TWI382982B - 乙烯基吲唑基化合物 - Google Patents
乙烯基吲唑基化合物 Download PDFInfo
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- TWI382982B TWI382982B TW099113702A TW99113702A TWI382982B TW I382982 B TWI382982 B TW I382982B TW 099113702 A TW099113702 A TW 099113702A TW 99113702 A TW99113702 A TW 99113702A TW I382982 B TWI382982 B TW I382982B
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- VAYFASAXLKWTOV-UHFFFAOYSA-N tert-butyl-[(3-iodo-2h-indazol-5-yl)oxy]-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=C2NN=C(I)C2=C1 VAYFASAXLKWTOV-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
成纖維細胞生長因子(FGF)已公認為許多生理學過程(諸如發育期形態發生及血管生成)之重要介體。成纖維細胞生長因子受體(FGFR)系列係由四個成員(FGFR1-FGFR4)組成，其為由細胞外似免疫球蛋白(Ig)結構域、疏水性跨膜區域及包括酪胺酸激酶域之細胞質部分組成之醣蛋白。FGF結合可導致FGFR之二聚化，接著，發生受體自體磷酸化及下游訊號路徑之活化。受體活化足以使參與多元化過程(諸如細胞生長、細胞新陳代謝及細胞存活)調控之特定下游訊號配合體得到募集並活化。因此，FGF/FGFR訊號路徑可多效性作用於對腫瘤細胞增殖、遷移、入侵、及血管生成具關鍵性之許多生物性過程。
相關技藝中習知乙烯基吲唑可用於治療癌症。參見，例如WO0210137及WO2003101968。FGFR抑制劑亦係相關技藝中習知。參見，例如WO2002022598。
本發明提供一種茲認為具有治療增生性疾病(諸如癌症)及尤其治療因FGF及/或FGFR之調節異常所介導之疾病之臨床應用之新穎乙烯基吲唑基化合物。
此外，本發明之一些化合物具有比一些先前習知之FGFR抑制劑優異之FGFR1及FGFR3效能。
本發明提供一種化合物，其為(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)乙醇或其醫藥可接受鹽。
本發明亦提供一種化合物，其為(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)乙醇或其醫藥可接受鹽。
本發明提供一種治療癌症之方法，其中該癌症選自由如下組成之群：哺乳動物之乳腺癌、非小細胞肺癌(NSCL)、膀胱癌、胃癌、胰腺癌、前列腺癌、結腸癌、多發性骨髓瘤、肝癌、黑色素瘤、頭頸部癌、甲狀腺癌、腎細胞癌、神經膠質母細胞瘤、及睪丸癌，其包括對需要該治療之哺乳動物投與有效劑量之如本發明之化合物或鹽。
本發明亦提供一種醫藥組合物，其包含與一種或多種醫藥可接受之載劑、稀釋劑、或賦形劑組合之本發明之化合物或鹽。在一個具體實施例中，該組合物進一步包括一種或多種其他治療劑。
本發明亦提供一種用於治療之本發明之化合物或鹽。此外，本發明提供一種以本發明之化合物或鹽於製造用於治療癌症之藥物之用途。具體言之，該等癌症係選自由如下組成之群：乳腺癌、肺癌、膀胱癌、胃癌、胰腺癌、前列腺癌、結腸癌、多發性骨髓瘤AML、肝癌、黑色素瘤、頭頸部癌、甲狀腺癌、腎細胞癌、神經膠質母細胞瘤、及睪丸癌。更具體言之，該等癌症係選自由如下組成之群：乳腺癌、非小細胞肺癌、膀胱癌、胃癌、胰腺癌、前列腺癌、結腸癌、多發性骨髓瘤、肝癌、黑色素瘤、頭頸部癌、甲狀腺癌、腎細胞癌、神經膠質母細胞瘤、及睪丸癌。最具體言之，該癌症為非小細胞肺癌。最具體言之，該癌症為胃癌。最具體言之，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如下組成之群之癌症之包括如本發明化合物或鹽作為活性組分之醫藥組合物：乳腺癌、非小細胞肺癌、膀胱癌、胃癌、胰腺癌、前列腺癌、結腸癌、多發性骨髓瘤、肝癌、黑色素瘤、頭頸部癌、甲狀腺癌、腎細胞癌、神經膠質母細胞瘤、及睪丸癌。
熟習此項相關技藝之人士瞭解，外消旋(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)乙醇基本上可用於描述藉由改用外消旋1-(3,5-二氯吡啶-4-基)乙醇替代(S)-1-(3,5-二氯吡啶-4-基)乙醇作為起始物得到之(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。此外，熟習此項相關技藝之人士瞭解，(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)乙醇包括一個對掌性中心。較佳之，(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)乙醇係以單對映體之形式存在。該單對映體可藉由對掌性試劑開始製備或藉由立體選擇性或立體專一性合成技術製備。或者，可藉由標準對掌性層析法或結晶技術使該單對映體自混合物分離。
熟習此項相關技藝之讀者瞭解，本發明之所有化合物皆可形成鹽。本發明之該等化合物為胺類，因此可與許多種無機及有機酸中任一者反應形成醫藥可接受酸加成鹽。該等醫藥可接受酸加成鹽及常用製法係相關技藝所習知之方法。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，編號1，1977年1月。
本發明之化合物可根據以下製法及實例中之說明製備。以下製法及實例之命名係採用ChemDrawUltra 10.0中之Struct=Name命名法得到。
將四氫呋喃(THF,3 L)及二異丙基胺(DIPA,315 mL,2.24 mol)添加至三頸12 L圓底燒瓶且冷卻至-78℃。慢慢添加正丁基鋰(1.6 M己烷溶液,1400 mL,2.24 mol)。在完成添加且已使溫度穩定在-78℃之後，慢慢添加3,5-二氯吡啶溶液(296.7 g,2.00 mol)，可立即得到黃色溶液，然後變成鐵銹色懸浮液。在完成添加且溫度穩定在-78℃之後，慢慢添加含在THF(600 mL)中之乙醛(230 mL,4.05 mol)。在-78℃下繼續攪拌。3小時後，移去乾冰浴並滴加飽和氯化銨水溶液(1 L)中止反應。使該反應在攪拌下升溫至室溫(RT)過夜。利用甲基第三丁基醚(MTBE,2 L)、飽和氯化銨水溶液(1 L)及水(2 L)稀釋該混合物。分溶，且利用飽和氯化鈉水溶液(鹽水)洗滌有機相。利用MTBE(1.5 L)萃取水相。合併有機層，經過硫酸鈉乾燥，過濾，然後真空濃縮。藉由矽膠層析[25%乙酸乙酯(EA)之乙烷溶液]純化殘餘物，得到標題化合物之紅色油狀物。產率：352 g(90%)。MS(ES) m/z 192[M+1]+
。
在利用90%庚烷/10%乙醇洗脫之CHIRALPAKAD-H管柱上分離上述反應所獲得之立體異構體混合物。波峰2為所需要之對映體。使產品樣本溶於CDCl3
(最終濃度100 mg/mL)中，以確立絕對組態。採用裝備有BaF2
窗及100 mm光路徑之IR測光管之ChiralIR FT VCD分光光度計(BioTools Inc.)獲得具有4 cm-1
解析度之圓振二色光譜(VCD)及紅外(IR)光譜。收集150 μL樣本之VCD及IR 6小時。在無濾波或進一步之數據處理下出示該數據。藉由Linux叢集系統(Linux cluster)，進行B3PW91/6-31G**之Gaussian運算，由最佳之最低能量構像異構物得到振動頻率及吸光度與VCD強度，然後，採用6 cm-1
圓振二色光譜之洛仁子(Lorentzian)頻寬模擬相應之光譜。以上分析顯示該產品為S異構體。產率：84.37 g(27%)。MS(ES) m/z 192[M+1]+
。
使(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)中，然後使該燒瓶在冰浴中冷卻。添加三乙胺(TEA,3.5 mL,25.11 mmol)，接著，逐滴添加甲磺醯氯(2.2 mL,28.42 mmol)。移去該冰浴且使反應升溫至RT。4小時後，利用水(100 mL)中止反應，繼而分離各層。利用DCM(50 mL)萃取水性層，接著，再利用20%異丙醇(IPA)/氯仿(50 mL)萃取。合併有機萃取物，經過無水硫酸鈉乾燥，過濾，然後，真空濃縮。產率：7.15 g(100%)。MS(ES) m/z 270[M+1]+
。
於裝備有磁鐵攪拌子、氮氣罩及內部溫度探針之1 L之三頸燒瓶中，使2-(2-溴代乙氧基)四氫-2H-哌喃(34 g,156 mmol)溶於乙腈(ACN,400 mL)中。添加4-碘代吡唑(29.34 g,149.74 mmol)，接著，添加碳酸銫(73.4 g,223.02 mmol)。使該混合物於RT下攪拌18小時。通過CELITE過濾該反應混合物，利用ACN洗滌濾餅，然後使濾液濃縮，得到金色油狀物。未進一步純化即使用。產率：47.819 g(99%)。MS(ES) m/z 323[M+1]+
。
在10 L反應容器中添加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)。使該混合物冷卻至0℃，然後，在0.5小時內添加第三丁基二甲基氯矽烷(253.16 g,1.68 mol)。於18℃下，使該混合物攪拌3小時。慢慢加水(2.5 L)至具有處於5℃冰浴之反應中，以維持約20℃之內部溫度。將該混合物轉移至分液漏斗，且利用EA(2×2.5 L)萃取。合併該萃取物，然後利用水(3×2.5 L)及鹽水洗滌。經過無水硫酸鈉乾燥有機溶液，過濾，然後，蒸發而得到紅色油狀物。使該油狀物通過矽膠填料且利用洗提液(0%至30% EA之己烷溶液)洗提，得到標題化合物，為橙色油狀物結晶。產率：300 g(100%)。MS(ES) m/z 249[M+1]+
。
使在DCM(4.00 L)中之5-(第三丁基二甲基矽烷氧基)-1H-吲唑(300.00 g,1.21 mol)之溶液在10 L夾套反應容器中冷卻至10℃。以0.5小時時間分批添加N-碘代琥珀醯亞胺(298.89 g,1.33 mol)至所得溶液。於RT下，使該混合物攪拌3小時，而由液相色譜-質譜(LC-MS)及薄層層析(TLC)顯示已完全轉化。使該混合物冷卻至10℃，然後，利用水(2.5 L)中止反應。將該混合物轉移至分液漏斗且以DCM(2.5 L)萃取水性層。利用10%之硫代硫酸鈉水溶液(5 L)及鹽水洗滌合併之有機萃取物。經過硫酸鎂乾燥有機溶液，過濾，然後真空濃縮，得到標題化合物之橙色固體。產率：388 g(90%)。MS(ES) m/z 375[M+1]+
。
使在DCM(2.50 L)及THF(1.00 L)中之5-(第三丁基二甲基矽烷氧基)-3-碘基-1H-吲唑(387.00 g,1.08 mol)之溶液在10 L夾套反應容器中冷卻至10℃。將甲磺酸(14.0 mL,216.02 mmol)添加至所得混合物，接著，以0.5小時時間添加3,4-二氫-2H-哌喃(296 mL,3.24 mol)，觀察到輕度放熱。於RT下，使該混合物攪拌3小時。使該混合物冷卻至10℃，然後，利用飽和碳酸氫鈉水溶液(2 L)中止反應。利用水(2 L)稀釋該混合物，然後，利用DCM(2 L)萃取水性層。利用水(2 L)及鹽水洗滌已合併之有機萃取物。經過無水硫酸鈉乾燥該有機混合物，過濾，然後，真空濃縮。利用洗提液(0%至10%之EA/己烷)使殘餘物通過矽膠填料洗提，得到標題化合物。產率：150 g(31%)。MS(ES) m/z 459[M+1]+
。
在裝備有磁鐵攪拌器、溫度探針、及具有隔板之冷凝器之500 mL之三頸圓底燒瓶中，以氮氣沖刷含在DMF(150 mL)中之5-(第三丁基二甲基矽烷氧基)-3-碘基-1-(四氫-2H-哌喃-2-基)-1H-吲唑(14 g,30.54 mmol)之混合物。將三丁胺(TBA,6.7 g,36.1 mmol)及4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧硼戊環(7.0 g,43.18 mmol)添加至所得溶液，然後繼續沖刷10分鐘。將雙(三苯基膦)氯化鈀(II)(0.45 g,0.63 mmol)添加至所得混合物，然後，再繼續沖刷0.5小時。在95至100℃下，使混合物加熱18小時。使反應混合物冷卻至40℃以下，然後，注入4-碘基-1-(2-(四氫-2H-哌喃-2-基氧基)乙基)-1H-吡唑(9.8 g,30.42 mmol)。將氫氧化鋇八水合物(19.3 g,60.3 mmol)及水(13 mL)添加至所得混合物，然後，繼續沖刷10分鐘。將1,1'-雙(二苯基膦基)二茂鐵氯化鈀(II) DCM錯合物(1.3 g,1.56 mmol)添加至反應物，然後，繼續沖刷0.5小時。在氮氣下，使該混合物於95℃下加熱3小時。利用EA稀釋該混合物，接著通過Celite填料過濾。利用鹽水(400 mL)洗滌該填料，然後使過濾液分層。利用鹽水洗滌有機層並利用EA萃取合併之水性層。合併有機溶液且濃縮得到棕色油狀物。使該油狀物溶於DCM(100 mL)中且加至矽膠填料上。利用洗提液(依序使用50% EA之己烷溶液，及70% EA之己烷溶液)洗提該填料，得到淺棕色油狀物。利用MTBE(100 mL)進行濕磨，得到標題化合物之固體。產率：5 g(37%)。MS(ES) m/z 439[M+1]+
。
在裝備有內部溫度探針、回流冷凝器、氮氣罩及磁鐵攪拌器之三頸250 mL圓底燒瓶中添加含(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)之ACN(92 mL)漿液，且升溫至60℃。將(S)-1-(3,5-二氯吡啶-4-基)甲磺酸乙酯(7.03 g,26.02 mmol)添加至該懸浮液並攪拌過夜。使該反應混合物冷卻至RT，過濾，然後，利用ACN洗滌固體。使過濾液濃縮，然後，藉由矽膠層析(2-4%(2 M氨之甲醇溶液)/DCM)純化殘餘物。合併產物部分，然後，真空濃縮而得到白色泡沫狀物。產率：12.5 g(86%)。MS(ES) m/z 612[M+1]+
。
在裝備有加料漏斗、氮入口、內部溫度探針及磁鐵攪拌器之三頸250 mL圓底燒瓶中添加甲醇(57 mL)，然後在冰浴中冷卻。使乙醯氯(20 mL,281.03 mmol)通過加料漏斗慢慢加至所得溶液。使溶於甲醇(40 mL)中之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,11.59 mmol)通過加料漏斗加至該溶液。完成添加之後，移去冰浴，升溫至RT並使該混合物攪拌4小時。真空濃縮反應混合物而得到黃色泡沫狀物。使該黃色泡沫狀物溶於甲醇(10 mL)中，然後，慢慢加至飽和碳酸氫鈉水溶液(120 mL)。於RT下，使該混合物攪拌30分鐘。過濾該混合物，利用水(100 mL)洗滌固體，然後，真空乾燥。使該固體自熱EA/甲醇/己烷再結晶而得到標題化合物之白色固體。產率：2.1 g(41%)。MS(ES) m/z 444[M+1]+
。
FGF/FGFR路徑之異常調節涉及許多形式之人類惡性腫瘤中。FGFR及FGF在很多癌症中通常為過度表現，且彼者之表現通常與不良預後有關。在數種類型之腫瘤(包括乳房、NSCLC、膀胱、胃、前列腺、結腸、及多發性骨髓瘤)中已發現FGFR激酶域中之活化突變。在許多乳癌、胃癌、及多發性骨髓瘤患者中亦可檢測到FGFR位置之基因組擴增。同樣，在眾多不同類型之腫瘤(諸如膀胱癌、多發性骨髓瘤、前列腺癌、及肺癌)中已發現FGFR及FGF之過度表現。可能因FGFR系列路徑抑制劑療法獲益之其他癌症包括AML、肝癌、黑色素瘤、頭頸部癌、甲狀腺癌、胰腺癌、腎細胞癌、神經膠質母細胞瘤、及睪丸癌。除了彼者在腫瘤形成及進展中之角色之外，FGF及FGFR尤其在腫瘤生長期間，亦為血管生成之關鍵調節劑。FGF/FGFR軸線在其他腫瘤基質細胞(諸如與成纖維有關之癌症)強化中亦扮演重要的角色。FGF之向上調節亦針對抗血管生成性及其他化學療法產生抗性。最後，FGFR之小分子抑制劑在數種臨床前腫瘤模式中已顯示具有抗瘤活性且正在進行臨床研究。綜觀言之，FGF/FGFR路徑係癌細胞之數種重要之細胞過程中必不可少。由於該等原因，靶向FGFR及/或FGF訊號傳導之療法可直接影響腫瘤細胞及腫瘤血管生成。
如下所述，以基本上如下說明之至少一種分析法測試所有實例化合物：FGFR1酵素分析法(濾膜結合性)、FGFR3酵素分析法(濾膜結合性)、以RT-112細胞為主之FGF9所誘發p-ERK之分析法(於BSA存在下)、於人類臍靜脈內皮細胞(Human Umbilical Vein Endothelial Cells)(HUVEC)中進行以細胞為主ERK磷酸化之AlphaScreen SureFire檢測法(Thr202/Tyr204)、活體內FGFR靶向抑制分析法、及RT112人類膀胱癌及其他癌症之異種移植模式。該等分析法顯示，所測試之化合物為FGFR系列路徑抑制劑且具有抗癌活性。
在包含10 mM 4-(2-羥乙基)-1-哌嗪乙烷-磺酸(HEPES)pH 7.5、8 mM參(羥甲基)胺基甲烷(Tris-HCl) pH 7.5、5.0 mM二硫蘇醣醇(DTT)、10.0 μM腺苷三磷酸(ATP)、10 mM MnCl2
、150 mM NaCl、0.01% TRITONX-100、0.5 μCi33
P-ATP、及0.05 μg/μL聚(Glu-Tyr)之50 μL緩衝液中，培養FGFR1或FGFR3激酶(0.15 ng/μL人類FGFR1或0.32 ng/μL人類FGFR3)。於RT下，在50 μL之體積中反應30分鐘，然後，經由添加130 μL之10% H3
PO4
中止反應。將該反應液(120 μL)轉移至96孔之1.0 μm玻璃纖維濾板，於RT下，培養20-30分鐘，然後，利用0.5% H3
PO4
在TITERTEKZoom上洗滌3次。使孔風乾後，再添加40 μL MicroScintTM
20(Packard)，然後在Wallac Micobeta計數器上計數。針對化合物之抑制作用時，化合物係在二甲亞碸(DMSO)中形成10 mM儲備液提供。以20% DMSO連續稀釋化合物1：3，得到10個點之濃度-效應曲線，在反應板中稀釋1：5(最終於4%最終DMSO濃度中形成20 μM至0.001 μM)後，添加該反應混合物至濾板，以測定化合物活性。當僅由包括0.1 M乙二胺四乙酸(EDTA)之對照孔建立基線時，對照孔包括4%之DMSO。隨後由各分析板之對照組孔及10點濃度效應數據採用ActivityBase軟體(IDBS)，使用4-參數對數形方程式(logistic equation)分別計算10種濃度之各抑制百分比數值，並由所得曲線擬合估算絕對IC50
值。FGFR1及FGFR3酵素分析法對所估算IC50
之最小有效比(MSR)分別為1.38及1.47。在該等分析法中，實例1對FGFR1及FGFR3之IC50
結果經估算分別為0.0077及0.0064 μM。該數據顯示，本發明某些化合物為強力之FGFR1及FGFR3酵素抑制劑。
取人類RT112膀胱癌細胞依5,000個細胞/孔之密度接種於CELLBIND® 96孔板(Corning 3340)中補充有10%胎牛血清(FBS,Gibco 10082-147)及1%之青黴素/鏈黴素溶液(Gibco 15140-122)之100 μL RPMI 1640(Gibco 11875-085)中，然後於37℃下培養過夜。第二天清晨，移去生長介質，且換成補充有20 mg/mL牛血清白蛋白(BSA)之100 μL RPMI 1640。於37℃下培養3小時後，以RPMI 1640(其包含20 mg/mL BSA之6% DMSO溶液)3x連續稀釋化合物，各取
20 μL加至各孔。此舉可得到在1% DMSO中之10至0.005 μM範圍內之10個點之劑量-效應曲線。於37℃下繼續培養1小時。利用50 μL之含在無血清RPMI中之50 μg/mL FGF9(R&D Systems 273-F9)溶液刺激該等細胞，得到500 ng/mL FGF9之最終濃度。添加30 μL 25%甲醛之磷酸鹽緩衝生理鹽水(PBS)溶液(甲醛最終濃度3.7%)固定細胞，然後，於RT下培養30分鐘。利用PBS洗滌細胞3次，接著添加100 μL冷甲醇且於-20℃下培養30分鐘。移去該甲醇，繼而利用包括0.1% TRITON® X-100(PBST)之PBS處理該等細胞，利用PBS洗滌細胞3次，然後於RT下培養15分鐘。然後，於4℃下，使細胞在50 μL 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%磷酸酶抑制劑混合物2(Sigma P5726)、及0.01%蛋白酶抑制劑混合物(Sigma P8340))中之1：400稀釋液中輕搖培養過夜。第二天清晨，利用PBST將板洗滌2次，繼而利用PBS洗滌2次，接著，黑暗中，於RT下，在80 μL Alexa Fluor 488山羊抗兔子IgG H+L二級抗體(Invitrogen A11034)於PBS(含有1% BSA及0.01%磷酸鹽抑制劑混合液1、0.01%磷酸鹽抑制劑混合液2、及0.01%蛋白酶抑制劑混合液)中之1：1000稀釋液中培養1小時。利用PBS洗滌細胞3次，接著，添加100 μL碘化丙啶(PI)(Molecular Probe P-3566)在PBS中之1：200稀釋液，然後在黑暗中培養1小時。利用分別針對Alexa 488及PI採用濾光器500-530 nM及575-640 nM之ACUMEN
EXPLORERTM
(TTP LabTech Ltd.)判別每孔之p-ERK陽性細胞及總細胞。隨後，由採用Alexa 488值之pERK/孔之總平均強度利用在同一分析板上進行得到之MIN(10 μM在DMSO中之陽性化合物)及MAX(單獨之DMSO)對照組數值換算成抑制%。該抑制百分比數值及該10個點之濃度效應數據隨後採用4參數S型劑量效應方程式分析，且由所得曲線估計得到相對IC50
值。該利用BSA分析FGF9所誘發p-ERK之分析法對所估計IC50
之最小有效比(MSR)為2.7。實例1在該分析法中之IC50
估計為0.0004 μM。該數據證實，本發明某些化合物為人類癌細胞中FGF9所誘發ERK磷酸化之強力抑制劑。
化合物對FGF受體1之抑制作用可經由監控人類臍靜脈內皮細胞(HUVEC)中，受到鹼性成纖維細胞生長因子(b-FGF)刺激作用所產生之ERK(pERK)磷酸化效應來測定。所形成之pERK濃度可採用ALPHASCREEN® SUREFIRE®系統(TGR Biosciences,TGRES50K)測定。此係利用夾心免疫分析法捕捉磷酸化分析物後，採用經抗體塗覆之ALPHASCREEN®粒子(Perkin Elmer)檢測，以得到增強訊號之均質分析模式。
回收HUVEC細胞，並維持於由內皮細胞基礎培養基(Clonetics,CC-3132)(補充10% FBS、0.4%牛腦提取物、0.1%氫化可體松、0.1%硫酸健大黴素兩性黴素-B(GA-
1000)、及0.1%上皮細胞生長因子)組成之生長介質中，進行人類重組直到傳代7次。就該分析法而言，藉由標準程序收穫細胞，然後進行計數。使細胞(20,000個/孔)以含於100 μL生長介質中之形式塗覆於96孔塗佈聚-D-離胺酸之分析板(BD,354640)中。分析板在37℃，5% CO2
下培養過夜。分析當天，於37℃，5% CO2
下，使細胞在包含1.5% FBS及20 mg/mL BSA之100 μL EBM(內皮細胞基礎)介質中，進行血清飢餓處理3小時，然後在37℃下，利用20 μL在飢餓處理介質中之經3x連續稀釋之化合物處理1小時。此等可得到含在1% DMSO中之10-0.005 μM範圍內之10個點之濃度-效應曲線。在1小時之化合物處理之後，於37℃下，利用50 μL b-FGF(Sigma,F0291，最終b-FGF濃度為50 ng/mL)刺激細胞15分鐘。在包含細胞及50 μL刺激因子b-FGF之孔中產生最高(MAX)訊號，而具有10 μM陽性對照化合物及50 μl刺激因子b-FGF之細胞則為最低(MIN)訊號。然後，移去該介質，接著，每孔添加50 μL之1x SUREFIRE®溶胞液(TGR Biosciences SUREFIRE® Kit component)且於RT下繼續輕搖培養10分鐘。進行pERK檢測時，將6 μL溶胞物及10 μL反應混合物(60份反應緩衝液/10份活化緩衝液/各0.6份供體及受體珠粒，Perkin Elmer,6760617R)轉移至384孔之淺孔板(Perkin Elmer,6006280)。將該分析板密封，然後於RT下輕搖培養2小時，且然後採用標準ALPHASCREEN®裝置(Ex680nm
及Em520-620nm
)，在裝備有TurboModule之Perkin Elmer EnVision平板讀數器上讀取。由各分析板上之MAX(單獨使用DMSO時)及MIN(10 μM含在DMSO中之陽性對照化合物)對照組測定之發射數據轉化成抑制%，然後採用ACTIVITYBASE4.0將10個點之化合物濃度數據擬合至4參數對數形方程式並估計絕對IC50
值。ERK磷酸化((Thr202/Tyr204)分析法之ALPHASCREENSUREFIRE測法之IC50
值之最小有效比(MSR)為2.1。該分析法中，實例1之IC50
估計為0.0006 μM。該數據證實，本發明某些化合物為人類臍靜脈內皮細胞中bFGF所誘發ERK磷酸化之強力抑制劑。
將雌性無毛小鼠(CD1/nu/nu)先馴化1週後再進行處理。將動物分成陽性對照組、陰性對照組及化合物處理組。化合物(在10%之阿拉伯膠中調配)、陽性對照組(10%阿拉伯膠)、及陰性對照組(10%阿拉伯膠)係藉由胃管投與。化合物劑量在0.15至25 mg/kg之範圍內。2小時後，利用在生理食鹽水中新鮮製備之小鼠bFGF(6 μg/隻動物，Biosource PMG0033)經靜脈內投與該化合物處理組及該陽性對照組。陰性對照組係經靜脈內投與生理食鹽水處理。靜脈投藥後10分鐘，殺死小鼠。取出動物心臟且在300 μL之冰冷溶胞液(RIPA;Boston BioProduct BP-115)(其中包含稀釋1:100之抑制劑(磷酸酶抑制劑混合液I Sigma P2850；磷酸酶抑制劑混合液II Sigma P5726及蛋白酶抑制劑混合液Sigma P8340)))中均質化10秒鐘。使均質物在14,000 RPM下離心15分鐘，繼而將上清液轉移至96孔板。蛋白質含量可藉由COOMASSIE PLUSTM
蛋白質分析法(Pierce目錄編號1856210)測得。分析程序係依該等各製造商的建議(參見包括於分析套組中之說明書)。
採用MSD磷酸-Erk ELISA(Meso Scale Discovery，目錄號：N41CB-1)分析心臟組織之均質物，以測定組織之磷酸-Erk含量。ELISA程序係依該等各製造商的建議(參見包括於分析套組中之說明書，唯一之修改為：將0.2%十二烷基硫酸鈉加至溶胞液中)。採用陽性對照組作為最小磷酸-Erk抑制性(0%)及以陰性對照組作為最大磷酸-Erk抑制性(100%)。化合物處理組之抑制%係相對於最大及最小抑制性計算。TEC90
係由劑量效應試驗中計算且為在該時間點達到90%抑制性時所需要之濃度。例如，該實例1化合物所估計之TEC90
為28 nM。該數據證實，本發明某些化合物為活體內bFGF所誘發ERK磷酸化之強力抑制劑。
為評估該化合物抵抗Kdr之活性，將雌性無毛小鼠(CD1/nu/nu)馴化且除了改用VEGF誘發Kdr自體磷酸化{VEGF(6 μg/隻動物，R & D系統493-MV/CF)之外，按以上所述般處理。取得心臟組織，且按以上所述般進行均質化。採用MSD磷酸-Kdr ELISA(Meso Scale Discovery，目錄號：N41ZA-1)分析所得之均質物，以測得組織中磷酸-Kdr含量。ELISA程序係依該等各製造商的建議(參見包括於分析套組中之說明書，唯一之修改為：將0.2%十二烷基硫酸鈉加至溶胞液中)。陽性對照組係利用含在生理食鹽水中之VEGF(96 ug/隻動物)經靜脈內投與處理(0%之最小p-KDR抑制性)。陰性對照組係利用含在生理食鹽水中之VEGF(96 μg/隻動物)經靜脈內投與處理(100%之最大p-KDR抑制性)。相對於最大及最小抑制組計算化合物處理組之抑制%。由劑量效應試驗計算TED50
，且為在該時間點達到50%抑制性時所需要之濃度。例如，該實例1化合物經估計之TED50
為1.34 mg/kg。TEC90
係由劑量效應試驗計算，且為在該時間點達到90%抑制性時所需要之濃度。例如，該實例1化合物經估計之TEC90
為252 nM。該數據證實，相較於一些先前已知之FGFR抑制劑，本發明某些化合物為活體內VEGF所誘發Kdr磷酸化之較低效抑制劑。
使人類膀胱癌細胞RT112(歐洲細胞培養物收集處(European Collection of Cell Cultures))、人類多發性骨髓瘤細胞OPM-2(德國微生物及細胞培養物收集處(German Collection of Microorganisms and Cell Cultures))、人類非小細胞肺癌(NSCL)細胞NCI-H460(美國菌種培養物收集處)、人類胰腺癌細胞BxPC-3(美國菌種培養物收集處)或人類胃癌細胞SNU-16(美國菌種培養物收集處)中之一者在根據KOREAN CELL LINE BANK(KCLB)建議之培養液中擴增、收穫並經皮下注射至無毛鼠之側腹上。當腫瘤已確定(植入後7至21天)，使動物隨機分成對照組及測試組。測試化合物係在合適之媒劑(亦即，在10%阿拉伯膠中調配)中製得，而該測試化合物及媒劑對照組係藉由胃管強飼法投藥。在處理過程期間，1週2次測量腫瘤體積，來測定腫瘤效應，且以相對於該媒劑對照組之腫瘤體積之抑制%表示。該實例1化合物證實在數種異種移植腫瘤模式中具有取決於劑量之抗腫瘤活性。例如，在膀胱腫瘤模式(RT-112)中，當以3 mg/kg(QD進行21天)給藥時，達到41.3%抑制性；當以3 mg/kg(BID進行21天)給藥時，達到85.9%抑制性。在胃腫瘤模式(SNU-16)中，當以3 mg/kg(QD進行17天)給藥時，達到62%抑制性；當以3 mg/kg(BID進行17天)給藥時，達到83%抑制性。在多發性骨髓瘤模式(OPM-2)中，當以3 mg/kg(QD進行21天)給藥時，達到68%抑制性；當以3 mg/kg(BID進行21天)給藥時，達到84%抑制性。在NSCLC腫瘤模式(NCI-H460)中，當以3 mg/kg(QD進行17天)給藥時，達到46%抑制性；當以3 mg/kg(BID進行17天)給藥時，達到69%抑制性。在胰腺腫瘤模式(BxPC-3)中，當以3 mg/kg(QD進行21天)給藥時，達到1%抑制性；當以3 mg/kg(BID進行21天)給藥時，達到55%抑制性。該數據證實，本發明某些化合物為數種動物模式中異種移植人類腫瘤生長之抑制劑。
本發明之化合物較佳調配成可藉由多種路徑投與之醫藥組合物。最佳言之，該等組合物可用於經口投與或經靜脈內投與。該等醫藥組合物及製造該等醫藥組合物之方法在文獻中為吾人習知。參見，例如REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY(D. Troy等人，eds.,21st
ed.,Lippincott Williams & Wilkins,2005)。
本發明之化合物一般可在寬劑量範圍內發揮作用。例如，每日之劑量通常介於約0.5至約100 mg/kg體重之範圍內。在一些實例中，低於前述範圍下限之劑量濃度可能遠遠足夠，而在其他情況下，仍可在不引起任何人類副作用下採用較大劑量，及因此，上限劑量範圍並未以任一方式限制本發明之申請專利範圍。吾人瞭解，實際上所投與之化合物量可在根據相關情況(包括待治療之病症，所選擇之投藥路徑，經投與之該實際化合物或該等化合物，個別患者之年齡、體重及反應，及患者症狀之嚴重度)下，由醫師決定。
Claims (8)
- 一種化合物，其為(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、或其醫藥可接受鹽。
- 如請求項1之化合物，其為(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、或其醫藥可接受鹽。
- 一種醫藥組合物，及包含與醫藥可接受之載劑、稀釋劑或賦形劑組合之如請求項1或2中任一項之化合物或鹽。
- 如請求項1或2中任一項之化合物或鹽，其係用於醫療。
- 如請求項1或2中任一項之化合物或鹽，其係用於治療癌症。
- 如請求項5之化合物，其中該癌症為非小細胞肺癌。
- 如請求項5之化合物，其中該癌症為胃癌。
- 如請求項5之化合物，其中該癌症為多發性骨髓瘤。
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