TW201427982A - 治療不適合二甲雙胍療法之患者糖尿病之方法 - Google Patents
治療不適合二甲雙胍療法之患者糖尿病之方法 Download PDFInfo
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- TW201427982A TW201427982A TW103110365A TW103110365A TW201427982A TW 201427982 A TW201427982 A TW 201427982A TW 103110365 A TW103110365 A TW 103110365A TW 103110365 A TW103110365 A TW 103110365A TW 201427982 A TW201427982 A TW 201427982A
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Abstract
本發明係關於以下發現:某些DPP-4抑制劑特別適於治療及/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的代謝疾病、特別是糖尿病。
Description
本發明係關於用於治療及/或預防不適合正常二甲雙胍療法(由於對二甲雙胍難耐受或禁忌)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)的醫藥組合物及組合,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型糖尿病係在世界範圍內患病率日益增加之常見疾病且可伴隨有大血管併發症(例如,心血管疾病)、及/或微血管併發症(例如,失明、腎病及/或腎損傷或衰竭)。
患糖尿病之人群可出現腎損傷的原因有許多。糖尿病之典型長期併發症之一係糖尿病性腎病,在某些情形下其可發展成腎衰竭。
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,此部分地由於現有抗高血糖療法在長期功效、耐受性及給藥不便方面的限制。
二甲雙胍係改良患有II型糖尿病之患者的葡萄糖耐受性之抗高血糖劑。二甲雙胍可單獨使用或與其他抗高血糖藥劑組合使用以改良響應二甲雙胍之II型糖尿病患者之血糖控制。二甲雙胍亦可在治療肥胖
糖尿病患者或患有多囊卵巢症候群之患者中頗具價值。然而,利用二甲雙胍治療可伴隨有不良症狀,例如,胃腸症狀或有時嚴重副作用乳酸酸中毒(其可致命),一個公認的危險因素係降低腎功能。此外,由於二甲雙胍在很大程度上由腎經由腎小球過濾及腎小管分泌而無變化的排除,故其對患有腎疾病或腎損傷之患者禁忌。因此,習用二甲雙胍療法可由於(例如)對二甲雙胍難耐受或禁忌而不適於某些患者。由此不適用二甲雙胍之患者的數量可相當大且可包括相當大百分比的原本將受益於此藥劑的患者。因此,業內仍需要為該等不適用二甲雙胍療法之糖尿病患者提供有效、安全及可耐受的抗糖尿病療法。
在糖尿病治療之監測中,HbA1c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HbA1c在「血糖記憶」意義上反映前4-12周之平均血糖濃度。其HbA1c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HbA1C濃度平均改良。該HbA1C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% HbA1c之期望目標範圍。
在血糖控制內,除改良HbA1c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90-130毫克/dL或<110毫克/dL,且餐後2小時血漿葡萄糖之建議期望目標範圍係<180毫克/dL或<140毫克/dL。
在本發明含義內,不適用二甲雙胍療法之患者包括- 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(例如,60-70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80歲之個體。因此,不適用二甲雙胍療法之患者亦可包括(但不限於)(例如)60-65歲或特別是80歲之老年患者。
在本發明含義內,不適用二甲雙胍療法之患者的特別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130-150μmol/l、或1.5mg/dl(136μmol/l),且在女性中1.4mg/dl(124μmol/l))或異常肌酸酐清除率(例如,腎小球濾過率(GFR)30-
60ml/min,例如中度或嚴重腎損傷,包括ESRD)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1.7mg/dL及女性中1.5mg/dL之血清肌酸酐濃度)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3.0mg/dL及女性中>1.5至2.5mg/dL之血清肌酸酐濃度)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之血清肌酸酐濃度)表示。患有晚期腎疾病之患者需要透析(例如,血液透析或腹膜透析)。
對於其他更詳細實例而言,患有腎疾病、腎功能障礙或腎損傷之患者包括患有慢性腎功能不全或損傷之患者,可根據腎小球濾過率(GFR,ml/min/1.73m2)將其分成5個疾病階段:階段1之特徵在於正常GFR90加上持久蛋白尿或已知結構性或遺傳性腎疾病;階段2之特徵在於GFR輕微降低(GFR 60-89),說明輕微腎損傷;階段3之特徵在於GFR中度降低(GFR 30-59),說明中度腎損傷;階段4之特徵在於GFR嚴重降低(GFR 15-30),說明嚴重腎損傷;且終端階段5之特徵在於需要透析或GFR<15,說明確立腎衰竭(晚期腎疾病,ESRD)。
由二甲雙胍引起之某些其他不耐受(胃腸)副作用(例如,噁心、嘔吐、積氣、腹瀉)可與藥劑之劑量有關且因此若減少二甲雙胍之劑量可使該等副作用最小化。在本發明患者內,除彼等不應或不能使用二甲雙胍之患者外,亦存在僅可以降低劑量使用二甲雙胍之大量患者,因此二甲雙胍之劑量必須基於有效性、安全性及耐受性高度單獨調節(例如,經由劑量滴定),經常作為有效性及安全性/耐受性間之折衷方法。因此,業內亦仍需要為由於對二甲雙胍降低之耐受性、不耐受或禁忌而需要低劑量二甲雙胍療法之該等糖尿病患者提供較好(例如,更有效)的抗糖尿病療法。
二甲雙胍通常係以自約500毫克至2000毫克高達2500毫克/天變化的劑量、使用自約100毫克至500毫克或200毫克至850毫克(每天1-3次)、或約300毫克至1000毫克(每天一次或兩次)之各種給藥方案給與,或以約100毫克至1000毫克或較佳500毫克至1000毫克(每天一次或兩次)或約500毫克至2000毫克(每天一次)之劑量給與緩釋二甲雙胍。特定劑量強度可係250、500、625、750、850及1000毫克的二甲雙胍鹽酸鹽。
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-末端解離。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]三唑并[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]三唑并[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號中及揭示於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。
因此,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Januvia®購得。西他列汀/二甲雙胍組合之錠劑調配物可以商品名Janumet®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,
維格列汀特別揭示於美國專利第6,166,063號中及揭示於WO 00/34241之實例1中。維格列汀之特定鹽揭示於WO 2007/019255中。維格列汀以及維格列汀錠劑調配物之結晶形式揭示於WO 2006/078593中。維格列汀可如WO 00/34241或WO 2005/067976中所
闡述調配。經改良釋放維格列汀調配物闡述於WO 2006/135723中。
因此,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。
維格列汀之錠劑調配物可以商品名Galvus®購得。維格列汀/二甲雙胍組合之錠劑調配物可以商品名Eucreas®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-亞甲基丙腈,
薩格列汀特別揭示於美國專利第6,395,767號及WO 01/68603之實例60中。
在一實施例中,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。在又一實施例中,薩格列汀呈游離鹼形式。在又一實施例中,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鹽及游離鹼的結晶形式揭示於WO 2008/131149中。製備薩格列汀之方法亦揭示於WO 2005/106011及WO 2005/115982中。薩格列汀可以錠劑形式調配,如WO 2005/117841中所闡述。
因此,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
阿格列汀特別揭示於US 2005/261271、EP 1586571及WO 2005/095381中。
在一實施例中,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。苯甲酸阿格列汀之多晶型揭示於WO 2007/035372中。製備阿格列汀之方法揭示於WO 2007/112368中且特別揭示於WO 2007/035629中。阿格列汀(即其苯甲酸鹽)可以錠劑形式調配並投與,如WO 2007/033266中所闡述。阿格列汀與二甲雙胍或吡格列酮(pioglitazone)之調配物分別闡述於WO 2008/093882或WO 2009/011451中。
因此,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。該等化合物可以醫藥組合物形式調配,如WO 2007/017423中所闡述。
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。製備此化合物(尤其是其二鹽酸鹽)之方法亦揭示於WO 2008/031749、WO 2008/031750及WO 2008/055814中。此化合物可以醫藥調配物形式調配,如WO 2007/017423中所闡述。
因此,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)六氫吡嗪-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。
因此,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。因此,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-1,2,4-三唑-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。明確提出申請之鹽包含甲烷磺酸鹽及對甲苯磺酸鹽。因此,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。明確提出申請之鹽包括琥珀酸鹽(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。因此,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。因此,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)六氫吡嗪-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。因此,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:該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。因此,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:該化合物及其製備方法揭示於WO 2005/075421、US 2008/146818及WO 2008/114857中。因此,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明確地併入本文中。
在本發明範疇內,現在已令人吃驚地發現,如本文所定義之DPP-4抑制劑具有令人吃驚及特別有利的特性,該等特性使得其特別適於治療及/或預防(包括預防進展)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(例如由於對二甲雙胍難耐受或禁忌而不適用二甲雙胍療法之患者或需要二甲雙胍劑量減少之患者)的代謝疾病、特別是II型糖尿病。
因此,本發明提供如本文定義之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的代謝疾病、特別是II型糖尿病。
本發明進一步提供如本文定義之DPP-4抑制劑的用途,其用於製造供治療及/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的代謝疾病、特別是II型糖尿病,該醫藥組合物包含如本文定義之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的代謝疾病、特別是II型糖尿病,該組合包含如本文定義之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定義之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的代謝疾病、特別是II型糖尿病,該醫藥組合物包含如本文定義之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)有效量之如本文定義的DPP-4抑制劑,其視情況單獨投與或與有效量之一種、兩種或更多種其他活性物質(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。
此外,如本文定義之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、減緩代謝病症之進展、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HbA1c;- 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進展、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;該等糖尿病患者由於對二甲雙胍難耐受或禁忌而不適合二甲雙胍療法。
在不適用二甲雙胍療法之患者中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定義之DPP-4抑制劑的用途,其用於製造用於一或多個以下目的之藥劑:
- 預防、減緩代謝病症或疾病之進展、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)、空腹血液葡萄糖異常(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HbA1c;- 預防、減緩、延遲或逆轉葡萄糖耐受不良(IGT)、空腹血液葡萄糖異常(IFG)、胰島素抗性及/或自代謝症候群至II型糖尿病之進展;- 預防糖尿病併發症、降低其風險、減緩其進展、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、視網膜病變、神經病、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、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、心力衰竭、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;- 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不利影響的危險;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及/或患有腎疾病、腎功能障礙、或腎功能不全或損傷之患者(包括患有慢性腎功能不全之患者)中,其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。
此外,根據本發明之又一實施例,提供一種如本文定義之DPP-4抑制劑,其用於治療及/或預防患有腎疾病、腎功能障礙、或腎功能不全或損傷之患者(包括患有慢性腎功能不全之患者)的代謝性病症或疾病、尤其糖尿病(特別是II型糖尿病)(包括降低其發生或進展之危險),其視情況與一或多種其他活性物質(例如,選自彼等本文所提及者)組合。
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、較佳地經口活性DPP-4抑制劑。
本發明之特別實施例涉及DPP-4抑制劑,其用於治療具有不充分血糖控制之患者的II型糖尿病,該等患者由於對二甲雙胍難耐受或禁忌而不適合二甲雙胍療法。
本發明之另一特別實施例涉及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(特別是患有腎疾病、腎功能障礙或腎損傷之患者)的代謝疾病(特別是II型糖尿病),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比降低之劑量量或有利地相同劑量量投與給該等患者,因此,例如,該DPP-4抑制劑不需針對腎功能不良下調劑量。
本發明之特別實施例涉及DPP-4抑制劑,其用於治療由於對二甲雙胍難耐受或禁忌(例如,任何彼等上文或下文定義之難耐受或禁忌
症)而不適用二甲雙胍療法之患者的II型糖尿病。
在本發明含義內,本發明療法所關注患者的特別子群涉及患有慢性腎功能不全或損傷(特別是中度、嚴重或終端階段)之患者。
患有腎疾病、腎功能障礙或腎損傷之患者需要基於(特別是)個別藥物之性質及特性(例如,其藥物動力學、藥效學、新陳代謝、排除途徑)及患者之腎損傷等級謹慎評定其藥劑及給藥方案之適當選擇。
出於本發明目的可建議之DPP-4抑制劑(尤其對於患有腎功能不良之患者)可為該經口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分泌排除。
更詳細地,特別適合本發明目的之DPP-4抑制劑(尤其對於患有腎功能不良之患者)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排泄(例如,>80%或甚至>90%所投與之口服劑量),及/或其中腎排泄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排泄出(例如,在口服服用放射性標記碳(14C)物質後,尿及糞便中平均所排泄放射性為>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或不抑制其活性,且視情況,與母體化合物相比,其快速排除(例如,末端半衰期20h、或較佳約16h,例如15.9h)。
在一實施例中,具有3-胺基-六氫吡啶-1-基取代基之DPP-4抑制劑的(主要)代謝產物(其可在藥理上無活性)係3-胺基-六氫吡啶-1-基部分之胺基經羥基替代以形成3-羥基-六氫吡啶-1-基部分之衍生物。
可對本發明目的具有吸引力的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RA,AUC 1.4)、及/或較佳在每天使用一次時保持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小時血液葡萄糖偏移顯著降低達80%(在療法的第一天時即已達到此降低),且在第一天尿中所排泄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%。
因此,本發明亦涉及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)經由腎排泄(例如根據放射性標記碳(14C)物質口服劑量之排除量測)。
此外,本發明涉及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排泄(例如根據放射性標記碳(14C)物質口服劑量之排除量測)。
此外,本發明涉及DPP-4抑制劑,其用於治療及/或預防代謝疾病(尤其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排泄出(例如,在經口給與放射性標記碳(14C)物質後,尿及糞便中平均所排泄放射性為>70%、或>80%、或較佳90%),該DPP-4抑制劑係非實質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抑制劑係以下DPP-4抑制劑中之任一種:
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)六氫吡嗪-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-1,2,4-三唑-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)六氫吡嗪-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(包括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、溶合物及多晶型形式。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習知。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。因此,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中所闡述來獲得,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中所闡述來獲得,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中所闡述獲得,其揭示內容併入本文中。上文特別提及之彼等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2.5/500毫克、2.5/850毫克及2.5/1000毫克。
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0.001-100毫克/公斤體重、較佳地以0.1-15毫克/公斤之劑量使用,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含(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,隨後流化床乾燥;˙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、黏結劑聚維酮、崩解劑玉米澱粉、及硬脂酸鎂作為潤滑劑,其中聚維酮及/或玉米澱粉為可選的。
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0.1毫克至10毫克、較佳0.25毫克至5毫克,且當經口投與時,為0.5毫克至100毫克、較佳2.5毫克至50毫克或0.5毫克至10毫克、更佳2.5毫克至10毫克或1毫克至5毫克,在每一情形下皆係每天投與1-4次。因此,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)0.5毫克至10毫克/患者/天、較佳2.5毫克至10毫克或1毫克至5毫克/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0.1-100毫克之劑量範圍含有活性成份。因此,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0.5毫克、1毫克、2.5毫克、5毫克及10毫克。
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70公斤體重)之本文所提及DPP-4抑制劑的劑量通常可為約0.5毫克至約350毫克、例如約10毫克至約250毫克、較佳20-200毫克、更佳20-100毫克活性部分/人/天,或約0.5毫克至約20毫克、較佳2.5-10毫克/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200毫克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25毫克與200毫克活性部分之間。西他列汀之推薦劑量針對活性部分(游離鹼無水物)計算為100毫克,每天一次。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200毫克。西他列汀之特定單位劑量強度(例如每個錠劑)係25、50及100毫克。醫藥組合物中使用等量的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257毫克。將劑量經調節之25毫克及50毫克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50/500毫克及50/1000毫克。
DPP-4抑制劑維格列汀之劑量範圍通常介於每日10毫克與150毫克之間、具體而言介於每日25毫克與150毫克、25毫克與100毫克或25毫克與50毫克或50毫克與100毫克之間。每日口服劑量之特定實例係25、30、35、45、50、55、60、80、100或150毫克。在更具體態樣中,維格列汀之日投與量可介於25毫克與150毫克之間或介於50毫克與100毫克之間。在另一更具體態樣中,維格列汀之日投與量可係50毫克或100毫克。活性成份之施用每天可至多發生三次、較佳地每天一次或兩次。特定劑量強度為50毫克或100毫克維格列汀。維格列汀/二甲雙胍雙重組合之典型劑量強度係50/850毫克及50/1000毫克。
阿格列汀可以如下日劑量投與患者:介於5毫克/天與250毫克/天
之間,視情況介於10毫克與200毫克之間,視情況介於10毫克與150毫克之間,且視情況介於10毫克與100毫克阿格列汀之間(在每一情形下皆基於阿格列汀之游離鹼形式的分子量)。因此,可使用之特定劑量量包括(但不限於)每天10毫克、12.5毫克、20毫克、25毫克、50毫克、75毫克及100毫克阿格列汀。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患者:介於2.5毫克/天與100毫克/天之間,視情況介於2.5毫克與50毫克之間。可使用之特定劑量包括(但不限於)每天2.5毫克、5毫克、10毫克、15毫克、20毫克、30毫克、40毫克、50毫克及100毫克薩格列汀。薩格列汀/二甲雙胍雙重組合之典型劑量強度係2.5/500毫克及2.5/1000毫克。
本發明DPP-4抑制劑之特別實施例係指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<100毫克或<70毫克/患者/天、較佳<50毫克、更佳<30毫克或<20毫克、甚至更佳1毫克至10毫克/患者/天(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1毫克至5毫克(更具體而言為5毫克),較佳地每天一次經口投與、更佳地在一天中任何時間在有或無食物情況下投與。
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、24小時持續作用及寬治療窗。在每日一次服用1、2.5、5或10毫克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1毫克劑量下平均累積比RA,AUC 1.4)及保持DPP-4抑制之持久效應(例如,在5毫克及10毫克劑量量下
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時間間隔有>80%抑制)、以及以2.5毫克之劑量餐後2小時血液葡萄糖偏移顯著降低達80%(在第一天時即已達到此降低),且其中在第一天尿中所排泄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-約70mL/min,例如對於5毫克劑量,腎清除率係約70ml/min)。在患有II型糖尿病人群中,BI 1356展現與安慰劑相似的安全性及耐受性。採用約5毫克之低劑量,BI 1356可作為每日一次的可靠經口藥物,且DPP-4抑制可持續整個24h。在治療口服劑量量下,BI 1356主要經肝排泄且僅有一小部分(約<7%的經口投與劑量)經腎排泄。BI 1356首要經膽排泄而無變化。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。
由於不同代謝功能病症通常同時發生,因此經常需要使多種不同活性成份相互組合。因此,視所診斷之功能病症而定,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抑制劑除其用於單治療外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
配藥之醫藥調配物可作為醫藥組合物購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磺醯脲,例如格列本脲(glibenclamide)、甲苯磺丁脲(tolbutamide)、格列美脲(glimepiride)、格列吡嗪(glipizide)、格列喹酮(gliquidon)、格列波脲(glibornuride)及格列齊特(gliclazide);那格列胺(nateglinide);瑞格列奈(repaglinide);噻唑啶二酮,例如羅格列酮(rosiglitazone)及吡格列酮(pioglitazone);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(indeglitazar)、AVE0897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-葡糖苷酶封阻劑,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)、谷賴胰島素(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Exendin-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(例如,trodusquemine);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(50毫克至600毫克),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;β 3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;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。
配藥吡格列酮之劑量通常為約1-10毫克、15毫克、30毫克、或45毫克,每天一次。
羅格列酮通常以4毫克至8毫克劑量給予,每天一次(或分成兩次)(典型劑量強度係2、4及8毫克)。
格列本脲(glyburide)通常以2.5-5至20毫克之劑量給予,每天一次(或分成兩次)(典型劑量強度係1.25、2.5及5毫克),或微粉化格列本脲以0.75-3至12毫克之劑量給予,每天一次(或分成兩次)(典型劑量強度係1.5、3、4.5及6毫克)。
格列吡嗪通常以2.5至10-20毫克之劑量每天給予一次(高達40毫克,分兩次)(典型劑量強度係5毫克及10毫克),或延長釋放之格列吡嗪以5-10毫克(高達20毫克)之劑量每天給予一次(典型劑量強度係2.5、5及10毫克)。
格列美脲通常以1-2至4毫克(高達8毫克)之劑量給予,每天一次(典型劑量強度係1、2及4毫克)。
格列本脲/二甲雙胍雙重組合物通常以1.25/250毫克(每日一次)至10/1000毫克(每日兩次)之劑量給予(典型劑量強度係1.25/250、2.5/500及5/500毫克)。
格列吡嗪/二甲雙胍雙重組合通常以2.5/250至10/1000毫克之劑量給予,每日兩次(典型劑量強度係2.5/250、2.5/500及5/500毫克)。
格列美脲/二甲雙胍雙重組合通常以1/250至4/1000毫克之劑量給予,每日兩次。
羅格列酮/格列美脲雙重組合通常以4/1毫克(每日一次或兩次)至4/2毫克(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8/4毫克)。
吡格列酮/格列美脲雙重組合通常以30/2至30/4毫克(每日一次)之劑量給予(典型劑量強度係30/4及45/4毫克)。
羅格列酮/二甲雙胍雙重組合通常以1/500至4/1000毫克(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4/1000毫克)。
吡格列酮/二甲雙胍雙重組合通常以15/500毫克(每日一次或兩次)至15/850毫克(每日三次)之劑量給予(典型劑量強度係15/500及15/850毫克)。
非磺醯脲胰島素促分泌那格列胺通常以60至120毫克之劑量與膳食一起給予(高達360毫克/天,典型劑量強度係60及120毫克);瑞格列
奈通常以0.5至4毫克之劑量與膳食一起給予(高達16毫克/天,典型劑量強度係0.5、1及2毫克)。瑞格列奈/二甲雙胍雙重組合可以1/500及2/850毫克之劑量強度使用。
阿卡波糖通常以25至100毫克之劑量與膳食一起給予(高達300毫克/天,典型劑量強度係25、50及100毫克)。米格列醇通常以25至100毫克之劑量與膳食一起給予(高達300毫克/天,典型劑量強度係25、50及100毫克)。
出於本發明目的,與本發明DPP-4抑制劑組合使用之特定抗糖尿病配藥可包括(但不限於):特別是對於患有中度腎損傷之患者,格列本脲(降低之劑量)、格列美脲(降低之劑量)、格列喹酮(降低之劑量)、瑞格列奈、阿卡波糖、米格列醇、羅格列酮及吡格列酮;以及特別是對於患有嚴重腎損傷之患者,瑞格列奈(降低之劑量)、吡格列酮及胰島素及胰島素類似物。
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);煙酸及其衍生物,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;LDL受體調節劑;及ApoB100反義RNA。
配藥阿托伐他汀之劑量通常為1毫克至40毫克或10毫克至80毫克,每天一次。
降低血壓之組合配藥的實例係β-封阻劑,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,例如氫氯噻嗪(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);鈣通道封阻劑,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受體封阻劑(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)。
配藥替米沙坦之劑量通常為每天20毫克至320毫克、或40毫克至160毫克。
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西布曲明(sibutramine);四氫泥泊司他汀(tetrahydrolipstatin)(奧利司他(orlistat));西替利司他(cetilistat)、阿利茨默(alizyme);右芬氟拉明(dexfenfluramine);阿索開(axokine);大麻素受體1拮抗劑,例如CB1拮抗劑利莫納班(rimonobant);MCH-1受體拮抗劑;MC4受體激動劑;NPY5以及NPY2拮抗劑;β 3-AR激動劑,例如SB-418790及AD-9677;5HT2c受體激動劑,例如APD 356/氯卡色林(lorcaserin);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;多肽格那啉(Ghrelin)受體調節劑;Pyy 3-36;阿立新(orexin)受體拮抗劑;及特索芬辛(tesofensine)。
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(50毫克至600毫克),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。
對於本文所提及藥物在患有腎疾病、腎功能障礙或腎功能不全之患者中之使用,在某些情形下-視個別藥物(例如,其藥物動力學、藥效學、新城代謝、排除途徑)及患者腎損傷之等級而定-對於腎功能不良之患者可能需要調節或降低其劑量。
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之各種修改。此等修改意欲屬於隨附申請專利範圍之範疇。
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。
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、平行組試驗中,比較本發明DPP-4抑制劑(例如,每日一次經口投與之5毫克BI 1356)與安慰劑在由於對二甲雙胍難耐受或禁忌而不適用二甲雙胍療法之患有II型糖尿病及不充分血糖控制(例如,HbA1c 7%至10%)的患者中經18周治療階段、之後34周雙盲擴展階段(安慰劑換為格列美脲)之安全性及功效。
不適用二甲雙胍療法之患者定義如下:標籤指明的二甲雙胍療法禁忌症,例如:腎疾病、腎功能不全(例如,如本地認可之二甲雙胍的產品資訊所規定)、由研究者臨床判斷之脫水、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(患者病史中之目前病況)、遺傳性半乳糖不耐受;或由二甲雙胍引起之已記錄不耐受副作用,例如:噁心、嘔吐、腹瀉、腸積氣、嚴重腹部不適。
在此研究中,研究本發明DPP-4抑制劑與磺醯脲藥物(格列美脲)相比在此患者群體中經18周較短期治療時期之功效,且研究經最長52
周之較長期治療時期之安全性/耐受性。
藉由測定HbA1c值、藉由與初始值及/或無效對照組之值比較,測試治療是否成功。與初始值及/或安慰劑值相比,HbA1c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。空腹葡萄糖濃度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HbA1c<7%或<6.5%)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,腎副反應、低血糖症發作或諸如此類)之發病率及強度或重量增加)研究在格列美脲療法下與DPP-4抑制劑治療相比的治療安全性及耐受性。
對於其他實例而言,在隨機、雙盲、平行組試驗中,比較本發明DPP-4抑制劑(例如,5毫克BI 1356)與安慰劑在患有嚴重慢性腎損傷之II型糖尿病男性及女性患者(GFR<30ml/min,其未正在慢性透析)(包括服用胰島素及/或磺醯脲背景藥劑之患者)中經52周治療階段之安全性、功效及耐受性。
藉由評定患者之狀況研究治療之安全性及耐受性。功效可藉由在12周治療後HbA1c偏離基線之變化、藉由空腹血漿葡萄糖參數之變化、或藉由52周後胰島素及/或磺醯脲劑量與基線相比且隨時間的變化來研究。
用於本發明目的之DPP-4抑制劑的新陳代謝及排除特性:可使用經口投與之放射性標記(例如,[14C]標記)DPP-4抑制劑研究本發明DPP-4抑制劑在人類個體中之排泄途徑、質量平衡及新陳代謝,例如,如下針對測定化合物是否適於本發明目的所述:在經口投與10毫克[14C]BI 1356/個體(例如,健康男性志願者)後,總放射性首要經由糞便排除,其中平均83.8%之投與劑量在16天
內排泄出。在給藥9天後,腎排泄佔所投與劑量之6.6%。總放射性之回收率介於所投與劑量之86.1%-95.1%間(平均:90.4%)。
在經口投與[14C]BI 1356後,在所有研究基質中,母體化合物係最豐富的放射性物質。在經口投與後,在血漿中母體化合物[14C]BI 1356平均佔試樣放射性之74%(試樣池:1.5+3+6h)。鑑別血漿中之無活性主要代謝產物,其中在合併試樣(pooled sample)中16.9%試樣具有放射性。母體化合物[14C]BI 1356在經口給與後無變化的排泄於尿及糞便中,其中平均所排泄放射性為90%。在排泄物中,代謝產物(包括主要代謝產物)個別地佔<10%。
Claims (25)
- 一種經口投與之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的代謝疾病。
- 如請求項1之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用二甲雙胍療法之患者的代謝疾病。
- 如請求項1之DPP-4抑制劑,其用於治療及/或預防由於對二甲雙胍降低之耐受性、不耐受或禁忌而需要降低劑量的二甲雙胍療法之患者的代謝疾病。
- 如請求項1至3中任一項之DPP-4抑制劑,其用於治療及/或預防具有選自以下之至少一種禁忌症的患者之II型糖尿病:腎疾病、腎損傷或腎功能障礙、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。
- 如請求項4之DPP-4抑制劑,其用於治療及/或預防患有腎疾病、腎損傷或腎功能障礙之患者的II型糖尿病。
- 如請求項1至3中任一項之DPP-4抑制劑,其係或者,在第一實施例(實施例A)中,
- 如請求項1至3中任一項之DPP-4抑制劑,其中該DPP-4抑制劑係 選自由以下組成之群: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,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,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,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,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,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,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,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,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,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,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)-黃嘌呤及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,或其醫藥上可接受之鹽。
- 如請求項1至3中任一項之DPP-4抑制劑,其中該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。
- 如請求項1至3中任一項之DPP-4抑制劑,其中該DPP-4抑制劑係選自由以下組成之群: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)六氫吡嗪-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-1,2,4-三唑-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)六氫吡嗪-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。
- 如請求項1至3中任一項之DPP-4抑制劑,其用於治療及/或預防患有腎疾病、腎損傷或腎功能障礙之患者的II型糖尿病,其中該DPP-4抑制劑係以與用於具有正常腎功能之患者相同的劑量用於該等患者。
- 如請求項1至3中任一項之DPP-4抑制劑,其特徵在於該DPP-4抑制劑及其主要活性代謝產物具有相對較寬之治療窗及/或首要經由肝臟代謝或膽汁分泌排除。
- 如請求項1至3中任一項之DPP-4抑制劑,其中該DPP-4抑制劑主要經由肝排泄。
- 如請求項1至3中任一項之DPP-4抑制劑,其中經由腎排泄代表次要排除途徑。
- 如請求項1至3中任一項之DPP-4抑制劑,其中該DPP-4抑制劑主要無變化的排泄出。
- 如請求項1至3中任一項之DPP-4抑制劑,其中經由新陳代謝之排除代表次要排除途徑。
- 如請求項1至3中任一項之DPP-4抑制劑,其中該DPP-4抑制劑具有與安慰劑相似的安全性及耐受性及/或首要經由肝以母體藥物排除。
- 如請求項1至3中任一項之DPP-4抑制劑,其中該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之治療窗。
- 如請求項1至3中任一項之DPP-4抑制劑,其用於患有輕微、中度或嚴重腎損傷或晚期腎疾病之患者。
- 如請求項1至3中任一項之DPP-4抑制劑,其與選自以下之一或多種其他活性物質組合使用:抗糖尿病藥、降低血糖濃度之活性物質、降低血液中脂濃度之活性物質、升高血液中HDL濃度之活性物質、降低血壓之活性物質、治療動脈粥樣硬化所需之活性物質、及治療肥胖症所需之活性物質。
- 如請求項1至3中任一項之DPP-4抑制劑,其與一或多種選自瑞格列奈(repaglinide)、吡格列酮(pioglitazone)、及胰島素及胰島素類似物之其他活性物質組合使用。
- 如請求項1至3中任一項之DPP-4抑制劑,其用於治療及/或預防遭受與二甲雙胍相關之胃腸副作用的患者之II型糖尿病,例如至少一種選自以下之胃腸副作用:噁心、嘔吐、腹瀉、腸積氣、及嚴重腹部不適。
- 一種用於經口治療糖尿病患者之DPP-4抑制劑,其特徵在於<10%、較佳7%之所投與口服劑量經由腎排泄。
- 如請求項22之DPP-4抑制劑,其特徵在於其首要經由膽汁無變化的排泄出。
- 如請求項22或23之DPP-4抑制劑,其特徵在於>80%、較佳90%之該所投與口服劑量係以母體藥物無變化的排泄出。
- 如請求項22或23之DPP-4抑制劑,其特徵在於其主要代謝產物在藥理上無活性。
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- 2009-08-05 CN CN201510477492.8A patent/CN105126105A/zh active Pending
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