TWI639585B - 非類固醇抗雄激素及具有吡啶部份的選擇性雄激素受體調節劑 - Google Patents
非類固醇抗雄激素及具有吡啶部份的選擇性雄激素受體調節劑 Download PDFInfo
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- TWI639585B TWI639585B TW103144323A TW103144323A TWI639585B TW I639585 B TWI639585 B TW I639585B TW 103144323 A TW103144323 A TW 103144323A TW 103144323 A TW103144323 A TW 103144323A TW I639585 B TWI639585 B TW I639585B
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Abstract
係提供一種具下列結構之化合物或其鹽類:
係用於治療或降低雄激素-依賴性疾病,如前列腺癌、良性前列腺增生、多囊性卵巢症候群、痤瘡、多毛症、脂溢性皮炎、雄激素性脫髮、雄性禿、肌肉萎縮和無力、肌少症、男性性腺功能減退症、勃起功能障礙、女性性功能障礙及骨質疏鬆。其可與醫藥上可接受之稀釋劑或載體一同配製,或製造為任何醫藥藥劑形式。亦揭示具有其他活性醫藥試劑之組合物。
Description
本發明相關於一種雄激素活性抑制劑,例如對於雄激素受體具拮抗劑活性之非類固醇化合物。更特別的是,本發明相關於某些非類固醇化合物,其具特定之側鏈(如含有一吡啶部分),其與雄激素受體之螺旋12相互作用,且其代謝物會透過作用於雄激素受體而阻斷雄激素作用,而在某些或所有雄激素-敏感組織中不會活化此受體。本發明之某些化合物為選擇性雄激素受體調節劑(SARMs),其在某些組織中(如前列腺)具希望之拮抗劑活性,而在某些其他組織中具有希望之促效劑活性(如肌肉、性功能...)。
在某些雄激素-依賴性疾病之治療過程中,大幅降低或理想上消除雄激素-誘發之作用是相當重要的。就此目的而言,希望可以“抗雄激素”阻斷進入雄激素受體,因此預防雄激素結合至與活化這些受體,亦可降低可活化受體之濃度。甚至在無雄激素存在下,未結合之雄激素受體
可能具生物性活性。因此,結合並阻斷受體之抗雄激素可產生更佳之治療結果,與僅抑制雄激素產生之療法相較。
抗雄激素對於減慢或停止雄激素-依賴性疾病之進展,具有助益性療效,如其啟動或進展需要雄激素受體或雄激素受體調節劑活化之幫助之疾病。
希望抗雄激素可用於治療中,以降低雄激素受體之活化,具有良好之雄激素受體親和性,並缺乏有興趣組織之內生性雄激素活性。前者係指抗雄激素結合至雄激素受體之能力,因此可阻斷雄激素接近受體。後者係指抗雄激素一旦結合上去,對於受體之作用。某些抗雄激素可具有內生性雄激素活性(“促效劑活性”),會不希望地活化預期應被阻斷之雄激素受體。換言之,具有不希望內生性雄激素活性之抗雄激素,會成功地結合至雄激素受體,如預期地阻斷這些受體與天然雄激素結合,但其本身會不希望地活化組織中之受體,而該處希望能排除抗雄激素作用,此種化合物為雄激素受體拮抗劑/促效劑之混合物。
已知之非類固醇抗雄激素如氟他胺(flutamid)、康士得(casodex)與安納左(anandron),缺乏不希望之雄激素活性,但可能有較低的受體親和力,與類固醇抗雄激素相較(即,具有經修飾之類固醇核心,以提供抗雄激素活性之雄激素衍生物)。然而,類固醇抗雄激素被認為更常具有不希望的促效劑特性,與非類固醇抗雄激素相較。近來,已報導有一些新的非類固醇抗雄激素具有長取代基,並具有比上述非類固醇抗雄激素更好的活性(Tucker等人,
1988;Balog等人,2004;Kinoyama等人,2004;Kinoyama等人,2005;Kinoyama等人,2006;McGinley與Koh,2007;Salvati等人,2008;Zhou等人,2009;Xiao等人,2010;Duke III等人,2011;Guo等人,2011;Guo等人,2012;Yang等人,2013;Gryder等人,2013)與揭示於(US 5,411,981、US 6,071,957、US 7,141,578、US 7,001,911、EP 0 100 172、FR 2671348、FR 2693461、EP 002 892、EP 0 494 819、EP 0 578 516、EP 0 580 459、WO 95/18794、WO 96/19458、WO 97/00071、WO 97/19064、WO 97/23464、WO 98/53826、JP 200288073A、WO 00/37430WO 01/16108、WO 01/16133、WO 02/24702、WO 2004/099188、WO 2004/111012、WO 2004/113309、WO 2005/040136、WO 2006/124118、WO 2007/005887、WO 2007/127010、WO 2008/044033、WO 2008/124000、WO 2009/055053、WO 2009/119880、WO 2010/143803、WO 2012/050868、WO 2012/143599、US 2010/0331418、US 2012/0184580、US 2012/0251551、US 2013/0116258、US 2013/0197009)。此外,抗雄激素之回顧請見Mohler等人,2012、Liu等人,2010,以及Singh等人,2000,所著。
然而,具有非常高的雄激素受體親和力,且缺乏不希望之促效劑特性之類固醇抗雄激素,係揭示於WO2005/066194中。這些化合物於位置18具有特定側鏈,其與螺旋12相互作用。類似地,具有非常高的雄激素受體親和力,且缺乏不希望之促效劑特性之非類固醇抗雄激素,
揭示於WO 2006/133567。此外,此二專利申請案皆揭示一些化合物,作為選擇性雄激素受體調節劑劑(SARMs)。
類固醇抗雄激素、雄激素與選擇性雄激素受體調節劑(SARMs),其於17β-位置具有4-吡啶甲基側鏈,揭示於WO 2008/124922。抗雄激素EM-5854之生物特徵最近已報導(Gauthier等人,2012)。
因此技術上仍需要一種非類固醇抗雄激素,對於雄激素受體具高親和力,而實質上缺乏不希望之促效劑特性,並具有良好之非經腸胃或口服生物可獲得性,用於系統性用途。
吾人已合成出一系列新穎之非類固醇抗雄激素,具有可修飾類固醇骨架與雄激素受體之作用之側鏈。
選擇性雄激素受體調節劑(SARMs)為新穎之化合物家族,在某些組織(如前列腺)具有希望之拮抗劑活性,而在其他組織(如骨骼或肌肉)則不具活性,或具希望之促效劑活性。某些已報導於WO 02/00617、WO 2005/120483、US 7,803,970、US 7,427,682、US 7,268,232、US 7,759,520。某些此類SARMs已進行臨床試驗,用於建立肌肉並促進骨骼生長(Ostarine developed by GTx in the United States)、性腺功能減退症、良性前列腺增生、骨質疏鬆症和女性性功能障礙(LGD 2226 2941,由位於美國之Ligand發展)或與年齡有關之衰退(BMS 564929,由位於美國之Bristol-Myers Squibb發展)。此外,選擇性雄激素受體調節劑回顧於Zhang與Sui,2013、Zhang等人,2009、Mohler等人,2009、Jones
2009,與Chengalvala等人,2003(請見此述之參考資料)。某些其他SARMs已於最近描述(Nique等人,2012a;Nique等人,2012b;Nagata等人,2012;Poutiainen等人,2012;Varchi等人,2012;Zhang等人,2013;Cozzoli等人,2013),並揭示(WO 2012/047617、WO 2012/143599、WO 2013/014627、WO 2013/055577、WO 2013/057372、WO 2013/128421、WO 2013/152170、US 2012/0004270、US 2012/0041046、US 2013/0041007、US 2013/0217762)。
SARMs亦為潛在之藥物,用於預防或治療骨質減少、骨折、牙槽骨喪失、骨重建、截骨術、消耗性疾病(癌症)、淨體重損失、肥胖、肌肉損傷、潮熱、牙周病、牙周炎、下頜骨損失、斯耶格倫症候群徵、乾眼症、皮膚乾燥、乳腺癌、肌肉萎縮、肌少症、癌症惡病質、脆弱、男性激素避孕、勃起功能障礙、性慾減退、痤瘡、多毛症、脂溢性皮炎、雄激素脫髮、多囊性卵巢症、性早熟、睾丸女性化、潮熱、代謝症候群、男性乳房發育症、子宮內膜異位症,以及可能之前列腺癌,當選擇性雄激素受體調節劑(SARM)理想地在前列腺不具雄激素活性時。
在吾人的抗雄激素發展計劃過程中,吾人合成了一系列的非類固醇化合物,其具有選擇性雄激素受體調節劑的生物特性。尤其是,我們一直致力於研究適用於治療良性前列腺增生症,及預防前列腺癌之生物學特性之化合物。為了此目的,SARMs在雄激素敏感細胞中,必須具有強效抗雄激素活性,且在這些細胞中具有無或可忽略之
促效劑活性。該化合物亦必須在肌肉中具有良好的合成代謝活性,以避免老化自然產生之骨骼肌萎縮,並使用當前可用的抗雄激素。
本發明之目的為提供一種抗雄激素,對於雄激素受體具有良好之親和力,而實質上缺乏雄激素活性。這些抗雄激素可用於治療與預防雄激素-依賴性疾病,如下列所描述的。
本發明之一目的為提供一種化合物,其具有下列特性:a)結合至雄激素受體;b)直接或間接干擾雄激素受體之螺旋12,藉由夠窄與夠長以通過該通道之鏈,與螺旋12之雄激素結合位置聯結;c)當雄激素受體與一促效劑結合時,可觀察到其阻斷正常之螺旋12位置。
本發明之一目的為提供如下式之化合物:
其中n為0至6之一整數;其中m為0至1之一整數;其中J與Y獨立地為一直接鍵結,或選自於由-O-、-CO-、
-CH2-、-S-、-SO-、-SO2-、-NH-、-CHR1-、-C(R1)2-與-NR1-組成之族群;其中Ra與Rb獨立地選自於由氫、鹵素、-OCH3、C1-C3烷基、C2-C3烯基、腈基、三氟甲基、醯胺、胺,以及烷基碸組成之族群;其中R1係選自於由氫、鹵素以及C1-C3烷基組成之族群;其中R2係選自於由氫、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2、C1-C3烷基,以及三氟甲基組成之族群;其中R3係選自於由鹵素、腈基、-COCH3、-SO2CH3,以及-NO2組成之族群;其中R4與R5獨立地選自於由氫、C1-C6烷基、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2,以及三氟甲基組成之族群,或R4與R5共同形成一環,其任擇地具一雜原子,選自於由氮、氧與硫組成之族群;其中R6與R7獨立地選自於由氫與C1-C6烷基組成之族群,或R6與R7共同形成一環,其任擇地具一雜原子,選自於由氮、氧與硫組成之族群;其中W選自於由氧與硫組成之族群;其中G1、G2、G3、G4與G5獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最多二個氮或氧化氮;其中G6、G7、G8、G9與G10獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最少一個氮或氧化氮;
以及其中Y連結至G1、G2或G4;或其醫藥上可接受之鹽類。
在一實施例中,為具下式之一化合物:
其中Ra與Rb獨立地選自於由氫、鹵素、-OCH3、C1-C3烷基、C2-C3烯基、腈基、三氟甲基、醯胺、胺,以及烷基碸組成之族群;其中R1選自於由氫、氟與甲基組成之族群;其中R2選自於由氫、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2、C1-C3烷基,以及三氟甲基組成之族群;其中W選自於由氧與硫組成之族群;其中G2與G3獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最多一個氮或氧化氮;以及其中G6與G7獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最少一個氮或氧化氮;或醫藥上可接受之鹽類。
在一實施例中,為具下式之化合物:
其中n為0至6之一整數;其中m為0至1之一整數;其中J獨立地為一直接鍵結或選自於由-O-、-CO-、-CH2-、-S-、-SO-、-SO2-、-NH-、-CHR1-、-C(R1)2-與-NR1-組成之族群;其中Ra與Rb獨立地選自於由氫、鹵素、-OCH3、C1-C3烷基、C2-C3烯基、腈基、三氟甲基、醯胺、胺,以及烷基碸組成之族群;其中R1選自於由氫、鹵素與C1-C3烷基組成之族群;其中R2選自於由氫、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2、C1-C3烷基,以及三氟甲基組成之族群;其中R3選自於由鹵素、腈基、-COCH3、-SO2CH3,以及-NO2組成之族群;其中R4與R5獨立地選自於由氫、C1-C6烷基、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2,以及三氟甲基組成之族群,或R4與R5共同形成一環,其任擇地具一雜原子,選自於由氮、氧與硫組成之族群;其中R6與R7獨立地選自於由氫與C1-C6烷基組成之族群,或R6與R7共同形成一環,其任擇地具一雜原子,選自於由氮、氧與硫組成之族群;其中W選自於由氧與硫組成之族群;其中L1、L2、L3與L4獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最多二個氮或氧化氮;以及其中L5、L6、L7與L8獨立地選自於由碳、次甲基、氮與氧化
氮組成之族群,其在環上具有最少一個氮或氧化氮;或其醫藥上可接受之鹽類組成之族群。
在另一實施例中,為具下式之化合物:
其中Ra與Rb獨立地選自於由氫、鹵素、-OCH3、C1-C3烷基、C2-C3烯基、腈基、三氟甲基、醯胺、胺,以及烷基碸組成之族群;其中R1選自於由氫、氟與甲基組成之族群;其中R2選自於由氫、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2、C1-C3烷基,以及三氟甲基組成之族群;其中W選自於由氧與硫組成之族群;以及其中L5、L6、L7與L8獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最少一個氮或氧化氮;或其醫藥上可接受之鹽類。
在另一實施例中,為具下式之化合物:
其中R1選自於由氟與甲基組成之族群;其中R2選自於由氫、鹵素、-OCH3、-SCH3、烷基亞碸、
烷基碸、腈基、-NO2、C1-C3烷基與三氟甲基組成之族群;以及其中W選自於由氧與硫組成之族群。
在另一實施例中,本發明提供一種醫藥組成物,包含醫藥上可接受之稀釋劑或載體,以及治療有效量之至少一化合物,其:a)結合至雄激素受體;b)直接或間接干擾雄激素受體之螺旋12,藉由夠窄與夠長以通過該通道之鏈,與螺旋12之雄激素結合位置聯結;c)當雄激素受體與一促效劑結合時,可觀察到其阻斷正常之螺旋12位置。
在另一實施例中,本發明提供一種醫藥組成物,包含醫藥上可接受之稀釋劑或載體,以及治療有效量之至少一化合物,其具下式:
其中n為0至6之一整數;其中m為0至1之一整數;其中J與Y獨立地為一直接鍵結,或選自於由-O-、-CO-、-CH2-、-S-、-SO-、-SO2-、-NH-、-CHR1-、-C(R1)2-與-NR1-組成之族群;其中Ra與Rb獨立地選自於由氫、鹵素、-OCH3、C1-C3烷基、
C2-C3烯基、腈基、三氟甲基、醯胺、胺,以及烷基碸組成之族群;其中R1係選自於由氫、鹵素以及C1-C3烷基組成之族群;其中R2係選自於由氫、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2、C1-C3烷基,以及三氟甲基組成之族群;其中R3係選自於由鹵素、腈基、-COCH3、-SO2CH3,以及-NO2組成之族群;其中R4與R5獨立地選自於由氫、C1-C6烷基、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2,以及三氟甲基組成之族群,或R4與R5共同形成一環,其任擇地具一雜原子,選自於由氮、氧與硫組成之族群;其中R6與R7獨立地選自於由氫與C1-C6烷基組成之族群,或R6與R7共同形成一環,其任擇地具一雜原子,選自於由氮、氧與硫組成之族群;其中W選自於由氧與硫組成之族群;其中G1、G2、G3、G4與G5獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最多二個氮或氧化氮;其中G6、G7、G8、G9與G10獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最少一個氮或氧化氮;以及其中Y連結至G1、G2或G4;或其醫藥上可接受之鹽類。
在另一實施例中,本發明提供一種醫藥組成物,
包含醫藥上可接受之稀釋劑或載體,以及治療有效量之至少一化合物,其具下式:
其中Ra與Rb獨立地選自於由氫、鹵素、-OCH3、C1-C3烷基、C2-C3烯基、腈基、三氟甲基、醯胺、胺,以及烷基碸組成之族群;其中R1選自於由氫、氟與甲基組成之族群;其中R2選自於由氫、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2、C1-C3烷基,以及三氟甲基組成之族群;其中W選自於由氧與硫組成之族群;其中G2與G3獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最多一個氮或氧化氮;以及其中G6與G7獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最少一個氮或氧化氮;或醫藥上可接受之鹽類。
在另一實施例中,本發明提供一種醫藥組成物,包含醫藥上可接受之稀釋劑或載體,以及治療有效量之至少一化合物,其具下式:
其中n為0至6之一整數;其中m為0至1之一整數;其中J獨立地為一直接鍵結或選自於由-O-、-CO-、-CH2-、-S-、-SO-、-SO2-、-NH-、-CHR1-、-C(R1)2-與-NR1-組成之族群;其中Ra與Rb獨立地選自於由氫、鹵素、-OCH3、C1-C3烷基、C2-C3烯基、腈基、三氟甲基、醯胺、胺,以及烷基碸組成之族群;其中R1選自於由氫、鹵素與C1-C3烷基組成之族群;其中R2選自於由氫、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2、C1-C3烷基,以及三氟甲基組成之族群;其中R3選自於由鹵素、腈基、-COCH3、-SO2CH3,以及-NO2組成之族群;其中R4與R5獨立地選自於由氫、C1-C6烷基、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2,以及三氟甲基組成之族群,或R4與R5共同形成一環,其任擇地具一雜原子,選自於由氮、氧與硫組成之族群;其中R6與R7獨立地選自於由氫與C1-C6烷基組成之族群,或R6與R7共同形成一環,其任擇地具一雜原子,選自於由氮、氧與硫組成之族群;其中W選自於由氧與硫組成之族群;
其中L1、L2、L3與L4獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最多二個氮或氧化氮;以及其中L5、L6、L7與L8獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最少一個氮或氧化氮;或其醫藥上可接受之鹽類組成之族群。
在另一實施例中,本發明提供一種醫藥組成物,包含醫藥上可接受之稀釋劑或載體,以及治療有效量之至少一化合物,其具下式:
其中Ra與Rb獨立地選自於由氫、鹵素、-OCH3、C1-C3烷基、C2-C3烯基、腈基、三氟甲基、醯胺、胺,以及烷基碸組成之族群;其中R1選自於由氫、氟與甲基組成之族群;其中R2選自於由氫、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2、C1-C3烷基,以及三氟甲基組成之族群;其中W選自於由氧與硫組成之族群;以及其中L5、L6、L7與L8獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最少一個氮或氧化氮;或其醫藥上可接受之鹽類。
在另一實施例中,本發明提供一種醫藥組成物,
包含醫藥上可接受之稀釋劑或載體,以及治療有效量之至少一化合物,其具下式:
其中R1選自於由氟與甲基組成之族群;其中R2選自於由氫、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2、C1-C3烷基與三氟甲基組成之族群;以及其中W選自於由氧與硫組成之族群。
在另一實施例中,本發明係提供局部或系統性醫藥組成物,包含本發明之化合物,以及醫藥上可接受之稀釋劑或載體。
在另一觀點中,本發明化合物或含其之醫藥組成物,可用於治療或預防雄激素-加劇之皮膚疾病,如痤瘡、多毛症、脂溢性皮炎、雄激素脫髮、雄性禿及類似疾病。
在另一實施例中,本發明化合物或含其之醫藥組成物,可用於治療或預防雄激素-加劇之系統性疾病,如前列腺癌、良性前列腺增生、性早熟、多囊卵巢症候群、超雄激素症候群,及類似疾病。
在另一實施例中,雄激素-加劇之治療與預防處方包括使用於此揭示之化合物,作為組合療法之一部分,其更進一步利用其他活性化合物,選自於由5α-還原酶制劑、第5型及/或第15型17β-羥基類固醇脫氫酶抑制劑、17α-羥化
酶/17,20-解離酶抑制劑,以及其他雄激素生合成抑制劑組成之族群。
在另一實施例中,雄激素-加劇之治療與預防處方包括使用於此揭示之化合物,以及睪丸切除術,或投以LHRH促效劑或拮抗劑。
在另一觀點中,本發明之化合物具組織特異性抗雄激素活性與組織特異性雄激素活性,可用於治療或降低發展為與雄激素刺激損失相關之疾病之風險。
另一目的為提供一種選擇性雄激素受體調節劑,或含其之醫藥組成物,以治療(或降低風險)與雄激素刺激損失相關之疾病,如肌肉萎縮和無力、皮膚萎縮、骨質流失、骨質疏鬆、貧血、動脈粥樣硬化、心血管疾病、能量損失、幸福感喪失、性慾減退、男性性腺功能低下、肌少症、陽痿、勃起功能障礙、女性性功能障礙、第2型糖尿病或腹部脂肪堆積。
另一目的為提供治療或降低發展為與雄激素刺激損失相關之疾病之風險,該疾病如肌肉萎縮和無力、皮膚萎縮、骨質流失、骨質疏鬆、貧血、動脈粥樣硬化、心血管疾病、能量損失、幸福感喪失、性慾減退、男性性腺功能低下、肌少症、陽痿、勃起功能障礙、女性性功能障礙、第2型糖尿病或腹部脂肪堆積。
在另一觀點中,本發明化合物係用於製造治療此述疾病之藥物。
另一目的係提供一種醫藥化合物,具有良好之系
統性生物可獲得性。
圖1顯示甲基雄二烯醇酮(R1881)、睪固酮(TESTO)、比卡魯安(bicalutamide)、羥基氟他胺(OH-FLU)、EM-9150與EM-9156之濃度增加,對於[3H]R1881結合至人類雄激素受體之影響。於0-4℃下,與4nM[3H]R1881共同靜置16小時,在指定濃度之未經標記化合物存在或不存在下。
圖2顯示甲基雄二烯醇酮(R1881)、睪固酮(TESTO)、羥基氟他胺(OH-FLU)、比卡魯安(bicalutamide)、EM-9150與EM-9156之濃度增加,對於[3H]R1881結合至大鼠前列腺雄激素受體之影響。於0-4℃下,與4nM[3H]R1881共同靜置16小時,在指定濃度之未經標記化合物存在或不存在下。
圖3顯示羥基氟他胺(OH-FLU)、比卡魯安(bicalutamide)、EM-9150與EM-9156之濃度增加,對於基礎與經二羥基雄激素(DHT;0.3nM)-刺激之細胞增生之影響,於培養之雄激素-敏感小鼠乳房Shionogi細胞中。以初始密度2 x 104細胞/2-cm2孔植入後24小時,細胞暴露於指定濃度之化合物中10日。每2或3日更換一次培養液。數據以三培養盤之平均值±SEM表示。當SEM與符號重疊時,僅顯示符號。
圖4顯示比卡魯安(bicalutamide)、EM-9150與EM-9156之濃度增加,對於基礎與經R1881(1.0nM)-刺激之前列腺特異性抗原(PSA)量之影響,與人類前列腺癌LNCaP
細胞靜置72小時後,於培養液中測量。數據以三培養盤之平均值±SEM表示。當SEM與符號重疊時,僅顯示符號。
圖5顯示EM-9150,以及其兩個代謝物(EM-9156與EM-9260),在單次口服投藥20mg EM-9150/kg至8周大雄性大鼠後之血清含量。由LC-MS/MS測量之血漿濃度,係以每組3隻動物之平均值±SEM表示,並用於計算曲線下面積(AUC0-24h)。
圖6顯示氟他胺(FLU)、比卡魯安(bicalutamide)、EM-9150與EM-9156之劑量增加(0.03至3mg/大鼠:ca 0.3至30mg/kg),每日投藥共7日,對於帶有DHT植入物之去勢(CX)未成熟雄性大鼠之腹部前列腺重量之影響。數據以每組5隻動物之平均值±SEM表示。DHT-刺激之前列腺重量抑制值,係以百分比表示。化合物係以0.4%水性甲基纖維素之懸浮液投藥。
圖7以0.3與3mg/大鼠(ca 3與30mg/kg)之比卡魯安(bicalutamide)、EM-9150與EM-9156治療,每日投藥共7日,對於去勢(CX)未成熟雄性大鼠之腹部前列腺重量之影響,以證實雄激素活性之不存在。數據以平均值±SEM(n=5)表示。化合物係以0.4%水性甲基纖維素之懸浮液投藥。
圖8顯示以0.1mg/大鼠或0.5mg/大鼠之EM-9251治療,每日投藥共7日,對於完整、去勢,以及去勢但帶有DHT植入物之未成熟雄性大鼠之腹部前列腺、儲精囊與球海綿體肌重量之影響。數據以每組3隻動物之平均值±SEM表示。
我們的化合物特別設計為妨礙雄激素受體之可動羧端螺旋12之重新定位,因此可阻斷配體-結合區域(ARLBD)內之配體-依賴性轉活化功能(AF-2)。此觀念之發展乃為了獲得新族群之抗雄激素,已描述人類雄激素受體配體-結合區域(hARLBD)與促效劑EM-5744,一種5α-二氫睪固酮衍生物,其於位置18帶有碳鏈(-CH2OCH2-3,5-F2-Ph),錯合之結構特徵(Cantin等人,2007);於位置18帶有碳鏈之拮抗性類固醇衍生物(WO 2005/066194);以及拮抗性非類固醇衍生物(WO 2006/133567),其模擬WO 2005/066194之類固醇衍生物。
本發明為WO 2006/133567之化合物之增進,其中末端二級與三級胺、亞碸與其他官能基,以一吡啶部分取代。
[下表為世界專利申請公開案WO 2006/133567之較佳化合物,與本發明之較佳化合物(即EM-9150)之比較。表1顯示體外數據,其包括結合至人類與大鼠雄激素受體,以及小鼠乳癌Shionogi細胞與人類前列腺癌LNCaP細胞之抗雄激素活性。表1亦顯示體內數據,其包括對於未成熟大鼠之腹部前列腺之拮抗活性,詳細解釋一節中說明下表數據如何收集與報導。
表1之說明:
在第1行中,抗雄激素以實驗室名稱報導。
第2行代表抗雄激素之相對結合親和性(RBA),以經轉染細胞之人類雄激素受體相對於R1881之百分比(%)報導,以下式計算:% RBA=100xIC50 R1881/IC50(化合物)較高值為較佳。
第3行代表抗雄激素之相對結合親和性(RBA),以前列腺細胞質之大鼠雄激素受體相對於R1881之百分比(%)報導,以下式計算:% RBA=100xIC50 R1881/IC50(化合物)較高值為較佳。
第4行代表抑制50%(IC50)DHT-刺激之Shionogi小鼠乳癌細胞數目之劑量(以nM表示)。較低值為較佳。
第5行代表10-7M化合物對於R1881-刺激人類前列腺LNCaP細胞之PSA抑制量%。較高值為較佳。
第6行代表口服抗雄激素對於大鼠前列腺之藥效%,劑量為0.1mg/動物,以抑制百分比表示。
抑制百分比(% inhib)係以下式計算:%抑制=100-[W(化合物)-W(控制組CX)/W(控制組DHT)-W(控制組CX)]x100。
W為前列腺重量。
較高值為較佳。
第7行代表大鼠前列腺之口服抗雄激素藥效%,劑量為0.5
mg/動物,以抑制百分比表示。
抑制百分比(% inhib)係以下式計算:%抑制=100-[W(化合物)-W(控制組CX)/W(控制組DHT)-W(控制組CX)]x100。
W為前列腺重量。
較高值為較佳。
世界專利申請公開案WO/2006/133567中之較佳化合物為EM-7365、EM-7105、EM-7148與EM-8360,以及本發明之一較佳化合物(EM-9150)。表1中所包含之EM-9156,為一種已知之活性代謝物EM-9150。化合物EM-7365、EM-7105、EM-7148與EM-8360為硫尿囊素衍生物(WO/2006/133567之D部分),而EM-9150為尿囊素衍生物。由我們的數據可知,硫尿囊素與尿囊素衍生物有重要不同處,尤其是在體外試驗中。為了獲得二申請案中之二組化合物最可能之比較,我們亦將某些對應之尿囊素或硫尿囊素衍生物包括於表1中。於是,我們在表1中插入EM-7133,其為硫尿囊素EM-7105之對應尿囊素。以相同方法,我們在表1中插入EM-9052,其為尿囊素EM-9150對應之硫尿囊素。就該表中之其他化合物而言,我們並無可得之對應化合物。EM-7365、EM-7105、EM-7148及EM-8360,與EM-9150間之生物活性比較,主要觀察到a)EM-9150與EM-7105、EM-7148與EM-8360具相等之體內活性(但EM-7365較不具活性),以第7行之大鼠前列腺重量抑制百分比為基準,劑量為0.5mg(即EM-7365之22%,與EM-7105、
EM-7148、EM-8360與EM-9150之51%、58%、56%與55%相較);b)EM-9150具較佳之人類雄激素受體親和性,與EM-7365、EM-7105、EM-7148與EM-8360相較(第2行,RBA:74對應24、41、11與18);c)EM-9150具較佳之大鼠雄激素受體親和性,與EM-7105相較(第3行,RBA:6.5對應3.9);d)EM-9150對於DHT-刺激Shionogi小鼠乳癌細胞具可比擬之抗增生活性,與EM-7365、EM-7105、EM-7148與EM-8360相較,但可能不具有明顯差異(第4行,IC50單位為nM:13,對應6.0、9.4、9.2與7.1);以及),10-7M之EM-9150對於R1881-刺激人類前列腺癌LNCaP細胞之PSA量更具效果,與EM-7105、EM-7148與EM-8360相較(第5行,抑制百分比:57對應26、33與46)。最重要的是,在本申請案(EM-9150,RBA=74),與在世界專利申請公開案WO/2006/133567中(EM-7334與EM-7612,RBA=0.5),EM-9150對於人類雄激素受體具最佳親和力,就尿囊素衍生物而言。可比擬之硫尿囊素與尿囊素(即EM-9052對應EM-9150,以及EM-7105對應EM-7333)間之最重要差異,為人類雄激素受體(RBA(hAR))之親和性。事實上,EM-9052結合至人類雄激素受體,為EM-9150之27倍(RBA:2010對應74),以及EM-7105結合為EM-7333之約140倍(RBA:41對應~0.3)。儘管所有的尿囊素與相對應之硫尿囊素(WO 2006/133567)之人類雄激素受體親和性為未知,吾人認為其值不應超過5-10,且應遠小於EM-9150(RBA=74)。我們亦觀察到硫尿囊素可於體內轉化為尿囊素,因此提出當投至體內時,化
合物EM-7365、EM-7105、EM-7148與8360之總體外活性可能較預期不具活性。EM-9156為EM-9150之活性代謝物,具類似於EM-9150之生物活性。結論為,EM-9150具較高之人類雄激素受體RBA,與表1所述之硫尿囊素衍生物,得自WO 2006/133567(EM-7365、EM-7105、EM-7148與EM-8360)相較。事實上,EM-9150之RBA(hAR)為1.8至6.7倍,與討論之硫尿囊素衍生物相較。EM-9150會抑制2倍,以及更高之PSA量,於人類LNCaP細胞中,與硫尿囊素相較。提及之觀察,尤其是對於人類雄激素受體較高之結合親和性,強烈顯示有較佳之EM-9150體內人類活性,與WO 2006/133567公開案中之最佳硫尿囊素衍生物相較,即使其體內大鼠拮抗活性相似。
上述之相同比較亦於我們的最佳選擇性雄激素受體調節劑(請見表4),與WO 2006/133567中所述之選擇性雄激素受體調節劑(請見表3)進行,並呈現出本發明之化合物優於WO 2006/133567之化合物。
本發明包括喹啉與異喹啉衍生物取代苯基吡啶部分。喹啉與異喹啉片段為苯基吡啶部分之融合環。同樣地,喹啉部分為苯基吡之融合環;喹唑啉為苯基嘧啶之融合環,以及林與呔為苯基之融合環。
之較佳右半部份
係由
或相對應之氧化氮組成,當L5、L6、L7與L8基團之一為氮或氧化氮;或
或相對應之氧化氮當L5、L6、L7與L8基團之二者為氮或氧化氮時較佳m為0;其中n為3;其中J為氧;其中G1、G8與G10為碳或次甲基;其中Y為直接鍵結;其中J與Y互相位於對位;以及其中G6或G7或G9為氮或氧化氮。
較佳R1為氫或甲基。
較佳R2為氟、氯或三氟甲基。
較佳R3為腈基。
較佳R4與R5為氫。
較佳R6與R7為甲基。
較佳m為0。
較佳W為氧或硫。
較佳n為3。
較佳J為氧。
較佳G1、G2、G3、G4、G5、G8與G10獨立地為碳或次甲基。
較佳G6、G7與G9獨立地為氮、氧化氮、碳或次甲基。
較佳Ra與Rb獨立地為氫、氟、氯、三氟甲基、甲基或腈基。
較佳Y為一直接鍵結,且位於J之對位。
在較佳實施例中,二或較佳多個較佳例可組合使用。
尤佳為具分子結構選自於由下列組成之族群之抗雄激素,以及包含這些之醫藥組成物:
除了該較佳化合物一節(表3),EM-9150與其代謝物EM-9156之生物特性呈現於圖1-7。簡言之,臨床前試驗顯示出EM-9150為比卡魯安(bicalutamide)(Casodex,CAS)及OH-氟他胺(OH-FLU),為氟他胺(flutamide)(FLU)之活性代謝物之247倍與352倍,EM-9156則為57倍與81倍,可取
代來自人類AR之代謝性穩定之雄激素甲基雄二烯醇酮(R1881)(以圖1為例)。在大鼠AR試驗中,EM-9150藥效為比卡魯安(bicalutamide)及OH-氟他胺之32倍與65倍,而EM-9156為27倍與53倍(圖2)。在小鼠雄激素-敏感之Shionogi癌細胞中,EM-9150為OH-氟他胺及比卡魯安(bicalutamide)之5.2-倍與14.6-倍,而EM-9156為4.5-倍與12-7-倍,在逆向DHT-刺激細胞情況下,除了無10-7M細胞基礎值之刺激外(以圖3為例)。在人類前列腺癌細胞株LNCaP中,在阻斷R1881-刺激之PSA分泌方面,EM-9150與EM-9156為比卡魯安(bicalutamide)之11.0倍與9.2倍,除了無10-7M基礎值刺激之外(圖4)。EM-9150與其代謝物,EM-9156與EM-9260之平均血漿含量,可產生AUC0-24hr值為123、1708與14931ng.hr/mL,在單次口服投以20mg EM-9150/kg至雄性大鼠後(圖5)。在每日口服投藥,共7日之後,EM-9150與EM-9156對於未成熟去勢大鼠之腹部前列腺重量,未顯示出促效劑活性(圖7),而補充有DHT之未成熟去勢大鼠之拮抗劑活性,則可與比卡魯安(bicalutamide)與氟他胺(flutamide)相比擬(以圖6為例)。
在某些情況下(如於某些濃度下),本發明化合物,以及含其之醫藥組成物,可為雄激素性,並可依據本發明使用,以預防與治療雄激素有助益之疾病,如肌肉萎縮與無力、腹部脂肪堆積、皮膚萎縮、貧血、骨質流失、骨質疏鬆症、動脈粥樣硬化、心血管疾病、第2型糖尿病、能量損失、幸福感喪失、性慾減退、男性性腺功能低下、肌少
症、陽痿、勃起功能障礙或女性性功能障礙。前述可使用雄激素之疾病,係由Negro-Vilar,1999(肌肉萎縮與無力、骨質疏鬆、貧血、心血管疾病、男性性功能減退、性慾衰退和腹部脂肪堆積)、Liu等人,2003(心血管疾病、腹部脂肪堆積、動脈粥樣硬化、第2型糖尿病、性慾衰退和勃起功能障礙)、Labrie 2004(肌肉萎縮與無力、骨質流失、骨質疏鬆症、腹部脂肪堆積、皮膚萎縮、能量損失、幸福感喪失、性慾衰退和第2型糖尿病)、Labrie等人,2014(肌肉萎縮與無力,以及女性性功能障礙)、Labrie等人,2009(肌肉萎縮與無力、腹部脂肪堆積、骨質流失、第2型糖尿病、性慾衰退和女性性功能障礙)、Pelletier等人,2012與2013(女性性功能障礙)、Bhasin等人,2011(骨質疏鬆症、心血管疾病、第2型糖尿病、肌少症和勃起功能障礙),以及Aucoin等人,2006(性慾減退、陽痿、勃起功能障礙)支持。
尤佳為具分子結構選自於由下列組成之族群之選擇性雄激素受體調節劑,以及包含這些之醫藥組成物:
除了較佳化合物一節(表4),EM-9251之一生物活性係示於圖8。臨床前體內試驗顯示出EM-9251,在口服投
藥至未成熟去勢大鼠7日後,觀察到對於前列腺與儲精囊之促效劑-拮抗劑混合活性,以及球海綿體肌之促效劑活性。然而,在未成熟完整大鼠中,觀察到對於前列腺與儲精囊之拮抗劑活性,以及球海綿體肌之促效劑活性。
在吾人的抗雄激素發展計畫中,尤其是尿囊素與具有苯基吡啶鏈之硫尿囊素衍生物,我們發現具有SARM特性之化合物(描述於本文件中)。起始於純抗雄激素,我們觀察到分子尺寸由左至右有些微增加,可提供SARM。這些化合物之較佳取代基為R1、R2、W、Ra與Rb(請見段落[0015]-[0018]之化學式)。例如,當將弱抗雄激素EM-9173之R2更換為較大基團,可觀察到EM-9116與EM-8940轉變為較佳之抗雄激素,具有較高之雄激素受體親和性(F換為Cl:EM-9116;Cl換為CF3:EM-8940)。然而,當我們於R1位置引入甲基,EM-9247便成為具有某些促效劑活性之抗雄激素。之後,當我們將W位置(EM-8691)之氧更換為硫,可獲得強效之SARM,具雄激素受體高親和性。最後,於Ra位置(EM-8821)引入三氟甲基,可提供較弱之SARM,具有降低之親和性。相對於我們的類似物之類固醇抗雄激素作用(WO 2008/124922),當取代基尺寸增加時,並未觀察到雄激素作用。因此,在此化合物家族中並無法進行明顯的生物活性良好預測,儘管觀察到某些趨勢。
已研究表3-5中描述之某些化合物之代謝(請見流程1)。例如,當EM-9150口服投藥至大鼠中,EM-9156係於循環系統中測得。此轉換由吡啶部分氧化為吡啶氧化氮部分開始。觀察到逆向流程,亦即EM-9156還原至EM-9150,但與EM-9150氧化為EM-9156相較,為較不希望的。此外,EM-9150與EM-9156經N-去烷基化,得EM-9260,相對應之4,4-二甲基-2,5-二氧-1-咪唑啶基(尿囊素)衍生物。圖5顯示3隻大鼠於口服接受20mg/kg之EM-9150,24小時後,EM-9150、EM-9156與EM-9260之血漿濃度。這些結果顯示在這些情況下,EM-9150、EM-9156與EM-9260之AUC0-24h值為123、1708與14931ng.h/Ml之。結果為,EM-9150之體內結果應以三成分,亦即EM-9150與其二代謝物EM-9156與EM-9260之作用之總和解釋。
表2摘錄化合物EM-9150、EM-9156與EM-9260之生物特性,除了具有另一組三個合物,亦即EM-9251、EM-9252與EM-9289,具有相同之代謝路徑之外。依據表2,第1組化合物(EM-9150、EM-9156與EM-9260)為抗雄激素,在試驗模式中(對於Shionogi細胞有體外抗雄激素活性(第2行)、對於大鼠前列腺、儲精囊與球海綿體肌有體內抗雄激素活性(第4-6行),以及對於大鼠前列腺、儲精囊與球海綿體肌無體內雄激素活性(第7-9行))。另一方面,第2組化合物(EM-9251、EM-9252與EM-9289)為選擇性雄激素受體調節劑(SARMs),於試驗模型中(對於Shionogi細胞之混合體外活性(第2行)、對於大鼠前列腺與儲精囊有混合體內活性(第4、5、7與8行),以及對於球海綿體肌有體內雄激素活性(第6與9行)。
表2之附註:
第1行報導抗雄激素或SARMs分子結構與實驗室名稱。
第2行代表抑制50%(IC50)DHT-刺激Shionogi小鼠乳癌細胞數目之劑量(單位為nM)。較低值為較佳。
第3行代表轉染細胞中抗雄激素或SARMs對於人類雄激素受體之相對結合親和性(RBA),以百分比(%)表示,相對於R1881,以下式計算:% RBA=100xIC50 R1881/IC50(化合物)較高值為較佳。
第4行代表大鼠前列腺中之抗雄激素藥效%,以抑制百分比表示。
抑制百分比以下式計算:%抑制=100-[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為前列腺重量。
較高值為較佳。
第5行代表大鼠儲精囊中之抗雄激素藥效%,以抑制百分比表示。
抑制百分比以下式計算:%抑制=100-[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為儲精囊重量。
較高值為較佳。
第6行代表大鼠球海綿體肌中之抗雄激素藥效%,以抑制百分比表示。
抑制百分比以下式計算:%抑制=100-[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為球海綿體肌重量。
第7行代表大鼠前列腺中之雄激素藥效%,以刺激百分比表示。
刺激百分比係依據下式計算:%刺激=[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為前列腺重量。
較低值為較佳。
第8行代表大鼠儲精囊中之雄激素藥效%,以刺激百分比表示。
刺激百分比係依據下式計算:%刺激=[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為儲精囊之重量。
較低值為較佳。
第9行代表大鼠球海綿體肌中之雄激素藥效%,以刺激百分比表示。
刺激百分比係依據下式計算:%刺激=[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為球海綿體肌重量。
本發明之抗雄激素或SARMs較佳係與醫藥上可接受之稀釋劑、賦形劑或載體(包括膠囊),一同配製為醫藥組成物,於先前技藝所使用抗雄激素之一般抗雄激素濃度
下。考慮到本發明化合物之藥效較強,參與之醫師可能會修改濃度及/或劑量,以調整每一病患之特定反應之劑量。較佳為,特別在一開始的時候,參與的醫師可監測各病患之總反應,以及抗雄激素或SARM之血清含量(與下述較佳之血清濃度相較),調整必需劑量,當病患對於治療之代謝或反應為非典型時。如下述之更詳細討論,載體、賦形劑或稀釋劑包括固體與液體。當組成物以非立即使用方式製備時,一般包括技術上已知之防腐劑(如苯甲醇)。本發明之新穎組成物可用於治療雄激素-相關疾病,或降低類似疾病。當系統性投藥時(如用於治療前列腺癌、良性前列腺增生、性早熟、多囊性卵巢症候群、與雄激素刺激損失相關之疾病(男性性腺功能減退症、女性性功能障礙、勃起功能障礙和肌少症)以及其他不是主要影響皮膚之疾病),可使用技術上已知為醫藥上可接受之系統性用途之一般稀釋劑或載體,如生理食鹽水、水、乙醇水溶液、油等。該載體通常為各成分之混合物。
當配製為系統性用途時,抗雄激素或SARMs可以一般方式製備用於如口服或注射投藥。抗雄激素可以如口服路徑投藥。本發明之化合物可與一般醫藥賦形劑(如噴霧乾燥乳糖與硬脂酸鎂)配製為藥錠或膠囊,以口服投藥。當然,亦可加入味道增進物質,在口服投藥形式中。當希望口服攝入膠囊時,任何技術上已知之醫藥膠囊,皆可填充入本發明之活性成分,具有或不具額外之稀釋劑與此述之其他添加物。
該活性物質可與固體、粉體載體物質如檸檬酸鈉、碳酸鈣或磷酸鈣,以及黏著劑如聚乙烯吡咯酮、明膠或纖維素衍生物,亦可加入潤滑劑如硬脂酸鎂、月桂酸硫酸鈉、“Carbowax”或聚乙二醇,混合製備為藥錠或糖衣丸心。
在其他形式中,可使用栓劑膠囊如硬明膠,以及密封軟明膠膠囊,包含軟化劑或塑化劑如甘油。該栓劑膠囊含有活性物質,較佳為顆粒形式,如為與填充劑如乳糖、醣類、甘露醇、澱粉如馬鈴薯澱粉或分支澱粉、纖維素衍生物或高度分散之矽酸之混合物。在軟明膠膠囊中,該活性物質較佳溶解於或懸浮於適當液體中,如蔬菜油或液體聚乙二醇。
可使用乾式傳送系統,如描述於美國專利號3,742,951,3,797,494或4,568,343者。
此外,活性成分可置於經皮貼片中,具技術上已知之結構,如揭示於歐洲專利號0279982者。
美國專利號5,064,654,5,071,644或5,071,657中描述之溶劑或裝置,亦可用於加速經皮穿透,當希望有系統性效果時。當用於治療系統性疾病時,施加至皮膚處應變更,以預防抗雄激素之局部濃度過量。
在某些實施例中,本發明之抗雄激素可用於治療雄激素-相關之皮膚疾病,如痤瘡、脂溢性皮炎、多毛症、雄激素脫髮與雄性禿。當用於這些目的時,該抗雄激素較佳與一般局部載體或稀釋劑共同局部投藥。當局部使用時,較佳該稀釋劑或載體不會促進活性成分經皮穿透至血流或
其他組織中,該處它們會導致不希望之系統性效果。
當該化合物於皮膚用或局部用載體或稀釋劑中投藥時,該載體或稀釋劑可選用化妝品與醫藥技術中已知之任一者,如凝膠、乳霜、乳液、油膏、液體或非液體載體、乳化劑、溶劑、液體稀釋劑或其他類似載劑,不會對於皮膚或其他活體動物組織產生不良作用。該載體或稀釋劑通常為數個成分之混合物,包括但不侷限於液體醇、液體二醇、液體聚烷二醇、水、液體醯胺、液體酯類、液體羊毛脂、羊毛脂衍生物與類似材料。醇類包括單元或多元醇,包括乙醇、甘油、山梨醇、異丙醇、二乙二醇、丙二醇、乙二醇、己二醇、甘露醇與甲氧基乙醇。典型載體亦包括醚類,如二乙基與二丙基醚、甲氧基聚氧基乙醚、碳蠟、聚乙二醇、聚氧乙烯與山梨醇。一般而言,局部載體包括水與醇類,以使親水性與親油性溶解度達最大化,如乙醇或異丙醇與水之混合物。
局部載體亦可包括各種其他成分,一般用於油膏與乳液中,以及化妝品與醫藥技術中已知者。例如,可存在香料、抗氧化劑、香精、成膠劑、增稠劑如羧基甲基纖維素、界面活性劑、穩定劑、柔軟劑、增色劑與其他類似試劑。
油膏、乳霜、凝膠或乳液之活性成分濃度一般為約0.1至20%,較佳為0.5至5%,最佳為2%重(相對於乳液、乳霜、凝膠或油膏之總重量)。在較佳範圍中,當施加乳液、油膏、凝膠或乳霜時,為較小量或較低頻率時,較高濃度
才可達到適當之劑量。
此述數種製備典型乳液與凝膠之非限制範例。除了載劑之外,此技術領域者可選擇其他載劑,以符合特定皮膚需求。
當抗雄激素或SARMs系統性投藥時,較佳以口服或非經腸胃投藥。自然地,當希望之作用位置為皮膚時,局部投藥為較佳。
活性抗雄激素或SARM之濃度,可依據醫藥組成物之投藥方法,以已知方式而改變。適用於口服投藥之組成物較佳包括至少一抗雄激素,其中於該醫藥組成物中之所有此類抗雄激素總濃度為組成物(重量)之約1%至95%,較佳約5%至約20%。當使用抗雄激素組合時,所有抗雄激素總和之總劑量應相等於上述引用之劑量範圍。抗雄激素之血液量為較佳之適當劑量標準,其考慮到在吸收與代謝方面之個體變異。
當製備用於非經腸胃之注射時,該抗雄激素或SARM較佳於濃度約0.1mg/ml至約200mg/ml(較佳約2.5mg/ml至約100mg/ml)下加入。
希望有系統性活性時,必須僅以可使血清濃度達希望含量之方式與劑量,投以抗雄激素或SARM。血清抗雄激素濃度一般維持於0.1至1000微克每升,較佳為50至1000微克每升,最佳為50至500微克每升。適當之血清量亦可以病患對於治療之反應評估。
就典型病患而言,當口服投藥時,抗雄激素或
SARM達到希望血清濃度之適當劑量為10至1500毫克活性成分每日每50kg體重。當注射投藥時,建議為約2至1000,較佳為5至100mg每日每50kg體重。
就局部使用而言,乳液、油膏、凝膠或乳霜應完全搓揉至皮膚中,看不出有過量物,且該區域之皮膚較佳不清洗至少30分鐘。施加量應提供至少0.02毫克之抗雄激素或SARM每平方公分(較佳為0.1至1mg/cm2)每次施加。希望施加該局部組成物至患處每日1至6次,如每日3次,大約規律之間隔。
在本發明之某些實施例中,本發明之抗雄激素係用於與另一活性成分組合,作為組合療法之一部分。例如,新穎之抗抗雄激素可用於與單獨5α-還原酶抑制劑、第5型或第15型17β-羥基類固醇脫氫酶抑制劑(前列腺短鏈脫氫酶還原酶1抑制劑),或17α-羥化酶/17,20-解離酶(CYP17)抑制劑,其可加入相同之醫藥組成物中,作為抗雄激素,或可單獨投藥。因此組合療法可包括以可抑制產生二氫睪固酮或其前驅物之一或多種化合物治療。在本發明某些較佳實施例中,該局部醫藥組成物更包括一類固醇5α-還原酶活性抑制劑。此類抑制劑之一(“柔沛(Propecia)或波司卡(Proscar)”)可商業上購自Merck Sharp與Dohme。另一抑制劑«度他雄胺(dutasteride)»其抑制5α-還原酶共-酵素二者,亦可商業上購自GlaxoSmithKline。第5型17β-羥基類固醇脫氫酶抑制劑(更特別地為化合物EM-1404)係揭示於國際專利公開號WO 99/46279。EM-1791,一種第15型17β-羥基類固
醇脫氫酶抑制劑,係描述於WO 2005/066194。17α-羥化酶/17,20-解離酶(CYP17)抑制劑係選自於包含酮康唑(ketoconazole)、阿比特龍醋酸鹽(阿比特龍醋酸鹽(Abiraterone acetate))、蓋勒特龍(galeterone)(VN/124-1,TOK-001)與歐特龍(orteronel)(TAK-700)之族群。
當5α-還原酶抑制劑用於組合治療中,依據本發明之描述,口服劑量較佳介於0.1mg至100mg每日每50kg體重,較佳介於0.5mg/日至10mg/日,如5.0mg每日之非那雄胺(finasteride)或0.5mg每日之度他雄胺(dutasteride)。
當第5型17β-羥基類固醇脫氫酶抑制劑使用於組合療法中時,依據本發明之描述,口服劑量較佳介於5mg至500mg每日每50kg體重,較佳介於10mg/日至400mg/日,如300mg每日之EM-1404。
當第5型或第15型17β-羥基類固醇脫氫酶抑制劑用於組合療法中時,依據本發明之描述,口服劑量較佳介於10mg至1000mg每日每50kg體重,較佳介於25mg/日至1000mg/日,如200mg每日EM-1404或EM-2881。
當17α-羥化酶/17,20-解離酶(CYP17)抑制劑用於組合療法中時,依據本發明之描述,口服劑量較佳介於10mg至5000mg每日每50kg體重,較佳介於100mg/日至3000mg/日,如1000mg每日阿比特龍醋酸鹽(Abiraterone acetate)。
在本發明之某些實施例中,本發明之抗雄激素係用於與睪丸切除術結合,或與LHRH促效劑或拮抗劑共同作為組合療法之一部分。較佳之LHRH促效劑為亮丙瑞林醋酸
鹽(leuprolide acetate),商標“Lupron”,得自Abbott Laboratories Ltd.、“Viadur”得自Bayer AG、“Eligard”得自Sanofi-Aventis,以及“Prostap SR”與“Prostap 3”,得自Takeda UK、戈舍瑞林醋酸鹽(Goserelin acetate)商標名為“Zoladex”與“Zoladex LA”,得自AstraZeneca、那法瑞林(Nafarelin)商標名為“Synarel”,得自Searle(now part of Pfizer)、布舍瑞林醋酸鹽(Buserelin acetate)商標名為“Suprefact”或“Suprefact Depot”,得自Sanofi-Aventis,以及“CinnaFact”得自CinnaGen、組胺瑞林(Histrelin)商標名為“Vantas”與“Supprelin LA”,得自Endo Pharmaceuticals、曲普瑞林醋酸鹽(Triptorelin acetate)或樸酸鹽,商標名“Decapeptyl”,得自Ipsen、“Diphereline”與“Gonapeptyl”得自Ferring Pharmaceuticals,以及“Trelstar”得自Watson。較佳之LHRH拮抗劑為阿巴瑞克(Abarelix),商標名“Plenaxis”,得自Speciality European Pharma、替維瑞克(Teverelix)由Ardana研發、西曲瑞克醋酸鹽(Cetrorelix acetate),商標名為“Cetrotide”,得自Merck Serono、加尼瑞克(Ganirelix acetate)商標名為“Antagon”,得自Organon International、依妥瑞克(Iturelix)drf商標名為“Antide”,得自Serono、阿西林(Acyline)由Merrion Pharmaceuticals發展、地加瑞克(Degarelix)商標名為“Firmagon”,得自Ferring Pharmaceuticals,以及歐尼瑞克(Ornirelix)由Oakwood Laboratories發展。其他LHRH拮抗劑為阿札林B(Azaline B)(Salk Institute)、歐札瑞克(Ozarelix)(Spectrum Pharmaceuticals)、LXT-101(Department
of Pharmaceutical Chemistry,Beijing Institute of Pharmacology and Toxicology)、依麗購(Elagolix)(Neurocrine Biosciences),以及TAK-013與TAK-385(Takeda)。任何FDA-核准之LHRH(或GnRH)促效劑或拮抗劑皆可使用。
LHRH促效劑或拮抗劑之最佳投藥路徑為皮下或肌肉內儲存式注射。LHRH促效劑或拮抗劑可投藥劑量較佳為約10至1500μg每日,LHRH促效劑為約250μg每日(較佳50μg至500μg每日),LHRH拮抗劑為約100至2000μg每日,依據經銷商之建議。
需要治療或降低特定疾病啟動之風險之病患,為經診斷患有此種疾病或容易得到此疾病者。本發明特別適用於由於遺傳、環境因素或其他已知之風險因子,而較一般得到與本發明相關病症之族群具有更高之風險之個體。
除非另有指出,本發明活性化合物之劑量,在治療與預防目的下皆相同。此述討論之每一活性成分之劑量皆相同,不論待治療(或預防)之疾病。
當二或多種不同活性試劑作為組合療法之一部分時(如酵素抑制劑與抗雄激素),係投以複數個不同之化合物,而非具有多重活性之單一化合物。
除非另有指出,術語“化合物”與任一相關之分子結構,可包括任何可能之立體異構物,為外消旋混合物形式或光學活性形式。
除非另有指出或內文明顯看出,此述之劑量係指活性化合物之重量,不受醫藥賦形劑、稀釋劑、載體或其
他成分影響,儘管此額外之成分希望被包括進去,如範例中所示。一般用於醫藥產業中之任一劑量形式(膠囊、藥錠、注射或類似形式),皆適用於此,以及術語“賦形劑”、“稀釋劑”或“載體”包括一般工業上會包含之此類非活性成分,與活性成分一同包含入此藥劑形式。
所有於此討論使用於組合療法之活性成分,可配製為醫藥組成物,其亦包括一或多種其他活性成分。此外,每一者皆可單獨投藥,但足以同時投藥,使得病患血液中含量上升或可同時享受每一活性成分(或策略)之助益。在本發明之某些較佳實施例中,例如,一或多種活性成分係配製為單一醫藥組成物。在本發明之其他實施例中,係提供一套組,其包括至少二單獨之容器,其中至少一其他容器裝有活性成分。二或多個不同容器係用於本發明之組合療法中。於此討論之組合療法亦包括使用組合物之一活性成分,以製造治療(或預防)有問題之疾病之藥物,其中該治療或預防更包括另一活性成分,或組合之策略。例如,在前列腺癌中,可使用LHRH促效劑或拮抗劑或第3型17β-羥基類固醇脫氫酶抑制劑。
下表列出較佳化合物與其特性與藥效。表3、4與5顯示體外數據,其包括結合至人類雄激素受體,以及對於小鼠乳癌Shionogi細胞具抗雄激素活性。表3、4與5亦顯示體內數據,其包括對於未成熟大鼠之三組織(腹部前列腺、儲精囊與球海綿體肌)之拮抗劑活性。此外,表4與5報
導對於相同組織之促效劑活性。對於數據如何收集與報導之詳細解釋附於表後。
表3之附註:
第1行報導抗雄激素之實驗室名稱。
第2行報導抗雄激素之分子結構。
第3行代表抑制50%(IC50)DHT-刺激Shionogi小鼠乳癌細胞數目之劑量(單位為nM)。較低值為較佳。
第4行代表轉染細胞中抗雄激素對於人類雄激素受體之相對結合親和性(RBA),以百分比(%)表示,相對於R1881,以下式計算:% RBA=100xIC50 R1881/IC50(化合物)較高值為較佳。
第5行代表大鼠前列腺中之抗雄激素藥效%,以抑制百分比表示。
抑制百分比以下式計算:%抑制=100-[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為前列腺重量。
較高值為較佳。
第6行代表大鼠儲精囊中之抗雄激素藥效%,以抑制百分比表示。
抑制百分比以下式計算:%抑制=100-[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為儲精囊重量。
較高值為較佳。
第7行代表大鼠球海綿體肌中之抗雄激素藥效%,以抑制百分比表示。
抑制百分比以下式計算:%抑制=100-[W(化合物)-W(控制組CX)/W(DHT)-W(控制
組CX)]x100。
W為球海綿體肌重量。
較高值為較佳。
表4之附註:
第1行報導SARMs之分子結構與實驗室名稱。
第2行代表抑制50%(IC50)DHT-刺激Shionogi小鼠乳癌細胞數目之劑量(單位為nM)。較低值為較佳。
第3行代表轉染細胞中SARMs對於人類雄激素受體之相對結合親和性(RBA),以百分比(%)表示,相對於R1881,以下式計算:% RBA=100xIC50 R1881/IC50(化合物)較高值為較佳。
第4行代表大鼠前列腺中之抗雄激素藥效%,以抑制百分比表示。
抑制百分比以下式計算:%抑制=100-[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為前列腺重量。
較高值為較佳。
第5行代表大鼠儲精囊中之抗雄激素藥效%,以抑制百分比表示。
抑制百分比以下式計算:%抑制=100-[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為儲精囊重量。
較高值為較佳。
第6行代表大鼠球海綿體肌中之抗雄激素藥效%,以抑制百分比表示。
抑制百分比以下式計算:%抑制=100-[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為球海綿體肌重量。
較低值為較佳。
第7行代表大鼠前列腺中之雄激素藥效%,以刺激百分比表示。
刺激百分比係依據下式計算:%刺激=[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為前列腺重量。
較低值為較佳。
第8行代表大鼠儲精囊中之雄激素藥效%,以刺激百分比表示。
刺激百分比係依據下式計算:%刺激=[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為儲精囊之重量。
較低值為較佳。
第9行代表大鼠球海綿體肌中之雄激素藥效%,以刺激百分比表示。
刺激百分比係依據下式計算:%刺激=[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為球海綿體肌重量。
較高值為較佳。
表5之附註:
第1行報導抗雄激素或SARMs之分子結構與實驗室名稱。
第2行代表抑制50%(IC50)DHT-刺激Shionogi小鼠乳癌細胞數目之劑量(單位為nM)。較低值為較佳。
第3行代表轉染細胞中抗雄激素或SARMs對於人類雄激素受體之相對結合親和性(RBA),以百分比(%)表示,相對於R1881,以下式計算:% RBA=100xIC50 R1881/IC50(化合物)較高值為較佳。
第4行代表大鼠前列腺中之抗雄激素藥效%,以抑制百分比表示。
抑制百分比以下式計算:%抑制=100-[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為前列腺重量。
較高值為較佳。
第5行代表大鼠儲精囊中之抗雄激素藥效%,以抑制百分比表示。
抑制百分比以下式計算:%抑制=100-[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為儲精囊重量。
較高值為較佳。
第6行代表大鼠球海綿體肌中之抗雄激素藥效%,以抑制百分比表示。
抑制百分比以下式計算:%抑制=100-[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為球海綿體肌重量。
第7行代表大鼠前列腺中之雄激素藥效%,以刺激百分比表示。
刺激百分比係依據下式計算:%刺激=[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為前列腺重量。
較低值為較佳。
第8行代表大鼠儲精囊中之雄激素藥效%,以刺激百分比表示。
刺激百分比係依據下式計算:%刺激=[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為儲精囊之重量。
較低值為較佳。
第9行代表大鼠球海綿體肌中之雄激素藥效%,以刺激百分比表示。
刺激百分比係依據下式計算:%刺激=[W(化合物)-W(控制組CX)/W(DHT)-W(控制組CX)]x100。
W為球海綿體肌重量。
製備經人類雄激素受體(hAR)轉染之人類胚胎腎(HEK-293)細胞:細胞培養於6-孔Falcon瓶中,約3 X 105細胞/孔,於Dulbecco’s修飾Eagle’s培養液(DMEM),補充有10%胎牛血清,於37℃、95%空氣、5% CO2濕潤空氣下培養。5μg pCMVneo-hAR質體係使用轉染套組(Life Technologies,Ontario,Canada)進行轉染。於37℃培養6小時後,轉染培養液移除,並加入2ml之DMEM。細胞繼續培養48小時,之後轉移至10cm培養皿中,並培養於含有700μg/ml G-418之DMEM中,以抑制未經轉染細胞之生長。含G-418之培養液每二天更換一次,直至觀察到恆定之菌落。陽性菌落經PCR篩選。經hAR轉染之HEK 293細胞係經冷凍,至用於結合試驗中。
HEK-293 hAR細胞之細胞質製備:在進行結合試驗當天早上,HEK-293 hAR細胞沈澱物經解凍並懸浮於緩衝液A中(25mM Tris-HCl、1.5mM EDTA鈉鹽、10mM α-單硫甘油、10%甘油,以及10mM鉬酸鈉,pH 7.4;625 000細胞/0.1ml)。細胞懸浮液經超音波震盪三次,期間為30秒(間隔冷卻),之後於105 000 x g離心90分鐘。
大鼠前列腺細胞質製備:於進行結合試驗當天早晨,自24h-去勢大鼠中收集之腹部前列腺,以緩衝液A進行
均質化(1g組織於5mL中),均質物如上述離心。
雄激素結合係使用氫氧磷灰石(HAP)試驗測量。簡言之,具放射活性之類固醇[3H]R1881溶解於乙醇中,以緩衝液B(10mM Tris-HCl、1.5mM EDTA鈉鹽、10mM α單硫甘油,pH 7.4)稀釋。細胞分液或前列腺細胞質製備物(0.1ml)之後與5nM[3H]R1881(0.1ml,~100 000cpm),在指定濃度之未經標記之化合物(0.1ml,製備於含有30%乙醇之緩衝液B中)存在或不存在下,於0-4℃靜置16-18小時。加入醋酸曲安奈德(Triamcinolone acetonide)(TAC;100nM)以遮蔽黃體酮受體。未結合之類固醇於0-4℃,以0.3ml HAP製備於緩衝液P中(50mM Tris-HCl、10mM KH2PO4,pH 7.4)40分鐘而製備。與HAP靜置並於1000 x g離心10分鐘後,沈澱物以緩衝液P清洗3次。之後,沈澱物與1ml乙醇於室溫下靜置60分鐘,萃取出放射活性物。離心後,上清液倒入閃爍小瓶中,沈澱物再次以乙醇萃取。加入閃爍液體後,於液體閃爍計數器中測量放射活性。
測試化合物之劑量-反應曲線以及IC50值(導致[3H](R1881)50%取代之化合物濃度),係使用加權迭代非線性最小平方回歸計算。
相對結合親和性(RBA)係使用下式計算:RBA(%)[IC50(R1881)/IC50(化合物)]x 100
體外雄激素/抗雄激素活性係使用Shionogi小鼠乳癌細胞(107株)測量(Labrie等人,1988a;Labrie等人,1988b;Labrie等人,1988c)。
最少必需培養液(MEM)與非必需胺基酸係購自Gibco BRL(NY,USA),而經活性炭處理之胎牛血清(FBS)購自Wisent Inc.(Montreal,Canada)。二氫睪固酮(DHT)得自Steraloids(Wilton,NH),而該待測試之化合物係於吾人實驗室合成。
Shionogi細胞常規地培養於MEM,補充有100nM DHT、5%(v/v)活性炭處理FBS、100 IU盤尼西林/ml、50μg鏈黴素硫酸鹽/ml,以及1%(v/v)非必需胺基酸,如先前所述(Labrie等人,1988a;Labrie等人,1988b;Labrie等人,1988c)。細胞培養於37℃濕潤大氣,5% CO2與95%空氣下。細胞於接近全滿時,以0.1%胰蛋白(Wisent Inc.)之Hepes緩衝液,其含有3mM乙二胺四醋酸(EDTA)(pH 7.2)緩和消化方式進行繼代培養。之後細胞經離心沈澱、再懸浮於培養液中,並重新植入。
細胞植入於24-孔盤中,密度為18 000細胞/孔,並可附著至培養盤表面24小時。之後,培養液更換為新鮮培養液,含有2%(v/v)活性炭處理FBS,以及指定濃度之化合物,其由1000倍儲存溶液中稀釋於99%再蒸餾乙醇中,
在DHT(0.3nM)存在或不存在下。控制組細胞僅接受乙醇載劑(0.1% EtOH,v/v)。此乙醇濃度不會影響細胞生長。濃度增加之指定試劑加入三重複盤中,細胞生長10日,每2-3日更換一次培養液。細胞數目以測量DNA含量而定,如先前所述(Simard等人,1990)。
測試化合物之劑量-反應曲線,以及IC50值,係使用加權迭代非線性最小平方回歸計算。所有結果皆以平均值±SEM表示,除了當SEM與符號重疊時,僅顯示符號。IC50為該化合物可抑制50% DHT對於細胞生長之作用時之濃度。特定濃度之化合物(即10-7M)之基礎刺激百分比,係計算為[(具該化合物之DNA含量-不具該化合物之DNA含量)/不具該化合物之DNA含量]x 100。
LNCaP細胞如先前所述培養(Qi et al.2001)。簡言之,LNCaP細胞於每一次實驗前,於1.0ml RPMI 1640,補充有賀爾蒙耗盡之0.25% FCS培養6日。在實驗一開始,一半之培養液(0.5ml)經0.5ml相同培養液,但含有適當濃度之測試化合物取代,在1.0nM之R1881存在或不存在下。LNCaP細胞與化合物靜置72小時後,移除0.5ml培養液,以測定PSA。PSA含量係使用PSA[125I]IRMA套組測量(REF:RK-10CT),得自Izotop(Institute of Isotopes Ltd,Budapest,Hungary)。
完整6週大雄性大鼠(Crl:CD(SD))稱重150-205g,得自Charles-River Canada Inc.(St-Constant,Quebec,Canada),每籠圈養至多3隻,於塑膠箱中,為溫度(19℃至25℃)-與光(12小時光照/日)-控制環境。牠們於實驗室條件下馴化2週,在進行藥物動力學(PK)試驗之前。大鼠餵養嚙齒動物飼料(PMI Nutrition International Certified Rodent Chow No.5CR4(14%蛋白質)),並任意飲用自來水。動物於投藥時測量體重,為165-200g。
EM-9150經由胃管灌食法口服投藥(在下午),劑量為20mg/kg(5ml/kg),至9隻完整雄性大鼠中。EM-9150以0.4%水性甲基纖維素(MeC)懸浮液投藥。血液樣本(~0.4mL/時間點/大鼠)以頸靜脈穿刺,於投藥後0.5、1、2、3.5、7與24小時,收集自3隻動物/時間點。血液樣本置入含有EDTA(K3)作為抗凝血劑之管中,並於4℃,2700rpm離心10分鐘。所得血漿分離,並轉移至2聚丙烯管中,以乾冰立即冷凍,並維持於冷凍庫中,維持-80℃直至進行分析。
EM-9150與其代謝物EM-9156與EM-9260之血漿濃度,係使用經GLP-認證之具質譜儀偵測之液相層析試驗(LC-MS/MS)測量。每一化合物之血漿濃度對應時間係繪製成圖(圖5),並用計算血漿濃度曲線下面積,自投藥後0至24
小時[AUC(0-24h)]。AUC(0-24小時)值係使用線性梯形法計算。
去勢雄性Sprague-Dawley大鼠(Crl:CD(SD)Br),稱重275-375g,用於藥物動力學試驗。動物自投藥前一天下午約16點開始禁食(僅飲水)。
EM-9150經由胃管灌食法口服投藥(在早上),劑量為0.5mg/動物(1.0ml/動物;3隻動物/化合物)。EM-9150溶於二甲基亞碸(DMSO,10%最終濃度),並以0.9% NaCl-1%明膠之溶液/懸浮液投藥)。於異氟醚麻醉下,血液樣本(~0.5mL/時間點)以頸靜脈穿刺,於投藥後1、2、3、4、7與24小時收集。血液樣本置入含有EDTA(K3)作為抗凝血劑之管中,並於4℃,1700-2400g離心10分鐘。所得血漿以乾冰立即冷凍,並維持於冷凍庫中,維持-80℃直至進行分析。在投藥後7小時收集血液後,自每組一隻大鼠中收集腹部前列腺與球海綿體肌,以測定前列腺內與肌肉內之EM-9150與其代謝物EM-9156之濃度。前列腺與球海綿體肌於液態氮中冷卻,並維持於-80℃直至使用。緩衝液與乙醇-丙酮溶液加入組織中,並以Polytron均質化。收集上清液。蒸發至乾燥,並於緩衝液中重新配製。
EM-9150與其代謝物EM-9156之血漿濃度,係使用具質譜儀偵測之液相層析試驗(LC-MS/MS)測量。每一化
合物之血漿濃度對應時間係繪製成圖(圖5),並用計算血漿濃度曲線下面積,自投藥後0至24小時[AUC(0-24h)]。AUC(0-24h)值係使用線性梯形法計算。化合物之前列腺內與肌肉內濃度亦以LC-MS/MS測量。
22至24-天大之未成熟雄性大鼠(Crl:CD(SD)Br),於處理一開始時稱重為60-80g,得自Charles-River,Inc.(St-Constant,Quebec,Canada),每籠圈養至多5隻,於塑膠箱中,為溫度(23±1℃)-與光(12小時光照/日,於7點15分照光)-控制環境。牠們於實驗室條件下馴化2週,在進行藥物動力學(PK)試驗之前。大鼠餵養嚙齒動物飼料,並任意飲用自來水。化合物於去勢大鼠中進行測試,補充有(拮抗劑活性)或未補充有(促效劑活性)雄激素。到達當日,指定動物在異氟醚麻醉下(試驗日1)經去勢(CX),經由陰囊路線,之後隨機分配,每組3至5隻動物。在去勢時,二氫睪固酮(DHT;1cm長度之純DHT於矽膠管中,具內直徑與外直徑分別為0.078與0.125英吋)之矽膠植入物,皮下插入至指定升高抗雄激素活性之動物之腹部區域。在完整動物實驗中,可省卻去勢與矽膠植入物植入步驟。
經測試化合物係每日口服投藥,共7日,自試驗日2至試驗日8,劑量範圍為0.1至0.5mg/動物。化合物溶解於二甲基亞碸(DMSO,10%最終濃度)中,並以0.9%
NaCl-1%明膠溶液/懸浮液投藥,或以0.4%水性甲基纖維素懸浮液投藥。控制組動物在7日期間內僅接受對應載劑。某些動物以抗雄激素處理,以氟他胺(flutamide)或康士得(Casodex)作為參考物。經異氟醚麻醉之動物,於試驗第9日以頸椎脫位法犧牲,約為最後一次投藥後24小時。腹部前列腺、儲精囊與球海綿體肌快速取出並稱重。
就拮抗劑活性而言,抑制百分比係以下式計算:%抑制=100-[[W(化合物)-W(控制組CX)/W(控制組DHT)-W(控制組CX)]x100]。
就促效劑活性而言,刺激百分比對應DHT係以下式計算:%刺激=[W(化合物)-W(控制組CX)/W(控制組DHT)-W(控制組CX)]x100。
就完整動物之計算,控制組DHT以控制組完整動物取代,%刺激減去100%。
W為前列腺、儲精囊或球海綿體肌之重量。
係合成一系列之非類固醇化合物,具有芳基尿囊素或芳基硫尿囊素骨架,具有含苯基吡啶或喹啉或異喹啉之側鏈,可修飾非類固醇骨架與雄激素受體之交互作用。如表1至5及圖1與2所示,這些化合物顯示對於人類雄激素受體(以及大鼠雄激素受體)之親和性,具相對結合親和性(RBA)範圍為中度約0.1%至高度3310%(就EM-8851而言),
與R1881之100%相較,其為一種已知之合成與代謝抵抗性合成雄激素,具類似於最具藥效之天然雄激素DHT(二氫睪固酮)之人類雄激素受體親和性。這些新穎化合物之報導RBAs較抗雄激素參考物,亦即羥基氟他胺與比卡魯安(bicalutamide)(0.21%與0.3%)高。例如,某些較佳抗雄激素,亦即EM-9150(74±19%)、EM-9198(22%)、EM-9204(22%)與EM-9205(17.9%)之RBA值為352、105、105與85倍高於羥基氟他胺之RBA值。此外,較佳SARMs,亦即EM-9251(253%)、EM-9253(125%)、EM-9290(197%)與EM-9309(157%)之RBA值為1200、595、938與748倍較高於羥基氟他胺之RBA值。某些取代基之變異對於雄激素受體親和性之影響已於先前段落[0071]討論。
本發明之所有抗雄激素皆顯示出對於Shionogi小鼠乳癌細胞,具有效與純之抗雄激素活性,以及體內對於大鼠前列腺與儲精囊重量之影響。這些化合物會逆轉該0.3nM DHT-誘發之細胞增生,具IC50值範圍為2.6nM(EM-9028)至126nM,而羥基氟他胺與比卡魯安(bicalutamide)之IC50值為67±2nM與190±36nM(表1、2、3與5,以及圖3)。因此,某些較佳抗雄激素,亦即EM-9150(13±3nM)、EM-9198(5.3nM)、EM-9204(7.0nM)與EM-9205(14.8nM)之IC50值為5.2、6.4、4.8與2.3倍高於羥基氟他胺之IC50值,當與相同實驗相較時。
本發明對於DHT-誘發之Shionogi細胞增生最具
活性之抗雄激素,亦即EM-8900、EM-9025、EM-9028、EM-9039與EM-9043(IC50=2.6至4.3nM)約為7至22倍有效於羥基氟他胺。最重要的是,這些化合物並無對於Shionogi細胞增生基礎值具任何活性,因此表示其純粹具有抗雄激素活性。
本發明之抗雄激素顯示對於前列腺特異性抗原(PSA)量之有效抑制,於與人類前列腺癌LNCaP細胞(表1與圖4)靜置72小時後之培養液中測量。例如,在阻斷R1881-刺激之PSA分泌方面,EM-9150為10倍更有效於比卡魯安(bicalutamide),除了於10-7M基礎值無刺激之外(圖4)。相同之結果係於EM-9156與其他化合物觀察到。
這些化合物顯示出相同之絕佳口服生物可獲得(圖5)。這些化合物之代謝已於段落[0048]、[0072]與[0073]討論。例如,在口服投藥0.5mg之EM-9150/大鼠7小時後,EM-9150之血漿、前列腺內與肌肉內濃度測量值分別為0.9ng/ml、2.9ng/g與1.2ng/g,以及EM-9156,其活性代謝物之一,測量值為22.3ng/ml、19.3ng/g與12.7ng/g。此實驗確認二化合物皆能到達目標組織。EM-9150於大鼠前列腺之濃度為約3倍高於血漿濃度,與EM-9156相較,其中二濃度皆類似但高於EM-9150。此現象非常重要,由於主要代謝物EM-9260代表約90%之血漿暴露於EM-9150,並未良好結合至雄激素受體(RBA=~0.1%),相對於EM-9150與EM-9156,其觀察到非常良好之親和性(RBA=74±19%與17±4%)(表2,圖5)。此外,這三個抗雄激素化合物具體外
與體內活性。
這些化合物之主要目的為顯示出於雄性大鼠中有效與純之抗雄激素體內活性。如表1、2、3與5與圖6,在去勢之未成熟雄性大鼠中,帶有DHT植入物,每日口服投藥0.5mg/大鼠這些化合物,對於DHT對於腹部前列腺與儲精囊重量之刺激作用可逆轉32-71%與44-96%,而相同劑量之氟他胺(flutamide)(0.5mg/大鼠)為達到可比較抑制(對於前列腺與儲精囊重量抑制48%與83%)所必須。於0.5mg/大鼠劑量下,某些較佳抗雄激素,亦即EM-9150、EM-9198、EM-9204與EM-9205,對於腹部前列腺達到之抑制為55%、52%、62%與65%,對於儲精囊-DHT刺激重量之抑制為92%、90%、91%與87%(表3)。圖6顯示對於7-日每日治療,劑量增加之氟他胺(flutamide)(FLU)、比卡魯安(bicalutamide)與EM-9150之對於去勢(CX)未成熟雄性大鼠,帶有DHT植入物,之腹部前列腺重量之影響。這些化合物具有類似之活性,但比卡魯安(bicalutamide)似乎於較高劑量達到高原,該案例並非EM-9150。本發明描述之抗雄激素亦抑制具DHT植入物之大鼠模式中之球海綿體肌重量。
有趣的是,每日口服投藥這些化合物至去勢未成熟大鼠中,對於腹部前列腺與儲精囊重量,包括球海綿體肌重量,不具刺激作用,因此顯示這些化合物發揮純抗雄激素活性,不具任何內生性雄激素活性(表3與5,以及圖7)。
本數據顯示本發明描述之非類固醇抗雄激素,對於雄激素-敏感參數更具藥效,與目前可獲得之抗雄激素相
較,因此表示這些化合物應發展為系統性抗雄激素,用於治療雄激素-依賴性疾病,尤其是前列腺癌。
由於在阻斷雄激素R1881對於人類LNCaP細胞之PSA分泌之刺激作用方面,EM-9150與EM-9156為10倍有效於比卡魯安(bicalutamide),且在大鼠中有類似之體內活性,除了無促效劑作用之外,本數據顯示假設在人類與大鼠中有類似之代謝,EM-9150與EM-9156可為10倍有效於比卡魯安(bicalutamide),就治療患有前列腺癌之男性而言。
如表2、4與5所示,本發明之SARMs通常對於Shionogi細胞增生具有混合之雄激素/抗雄激素活性。某些較佳SARMs,亦即EM-9251(67.7nM)、EM-9253(29.9nM)、EM-9290(64.8nM)與EM-9309(66.9nM)之IC50值,類似於羥基氟他胺(67±2nM)之IC50值,除了於10-7M對於基礎值之刺激之外,除了EM-9253(38%、25%與13%)之外。
在動物模式中,前列腺為良好辨識之雄激素活性參數,而雄激素-敏感球海綿體肌,其位於肛提肌旁(Poortmans與Wyndaele;1998),為評估合成代謝活性之有價值工具。如表2、4與5,以及圖8所示,本發明之SARMs於未成熟大鼠模式中,顯示出混合雄激素/抗雄激素活性。事實上,這些化合物對於CX大鼠之前列腺與儲精囊具輕度至中度刺激效果,而在肌肉中觀察到強雄激素效果。另一方面,這些化合物會逆轉前列腺之DHT-誘發之刺激,但這些化合物並未於肌肉中發揮抗雄激素活性(儲精囊顯示於
此模式中有可變結果(抑制、刺激或無作用))。此外,在完整大鼠模式中,我們觀察到在某些案例中(即EM-9251),有清楚之前列腺與儲精囊抑制,但對於肌肉永遠是刺激。因此,EM-9251抑制完整之大鼠前列腺與儲精囊25±4%與35±7%,而刺激球海綿體肌77±6%(圖8)。
在劑量0.1mg/大鼠時,本發明SARMs可達到最大刺激,亦即EM-8664、EM-8730、EM-8796、EM-8887與EM-8977分別對於球海綿體肌為177%、178%、168%、214%與194%(表4與5)。在相同劑量下,某些較佳SARMs,亦即EM-9251、EM-9253、EM-9290與EM-9309,可達到刺激119±24、114±18、88±2與107±9(表4)。在表4中,我們發現硫尿囊素衍生物對於球海綿體肌具較高刺激,與尿囊素衍生物相較。另一方面,硫尿囊素衍生物對於儲精囊具大鼠儲精囊DHT-誘發刺激逆轉(或失活)作用,與尿囊素衍生物相較,其觀察到抑制作用(表4,第5行)。SARMs之次族群亦參與。
表2、4與5之第6行,球海綿體肌抑制百分比之負值,為第9行觀察到的SARM化合物對於球海綿體肌刺激之進一步證明。
這些SARMs之一主要特色為其於雄性大鼠中,顯示出某些有效抗雄激素體內活性,但具有某些促效劑活性。如表2、4與5所示,在帶有DHT植入物之去勢未成熟雄性大鼠中,每日口服投藥0.5mg/大鼠這些化合物,會逆轉0-61% DHT對於腹部前列腺重量之刺激作用,而相同劑量之氟他胺(flutamide)(0.5mg/大鼠),為達到可與最佳案例
(對於前列腺之抑制達48%)比擬之抑制所需之劑量。在劑量0.5mg/大鼠時,某些較佳SARMs,亦即EM-9251、EM-9253與EM-9290,對於腹部前列腺-DHT刺激重量達到之某些抑制為45%、30%與41%(表2與4)。
具有上述之活性,本發明SARMs可用於治療與預防良性前列腺增生,以及預防前列腺癌。此亦可避免在治療肌少症以及其他需要雄激素活性之疾病/醫療問題時:雄性性腺功能減退、性慾減退、勃起功能障礙,以及以陰道神經密度為指標之女性性功能障礙,對於前列腺與儲精囊之刺激,Pelletier等人2012與2013。
質子NMR光譜係於Bruker Avance 400 MHz儀器上測量。係使用下列縮寫:s,單峰;d,雙峰;dd,雙峰的雙峰;t,三峰;q,四峰;p,五峰;b,寬峰;以及m,多重峰。化學位移(d)以氯仿(7.26ppm,1H)、丙酮(2.05ppm,1H)或甲醇(3.33ppm,1H)為參考,並表示為ppm。薄層層析法(TLC)係於0.25mm Kiesel凝膠60F254板上進行(E.Merck,Darmstadt,FRG)。就快速層析法而言,係使用Merck-Kiesel凝膠60(230-400 mesh A.S.T.M.)。除非另有指出,起始材料與反應物係以化學方式獲得,並以此方式使用或以標準方法純化。所有經純化與除水之溶劑與反應物皆儲存於氬氣下。無水反應係於惰性大氣下進行,並於氬氣下設定組合與冷卻。有機溶液通常以硫酸鈉除水,於迴旋濃縮儀中減壓蒸發。起始材料與試劑主要得自Aldrich Chemical Company,Inc.(Milwaukee,Wisconsin)。
氰化鈉(30.7g,0.62mol)與氯化銨(39.5g,0.74mol)之28%氫氧化銨水溶液(240mL,1.7mol),係以機械式攪拌器攪拌,冷卻至0℃,緩慢地以丙酮(1)(36.8mL,0.50mol)處理,並在移除冰水浴之後攪拌整夜。反應混合物以二氯甲烷萃取(3 x 300mL)。合併之有機層以硫酸鈉除水、過濾並於真空下蒸發,得化合物2,為澄清液體(40g,95%)。1H NMR(400MHz,CDCl3)δ:1.48(s,6H,2 Me),1.64(bs,2H,NH2)。
4-溴吡啶氯化氫(52.8g,0.27mol)與3-氯-4-甲氧基苯基硼酸(3)(60.8g,0.33mol)之甲苯-乙醇-水溶液(2:2:1,675mL)混合物,以氬氣沖洗15分鐘,緩慢地以碳酸鈉處理(115g,1.08mol),以氬氣額外沖洗10分鐘,以四(三苯基膦)鈀(0)處理(7.87g,6.81mmol),並於90℃加熱4小時。反應混合物冷卻至室溫、蒸發(甲苯與乙醇)、以水稀釋(1.1L)、以濃HCl酸化至pH 1,並於Buchner漏斗上過濾。濾液以氫氧化鈉顆粒中和,之後以碳酸鈉中和至pH 7。懸浮液於Buchner漏斗上過濾,所得固體4乾燥整夜,並使用於下一步驟不需進一步純化(53.9g,90%)。
化合物4(53.9g,0.25mol)與吡啶氯化氫(280g,2.4mol)之混合物,加熱至220℃,3小時,冷卻至室溫,倒入水中(1.2L)、以碳酸鈉中和至pH 7,並於Buchner漏斗上
過濾。所得固體5乾燥整夜不需進一步純化(38.3g,76%)。1H NMR(400MHz,丙酮-d6)δ:7.15(d,1H,Ar),7.65(m,3H,Ar與Pyr),7.8(s,1H,Ar),8.6(d,2H,Pyr),9.2(bs,1H,OH)。
在氬氣大氣下,三光氣(8.31g,28mmol)之二氯甲烷溶液(700mL)係冷卻至0℃,以碳酸氫鈉(33.6g,400mmol)與4-胺基-2-氯苯甲腈(6)(12.2g,80mmol)部分地處理,並以機械式攪拌器攪拌15分鐘,以及於移除冰水浴後攪拌2小時。含有粗異氰酸酯衍生物之反應混合物冷卻至0℃,緩慢地經三乙基胺(25.7mL,184mmol)與2-胺基-2-甲基丙腈基(2)(7.4mL,80mmol)處理,並於移除冰水浴後攪拌2小時。反應混合物於Buchner漏斗上過濾,濾液真空蒸發。粗尿素中間物7溶解於甲醇中(200mL)。溶液以機械式攪拌器攪拌,以10%氫氯酸水溶液處理至pH 1,並回流2小時。反應混合物以冰水浴成功地冷卻至室溫,並以冷水處理(250mL)。懸浮液經過濾,之後濾液以二氯甲烷萃取(2 x 300mL)。合併之有機層經真空蒸發。殘餘物溶解於甲醇中(100mL),所得溶液以冰水處理(125mL)並過濾。合併之固體乾燥整夜,並稀釋於二氯甲烷中(850mL)。懸浮液以機械攪拌器攪拌2小時並過濾,濾液於真空下蒸發,得希望之EM-9260(18.0g,85%)。1H NMR(400MHz,丙酮-d6)δ:1.53(s,6H,2 Me),7.74(bs,1H,NH),7.81(dd,J=1.9與8.5Hz,1H,Ar),7.95(d,J=1.9Hz,1H,Ar),8.00(d,J=8.5Hz,
1H,Ar)。
在氬氣環境下,氫化鈉懸浮液(2.27g,0.095mol,以己烷潤洗)之無水N,N-二甲基甲醯胺(45mL)冷卻至0℃,並緩慢地以3-溴-1-濾丙烷(4.9mL,0.049mol)與EM-9260(10.0g,0.038mol)之無水N,N-二甲基甲醯胺溶液(30mL)處理。反應混合物攪拌5小時,並在此期間逐漸回溫至室溫。之後,反應混合物倒入冰水中(300mL),並於Buchner漏斗上過濾。所得固體8乾燥整夜,並用於下一步驟不需進一步純化(11.0g,85%)。1H NMR(400MHz,丙酮-d6)δ:1.6(s,6H,2 Me),2.2(m,2H,CH2),3.5(t,2H,CH2Cl),3.7(t,2H,CH2N),7.8(d,1H,Ar),7.9(s,1H,Ar),8.0(d,1H,Ar)。
化合物8(55.0g,0.16mol)與化合物5(36.4g,0.18mol)之無水N,N-二甲基甲醯胺(325mL)混合物,係以碳酸銫(68.5g,0.21mol)處理,並於80℃加熱6小時。反應混合物冷卻至室溫,以丙酮稀釋(1L),倒入冰水中(2L),並於Buchner漏斗上過濾。所得淡橘色固體EM-9150乾燥整夜,不需進一步純化(70.6g,86%)。1H NMR(400MHz,丙酮-d6)δ:1.60(s,6H,2 Me),2.32(p,J=6.6Hz,2H,CH2),3.71(t,J=7.0Hz,2H,CH2N),4.35(t,J=5.9Hz,2H,CH2O),7.27(d,J=8.6Hz,1H,Ar),7.65(d,J=6.1Hz,2H,Pyr),7.76(dd,J=2.3與8.6Hz,1H,Ar),7.79(dd,J=1.9與8.5Hz,1H,Ar),7.85(d,J=2.3Hz,1H,Ar),7.88(d,J=1.9Hz,1H,
Ar),7.97(d,J=8.5Hz,1H,Ar),8.62(d,J=6.2Hz,2H,Pyr)。
EM-9150(100.7g,0.198mol)之1,4-二噁烷溶液(1.5L),微加熱以完全溶解,緩慢地以濃鹽酸(14.75M)(14.8mL,0.218mol)處理。反應混合物攪拌0.5小時並過濾。合併之EM-9287為淡米色固體,經乾燥。1H NMR(400MHz,甲醇-d4)δ:1.60(s,6H,2 Me),2.33(p,J=5.7Hz,2H,CH2),3.72(t,J=6.6Hz,2H,CH2N),4.41(t,J=5.5Hz,2H,CH2O),7.35(d,J=8.8Hz,1H,Ar),7.70(dd,J=1.9與8.5Hz,1H,Ar),7.74(d,J=1.8Hz,1H,Ar),7.87(d,J=8.6Hz,1H,Ar),8.01(dd,J=2.4與8.7Hz,1H,Ar),8.11(d,J=2.4Hz,1H,Ar),8.36(d,J=7.0Hz,2H,Pyr),8.81(d,J=6.9Hz,2H,Pyr)。粗EM-9287懸浮於水中(1.5L),並以7N氫氧化鈉(31mL,0.22mol)處理。反應混合物攪拌1小時並過濾。所得之EM-9150為淡黃色固體,乾燥得83.7g(83%),並進一步快速層析法純化(矽膠凝膠,4個分離物為約20g,30-80%丙酮於二氯甲烷中),得83.0g純EM-9150(化學純度為99.3%,HPLC)。
EM-9150(550mg,1.08mmol)之甲醇-水/5:2(20mL)懸浮液,加入單過氧酞酸鎂(MMPP)(1.33g,2.7mmol)。溶液於50℃加熱整夜。反應完全後(TLC),混合物以飽和碳酸氫鈉水溶液稀釋,並以二氯甲烷萃取(3 x)。合併之有機
層以硫酸鈉除水、過濾並減壓濃縮。粗化合物經快速層析法純化(矽膠,20%丙酮-二氯甲烷),得332mg(58%)EM-9156。1H NMR(400MHz,丙酮-d6)δ:1.59(s,6H,2 Me),2.31(p,J=6.4Hz,2H,CH2),3.70(t,J=7.0Hz,2H,CH2N),4.34(t,J=5.8Hz 2H,CH2O),7.25(d,J=8.7Hz,1H,Ar),7.71(m,3H,Ar與Pyr),7.78(dd,J=1.9與8.5Hz,1H,Ar),7.82(d,J=2.3Hz,1H,Ar),7.88(d,J=1.9Hz,1H,Ar),7.97(d,J=8.5Hz,1H,Ar),8.17(d,J=7.4Hz,2H,Pyr)。EM-9288,EM-9156之氯化氫鹽類,係使用EM-9287描述之流程製備。1H NMR(400MHz,甲醇-d4)δ:1.60(s,6H,2 Me),2.32(p,J=5.6Hz,2H,CH2),3.72(t,J=6.7Hz 2H,CH2N),4.38(t,J=5.4Hz,2H,CH2O),7.31(d,J=8.7Hz,1H,Ar),7.70(dd,J=1.9與8.5Hz,1H,Ar),7.75(d,J=1.8Hz,1H,Ar),7.88(m,2H,Ar),7.99(d,J=1.5Hz,1H,Ar),8.16(bs,2H,Pyr),8.71(bs,2H,Pyr)。
在氬氣大氣下,三光氣(2.08g,7.01mmol)之二氯甲烷溶液(200mL)係冷卻至0℃,以碳酸氫鈉(33.6g,400mmol)與3-氯-4-氰基-2-甲基苯胺(9)(得自Li,J.J.等人,J.Med.Chem.,2007,50(13),3015-3025,補充資料之S2與S3頁所述之流程)(3.33g,20mmol)部分地處理,並以機械式攪拌器攪拌15分鐘,以及於移除冰水浴後攪拌2小時。含有粗異氰酸酯衍生物之反應混合物冷卻至0℃,緩慢地經三乙
基胺(6.2mL,44mmol)與2-胺基-2-甲基丙腈基(2)(1.9mL,21mmol)處理,並於移除冰水浴後攪拌整夜。反應混合物於Buchner漏斗上過濾,濾液真空蒸發。粗尿素中間物10溶解於甲醇中(100mL)。溶液以機械式攪拌器攪拌,以10%氫氯酸水溶液處理至pH 1,並回流4小時。反應混合物以冰水浴連續冷卻至室溫,並以冷水處理(200mL)。懸浮液經過濾,之後濾液以二氯甲烷萃取(3 x 150mL。合併之有機層經真空蒸發。固體合併得希望之EM-9289(4.04g,73%)。1H NMR(400MHz,丙酮-d6)δ:1.55(s,3H,Me),1.56(s,3H,Me),2.29(s,3H,芳香基之Me),7.52(d,J=8.3Hz,1H,Ar),7.70(bs,1H,NH),7.88(dd,J=0.4與8.3Hz,1H,Ar)。
在氬氣大氣下,氫化鈉之懸浮液(60%分散於礦物油中,75mg,1.9mmol)與EM-9289(420mg,1.5mmol)之無水N,N-二甲基甲醯胺溶液(9mL)攪拌30分鐘,並緩慢地以1,3-二溴丙烷(0.75mL,7.4mmol)處理。反應混合物於50℃下加熱5小時。之後,反應混合物冷卻至室溫,以水稀釋(50mL),並以醚類萃取(4 x 25mL)。合併之有機層以硫酸鈉除水、過濾並減壓濃縮。粗化合物經快速層析法(矽膠,0-100%丙酮-己烷)純化,得400mg(70%)之化合物11。
化合物11(100mg,0.25mmol)與化合物5(70mg,0.34mmol)之丙酮(3mL)混合物,係以碳酸銫(148mg,0.46mmol)處理,並於60℃加熱2小時。反應混合物於室溫下冷
卻,並於CeliteTM上過濾。濾液減壓蒸發,殘餘物(溶於二氯甲烷)以矽膠過濾。粗化合物經快速層析法純化(矽膠,20%丙酮-二氯甲烷),得116mg(89%)之EM-9251。1H NMR(400MHz,丙酮-d6)δ:1.61(s,3H,Me),1.62(s,3H,Me),2.29(s,3H,芳香基之Me),2.32(p,J=6.4Hz,2H,CH2),3.69(dt,J=1.9與7.2Hz,2H,CH2N),4.32(dt,J=1.2與6.0Hz,2H,CH2O),7.27(d,J=8.6Hz,1H,Ar),7.50(d,J=8.3Hz,1H,Ar),7.65(d,J=6.1Hz,2H,Pyr),7.76(dd,J=2.3與8.6Hz,1H,Ar),7.85(dd,J=0.4與8.3Hz,1H,Ar),7.87(d,J=2.3Hz,1H,Ar),8.62(d,J=6.1Hz,2H,Pyr)。
EM-9252之製備起始自EM-9251,藉由使用EM-9156所述之流程,除了以乙酸乙酯取代二氯甲烷進行萃取之外。粗化合物經快速層析法純化(矽膠,5%甲醇-二氯甲烷),得48mg(80%)之EM-9252。1H NMR(400MHz,丙酮-d6)δ:1.60(s,3H,Me),1.62(s,3H,Me),2.29(s,3H,芳香基之Me),2.31(p,J=7.3Hz,2H,CH2),3.69(dt,J=1.8與7.0Hz,2H,CH2N),4.32(dt,J=1.3與5.9Hz,2H,CH2O),7.25(d,J=8.7Hz,1H,Ar),7.50(d,J=8.3Hz,1H,Ar),7.71(d,J=7.4Hz,2H,Pyr),7.72(dd,J=2.5與8.6Hz,1H,Ar),7.85(d,J=2.4Hz,1H,Ar),7.86(dd,J=0.4與7.5Hz,1H,Ar),8.16(d,J=7.4Hz,2H,Pyr)。
3-氯-4-氰苯胺(6)(1.12g,7.3mmol)之水懸浮液(15mL)係緩慢地經硫光氣(0.84mL,11mmol)處理,並攪拌2小時。反應混合物以水稀釋,並以二氯甲烷萃取(3 x)。合併之有機層以硫酸鎂除水、過濾並減壓濃縮。粗異硫氰酸酯12係用於下一步驟不需進一步純化。
異硫氰酸酯12(1.43g,7.3mmol)、2-(3-羥基-丙基胺基)-2-甲基-丙腈基(13)(得自WO 2006/133567,第58頁描述之流程),與三乙基胺基(0.1mL,0.7mmol)之無水四氫呋喃溶液(35mL),回流1小時。反應混合物冷卻至室溫,
並減壓濃縮。粗醇類14係用於下一步驟不需進一步純化。
醇類14(2.47g,7.3mmol)之甲醇與2N氫氯酸水溶液之1:1比例之混合物溶液(36mL),係回流1小時。之後,反應混合物於室溫下冷卻,以水稀釋,並以二氯甲烷萃取(3 x)。合併之有機層以硫酸鈉除水、過濾並減壓濃縮。粗化合物經層析法純化(Biotage系統,矽膠,20-30%丙酮-己烷),得1.58g(64%,3步驟)化合物15。
在氬氣大氣下,醇類15(102mg,0.30mmol)、酚類5(60mg,0.29mmol)與三苯基膦(81mg,0.31mmol)之無水四氫呋喃溶液(3mL),係冷卻至0℃,並緩慢地以二異丙基偶氮二羧酸酯(DIAD)(0.06mL,0.3mmol)處理。反應混合物在移除冰水浴後攪拌整夜。反應混合物減壓濃縮。粗化合物(溶於丙酮中)係於矽膠上過濾。粗化合物經快速層析法純化(矽膠,40%丙酮-己烷),得32mg(21%)之EM-9052。1H NMR(400MHz,丙酮-d6)δ:1.67(s,6H,2 Me),2.46(m,2H,CH2),4.08(m,2H,CH2N),4.36(t,J=6.0Hz,2H,CH2O),7.29(d,J=8.6Hz,1H,Ar),7.66(m,3H,Ar與Pyr),7.77(dd,J=2.3與8.6Hz,1H,Ar),7.84(d,J=1.9Hz,1H,Ar),7.88(d,J=2.3Hz,1H,Ar),8.04(d,J=8.3Hz,1H,Ar),8.59(d,J=6.1Hz,2H,Pyr)。
在氬氣大氣下,化合物16(得自化合物15之相同流程(除了在開始之前蒸發甲醇,而不以水稀釋),產率為24%,起始於3-氯-4-氰基-2-甲基苯胺(9)(得自Li,J.J.et al.J.Med.Chem.2007,50(13),3015-3025,補充資料,S2與S3頁所述之流程))(89mg,0.25mmol)之二氯甲烷溶液(1mL),係冷卻至0℃,經1,4-二吖雙環[2.2.2]辛烷(DABCO)(62mg,0.55mmol)與p-甲苯磺醯氯(75mg,0.39mmol)處理,並在移除冰水浴後攪拌1小時。反應混合物以飽和氯化銨水溶液稀釋,並以二氯甲烷萃取(2 x)。合併之有機層以硫酸鈉除水、過濾並減壓濃縮。粗甲苯磺酸酯17係使用於下一步驟不需純化。
在氬氣大氣下,酚類5(78mg,0.38mmol)之N,N-
二甲基甲醯胺溶液(1mL),係以氫化鈉(60%分散於礦物油中,19mg,0.48mmol)處理,攪拌30分鐘,以甲苯磺酸酯17(128mg,0.25mmol)之N,N-二甲基甲醯胺溶液(2mL)處理,並於80℃加熱15分鐘。反應混合物於室溫下冷卻、以醚稀釋,並以水清洗(2 x)。有機層以硫酸鈉除水、過濾並減壓濃縮。粗化合物(溶於二氯甲烷中)於矽膠上過濾。粗化合物亦經二快速層析法純化(矽膠,30%丙酮-己烷,以及20-50%醚-二氯甲烷),得58mg(43%)之EM-8799。1H NMR(400MHz,丙酮-d6)δ:1.69(s,3H,Me),1.69(s,3H,Me),2.27(s,3H,芳香基之Me),2.47(p,J=7.1Hz,2H,CH2),4.07(m,2H,CH2N),4.35(t,J=6.0Hz,2H,CH2O),7.29(d,J=8.6Hz,1H,Ar),7.55(d,J=8.2Hz,1H,Ar),7.66(d,J=6.2Hz,2H,Pyr),7.77(dd,J=2.3與8.6Hz,1H,Ar),7.88(d,J=2.1Hz,1H,Ar),7.90(d,J=7.6Hz,1H,Ar),8.62(d,J=6.0Hz,2H,Pyr)。
EM-8798以EM-8799所描述之相同流程製備。化合物19以化合物17之相同流程大量製備,起始自化合物18,其以化合物15之相同流程製備(除了使用飽和碳酸氫鈉水溶液,取代水稀釋反應混合物之外),起始自4-氰基-2-甲基-3-三氟甲基苯胺(得自US 2004/0181064,41-42頁所述之流程)產率為52%。粗EM-8798經快速層析法純化(矽膠,30%丙酮-己烷),得55mg希望之化合物,產率為42%。1H NMR(400MHz,丙酮-d6)δ:1.71(s,6H,Me),2.35(d,J=2.1Hz,3H,芳香基之Me),2.48(p,J=7.1Hz,2H,CH2),4.09(m,2H,CH2N),4.35(t,J=6.0Hz,2H,CH2O),7.29(d,J=8.6Hz,1H,Ar),7.66(d,J=6.2Hz,2H,Pyr),7.77(dd,J=2.3與8.6Hz,1H,Ar),7.87(d,J=7.9Hz,1H,Ar),7.89(d,J=2.2Hz,1H,Ar),8.06(d,J=8.2Hz,1H,Ar),8.62(d,J=6.1Hz,
2H,Pyr)。
EM-9025以EM-8799描述之相同流程製備。化合物21以化合物17之相同流程大量製備,起始自化合物20,其以化合物15之相同流程製備(除了在開始之前蒸發甲醇,而不以水稀釋),起始自4-氰基-3-氟苯胺,產率為33%。化合物22得自如WO 2009/079412(第97頁)所述之流程,使用1-溴-4-(甲氧基甲氧基)苯與4-吡啶硼酸,產率為57%,3步驟。粗EM-9025(二氯甲烷取代醚類進行萃取,省略以矽膠過濾)經快速層析法純化(矽膠,40%丙酮-己烷),得46mg希望之化合物,產率為35%。1H NMR(400MHz,丙酮-d6)δ:1.65(s,6H,2 Me),2.41(m,2H,CH2),4.03(m,2H,CH2N),4.24(t,J=6.2Hz,2H,CH2O),7.12(d,J=8.8Hz,2H,Ar),7.55(dd,J=1.4與8.3Hz,1H,Ar),7.61(d,J=1.8Hz,1H,
Ar),7.62(d,J=6.1Hz,2H,Pyr),7.77(d,J=8.8Hz,2H,Ar),8.00(dd,J=7.4與8.2Hz,1H,Ar),8.59(d,J=6.2Hz,2H,Pyr)。
3-溴丙醇(23)(2.0g,14mmol)之二氯甲烷溶液
(50mL),係以乙醯氯(1.2mL,17mmol)處理,攪拌20分鐘,以吡啶(1.4mL,17mmol)處理並攪拌30分鐘。反應混合物以醚類稀釋、以水與飽和碳酸氫鈉水溶液清洗、以硫酸鈉除水、過濾,並減壓濃縮。粗醋酸酯24(2.25g,86%)係使用於適當步驟中不需進一步純化。
2-(Fmoc-胺基)異丁酸(25)(6.48g,20.0mmol)之二氯甲烷溶液(180mL),係以草醯氯(2.6mL,30mmol)與數滴N,N-二甲基甲醯胺處理,並攪拌1小時。反應混合物減壓濃縮。粗醯基氯化物26使用於下一步驟不需進一步純化。
醯基氯化物26(6.84g,20.0mmol)之無水四氫呋喃(90mL),係以4-氰基-3-三氟甲基苯胺(27)(3.36g,18.1mmol)與碳酸氫鈉(1.90g,22.6mmol)處理,並於60℃加熱1.5小時。反應混合物於室溫下冷卻,以醚類稀釋,並以碳酸氫鈉水溶液(2 x)與水清洗。有機層以硫酸鈉除水、過濾並減壓濃縮。粗醯胺28係使用於下一步驟不需進一步純化。
醯胺28(8.9g,18mmol)之N,N-二甲基甲醯胺溶液(60mL),係以1.0M四丁基氟化銨之四氫呋喃溶液(27mL,27mmol)處理,並攪拌整夜。反應混合物以醚類稀釋,並以碳酸氫鈉水溶液(2 x)與水清洗。有機層以硫酸鈉除水、過濾並減壓濃縮。粗化合物經層析法純化(Biotage系統,矽膠,
50-100%乙酸乙酯-己烷),得2.5g(51%,3步驟)之胺類29。
胺類29(2.5g,9.2mmol)之無水四氫呋喃溶液(45mL),係於0℃冷卻,以二異丙基胺(2.4mL,14mmol)與氯乙醯氯(0.81mL,10mmol)處理,並在移除冰水浴後攪拌1小時。反應混合物以水稀釋,並以二氯甲烷萃取(3 x)。合併之有機層以硫酸鈉除水、過濾並減壓濃縮。粗二醯胺30(3.58g)係使用於下一步驟不需進一步純化。
二醯胺30(3.21g,9.2mmol)之無水四氫呋喃(185mL)係緩慢地以碳酸銫(7.55g,23mmol)處理,並攪拌整夜。反應混合物於CeliteTM上過濾。濾液減壓蒸發。粗化合物經快速層析法純化(矽膠,15-20%丙酮-二氯甲烷),得1.76g(61%,2步驟)之環二醯胺31。1H NMR(400MHz,丙酮-d6)δ:1.58(s,6H,Me),4.59(s,2H,CH2),7.60(bs,1H,NH),7.97(dd,J=2.0與8.4Hz,1H,Ar),8.14(d,J=2.4Hz,1H,Ar),8.15(d,J=8.0Hz,1H,Ar)。
在氬氣大氣下,環二醯胺31(106mg,0.34mmol)之無水N,N-二甲基甲醯胺溶液(1.6mL),係以0.5M雙(三甲基矽基)醯胺鉀之甲苯溶液(0.81mL,0.40mmol)處理,攪拌5分鐘,以3-溴丙基醋酸酯(24)(88mg,0.49mmol)之無水N,N-二甲基甲醯胺溶液(0.5mL)處理,並攪拌45分鐘。之後,反應混合物以醚類稀釋、以水清洗(2 x)、以硫酸鈉除
水、過濾並減壓濃縮。粗化合物以快速層析法純化(矽膠,20%丙酮-己烷),得63mg(45%)醋酸酯32(亦得O-烷基化產物(22mg,16%),與起始材料31(24mg,22%))。
醋酸酯32(63mg,0.15mmol)之甲醇溶液(2mL)係以碳酸鉀(75mg,0.54mmol)處理,並攪拌0.5小時。反應混合物以醚類稀釋、以水清洗(2 x)、以硫酸鈉除水、過濾並減壓濃縮。粗醇類33使用於下一步驟不需進一步純化。1H NMR(400MHz,丙酮-d6)δ:1.66(s,6H,2 Me),1.81(p,J=7.1Hz,2H,CH2),3.56(q,J=5.9Hz,2H,CH2O),3.63(t,J=7.3Hz,2H,CH2N),3.82(t,J=5.8Hz,1H,OH),4.65(s,2H,NCH2CO),7.97(dd,J=1.9與8.5Hz,1H,Ar),8.15(d,J=1.8Hz,1H,Ar),8.15(d,J=8.3Hz,1H,Ar)。
在氬氣大氣下,醇類33(44mg,0.12mmol)、酚類22(20mg,0.12mmol)與三苯基膦(35mg,0.13mmol)之無水四氫呋喃溶液(1.5mL),係冷卻至0℃,並緩慢地以二異丙基偶氮二羧酸酯(DIAD)(0.025mL,0.13mmol)處理。反應混合物於移除冰水浴後,攪拌60小時。反應混合物減壓濃縮。粗化合物(溶解於丙酮中)於矽膠上過濾。粗化合物以快速層析法純化(矽膠,50%丙酮-己烷),得18.5mg(30%,2步驟)之EM-9126。1H NMR(400MHz,丙酮-d6)δ:1.69(s,6H,2 Me),2.17(m,2H,CH2),3.72(m,2H,CH2N),4.18(t,J=6.2Hz,2H,CH2O),4.64(s,2H,NCH2CO),7.10(d,J=8.8
Hz,2H,Ar),7.62(d,J=6.2Hz,2H,Pyr),7.76(d,J=8.8Hz,2H,Ar),7.97(dd,J=1.9與8.6Hz,1H,Ar),8.15(2s,2H,Ar),8.59(d,J=6.1Hz,2H,Pyr)。
4-氰基-3-三氟甲基苯胺(27)(2.01g,10.8mmol)與碳酸氫鈉(2.25g,26.8mmol)之二氯甲烷懸浮液(50mL)於0℃冷卻,緩慢地以20%光氣之甲苯溶液(11mL,20.9mmol)處理,並於移除冰水浴後攪拌2小時。反應混合物經過濾並減壓濃縮。粗異氰酸酯34使用於下一步驟不需進一步純化。
異氰酸酯35(2.29g,10.8mmol)、2-胺基-2-甲基丙腈基(2)(1.1g,13mmol)與三乙基胺(0.15mL,1.1mmol)之無水四氫呋喃溶液(40mL)係回流1小時。反應混合物冷卻至室溫並減壓濃縮。粗化合物35使用於下一步驟不需進一步純化。
化合物35(3.19g,10.8mmol)之甲醇與2N氫氯酸水溶液之1:1比例之混合溶液(36mL),係回流0.5小時。之後,反應混合物於室溫下冷卻、以水稀釋、並以二氯甲烷萃取(3 x)。合併之有機層以硫酸鈉除水、過濾並減壓濃縮,得3.07g(96%,3步驟)之化合物36。粗化合物36使用於下一步驟不需進一步純化。
在氬氣大氣下,化合物36(501mg,1.69mmol)與4-溴芐基溴(630mg,2.5mmol)之無水N,N-二甲基甲醯胺溶液(8mL),係於0℃冷卻,以氫化鈉(60%分散於礦物油中,100mg,2.5mmol)處理,並於移除冰水浴後攪拌0.5小時。之後,反應混合物以醚類稀釋,以水清洗(2 x)、以硫酸鈉除水、過濾並減壓濃縮。粗化合物以層析法純化(Biotage系統,矽膠,0-30%丙酮-己烷),得786mg(100%)之溴化物37。
在氬氣大氣下,溴化物37(100mg,0.21mmol)、4-吡啶硼酸(41mg,0.33mmol)與三磷酸鉀(136mg,0.64
mmol)之無水N,N-二甲基甲醯胺懸浮液(2mL),係以氮氣起泡10分鐘,以四(三苯基膦)鈀(0)(25mg,0.022mmol)處理,並於100℃加熱1小時。之後,反應混合物冷卻至室溫、以醚類稀釋、以水清洗(2 x)、以硫酸鈉除水、過濾並減壓濃縮。粗化合物以二快速層析法純化(矽膠,30%丙酮-己烷,與2%甲醇-二氯甲烷),得55mg(56%)之EM-9199。1H NMR(400MHz,丙酮-d6)δ:1.52(s,6H,2 Me),4.80(s,2H,CH2),7.67(m,4H,Ar與Pyr),7.79(d,J=8.4Hz,2H,Ar),8.23(m,2H,Ar),8.34(s,1H,Ar),8.64(d,J=6.1Hz,2H,Pyr)。
4-溴苯胺(38)(2.05g,11.9mmol)、乙基α-溴異丁
酸酯(3.0mL,20mmol)與碳酸氫鈉(1.5g,18mmol)之混合物,係於140℃下加熱6小時。反應混合物冷卻至室溫、以矽膠與快速層析法處理(10%醚類-己烷),得1.06g(31%)之酯類39,為油狀物。
在氬氣大氣下,酯類39(1.17g,4.09mmol)之無水四氫呋喃溶液(14mL)係於0℃冷卻,以4-氰基-3-三氟甲基苯基異氰酸酯(34)(0.87mg,4.1mmol)與三乙基胺(0.57mL,4.1mmol)處理,於移除冰水浴後攪拌整夜,以相同量之異氰酸酯(34)與三乙基胺處理,並攪拌1小時。之後,反應混合物以醚類稀釋,以水清洗(2 x)、以硫酸鈉除水、過濾並減壓濃縮。粗化合物經快速層析法純化(矽膠,10%丙酮-己烷),得750mg溴化物40與乙基(4-氰基-3-三氟甲基苯基)胺基甲酸酯之1:2.2比例之混合物。
在氬氣大氣下,不純溴化物40(150mg,0.15mmol)、4-吡啶硼酸(80mg,0.65mmol)與三磷酸鉀(212mg,1.00mmol)之無水N,N-二甲基甲醯胺懸浮液(3mL),係以氬氣起泡10分鐘,以四(三苯基膦)鈀(0)(44mg,0.038mmol)處理,並於90℃加熱3小時(不完全反應)。之後,反應混合物冷卻至室溫、以醚類稀釋、以水清洗(2 x)、以硫酸鈉除水、過濾並減壓濃縮。粗化合物粗化合物經二快速層析法純化(矽膠,20%丙酮-己烷,以及10%丙酮-二氯甲烷),得45mg(12%,二步驟)之EM-9340。1H NMR(400MHz,丙
酮-d6)δ:1.66(s,6H,2 Me),7.66(d,J=8.6Hz,2H,Ar),7.73(d,J=6.1Hz,2H,Pyr),7.95(d,J=8.7Hz,2H,Ar),8.21(dd,J=1.6與8.5Hz,1H,Ar),8.26(d,J=8.5Hz,1H,Ar),8.32(d,J=1.3Hz,1H,Ar),8.69(d,J=6.1Hz,2H,Pyr)。
在氬氣大氣下,4-(4-溴苯基)-1-丁醇(41)(得自Ando T.等人,Bull.Chem.Soc.Jpn.,1980,53(8),2348-2356所述之方法)(3.44g,15mmol)、三苯基膦(4.6g,17mmol)與四溴甲烷(7.5g,23mmol)之二氯甲烷懸浮液(200mL)係攪拌整夜。反應混合物以水中止反應,並以二氯甲烷萃取
(3 x)。合併之有機層以硫酸鈉除水並減壓濃縮。粗化合物經層析法純化(Biotage系統,矽膠,0-10%丙酮-己烷),得2.43g(55%)之溴化物42。
在氬氣大氣下,氫化鈉(60%分散於礦物油中,120mg,3.0mmol)與EM-9289(560mg,2.0mmol)之無水N,N-二甲基甲醯胺懸浮液(10mL)係攪拌30分鐘,於0℃冷卻,緩慢地以溴化物42(900mg,3.1mmol)之無水N,N-二甲基甲醯胺溶液(2mL)處理,並於移除冰水浴後攪拌整夜。之後,反應混合物以水稀釋,並以二氯甲烷(2 x)與乙酸乙酯(2 x)萃取。合併之有機層以硫酸鈉除水、過濾並減壓濃縮。粗化合物經層析法純化(Biotage系統,矽膠,0-20%丙酮-己烷),得435mg(45%)溴化物43。1H NMR(400MHz,丙酮-d6)δ:1.54(s,3H,Me),1.56(s,3H,Me),1.73(m,4H,CH2),2.28(s,3H,芳香基之Me),2.68(t,J=7.2Hz,2H,芐基之CH2),3.45(t,J=7.3Hz,2H,CH2N),7.21(d,J=8.4Hz,2H,Ar),7.45(d,J=8.4Hz,2H,Ar),7.51(d,J=8.3Hz,1H,Ar),7.87(d,J=8.3Hz,1H,Ar)。
在氬氣大氣下,溴化物43(214mg,0.438mmol)、4-吡啶硼酸(65mg,0.53mmol)與三磷酸鉀(280mg,1.3mmol)之無水N,N-二甲基甲醯胺懸浮液(12mL),以氬氣起泡15分鐘,以四(三苯基膦)鈀(0)(76mg,0.066mmol)處理,並於80℃加熱整夜。之後,反應混合物冷卻至室溫,以水
稀釋,並以二氯甲烷(3 x)與乙酸乙酯萃取。合併之有機層以硫酸鈉除水、過濾並減壓濃縮。粗化合物以快速層析法純化(矽膠,0-20%丙酮-甲苯),得25mg(12%)之EM-9336。1H NMR(400MHz,丙酮-d6)δ:1.55(s,3H,Me),1.57(s,3H,Me),1.78(m,4H,CH2),2.28(s,3H,芳香基之Me),2.77(t,J=7.1Hz,2H,芐基之CH2),3.48(t,J=7.1Hz,2H,CH2N),7.41(d,J=8.3Hz,2H,Ar),7.52(d,J=8.3Hz,1H,Ar),7.65(d,J=6.1Hz,2H,Pyr),7.72(d,J=8.3Hz,2H,Ar),7.87(d,J=8.3Hz,1H,Ar),8.62(d,J=6.1Hz,2H,Pyr)。
下列表3之化合物得自範例1-10描述之流程。呈現每一化合物之1H NMR描述(除了已於範例1-10呈現之化合物之外):
EM-8840
1H NMR(400MHz,丙酮-d6)δ:1.68(s,6H,2 Me),2.41(m,2H,CH2),4.05(m,2H,CH2N),4.23(t,J=6.2Hz,2H,CH2O),7.12(d,J=8.8Hz,2H,Ar),7.44(bs,1H,Pyr),7.67(d,J=8.8Hz,2H,Ar),7.99(d,J=7.9Hz,1H,Pyr),8.03(dd,J=1.8與8.3Hz,1H,Ar),8.17(d,J=1.7Hz,1H,Ar),8.25(d,J=8.3Hz,1H,Ar),8.6(bs,1H,Pyr),8.9(bs,1H,Pyr)。
EM-8841
1H NMR(400MHz,丙酮-d6)δ:1.68(s,6H,2 Me),2.42(m,2H,CH2),4.05(m,2H,CH2N),4.24(t,J=6.2Hz,2H,CH2O),7.12(d,J=8.8Hz,2H,Ar),7.62(d,J=5.9Hz,2H,Pyr),7.77(d,J=8.8Hz,2H,Ar),8.03(dd,J=1.6與8.3Hz,
1H,Ar),8.17(d,J=1.8Hz,1H,Ar),8.25(d,J=8.3Hz,1H,Ar),8.60(bs,2H,Pyr)。
EM-8851
1H NMR(400MHz,丙酮-d6)δ:1.66(s,6H,2 Me),2.42(m,2H,CH2),4.05(m,2H,CH2N),4.27(t,J=6.2Hz,2H,CH2O),6.93(dd,J=2.4與13.1Hz,1H,Ar),6.98(dd,J=2.5與8.5Hz,1H,Ar),7.55(bs,2H,Pyr),7.60(t,J=8.9Hz,1H,Ar),8.03(dd,J=1.7與8.2Hz,1H,Ar),8.17(d,J=1.8Hz,1H,Ar),8.25(d,J=8.3Hz,1H,Ar),8.7(bs,2H,Pyr)。
EM-8871
1H NMR(400MHz,丙酮-d6)δ:1.67(s,6H,2 Me),2.42(m,2H,CH2),4.05(m,2H,CH2N),4.27(t,J=6.2Hz,2H,CH2O),7.09(ddd,J=1.1,2.3與8.2Hz,1H,Ar),7.37(m,2H,Ar),7.46(t,J=8.2Hz,1H,Ar),7.66(d,J=6.2Hz,2H,Pyr),8.02(dd,J=1.8與8.2Hz,1H,Ar),8.16(d,J=1.5Hz,1H,Ar),8.25(d,J=8.3Hz,1H,Ar),8.64(d,J=6.1Hz,2H,Pyr)。
EM-8872
1H NMR(400MHz,丙酮-d6)δ:1.68(s,6H,2 Me),2.45(m,2H,CH2),4.07(m,2H,CH2N),4.35(t,J=6.1Hz,2H,CH2O),7.31(t,J=8.7Hz,1H,Ar),7.64(m,4H,Ar與Pyr),8.02(dd,J=1.7與8.2Hz,1H,Ar),8.15(d,J=1.6Hz,1H,Ar),8.25(d,J=8.2Hz,1H,Ar),8.62(d,J=6.2Hz,2H,Pyr)。
EM-8888
1H NMR(400MHz,丙酮-d6)δ:1.68(s,6H,2 Me),2.42(m,2H,CH2),4.05(m,2H,CH2N),4.27(t,J=6.1Hz,2H,CH2O),7.09(dd,J=2.6與8.6Hz,1H,Ar),7.18(d,J=2.5Hz,1H,Ar),7.42(d,J=8.7Hz,1H,Ar),7.43(d,J=6.0Hz,2H,Pyr),8.03(dd,J=1.5與8.2Hz,1H,Ar),8.17(d,J=1.5Hz,1H,Ar),8.26(d,J=8.2Hz,1H,Ar),8.64(d,J=6.1Hz,2H,Pyr)。
EM-8890
1H NMR(400MHz,丙酮-d6)δ:1.68(s,6H,2 Me),2.45(m,2H,CH2),4.07(m,2H,CH2N),4.34(t,J=6.1Hz,2H,CH2O),7.34(m,5H,Ar與Pyr),8.03(dd,J=1.7與8.1Hz,1H,Ar),8.17(d,J=1.5Hz,1H,Ar),8.26(d,J=8.2Hz,1H,Ar),8.63(d,J=6.0Hz,2H,Pyr)。
EM-8900
1H NMR(400MHz,丙酮-d6)δ:1.67(s,6H,2 Me),2.47(m,2H,CH2),4.04(m,2H,CH2N),4.40(t,J=5.9Hz,2H,CH2O),7.43(d,J=8.6Hz,1H,Ar),7.71(d,J=6.1Hz,2H,Pyr),8.05(m,3H,Ar),8.17(d,J=1.7Hz,1H,Ar),8.26(d,J=8.2Hz,1H,Ar),8.64(d,J=6.1Hz,2H,Pyr)。
EM-8908
1H NMR(400MHz,丙酮-d6)δ:1.68(s,6H,2 Me),2.51(s,3H,Me),2.40(m,2H,CH2),4.04(m,2H,CH2N),4.22(t,J=6.2Hz,2H,CH2O),7.09(d,J=8.8Hz,2H,Ar),7.28(d,J=7.9Hz,1H,Pyr),7.63(d,J=8.8Hz,2H,Ar),7.86(dd,J=
2.5與8.0Hz,1H,Pyr),8.03(dd,J=2.0與8.0Hz,1H,Ar),8.17(d,J=1.7Hz,1H,Ar),8.26(d,J=8.2Hz,1H,Ar),8.70(d,J=2.3,Hz,1H,Pyr)。
EM-8923
1H NMR(400MHz,丙酮-d6)δ:1.68(s,6H,2 Me),2.41(m,2H,CH2),4.05(m,2H,CH2N),4.23(t,J=6.2Hz,2H,CH2O),7.11(d,J=8.6Hz,2H,Ar),7.14(dd,J=2.9與8.3Hz,1H,Pyr),7.65(d,J=8.8Hz,2H,Ar),8.03(dd,J=1.7與8.2Hz,1H,Ar),8.16(d,J=2.5Hz,1H,Ar),8.19(dd,J=2.6與8.4Hz,1H,Pyr),8.26(d,J=8.3Hz,1H,Ar),8.45(d,J=2.4Hz,1H,Pyr)。
EM-8929
1H NMR(400MHz,丙酮-d6)δ:1.67(s,6H,2 Me),2.41(m,2H,CH2),4.04(m,2H,CH2N),4.23(t,J=6.2Hz,2H,CH2O),7.11(d,J=8.8Hz,2H,Ar),7.68(d,J=7.3Hz,2H,Pyr),7.74(d,J=8.8Hz,2H,Ar),8.02(dd,J=1.8與8.3Hz,1H,Ar),8.15(s,1H,Ar),8.16(d,J=7.3Hz,2H,Pyr),8.26(d,J=8.3Hz,1H,Ar)。
EM-9000
1H NMR(400MHz,丙酮-d6)δ:1.60(s,6H,2 Me),2.27(p,J=6.8Hz,2H,CH2),3.67(t,J=7.2Hz,2H,CH2N),4.22(t,J=6.1Hz,2H,CH2O),7.08(d,J=8.8Hz,2H,Ar),7.66(d,J=7.3Hz,2H,Pyr),7.71(d,J=8.8Hz,2H,Ar),8.14(dd,J=2.0與8.3Hz,1H,Ar),8.15(d,J=7.2Hz,2H,Pyr),8.19(d,J
=8.5Hz,1H,Ar),8.26(d,J=1.6Hz,1H,Ar)。
EM-9011
1H NMR(400MHz,丙酮-d6)δ:1.66(s,6H,2 Me),2.41(m,2H,CH2),4.04(m,2H,CH2N),4.27(t,J=6.2Hz,2H,CH2O),6.93(dd,J=2.4與13.1Hz,1H,Ar),6.98(dd,J=2.4與8.7Hz,1H,Ar),7.54(dt,J=1.6與4.5Hz,2H,Pyr),7.55-763(m,3H,Ar),8.00(t,J=7.8Hz,1H,Ar),8.63(d,J=6.1Hz,2H,Pyr)。
EM-9037
1H NMR(400MHz,丙酮-d6)δ:1.66(s,6H,2 Me),2.42(m,2H,CH2),4.04(m,2H,CH2N),4.27(t,J=6.1Hz,2H,CH2O),6.93(dd,J=2.4與13.0Hz,1H,Ar),6.98(dd,J=2.8與8.4Hz,1H,Ar),7.54(dt,J=1.6與4.5Hz,2H,Pyr),7.60(t,J=8.9Hz,1H,Ar),7.67(dd,J=1.9與8.3Hz,1H,Ar),7.85(d,J=1.9Hz,1H,Ar),8.05(d,J=8.4Hz,1H,Ar),8.63(d,J=6.2Hz,2H,Pyr)。
EM-9039
1H NMR(400MHz,丙酮-d6)δ:1.66(s,6H,2 Me),2.41(m,2H,CH2),4.04(m,2H,CH2N),4.24(t,J=6.2Hz,2H,CH2O),7.12(d,J=8.9Hz,2H,Ar),7.62(d,J=6.2Hz,2H,Pyr),7.67(dd,J=1.9與8.3Hz,1H,Ar),7.77(d,J=8.8Hz,2H,Ar),7.85(d,J=1.9Hz,1H,Ar),8.04(d,J=8.4Hz,1H,Ar),8.59(d,J=6.2Hz,2H,Pyr)。
EM-9043
1H NMR(400MHz,甲醇-d4)δ:1.64(s,6H,2 Me),2.43(m,2H,CH2),4.03(m,2H,CH2N),4.28(t,J=5.9Hz,2H,CH2O),7.21(m,2H,Ar),7.94(m,3H,Ar),8.08(d,J=1.5Hz,1H,Ar),8.14(d,J=8.3Hz,1H,Ar),8.22(m,2H,Pyr),8.77(m,2H,Pyr)。
EM-9049
1H NMR(400MHz,丙酮-d6)δ:1.66(s,6H,2 Me),2.41(m,2H,CH2),4.04(m,2H,CH2N),4.23(t,J=6.2Hz,2H,CH2O),7.11(d,J=8.8Hz,2H,Ar),7.42(ddd,0.7,4.8與7.9Hz,1H,Pyr),7.67(m,3H,Ar),7.85(d,J=1.8Hz,1H,Ar),7.99(dt,J=0.7與7.9Hz,1H,Pyr),8.04(d,J=8.3Hz,1H,Ar),8.52(dd,J=1.5與4.7Hz,1H,Pyr),8.84(d,J=1.8Hz,1H,Pyr)。
EM-9050
1H NMR(400MHz,丙酮-d6)δ:1.67(s,6H,2 Me),2.40(m,2H,CH2),4.03(m,2H,CH2N),4.50(t,J=6.2Hz,2H,CH2O),6.97(dd,J=0.4與8.6Hz,1H,Pyr),7.67(d,J=6.2Hz,2H,Pyr),8.03(dd,J=1.7與8.3Hz,1H,Ar),8.13(dd,J=2.6與8.6Hz,1H,Pyr),8.17(d,J=1.7Hz,1H,Ar),8.25(d,J=8.3Hz,1H,Ar),8.61(dd,J=0.3與2.5Hz,1H,Pyr),8.64(d,J=5.9Hz,2H,Pyr)。
EM-9055
1H NMR(400MHz,丙酮-d6)δ:1.61(s,6H,2 Me),2.31(p,J=6.5Hz,2H,CH2),3.70(t,J=7.1Hz,2H,CH2N),4.33(t,J
=6.0Hz,2H,CH2O),7.28(t,J=8.8Hz,1H,Ar),7.63(m,4H,Ar與Pyr),8.13(dd,J=1.8與8.5Hz,1H,Ar),8.18(d,J=8.4Hz,1H,Ar),8.24(d,J=1.5Hz,1H,Ar),8.62(d,J=5.4Hz,2H,Pyr)。
EM-9066
1H NMR(400MHz,丙酮-d6)δ:1.60(s,6H,2 Me),2.29(p,J=7.1Hz,2H,CH2),3.68(t,J=7.2Hz,2H,CH2N),4.26(t,J=6.1Hz,2H,CH2O),6.91(dd,J=2.4與13.1Hz,1H,Ar),6.96(dd,J=2.6與8.6Hz,1H,Ar),7.53(dt,J=1.6與4.5Hz,2H,Pyr),7.58(t,J=8.9Hz,1H,Ar),8.15(dd,J=1.7與8.4Hz,1H,Ar),8.20(d,J=8.5Hz,1H,Ar),8.26(d,J=1.8Hz,1H,Ar),8.63(d,J=6.1Hz,2H,Pyr)。
EM-9067
1H NMR(400MHz,丙酮-d6)δ:1.60(s,6H,2 Me),2.28(p,J=7.0Hz,2H,CH2),3.67(t,J=7.2Hz,2H,CH2N),4.25(t,J=6.1Hz,2H,CH2O),6.90(dd,J=2.4與13.3Hz,1H,Ar),6.95(dd,J=2.6與8.6Hz,1H,Ar),7.59(m,3H,Ar與Pyr),8.15(dd,J=1.7與8.5Hz,1H,Ar),8.19(m,3H,Ar與Pyr),8.26(dd,J=0.4與1.3Hz,1H,Ar)。
EM-9070
1H NMR(400MHz,丙酮-d6)δ:1.66(s,6H,2 Me),1.93(m,2H,CH2),2.09(m,2H,CH2),3.93(m,2H,CH2N),4.16(t,J=6.2Hz,2H,CH2O),7.09(d,J=8.8Hz,2H,Ar),7.41(ddd,J=0.8,4.8與8.0Hz,1H,Pyr),7.65(d,J=8.8Hz,2H,Ar),
7.98(ddd,J=1.7,2.4與7.9Hz,1H,Pyr),8.03(dd,J=1.6與8.3Hz,1H,Ar),8.18(d,J=1.9Hz,1H,Ar),8.25(d,J=8.3Hz,1H,Ar),8.52(dd,J=1.6與4.7Hz,1H,Pyr),8.83(dd,J=0.7與2.3Hz,1H,Pyr)。
EM-9089
1H NMR(400MHz,丙酮-d6)δ:1.61(s,6H,2 Me),2.31(p,J=6.6Hz,2H,CH2),3.70(t,J=7.2Hz,2H,CH2N),4.32(t,J=6.1Hz,2H,CH2O),7.31-739(m,5H,Ar與Pyr),8.15(dd,J=1.8與8.5Hz,1H,Ar),8.21(d,J=8.5Hz,1H,Ar),8.27(d,J=1.7Hz,1H,Ar),8.63(bs,2H,Pyr)。
EM-9092
1H NMR(400MHz,丙酮-d6)δ:1.68(s,6H,2 Me),2.45(m,2H,CH2),4.07(m,2H,CH2N),4.35(t,J=6.2Hz,2H,CH2O),7.54(dd,J=3.0與8.8Hz,1H,Pyr),7.99(d,J=6.2Hz,2H,Pyr),8.03(dd,J=1.8與8.3Hz,1H,Ar),8.06(d,J=8.8Hz,1H,Pyr),8.16(d,J=1.7Hz,1H,Ar),8.25(d,J=8.3Hz,1H,Ar),8.47(d,J=2.8Hz,1H,Pyr),8.65(d,J=6.2Hz,2H,Pyr)。
EM-9111
1H NMR(400MHz,丙酮-d6)δ:1.60(s,6H,2 Me),2.31(p,J=7.1Hz,2H,CH2),3.70(t,J=7.2Hz,2H,CH2N),4.33(t,J=6.1Hz,2H,CH2O),7.52(dd,J=3.0與8.8Hz,1H,Pyr),7.98(d,J=6.2Hz,2H,Pyr),8.04(d,J=8.9Hz,1H,Pyr),8.15(dd,J=1.8與8.3Hz,1H,Ar),8.19(d,J=8.3Hz,1H,
Ar),8.26(d,J=1.8Hz,1H,Ar),8.45(d,J=2.7Hz,1H,Pyr),8.64(d,J=6.2Hz,2H,Pyr)。
EM-9114
1H NMR(400MHz,丙酮-d6)δ:1.60(s,6H,2 Me),2.26(p,J=7.3Hz,2H,CH2),3.66(t,J=7.3Hz,2H,CH2N),4.50(t,J=6.3Hz,2H,CH2O),6.96(dd,J=0.6與8.6Hz,1H,Pyr),7.66(d,J=6.1Hz,2H,Pyr),8.12(dd,J=2.6與8.6Hz,1H,Pyr),8.16(dd,J=1.8與8.5Hz,1H,Ar),8.20(d,J=8.4Hz,1H,Ar),8.28(dd,J=0.4與1.3Hz,1H,Ar),8.60(dd,J=0.5與2.6Hz,1H,Pyr),8.64(d,J=5.3Hz,2H,Pyr)。
EM-9115
1H NMR(400MHz,丙酮-d6)δ:1.69(s,6H,2 Me),2.28(p,J=7.0Hz,2H,CH2),3.67(t,J=7.1Hz,2H,CH2N),4.26(t,J=6.1Hz,2H,CH2O),6.91(dd,J=2.4與13.1Hz,1H,Ar),6.97(dd,J=2.6與8.7Hz,1H,Ar),7.53(dt,J=1.5與4.5Hz,2H,Pyr),7.59(t,J=8.9Hz,1H,Ar),7.81(dd,J=1.9與8.5Hz,1H,Ar),7.93(d,J=1.9Hz,1H,Ar),7.99(d,J=8.5Hz,1H,Ar),8.63(d,J=5.3Hz,2H,Pyr)。
EM-9116
1H NMR(400MHz,丙酮-d6)δ:1.58(s,6H,2 Me),2.27(p,J=7.0Hz,2H,CH2),3.66(t,J=7.2Hz,2H,CH2N),4.23(t,J=6.1Hz,2H,CH2O),7.10(d,J=8.8Hz,2H,Ar),7.62(d,J=6.1Hz,2H,Pyr),7.76(d,J=8.9Hz,2H,Ar),7.80(dd,J=1.9與8.5Hz,1H,Ar),7.93(d,J=1.9Hz,1H,Ar),7.98(d,J
=8.5Hz,1H,Ar),8.59(d,J=6.1Hz,2H,Pyr)。
EM-9117
1H NMR(400MHz,丙酮-d6)δ:1.58(s,6H,2 Me),2.27(p,J=6.9Hz,2H,CH2),3.66(t,J=7.1Hz,2H,CH2N),4.25(t,J=6.1Hz,2H,CH2O),6.91(dd,J=2.4與13.3Hz,1H,Ar),6.95(dd,J=2.5與8.5Hz,1H,Ar),7.59(m,3H,Ar與Pyr),7.80(dd,J=1.9與8.5Hz,1H,Ar),7.93(d,J=1.8Hz,1H,Ar),7.99(d,J=8.5Hz,1H,Ar),8.19(d,J=7.3Hz,2H,Pyr)。
EM-9118
1H NMR(400MHz,丙酮-d6)δ:1.58(s,6H,2 Me),2.26(p,J=7.0Hz,2H,CH2),3.66(t,J=7.2Hz,2H,CH2N),4.22(t,J=6.1Hz,2H,CH2O),7.08(d,J=8.9Hz,2H,Ar),7.66(d,J=7.3Hz,2H,Pyr),7.72(d,J=8.9Hz,2H,Ar),7.80(dd,J=1.9與8.5Hz,1H,Ar),7.92(d,J=1.9Hz,1H,Ar),7.98(d,J=8.5Hz,1H,Ar),8.14(d,J=7.3Hz,2H,Pyr)。
EM-9119
1H NMR(400MHz,丙酮-d6)δ:1.66(s,6H,2 Me),2.41(m,2H,CH2),4.03(m,2H,CH2N),4.26(t,J=6.2Hz,2H,CH2O),6.92(dd,J=2.3與13.3Hz,1H,Ar),6.98(dd,J=2.7與8.6Hz,1H,Ar),7.60(m,3H,Ar與Pyr),7.67(dd,J=1.9與8.3Hz,1H,Ar),7.85(d,J=1.8Hz,1H,Ar),8.05(d,J=8.3Hz,1H,Ar),8.19(d,J=7.3Hz,2H,Pyr)。
EM-9120
1H NMR(400MHz,丙酮-d6)δ:1.66(s,6H,2 Me),2.41(m,
2H,CH2),4.03(m,2H,CH2N),4.23(t,J=6.2Hz,2H,CH2O),7.10(d,J=8.9Hz,2H,Ar),7.67(m,3H,Ar與Pyr),7.74(d,J=8.8Hz,2H,Ar),7.85(d,J=1.9Hz,1H,Ar),8.04(d,J=8.3Hz,1H,Ar),8.15(d,J=7.3Hz,2H,Pyr)。
EM-9176
1H NMR(400MHz,丙酮-d6)δ:1.57(s,6H,2 Me),2.26(p,J=6.6Hz,2H,CH2),3.66(t,J=7.2Hz,2H,CH2N),4.22(t,J=6.1Hz,2H,CH2O),7.08(d,J=8.9Hz,2H,Ar),7.66(d,J=7.3Hz,2H,Pyr),7.71(m,4H,Ar),7.94(t,J=8.0Hz,1H,Ar),8.15(d,J=7.3Hz,2H,Pyr)。
EM-9180
1H NMR(400MHz,丙酮-d6)δ:1.64(s,6H,2 Me),3.87(t,J=5.7Hz,2H,CH2N),4.36(t,J=5.7Hz,2H,CH2O),7.10(d,J=8.9Hz,2H,Ar),7.65(d,J=7.3Hz,2H,Pyr),7.72(d,J=8.9Hz,2H,Ar),8.15(d,J=7.4Hz,2H,Pyr),8.17(dd,J=1.7與8.3Hz,1H,Ar),8.20(d,J=8.5Hz,1H,Ar),8.29(d,J=1.3Hz,1H,Ar)。
EM-9198
1H NMR(400MHz,丙酮-d6)δ:1.59(s,6H,2 Me),2.30(p,J=6.7Hz,2H,CH2),3.69(t,J=7.0Hz,2H,CH2N),4.33(t,J=6.0Hz,2H,CH2O),7.29(t,J=8.8Hz,1H,Ar),7.63(m,4H,Ar與Pyr),7.79(dd,J=1.9與8.5Hz,1H,Ar),7.90(d,J=1.9Hz,1H,Ar),7.97(d,J=8.5Hz,1H,Ar),8.62(d,J=6.1Hz,2H,Pyr)。
EM-9200
1H NMR(400MHz,丙酮-d6)δ:1.52(s,6H,2 Me),4.80(s,2H,CH2),7.45(ddd,J=0.7,4.7與7.9Hz,1H,Pyr),7.65(d,J=8.3Hz,2H,Ar),7.71(d,J=8.4Hz,2H,Ar),8.03(ddd,J=1.7,2.3與7.9Hz,1H,Pyr),8.23(m,2H,Ar),8.34(s,1H,Ar),8.57(dd,J=1.5與4.7Hz,1H,Pyr),8.88(d,J=1.7Hz,1H,Pyr)。
EM-9201
1H NMR(400MHz,丙酮-d6)δ:1.93(m,4H,CH2 of cyclopentyl group),2.13(m,2H,CH2 of cyclopentyl group),2.19(m,2H,CH2 of cyclopentyl group),2.31(p,J=7.1Hz,2H,CH2),3.63(t,J=7.2Hz,2H,CH2N),4.26(t,J=6.0Hz,2H,CH2O),6.91(dd,J=2.4與13.1Hz,1H,Ar),6.96(dd,J=2.5與8.6Hz,1H,Ar),7.53(dt,J=1.5與4.5Hz,2H,Pyr),7.59(t,J=8.9Hz,1H,Ar),7.81(dd,J=1.9與8.5Hz,1H,Ar),7.94(d,J=1.9Hz,1H,Ar),7.98(d,J=8.5Hz,1H,Ar),8.63(d,J=5.7Hz,2H,Pyr)。
EM-9204
1H NMR(400MHz,丙酮-d6)δ:1.60(s,3H,Me),1.62(s,3H,Me),2.17(d,J=2.3Hz,3H,芳香基之Me),2.30(p,J=6.7Hz,2H,CH2),3.67(2t,J=7.1Hz,2H,CH2N),4.32(t,J=6.1Hz,2H,CH2O),7.29(t,J=8.6Hz,1H,Ar),7.36(dd,J=0.7與8.3Hz,1H,Ar),7.59-7.67(m,4H,Ar與Pyr),7.78(t,J=7.7Hz,1H,Ar),8.61(d,J=6.1Hz,2H,Pyr)。
EM-9205
1H NMR(400MHz,丙酮-d6)δ:1.59(s,3H,Me),1.62(s,3H,Me),2.17(d,J=2.2Hz,3H,芳香基之Me),2.28(p,J=7.0Hz,2H,CH2),3.66(t,J=7.2Hz,2H,CH2N),4.25(t,J=6.1Hz,2H,CH2O),6.91(dd,J=2.4與13.1Hz,1H,Ar),6.96(dd,J=2.5與8.6Hz,1H,Ar),7.38(dd,J=0.7與8.3Hz,1H,Ar),7.53(dt,J=1.6與4.5Hz,2H,Pyr),7.59(t,J=8.9Hz,1H,Ar),7.79(dd,J=7.5與7.9Hz,1H,Ar),8.63(d,J=6.1Hz,2H,Pyr)。
EM-9208
1H NMR(400MHz,丙酮-d6)δ:1.59(s,3H,Me),1.62(s,3H,Me),2.17(d,J=2.2Hz,3H,芳香基之Me),2.27(p,J=7.0Hz,2H,CH2),3.65(t,J=7.2Hz,2H,CH2N),4.24(t,J=6.1Hz,2H,CH2O),6.91(dd,J=2.4與13.3Hz,1H,Ar),6.95(dd,J=2.5與8.5Hz,1H,Ar),7.37(d,J=8.4Hz,1H,Ar),7.58(d,J=7.2Hz,2H,Pyr),7.60(t,J=9.2Hz,1H,Ar),7.79(dd,J=7.3與7.8Hz,1H,Ar),8.18(d,J=7.3Hz,2H,Pyr)。
EM-9221
1H NMR(400MHz,丙酮-d6)δ:1.58(s,6H,2 Me),2.25(p,J=7.2Hz,2H,CH2),2.32(s,3H,芳香基之Me),3.65(t,J=7.2Hz,2H,CH2N),4.19(t,J=6.1Hz,2H,CH2O),6.89(dd,J=2.5與8.4Hz,1H,Ar),6.92(d,J=2.4Hz,1H,Ar),7.23(d,J=8.4Hz,1H,Ar),7.35(d,J=7.2Hz,2H,Pyr),7.81(dd,J=1.9與8.5Hz,1H,Ar),7.93(d,J=1.8Hz,1H,Ar),7.99(d,
J=8.5Hz,1H,Ar),8.16(d,J=7.2Hz,2H,Pyr)。
EM-9225
1H NMR(400MHz,丙酮-d6)δ:1.58(s,6H,2 Me),2.25(p,J=7.2Hz,2H,CH2),3.64(t,J=7.3Hz,2H,CH2N),4.49(t,J=6.2Hz,2H,CH2O),6.93(dd,J=0.6與8.7Hz,1H,Pyr),7.71(d,J=7.4Hz,2H,Pyr),7.82(dd,J=1.9與8.5Hz,1H,Ar),7.95(d,J=1.9Hz,1H,Ar),7.99(d,J=8.5Hz,1H,Ar),8.09(dd,J=2.6與8.7Hz,1H,Pyr),8.19(d,J=7.3Hz,2H,Pyr),8.58(d,J=2.1Hz,1H,Pyr)。
EM-9226
1H NMR(400MHz,丙酮-d6)δ:1.59(s,6H,2 Me),2.29(p,J=6.7Hz,2H,CH2),3.68(t,J=7.0Hz,2H,CH2N),4.32(t,J=6.0Hz,2H,CH2O),7.26(t,J=8.7Hz,1H,Ar),7.56(ddd,J=1.1,2.2與8.5Hz,1H,Ar),7.59(dd,J=2.3與12.4Hz,1H,Ar),7.69(d,J=7.4Hz,2H,Pyr),7.78(dd,J=1.9與8.5Hz,1H,Ar),7.89(d,J=1.9Hz,1H,Ar),7.97(d,J=8.5Hz,1H,Ar),8.16(d,J=7.4Hz,2H,Pyr)。
EM-9227
1H NMR(400MHz,丙酮-d6)δ:1.55(s,6H,2 Me),4.82(s,2H,CH2),7.47(d,J=11.6Hz,1H,Ar),7.49(dd,J=1.6與9.4Hz,1H,Ar),7.57(dt,J=1.6與4.5Hz,2H,Pyr),7.63(t,J=8.0Hz,1H,Ar),8.22(m,2H,Ar),8.33(s,1H,Ar),8.67(d,J=6.1Hz,2H,Pyr)。
EM-9228
1H NMR(400MHz,丙酮-d6)δ:1.55(s,6H,2 Me),4.81(s,2H,CH2),7.45(d,J=10.7Hz,1H,Ar),7.48(d,J=6.8Hz,1H,Ar),7.64(m,3H,Ar與Pyr),8.22(m,4H,Ar與Pyr),8.33(s,1H,Ar)。
EM-9261
1H NMR(400MHz,丙酮-d6)δ:1.62(s,6H,2 Me),2.26(p,J=6.0Hz,2H,CH2),3.70(t,J=6.8Hz,2H,CH2N),3.81(s,3H,OMe),4.27(t,J=5.7Hz,2H,CH2O),7.09(d,J=8.3Hz,1H,Ar),7.33(d,J=2.0Hz,1H,Ar),7.36(dd,J=2.1與8.2Hz,1H,Ar),7.63(d,J=6.2Hz,2H,Pyr),7.72(dd,J=1.9與8.5Hz,1H,Ar),7.77(d,J=1.7Hz,1H,Ar),7.93(d,J=8.6Hz,1H,Ar),8.58(d,J=6.1Hz,2H,Pyr)。
EM-9267
1H NMR(400MHz,丙酮-d6)δ:1.59(s,6H,2 Me),2.28(p,J=7.1Hz,2H,CH2),3.67(t,J=7.2Hz,2H,CH2N),4.24(t,J=6.1Hz,2H,CH2O),7.12(d,J=8.9Hz,2H,Ar),7.55(dd,J=5.0與7.0Hz,1H,Pyr),7.67(dd,J=1.5與8.9Hz,2H,Ar),7.80(dd,J=2.0與8.5Hz,1H,Ar),7.93(d,J=1.8Hz,1H,Ar),7.98(d,J=8.6Hz,1H,Ar),8.44(dd,J=0.9與5.0Hz,1H,Pyr),8.52(d,J=2.9Hz,1H,Pyr)。
EM-9342
1H NMR(400MHz,丙酮-d6)δ:1.65(s,3H,Me),1.71(s,3H,Me),2.48(t,J=2.1Hz,3H,芳香基之Me),7.50(ddd,J=0.8,4.8與7.9Hz,1H,Pyr),7.65(d,J=8.6Hz,2H,Ar),7.87
(d,J=8.6Hz,2H,Ar),7.97(d,J=8.3Hz,1H,Ar),8.10(m,2H,Ar與Pyr),8.62(dd,J=1.5與4.8Hz,1H,Pyr),8.94(d,J=1.7Hz,1H,Pyr)。
EM-9343
1H NMR(400MHz,丙酮-d6)δ:1.51(s,3H,Me),1.53(s,3H,Me),2.35(s,3H,芳香基之Me),4.78(s,2H,CH2),7.61(d,J=8.3Hz,1H,Ar),7.65(d,J=8.6Hz,2H,Ar),7.67(d,J=6.3Hz,2H,Pyr),7.81(d,J=8.3Hz,2H,Ar),7.91(dd,J=0.4與8.3Hz,1H,Ar),8.64(d,J=5.9Hz,2H,Pyr)。
EM-9344
1H NMR(400MHz,丙酮-d6)δ:1.65(s,3H,Me),1.72(s,3H,Me),2.48(t,J=2.1Hz,3H,芳香基之Me),7.67(d,J=8.6Hz,2H,Ar),7.72(d,J=6.1Hz,2H,Pyr),7.95(d,J=8.7Hz,2H,Ar),7.97(d,J=9.4Hz,1H,Ar),8.09(d,J=8.2Hz,1H,Ar),8.68(d,J=6.1Hz,2H,Pyr)。
EM-9345
1H NMR(400MHz,丙酮-d6)δ:1.51(s,3H,Me),1.52(s,3H,Me),2.34(s,3H,芳香基之Me),4.76(s,2H,CH2),7.60(d,J=8.4Hz,1H,Ar),7.63(d,J=8.4Hz,2H,Ar),7.74(d,J=7.3Hz,2H,Pyr),7.78(d,J=8.4Hz,2H,Ar),7.90(dd,J=0.3與8.3Hz,1H,Ar),8.19(d,J=7.3Hz,2H,Pyr)。
表4之化合物得自範例1-10所述之流程。係呈現每一化合物之1H NMR(除了已於範例1-10所示之化合物之外):
EM-8656
1H NMR(400MHz,丙酮-d6)δ:1.68(s,3H,Me),1.68(s,3H,Me),2.27(s,3H,芳香基之Me),2.42(p,J=7.3Hz,2H,CH2),4.04(m,2H,CH2N),4.23(t,J=6.2Hz,2H,CH2O),7.12(d,J=8.8Hz,2H,Ar),7.42(ddd,0.7,4.8與7.9Hz,1H,Pyr),7.55(d,J=8.3Hz,1H,Ar),7.67(d,J=8.8Hz,2H,Ar),7.90(d,J=8.3Hz,1H,Ar),7.99(m,1H,Pyr),8.52(dd,J=1.5與4.7Hz,1H,Pyr),8.84(d,J=1.9Hz,1H,Pyr)。
EM-8664
1H NMR(400MHz,丙酮-d6)δ:1.67(s,3H,Me),1.68(s,3H,Me),2.27(s,3H,芳香基之Me),2.42(p,J=7.3Hz,2H,CH2),4.04(m,2H,CH2N),4.24(t,J=6.2Hz,2H,CH2O),7.12(d,J=8.9Hz,2H,Ar),7.55(d,J=8.2Hz,1H,Ar),7.62(d,J=6.2Hz,2H,Pyr),7.77(d,J=8.8Hz,2H,Ar),7.90(dd,J=0.4與8.3Hz,1H,Ar),8.59(d,J=6.1Hz,2H,Pyr)。
EM-8685
1H NMR(400MHz,丙酮-d6)δ:1.68(s,3H,Me),1.69(s,3H,Me),2.27(s,3H,芳香基之Me),2.42(p,J=7.3Hz,2H,CH2),4.05(m,2H,CH2N),4.24(t,J=6.2Hz,2H,CH2O),7.16(d,J=8.8Hz,2H,Ar),7.55(d,J=8.2Hz,1H,Ar),7.75(d,J=8.8Hz,2H,Ar),7.90(d,J=8.2Hz,1H,Ar),9.03(s,2H,Pyr),9.09(s,1H,Pyr)。
EM-8691
1H NMR(400MHz,丙酮-d6)δ:1.69(s,3H,Me),1.70(s,3H,
Me),2.35(d,J=2.0Hz,3H,芳香基之Me),2.42(p,J=7.2Hz,2H,CH2),4.04(m,2H,CH2N),4.24(t,J=6.2Hz,2H,CH2O),7.12(d,J=8.8Hz,2H,Ar),7.62(d,J=6.2Hz,2H,Pyr),7.77(d,J=8.8Hz,2H,Ar),7.88(d,J=8.2Hz,1H,Ar),8.06(d,J=8.2Hz,1H,Ar),8.59(d,J=6.2Hz,2H,Pyr)。
EM-8714
1H NMR(400MHz,丙酮-d6)δ:1.68(s,3H,Me),1.69(s,3H,Me),2.26(s,3H,芳香基之Me),2.45(p,J=7.2Hz,2H,CH2),4.06(m,2H,CH2N),4.33(t,J=6.1Hz,2H,CH2O),7.30(t,J=8.6Hz,1H,Ar),7.44(ddd,0.7,4.8與8.0Hz,1H,Pyr),7.51(ddd,1.1,2.2與9.6Hz,1H,Ar),7.54(d,J=8.3Hz,1H,Ar),7.57(dd,J=2.2與12.6Hz,1H,Ar),7.90(d,J=8.2Hz,1H,Ar),8.02(m,1H,Pyr),8.55(dd,J=1.5與4.7Hz,1H,Pyr),8.87(dd,J=0.6與2.3Hz,1H,Pyr)。
EM-8715
1H NMR(400MHz,丙酮-d6)δ:1.68(s,3H,Me),1.69(s,3H,Me),2.26(s,3H,芳香基之Me),2.45(p,J=7.3Hz,2H,CH2),4.06(m,2H,CH2N),4.33(t,J=6.1Hz,2H,CH2O),7.26(t,J=8.7Hz,1H,Ar),7.30(ddd,1.1,4.8與7.4Hz,1H,Pyr),7.54(d,J=8.2Hz,1H,Ar),7.90(m,4H,Ar與Pyr),7.97(dd,J=2.1與13.0Hz,1H,Ar),8.64(ddd,J=0.9,1.7與4.7Hz,1H,Pyr)。
EM-8723
1H NMR(400MHz,丙酮-d6)δ:1.68(s,3H,Me),1.69(s,3H,
Me),2.26(s,3H,芳香基之Me),2.45(p,J=7.2Hz,2H,CH2),4.06(m,2H,CH2N),4.34(t,J=6.1Hz,2H,CH2O),7.31(t,J=8.6Hz,1H,Ar),7.54(d,J=8.3Hz,1H,Ar),7.60-7.68(m,4H,Ar與Pyr),7.89(d,J=8.3Hz,1H,Ar),8.61(d,J=6.1Hz,2H,Pyr)。
EM-8772
1H NMR(400MHz,丙酮-d6)δ:1.69(s,3H,Me),1.70(s,3H,Me),2.35(d,J=2.1Hz,3H,芳香基之Me),2.48(p,J=7.4Hz,2H,CH2),4.04(m,2H,CH2N),4.40(t,J=5.9Hz,2H,CH2O),7.43(d,J=8.7Hz,1H,Ar),7.71(d,J=6.2Hz,2H,Pyr),7.89(d,J=8.2Hz,1H,Ar),8.05(m,3H,Ar),8.64(d,J=6.2Hz,2H,Pyr)。
EM-8773
1H NMR(400MHz,丙酮-d6)δ:1.67(s,3H,Me),1.67(s,3H,Me),2.27(s,3H,芳香基之Me),2.47(p,J=7.3Hz,2H,CH2),4.02(m,2H,CH2N),4.40(t,J=5.9Hz,2H,CH2O),7.43(d,J=8.6Hz,1H,Ar),7.56(d,J=8.2Hz,1H,Ar),7.70(d,J=6.1Hz,2H,Pyr),7.90(d,J=8.3Hz,1H,Ar),8.05(s,1H,Ar),8.08(dd,J=2.1與8.7Hz,1H,Ar),8.64(d,J=6.1Hz,2H,Pyr)。
EM-8793
1H NMR(400MHz,丙酮-d6)δ:1.70(s,3H,Me),1.70(s,3H,Me),2.34(q,J=2.1Hz,3H,芳香基之Me),2.45(p,J=7.1Hz,2H,CH2),4.06(m,2H,CH2N),4.34(t,J=6.1Hz,2H,
CH2O),7.31(t,J=8.6Hz,1H,Ar),7.60-7.68(m,4H,Ar與Pyr),7.86(d,J=8.2Hz,1H,Ar),8.05(d,J=8.2Hz,1H,Ar),8.62(bs,2H,Pyr)。
EM-8796
1H NMR(400MHz,丙酮-d6)δ:1.68(s,3H,Me),1.68(s,3H,Me),2.27(s,3H,芳香基之Me),2.43(p,J=7.3Hz,2H,CH2),4.04(m,2H,CH2N),4.27(t,J=6.2Hz,2H,CH2O),6.93(dd,J=2.4與13.1Hz,1H,Ar),6.98(dd,J=2.5與8.5Hz,1H,Ar),7.54(d,J=6.1Hz,2H,Pyr),7.55(d,J=8.2Hz,1H,Ar),7.60(t,J=8.9Hz,1H,Ar),7.90(dd,J=0.4與8.3Hz,1H,Ar),8.63(d,J=6.1Hz,2H,Pyr)。
EM-8797
1H NMR(400MHz,丙酮-d6)δ:1.69(s,3H,Me),1.70(s,3H,Me),2.35(d,J=2.1Hz,3H,芳香基之Me),2.43(p,J=7.2Hz,2H,CH2),4.05(m,2H,CH2N),4.27(t,J=6.1Hz,2H,CH2O),6.93(dd,J=2.4與13.1Hz,1H,Ar),6.98(dd,J=2.4與8.6Hz,1H,Ar),7.54(dt,J=1.6與4.5Hz,2H,Pyr),7.60(t,J=8.9Hz,1H,Ar),7.88(d,J=8.3Hz,1H,Ar),8.06(d,J=8.2Hz,1H,Ar),8.63(d,J=6.2Hz,2H,Pyr)。
EM-8815
1H NMR(400MHz,丙酮-d6)δ:1.66(s,3H,Me),1.67(s,3H,Me),2.27(s,3H,芳香基之Me),2.40(p,J=7.3Hz,2H,CH2),4.03(m,2H,CH2N),4.52(t,J=6.3Hz,2H,CH2O),6.97(dd,J=0.6與8.7Hz,1H,Pyr),7.55(d,J=8.3Hz,1H,
Ar),7.67(d,J=6.1Hz,2H,Pyr),7.90(dd,J=0.3與8.3Hz,1H,Ar),8.13(dd,J=2.6與8.7Hz,1H,Pyr),8.61(dd,J=0.4與2.5Hz,1H,Pyr),8.64(d,J=5.8Hz,2H,Pyr)。
EM-8820
1H NMR(400MHz,丙酮-d6)δ:1.68(s,3H,Me),1.69(s,3H,Me),2.27(s,3H,芳香基之Me),2.45(p,J=7.3Hz,2H,CH2),4.07(m,2H,CH2N),4.33(t,J=6.1Hz,2H,CH2O),7.32-7.40(m,5H,Ar與Pyr),7.55(d,J=8.3Hz,1H,Ar),7.90(d,J=8.3Hz,1H,Ar),8.64(bs,2H,Pyr)。
EM-8821
1H NMR(400MHz,丙酮-d6)δ:1.70(s,3H,Me),1.71(s,3H,Me),2.27(d,J=2.1Hz,3H,芳香基之Me),2.46(p,J=7.2Hz,2H,CH2),4.08(m,2H,CH2N),4.34(t,J=6.1Hz,2H,CH2O),7.32-7.41(m,5H,Ar與Pyr),7.88(d,J=8.2Hz,1H,Ar),8.06(d,J=8.2Hz,1H,Ar),8.65(bs,2H,Pyr)。
EM-8827
1H NMR(400MHz,丙酮-d6)δ:1.67(s,3H,Me),1.67(s,3H,Me),2.25(s,3H,芳香基之Me),2.44(p,J=7.3Hz,2H,CH2),4.05(m,2H,CH2N),4.33(t,J=6.3Hz,2H,CH2O),7.54(d,J=8.3Hz,1H,Ar),7.54(d,J=8.8Hz,1H,Pyr),7.89(dd,J=0.3與8.3Hz,1H,Ar),8.02(bs,2H,Pyr),8.05(d,J=8.8Hz,1H,Pyr),8.45(d,J=2.8Hz,1H,Pyr),8.68(bs,2H,Pyr)。
EM-8828
1H NMR(400MHz,丙酮-d6)δ:1.66(s,3H,Me),1.67(s,3H,Me),2.26(s,3H,芳香基之Me),2.40(p,J=7.4Hz,2H,CH2),4.03(m,2H,CH2N),4.23(t,J=6.1Hz,2H,CH2O),7.10(d,J=8.9Hz,1H,Pyr),7.49(d,J=8.6Hz,1H,Pyr),7.54(d,J=8.4Hz,1H,Ar),7.57(dd,J=3.1與8.9Hz,1H,Pyr),7.64(dd,J=2.9與8.7Hz,1H,Pyr),7.87(d,J=3.0Hz,1H,Pyr),7.90(d,J=8.3Hz,1H,Ar),8.24(d,J=2.9Hz,1H,Pyr)。
EM-8887
1H NMR(400MHz,丙酮-d6)δ:1.68(s,3H,Me),1.69(s,3H,Me),2.27(s,3H,芳香基之Me),2.43(p,J=7.3Hz,2H,CH2),4.05(m,2H,CH2N),4.27(t,J=6.1Hz,2H,CH2O),7.09(dd,J=2.5與8.6Hz,1H,Ar),7.18(d,J=2.5Hz,1H,Ar),7.42(d,J=8.5Hz,1H,Ar),7.43(d,J=6.0Hz,2H,Pyr),7.55(d,J=8.3Hz,1H,Ar),7.90(d,J=8.0Hz,1H,Ar),8.64(d,J=6.0Hz,2H,Pyr)。
EM-8889
1H NMR(400MHz,丙酮-d6)δ:1.70(s,3H,Me),1.70(s,3H,Me),2.35(q,J=2.1Hz,3H,芳香基之Me),2.43(p,J=7.3Hz,2H,CH2),4.06(m,2H,CH2N),4.27(t,J=6.1Hz,2H,CH2O),7.09(dd,J=2.5與8.6Hz,1H,Ar),7.18(d,J=2.5Hz,1H,Ar),7.42(d,J=8.6Hz,1H,Ar),7.43(d,J=6.0Hz,2H,Pyr),7.88(d,J=8.3Hz,1H,Ar),8.07(d,J=8.2Hz,1H,Ar),8.64(d,J=6.1Hz,2H,Pyr)。
EM-8913
1H NMR(400MHz,甲醇-d4)δ:1.64(s,6H,Me),2.26(s,3H,芳香基之Me),2.41(p,J=6.5Hz,2H,CH2),4.01(m,2H,CH2N),4.22(t,J=6.0Hz,2H,CH2O),7.14(d,J=8.9Hz,2H,Ar),7.44(d,J=8.2Hz,1H,Ar),7.78(d,J=8.9Hz,2H,Ar),7.81(d,J=8.5Hz,1H,Ar),7.85(d,J=7.3Hz,2H,Pyr),8.59(d,J=7.3Hz,2H,Pyr)。
EM-8922
1H NMR(400MHz,丙酮-d6)δ:1.67(s,3H,Me),1.68(s,3H,Me),2.27(s,3H,芳香基之Me),2.42(p,J=7.3Hz,2H,CH2),4.04(m,2H,CH2N),4.23(t,J=6.2Hz,2H,CH2O),7.11(d,J=8.8Hz,2H,Ar),7.14(dd,J=2.8與8.7Hz,1H,Pyr),7.55(d,J=8.3Hz,1H,Ar),7.65(d,J=8.8Hz,2H,Ar),7.90(d,J=8.2Hz,1H,Ar),8.19(dt,J=2.1與8.7Hz,1H,Pyr),8.45(s,1H,Pyr)。
EM-8933
1H NMR(400MHz,丙酮-d6)δ:1.68(s,3H,Me),1.69(s,3H,Me),2.27(s,3H,芳香基之Me),2.45(p,J=7.4Hz,2H,CH2),4.06(m,2H,CH2N),4.35(t,J=6.1Hz,2H,CH2O),7.45(dd,J=2.7與8.7Hz,1H,Ar),7.53(d,J=2.9Hz,1H,Ar),7.55(d,J=8.7Hz,1H,Ar),7.57(d,J=6.1Hz,2H,Pyr),7.66(d,J=8.7Hz,1H,Ar),7.90(d,J=8.3Hz,1H,Ar),8.71(d,J=5.7Hz,2H,Pyr)。
EM-8974
1H NMR(400MHz,丙酮-d6)δ:1.69(s,3H,Me),1.70(s,3H,Me),2.35(q,J=2.1Hz,3H,芳香基之Me),2.42(p,J=7.2Hz,2H,CH2),4.06(m,2H,CH2N),4.26(t,J=6.2Hz,2H,CH2O),7.14(d,J=8.9Hz,2H,Ar),7.55(dd,J=5.0與7.0Hz,1H,Pyr),7.68(dd,J=1.5與8.8Hz,2H,Ar),7.89(d,J=8.5Hz,1H,Ar),8.08(d,J=8.6Hz,1H,Ar),8.45(dd,J=0.9與4.9Hz,1H,Pyr),8.53(d,J=2.9Hz,1H,Pyr)。
EM-8977
1H NMR(400MHz,丙酮-d6)δ:1.68(s,3H,Me),1.69(s,3H,Me),2.27(s,3H,芳香基之Me),2.43(p,J=7.2Hz,2H,CH2),4.05(m,2H,CH2N),4.25(t,J=6.0Hz,2H,CH2O),7.13(d,J=8.8Hz,2H,Ar),7.42(d,J=4.9Hz,1H,Pyr),7.53(d,J=8.6Hz,2H,Ar),7.55(d,J=8.1Hz,1H,Ar),7.90(d,J=8.4Hz,1H,Ar),8.53(d,J=4.9Hz,1H,Pyr),8.65(s,1H,Pyr)。
EM-8993
1H NMR(400MHz,丙酮-d6)δ:1.67(s,3H,Me),1.68(s,3H,Me),2.27(s,3H,芳香基之Me),2.40(p,J=7.3Hz,2H,CH2),3.10(s,6H,NMe2),4.03(m,2H,CH2N),4.19(t,J=6.2Hz,2H,CH2O),6.68(d,J=8.8Hz,1H,Pyr),7.03(d,J=8.8Hz,2H,Ar),7.52(d,J=8.8Hz,1H,Ar),7.55(d,J=8.3Hz,1H,Ar),7.74(dd,J=2.6與8.8Hz,1H,Pyr),7.90(d,J=8.3Hz,1H,Ar),8.37(d,J=2.0Hz,1H,Pyr)。
EM-8996
1H NMR(400MHz,丙酮-d6)δ:1.67(s,3H,Me),1.68(s,3H,Me),2.27(s,3H,芳香基之Me),2.41(p,J=7.3Hz,2H,CH2),3.11(s,6H,NMe2),4.03(m,2H,CH2N),4.22(t,J=6.2Hz,2H,CH2O),6.69(d,J=8.5Hz,1H,Pyr),6.85(dd,J=2.4與12.8Hz,1H,Ar),6.89(dd,J=2.5與8.4Hz,1H,Ar),7.41(t,J=8.9Hz,1H,Ar),7.55(d,J=8.3Hz,1H,Ar),7.66(d,J=8.9Hz,1H,Pyr),7.90(d,J=8.1Hz,1H,Ar),8.27(s,1H,Pyr)。
EM-9036
1H NMR(400MHz,丙酮-d6)δ:1.68(s,3H,Me),1.68(s,3H,Me),2.27(s,3H,芳香基之Me),2.42(p,J=7.3Hz,2H,CH2),4.04(m,2H,CH2N),4.27(t,J=6.1Hz,2H,CH2O),7.09(dd,J=2.6與8.6Hz,1H,Ar),7.18(d,J=2.5Hz,1H,Ar),7.42(d,J=9.3Hz,1H,Ar),7.48(d,J=7.3Hz,2H,Pyr),7.55(d,J=8.2Hz,1H,Ar),7.90(d,J=8.1Hz,1H,Ar),8.20(d,J=7.2Hz,2H,Pyr)。
EM-9253
1H NMR(400MHz,丙酮-d6)δ:1.60(s,3H,Me),1.62(s,3H,Me),2.28(p,J=6.9Hz,2H,CH2),2.29(s,3H,芳香基之Me),3.66(t,J=7.2Hz,2H,CH2N),4.25(t,J=6.1Hz,2H,CH2O),6.91(dd,J=2.4與13.1Hz,1H,Ar),6.96(dd,J=2.3與8.5Hz,1H,Ar),7.51(d,J=8.7Hz,1H,Ar),7.53(d,J=4.6Hz,2H,Pyr),7.59(t,J=8.9Hz,1H,Ar),7.87(d,J=8.2Hz,1H,Ar),8.63(d,J=6.1Hz,2H,Pyr)。
EM-9254
1H NMR(400MHz,丙酮-d6)δ:1.59(s,3H,Me),1.61(s,3H,Me),2.27(p,J=6.9Hz,2H,CH2),2.29(s,3H,芳香基之Me),3.65(t,J=7.2Hz,2H,CH2N),4.24(t,J=6.1Hz,2H,CH2O),6.91(dd,J=2.4與13.3Hz,1H,Ar),6.95(dd,J=2.5與8.5Hz,1H,Ar),7.51(d,J=8.3Hz,1H,Ar),7.58(d,J=8.4Hz,2H,Pyr),7.60(t,J=9.2Hz,1H,Ar),7.86(dd,J=0.4與8.3Hz,1H,Ar),8.18(d,J=7.4Hz,2H,Pyr)。
EM-9290
1H NMR(400MHz,丙酮-d6)δ:1.60(s,3H,Me),1.62(s,3H,Me),2.27(p,J=7.2Hz,2H,CH2),2.29(s,3H,芳香基之Me),3.66(t,J=7.2Hz,2H,CH2N),4.25(t,J=6.1Hz,2H,CH2O),7.08(dd,J=2.5與8.6Hz,1H,Ar),7.16(d,J=2.5Hz,1H,Ar),7.41(d,J=8.6Hz,1H,Ar),7.43(d,J=6.1Hz,2H,Pyr),7.52(d,J=8.3Hz,1H,Ar),7.87(dd,J=0.4與8.3Hz,1H,Ar),8.64(d,J=6.0Hz,2H,Pyr)。
EM-9291
1H NMR(400MHz,丙酮-d6)δ:1.60(s,3H,Me),1.62(s,3H,Me),2.27(p,J=7.0Hz,2H,CH2),2.29(s,3H,芳香基之Me),3.66(t,J=7.2Hz,2H,CH2N),4.24(t,J=6.1Hz,2H,CH2O),7.07(dd,J=2.6與8.6Hz,1H,Ar),7.16(d,J=2.5Hz,1H,Ar),7.45(d,J=8.6Hz,1H,Ar),7.47(d,J=7.2Hz,2H,Pyr),7.51(d,J=8.3Hz,1H,Ar),7.87(dd,J=0.4與8.3Hz,1H,Ar),8.20(d,J=7.3Hz,2H,Pyr)。
EM-9297
1H NMR(400MHz,丙酮-d6)δ:1.60(s,3H,Me),1.62(s,3H,Me),2.29(s,3H,芳香基之Me),2.30(p,J=6.8Hz,2H,CH2),3.69(dt,J=1.5與7.7Hz,2H,CH2N),4.31(t,J=6.1Hz,2H,CH2O),7.29(t,J=8.6Hz,1H,Ar),7.50(d,J=8.3Hz,1H,Ar),7.60-7.67(m,4H,Ar與Pyr),7.86(d,J=8.2Hz,1H,Ar),8.61(d,J=6.2Hz,2H,Pyr)。
EM-9300
1H NMR(400MHz,丙酮-d6)δ:1.59(s,3H,Me),1.61(s,3H,Me),2.27(p,J=6.7Hz,2H,CH2),2.29(s,3H,芳香基之Me),3.65(t,J=7.2Hz,2H,CH2N),4.22(t,J=6.1Hz,2H,CH2O),7.11(d,J=8.8Hz,2H,Ar),7.51(d,J=8.3Hz,1H,Ar),7.62(d,J=6.2Hz,2H,Pyr),7.76(d,J=8.8Hz,2H,Ar),7.86(d,J=8.3Hz,1H,Ar),8.59(d,J=6.1Hz,2H,Pyr)。
EM-9301
1H NMR(400MHz,丙酮-d6)δ:1.60(s,3H,Me),1.62(s,3H,Me),2.28(s,3H,芳香基之Me),2.31(p,J=6.8Hz,2H,CH2),3.69(dt,J=1.3與7.6Hz,2H,CH2N),4.30(t,J=6.1Hz,2H,CH2O),7.27(t,J=8.7Hz,1H,Ar),7.50(d,J=8.3Hz,1H,Ar),7.57(ddd,J=1.1,2.2與8.6Hz,1H,Ar),7.63(dd,J=2.3與12.7Hz,1H,Ar),7.71(d,J=7.4Hz,2H,Pyr),7.86(dd,J=0.4與8.3Hz,1H,Ar),8.17(d,J=7.4Hz,2H,Pyr)。
EM-9305
1H NMR(400MHz,丙酮-d6)δ:1.59(s,3H,Me),1.61(s,3H,Me),2.26(p,J=6.8Hz,2H,CH2),2.29(s,3H,芳香基之Me),3.65(t,J=7.2Hz,2H,CH2N),4.21(t,J=6.2Hz,2H,CH2O),7.09(d,J=8.9Hz,2H,Ar),7.51(d,J=8.3Hz,1H,Ar),7.68(d,J=7.4Hz,2H,Pyr),7.73(d,J=8.9Hz,2H,Ar),7.86(d,J=8.2Hz,1H,Ar),8.16(d,J=7.4Hz,2H,Pyr)。
EM-9309
1H NMR(400MHz,丙酮-d6)δ:1.58(s,3H,Me),1.61(s,3H,Me),2.30(s與p,5H,芳香基之Me與CH2),3.65(t,J=7.3Hz,2H,CH2N),4.38(t,J=5.8Hz,2H,CH2O),7.41(d,J=8.7Hz,1H,Ar),7.53(d,J=8.3Hz,1H,Ar),7.70(d,J=6.2Hz,2H,Pyr),7.87(d,J=8.4Hz,1H,Ar),8.04(s,1H,Ar),8.07(dd,J=2.3與8.5Hz,1H,Ar),8.64(d,J=6.1Hz,2H,Pyr)。
EM-9310
1H NMR(400MHz,丙酮-d6)δ:1.60(s,3H,Me),1.62(s,3H,Me),2.27(p,J=6.8Hz,2H,CH2),2.29(s,3H,芳香基之Me),3.66(t,J=7.2Hz,2H,CH2N),4.23(t,J=6.1Hz,2H,CH2O),7.11(d,J=8.8Hz,2H,Ar),7.42(d,J=4.9Hz,1H,Pyr),7.52(d,J=8.5Hz,1H,Ar),7.52(d,J=8.8Hz,2H,Ar),7.87(d,J=8.4Hz,1H,Ar),8.53(d,J=4.9Hz,1H,Pyr),8.65(s,1H,Pyr)。
EM-9311
1H NMR(400MHz,丙酮-d6)δ:1.60(s,3H,Me),1.62(s,3H,Me),2.27(p,J=6.8Hz,2H,CH2),2.29(s,3H,芳香基之
Me),3.66(t,J=7.2Hz,2H,CH2N),4.23(t,J=6.1Hz,2H,CH2O),7.12(d,J=8.9Hz,2H,Ar),7.51(d,J=8.3Hz,1H,Ar),7.55(dd,J=5.0與7.0Hz,1H,Pyr),7.67(dd,J=1.4與8.8Hz,2H,Ar),7.86(d,J=8.3Hz,1H,Ar),8.45(d,J=4.9Hz,1H,Pyr),8.53(d,J=2.8Hz,1H,Pyr)。
EM-9313
1H NMR(400MHz,丙酮-d6)δ:1.60(s,3H,Me),1.62(s,3H,Me),2.27(p,J=6.7Hz,2H,CH2),2.29(s,3H,芳香基之Me),3.66(t,J=7.2Hz,2H,CH2N),4.22(t,J=6.1Hz,2H,CH2O),7.09(d,J=8.8Hz,2H,Ar),7.43(d,J=6.8Hz,1H,Pyr),7.50(d,J=8.8Hz,2H,Ar),7.51(d,J=8.3Hz,1H,Ar),7.86(d,J=8.3Hz,1H,Ar),8.15(dd,J=1.8與6.8Hz,1H,Pyr),8.35(d,J=1.7Hz,1H,Pyr)。
EM-9318
1H NMR(400MHz,丙酮-d6)δ:1.60(s,3H,Me),1.61(s,3H,Me),2.27(p,J=6.8Hz,2H,CH2),2.29(s,3H,芳香基之Me),3.65(t,J=7.2Hz,2H,CH2N),4.22(t,J=6.1Hz,2H,CH2O),7.11(d,J=8.9Hz,2H,Ar),7.51(d,J=8.3Hz,1H,Ar),7.57(dd,J=6.9與9.7Hz,1H,Pyr),7.62(dd,J=1.5與8.8Hz,2H,Ar),7.86(d,J=8.4Hz,1H,Ar),8.08(dd,J=1.0與6.8Hz,1H,Pyr),8.29(dd,J=1.7與6.6Hz,1H,Pyr)。
EM-9319
1H NMR(400MHz,丙酮-d6)δ:1.58(s,3H,Me),1.60(s,3H,Me),2.30(s與p,5H,芳香基之Me與CH2),3.65(t,J=7.3Hz,
2H,CH2N),4.38(t,J=5.9Hz,2H,CH2O),7.39(d,J=8.6Hz,1H,Ar),7.52(d,J=8.3Hz,1H,Ar),7.76(d,J=7.3Hz,2H,Pyr),7.87(d,J=8.3Hz,1H,Ar),8.02(s,1H,Ar),8.04(dd,J=2.2與8.7Hz,1H,Ar),8.18(d,J=7.3Hz,2H,Pyr)。
EM-9333
1H NMR(400MHz,丙酮-d6)δ:1.60(s,3H,Me),1.63(s,3H,Me),2.29(s,3H,芳香基之Me),2.31(p,J=6.0Hz,2H,CH2),3.68(t,J=7.2Hz,2H,CH2N),4.31(t,J=6.1Hz,2H,CH2O),7.32-7.40(m,5H,Ar與Pyr),7.52(d,J=8.3Hz,1H,Ar),7.87(d,J=8.3Hz,1H,Ar),8.63(d,J=5.9Hz,2H,Pyr)。
EM-9334
1H NMR(400MHz,丙酮-d6)δ:1.60(s,3H,Me),1.63(s,3H,Me),2.29(s,3H,芳香基之Me),2.31(p,J=6.0Hz,2H,CH2),3.68(t,J=7.2Hz,2H,CH2N),4.31(t,J=6.1Hz,2H,CH2O),7.34(m,3H,Ar與Pyr),7.38(d,J=2.5Hz,1H,Ar),7.45(d,J=8.5Hz,1H,Ar),7.52(d,J=8.3Hz,1H,Ar),7.87(d,J=8.4Hz,1H,Ar),8.20(d,J=7.2Hz,2H,Pyr)。
EM-9337
1H NMR(400MHz,丙酮-d6)δ:1.64(s,3H,Me),1.66(s,3H,Me),2.29(s,3H,芳香基之Me),3.87(m,2H,CH2N),4.37(m,2H,CH2O),7.14(d,J=8.8Hz,2H,Ar),7.53(d,J=8.3Hz,1H,Ar),7.63(d,J=5.5Hz,2H,Pyr),7.78(d,J=8.8Hz,2H,Ar),7.88(d,J=8.3Hz,1H,Ar),8.60(bs,2H,Pyr)。
EM-9339
1H NMR(400MHz,丙酮-d6)δ:1.64(s,3H,Me),1.66(s,3H,Me),2.28(s,3H,芳香基之Me),3.86(m,2H,CH2N),4.36(m,2H,CH2O),7.12(d,J=8.9Hz,2H,Ar),7.53(d,J=8.3Hz,1H,Ar),7.68(d,J=7.3Hz,2H,Pyr),7.74(d,J=8.9Hz,2H,Ar),7.88(dd,J=0.4與8.3Hz,1H,Ar),8.16(d,J=7.3Hz,2H,Pyr)。
表5之化合物得自範例1-10所述之流程。係呈現每一化合物之1H NMR:
EM-8728
1H NMR(400MHz,丙酮-d6)δ:1.68(s,3H,Me),1.69(s,3H,Me),2.27(s,3H,芳香基之Me),2.47(p,J=7.2Hz,2H,CH2),4.07(m,2H,CH2N),4.31(t,J=6.1Hz,2H,CH2O),7.34(d,J=2.7Hz,1H,喹啉),7.43(t,J=2.1Hz,1H,喹啉),7.45(t,J=3.0Hz,1H,喹啉),7.55(d,J=8.3Hz,1H,Ar),7.89(d,J=8.3Hz,1H,Ar),7.96(d,J=9.2Hz,1H,喹啉),8.19(d,J=8.3Hz,1H,喹啉),8.75(dd,J=1.5與4.1Hz,1H,喹啉)。
EM-8729
1H NMR(400MHz,丙酮-d6)δ:1.73(s,3H,Me),1.77(s,3H,Me),2.20(s,3H,芳香基之Me),2.52(m,2H,CH2),4.10(m,1H,CH2N),4.24(m,1H,CH2N),4.42(m,2H,CH2O),7.21(m,2H,喹啉),7.52(m,3H,喹啉與Ar),7.78(d,J=8.2Hz,1H,Ar),8.30(dd,J=1.7與8.3Hz,1H,喹啉),8.86(dd,J=1.7與4.1Hz,1H,喹啉)。
EM-8730
1H NMR(400MHz,丙酮-d6)δ:1.69(s,3H,Me),1.69(s,3H,Me),2.27(s,3H,芳香基之Me),2.49(p,J=7.3Hz,2H,CH2),4.09(m,2H,CH2N),4.34(t,J=6.3Hz,2H,CH2O),7.28(dd,J=2.5與8.9Hz,1H,喹啉),7.35(dd,J=4.3與8.2Hz,1H,喹啉),7.42(d,J=2.3Hz,1H,喹啉),7.56(d,J=8.3Hz,1H,Ar),7.87(d,J=9.0Hz,1H,喹啉),7.89(d,J=8.3Hz,1H,Ar),8.23(dd,J=1.0與8.1Hz,1H,喹啉),8.82(dd,J=1.6與4.2Hz,1H,喹啉)。
EM-8786
1H NMR(400MHz,丙酮-d6)δ:1.60(s,3H,Me),1.63(s,3H,Me),2.29(s,3H,芳香基之Me),2.33(p,J=6.9Hz,2H,CH2),3.70(t,J=7.2Hz,2H,CH2N),4.32(t,J=6.1Hz,2H,CH2O),7.27(dd,J=2.6與9.0Hz,1H,喹啉),7.35(dd,J=4.3與8.2Hz,1H,喹啉),7.41(d,J=2.4Hz,1H,喹啉),7.52(d,J=8.2Hz,1H,Ar),7.85(d,J=8.3Hz,1H,Ar),7.86(d,J=9.0Hz,1H,喹啉),8.23(d,J=7.9Hz,1H,喹啉),8.81(dd,J=1.7與4.2Hz,1H,喹啉)。
EM-8869
1H NMR(400MHz,甲醇-d4)δ:1.64(s,6H,Me),2.24(s,3H,芳香基之Me),2.46(p,J=6.4Hz,2H,CH2),4.03(m,2H,CH2N),4.31(t,J=6.0Hz,2H,CH2O),7.32(d,J=2.0Hz,1H,異喹啉),7.36(dd,J=2.4與8.9Hz,1H,異喹啉),7.43(d,J=8.2Hz,1H,Ar),7.73(d,J=5.6Hz,1H,異喹啉),
7.78(d,J=8.3Hz,1H,Ar),8.02(d,J=9.0Hz,1H,異喹啉),8.33(bs,1H,異喹啉),9.08(bs,1H,異喹啉)。
EM-8989
1H NMR(400MHz,丙酮-d6)δ:1.68(s,6H,Me),2.48(m,2H,CH2),4.08(m,2H,CH2N),4.35(t,J=6.1Hz,2H,CH2O),7.46(dd,J=2.5與8.9Hz,1H,異喹啉),7.51(d,J=2.4Hz,1H,異喹啉),7.70(d,J=5.6Hz,1H,異喹啉),7.90(d,J=8.9Hz,1H,異喹啉),8.03(dd,J=1.8與8.3Hz,1H,Ar),8.17(d,J=1.8Hz,1H,Ar),8.25(d,J=8.3Hz,1H,Ar),8.38(d,J=5.6Hz,1H,異喹啉),9.17(s,1H,異喹啉)。
EM-8990
1H NMR(400MHz,丙酮-d6)δ:1.68(s,6H,Me),2.47(m,2H,CH2),4.08(m,2H,CH2N),4.31(t,J=6.1Hz,2H,CH2O),7.35(d,J=2.8Hz,1H,喹啉),7.44(m,2H,喹啉),7.96(d,J=9.2Hz,1H,喹啉),8.03(dd,J=1.7與8.3Hz,1H,Ar),8.17(d,J=1.7Hz,1H,Ar),8.20(dd,J=1.0與8.4Hz,1H,喹啉),8.25(d,J=8.3Hz,1H,Ar),8.74(dd,J=1.7與4.2Hz,1H,喹啉)。
EM-8991
1H NMR(400MHz,丙酮-d6)δ:1.69(s,6H,Me),2.48(m,2H,CH2),4.09(m,2H,CH2N),4.34(t,J=6.2Hz,2H,CH2O),7.28(dd,J=2.5與8.9Hz,1H,喹啉),7.35(dd,J=4.3與8.2Hz,1H,喹啉),7.42(d,J=2.4Hz,1H,喹啉),7.87(d,J=9.0Hz,1H,喹啉),8.03(dd,J=1.7與8.3Hz,1H,Ar),
8.17(d,J=1.7Hz,1H,Ar),8.23(dd,J=1.3與8.1Hz,1H,喹啉),8.25(d,J=8.3Hz,1H,Ar),8.82(dd,J=1.7與4.3Hz,1H,喹啉)。
EM-9010
1H NMR(400MHz,丙酮-d6)δ:1.68(s,6H,Me),2.49(m,2H,CH2),4.09(m,2H,CH2N),4.37(t,J=6.1Hz,2H,CH2O),7.51(d,J=2.8,1H,喹唑啉),7.70(dd,J=2.8與9.2Hz,1H,喹唑啉),7.96(d,J=9.2Hz,1H,喹唑啉),8.03(dd,J=1.8與8.3Hz,1H,Ar),8.16(d,J=1.8Hz,1H,Ar),8.26(d,J=8.3Hz,1H,Ar),9.14(s,1H,喹唑啉),9.40(s,1H,喹唑啉)。
EM-9021
1H NMR(400MHz,丙酮-d6)δ:1.68(s,6H,Me),2.47(m,2H,CH2),4.08(m,2H,CH2N),4.35(t,J=6.2Hz,2H,CH2O),7.33(m,2H,異喹啉),7.65(d,J=5.8Hz,1H,異喹啉),8.02(d,J=8.1Hz,1H,Ar),8.03(d,J=9.7Hz,1H,異喹啉),8.17(d,J=1.8Hz,1H,Ar),8.25(d,J=8.3Hz,1H,Ar),8.41(d,J=5.7Hz,1H,異喹啉),9.14(s,1H,異喹啉)。
EM-9028
1H NMR(400MHz,丙酮-d6)δ:1.68(s,6H,Me),2.46(m,2H,CH2),4.07(m,2H,CH2N),4.33(t,J=6.1Hz,2H,CH2O),7.38(dd,J=6.0與8.3Hz,1H,喹啉),7.44(m,2H,喹啉),7.73(d,J=8.5Hz,1H,喹啉),8.03(dd,J=1.7與8.3Hz,1H,Ar),8.17(d,J=1.7Hz,1H,Ar),8.25(d,J=8.2Hz,
1H,Ar),8.35(dd,J=0.7與6.0Hz,1H,喹啉),8.54(d,J=9.1Hz,1H,喹啉)。
EM-9090
1H NMR(400MHz,丙酮-d6)δ:1.60(s,6H,Me),2.32(p,J=7.1Hz,2H,CH2),2.62(s,3H,Me of喹啉),3.70(t,J=7.2Hz,2H,CH2N),4.27(t,J=6.1Hz,2H,CH2O),7.27(d,J=2.8Hz,1H,喹啉),7.32(d,J=8.4Hz,1H,喹啉),7.37(dd,J=2.8與9.1Hz,1H,喹啉),7.84(d,J=9.1Hz,1H,喹啉),8.06(d,J=8.4Hz,1H,喹啉),8.14(dd,J=1.8與6.7Hz,1H,Ar),8.19(d,J=8.5Hz,1H,Ar),8.27(d,J=1.8Hz,1H,Ar)。
EM-9093
1H NMR(400MHz,丙酮-d6)δ:1.60(s,6H,Me),2.33(p,J=7.1Hz,2H,CH2),2.55(s,3H,Me of喹啉),3.70(t,J=7.2Hz,2H,CH2N),4.31(t,J=6.1Hz,2H,CH2O),7.39(dd,J=2.6與9.4Hz,1H,喹啉),7.43(d,J=2.7Hz,1H,喹啉),7.44(d,J=8.6Hz,1H,喹啉),7.64(d,J=8.5Hz,1H,喹啉),8.15(dd,J=1.7與8.5Hz,1H,Ar),8.20(d,J=8.4Hz,1H,Ar),8.26(d,J=2.0Hz,1H,Ar),8.56(d,J=9.4Hz,1H,喹啉)。
EM-9302
1H NMR(400MHz,丙酮-d6)δ:1.61(s,3H,Me),1.63(s,3H,Me),2.29(s,3H,芳香基之Me),2.34(p,J=6.5Hz,2H,CH2),3.70(dt,J=1.8與7.1Hz,2H,CH2N),4.35(t,J=6.2Hz,2H,CH2O),7.32(dd,J=6.1與8.4Hz,1H,喹啉),7.38
(dd,J=1.6與9.0Hz,1H,喹啉),7.53(d,J=8.3Hz,1H,Ar),7.82(d,J=8.3Hz,1H,Ar),7.85(d,J=8.3Hz,1H,喹啉),7.98(d,J=9.0Hz,1H,喹啉),8.01(d,J=2.5Hz,1H,喹啉),8.48(dd,J=0.7與6.1Hz,1H,喹啉)。
以下描述數個利用較佳活性抗雄激素EM-9150,用於系統性用途之醫藥組成物,但僅用於示範而非用於限制。本發明之其他抗雄激素或SARMs或其組合,可用於取代(或外加)EM-9150。活性成分之濃度可於廣範圍中變化,如此所述。其他可包括之成分之含量與種類為技術上已知。
其他抗雄激素(即EM-9198,EM-9204或EM-9205)或SARMs(即EM-9251、EM-9253、EM-9290或EM-9309)可取代上述配方中之EM-9150。就組合療法而言,5α-還原酶抑制劑、第5型17β-羥基類固醇脫氫酶抑制劑、第15型17β-羥基類固醇脫氫酶抑制劑,以及17α-羥化酶/17,20-解離酶抑制劑可以重量%加入(按比例減少其他成分)。一種以上之抗雄激素
或SARM,或一種以上之抑制劑可包括於醫藥組成物中。
範例K
藥錠
套組範例
下列描述數種利用較佳活性抗雄激素EM-9150與較佳LHRH促效劑亮丙瑞林醋酸酯(Leuprolide acetate)(Lupron
depot)之套組,僅用於說明而非限制。本發明之其他化合物或其組合物,可用於取代(或外加)EM-9150與亮丙瑞林醋酸酯(Leuprolide acetate)。LHRH拮抗劑可用於取代LHRH促效劑。活性成分之濃度可於廣範圍中變化,如此所討論。可包括之其他成分之含量與種類,為技術上已知。
其他抗雄激素(即EM-9198、EM-9204或EM-9205)或SARMs(即EM-9251、EM-9253、EM-9290或EM-9309),
可取代上述配方之EM-9150。在其他組合治療中,5α-還原酶抑制劑、第5型17β-羥基類固醇脫氫酶抑制劑、第15型17β-羥基類固醇脫氫酶抑制劑,以及17α-羥化酶/17,20-解離酶抑制劑,可以一額外容器加入至含有該抗雄激素或SARM之第一容器中,以提供一套組,以及任擇地含有LHRH促效劑或LHRH拮抗劑之第三容器。該抑制劑可包括於相同配方中,除了第一容器中之抗雄激素或SARM,以及第二容器之LHRH促效劑或LHRH拮抗劑之外,以提供一套組。一種以上之抗雄激素或SARM,或一種以上之LHRH促效劑或LHRH拮抗劑,或一種以上之抑制劑可包括於套組中。
本發明已以較佳實施例與範例描述,但未受其限制。熟習此技術領域者應可立即了解到較廣之可應用性,且本發明範疇僅受到本發明申明之申請專利範圍,或本專利申請案申明之優先權(直接或間接)限制。
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Claims (29)
- 一種如下式之化合物:其中n為0至6之一整數;其中m為0至1之一整數;其中J與Y獨立地為一直接鍵結,或選自於由-O-、-CO-、-CH2-、-S-、-SO-、-SO2-、-NH-、-CHR1-、-C(R1)2-與-NR1-組成之族群;其中Ra與Rb獨立地選自於由氫、鹵素、-OCH3、C1-C3烷基、C2-C3烯基、腈基、三氟甲基、醯胺、胺,以及烷基碸組成之族群;其中R1係選自於由氫、鹵素以及C1-C3烷基組成之族群;其中R2係選自於由氫、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2、C1-C3烷基,以及三氟甲基組成之族群;其中R3係選自於由鹵素、腈基、-COCH3、-SO2CH3,以及-NO2組成之族群;其中R4與R5獨立地選自於由氫、C1-C6烷基、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2,以及三氟甲基組成之族群,或R4與R5共同形成一環,該環任擇地具有一選自於由氮、氧與硫組成之族群的雜原子;其中R6與R7獨立地選自於由氫與C1-C6烷基組成之族群,或R6與R7共同形成一環,該環任擇地具有一選自於由氮、氧與硫組成之族群的雜原子;其中W選自於由氧與硫組成之族群;其中G1、G2、G3、G4與G5獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最多二個氮或氧化氮;其中G6、G7、G8、G9與G10獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最少一個氮或氧化氮;以及其中Y連結至G1、G2或G4;或其醫藥上可接受之鹽類。
- 如請求項1之化合物,其中m為0;其中n為3;其中J為氧;其中G1、G8與G10為碳或次甲基;其中Y為一直接鍵結;其中J與Y互相位於對位;且其中G6或G7或G9為氮或氧化氮。
- 一種如下式之化合物其中n為0至6之一整數;其中m為0至1之一整數;其中J獨立地為一直接鍵結或選自於由-O-、-CO-、-CH2-、-S-、-SO-、-SO2-、-NH-、-CHR1-、-C(R1)2-與-NR1-組成之族群;其中Ra與Rb獨立地選自於由氫、鹵素、-OCH3、C1-C3烷基、C2-C3烯基、腈基、三氟甲基、醯胺、胺,以及烷基碸組成之族群;其中R1選自於由氫、鹵素與C1-C3烷基組成之族群;其中R2選自於由氫、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2、C1-C3烷基,以及三氟甲基組成之族群;其中R3選自於由鹵素、腈基、-COCH3、-SO2CH3,以及-NO2組成之族群;其中R4與R5獨立地選自於由氫、C1-C6烷基、鹵素、-OCH3、-SCH3、烷基亞碸、烷基碸、腈基、-NO2,以及三氟甲基組成之族群,或R4與R5共同形成一環,該環任擇地具有一選自於由氮、氧與硫組成之族群的雜原子;其中R6與R7獨立地選自於由氫與C1-C6烷基組成之族群,或R6與R7共同形成一環,該環任擇地具一有選自於由氮、氧與硫組成之族群的雜原子;其中W選自於由氧與硫組成之族群;其中L1、L2、L3與L4獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最多二個氮或氧化氮;以及其中L5、L6、L7與L8獨立地選自於由碳、次甲基、氮與氧化氮組成之族群,其在環上具有最少一個氮或氧化氮;或其醫藥上可接受之鹽類組成之族群。
- 一種醫藥組成物,其包含至少一如請求項1至10任一項定義之化合物,以及醫藥上可接受之稀釋劑或載體。
- 一種醫藥組成物,其用於治療或降低發展為前列腺癌、良性前列腺增生、痤瘡、脂溢性皮膚炎、多毛症、雄激素性脫髮、雄性禿、多囊卵巢症候群、性早熟或超雄激素症候群之風險,該醫藥組成物包含治療有效量之至少一如請求項1至10任一項定義之化合物,以及醫藥上可接受之稀釋劑或載體。
- 一種醫藥組成物,其用於治療或降低發展為與雄激素刺激損失有關之疾病之風險,該疾病由肌肉萎縮和無力、皮膚萎縮、骨質流失、骨質疏鬆、貧血、動脈粥樣硬化、心血管疾病、能量損失、幸福感喪失、性慾減退、男性性腺功能低下、肌少症、陽痿、勃起功能障礙、女性性功能障礙、第2型糖尿病或腹部脂肪堆積所組成,該醫藥組成物包含治療有效量之至少一如請求項1、2與4至10任一項定義之化合物,以及醫藥上可接受之稀釋劑或載體。
- 一種醫藥組成物,其用於治療或降低發展為前列腺癌或良性前列腺增生之風險,該醫藥組成物包含治療有效量之至少一如請求項1至10任一項定義之化合物,以及醫藥上可接受之稀釋劑或載體。
- 如請求項11至14任一項之醫藥組成物,其中該稀釋劑或載體適用於口服投藥。
- 一種治療有效量之至少一如請求項1至10任一項定義之化合物於製備藥物上的用途,該藥物供用於治療或降低發展為前列腺癌之風險。
- 如請求項16之用途,其中該藥物包含治療有效量之至少一選自於由第15型17β-羥基類固醇脫氫酶抑制劑、第5型17β-羥基類固醇脫氫酶抑制劑、5α-還原酶抑制劑及17α-羥化酶/17,20-解離酶抑制劑所組成之族群的雄激素-合成酶抑制劑。
- 如請求項17之用途,其中該藥物包含5α-還原酶抑制劑及第15型17β-羥基類固醇脫氫酶抑制劑。
- 如請求項16之用途,其中該藥物之使用是伴隨睪丸切除術或LHRH促效劑或拮抗劑之投藥。
- 如請求項17之用途,其中該藥物之使用是伴隨睪丸切除術或LHRH促效劑或拮抗劑之投藥。
- 如請求項18之用途,其中該藥物之使用是伴隨睪丸切除術或LHRH促效劑或拮抗劑之投藥。
- 一種治療有效量之至少一如請求項1至10任一項定義之化合物於製備一藥物的用途,該藥物供用於治療或降低發展為良性前列腺增生之風險。
- 如請求項22之用途,其中該藥物包含治療有效量之至少一選自於由抗雌激素、芳香酶抑制劑、第15型17β-羥基類固醇脫氫酶抑制劑、第5型17β-羥基類固醇脫氫酶抑制劑、5α-還原酶抑制劑、17α-羥化酶/17,20-解離酶抑制劑及雄激素合成酶抑制劑所組成之族群的抑制劑。
- 如請求項23之用途,其中該藥物包含5α-還原酶抑制劑與第15型17β-羥基類固醇脫氫酶抑制劑。
- 一種治療有效量之至少一如請求項1至10任一項定義之化合物於製備一藥物的用途,該藥物供用於治療或降低發展為前列腺癌、良性前列腺增生、痤瘡、脂溢性皮膚炎、多毛症、雄激素性脫髮、雄性禿、多囊卵巢症候群、性早熟或超雄激素症候群之風險。
- 一種治療有效量之至少一如請求項1、2與4至10任一項定義之化合物於製備一藥物上的用途,該藥物供用於治療或降低發展成與雄激素刺激損失有關疾病之風險,該疾病係選自於由下列所組成之群組:肌肉萎縮和無力、皮膚萎縮、骨質流失、骨質疏鬆、貧血、動脈粥樣硬化、心血管疾病、能量損失、幸福感喪失、性慾減退、男性性腺功能低下、肌少症、陽痿,勃起功能障礙、女性性功能障礙、第2型糖尿病或腹部脂肪堆積。
- 一種治療有效量之至少一如請求項1至10任一項定義之化合物於製備一藥物上的用途,該藥物供用於治療或降低發展成(a)痤瘡、脂溢性皮炎、多毛症、雄激素脫髮或雄性禿;或(b)前列腺癌、良性前列腺增生、多囊卵巢症候群、性早熟或超雄激素症候群;或(c)肌肉萎縮和無力、皮膚萎縮、骨質流失、骨質疏鬆、貧血、動脈粥樣硬化、心血管疾病、能量損失、幸福感喪失、性慾減退、男性性腺功能低下、肌少症、陽痿、勃起功能障礙、女性性功能障礙、第2型糖尿病或腹部脂肪堆積之風險。
- 如請求項16至27任一項之用途,其中該化合物係經醫藥上可接受之稀釋劑或載體配製。
- 一種套組,包含第一容器,其含有治療有效量之至少一如請求項1至10任一項定義之化合物,且更包含第二容器,其包含治療有效量之至少一LHRH促效劑或LHRH拮抗劑。
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AU2014366802A1 (en) | 2016-06-09 |
JP2016540819A (ja) | 2016-12-28 |
AR098887A1 (es) | 2016-06-22 |
EA032467B1 (ru) | 2019-05-31 |
CA2933693C (en) | 2018-03-20 |
TW201607931A (zh) | 2016-03-01 |
EA201691267A1 (ru) | 2017-01-30 |
CA2933693A1 (en) | 2015-06-25 |
BR112016014326B1 (pt) | 2022-08-23 |
DK3083590T3 (da) | 2020-03-09 |
US9682960B2 (en) | 2017-06-20 |
BR112016014326A2 (zh) | 2017-08-08 |
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