TWI520738B - Dpp-4抑制劑於已接受抗糖尿病藥物療法而血糖控制仍不足之患者之用途 - Google Patents
Dpp-4抑制劑於已接受抗糖尿病藥物療法而血糖控制仍不足之患者之用途 Download PDFInfo
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- TWI520738B TWI520738B TW098134981A TW98134981A TWI520738B TW I520738 B TWI520738 B TW I520738B TW 098134981 A TW098134981 A TW 098134981A TW 98134981 A TW98134981 A TW 98134981A TW I520738 B TWI520738 B TW I520738B
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- sulfonylurea
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- insulin
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Description
本發明係關於用於治療及/或預防已接受口服及/或非口服抗糖尿病藥物(特別是促胰島素分泌劑,例如磺脲或格列奈類(glinide)藥物)療法而血糖控制仍不足之患者的代謝疾病、特別是糖尿病(尤其II型糖尿病)及與其有關之病況的某些DPP-4抑制劑、以及該等DPP-4抑制劑在該治療及/或預防中之用途。本發明亦涵蓋用於治療及/或預防該等患者之代謝疾病(特別是糖尿病)的醫藥組合物,其包含如本文所定義之DPP-4抑制劑以及視情況一或多種其他活性物質。
II型糖尿病係由涉及胰島素抗性及胰島素分泌不良之雙重內分泌效應的複雜病理生理學引起之普通慢性及漸進性疾病。II型糖尿病之治療通常開始於飲食及鍛煉,之後進行口服抗糖尿病藥單一療法,且儘管習用單一療法最初可控制某些患者之血糖,然而其可伴隨有高繼發性失效率。至少在某些患者中且在有限時間段內,可藉由組合多種口服藥物達成在單一藥劑之長期療法期間不能維持之血糖降低來克服用於維持血糖控制之單一藥劑療法的限制。現有資料支持以下結論:在患有II型糖尿病之大多數患者中,單一療法將失效且需要多種藥物進行治療。
但是,由於II型糖尿病係漸進性疾病,故即使對組合療法具有良好初始反應之患者最終亦會需要增大劑量或用胰島素進一步治療,此乃因血糖含量極難以長時間維持穩定。因而,儘管現存組合療法具有增強血糖控制之潛能,但其並非沒有限制(尤其關於長期功效)。另外,許多結果指示低血糖症之風險可隨組合療法增大,且對多種藥劑之需要亦可降低患者依從性。另外,服用多種抗高血糖藥物會增大與患者可能正服用之其他藥劑發生藥物動力學相互作用的可能性。
因而,對於許多患者而言,該等現存藥物療法儘管治療但仍會造成血糖控制之漸進性損傷且尤其不能長期充分控制糖血症,且因而不能達成及維持後期或晚期II型糖尿病中之代謝控制,該等糖尿病包括儘管已接受習用口服或非口服抗糖尿病藥劑而血糖控制仍不充分之糖尿病、繼發性藥物失效及/或適於用胰島素治療之糖尿病。
因此,儘管高血糖症之強化治療可降低慢性損害之發病率,但許多患有II型糖尿病之患者仍不能得以充分治療,此部分地由於習用抗高血糖療法在長期功效、耐受性及給藥不便方面之限制。
此治療失效之高發病率係患有II型糖尿病之患者的高比率長期高血糖症-伴隨性併發症或慢性損傷(包括微血管及大血管併發症,例如,糖尿病性腎病、視網膜病變或神經病、或心血管併發症)之主要促成因素。
習用於療法(例如,一線或二線、及/或單一或(初始或附加)組合療法)之口服抗糖尿病藥物包括(但不限於)二甲雙胍(metformin)、磺脲、噻唑啶二酮類、格列奈類及α-葡糖苷酶抑制劑。
習用於療法(例如,一線或二線、及/或單一或(初始或附加)組合療法)之非口服抗糖尿病藥物包括(但不限於)GLP-1或GLP-1類似物、及胰島素或胰島素類似物。
然而,使用該等習用抗糖尿病或抗高血糖藥劑可伴隨有各種副作用。舉例而言,二甲雙胍可伴隨有乳酸性酸中毒或胃腸副作用;磺醯脲、格列奈類及胰島素或胰島素類似物可伴隨有低血糖症及體重增加;噻唑啶二酮類可伴隨有水腫、骨折、體重增加及心臟衰竭/對心臟的不利作用;且α-葡糖苷酶阻斷劑及GLP-1或GLP-1類似物可伴隨有胃腸道不良作用(例如,消化不良、胃腸脹氣或腹瀉、或噁心或嘔吐)。
磺脲(SU)以及格列奈類會刺激胰島素以非葡萄糖依賴性方式自胰腺β細胞分泌且一般及經常用作II型糖尿病之一線或二線(單一或組合)治療(尤其適於非肥胖患者及/或不適用二甲雙胍療法或二甲雙胍療法無效之患者)。
然而,如上所述,一些患者並非總是對該等習用口服抗糖尿病藥劑反應良好(尤其在長期治療方面),且可顯示儘管已接受磺脲藥物治療而血糖控制仍不足或惡化(繼發性SU失效)。此外,進行長期磺醯脲療法之患者會經歷胰腺β細胞功能隨時間流逝而降低或耗盡。
對於彼等處於單獨磺醯脲(單一療法)不能有效控制血糖含量之病況的患者,端視疾病階段可能需要變換為其他口服藥劑(例如,變換為二甲雙胍/噻唑啶二酮)或SU組合療法(包括附加及初始雙重及三重SU組合療法)、尤其磺醯脲與二甲雙胍及/或與噻唑啶二酮組合、及/或與胰島素組合或(最終)轉變至胰島素(例如,端視疾病階段,每日一次基礎胰島素、每日兩次預混胰島素或每日三次胰島素)。然而,即使在組合療法中,尤其隨時間流逝,一些患者亦可顯示儘管已接受組合治療而血糖控制仍不足或惡化。
因而,隨時間流逝而功效持續性損失係使用包括格列奈類及磺醯脲在內之促胰島素分泌劑的主要關注問題(繼發性SU失效)。此外,磺醯脲會增大胰島素之血漿濃度且可造成低血糖症,其係除體重增加外之又一主要副作用,特別是伴隨腎損傷及/或在老年患者中。因而,在SU藥物療法中,一方面,就功效而言,有時可需要增大磺醯脲劑量,而另一方面,就安全/耐受性而言,有時可需要降低磺醯脲劑量,因而在SU藥物療法中通常需要採取令人不滿意之折衷方案。
因此,業內仍需要為患有後期或晚期II型糖尿病之該等患者提供有效、安全及可耐受抗糖尿病療法,該等患者包括服用習用口服及/或非口服抗糖尿病藥物(例如二甲雙胍、磺脲、噻唑啶二酮類、格列奈類及/或α-葡糖苷酶抑制劑、及/或GLP-1或GLP-1類似物、及/或胰島素或胰島素)而血糖控制不充分之患者。
此外,業內仍需要為繼發性口服抗糖尿病藥物失效之糖尿病患者提供充分血糖控制。
此外,業內仍需要預防繼發性口服抗糖尿病藥物失效(包括預防或減緩其加劇)。
此外,業內仍需要預防與抗糖尿病療法相關之副作用或降低其風險。
在糖尿病治療之監測中,HbAlc值(血紅蛋白B鏈非酶促糖化作用之產物)異常重要。由於其形成基本上依賴於血糖濃度及紅細胞壽命,故HbAlc在「血糖記憶」意義上反映前4-12周之平均血糖濃度。其HbAlc濃度藉由更強化糖尿病治療長期得以良好控制之糖尿病患者(亦即,在試樣中<6.5%之總血紅蛋白)明顯較好地防止糖尿病性微血管病。糖尿病之現有治療可在糖尿病患者中產生大約1.0-1.5%之HbAlC濃度平均改良。該HbAlC濃度減少並不足以在所有糖尿病患者中使其達成<7.0%、較佳<6.5%且更佳<6%HbAlc之期望目標範圍。
在血糖控制內,除改良HbAlc濃度外,對II型糖尿病患者之其他建議治療目標係改良空腹血漿葡萄糖(FPG)及餐後血漿葡萄糖(PPG)濃度至正常或盡可能接近正常。餐前(空腹)血漿葡萄糖之建議期望目標範圍係90-130mg/dL(或90-130mg/dL)或<110mg/dL,且餐後2小時血漿葡萄糖之建議期望目標範圍係<180mg/dL或<140mg/dL。
在本發明含義內,儘管已接受口服抗糖尿病藥物療法而血糖控制仍不足之患者包括(但不限於)儘管已接受該藥物治療而仍具有7.0%至10%(或7.5%至11%、或7.5%至10%)之HbAlc值的患者。
在本發明含義內,繼發性口服抗糖尿病藥物失效之糖尿病患者的一實施例涉及不適用二甲雙胍療法之患者,其包括
- 禁忌用二甲雙胍療法之患者,例如具有一或多種標籤指明的二甲雙胍療法禁忌症之患者,例如具有至少一種選自以下之禁忌症的患者:腎疾病、腎損傷或腎功能障礙(例如,如本地認可之二甲雙胍的產品資訊所規定),脫水、不穩定性或急性充血性心臟衰竭、急性或慢性代謝性酸中毒、及遺傳性半乳糖不耐受;及
- 遭受一或多個由二甲雙胍引起之不耐受副作用、特別是與二甲雙胍相關之胃腸副作用的患者,例如遭受選自以下之至少一種胃腸副作用的患者:噁心、嘔吐、腹瀉、腸積氣、及嚴重腹部不適。
此外,由於對副作用之敏感性增加,故老年患者(-70歲)之治療應經常伴隨有腎功能之謹慎監測。除非肌酸酐清除率之量測證實不會降低腎功能,否則通常不建議二甲雙胍用於老年個體、特別是歲之個體。因而,不適用二甲雙胍療法之患者亦可包括(但不限於)(例如)-65歲或特別是歲之老年患者。
在本發明含義內,繼發性口服抗糖尿病藥物失效之糖尿病患者的又一實施例涉及患有腎疾病、腎功能障礙、或腎功能不全或損傷(包括輕微、中度及嚴重腎損傷)之患者,如由(例如)升高之血清肌酸酐濃度(例如,血清肌酸酐濃度高於其年齡所具有之正常上限,例如,在男性中μmol/l、或,且在女性中mg/dl())或異常肌酸酐清除率(例如,腎小球濾過率(GFR))所表示。
在此上下文中,對於更詳細實例而言,輕微腎損傷可由(例如)50-80ml/min之肌酸酐清除率(大約對應於男性中及女性中之血清肌酸濃度)表示;中度腎損傷可由(例如)30-50ml/min之肌酸酐清除率(大約對應於男性中>1.7至及女性中>1.5至之血清肌酸濃度)表示;且嚴重腎損傷可由(例如)<30ml/min之肌酸酐清除率(大約對應於男性中>3.0mg/dL及女性中>2.5mg/dL之血清肌酸濃度)表示。患有晚期腎疾病之患者需要透析。
亦稱為CD26之酶DPP-4(二肽基肽酶IV)係絲胺酸蛋白酶,已知其可導致二肽自N末端具有脯胺酸或丙胺酸殘基之許多蛋白質的N-末端裂解。由於此特性,DPP-4抑制劑干擾包括肽GLP-1在內之生物活性肽的血漿濃度,且將其視為治療糖尿病之頗具前景的藥物。
舉例而言,DPP-4抑制劑及其用途、特別是其在代謝(尤其糖尿病)疾病中之用途揭示於WO 2002/068420、WO 2004/018467、WO 2004/018468、WO 2004/018469、WO 2004/041820、WO 2004/046148、WO 2005/051950、WO 2005/082906、WO 2005/063750、WO 2005/085246、WO 2006/027204、WO 2006/029769或WO 2007/014886中;或揭示於WO 2004/050658、WO 2004/111051、WO 2005/058901或WO 2005/097798中;或揭示於WO 2006/068163、WO 2007/071738或WO 2008/017670中;或揭示於WO 2007/128721或WO 2007/128761中。
作為其他DPP-4抑制劑,可提及以下化合物:
- 西他列汀(Sitagliptin)(MK-0431),其具有以下結構式A,其係(3R)-3-胺基-1-[3-(三氟甲基)-5,6,7,8-四氫-5H-[1,2,4]***并[4,3-a]吡嗪-7-基]-4-(2,4,5-三氟苯基)丁-1-酮,亦稱為(2R)-4-側氧基-4-[3-(三氟甲基)-5,6-二氫[1,2,4]***并[4,3-a]吡嗪-7(8H)-基]-1-(2,4,5-三氟苯基)丁-2-胺,
在一個實施例中,西他列汀呈其磷酸二氫鹽之形式,即磷酸西他列汀。在又一實施例中,磷酸西他列汀呈結晶無水物或單水合物之形式。此類實施例係指磷酸西他列汀單水合物。西他列汀游離鹼及其醫藥上可接受之鹽揭示於美國專利第6,699,871號及WO 03/004498之實例7中。結晶磷酸西他列汀單水合物揭示於WO 2005/003135及WO 2007/050485中。
因而,關於(例如)有關該化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
西他列汀之錠劑調配物可以商品名購得。西他列汀/二甲雙胍組合之錠劑調配物可以商品名購得。
- 維格列汀(Vildagliptin)(LAF-237),其具有以下結構式B,其係(2S)-{[(3-羥基金剛烷-1-基)胺基]乙醯基}吡咯啶-2-甲腈,亦稱為(S)-1-[(3-羥基-1-金剛烷基)胺基]乙醯基-2-氰基-吡咯啶,
維格列汀具體揭示於美國專利第6,166,063號及WO 00/34241之實例1中。維格列汀之具體鹽揭示於WO 2007/019255中。維格列汀之結晶形式以及維格列汀錠劑調配物揭示於WO 2006/078593中。維格列汀可如WO 00/34241或WO 2005/067976中所述來調配。以改良方式釋放之維格列汀調配物闡述於WO 2006/135723中。
因而,關於(例如)有關該化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
預期維格列汀之錠劑調配物可以商品名購得。維格列汀/二甲雙胍組合之錠劑調配物可以商品名購得。
- 薩格列汀(Saxagliptin)(BMS-477118),其具有以下結構式C,其係(1S,3S,5S)-2-{(2S)-2-胺基-2-(3-羥基金剛烷-1-基)乙醯基}-2-氮雜二環[3.1.0]己烷-3-甲腈,亦稱為(S)-3-羥基金剛烷基甘胺酸-L-順式-4,5-亞甲基脯胺酸腈,
薩格列汀具體揭示於美國專利第6,395,767號及WO 01/68603之實例60中。
在一個實施例中,薩格列汀呈其HCl鹽或其單苯甲酸鹽形式,如WO 2004/052850中所揭示。在另一實施例中,薩格列汀呈游離鹼形式。在再一實施例中,薩格列汀呈游離鹼之單水合物形式,如WO 2004/052850中所揭示。薩格列汀之HCl鹽及游離鹼的結晶型揭示於WO 2008/131149中。用於製備薩格列汀之方法亦揭示於WO 2005/106011及WO 2005/115982中。薩格列汀可如WO 2005/117841中所述調配於錠劑中。
因而,關於(例如)有關該化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
- 阿格列汀(Alogliptin)(SYR-322),其具有以下結構式E,其係2-({6-[(3R)-3-胺基六氫吡啶-1-基]-3-甲基-2,4-二側氧基-3,4-二氫-2H-嘧啶-1-基}甲基)苄腈
阿格列汀具體揭示於US 2005/261271、EP 1586571及WO 2005/095381中。在一個實施例中,阿格列汀呈其苯甲酸鹽、其鹽酸鹽或其甲苯磺酸鹽之形式,各自皆如WO 2007/035629中所揭示。此類實施例係指苯甲酸阿格列汀。阿格列汀苯甲酸鹽之多晶形體揭示於WO 2007/035372中。用於製備阿格列汀之方法揭示於WO 2007/112368中且具體揭示於WO 2007/035629中。阿格列汀(即其苯甲酸鹽)可如WO 2007/033266中所述調配於錠劑中並投與。阿格列汀與二甲雙胍或吡格列酮(pioglitazone)之調配物分別揭示於WO 2008/093882或WO 2009/011451中。因而,關於(例如)有關該化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
- (2S)-1-{[2-(5-甲基-2-苯基-噁唑-4-基)-乙基胺基]-乙醯基}-吡咯啶-2-甲腈或其醫藥上可接受之鹽(較佳為甲磺酸鹽),或(2S)-1-{[1,1,-二甲基-3-(4-吡啶-3-基-咪唑-1-基)-丙基胺基]-乙醯基}-吡咯啶-2-甲腈或其醫藥上可接受之鹽:該等化合物及其製備方法揭示於WO 03/037327中。前面的化合物之甲磺酸鹽以及其結晶多晶型揭示於WO 2006/100181中。後面的化合物之富馬酸鹽以及其結晶多晶型揭示於WO 2007/071576中。該等化合物可如WO 2007/017423中所述調配於醫藥組合物中。因此,關於(例如)有關該等化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
- (S)-1-((2S,3S,11bS)-2-胺基-9,10-二甲氧基-1,3,4,6,7,11b-六氫-2H-吡啶并[2,1-a]異喹啉-3-基)-4-氟甲基-吡咯啶-2-酮或其醫藥上可接受之鹽:
該化合物及其製備方法揭示於WO 2005/000848中。用於製備該化合物(具體而言其二鹽酸鹽)之方法亦揭示於WO 2008/031749、WO 2008/031750及WO 2008/055814中。該化合物可如WO 2007/017423中所述調配於醫藥組合物中。因而,關於(例如)有關該化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
- (3,3-二氟吡咯啶-1-基)-((2S,4S)-4-(4-(嘧啶-2-基)哌嗪-1-基)吡咯啶-2-基)甲酮(亦稱為戈塞列汀(gosogliptin))或其醫藥上可接受之鹽:該化合物及其製備方法揭示於WO 2005/116014及US 7291618中。
因而,關於(例如)有關該化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
- (1((3S,4S)-4-胺基-1-(4-(3,3-二氟吡咯啶-1-基)-1,3,5-三嗪-2-基)吡咯啶-3-基)-5,5-二氟六氫吡啶-2-酮或其醫藥上可接受之鹽:
該化合物及其製備方法揭示於WO 2007/148185及US 20070299076中。因而,關於(例如)有關該化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
- (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-***-1-基甲基)環戊基胺基]-乙醯基}-4-氟吡咯啶-2-甲腈(亦稱為米格列汀(melogliptin))或其醫藥上可接受之鹽:
該化合物及其製備方法揭示於WO 2006/040625及WO 2008/001195中。具體提及之鹽包含甲烷磺酸鹽及對甲苯磺酸鹽。因而,關於(例如)有關該化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
- (R)-2-[6-(3-胺基-六氫吡啶-1-基)-3-甲基-2,4-二側氧基-3,4-二氫-2H-嘧啶-1-基甲基]-4-氟-苄腈或其醫藥上可接受之鹽:
該化合物及其製備方法及用途揭示於WO 2005/095381、US 2007060530、WO 2007/033350、WO 2007/035629、WO 2007/074884、WO 2007/112368、WO 2008/114807、WO 2008/114800及WO 2008/033851中。具體提及之鹽包含琥珀酸鹽(WO 2008/067465)、苯甲酸鹽、苯磺酸鹽、對甲苯磺酸鹽、(R)-扁桃酸鹽及鹽酸鹽。因而,關於(例如)有關該化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
- 5-{(S)-2-[2-((S)-2-氰基-吡咯啶-1-基)-2-側氧基-乙基胺基]-丙基}-5-(1H-四唑-5-基)-10,11-二氫-5H-二苯并[a,d]環庚烯-2,8-二甲酸雙-二甲基醯胺或其醫藥上可接受之鹽:
該化合物及其製備方法揭示於WO 2006/116157及US 2006/270701中。因而,關於(例如)有關該化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
- 3-{(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)哌嗪-1-基]吡咯啶-2-基羰基}噻唑啶(亦稱為特力列汀(teneligliptin))或其醫藥上可接受之鹽:該化合物及其製備方法揭示於WO 02/14271中。特定鹽揭示於WO 2006/088129及WO 2006/118127中(尤其包括鹽酸鹽、氫溴酸鹽)。使用此化合物之組合療法闡述於WO 2006/129785中。因而,關於(例如)有關該化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
- [(2R)-1-{[(3R)-吡咯啶-3-基胺基]乙醯基}吡咯啶-2-基]硼酸(亦稱為度特列汀(dutogliptin))或其醫藥上可接受之鹽:此化合物及其製備方法揭示於WO 2005/047297、WO 2008/109681及WO 2009/009751中。特定鹽揭示於WO 2008/027273中(包括檸檬酸鹽、酒石酸鹽)。此化合物之調配物闡述於WO 2008/144730中。因而,關於(例如)有關該化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
- (2S,4S)-1-[2-[(4-乙氧基羰基二環[2.2.2]辛-1-基)胺基]乙醯基]-4-氟吡咯啶-2-甲腈或其醫藥上可接受之鹽:此化合物及其製備方法揭示於WO 2005/075421、US 2008/146818及WO 2008/114857中。因而,關於(例如)有關該化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
- 2-({6-[(3R)-3-胺基-3-甲基六氫吡啶-1-基]-1,3-二甲基-2,4-二側氧基-1,2,3,4-四氫-5H-吡咯并[3,2-d]嘧啶-5-基}甲基)-4-氟苄腈或其醫藥上可接受之鹽、或6-[(3R)-3-胺基-六氫吡啶-1-基]-5-(2-氯-5-氟-苄基)-1,3-二甲基-1,5-二氫-吡咯并[3,2-d]嘧啶-2,4-二酮或其醫藥上可接受之鹽:該等化合物及其製備方法分別揭示於WO 2009/084497及WO 2006/068163中。因此,關於(例如)有關該等化合物或其鹽之製造、調配或使用方法的細節,可參考該等文件。
為避免任何疑問,上文所引用各上述文件之揭示內容的全文以引用方式具體地併入本文中。
在本發明範疇內,現在已令人吃驚地發現如本文所定義DPP-4抑制劑具有意想不到及特別有利的特性,此等特性使得其特別適於治療及/或預防後期或晚期II型糖尿病患者(包括儘管已接受口服及/或非口服抗糖尿病藥物療法而血糖控制仍不足及/或適於用胰島素治療之患者)的代謝疾病、特別是與糖尿病(尤其II型糖尿病)有關之病況(例如,糖尿病併發症)(包括預防或減緩其加劇)。
因而,本發明提供如本文所定義DPP-4抑制劑,其用於治療儘管已接受一或多種選自二甲雙胍、磺脲、噻唑啶二酮類、格列奈類及α-葡糖苷酶抑制劑之習用口服抗糖尿病藥物療法(包括單一、雙重或三重藥劑)而血糖控制仍不足的患者。
在另一實施例中,本發明提供如本文所定義DPP-4抑制劑,其用於治療儘管已接受一種、兩種或三種選自以下之習用口服或非口服抗糖尿病藥物療法(包括單一、雙重或三重藥劑)而血糖控制仍不足之患者:二甲雙胍、磺脲、噻唑啶二酮類、格列奈類、α-葡糖苷酶阻斷劑、GLP-1及GLP-1類似物、及胰島素及胰島素類似物;例如儘管已接受二甲雙胍、磺脲、吡格列酮或(基礎)胰島素之單一療法、或儘管已接受二甲雙胍/吡格列酮、二甲雙胍/磺脲、二甲雙胍/(基礎)胰島素、磺脲/吡格列酮、磺脲/(基礎)胰島素或吡格列酮/(基礎)胰島素組合之雙重組合療法。
本發明進一步提供如本文所定義DPP-4抑制劑,其用於治療儘管已接受磺脲單一療法、或儘管已接受二甲雙胍/磺脲、磺脲/吡格列酮或磺脲/(基礎)胰島素組合之雙重組合療法而血糖控制仍不足之糖尿病患者。
具體而言,本發明提供如本文所定義DPP-4抑制劑,其用於治療已接受磺脲藥物療法而血糖控制仍不足之患者。
本發明進一步提供如本文所定義DPP-4抑制劑,其用於治療及/或預防儘管已接受磺脲藥物療法而血糖控制仍不足之患者的代謝疾病、特別是II型糖尿病。
本發明進一步提供如本文所定義DPP-4抑制劑,其用於治療及/或預防繼發性磺脲失效之糖尿病。
本發明進一步提供如本文所定義DPP-4抑制劑的用途,其用於製造供治療及/或預防儘管已接受磺脲藥物療法而血糖控制仍不足之患者的代謝疾病、特別是II型糖尿病之醫藥組合物。
本發明進一步提供一種醫藥組合物,其用於治療及/或預防儘管已接受磺脲藥物療法而血糖控制仍不足之患者的代謝疾病、特別是II型糖尿病,該醫藥組合物包含如本文所定義之DPP-4抑制劑及視情況一或多種醫藥上可接受之載劑及/或稀釋劑。
本發明進一步提供包括成份套組之固定或不固定組合,其用於治療及/或預防儘管已接受磺脲藥物療法而血糖控制仍不足之患者的代謝疾病、特別是II型糖尿病,該組合包含如本文所定義之DPP-4抑制劑及視情況一或多種其他活性物質,例如任何彼等本文所提及者。
本發明進一步提供如本文所定義DPP-4抑制劑與一或多種其他活性物質(例如,任何彼等本文所提及者)組合之用途,其用於製造供治療及/或預防儘管已接受磺脲藥物療法而血糖控制仍不足之患者的代謝疾病、特別是II型糖尿病之醫藥組合物。
本發明進一步提供一種醫藥組合物,其用於治療及/或預防儘管已接受磺脲藥物療法而血糖控制仍不足之患者的代謝疾病、特別是II型糖尿病,該醫藥組合物包含如本文所定義之DPP-4抑制劑及視情況一或多種其他活性物質,例如,任何彼等本文所提及者,例如單獨、依次、同時、並行或按時間順序交叉使用該等活性成份。
本發明進一步提供治療及/或預防儘管已接受磺脲藥物療法而血糖控制仍不足之患者的代謝疾病、特別是II型糖尿病之方法,該方法包含投與給需要其之個體(特別是人類患者)有效量之如本文所定義DPP-4抑制劑,其視情況單獨投與或與有效量之一或多種其他活性物質(例如,任何彼等本文所提及者)組合(例如)單獨、依次、同時、並行或按時間順序交叉投與。
另外,本發明提供如本文所定義DPP-4抑制劑,視情況(附加或初始)與一種或兩種選自以下之習用抗高血糖藥劑組合:二甲雙胍、磺脲、噻唑啶二酮類(例如吡格列酮)、格列奈類、α-葡糖苷酶阻斷劑、GLP-1或GLP-1類似物及胰島素或胰島素類似物,其用於儘管已接受(例如,若適用,儘管已接受最大耐受口服劑量之)一種、兩種或三種選自以下之抗高血糖藥劑療法(例如,儘管已接受二甲雙胍、磺脲、吡格列酮或(基礎)胰島素單一療法、或儘管已接受二甲雙胍/吡格列酮、二甲雙胍/磺脲、二甲雙胍/(基礎)胰島素、磺脲/吡格列酮、磺脲/(基礎)胰島素或吡格列酮/(基礎)胰島素組合之雙重組合療法)而血糖控制仍不足之患者:二甲雙胍、磺脲、噻唑啶二酮類、格列奈類、α-葡糖苷酶阻斷劑、GLP-1或GLP-1類似物、及胰島素或胰島素類似物。
在本發明之又一實施例中,提供如本文所定義DPP-4抑制劑,視情況與一種選自以下之習用抗高血糖藥劑組合:二甲雙胍、磺脲、噻唑啶二酮類(例如吡格列酮)、格列奈類、α-葡糖苷酶阻斷劑、GLP-1及GLP-1類似物、及胰島素及胰島素類似物,其用於單獨服用該習用抗高血糖藥劑不能足夠控制之II型糖尿病患者的(二線)療法。
在本發明之又一實施例中,提供如本文所定義DPP-4抑制劑,視情況與兩種選自以下之習用抗高血糖藥劑組合:二甲雙胍、磺脲、噻唑啶二酮類(例如吡格列酮)、格列奈類、α-葡糖苷酶阻斷劑、GLP-1及GLP-1類似物、及胰島素及胰島素類似物,其用於服用該等習用抗高血糖藥劑之雙重組合不能足夠控制之II型糖尿病患者的(三線)療法。
在本發明之又一實施例中,提供如本文所定義DPP-4抑制劑與選自由二甲雙胍、吡格列酮、磺脲及胰島素組成之群之習用抗高血糖藥劑組合;其用於單獨服用習用抗高血糖藥劑而血糖控制不足之II型糖尿病患者的療法。
在本發明之又一實施例中,提供如本文所定義DPP-4抑制劑與兩種選自由下列組合組成之群之習用抗高血糖藥劑組合:二甲雙胍及吡格列酮、二甲雙胍及磺脲、二甲雙胍及胰島素、磺脲及吡格列酮、磺脲及胰島素、及吡格列酮及胰島素;其用於服用兩種習用抗高血糖藥劑而血糖控制不足之II型糖尿病患者的療法。
具體而言,本發明提供如本文所定義DPP-4抑制劑與磺脲之組合,其用於治療儘管已接受最大耐受劑量之磺脲單一療法而血糖控制仍不足之II型糖尿病患者。
此外,本發明提供如本文所定義DPP-4抑制劑與磺脲及二甲雙胍之組合,其用於治療儘管已接受磺脲及二甲雙胍雙重組合療法而血糖控制仍不足之II型糖尿病患者。
此外,本發明提供如本文所定義DPP-4抑制劑與磺脲及吡格列酮之組合,其用於治療儘管已接受磺脲及吡格列酮雙重組合療法而血糖控制仍不足之II型糖尿病患者。
此外,本發明提供如本文所定義DPP-4抑制劑與磺脲及胰島素之組合,其用於治療儘管已接受磺脲及胰島素雙重組合療法而血糖控制仍不足之II型糖尿病患者。
此外,如本文所定義DPP-4抑制劑可在糖尿病患者中用於一或多個用於以下用途之方法中
- 預防代謝病症、減緩代謝病症之加劇、延遲或治療代謝病症;
- 改良血糖控制及/或減少空腹血漿葡萄糖、餐後血漿葡萄糖及/或糖基化血紅蛋白HbAlc;
- 預防選自由糖尿病併發症組成之群之病況或病症、減緩該病況或病症的加劇、延遲或治療該病況或病症;
- 減輕重量或防止重量增加或促進重量減輕;
- 預防或治療胰腺β細胞變性及/或改良及/或恢復胰腺β細胞功能及/或刺激及/或恢復胰腺胰島素分泌功能;及/或
- 維持及/或改良胰島素敏感性及/或治療或預防高胰島素血症及/或胰島素抗性;該糖尿病患者儘管已接受口服抗糖尿病藥物、特別是磺脲藥物療法而血糖控制仍不足(繼發性SU失效)。
在繼發性口服抗糖尿病藥物失效之患者中可藉由本發明療法改善之該等代謝疾病或病症的實例包括(但不限於)I型糖尿病、II型糖尿病、葡萄糖耐受不良、胰島素抗性、高血糖症、高血脂症、高膽固醇血症、血脂異常、代謝症候群X、肥胖症、高血壓、慢性全身性炎症、視網膜病變、神經病、腎病、動脈粥樣硬化、內皮功能障礙及骨質疏鬆症。
本發明進一步提供如本文所定義DPP-4抑制劑、視情況與一或多種其他活性物質(例如,任何彼等本文所提及者)組合之用途,其用於製造用於一或多個下列目的之藥劑:
- 預防病症或疾病、減緩該代謝病症或疾病之加劇、延遲或治療該代謝病症或疾病,例如,I型糖尿病、II型糖尿病、葡萄糖耐受不良(IGT)、空腹血糖異常(IFG)、高血糖症、餐後高血糖症、超重、肥胖症、血脂異常、高血脂症、高膽固醇血症、高血壓、動脈粥樣硬化、內皮功能障礙、骨質疏鬆症、慢性全身性炎症、視網膜病變、神經病、腎病及/或代謝症候群;
- 改良血糖控制及/或減少空腹血漿葡萄糖、餐後血漿葡萄糖及/或糖基化血紅蛋白HbAlc;
- 預防、減緩、延遲或逆轉葡萄糖耐受不良(IGT)、空腹血糖異常(IFG)、胰島素抗性及/或自代謝症候群至II型糖尿病之加劇;
- 預防糖尿病併發症、降低其風險、減緩其加劇、延遲或治療該糖尿病併發症,例如微血管及大血管疾病,例如腎病、微量白蛋白尿或巨白蛋白尿、蛋白尿、視網膜病變、白內障、神經病、學習或記憶力損傷、神經退化性或認知病症、心血管或腦血管疾病、組織缺血、糖尿病足或潰瘍、動脈粥樣硬化、高血壓、內皮功能障礙、心肌梗塞、急性冠狀動脈症候群、不穩定型心絞痛、穩定型心絞痛、外周動脈閉塞性疾病、心肌病、心臟衰竭、心率失調、血管狹窄、及/或中風;
- 減輕體重或防止體重增加或促進體重減輕;
- 預防、減緩、延遲或治療胰腺β細胞變性及/或胰腺β細胞功能衰退及/或改良及/或恢復胰腺β細胞功能及/或刺激及/或恢復胰腺胰島素分泌功能;
- 預防、減緩、延遲或治療非酒精性脂肪肝疾病(NAFLD),包括肝臟脂肪變性、非酒精性脂肝炎(NASH)及/或肝纖維化;
- 預防II型糖尿病、減緩其加劇、延遲或治療該II型糖尿病,該II型糖尿病對習用(口服)抗高血糖單一或組合療法初始或繼發性失效;
- 達成充足治療效果所需之習用抗高血糖藥劑的劑量減少;
- 降低與習用抗高血糖藥劑相關之副作用的風險;及/或
- 維持及/或改良胰島素敏感性及/或治療或預防高胰島素血症及/或胰島素抗性;特別是在儘管已接受一或多種選自以下之習用口服或非口服抗糖尿病藥物之單一或雙重或三重組合療法而血糖控制仍不足的患者中:二甲雙胍、磺脲、噻唑啶二酮類(例如吡格列酮)、格列奈類、α-葡糖苷酶阻斷劑、GLP-1及GLP-1類似物、及胰島素及胰島素類似物。
本發明之具體實施例涉及如本文所定義DPP-4抑制劑,其用於達到及/或維持繼發性磺脲失效之II型糖尿病患者的血糖控制。
本發明之另一具體實施例涉及如本文所定義DPP-4抑制劑,其用於預防(包括預防或減緩加劇)繼發性SU失效之糖尿病。
本發明之另一具體實施例涉及如本文所定義DPP-4抑制劑,其用於預防與SU抗糖尿病療法相關之副作用(例如,低血糖症及/或體重增加)或降低其風險(或甚至用於減肥)。
本發明之另一具體實施例涉及如本文所定義DPP-4抑制劑,其用於治療繼發性磺脲失效之糖尿病,其中該DPP-4抑制劑係用於採用磺脲單一或雙重藥劑之附加或初始組合療法(例如,作為對使用或不使用二甲雙胍之SU藥物療法的附加療法)、或用作磺脲藥劑之替代物,視情況與一或多種其他治療劑(例如,二甲雙胍及/或噻唑啶二酮(例如吡格列酮))相組合。
本發明之另一具體實施例涉及如本文所定義DPP-4抑制劑,其在儘管已接受磺脲藥物(例如,格列本脲(glibenclamide)、格列吡嗪(glipizide)或格列美脲(glimepiride),使用或不使用二甲雙胍)療法而血糖控制仍不足(例如,具有7.5%至10%或7.5%至11%之HbAlc)之患者中用於改良(例如,偏離基線平均降低)HbAlc及/或FPG、降低葡萄糖偏移及/或改良胰島素分泌。
熟習此項技術者根據上文及下文說明將易知本發明之其他態樣。
在本發明含義內,DPP-4抑制劑包括(但不限於)上文及下文所提及之彼等DPP-4抑制劑中的任一種、較佳地經***性DPP-4抑制劑。
本發明之一實施例涉及一種DPP-4抑制劑,其用於治療及/或預防繼發性口服抗糖尿病藥物失效之II型糖尿病患者的代謝疾病(特別是II型糖尿病),其中該等患者進一步遭受腎疾病、腎功能障礙或腎損傷,特別地,其特徵在於該DPP-4抑制劑係以與具有正常腎功能之患者相同的劑量量投與給該等患者,因而,例如,該DPP-4抑制劑不需針對腎功能損傷下調劑量。
本發明之另一實施例涉及一種DPP-4抑制劑,其用於治療及/或預防繼發性口服抗糖尿病藥物失效之II型糖尿病患者的代謝疾病(特別是II型糖尿病),其中該等患者由於對二甲雙胍難耐受或禁忌(例如,任何彼等上文或下文所定義不耐受或禁忌症)亦對二甲雙胍療法失效或不適用二甲雙胍療法或需要降低二甲雙胍劑量。
出於本發明上述目的可建議之DPP-4抑制劑(尤其對於患有腎功能損傷之患者)可為經口DPP-4抑制劑,該DPP-4抑制劑及其活性代謝產物較佳具有相對較寬(例如,約>100倍)之治療窗及/或尤其其首要經由肝臟代謝或膽汁***排除。
更詳細地,特別適合本發明上述目的之DPP-4抑制劑(尤其對於患有腎功能損傷之患者)可為經口投與之DPP-4抑制劑,其具有相對較寬(例如,>100倍)之治療窗及/或其滿足一或多個以下藥物動力學特性(較佳在其治療口服劑量量下):
- DPP-4抑制劑實質上或主要經由肝***(例如,>80%或甚至>90%所投與之口服劑量),及/或其中腎***實質上不代表排除途徑或僅代表次要排除途徑(例如,<10%、較佳<7%所投與之口服劑量,例如根據放射性標記碳(14C)物質口服劑量之排除量測);
- DPP-4抑制劑主要以母體藥物無變化的***出(例如,在口服服用放射性標記碳(14C)物質後,尿及糞便中平均所***放射性為>70%、或>80%、或較佳90%),及/或其非實質地或僅有一小部分(例如,<30%、或<20%、或較佳10%)經由新陳代謝排除;
- DPP-4抑制劑之(主要)代謝產物在藥理上無活性。舉例而言,主要代謝產物不結合至目標酶DPP-4,且視情況,與母體化合物相比,其快速排除(例如,代謝產物之終末半衰期、或較佳約16h,例如15.9h)。
可對本發明上述目的具有吸引力的DPP-4抑制劑之其他特性可為以下之一或多者:快速達到穩態(例如,在用治療口服劑量量治療之第二天與第五天間達到穩態血漿濃度(大於穩態血漿濃度之90%))、較少累積(例如,在治療口服劑量量下平均累積比)、及/或較佳在每日使用一次時保持DPP-4抑制之持久效應(例如,在治療口服劑量量下具有幾乎完全(>90%)DPP-4抑制、在每天一次攝取治療口服藥物劑量後經24h時間間隔有>80%抑制)、在治療劑量量下餐後2小時血糖偏移顯著降低達(在療法的第一天時即已達到此降低),且在第一天尿中所***無變化母體化合物之累積量低於所投與劑量之1%且在穩態下增加至不超過約3-6%。
因而,本發明亦涉及一種DPP-4抑制劑,其用於治療及/或預防由於對二甲雙胍難耐受或禁忌而不適合二甲雙胍療法之患者(更具體而言,患有腎疾病、腎功能障礙或腎損傷之患者)的代謝疾病(尤其II型糖尿病),其特徵在於該DPP-4抑制劑係非實質地或僅有一小部分(例如,<10%、較佳<7%的所投與之口服劑量)經由腎***(例如根據放射性標記碳(14C)物質口服劑量之排除量測)。
此外,本發明亦涉及一種DPP-4抑制劑,其用於治療及/或預防由於對二甲雙胍難耐受或禁忌而不適合二甲雙胍療法之患者(更具體而言,患有腎疾病、腎功能障礙或腎損傷之患者)的代謝疾病(尤其II型糖尿病),其特徵在於該DPP-4抑制劑係實質上或主要經由肝***(例如根據放射性標記碳(14C)物質口服劑量之排除量測)。
此外,本發明亦涉及一種DPP-4抑制劑,其用於治療及/或預防由於對二甲雙胍難耐受或禁忌而不適合二甲雙胍療法之患者(更具體而言,患有腎疾病、腎功能障礙或腎損傷之患者)的代謝疾病(尤其II型糖尿病),其特徵在於該DPP-4抑制劑主要以母體藥物無變化的***出(例如,在口服服用放射性標記碳(14C)物質後,尿及糞便中平均所***放射性為>70%、或>80%、或較佳90%),該DPP-4抑制劑非實質地或僅有一小部分經由新陳代謝排除,及/或該DPP-4抑制劑之主要代謝產物在藥理上無活性或具有相對較寬治療窗。
在第一實施例(實施例A)中,在本發明上下文中DPP-4抑制劑係式(I)之DPP-4抑制劑中之任一種:
或式(II)
或式(III)
或式(IV)
其中R1表示([1,5]啶-2-基)甲基、(喹唑啉-2-基)甲基、(喹喔啉-6-基)甲基、(4-甲基-喹唑啉-2-基)甲基、2-氰基-苄基、(3-氰基-喹啉-2-基)甲基、(3-氰基-吡啶-2-基)甲基、(4-甲基-嘧啶-2-基)甲基、或(4,6-二甲基-嘧啶-2-基)甲基且R2表示3-(R)-胺基-六氫吡啶-1-基、(2-胺基-2-甲基-丙基)-甲基胺基或(2-(S)-胺基-丙基)-甲基胺基,或其醫藥上可接受之鹽。
在第二實施例(實施例B)中,在本發明上下文中DPP-4抑制劑係選自由以下組成之群之DPP-4抑制劑:西他列汀、維格列汀、薩格列汀、阿格列汀,(2S)-1-{[2-(5-甲基-2-苯基-噁唑-4-基)-乙基胺基]-乙醯基}-吡咯啶-2-甲腈,(2S)-1-{[1,1,-二甲基-3-(4-吡啶-3-基-咪唑-1-基)-丙基胺基]-乙醯基}-吡咯啶-2-甲腈,(S)-1-((2S,3S,11bS)-2-胺基-9,10-二甲氧基-1,3,4,6,7,11b-六氫-2H-吡啶并[2,1-a]異喹啉-3-基)-4-氟甲基-吡咯啶-2-酮,(3,3-二氟吡咯啶-1-基)-((2S,4S)-4-(4-(嘧啶-2-基)哌嗪-1-基)吡咯啶-2-基)甲酮,(1((3S,4S)-4-胺基-1-(4-(3,3-二氟吡咯啶-1-基)-1,3,5-三嗪-2-基)吡咯啶-3-基)-5,5-二氟六氫吡啶-2-酮,(2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-***-1-基甲基)環戊基胺基]-乙醯基}-4-氟吡咯啶-2-甲腈,(R)-2-[6-(3-胺基-六氫吡啶-1-基)-3-甲基-2,4-二側氧基-3,4-二氫-2H-嘧啶-1-基甲基]-4-氟-苄腈,5-{(S)-2-[2-((S)-2-氰基-吡咯啶-1-基)-2-側氧基-乙基胺基]-丙基}-5-(1H-四唑-5-基)-10,11-二氫-5H-二苯并[a,d]環庚烯-2,8-二甲酸雙-二甲基醯胺,3-{(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)哌嗪-1-基]吡咯啶-2-基羰基}噻唑啶,[(2R)-1-{[(3R)-吡咯啶-3-基胺基]乙醯基}吡咯啶-2-基]硼酸,(2S,4S)-1-[2-[(4-乙氧基羰基二環[2.2.2]辛-1-基)胺基]乙醯基]-4-氟吡咯啶-2-甲腈,2-({6-[(3R)-3-胺基-3-甲基六氫吡啶-1-基]-1,3-二甲基-2,4-二側氧基-1,2,3,4-四氫-5H-吡咯并[3,2-d]嘧啶-5-基}甲基)-4-氟苄腈,及6-[(3R)-3-胺基-六氫吡啶-1-基]-5-(2-氯-5-氟-苄基)-1,3-二甲基-1,5-二氫-吡咯并[3,2-d]嘧啶-2,4-二酮,或其醫藥上可接受之鹽。
關於第一實施例(實施例A),較佳之DPP-4抑制劑係以下化合物中之任一種或全部及其醫藥上可接受之鹽:
‧ 1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-六氫吡啶-1-基)-黃嘌呤(對照WO 2004/018468,實例2(142)):
‧ 1-[([1,5]啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-六氫吡啶-1-基)-黃嘌呤(對照WO 2004/018468,實例2(252)):
‧ 1-[(喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-六氫吡啶-1-基)-黃嘌呤(對照WO 2004/018468,實例2(80)):
‧ 2-((R)-3-胺基-六氫吡啶-1-基)-3-(丁-2-炔基)-5-(4-甲基-喹唑啉-2-基甲基)-3,5-二氫-咪唑并[4,5-d]嗒嗪-4-酮(對照WO 2004/050658,實例136):
‧ 1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(2-胺基-2-甲基-丙基)-甲基胺基]-黃嘌呤(對照WO 2006/029769,實例2(1)):
‧ 1-[(3-氰基-喹啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-六氫吡啶-1-基)-黃嘌呤(對照WO 2005/085246,實例1(30)):
‧ 1-(2-氰基-苄基)-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-六氫吡啶-1-基)-黃嘌呤(對照WO 2005/085246,實例1(39)):
‧ 1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-[(S)-(2-胺基-丙基)-甲基胺基]-黃嘌呤(對照WO 2006/029769,實例2(4)):
‧ 1-[(3-氰基-吡啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-六氫吡啶-1-基)-黃嘌呤(對照WO 2005/085246,實例1(52)):
‧ 1-[(4-甲基-嘧啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-六氫吡啶-1-基)-黃嘌呤(對照WO 2005/085246,實例1(81)):
‧ 1-[(4,6-二甲基-嘧啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-六氫吡啶-1-基)-黃嘌呤(對照WO 2005/085246,實例1(82)):
‧ 1-[(喹喔啉-6-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R)-3-胺基-六氫吡啶-1-基)-黃嘌呤(對照WO 2005/085246,實例1(83)):
該等DPP-4抑制劑不同於結構上相當之DPP-4抑制劑,此乃因當與其他醫藥活性物質組合時,其將優越效能及持久效應與有利的藥理學特性、受體選擇性及有利的副作用性質組合或帶來意想不到之治療優點或改良。其製備揭示於所提及之公開案中。
在本發明實施例A之上述DPP-4抑制劑中,更佳之DPP-4抑制劑係1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-六氫吡啶-1-基)-黃嘌呤,特別是其游離鹼(其亦稱為BI 1356)。
除非另有說明,否則根據本發明,應瞭解上文及下文所提及活性化合物(包含DPP-4抑制劑)之定義亦包含其醫藥上可接受之鹽以及其水合物、溶劑化物及多晶型形式。關於其鹽、水合物及多晶型形式,特別提及者係彼等在本文中所提及者。
關於實施例A,用於本發明實施例A之DPP-4抑制劑的合成方法已為熟練技術人員所熟知。有利地,本發明實施例A之DPP-4抑制劑可使用如文獻中所闡述之合成方法來製備。因而,舉例而言,式(I)之嘌呤衍生物可如WO 2002/068420、WO 2004/018468、WO 2005/085246、WO 2006/029769或WO 2006/048427中所述來獲得,其揭示內容併入本文中。式(II)之嘌呤衍生物可如(例如)WO 2004/050658或WO 2005/110999中所述來獲得,其揭示內容併入本文中。式(III)及(IV)之嘌呤衍生物可如(例如)WO 2006/068163、WO 2007/071738或WO 2008/017670中所述獲得,其揭示內容併入本文中。上文具體提及之彼等DPP-4抑制劑之製備揭示於與本發明相關之所提及公開案中。特定DPP-4抑制劑之多晶形晶體改良及調配物分別揭示於WO 2007/128721及WO 2007/128724中,其揭示內容之全文併入本文中。特定DPP-4抑制劑與二甲雙胍或其他組合配藥之調配物闡述於PCT/EP2009053978中,其揭示內容之全文併入本文中。BI 1356/二甲雙胍雙重組合之典型劑量強度係2.5/500mg、2.5/850mg及2.5/1000mg。
關於實施例B,用於實施例B之DPP-4抑制劑的合成方法闡述於科學文獻中及/或公開專利文件、特別是彼等本文所引用者中。
對於在溫血脊椎動物(特別是人類)中之醫藥應用而言,本發明化合物通常以0.001-100mg/kg體重、較佳地以0.1-15mg/kg之劑量使用,在每一情形下皆係每天使用1-4次。出於此目的,視情況與其他活性物質組合之化合物可與一或多種惰性習用載劑及/或稀釋劑一起納入,例如與玉米澱粉、乳糖、葡萄糖、微晶纖維素、硬脂酸鎂、聚乙烯吡咯啶酮、檸檬酸、酒石酸、水、水/乙醇、水/甘油、水/山梨糖醇、水/聚乙二醇、丙二醇、十六烷基硬脂醇、羧甲基纖維素或脂肪物質(例如,硬脂肪)或其適當混合物一起納入到習用蓋侖製劑(例如,素錠或包衣錠劑、膠囊、粉劑、懸浮液或栓劑)中。
因此,包含如本文所定義DPP-4抑制劑之本發明醫藥組合物係由熟練技術人員使用如業內所述醫藥上可接受調配物賦形劑來製備。此等賦形劑之實例包括(但不限於)稀釋劑、黏結劑、載劑、填充劑、潤滑劑、流動促進劑、結晶延緩劑、崩解劑、增溶劑、著色劑、pH調節劑、表面活性劑及乳化劑。
用於實施例A化合物之適宜稀釋劑的實例包括纖維素粉末、磷酸氫鈣、赤藻糖醇、經羥丙基低取代之纖維素、甘露糖醇、預膠凝澱粉或木糖醇。在彼等稀釋劑中,欲強調甘露糖醇、經羥丙基低取代之纖維素及預膠凝澱粉。
用於實施例A化合物之適宜潤滑劑的實例包括滑石粉、聚乙二醇、山崳酸鈣、硬脂酸鈣、氫化蓖麻油或硬脂酸鎂。在彼等潤滑劑中,欲強調硬脂酸鎂。
用於實施例A化合物之適宜黏結劑的實例包括共聚維酮(乙烯基吡咯啶酮與其他乙烯基衍生物之共聚物)、羥丙基甲基纖維素(HPMC)、羥丙基纖維素(HPC)、聚乙烯基吡咯啶酮(聚維酮)、預膠凝澱粉、或經羥丙基低取代之纖維素(L-HPC)。在彼等黏結劑中,欲強調共聚維酮及預膠凝澱粉。
用於實施例A化合物之適宜崩解劑的實例包括玉米澱粉或交聚維酮。在彼等崩解劑中,欲強調玉米澱粉。
製備本發明實施例A之DPP-4抑制劑之醫藥調配物的適宜方法係
‧ 將呈粉末混合物形式之活性物質與適宜製錠賦形劑直接製錠;
‧ 用適宜賦形劑製粒且隨後與適宜賦形劑混合且隨後製錠以及包膜;或
‧ 將粉末混合物或顆粒包裝成膠囊。
適宜製粒方法係
‧ 在強力混合器中濕式製粒,之後流化床乾燥;
‧ 一罐式製粒;
‧ 流化床製粒;或
‧ 用適宜賦形劑乾式製粒(例如,藉由滾筒壓縮)且隨後製錠或包裝成膠囊。
本發明實施例A之DPP-4抑制劑的實例性組合物包含第一稀釋劑甘露糖醇、具有額外黏結劑特性之作為第二稀釋劑的預膠凝澱粉、黏結劑共聚維酮、崩解劑玉米澱粉、及硬脂酸鎂作為潤滑劑,其中共聚維酮及/或玉米澱粉可為可選的。
關於本發明DPP-4抑制劑之劑型、調配物及投與細節,可參考科學文獻及/或公開之專利文件、特別是彼等本文所引用者。
關於第一實施例(實施例A),當實施例A中本文所提及之DPP-4抑制劑經靜脈內投與時,其通常所需之劑量為0.1mg至10mg、較佳0.25mg至5mg,且當經口投與時,為0.5mg至100mg、較佳2.5mg至50mg或0.5mg至10mg、更佳2.5mg至10mg或1mg至5mg,在每一情形下皆係每天投與1-4次。因而,當經口投與時,1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-六氫吡啶-1-基)-黃嘌呤之劑量為(例如)0.5mg至10mg/患者/天、較佳2.5mg至10mg或1mg至5mg/患者/天。
用包含實施例A中本文所提及之DPP-4抑制劑的醫藥組合物所製備之劑型以0.1-100mg之劑量範圍含有活性成份。因而,例如,1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-六氫吡啶-1-基)-黃嘌呤之特定劑量強度為0.5mg、1mg、2.5mg、5mg及10mg。
關於第二實施例(實施例B),在實施例B中欲投與哺乳動物(例如人類,例如約70kg體重)之本文所提及DPP-4抑制劑的劑量通常可為約0.5mg至約350mg、例如約10mg至約250mg、較佳20-200mg、更佳20-100mg活性部分/人/天,或約0.5mg至約20mg、較佳2.5-10mg/人/天,較佳地分成1-4個單獨劑量,該等劑量的(例如)大小可相同。單獨劑量強度包含(例如)10、25、40、50、75、100、150及200mg DPP-4抑制劑活性部分。
DPP-4抑制劑西他列汀之劑量強度通常介於25mg與200mg活性部分之間。西他列汀之推薦劑量針對活性部分(游離鹼無水物)計算為100mg,每日一次。西他列汀游離鹼無水物(活性部分)之單位劑量強度係25、50、75、100、150及200mg。西他列汀之特定單位劑量強度(例如每個錠劑)係25、50及100mg。醫藥組合物中使用等量之磷酸西他列汀單水合物與西他列汀游離鹼無水物,即分別為32.13、64.25、96.38、128.5、192.75、及257mg。將劑量經調節的25及50mg西他列汀用於腎衰竭患者。西他列汀/二甲雙胍雙重組合之典型劑量強度係50/500mg及50/1000mg。
DPP-4抑制劑維格列汀之劑量範圍通常介於每日10與150mg之間、具體而言介於每日25與150mg、25與100mg或25與50mg或50與100mg之間。日口服劑量之特定實例係25、30、35、45、50、55、60、80、100或150mg。在一更具體態樣中,維格列汀之日投與量可介於25mg與150mg之間或介於50mg與100mg之間。在另一更具體態樣中,維格列汀之日投與量可為50mg或100mg。活性成份之施用每日可至多發生三次、較佳地每日一次或兩次。特定劑量強度為50mg或100mg維格列汀。維格列汀/二甲雙胍雙重組合之典型劑量強度係50/850mg及50/1000mg。
阿格列汀可以如下日劑量投與給患者:介於5mg/天與250mg/天之間,視情況介於10mg與200mg之間,視情況介於10mg與150mg之間,且視情況介於10mg與100mg阿格列汀之間(在每一情形下皆基於阿格列汀之游離鹼形式的分子量)。因而,可使用之具體劑量包括(但不限於)每天10mg、12.5mg、20mg、25mg、50mg、75mg及100mg阿格列汀。阿格列汀可以其游離鹼形式或醫藥上可接受之鹽形式投與。
薩格列汀可以如下日劑量投與給患者:介於2.5mg/天與100mg/天之間,視情況介於2.5mg與50mg之間。可使用之具體劑量包括(但不限於)每天2.5mg、5mg、10mg、15mg、20mg、30mg、40mg、50mg及100mg薩格列汀。薩格列汀/二甲雙胍雙重組合之典型劑量強度係2.5/500mg及2.5/1000mg。
本發明DPP-4抑制劑之具體實施例涉及彼等以低劑量量治療有效之經口投與的DPP-4抑制劑,例如以<100mg或<70mg/患者/天、較佳<50mg、更佳<30mg或<20mg、甚至更佳1mg至10mg(若需要,分成1-4個單獨劑量,特別是1或2個單獨劑量,其大小可相同)、特別是1mg至5mg(更具體而言為5mg)/患者/天,較佳地每日一次經口投與、更佳地在一天中任何時間在有或無食物情況下投與。因而,舉例而言,日口服量5mg BI 1356可以每日1次之給藥方案(即,5mg BI 1356,每天1次)或以每日2次之給藥方案(即,2.5mg BI 1356,每天2次)在一天中任何時間在有或無食物情況下給予。
在本發明含義內欲強調之尤佳DPP-4抑制劑係1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-六氫吡啶-1-基)-黃嘌呤(亦稱為BI 1356)。BI 1356呈現高效能、24h持續作用及寬治療窗。在每日一次服用1、2.5、5或10mg BI 1356之多個口服劑量達12天的II型糖尿病患者中,BI 1356展現有利的藥效學及藥物動力學性質(例如,參見下表1):快速達到穩態(例如,在所有劑量組中,在治療第二天與第五天間達到穩態血漿濃度(大於在第13天時給藥前血漿濃度的90%))、較少累積(例如,在高於1mg劑量下平均累積比)及保持DPP-4抑制之持久效應(例如,在5mg及10mg劑量量下具有幾乎完全(>90%)DPP-4抑制,即在穩態下分別為92.3及97.3%抑制,及在攝取藥物後經24h時間間隔>80%抑制)、以及以之劑量餐後2小時血糖偏移顯著降低達(在第一天時即已達到此降低),且其中在第一天尿中所***無變化母體化合物之累積量低於所投與劑量之1%且在第12天時增加至不超過約3-6%(對於所投與之口服劑量,腎清除率CLR,ss係約14至約70mL/min,例如對於5mg劑量,腎清除率係約70ml/min)。在患有II型糖尿病之人群中,BI 1356展現與安慰劑相似的安全性及耐受性。採用約之低劑量,BI 1356可作為每日一次的可靠口服藥物,且DPP-4抑制可持續整個24h。在治療口服劑量量下,BI 1356主要經由肝***且僅有一小部分(約<7%的口服投與劑量)經由腎***。BI 1356首要經由膽汁無變化的***出。經腎排除之BI 1356部分隨時間及劑量之增加僅略有增加,因此根據患者的腎功能可能無需改變BI 1356之劑量。非腎排除之BI 1356由於其低累積可能性及寬安全邊際量可對腎功能不全及糖尿病性腎病患病率較高之患者人群具有明顯益處。
由於不同代謝功能紊亂通常同時發生,因此經常需要使多種不同活性成份相互組合。因此,視所診斷之功能紊亂而定,若使DPP-4抑制劑與習用於各個病症之活性物質組合,可獲得經改良的治療結果,該等活性物質係(例如)一或多種選自其他抗糖尿病物質中之活性物質,尤其降低血液中血糖濃度或脂濃度、升高血液中HDL濃度、降低血壓或治療動脈粥樣硬化或肥胖症所需之活性物質。
上述DPP-4抑制劑除其用於單一治療法亦可與其他活性物質結合使用,藉此可獲得經改良之治療結果。此組合治療可作為該等物質之自由組合或以固定組合(例如以錠劑或膠囊)之形式給予。為此所需組合配藥之醫藥調配物在商業上可作為醫藥組合物獲得或者可藉由熟練技術人員使用習用方法來調配。可作為醫藥組合物購得之活性物質在先前技術之許多地方皆有闡述,例如醫藥工業聯邦協會之「Rote Liste」每年出版的藥物目錄中,或每年更新的關於處方藥之製造商資訊彙編(稱為「醫生案頭參考」)中。
抗糖尿病組合配藥之實例係二甲雙胍、磺醯脲,例如格列本脲、甲苯磺丁脲(tolbutamide)、格列美脲、格列吡嗪、格列喹酮(gliquidon)、格列波脲(glibornuride)及格列齊特(gliclazide);那格列奈(nateglinide);瑞格列奈(repaglinide);噻唑啶二酮類,例如羅格列酮(rosiglitazone)及吡格列酮;PPARγ調節劑,例如美塔格列生(metaglidase);PPAR-γ激動劑,例如GI 262570;PPAR-γ拮抗劑;PPAR-γ/α調節劑,例如特撒格列查(tesaglitazar)、穆格列查(muraglitazar)、阿格列查(aleglitazar)、及英格列查(indeglitazar)及KRP297;PPAR-γ/α/δ調節劑;AMPK-激活劑,例如AICAR;乙醯基-CoA羧化酶(ACC1及ACC2)抑制劑;二醯甘油-乙醯基轉移酶(DGAT)抑制劑;胰腺β細胞GCRP激動劑,例如SMT3-受體-激動劑及GPR119;11β-HSD-抑制劑;FGF19激動劑或類似物;α-葡糖苷酶阻斷劑,例如阿卡波糖(acarbose)、伏格列波糖(voglibose)及米格列醇(miglitol);α2-拮抗劑;胰島素及胰島素類似物,例如人胰島素、賴脯胰島素(insulin lispro)、賴麸胰島素(insulin glusilin)、r-DNA-門冬胰島素(insulinaspart)、NPH胰島素、地特胰島素(insulin detemir)、鋅胰島素懸浮液及甘精胰島素(insulin glargin);腸抑胃肽(GIP);普蘭林肽(pramlintide)、達瓦林肽(davalintide);白糊精及白糊精類似物或GLP-1及GLP-1類似物,例如Exendi n-4,例如依澤那太(exenatide)、依澤那太LAR、利拉魯肽(liraglutide)、他司魯肽(taspoglutide)、AVE-0010、LY-2428757、LY-2189265、塞馬魯肽(semaglutide)或阿必魯肽(albiglutide);SGLT2-抑制劑,例如KGT-1251;蛋白酪胺酸磷酸酶之抑制劑;葡萄糖-6-磷酸酶之抑制劑;果糖-1,6-雙磷酸酶調節劑;糖原磷酸化酶調節劑;胰高血糖素受體拮抗劑;磷酸烯醇丙酮酸羧激酶(PEPCK)抑制劑;丙酮酸脫氫酶激酶(PDK)抑制劑;酪胺酸激酶抑制劑(50mg至600mg),例如PDGF-受體-激酶(參見,EP-A-564409、WO 98/35958、US 5093330、WO 2004/005281、及WO 2006/041976);葡糖激酶/調節蛋白調節劑,包括葡糖激酶激活劑;糖原合酶激酶抑制劑;含有SH2結構域肌醇5-磷酸酶2型(SHIP2)之抑制劑;IKK抑制劑,例如高劑量水楊酸酯;JNK1抑制劑;蛋白激酶C-θ抑制劑;β3激動劑,例如利托貝隆(ritobegron)、YM 178、索拉貝隆(solabegron)、他利貝隆(talibegron)、N-5984、GRC-1087、雷法貝隆(rafabegron)、FMP825;醛糖還原酶抑制劑,例如AS 3201、折那司他(zenarestat)、fidarestat(非達司他)、依帕司他(epalrestat)、然尼司他(ranirestat)、NZ-314、CP-744809及CT-112;SGLT-1或SGLT-2抑制劑,例如達格列嗪(dapagliflozin)、舍格列嗪(sergliflozin)、阿格列嗪(atigliflozin)、拉格列嗪(larnagliflozin)或坎那格列嗪(canagliflozin)(或來自WO 2009/035969之式(I-S)或(I-K)化合物);KV 1.3通道抑制劑;GPR40調節劑;SCD-1抑制劑;CCR-2拮抗劑;多巴胺受體激動劑(溴隱亭(bromocriptine mesylate)/Cycloset);及其他DPP IV抑制劑。
二甲雙胍通常係以自約500mg至2000mg高達2500mg/天變化的劑量、使用自約100mg至500mg或200mg至850mg(每天1-3次)、或約300mg至1000mg(每天一次或兩次)之各種給藥方案給予,或以約100mg至1000mg或較佳500mg至1000mg(每天一次或兩次)或約500mg至2000mg(每天一次)之劑量給予緩釋二甲雙胍。特定劑量強度可為250、500、625、750、850及1000mg二甲雙胍鹽酸鹽。
吡格列酮之劑量通常為約1-10mg、15mg、30mg、或45mg,每天一次。
羅格列酮通常以4mg至8mg劑量給予,每天一次(或分成兩次)(典型劑量強度係2、4及8mg)。
格列本脲(Glibenclamide或glyburide)通常以2.5-5至20mg之劑量給予,每天一次(或分成兩次)(典型劑量強度係1.25、2.5及5mg),或微粉化格列本脲以0.75-3至12mg之劑量給予,每天一次(或分成兩次)(典型劑量強度係1.5、3、4.5及6mg)。
格列吡嗪通常以2.5至10-20mg之劑量每天給予一次(高達40mg,分兩次)(典型劑量強度係5mg及10mg),或延長釋放之格列吡嗪以5-10mg(高達20mg)之劑量每天給予一次(典型劑量強度係2.5、5及10mg)。
格列美脲通常以1-2至4mg(高達8mg)之劑量給予,每天一次(典型劑量強度係1、2及4mg)。
格列本脲/二甲雙胍雙重組合通常以1.25/250mg(每日一次)至10/1000mg(每日兩次)之劑量給予(典型劑量強度係1.25/250、2.5/500及5/500mg)。
格列吡嗪/二甲雙胍雙重組合通常以2.5/250至10/1000mg之劑量給予,每日兩次(典型劑量強度係2.5/250、2.5/500及5/500mg)。
格列美脲/二甲雙胍雙重組合通常以1/250至4/1000mg之劑量給予,每日兩次。
羅格列酮/格列美脲雙重組合通常以4/1mg(每日一次或兩次)至4/2mg(每日兩次)之劑量給予(典型劑量強度係4/1、4/2、4/4、8/2及8/4mg)。
吡格列酮/格列美脲雙重組合通常以30/2至30/4mg(每日一次)之劑量給予(典型劑量強度係30/4及45/4mg)。
羅格列酮/二甲雙胍雙重組合通常以1/500至4/1000mg(每日兩次)之劑量給予(典型劑量強度係1/500、2/500、4/500、2/1000及4/1000mg)。
吡格列酮/二甲雙胍雙重組合通常以15/500mg(每日一次或兩次)至15/850mg(每日三次)之劑量給予(典型劑量強度係15/500及15/850mg)。
非磺醯脲胰島素促分泌那格列奈通常以60至120mg之劑量與膳食一起給予(高達360mg/天,典型劑量強度係60及120mg);瑞格列奈通常以0.5至4mg之劑量與膳食一起給予(高達16mg/天,典型劑量強度係0.5、1及2mg)。瑞格列奈/二甲雙胍雙重組合可以1/500及2/850mg之劑量強度使用。
阿卡波糖通常以25至100mg之劑量與膳食一起給予(高達300mg/天,典型劑量強度係25、50及100mg)。米格列醇通常以25至100mg之劑量與膳食一起給予(高達300mg/天,典型劑量強度係25、50及100mg)。常用於單一或雙重或三重(附加或初始)組合療法之習用抗糖尿病藥及抗高血糖藥可包括(但不限於)二甲雙胍、磺脲、噻唑啶二酮類、格列奈類、α-葡糖苷酶阻斷劑、GLP-1及GLP-1類似物、以及胰島素及胰島素類似物,例如彼等本文中藉由實例指示之藥劑,包括其組合。
降低血液中脂濃度之組合配藥實例係HMG-CoA-還原酶抑制劑,例如辛伐他汀(simvastatin)、阿托伐他汀(atorvastatin)、洛伐他汀(lovastatin)、氟伐他汀(fluvastatin)、普伐他汀(pravastatin)、皮塔伐他汀(pitavastatin)及羅舒伐他汀(rosuvastatin);祛脂乙酸製劑,例如苯紮貝特(bezafibrate)、非諾貝特(fenofibrate)、氯貝丁酯(clofibrate)、吉非貝齊(gemfibrozil)、依託貝特(etofibrate)及益多酯(etofyllinclofibrate);菸酸及其衍生物,例如阿昔莫司(acipimox);PPAR-α激動劑;PPAR-δ激動劑;醯基-輔酶A:膽固醇醯基轉移酶(ACAT;EC 2.3.1.26)之抑制劑,例如阿伐麥布(avasimibe);膽固醇吸收抑制劑,例如依折麥布(ezetimib);結合至膽汁酸之物質,例如考來烯胺(cholestyramine)、考來替泊(colestipol)及考來維侖(colesevelam);膽汁酸轉運抑制劑;HDL調節活性物質,例如D4F、反向D4F、LXR調節活性物質及FXR調節活性物質;CETP抑制劑,例如托徹普(torcetrapib)、JTT-705(達徹普)(dalcetrapib)或得自WO 2007/005572之化合物12(阿那匹曲(anacetrapib));LDL受體調節劑;及ApoB100反義RNA。
阿托伐他汀之劑量通常為1mg至40mg或10mg至80mg,一天1次。
降低血壓之組合配藥的實例係β-阻斷劑,例如阿替洛爾(atenolol)、比索洛爾(bisoprolol)、塞利洛爾(celiprolol)、美托洛爾(metoprolol)及卡維地洛(carvedilol);利尿劑,例如氫***(hydrochlorothiazide)、氯噻酮(chlortalidon)、希帕胺(xipamide)、呋塞米(furosemide)、吡咯他尼(piretanide)、托拉塞米(torasemide)、螺內酯、依普利酮(eplerenone)、阿米洛利(amiloride)及氨苯蝶啶(triamterene);鈣通道阻斷劑,例如胺氯地平(amlodipine)、硝苯地平(nifedipine)、尼群地平(nitrendipine)、尼索地平(nisoldipine)、尼卡地平(nicardipine)、非洛地平(felodipine)、拉西地平(lacidipine)、樂卡地平(lercanipidine)、馬尼地平(manidipine)、伊拉地平(isradipine)、尼伐地平(nilvadipine)、維拉帕米(verapamil)、戈洛帕米(gallopamil)及地爾硫卓(diltiazem);ACE抑制劑,例如雷米普利(ramipril)、賴諾普利(lisinopril)、西拉普利(cilazapril)、喹那普利(quinapril)、卡托普利(captopril)、依那普利(enalapril)、貝那普利(benazepril)、培哚普利(perindopril)、福辛普利(fosinopril)及群多普利(trandolapril);以及血管緊張素II受體阻斷劑(ARB),例如替米沙坦(telmisartan)、坎地沙坦(candesartan)、纈沙坦(valsartan)、洛沙坦(losartan)、厄貝沙坦(irbesartan)、奧美沙坦(olmesartan)及依普羅沙坦(eprosartan)。
替米沙坦之劑量通常為每天20mg至320mg或40mg至160mg。
升高血液中HDL濃度之組合配藥實例係膽固醇酯轉運蛋白(CETP)抑制劑;內皮脂酶抑制劑;ABC1調節劑;LXRα拮抗劑;LXRβ激動劑;PPAR-δ激動劑;LXRα/β調節劑及增加載脂蛋白A-I之表現及/或血漿濃度之物質。
用於治療肥胖症之組合配藥實例係***(sibutramine);四氫泥泊司他汀(tetrahydrolipstatin)(奧利司他(orlistat));阿利茨默(alizyme);右芬氟拉明(dexfenfluramine);阿索開(axokine);***素受體1拮抗劑,例如CB1拮抗劑瑞莫納班(rimonobant);MCH-1受體拮抗劑;MC4受體激動劑;NPY5以及NPY2拮抗劑;β3-AR激動劑,例如SB-418790及AD-9677;5HT2c受體激動劑,例如APD 356;筒箭毒鹼抑制劑;Acrp30及脂連素;硬脂醯基CoA去飽和酶(SCD1)抑制劑;脂肪酸合酶(FAS)抑制劑;CCK受體激動劑;格那啉(Ghrelin)受體調節劑;Pyy 3-36;阿立新(orexin)受體拮抗劑;及特索芬辛(tesofensine);以及安非他酮(bupropion)/納曲酮(naltrexone)、安非他酮/唑尼沙胺(zonisamide)、托吡酯(topiramate)/芬特明(phentermine)及普蘭林肽/美曲普汀(metreleptin)之雙重組合。
治療動脈粥樣硬化之組合配藥實例係磷脂酶A2抑制劑;酪胺酸激酶抑制劑(50mg至600mg),例如PDGF-受體-激酶(參見EP-A-564409、WO 98/35958、US 5093330、WO 2004/005281、及WO 2006/041976);oxLDL抗體及oxLDL疫苗;apoA-1 Milano;ASA;及VCAM-1抑制劑。
本發明之範疇並不限於本文所述具體實施例。除本文所述之彼等以外,彼等熟習此項技術者由本發明揭示內容應可明瞭本發明各種修改。所述修改意欲屬於隨附權利要求的範疇。
本文所引用之所有專利申請案之全文皆以引用方式併入本文中。
由以下實例可明瞭本發明其他實施例、特徵及優點。以下實例用於以實例方式闡釋本發明之原理,而非對其加以限制。
諸如格列本脲等磺醯脲(SU)係糖尿病治療中最常用藥物之一。長期用SU治療會造成升高之基礎胰島素分泌及降低之葡萄糖刺激胰島素分泌。該等特徵可對低血糖症及繼發性藥物失效之發生起重要作用。Db/db小鼠代表證實胰島素抗性及血漿葡萄糖高含量之II型糖尿病的動物模型。另外,與動物年齡有關,衰老db/db小鼠之胰腺β細胞不能用增強之胰島素分泌補償高葡萄糖偏移。因此,此模型適用於研究與DPP-4抑制劑(例如BI 1356)比較之格列本脲誘發的繼發性藥物失效。
自Germany之Charles River獲得5週齡雌性db/db小鼠。將動物以5-6只動物為一群組在12:12 L/D循環(在04:00 AM開燈且在04:00 PM關燈)下圈養於溫度及濕度控制室中。所有動物均可隨意地自由獲得常規齧齒動物飼料(Altromin standard 1324號飼料,Denmark)及水。
在實驗第0-59天每日08.00 AM藉由經口管飼法使用連接至3ml注射器之胃管(luer-lockTM,Becton)投與化合物溶液。使用含有12只動物之群組:媒劑,0.5%纖維素羥乙基醚;BI 1356 3mg/kg;格列本脲3mg/kg。在前兩周每日記錄一次體重食物攝取及水攝取且其餘時期每週記錄兩次。在實驗第54天時測定處於半飼餵狀態之血糖及HbAlc值,在第59天實施OGTT(2g/kg)。
在第54天10.00 AM時,測定血液試樣之「飼餵」等級血糖及HbAlc。在血液取樣前2小時,將動物轉移至無食物之清潔籠子中,之後進行血液取樣。在第59天時,實施OGTT(2g/kg),之後使動物禁食過夜並以t=15min檢測胰島素。
血糖:對於各數據點而言,將來自尾部尖端之10μl血液吸入微毛細管中並使用Bi osen S線葡萄糖分析儀量測。
胰島素:對於各數據點而言,自尾部靜脈吸收100μl血液,收集於EDTA管中。使用小鼠內分泌免疫測定板(LINCOplexTM,使用Luminex100TM系統分析;LincoResearch,Missouri,USA)量測胰島素。
HbAlc:使用全自動分析儀(Bayer)上之標準酶分析套組量測。
圖1及2展示5週齡雌性db/db小鼠在用指定化合物治療54天後之HbAlc及葡萄糖值。DPP-4抑制劑BI 1356與對照相比改良HbAlc以及葡萄糖值。相反,濃度為3mg/kg之磺醯脲格列本脲與對照及BI 1356相比損害葡萄糖以及HbAlc值。
圖3展示在OGTT測試期間胰島素之增加。僅用BI 1356治療之動物能夠響應葡萄糖含量增加而上調胰島素。
因而,在代表β細胞及SU誘發之繼發性藥物失效的動物模型中,關於胰島素分泌及降低HbAlc及葡萄糖,DPP-4抑制劑BI 1356優於格列本脲。
可使用臨床試驗測試本發明DPP-4抑制劑對於本發明目的之可用性:舉例而言,在隨機、雙盲、安慰劑對照、平行組試驗中,在儘管已接受一種或兩種習用抗高血糖藥劑(例如,磺脲藥物)療法而血糖控制仍不足(HbAlc為7.0%至10%或7.5%至10%或11%)之II型糖尿病患者中測試本發明DPP-4抑制劑(例如,每日一次口服投與之5mg BI 1356)的安全性及功效。
在用磺脲藥物之研究中,研究本發明DPP-4抑制劑相對添加至磺脲背景療法之安慰劑的功效及安全性(2周安慰劑導入期;18周雙盲治療、之後在研究藥劑終止後隨訪1周;在貫穿整個試驗持續期內以無變化劑量投與用磺脲藥物之背景療法,包括安慰劑導入期)。
藉由測定HbAlc值、藉由與初始值及/或安慰劑組之值比較,測試治療是否成功。與初始值及/或安慰劑值相比,HbAlc值顯著變化證實DPP-4抑制劑之治療功效。亦可藉由測定空腹血漿葡萄糖值、藉由與初始值及/或安慰劑組之值比較測試治療是否成功。空腹葡萄糖含量顯著降低證實治療有效。此外,出現治療達標響應(亦即,在治療下HbAlc<7%)證實治療有效。
藉由評定患者之病況及偏離基線之相關變化(例如副反應(例如,低血糖症發作或諸如此類)之發病率及強度或重量增加)研究治療之安全性及耐受性。
圖1及2展示5週齡雌性db/db小鼠在用指定化合物治療54天後之HbAlc及葡萄糖值。DPP-4抑制劑BI 1356與對照相比改良HbAlc以及葡萄糖值。相反,濃度為3mg/kg之磺醯脲格列本脲與對照及BI 1356相比損害葡萄糖以及HbAlc值。
圖3展示在OGTT測試期間胰島素之增加。僅用BI 1356治療之動物能夠響應葡萄糖含量增加而上調胰島素。
(無元件符號說明)
Claims (26)
- 一種DPP-4抑制劑之用途,其係
- 如請求項1之用途,其中該糖尿病及/或糖尿病併發症係II型糖尿病及/或選自微血管及大血管疾病之糖尿病併發症。
- 如請求項1或2之用途,其中該醫藥組合物用於治療及/或預防儘管已接受單獨磺脲藥物療法而血糖控制仍不足之患者的糖尿病及/或糖尿病併發症。
- 如請求項1或2之用途,其中該醫藥組合物用於治療及/或預防儘管已接受磺脲藥物與二甲雙胍組合療法而血糖控 制仍不足之患者的糖尿病及/或糖尿病併發症。
- 如請求項1或2之用途,其中該醫藥組合物用於達成及/或維持繼發性磺脲失效之II型糖尿病患者的血糖控制。
- 如請求項1或2之用途,其中該組合物中之DPP-4抑制劑用於與該磺脲組合使用,且視情況與一或多種其他治療劑相組合。
- 如請求項6之用途,其中該一或多種其他治療劑係選自二甲雙胍及噻唑啶二酮。
- 如請求項7之用途,其中該噻唑啶二酮係吡格列酮(pioglitazone)。
- 如請求項1或2之用途,其中該磺脲係選自格列本脲(glibenclamide)、格列吡嗪(glipizide)及格列美脲(glimepiride)。
- 如請求項1或2之用途,其中該組合物中之DPP-4抑制劑用於採用該磺脲及二甲雙胍或不採用二甲雙胍的附加組合療法,該磺脲選自格列本脲、格列吡嗪及格列美脲。
- 如請求項1或2之用途,其中該醫藥組合物用於在該等患者中改良HbA1c、FPG及/或PPG、降低葡萄糖偏移及/或改良胰島素分泌。
- 如請求項1或2之用途,其中該醫藥組合物用於治療適於一線或二線磺脲療法之患者的糖尿病。
- 如請求項1或2之用途,其中該醫藥組合物用於治療適於磺脲加上二甲雙胍、或磺脲加上噻唑啶二酮、或磺脲加上胰島素之雙重磺脲組合療法之患者的糖尿病。
- 如請求項1或2之用途,其中該醫藥組合物用於治療適於二甲雙胍、磺脲及噻唑啶二酮,或二甲雙胍、磺脲及胰島素,或磺脲、噻唑啶二酮及胰島素之三重組合療法之患者的糖尿病。
- 如請求項1或2之用途,其中該醫藥組合物用於治療適於胰島素療法之患者的糖尿病。
- 如請求項1或2之用途,其中該等患者儘管已接受磺脲藥物療法而仍具有7.0%至11%之不適當HbA1c值。
- 如請求項1或2之用途,其中該醫藥組合物用於在該等患者中預防繼發性磺脲失效之糖尿病或減緩其加劇。
- 如請求項1或2之用途,其中該等患者由於對二甲雙胍難耐受或禁忌而不適用二甲雙胍療法或需要降低劑量之二甲雙胍療法。
- 如請求項18之用途,其中該等患者為腎損傷及/或老年患者。
- 如請求項1或2之用途,其中該醫藥組合物中之DPP-4抑制劑用於與吡格列酮或二甲雙胍組合使用。
- 如請求項1之用途,其中該醫藥組合物用於治療及/或預防儘管已接受磺脲療法而血糖控制仍不足之患者的糖尿病及/或糖尿病併發症,其中該醫藥組合物係與磺脲組合使用。
- 如請求項1或2之用途,其中該醫藥組合物用於治療儘管已接受單獨磺脲藥物療法而血糖控制仍不足之患者的II型糖尿病,其中該醫藥組合物係與該磺脲藥物組合使 用。
- 如請求項1或2之用途,其中該醫藥組合物用於治療儘管已接受磺脲藥物及二甲雙胍組合療法而血糖控制仍不足之患者的II型糖尿病,其中該醫藥組合物係與該磺脲藥物及二甲雙胍組合使用。
- 如請求項1或2之用途,其中該患者為儘管已接受二甲雙胍、磺脲、吡格列酮或(基礎)胰島素單一療法,或儘管已接受二甲雙胍/吡格列酮、二甲雙胍/磺脲、二甲雙胍/(基礎)胰島素、磺脲/吡格列酮、磺脲/(基礎)胰島素或吡格列酮/(基礎)胰島素組合之組合療法而血糖控制仍不足之患者。
- 如請求項1或2之用途,其中該之醫藥組合物用於治療已接受一種選自以下之抗高血糖藥物療法而血糖控制仍不足之患者的II型糖尿病:二甲雙胍、磺脲、噻唑啶二酮類、格列奈類、α-葡糖苷酶阻斷劑及胰島素或胰島素類似物,特徵在於該醫藥組合物中之DPP-4抑制劑用於與該一種抗高血糖藥物組合使用。
- 如請求項1或2之用途,其中該醫藥組合物用於治療已接受二種選自以下之抗高血糖藥物療法而血糖控制仍不足之患者的II型糖尿病:二甲雙胍、磺脲、噻唑啶二酮類、格列奈類、α-葡糖苷酶阻斷劑及胰島素或胰島素類似物,特徵在於該醫藥組合物中之DPP-4抑制劑用於與該二種抗高血糖藥物組合使用。
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TW098134981A TWI520738B (zh) | 2008-10-16 | 2009-10-15 | Dpp-4抑制劑於已接受抗糖尿病藥物療法而血糖控制仍不足之患者之用途 |
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US (3) | US20110275561A1 (zh) |
EP (2) | EP2349240A1 (zh) |
JP (5) | JP2012505859A (zh) |
KR (6) | KR20240046643A (zh) |
CN (3) | CN108042543A (zh) |
AR (1) | AR073876A1 (zh) |
AU (1) | AU2009305419B2 (zh) |
CA (1) | CA2738367C (zh) |
CO (1) | CO6361917A2 (zh) |
EA (1) | EA026810B1 (zh) |
EC (1) | ECSP11010971A (zh) |
IL (1) | IL211370A0 (zh) |
MA (1) | MA32872B1 (zh) |
MX (3) | MX2011003774A (zh) |
NZ (2) | NZ591996A (zh) |
PE (1) | PE20110396A1 (zh) |
TN (1) | TN2011000176A1 (zh) |
TW (1) | TWI520738B (zh) |
UY (1) | UY32177A (zh) |
WO (1) | WO2010043688A1 (zh) |
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BRPI0907077A2 (pt) | 2008-03-26 | 2016-07-26 | Oramed Ltd | métodos e composições para administração oral de proteínas |
AR071175A1 (es) | 2008-04-03 | 2010-06-02 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un inhibidor de la dipeptidil-peptidasa-4 (dpp4) y un farmaco acompanante |
BRPI0916997A2 (pt) | 2008-08-06 | 2020-12-15 | Boehringer Ingelheim International Gmbh | Inibidor de dpp-4 e seu uso |
UY32030A (es) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "tratamiento para diabetes en pacientes inapropiados para terapia con metformina" |
EP2344195A2 (en) | 2008-09-10 | 2011-07-20 | Boehringer Ingelheim International GmbH | Combination therapy for the treatment of diabetes and related conditions |
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JP2012512848A (ja) | 2008-12-23 | 2012-06-07 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 有機化合物の塩の形態 |
AR074990A1 (es) * | 2009-01-07 | 2011-03-02 | Boehringer Ingelheim Int | Tratamiento de diabetes en pacientes con un control glucemico inadecuado a pesar de la terapia con metformina |
EA022349B1 (ru) | 2009-02-13 | 2015-12-30 | Бёрингер Ингельхайм Интернациональ Гмбх | Фармацевтическая композиция, включающая ингибитор sglt2, ингибитор дпп-iv и другой антидиабетический агент, и ее применение |
JP5789252B2 (ja) | 2009-05-07 | 2015-10-07 | インテリカイン, エルエルシー | 複素環式化合物およびその使用 |
BR112012012641A2 (pt) | 2009-11-27 | 2020-08-11 | Boehringer Ingelheim International Gmbh | TRATAMENTO DE PACIENTES DIABÉTICOS GENOTIPADOS COM INIBIDORES DE DPP-lVTAL COMO LINAGLIPTINA |
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CN103298474B (zh) | 2010-11-10 | 2016-06-29 | 无限药品股份有限公司 | 杂环化合物及其用途 |
AU2016202261B2 (en) * | 2010-11-15 | 2017-11-30 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
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US8962636B2 (en) | 2011-07-15 | 2015-02-24 | Boehringer Ingelheim International Gmbh | Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
WO2013171166A1 (en) * | 2012-05-14 | 2013-11-21 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp-4 inhibitor for use in the treatment of sirs and/or sepsis |
EP2849755A1 (en) | 2012-05-14 | 2015-03-25 | Boehringer Ingelheim International GmbH | A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome |
WO2013174768A1 (en) * | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in the treatment of autoimmune diabetes, particularly lada |
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PE20090597A1 (es) * | 2007-08-16 | 2009-06-06 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un derivado de pirazol-o-glucosido |
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BRPI0920699A2 (pt) * | 2008-10-16 | 2020-09-01 | Boehringer Ingelheim International Gmbh | uso de um inibidor de dpp-4 no tratamento de diabetes em pacientes com controle insuficiente da glicemia apesar de terapia com um fármaco antidiabético oral ou não-oral |
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