TWI418554B - 結晶形(r)-(e)-2-(4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1h-吲唑-3-基)乙烯基)-1h-吡唑-1-基)乙醇 - Google Patents
結晶形(r)-(e)-2-(4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1h-吲唑-3-基)乙烯基)-1h-吡唑-1-基)乙醇 Download PDFInfo
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- TWI418554B TWI418554B TW100134428A TW100134428A TWI418554B TW I418554 B TWI418554 B TW I418554B TW 100134428 A TW100134428 A TW 100134428A TW 100134428 A TW100134428 A TW 100134428A TW I418554 B TWI418554 B TW I418554B
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Description
已認為纖維母細胞生長因子(FGF)為諸多生理過程(諸如在發育及血管新生期間之形態發生)之重要介體。纖維母細胞生長因子受體(FGFR)家族由四個成員(FGFR1至FGFR4)組成,其為由細胞外免疫球蛋白(Ig)類結構域、疏水跨膜區及含有酪胺酸激酶域之細胞質部分構成之糖蛋白。FGF結合導致FGFR二聚化,接著導致受體自體磷酸化及下游信號傳導路徑激活。受體激活足以募集及激活特定下游信號傳導搭配物,其參與調控多種過程,諸如細胞生長、細胞代謝及細胞存活。因此,FGF/FGFR信號傳導路徑對於在腫瘤細胞增殖、轉移、入侵及血管新生中非常關鍵的諸多生物過程具有多效性效應。
此項技術中已知乙烯基吲唑可用於癌症治療。參見例如WO 200210137及WO 2003101968。在此項技術中亦已知FGFR抑制劑。參見例如WO 2002022598。
PCT/US2010/033487揭示一種非晶形(R)-(E)-2-(4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)乙烯基)-1H-吡唑-1-基)乙醇,其為不良的結晶體且可用作FGFR抑制劑。
本發明提供一種結晶形(R)-(E)-2-(4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)乙烯基)-1H-吡唑-1-基)乙醇,其為FGFR之強力抑制劑,且相對於先前形式,可提供以下有利性質:大規模高效固體處理性質、容易藉由結晶純化及在醫藥加工及儲存條件下之熱力學穩定性。在一個實施例中,結晶形(R)-(E)-2-(4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)乙烯基)-1H-吡唑-1-基)乙醇為單水合物形式。
本發明亦提供結晶形(R)-(E)-2-(4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)乙烯基)-1H-吡唑-1-基)乙醇,其特徵為X射線粉末繞射圖案(Cu輻射,λ=1.54059)包含一個位於14.65之峰及一或多個位於3.54、12.51或19.16(2θ+/- 0.1°)之峰。
本發明提供一種治療哺乳動物癌症之方法,其中該癌症係選自由乳癌、非小細胞肺癌(NSCL)、膀胱癌、胃癌、胰臟癌、***癌、結腸癌、多發性骨髓瘤、肝癌、黑色素瘤、頭頸癌、甲狀腺癌、腎細胞癌、神經膠母細胞瘤及睪丸癌組成之群,其包含向需要該治療之哺乳動物投與有效量的本發明之化合物或鹽。
本發明亦提供醫藥組合物,其包含本發明之化合物或鹽合併一或多種醫藥學上可接受之載劑、稀釋劑或賦形劑。在一特定實施例中,該組合物進一步包含一或多種其他治療劑。
本發明亦提供用於療法中之本發明之化合物或鹽。此外,本發明提供本發明之化合物或鹽用於製造用以治療癌症之藥劑的用途。此外,本發明提供本發明之化合物或鹽用於治療癌症的用途。詳言之,該等癌症係選自由乳癌、肺癌、膀胱癌、胃癌、胰臟癌、***癌、結腸癌、多發性骨髓瘤AML、肝癌、黑色素瘤、頭頸癌、甲狀腺癌、腎細胞癌、神經膠母細胞瘤及睪丸癌組成之群。更尤其地,該等癌症係選自由乳癌、非小細胞肺癌、膀胱癌、胃癌、胰臟癌、***癌、結腸癌、多發性骨髓瘤、肝癌、黑色素瘤、頭頸癌、甲狀腺癌、腎細胞癌、神經膠母細胞瘤及睪丸癌組成之群。最尤其地,該癌症為非小細胞肺癌。最尤其地,該癌症為胃癌。最尤其地,該癌症為多發性骨髓瘤。此外,本發明提供一種用於治療選自由乳癌、非小細胞肺癌、膀胱癌、胃癌、胰臟癌、***癌、結腸癌、多發性骨髓瘤、肝癌、黑色素瘤、頭頸癌、甲狀腺癌、腎細胞癌、神經膠母細胞瘤及睪丸癌組成之群的癌症的醫藥組合物,其包含本發明之化合物或鹽作為活性成份。
熟習此項技術之讀者將瞭解,所有本發明之化合物皆能夠形成鹽。本發明之化合物為胺,且因此可與許多無機酸及有機酸中之任一者反應以形成醫藥學上可接受之酸加成鹽。該等醫藥學上可接受之酸加成鹽及其通用製備方法為此項技術中所熟知,參見例如P. Stahl等人,HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES,SELECTION AND USE,(VCHA/Wiley-VCH,2008);S.M. Berge等人,「Pharmaceutical Salts」,Journal of Pharmaceutical Sciences
,第66卷,第1期,1977年1月。
如本文中所用,術語「分離的」意謂結晶形(R)-(E)-2-(4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)乙烯基)-1H-吡唑-1-基)乙醇具有99%純度。
本發明之化合物基本上可如以下製備及實例中所說明來製備。以下製備及實例之命名係使用ChemDrawUltra 10.0中之Struct=Name命名特徵完成。
向3頸12 L圓底燒瓶中添加四氫呋喃(THF,3 L)及二異丙胺(DIPA,315 mL,2.24 mol)並冷卻至-78℃。緩慢添加正丁基鋰(1.6 M於己烷中,1400 mL,2.24 mol)。添加完成及溫度設置在-78℃後,緩慢添加3,5-二氯吡啶(296.7 g,2.00 mol)溶液,其立即形成黃色溶液並轉變為鐵銹色懸浮液。添加完成及溫度設置在-78℃後,緩慢添加THF(600 mL)中之乙醛(230 mL,4.05 mol)。在-78℃下繼續攪拌。3小時後,移除乾冰浴並藉由逐滴添加飽和氯化銨水溶液(1 L)開始淬滅反應。在攪拌下使反應升溫至室溫(RT)隔夜。用甲基第三丁基醚(MTBE,2 L)、飽和氯化銨水溶液(1 L)及水(2 L)稀釋混合物。用飽和氯化鈉水溶液(鹽水)分配並洗滌有機物。用MTBE(1.5 L)萃取水相。合併有機層,用硫酸鈉乾燥,過濾並在真空中濃縮。藉由矽膠層析法[含25%乙酸乙酯(EA)之己烷]純化殘餘物以得到紅色油狀標題化合物。產率:352 g(90%)。MS(ES)m/z
192[M+1]+
。
在CHIRALPAKAD-H管柱上用90%庚烷/10%乙醇溶離以分離自製劑1所得之立體異構體混合物。峰2為所要之對映異構體。將產物之樣品溶解於CDCl3
(最終濃度100 mg/mL)以創建絕對組態。使用ChiralIR FT VCD光譜儀(BioTools Inc)獲得振動圓二色性(VCD)及解析度為4 cm-1之紅外(IR)光譜,該光譜儀具有配備有BaF2
窗口之IR小室及100 mm之路徑長度。用150 μL樣品採集VCD及IR,持續6小時。呈現不經過平滑處理或進一步數據處理之數據。藉由在Linux叢集上於B3PW91/6-31G**位準使用高斯(Gaussian)優化最低能量構象異構體來獲得振動頻率及吸收及VCD強度,且使用6 cm-1振動圓二色性之洛倫茲頻寬(Lorentzian bandwidth)模擬相應的光譜。以上分析顯示產物為S異構體。產率:84.37 g(27%)。MS(ES)m/z
192[M+1]+
。
將(S)-1-(3,5-二氯吡啶-4-基)乙醇(5.02 g,26.14 mmol)溶於二氯甲烷(DCM,100 mL),且在冰浴中冷卻燒瓶。添加三乙胺(TEA,3.5 mL,25.11 mmol),接著逐滴添加甲烷磺醯氯(2.2 mL,28.42 mmol)。移除冰浴且使反應升溫至室溫。4小時後,用水(100 mL)淬滅反應並分離各層。用DCM(50 mL),接著用20%異丙醇(IPA)/三氯甲烷(50 mL)萃取水層。合併有機萃取物,用無水硫酸鈉乾燥,過濾且在真空中濃縮。產率:7.15 g(100%)。MS(ES)m/z
270[M+1]+
。
在配備有磁性攪拌子、氮氣層及內部溫度探針之1 L 3頸燒瓶中,將2-(2-溴乙氧基)四氫-2H-哌喃(34 g,156 mmol)溶於乙腈(ACN,400 mL)中。添加4-碘吡唑(29.34 g,149.74 mmol),接著添加碳酸銫(73.4 g,223.02 mmol)。在室溫下攪拌混合物18小時。經由CELITE過濾反應混合物,用ACN洗滌濾餅且將濾液濃縮成金黃色油狀物。不經進一步純化即可使用。產率:47.819 g(99%)。MS(ES)m/z
323[M+1]+
。
向10 L反應容器中裝載N,N-二甲基甲醯胺(DMF,2.50 L)、5-羥基吲唑(150.20 g,1.12 mol)及1H-咪唑(114.35 g,1.68 mol)。冷卻混合物至0℃並經0.5小時添加第三丁基二甲基氯矽烷(253.16 g,1.68 mol)。在18℃下攪拌混合物3小時。向反應中緩慢添加水(2.5 L),同時用5℃冰浴保持內部溫度在20℃左右。將混合物轉移至分液漏斗中並用EA(2×2.5 L)萃取。合併萃取物並用水(3×2.5 L)與鹽水洗滌。將有機溶液用無水硫酸鈉乾燥,過濾並蒸發成紅色油狀物。將油狀物通過矽膠墊並用溶離劑(含0%至30% EA之己烷)溶離以得到呈橙色油狀之標題化合物,其會發生結晶。產率:300 g(100%)。MS(ES)m/z
249[M+1]+
。
於10 L夾套反應器容器中,將5-(第三丁基二甲基矽烷氧基)-1H-吲唑(300.00 g,1.21 mol)之DCM(4.00 L)溶液冷卻至10℃。經0.5小時向所得溶液中分數次添加N-碘代丁二醯亞胺(298.89 g,1.33 mol)。在室溫下攪拌混合物3小時以發生完全轉化,如藉由液相層析質譜法(LC-MS)及薄層層析法(TLC)所指示。將混合物冷卻至10℃並用水(2.5 L)淬滅。將混合物轉移至分液漏斗中並將水層萃取至DCM(2.5 L)中。用10%硫代硫酸鈉水溶液(5 L)與鹽水洗滌合併的有機萃取物。用硫酸鎂乾燥有機溶液,過濾且在真空中濃縮以得到橙色固態標題化合物。產率:388 g(90%)。MS(ES)m/z
375[M+1]+
。
於10 L夾套反應器容器中,將5-(第三丁基二甲基矽烷氧基)-3-碘-1H-吲唑(387.00 g,1.08 mol)於DCM(2.50 L)及THF(1.00 L)中之溶液冷卻至10℃。經0.5小時向所得混合物中添加甲磺酸(14.0 mL,216.02 mmol),接著添加3,4-二氫-2H-哌喃(296 mL,3.24 mol),可觀察到輕微放熱。在室溫下攪拌混合物3小時。將反應冷卻至10℃並用飽和碳酸氫鈉水溶液(2 L)淬滅。用水(2 L)稀釋混合物並用DCM(2 L)萃取水層。用水(2 L)與鹽水洗滌合併的有機萃取物。用無水硫酸鈉乾燥有機混合物,過濾並在真空中濃縮。用溶離劑(0%至10% EA/己烷)經由矽膠墊溶離殘餘物以得到標題化合物。產率:150 g(31%)。MS(ES)m/z
459[M+1]+
。
在配備有磁性攪拌子、溫度探針及有隔板之冷凝器的500 mL 3頸圓底燒瓶中,向5-(第三丁基二甲基矽烷氧基)-3-碘-1-(四氫-2H-哌喃-2-基)-1H-吲唑(14 g,30.54 mmol)於DMF(150 mL)中之混合物充氮氣10分鐘。向所得溶液中添加三丁胺(TBA,6.7 g,36.1 mmol)及4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧硼(7.0 g,43.18 mmol),並持續充氣10分鐘。向所得混合物中添加氯化雙(三苯基膦)鈀(II)(0.45 g,0.63 mmol)並再繼續充氣0.5小時。在95-100℃下加熱混合物18小時。將反應混合物冷卻至40℃以下並添加4-碘-1-(2-(四氫-2H-哌喃-2-基氧基)乙基)-1H-吡唑(9.8 g,30.42 mmol)。向所得混合物中添加氫氧化鋇八水合物(19.3 g,60.3 mmol)及水(13 mL)並繼續充氣10分鐘。向反應中添加氯化1,1'-雙(二苯基膦)二茂鐵鈀(II)-DCM錯合物(1.3 g,1.56 mmol)並繼續充氣0.5小時。在氮氣下,在95℃下加熱混合物3小時。用EA稀釋混合物並經由Celite墊過濾。用鹽水(400 mL)洗滌濾墊並分離濾液層。用鹽水洗滌有機層並用EA萃取合併之水層。合併有機溶液並濃縮成棕色油狀物。將油狀物溶於DCM(100 mL)中並添加至矽膠墊。用溶離劑(含50% EA之己烷,接著使用含70% EA之己烷)溶離濾墊,以得到淡棕色油狀物。用MTBE(100 mL)濕磨,得到固態標題化合物。產率:5 g(37%)。MS(ES)m/z
439[M+1]+
。
在配備有內部溫度探針、回流冷凝器、氮氣層及磁性攪拌子之3頸250 mL圓底燒瓶中,由(E)-1-(四氫-2H-哌喃-2-基)-3-(2-(1-(2-(四氫-2H-哌喃-2-基氧基)乙基)-1H-吡唑-4-基)乙烯基)-1H-吲唑-5-醇(10.0 g,22.83 mmol)及碳酸銫(7.88 g,23.94 mmol)在ACN(92 mL)中形成漿物,並升溫至60℃。向懸浮液中添加甲磺酸(S)-1-(3,5-二氯吡啶-4-基)乙酯(7.03 g,26.02 mmol)並攪拌隔夜。冷卻反應混合物至室溫,過濾並用ACN洗滌固體。濃縮濾液並用矽膠層析法(2%至4%(含2 M氨之甲醇)/DCM)純化殘餘物。合併各產物部分並在真空中濃縮成白色泡沫。產率:12.5 g(86%)。MS(ES)m/z
612[M+1]+
。
向配備有加料漏斗、氮氣入口、內部溫度探針及磁性攪拌器之3頸250 mL圓底燒瓶中裝載甲醇(57 mL)並在冰浴中冷卻。經由加料漏斗向所得溶液中緩慢添加乙醯氯(20 mL,281.03 mmol)。經由加料漏斗向溶液中添加5-((R)-1-(3,5-二氯吡啶-4-基)乙氧基)-1-(四氫-2H-哌喃-2-基)-3-((E)-2-(1-(2-(四氫-2H-哌喃-2-基氧基)乙基)-1H-吡唑-4-基)乙烯基)-1H-吲唑(7.1 g,1.59 mmol)之甲醇(40 mL)溶液。添加完畢後,移除冰浴,升溫至室溫並攪拌混合物4小時。在真空中將反應混合物濃縮成黃色泡沫。將黃色泡沫溶於甲醇(10 mL)並緩慢添加至飽和碳酸氫鈉水溶液(120 mL)中。在室溫下攪拌混合物30分鐘。過濾混合物,用水(100 mL)洗滌固體並在真空下乾燥。自熱EA/甲醇/己烷中再結晶固體以得到白色固態標題化合物。產率:2.1 g(41%)。MS(ES)m/z
444[M+1]+
。
用氮氣淨化反應容器,並裝載(R)-(E)-2-(4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)乙烯基)-1H-吡唑-1-基)乙醇及由11%水/乙腈組成之溶劑混合物。將所得懸浮液加熱至66-68℃之內部溫度以產生溶液。將溶液緩慢冷卻至56-58℃,接著用晶種於11%水/乙腈混合物中之懸浮液種晶並緩慢攪拌。將反應混合物先冷卻至48-50℃,接著冷卻至19-20℃。藉由在氮氣流存在下,在至少80%相對濕度下經過固態餅過濾來分離產物。接著將氮氣流中之濕度改變至40%,並繼續乾燥,從而產生標題化合物。應注意晶種如下類似地獲得:用氮氣淨化反應容器並裝載(R)-(E)-2-(4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)乙烯基)-1H-吡唑-1-基)乙醇及由11%水/乙腈組成之溶劑混合物。將所得懸浮液加熱至70℃之內部溫度以產生溶液。接著緩慢冷卻溶液,使其結晶,過濾並乾燥。該化合物為FGFR之強力抑制劑,且相對於先前形式可具有如下有利性質:大規模高效固體處理性質,容易藉由結晶純化,及在醫藥加工及儲存條件下之熱力學穩定性。
使用配備有CuKα輻射(λ=1.54059Å(電壓:45kV,及安培數:40mA))的PANalytical X'PertTM
Pro MPD PW3040 Pro繞射儀採集XRPD圖案,該CuKα輻射係用Optix長細焦點光源(long fine-focus source)產生。將試樣包夾於3微米厚之薄膜之間,在傳輸幾何學中分析,且以每秒1轉旋轉以優化取向統計。分析之前,分析矽試樣(NIST標準參考材料640c)以驗證矽111峰之位置。針對該材料分析一個Panalytical圖案,且經由與單晶分析之模擬XRPD圖案對比來評估較佳取向及粒子統計效應。使用橢圓漸變多層鏡將光源之CuKα
X射線通過試樣聚焦至偵測器上。使用距離試樣240 mm之掃描位置靈敏偵測器(X'Celerator)採集繞射圖案。用0.017度2θ之步長及1.2度/分鐘之掃描速率及0.5度發散狹縫及0.25度散射狹縫,自1.01至39.99度2θ採集數據。使用射束阻擋器最小化空氣散射所產生之背景。將索勒狹縫(soller slit)用於入射光線及繞射光線以最小化軸向發散(axial divergence)。表1顯示觀測峰。所用能量臨限為5%。
因此,實例1之適當製備的樣品的特徵可為使用CuKα輻射之X射線繞射圖案具有如表1描述之繞射峰(2θ值),尤其具有位於14.65之峰合併一或多個位於3.54、12.51及19.16之峰;且更尤其具有位於14.65之峰;繞射角之公差為0.1度、更佳0.01度。
FGF/FGFR路徑之異常調節涉及於許多形式的人類惡性病中。FGFR及FGF通常在多種癌症中過度表現,且其表現通常導致不良預後。已於若干類型之腫瘤中發現FGFR激酶域之激活突變,該等腫瘤包括乳癌、NSCLC、膀胱癌、胃癌、***癌、結腸癌及多發性骨髓瘤。亦在諸多乳癌、胃癌及肺癌患者中偵測到FGFR基因座之染色體組擴增。亦已在諸多不同類型之腫瘤中發現FGFR或FGF之過度表現,諸如膀胱癌、多發性骨髓瘤、***癌及肺癌。可得益於FGFR家族路徑抑制劑療法之其他癌症包括AML、肝癌、黑色素瘤、頭頸癌、甲狀腺癌、胰臟癌、腎細胞癌、神經膠母細胞瘤及睪丸癌。除了在腫瘤形成及發展中之作用,FGF及FGFR亦為血管新生之關鍵性調節因子,尤其在腫瘤生長過程中。FGF/FGFR軸亦在增加諸如癌症相關纖維母細胞之其他腫瘤基質細胞方面具有重要作用。上調FGF亦導致對抗血管新生療法及其他化學療法產生抗性。最後,FGFR之小分子抑制劑已於若干臨床前腫瘤模型中證實其抗腫瘤活性並正在臨床開發中。總而言之,FGF/FGFR路徑對癌細胞中之若干重要細胞過程必不可少。由於該等原因,基於以FGFR及/或FGF信號傳導為目標之療法可直接影響腫瘤細胞及腫瘤血管新生。
基本上如以下檢測法中所述來測試製劑10:FGFR1酶檢測法(過濾結合(Filter Binding))、FGFR3酶檢測法(過濾結合)、基於RT-112細胞中FGF9誘導之p-ERK的檢測法(在BSA存在下)及基於人臍靜脈內皮細胞(HUVEC)中ERK磷酸化(Thr202/Tyr204)之AlphaScreen SureFire偵測的檢測法。該等檢測法證實製劑10為FGFR家族路徑抑制劑且具有抗癌活性。因此,生成非晶形(R)-(E)-2-(4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)乙烯基)-1H-吡唑-1-基)乙醇表明生成本發明之化合物。該化合物之結晶型仍為有利的,因為相對於先前形式,其可提供以下性質:大規模高效固體處理性質,容易藉由結晶純化,及在醫藥加工及儲存條件下之熱力學穩定性。
在50 μL含有10 mM 4-(2-羥乙基)-1-哌嗪乙磺酸(HEPES)(pH 7.5)、8 mM參(羥甲基)胺基甲烷(Tris-HCl)(pH 7.5)、5.0 mM二硫蘇糖醇(DTT)、10.0 μM三磷酸腺苷(ATP)、10 mM MnCl2
、150 mM NaCl、0.01% TRITONX-100、0.5 μCi33
P-ATP及0.05 μg/μL聚(麩胺酸-酪胺酸)之緩衝液中培育FGFR1或FGFR3激酶(0.15 ng/μL人FGFR1或0.32 ng/μL人FGFR3)。在室溫下以50 μL之體積進行反應30分鐘,接著藉由添加130 μL之10% H3
PO4
淬滅反應。轉移反應物(120 μL)至96孔1.0 μm玻璃纖維過濾板,在室溫下培育20-30分鐘並接著在TITERTEKZoom上用0.5% H3
PO4
洗滌3次。將孔風乾後添加40 μL MicroScintTM
20(Packard),接著在Wallac Micobeta計數器上計數。對於化合物抑制,以二甲亞碸(DMSO)中之10 mM儲液形式提供化合物。將化合物以1:3連續稀釋於20% DMSO中以產生10點濃度反應曲線,且以1:5稀釋(於4%最終DMSO濃度中稀釋至20 μM至0.001 μM最終濃度)至反應板中,接著將反應混合物添加至過濾板中以測定化合物活性。對照孔僅含有4% DMSO,根據含有0.1 M四乙酸乙二胺(EDTA)之對照孔建立基線。自各板上之對照孔計算10點濃度中各濃度的抑制百分率值,隨後使用ActivityBase軟體(IDBS)用四參數邏輯斯諦方程式分析10點濃度反應數據,且自所得曲線擬合估算絕對IC50
值。FGFR1及FGFR3酶檢測之估算IC50
的最小顯著比率(MSR)分別為1.38及1.47。該等檢測中,製劑10之FGFR1及FGFR3之IC50
結果分別估算為0.0077 μM及0.0064 μM。該數據證明製劑10為強力FGFR1及FGFR3酶抑制劑。
在CELLBIND96孔分析盤(Corning 3340)中,將人RT112膀胱癌細胞以每孔5,000個細胞之密度接種於100 μL補充有10%胎牛血清(FBS,Gibco 10082-147)及1%青黴素/鏈黴素溶液(Gibco 15140-122)之RPMI 1640(Gibco 11875-085)中,且在37℃培育隔夜。次日早晨移除生長培養基並用100 μL補充有20 mg/mL胎牛血清(BSA)的RPMI 1640替換。在37℃培育3小時後,添加20 μL於RPMI 1640(含有於6% DMSO中之20 mg/mL BSA)中3次連續稀釋之化合物。得到在1% DMSO中在10-0.005 μM範圍內變化之10點劑量反應曲線。在37℃下繼續培育1小時。用50 μL於無血清RPMI中之50 μg/mL FGF9(R&D Systems 273-F9)溶液刺激細胞,以得到500 ng/mL FGF9之最終濃度。藉由添加30 μL於磷酸鹽緩衝鹽水(PBS)中之25%甲醛溶液(3.7%甲醛最終濃度)固定細胞,且在室溫下培育30分鐘。用PBS洗滌細胞3次,接著添加100 μL冷甲醇,並在-20℃下培育30分鐘。移除甲醇並用含有0.1% TRITONX-100之PBS(PBST)處理細胞,用PBS洗滌3次並在室溫下培育15分鐘。將細胞在4℃下,在50 μL之p-p44/42 MAPK一級抗體(Cell Signaling 9101S)於PBS(補充有2% BSA、0.01%磷酸酶抑制劑混合液1(Sigma P2850)、0.01%磷酸酶抑制劑混合液2(Sigma P5726)及0.01%蛋白酶抑制劑混合液(Sigma P8340))中的1:400稀釋液中,在平緩震盪下培育隔夜。次日早晨,將分析盤用PBST洗滌2次及用PBS洗滌2次,隨後在80 μL之Alexa Fluor 488山羊抗兔IgG H+L二級抗體(Invitrogen A11034)於PBS(含有1% BSA及0.1%磷酸酶抑制劑混合液1、0.01%磷酸酶抑制劑混合液2及0.01%蛋白酶抑制劑混合液)中之1:1000稀釋液中,在室溫下於暗處培育1小時。用PBS洗滌細胞3次,接著添加100 μL之碘化丙錠(PI)(Molecular Probe P-3566)於PBS之1:200稀釋液,並於暗處培育1小時。藉由ACUMEN EXPLORERTM
(TTP LabTech公司),針對Alexa 488及PI分別使用500-530 nM及575-640 nM光學濾光片,鑑定每孔之p-ERK陽性細胞數及總細胞數。隨後使用自同一個分析盤上操作之MIN(含10 μM陽性對照化合物之DMSO)與MAX(僅DMSO)對照組獲得的數值,將使用Alexa 488值之pERK/孔之總平均強度換算為抑制百分率。隨後使用4參數S型劑量反應方程式分析抑制百分率值及10點濃度反應數據,且自所得曲線估算相對IC50
值。BSA存在下FGF9誘導之p-ERK檢測法的估算IC50
的最小顯著比率(MSR)為2.7。此檢測法中製劑10之IC50
估算為0.0004 μM。該數據證實製劑10為人類癌症細胞中FGF9所誘導ERK磷酸化之強力抑制劑。
藉由監測人臍內皮細胞(HUVEC)中對鹼性纖維母細胞生長因子(b-FGF)刺激有反應的ERK磷酸化(pERK)來量測化合物對FGF受體1抑制之效應。使用ALPHASCREENSUREFIRE系統(TGR Biosciences,TGRES50K)來量測所形成之pERK的含量。此為使用磷酸化分析物之免疫夾層捕捉的均質檢測格式,接著使用抗體包覆之ALPHASCREEN珠粒(Perkin Elmer)產生擴增信號來偵測。
回收HUVEC細胞,並將其維持於由補充有10% FBS、0.4%牛腦提取物、0.1%氫皮質酮、0.1%硫酸慶大黴素(gentamicin sulfate)雙性黴素B(amphotericin-B)及0.1%表皮生長因子之內皮細胞基礎培養基(Clonetics,CC-3132)組成之生長培養基中,進行人類重組直至第7代。對於本檢測,藉由標準程序收穫細胞並接著計數。將細胞(20,000/孔)於100 μL生長培養基中接種於塗覆聚D-離胺酸之96孔分析盤(BD,354640)中。在37℃、5% CO2
下,將分析盤培育隔夜。
檢測當天,在37℃、5% CO2
下,在100 μL含有1.5% FBS及20 mg/mL BSA之內皮細胞基礎(EBM)培養基中使細胞血清饑餓3小時,接著在37℃下用20 μM於饑餓培養基中3次連續稀釋之化合物處理1小時。產生在1% DMSO中在10-0.005 μM範圍內變化之10點劑量反應曲線。化合物處理1小時後,在37℃下用50 μL b-FGF(Sigma,F0291,最終b-FGF濃度50 ng/mL)刺激細胞15分鐘。在含有細胞及50 μL刺激劑b-FGF之孔中產生MAX信號,且含有10 μM陽性對照化合物及50 μL刺激劑b-FGF之細胞作為MIN。接著移除培養基,且每孔添加50 μL之1x SUREFIRE溶菌緩衝液(TGR Biosciences SUREFIRE套組組分),並在室溫下在平緩震盪下繼續培育10分鐘。對於pERK偵測,將6 μL溶菌液及10 μL反應混合物(60份反應緩衝液/10份激活緩衝液/各0.6份供體及受體珠粒,Perkin Elmer,6760617R)轉移至384孔淺孔分析盤(proxiplate)(Perkin Elmer,6006280)。密封該分析盤且在室溫下在平緩震盪下將其培育2小時,接著使用標準ALPHASCREEN設置(Ex680nm
及Em520-620nm
)在配備有TurboModule之Perkin Elmer EnVision分析盤讀數器上讀數。將發射數據轉化為自各分析盤上之MAX(僅DMSO)及MIN(含10 μM陽性對照化合物之DMSO)對照測定之抑制百分率,接著使用ACTIVITYBASE4.0將10點化合物濃度數據與四參數邏輯斯諦方程式擬合,且估算IC50
。ERK磷酸化(Thr202/Tyr204)之ALPHASCREENSUREFIRE偵測檢測法的IC50
的最小顯著比率(MSR)為2.1。本檢測法中製劑10之IC50
被估算為0.0006 μM。該數據證實製劑10為人臍內皮細胞中bFGF誘導之ERK磷酸化之強力抑制劑。
本發明之化合物較佳調配為經由多種途徑投與之醫藥組合物。該等組合物最佳用於口服或靜脈內投藥。該等醫藥組合物及其製備方法在此項技術中皆已為人所熟知。參見例如REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY(D. Troy等人編,第21版,Lippincott Williams & Wilkins,2005)。
本發明之化合物通常在廣泛劑量範圍內有效。例如,每天劑量通常在每公斤體重約0.5 mg至約100 mg之範圍內。在一些情況下,低於上述範圍之下限的劑量濃度可為足夠的,而在其他情況下,可採用更大之劑量而不會引起任何有害副作用,且因此無論如何以上劑量範圍不欲限制本發明之範疇。應瞭解實際上投與之化合物量將由醫生根據相關環境決定,包括欲治療之病症、選擇之投藥途徑、投與之一或多種實際化合物、個別患者之年齡、體重及反應、及患者症狀之嚴重性。
Claims (9)
- 一種化合物,其為結晶形單水合(R)-(E)-2-(4-(2-(5-(1-(3,5-二氯吡啶-4-基)乙氧基)-1H-吲唑-3-基)乙烯基)-1H-吡唑-1-基)乙醇,其中該化合物之特徵為X射線粉末繞射圖案(Cu輻射,λ=1.54059Å)包含位於14.65之峰。
- 如請求項1之化合物,其已單離出。
- 如請求項1或2之化合物,其進一步包含位於3.54(2θ+/-0.1°)之峰。
- 如請求項1或2之化合物,其進一步包含位於12.51(2θ+/-0.1°)之峰。
- 如請求項3之化合物,其進一步包含位於12.51(2θ+/-0.1°)之峰。
- 2及5中任一項之化合物,其進一步包含位於19.16(2θ+/-0.1°)之峰。
- 如請求項3之化合物,其進一步包含位於19.16(2θ+/-0.1°)之峰。
- 如請求項4之化合物,其進一步包含位於19.16(2θ+/-0.1°)之峰。
- 一種醫藥組合物,其包含如請求項1至8中任一項之化合物與醫藥學上可接受之載劑、稀釋劑或賦形劑之組合。
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KR20210018265A (ko) | 2018-05-04 | 2021-02-17 | 인사이트 코포레이션 | Fgfr 억제제의 고체 형태 및 이의 제조 방법 |
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CN114364798A (zh) | 2019-03-21 | 2022-04-15 | 欧恩科斯欧公司 | 用于治疗癌症的Dbait分子与激酶抑制剂的组合 |
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