TWI395748B - 環丙基化合物 - Google Patents
環丙基化合物 Download PDFInfo
- Publication number
- TWI395748B TWI395748B TW098141556A TW98141556A TWI395748B TW I395748 B TWI395748 B TW I395748B TW 098141556 A TW098141556 A TW 098141556A TW 98141556 A TW98141556 A TW 98141556A TW I395748 B TWI395748 B TW I395748B
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- TW
- Taiwan
- Prior art keywords
- compound
- pharmaceutically acceptable
- solution
- acceptable salt
- glucose
- Prior art date
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- 229910052708 sodium Inorganic materials 0.000 description 1
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- C07D277/38—Nitrogen atoms
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Description
糖尿病為一種有害影響壽命及生活品質之進行性疾病。無論單獨或組合之現有的口服治療，在糖尿病患者中皆未顯示足夠或持續的降血糖效能。因此，仍然需要為糖尿病患者改良治療法。
葡萄糖激酶活化劑(GKA)代表一類主要藉由在胰臟β細胞及肝臟中之調節作用而降低血糖之降血糖劑。已揭示多種用於治療糖尿病之合成GKA，例如WO 04/063179中所揭示之彼等物。仍需用於治療糖尿病患者之替代性GKA。
據顯示，葡萄糖激酶(GK)對於調節葡萄糖在神經元中之感應具關鍵性。GK在下丘腦中之活化會減緩對胰島素引起的低血糖之反調節反應。因此，在腦中以GKA活化GK時，可能因低葡萄糖濃度而降低腎上腺素、正腎上腺素、及胰高血糖素之分泌，而增加患低血糖的風險。具有有限的血腦屏障通透性之GKA化合物會產生嚴重的低血糖之可能性不大。
已發現本發明之化合物可在活體外及活體內活化葡萄糖激酶。已發現本發明之化合物顯示較現有GKA之改良效力。已發現本發明之化合物顯示有限之血腦屏障通透性。
本發明係關於活化葡萄糖激酶之化合物、含有其等作為活性成份之醫藥組合物、用於治療與葡萄糖激酶功能異常相關之疾病之方法、及其等用於治療糖尿病，特定言之II型糖尿病之用途。
本發明提供一種下列結構式之化合物或其醫藥上可接受的鹽：
本發明之化合物具有兩個立構中心(*)及因此可能有四種立體異構體。無論純或部份純之每個立體異構體及外消旋或非對映混合物皆計畫包含於本發明之範圍內。
本發明化合物之較佳立體異構體具有下列結構式：
本發明提供一種醫藥組合物，其包括本發明之化合物、或其醫藥上可接受的鹽、及一種醫藥上可接受的稀釋劑或載劑。
本發明提供一種用於治療之結構式I化合物、或其醫藥上可接受的鹽。本發明亦提供一種用於治療糖尿病，特定言之II型糖尿病之結構式I化合物、或其醫藥上可接受的鹽。在本發明之另一態樣中，提供一種以結構式I化合物或其醫藥上可接受的鹽於製造用於治療糖尿病，特定言之II型糖尿病之醫藥品上之用途。
本發明提供一種治療糖尿病之方法，其包括對有此需要的人或動物投與有效量之結構式I化合物、或其醫藥上可接受的鹽。本發明亦提供一種治療II型糖尿病之方法，其包括對有此需要的人或動物投與有效量之結構式I化合物、或其醫藥上可接受的鹽。
本發明提供一種用於治療之醫藥組合物，其包括本發明之化合物、或其醫藥上可接受的鹽。本發明提供一種用於糖尿病、特定言之II型糖尿病之醫藥組合物，其包括本發明之化合物、或其醫藥上可接受的鹽。
如文中所用，術語「醫藥上可接受的鹽」係指對活有機體實質上無毒性之本發明化合物之鹽。此項技術中熟知該等鹽及製備其等之普遍方法。參見，例如P. Stahl等人，Handbook of Pharmaceutical Salts: Properties Selection and Use,(VCHA/Wiley-VCH,2002)；及J. Pharm. Sci. 66,2-19(1977)。醫藥上可接受的鹽較佳為鹽酸鹽。
本發明之化合物較佳調配為以多種途徑投與的醫藥組合物。該等組合物最佳用於經口投與。此項技術中熟知該等醫藥組合物及製備其等之方法。參見，例如Remington: The Science and Practice of Pharmacy(A,Gennaro等人編輯，第19版，Mack Publishing Co.,1995)。
在本發明之進一步態樣中，由本發明化合物與一或多種活性物質組合投藥。該等活性物質包括例如二甲雙胍。
組合投與包含同時、順序或分開投與。
下列實例之化合物名稱係使用AutoNom 2000而產生。
在惰性氣體氛圍下，於無水溶劑中進行所有的對水敏感或對空氣敏感之反應。在以電噴灑模式操作之Agilent 1100 MSD光譜儀上獲得質譜(MS)。於20℃下之JASCO DIP-370數據化偏光計上使用鈉D線，在氯仿中取得旋光度。
在室溫下，攪拌含(4-環丙烷磺醯基-苯基)-氧代-乙酸乙酯(250g，806mmol)與對甲苯磺醯基醯肼(187g，984mmol)之1.5L乙醇之混合物直至獲得淺黃色溶液。然後加入濃鹽酸(20mL，233mmol)，及回流下加熱所得混合物3.5小時。移除揮發物，產生透明淺黃色油，將其溶於1.5L乙酸乙酯中。隨後，該溶液係以1L飽和碳酸氫鈉水溶液沖洗，然後以1L飽和氯化鈉水溶液沖洗。以乙酸乙酯(2×500ml)對水相進行反萃取，及合併有機層，在硫酸鎂上乾燥，及過濾。充分攪拌該腙粗產物溶液(~2.1L，推測含有363g腙中間物)同時緩慢地加入三乙胺(100mL，890mmol)。使所得溶液靜置過夜，在此期間有一些固體沈澱。以乙酸乙酯稀釋該混合物至3L體積，形成溶液，以1L水沖洗，如需打破任何乳液，可再以兩份500mL水與飽和氯化鈉水溶液合併沖洗。然後在硫酸鎂上乾燥所得的有機相，過濾，及濃縮，產生潮濕固體，將其與甲基第三丁基醚一起磨碎。過濾所得的漿液，產生一種淺黃色固體，其在真空下乾燥，產生155g標題化合物。使濾液濃縮成油狀物，如上磨碎，直至獲得自由流動之固體。過濾分離該固體並乾燥，再產生10g標題化合物。LCMS(m/e):295(M+H)。
在惰性氣體氛圍下，將含肆[N-酞醯基-(R)-第三-白胺醯基(leucinato)]二銠雙(乙酸乙酯)加成物(120mg，84μmol)之乙烯基環己烷溶液(40mL)滴加至保持25-30℃之含乙烯基環己烷(300mL，2.72mol)之150mL無水二氯甲烷中，同時分批添加(4-環丙烷磺醯基-苯基)-重氮基-乙酸乙酯(169.40g，575.5mmol)。調整添加速率以保持40℃之內部溫度。約1.5小時後完成該添加，且在30℃下另攪拌該反應混合物2小時。隨後在真空下移除揮發物，產生粗產物(1R,2S)-2-環己基-1-(4-環丙烷磺醯基-苯基)-環丙烷羧酸乙酯之黏性棕色油(218g，579mmol)，將其溶於1.1L甲醇中，產生黃棕色溶液，將5N氫氧化鈉水溶液(500mL，2.5mmol)緩慢加入其中。然後在50℃下攪拌所得漿液1小時，在此期間形成溶液。在真空下移除甲醇，及加入1L乙酸乙酯。藉由添加約550mL 5%鹽酸水溶液而酸化所得混合物，分離兩層。隨後以兩份500mL乙酸乙酯萃取水層。合併有機相，以500mL飽和氯化鈉水溶液沖洗，在硫酸鎂上乾燥，過濾，及濃縮，產生淺黃色濕固體。然後將該物質溶於1L甲醇中。接著以1.5小時時間將水(1L)加入該經攪拌的溶液中。室溫下攪拌所得漿液30分鐘，及然後過濾。濾墊經1:1甲醇/水沖洗，且乾燥，產生標題化合物之淺黃色晶體(166g)。MS準確質量計算值為349.14735；實驗值為349.14679(使用電噴灑電離化之Agilent 1100 LC-TOF)；=-31°。
以含10%乙醇之含0.05%三氟乙酸之己烷溶液在35℃下洗提AD-H柱(150mm)之對掌性層析法分離該等對映體，比較相當於對映體之兩峰的積分值，確定該酸之對映體過量為97.7%。
在惰性氣體氛圍下，將硫雜環丙烷(550mL，9.2mol)加入含有吡咯啶(543mL，6.57mol)之2.5L無水二氧雜環己烷之混合物中。緩慢升溫，且當內部溫度達到54℃時，在冰浴中冷卻該反應混合物。一旦溫度降至45℃，移除該冷卻浴且加熱該反應混合物至60℃。3小時後，冷卻該混合物至室溫且於真空下濃縮。然後於6mm Hg下蒸餾該殘留物，且收集沸點在50℃之餾份，產生2-吡咯啶-1-基-乙硫醇之無色油(643g)。MS(m/e):132(M+H)。
將碳酸氫鈉(1.232kg，14.7mol)緩慢地逐份加入含有5-溴-噻唑-2-基胺氫溴酸鹽(1.53Kg，5.87mol)之7.5L異丙醇之混合物中。然後，以15分鐘時間添加2-吡咯啶-1-基-乙硫醇(1.060Kg，8.07mol)，且60℃下攪拌所得混合物96小時。以1小時時間將溫度升至70℃，且隨後冷卻該混合物至室溫。在真空下移除大部分異丙醇，且將殘留物溶於4L異丙醇/氯仿溶液(1:9)中。添加飽和碳酸氫鈉水溶液(4L)，並攪拌所得混合物30分鐘。分離層且以三份4L異丙醇/氯仿溶液(1:9)萃取水相。合併有機層，在硫酸鈉上乾燥，過濾，及在真空下濃縮。所得殘留物與3L乙醚一起磨碎，且濾出，產生第一份標題化合物的淺黃色固體(410g)。濃縮濾液為橘色固體，其與2L乙醚一起磨碎，過濾分離出米色固體。接著將該固體溶於2L甲醇中，且於45℃下加熱該溶液30分鐘。冷卻至室溫時，形成固體。過濾分離該物質，與乙醚一起進行如上磨碎，及在真空下乾燥，再產生310g標題化合物。MS(m/e):230[M+H]。
在惰性氣體氛圍下，於15分鐘內將草醯氯(146.89mL，1.69mol)加入含有(1R,2S)-2-環己基-1-(4-環丙烷磺醯基-苯基)-環丙烷羧酸(295.00g，0.847mol)之經攪拌的10L無水二氯甲烷溶液中。然後，立刻加入二甲基甲醯胺(654.61μL，8.5mmol)，且攪拌所得溶液過夜。隨後在40℃下，真空移除揮發物，產生油狀物，溶於3L無水二氯甲烷中。重建惰性氣體氛圍，且將該溶液冷卻至<5℃。然後，以20分鐘時間滴加三乙胺(177mL 1.27mol)，得到深色溶液。加入硫酸鈉(120.25g，0.847mol)，隨後加入5-(2-吡咯啶-1-基-乙基磺醯基)-噻唑-2-基胺(213.60g，0.931mol)。將內部溫度升至20℃。冷卻時，攪拌該反應混合物10分鐘，且隨後使其回升至室溫。攪拌過夜後，將該反應混合物傾倒於3L水中。攪拌所得混合物若干分鐘，且隨後分離兩層。以1L二氯甲烷萃取水層，且合併二氯甲烷溶液，在MgSO4
上乾燥，過濾，及於40℃下真空濃縮。將所得油(556g)製成二氯甲烷溶液施加於矽膠管柱上。以1:12:7 2M氨之甲醇溶液/甲基第三丁基醚/庚烷，隨後以1:19 2M氨(甲醇溶液)/乙酸乙酯洗提該管柱，產生棕色發泡體(351g)。取320g該物質自甲基第三丁基醚及庚烷中結晶，然後於45℃下乾燥2天，得到標題化合物之灰白固體(279.4g)。LCMS(m/e):560(M+H)；。
於大腸桿菌中，表現呈標記(His)6
之融合蛋白質之人類胰島GK同型異構物，且以金屬螯合物親和層析純化，參見，例如Tiedge等人，Biochem. Biophys. Acta 1337,175-190,1997。純化後，酶在25mM磷酸鈉、150mM氯化鈉、100mM咪唑、1mM二硫蘇糖醇、50%甘油中製成0.8mg/ml之濃度，在-80℃下等份保存。在平底96孔板中之100μL的最終培養體積中進行分析。該培養混合物係由25mM 4-(2-羥乙基)-1-哌嗪乙烷磺酸(HEPES)(pH7.4)、50mM氯化鉀、2.5mM氯化鎂、2mM二硫蘇糖醇、來自腸系膜明串珠菌(Leuconostoc mesenteroides
)之4U/ml葡萄糖-6-磷酸脫氫酶、5mM ATP、1mM NAD及指定濃度之葡萄糖組成。將試驗化合物溶於二甲亞碸中且隨後加入反應混合物中，使二甲亞碸之最終濃度為10%。藉由加入20μL GK開始該反應，且於37℃下進行20分鐘。使用微分析板讀數機讀取340nm下所增加的吸光度，作為NADH形成量之測定值。由吸光度計算EC50
。
在10mM葡萄糖下，實例1活化GK之EC50
=42±42nM(n=5)。在更低葡萄糖濃度下，亦可隨濃度相關的方式增加酶活性。
於37℃，5% CO2
，95%濕度下，將大鼠胰島瘤INS-1E細胞保持在補充有11mM葡萄糖、5%胎牛血清、50μM2-巰基乙醇、1mM丙酮酸鹽、10mM HEPES及抗生素之1640培養基中。在分析之前，細胞經胰蛋白酶作用、離心成粒及依30,000細胞/孔之密度接種於96-孔組織培養分析板中。使細胞附著且於37℃，5% CO2
下培養48小時。在分析當日，以200μL補充有0.1%牛血清白蛋白(BSA)之厄爾(Earle)平衡鹽溶液(EBSS)緩衝劑沖洗細胞且於其中培養。培養30分鐘後，移除該緩衝劑且將100μL含0.1% BSA、8mM葡萄糖及化合物之EBSS緩衝劑加入細胞中。隨即將20μL CellTiter 96AQueous One Solution Reagent單溶液試劑加入細胞中，且於37℃再培養該細胞一小時。培養結束時，讀取490nm下之吸光度。由吸光度計算EC50
。
在大鼠胰島瘤INS1-E細胞中，實例1刺激葡萄糖代謝(EC50
平均值=579±139nM，n=4)。
因此，顯示本發明之該等化合物可在活體外活化GK。
使體重225-250g之雄性Wistar大鼠保持規律飲食及在正常光週期下適應。對於該研究，先使該等大鼠禁食過夜，然後稱取其精確體重，並隨機分為體重相似的若干組(每組n=4)。將化合物懸浮於槽式音波處理器中之1:1 Solutol/乙醇混合物(總體積之10%)中。然後，以9體積之10% Solutol水溶液稀釋所得的懸浮液，且以1、3、6、10、20、及30mg/kg口服劑量經口投與該化合物。投與該化合物2小時後，經口投與該等大鼠2g/kg葡萄糖丸藥。於投與葡萄糖後0、15、30、60、90及120分鐘時，經由尾部抽血收集血。每樣品採集400μL體積，所收集的血樣置於含乙二胺四乙酸(EDTA)試管中，且使該等樣品保持於冰上。分離血漿並於-20℃下儲存，直至對樣品進行葡萄糖與化合物接觸之分析。計算每組之血漿葡萄糖曲缐(葡萄糖AUC)下面積，以該葡萄糖AUC相對於對照組之下降百分比作為該化合物降低血漿葡萄糖之效力測定值。
實例1隨劑量變化之相關方式，對禁食及進食後之葡萄糖濃度皆可降低血漿葡萄糖。使用高劑量(30mg/kg)時，可觀察到葡萄糖AUC相對於未處理對照組之降低值最大，且降低42%。數據之內插法顯示，化合物在血漿中之平均濃度為99ng/ml(179nM)(相當於6.9mg/kg化合物劑量)時，葡萄糖AUC降低20%。
因此，顯示本發明之該等化合物可在活體內活化GK。
製備10mM化合物之二甲亞碸儲備溶液。然後以900μL丙二醇稀釋100μL該儲備溶液，製得1mM之劑量溶液。將該劑量以IV丸藥(2.2mL/kg)經由尾部靜脈投與六隻雄性CF-1小鼠(約23g)，使目標劑量為2.17μmol/kg。使用CO2
及頸椎脫位對該等小鼠實施安樂死。三隻小鼠在給葯5分鐘後殺死及三隻小鼠在給葯60分鐘後殺死，經由心臟穿刺自每個動物收集血，且使用EDTA鈉製備血漿，轉移至聚丙烯樣品管中，立即使用乾冰冷凍。收集每個動物之全腦，且自中線切割，將每一半轉移至聚丙烯樣品管中及立即使用乾冰冷凍。對一份血漿使用兩份萃取溶劑(10%四氫呋喃之乙腈溶液)且以漩渦混合器進行混合，使蛋白質沉澱，製得用於分析之血漿樣品。對於腦組織，假定1mg腦組織1μL體積，及將兩份萃取溶劑加入一份組織中。立即使用超音波細胞破碎儀對該等樣品進行均質化。將已知濃度化合物加至空白小鼠血漿中，製得校準標準且隨後作為血漿樣品進行處理。於6000 RCF下離心所有樣品5分鐘。取每個樣品之等份上清液轉移至聚丙烯96孔板且密封，用於LC-MS/MS分析。
使用配備有渦輪電離噴灑源之Sciex API 4000三重四極桿質譜儀進行MS/MS。使用加熱至50℃及以0.6mL/分鐘之恆定流速操作之Phenomenex Hyrdro RP分析柱(100×2.0mm，4μ)進行高效液相層析法。使用的流動相梯度係由以下組成：初流動相60:40 5mM甲酸銨水溶液：5mM甲酸銨之甲醇溶液，保持1分鐘，隨後2分鐘線性梯度至10:90 5mM甲酸銨水溶液：5mM甲酸銨之甲醇溶液，且最終保持1分鐘。0-2.8分鐘之柱流出物為廢棄物，且然後將2.8-4.0分鐘之柱流出物導入質譜儀。所檢測的過渡MS/MS為560/84。比較波峰面積值與源自校準標準之標稱濃度及其等相應的波峰面積之二次方程式加權1/x2
，定量試驗樣品中之化合物。定量之上限與下限係反推算所回收校準標準物，超過理論值+/-20%而確定。使用16μL血漿/gm小鼠腦之文獻因子校正腦組織濃度中血漿之影響。
實例1之活體內血腦屏障通透性導致服藥五分鐘後之腦/血漿比平均值為0.17且此時之平均總腦濃度為0.539nmol/g。
已顯示本發明之該等化合物具有有限的血腦屏障通透性，因此提供嚴重低血糖症之可能性有限。
Claims (11)
- 一種下列結構式之化合物或其醫藥上可接受的鹽，
- 如請求項1之化合物或其醫藥上可接受的鹽，其具有下列結構式：
- 一種醫藥組合物，其包括如請求項1或2之化合物、或其醫藥上可接受的鹽、及一種醫藥上可接受的稀釋劑或載劑。
- 如請求項1或2之化合物或其醫藥上可接受的鹽，其係用於治療。
- 如請求項1或2之化合物或其醫藥上可接受的鹽，其係用於治療糖尿病。
- 如請求項5之化合物或其醫藥上可接受的鹽，其係用於治療II型糖尿病。
- 一種如請求項1或2之化合物或其醫藥上可接受的鹽於製造治療糖尿病之醫藥上的用途。
- 如請求項7之用途，其係用於治療II型糖尿病。
- 如請求項3之醫藥組合物，其係用於治療。
- 一種用於治療糖尿病之醫藥組合物，其包括如請求項1或2之化合物，或其醫藥上可接受的鹽。
- 如請求項10之醫藥組合物，其係用於治療II型糖尿病。
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- 2009-12-11 EA EA201170845A patent/EA019055B1/ru not_active IP Right Cessation
- 2009-12-11 CN CN200980150686XA patent/CN102256952B/zh active Active
- 2009-12-11 ES ES09768316T patent/ES2435242T3/es active Active
-
2011
- 2011-05-27 ZA ZA2011/03944A patent/ZA201103944B/en unknown
- 2011-05-30 IL IL213210A patent/IL213210A/en active IP Right Grant
- 2011-06-09 TN TN2011000294A patent/TN2011000294A1/fr unknown
- 2011-06-14 MA MA33945A patent/MA32902B1/fr unknown
- 2011-06-17 CR CR20110342A patent/CR20110342A/es unknown
- 2011-06-17 EC EC2011011150A patent/ECSP11011150A/es unknown
- 2011-06-17 DO DO2011000197A patent/DOP2011000197A/es unknown
- 2011-06-23 CO CO11079303A patent/CO6382120A2/es active IP Right Grant
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006058923A1 (en) * | 2004-12-03 | 2006-06-08 | Novo Nordisk A/S | Heteroaromatic glucokinase activators |
| WO2008084872A1 (ja) * | 2007-01-10 | 2008-07-17 | Mitsubishi Tanabe Pharma Corporation | ヒドラゾン誘導体 |
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