2CH3)2),2.94(t,2H,J=5.5赫茲,OCH2CH 2 N(CH2CH3)2),2.73-2.66(m,4H,OCH2CH2N(CH 2 CH3)2),2.45(s,3H,CH3),2.40(s,3H,CH3),1.11-1.04(m,6H,OCH2CH2N(CH2CH 3 )2)。
化合物52、54及58係衍生自1,5-雙-(3-羥基-苯基)-戊-1,4-二烯-3-酮(藉由顯示在反應方案4中的方法合成),其藉由於碳酸氫鉀存在下,在DMF中讓該酮與1-溴丁烷(3.0當量及1.2當量,各別對化合物52及54來說)或1-溴-3-氯丙烷(1.2當量,對化合物58來說)反應。在室溫下(對化合物52及58來說)或在80℃下(對化合物58來說)攪拌該反應混合物過夜,或以TLC監視。在減壓下蒸發溶劑及將殘餘物分配在醋酸乙酯與水中。以水清洗有機層兩次,及以醋酸乙酯萃取水性洗滌液兩次。在Na2SO4上乾燥後,過濾及濃縮,藉由CombiFlash系統使用正己烷/醋酸乙酯沖提液來純化油狀粗產物,以提供想要的化合物52、54及58。
化合物52:黃色結晶固體;ESI MS m/z:379.17[M+H]+1H NMR(400 MHz,CDCl3) d:7.61(d,2H,J=16.0赫茲,H-1,5),7.30-7.26(m,2H,芳香環H),7.16-7.15(m,2H,芳香環H),7.10(br,2H,芳香環H),7.02(dd,2H,J=16.0,2.0赫茲,H-2,4),6.93-6.91(m,2H,芳香環H),3.97(t,4H,J=6.8赫茲,-OCH 2 CH2CH2CH3),1.79-1.72(m,4H,OCH2CH 2 CH2CH3),1.51-1.45(m,4H,OCH2CH2CH 2 CH3),0.98-0.94(m,6H,OCH2CH2CH2CH 3 )。
化合物54:帶黃色固體;ESI MS m/z:323.08[M+H]+1H NMR(400 MHz,CD3OD) d:7.68(dd,2H,J=15.6,4.4赫茲,H-1,5),7.32-7.24(m,4H,芳香環H),7.18-7.16(m,2H,芳香環H),7.11(br,2H,芳香環H),7.04(dd,2H,J=15.6,4.0赫茲,H-2,4),6.95-6.88(m,2H,芳香環H),3.99(t,2H,J=12.8,6.8赫茲,OCH 2 CH2CH2CH3),1.81-1.74(m,2H,OCH2CH 2 CH2CH3),1.53-1.47(m,2H,OCH2CH2CH 2 CH3),0.99-0.96(m,3H,OCH2CH2CH2CH 3 )。
化合物58:淺黃色固體;ESI MS m/z:329.12[M+H]+1H NMR(400 MHz,CDCl3) d:7.67(d,2H,J=16.0赫茲,H-1,5),7.34-7.23(m,2H,芳香族H),7.22(d,1H,J=8.0赫茲,芳香環H),7.16(d,1H,J=8.0赫茲,芳香環H),7.13(t,1H,J=2.4赫茲,芳香環H),7.11(t,1H,J=2.0赫茲,芳香環H),7.03(dd,2H,J=16.0,2.4赫茲,H-2,4),6.97-6.94(m,1H,芳香環H),6.91-6.88(m,1H,芳香環H),4.26(t,2H,J=6.0赫茲,-OCH 2 CH2Cl),3.82(t,2H,J=6.0赫茲,-OCH2CH 2 Cl)。
化合物55-57及59係衍生自化合物58(對化合物57及59來說)或化合物58的類似物,其中R1基團係以3-氯丙氧基置換(反應方案8)。在化合物58於DMF中的溶液中加入哌啶(~4當量)。將所產生的反應混合物加熱至80℃及攪拌過夜。在冷卻至室溫後,在減壓下蒸發溶劑及將殘餘物分配在醋酸乙酯與水中。以水清洗有機相兩次及以醋酸乙酯萃取水性洗滌液兩次。在Na2SO4上乾燥後,過濾及濃縮,藉由CombiFlash系統使用二氯甲烷/甲醇沖提液來純化粗產物,然後從甲醇結晶以提供化合物57。非晶相,ESI MS m/z:378.25[M+H]+1H NMR(400 MHz,CD3OD) d:7.60(d,1H,J=16.0赫茲,H-1),7.57(d,1H,J=16.0赫茲,H-5),7.27-7.22(m,2H,芳香環H),7.15-7.11(m,2H,芳香環H),7.02(t,1H,J=2.0赫茲,芳香環H),6.97(d,1H,J=16.0赫茲,H-2),6.92(d,1H,J=16.0赫茲,H-4),6.88-6.84(m,3H,芳香環H),4.13(t,2H,J=5.6赫茲,OCH 2 CH2N(CH2CH2)2CH2),2.82(t,2H,J=5.6赫茲,OCH2CH 2 N(CH2CH2)2CH2),2.58(br,4H,OCH2CH2N(CH 2 CH2)2CH2),1.68-1.63(m,4H,OCH2CH2N(CH2CH 2 )2CH2),1.48-1.45(m,2H,OCH2CH2N(CH2CH2)2CH 2 )。
以與如上所述相同的方式,藉由讓經3-氯丙氧基取代的1,5-雙-(3-經取代的-苯基)-戊-1,4-二烯-3-酮與二乙胺反應來合成化合物55。產率:40%,非晶相,ESI MS m/z:380.25[M+H]+1H NMR(400 MHz,CD3OD) d:7.72(d,1H,J=16.0赫茲,H-1),7.71(d,1H,J=16.0赫茲,H-5),7.35-7.25(m,4H,芳香環H),7.23-7.21(m,1H,芳香環H),7.15(d,2H,J=16.0赫茲,H-2,4),7.10(t,1H,J=2.0赫茲,芳香環H),7.01-6.98(m,1H,芳香環H),6.86-6.83(m,1H,芳香環H),4.11(t,2H,J=6.4赫茲,OCH 2 CH2CH2N(CH2CH3)2),2.99-2.95(m,2H,OCH2CH2CH 2 N(CH2CH3)2),2.88(q,4H,J=7.2赫茲,OCH2CH2CH2N(CH 2 CH3)2),2.10-2.03(m,2H,OCH2CH 2 CH2N(CH2CH3)2),1.18(t,6H,J=7.2赫茲,OCH2CH2CH2N(CH2CH 3 )2)。
以與如上所述相同的方式,藉由讓經3-氯丙氧基取代的1,5-雙-(3-經取代的-苯基)-戊-1,4-二烯-3-酮與哌啶反應來合成化合物56。非晶相。ESI MS m/z:392.25[M+H]+1H NMR(400 MHz,CD3OD) d:7.72(d,1H,J=16.0赫茲,H-1),7.70(d,1H,J=16.0赫茲,H-5),7.34-7.21(m,4H,芳香環H),7.23(d,1H,J=16.0赫茲,H-2),7.15(d,1H,J=16.0赫茲,H-4),7.16-7.15(m,1H,芳香環H),7.09(t,1H,J=2.4赫茲,芳香環H),6.99-6.96(m,1H,芳香環H),6.86-6.83(m,1H,芳香環H),4.06(t,2H,J=6.4赫茲,-OCH 2 CH2CH2N(CH2CH2)2CH2),2.62-2.54(m,6H,-OCH2CH2CH 2 N(CH 2 CH2)2CH2),2.05-1.98(m,2H,OCH2CH 2 CH2N(CH2CH2)2CH2),1.66-1.61(m,4H,OCH2CH2CH2N(CH2CH 2 )2CH2),1.51-1.49(m,2H,OCH2CH2CH2N(CH2CH 2 )2CH 2 )。
以與如上所述相同的方式,藉由讓化合物58與哌啶反應來合成化合物59。產率:35%,非晶相,ESI MS m/z:380.25[M+H]+1H NMR(400 MHz,CD3OD) d:7.72(d,1H,J=16.0赫茲,H-1),7.70(d,1H,J=16.0赫茲,H-5),7.35-7.21(m,5H,芳香環H),7.14(d,2H,J=16.0赫茲,H-2,4),7.09(t,1H,J=2.0赫茲,芳香環H),7.02-6.99(m,1H,芳香環H),6.86-6.83(m,1H,芳香環H),4.19(t,2H,J=5.6赫茲,OCH 2 CH2N(CH2CH2)2O),3.71(t,4H,J=4.8赫茲,OCH2CH2N(CH2CH 2 )2O),2.84-2.81(m,2H,OCH2CH 2 N(CH2CH2)2O),2.61(t,4H,J=4.8赫茲,OCH2CH2N(CH 2 CH2)2O)。
藉由於K2CO3(2.5當量)存在下,在DMF中讓化合物16與1當量的(2-溴-乙基)-二乙基-胺氫溴酸反應來合成化合物45(反應方案7)。在室溫下攪拌該反應混合物過夜,或以TLC監視。在減壓下蒸發溶劑及將殘餘物分配在二氯甲烷與水中。以水清洗有機相三次(或至pH~6-7),及以二氯甲烷萃取水性洗滌液兩次。在Na2SO4上乾燥後,過濾及濃縮,藉由CombiFlash系統使用二氯甲烷/甲醇沖提液來純化油狀粗產物以提供想要的產物,如為黃色固體。ESI MS m/z:475.13[M+H]+1H NMR(400 MHz,CD3OD) d:7.75(d,1H,J=11.6赫茲,亞苄基CH=),7.38(s,br,1H,亞苄基CH=),7.28(s,br,1H,芳香環H),7.11-6.84(m,7H,芳香環H),5.04(s,2H,哌啶-4-酮),4.91(s,2H,哌啶-4-酮),4.21(m,2H,OCH 2 CH2N(CH2CH3)2),3.14(m,2H,OCH2CH 2 N(CH2CH3)2),2.87(m,4H,OCH2CH2N(CH 2 CH3)2),1.17(m,6H,OCH2CH2N(CH2CH 3 )2),0.87(m,1H,環丙羰基CH),0.74(m,2H,環丙羰基CH 2 ),0.62(m,2H,環丙羰基CH 2 )。
以與如上所述相同的方式合成化合物46,除了使用2當量的(2-溴-乙基)-二乙基-胺氫溴酸及5當量的K2CO3外。
化合物46:黃色固體;ESI MS m/z:574.21[M+H]+1H NMR(400 MHz,CD3OD) d:7.75(d,1H,J=11.6赫茲,亞苄基CH=),7.38(s,br,1H,亞苄基CH=),7.28(s,br,1H,芳香環H),7.11-6.84(m,7H,芳香環H),5.05(s,2H,哌啶-4-酮),4.91(s,2H,哌啶-4-酮),4.49(m,2H,OCH 2 CH2N(CH2CH3)2),3.86(m,2H,OCH 2 CH2N(CH2CH3)2),3.55(q,4H,J=7.6赫茲,OCH2CH2N(CH 2 CH3)2),3.49(t,2H,J=6.4赫茲,OCH2CH 2 N(CH2CH3)2),2.87(t,2H,J=6.4赫茲,OCH2CH 2 N(CH2CH3)2),2.62(q,4H,J=7.6赫茲,OCH2CH2N(CH 2 CH3)2),1.38(t,6H,J=7.6赫茲,OCH2CH2N(CH2CH 3 )2),1.05(t,J=7.6赫茲,6H,OCH2CH2N(CH2CH 3 )2),0.87(m,1H,環丙羰基CH),0.74(m,2H,環丙羰基CH 2 ),0.64(m,2H,環丙羰基CH 2 )。
藉由在CH2Cl2中各別讓化合物19及59與乙磺醯基氯(~1.3當量)及Et3N(~1.5當量)反應來合成化合物48及76(反應方案8)。在室溫下進行反應伴隨著攪拌4-5小時。在完成後,將該反應混合物傾入水中及以水清洗兩次。以CH2Cl2萃取水層兩次。在以CombiFlash系統使用CH2Cl2/MeOH沖提液純化後,獲得定量的化合物48,如為淺棕色固體。ESI MS m/z:458.21[M+H]+1H NMR(400 MHz,CD3OD) d:7.72(d,1H,J=16.0赫茲,H-1),7.71(d,1H,J=16.0赫茲,H-5),7.64(d,1H,J=7.6赫茲,芳香環H),7.61(t,1H,J=2.0赫茲,芳香環H),7.46(t,1H,J=8.0赫茲,芳香環H),7.34-7.29(m,2H,芳香環H),7.24-7.23(m,2H,芳香環H),7.24(d,1H,J=16.0赫茲,H-2),7.19(d,1H,J=16.0赫茲,H-4),6.99-6.97(m,1H,芳香環H),4.11(t,2H,J=5.6赫茲,OCH 2 CH2N(CH2CH3)2),3.40(q,2H,J=7.6 赫茲,SO2CH 2 CH3),2.91(t,2H,J=5.6赫茲,OCH2CH 2 N(CH2CH3)2),2.67(q,4H,J=7.2赫茲,OCH2CH2N(CH 2 CH3)2),1.47(t,3H,J=7.6赫茲,SO2CH2CH 3 ),1.08(t,J=7.2赫茲,6H,OCH2CH2N(CH2CH 3 )2)。
化合物76:非晶相。ESI MS m/z:470.1[M+H]+1H NMR(400 MHz,CDCl3) d:7.67(dd,2H,J=16.0,4.4赫茲,H-1,5),7.54-7.50(m,2H,芳香環H),7.43(t,1H,J=7.6赫茲,芳香環H),7.32(m,2H,芳香環H),7.20-7.15(m,2H,芳香環H),7.05(dd,2H,J=16.0,4.4赫茲,H-2,4),6.95-6.92(m,1H,芳香環H),4.30(t,2H,J=4.8赫茲,OCH 2 CH2N(CH2CH2)2CH2),3.30(q,2H,J=7.6赫茲,SO2CH 2 CH3),3.01(t,2H,J=4.8赫茲,OCH2CH 2 N(CH2CH2)2CH2),2.78(br,4H,OCH2CH2N(CH 2 CH2)2CH2),1.76(br,4H,OCH2CH2N(CH2CH 2 )2CH2),1.56-1.52(m,5H,SO2CH2CH 3 ,及OCH2CH2N(CH2CH2)2CH 2 )。
反應方案9
藉由在丙酮中讓化合物19與琥珀酸反應來製備化合物47。參見上述反應方案9。
在琥珀酸(0.397克,3.36毫莫耳)於丙酮(9.5毫升)中的溶液中,慢慢加入在3-4毫升丙酮中之化合物19(1.23克,3.36毫莫耳)伴隨著攪拌。在加入期間,形成及析出淺黃色結晶固體。在室溫下攪拌2小時後,將該反應混合物貯存在冰箱中過夜。藉由過濾收集固體及以丙酮清洗以提供化合物47,如為淺黃色結晶固體,產率85%。
化合物47:mp. 104-106℃;ESI MS m/z:366.30[M-C4H6O4+1]+1H NMR(400 MHz,CD3OD) d:7.72(d,1H,J=16.0赫茲,H-1),7.70(d,1H,J=16.0赫茲,H-5),7.39-7.32(m,3H,芳香族H),7.26(d,1H,J=16.0赫茲,H-2),7.23(t,1H,J=8.0赫茲,芳香族H),7.14(d,1H,J=16.0赫茲,H-4),7.13-7.09(m,2H,芳香族H),7.07-7.04(m,1H,芳香族H),6.86-6.84(m,1H,芳香族H),4.37(t,2H,J=5.2赫茲,OCH 2 CH2N(CH2CH3)2),3.50(t,2H,J=5.2赫茲,OCH2CH 2 N(CH2CH3)2),3.23(q,4H,J=7.2赫茲,OCH2CH2N(CH 2 CH3)2),2.49(s,4H,琥珀酸-CH 2 CH 2 COOH),1.32(t,6H,J=7.2赫茲,OCH2CH2N(CH2CH 3 )2)。
以類似的方式從化合物48製備化合物49。參見上述反應方案9。
化合物49:棕色黏油。ESI MS m/z:458.21[M-C4H6O4+1]+1H NMR(400 MHz,CD3OD) d:7.77(d,2H,J=16.0赫茲,H-1,5),7.67(d,1H,J=8.0赫茲,芳香環H),7.65(t,1H,J=2.0赫茲,芳香環H),7.51(t,1H,J=8.0赫茲,芳香環H),7.38-7.33(m,4H,芳香環H),7.30(d,1H,J=16.0赫茲,H-2),7.26(d,1H,J=16.0赫茲,H-4),7.08-7.05(m,1H,芳香環H),4.34(t,2H,J=5.2赫茲,OCH 2 CH2N(CH2CH3)2),3.44(t,2H,J=5.2赫茲,OCH2CH 2 N(CH2CH3)2),3.42(q,2H,J=7.2赫茲,SO2CH 2 CH3),3.18(q,4H,J=7.2赫茲,OCH2CH2N(CH 2 CH3)2),2.49(s,4H,琥珀酸-CH 2 CH 2 COOH),1.49(t,3H,J=7.2赫茲,SO2CH2CH 3 ),1.30(t,6H,J=7.2赫茲,OCH2CH2N(CH2CH 3 )2)。
藉由在丙酮中讓化合物48與磷酸(85%水溶液)反應來製備化合物50。參見上述反應方案9。
在化合物48(0.28克,3.36毫莫耳)於丙酮(0.5毫升)中的溶液中,在0℃下慢慢加入85%H3PO4水溶液(1當量的H3PO4,0.6毫莫耳)伴隨著攪拌。在室溫下攪拌後1小時,將該反應混合物貯存在冰箱中過夜。在蒸發溶劑後,將殘餘物溶解在7毫升H2O中,然後冷凍。冷凍乾燥法提供化合物50,如為黃色結晶固體,產率95%。
化合物50:ESI MS m/z:458.21[M-H3PO4+1]+1H NMR(400 MHz,CD3OD) d:7.78(d,2H,J=16.0赫茲,H-1,5),7.69(d,1H,J=7.6赫茲,芳香環H),7.65(t,1H,J=1.6赫茲,芳香環H),7.51(t,1H,J=8.0赫茲,芳香環H),7.39-7.35(m,4H,芳香環H),7.30(d,1H,J=16.0赫茲,H-2),7.27(d,1H,J=16.0赫茲,H-4),7.11-7.06(m,1H,芳香環H),4.43(t,2H,J=4.8赫茲,OCH 2 CH2N(CH2CH3)2),3.60(t,2H,J=4.8赫茲,OCH2CH 2 N(CH2CH3)2),3.42(q,2H,J=7.2赫茲,SO2CH 2 CH3),3.33(q,4H,J=7.2赫茲,OCH2CH2N(CH 2 CH3)2),1.49(t,3H,J=7.2赫茲,SO2CH2CH 3 ),1.37(t,6H,J=7.2赫茲,OCH2CH2N(CH2CH 3 )2)。
從化合物19,以類似的方式製備化合物51,如為明黃色結晶固體。參見上述反應方案9。
化合物51:ESI MS m/z:366.30[M-H3PO4+1]+1H NMR(400 MHz,CD3OD) d:7.74(d,1H,J=16.0赫茲,H-1),7.72(d,1H,J=16.0赫茲,H-5),7.39-7.35(m,3H,芳香族H),7.28(d,1H,J=16.0赫茲,H-2),7.24(t,1H,J=7.6赫茲,芳香族H),7.16(d,1H,J=16.0赫茲,H-4),7.17-7.15(m,1H,芳香族H),7.11-7.06(m,2H,芳香族H),6.87-6.84(m,1H,芳香族H),4.42(t,2H,J=4.8赫茲,OCH 2 CH2N(CH2CH3)2),3.61(t,2H,J=4.8赫茲,OCH2CH 2 N(CH2CH3)2),3.33(q,4H,J=7.2赫茲,OCH2CH2N(CH 2 CH3)2),1.37(t,6H,J=7.2赫茲,OCH2CH2N(CH2CH 3 )2)。
藉由讓化合物48與2.0 M氯化氫乙基醚溶液反應來製備化合物79,如為黃色結晶固體。
在化合物48於甲醇中的溶液中,在0℃下慢慢加入2.0 M氯化氫乙基醚溶液伴隨著攪拌。在室溫下攪拌1小時後,將該反應混合物貯存在冰箱中過夜。蒸發溶劑及以三級丁基甲基醚清洗殘餘物三次。冷凍乾燥法提供定量產率的化合物79,如為黃色結晶固體。
在化合物48於甲醇中的溶液中,在0℃下慢慢加入2.0 M氯化氫乙基醚溶液伴隨著攪拌。在室溫下攪拌1小時後,將該反應混合物貯存在冰箱中過夜。蒸發溶劑及以三級丁基甲基醚清洗殘餘物三次。冷凍乾燥法提供定量產率的化合物79,如為黃色結晶固體。ESI MS m/z:458.21[M-HCl+1]+1H NMR(400 MHz,CD3OD) d:7.80(d,2H,J=16.0赫茲,H-1,5),7.71(d,1H,J=8.0赫茲,芳香環H),7.67(t,1H,J=2.4赫茲,芳香環H),7.53(t,1H,J=8.0赫茲,芳香環H),7.42-7.41(m,2H,芳香環H),7.39-7.37(m,2H,芳香環H),7.32(d,1H,J=16.0赫茲,H-2),7.29(d,1H,J=16.0赫茲,H-4),7.13-7.10(m,1H,芳香環H),4.44(t,2H,J=4.8赫茲,OCH 2 CH2N(CH2CH3)2),3.65(t,2H,J=4.8赫茲,OCH2CH 2 N(CH2CH3)2),3.43(q,2H,J=7.6赫茲,SO2CH 2 CH3),3.37(q,4H,J=7.2赫茲,OCH2CH2N(CH 2 CH3)2),1.51(t,3H,J=7.6赫茲,SO2CH2CH 3 ),1.40(t,6H,J=7.2赫茲,OCH2CH2N(CH2CH 3 )2)。
化合物60及61之合成 反應方案10
從a-溴甲基-苯乙腈合成化合物60及61。在a-溴甲基-苯乙腈(15.3毫莫耳)於甲苯(30毫升)中的溶液中,在30分鐘內,於0℃下加入於THF中的DIBAL-H(1.0 M,1.4當量)。在0℃下攪拌2小時後,將該反應混合物傾入40毫升二氯甲烷與100毫升10%HCl之混合物中。攪拌所得的混合物1小時,以水然後鹽水清洗有機層,及以二氯甲烷萃取水層兩次。在Na2SO4上乾燥後,過濾及濃縮,將所獲得的半油狀產物貯存在冰箱中,以定量的產率提供3-(溴甲基)苯甲醛,如為白色結晶固體。遵循敍述在反應方案4中的程序,讓所產生的化合物與丙酮在乙醇中反應產生化合物61,如為淺黃色結晶固體。ESI MS m/z:420.9[M+H]+1H NMR(400 MHz,CDCl3) d:7.71(d,2H,J=16.0赫茲,H-1,5),7.63-7.60(m,2H,芳香環H),7.54-7.50(m,2H,芳香環H),7.44-7.37(m,4H,芳香環H),7.08(d,2H,J=16.0赫茲,H-2,4),4.50(s,4H,-CH 2 Br)。
藉由讓在CH2Cl2中的化合物61與乙磺醯基氯(2當量)、亞硫酸鈉(4當量)、碳酸氫鈉(4當量)在水中之混合物反應獲得化合物60。在35-36℃下攪拌所得的混合物過夜。以二氯甲烷稀釋該反應混合物,以水然後鹽水清洗,及在Na2SO4上乾燥。以CombiFlash系統使用正己烷類/EtOAc沖提液來純化粗產物以獲得想要的產物,如為淺黃色固體。產率:44%。ESI MS m/z:447.1[M+H]+1H NMR(400 MHz,CDCl3) d:7.55(d,2H,J=16.0赫茲,H-1,5),7.53(br,2H,芳香族的H),7.47-7.25(m,2H,芳香環H),7.42-7.38(m,4H,芳香環H),6.70(d,2H,J=16.0赫茲,H-2,4),4.57(s,4H,-CH 2 SO2CH2CH3),2.82-2.70(m,4H,-CH2SO2CH 2 CH3),1.30(t,6H,J=7.2赫茲,-CH2SO2CH 2 CH 3 )。
生物學試驗 在人類Lernert’s T細胞淋巴瘤KT-3的增生上之抑制效應
如下列所描述般測量本發明之化合物在人類Lennert’s T細胞淋巴瘤KT-3細胞(一種IL-6相依性細胞株)生長上的抑制效應。簡單地說,將KT-3細胞轉移至96井板的井中(2.5×103/井),及在包含盤尼西林(25 U/毫升)、鏈黴素(25微克/毫升)、10%熱滅活的胎牛血清(FBS)及hIL-6(2.5奈克/毫升,R & D系統)之RPMI-1640媒體(Gibco)中培養。在實驗井中,在將細胞平板化後,立即加入多種濃度的測試化合物(一式三份)。在對照井中,加入等體積的媒劑DMSO(0.1%v/v)。在以化合物或於媒劑中培養該等細胞48小時後,使用CellTiter Glo Luminescent Cell Viability Assay Kit(Promega,Madison,WI)評估細胞生存能力。使用Microplate冷光儀LB96V(EG &G BERTH HOLD),根據製造商的協定來定量所產生的發光。藉由將經化合物處理的細胞之發光值除以經媒劑處理的細胞之值來計算細胞存活比例。
化合物1-79在IL-6引發的KT-3細胞增生上全部顯示出抑制效應。某些化合物(即,化合物6、16、18、19、26、27、35、36、45-51、56、57及79)未預期地具有IC50值(抑制細胞生長50%的化合物濃度)等於或甚至低於0.05 M。此外,化合物1-79全部以劑量相依方式抑制KT-3細胞增生。
抑制多種人類腫瘤細胞株之生長
如下列所描述般測量化合物6在下列細胞之生長上的抑制效應:結腸癌細胞(HCT116、HT29、SW480及SW620)、結腸腺癌細胞(Colo205)、前列腺腺癌細胞(PC-3及Du145)、前列腺癌細胞(CWR22RV及LNCap)、非小細胞肺癌細胞(NCI-H1299)、肺腺癌細胞(A549)、大細胞肺癌細胞(NCI-H460)、乳房轉移性癌細胞(MDA-MB-453)、乳腺管癌細胞(T-47D)、乳房腺癌細胞(MCF7)、肝細胞癌細胞(Huh-7及HepG2)、胰臟癌細胞(PANC-1)、子宮頸腺癌細胞(Hela)、IL-6相依性之Lennert’s T細胞淋巴瘤細胞(KT-3)、IL-6相依性之多發性骨髓瘤細胞(INA-6)、多發性骨髓瘤細胞(KMM-1及U266)、骨髓性白血病細胞(HL-60)及T細胞白血病細胞(Jurkat)。簡單地說,以1×103至4×103/井之密度範圍將腫瘤細胞播種在96井Microtest III組織培養板(Falcon,NJ)中。在包含盤尼西林(25單位/毫升)、鏈黴素(25微克/毫升)及10%熱滅活的FBS之DMEM(Gibco)中培養12小時後,以多種濃度範圍(從0至5 μM)的化合物6處理細胞72小時。然後,使用以四唑鎓為基底的量熱分析(MTT)來評估腫瘤細胞的生存能力,如在Su等人,J Mol Cell Cardiol. 1998;30:587-598中所描述。在37℃下,以該MTT染料(5毫克/毫升)培養該等細胞3小時。以MTT溶解緩衝液(50%DMF,24 mM HCl,2%醋酸,5%SDS)溶解所產生的甲結晶,及使用Benchmark微板讀出器(Bio-Rad,Hercules,CA)測量在595奈米處的吸收度。藉由經化合物處理的細胞之吸收值對經媒劑處理的細胞來計算細胞存活比例。
化合物6在全部經測試的腫瘤細胞之生長上顯示出劑量相依的抑制效應,且具有範圍0.02至5.5 μM的IC50值。
在KT-3細胞中的MRG、STAT1、STAT3及STAT5蛋白質之西方墨點法(Western blot)分析
如在Kawashima等人,J. Immunol. 2001,167:3652-3660中所描述般進行西方墨點法分析,伴隨著少量修改。簡單地說,以1、5或20 μM化合物6或媒劑單獨在上述包含IL-6的媒體中處理KT-3細胞。在培養後的不同時間點處(即,在處理後之0.5、1、3及6小時處)採集細胞,及使用溶解緩衝液(1.0% Triton X-100,50 mM Tris-HCl(pH 7.5),0.1 mM EDTA,150 mM NaCl,200 μM Na3VO4,50 mM NaF,1 mM二硫蘇糖醇,0.4 mM苯基甲基碸基氟,3微克/毫升的抗蛋白酶肽,2微克/毫升的胃蛋白酶抑制素A,1微克/毫升的亮肽素(leupeptin)),以2×107細胞/毫升,於冰上溶解細胞30分鐘。藉由在12,000×克下離心15分鐘採集細胞溶成物。讓該樣品(1×105細胞當量/線道)接受硫酸十二烷酯鈉-聚丙烯醯胺凝膠電泳,隨後轉移到Immobilon過濾器(Millipore)上。在以5%BSA阻斷後,以抗-pSTAT3、STAT3、STAT5、STAT1、MRG或肌動蛋白Abs探測該過濾器。從Santa Cruz Biotechnology購得該兔多株抗-STAT3、抗-STAT5、抗-STAT1及抗肌動蛋白抗體(Abs)、及老鼠單株抗-pSTAT3 Ab(B-7)。如先前在Hirose等人,J. Biol. Chem. 276:5821-5828中所描述般製備經親和純化的抗-MRG Ab。該過濾器進一步以結合HRP的二級抗體培養。最後,使用增強型化學發光(Enhanced Chemiluminescence)(ECL)系統(Amersham)顯現出蛋白質。
結果顯示出化合物6以時間及劑量相依的方式向下調節MRG(MgcRacGAP,一種演化保守(evolutionarily conserved)的GTP酶-活化)蛋白質、STAT3及STAT5蛋白質,及抑制在KT-3細胞中的STAT3蛋白質之磷酸化。比較上,此化合物於測試條件下在KT3細胞中的STAT1之表現性上不具有效應。
在老鼠異種移植物模型中於人類結腸癌(HCT-116)上的抑制效應
在機構動物照顧及使用委員會(Institutional Animal Care and Use Committee)認可的協定下並遵循動物適合且人道使用在研究之機構指導方針來進行活體內實驗。從Harlan Laboratory購買六週大的無胸腺母裸小鼠。八隻老鼠每隻在左側齒面皮下注射1x106與Matrigel(BD Bioscience)混合的HCT-116細胞。在注射後,於治療前,允許腫瘤生長5天至可摸到的大小(體積~100立方毫米)。將老鼠隨機分成二組(n=每組4隻)。對照組僅注射媒劑溶液(即,10%DMSO及90%玉米胚芽油),同時實驗組從第0(起始注射日)至4天及從第7至10天接受每日注射(i.p.)化合物6(以劑量40毫克/公斤體重,溶解在媒劑溶液中)。使用游標卡尺一週測量腫瘤大小兩次且使用下式計算:長度×寬度×高度×0.5236,如在Rockwell等人,J Natl. Cancer Inst. 1972;49:735-747中所描述。
結果顯示出化合物6在異種移植物老鼠模型中抑制人類結腸癌生長。
其它具體實例
在本專利說明書中所揭示的全部特徵可以任何組合結合。在本專利說明書中所揭示的每種特徵可由提供相同、相當或類似目的之另一種特徵置換。因此,除非有明確地描述,否則所揭示的每種特徵僅為相等或類似特徵的一般系列之實施例。
熟習該項技術者可從上述容易地查明本發明之基本特徵,及可沒有離開其精神及範圍製得本發明的多種改變及改質,以讓其適應多種用途及條件。因此,其它具體實例亦在下列申請專利範圍的範圍內。

Claims (12)

  1. 一種下式之化合物, 其中X及Y各自獨立地係H、烷基或鹵基;及R1、R2、R3、R4、R5、R1’、R2’、R3’、R4’及R5’各自獨立地係H、烷基、鹵基、OH、Rc-O-、RdS(O)2-O-、(Rd)2P(O)-O-或(RdO)2P(O)-O-,Rc係未經取代的烷基或經鹵基、OH、烷氧基、胺基、或環烷基取代的烷基,及Rd係H、OH、烷基、或烷氧基;其中R1、R2、R3、R4、R5、R1’、R2’、R3’、R4’及R5’之至少一個係RdS(O)2-O-、(Rd)2P(O)-O-或(RdO)2P(O)-O-。
  2. 如申請專利範圍第1項之化合物,其中X及Y各為H。
  3. 如申請專利範圍第2項之化合物,其中R2係RdS(O)2-O-、(Rd)2P(O)-O-或(RdO)2P(O)-O-。
  4. 如申請專利範圍第3項之化合物,其中R2’係R-O-,R係經胺基取代的烷基。
  5. 如申請專利範圍第3項之化合物,其中R2’係RdS(O)2-O-、(Rd)2P(O)-O-或(RdO)2P(O)-O-。
  6. 如申請專利範圍第5項之化合物,其中R1’、R3’及R4’之一係RdS(O)2-O-、(Rd)2P(O)-O-或(RdO)2P(O)-O-。
  7. 如申請專利範圍第3項之化合物,其中R2係C2H5S(O)2-O-、(C2H5)2P(O)-O-或(C2H5O)2P(O)-O-。
  8. 一種化合物,其中該化合物係選自於下列化合物所組成之群:
  9. 一種使用如申請專利範圍第1項之化合物於製造用於治療患者的癌之藥劑的用途。
  10. 如申請專利範圍第9項之用途,其中該癌係結腸癌、前列腺癌、肺癌、腎臟癌、膀胱癌、乳房癌、肝細胞癌、胰癌、胃癌、子宮頸癌、卵巢癌、神經膠質瘤、黑腫瘤、淋巴瘤、多發性骨髓瘤及白血病。
  11. 一種使用如申請專利範圍第8項之化合物於製造用於治療患者的癌之藥劑的用途。
  12. 如申請專利範圍第11項之用途,其中該癌係結腸癌、前列線癌、肺癌、腎臟癌、膀胱癌、乳房癌、肝細胞癌、胰癌、胃癌、子宮頸癌、卵巢癌、神經膠質瘤、黑腫瘤、淋巴瘤、多發性骨髓瘤及白血病。
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