TW201504238A - 新穎之吲嗪化合物、其製備方法及含彼之醫藥組合物 - Google Patents
新穎之吲嗪化合物、其製備方法及含彼之醫藥組合物 Download PDFInfo
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- TW201504238A TW201504238A TW103123060A TW103123060A TW201504238A TW 201504238 A TW201504238 A TW 201504238A TW 103123060 A TW103123060 A TW 103123060A TW 103123060 A TW103123060 A TW 103123060A TW 201504238 A TW201504238 A TW 201504238A
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Abstract
本發明係關於式(I)化合物,
□其中Ra、Rb、Rc、Rd、T、R3、R4、R5、X、Y及Het如說明書中所定義。
本發明亦關於藥物。
Description
本發明係關於新穎之吲嗪化合物、其製備方法及含彼之醫藥組合物。
本發明之化合物為新穎的且在細胞凋亡及癌學領域中具有極有價值的藥理學特徵。
細胞凋亡或計畫性細胞死亡為對於胚胎發育及維護組織穩定關鍵的生理過程。
凋亡型細胞死亡涉及形態變化,諸如核凝聚、DNA分裂以及諸如卡斯蛋白酶之活化的生化現象,其對於細胞之關鍵結構組分造成損害,因此誘發其分解及死亡。細胞凋亡過程之調節為複雜的且涉及若干細胞內信號傳導路徑之活化或壓制(Cory S.等人,Nature Review Cancer,2002,2,647-656)。
細胞凋亡之失調與某些病變有關。增加之細胞凋亡與神經退化性疾病,諸如帕金森氏病(Parkinson's disease)、阿茲海默氏病(Alzheimer's disease)及局部缺血相關聯。相反,實施細胞凋亡中之缺陷在癌症及其化學抗性的發展、自體免疫疾病、發炎疾病及病毒感染中起顯著作用。因此,不存在細胞凋亡為癌症之表型特徵中之一者(Hanahan D.等人,Cell 2000,100,57-70)。
Bcl-2家族之抗細胞凋亡蛋白質與許多病變相關聯。在許多類型之癌症,諸如結腸直腸癌、乳癌、小細胞肺癌、非小細胞肺癌、膀胱癌、卵巢癌、前列腺癌、慢性淋巴性白血病、濾泡性淋巴瘤、骨髓
瘤、前列腺癌等中描述Bcl-2家族之蛋白質之參與。Bcl-2家族之抗細胞凋亡蛋白質之過度表現與腫瘤形成、對化學治療之抗性及受癌症影響之患者的臨床預後有關。因此,存在對抑制Bcl-2家族之蛋白質之抗細胞凋亡活性之化合物的治療需要。
除新穎之外,本發明之化合物具有促細胞凋亡特性,使得可能將其用於包含細胞凋亡中之缺陷的病變中,諸如治療癌症、自體免疫疾病及免疫系統疾病中。
本發明更尤其係關於式(I)化合物:
其中:
◆X及Y表示碳原子或氮原子,應理解X及Y可不同時表示兩個碳原子或兩個氮原子,
◆基團之Het部分表示由5、6或7個環成員構成的視情況經取代之芳族或非芳族環,除由X或Y表示之氮以外,其可含有1至3個獨立地選自氧、硫及氮之雜原子,應理解所述氮可經表示氫原子、直鏈或分支鏈(C1-C6)烷基或基團-C(O)-O-Alk之基團取代,其中Alk為直鏈或分支鏈(C1-C6)烷基,◆T表示氫原子、視情況經一至三個鹵素原子取代之直鏈或分支鏈(C1-C6)烷基、基團(C2-C4)烷基-NR1R2或基團(C1-C4)烷基-OR6,
◆R1及R2彼此獨立地表示氫原子或直鏈或分支鏈(C1-C6)烷基,或R1及R2與攜有其之氮原子一起形成雜環烷基,◆R3表示直鏈或分支鏈(C1-C6)烷基;直鏈或分支鏈(C2-C6)烯基;直鏈或分支鏈(C2-C6)炔基;環烷基;(C3-C10)環烷基-(C1-C6)烷基,其中烷基部分為直鏈或分支鏈的;雜環烷基;芳基或雜芳基,應理解前述基團之碳原子或其可能的取代基之碳原子中之一或多者可經氘化,◆R4表示芳基、雜芳基、環烷基或直鏈或分支鏈(C1-C6)烷基,應理解前述基團之碳原子或其可能的取代基之碳原子中之一或多者可經氘化,◆R5表示氫或鹵素原子、直鏈或分支鏈(C1-C6)烷基或直鏈或分支鏈(C1-C6)烷氧基,◆R6表示氫原子或直鏈或分支鏈(C1-C6)烷基,◆Ra、Rb、Rc及Rd各獨立於其餘者表示R7、鹵素原子、直鏈或分支鏈(C1-C6)烷氧基、羥基、直鏈或分支鏈(C1-C6)多鹵烷基、三氟甲氧基、-NR7R7'、硝基、R7-CO-(C0-C6)烷基-、R7-CO-NH-(C0-C6)烷基-、NR7R7'-CO-(C0-C6)烷基、NR7R7'-CO-烷基(C0-C6)-O-、R7-SO2-NH-(C0-C6)烷基-、R7-NH-CO-NH-(C0-C6)烷基-、R7-O-CO-NH-(C0-C6)烷基-、雜環烷基,或成對的(Ra,Rb)、(Rb,Rc)或(Rc,Rd)中之一者之取代基連同攜有其之碳原子一起形成由5至7個環成員構成之環,其可含有1至2個選自氧及硫之雜原子,亦應理解上文定義之環之一或多個碳原子可經氘化或經1至3個選自鹵素及直鏈或分支鏈(C1-C6)烷基之基團取代,◆R7及R7'各彼此獨立地表示氫、直鏈或分支鏈(C1-C6)烷基、直鏈或分支鏈(C2-C6)烯基、直鏈或分支鏈(C2-C6)炔基、芳基或雜芳基或R7及R7'連同攜有其之氮原子一起形成由5至7個環成員構成之雜環,應理解:
- 「芳基」意謂苯基、萘基、聯苯基或茚基,- 「雜芳基」意謂任何由5至10個環成員構成之單環基或雙環基,其具有至少一個芳族部分且含有1至4個選自氧、硫及氮(包括四級氮)之雜原子,- 「環烷基」意謂任何含有3至10個環成員之單環或雙環非芳族碳環基,- 「雜環烷基」意謂任何由3至10個環成員構成,且含有1至3個選自氧、硫、SO、SO2及氮之雜原子的單環或雙環非芳族縮合基團或螺基,如此定義之芳基、雜芳基、環烷基及雜環烷基及基團烷基、烯基、炔基及烷氧基可能經1至3個選自視情況經取代之直鏈或分支鏈(C1-C6)烷基、(C3-C6)螺、視情況經取代之直鏈或分支鏈(C1-C6)烷氧基、(C1-C6)烷基-S-、羥基、側氧基(或適當時,N-氧化物)、硝基、氰基、-COOR'、-OCOR'、NR'R"、直鏈或分支鏈(C1-C6)多鹵烷基、三氟甲氧基、(C1-C6)烷基磺醯基、鹵素、視情況經取代之芳基、雜芳基、芳氧基、芳硫基、環烷基、視情況經一或多個鹵素原子或烷基取代之雜環烷基的基團取代,應理解R'及R"各彼此獨立地表示氫原子或視情況經取代之直鏈或分支鏈(C1-C6)烷基,
式(I)中定義的基團之Het部分可能經1至3個選自直鏈或分支鏈(C1-C6)烷基、羥基、直鏈或分支鏈(C1-C6)烷氧基、NR1'R1"及鹵素之基團取代,應理解R1'及R1"如上文提及之基團R'及R"所定義,其對映異構體及非對映異構體及其與醫藥學上可接受之酸或鹼之加成鹽。
在醫藥學上可接受之酸中可提及(但不限於)鹽酸、氫溴酸、硫酸、膦酸、乙酸、三氟乙酸、乳酸、丙酮酸、丙二酸、丁二酸、戊二
酸、反丁烯二酸、酒石酸、順丁烯二酸、檸檬酸、抗壞血酸、甲烷磺酸、樟腦酸、草酸等。
在醫藥學上可接受之鹼中可提及(但不限於)氫氧化鈉、氫氧化鉀、三乙胺、第三丁胺等。
有利地,基團
表示以下基團中之一者:視情況經胺基取代之5,6,7,8-四氫吲嗪;吲嗪;視情況經甲基取代之1,2,3,4-四氫吡咯并[1,2-a]吡嗪;吡咯并[1,2-a]嘧啶。基團5,6,7,8-四氫吲嗪及吲嗪為更尤佳的。
在本發明之較佳化合物中,T表示氫原子、甲基(且更尤其為(R)-甲基)、基團2-(嗎啉-4-基)乙基、3-(嗎啉-4-基)丙基、-CH2-OH、2-胺基乙基、2-(3,3-二氟哌啶-1-基)乙基、2-[(2,2-二氟乙基)胺基]乙基或2-(3-甲氧基氮雜環丁-1-基)乙基。
較佳地,Ra及Rd各表示氫原子,且(Rb,Rc)連同攜有其之碳原子一起形成1,3-二氧雜環戊烷基或1,4-二噁烷基;或Ra、Rc及Rd各表示氫原子且Rb表示氫、鹵素、甲基或甲氧基;或Ra、Rb及Rd各表示氫原子且Rc表示羥基或甲氧基。更佳地,Ra及Rd各表示氫原子,且(Rb,Rc)連同攜有其之碳原子一起形成1,3-二氧雜環戊烷基;或Ra、Rc及Rd各表示氫原子且Rb表示鹵素。
R4基團較佳為4-羥基苯基。
在本發明之較佳化合物中,R3表示直鏈(C1-C6)烷基、芳基或雜芳基,後兩個基團可能經1至3個選自鹵素、直鏈或分支鏈(C1-C6)烷基、直鏈或分支鏈(C1-C6)烷氧基、氰基及雜環烷基-(C1-C6)烷基(其中烷基部分為直鏈或分支鏈的)之基團取代。更佳地,R3表示選自以下之群的雜芳基:1H-吲哚、2,3-二氫-1H-吲哚、1H-吲唑、吡啶、1H-吡咯并[2,3-b]吡啶、1H-吡唑、咪唑并[1,2-a]吡啶、吡唑并[1,5-a]嘧
啶、[1,2,4]三唑并[1,5-a]嘧啶及1H-吡唑并[3,4-b]吡啶,其全部可經直鏈或分支鏈(C1-C6)烷基取代。
本發明之較佳化合物包括於以下之群:- N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-{1-[2-(嗎啉-4-基)乙基]-1H-吲哚-5-基}-5,6,7,8-四氫吲嗪-1-甲醯胺,- N-(4-羥基苯基)-3-(6-{[(3S)-3-[2-(嗎啉-4-基)乙基]-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-苯基-5,6,7,8-四氫吲嗪-1-甲醯胺,- N-{3-氟-4-[2-(嗎啉-4-基)乙氧基]苯基}-N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)吲嗪-1-甲醯胺,- N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-(吡啶-4-基)吲嗪-1-甲醯胺,- N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-(2-甲基吡啶-4-基)吲嗪-1-甲醯胺,- N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-(1-甲基-1H-吡咯并[2,3-b]吡啶-5-基)吲嗪-1-甲醯胺,- N-(4-羥基苯基)-3-(6-{[(3R)-3-[3-(嗎啉-4-基)丙基]-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-苯基-5,6,7,8-四氫吲嗪-1-甲醯胺,- N-(2,6-二甲基吡啶-4-基)-N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)吲嗪-1-甲醯胺,
- N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-(吡啶-4-基)-5,6,7,8-四氫吲嗪-1-甲醯胺,- 3-(5-氯-2-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}苯基)-N-(4-羥基苯基)-N-(1-甲基-1H-吡咯并[2,3-b]吡啶-5-基)吲嗪-1-甲醯胺,- N-(4-羥基苯基)-N-(2-甲氧基吡啶-4-基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)吲嗪-1-甲醯胺,其對映異構體及非對映異構體及其與醫藥學上可接受之酸或鹼之加成鹽。
本發明亦關於一種製備式(I)化合物之方法,該方法特徵在於將式(II)化合物用作起始物質:
其中Ra、Rb、Rc及Rd如關於式(I)所定義,式(II)化合物在鈀催化劑、鹼、膦及式(III)化合物存在下於水性或有機介質中進行赫克反應(Heck reaction):
其中基團X、Y及Het如關於式(I)所定義,以獲得式(IV)化合物:
其中Ra、Rb、Rc、Rd、X、Y及Het如關於式(I)所定義,使式(IV)化合物之醛官能基氧化為羧酸以形成式(V)化合物:
其中Ra、Rb、Rc、Rd、X、Y及Het如關於式(I)所定義,隨後使式(V)化合物與式(VI)化合物經受肽偶合:
其中T及R5如關於式(I)所定義,以產生式(VII)化合物:
其中Ra、Rb、Rc、Rd、T、R5、X、Y及Het如關於式(I)所定義,式(VII)化合物之酯官能基經水解以產生對應羧酸或羧酸鹽,其可轉化成酸衍生物,諸如對應醯氯或酸酐,隨後與胺NHR3R4偶合以產生式(I)化合物,其中R3及R4具有與對於式(I)相同之含義,可根據習知分離技術純化式(I)化合物,其在需要時轉化成其與醫藥學上可接受之酸或鹼之加成鹽,且根據習知分離技術將其視情況分離為其異構體,應理解,在上述方法過程中視為適當的任何時間,可根據合成要求保護合成之試劑或中間物的某些基團(羥基、胺基……)接著進行脫除保護基。
更特定言之,當胺NHR3R4之基團R3或R4中之一者經羥基官能基取代時,後者可在與由式(VII)化合物形成之羧酸,或與其對應酸衍生物的任何偶合之前預先進行保護反應,所得受保護之式(I)化合物隨後進行脫除保護基反應且隨後視情況轉化成其與醫藥學上可接受之酸或鹼之加成鹽中之一者。
式(II)、(III)、(VI)之化合物及胺NHR3R4為市售的或可由熟習此項技術者使用文獻中所述之習知化學反應獲得。
本發明化合物之藥理學研究已顯示其具有促細胞凋亡特性。再
活化癌細胞中之細胞凋亡過程之能力主要在治療癌症、自體免疫疾病及免疫系統疾病中引起治療興趣。
更特定言之,本發明化合物將適用於治療耐化學或耐放射線癌症,及惡性血液病及小細胞肺癌。
在設想之癌症治療中,可提及(但不意味著限於)膀胱癌、腦癌、乳房癌及子宮癌、慢性淋巴性白血病、結腸直腸癌、食道癌及肝癌、淋巴母細胞性白血病、非霍奇金淋巴瘤(non-Hodgkin lymphomas)、黑色素瘤、惡性血液病、骨髓瘤、卵巢癌、非小細胞肺癌、前列腺癌及小細胞肺癌。在非霍奇金淋巴瘤中,可更佳提及濾泡性淋巴瘤、套細胞淋巴瘤、彌漫性大B細胞淋巴瘤、小淋巴球性淋巴瘤及邊緣區B細胞淋巴瘤。
本發明亦關於包含至少一種式(I)化合物以及一或多種醫藥學上可接受之賦形劑之醫藥組合物。
在本發明之醫藥組合物中,更尤其可提及適合於經口、非經腸、經鼻、經皮或透皮、經直腸、經舌、經眼或經呼吸道投與之彼等醫藥組合物,尤其為錠劑或糖衣丸劑、舌下錠、藥囊、藥包、膠囊、直腸給藥劑型(glossette)、口含錠、栓劑、乳膏、軟膏、皮膚凝膠劑及可飲用或可注射安瓿。
劑量根據患者性別、年齡及體重、投與途徑、治療適應症之性質或任何相關治療而變化,且在以一或多次投與形式的0.01mg至1g/24小時範圍內。
此外,本發明亦關於式(I)化合物與選自遺傳毒性劑、有絲分裂毒物、抗代謝物、蛋白酶體抑制劑、激酶抑制劑及抗體之抗癌劑的結合物,且亦關於包含該類型之結合物之醫藥組合物及其在製造用於治療癌症之藥物中之用途。
本發明化合物亦可與放射線療法一起用於治療癌症。
最後,本發明化合物可連接於單株抗體或其片段或連接於可與單株抗體相關或不相關之骨架蛋白質。
必須將抗體片段理解為Fv、scFv、Fab、F(ab')2、F(ab')、scFv-Fc型或雙功能抗體之片段,其一般與其起源之抗體具有相同結合特異性。根據本發明,可藉由諸如藉由酶,諸如胃蛋白酶或番木瓜蛋白酶之分解及/或藉由二硫橋鍵之裂解(藉由化學還原)的方法以抗體為起始物獲得本發明之抗體片段。以另一方式,可藉由熟習此項技術者同樣熟知之基因重組技術或者藉由藉助於例如自動肽合成器,諸如由Applied Biosystems公司供應之彼等自動肽合成器之肽合成等獲得本發明中包含之抗體片段。
可與單株抗體相關或不相關之骨架蛋白質理解為意謂含有或不含免疫球蛋白摺疊且產生類似於單株抗體之結合能力的蛋白質。熟習此項技術者知曉如何選擇蛋白質骨架。更特定言之,已知待選擇之該種骨架應呈現如下若干特徵(Skerra A.,J.Mol.Recogn.,13,2000,167-187):系統發生學上良好保留;具有熟知三維分子組織(諸如晶體學或NMR)之穩定架構;小尺寸;無或僅較低程度之轉譯後修飾;易於產生、表現及純化。該種蛋白質骨架可為(但不限於)選自由以下組成之群的結構:纖維結合蛋白且較佳為第十纖維結合蛋白III型域(FNfn10)、脂質運載蛋白、抗運載蛋白(Skerra A.,J.Biotechnol.,2001,74(4):257-75)、來自葡萄球菌蛋白A、硫氧還原蛋白A或任何具有諸如「錨蛋白重複序列」(Kohl等人,PNAS,2003,第100卷,第4期,1700-1705)、「犰狳重複序列」、「富白胺酸重複序列」或「三十四肽重複序列」之重複域之蛋白的B域之蛋白Z衍生物。亦可提及來自毒素(諸如蠍、昆蟲、植物或軟體動物毒素)或神經元氧化氮合成酶之蛋白抑制劑(PIN)的骨架衍生物。
以下製備及實例說明本發明而不以任何方式對其進行限制。
所有試劑及無水溶劑均自商業來源獲得且不經進一步純化或乾燥即使用。在具有預填充矽膠筒(SiliaSepTM F60(40-63μm,60Å)之ISCO CombiFlash Rf 200i裝置上進行急驟層析。以塗佈有Merck Type 60 F254矽膠之5×10cm板進行薄層層析。藉由CEM Discover® SP裝置進行微波加熱。
本發明化合物藉由在耦接至具有多模式源之6140質量偵測器(m/z範圍150至1000原子質量單位或amu)之Agilent HP1200炔速解析裝置或耦接至具有電噴霧電離源之1946D質量偵測器(m/z範圍150至1000 amu)之Agilent HP1100裝置上進行之高效液相層析耦聯質譜分析(HPLC-MS)來表徵。以下所列之條件及方法對於兩種機器為相同的。
偵測:230、254及270nm下之UV偵測.
注射體積:2μL
移動相:A-水+10mMol/甲酸銨+在約pH 3.5下之0.08%(v/v)甲酸
B-95%乙腈+5% A+0.08%(v/v)甲酸
管柱:Gemini 5μm,C18,30mm×4.6mm(Phenomenex).
溫度:35℃.
梯度:
管柱:Gemini 5μm,C18,30mm×4.6mm(Phenomenex).
溫度:35℃.
梯度:
向置放在0℃下的2-哌啶-甲酸(0.310mmol)於300mL甲酸中之40g外消旋混合物之溶液中逐滴添加200mL(2.15 mmol)乙酸酐。隨後將批料在環境溫度下攪拌隔夜。隨後,將反應混合物冷卻至0℃、藉由添加250mL水水解且在0℃下攪拌半小時,隨後濃縮至乾燥。將藉此獲得之油狀物溶解於200mL甲醇中且接著濃縮至乾燥。獲得產率為98%的呈油狀物之標題產物。將其不經另外純化而直接用於下一步驟中。
1 H NMR:δ(400MHz;dmso-d6;300K):13.0(m,1H OH);8.0-8.05(2s,1H醛);4.9-4.5(2d,1H α至N及COOH);4.1-2.6(m,2H α至N);2.2-1.2(m,6H哌啶)
IR:ν:-OH:2000-3000cm-1酸;ν:>C=O 1703cm-1寬帶
向10g步驟A中獲得之羧酸(63.6mmol)於65mL二氯甲烷中之溶液中依次添加13.4g甲苯磺醯氯(70.4mmol)、11.5mL 2-氯丙烯酸甲酯
(113.5mmol)且接著逐滴添加17.8mL N,N,N-三乙胺(127.2mmol)。隨後將反應混合物回流1小時30分鐘。隨後將其置放在環境溫度下,且隨後添加5mL 2-氯丙烯酸甲酯(48.9mmol)且逐滴添加9mL N,N,N-三乙胺(64mmol)。將批料回流隔夜。
隨後將反應混合物用二氯甲烷稀釋、依次用1N HCl溶液、飽和NaHCO3溶液且接著用飽和NaCl溶液洗滌直至獲得中性pH。隨後將有機相經MgSO4乾燥、過濾、濃縮至乾燥且經矽膠(庚烷/AcOEt梯度)之層析來純化。獲得呈油狀物之標題產物。
1 H NMR:δ(400MHz;CDCl3;300K):6.55-6.40(d,2H,四氫吲嗪);3.91(t,3H甲酯);3.78(s,3H四氫吲嗪);3.08(t,2H,四氫吲嗪);1.95-1.85(m,4H,四氫吲嗪)
IR:ν:>C=O 1692cm-1酯
向步驟B中獲得之6.4g酯(35.7mmol)於12mL N,N-二甲基乙醯胺中之溶液中依次添加12.3g 6-溴-1,3-苯并間二氧雜環戊烯-5-甲醛(53.6mmol)及7g乙酸鉀(71.4mmol),且接著將批料在氬氣下攪拌20分鐘。隨後添加1.3g鈀催化劑PdCl2(PPh3)2(1.8mmol)。隨後將反應混合物在130℃下加熱一小時,隨後添加139μL H2O至其中。在該相同溫度下維持加熱隔夜。使混合物返回至環境溫度且隨後用AcOEt將其稀釋。添加骨炭(2g/g產物)且將批料在環境溫度下攪拌1小時且接著過濾。隨後用水洗滌有機相、經硫酸鎂乾燥且濃縮至乾燥。將藉此獲得之粗產物經矽膠純化(庚烷/ACOEt梯度)。獲得呈油狀物之標題產物。
1 H NMR:δ:(400MHz;dmso-d6;353°K):9.65(s,1H,H醛);7.3-7.15(2s,2H,芳族Hs);6.45(s,1H四氫吲嗪);6.20(s,2H亞甲二氧基);3.70(s,3H甲酯);3.5-4.0(m,2H四氫吲嗪);3.05(m,2H四氫吲
嗪);1.85(m,4H四氫吲嗪)
IR:ν:>C=O 1695cm-1酯;ν:>C=O 1674cm-1
製備含有9.3mL丙酮及8.8mL(80.24mmol)2-甲基-2-丁烯中之步驟C中獲得的3.37g化合物(10.3mmol)之溶液且置放於0℃下。逐滴添加9.3mL含有3.3g NaClO2(36.05mmol)及3.6g Na2PO4(25.75mmol)之混合物的水溶液。隨後在環境溫度下攪拌批料7小時。隨後濃縮反應混合物以移除丙酮。隨後,將隨後獲得之固體濾出、用水洗滌且接著在40℃下於真空中乾燥隔夜。獲得呈固體之標題產物,將其不經另外純化而隨後使用。
1 H NMR:δ(400MHz;dmso-d6;300K):12.10(m,1H,H羧酸);7.40-6.88(2s,2H,芳族Hs);6.20(s,1H,H四氫吲嗪);6.18(s,2H,H亞甲二氧基);3.70(s,3H,甲酯);3.55(t,2H四氫吲嗪);3.00(t,2H四氫吲嗪);1.80(m,4H,H四氫吲嗪)
IR:ν:-OH:3000-2000cm-1酸;ν:>C=O 1686-1676cm-1酯+酸;ν:>C=C<1608cm-1
向置放在0℃下的五氟苯酚於520mL無水醚中之溶液中依次逐份添加49g 1-乙基-3-(3'-二甲胺基丙基)-碳化二亞胺(286mmol)及12mL甲酸(312mmol)。將批料在環境溫度下攪拌2小時。隨後添加32g 3-甲基1,3-哌嗪二甲酸1-第三丁酯(130mmol)及18mL三乙胺(130mmol)溶解於520mL CH2Cl2中之混合物。在環境溫度下攪拌批料隔夜。將反應混合物藉由1N HCl水溶液水解且用CH2Cl2萃取。隨後將有機相合
併且接著用NaHCO3飽和水溶液且接著用飽和NaCl水溶液洗滌直至中性。在經MgSO4乾燥之後,過濾且濃縮至乾燥,將產物藉由經矽膠(石油醚/AcOEt梯度:0%-30%)之層析分離。獲得呈油狀物之標題產物。
IR:ν:C=O:1674-1745cm-1
m/z(C12H20N2O5):272.1(M+);295.121(M+Na)+;567.253(2M+Na)+
向步驟A中獲得之28g化合物(103mmol)於515mL二噁烷中之溶液中添加溶解於100mL H2O中之4.8g LiOH(113mmol)。將批料在環境溫度下攪拌4小時。隨後將反應混合物濃縮至乾燥且接著用乙酸乙酯共蒸發若干次。獲得呈固體之標題產物且直接用於以下環化步驟中。
13 C NMR:δ(500MHz;dmso-d6;300K):46(s,C哌嗪);42-38(m,C哌嗪);58-53(s,C哌嗪);28.5(s,C tBu)
IR:ν:C=O:1650cm-1;2800cm-1
向步驟B中獲得之29g化合物(103mmol)於800mL二氯甲烷中之懸浮液中依次添加24g甲苯磺醯氯(124mmol)、12.6mL 2-氯丙烯酸甲酯(124mmol)且接著添加35mL三乙胺(247mmol)。將批料在回流下攪拌2小時。在冷卻之後,將反應混合物用乙酸乙酯稀釋且將有機相用飽和NaCl溶液洗滌直至中性。在經MgSO4乾燥之後,過濾且濃縮至乾燥,藉由經矽膠(石油醚/AcOEt梯度:0%-20%)之層析分離呈固體之標題產物。
1 H NMR:δ(400MHz;dmso-d6;300K):6.8-6.43(m,2H,H吡咯);4.75-3.75(m,6H,H哌嗪);3.73(s,3H,H COOCH3);1.48(s,9H,
H tBu)
IR:ν:C=O(共軛酯):1712cm-1;C=O(胺基甲酸酯):1677cm-1
該程序係根據製備1之步驟C及D中所述之方案,以2-溴-4-氯苯甲醛替換用於步驟C中之6-溴-1,3-苯并間二氧雜環戊烯-5-甲醛。
該程序係根據製備1之方法,以2-溴-4-氯苯甲醛替換用於步驟C中之6-溴-1,3-苯并間二氧雜環戊烯-5-甲醛。
該程序係根據製備2之步驟A-C中所述之方法。
1 H NMR:δ(400MHz;dmso-d6;300K):6.8-6.43(m,2H,H吡咯);4.75-3.75(m,6H,H哌嗪);3.73(s,3H,H COOCH3);1.48(s,9H,H tBu)
IR:ν:C=O(共軛酯):1712cm-1;C=O(胺基甲酸酯):1677cm-1
該程序係根據製備1之步驟C及D中所述之方案,以7-溴-2,3-二氫-1,4-苯并二氧雜環己烯-6-甲醛替換用於步驟C中之6-溴-1,3-苯并間二氧雜環戊烯-5-甲醛。
向16.2mL吡啶(200mmol)於120毫升乙酸乙酯中之溶液中逐份添加27.8g(200mmol)溴乙酸。隨後將批料在環境溫度下攪拌隔夜。將藉此獲得之沈澱物濾出且接著用冷乙酸乙酯洗滌。在乾燥之後,獲得
呈粉末之標題產物,將其直接用於下一步驟中。
1 H NMR:δ(400MHz;dmso-d6;300K):9.15(d,2H,芳族Hs吡啶);8.7(t,1H,芳族H);8.25(t,2H,芳族H);5.65(s,2H,H CH2COOH)
IR:ν:C=O:1732cm-1;-OH酸:2800cm-1
向6.55g步驟A中獲得之吡啶鎓鹽(30mmol)於240mL甲苯中之懸浮液中依次添加16.7mL丙烯酸甲酯(150mmol)、4.2mL三乙胺(30mmol)且接著逐份添加20.9g MnO2(240mmol)。隨後將批料在90℃下加熱3小時。在冷卻之後,將反應混合物經矽藻土之濾餅過濾且濃縮至乾燥。隨後藉由經矽膠(庚烷/AcOEt梯度:0%-10%)之純化分離呈油狀物之標題產物,其於冷態下結晶。
1 H NMR:δ(300MHz;dmso-d6;300K):8.5(d,1H,H吲嗪);8.05(d,1H,H吲嗪);7.6(s,1H,H吲嗪);7.15(m,2H,H吲嗪);6.85(m,1H,H吲嗪);4.25(q,2H,-C(O)CH2CH3);1.35(t,3H,-C(O)CH2CH3)
IR:ν:C=O酯:1675cm-1;芳族C=C部分:1634cm-1
該程序係根據製備1之步驟C及D中所述之方案,以2-溴-4-氯苯甲醛替換用於步驟C中之6-溴-1,3-苯并間二氧雜環戊烯-5-甲醛。
該程序係根據製備2中所述之方案,以2-溴-4-氟苯甲醛替換用於步驟D中之2-溴-4-氯苯甲醛。
該程序係根據製備2中所述之方案,以6-溴-1,3-苯并間二氧雜環戊烯-5-甲醛替換用於步驟D中之2-溴-4-氯苯甲醛。
將24g 1,4-二氧雜-8-氮雜螺[4.5]癸烷-9甲酸甲酯(111mmol)溶解於80mL乙酸乙酯及80mL二氯甲烷中。添加26g(4-硝基苯基)甲酸酯(155mmol)且將批料在環境溫度下攪拌1小時。將反應混合物蒸發至乾燥且溶解於乙酸乙酯中。隨後將有機相依次用1N NaOH溶液、水且接著用飽和NH4Cl溶液洗滌直至獲得中性pH。隨後將其經硫酸鎂乾燥、過濾且濃縮至乾燥。將藉此獲得之油狀物藉由急驟層析(庚烷/乙酸乙酯梯度)來純化。獲得呈油狀物之標題產物。
1 H NMR:δ(400MHz;dmso-d6;300K):8.15(s,1H,CHO);5.0-4.75(m,1H,三級H);4.3-3.7(m,5H,4H伸乙二氧基+1H脂族哌啶);3.70(s,3H,Me);3.4-2.9(2m,1H,H脂族哌啶);2.3-1.75(m,2H,H脂族哌啶);1.7-1.5(m,2H,H脂族哌啶)
將15.25g步驟A中獲得之化合物(62.7mmol)溶解於160mL二噁烷中。逐滴添加125mL 1M KOH之溶液且將批料在環境溫度下攪拌1小時。隨後添加125mL 1M HCl且用二氯甲烷萃取化合物。將有機相經MgSO4乾燥、過濾且濃縮至乾燥。獲得呈粉末之標題產物。
1 H NMR:δ(400MHz;dmso-d6;300K)13.5-12(m,1H,OH);8.1+8.0(2s,1H,CHO);4.9+4.6(2m,1H,三級H);4.0-3.8(m,4H,伸乙二氧基);4.2+3.7(2ms,1H,H脂族哌啶);3.4+2.9(2m,1H,H脂族哌啶);2.4-1.5(m,4H,H脂族哌啶)
IR:ν:OH:3500-2000cm-1;-C=O(酸+醛):1731+1655cm-1
向13.5g(62.7mmol)步驟B中獲得之酸於380mL二氯甲烷中之溶液中依次添加39.5mL(238.4mmol)三乙胺且接著逐份添加12.5g(65.6mmol)對甲苯磺醯氯及23.7mL(238.4mmol)氯丙烯酸甲酯。將批料在80℃下攪拌18小時。隨後將反應混合物經矽藻土過濾。隨後將濾液用飽和NaHCO3溶液且接著用飽和NH4Cl溶液洗滌。將有機相經MgSO4乾燥、過濾且濃縮至乾燥。將藉此獲得之油狀物藉由急驟層析(庚烷/乙酸乙酯梯度)來純化。獲得呈固體之產物。
1 H NMR:δ(400MHz;dmso-d6;300K)6.70(d,1H,吡咯);6.40(d,1H,吡咯);4.05(t,2H,H脂族,哌啶);4.00(m,4H,伸乙二氧基);3.70(s,3H,甲基);3.15(s,2H,H脂族哌啶);2.05(t,2H,H脂族哌啶)
IR:ν:-C=O(酯):1689cm-1
該程序係根據製備1之步驟C之方法。
該程序係根據製備1之步驟D之方法。
該程序係根據製備5中所述之方案,以6-溴-1,3-苯并間二氧雜環戊烯-5-甲醛替換用於步驟C中之2-溴-4-氯苯甲醛。
該程序係根據製備1中所述之方案,以2-溴-4-甲基苯甲醛替換用於步驟C中之6-溴-1,3-苯并間二氧雜環戊烯-5-甲醛。
該程序係根據製備1中所述之方案,以2-溴-苯甲醛替換用於步驟C中之6-溴-1,3-苯并間二氧雜環戊烯-5-甲醛。
向6.2g 2-嘧啶-2-基乙酸甲酯(40.75mmol)於250mL丙酮中之溶液中依次添加14.04g(167mmol)呈粉末之NaHCO3、13.2mL(203.75mmol)氯乙醛且接著添加3.54g(40.75mmol)溴化鋰。將批料在60℃下加熱24小時。隨後將反應混合物濃縮至乾燥、溶解於乙酸乙酯中、用水洗滌、經MgSO4乾燥、過濾且接著濃縮至乾燥。隨後將藉此獲得之固體藉由經矽膠(AcOEt)之層析來純化。獲得呈油狀物之預期產物。
經驗式:C8H8N2O2
LC/MS:m/z=[M+H]+=177
向3.93g步驟A中獲得之化合物(22.3mmol)於80mL無水二甲基乙醯胺中之溶液中添加7.66g(33.45mmol)6-溴-1,3-苯并間二氧雜環戊烯-5-甲醛及4.4g(44.6mmol)乙酸鉀。將批料在氮氣下脫氣15分鐘。隨後添加1.56g(2.23mmol)PdCl2(PPh3)4催化劑。將反應混合物在惰性氛圍下於130℃下加熱16小時。在乾燥之後,將殘餘物溶解於二氯甲烷中;將批料經矽藻土之濾餅過濾且接著將濾液用水洗滌、經MgSO4乾燥且濃縮至乾燥。隨後將黑色固體在矽膠上層析(CH2Cl2/MeOH 5%)。獲得呈固體之預期產物。
經驗式:C17H12N2O3
LC/MS:m/z=[M+H]+=325
向冷卻至0℃的2.91g(8.97mmol)步驟B中獲得之醛於140mL丙酮中之溶液中添加2-甲基丁烯且接著逐滴添加2.8g(17.94mmol)NaH2PO4.2H2O及2.84g(31.4mmol)NaClO2溶解於30mL水中之混合物。將批料在環境溫度下攪拌4小時。隨後將反應混合物在真空中濃縮以移除丙酮、置放在0℃下且接著藉由逐滴添加5N HCl溶液酸化至pH=2-3。觀測到形成沈澱物,將其濾出、用水且接著用二乙醚洗滌且在真空中乾燥。
1 H NMR:δ(400MHz;dmso-d6;300K):12.7(m,1H,COOH);8.45(d,1H,芳族H,H吡咯并[1,2-a]嘧啶);8.19(d,1H,芳族H,H吡咯并[1,2-a]嘧啶);6.9(dd,1H,芳族H,H吡咯并[1,2-a]嘧啶);7.51(s,1H,芳族H);7.21(s,1H,芳族H);7.07(s,1H,芳族H);6.2(s,2H,脂族Hs,O-CH 2 -O);3.8(s,3H,脂族Hs,COOCH3)
IR:ν-OH-:3300至1800cm-1;ν-CO-:1705cm-1,ν>C=C<:1616cm-1
該程序係根據製備1中所述之方案,以2-溴-4-甲氧基苯甲醛替換用於步驟C中之6-溴-1,3-苯并間二氧雜環戊烯-5-甲醛。
該程序係根據製備1中所述之方案,以2-溴-5-甲氧基苯甲醛替換用於步驟C中之6-溴-1,3-苯并間二氧雜環戊烯-5-甲醛。
該程序係根據製備1之方法,以7-溴-2,3-二氫-1,4-苯并二氧雜環
己烯-6-甲醛替換用於步驟C中之6-溴-1,3-苯并間二氧雜環戊烯-5-甲醛。
該程序係根據製備5之方法,以2-溴-苯甲醛替換用於步驟C中之2-溴-4-氯苯甲醛。
該程序係根據製備5之方法,以2-溴-4-氟苯甲醛替換用於步驟C中之2-溴-4-氯苯甲醛。
該程序係根據製備1之方法,以2-溴-4-氟苯甲醛替換用於步驟C中之6-溴-1,3-苯并間二氧雜環戊烯-5-甲醛。
向30.2g[(3S)-1,2,3,4-四氫異喹啉-3-基]甲醇(185mmol)於750mL二氯甲烷中之溶液中依次添加91.71g甲苯磺醯氯(481mmol)且接著逐滴添加122.3mL N,N,N-三乙胺(740mmol)。隨後將反應混合物在環境溫度下攪拌20小時。隨後將其用二氯甲烷稀釋,依次用1M HCl溶液、飽和NaHCO3溶液且接著用飽和NaCl溶液洗滌直至中性。隨後將有機相經MgSO4乾燥、過濾且濃縮至乾燥。隨後將獲得之固體溶解於最小體積之二氯甲烷中且接著添加環己烷直至形成沈澱物。隨後將此沈澱物濾出且用環己烷洗滌。在乾燥之後,獲得呈晶體之標題產物。
1 H NMR:δ(400MHz;dmso-d6;300K):7.75(d,2H,芳族Hs,鄰O-甲苯磺醯基);7.6(d,2H,芳族Hs,鄰N-甲苯磺醯基);7.5(d,2H,芳族Hs,間O-甲苯磺醯基);7.3(d,2H,芳族Hs,間N-甲苯磺醯基);7.15-6.9(m,4H,芳族Hs,四氫異喹啉);4.4-4.15(dd,2H,脂族Hs,四
氫異喹啉);4.25(m,1H,脂族H,四氫異喹啉);4.0-3.8(2dd,2H,脂族Hs,CH 2 -O-甲苯磺醯基);2.7(2dd,2H,脂族Hs,四氫異喹啉);2.45(s,3H,O-SO2-Ph-CH 3 );2.35(s,3H,N-SO2-Ph-CH 3 )
IR:ν:-SO2:1339-1165cm-1
向8.15g(214.8mmol)LiAlH4於800mL甲基第三丁基醚(MTBE)中之懸浮液中添加溶解於200mL MTBE中之步驟A中獲得的101.2g二甲苯磺醯基化合物(214.8mmol)。隨後將批料在50℃下加熱2小時。使其冷卻且置放在0℃下,且隨後逐滴添加12mL 5N NaOH溶液。將批料在環境溫度下攪拌45分鐘。隨後將藉此獲得之固體濾出且用MTBE且接著用二氯甲烷洗滌。隨後將濾液濃縮至乾燥。隨後獲得呈固體之標題產物。
1 H NMR:δ(400MHz;dmso-d6;300K):7.70(d,2H,芳族Hs,鄰N-甲苯磺醯基);7.38(d,2H,芳族Hs,間N-甲苯磺醯基);7.2-7.0(m,4H,芳族Hs,四氫異喹啉);4.4(m,2H,脂族Hs,四氫異喹啉);4.3(m,1H,脂族H,四氫異喹啉);2.85-2.51(2dd,2H,脂族Hs,四氫異喹啉);2.35(s,3H,N-SO2-Ph-CH 3 );0.90(d,3H,四氫異喹啉-CH 3 )
IR:ν:-SO2:1332-1154cm-1
向31.15g(103.15mmol)步驟B中獲得的單甲苯磺醯基化合物於500mL無水甲醇中之溶液中逐份添加3.92g(161mmol)鎂粉。將批料在超音波存在下攪拌96小時。隨後將反應混合物過濾且將固體用甲醇洗滌若干次。隨後將濾液濃縮至乾燥。在藉由經矽膠(二氯甲烷/EtOH/NH4OH)之管柱層析純化之後,獲得呈油狀物之標題產物。
1 H NMR:δ(400MHz;dmso-d6;300K):7.05(m,4H,芳族Hs,四氫異喹啉);3.90(m,2H,脂族Hs,四氫異喹啉);2.85(m,1H,脂族H,
四氫異喹啉);2.68-2.4(2dd,2H,脂族Hs,四氫異喹啉);1.12(d,3H,四氫異喹啉-CH 3 );2.9-2.3(m,寬峰,1H,HN(四氫異喹啉))
IR:ν:-NH:3248cm-1
向14.3g(97.20mmol)步驟C中獲得之化合物於20mL無水乙醇中之溶液中逐滴添加100mL HCl於醚中之1M溶液。將批料在環境溫度下攪拌1小時且接著過濾。將藉此獲得之晶體用乙基醚洗滌。在乾燥之後,獲得呈晶體之標題產物。
1 H NMR:δ(400MHz;dmso-d6;300K):9.57(m,寬峰,2H,NH 2 +(四氫異喹啉);7.22(m,4H,芳族Hs,四氫異喹啉);4.27(s,2H,脂族Hs,四氫異喹啉);3.52(m,1H,脂族H,四氫異喹啉);3.03--2.85(2dd,2H,脂族Hs,四氫異喹啉);1.39(d,3H,四氫異喹啉-CH 3 )
IR:ν:-NH2 +:3000-2300cm-1;ν:芳族-CH:766cm-1
向3g(10.30mmol)[(3S)-2-(第三丁氧基羰基)-1,2,3,4-四氫異喹啉-3-基]乙酸於100mL二氯甲烷中之溶液中逐滴添加1.10mL(11.32mmol)嗎啉且再逐滴添加4.3mL(30.9mmol)三乙胺、2.20g(12.40mmol)1,2-二氯甲烷及1.70g(1.68mmol)羥基苯并三唑。將批料在環境溫度下攪拌15小時。隨後將反應混合物用二氯甲烷稀釋且依次用1M HCl溶液、飽和NaHCO3溶液且接著用飽和NaCl溶液洗滌直至中性。隨後將有機相經MgSO4乾燥、過濾且濃縮至乾燥。在藉由經矽膠(二氯甲烷/MeOH)之管柱層析純化之後,獲得呈油狀物之標題產物。
1 H NMR:δ(400MHz;dmso-d6;300K):7.20-7.10(m,4H,芳族Hs,四氫異喹啉);4.70(m,1H,脂族Hs,CH四氫異喹啉);4.75-4.20
(2m,2H,脂族Hs,CH2 α至N四氫異喹啉);3.60(m,8H,脂族Hs,嗎啉);3.00及2.70(2dd,2H,脂族H,四氫異喹啉);2.50-2.20(2d,2H,脂族Hs,CH2CO);1.40(s,9H,tBu)
IR:ν:C=O:1687;1625cm-1
向2.88g(7.18mmol)步驟A中獲得之化合物於16mL二氯甲烷中之溶液中逐滴添加80mL(80mmol)HCl於醚中之1M溶液。將批料在環境溫度下攪拌15小時且接著將懸浮液過濾且用醚洗滌沈澱物。在乾燥之後,獲得呈固體之標題產物。
1 H NMR:δ(400MHz;dmso-d6;300K):9.80-9.50(m,2H,NH2 +);7.30-7.10(m,4H,芳族Hs,四氫異喹啉);4.30(m,2H,脂族Hs,CH2 α至N四氫異喹啉);3.80(m,1H,脂族Hs,CH四氫異喹啉);3.70-3.40(2m,8H,脂族Hs,嗎啉);3.15及2.8(m,4H,脂族H,CH2四氫異喹啉及CH2CO)
IR:ν:-NH2 +:2800-1900cm-1;ν:C=O:1620cm-1
製備步驟B中獲得的2.2g(7.44mmol)化合物於22mL MTBE及5mL二氯甲烷中之溶液。在0℃下之冰浴中冷卻之後,向其中逐滴添加15mL(15mmol)四氫呋喃中之1M LiAlH4溶液。隨後在環境溫度下攪拌批料6小時。將其置放在0℃下,且隨後逐滴添加1mL 5N NaOH溶液。將批料在環境溫度下攪拌45分鐘。隨後將固體濾出且用MTBE且接著用二氯甲烷洗滌且將濾液濃縮至乾燥。將藉此獲得之油狀物用二氯甲烷稀釋且逐滴添加6.3mL HCl於醚中之1M溶液。將批料在環境溫度下攪拌1小時且接著過濾。將藉此獲得之晶體用乙基醚洗滌。在乾燥之後,獲得呈固體之標題產物。
1 H NMR:δ(400MHz;dmso-d6;300K):11.35+9.80(2m,2H,
NH2 +);10.00(m,H,NH+);7.20(m,4H,芳族Hs,四氫異喹啉);4.30(s,2H,脂族Hs,CH2 α至N四氫異喹啉);4.00+3.85(2m,4H,脂族Hs,CH2 α至N嗎啉);3.70(m,1H,脂族Hs,CH四氫異喹啉);3.55-3.30(m,4H,脂族Hs,CH α至O嗎啉及CH2-嗎啉);3.15(dd,1H,脂族H,CH2四氫異喹啉);3.10(m,2H,脂族H,CH α至O嗎啉);2.90(dd,1H,脂族H,CH2四氫異喹啉);2.30+2.15(2m,2H,脂族H,CH2-四氫異喹啉)
IR:ν:NH+/-NH2 +:在3500與2250cm-1之間;ν:C=C:弱1593cm-1;ν:芳族C-H:765cm-1
基於來自文獻(Jinlong Jiang等人Bioorganic & Medicinal Chemistry Letters,14,1795,2004)之方案以(3S)-2-[(苯甲氧基)羰基]-1,2,3,4-四氫異喹啉-3-甲酸為起始物獲得標題化合物。
向置放在0℃下的10.6g步驟A之化合物(35.6mmol)於350mL無水CH2Cl2中之溶液中依次添加10.1mL三乙胺(71.2mmol)且接著逐滴添加3.1mL甲烷磺醯氯(39mmol)。隨後將反應混合物在環境溫度下攪拌2小時。隨後藉由緩慢添加水進行水解。將產物藉由CH2Cl2萃取若干次。隨後將有機相合併且依次用1N HCl溶液、飽和NaCl溶液、飽和NaHCO3溶液及飽和NaCl溶液洗滌直至中性。隨後將其經MgSO4乾燥且濃縮至乾燥。在藉由經矽膠(石油醚/AcOEt梯度)之層析純化之後,獲得呈發泡體之預期產物。
LC/MS:m/z=(M+H)+=375
向15.4g步驟B中獲得之化合物(41.02mmol)於250mL無水DMSO
中之溶液中添加22g(449mmol)氰化鈉。隨後將批料在60℃下加熱12小時。使其冷卻且接著藉由添加乙酸乙酯來稀釋反應混合物。隨後藉由飽和NaHCO3溶液進行水解。在用乙酸乙酯再萃取兩次之後,將有機相合併、用H2O洗滌、經MgSO4乾燥且濃縮至乾燥。在藉由經矽膠(己烷/AcOEt 7/3)之層析純化之後,獲得呈油狀物之預期產物。
LC/MS:m/z=[M+H]+=307.1
向置放在0℃下的15.4g步驟C中獲得之化合物(50.3mmol)於300mL無水THF中之溶液中逐滴添加BH3-THF之1N溶液。使反應混合物逐漸返回至環境溫度且接著將批料攪拌14小時。隨後藉由緩慢添加飽和NH4Cl溶液使反應混合物水解。在用乙酸乙酯萃取兩次之後,將有機相合併且經MgSO4乾燥。在濃縮至乾燥之後,獲得呈發泡體之預期產物,將其不經純化即直接用於下一保護步驟中。
向15.6g步驟D中獲得之化合物(50.3mmol)於670mL CH2Cl2中之溶液中依次逐份添加13.2g(60.36mmol)Boc2O、14mL三乙胺(100.6mmol)及催化量之DMAP。將批料在環境溫度下攪拌5小時。隨後用水將反應混合物水解且用CH2Cl2萃取兩次。將有機相合併、用水洗滌且經MgSO4乾燥。在濃縮至乾燥且藉由經矽膠(庚烷/AcOEt梯度)之層析純化之後,獲得呈油狀物之預期產物。
LC/MS:m/z=(M+H)+=411
向10.4g步驟E中獲得之化合物(25.5mmol)於210mL無水MeOH中之溶液中添加2.71g(2.55mmol)Pd/C 10%。將批料脫氣30分鐘且隨後在氫氣氛圍下攪拌16小時。隨後將反應混合物過濾且濃縮至乾燥。
獲得呈固體之預期產物,將其溶解於戊烷/Et2O(90/10)之混合物中、濕磨且過濾。在乾燥之後,獲得呈固體之產物。
1 H NMR:δ(400MHz;dmso-d6;300K):7.1-6.98(m,4H,芳族Hs,四氫異喹啉);6.83(m,1H,CH2 NHBoc);3.85(s,2H,脂族Hs,四氫異喹啉);3.09(q,2H,CH 2 NHBoc);2.73(m,1H,脂族Hs,四氫異喹啉);2.70及2.39(2m,2H,脂族Hs,四氫異喹啉);1.63(m,2H,脂族Hs);1.38(s,9H,NHCOOtBu)
IR:ν:>NH:3378,-3201cm-1(胺,醯胺);ν:>C=O:1683cm-1(醯胺);ν:>NH:1524cm-1(醯胺);ν:>C=O:1168cm-1
LC/MS:m/z=[M+H]+=277
該程序與製備1'之步驟A之程序相同。
向1g NaH(60%)(25.08mmol)於30mL MTBE中之懸浮液中逐滴添加5g 3-N-嗎啉基-3-側氧基丙酸第三丁酯(21.81mmol)於20mL無水MTBE中之溶液。將此懸浮液在環境溫度下攪拌1小時且接著添加呈粉末的步驟A中獲得之化合物。將批料在60℃下攪拌30小時。添加100mL飽和氯化銨溶液。用二氯甲烷萃取所得溶液。隨後將有機相經MgSO4乾燥、過濾且濃縮至乾燥。在藉由經矽膠(二氯甲烷/MeOH)之管柱層析純化之後,獲得呈油狀物之預期產物。
1 H NMR:(500MHz,dmso-d6)δ ppm:7.63/7.59(2d,2 H),7.3/7.26(2d,2 H),7.13(m,2 H),7.09/6.97(2t,2 H),4.64/4.55/4.36/4.28(2AB,2 H),4.25/4.11(2m,1 H),3.81(m,1 H),
3.73-3.48(m,4 H),3.57-3.32(m,4 H),2.51(m,2 H),2.32/2.31(2s,3 H),1.88/1.79(2m,2 H),1.39/1.38(2s,9 H)
IR(ATR)cm-1:ν:>C=O:1731(酯);ν:>C=O:1644(醯胺);ν:-SO2:1334-1156;ν:>C-O-C<:1115;γ:>CH-Ar:815-746-709
向9.5g(17.97mmol)步驟B中獲得之化合物於40mL二噁烷中之溶液中逐滴添加20mL HCl於二噁烷中之4M溶液。將批料在環境溫度下攪拌48小時且接著將溶液濃縮至乾燥。在乾燥之後,獲得呈油狀物之預期產物。
1 H NMR:(400MHz,dmso-d6)δ ppm:12.75(m,1 H),7.6(2*d,2 H),7.3(2*d,2 H),7.1/6.95(2*m,4 H),4.7-4.2(d,2 H),4.25/4.12(2*m,1 H),3.9-3.3(m,9 H),2.55(d,2 H),2.3(2*s,3 H),1.8(t,2 H)
IR(ATR)cm-1:ν:-OH:3500 à 2000;ν:>C=O:1727(酸);ν:>C=O:1634(醯胺);ν:-SO2:1330-1155
向7.80g(16.51mmol)步驟C中獲得之化合物於100mL DMSO中之溶液中添加1.16g(19.83mmol)固體氯化鈉且接著逐滴添加5mL水。將批料在130℃下攪拌1小時且接著將溶液濃縮至¾。隨後將反應混合物用二氯甲烷稀釋且依次用飽和氯化鋰溶液且接著用飽和NaCl溶液洗滌。隨後將有機相經MgSO4乾燥、過濾且濃縮至乾燥。在藉由經矽膠(環己烷/乙酸乙酯)之管柱層析純化之後,獲得呈油狀物之預期產物。
1 H NMR:(400MHz,dmso-d6)δ ppm:7.65(d,2 H),7.3(d,2 H),7.15/7(2 m,4 H),4.6(d,1 H),4.25(d,1 H),4.2(m,1 H),3.5(m,4 H),
3.4(2 m,4 H),2.6(2 dd,2 H),2.35(s,3 H),2.3(m,2 H),1.5(quad.,2 H)
IR(ATR)cm-1:ν:>C=O:1639;ν:-SO2:1331-1156;γ:>CH-Ar:815-675
經5分鐘向6.0g(14.0mmol)步驟D中獲得之化合物於60mL MTBE及14mL二氯甲烷中之溶液中逐份添加1.06g(28mmol)LAH。將批料在環境溫度下攪拌15小時。逐滴添加1.5mL水且進行攪拌15分鐘。隨後逐滴添加1.5mL 5M氫氧化鈉溶液且進行攪拌15分鐘。隨後將反應混合物用MTBE及二氯甲烷稀釋。隨後將懸浮液過濾且將沈澱物用MTBE及二氯甲烷洗滌。隨後將有機相經MgSO4乾燥、過濾且濃縮至乾燥。在藉由經矽膠(二氯甲烷/EtOH/NH4OH)之管柱層析純化之後,獲得呈油狀物之預期產物。
1 H NMR:(400MHz,dmso-d6)δ ppm:7.68(d,2 H),7.32(d,2 H),7.1(massif,4 H),4.65/4.23(AB,2 H),4.2(m,1 H),3.55(t,4 H),2.7/2.6(ABx,2 H),2.35(s,3 H),2.25(t,4 H),2.2(t,2 H),1.4/1.3(2m,4 H).
IR(ATR)cm-1:ν:-SO2:1333-1158
向1.50g(3.62mmol)步驟E中獲得之化合物於20mL無水甲醇中之溶液中逐份添加2.0g(82.3mmol)鎂粉。將批料在超音波存在下攪拌96小時。隨後將反應混合物過濾,將固體用甲醇洗滌若干次,且將濾液濃縮至乾燥。在藉由經矽膠(二氯甲烷/EtOH/NH4OH)之管柱層析純化之後,獲得呈油狀物之預期產物。
1 H NMR:(400MHz,dmso-d6)δ ppm:7.3(d,2 H),7.1(t,2 H),
7.1(d+t,3 H),7(d,2 H),3.9(s,2 H),3.55(t,4 H),2.75(m,1 H),2.72/2.45(dd,2 H),2.35(t,4 H),2.25(t,2 H),1.6(m,2 H),1.45(m,2 H)
IR(ATR)cm-1:ν:>NH2+/NH+:3500-2300;ν:>C-O-C<:1115
經驗式:C16H24N2O
[M+H]+,計算值:261.1961
[M+H]+,量測值:261.1959
該程序係根據製備2'之方法,以3,3-二氟-1-哌啶替換用於步驟A中之嗎啉。
1 H NMR:δ(400MHz;dmso-d6;300K):11.3(m,1H,NH +);10.2-9.8(m,2H,NH 2 +);7.25(m,4H,芳族Hs,四氫異喹啉);4.3(寬峰s,2H,脂族Hs,CH四氫異喹啉);4.0-3.3(m,7H,脂族Hs);3.15-2.95(dd,2H,脂族Hs,CH四氫異喹啉);2.4-1.9(m,6H,脂族Hs,H3,3-二氟-1-哌啶)
IR:ν:NH+/NH2 +:在300與2500cm-1之間;ν:C-F:1204cm-1
該程序係根據製備2'之方法,以3-甲氧基氮雜環丁烷替換用於步驟A中之嗎啉。
1 H NMR:δ(400MHz;dmso-d6;300K):11.3(m,1H,NH+);10.00(m,2H,NH2 +);7.20(m,4H,芳族Hs,四氫異喹啉);4.4(m,1H,脂族H,3-甲氧基氮雜環丁烷);4.30(s,2H,脂族Hs,四氫異喹啉);4.2-3.45(m,4H,3-甲氧基氮雜環丁烷);4.2-3.6(m,3H,脂族Hs);3.1及2.95
(dd,2H,脂族Hs);3.25(s,3H,OCH 3 )
該程序係根據製備1'之方法,以[(3R)-1,2,3,4-四氫異喹啉-3-基]甲醇替換用於步驟A中之[(3S)-1,2,3,4-四氫異喹啉-3-基]甲醇。
根據文獻(S.Knaggs等人,有機& Biomolecular Chemistry,3(21),4002-4010;2005)中所述之方案在咪唑及第三丁基(二甲基)矽烷基氯存在下以THF中之4-胺基苯酚為起始物獲得標題化合物。
1 H NMR:δ(400MHz;dmso-d6;300K):6.45-6.55(dd,4H,芳族Hs);4.60(m,2H,NH 2 -Ph);0.90(s,9H,Si(CH2)2CH(CH 3 )2);0.10(s,6H,Si(CH 2 )2CH(CH3)2)
IR:ν:-NH2 +:3300-3400cm-1
向30.8g(0.137mol)步驟A之化合物於525mL無水甲苯中之溶液中依次添加29.8g第三丁酸鈉(0.310mol)、4.55g Pd2(dba)3(亦稱為參(二苯亞甲基丙酮)二鈀(0))(4.96mmol)、4.81g 2-二-第三丁基膦基-2',4',6'三-異丙基-1,1'-聯苯(9.91mmol)及12.8mL 4-溴-1-甲基-1H-吡唑(0.124mol)。將批料在氬氣下脫氣30分鐘且接著回流3小時。使其冷卻。將反應混合物濃縮至乾燥且接著溶解於二氯甲烷中、經矽藻土過濾且接著再次濃縮至乾燥。隨後將殘餘物藉由經矽膠(梯度CH2Cl2/AcOEt)之層析純化以提供呈固體之預期產物。
1 H NMR:δ(400MHz;dmso-d6;300K):7.55(s,1H,吡唑);7.23(s,1H,吡唑);7.18(寬峰s,1H,NH 2 -Ph);6.64(m,4H,芳族Hs);3.77(s,3H,CH 3 -吡唑);0.90(s,9H,Si(CH2)2CH(CH 3 )2);0.12(s,6H,Si
(CH 2 )2CH(CH3)2)
IR:ν-NH+:3275cm-1;ν Ar及C=N:1577及1502cm-1;ν-Si-C-:1236cm-1;ν-Si-O-:898cm-1;ν-Si-C-:828,774cm-1
該程序係根據製備1"之方法,以5-溴-1-甲基-1H-吲哚替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
向置放在0℃下的NaH(4.5g;112mmol)於無水THF(300mL)中之懸浮液中逐份添加5-溴-1H-吲哚(10.4g;51mmol)。在於0℃下攪拌20分鐘之後,經1小時逐份添加4-(2-氯乙基)嗎啉鹽酸鹽(10.4g;56mmol)。在環境溫度下攪拌隔夜之後,將反應混合物置放在80℃下5小時。隨後將其倒入水性碳酸氫鈉及二氯甲烷之混合物。用二氯甲烷萃取水相。將有機相經MgSO4乾燥且濃縮至乾燥,且將殘餘物藉由經矽膠(CH2Cl2/MeOH梯度)之層析純化以提供呈油狀物之預期產物。
1 H NMR:δ(400MHz;CDCl3;300K):7.75(d,1H);7.30(dd,1H);7.20(d,1H);7.15(d,1H);6.40(d,1H);4.20(t,2H);3.70(m,4H);2.75(t,2H);2.45(m,4H)
該程序係根據製備1"之方法,以步驟A中獲得之化合物替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
1 H NMR:δ(400MHz;dmso-d6;300K):7.35(d,1H);7.15(s,1H);6.85(d,3H);6.70(d,2H);7.30(d,1H);6.25(d,1H),4.20(t,2H);3.55
(m,4H);2.65(t,2H);2.45(m,4H);1.45(s,9H),0.15(s,6H)
該程序係根據製備2"之方法,以5-溴-2,3-二氫-1H-吲哚替換用於步驟A中之5-溴吲哚。
該程序係根據製備1"之方法,以1-溴-4-氟苯替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
該程序係根據製備1"之方法,以4-溴-2-氟-1-甲苯替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
該程序係根據製備1"之方法,以5-溴-1-甲基-1H-吲唑替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
在環境溫度下向12g 4-苯胺苯酚(64.7mmol)於200mL乙腈中之溶液中添加6.7g咪唑(97.05mmol)及11.7g第三丁基-(氯基)二甲基矽烷(77.64mmol)。將批料在70℃下攪拌4小時。隨後將反應混合物倒入至水中且用醚萃取。隨後將有機相經硫酸鎂乾燥,隨後過濾且蒸發至乾燥。隨後將藉此獲得之粗產物藉由經矽膠(石油醚/二氯甲烷梯度)之層析純化。獲得呈粉末之標題產物。
1 H NMR:δ(400MHz;dmso-d6;300K):7.84(s,1H NH);7.17(t,2H苯胺);6.98(d,2H苯氧基);6.94(d,2H苯胺);6.76(d,2H苯氧基);6.72(t,1H苯胺);0.95(s,9H第三丁基);0.15(s,6H二甲基)
IR:ν:>NH:3403cm-1;>Ar:1597cm-1
向4-羥基-N-苯基-苯胺(30g;162mmol)於乙腈(400mL)中之溶液中添加58g Cs2CO3(178mmol)且在環境溫度下進行攪拌15分鐘。隨後逐滴添加溴甲苯(22.5mL;178mmol)且接著將反應混合物回流4小時。在過濾且用乙腈沖洗之後,將濾液濃縮且經矽膠(石油醚/AcOEt梯度)層析。隨後獲得呈無色固體之標題產物。
該程序係根據製備3"之方法,以4-溴-2-氟苯酚替換用於步驟A中之5-溴-1H-吲哚。
1 H NMR:δ(400MHz;dmso-d6;300K):7.75(d,1H);7(dd,1H);6.9(d,2H);6.75(m,3H);6.7(ddd,1H);4.05(t,2H);3.6(t,4H);2.65(t,2H);2.45(t,4H);0.95(s,9H);0.2(s,6H)
該程序係根據製備1"之方法,以4-溴吡啶替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν-NH-:3200及2500cm-1;ν-Si-O-:902cm-1;ν-Si-C-:820cm-1
該程序係根據製備1"之方法,以3-溴苯甲腈替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
該程序係根據製備1"之方法,以1-溴-3-氟苯替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
該程序係根據製備1"之方法,以4-溴-1,2-二氟苯替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
向4-溴苯甲醛(500mg;2.7mmol)於12mL二氯甲烷中之溶液中以所述順序添加3,3-二氟哌啶鹽酸鹽(470mg;3mmol)、三乙醯氧基硼氫化鈉(860mg;4mmol)及乙酸(0.17mL;3mmol)。在環境溫度下攪拌1小時之後,將反應混合物倒入水性碳酸氫鈉及二氯甲烷之混合物。用二氯甲烷萃取水相。將有機相經MgSO4乾燥、濃縮至乾燥且將殘餘物藉由經矽膠(CH2Cl2/MeOH梯度)之層析純化以提供呈油狀物之預期產物。
1 H NMR:δ(400MHz;dmso-d6;300K):7.55(dd,2H);7.25(dd,2H);3.55(s,2H);2.7(t,2H);2.35(t,2H);1.85(m,2H);1.65(m,2H)
該程序係根據製備1"之方法,以1-[(4-溴苯基)甲基]-3,3-二氟-哌啶替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
該程序係根據製備1"之方法,以6-溴-喹啉替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν-NH-:3300cm-1
該程序係根據製備1"之方法,以4-溴-2-甲基-吡啶替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν-NH-:3200及3100cm-1
該程序係根據製備1"之方法,以5-溴-1-甲基-1H-吡咯并[2,3-b]吡啶(根據來自文獻:Heterocycles,60(4),865,2003之方案獲得)替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν:-NH-:3278cm-1;ν:芳族-C=C-部分:1605cm-1
該程序係根據製備1"之方法,以3-溴-吡啶替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
向4-溴苯乙酸(4g;18.6mmol)及3,3-二氟哌啶鹽酸鹽(2.5g;20.4mmol)於二氯甲烷(190mL)中之溶液中添加EDC(3.8g;22.3mmol)、HOBt(3g;22.3mmol)及三乙胺(1.3mL;593mmol)。將反應混合物在環境溫度下攪拌17小時且隨後倒入水性碳酸氫鈉及乙酸乙酯之混合物。水相以乙酸乙酯萃取。將有機相用0.1N鹽酸、水及鹽水洗滌,隨後經MgSO4乾燥且濃縮至乾燥。將殘餘物藉由經矽膠(石油醚/乙酸乙酯梯度)之層析純化以提供呈固體之預期產物。
1 H NMR:δ(400MHz;dmso-d6;300K):7.5(d,2H);7.2(d,2H);3.8(t,2H);3.7(s,3H);3.5(t,2H);2(m,2H);1.6(m,2H)
向步驟A之化合物(4.6g;14.5mmol)於無水THF(145mL)中之溶液中添加硼烷二甲基硫於THF(14.5mL;14.5mmol)中之1M溶液。將反應混合物經3小時在80℃下加熱且接著於減壓下蒸發溶劑。將殘餘
物用甲醇(50mL)且接著用5N HCl(5.8mL)處理。在環境溫度下攪拌隔夜及回流3小時之後,將反應混合物之pH用飽和碳酸氫鈉溶液調節至8;隨後用二氯甲烷萃取水相。將有機相經MgSO4乾燥且濃縮至乾燥,且將殘餘物藉由經矽膠(CH2Cl2/MeOH梯度)之層析純化以提供呈油狀物之預期產物。
1 H NMR:δ(400MHz;dmso-d6;300K):7.45(d,2H);7.20(d,2H);2.71(m,2H);2.69(t,2H);2.58(dd,2H);2.45(dd,2H);1.86(m,2H);1.63(m,2H)
該程序係根據製備1"之方法,以步驟B之化合物替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
1 H NMR:δ(400MHz;dmso-d6;300K):7.7(s,1H);7.45(d,2H);7.39(t,2H);7.31(t,1H);7.0(m,4H);6.9(d,2H);6.81(d,2H);5.05(s,2H);2.7(t,2H);2.6(t,2H);2.5(t,2H);2.45(t,2H);1.89(m,2H);1.68(m,2H)
該程序係根據製備19"之方法,以3,3-二氟吡咯啶鹽酸鹽替換步驟A中之3,3-二氟哌啶鹽酸鹽。
1 H NMR:δ(400MHz;dmso-d6;300K):7.7(s,1H);7.45(d,2H);7.35(t,2H);7.34(t,1H);7.05-6.85(m,8H);5.05(s,2H);2.9(t,2H);2.75-2.25(m,8H)
該程序係根據製備1"之方法,以4-溴-2,6-二甲基吡啶替換用於步
驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν:-NH-:3300及2700cm-1;ν:-Si-O-:900cm-1;ν:-Si-C-:823cm-1
該程序係根據製備2"之方法,以4-溴-1H-吡唑替換用於步驟A中之5-溴吲哚。
1 H NMR:δ(400MHz;dmso-d6;300K):7.61(s,1H);7.25(s,1H);7.18(s,1H);6.65(m,4H);4.15(t,2H);3.55(t,4H);2.7(t,2H);2.4(t,4H);0.95(s,9H);0.15(s,6h)
該程序係根據製備1"之方法,以4-溴-3-氟-吡啶替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν-NH-:3200及3000cm-1;ν-Si-O-:900cm-1;ν-Si-C-:820cm-1
該程序係根據製備1"之方法,以7-溴吡啶[1,2-a]吡啶(根據文獻:WO 2008124323 A1中之方案以4-溴吡啶-2-胺為起始物製備)替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν-NH-:3300-3000cm-1;ν-C=N-:1652cm-1;ν-C=C-:1610cm-1;
ν-Si-C-:1236cm-1;ν-Si-O-:898cm-1;ν-Si-C-:828,774cm-1
該程序係根據製備1"之方法,以7-溴-2-甲基-咪唑并[1,2-a]吡啶
(根據文獻:A.J.Helliot等人J.Heterocyclic Chemistry 19,1437,1982中之方案以4-溴吡啶-2-胺為起始物製備)替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν-NH-:3300-3000cm-1;ν-C=N-:1652cm-1;ν-C=C-:1610cm-1;
ν-Si-C-:1236cm-1;ν-Si-O-:898cm-1;ν-Si-C-:828,774cm-1
該程序係根據製備1"之方法,以3-溴-6-甲基-吡啶替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν-NH-:3251cm-1;ν芳族-C=C-部分:1605cm-1
該程序係根據製備1"之方法,以3-溴-5-氟-吡啶替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν-NH-:3400-3000cm-1;ν-C-F-:1245cm-1
該程序係根據製備1"之方法,以4-溴-2-甲氧基-吡啶替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν-NH-:3200及3000cm-1;ν芳族-C=C-部分:1618,1601cm-1
該程序係根據製備1"之方法,以4-溴-2-(丙-2-基)吡啶替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν-NH-:3300及3100cm-1
該程序係根據製備1"之方法,以6-溴吡唑[1,5-a]嘧啶替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν-NH-:3272cm-1;ν-C=N-:1634cm-1;ν-C=C-:1616cm-1
該程序係根據製備1"之方法,以根據文獻(WO 2011015343)以4H-1,2,4-三唑-3-胺及2-溴丙二醛為起始物製備之6-溴-3,3a-二氫[1,2,4]三唑并[1,5-a]-嘧啶替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν-NH-:3244cm-1
該程序係根據製備1"之方法,以根據文獻(WO 2009117269)以4-溴吡啶為起始物製備之1-氧化4-溴吡啶替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
IR:ν-NH-:3246cm-1;ν芳族-C=C-部分:1618cm-1
經驗式:C17H24N2O2Si
[M]+.量測之m/z:316
[M-O]+.量測之m/z:300
[M-C4H9]+.量測之m/z:259
該程序係根據製備1"之方法,以根據文獻以4-溴吡啶為起始物製備之氯化4-溴-1-甲基-吡啶-1-鎓替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
該程序係根據製備1"之方法,以根據文獻(WO 2006052568)製備之5-溴-1-甲基-吡唑并[3,4-b]吡啶替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
1 H NMR(400MHz,dmso-d6)δ ppm:8.33(d,1 H),7.94(bs,1 H),7.92(s,1 H),7.71(d,1 H),6.95(d,2 H),6.76(d,2 H),4.01(s,3 H),0.95(s,9 H),0.17(s,6 H)
IR(ATR)cm -1 :3290 ν>OH;1503 ν Ar;1249 γ-Si-CH3
該程序係根據製備1"之方法,以根據文獻(WO 2011015343及WO2011049917)製備之6-溴-3-甲基-吡唑并[1,5-a]嘧啶替換用於步驟B中之4-溴-1-甲基-1H-吡唑。
1 H NMR(400MHz,dmso-d6)δ ppm:8.49(d,1 H),8.4(d,1 H),7.98(m,1 H),7.87(s,1 H),7(d,2 H),6.81(d,2 H),2.29(s,3 H),0.98(s,9 H),0.2(s,6 H)
IR(ATR)cm -1 :3257 ν>NH
根據文獻(Surry D.S.等人,Chemical Science,2011,2,27-50,Charles M.D.等人,Organic Letters,2005,7,3965-3968)中所述之方法獲得胺NHR3R4,其中R3及R4各彼此獨立地表示芳基或雜芳基。保護製備8"中所述之4-苯胺苯酚之羥基官能基之反應可在各種具有一或多個羥基官能基之二級胺NHR3R4(如上文所定義)可商購時應用於該等二級胺。或者,可以保護形式,亦即以羥基官能基已經預先保護之試劑為起始物直接合成具有至少一個羥基取代基之二級胺。在保護基中,第三丁基(二甲基)矽烷氧基及苯甲氧基尤佳。
在用於合成本發明化合物的具有羥基取代基之胺NHR3R4中可提及:4-(4-甲苯胺基)酚、4-(4-氯苯胺基)酚、4-(3-氟-4-甲基苯胺基)酚、4-[4-(三氟甲氧基)苯胺基]-酚、4-[4-羥基苯胺基]酚、{4-[(1-甲基-1H-吲哚-6-基)胺基]苯基}甲醇、4-(2,3-二氫-1H-吲哚-6-基胺基)酚、4-[(1-甲基-2,3-二氫-1H-吲哚-6-基)胺基]酚、4-[(1-甲基-1H-吲哚-6-基)胺基]酚、4-[(1-甲基-1H-吲哚-6-基)胺基]環己醇、4-[(1-甲基-1,2,3,4-四氫-6-喹啉基)胺基]酚、4-[(4-甲基-3,4-二氫-2H-1,4-苯并噁嗪-7-基)胺基]酚、4-[4-(二乙胺基)苯胺基]酚、4-(2,3-二氫-1H-茚-5-基胺基)酚、4-[(1-甲基-1H-吲唑-5-基)胺基]酚、4-[(1'-甲基-1',2'-二氫螺[環丙烷-1,3'-吲哚]-5'-基)胺基]酚、4-[(1,3,3-三甲基-2,3-二氫-1H-吲哚-5-基)胺基]酚、4-[4-甲氧基-3-(三氟甲基)苯胺基]酚、4-[4-(甲硫基)-3-(三氟甲基)苯胺基]酚、2-氟-4-[(1-甲基-1H-吲哚-5-基)胺基]酚、4-[(1-乙基-1H-吲哚-5-基)胺基]酚、4-[(1-乙基-2,3-二氫-1H-吲哚-5-基)胺基]酚、4-[(1-異丙基-2,3-二氫-1H-吲哚-5-基)胺基]酚、4-(丁胺基)酚、3-[(1-甲基-1H-吲哚-5-基)胺基]-1-丙醇、4-[(1-甲基-1H-吲哚-5-基)胺基]-1-丁醇、4-[(3-氟-4-甲基苯基)胺基]酚、4-[(3-氯-4-甲基苯基)胺基]酚、4-[(4-氟苯基)胺基]酚、4-[(1-甲基-1H-吡咯并[2,3-b]吡啶-5-基)胺基]酚、4-[(4-氟苯基)胺基]酚、4-[(2-氟苯基)胺基]酚、4-[(3-氟苯基)胺基]酚、4-[(2,4-二氟苯基)胺基]酚、4-[(3,4-二氟苯基)胺基]酚、3-[(4-羥基苯基)胺基]苯甲腈、4-[(3-甲氧基苯基)胺基]酚、4-[(3,5-二氟苯基)胺基]酚、4-[(3-甲基苯基)胺基]酚、4-[(4-羥基苯基)胺基]苯甲腈、4-[(3-氯苯基)胺基]酚、4-(嘧啶-2-基胺基)酚、4-[(環丁基甲基)胺基]酚、2-[(4-羥基苯基)胺基]苯甲腈、4-{[(1-甲基-1H-吡唑-4-基)甲基]胺基}酚、4-[(環丙基甲基)胺基]酚、4-{[(1-甲基-1H-吡唑-3-基)甲基]胺基}酚、4-(丁-2-炔-1-基胺基)酚、4-(吡嗪-2-基胺基)酚、4-(吡啶-2-基胺基)酚、4-(噠嗪-3-基胺基)酚、4-(嘧啶-5-基胺基)酚、4-
(吡啶-3-基胺基)酚、4-[(3,5-二氟-4-甲氧基苯基)胺基]酚、4-(吡啶-4-基胺基)酚、4-[(3-氟-4-甲氧基苯基)胺基]酚、2-(苯胺基)嘧啶-5-醇、5-[(4-羥基苯基)胺基]-2-甲氧基苯甲腈、4-{[3-(三氟甲基)苯基]胺基}酚、4-(甲胺基)酚、4-(乙胺基)酚及4-(丙-2-基胺基)酚。
以上列出之二級胺之羥基官能基在與如前述一般方法中定義之式(VII)化合物之酸衍生物的任何偶合之前藉由適合之保護基預先保護。
在環境溫度下向2g製備1之化合物於20mL二氯甲烷中之溶液中添加5.5mL N,N,N-三乙胺(6.96mmol)、製備1'之化合物(6.96mmol),且接著添加0.94g羥基苯并三唑(HOBT)及1.34g 1-乙基-3-(3'-二甲胺基丙基)-碳化二亞胺(EDC)(6.96mmol)。隨後將反應混合物在環境溫度下攪拌隔夜;隨後將其倒入至氯化銨溶液上且用乙酸乙酯萃取。隨後將有機相經硫酸鎂乾燥,且接著過濾且蒸發至乾燥。隨後將藉此獲得之粗產物藉由經矽膠(庚烷/AcOEt梯度)之層析純化以產生預期產物。
1 H NMR:δ(400MHz;dmso-d6;300K):7.2-6.8(m,4H,芳族Hs,H四氫異喹啉);7.10(s,1H,芳族H,苯并間二氧雜環戊烯);6.92(s,1H,芳族H,苯并間二氧雜環戊烯);6.25(m,1H,H四氫吲嗪);6.10(s,2H,脂族Hs,OCH 2 O);4.80(m,1H,脂族H,H四氫異喹啉);4.20(m,1H,脂族H,H四氫異喹啉);4.1-3.5(m,3H);3.60(s,3H,COOCH 3 );2.90(m,2H,脂族Hs,H四氫吲嗪);2.45(m,2H,脂族Hs,H四氫異喹
啉);1.70(m,4H,脂族Hs,H四氫吲嗪);0.80(m,3H,脂族Hs,CH 3 -THIQ).
IR:ν:>C=O 1694cm-1(共軛酯);ν:>C=O 1624cm-1(醯胺);ν:>C-Ar 772-742cm-1
向於24mL二噁烷中含有8.26mmol步驟A之化合物之溶液中添加氫氧化鋰溶液(675mg,16.1mmol)。將批料持續2小時30分鐘之時段置放於140W、100℃下之微波烘箱中。隨後將反應混合物過濾且蒸發。將藉此獲得之固體在P2O5存在下在烘箱中於40℃下乾燥。
在0℃下向於47mL二氯甲烷中含有4.73mmol步驟B之化合物之溶液中逐滴添加1.2mL乙二醯氯。將反應混合物在環境溫度下攪拌11小時且隨後用二氯甲烷共蒸發若干次。將藉此獲得之產物懸浮於37mL二氯甲烷中且隨後添加至在0.6mL吡啶(7.1mmol)存在下的於10mL二氯甲烷中含有7.1mmol製備2"中獲得之化合物之溶液。將批料在環境溫度下攪拌隔夜。將反應混合物濃縮、藉由經矽膠(二氯甲烷/甲醇梯度)之層析純化以產生預期產物。
向於4mL甲醇中含有2.3mmol步驟C中獲得之化合物之溶液中添加溶解於8mL甲醇中之0.646g(11.5mmol)氫氧化鉀。將批料在環境溫度下攪拌30分鐘。隨後將反應混合物用二氯甲烷稀釋且依次用1N
HCl溶液、飽和NaHCO3溶液且接著用飽和NaCl溶液洗滌直至獲得中性pH。隨後將有機相經硫酸鎂乾燥、過濾且蒸發。將藉此獲得之粗產物經矽膠(二氯甲烷/甲醇梯度)純化且接著凍乾以提供預期產物。
經驗式:C42H38CN4O5
[M+H]+,計算值:679.2920
[M+H]+,量測值:679.2908
該程序係根據實例1之步驟A-D中所述之方法使用適當試劑。在經矽膠之純化步驟(參見步驟D)之後,隨後將固體溶解於二氯甲烷中且添加2mL醚中之1N HCl。將完整批料攪拌1小時且接著蒸發至乾燥。將藉此獲得之鹽酸鹽溶解於水/乙腈之混合物中直至完全溶解且隨後凍乾。
%C=69.32:68.93;%H=5.94:5.74;%N=8.6:8.51;%Cl-=4.35:4.6
除非另外說明,否則在步驟A中使用(i)根據製備1至18中之一者獲得之適當酸及(ii)根據製備1'至7'中之一者獲得之適當四氫異喹啉化合物,且在步驟C中使用(iii)適合之NHR
3
R
4
胺(在製備1"至36"中提出非窮舉清單)根據實例1之方法合成以下實例之化合物。
該程序係根據實例1之方法,一方面,以製備2之化合物替換用於步驟A中之製備1之化合物,且另一方面,以N-(4-{[第三丁基(二甲
基)矽烷基]氧基}苯基)-1-甲基-1H-吲哚-5-胺替換用於步驟C中之製備1"之化合物,應理解藉此獲得之產物不進行如實例1之步驟D中所述的在醚中之HCl存在下轉化為鹽之步驟。在環境溫度下將藉此獲得之化合物在二氯甲烷中之10當量三氟乙酸(10mL/mmol)存在下脫除保護基隔夜。隨後藉由將反應混合物濃縮至乾燥而分離產物。最後,在醚中之HCl存在下對其進行轉化為鹽之步驟。
%C=67.99:65.52;%H=5.28:4.49;%N=9.91:9.24;%Cl=10.03:9.95;%Cl-=5.02:5.45
經驗式:C40H36ClN5O3
[M+H]+,計算值:670.2585
[M+H]+,量測值:670.2587
%C=70.85(71.65);%H=5.39(5.88);%N=9.11(9.28);%Cl=4.48(4.7)
該程序係根據實例1之步驟A-C中所述之方案使用製備3之化合物及步驟A中之1,2,3,4-四氫異喹啉及步驟C中之製備4"之化合物。
在環境溫度下向1.3g(1.45mmol)步驟A之化合物於13mL乙酸中之溶液中添加氰基硼氫化鈉(900mg;15mmol)。在攪拌2小時之後,將反應混合物濃縮至乾燥,且接著用甲醇(8mL)稀釋且用氫氧化鉀於甲醇(6.3mL;6.3mmol)中之1M溶液處理。在置於環境溫度下1小時之後,將反應混合物濃縮至乾燥,且接著經矽膠(二氯甲烷/甲醇梯度)層析且接著凍乾以提供呈粉末之預期產物。
%C=70.74(71.46);%H=5.74(6.13);%N=9(9.26);%Cl=4.46(4.69)
該程序類似於關於實例7、步驟A描述之程序,以製備4之化合物替代製備2之化合物。
%C=69.39:69.13;%H=5.69:4.98;%N=9.41:9.37;%Cl-=4.76:4.65
該程序係根據實例1之步驟A-C中所述之方案使用步驟A中之製備2及1'之化合物,及步驟C中之製備2"之化合物。
向步驟A之化合物(1.1g;1.25mmol)於甲醇(6mL)中之溶液中添加氫氧化鉀於甲醇(6.2mL;6.2mmol)中之1M溶液。在置於環境溫度下2小時之後,在真空中將甲醇蒸發且將殘餘物溶解於由二氯甲烷及飽和碳酸氫鈉溶液組成之混合物中。將合併之有機相經MgSO4乾燥且濃縮至乾燥。將獲得之殘餘物藉由經矽膠(CH2Cl2/MeOH梯度)之層析純化以提供呈固體之預期產物。
IR:ν:NH:3450cm-1;ν:CO:1745-1620cm-1
在環境溫度下向步驟B之化合物(0.7g;0.93mmol)於二氯甲烷(7mL)中之溶液中添加三乙胺(0.2mL;1.39mmol)且接著添加特戊醯氯(0.11mL;0.93mmol)。在環境溫度下攪拌2小時之後,將反應混合物用水及鹽水洗滌、經MgSO4乾燥且濃縮至乾燥。將獲得之殘餘物不經分析即用於下一步驟中。
在0℃下向前述步驟之化合物(0.82g;0.93mmol)於二氯甲烷(9mL)中之溶液中逐滴添加三氟乙酸(0.7mL;13.9mmol)。在環境溫度下攪拌15小時之後,將飽和碳酸氫鈉溶液緩慢添加至反應混合物且接著將各相分離。用二氯甲烷萃取水相。將合併之有機相經MgSO4乾燥且濃縮至乾燥。將獲得之殘餘物藉由經矽膠(CH2Cl2/MeOH梯度)之層
析純化以提供呈固體之預期產物。
LC/MS:m/z=[M+H]+=754.30
在環境溫度下向前述步驟之化合物(0.41g;0.54mmol)於二氯甲烷(2mL)中之溶液中添加甲醛(48μL;1.74mmol)且接著添加三乙醯氧基硼氫化鈉(161mg;0.76mmol)。在環境溫度下攪拌2小時之後,將反應混合物用二氯甲烷稀釋且接著用飽和碳酸氫鈉溶液洗滌。將有機相經MgSO4乾燥且濃縮至乾燥。將獲得之殘餘物藉由經矽膠(CH2Cl2/MeOH梯度)之層析純化。獲得呈固體之預期產物。
LC/MS:m/z=[M+H]+=768.32
向前述步驟之化合物(0.25g;0.32mmol)於二噁烷(1mL)中之溶液中添加氫氧化鋰(27mg;0.65mmol)於水(1mL)中之溶液。在環境溫度下攪拌5小時之後,將反應混合物濃縮且用飽和碳酸氫鈉溶液稀釋。用CH2Cl2萃取水相。將有機相經MgSO4乾燥且濃縮至乾燥。將獲得之殘餘物藉由經矽膠(CH2Cl2/MeOH梯度)之層析純化。隨後獲得呈固體之預期產物。
%C=71.97:71.51;%H=5.6:5.25;%N=10.24:10.12
%C=69:69.16;%H=5.41:4.82;%N=8.75:8.69;%Cl-=4.43:4.13
該程序係根據實例1之方法,一方面,以製備6之化合物替換用於步驟A中之製備1之化合物,且另一方面,以製備5"之化合物替換用於步驟C中之製備1"之化合物,應理解藉此獲得之產物不進行如實例1之步驟D中所述的在醚中之HCl存在下轉化為鹽之步驟。在環境溫度下將藉此獲得之化合物在二氯甲烷中之10當量三氟乙酸(10mL/mmol)存在下脫除保護基隔夜。隨後藉由將反應混合物濃縮至乾燥而分離產物。最後,在醚中之HCl存在下對其進行轉化為鹽之步驟。
%C=67.83:67.41;%H=5.08:4.61;%N=8.55:8.39;%Cl-=5.41:5.28
該程序係根據實例1之方法,一方面,以製備6之化合物替換用於步驟A中之製備1之化合物,且另一方面,以製備6"之化合物替換用於步驟C中之製備1"之化合物,應理解藉此獲得之產物不進行如實例1之步驟D中所述的在醚中之HCl存在下轉化為鹽之步驟。在環境溫度下將藉此獲得之化合物在二氯甲烷中之10當量三氟乙酸(10mL/mmol)存在下脫除保護基隔夜。隨後藉由將反應混合物濃縮至乾燥而分離產物。最後,在醚中之HCl存在下對其進行轉化為鹽之步驟。
%C=68.21:68.29;%H=5.27:4.91;%N=8.37:8.34;%Cl-=5.3:5.17
該程序係根據實例1之方法,一方面,以製備7之化合物替換用於步驟A中之製備1之化合物,且另一方面,以N-(4-{[第三丁基(二甲基)矽烷基]氧基}苯基)-1-甲基-1H-吲哚-5-胺替換用於步驟C中之製備1"之化合物,應理解藉此獲得之產物不進行如實例1之步驟D中所述的在醚中之HCl存在下轉化為鹽之步驟。在環境溫度下將藉此獲得之化合物在二氯甲烷中之10當量三氟乙酸(10mL/mmol)存在下脫除保護基隔夜。隨後藉由將反應混合物濃縮至乾燥而分離產物。最後,在醚中之HCl存在下對其進行轉化為鹽之步驟。
%H=5.2:4.83;%N=11.72:11.64;%Cl-=4.94:5.34;%C=66.99:66.19
該程序係根據實例1之方法,一方面,以製備2之化合物替換用於步驟A中之製備1之化合物,且另一方面,以N-(4-{[第三丁基(二甲基)矽烷基]氧基}苯基)-1-甲基-1H-吲哚-5-胺替換用於步驟C中之製備1"之化合物,應理解藉此獲得之產物不進行如實例1之步驟D中所述的在醚中之HCl存在下轉化為鹽之步驟。在環境溫度下將藉此獲得之化合物在二氯甲烷中之10當量三氟乙酸(10mL/mmol)存在下脫除保護基隔夜。隨後藉由將反應混合物濃縮至乾燥而分離產物。最後,在醚中之HCl存在下對其進行轉化為鹽之步驟。
%C=66.19:65.83;%H=5.13:4.99;%N=11.88:11.85;%Cl-=5.01:5.36
%C=69.42:69.47;%H=5.96:5.58;%N=7.36:7.36;%Cl-=4.66:4.42
%C=67.76:67.81;%H=5.81:5.63;%N=10.31:10.13;%Cl-=4.35:4.22
該程序係根據實例1之步驟A之方案,以製備8之化合物替換製備1之化合物。
將溶解於75mL THF中之4.47mmol步驟A之化合物在37mL 1M HCl存在下於回流下攪拌15小時。將100mL水及100mL乙酸乙酯添加至反應混合物。隨後添加4g呈粉末之NaHCO3(4.7mmol)直至獲得鹼性pH。用乙酸乙酯萃取化合物;將有機相經MgSO4乾燥、過濾且濃
縮至乾燥。
向4.47mmol步驟B中獲得之化合物於30mL甲醇中之溶液中逐份添加558mg(14.75mmol)硼氫化鈉。將反應混合物在環境溫度下攪拌1小時。隨後添加50mL 1M HCl且將甲醇蒸發掉。隨後使用NaHCO3將水相中和且接著用二氯甲烷萃取。將有機相依次用H2O洗滌、經MgSO4乾燥、過濾且濃縮至乾燥。將藉此獲得之油狀物藉由急驟層析(二氯甲烷/乙醇-氨梯度)純化以產生預期產物。
向冷卻至0℃的331mg(8.26mmol)氫化鈉於15mL無水THF中之懸浮液中添加4.13mmol步驟C中獲得之化合物。將所得懸浮液在0℃下攪拌15分鐘且接著緩慢添加(經15分鐘)790μL(9.1mmol)烯丙基溴於10mL THF中之溶液。將反應混合物在0℃下攪拌1小時,且接著在環境溫度下攪拌15小時。將所得溶液用飽和NH4Cl水溶液水解。用乙酸乙酯萃取化合物;將有機相經MgSO4乾燥、過濾且濃縮至乾燥。將藉此獲得之油狀物藉由急驟層析(環己烷/乙酸乙酯梯度)純化以產生預期產物。
該程序係根據實例1之步驟B及C中所述之方法使用適當試劑。
隨後在甲醇及二氯甲烷之混合物中之1,3-二甲基嘧啶-2,4,6(1H,3H,5H)-三酮(亦稱作二甲基巴比妥酸鹽)及肆(三苯基膦)鈀存在下進行對烯丙基脫除保護基之反應。
在環境溫度下向步驟F之化合物(550mg;0.72mmol)於二氯甲烷(6mL)中之溶液中添加三乙胺(300μL;1.8mmol)及甲磺醯氯(0.14mL;1.8mmol)。在攪拌20分鐘之後,將反應混合物濃縮至乾燥且接著用10mL DMSO稀釋。向其中添加470mg粉末形式之NaN3(7.2mmol)。將反應混合物在環境溫度下保持20小時且接著在50℃下保持20小時。隨後將其倒入至二氯甲烷及水之混合物上。將有機相用水且接著用鹽水洗滌3次、經MgSO4乾燥且接著濃縮至乾燥以產生預期產物,將其用於下一步驟中。
在環境溫度下向550mg步驟G之化合物(0.7mmol)於乙醇(10mL)中之溶液中添加20mg Pd/C 10%。在1巴之氫氣下攪拌15小時之後,使反應混合物穿過Whatman過濾器且濃縮至乾燥。在藉由經矽膠(二氯甲烷/甲醇梯度)之管柱層析純化之後,隨後將固體溶解於二氯甲烷中,且添加2mL醚中之1N HCl。將完整批料攪拌1小時且接著蒸發至乾燥。將藉此獲得之鹽酸鹽溶解於水/乙腈之混合物中直至完全溶解且接著凍乾以產生呈粉末之預期化合物。
%C=69.17:68.68;%H=5.51:5.09;%N=8.27:8.41;%Cl-=5.24:5.28
該程序係根據實例1之步驟A中之方法使用(3S)-1,2,3,4-四氫異喹啉-3-基甲醇。
向NaH(703mg;17.6mmol)於THF(20mL)中之懸浮液中添加7.8g步驟A之化合物(16mmol)溶解於THF(50mL)及DMF(30mL)之混合物中之溶液。在攪拌1小時之後,添加烯丙基溴(1.7mL;19mmol)。將反應混合物在環境溫度下攪拌48小時且隨後倒入至乙酸乙酯及水之混合物上。將有機相用水及飽和LiOH溶液洗滌3次、經MgSO4乾燥且濃縮至乾燥。在藉由經矽膠(二氯甲烷/甲醇梯度)之層析純化之後,獲得呈固體之預期產物。
1 H NMR:δ:(500MHz;dmso-d6;300K):7.2-6.9(m,4H);7.05(m,1H);6.9(m,1H);6.45-6.1(m,1H);6.15(m,2H);5.9-5.65(m,1H);5.2-5.0(m,2H);5.05-3.8(m,1H);4.85-4.25(m,2H);4.3-3.45(m,7H);3.4-2.4(m,6H);1.95-1.45(m,4H)
該程序係根據實例1之步驟B及C之方法使用4-(苯甲氧基)-N-苯基
苯胺(參見製備9")。
向5.1g(6.65mmol)步驟C之化合物於二氯甲烷(7mL)及甲醇(2mL)之混合物中之懸浮液中添加二甲基巴比妥酸(2.1g;13.3mmol)及肆(三苯基膦)鈀(0)(300mg;0.3mmol)。在45℃下攪拌15小時之後,將反應混合物倒入至乙酸乙酯及水之混合物上。將有機相用水洗滌兩次、經MgSO4乾燥、濃縮至乾燥且用甲醇(5mL)稀釋。隨後將批料在Pd/C(100mg)存在下於氫氣氛圍下攪拌24小時。隨後將反應混合物穿過Whatman過濾器、濃縮至乾燥、隨後經矽膠(二氯甲烷/甲醇梯度)層析且最後凍乾以產生呈粉末之預期產物。
%C=72.38(73);%H=5.22(5.5);%N=6.59(6.55)
%C=67.12:66.79;%H=5.26:4.98;%N=6.96:7.17;%Cl-=4.4:4.77
%C=66.99(66.79);%H=4.93(5.1);%N=7.11(7.08);%Cl-=4.46(4.48)
%C=72.26:72.51;%H=6.48:6.13;%N=7.66:7.71;%Cl=4.85:4.95;%Cl-=4.85:4.64
%C=72:71.11;%H=6.32:5.94;%N=7.81:7.65;%Cl-=4.94:5.08
%C=69.24:69.12;%H=4.74:4.23;%N=8.5:8.45;%Cl-=5.38:5.2
%C=68.11:66.66;%H=5.32:4.93;%N=9.24:8.84;%Cl-=4.68:5.78
經驗式:C43H39N5O6
[M+H]+,計算值:655.2915
[M+H]+,量測值:655.2915
%C=68.74:68.59;%H=5.64:5.5;%N=8.91:8.98;%Cl-=4.51:4.48
%C=67.81:67.45;%H=5.69:5.61;%N=7.19:7.42;%Cl-=4.55:4.84
%C=66.28:66.56;%H=5.44:5.25;%N=7.03:7.21;%Cl-=4.45:4.32
%C=69.24:70.16;%H=5.81:5.79;%N=7.34:7.47;%Cl-=4.64:4.58
%C=67.1:67.68;%H=5.63:5.4;%N=7.28:7.34;%Cl-=4.61:4.59
%C=70.72:70.05;%H=6.34:5.95;%N=7.5:7.33;%Cl-=4.74:4.74
%C=70.72:68.96;%H=6.34:5.78;%N=7.5:7.24;%Cl-=4.74:4.62
經驗式:C44H46 N4O5
[M+H]+,計算值:711.3546
[M+H]+,量測值:711.3540
%C=68.31:69.12;%H=5.22:4.93;%N=7.08:6.96;%Cl-=4.48:4.07
%C=71.13:71.29;%H=4.69:4.39;%N=7.9:8.14;%Cl-=5:4.5
%C=69.59:69.81;%H=4.94:4.53;%N=8.32:8.59;%Cl-=5.27:5.01
%C=69.14:70.09;%H=4.81:4.55;%N=9.83:10.09;%Cl-=4.98:3.26
%C=69.24:70.21;%H=4.74:4.42;%N=8.5:8.51;%Cl-=5.38:3.33
%C=68.61:67.96;%H=5.38:5.14;%N=6.96:6.76;%Cl-=4.4:4.36
%C=68.31:68.51;%H=5.22:4.85;%N=7.08:6.83;%Cl-=4.48:4.48
在環境溫度下向2g製備1之化合物於20mL二氯甲烷中之溶液中添加5.5mL N,N,N-三乙胺(6.96mmol)、製備3'之化合物(6.96mmol),
且接著添加0.94g羥基苯并三唑(HOBT)及1.34g 1-乙基-3-(3'-二甲胺基丙基)-碳化二亞胺(EDC)(6.96mmol)。隨後將反應混合物在環境溫度下攪拌隔夜,且隨後將其倒入至氯化銨溶液上且用乙酸乙酯萃取。隨後將有機相經硫酸鎂乾燥,且接著過濾且蒸發至乾燥。隨後將藉此獲得之粗產物藉由經矽膠(庚烷/AcOEt梯度)之層析純化以產生預期產物。
1 H NMR:δ(400MHz;dmso-d6;300K):7.2-6.8(m,4H,芳族Hs,H四氫異喹啉);7.15-6.90(m,4H,芳族H,四氫異喹啉);7.00-6.80(m,2H,芳族H,苯并間二氧雜環戊烯);6.68+6.55+6.25(m,1H,NH);6.50-6.05(m,1H,芳族H,四氫吲嗪);6.12(m,2H,脂族Hs,OCH 2 O);4.95+4.20+4.10(m,2H,脂族H,CH2N四氫異喹啉);4.85+4.78+3.80(m,1H,脂族H,CH四氫異喹啉);4.00-3.40(m,2H,脂族Hs,CH 2 N四氫吲嗪);3.70-3.50(m,3H,COOCH 3 );2.95-2.45(m,2H,脂族Hs,CH 2 NHBoc);2.98-2.30(m,2H,脂族Hs,CH 2 C四氫吲嗪);3.00+2.60+2.42(m,2H,脂族Hs,CH 2 CH四氫吲嗪);1.95-1.40(m,4H,脂族Hs,CH2CH2四氫吲嗪);1.35-1.25(m,9H,脂族Hs,tBu);1.50-1.15(m,2H,脂族Hs,CH 2 CH2NHBoc)
向於24mL二噁烷中含有8.26mmol步驟A之化合物之溶液中添加氫氧化鋰溶液(675mg,16.1mmol)。將批料持續2小時30分鐘之時段置放於140W、100℃下之微波烘箱中。隨後將反應混合物過濾且蒸發。將藉此獲得之固體在P2O5存在下在烘箱中於40℃下乾燥。
在0℃下向於47mL二氯甲烷中含有4.73mmol步驟B之化合物之溶液中逐滴添加1.2mL乙二醯氯。將反應混合物在環境溫度下攪拌11小時且隨後用二氯甲烷共蒸發若干次。將藉此獲得之產物懸浮於37mL二氯甲烷中且隨後添加至在0.6mL吡啶(7.1mmol)存在下的於10mL二氯甲烷中含有7.1mmol製備8"中獲得之化合物之溶液。將批料在環境溫度下攪拌隔夜。
將反應混合物濃縮且藉由經矽膠(二氯甲烷/甲醇梯度)之層析純化以產生預期產物。
1 H NMR:δ(400MHz;dmso-d6;300K):7.0(m,11H,芳族Hs,Ph+4H,四氫異喹啉+2H,PhO);6.80-6.65(m,2H,芳族Hs,PhO);6.95-6.85(m,2H,芳族H,苯并間二氧雜環戊烯);6.70+6.40(3tl,1H,NH);6.10(m,2H,脂族Hs,OCH 2 O);5.25-4.85(m,1H,芳族H,四氫吲嗪);5.00+4.00(m,2H,脂族H,CH 2 N四氫異喹啉);4.90-3.60(m,1H,脂族H,CH四氫異喹啉);4.10-3.40(m,2H,脂族Hs,CH 2 N四氫吲嗪);3.00-2.50(m,2H,脂族Hs,CH 2 C四氫吲嗪);3.00+2.40(m,2H,脂族Hs,CH 2 CH四氫吲嗪);3.00-2.50(m,2H,脂族Hs,CH 2 NHBoc);1.80-1.50(m,4H,脂族Hs,CH 2 CH 2 四氫吲嗪);1.50-1.30(m,2H,脂族Hs,CH 2 CH2NHBoc);1.35(2s,9H,脂族Hs,tBu);0.90(s,9H,脂族Hs,tBu-Si);0.10(m,6H,脂族Hs,Me-Si)
向800mg(0.92mmol)步驟C之化合物於10mL甲醇中之溶液中添加258mg(4.60mmol)KOH。在環境溫度下攪拌3小時之後,將反應混合物用6mL二噁烷中之4M HCl溶液處理。在環境溫度下攪拌2小時
之後,將反應混合物濃縮且用NaHCO3飽和水溶液處理且用二氯甲烷萃取。隨後將有機相經硫酸鎂乾燥,且接著過濾且蒸發至乾燥。隨後將藉此獲得之粗產物藉由經矽膠(二氯甲烷/甲醇梯度)之層析純化。隨後將化合物溶解於5mL二氯甲烷中,且添加2.5mL醚中之1M HCl。將化合物濾出且在真空中乾燥。獲得呈發泡體之預期產物。
%C=69.51:69.53;%H=5.69:5.27;%N=8.11:8.04;%Cl-=5.13:5.2
經驗式:C40H38N4O5
[M+H]+,計算值:655.2915
[M+H]+,量測值:655.2915
1 H NMR:δ(400MHz;dmso-d6;300K):9.55+9.45(2s,1H,OH);7.80+7.75(2s,3H,NH3 +);7.46-6.55(m,11H,芳族Hs,Ph+4H,四氫異喹啉+2H,PhO);6.90-6.55(m,2H,芳族Hs,PhO);7.00-6.70(若干s,2H,芳族H,苯并間二氧雜環戊烯);5.35-5.00(若干s,1H,芳族H,四氫吲嗪);6.10(若干s,2H,脂族Hs,OCH 2 O);5.00-3.35(若干m,4H,脂族H,CH 2 N四氫異喹啉+CH 2 N四氫吲嗪);4.85+4.75+3.60(若干m,1H,脂族H,CH四氫異喹啉);2.85-2.45(若干m,2H,脂族Hs,CH 2 NH2);3.00-2.45(若干m,2H,脂族Hs,CH 2 C四氫吲嗪);3.05+2.30(若干m,2H,脂族Hs,CH 2 CH四氫異喹啉);1.85-1.40(若干m,2H,脂族Hs,CH 2 四氫異喹啉);1.95-1.35(若干m,2H,脂族Hs,CH 2 四氫異喹啉);1.75-1.40(若干m,2H,脂族Hs,CH 2 CH2NH2)
IR:ν:-OH:3375cm-1(酚);ν:-NH3+:3500-2300cm-1(一級胺之鹽);ν:>C=O 1612cm-1+凸肩(醯胺)
%C=69.71:69.62;%H=6.11:5.67;%N=7.23:7.12;%Cl-=4.57:4.81
%C=69.91:69.68;%H=5.13:4.78;%N=8.15:8.03;%Cl-=5.16:5.16
%C=74.86:74.88;%H=5.64:5.31;%N=6.72:6.78
%C=67.96:68.34;%H=5.7:5.4;%N=7.04:6.97;%Cl-=4.46:4.27
%C=68.82:69.46;%H=5.32:4.95;%N=8.45:8.48;%Cl-=5.35:4.6
該方法類似於實例37之步驟A中所述之方法。
向337mg NaH(60%)(8.41mmol)於13mL二甲基甲醯胺中之懸浮液中逐滴添加1.01g(1.68mmol)步驟A之化合物於13mL二甲基甲醯胺中之溶液。將所得懸浮液在環境溫度下攪拌15分鐘且隨後添加13mL二甲基甲醯胺中之1.08g(5.04mmol)三氟甲烷磺酸2,2-二氟乙酯。將批料在環境溫度下攪拌2小時。添加20mL飽和氯化銨之溶液。用乙酸乙酯萃取溶液。隨後將有機相經MgSO4乾燥、過濾且濃縮至乾燥。在藉由經矽膠(環己烷/乙酸乙酯)之管柱層析純化之後,獲得呈油狀物之預期產物。
經驗式:C37H43CN3O7
[M+H]+,計算值:680.3142
[M+H]+,量測值:680.3145
1 H NMR:δ(400MHz;dmso-d6;300K):7.25-6.90(m,4H,芳族Hs,四氫異喹啉);7.10-6.75(m,2H,芳族H,苯并間二氧雜環戊烯);6.40-6.05(m,1H,芳族H,四氫吲嗪);6.10(m,2H,脂族Hs,OCH 2 O);6.25-5.90(m,1H,脂族Hs,CHF 2 );4.95-4.10(m,2H,脂族H,CH 2 N四氫異喹啉);4.80+3.80(2m,1H,脂族H,CH四氫異喹啉);4.10-4.00(m,2H,CH2Et);4.05-3.40(m,2H,脂族H,CH 2 N四氫吲嗪);3.60-2.60(m,
4H,脂族H,CH 2 CHF2+CH 2 NBoc);3.00-2.35(m,2H,脂族Hs,CH 2 C四氫吲嗪);3.00+2.45(m,2H,脂族Hs,CH 2 CH四氫異喹啉);1.95+1.40(m,4H,脂族Hs,CH 2 CH 2 四氫吲嗪);1.40(m,9H,脂族Hs,tBu);1.65-1.20(m,2H,脂族Hs,CH 2 CH2NBoc);1.18+1.10(2t,3H,脂族Hs CH 3 Et)
該方法類似於實例37之步驟B及C中所述之方法。
1 H NMR:δ(400MHz;dmso-d6;300K):7.30-6.60(m,9H,芳族Hs,4H四氫異喹啉+Ph);6.90-6.70(m,2H,芳族H,苯并間二氧雜環戊烯);6.80-6.60(m,4H,PhO);6.10(m,2H,脂族Hs,OCH 2 O);6.20-5.90(m,1H,脂族Hs,CHF 2 );5.50-4.80(4s,1H,芳族H,四氫吲嗪);5.20-4.00(m,2H,脂族H,CH 2 N四氫異喹啉);4.80+4.70+3.50(3m,1H,脂族H,CH四氫異喹啉);4.20-3.40(m,2H,脂族H,CH 2 N四氫吲嗪);3.60-3.10(m,4H,脂族H,CH 2 CHF2+CH 2 NBoc);3.00+2.60(m,2H,脂族Hs,CH 2 CH四氫異喹啉);3.00-2.50(m,2H,脂族Hs,CH 2 C四氫吲嗪);1.80+1.50(m,4H,脂族Hs,CH 2 CH 2 四氫吲嗪);1.60-1.30(m,2H,脂族Hs,CH 2 CH2NBoc);1.40-1.30(m,9H,脂族Hs,tBu);0.90(4s,9H,脂族Hs,tBu-Si);0.10(4s,6H,脂族Hs,Me-Si)
向933mg(1.00mmol)步驟C之化合物於10mL甲醇中之溶液中添加280mg(5.00mmol)KOH。在環境溫度下攪拌3小時之後,將反應
混合物用6mL二噁烷中之4M HCl溶液處理。在環境溫度下攪拌2小時之後,將反應混合物濃縮且用NaHCO3飽和水溶液處理且接著用二氯甲烷萃取。隨後將有機相經硫酸鎂乾燥,且接著過濾且蒸發至乾燥。隨後將藉此獲得之粗產物藉由經矽膠(二氯甲烷/甲醇梯度)之層析純化以產生呈發泡體之預期產物。
%C=70.18:69.79;%H=5.61:5.67;%N=7.79:7.7
經驗式:C42H40F2N4O5
[M+H]+,計算值:655.2915
[M+H]+,量測值:655.2915
%C=72.91:72.73;%H=6.12:5.67;%N=7.73:7.74
%C=66.27:66.05;%H=5.43:5.27;%N=11.04:11.07;%Cl-=4.66:4.61
經驗式:C38H29FN4O5
[M+H]+,計算值:641.2195
[M+H]+,量測值:641.2195
%C=69.72:69.53;%H=5.53:5.6;%N=11.29:10.85
%C=70.9:70.89;%H=5.79:5.56;%N=10.88:10.8
%C=68.42:68.17;%H=4.65:4.48;%N=8.63:8.48;%Cl-=5.46:5.13
%C=72.12:71.58;%H=4.84:4.84;%N=10.51:10.48
%C=68.81:68.28;%H=4.62:4.59;%N=10.03:9.66;%Cl-=5.08:4.81
%C=76.05:75.88;%H=5.26:5.24;%N=11.09:11.09
%C=69.14:69.65;%H=4.81:4.75;%N=9.83:9.79;%Cl-=4.98:4.7
%C=69.59:68.78;%H=4.94:5;%N=8.32:8.33;%Cl-=5.27:5.18
%C=71.24:70.77;%H=4.56:4.36;%N=8.75:8.82
經驗式:C39H32N4O6
[M+H]+,計算值:653.2395
[M+H]+,量測值:653.2385
%C=74.17(74.62);%H=5.43(5.44);%N=6.87(6.87)
%C=70.23:69.95;%H=5.32:5.4;%N=7.99:7.99;%Cl-=5.06:4.92
%C=70.68:70.47;%H=4.56:4.61;%N=12.68:12.45
%C=71.85(72.11);%H=4.78(5.04);%N=10.79(11.68)
%C=72.31(71.62);%H=5.6(5.68);%N=10.94(11.6)
%C=74.08(74.48);%H=4.82(4.9);%N=8.59(9.39)
%C=73.14(73.95);%H=4.83(4.96);%N=10.29(10.78)
%C=74.61(73.98);%H=5.26(5.54);%N=8.94(9.33)
%C=73.59(73.49);%H=5.22(5.55);%N=9.93(10.71)
%C=68.57(68.77);%H=3.92(4.4);%N=14.21(14.77)
經驗式:C38H29N7O5
[M+H]+,計算值:664.2303
[M+H]+,量測值:664.2310
%C=69.7(71.46);%H=4.43(4.73);%N=8.54(8.77)
經驗式:C38H30N4O6
[M+H]+,計算值:639.2238
[M+H]+,量測值:639.2234
%C=71.97(72.25);%H=5.21(5.08);%N=8.99(9.11);%Cl-=5.32(5.76)
經驗式:C37H30N4O3
[M+H]+,計算值:579.2391
[M+H]+,量測值:579.2403
%C=67.63(68.06);%H=5.27(5.95);%N=10.08(10.13);%Cl-=4.53(4.27)
經驗式:C47H48N6O6
[M+H]+,計算值:793.3708
[M+H]+,量測值:793.3704
步驟A:N-[4-[第三丁基(二甲基)矽烷基]氧基苯基]-3-[6-[(3R)-3-甲基-3,4-二氫-1H-異喹啉-2-羰基]-1,3-苯并間二氧雜環戊烯-5-基]-N-(1-甲基-1H-吡唑并[3,4-b]吡啶-5-基)吲嗪-1-甲醯胺
根據實例86之步驟A之方法,以製備35"之化合物替換製備36"之化合物而獲得標題產物。
LCMS:[M+H]+=791.4對791.3計算值
步驟B:N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-(1-甲基-1H-吡唑并[3,4-b]吡啶-5-基)吲嗪-1-甲醯胺
該程序係根據類似於實例1之步驟D中所述之方案的方案。在醚中之HCl存在下對藉此獲得之產物進行轉化為鹽之步驟。
IR(ATR)cm -1 : 2500至3000 ν-OH,1614 ν>C=O醯胺,1236 ν>C-O-C<,740 γ>CH-Ar
%C=71.07(70.99);%H=4.45(4.77);%N=12.37(12.42)
經驗式:C40H32N6O5
[M+H]+,計算值:677.2507
[M+H]+,量測值:677.2510
步驟A
:碘化4-[(4-羥基苯基){[3-(6-{[(3R)-3-甲基-3,4-二氫異喹
啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)吲嗪-1-基]羰基}胺基]-1-甲基吡錠
將實例21之化合物(311mg,0.5mmol)溶解於二氯甲烷中且用飽和碳酸氫鈉水溶液洗滌。在將有機相經硫酸鎂乾燥且蒸發至乾燥之後,將殘餘物溶解於乙醇(30mL)中。隨後添加碘代甲烷(45μL,0.7mmol)且將反應混合物加熱至40℃。將藉此獲得之溶液蒸發至乾燥。使用二氯甲烷及甲醇作為溶劑將粗反應產物經矽膠管柱純化。獲得呈白色粉末形式之化合物,其直接用於下一步驟中。
1 H NMR(500MHz,dmso-d6)δ ppm:9.95(bs,1 H),8.6-8.45(m,2 H),8.35-8.05(若干m,1 H),8.3-8(若干m,1 H),7.45-6.7(若干m,8 H),7.4-6.9(若干m,4 H),6.45-6.3(若干s,1 H),6.45-6.3(m,2 H),6.15(s,2 H),5.05-3.55(若干d,2 H),4.75/3.8(m+m,1 H),4.15(2*s,3 H),2.95-2.1(若干m,2 H),1-0.15(若干m,3 H)
步驟B
:氯化4-[(4-羥基苯基){[3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)吲嗪-1-基]羰基}胺基]-1-甲基吡錠
將上一步驟之化合物(320mg,0.42mmol)溶解於甲醇(20mL)中,接著經10分鐘逐份添加碳酸銀(173mg,0.628mmol)。將所得懸浮液在環境溫度下攪拌1小時;將沈澱物濾出且用甲醇洗滌。將濾液濃縮至乾燥接著用50mL 2N鹽酸溶液處理、在60℃下加熱30分鐘接著蒸發至乾燥。在使用0.1%鹽酸溶液及乙腈作為溶劑經二氧化矽C18管柱純化之後獲得最終產物。獲得呈白色粉末形式之標題化合物,將其於水/乙腈之混合物中凍乾。
IR(ATR)cm -1 : 3388 ν-OH酚,1650+1627 ν>C=O醯胺
經驗式:C39H33N4O5
[M]+,計算值=637.2445.
[M]+,量測值=637.2431
根據實例3之方法使用製備7之酸、適當1,2,3,4-四氫異喹啉或根據製備1'至7'中之一者獲得之適當化合物及適合之NHR
3
R
4
胺合成實例72、73、77、78-80、84及85之化合物。
LC/MS(C33H32N4O5)565[M+H]+;RT 1.47(方法B),應理解RT指示滯留時間
LC/MS(C34H34N4O5)579[M+H]+;RT 1.55(方法B)
LC/MS(C33H31N3O5)550[M+H]+;RT 1.24(方法B)
LC/MS(C34H33N3O5)564[M+H]+;RT 1.30(方法B)
LC/MS(C36H37N3O5)592[M+H]+;RT 1.39(方法B)
LC/MS(C34H34N4O5)579[M+H]+;RT 1.50(方法B)
LC/MS(C34H42N4O4)571[M+H]+;RT 1.79(方法B)
LC/MS(C36H38N4O5)607[M+H]+;RT 1.65(方法B)
LC/MS(C35H36N4O5)593[M+H]+;RT 1.58(方法B)
LC/MS(C34H33N3O5)564[M+H]+;RT 2.48(方法A)
LC/MS(C34H33N3O5)564[M+H]+;RT 2.55(方法A)
LC/MS(C33H27N3O5)546[M+H]+;RT 2.40(方法A)
LC/MS(C32H30N4O5)551[M+H]+;RT 1.45(方法B)
LC/MS(C33H32N4O5)565[M+H]+;RT1.49(方法B)
步驟A:N-[4-[第三丁基(二甲基)矽烷基]氧基苯基]-3-[6-[(3R)-3-甲基-3,4-二氫-1H-異喹啉-2-羰基]-1,3-苯并間二氧雜環戊烯-5-基]-N-(3-甲基吡唑并[1,5-a]嘧啶-6-基)吲嗪-1-甲醯胺
向0.6g 3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)吲嗪-1-甲酸(1.3mmol)於6mL二氯乙烷中之溶液中添加0.18mL 1-氯-N,N,2-三甲基-丙-1-烯-1-胺(2mmol)。將反應混合物在環境溫度下攪拌2小時且隨後添加0.8g製備36"之化合物(2.2mmol)。將批料回流20小時且隨後冷卻且用二氯甲烷及飽和NaHCO3溶液之混合物稀釋。在分離各相之後,將有機相經MgSO4乾燥且濃縮至乾燥。將藉此獲得之粗產物藉由經矽膠(二氯甲烷/甲醇梯度)之層析純化。
LC/MS:[M+H]+=791.4對791.3計算值
步驟B:N-(4-羥基苯基)-3-[6-[(3R)-3-甲基-3,4-二氫-1H-異喹啉-2-羰基]-1,3-苯并間二氧雜環戊烯-5-基]-N-(3-甲基吡唑并[1,5-a]嘧啶-6-基)吲嗪-1-甲醯胺鹽酸鹽
該程序係根據類似於實例1之步驟D中所述之方案的方案。在醚中之HCl存在下對藉此獲得之產物進行轉化為鹽之步驟。
IR(ATR)cm -1 : 2500至3000 ν-OH,1614 ν>C=O醯胺,1236 ν>C-O-C<,
740 γ>CH-Ar
經驗式:C40H32N6O5
[M+H]+,計算值:677.2507
[M+H]+,量測值:677.2506
在微量培養盤(384孔)上進行螢光偏振測試。將最終濃度為2.50×10-8M的經標記(histag-Bcl-2,使得Bcl-2對應於UniProtKB®主寄存編號:P10415)之Bcl-2蛋白與緩衝溶液(Hepes 10mM,NaCl 150mM,Tween20 0.05%,pH 7.4)中的1.00×10-8M之最終濃度下之螢光肽(Fluorescein-REIGAQLRRMADDLNAQY)在存在或不存在測試化合物之濃度增加之情況下混合。在培育2小時之後,量測螢光偏振。
將結果以IC50(抑制螢光偏振50%之化合物濃度)表示且呈現於下表1中。
結果顯示本發明化合物抑制上文描述之Bcl-2蛋白與螢光肽之間的相互作用。
在RS4;11白血病腫瘤線上進行細胞毒性研究。
將細胞分佈至微量培養盤上且曝露於測試化合物48小時。隨後藉由比色分析,微量細胞培養四唑鎓分析定量細胞活力(Cancer Res.,1987,47,939-942)。
將結果表示為IC50(抑制細胞活力50%之化合物濃度)且呈現於下表1中。
結果顯示本發明化合物為細胞毒性的。
ND:未測定
對於部分抑制劑,指定給定濃度之測試化合物之螢光偏振抑制%。因此,25.1% @10μM意謂對於等於10μM之濃度的測試化合物觀測到25.1%螢光偏振抑制。
在RS4;11白血病細胞之異種移植模型中評估本發明化合物活化卡斯蛋白酶3之能力。
將1×107個RS4;11細胞皮下地移植至免疫抑制小鼠(SCID菌株)中。在移植之後的25至30日,以各種化合物經口處理動物。在處理後的16小時,將腫瘤塊回收且溶解,且在腫瘤溶解物中量測卡斯蛋白酶3活性。
藉由分析螢光生成分解產物之外觀(DEVDase活性,Promega)進行此酶促量測。將其以對應於兩個卡斯蛋白酶活性:處理之小鼠之活性除以對照小鼠之活性之間的比之活化係數形式表示。
獲得之結果顯示本發明化合物能夠於RS4;11腫瘤細胞中活體內誘發細胞凋亡。
在RS4;11白血病細胞之異種移植模型中評估本發明化合物活化卡斯蛋白酶3之能力。
將1×107個RS4;11細胞皮下地移植至免疫抑制小鼠(SCID菌株)中。在移植之後的25至30日,用各種化合物經口處理動物。在處理之
後,將腫瘤塊回收(在時段T之後)且溶解,且在腫瘤溶解物中定量卡斯蛋白酶3之分解(活化)形式。
使用專門分析卡斯蛋白酶3之分解形式的「Meso Scale Discovery(MSD)ELISA平台」測試進行定量。將其以對應於處理之小鼠中之分解卡斯蛋白酶3的量除以對照小鼠中之分解卡斯蛋白酶3的量之間的比之活化係數形式表示。
結果顯示本發明化合物能夠於RS4;11腫瘤細胞中活體內誘發細胞凋亡。
在RS4;11白血病細胞之異種移植模型中評估本發明化合物之抗腫瘤活性。
將1×107個RS4;11細胞皮下地移植至免疫抑制小鼠(SCID菌株)中。在移植之後的25至30日,當腫瘤塊已達到約150mm3時,在兩種不同方案(持續兩週的5日/週之每日處理,或持續兩週的每週兩次處理)中用各種化合物經口處理小鼠。自處理開始時每週量測腫瘤塊兩
次。
因此獲得之結果顯示本發明化合物能夠在處理時段期間誘發顯著腫瘤退化。
Claims (24)
- 一種式(I)化合物,
- 如請求項1之式(I)化合物,其中基團表示以下基團中之一者:視情況經胺基取代之5,6,7,8-四氫吲嗪;吲嗪;視情況經甲基取代之1,2,3,4-四氫吡咯并[1,2-a]吡嗪;吡咯并[1,2-a]嘧啶。
- 如請求項1或2之式(I)化合物,其中T表示氫原子、甲基、基團2-(嗎啉-4-基)乙基、3-(嗎啉-4-基)丙基、-CH2-OH、2-胺基乙基、2-(3,3-二氟哌啶-1-基)乙基、2-[(2,2-二氟乙基)胺基]乙基或2-(3-甲氧基氮雜環丁-1-基)乙基。
- 如請求項1至3中任一項之式(I)化合物,其中Ra及Rd各表示氫原子,且(Rb,Rc)連同攜有其之碳原子一起形成1,3-二氧雜環戊烷基或1,4-二噁烷基;或Ra、Rc及Rd各表示氫原子且Rb表示氫、鹵素、甲基或甲氧基;或Ra、Rb及Rd各表示氫原子且Rc表示羥基或甲氧基。
- 如請求項1至4中任一項之式(I)化合物,其中R4表示4-羥基苯基。
- 如請求項1至5中任一項之式(I)化合物,其中R3表示直鏈(C1-C6)烷基、芳基或雜芳基,後兩個基團可能經1至3個選自鹵素、直鏈或分支鏈(C1-C6)烷基、直鏈或分支鏈(C1-C6)烷氧基及氰基之基團取代。
- 如請求項1至6中任一項之式(I)化合物,其中R3表示選自以下群的雜芳基:1H-吲哚、2,3-二氫-1H-吲哚、1H-吲唑、吡啶、1H-吡咯并[2,3-b]吡啶、1H-吡唑、咪唑并[1,2-a]吡啶、吡唑并[1,5-a]嘧啶、[1,2,4]三唑并[1,5-a]嘧啶及1H-吡唑并[3,4-b]吡啶,其全部可經直鏈或分支鏈(C1-C6)烷基取代。
- 如請求項1之式(I)化合物,其選自以下群:N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-{1-[2-(嗎啉-4-基)乙基]- 1H-吲哚-5-基}-5,6,7,8-四氫吲嗪-1-甲醯胺,N-(4-羥基苯基)-3-(6-{[(3S)-3-[2-(嗎啉-4-基)乙基]-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-苯基-5,6,7,8-四氫吲嗪-1-甲醯胺,N-{3-氟-4-[2-(嗎啉-4-基)乙氧基]苯基}-N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)吲嗪-1-甲醯胺,N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-(吡啶-4-基)吲嗪-1-甲醯胺,N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-(2-甲基吡啶-4-基)吲嗪-1-甲醯胺,N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-(1-甲基-1H-吡咯并[2,3-b]吡啶-5-基)吲嗪-1-甲醯胺,N-(4-羥基苯基)-3-(6-{[(3R)-3-[3-(嗎啉-4-基)丙基]-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-苯基-5,6,7,8-四氫吲嗪-1-甲醯胺,N-(2,6-二甲基吡啶-4-基)-N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)吲嗪-1-甲醯胺,N-(4-羥基苯基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)-N-(吡啶-4-基)-5,6,7,8-四氫吲嗪-1-甲醯胺,3-(5-氯-2-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}苯基)- N-(4-羥基苯基)-N-(1-甲基-1H-吡咯并[2,3-b]吡啶-5-基)吲嗪-1-甲醯胺,N-(4-羥基苯基)-N-(2-甲氧基吡啶-4-基)-3-(6-{[(3R)-3-甲基-3,4-二氫異喹啉-2(1H)-基]羰基}-1,3-苯并間二氧雜環戊烯-5-基)吲嗪-1-甲醯胺,其對映異構體及非對映異構體,及其與醫藥學上可接受之酸或鹼之加成鹽。
- 一種用於製備如請求項1之式(I)化合物之方法,其特徵在於將式(II)化合物用作起始物質:
- 如請求項9之用於製備式(I)化合物之方法,其中基團R3或R4中之一者經羥基官能基取代,其中該胺NHR3R4在與由該式(VII)化合物形成之羧酸或與其對應酸衍生物的任何偶合之前預先進行保護該羥基官能基之反應,所得受保護之式(I)化合物隨後進行脫除保護基反應隨後視情況轉化成其與醫藥學上可接受之酸或鹼之加成鹽中之一者。
- 一種醫藥組合物,其包含如請求項1至8中任一項之式(I)化合物或其與醫藥學上可接受之酸或鹼之加成鹽,以及一或多種醫藥學上可接受之賦形劑。
- 如請求項11之醫藥組合物,其用作促細胞凋亡劑。
- 如請求項11之醫藥組合物,其用於治療癌症、自體免疫疾病及免疫系統疾病。
- 如請求項11之醫藥組合物,其用於治療膀胱癌、腦癌、乳房癌及子宮癌、慢性淋巴性白血病、結腸直腸癌、食道癌及肝癌、淋巴母細胞性白血病、非霍奇金淋巴瘤(non-Hodgkin lymphoma)、黑色素瘤、惡性血液病、骨髓瘤、卵巢癌、非小細胞肺癌、前列腺癌及小細胞肺癌。
- 一種如請求項11之醫藥組合物之用途,其用於製造用作促細胞凋亡劑之藥物。
- 一種如請求項11之醫藥組合物之用途,其用於製造預期用於治療癌症、自體免疫疾病及免疫系統疾病之藥物。
- 一種如請求項11之醫藥組合物之用途,其用於製造預期用於治療以下疾病之藥物:膀胱癌、腦癌、乳房癌及子宮癌、慢性淋巴性白血病、結腸直腸癌、食道癌及肝癌、淋巴母細胞性白血病、非霍奇金淋巴瘤、黑色素瘤、惡性血液病、骨髓瘤、卵巢癌、非小細胞肺癌、前列腺癌及小細胞肺癌。
- 如請求項1至8中任一項之式(I)化合物或其與醫藥學上可接受之酸或鹼之加成鹽,其用於治療膀胱癌、腦癌、乳房癌及子宮癌、慢性淋巴性白血病、結腸直腸癌、食道癌及肝癌、淋巴母細胞性白血病、非霍奇金淋巴瘤、黑色素瘤、惡性血液病、骨髓瘤、卵巢癌、非小細胞肺癌、前列腺癌及小細胞肺癌。
- 一種如請求項1至8中任一項之式(I)化合物或其與醫藥學上可接 受之酸或鹼之加成鹽之用途,其用於製造預期用於治療以下疾病之藥物:膀胱癌、腦癌、乳房癌及子宮癌、慢性淋巴性白血病、結腸直腸癌、食道癌及肝癌、淋巴母細胞性白血病、非霍奇金淋巴瘤、黑色素瘤、惡性血液病、骨髓瘤、卵巢癌、非小細胞肺癌、前列腺癌及小細胞肺癌。
- 一種如請求項1至8中任一項之式(I)化合物與選自遺傳毒性劑、有絲分裂毒物、抗代謝物、蛋白酶體抑制劑、激酶抑制劑及抗體之抗癌劑之結合物。
- 一種醫藥組合物,其包含如請求項20之結合物以及一或多種醫藥學上可接受之賦形劑。
- 如請求項20之結合物,其用於治療癌症。
- 一種如請求項20之結合物之用途,其用於製造用於治療癌症之藥物。
- 如請求項1至8中任一項之式(I)化合物,其與放射線療法一起用於治療癌症。
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