TWI483937B - Cgrp受體拮抗劑 - Google Patents
Cgrp受體拮抗劑 Download PDFInfo
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- TWI483937B TWI483937B TW100111106A TW100111106A TWI483937B TW I483937 B TWI483937 B TW I483937B TW 100111106 A TW100111106 A TW 100111106A TW 100111106 A TW100111106 A TW 100111106A TW I483937 B TWI483937 B TW I483937B
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- cgrp
- compound
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- receptor
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Classifications
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
Landscapes
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Description
本發明大體上係關於化合物(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-側氧基丙-2-基)-4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-甲醯胺(化合物I或式I化合物),包括醫藥學上可接受之鹽,其為CGRP受體拮抗劑。本發明亦係關於醫藥組合物及使用化合物治療CGRP相關病症之方法,該等病症包括偏頭痛、神經性血管擴張、神經性炎症、熱損傷、循環性休克、與停經相關之潮紅、諸如哮喘之氣管發炎疾病、慢性阻塞性肺病(COPD)及癌症。
本專利申請案主張2010年3月30日申請之美國臨時專利申請案第61/319,015號之權利。
降鈣素基因相關肽(Calcitonin gene-related peptide;CGRP)為一種最初於1982年(Amara,S. G.等人,Science 1982,298,240-244)鑑別之天然存在之含有37個胺基酸的肽。該肽之兩種形式經表現(αCGRP及βCGRP),其在大鼠及人類中分別相差1個及3個胺基酸。該肽廣泛分佈於周邊神經系統(PNS)與中樞神經系統(CNS)中,主要定位於感官傳入及中樞神經元中,且顯示許多生物作用,包括血管擴張。
當自細胞釋放時,CGRP與特異性細胞表面G蛋白偶合受體結合且主要藉由活化細胞內腺苷酸環化酶而發揮其生物作用(Poyner,D. R.等人,Br J Pharmacol 1992,105,441-7;Van Valen,F.等人,Neurosci Lett 1990,119,195-8.)。已基於肽片段CGRP(8-37)之拮抗劑性質及CGRP之線性類似物活化CGRP2受體之能力提出兩種CGRP受體CGRP1及CGRP2(Juaneda,C.等人,TiPS 2000,21,432-438)。然而,缺乏CGRP2受體之分子證據(Brain,S. D.等人,TiPS 2002,23,51-53)。CGRP1受體具有3種組分:(i)7跨膜降鈣素受體樣受體(CRLR);(ii)第1型單跨膜受體活性調節蛋白(RAMP1);及(iii)細胞內受體組分蛋白(RCP)(Evans B. N. 等人,J Biol Chem. 2000,275,31438-43)。RAMP1為CRLR轉運至質膜及配位體與CGRP受體結合所需(McLatchie,L. M.等人,Nature 1998,393,333-339)。RCP為信號轉導所需(Evans B. N.等人,J Biol Chem. 2000,275,31438-43)。小分子拮抗劑與CGRP受體結合存在已知物種特異性差異,其中可見拮抗人類受體之親和力通常大於拮抗其他物種之親和力(Brain,S. D.等人,TiPS 2002,23,51-53)。RAMP1之胺基酸序列決定物種選擇性,詳言之,胺基酸殘基Trp74決定人類受體之表型(Mallee等人,J Biol Chem 2002,277,14294-8)。
受體層面上之CGRP抑制劑假定適用於已發生CGRP受體過度活化之病理生理病狀。一些此等病狀包括神經性血管擴張、神經性炎症、偏頭痛、叢集性頭痛(cluster headache)及其他頭痛、熱損傷、循環性休克、停經期潮紅及哮喘。CGRP受體活化已牽涉於偏頭痛之發病機制中(Edvinsson L. CNS Drugs 2001;15(10):745-53;Williamson,D. J. Microsc. Res. Tech. 2001,53,167-178.;Grant,A. D. Brit. J. Pharmacol. 2002,135,356-362.)。在偏頭痛期間,CGRP之血清含量升高(Goadsby PJ等人,Ann Neurol 1990;28:183-7)且用抗偏頭痛藥物進行治療使CGRP含量恢復正常,同時減輕頭痛(Gallai V.等人,Cephalalgia 1995;15: 384-90)。相較於對照,偏頭痛患者展現基礎CGRP含量升高(Ashina M等人,Pain 2000,86(1-2):133-8.2000)。靜脈內CGRP輸注引起偏頭痛患者持續頭痛(Lassen LH等人,Cephalalgia 2002年2月;22(1):54-61)。於犬及大鼠中進行之臨床前研究報導用肽拮抗劑CGRP(8-37)全身性阻斷CGRP不會改變靜止全身性血流動力學及區域血流量(Shen,Y-T.等人,J Pharmacol Exp Ther 2001,298,551-8)。因此,CGRP受體拮抗劑可提供避免與非選擇性5-HT1B/1D促效劑『曲普坦(triptan)』(例如舒馬普坦(sumatriptan))相關之心血管主動血管收縮傾向的偏頭痛新穎治療。
CGRP拮抗劑已在人類臨床試驗中顯示功效。參見Davis CD,Xu C.Curr Top Med Chem
. 2008 8(16):1468-79;Benemei S,Nicoletti P,Capone JG,Geppetti P.Curr Opin Pharmacol
. 2009 9(1):9-14. Epub 2009年1月20日;Ho TW,Ferrari MD,Dodick DW,Galet V,Kost J,Fan X,Leibensperger H,Froman S,Assaid C,Lines C,Koppen H,Winner PK.Lancet
. 2008 372:2115. Epub 2008年11月25日;Ho TW,Mannix LK,Fan X,Assaid C,Furtek C,Jones CJ,Lines CR,Rapoport AM;Neurology
2008 70:1304. Epub 2007年10月3日。
本發明提供技術優勢,例如化合物具有新穎性且抑制CGRP。另外,化合物提供醫藥用途優勢,例如在其作用機制、結合、抑制功效、目標選擇性、溶解性、安全概況或生物可用性之一或多個方面。
CGRP受體拮抗劑已揭示於包括WO2003/104236之PCT公開案中。
本發明涵蓋(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-側氧基丙-2-基)-4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-甲醯胺(化合物I或式I化合物)及醫藥組合物及調節CGRP及治療患有與CGRP或CGRP受體信號傳導程度異常相關之醫學病狀之患者的方法。
本發明包括化合物之所有醫藥學上可接受之鹽形式。醫藥學上可接受之鹽為相對離子不顯著促進化合物之生理活性或毒性且如此充當藥理學等效物的鹽。此等鹽可採用市售試劑根據常見有機技術製備。一些陰離子鹽形式包括乙酸鹽、醋硬脂酸鹽(acistrate)、苯磺酸鹽、溴化物、氯化物、檸檬酸鹽、反丁烯二酸鹽、葡萄糖醛酸鹽、氫溴酸鹽、鹽酸鹽、氫碘酸鹽、碘化物、乳酸鹽、順丁烯二酸鹽、甲磺酸鹽、硝酸鹽、雙羥萘酸鹽、磷酸鹽、丁二酸鹽、硫酸鹽、酒石酸鹽、甲苯磺酸鹽及羥萘甲酸鹽。一些陽離子鹽形式包括銨、鋁、苄星(benzathine)、鉍、鈣、膽鹼、二乙胺、二乙醇胺、鋰、鎂、葡甲胺(meglumine)、4-苯基環己胺、哌嗪、鉀、鈉、緩血酸胺(tromethamine)及鋅。
本發明意欲包括存在於本發明化合物中之原子的所有同位素。同位素包括具有相同原子序數但質量數不同的彼等原子。舉例而言且不加限制,氫同位素包括氘及氚。碳同位素包括13
C及14
C。本發明之經同位素標記化合物一般可藉由熟習此項技術者已知之習知技術或藉由與本文所述方法類似之方法,使用適當經同位素標記試劑替代否則採用之非標記試劑加以製備。此等化合物可具有多種潛在用途,例如在測定生物活性中用作標準物及試劑。在穩定同位素之情況下,此等化合物可具有有利調節生物、藥理學或藥物動力學性質的潛力。
縮寫一般遵循此項技術中使用之慣例。說明書及實例中使用之化學縮寫如下進行定義:「NaHMDS」表示雙(三甲基矽烷基)胺基鈉;「DMF」表示N,N-二甲基甲醯胺;「MeOH」表示甲醇;「NBS」表示N-溴代丁二醯亞胺;「Ar」表示芳基;「TFA」表示三氟乙酸;「LAH」表示氫化鋰鋁;「BOC」;「DMSO」表示二甲亞碸;「h」表示小時;「rt」表示室溫或滯留時間(上下文將指示);「min」表示分鐘;「EtOAc」表示乙酸乙酯;「THF」表示四氫呋喃;「EDTA」表示乙二胺四乙酸;「Et2
O」表示乙醚;「DMAP」表示4-二甲基胺基吡啶;「DCE」表示1,2-二氯乙烷;「ACN」表示乙腈;「DME」表示1,2-二甲氧基乙烷;「HOBt」表示1-羥基苯并三唑水合物;「DIEA」表示二異丙基乙胺,「Nf」表示CF3
(CF2
)3
SO2
-;且「TMOF」表示原甲酸三甲酯。
如本文所用之縮寫如下進行定義:「1×」表示1次,「2×」表示2次,「3×」表示3次,「℃」表示攝氏度,「eq」表示當量,「g」表示公克,「mg」表示毫克,「L」表示公升,「mL」或「ml」表示毫升,「μL」表示微升,「N」表示當量,「M」表示莫耳濃度,「mmol」表示毫莫耳,「min」表示分鐘,「h」表示小時,「rt」表示室溫,「RT」表示滯留時間,「atm」表示大氣壓,「psi」表示磅/平方吋,「conc.」表示濃縮物,「sat」或「sat'd」表示飽和,「MW」表示分子量,「mp」表示熔點,「ee」表示對映異構過量,「MS」或「Mass Spec」表示質譜,「ESI」表示電噴霧電離質譜,「HR」表示高解析度,「HRMS」表示高解析度質譜,「LCMS」表示液相層析質譜,「HPLC」表示高壓液相層析,「RP HPLC」表示逆相HPLC,「TLC」或「tlc」表示薄層層析,「NMR」表示核磁共振光譜學,「1
H」表示質子,「δ」表示德耳塔(delta),「s」表示單峰,「d」表示雙重峰,「t」表示三重峰,「q」表示四重峰,「m」表示多重峰,「br」表示寬峰,「Hz」表示赫茲,且「α」、「β」、「R」、「S」、「E」及「Z」為熟習此項技術者熟知之立體化學符號。
化合物I可根據流程1製備。此合成具有14個化學步驟且高度彙集,在最後3步中偶合3個主要片段。因而,合成以製備主要片段A(流程2)及B(流程3)開始。
片段A之合成以N
-Boc-4-哌啶酮與自亞磷羧基乙酸三甲酯產生之亞烷(ylide)的霍納爾-埃蒙斯反應(Horner-Emmons reaction)開始,以極佳產率產生4-(2-甲氧基-2-側氧基亞乙基)哌啶-1-甲酸第三丁酯(流程2)。由鈀/碳介導之催化氫化還原不飽和雙鍵。用LDA處理4-(2-甲氧基-2-側氧基乙基)哌啶-1-甲酸第三丁酯產生烯醇化物,其在用2-硝基苯甲醛捕獲之後提供硝基醇。於乙酸中用鐵還原硝基,隨後於二噁烷中用氯化氫處理,完成片段A之合成。
吲唑胺基酸B之合成以在單氯化碘作用下進行2,6-二甲基苯胺之碘化開始(流程3)。此中間物暫時閒置。N
-CBZ-L-絲胺酸甲酯經受一鍋(one-pot)甲烷磺醯化/消除反應,得到N
-CBZ-去氫丙胺酸甲酯。使用現有之碘化物及去氫丙胺酸,其在使用乙酸鈀(II)之情況下於海克偶合(Heck coupling)中有效偶合,以65%產率得到產物。此時,利用(-)-四氟硼酸1,2-雙((2R
,5R
)-2,5-二乙基磷基)苯(環辛二烯)銠(I)及氫氣(60 psi)使用催化不對稱氫化安裝對掌性中心,得到約96% ee之對掌性胺基酸。接著在亞硝酸異戊酯作用下形成吲唑環。所得吲唑具有高度結晶性。自丙酮/己烷再結晶一次可得到極佳純度且具有改良之99.8% ee的吲唑胺基酸。在氫化條件下移除CBZ保護基完成片段B之製備。吲唑胺基酸B亦可使用外消旋胺基酸或酮酸之酶促拆分加以製備(Hanson,Ronald L.;Davis,Brian L.;Goldberg,Steven L.;Johnston,Robert M.;Parker,William L.;Tully,Thomas P.;Montana,Michael A.;Patel,Ramesh N. Process Research and Development,Bristol-Myers Squibb,New Brunswick,NJ,USA. Organic Process Research & Development(2008),12(6),1119-1129.)。
片段A及B在使用碳酸N,N'
-二丁二醯亞胺酯之情況下有效偶合以安裝脲部分,產率為78%(流程4)。用氫氧化鋰使甲酯皂化產生接近定量產率之羧酸。酸與1-(1-甲基哌啶-4-基)哌嗪之介導偶合完成化合物I之合成。急驟層析得到呈非晶形粉末狀之產物,其可自丙酮中結晶,得到呈精細白色結晶粉末狀之化合物I。
4-(2-甲氧基-2-側氧基亞乙基)哌啶-1-甲酸第三丁酯
。將含氫化鈉之礦物油(60%,7.92 g,198.02 mmol)用己烷洗滌,接著懸浮於二甲基甲醯胺(220 mL)中。冷卻混合物至0℃。逐滴添加亞磷羧基乙酸三甲酯(29.0 mL,189.82 mmol)至經攪拌的反應混合物中。在0℃下20分鐘之後,向混合物中逐滴添加N
-第三丁氧基羰基-4-哌啶酮(30.41 g,152.62 mmol)於二甲基甲醯胺(80 mL)中之溶液。反應物在室溫下攪拌3小時且接著用乙醚(650 mL)稀釋。混合物用水洗滌1次且水層用乙醚萃取1次。合併之有機層用水洗滌4次且棄去水相。有機相用鹽水洗滌且經硫酸鎂乾燥,過濾且濃縮至乾燥。以92%產率獲得呈白色固體狀之標題化合物。1
H-NMR(300 MHz,CDCl3
):δ=5.68(s,1 H),3.66(s,3 H),3.40-3.51(m,4 H),2.90(t,J
=5.49,2 H),2.25(t,J
=5.49,2 H),1.44(s,9 H)。
4-(2-甲氧基-2-側氧基乙基)哌啶-1-甲酸第三丁酯
。用50%含水的10%鈀/碳(3.3 g)小心處理4-(2-甲氧基-2-側氧基亞乙基)哌啶-1-甲酸第三丁酯(35.71 g,140 mmol)於1:1乙酸乙酯/甲醇(220 mL)之混合物中的溶液。向反應容器中裝入55 psi之氫氣且在室溫下在Parr裝置上震盪混合物16小時。接著過濾反應混合物以移除催化劑且在真空中濃縮濾液。以97%產率獲得呈澄清無色油狀之標題化合物。1
H-NMR(300 MHz,CDCl3
):δ=4.04(d,J
=10.25,2 H),3.64(s,3 H),2.68(t,J
=12.44,2 H),2.21(d,J
=6.95,2 H),1.98-1.77(m,1 H),1.64(d,J
=13.54,2 H),1.41(s,9 H),1.25-0.99(m,2 H)。
4-[2-羥基-1-甲氧基羰基-2-(2-硝基-苯基)-乙基]-哌啶-1-甲酸第三丁酯。
將N,N
-二異丙胺(4.40 mL,31.3 mmol)溶解於四氫呋喃(50 mL)中。冷卻混合物至-78℃。逐滴添加丁基鋰(2.5 M於己烷中,12.4 mL,31 mmol)至經攪拌的溶液中。在-78℃下攪拌30分鐘之後,向混合物中逐滴添加4-(2-甲氧基-2-側氧基乙基)哌啶-1-甲酸第三丁酯(6.65 g,25.8 mmol)於四氫呋喃(15 mL)中之溶液。在-78℃下繼續攪拌1小時。接著向混合物中逐滴添加2-硝基苯甲醛(3.90 g,25.8 mmol)於四氫呋喃(20 mL)中之溶液,且接著在-78℃下再繼續攪拌2.5小時。反應物用冷氯化銨水溶液淬滅且接著用水稀釋。混合物用乙酸乙酯萃取2次且棄去水相。物質經乾燥(硫酸鎂),過濾且濃縮至乾燥。矽膠層析以94%產率得到呈淺黃色泡沫狀之所要產物。MS m/e(M-C4
H8
+H)+
=353.1。
4-(4-羥基-2-側氧基-1,2,3,4-四氫-喹啉-3-基)-哌啶-1-甲酸第三丁酯
。在配備有氮氣入口、溫度計及機械攪拌器之3頸燒瓶中,將4-[2-羥基-1-甲氧基羰基-2-(2-硝基-苯基)-乙基]-哌啶-1-甲酸第三丁酯(9.93 g,24.3 mmol)溶解於乙酸(1.75 mol,100 mL)中。在攪拌下添加鐵粉(8.90 g,159 mmol)至容器中。將經攪拌的混合物緩慢加熱至80℃,持續30分鐘,且接著冷卻至室溫。其接著用乙酸乙酯稀釋且經由矽藻土墊過濾。依次用20%甲醇/乙酸乙酯及甲醇洗滌固體。濃縮濾液且使殘餘物分配於乙酸乙酯與重碳酸鈉水溶液之間。分離各層。所得水相用乙酸乙酯萃取2次。合併有機層。混合物用水洗滌2次且棄去水相。物質經乾燥(硫酸鎂),過濾且濃縮至乾燥。矽膠層析以77%產率得到呈淺黃色泡沫狀之標題化合物。MS m/e(M-H)-
=345.1。
3-(哌啶-4-基)喹啉-2(1H)鹽酸鹽
。用含HCl之二噁烷(4 N,40 mmol,10 mL)處理經攪拌的4-(4-羥基-2-側氧基-1,2,3,4-四氫-喹啉-3-基)-哌啶-1-甲酸第三丁酯(5.60 g,16.2 mmol)於乙酸乙酯(70 mL)中之溶液。在室溫下攪拌混合物45分鐘。接著再添加含HCl之二噁烷(4 N,120 mmol,30 mL)且在室溫下繼續攪拌16小時。藉由過濾收集所得固體且用乙酸乙酯洗滌。接著將其懸浮於5%水-異丙醇(100 mL)中且將混合物升溫至回流並攪拌20分鐘。將混合物冷卻至室溫且在室溫下攪拌16小時。藉由過濾收集固體,用異丙醇洗滌,且在高真空下乾燥。以75%產率獲得呈白色固體狀之標題化合物。1
H-NMR(DMSO-d6
)δ11.85(s,1 H),9.02(bs,1 H),8.88(bs,1 H),7.70(t,J
=3.81 Hz,2 H),7.53-7.30(d,J
=8.24 Hz,1 H),7.17(t,J
=7.48 Hz,2 H),3.36(d,J
=12.51 Hz,2 H),3.10-2.94(m,3 H),2.01(d,J
=13.43 Hz,2 H),1.87-1.73(m,2 H);MS m/e (M+H)+
=229.0。
4-碘-2,6-二甲基苯胺鹽酸鹽
。在室溫下經1小時向重碳酸鈉(126 g,1.5 mol)及2,6-二甲基苯胺(61.5 mL,500 mmol)於甲醇(700 mL)中之懸浮液中添加單氯化碘(1.0 M於二氯甲烷中,550 mL,550 mmol)。在完成添加後,繼續攪拌3小時。過濾反應物以移除過量重碳酸鈉且在真空中移除溶劑。將殘餘物再溶解於乙醚(1.5 L)中且用鹽酸(2 M於乙醚中,375 mL,750 mmol)處理。將所得懸浮液於冷凍器(-15℃)中儲存隔夜。過濾固體且用乙醚洗滌直至其變為無色,得到126.5 g(89%)灰綠色粉末。1
H-NMR(DMSO-d6
)δ2.33(s,6 H),7.48(s,2 H),9.05(bs,3 H);13
C-NMR(DMSO-d6
)δ17.4,91.5,133.1,131.2,136.9。
2-(苯甲氧基羰基)丙烯酸甲酯
。向經火焰乾燥之配備有機械攪拌器之3頸圓底燒瓶中添加(S)-2-(苯甲氧基羰基)-3-羥基丙酸甲酯(129 g,509 mmol)、無水二氯甲烷(2 L)及甲烷磺醯氯(49.3 mL,636 mmol)。將混合物冷卻至-15℃且用三乙胺(213 mL,1527 mmol)逐滴處理以確保反應混合物之溫度不超過0℃。添加第一當量之三乙胺會放熱。在添加三乙胺之後,在0℃下攪拌混合物30分鐘。移除冷卻浴且在室溫下攪拌混合物1.5小時。藉由添加甲醇(21 mL)淬滅反應。用0.5%硫酸氫鉀洗滌混合物直至洗滌液之pH值為5,接著用飽和重碳酸鈉及鹽水洗滌,經硫酸鈉乾燥且濃縮。急驟層析(矽膠,1:9乙酸乙酯/己烷)得到111 g(92%)黏稠無色油狀物,其在靜置時結晶。1
H-NMR(DMSO-d6
)δ3.71(s,3 H),5.10(s,2 H),5.60(s,1 H),5.76(s,1 H),7.39-7.35(m,5 H),8.96(s,1 H);13
C-NMR(DMSO-d6
)δ52.3,65.9,127.8,128.1,128.3,128.8,133.3,136.3,153.5,163.7。
(Z)-3-(4-胺基-3,5-二甲基苯基)-2-(苯甲氧基羰基)丙烯酸甲酯
。將4-碘-2,6-二甲基苯胺鹽酸鹽(55 g,194 mmol)、2-(苯甲氧基羰基)丙烯酸甲酯(59.2 g,252 mmol)、氯化四丁銨(59.2 g,213 mmol)、乙酸鈀(II)(4.34 g,19.4 mmol)及四氫呋喃(1.2 L,用氮氣流脫氣30分鐘)裝入2 L圓底燒瓶中。攪拌混合物以使得形成懸浮液且接著用氮氣流脫氣30分鐘。添加三乙胺(110 mL,789 mmol)且在回流下加熱所得混合物3小時。冷卻至室溫後,反應混合物經由矽藻土墊過濾,用四氫呋喃(2×100 mL)洗滌,且濃縮。將殘餘物溶解於二氯甲烷中,用水(3×)及鹽水(2×)洗滌,經硫酸鈉乾燥,且濃縮。急驟層析(矽膠,使用1:9乙酸乙酯/二氯甲烷)得到棕褐色固體。使固體自溫熱甲醇(210 mL)及水(100 mL)中再結晶。混合物在室溫下保持隔夜,接著在0℃下保持2小時,且最終在-15℃下保持2小時。將所得固體過濾,用冰冷1:1甲醇/水洗滌且在高真空下乾燥隔夜,得到44.7 g(65%)淺棕褐色固體,其為Z/E異構體(73:27)之混合物。1
H-NMR(DMSO-d6
)δ,2.05(s,6 H),3.61(s,0.8 H),3.68(s,2.2 H),5.00(s,0.54 H),5.13(s,1.46 H),5.24(s,2 H),7.40-7.21(m,8 H),8.51(s,0.27 H),8.79(s,0.73 H);13
C-NMR(DMSO-d6
)δ17.8,51.7,65.3,119.4,120.0,120.3,127.3,127.7,128.3,130.9,135.8,137.2,146.9,154.7,166.0。
(R)-3-(4-胺基-3,5-二甲基苯基)-2-(苯甲氧基羰基)丙酸甲酯
。向經火焰乾燥之2 L Parr氫化瓶中裝入(Z)-3-(4-胺基-3,5-二甲基苯基)-2-(苯甲氧基羰基)丙烯酸甲酯(84.5 g,239 mmol)、二氯甲烷(300 mL)及甲醇(300 mL)。將瓶渦旋以使得形成淺棕色懸浮液。使用氮氣流使混合物脫氣30分鐘。向此混合物中快速添加(-)-四氟硼酸1,2-雙((2R
,5R
)-2,5-二乙基磷基)-苯(環辛二烯)銠(I)([(2R
,5R
)-Et-DuPhosRh]BF4
)(2.11 g,3.20 mmol)。立即將瓶連接至Parr氫化器。在氫氣(60 psi)及真空之5個循環後,將瓶加壓至65 psi且在室溫下攪拌懸浮液16小時。反應物已變得均質。濃縮反應混合物,且藉由急驟層析(矽膠,1:9乙酸乙酯/二氯甲烷)純化所得殘餘物,得到82.9 g(98%)。1
H-NMR(DMSO-d6
)δ2.04(s,6H),2.65(dd,J
=13.4,9.8 Hz,1H),2.82(dd,J
=13.7,5.2 Hz,1 H),3.62(s,3 H),4.15-4.10(m,1H),4.41(s,2 H),5.00(s,2 H),6.68(s,2 H),7.37-7.28(m,5H),7.70(d,J
=7.9 Hz,1 H);13
C-NMR(DMSO-d6
)δ17.7,35.9,51.7,56.1,65.3,120.4,124.0,127.5,127.7,128.2,128.3,136.9,142.6,155.9,172.5。
(R)-2-(苯甲氧基羰基)-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯
。將(R)-3-(4-胺基-3,5-二甲基苯基)-2-(苯甲氧基羰基)丙酸甲酯(50.0 g,140 mmol)稱量入經火焰乾燥之5 L 3頸圓底燒瓶中,隨後添加甲苯(2.4 L)及冰醋酸(120 mL,2.1 mol)。機械攪拌混合物以形成澄清溶液,且接著添加乙酸鉀(103 g,1.05 mol)。在室溫下向所得白色懸浮液中逐滴添加亞硝酸異戊酯(20.7 mL,154 mmol),且在室溫下攪拌所得混合物16小時。添加飽和重碳酸鈉(1 L),隨後小心添加固體重碳酸鈉以中和乙酸。用二氯甲烷(2 L)與鹽水(1.5 L)之混合物萃取混合物。分離後,用二氯甲烷(500 mL)萃取水層。合併之有機層經無水硫酸鈉乾燥且過濾。移除溶劑,得到棕褐色固體,用己烷(2 L)及甲苯(150 mL)將其洗滌。使固體自熱丙酮(260 mL)及己烷(700 mL)中再結晶。使略微混濁之混合物緩慢冷卻至室溫,接著冷卻至0℃,持續1.5小時,且最終冷卻至-15℃,持續1.5小時。過濾所得固體且用冰冷丙酮/己烷(1:1,200 mL)洗滌,得到39.1 g(76%產率)。分析型HPLC顯示UV純度>98%。對映異構過量(ee)測定為99.8%(條件:Chiralpak AD管柱,4.6×250 mm,10 μm;A=乙醇,B=0.05%二乙胺/庚烷;85%B,在1.0 mL/min下,持續55分鐘。R之滯留時間為44.6分鐘且S之滯留時間為28.8分鐘)。1
H-NMR(DMSO-d6
)δ2.48(s,3H),2.93(dd,J
=13.4,10.7 Hz,1H),3.10(dd,J
=13.7,4,9 Hz,1H),3.63(s,3H),4.32-4.27(m,1 H),4.97(s,2 H),7.03(s,1 H),7.24-7.22(m,2 H),7.29-7.27(m,3 H),7.41(s,1 H),7.83(d,J
=8.2 Hz,1H),7.99(s,1H),13.1(s,1H);13
C-NMR(DMSO-d6
)δ16.7,36.5,51.8,56.0,65.3,117.6,119.6,122.7,127.2,127.4,127.6,128.2,129.3,133.4,136.8,139,2,155.9,172.4。質譜:368.16(MH)+
。
( R)-2-胺基-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯
。向Parr氫化瓶中裝入(R)-2-(苯甲氧基羰基)-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯(11.0 g,29.9 mmol)及甲醇(75 mL)。懸浮液用氮氣淨化且用鈀(10%於木炭上,700 mg)處理。在氫氣(15 psi)下將瓶震盪隔夜。經由矽藻土墊過濾混合物以移除催化劑。濃縮溶離劑,得到7.7 g(定量)油狀物,其不經進一步純化即使用。1
H-NMR(CD3
OD)δ2.54(s,3 H),2.98(dd,J
=13.5,7.0 Hz,1 H),3.09(dd,J
=13.5,5.9 Hz,1 H),3.68(s,3 H),3.75(dd,J
=7.0,6.2 Hz,1 H),7.01(s,1 H),7.39(s,1 H),7.98(s,1 H)。質譜:232.34(M-H)-
。
(R)-3-(7-甲基-1H-吲唑-5-基)-2-(4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-甲醯胺基)丙酸甲酯
。在室溫下向(R)-2-胺基-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯鹽酸鹽(7.26 g,27.0 mmol)於二甲基甲醯胺(50 mL)中之溶液中依次添加碳酸N,N'
-二丁二醯亞胺酯(7.60 g,29.7 mmol)及三乙胺(11.29 mL,81 mmol)。將所得混合物攪拌30分鐘且以逐份方式用3-(哌啶-4-基)喹啉-2(1H)-酮(6.77 g,29.9 mmol)處理。使反應物攪拌24小時。將混合物濃縮,溶解於乙酸乙酯中,且依次用水、鹽水及0.5 N HCl(2×)洗滌。有機相經硫酸鎂乾燥,過濾且濃縮。藉由急驟層析(矽膠,20:1乙酸乙酯/甲醇)純化所得殘餘物,得到11.9 g(78%)。1
H-NMR(CD3
OD)δ13.0(s,1 H),11.8(s,1 H),7.98(s,1 H),7.63(d,J
=7.6 Hz,1 H),7.57(s,1 H),7.45-7.41(m,2 H),7.27(d,J
=8.2Hz,1 H),7.16(t,J
=7.9 Hz,1 H),7.03(s,1 H),6.85(d,J
=7.9 Hz,1 H),4.31-4.26(m,1 H),4.10-4.08(m,2 H),3.60(s,3 H),3.07-3.01(m,2 H),2.93-2.88(m,1 H),2.77-2.67(m,2 H),2.48(s,3 H),1.78-1.72(m,2 H),1.34-1.26(m,2 H)。質譜:488.52(MH)+
。
(R)-3-(7-甲基-1H-吲唑-5-基)-2-(4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-甲醯胺基)丙酸
。將(R)-3-(7-甲基-1H-吲唑-5-基)-2-(4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-甲醯胺基)丙酸甲酯(5.50 g,11.3 mmol)於四氫呋喃(50 mL)及甲醇(10 mL)中之溶液冷卻至0℃。經15分鐘向此溶液中逐滴添加單水合氫氧化鋰(0.95 g,22.6 mmol)於水(20 mL)中之冷(0℃)溶液。在室溫下再攪拌反應物3小時。濃縮混合物以移除有機溶劑。將所得殘餘物溶解於少量水中,冷卻至0℃,且用冷(0℃)1 N HCl處理直至達到pH 2。藉由過濾收集所得固體,用冷水及乙醚洗滌,且接著在高真空下乾燥隔夜,得到5.0 g(94%)白色固體。1
H-NMR(DMSO-d6
)δ13.05(bs,1 H),11.77(s,1 H),7.98(s,1 H),7.62(d,J
=8.0 Hz,1 H),7.55(s,1 H),7.44(d,J
=8.2Hz,1 H),7.42(s,1 H),7.27(d,J
=8.2 Hz,1 H),7.16(t,J
=7.6 Hz,1 H),7.05(s,1 H),6.65(d,J
=7.9 Hz,1 H),4.27-4.22(m,1 H),4.10-4.07(m,2 H),3.12-3.07(m,1 H),3.03-2.99(m,1 H),2.93-2.88(m,1 H),2.77-2.66(m,2 H),2.47(s,3 H),1.77-1.74(m,2 H),1.34-1.27(m,2 H)。質譜:474.30(MH)+
。
(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-側氧基丙-2-基)-4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-甲醯胺(I)
。向燒瓶中裝入(R)-3-(7-甲基-1H-吲唑-5-基)-2-(4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-甲醯胺基)丙酸(2.9 g,6.11 mmol)、三乙胺(3.00 mL,21.5 mmol)、1-(1-甲基哌啶-4-基)哌嗪(1.23 g,6.72 mmol)及二甲基甲醯胺(10 mL)。以逐份方式用四氟硼酸2-(1H-苯并三唑-1-基)-1,1,3,3-四甲(2.26 g,7.03 mmol)處理所得溶液。在室溫下使反應物攪拌隔夜。在真空下濃縮混合物以移除二甲基甲醯胺。將粗產物溶解於含7%甲醇之二氯甲烷中且使用含有2%氫氧化銨水溶液之含7%甲醇的二氯甲烷作為溶離劑藉由急驟層析純化。收集純溶離份且在真空下移除溶劑。使所要產物自熱丙酮中結晶,以77%產率得到化合物I
。分析型HPLC顯示230 nm下之UV純度為99.0%。對映異構過量(ee)測定為>99.9%(條件:Chiralpak AD管柱,4.6×250 mm,10 μm;溶離劑:70%(0.05%二乙胺)/庚烷/30%乙醇;在1.0 mL/min下,持續45分鐘。R之滯留時間為18.7分鐘且S之滯留時間為28.1分鐘)。1
H-NMR(500 MHz,DMSO-d6
)δppm 13.01(s,1 H),11.76(s,1 H),7.96(s,1 H),7.62(d,J
=7.10 Hz,1 H),7.60(s,1 H),7.42(m,1 H),7.36(s,1 H),7.26(d,J
=8.25 Hz,1 H),7.14(m,1 H),7.00(s,1 H),6.69(d,J
=8.25 Hz,1 H),4.78(q,J
=7.79 Hz,1 H),4.14(d,J
=12.37 Hz,2 H),3.54(dd,J
=9.16,4.58 Hz,1 H),3.24(m,1 H),3.11(m,1 H),2.97(m,1 H),2.89(m,2 H),2.69(m,4 H),2.32(m,1 H),2.21(m,1 H),2.07(m,4 H),1.95(t,J
=8.25 Hz,1 H),1.87(m,J
=11.28,11.28,3.55,3.44 Hz,1 H),1.76(t,J
=12.03 Hz,2 H),1.68(t,J
=11.11 Hz,2 H),1.53(t,J
=8.25 Hz,1 H),1.32(m,4 H),1.16(m,2 H);13
C-NMR(DMSO-d6
)δ16.80,27.30,30.51,30.51,30.67,35.50,38.04,41.74,44.00,44.16,45.35,45.78,48.14,48.39,51.45,54.76,54.76,60.61,114.53,117.79,119.29,119.34,121.57,122.78,127.46,127.79,129.29,129.79,133.31,133.72,136.98,137.41,139.12,156.50,161.50,170.42。精確質量分析:m/z 639.3770,[MH]+
,Δ=-0.2 ppm。旋光度:-27.36°(在589 nm下),濃度=4.71 mg/mL(於甲醇中)。
流程5:化合物I及比較化合物II及III。
水溶性
。將固體游離鹼與碳酸鹽及乙醇胺緩衝液混合。用HCl調節第三樣本之pH值。使用封閉在設定至25℃之培育箱內之混合器混合固體與媒劑。平衡後,取出上清液樣本,適當時加以稀釋,且藉由HPLC進行分析。
於水性介質中之溶解度,pH值依賴性
。在量測pH值溶解度概況期間結晶化合物I轉化成凝膠相。不存在與水平衡之結晶相會妨礙對可將化合物I調配成熱力學穩定溶液之pH值範圍進行可靠評估。產生化合物I之於水中可經平衡之結晶游離鹼形式的努力正在進行中。收集之關於凝膠相之資料列於表1中。
溶液狀態穩定性
。化合物I之溶液狀態穩定性評估為溫度、pH值、高強度光照(HIL)、緩衝液濃度及藥物濃度之函數。所用實驗矩陣展示於表2中。
丁二酸鹽緩衝液用於所有溶液。對於曝露於光中之樣本,根據ICH準則(120萬勒克司小時(lux hour)曝露於可見光且200瓦特小時/平方公尺(watt hour/m2
)曝露於UV)使用光穩定性腔室。在4、8及12週進行分析。
在溶液穩定性研究期間發現10種降解物。儲存12週後於樣本中發現之各降解物之百分比列於表3中。應注意在初始時間點時,降解物B及G為僅有之存在的降解物且其初始濃度分別為0.17%及0.06%。
對以足以允許質量測定之量存在之彼等降解物進行質譜評估。結果列於表4中。在降解物B下列有兩個峰,因為發現兩種降解物未由當前HPLC方法充分分離。降解物A及C對應於水解產物。
在所研究之最有利條件(表2中之條件I)下,化合物I顯示在40℃下12週後僅有0.3%降解。此表明可找到滿足至少1年之化學穩定性之ICH準則的水性調配物。
溶液穩定性:溫度影響
。溫度影響概述於表5中。降解速率隨溫度增加主要歸因於水解增強。在最高溫度下,降解自始至終發生直至產物C,但在較低溫度下,降解停在產物A處。
溶液穩定性:光照影響
。光照對穩定性之影響概述於表6中。對於曝露於光中之樣本,注意到有7種降解物,其中3種不出現在於任何其他條件下儲存之樣本中。水解(降解物A)因曝露於光中而得以增強。
溶液穩定性:pH值影響
。pH值對降解速率之影響概述於表7中。降解速率之增加與pH值呈相反變化且受水解增強支配。在pH 4下,降解發生直至水解產物C,但在pH 5及6下,降解停在水解產物A處。
溶液穩定性:緩衝液濃度影響
。丁二酸鹽緩衝液之較高濃度傾向於產生水解成降解物A之較高速率(表8)。
溶液穩定性:藥物濃度影響
。高藥物裝載量使水解速率減緩且限制水解形成降解物A(表9)。在研究期間,僅在高濃度樣本中偵測之降解物G的濃度不顯著增長且可能僅為雜質。降解物J僅可在最終時間點時偵測。
結合檢定
。SK-N-MC細胞膜組織勻漿充當受體源。人類神經母細胞瘤SK-N-MC細胞用於活體外檢定,因為其內源性表現與經選殖之人類CGRP受體序列一致的CGRP受體(Aiyar等人,2001)。在37℃下於5% CO2
中,使細胞生長於由補充有10%胎牛血清之含有厄爾氏鹽(Earle's salt)及L-麩醯胺酸之MEM組成的培養基中直至達到匯合。藉由用磷酸鹽緩衝鹽水沖洗2次收集細胞且在4℃下於由10 mM Tris(pH 7.4)及5 mM EDTA組成之低張溶解緩衝液中培育5-10分鐘。收集細胞並轉移至聚丙烯管中且使用polytron加以均質化。組織勻漿在32,000×g下離心30分鐘。使離心塊再懸浮於含有0.1%哺乳動物蛋白酶抑制劑混合液之冷低張溶解緩衝液中且檢定蛋白質濃度。接著等分膜組織勻漿且儲存在-80℃下直至檢定當天。
使用放射性配位體競爭檢定量測化合物I爭奪經放射性標記之([125
I]CGRP,Amersham Biosciences)內源性肽人類αCGRP(hαCGRP)之能力。化合物I首先溶解於100% DMSO中且使用100% DMSO進行連續稀釋。將化合物於檢定緩衝液(50 mM Tris-Cl(pH 7.5),5 mM MgCl2
,0.005% Triton X-100)中進一步稀釋25倍且轉移(50 μl)入96孔檢定板中。於檢定緩衝液中稀釋[125
I]-CGRP至600 pM,且添加50 μl體積至各孔中(檢定中之最終濃度為15 pM)。解凍SK-N-MC膜離心塊,於含有新鮮0.1%哺乳動物蛋白酶抑制劑混合液之檢定緩衝液中稀釋,且如先前所述加以均質化。接著以100 μl體積添加每孔5至10 μg蛋白質。接著在室溫(25℃)下培育檢定板2小時。藉由添加過量冷洗滌緩衝液(20 mM Tris-Cl(pH 7.5),0.1% BSA)終止檢定,隨後即刻經預浸泡於0.5% PEI中之玻璃纖維過濾器過濾。非特異性結合以1 μM β-CGRP加以定義。使用γ閃爍計數器量測蛋白質結合放射能。IC50
定義為抑制50%放射性配位體結合所需之化合物濃度。
結果。
化合物I顯示以濃度依賴性方式抑制[125
I]CGRP與內源性表現於SK-N-MC細胞膜中之CGRP受體結合。平均K i
為22.7±1.6 pM。
方法
。使用飽和結合實驗詳細研究內源性CGRP肽與化合物I之間之相互作用的性質。簡言之,在無(對照條件)或存在(測試條件)兩種濃度(30 pM及100 pM)之一之化合物I的情況下增加[125
I]CGRP濃度來量測[125
I]CGRP與SK-N-MC細胞膜製備物的結合。使用Kell軟體(Biosoft,Cambridge,UK)用雙曲線方程分析飽和資料以估計解離常數(Kd
)及最大結合位點數(B 最大
)。量測並比較添加化合物I對[125
I]CGRP之結合參數(K d
、B 最 大
)之影響。
結果
。化合物I以濃度依賴性方式使[125
I]CGRP結合之解離常數K d
增加(使其親和力降低),而不顯著改變[125
I]CGRP結合之最大結合位點數(B 最 大
)。此指示化合物I抑制[125
I]CGRP與人類受體結合之競爭機制(表10)。
方法
。使CGRP受體複合物與Gs種類之G蛋白偶合。CGRP與此複合物之結合導致經由腺苷酸環化酶之Gs依賴性活化而產生環AMP(3'5'-環單磷酸腺苷)。
化合物I之功能性拮抗作用係藉由量測其抑制所附著之完整SK-N-MC細胞中經CGRP刺激之環AMP形成的能力加以測定。SK-N-MC細胞在室溫下僅與0.3 nM CGRP一起培育30分鐘,或與各種濃度之化合物I一起預培育15分鐘,隨後添加0.3 nM CGRP且接著再培育30分鐘。使用「溶解試劑(Lysis Reagent)」萃取產生之環AMP(cAMP)且使用RPA559 cAMP SPA直接篩檢檢定套組(Direct Screening Assay Kit)(Amersham Pharmacia Biotech)藉由放射免疫檢定測定其濃度。IC50
值定義為抑制50%之經0.3 nM CGRP刺激之cAMP產生所需的化合物濃度。Y最大
定義為經0.3 nM CGRP刺激之cAMP產生的最大抑制百分比。
結果
。化合物I顯示以濃度依賴性方式抑制所附著之完整SK-N-MC細胞中經CGRP刺激的cAMP產生,其中IC50
為38.6±4.2 pM,且Y最大
為95.4(±1.3)%。所觀測之最大(約100%)抑制指示對CGRP受體之完全拮抗。
方法。
謝爾德分析用於表徵化合物I之拮抗作用之性質。用單獨CGRP或在各種濃度之化合物I存在下用CGRP產生經CGRP刺激之cAMP產生的劑量反應。特定言之,在有或無5種不同濃度之化合物I之情況下檢定CGRP對cAMP之劑量依賴性刺激。在X軸上相對於Y軸上劑量比率減1繪製化合物I之濃度(劑量比率定義為在化合物I存在下CGRP之EC50
除以單獨CGRP之EC50
)。接著用X軸與Y軸兩者之對數變換進行線性回歸。不顯著不同於數目1之斜率指示競爭性拮抗作用。K b
為拮抗劑解離常數。
結果
。化合物I之謝爾德分析揭示平均斜率為1.02±0.04且拮抗劑解離常數K b
為21.5±9.4 pM。在遞增濃度之化合物I存在下CGRP濃度-反應的平行向右移位指示化合物I對經CGRP刺激之cAMP產生的競爭性拮抗作用。來自謝爾德曲線之1.02之斜率進一步支持化合物I與CGRP功能之間的競爭性相互作用。21.5 pM之K b
與結合K i
(22.7 pM)一致。
逆轉離體人類顱內動脈中CGRP誘導之擴張為了提供模擬臨床條件(其中偏頭痛相關之CGRP在起始療法之前釋放)之離體量測,首先藉由CGRP擴張血管且接著用化合物I逆轉擴張。在此逆轉方案中,拮抗劑後處理逆轉CGRP誘導之動脈擴張(使用單次促效劑劑量及多次拮抗劑劑量)。簡而言之,將安裝有電線之動脈環用鉀離子收縮(以模擬內源性狀況),用CGRP完全擴張,且用遞增濃度之CGRP拮抗劑化合物I逆轉擴張。化合物I後處理有效逆轉所產生之CGRP誘導的離體人類顱內動脈擴張。
組織樣本
。自組織採購供應商獲得人類動脈之剖檢樣本。所有血管皆於冰冷HEPES緩衝液(組成(mM):NaCl 130、KCl 4、KH2
PO4
1.2、MgSO4
1.2、CaCl2
1.8、葡萄糖6、NaHCO3
4、HEPES 10、EDTA 0.025)中加以運輸。接收後,將血管置於用碳合氧(carbogen)(5% CO2
及95%氧氣)飽和之冷克雷伯氏緩衝液(Kreb's buffer)(組成(mM):NaCl 118.4、KCl 4.7、KH2
PO4 1.2、MgSO4
1.2、CaCl2
1.8、葡萄糖10.1、NaHCO3
25)中。
方法
。將血管清除掉結締組織且切割成長度為4-5 mm之圓柱形區段。接著將血管安放於介於兩個不鏽鋼鉤之間的組織浴中;其中一個鉤經固定且另一個鉤與力位移傳感器(force displacement transducer)相連。使用資料獲取系統(Powerlab,AD Instruments,Mountain View,CA)連續記錄血管張力。控制含有克雷伯氏緩衝液及所安放血管之組織浴的溫度(37℃)及pH值(7.4)且用碳合氧對該等組織浴連續鼓泡。使動脈區段平衡約30-45分鐘直至達成穩定靜止狀況(0.25至0.5 g)。在檢定之前,用100 mM KCl灌注(調節)血管且隨後洗滌。
為了測試化合物I之抗擴張作用,首先用10 mM氯化鉀(KCl)收縮血管以模擬內源性狀況,接著用1 nM hαCGRP完全擴張,且最終藉由以半對數單位(允許計算EC50
)累積添加遞增濃度之化合物I使擴張逆轉。在各濃度下,藥物作用表示為各血管中CGRP誘導擴張之逆轉百分比。個別地進行各血管之資料分析,藉由非線性回歸分析相對於4參數邏輯函數擬合濃度-反應資料,以估計EC50
值。
結果
。化合物I顯示以EC50
=880±50 pM有效且完全逆轉CGRP誘導之離體人類顱內動脈擴張。
為了評估相對於一定範圍之CGRP濃度之功能性拮抗作用,將化合物I與個別動脈環一起預培育於組織浴中且接著產生CGRP濃度-反應曲線以達成完全擴張(使用多次促效劑及多次拮抗劑劑量)。拮抗劑之濃度較高會引起CGRP濃度-反應曲線中之『右移』,從而需要較大濃度之促效劑來克服拮抗劑之存在且達成完全擴張。簡而言之,將安裝有電線之動脈環與拮抗劑一起預培育,接著用KCl收縮(以模擬內源性狀況),且隨後添加遞增濃度之CGRP以達成完全鬆弛。化合物I預處理有效抑制CGRP誘導之離體人類顱內動脈擴張,且顯示CGRP濃度-反應曲線之平行向右移位。
方法
。將各安裝有電線之動脈環與單一濃度(0.1-30 nM)之拮抗劑化合物I一起預培育30分鐘,接著用10 mM KCl收縮(以模擬內源性狀況),隨後添加遞增濃度之CGRP以達成完全鬆弛。使KCl收縮穩定,以使得在施用CGRP之前,總拮抗劑預處理時間為約45分鐘。
結果。
化合物I引起離體人類顱內動脈中CGRP濃度-反應曲線之平行向右移位。謝爾德分析揭示91 pM之K b
。此等結果有利地與活體外結合(K i
=22.7 pM)及功能性(K b
=21.5 pM)檢定相當。
化合物I在狨猿(Marmoset)面部血流量方面之活體內功效為了評估新穎CGRP受體拮抗劑之活體內功效,狨猿接受一系列之4次hαCGRP靜脈內注射(間隔45分鐘)。首次注射充當基線對照,且隨後皮下傳遞測試物品。隨後3次CGRP攻毒提供對活體內功能性CGRP拮抗作用之評估。在本研究中,化合物I證明具有穩固的持續性CGRP拮抗作用。
方法
。將狨猿麻醉且面部血流量因以45分鐘時間間隔(-30、15、60及105分鐘)靜脈內(IV)投與hαCGRP而增加。藉由雷射都蔔勒流量計(laser Doppler flowmetry)量測在0分鐘傳遞之測試化合物對hαCGRP誘導之面部血流量變化的影響。有效化合物將抑制在15、60及105分鐘所見之hαCGRP誘導之面部血流量增加(相較於在-30分鐘所見之基線hαCGRP影響)。
個體
:重量為350-650 g之成年雄性及雌性普通狨猿(白鬢狨(Callithrix jacchus))充當個體。
麻 醉及準備
:動物藉由於吸氣室中吸入異氟烷(4-5%快速吸氣,以1-2.5%維持;Solomon等人,1999)而被麻醉。藉由經由插管及通風(同時監測血中含氣量(blood gas))傳遞恆定供應之空氣:氧氣(50:50)及異氟烷來維持麻醉。藉由置放在具有直腸探針之自動溫度控制表面上將體溫維持在38±0.5℃。藉由施用脫毛乳膏及/或剃毛自面部之一側或兩側移除小面積之軟毛(fur)(約1.5平方公分)。夾住手術區域且用必達淨(betadine)進行準備。將IV管線置於隱靜脈中以投與測試化合物及CGRP受體促效劑hαCGRP。另外,此IV管線提供取出血液樣本(最大2.5 ml,10%)用於監測血中含氣量及分析化合物血漿含量。IV投與5%右旋糖之溶液以維持血糖含量。藉由分別使用非侵襲入性臂套測壓法及脈搏血氧定量計量測血壓及心跳速率來監測麻醉深度。給與5-10 mg/kg IV胍乙啶(需要時補充5 mg/kg IV)以穩定面部血流量之峰通量,否則其會在重複刺激後顯示漸進性減小(Escott等人,1995)。藉由將自黏雷射都蔔勒流量探針附著於面部皮膚來監測微血管血流量。探針記錄穿過兩個雷射束之路徑之紅血球數目,乘以其速度(報導為通量之變化)。
藥物傳遞
:在頸背中SC投與測試化合物(0.1-0.6 ml/kg)。以10 μg/kg之劑量IV傳遞CGRP受體促效劑hαCGRP(1 ml/kg)。
測試方案
:為了評估活體內功效及作用持續時間,在藥物傳遞之前30分鐘(-0.5小時)藉由投與hαCGRP(10 μg/kg IV)來誘導面部血流量之控制增加。接著在時間零點(0分鐘)投與化合物I且以45分鐘時間間隔持續約2小時重複傳遞hαCGRP(在給藥後0.25、1及1.75小時收集資料)。化合物I係以0.003、0.01及0.03 mg/kg進行SC給藥。在各hαCGRP投藥之前即刻獲得血漿樣本。在測試之後,使動物返回至置放在溫度經控制之表面上之運輸籠中,該表面使動物保持溫曖直至完全蘇醒及可走動。可在14-21天之休息及清除期之後再次測試動物。
結果
。化合物I(0.003-0.03 mg/kg,SC)顯示以劑量依賴性方式抑制CGRP誘導之狨猿面部血流量增加。在0.03 mg/kg下,在給藥後0.25、1及1.75小時觀測到穩固(53-80%)抑制。在0.01 mg/kg下,在整個所有給藥後測試時間內可見顯著(35-40%)抑制。在0.003 mg/kg下,在0.25小時觀測到輕微(20%)但顯著之抑制,在隨後測試時間無作用。
比較功效相對於暴露(exposure)之關係,對於化合物I而言,血漿含量8 nM與顯著活體內功效相關且含量25 nM與最大功效相關。
化合物I及化合物III:大鼠中之1週比較鼻內刺激研究
。進行此研究以比較化合物I與化合物III當向雄性大鼠鼻內給與1週時的潛在鼻刺激。用化合物I或化合物III溶液(25、75或175 mg/L於225 mM丁二酸中,0.02%氯化苯甲烴銨,1.25%無水右旋糖,pH 5.8-6.2)以每鼻孔100 μL之劑量體積每日1次對雄性大鼠(10隻/組)鼻內滴注。使用此給藥範式,每日傳遞固定劑量之5、15或35 mg測試物品。因此,相對於體重校正之劑量因大鼠生長而隨時間減小。給與1個對照組丁二酸鹽媒劑且藉由鼻內滴注給與1個假對照組鹽水。評估之參數包括臨床觀測、體重、食物消耗、毒物動力學及鼻組織之組織學評估。
毒物動力學參數之值展示於表11中。
1
由於長期暴露而未測出。
2
在靜脈內投與1 mg/kg之後,基於大鼠中7.7 μM‧h之AUC0-24h
的絕對生物可用性。
3
估計之大鼠鼻黏膜表面積=14 cm2
化合物I之鼻內給藥提供大鼠中24小時之全身性暴露,且在此1週研究中之首天與末天給藥之間未觀測到差異。
鼻內投與化合物I耐受良好;生活中之研究結果侷限於所有劑量組及媒劑對照中流涎增加,且可能與用於研究之給藥體積過大相關。在給與鹽水之大鼠中未觀測到流涎。
對於兩種化合物均觀測到鼻刺激,但在整個劑量範圍內化合物I明顯導致比化合物III少的嗅上皮萎縮(表12)。觀測之病變類型與先前對化合物II所作之觀測一致。鼻研究結果之嚴重程度及發病率證明化合物I之鼻毒性概況優於化合物III之鼻毒性概況。
化合物I及化合物II:大鼠中之1週探索性鼻內刺激研 究
。亦直接比較化合物I與化合物II之鼻內刺激。用化合物I或化合物II溶液(75或175 mg/L於225 mM丁二酸中,1.25%無水右旋糖,pH 5.8-6.2)以每鼻孔12.5、25或100 μL之劑量體積每日1次對雄性大鼠(6隻/組)鼻內滴注。此研究中評估之唯一終點為鼻甲骨之組織學評估。
在評估之各劑量(體積×濃度)下,由化合物I引起之嗅上皮萎縮之嚴重程度明顯小於由化合物II產生之嚴重程度(表13)。
化合物II之劑量-反應關係與在其他研究中觀測之劑量-反應關係一致。體積增加與濃度增加兩者均促成更顯著之鼻毒性,但濃度可能為更重要之因素。
總而言之,相較於化合物II,化合物I顯示關於鼻刺激之優越性。
鼻傳遞之潛力
。CGRP拮抗劑之鼻內(IN)投藥途徑具有吸引力,因為其提供具有快速起作用之潛力的非侵入性傳遞。高滲透性鼻上皮障壁、經充分灌注之黏膜組織及有限之代謝能力/組織滯留時間為支持鼻內傳遞如化合物I之展現極其不良經口吸收之化合物的潛在適用特徵。
藉由比較經鼻傳遞與藉由IV途徑傳遞之化合物I的血漿濃度-時間概況及藥物動力學參數(C最大
、T最大
、AUC及生物可用性)於IN兔模型中評估鼻傳遞之可行性。給藥溶液濃度及傳遞體積包括在各研究之資料表中。媒劑組成描述於表下方之註腳中。
方法
。各組3隻重量在3-3.5 kg之範圍內之雄性紐西蘭白兔(New Zealand White rabbit)以下列療程之一接受單次劑量之藥物:0.5 mg/kg,經30秒IV快速注射;或0.3-3 mg/kg,用針筒微型噴霧器IN投與。在IN給藥之前,使兔稍微鎮靜以實現用吸入麻醉劑七氟烷(Sevoflurane)麻醉之目的。兔在2-5分鐘內恢復意識。在給藥前、給藥後2、5、10、15、30分鐘及1、2、4、6及24小時連續收集血液樣本於含肝素(heparin)之採血管中。血液樣本即刻在4℃下離心且分離之血漿儲存在-80℃下直至藉由LC/MS/MS檢定進行進一步分析。
結果
。藥物動力學概況指示化合物I在以溶液形式噴霧時自兔之鼻腔快速吸收。在所研究之所有劑量下,達到峰濃度之時間(T最大
)皆發生在0.2-0.3小時(15-20分鐘)內。在0.3、1及3 mg/kg下,絕對生物可用性在13至30%範圍內且C最大
在0.12至2.0 μM範圍內(表14)。
IV調配物:50 mM丁二酸鹽緩衝液/D5W媒劑,pH 5。
IN調配物:50 mM丁二酸鹽緩衝液,pH 5-6。
兔中化合物I之IN吸收極其快速。在5分鐘內量測到血漿含量>10 nM。給藥後持續至少6小時且在高劑量下多達24小時偵測到血漿中之藥物。
先前,就化合物II而言,當鼻內傳遞體積而非給藥濃度改變時,存在較大線性偏差。藉由保持化合物I傳遞體積恆定且改變給藥溶液濃度,IN AUC及C最大
展示朝向劑量依賴性線性之趨勢(表15)。此等參數之變化性亦隨劑量增加而增加。經仔細檢查,對於測試之3種劑量而言,IN生物可用性似乎隨劑量(或給藥濃度)增加而增加(表15)。
給藥濃度為10、30及100 mg/ml,於50 mM丁二酸鹽緩衝液媒劑(pH 5)中。
總而言之,相較於經口途徑,化合物I之鼻內投藥途徑提供快速全身性吸收及相對延長之血漿含量。高水溶性及改良之溶液穩定性有利支持鼻用噴霧產品於適當噴霧裝置中之耐久性(viability)。預期藥物溶液在人類鼻腔中之傳遞及其沈積比用臨床前IN動物模型可能獲得之結果更穩固及更可再現。化合物I調配物計劃以可再用多次劑量或拋棄式單位劑量鼻用噴霧裝置加以傳遞。
本發明之另一態樣為包含化合物I與醫藥學上可接受之佐劑、載劑或稀釋劑之醫藥組合物。
化合物I將一般以包含治療有效量之化合物I或醫藥學上可接受之鹽及醫藥學上可接受之載劑且可含有習知賦形劑的醫藥組合物形式給出。治療有效量為如由習此相關技藝之人士確定之為提供有意義之患者益處所需的量。醫藥學上可接受之載劑為具有可接受之安全概況的彼等通常已知載劑。組合物涵蓋所有常見固體及液體形式,包括膠囊劑、錠劑、口含劑及散劑以及液體懸浮液、糖漿、酏劑及溶液。固體組合物可以定時釋放或持續釋放調配物形式形成。組合物係使用常見調配技術及習知賦形劑(諸如黏合劑及濕潤劑)及媒劑(諸如水及醇)製備。
固體組合物通常以每劑提供約1至約1000 mg活性成分之劑量單位調配。固體劑量單位之一些實例為0.1 mg、1 mg、10 mg、100 mg、500 mg及1000 mg。液體組合物之單位劑量範圍一般為1-100 mg/mL。液體劑量單位之一些實例為0.1 mg/mL、1 mg/mL、10 mg/mL、25 mg/mL、50 mg/mL及100 mg/mL。
本發明涵蓋所有習知投藥模式,包括經口、非經腸、鼻內、舌下及經皮方法。通常,每日劑量將為每日每公斤體重0.01-100毫克。一般而言,經口投與需要較多化合物且非經腸投與需要較少化合物。然而,特定給藥方案應由醫師使用合理醫學判斷來確定。
本發明之另一態樣為鼻內投藥。
受體層面上之CGRP抑制劑假定適用於已發生CGRP受體過度活化之病理生理病狀。一些此等病狀包括神經性血管擴張、神經性炎症、偏頭痛、叢集性頭痛及其他頭痛、熱損傷、循環性休克、停經期潮紅及哮喘。CGRP受體活化已牽涉於偏頭痛之發病機制中(Edvinsson L. CNS Drugs 2001,15(10),745-53;Williamson,D. J. Microsc. Res. Tech. 2001,53,167-178.;Grant,A. D. Brit. J. Pharmacol. 2002,135,356-362.)。在偏頭痛期間,CGRP之血清含量升高(Goadsby P. J.等人,Ann. Neurol. 1990,28,183-7)且用抗偏頭痛藥物進行治療使CGRP含量恢復正常,同時減輕頭痛(Gallai V.等人,Cephalalgia 1995,15,384-90)。相較於對照,偏頭痛患者展現本底CGRP含量升高(Ashina M.等人,Pain 2000,86(1-2),133-8)。靜脈內CGRP輸注引起偏頭痛患者持續頭痛(Lassen L.H.等人,Cephalalgia. 2002,22(1),54-61)。於犬及大鼠中進行之臨床前研究報導用肽拮抗劑CGRP(8-37)全身性阻斷CGRP不改變靜止全身性血流動力學及區域血流量(Shen,Y-T.等人,J. Pharmacol. Exp. Ther. 2001,298,551-8)。因此,CGRP受體拮抗劑可提供避免與非選擇性5-HT1B/1D促效劑「曲普坦」(例如舒馬普坦)相關之心血管主動血管收縮傾向的偏頭痛新穎治療。
本發明之另一態樣為抑制CGRP受體之方法,其包含使CGRP受體與式I化合物或其醫藥學上可接受之鹽接觸。
本發明之另一態樣為治療與CGRP或CGRP受體信號傳導程度異常相關之病狀的方法,其包含向患者投與治療有效量之式I化合物。
本發明之另一態樣為式I化合物用於製造供治療與CGRP或CGRP受體信號傳導程度異常相關之病狀之藥物的用途。
本發明之另一態樣為治療偏頭痛或頭痛之方法。
本發明之另一態樣為治療神經性疼痛之方法。
本發明之另一態樣係關於治療以下病狀之方法:炎症(尤其神經性炎症)、疼痛、熱損傷、循環性休克、糖尿病、雷諾氏症候群(Reynaud's syndrome)、周邊動脈功能不全、蛛網膜下(subarachnoid)/顱出血、腫瘤生長、與停經相關之潮紅及可藉由投與包含如本文定義之式I化合物之醫藥組合物拮抗CGRP受體而實現治療的其他病狀。
本發明之另一態樣係關於選自由以下組成之群之方法:(a)消化道黏膜中之免疫調控;(b)對抗心臟過敏性損傷之保護作用;(c)刺激或阻止骨骼再吸收之介白素-1b(IL-1b)刺激;(d)調節脊髓神經元中NK1受體之表現及(e)氣管發炎疾病及慢性阻塞性肺病,包括哮喘。參見(a)Calcitonin Receptor-Like Receptor Is Expressed on Gastrointestinal Immune Cells. Hagner,Stefanie;Knauer,Jens;Haberberger,Rainer;Goeke,Burkhard;Voigt,Karlheinz;McGregor,Gerard Patrick. Institute of Physiology,Philipps University,Marburg,Germany. Digestion(2002),66(4),197-203;(b)Protective effects of calcitonin gene-related peptide-mediated evodiamine on guinea-pig cardiac anaphylaxis. Rang,Wei-Qing;Du,Yan-Hua;Hu,Chang-Ping;Ye,Feng;Tan,Gui-Shan;Deng,Han-Wu;Li,Yuan-Jian. School of Pharmaceutical Sciences,Department of Pharmacology,Central South University,Xiang-Ya Road 88,Changsha,Hunan,Naunyn-Schmiedeberg's Archives of Pharmacology(2003),367(3),306-311;(c)The experimental study on the effect calcitonin gene-related peptide on bone resorption mediated by interleukin-1. Lian,Kai;Du,Jingyuan;Rao,Zhenyu;Luo,Huaican. Department of Orthopedics,Xiehe Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan,Peop. Rep. China. Journal of Tongji Medical University(2001),21(4),304-307;(d)Calcitonin gene-related Peptide regulates expression of neurokininl receptors by rat spinal neurons. Seybold VS,McCarson KE,Mermelstein PG,Groth RD,Abrahams LG. J. Neurosci. 2003 23(5): 1816-1824. epartment of Neuroscience,University of Minnesota,Minneapolis,Minnesota 55455,及Department of Pharmacology,Toxicology,and Therapeutics,University of Kansas Medical Center,Kansas City,Kansas 66160;(e)Attenuation of antigen-induced airway hyperresponsiveness in CGRP-deficient mice. Aoki-Nagase,Tomoko;Nagase,Takahide;Oh-Hashi,Yoshio;Shindo,Takayuki;Kurihara,Yukiko;Yamaguchi,Yasuhiro;Yamamoto,Hiroshi;Tomita,Tetsuji;Ohga,Eijiro;Nagai,Ryozo;Kurihara,Hiroki;Ouchi,Yasuyoshi. Department of Geriatric Medicine,Graduate School of Medicine,University of Tokyo,Tokyo,Japan. American Journal of Physiology(2002),283(5,Pt. 1),L963-L970;(f)Calcitonin gene-related peptide as inflammatory mediator. Springer,Jochen;Geppetti,Pierangelo;Fischer,Axel;Groneberg,David A. Charite Campus-Virchow,Department of Pediatric Pneumology and Immunology,Division of Allergy Research,Humboldt-University Berlin,Berlin,Germany. Pulmonary Pharmacology & Therapeutics(2003),16(3),121-130;及(g)Pharmacological targets for the inhibition of neurogenic inflammation. Helyes,Zsuzsanna;Pinter,Erika;Nemeth,Jozsef;Szolcsanyi,Janos. Department of Pharmacology and Pharmacotherapy,Faculty of Medicine,University of Pecs,Pecs,Hung. Current Medicinal Chemistry: Anti-Inflammatory & Anti-Allergy Agents(2003),2(2),191-218。
本發明之另一態樣係關於治療癌症及增生性疾病及病狀之方法。亦已提出CGRP拮抗劑展示治療向腦轉移之惡性疾病,尤其對抗神經膠質瘤及乳癌之效用。CGRP拮抗劑可尤其適用於對抗低氧性腫瘤及預防轉移性植入。參見PCT申請公開案WO2010006168。
本發明之另一態樣係關於使用式I化合物與一或多種選自由COX-2抑制劑、NSAIDS、阿司匹靈(aspirin)、乙醯胺苯酚、曲普坦、麥角胺(ergotamine)及咖啡鹼組成之群之藥劑的組合治療偏頭痛的治療方法。
「偏頭痛」、「頭痛」及相關術語係如醫學專業人員所瞭解。偏頭痛涵蓋所有種類之偏頭痛,包括普通型偏頭痛、典型性偏頭痛、叢集性偏頭痛、閃電狀(fulgurating)偏頭痛、偏癱性(hemiplegic)偏頭痛、眼肌麻痹性(opthalmoplegic)偏頭痛及眼型(opthomalmic)偏頭痛。
「治療有效」意謂存在如由醫學專業人員所瞭解之有意義的患者益處。
「患者」意謂可受益於如由醫學專業人員所確定之治療的個人。
熟習此項技術者將顯而易知本發明不限於前述說明性實例,且其可在不脫離其基本屬性之情況下以其他特定形式實施。因此,希望實例在所有方面中皆視為具有說明性而非限制性,參考隨附申請專利範圍而非前述實例,且因此意欲具有申請專利範圍等效性之含義及範圍內之所有變化皆包括在本發明中。
Claims (7)
- 一種化合物(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-側氧基丙-2-基)-4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-甲醯胺,或其醫藥學上可接受之鹽
- 一種醫藥組合物,其包含治療有效量之(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-側氧基丙-2-基)-4-(2-側氧基-1,2-二氫喹啉-3-基)哌啶-1-甲醯胺以及醫藥學上可接受之佐劑、載劑或稀釋劑。
- 一種如請求項1之化合物或其醫藥學上可接受之鹽的用途,其係用於製造供治療與降鈣素基因相關肽(CGRP)受體過度活化或CGRP含量升高相關之病狀的藥物。
- 如請求項3之用途,其中該病狀為偏頭痛。
- 如請求項3之用途,其中該病狀為神經性疼痛。
- 一種如請求項1之化合物或其醫藥學上可接受之鹽的用途,其係用於製造供治療與CGRP含量升高相關之增生性疾病之藥物。
- 如請求項6之用途,其中該增生性疾病為乳癌或神經膠質瘤。
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US20240139171A1 (en) | 2021-03-02 | 2024-05-02 | Cgrp Diagnostics Gmbh | Treatment and/or reduction of occurrence of migraine |
WO2022217008A1 (en) | 2021-04-09 | 2022-10-13 | Teva Czech Industries S.R.O | Solid state forms of zavegepant and process for preparation thereof |
WO2023026205A1 (en) | 2021-08-24 | 2023-03-02 | Cgrp Diagnostics Gmbh | Preventative treatment of migraine |
WO2024046223A1 (zh) * | 2022-08-30 | 2024-03-07 | 熙源安健医药(上海)有限公司 | 吲唑甲酰胺类衍生物及其制备方法和用途 |
WO2024100599A1 (en) | 2022-11-09 | 2024-05-16 | Teva Czech Industries S.R.O. | Solid state forms of zavegepant hydrochloride and process for preparation thereof |
CN116003387B (zh) * | 2022-11-20 | 2024-03-26 | 药康众拓(北京)医药科技有限公司 | 一种氘代吲唑丙酰胺类化合物、药物组合物和用途 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003104236A1 (en) * | 2002-06-01 | 2003-12-18 | Bristol-Myers Squibb Company | Calcitonin gene related peptide receptor antagonists |
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EP1722792A1 (de) | 2004-03-03 | 2006-11-22 | Boehringer Ingelheim International GmbH | Ausgewählte cgrp-antagonisten, verfahren zu deren herstellung sowie deren verwendung als arzneimittel |
US7834007B2 (en) | 2005-08-25 | 2010-11-16 | Bristol-Myers Squibb Company | CGRP antagonists |
CN101495480B (zh) * | 2006-05-03 | 2013-07-10 | 百时美施贵宝公司 | 作为降钙素基因相关肽受体拮抗剂的受限化合物 |
WO2010006168A2 (en) | 2008-07-09 | 2010-01-14 | University Of Rochester | Methods of treating cancer using and agent that modulates activity of the calcitonin-gene related peptide ("cgrp") receptor |
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Non-Patent Citations (1)
Title |
---|
Degan A.P. "Carbamates as potent calcitonin gene-related peptide antagonists with improved solution stability", Bioorganic & Medicinal Chemistry Letters 19 (2009) 3555–3558. * |
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