TWI704142B - 抗癌劑1-((4-(4-氟-2-甲基-1h-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的製備方法、及其藥物的結晶形及其鹽類 - Google Patents
抗癌劑1-((4-(4-氟-2-甲基-1h-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的製備方法、及其藥物的結晶形及其鹽類 Download PDFInfo
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- TWI704142B TWI704142B TW105113816A TW105113816A TWI704142B TW I704142 B TWI704142 B TW I704142B TW 105113816 A TW105113816 A TW 105113816A TW 105113816 A TW105113816 A TW 105113816A TW I704142 B TWI704142 B TW I704142B
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Abstract
本發明涉及一種新的合成1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺(AL3818)的方法,可製備Al3818的穩定結晶形式,也可製備AL3818的鹽類和其結晶形式。本發明進一步測試AL3818和其鹽類的抗癌和抗眼病活性。新方法已概述在流程I中。
Description
本申請案主張2015年5月4日提交的美國臨時申請案62/156,734和2015年8月14日提交的美國臨時申請案62/205,272的權益。
本發明涉及一種新的合成1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺(AL3818)的方法,可製備Al3818的穩定結晶形式,也已經製備AL3818的鹽類和其結晶形式。本發明進一步測試AL3818和其鹽類的抗癌和抗眼病活性。
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺(AL3818)已經作為血管生成抑制劑在WO2008112407中公開結構,但具有極少製備方法。
縮寫和定義
為了易於參考,使用以下縮寫並且縮寫具有以下含義。
EtOH:乙醇,MeOH:甲醇,IPA:異丙醇,EtOAc:乙酸乙酯,RT:室溫,DIPEA:二異丙基乙胺,DCM:二氯甲烷,DMF:N,N-二甲基甲醯胺,DMAP:4-N,N-二甲氨基吡啶,MsCl:甲磺醯氯,THF:四氫呋喃,TFA:三氟乙酸,TEA:三乙胺,Pd/C:鈀/活性碳,
eq:當量,g:克,mg:毫克,ml:毫升,min:分鐘,bis=di:二或雙
DSC:差示掃描量熱,TGA:熱解重量分析,XRPD:X射線粉末衍射,Exo:放熱,Endo:吸熱。
ALL:急性淋巴細胞性或淋巴母細胞性白血病,CLL:慢性淋巴細胞性或淋巴母細胞性白血病,AML:急性骨髓性或骨髓白血病,CML:慢性骨髓性或骨髓白血病
除非另外指明,否則如本文所用的術語“C1~C6烷基”包括具有直鏈或分支鏈部分的1至6個飽和單價烴基團,包括(但不限於)甲基、乙基、正丙基、異丙基、正丁基、仲丁基、叔丁基等。
除非另外指明,否則如本文所用的術語“C1~C6烷氧基”包括-OC1~C6烷基,其中C1~C6烷基如上文所定義,如甲氧基和乙氧基。
本發明範圍
本發明涉及一種新的合成1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺(AL3818)的方法,在流程I中藉由使中間物(X1)與(Y1)在溶劑中在KI或NaI存在下縮合或使中間物(X2)與(Y2)在溶劑中縮合形成中間物(Z),使其脫除保護基得到最終化合物
(AL3818)。也可製備1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的穩定結晶形式和其鹽以及鹽的結晶形式。
其中R選自H或C1~C6烷氧基。
第1圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的結晶形式的DSC圖。
第2圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的結晶形式的TGA圖。
第3圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的結晶形式的XRPD圖。
第4圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的雙鹽酸鹽的結晶形式的DSC圖。
第5圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的雙鹽酸鹽的結晶形式的TGA圖。
第6圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的雙鹽酸鹽的結晶形式的XRPD圖。
第7圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的雙鹽酸鹽水合物的結晶形式的DSC圖。
第8圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的雙鹽酸鹽水合物的結晶形式的TGA圖。
第9圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的雙鹽酸鹽水合物的結晶形式的XRPD圖。
第10圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的雙馬來酸鹽的結晶形式的DSC圖。
第11圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的雙馬來酸鹽的結晶形式的TGA圖。
第12圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的雙馬來酸鹽的結晶形式的XRPD圖。
第13圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的丁二酸鹽的結晶形式的DSC圖。
第14圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的丁二酸鹽的結晶形式的TGA圖。
第15圖為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的丁二酸鹽的結晶形式的XRPD圖。
第16圖為AL3818和其鹽對於人類子宮內膜癌Ishikawa異種移植無胸腺小鼠的作用。
第17圖為AL3818鹽與卡鉑(Carboplatin,CBX)/太平洋紫杉醇(Paclitaxel,Taxol)的組合對於人類子宮內膜癌Ishikawa異種移植無胸腺小鼠的作用。
第18圖為經口給予AL3818對於鐳射誘導的CNV的作用。
第19圖為AL3818(0.15mg/kg體重)和玻璃體內抗VEGF抗體對於鐳射誘導的CNV的作用。
本發明涉及一種新的合成1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺(AL3818)的方法,在流程I中藉由使中間物(X1)與(Y1)在溶劑中在KI或NaI存在下縮合或使中間物(X2)與(Y2)在溶劑中縮合形成中間物(Z),使其脫除保護基得到最終化合物(AL3818)。
其中R選自H或C1~C6烷氧基,較佳選自H或-OMe;本發明涉及製備1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的穩定結晶形式;本發明涉及製備1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的鹽或穩定結晶鹽形式;
本發明涉及1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的雙鹽酸鹽、雙鹽酸鹽水合物、雙馬來酸鹽、丁二酸鹽、其穩定結晶鹽形式或穩定結晶游離鹼形式。
本發明涉及製備一種藥物組合物,其包含1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的穩定結晶形式和藥學上可接受的載劑;本發明涉及製備一種藥物組合物,其包含1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的鹽或穩定結晶鹽形式和藥學上可接受的載劑;本發明涉及一種1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的穩定結晶形式或鹽或穩定結晶鹽形式,其用於治療贅生性疾病的方法中;本發明涉及一種1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的穩定結晶形式或鹽或穩定結晶鹽形式,其用於製造用於治療贅生性疾病的方法的藥劑;本發明涉及一種1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的穩定結晶形式或鹽或穩定結晶鹽形式,其用於以單一療法形式或與選自基於鉑或基於紫杉烷(taxane)的藥劑的化療劑組合用於治療以下疾病的方法:實體腫瘤,選自肺癌、腎癌、結腸直腸癌、胃癌、黑素瘤、頭/頸癌、甲狀腺癌、胰腺癌、肝癌、前列腺癌、膀胱癌、腦癌、肉瘤、乳腺癌、卵巢癌、子宮頸癌或子宮內膜癌;和血癌,選自ALL、CLL、AML、CML或多發性骨髓瘤;本發明涉及1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的雙鹽酸鹽、雙鹽酸鹽水合物、雙馬來酸鹽、丁二酸鹽、
其穩定結晶鹽形式或穩定結晶游離鹼形式,其用於以單一療法形式或與選自基於鉑或基於紫杉烷的藥劑的化療劑組合用於治療以下疾病的:實體腫瘤,選自肺癌、腎癌、結腸直腸癌、胃癌、黑素瘤、頭/頸癌、甲狀腺癌、胰腺癌、肝癌、前列腺癌、膀胱癌、腦癌、肉瘤、乳腺癌、卵巢癌、子宮頸癌或子宮內膜癌;和血癌,選自ALL、CLL、AML、CML或多發性骨髓瘤;本發明涉及1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的雙鹽酸鹽、雙鹽酸鹽水合物、雙馬來酸鹽、丁二酸鹽、其穩定結晶鹽形式或穩定結晶游離鹼形式,其用於以單一療法形式或與選自基於鉑或基於紫杉烷的藥劑的化療劑組合用於治療以下疾病的方法:肺癌、結腸直腸癌、胃癌、甲狀腺癌、胰腺癌、肝癌、前列腺癌、肉瘤、乳腺癌、卵巢癌、子宮頸癌或子宮內膜癌。
本發明涉及1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的雙鹽酸鹽、雙鹽酸鹽水合物、雙馬來酸鹽、丁二酸鹽、其穩定結晶鹽形式或穩定結晶游離鹼形式,其用於與選自以下的免疫治療劑組合的方法:基於PD-1或PD-L1、SLAM7、溶瘤病毒療法、雙特異性T細胞銜接系統(BiTE)和嵌合抗原受體(CAR)T細胞療法的藥劑,如尼沃單抗(nivolumab)、派立珠單抗(pembrolizumab)、伊匹單抗(ipilimumab)、布林莫單抗(blinatumomab)、埃羅妥珠單抗(elotuzumab)、達土木單抗(daratumumab)、塔力莫基因拉帕沃克(talimogene laherparepvec),用於治療實體腫瘤,選自肺癌、腎癌、結腸直腸癌、胃癌、黑素瘤、頭/頸癌、甲狀腺癌、胰腺癌、肝癌、前列腺癌、膀胱癌、腦癌、肉瘤、乳腺癌、卵巢癌、子宮頸癌或子宮內膜癌;和血癌,選自ALL、CLL、AML、CML或多發性骨髓瘤。
本發明涉及一種新的合成1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺(AL3818)的方法,根據方法A藉由使
中間物(X1)與(Y1)在溶劑中在KI或NaI存在下縮合形成中間物(Z),使其脫除保護基得到最終化合物(AL3818)。
當R為H時,最終化合物(AL3818)是根據方法A1藉由使中間物(Z-1)在如MeOH的醇溶劑中在25℃-80℃下用HCOONH4(甲酸銨)和Pd/C脫除保護基0.1-4小時來製備。(Z-1)是藉由使中間物(X1)與(Y1-1)在KI或NaI以及K2CO3存在下在如丙酮或DMF的溶劑中在60℃~160℃的溫度下反應2~24小時來製備。
當R為4-OMe時,最終化合物(AL3818)是根據方法A2藉由使中間物(Z-2)在DCM中在0℃~30℃下用TFA脫除保護基1~24小時來製備。
(Z-2)是藉由使中間物(X1)與(Y1-2)在KI或NaI以及K2CO3存在下在如丙酮或DMF的溶劑中在60℃~160℃的溫度下反應2~24小時來製備。
本發明涉及一種新的合成1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺(AL3818)的方法,根據方法B藉由使中間物(X2)與(Y2)在溶劑中反應形成中間物(Z),使其脫除保護基得到最終化合物(AL3818)。
當R為H時,最終化合物(AL3818)是根據方法B1藉由使中間物(Z-1)在如MeOH的醇溶劑中在25℃~80℃下用HCOONH4(甲酸銨)和Pd/C脫除保護基0.1~4小時來製備。(Z-1)是藉由使中間物(X2-1)與(Y2)在如吡啶或二甲基吡啶的溶劑中在60℃~160℃的溫度下反應1-12小時來製備。
當R為4-OMe時,最終化合物(AL3818)是根據方法B2藉由使中間物(Z-2)在DCM中在0℃~30℃下用TFA脫除保護基1~24小時來製備。(Z-2)是藉由使中間物(X2-2)與(Y2)在如吡啶或二甲基吡啶的溶劑中在60℃~160℃的溫度下反應1~12小時來製備。
以下實例進一步說明本發明,但是不應解釋為以任何方式限制其範圍。
實例1
方法A、方法A1的代表
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺(AL3818)的製備方法
向1-(羥甲基)環丙基氨基甲酸苯甲酯(50g)和DCM(200ml)的攪拌混合物中添加DIPEA(39g)。將所得溶液用冰/水冷卻至0~5℃並且在此溫度下進一步攪拌15分鐘。經由加料漏斗逐滴添加MsCl(30g),使溫度保持在5℃以下約1.5小時。在添加完成之後,使反應混合物在0~5℃下攪拌30分鐘並且用飽和NaHCO3(150ml)淬滅。將溶液用150ml DCM萃取兩次。將合併的DCM層用0.1N HCl(400ml)、隨後用鹽水洗滌。將其經Na2SO4乾燥並且濃縮以獲得60克灰白色固體作為甲磺酸(1-(苯甲氧基羰基氨基)環丙基)甲酯(Y1-1),MS:(M+1)300。
向(Y1-1)(16g)、X1[(4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基-7-羥基喹啉,12g]、K2CO3(21g)和KI(21g)的攪拌混合物中添加DMF(100ml),將反應懸浮液在80℃下加熱10小時並且添加(Y1-1)(10g)以繼續在80℃下加熱10小時。將反應物接著用水(150ml)淬滅並且用150ml DCM萃取兩次。將合併的DCM層用2N NaOH(100ml)、隨後用水和鹽水洗滌。將其經Na2SO4乾燥並且濃縮,進一步從EtOH中再結晶以獲得9.5g黃色固體作為1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙基氨基甲酸苯甲酯(Z-1)。MS:(M+1)542。
向(Z-1)(9.5g)、HCOONH4(4.7g)和Pd/C(10%,濕潤50%,4.7g)的攪拌混合物中添加MeOH,將反應混合物在45℃下加熱1.5小時。接
著將其冷卻並且經由矽藻土過濾,進一步蒸發。添加2N HCl(200ml)並且用DCM/MeOH(10/1,100ml)萃取兩次。將水層用3N NaOH鹼化以調節至pH 11~12,從而生成固體沉澱物。將固體過濾並且用水洗滌至中性,進一步抽吸乾燥。將固體溶解於DCM/MeOH的混合物(250ml,10/1)中並且進一步用水和鹽水洗滌。將其用MgSO4乾燥並且過濾,進一步蒸發以得到5.5g淡黃色固體粗產物。藉由在緩慢攪拌下將粗產物溶解於DCM/MeOH(40ml,10/1)中以便用石油醚(40ml)濕磨2小時來進行進一步純化。過濾沉澱物並且在烘箱中乾燥得到4.4g最終結晶產物(MP:203~208℃),其可以藉由從EtOH中再結晶而進一步純化得到呈相同結晶形式的較純最終產物。MS:(M+1)408;1H NMR(DMSO-d6)δ 0.60~0.63(d,4H),2.41(s,1H),2.42~2.51(t,2H),3.31(s,2H),3.96(s,3H),4.04(s,2H),6.27(s,1H),6.31~6.32(m,1H),6.97~7.02(t,1H),7.20~7.22(d,1H),7.36(s,1H),7.60(s,1H),8.40~8.42(d,1H),11.41(s,1H)。MP:208~210℃;DSC熔化範圍(吸熱):207~220℃,峰值溫度=216℃。TGA證實為在約210℃下(在205~215℃之間)具有重量損失的非溶劑化材料。XRPD的圖案包含強度%大於10%的10個特徵峰,以如下d值和角度表示:
DSC、TGA和XPRD的圖形分別由第1圖、第2圖和第3圖表示。
實例2
方法A、方法A2的代表
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺(AL3818)的製備方法
其是根據實例1中所述的(Z-1)的製備程式,藉由使用1-(羥甲基)環丙基氨基甲酸4-甲氧基苯甲酯首先生成甲磺酸(1-((4-甲氧基苯甲氧基)羰基氨基)環丙基)甲酯(Y1-2),接著得到1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙基氨基甲酸4-甲氧基苯甲酯(Z-2)而類似地製備,MS:(M+1)572。
在0℃下,向(Z-2)(1.5g)於DCM(15ml)中的攪拌混合物中添加TFA(1.5ml)約30分鐘並且升溫至室溫。將反應物在室溫下攪拌2小時並且添加至水(30ml)中。將水層用DCM萃取兩次(100ml×2)並且用2N NaOH鹼化以調節至pH 11~12。將混合物用DCM(100ml×3)萃取並且進一步用鹽水(100ml)洗滌。將其用MgSO4乾燥並且過濾。蒸發溶液得到1.05g粗
最終產物。進行進一步純化以將粗產物溶解於DCM/MeOH中,用石油醚濕磨並且在烘箱中乾燥,得到0.8g具有相同結晶形式的最終純產物AL3818。
實例3
方法A、方法B1的代表
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺(AL3818)的製備方法
向1-((4-氯-6-甲氧基喹啉-7-基氧基)甲基)環丙基氨基甲酸苯甲酯(X2-1)(5g)、4-氟-2-甲基-1H-吲哚-5-醇(Y2)(5g)和DMAP(4g)的混合物中添加1,6-二甲基吡啶(15ml)。將反應物攪拌並且在135℃下加熱5小時,冷卻,接著在室溫下添加IPA同時緩慢攪拌2小時。過濾固體並且進一步用IPA洗滌,乾燥得到呈固體狀的5.2g(Z-1)。其接著是根據實例1中所述的(Z-1)的脫除保護基程式而類似地製備,得到具有相同結晶形式的最終化合物AL3818。
實例4
方法A、方法B2的代表
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺(AL3818)的製備方法
(Z-2)是根據實例3中所述的程式,藉由使用1-((4-氯-6-甲氧基喹啉-7-基氧基)甲基)環丙基氨基甲酸4-甲氧基苯甲酯(X2-2)和(Y2)而類似地製備。其接著是根據實例2中所述的(Z-2)的脫除保護基程式而類似地製備,得到具有相同結晶形式的最終化合物AL3818。
實例5
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺雙鹽酸鹽和其結晶的製備
向25ml燒瓶中添加含250mg游離鹼(AL3818)、0.625mL含4N HCl的二噁烷(2.5mmol,4eq.)的10ml EtOH,將反應物在75℃下加熱30分鐘,冷卻至室溫並且攪拌過夜。過濾固體並且用丙酮沖洗兩次。將其在烘箱中在50℃下乾燥4小時,得到126mg呈雙鹽酸鹽結晶形式的白色固體,並且進一步從EtOH中再結晶,得到呈相同結晶形式的較純產物。1H NMR(DMSO-d6)δ 1.09~1.24(m,4H),2.43(s,3H),4.08(s,3H),4.40(s,2H),6.32(s,1H),6.76(s,1H),7.05~7.11(t,1H),7.27~7.30(d,1H),7.65(s,1H),7.82(s,1H),8.64(s,2H),8.70~8.73(m,1H),11.51(s,1H)。氯離子色譜顯示2分子比率離子(16.1%)。DSC熔化範圍(放熱):249~280,峰值溫度=268℃。TGA證實為在約230℃下(在225~235℃之間)具有重量損失的非溶劑化材料。XRPD的圖案包含強度%大於10%的21個特徵峰或所有強度%的27個峰,以如下d值和角度表示:
DSC、TGA和XRPD的圖形分別由第4圖、第5圖和第6圖表示。
實例6
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺雙鹽酸鹽水合物和其結晶的製備
向10mL燒瓶中裝入140mg以上實例4的3818-2HCl鹽和0.7mL(×5鹽體積)含80% MeOH的H2O。將所得懸浮液加熱至70℃以形成溶液,冷卻至室溫並且進一步攪拌過夜。過濾固體並且用丙酮沖洗兩次。將其在烘箱中在50℃下乾燥4小時,獲得110mg呈結晶雙鹽酸鹽水合物形式的灰白色固體。1H NMR(DMSO-d6)δ 1.09(s,2H),1.22(s,2H),2.44(s,1H),2.52(s,2H),4.09(s,3H),4.44(s,2H),6.32(s,1H),6.81~6.82(d,1H),7.08~7.14(t,1H),7.29~7.32(d,1H),7.79(s,1H),7.85(s,1H),8.75~8.78(d,1H),8.85(s,2H),11.66(s.1H)。氯離子色譜顯示2分子比率離子(17.8%)。DSC熔化範圍(放熱):207~260℃,峰值溫度=226℃。TGA證實直到120℃(在115~125℃之間)的2.68%(~3%,1個水)重量損失並且在約170℃下(在165~175℃之間)的進一步重量損失。XRPD的圖案包含強度%大於10%的9個特徵峰或所有強度%的12個峰,以如下d值和角度表示:
DSC、TGA和XRPD的圖形分別由第7圖、第8圖和第9圖表示。
實例7
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺雙馬來酸鹽和其結晶的製備
向25mL燒瓶中添加含50mg游離鹼(AL3818)的1.5mL EtOH,將反應物在攪拌下加熱至70℃。向所得溶液中添加36mg(2.5eq)呈固體狀的馬來酸並且在70℃下攪拌0.5小時。將其冷卻至室溫並且攪拌過夜。過濾固體並且用丙酮沖洗兩次,在烘箱中在50℃下進一步乾燥4小時,獲得呈結晶固體狀的68mg,並且進一步從EtOH中再結晶,得到呈與兩個(雙)馬來酸鹽相同的結晶形式的較純產物。1H NMR(DMSO-d6)δ 0.73(s,2H),0.88(s,2H),3.43(s,2H),3.53(s,2H),3.59(s,2H),3.86(s,4H),3.97(s,3H),4.41(s,1H),6.07(s,2H),7.26(s,1H),7.44~7.50(t,1H),7.76~7.79(d,1H),7.88(s,1H),8.10~8.12(d,1H),8.55(s,1H),9.54(s.1H)。馬來酸根離子色譜顯示2分子比率離子(37.1%)。DSC熔化範圍(吸熱):165~202℃,峰值溫度=183℃。TGA證實為在約160℃下(在155~165℃之間)具有重量損失的非溶劑化材料。XRPD的圖案包含強度%大於10%的22個特徵峰或所有強度%的35個峰,以如下d值和角度表示:
DSC、TGA和XRPD的圖形分別由第10圖、第11圖和第12圖表示。
實例8
1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺丁二酸鹽和其結晶的製備
向50mL燒瓶中添加含100mg游離鹼(AL3818)的4mL EtOH,將反應物在攪拌下加熱至75℃。向所得溶液中添加36mg呈固體狀的丁二酸(0.308mmol,1.25eq)並且在75℃下攪拌0.5小時。將其冷卻至室溫並且攪拌過夜。過濾固體並且用丙酮沖洗兩次,在烘箱中在50℃下進一步乾燥4小時,獲得84mg結晶固體,並且進一步從EtOH中再結晶,得到呈相同結晶形式的較純產物。1H NMR(DMSO-d6)δ 0.72(s,4H),2.37~2.42(m,7H),3.99(s,3H),4.10(s,2H),6.27(s,1H),6.32~6.33(d,1H),6.97~7.02(t,1H),7.20~7.23(d,1H),7.39(s,1H),7.61(s,1H),8.42(s,2H),11.41(s,1H)。丁二酸根離子色譜顯示1分子比率離子(23.2%)。DSC熔化範圍:熔化範圍(吸熱):176~202℃,峰值溫度=198℃。TGA證實為在約180℃下(在175~185℃之間)具有重量損失的非溶劑化材料。XRPD的圖案包含強度%大於10%的11個特徵峰或所有強度%的19個峰:
DSC、TGA和XRPD的圖形分別由第13圖、第14圖和第15圖表示。
實例9
實例10
基於發明人使用AL3818游離鹼、其2HCl鹽、其雙馬來酸鹽和其丁二酸鹽的研究經歷,在根據實例9的MTT分析中預測以下腫瘤抑制結果。
預測對於以下各種細胞系的活體外抑制活性為2~10μM±1.7μM:實體腫瘤,如腎癌、黑素瘤、頭/頸癌、膀胱癌、腦癌;和血癌,如ALL、CLL、AML、CML和多發性骨髓瘤。
實例11
使用子宮內膜Ishikawa細胞系(異種移植物)的動物抗腫瘤活性活體內測試進行如下:
將充分生長的子宮內膜癌Ishikawa的腫瘤組織切成3mm小塊,並且將每一裸鼠皮下接種一小塊至右腋窩中。將動物分組並且給藥如下:
1)AL3818-H1(雙鹽酸鹽,2HCl),MW:480,3.54mg/kg
2)AL3818-H2(雙鹽酸鹽水合物,2HCl.H2O),MW:598,3.67mg/kg
3)AL3818-S(丁二酸鹽),MW:525,3.87mg/kg
4)AL3818-M(雙馬來酸鹽),MW:639,4.71mg/kg
5)AL3818-F(游離鹼),MW:407,3mg/kg
6)對照物
在13天之後,當腫瘤尺寸達到100mm3以上時,開始處理。根據腫瘤尺寸,排除腫瘤尺寸過大或尺寸不足的動物,並且將動物分組成具有類似平均腫瘤體積。接著,如上所述,每日經口給予動物0.5ml/20g的體積連續14天。在接種13天之後,一周使用卡尺測量大直徑a(mm)和小直徑b(mm)兩次。腫瘤體積藉由下式計算得到:TV=ab2/2。相對腫瘤體積如下計算:RTV=Vt/Vo,Vo表示在第一天處理時的腫瘤體積;Vt表示在每一測量日的腫瘤體積。在接種之後30天(D18),將動物處死並且藉由解剖獲得腫瘤。接著,測定個體體重和腫瘤重量,並且如下式計算。
腫瘤抑制活性在50~95%之間。結果在第16圖中示出。
實例12
基於發明人使用AL3818游離鹼、其HCl鹽(單或雙)、其雙馬來酸鹽和其丁二酸鹽的研究經歷,根據實例11預測以下活體內腫瘤抑制結果(異種移植物)。
預測對於以下各種細胞系的活體內腫瘤抑制活性為50%~100%:實體腫瘤,如肺癌、腎癌、結腸直腸癌、胃癌、黑素瘤、頭/頸癌、甲狀腺癌、胰腺癌、肝癌、前列腺癌、膀胱癌、腦癌、肉瘤、乳腺癌、卵巢癌、子宮頸癌和子宮內膜癌;和血癌,如ALL、CLL、AML、CML和多發性骨髓瘤。
實例13
AL3818雙HCl鹽和雙馬來酸鹽也與藉由使用以下基於鉑、基於紫杉烷或這兩個的化學療法組合來加以測試;如:組合順鉑、卡鉑、太平洋紫杉醇或順鉑/太平洋紫杉醇、卡鉑/太平洋紫杉醇。與卡鉑/太平洋紫杉醇組合的實驗是與實例11的描述類似地進行。腫瘤抑制活性在50至>100%之間。結果在第17圖中示出。
實例14
基於發明人使用AL3818游離鹼、其HCl鹽(單或雙)、其雙馬來酸鹽和其丁二酸鹽的研究經歷,根據實例13預測以下活體內組合化學療法(護理標準,如基於鉑、基於紫杉烷或這兩個的化學療法)腫瘤抑制結果(異種移植物),尤其與順鉑、卡鉑、太平洋紫杉醇或順鉑/太平洋紫杉醇、卡鉑/太平洋紫杉醇一起組合。
預測對於以下各種細胞系的活體內腫瘤抑制活性為50%至>100%消退:實體腫瘤,如肺癌、腎癌、結腸直腸癌、胃癌、黑素瘤、頭/頸癌、甲狀腺癌、胰腺癌、肝癌、前列腺癌、膀胱癌、腦癌、肉瘤、乳腺癌、卵巢癌和子宮頸癌;和血癌,如ALL、CLL、AML、CML和多發性骨髓瘤。
實例15
基於發明人使用AL3818游離鹼、其HCl鹽(單或雙)、其雙馬來酸鹽和其丁二酸鹽的研究經歷,預測以下活體內組合作用,其中與選自以下的免疫治療劑組合:基於PD-1或PD-L1、SLAM7、溶瘤病毒療法、雙特異性T細胞銜接系統(BiTE)或嵌合抗原受體(CAR)T細胞療法的藥劑,如(但不限於)尼沃單抗、派立珠單抗、伊匹單抗、布林莫單抗、埃羅妥珠單抗、達土木單抗、塔力莫基因拉帕沃克,用於治療實體腫瘤,選自肺癌、腎癌、結腸直腸癌、胃癌、黑素瘤、頭/頸癌、甲狀腺癌、胰腺癌、肝癌、前列腺癌、膀胱癌、腦癌、肉瘤、乳腺癌、卵巢癌、子宮頸癌或子宮內膜癌;和血癌,選自ALL、CLL、AML、CML或多發性骨髓瘤
預測對於以下各種細胞系的活體內腫瘤抑制活性為50%至>100%消退:實體腫瘤,如肺癌、腎癌、結腸直腸癌、胃癌、黑素瘤、頭/頸癌、甲狀腺癌、胰腺癌、肝癌、前列腺癌、膀胱癌、腦癌、肉瘤、乳腺癌、卵巢癌和子宮頸癌;和血癌,如ALL、CLL、AML、CML和多發性骨髓瘤。
實例16
鐳射誘導的脈絡膜新生血管(CNV)的小鼠模型
(1)對10至12周齡的C57 BL/6小鼠進行實驗。使用安裝在裂隙燈上的532nm二極體雷射器,使用50μm光斑尺寸、100ms持續時間和100mW鐳射能量誘導鐳射CNV。每只眼睛接受4次鐳射燒傷。AL3818-H1的儲備溶液是藉由將化合物溶解于水中達到25mg/mL濃度來製備,並且進一步在水中稀釋成250或25μg/ml工作溶液。小鼠是以每kg體重2.5或0.25mg的劑量,以每20克體重200μl的體積經口管飼,在鐳射處理之前一天開始,每天一次,直至之後10天為止。對照組小鼠將接受管飼與用於溶解化合物的水。到實驗結束時,對小鼠進行螢光血管造影以排除由程式引起的出血點和其它機械傷害。將
小鼠處死並且藉由用FITC結合的異凝集素B4和抗ICAM2抗體共染色的RPE/脈絡膜鋪片的免疫染色測量CNV尺寸。對於對照組0.25mg/kg和2.5mg/kg,我們檢查RPE/脈絡膜鋪片上的眼43、44和49。在免疫染色之後,在蔡司(Zeiss)螢光顯微鏡上獲取影像。在Image J軟體中測量CNV尺寸。我們的結果(第18圖)顯示用0.25或2.5mg/kg體重的AL3818處理的小鼠的鐳射誘導的CNV的平均尺寸幾乎減小70%。
(2)還研究在AL3818-M與抗VEGF抗體之間的潛在協同或累加作用。緊接在鐳射燒傷之後,小鼠藉由玻璃體內注射用1μg劑量來自安迪生物公司(R&D Systems)的單克隆VEGF中和抗體(mAb AF564)處理。我們具有4個實驗組:對照(用水處理)、AL3818-M、抗VEGF和AL3818-M+抗VEGF。總共分析75個鐳射光斑。對照組或僅AL3818-M組中的小鼠接受相同2μl體積生理食鹽水的玻璃體內注射。結果(第19圖)顯示用0.15mg/kg AL3818和1μg抗VEGF抗體處理的眼的鐳射CNV與對照組相比減少幾乎30%(P<0.01,單因素方差分析,鄧尼特事後檢驗(Dunnett post-hoc test))。
實例17
基於發明人使用AL3818游離鹼、其HCl鹽(單或雙)、其雙馬來酸鹽和其丁二酸鹽的研究經歷,根據實例16明確預測與如但不限於AMD(年齡相關性黃斑變性)的眼病的有效治療相關的活體內動物模型CNV功效;或也根據實例16明確預測這些化合物與抗VEGF抗體或VEGF捕獲劑(如但不限於蘭比珠單抗(ranibizumab)或阿柏西普(aflibercep))組合產生協同治療作用。
實例18
Claims (17)
- 如申請專利範圍第1項所述之合成1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺(AL3818)的方法,其中R進一步選自H或-OMe。
- 如申請專利範圍第1項所述之合成1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺(AL3818),其中,在製備中間物(Z)的方法中,R為H或-OMe時,KI是根據方法A1或A2的第一步與DMF一起在80℃下使用,二甲基吡啶是根據方法B1或B2的第一步在135℃下使用。
- 如申請專利範圍第1項所述之合成1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺(AL3818)的方法,其中R為H時,HCOONH4/Pd/C是在45℃下用於脫除保護基步驟;其中R為-OMe時,DCM/TFA(10/1)是在25℃下用於脫除保護基步驟。
- 一種如申請專利範圍第1項之方法所製得之1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的鹽類,其展現至少一個以下特徵,雙鹽酸鹽的DSC熔化範圍(放熱):249~280,峰值溫度=268℃,TGA證實為在約230℃下(在225~235℃之間)具有重量損失的非溶劑化材料,在第4圖、第5圖中示出;雙鹽酸鹽水合物的DSC熔化範圍(放熱):207~260℃,峰值溫度=226℃,TGA證實直到120℃(在115~125℃之間)的2.68%(~3%,1個水)重量損失、並且在約170℃下(在165~175℃之間)的進一步重量損失,在第7圖、第8圖中示出;雙馬來酸鹽的DSC熔化範圍(吸熱):165~202℃,峰值溫度=183℃,TGA證實為在約160℃下(在155~165℃之間)具有重量損失的非溶劑化材料,在第10圖、第11圖中示出;丁二酸鹽的DSC熔化範圍:熔化範圍(吸熱):176~202℃,峰值溫度=198℃,TGA證實為在約180℃下(在175~185℃之間)具有重量損失的非溶劑化材料,在第13圖、第14圖中示出。
- 一種藥物組合物,其包含如申請專利範圍第9項至第13項 中任一項所定義的化合物、其穩定結晶鹽形式或穩定結晶游離鹼形式作為活性成分,以及藥學上可接受的載劑。
- 如申請專利範圍第14項之藥物組合物,其包含選自1-((4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-6-甲氧基喹啉-7-基氧基)甲基)環丙胺的雙鹽酸鹽、雙鹽酸鹽水合物、雙馬來酸鹽、丁二酸鹽、其穩定結晶鹽形式或穩定結晶游離鹼形式作為活性成分,以及藥學上可接受的載劑。
- 一種如申請專利範圍第9項至第13項中任一項所述之化合物在製備治療贅生性疾病之藥物的用途,其係將該化合物、或該化合物和藥學上可接受的賦形劑的一藥物組成物、或使該化合物或該藥物組成物與一化療劑組合給予有需要的個體,其中該贅生性疾病為選自肺癌、甲狀腺癌、胰腺癌、前列腺癌、肉瘤、乳腺癌、卵巢癌、子宮頸癌或子宮內膜癌的實體腫瘤,該化療劑為卡鉑/太平洋紫杉醇。
- 一種如申請專利範圍第9項至第13項中任一項所述之化合物在製備治療眼病之藥物的用途,其係將該化合物、或該化合物和藥學上可接受的賦形劑的一藥物組成物、或使該化合物或該藥物組成物與一抗VEGF抗體給予有需要的個體。
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