TWI500423B - Dpp iv抑制劑之用途 - Google Patents
Dpp iv抑制劑之用途 Download PDFInfo
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- TWI500423B TWI500423B TW096115736A TW96115736A TWI500423B TW I500423 B TWI500423 B TW I500423B TW 096115736 A TW096115736 A TW 096115736A TW 96115736 A TW96115736 A TW 96115736A TW I500423 B TWI500423 B TW I500423B
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- Prior art keywords
- dpp
- inhibitor
- dose
- combination
- methyl
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Description
本說明書描述選定DPP IV抑制劑用於治療生理功能性病症及於降低處於危險中之患者群出現該等功能性病症之風險的用途。此外,本說明書描述上述DPP IV抑制劑聯合其他活性物質之用途,藉此可達成經改良之治療結果。此等應用可用以製備相應藥劑。
亦稱為CD26之酶DPP-IV為促進在N末端具有脯胺酸或丙胺酸基團之蛋白質中二肽裂解之絲胺酸蛋白酶。DPP-IV抑制劑藉此影響生物活性肽(包括肽GLP-1)之血漿含量且為用於治療糖尿病之極具價值的分子。
主要發生在30歲以下之青少年之第一型糖尿病歸類為自身免疫疾病。在相應遺傳素因下及在多種因素影響下,出現胰島炎,隨後破壞B細胞,以使得胰腺不再能產生大量胰島素(若能產生)。
第二型糖尿病並不歸類為自身免疫疾病且本身顯示空腹血糖含量超過每分升血漿125毫克葡萄糖;血糖值之量測為常規醫學分析中之標準程序。若空腹血糖含量超過每分升血漿99毫克葡萄糖之最大正常含量,但不超過每分升血漿125毫克葡萄糖之臨限值,則疑為糖尿病前期,其與糖尿病有關。此亦稱為病理性空腹葡萄糖(空腹葡萄糖異常)。糖尿病前期之另一徵象為葡萄糖耐受性異常,亦即在口服葡萄糖耐受性測試範疇內在空腹攝取75毫克葡萄糖後2小時血糖含量為每分升血漿140-199毫克葡萄糖。
若進行葡糖耐受性測試,則空腹攝取75公克葡萄糖後2小時,糖尿病患者之血糖含量將超過每分升血漿199毫克葡萄糖。在葡萄糖耐受性測試中,在空腹10-12小時之後向測試患者經口投與75公克葡萄糖且在即將攝取葡萄糖之前及在攝取葡萄糖之後1及2小時記錄血糖含量。在健康受檢者體內,血糖含量在攝取葡萄糖之前應介於每分升血漿60毫克與99毫克之間,在攝取葡萄糖之後1小時小於每分升200毫克且在2小時之後小於每分升140毫克。若在2小時之後,該值介於140毫克與199毫克之間,則將其視為葡萄糖耐受性異常或在某些狀況下視為葡萄糖不耐症。
在監測糖尿病之治療時,血紅蛋白B鏈之非酶促糖化產物,HbA1c值尤其重要。由於其形成主要視血糖含量及紅血球壽命而定,因此HbA1c在"血糖記憶"意義上反映先前4-12週之平均血糖含量。HbA1c含量已受較強化糖尿病治療良好控制較長時間(亦即試樣中總血紅蛋白<6.5%)之糖尿病患者受到顯著較好之保護而免於糖尿病微血管病變。糖尿病之有效治療可給予糖尿病患者HbA1c含量約1.0%-1.5%之平均改善。此HbA1C含量降低並不足以使所有糖尿病患者處於<6.5%且較佳<6% HbA1c之所要目標範圍內。
若可偵測到胰島素抗性,則此為存在糖尿病前期之複合代謝病症之尤其有力的徵象。因此,可能為維持葡萄糖體內平衡,某人需要多達他人2-3倍之胰島素。測定胰島素抗性之最可靠方法為正常葡萄糖血症-高胰島素血症夾鉗測試(euglycaemic-hyperinsulinaemic clamp test)。胰島素與葡萄糖之比率係在經組合之胰島素-葡萄糖輸注技術之範疇內測定。若葡萄糖吸收低於所探查背景群體之25個百分點,則存在胰島素抗性(WHO定義)。與夾鉗測試相比頗不費勁者為所謂的最小模型,其中在靜脈葡萄糖耐受性測試期間,血液中之胰島素及葡萄糖濃度係以固定時間間隔量測且由此計算胰島素抗性。另一種量測方法為數學HOMA模型。胰島素抗性係藉助於空腹血漿血糖濃度及空腹胰島素濃度來計算。在此方法中,不可能區別肝臟胰島素抗性與周邊胰島素抗性。此等方法並不真正適於在日常實踐中評估胰島素抗性。通常,日常臨床實踐中使用其他參數來評估胰島素抗性。較佳地,例如,使用患者之甘油三酯濃度,此係由於甘油三酯含量增加與存在胰島素抗性顯著相關。
為略微簡化,實務上假定若某人具有以下特徵中之至少2者,則其具有胰島素抗性:1)超重或肥胖2)高血壓3)血脂異常(血液中總脂質含量改變)4)至少一位已經確診葡萄糖耐受性異常或第二型糖尿病之近親。
超重意謂在體重指數(BMI)介於25 kg/m2
與30 kg/m2
之間的此情況下,BMI為體重(公斤)與身高(公尺)之平方的商。在顯性肥胖症中,BMI為30 kg/m2
或更高。
根據上述胰島素抗性之定義,直接可見若發現患者患有高血壓,則降血壓劑適合且指定用於治療胰島素抗性。
糖尿病前期之類似徵象為是否滿足代謝症候群之病狀,其主要特點為胰島素抗性。根據ATP IHINCEP準則(Journal of the American Medical Association 285:2486-2497,2001中之Executive Summary of the Third Report of the National Cholesterol Education Program(NCEP)),若患者具有以下特徵中之至少3者,則存在代謝症候群:1)腹部肥胖,定義為男性腰身>40吋或102公分且女性>35吋或94公分2)甘油三酯含量>150毫克/分升3)男性之HDL-膽固醇含量<40毫克/分升4)高血壓>130/>85 mm Hg 5)空腹血糖>110毫克/分升。
此代謝症候群之定義直接展示若發現患者患有高血壓,則降血壓劑適於治療代謝症候群。
甘油三酯血液含量超過150毫克/分升亦指示存在糖尿病前期。此推測係由HDL膽固醇之低血液含量來證實。在女性體內,低於每分升血漿55毫克之含量視為過低,而在男性體內,低於每分升血漿45毫克之含量視為過低。血液中甘油三酯及HDL膽固醇亦可藉由醫學分析中之標準方法來測定且例如描述於Thomas L(編者):"Labor und Diagnose",TH-Books mbH,Frankfurt Main 2000中。若空腹血糖含量亦超過每分升血漿99毫克葡萄糖,則糖尿病前期之推測進一步得以證實。
術語妊娠性糖尿病(妊娠糖尿病)表示在妊娠期間發展且通常在分娩之後又立即停止的一種糖疾病形式。妊娠性糖尿病係藉由在妊娠第24週與第28週之間進行的篩檢測試來確診。其通常為在投與50公克葡萄糖溶液之後一小時量測血糖含量之簡單測試。若此1 h含量超過140毫克/分升,則疑為妊娠性糖尿病。可藉由用75公克葡萄糖之標準葡萄糖耐受性測試來獲得最終確認。
高血糖症
描述在空腹狀態下(與<100毫克/分升之正常含量相比,100-125毫克/分升之高葡萄糖含量或>125毫克/分升之糖尿病性-高血糖含量)或在非空腹狀態下(>180毫克/分升之高葡萄糖含量),在血液中量測到極高葡萄糖含量的功能性病症。
臨床醫師對於腎上腺素激導性餐後徵候群
(反應性低血糖)意謂不相稱之高胰島素含量導致由在餐後快速消化之糖類與持續高胰島素含量之間的不平衡所引起之血糖含量下降(低血糖)的功能性病症。
術語糖尿病足
係指由糖尿病引起之足上病變,其主要原因為可歸因於不充分代謝控制之多發性神經病。糖尿病足係藉由在現有糖尿病情況下出現典型病變(例如潰瘍)來確診。
術語糖尿病相關潰瘍
係指糖尿病患者之潰瘍性發炎性皮膚缺陷。糖尿病相關潰瘍係藉由典型既往病歷及身體檢查(例如檢查足)來確診。
若糖尿病患者遭受總膽固醇增加或更通常在糖尿病性高脂質血症中血漿甘油三酯增加,伴以或不伴以HDL膽固醇降低,則使用術語糖尿病性高脂質血症
。
若總膽固醇並不升高,但HDL-膽固醇及LDL-膽固醇之分佈改變,亦即患者之HDL膽固醇含量過低(例如女性<55毫克/分升及男性<45毫克分升),則使用術語糖尿病性血脂異常
。
若主觀症狀或客觀檢查表明心臟不能達成必要的射血輸出,則使用術語心臟衰竭
。主觀症狀可為例如在受力狀態下或在靜止狀態下呼吸困難。客觀檢查包括根據超音之心臟之射血輸出減少(射血量減少)、根據X射線之肺充血,及/或步行距離減少。
一些選定DPP IV抑制劑尤其適於製備供治療性處理已經確診患有選自下列病症之醫學或生理功能性病症的患者之藥劑:糖尿病前期、葡萄糖不耐症(葡萄糖耐受性異常)、病理性空腹葡萄糖(空腹葡萄糖異常)、糖尿病足、糖尿病相關潰瘍、糖尿病性高脂質血症、糖尿病性血脂異常、最新診斷之第一型糖尿病(以維持胰島素自胰腺之殘餘分泌)、妊娠性糖尿病(妊娠糖尿病)、高血糖症、腎上腺素激導性餐後徵候群(反應性低血糖)或心臟衰竭。
此等藥劑亦可用以降低如下風險:儘管進行治療,患者仍會遭受葡萄糖代謝異常、HbA1c值升高、空腹葡萄糖值異常、顯性第二型糖尿病、糖尿病足、糖尿病相關潰瘍、糖尿病性高脂質血症或糖尿病性血脂異常,且儘管有療法,胰島素治療仍會變得必需或會出現大血管併發症。
此類大血管併發症之實例為心肌梗塞、急性冠狀動脈徵候群、不穩定型心絞痛、穩定型心絞痛、出血性中風或缺血性中風、周邊動脈阻塞性疾病、心肌病、左心功能不全、右心功能不全、綜合性心功能不全、心律異常及血管再狹窄。此等大血管併發症為熟習此項技術者已知且詳細描述於標準教科書中。
此外,該等物質適於在蘭格罕氏島(islets of Langerhans)或β細胞移植之後增強細胞之生命力及分泌能力,且藉此確保移植後之有利結果。該等物質亦可在蘭格罕氏島或β細胞之分離及移植階段期間,藉由將指定物質以1 nmol/l至1 μmol/l之合適濃度,較佳以1 nmol/l至100 nmol/l之濃度添加至習知分離或儲存介質中來使用。此使得待移植物質之品質改良。品質改良尤其係與GLP-1(胰高血糖素樣肽1)之量增加(較佳以1-100 nmol/l之濃度)組合獲得。本發明之另一目標為相應分離或儲存介質及藉由將DPP IV抑制劑添加至所用介質中來增強蘭格罕氏島或β細胞之生命力及分泌能力的相應方法。
最後,上述抑制劑適於治療多種形式之關節炎,但尤其為類風濕性關節炎。
本發明之選定DPP IV抑制劑可由式(I)
或式(II)來描述
其中R1
表示([1,5]萘啶-2-基)甲基、(喹唑啉-2-基)甲基、(喹喏啉-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-哌啶-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。
尤其較佳之DPP IV抑制劑為以下化合物及其治療活性鹽: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-哌啶-1-基)-黃嘌呤(參看WO 2004/018468,實例2(142)):
1-[([1,5]萘啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R
)
1-[([1,5]萘啶-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R
)-3-胺基-哌啶-1-基)-黃嘌呤(參看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-哌啶-1-基)-黃嘌呤(參看WO 2004/018468,實例2(80)):
2-((R)-3-胺基-哌啶-1-基)-3-(丁-2-炔基)-5-(4-甲基-喹唑啉-2-基甲基)-3,5-二氫-咪唑幷[4,5-d]噠嗪-4-酮(參看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(參看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-哌啶-1-基)-黃嘌呤(參看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-哌啶-1-基)-黃嘌呤(參看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(參看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-哌啶-1-基)-黃嘌呤(參看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-哌啶-1-基)-黃嘌呤(參看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-哌啶-1-基)-黃嘌呤(參看WO 2005/085246,實例1(82)):
1-[(喹喏啉-6-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-((R
)-3-胺基-哌啶-1-基)-黃嘌呤(參看WO 2005/085246,實例1(83)):
此等DPP IV抑制劑不同於結構上類似之DPP IV抑制劑,此係由於當其與其他醫藥活性物質組合時,其將特殊效能及持久作用與有利藥理特性、受體選擇性及有利副作用概況組合或產生出乎意料之治療優點或改良。其製備揭示於所提及之公開案中。
由於不同代謝功能性病症常同時出現,因此往往指定組合許多彼此不同之活性成份。因此,視所確診之功能性病症而定,若DPP IV抑制劑與選自其他抗糖尿病物質之活性物質,尤其降低血液中血糖含量或脂質含量、升高血液中HDL含量、降低血壓或指定用於治療動脈粥樣硬化或肥胖之活性物質組合,則可獲得經改良之治療結果。
當靜脈內投與時,DPP IV抑制劑之所需劑量為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,在各種情況下每天1至4次。為達成此目的,視情況與另一種活性物質組合之化合物可與一或多種習知惰性載劑及/或稀釋劑一起,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、十六十八醇(cetylstearylalcohol)、羧甲基纖維素或諸如硬脂之脂質或其合適混合物一起調配,以形成習知蓋倫製劑(galenic preparation),諸如錠劑、包衣錠劑、膠囊、散劑、懸浮液或栓劑。
因此本發明之DPP IV抑制劑係由熟習此項技術者使用如先前技術中所述之容許調配物賦形劑來製備。該等賦形劑之實例為稀釋劑、黏合劑、載劑、填充劑、潤滑劑、流動劑、結晶遲延劑、崩解劑、溶解劑、著色劑、pH值調節劑、界面活性劑及乳化劑。
合適稀釋劑之實例包括纖維素粉末、磷酸氫鈣、赤藻糖醇、(低取代)羥丙基纖維素、甘露糖醇、預膠化澱粉或木糖醇。
合適黏合劑之實例包括乙烯吡咯啶酮與其他乙烯基衍生物之共聚物(共聚乙烯吡咯酮)、羥丙基甲基纖維素(HPMC)、羥丙基纖維素(HPC)、聚乙烯吡咯啶酮(聚維酮(povidone))、預膠化澱粉或低取代羥丙基纖維素。
合適潤滑劑之實例包括滑石粉、聚乙二醇、蘿酸鈣、硬脂酸鈣、氫化蓖麻油或硬脂酸鎂。
合適崩解劑之實例包括玉米澱粉或交聯聚乙烯吡咯酮。
製備本發明之DPP IV抑制劑之醫藥調配物的合適方法為:將與合適之製錠賦形劑呈粉末混合物形式之活性物質直接製錠;與合適之賦形劑一起粒化且隨後與合適之賦形劑混合且隨後製錠以及薄膜包衣;或將粉末混合物或顆粒填充至膠囊中。
合適之粒化方法為在強力混合器中濕式粒化,隨後流化床乾燥;一鍋式粒化;流化床粒化;或與合適之賦形劑一起乾式粒化(例如藉由滾筒壓製)且隨後製錠或填充至膠囊中。
上述DPP IV抑制劑亦可與其他活性物質聯合使用,藉此可獲得經改良之治療結果。該組合治療可以該等物質之自由組合形式或以固啶組合形式,例如以錠劑或膠囊形式給予。為達成此目的所需之組合搭配物之醫藥調配物可以醫藥組合物形式購得或可由熟習此項技術者使用習知方法調配。可以醫藥組合物形式購得之活性物質於先前技術中多處加以描述,例如每年出版之藥物目錄,製藥工業聯合會之"Rote Liste"中,或每年更新之稱為"Physicians' Desk Reference"之處方藥物有關製造商資訊的彙編。
抗糖尿病藥組合搭配物之實例為二甲雙胍;磺醯基脲,諸如格列本脲(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);那格列奈(nateglinide);瑞格列奈(repaglinide);噻唑烷二酮,諸如羅格列酮(rosiglitazone)及吡格列酮(pioglitazone);PPAR γ調節劑,諸如美格利德(metaglidase);PPAR-γ促效劑,諸如GI 262570;PPAR-γ拮抗劑;PPAR-γ/α調節劑,諸如特沙他唑(tesaglitazar)、莫格他唑(muraglitazar)及KRP297;PPAR-γ/α/δ調節劑;AMPK-活化劑,諸如AICAR;乙醯輔酶A羧化酶(ACC1及ACC2)抑制劑;二醯甘油-乙醯轉移酶(DGAT)抑制劑;胰腺β細胞GCRP促效劑,諸如SMT3-受體促效劑及GPR119;11β-HSD抑制劑;FGF19促效劑或類似物;α-葡糖苷酶阻斷劑,諸如阿卡波糖(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,諸如人類胰島素、賴脯胰島素(insulin lispro)、胰島素格素林(glusilin)、r-DNA-門冬胰島素(insulinaspart)、NPH胰島素、胰島素迪特美(detemir)、胰島素鋅懸浮液及胰島素加列金(glargin);胃抑制肽(GIP);普蘭林肽(pramlintide);艾汀(amylin)或GLP-1及GLP-1類似物,諸如艾生丁-4(Exendin-4);SGLT2抑制劑,諸如KGT-1251;蛋白質酪胺酸-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;肝糖磷酸化酶調節劑;胰高血糖素受體拮抗劑;磷酸烯醇丙酮酸羧基激酶(phosphoenolpyruvatecarboxykinase,PEPCK)抑制劑;丙酮酸脫氫酶激酶(PDK)抑制劑;酪胺酸-激酶之抑制劑(50 mg至600 mg),諸如PDGF受體-激酶(參看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,包括葡糖激酶活化劑;肝糖合成酶激酶抑制劑;含有SH2-功能部位之2型肌醇5-磷酸酶(SHIP2);IKK抑制劑,諸如高劑量水楊酸鹽;JNK1抑制劑;蛋白激酶C-θ抑制劑;β3促效劑,諸如瑞妥貝隆(ritobegron)、YM 178、索拉貝隆(solabegron)、塔裏貝隆(talibegron)、N-5984、GRC-1087、拉法貝隆(rafabegron)、FMP825;醛糖還原酶抑制劑,諸如AS 3201、折那司他(zenarestat)、法地司他(fidarestat)、依帕司他(epalrestat)、阮尼司他(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;及其他DPPIV抑制劑。
11β-HSD1抑制劑之實例描述於以下專利中:WO 2007/013929、WO 2007/007688、WO 2007/003521、WO 2006/138508、WO 2006/135795、WO 2006/135667、WO 2006/134481、WO 2006/134467、WO 2006/132436、WO 2006/132197、WO 2006/113261、WO 2006/106423、WO 2006/106052、WO 2006/105127、WO 2006/104280、WO 2006/100502、WO 2006/097337、WO 2006/095822、WO 2006/094633、WO 2006/080533、WO 2006/074330、WO 2006/074244、WO 2006/068992、WO 2006/068991、WO 2006/068199、WO 2006/066109、WO 2006/055752、WO 2006/053024、WO 2006/051662、WO 2006/050908、WO 2006/049952、WO 2006/048750、WO 2006/048331、WO 2006/048330、WO 2006/040329、WO 2006/037501、WO 2006/030805、WO 2006/030804、WO 2006/017542、WO 2006/024628、WO 2006/024627、WO 2006/020598、WO 2006/010546、WO 2006/002349、WO 2006/002350、WO 2006/012173、WO 2006/012227、WO 2006/012226、WO 2006/000371、WO 2005/118538、WO 2005/116002、WO 2005/110992、WO 2005/110980、WO 2005/108359、WO 2005/108361、WO 2005/108360、WO 2005/108368、WO 2005/103023、WO 2005/097764、WO 2005/097759、WO 2005/095350、WO 2005/075471、WO 2005/063247、WO 2005/060963、WO 2005/047250、WO 2005/046685、WO 2005/044192、WO 2005/042513、WO 2005/016877、WO 2004/113310、WO 2004/106294、WO 2004/103980、WO 2004/089896、WO 2004/089380、WO 2004/089471、WO 2004/089470、WO 2004/089367、WO 2005/073200、WO 2004/065351、WO 2004/058741、WO 2004/056745、WO 2004/056744、WO 2004/041264、WO 2004/037251、WO 2004/033427、WO 2004/011410、WO 2003/104208、WO 2003/104207、WO 2003/065983、WO 2003/059267、WO 2003/044009、WO 2003/044000、WO 2003/043999、WO 2002/076435、WO 2001/090094、WO 2001/090093、WO 2001/090092、WO 2001/090091、WO 2001/090090、US 2007/049632、US 2006/148871、US 2006/025445、US 2006/004049、US 2005/277647、US 2005/261302、US 2005/245534、US 2005/245532、US 2005/245533及JP 2005/170939。11β-HSD1抑制劑之代表性實例為以下化合物:
及其鹽。
肝糖磷酸化酶調節劑之實例描述於以下專利中:WO 2006/126695、WO 2006/082401、WO 2006/082400、WO 2006/059165、WO 2006/059164、WO 2006/059163、WO 2006/056815、WO 2006/055463、WO 2006/055462、WO 2006/055435、WO 2006/053274、WO 2006/052722、WO 2005/085245、WO 2005/085194、WO 2005/073231、WO 2005/073230、WO 2005/073229、WO 2005/067932、WO 2005/020987、WO 2005/020986、WO 2005/020985、WO 2005/019172、WO 2005/018637、WO 2005/013981、WO 2005/013975、WO 2005/012244、WO 2004/113345、WO 2004/104001、WO 2004/096768、WO 2004/092158、WO 2004/078743、WO 2004/072060、WO 2004/065356、WO 2004/041780、WO 2004/037233、WO 2004/033416、WO 2004/007455、WO 2004/007437、WO 2003/104188、WO 2003/091213、WO 2003/084923、WO 2003/084922、WO 2003/074532、WO 2003/074531、WO 2003/074517、WO 2003/074513、WO 2003/074485、WO 2003/074484、WO 2003/072570、WO 2003/059910、WO 2003/037864、WO 2002/096864、WO 2002/020530、WO 2001/094300、WO 2000/123347、WO 1996/39384、WO 1996/39385、EP 1391460、EP 1136071、EP 1125580、EP 1088824、EP 0978279、JP 2004196702、US 2004/002495、US 2003/195243及US 5998463。
葡糖激酶活化劑之實例描述於以下專利中:WO 2007/017649、WO 2007/007910、WO 2007/007886、WO 2007/007042、WO 2007/007041、WO 2007/007040、WO 2007/006814、WO 2007/006761、WO 2007/006760、WO 2006/125972、WO 2006/125958、WO 2006/112549、WO 2006/059163、WO 2006/058923、WO 2006/049304、WO 2006/040529、WO 2006/040528、WO 2006/016194、WO 2006/016178、WO 2006/016174、WO 2005/121110、WO 2005/103021、WO 2005/095418、WO 2005/095417、WO 2005/090332、WO 2005/080360、WO 2005/080359、WO 2005/066145、WO 2005/063738、WO 2005/056530、WO 2005/054233、WO 2005/054200、WO 2005/049019、WO 2005/046139、WO 2005/045614、WO 2005/044801、WO 2004/081001、WO 2004/076420、WO 2004/072066、WO 2004/072031、WO 2004/063194、WO 2004/063179、WO 2004/052869、WO 2004/050645、WO 2004/031179、WO 2004/002481、WO 2003/095438、WO 2003/080585、WO 2003/055482、WO 2003/047626、WO 2003/015774、WO 2003/000267、WO 2003/000262、WO 2002/048106、WO 2002/046173、WO 2002/014312、WO 2002/008209、WO 2001/085707、WO 2001/085706、WO 2001/083478、WO 2001/083465、WO 2001/044216及WO 2000/058293。
葡糖激酶活化劑之代表性實例為以下化合物:
其中G1
表示環丙基或環丁基且G2
表示5-氟-噻唑-2-基、1-甲基-1H
-吡唑-3-基或吡嗪-2-基;及
其中G3
表示甲基或乙基且G4
表示噻唑-2-基、4-甲基-噻唑-2-基、5-甲基-噻唑-2-基或吡嗪-2-基,及其鹽。
SGLT1或SGLT2抑制劑之實例描述於以下專利中:WO 2006/108842、WO 2006/087997、WO 2006/080577、WO 2006/080421、WO 2006/073197、WO 2006/064033、WO 2006/062224、WO 2006/054629、WO 2006/037537、WO 2006/035796、WO 2006/018150、WO 2006/008038、WO 2006/002912、WO 2006/010557、WO 2006/011502、WO 2006/011469、WO 2005/121161、WO 2005/012326、WO 2005/095429、WO 2005/095372、WO 2005/095373、WO 2005/092877、WO 2005/085267、WO 2005/085265、WO 2005/085237、WO 2005/063785、WO 2005/021566、WO 2005/012243、WO 2005/012242、WO 2005/012326、WO 2005/012318、WO 2005/011592、WO 2004/113359、WO 2004/099230、WO 2004/089967、WO 2004/089966、WO 2004/087727、WO 2004/080990、WO 2004/058790、WO 2004/052903、WO 2004/052902、WO 2004/019958、WO 2004/018491、WO 2004/014932、WO 2004/014931、WO 2004/013118、WO 2003/099836、WO 2003/080635、WO 2003/020737、WO 2003/011880、WO 2003/000712、WO 2002/098893、WO 2002/088157、WO 2002/083066、WO 2002/068440、WO 2002/068439、WO 2002/064606、WO 2002/053573、WO 2002/044192、WO 2002/036602、WO 2002/028872、WO 2001/074835、WO 2001/074834、WO 2001/068660、WO 2001/027128、WO 2001/016147、JP 2005247834、JP 2004359630、JP 2004196788、JP 2003012686及US 2006/063722。
SGLT1或SGLT2抑制劑之代表性實例為以下化合物及其與天然胺基酸之鹽或錯合物:
及
其中G5
與G8
彼此獨立地表示氫、氟、氯、溴、氰基、甲基、乙基、異丙基、二氟甲基、三氟甲基、乙炔基、丙-1-炔-1-基、丁-1-炔-1-基、羥基、甲氧基、乙氧基、二氟甲氧基、環丙氧基、環丁氧基、環戊氧基或環己氧基;且G6
表示氟、氯、甲基、乙基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、三甲基矽烷基乙基、乙炔基、2-羥基丙-2-基乙炔基、2-甲氧基丙-2-基乙炔基、3-羥基-1-丙炔-1-基、3-甲氧基-1-丙炔-1-基、環丙基、環丁基、環戊基、環己基、環丙氧基、環丁氧基、環戊氧基、環己氧基、四氫呋喃-3-基氧基、四氫哌喃-4-基氧基、哌啶-4-基氧基、N-甲基哌啶-4-基氧基及N-乙醯基哌啶-4-基氧基;且G7
表示氫或氟;
其中G表示氟、氯、甲基、乙基、乙炔基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、環丁氧基、環戊氧基、3-四氫呋喃基氧基或4-四氫哌喃基氧基;
其中G表示氟、氯、甲基、乙基、乙炔基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、環丁氧基、環戊氧基、3-四氫呋喃基氧基或4-四氫哌喃基氧基;
其中G8
表示氫、甲氧基羰基或乙氧基羰基,且G9
表示氟、氯、甲基、乙基、乙炔基、甲氧基、乙氧基、二氟甲氧基、三氟甲氧基、環丁氧基、環戊氧基、3-四氫呋喃基氧基或4-四氫哌喃基氧基;及
其中:G10
表示C1-3
烷基或全氟-C1-3
烷基;G11
表示氫、C1-3
烷基或全氟-C1-3
烷基;G12
表示氟、氯、溴、C1-6
烷基、經1至3個氟原子取代之C1-6
烷基、C1-6
烷氧基、經1至3個氟原子取代之C1-6
烷氧基、C1-6
烷基硫基、C2-6
烯基、C2-6
炔基、全氟-C1-3
烷基、環丁氧基、環戊氧基、環己氧基、四氫呋喃基氧基或4-四氫哌喃基氧基;且G13
與G14
彼此獨立地表示氫、氟、氯、溴、C1-6
烷基、經1至3個氟原子取代之C1-6
烷基、C1-6
烷氧基、經1至3個氟原子取代之C1-6
烷氧基、C1-6
烷基硫基、C2-6
烯基、C2-6
炔基、全氟-C1-3
烷基;且G15
表示氫、C2-20
烷醯基、C1-6
烷氧基羰基或苯甲醯基。
抗糖尿病藥組合搭配物之一尤其較佳實例為約100 mg至500 mg或200 mg至850 mg(一天一至三次),或約300 mg至1000 mg一天一次或兩次劑量之二甲雙胍,或約100 mg至1000 mg或較佳500 mg至1000 mg一天一或兩次或約500 mg至2000 mg一天一次劑量之延遲釋放二甲雙胍。另一尤其較佳實例為約1-10 mg、15 mg、30 mg或45 mg一天一次劑量之吡格列酮。另一尤其較佳實例為約10 mg至50 mg或至多100 mg一天一至三次劑量之米格列醇。
降低血液中脂質含量之組合搭配物之實例為HMG-CoA還原酶抑制劑,諸如辛伐他汀(simvastatin)、阿托伐他汀(atorvastatin)、洛伐他汀(lovastatin)、氟伐他汀(fluvastatin)、普伐他汀(pravastatin)及羅素他汀(rosuvastatin);纖維酸酯,諸如苯紮貝特(bezafibrate)、非諾貝特(fenofibrate)、氯貝丁酯(clofibrate)、吉非羅齊(gemfibrozil)、依託貝特(etofibrate)及(etofyllinclofibrate);菸鹼酸及其衍生物,諸如阿昔莫司(acipimox);PPAR-α促效劑;PPAR-δ促效劑;醯基輔酶A:膽固醇醯基轉移酶(ACAT;EC2.3.1.26)抑制劑,諸如阿伐麥布(avasimibe);膽固醇再吸收抑制劑,諸如依折麥布(ezetimib);與膽汁酸結合之物質,諸如消膽胺(cholestyramine)、考來替潑(colestipol)及考來維侖(colesevelam);膽汁酸轉移抑制劑;HDL調節活性物質,諸如D4F、逆向D4F、LXR調節活性物質及FXR調節活性物質;CETP抑制劑,諸如托徹普(torcetrapib)、JTT-705或來自WO 2007/005572之化合物12;LDL受體調節劑;及ApoB100反義RNA。一尤其較佳實例為約1 mg至40 mg或10 mg至80 mg一天一次劑量之阿托伐他汀。
降血壓之組合搭配物之實例為β-阻斷劑,諸如阿廷諾(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,諸如二氫氯噻嗪、氯噻酮(chlortalidon)、氯磺水楊胺(xipamide)、呋喃苯胺酸(furosemide)、吡咯他尼(piretanide)、托拉塞米(torasemide)、螺內酯(spironolactone)、依普利酮(eplerenone)、胺氯吡嗪脒(amiloride)及胺苯喋啶(triamterene);鈣通道阻斷劑,諸如胺氯地平(amlodipine)、硝苯吡啶(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)、樂康比啶(lercanipidine)、馬尼地平(manidipine)、伊拉地平(isradipine)、尼伐地平(nilvadipine)、異搏定(verapamil)、加洛帕米(gallopamil)及硫氮酮(diltiazem);ACE抑制劑,諸如雷米普利(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),諸如替米沙坦(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)。尤其較佳之實例為每天50 mg至200 mg劑量之美托洛爾、每天2.5 mg至10 mg劑量之胺氯地平、每天2.5 mg至15 mg劑量之雷米普利、每天80 mg至160 mg劑量之纈沙坦及每天20 mg至320 mg或40 mg至160 mg劑量之替米沙坦。
增加血液中HDL含量之組合搭配物之實例為膽固醇酯轉移蛋白(CETP)抑制劑;內皮脂肪酶抑制劑;ABC1調節劑;LXRα拮抗劑;LXRβ促效劑;PPAR-δ促效劑;LXRα/β調節劑,及增加脂蛋白本體A-I之表現及/或血漿濃度之物質。
用於治療肥胖之組合搭配物之實例為諾美婷(sibutramine);四氫利普司他汀(tetrahydrolipstatin)(奧利司他(orlistat));艾利沙美(alizyme);右芬氟拉明(dexfenfluramine);阿索開(axokine);大麻鹼受體1拮抗劑,諸如CB1拮抗劑利蒙本特(rimonobant);MCH-1受體拮抗劑;MC4受體促效劑;NPY5以及NPY2拮抗劑;β3-AR促效劑,諸如SB-418790及AD-9677;5HT2c受體促效劑,諸如APD 356;肌肉抑制素(myostatin)抑制劑;Acrp30及脂締素(adiponectin);硬脂醯輔酶A脫飽和酶(SCD1)抑制劑;脂肪酸合成酶(FAS)抑制劑;CCK受體促效劑;胃內激素(Ghrelin)受體調節劑;Pyy3-36;阿來新(orexin)受體拮抗劑;及特索芬辛(tesofensine)。
用於治療動脈粥樣硬化之組合搭配物之實例為磷脂酶A2抑制劑;酪胺酸-激酶之抑制劑(50 mg至600 mg),諸如PDGF-受體-激酶(參看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。
用於治療心臟衰竭之組合搭配物之實例為β-阻斷劑,諸如阿廷諾、比索洛爾、塞利洛爾及美托洛爾;利尿劑,諸如二氫氯噻嗪、氯噻酮、氯磺水楊胺、呋喃苯胺酸、吡咯他尼、托拉塞米、螺內酯、依普利酮、胺氯吡嗪脒及胺苯喋啶;ACE抑制劑,諸如雷米普利、賴諾普利、西拉普利、喹那普利、卡托普利、依那普利、貝那普利、培哚普利、福辛普利及群多普利;以及血管緊張素II受體阻斷劑(ARB),諸如替米沙坦、坎地沙坦、纈沙坦、洛沙坦、厄貝沙坦、奧美沙坦及依普羅沙坦;心糖苷,諸如地高辛(digoxin)及毛地黃毒苷(digitoxin);組合α/β-阻斷劑,諸如卡維地洛(carvedilol);B-型利尿鈉肽(BNP)及BNP-衍生之肽及BNP-融合產物。尤其較佳之實例為每天50 mg至200 mg劑量之美托洛爾、每天2.5 mg至15 mg劑量之雷米普利、每天80 mg至160 mg劑量之纈沙坦、每天20 mg至320 mg或40 mg至160 mg劑量之替米沙坦、25-100 mg劑量之依普利酮、每天0.25 mg至0.6 mg劑量之地高辛、3.25 mg至100 mg劑量之卡維地洛、呈快速注射形式2 μg/kg隨後0.01 μg/kg/min劑量之BNP(例如奈西立(nesiritide))。
包含選定DPP IV抑制劑之藥物組合含有例如1.75 mg至10.5 mg格列本脲、500 mg至3000 mg甲苯磺丁脲、0.5-6 g格列美脲、2.5 mg至40 mg格列吡嗪、1-4×30 mg格列喹酮、至3×25 mg格列波脲、80 mg至160 mg格列齊特;500 mg至1000 mg,較佳500 mg、850 mg或1000 mg二甲雙胍;60 mg至180 mg那格列奈;0.25 mg至4 mg瑞格列奈;2 mg至45 mg噻唑烷二酮;200 mg至600 mg metaglidase;2.5 mg至5 mg PPAR γ/α調節劑;0.1 mg至100 mg α葡糖苷酶阻斷劑;1-250 IU胰島素;15 μg至120 μg普蘭林肽;5 mg至80 mg士他汀(statin);50 mg至1000 mg纖維酸酯;1000 mg至3000 mg菸鹼酸或衍生物;約250 mg阿昔莫司(acipimox);約10 mg膽固醇再吸收抑制劑;0.5 g至30 g膽汁酸結合物質;10 mg至600 mg且較佳10 mg至120 mg CETP抑制劑;2.5 mg至100 mg β-阻斷劑;3 mg至200 mg利尿劑;2.5 mg至500 mg鈣通道阻斷劑;1 mg至40 mg ACE抑制劑;5 mg至600 mg血管緊張素II受體阻斷劑;10 mg至15 mg諾美婷;約120 mg奧利司他;15 mg至30 mg右芬氟拉明;或5 mg至20 mg大麻鹼受體拮抗劑,25 mg至100 mg劑量之依普利酮;每天0.25 mg至0.6 mg劑量之地高辛;3.25 mg至100 mg劑量之卡維地洛;呈快速注射形式2 μg/kg隨後0.01 μg/kg/min劑量之BNP(例如奈西立)。
本發明之DPPIV抑制劑對治療特徵為病理性空腹葡萄糖及/或葡萄糖耐受性異常之糖尿病前期的功效可使用臨床研究來測試。在歷經較短時期(例如2-4週)之研究中,藉由在研究療法期結束後測定空腹葡萄糖值及/或餐後或負荷測試(口服葡萄糖耐受性測試或接受指定餐點後之食物耐受性測試)後之葡萄糖值且將其與開始研究之前的值比較及/或與安慰劑組之彼等值比較來檢驗治療之成功性。此外,果糖胺值可在療法前後測定且與初始值及/或安慰劑值相比較。空腹葡萄糖含量或非空腹葡萄糖含量顯著下降證明治療之功效。在歷經較長時期(12週或更長時間)之研究中,藉由測定HbA1c值,與初始值及/或與安慰劑組之值比較來測試治療之成功性。與初始值及/或安慰劑值相比,HbA1c值之顯著變化證明DPP IV抑制劑對治療糖尿病前期之功效。
治療患有病理性空腹葡萄糖及/或葡萄糖耐受性異常(糖尿病前期)之患者亦追求預防轉變成顯性第二型糖尿病之目標。治療之功效可在糖尿病前期患者經活性物質或活性物質之組合,或安慰劑或非藥物療法或其他藥劑治療較長時期(例如1-5年)之比較臨床研究中探查。在療法期間及在療法結束時,藉由測定空腹葡萄糖及/或負荷測試(例如,oGTT)來檢測多少患者出現顯性第二型糖尿病,亦即空腹葡萄糖含量>125 mg/dl及/或根據oGTT之2 h值>199 mg/dl。與其他形式治療中之一者相比較,當以活性物質或活性物質之組合治療時,出現顯性第二型糖尿病之患者數目顯著減少時,即證明活性物質或活性物質之組合對預防糖尿病前期轉變為顯性糖尿病之功效。
用本發明之活性物質治療第二型糖尿病患者除產生葡萄糖代謝狀況短暫改善以外,從長遠上預防代謝狀況劣化。患者經本發明之活性物質或活性物質之組合治療較長時期,例如1-6年,且與已經其他抗糖尿病藥劑治療之患者相比較可觀察到此結果。若未觀察到空腹葡萄糖及/或HbA1c值增加或僅觀察到其略有增加,則證明與經其他抗糖尿病藥劑治療之患者相比的治療成功。若與已經其他藥劑治療之患者相比,顯著較少百分比之經本發明之活性物質或本發明之活性物質之組合治療的患者在葡萄糖代謝位置處經受劣化(例如HbA1c值增加至>6.5%或>7%)達到指示用另外口服抗糖尿病藥劑或用胰島素或用胰島素類似物或用另一種抗糖尿病劑(例如GLP-1類似物)治療的程度,則進一步證明治療成功。
在進行不同持續時間(例如2週至12個月)之臨床研究中,治療成功係使用高胰島素血症正常葡萄糖血症葡萄糖夾鉗研究來檢查。在研究結束時,與初始值相比或與安慰劑組或給定不同療法之組相比,葡萄糖輸注速率之顯著升高證明活性物質或活性物質之組合對治療胰島素抗性之功效。
在對第二型糖尿病患者進行不同持續時間(例如2週至60個月)之臨床研究中,治療成功係藉由測定總膽固醇、LDL-膽固醇、HDL-膽固醇及血漿甘油三酯來檢查。在研究期間或在研究結束時,與初始值相比或與安慰劑組或給定不同療法之組相比,總膽固醇、LDL-膽固醇或血漿甘油三酯顯著下降及/或HDL-膽固醇含量升高證明活性物質或活性物質之組合對治療糖尿病性血脂異常或高脂質血症之功效。
在進行不同持續時間(例如1天至24個月)之臨床研究中,高血糖症患者之治療成功係藉由測定空腹葡萄糖或非空腹葡萄糖(例如在餐後或在oGTT或確定餐之負荷測試之後)來檢查。在研究期間或在研究結束時,與初始值相比或與安慰劑組或給定不同療法之組相比,此等葡萄糖值顯著下降證明活性物質或活性物質之組合對治療高血糖症之功效。
在進行較短時期(例如2-4週)之臨床研究中,治療成功係藉由在研究之治療時期結束時測定空腹葡萄糖值及/或在餐後或在負荷測試(確定餐後之口服葡萄糖耐受性測試或食物耐受性測試)之後的葡萄糖值且將其與開始研究之前的值比較及/或與安慰劑組之值比較來檢查。此外,果糖胺值可在治療前後測定且與初始值及/或安慰劑值相比較。空腹葡萄糖含量或非空腹葡萄糖含量顯著下降證明活性物質或活性物質之組合之功效。
在進行較長時間之研究(12週或更長時間)中,治療成功係測定HbA1c值(與初始值及安慰劑組相比)來檢查。與起始值及/或安慰劑值相比,HbA1c值之顯著變化證明活性物質或活性物質之組合對治療妊娠性糖尿病之功效。
妊娠性糖尿病患者在懷孕之後感染顯性第二型糖尿病之風險顯著增加。療法可具有預防向顯性第二型轉變之目標。為達成此目的,有妊娠性糖尿病史之女性經本發明之活性物質或本發明之活性物質之組合或經安慰劑或經非藥物療法或經其他藥劑治療較長時期(例如1-4年)。在治療期間及在治療結束時,藉由測定空腹葡萄糖及/或藉由負荷測試(例如,oGTT)來進行檢查以確定多少患者已發展顯性第二型糖尿病(空腹葡萄糖含量>125 mg/dl及/或oGTT後之2 h值>199 mg/dl)。與不同類型之療法相比,當以本發明之活性物質或本發明之活性物質之組合治療時,發展顯性第二型糖尿病之患者數目顯著減少證明活性物質或活性物質之組合對預防有妊娠性糖尿病史之女性之顯性糖尿病的功效。
用本發明之活性物質或本發明之活性物質之組合對第二型糖尿病或糖尿病前期患者的治療預防或減少微血管併發症(例如糖尿病性神經病、糖尿病性視網膜病、糖尿病性腎病、糖尿病足、糖尿病性潰瘍)或大血管併發症(例如心肌梗塞、急性冠狀動脈徵候群、不穩定型心絞痛、穩定型心絞痛、中風、周邊動脈阻塞性疾病、心肌病、心臟衰竭、心律異常、血管再狹窄)。第二型糖尿病或糖尿病前期患者經本發明之活性物質或本發明之活性物質之組合長期治療,例如歷時1-6年,且將其與已經其他抗糖尿病藥劑或經安慰劑治療之患者相比較。較少數目之單一併發症或多個併發症可證明與已經其他抗糖尿病藥劑或經安慰劑治療之患者相比的治療成功。在大血管事件、糖尿病足及/或糖尿病性潰瘍之情況下,藉由既往病歷及多種測試方法來計數。在糖尿病性視網膜病之情況下,治療成功係藉由電腦控制照明及評估眼睛背景或其他眼科方法來測定。在糖尿病性神經病之情況下,除既往病歷及臨床檢查以外,神經傳導率可例如使用校準音叉來量測。對於糖尿病性腎病,可在研究開始之前、在研究期間及在研究結束時探查以下參數:白蛋白之分泌、肌酸酐清除率、血清肌酸酐值、血清肌酸酐值倍增所歷經之時間、直至透析變成必需所歷經之時間。
本發明之活性物質或活性物質之組合之功效可在具有不同進行時間(例如12週至6年)之臨床研究中藉由測定空腹葡萄糖或非空腹葡萄糖(例如在餐後或在oGTT或確定餐之負荷測試之後)或HbA1c值來測試。在研究期間或在研究結束時,與初始值相比或與安慰劑組或給定不同療法之組相比,此等葡萄糖值或HbA1c值顯著下降證明活性物質或活性物質之組合對治療代謝症候群之功效。其實例為與在研究開始時之起始值相比或與經安慰劑或不同療法治療之患者組相比,收縮壓及/或舒張壓降低、血漿甘油三酯下降、總膽固醇或LDL膽固醇減少、HDL膽固醇增加或體重減輕。
為製備粒化溶液,在周圍溫度下將共聚乙烯吡咯酮溶解於純水中。將DPP IV抑制劑、甘露糖醇、預膠化澱粉及玉米澱粉在合適之混合器中混合以製備預混物。將該預混物用粒化溶液潤濕且隨後在混合器中以高剪切速率粒化。將濕顆粒經由篩孔尺寸為1.6 mm之篩進行篩檢。將該等顆粒在約60℃下在流化床乾燥器中乾燥直至獲得2-4%之乾燥失重值。壓製加工過之混合物以形成錠劑核心。
在合適之混合器中,在周圍溫度下將羥丙基甲基纖維素、聚乙二醇、滑石粉、二氧化鈦及氧化鐵懸浮於純水中以製備錠劑包衣用懸浮液。將錠劑核心用此懸浮液包衣直至獲得3%之重量增加。舉例而言,以下錠劑組合物可以此方式獲得:
此實驗係在成功分離蘭格罕氏島或胰腺β細胞之後,藉由將其在含有1 nmol/l至1 μmol/l濃度,較佳1 nmol/l及100 nmol/l濃度之DPP IV抑制劑的介質中儲存、運輸或培養以供將來移植而進行。
此外,在蘭格罕氏島或胰腺β細胞移植之後,患者(且此等亦可為動物)經DPP IV抑制劑以介於1 mg與200 mg之間的日劑量,較佳以5 mg及100 mg劑量之DPP IV抑制劑治療以增強該等移植物之生命力及分泌能力。此藉由在用葡萄糖或增加胰島素分泌之另一種藥劑刺激之後分析胰島素分泌來測試。此外,品質改良亦可在活體外或動物模型中使用Diabetologia 42:566,1999或Diabetes 48:738 1999(investigation of apoptosis and inhibition thereof)中所述之TUNEL技術來檢查。
對於治療第二型糖尿病或糖尿病前期而言,本發明之DPP IV抑制劑可與抗糖尿病活性物質二甲雙胍以自由組合或固定組合形式組合於錠劑中。治療有效劑量之DPP IV抑制劑(例如介於0.1 mg及100 mg之間的劑量)可與不同劑量之二甲雙胍,例如與單次劑量為500 mg、850 mg或1000 mg之二甲雙胍,總日劑量為500-2850 mg之二甲雙胍,或與500 mg、1000 mg、1500 mg或2000 mg延遲釋放形式之二甲雙胍組合。與二甲雙胍之該組合之臨床功效可在臨床研究中進行測試。對此,第二型糖尿病或糖尿病前期患者經單獨DPP IV抑制劑或經單獨二甲雙胍或經DPP IV抑制劑與二甲雙胍之組合治療。治療持續介於2週與6年之間的時間。DPP-IV抑制劑與二甲雙胍之組合引起空腹葡萄糖及/或非空腹葡萄糖及/或HbA1c值與單獨DPP IV抑制劑或單獨二甲雙胍相比顯著更大程度減少可證明該組合適當且有效。
對於治療第二型糖尿病或糖尿病前期而言,本發明之DPP IV抑制劑可與包含格列酮或噻唑烷二酮(例如吡格列酮或羅格列酮)之抗糖尿病活性物質組以自由組合或固定組合形式組合於錠劑中。治療有效劑量之DPP IV抑制劑(例如介於0.1 mg與100 mg之間劑量)可與不同劑量之吡格列酮(15 mg、30 mg或45 mg)或羅格列酮(2 mg、4 mg或8 mg,一天給予一或兩次)組合。與羅格列酮或吡格列酮之該組合之臨床功效可在臨床研究中進行測試。對此,第二型糖尿病或糖尿病前期患者經單獨DPP IV抑制劑或經單獨羅格列酮或吡格列酮或經DPP IV抑制劑與羅格列酮或吡格列酮之組合治療。治療持續介於2週與6年之間的時間。DPP-IV抑制劑與羅格列酮或吡格列酮之組合引起空腹葡萄糖及/或非空腹葡萄糖及/或HbA1c值與單獨DPP IV抑制劑或單獨羅格列酮或吡格列酮相比顯著更大程度減少可證明該組合適當且有效。
對於治療第二型糖尿病或糖尿病前期而言,本發明之DPP IV抑制劑可與包含SGLT-2抑制劑之抗糖尿病活性物質組以自由組合或固定組合形式組合於錠劑中。治療有效劑量之DPP IV抑制劑(例如介於0.1 mg與100 mg之間的劑量)可與不同劑量之SGLT-2抑制劑(0.5 mg至1000 mg)組合。與SGLT-2抑制劑之該組合之臨床功效可在臨床研究中進行測試。對此,第二型糖尿病或糖尿病前期患者經單獨DPP IV抑制劑或經單獨SGLT-2抑制劑或經DPP IV抑制劑與SGLT-2抑制劑之組合治療。治療持續介於2週與6年之間的時間。DPP-IV抑制劑與SGLT-2抑制劑之組合引起空腹葡萄糖及/或非空腹葡萄糖及/或HbA1c值與單獨DPP IV抑制劑或單獨SGLT-2抑制劑相比顯著更大程度減少可證明該組合適當且有效。
對於治療第二型糖尿病或糖尿病前期或代謝症候群患者而言,本發明之DPP IV抑制劑可與抗高血壓活性物質以自由組合或固定組合形式組合於錠劑中。治療有效劑量之DPP IV抑制劑(例如介於0.1 mg與100 mg之間的劑量)可與不同劑量之ACE-抑制劑(例如2.5 mg至15 mg雷米普利)、AT1-受體拮抗劑(例如20 mg至160 mg替米沙坦)、β-阻斷劑(例如50 mg至200 mg美托洛爾)或利尿劑(例如12.5 mg至25 mg二氫氯噻嗪)組合。與抗高血壓劑之該組合之臨床功效可在臨床研究中進行測試。對此,第二型糖尿病或糖尿病前期或代謝症候群患者經單獨DPP IV抑制劑或經單獨抗高血壓劑或經DPP IV抑制劑與抗高血壓劑之組合治療。治療持續介於2週與6年之間的時間。DPP-IV抑制劑與抗高血壓劑之組合降低空腹葡萄糖及/或非空腹葡萄糖及/或HbA1c值之程度至少與單獨DPP IV抑制劑差不多,且若DPP-IV抑制劑與抗高血壓劑之組合降低收縮壓及/或舒張壓之程度至少與單獨抗高血壓劑差不多,則可證明該組合適當且有效。
對於治療第二型糖尿病或糖尿病前期或代謝症候群或糖尿病性血脂異常或高脂質血症患者而言,本發明之DPP IV抑制劑可與降脂劑/HDL-升高劑以自由組合或固定組合形式組合於錠劑中。治療有效劑量之DPP IV抑制劑(例如介於0.1 mg與100 mg之間的劑量)可與不同劑量之士他汀(例如10 mg至80 mg阿托伐他汀或10 mg至80 mg辛伐他汀)、纖維酸酯(例如非諾貝特)、膽固醇吸收抑制劑或與諸如CETP-抑制劑(例如托徹普10 mg至120 mg一天一次或120 mg每天兩次)之HDL-升高物質組合。與降脂劑/HDL-升高劑之該組合之臨床功效可在臨床研究中進行測試。對此,第二型糖尿病或糖尿病前期或代謝症候群或糖尿病性血脂異常或高脂質血症患者經單獨DPP IV抑制劑或經單獨降脂劑/HDL-升高劑或經DPP IV抑制劑與降脂劑/HDL-升高劑之組合治療。治療持續介於2週與6年之間的時間。DPP-IV抑制劑與降脂劑/HDL-升高劑之組合降低空腹葡萄糖及/或非空腹葡萄糖及/或HbA1c值之程度至少與單獨DPP IV抑制劑差不多,且若DPP-IV抑制劑與降脂劑/HDL-升高劑之組合降低總膽固醇或LDL-膽固醇或血漿甘油三酯之程度或增加HDL-膽固醇值之程度至少與單獨降脂劑/HDL-升高劑差不多,則可證明該組合適當且有效。
對於治療急性心臟衰竭患者而言,本發明DPP IV抑制劑可與有利影響心臟衰竭之物質以自由組合或固定組合形式組合於錠劑中。治療有效劑量之DPP IV抑制劑(例如介於0.1 mg與100 mg之間的劑量)可與不同劑量之ACE-抑制劑(例如2.5 mg至15 mg雷米普利)、AT1-受體拮抗劑(例如20 mg至160 mg替米沙坦)、β-阻斷劑(例如50 mg至200 mg美托洛爾)、組合α/β-阻斷劑(例如3.25 mg至100 mg卡維地洛)、利尿劑(例如12.5 mg至25 mg二氫氯噻嗪)、鹽皮質激素受體拮抗劑(例如25 mg至100 mg依普利酮;及/或B-型利尿鈉肽(BNP))(例如呈快速注射形式22 μg/kg隨後0.01 μg/kg/min奈西立)、BNP衍生之肽或BNP-融合產物組合。BNP與DPP-IV抑制劑之組合在活體內產生較高濃度之全長BNP(1-32)。指定組合之臨床功效可在臨床研究中進行測試。治療持續介於1天與6年之間的時間。與其他療法相比,該組合引起臨床狀況顯著改善(較高心臟射血輸出及/或肺充血逆轉、及/或肺楔壓逆轉、及/或由急性心臟衰竭引起之死亡率降低)可證明該組合有效治療急性心臟衰竭。
本發明之DPP IV抑制劑可用以治療慢性心臟衰竭患者。此治療在活體內產生較高濃度之內源性全長BNP(1-32)。此治療之臨床功效可在臨床研究中進行測試。治療持續介於2週與6年之間的時間。與不同治療或安慰劑相比,本發明之DPP-IV抑制劑引起臨床狀況顯著改善(歸因於急性心臟衰竭之住院治療頻率較低、行走較長距離之能力、較高測力學負荷能力、較高心臟射血輸出及/或肺充血逆轉、及/或由慢性心臟衰竭引起之死亡率降低)可證明該組合有效治療慢性心臟衰竭。
Claims (64)
- 一種式(I)之DPP IV抑制劑或其鹽中之一者的用途,
- 一種式(I)之DPP IV抑制劑或其鹽中之一者的用途,
- 如請求項2之用途,其中藉由使用該藥劑,使儘管治療卻仍存在之葡萄糖代謝受損、儘管治療仍存在之HbA1c值升高、儘管治療仍存在之空腹葡萄糖值異常、胰島素治療之需求、糖尿病足、糖尿病相關潰瘍或大血管併發症之風險得以降低。
- 如請求項3之用途,其中該大血管併發症係選自心肌梗塞、急性冠狀動脈徵候群、不穩定型心絞痛、穩定型心絞痛、出血性中風或缺血性中風、周邊動脈阻塞性疾病、心肌病、左心功能不全、右心功能不全、綜合性心臟衰竭、心律異常及血管再狹窄。
- 如請求項1之用途,其中該藥劑係用於治療性處理妊娠性糖尿病。
- 如請求項1之用途,其中該藥劑係用於治療性處理腎上腺素激導性餐後徵候群。
- 如請求項1之用途,其中該藥劑係用於治療性處理心臟衰竭。
- 如請求項2之用途,其中藉由使用該藥劑,降低HbA1c值進一步升高、空腹葡萄糖惡化及對胰島素療法之需求之風險。
- 如請求項1至8中任一項之用途,其中該DPP IV抑制劑係與選自其他抗糖尿病藥之活性物質;降低血糖含量之活性物質;降低血液中脂質含量之活性物質;提高血液中HDL含量之活性物質;降低血壓之活性物質;或指定用 於治療動脈粥樣硬化或肥胖之活性物質組合。
- 如請求項9之用途,其中該DPP IV抑制劑係與另一種抗糖尿病藥或降血壓活性物質組合。
- 如請求項10之用途,其中該DPP IV抑制劑係與二甲雙胍(metformin)、磺醯基脲、那格列奈(nateglinide)、瑞格列奈(repaglinide)、噻唑烷二酮、α-葡糖苷酶阻斷劑、胰島素或胰島素類似物、GLP-1或GLP-1類似物、ACE抑制劑、血管緊張素II受體阻斷劑(ARB)、β-阻斷劑或利尿劑組合。
- 如請求項1至11中任一項之用途,其中該DPP IV抑制劑係以2.5mg至10mg之劑量經口投與。
- 如請求項1至11中任一項之用途,其中該DPP IV抑制劑係以2.5mg或5mg之劑量使用或存在而用於經口投與。
- 如請求項1至11中任一項之用途,其中該DPP IV抑制劑之日口服劑量為5mg。
- 一種式(I)之DPP IV抑制劑或其鹽中之一者的用途,
- 如請求項15之用途,其中該DPP IV抑制劑係以2.5mg至10mg之劑量經口投與。
- 如請求項15之用途,其中製備DPP IV抑制劑與另一種抗糖尿病活性物質或降血壓活性物質之藥劑組合。
- 如請求項15之用途,其中DPP IV抑制劑係與二甲雙胍、磺醯基脲、那格列奈(nateglinide)、瑞格列奈(repaglinide)、噻唑烷二酮、α-葡糖苷酶阻斷劑、胰島素或胰島素類似物、或GLP-1及GLP-1類似物組合。
- 如請求項15之用途,其中製備DPP IV抑制劑與二甲雙胍、吡格列酮、米格列醇、阿托伐他汀、纈沙坦或替米沙坦之藥劑組合。
- 如請求項15之用途,其中該藥劑組合係用於治療性處理已經確診生理功能性病症之患者,該生理功能性病症係選自糖尿病足、糖尿病相關潰瘍、妊娠性糖尿病、心臟衰竭及腎上腺素激導性餐後徵候群。
- 如請求項15之用途,其中藉由使用該藥劑組合,使儘管治療卻仍存在之葡萄糖代謝受損、儘管治療仍存在之HbA1c值升高、儘管治療仍存在之空腹葡萄糖值異常、 胰島素治療之需求、糖尿病足、糖尿病相關潰瘍或大血管併發症之風險得以降低。
- 如請求項21之用途,其中該大血管併發症係選自心肌梗塞、急性冠狀動脈徵候群、不穩定型心絞痛、穩定型心絞痛、出血性中風或缺血性中風、周邊動脈阻塞性疾病、心肌病、左心功能不全、右心功能不全、綜合性心臟衰竭、心律異常及血管再狹窄。
- 如請求項18或19之用途,其中二甲雙胍之劑量為300mg至1000mg一天一次或兩次,或延遲釋放二甲雙胍之劑量為500mg至1000mg一天一或兩次或500mg至2000mg一天一次。
- 如請求項18或19之用途,其中二甲雙胍之劑量係以500mg、850mg或1000mg之二甲雙胍作為單次劑量而二甲雙胍之總日劑量為500-2850mg,或延遲釋放形式之二甲雙胍之劑量為500mg、1000mg、1500mg或2000mg。
- 如請求項15至22中任一項之用途,其中該藥劑組合呈自由組合之形式。
- 如請求項15至22中任一項之用途,其中該藥劑組合呈固定組合之形式。
- 如請求項26之用途,其中該固定組合係為錠劑或膠囊。
- 如請求項15至22中任一項之用途,其中該DPP IV抑制劑係以2.5mg或5mg之劑量使用或存在而用於經口投與。
- 如請求項15至22中任一項之用途,其中該DPP IV抑制劑之日口服劑量為5mg。
- 一種用於蘭格罕氏島或β細胞之分離介質或儲存介質,其特徵為該介質含有1nmol/l至1μmol/l之DPP IV抑制劑以用於增強該等細胞之生命力及分泌能力,其特徵為該DPP IV抑制劑之結構如式(I)或其鹽中之一者所示,
- 一種增強蘭格罕氏島或β細胞之生命力及分泌能力之方法,其特徵為在該等蘭格罕氏島或β細胞之分離及移植階段期間,將如請求項30所定義之DPP IV抑制劑以介於1nmol/l與1μmol/l之間的濃度添加至該分離及儲存介質中。
- 一種以如請求項15所定義之DPP IV抑制劑於製造供治療與糖尿病相關之心臟衰竭之藥劑的用途。
- 如請求項1至8、15至22及32中任一項之用途,其中該DPP IV抑制劑係為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-哌啶-1-基)-黃嘌呤。
- 一種如請求項15所定義之DPP IV抑制劑與活性物質之藥劑組合,該DPP IV抑制劑係以2.5mg或5mg之劑量經口 投與,該活性物質係選自其他抗糖尿病藥之活性物質;降低血糖含量之活性物質;降低血液中脂質含量之活性物質;提高血液中HDL含量之活性物質;降低血壓之活性物質;及指定用於治療動脈粥樣硬化或肥胖之活性物質活性物質。
- 一種DPP IV抑制劑與二甲雙胍之藥劑組合,該DPP IV抑制劑係以2.5mg或5mg之劑量經口投與,其中該DPP IV抑制劑為式(I)或其鹽中之一者之DPP IV抑制劑,其特徵為R1 表示(4-甲基-喹唑啉-2-基)甲基,及R2 表示3-(R )-胺基-哌啶-1-基。
- 一種DPP IV抑制劑與格列酮或噻唑烷二酮之藥劑組合,該DPP IV抑制劑係以2.5mg或5mg之劑量經口投與,其中該DPP IV抑制劑為式(I)或其鹽中之一者之DPP IV抑制劑,其特徵為R1 表示(4-甲基-喹唑啉-2-基)甲基,及R2 表示3-(R )-胺基-哌啶-1-基。
- 如請求項36之藥劑組合,其中該格列酮為吡格列酮。
- 一種DPP IV抑制劑與替米沙坦之藥劑組合,其中該DPP IV抑制劑為式(I)或其鹽中之一者之DPP IV抑制劑,其特徵為R1 表示(4-甲基-喹唑啉-2-基)甲基,及R2 表示3-(R )-胺基-哌啶-1-基。
- 如請求項35之藥劑組合,其中二甲雙胍之劑量為300mg 至1000mg一天一次或兩次,或延遲釋放二甲雙胍之劑量為500mg至1000mg一天一或兩次或500mg至2000mg一天一次。
- 如請求項35之藥劑組合,其中二甲雙胍之劑量係以500mg、850mg或1000mg之二甲雙胍作為單次劑量而二甲雙胍之總日劑量為500-2850mg,或延遲釋放形式之二甲雙胍之劑量為500mg、1000mg、1500mg或2000mg。
- 如請求項34至40中任一項之藥劑組合,其中該藥劑組合呈自由組合之形式。
- 如請求項34至40中任一項之藥劑組合,其中該藥劑組合呈固定組合之形式。
- 如請求項42之藥劑組合,其中該固定組合係為錠劑或膠囊。
- 如請求項34至40中任一項之藥劑組合,其中該DPP IV抑制劑之日口服劑量為5mg。
- 一種DPP IV抑制劑之用途,該DPP IV抑制劑係為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-哌啶-1-基)-黃嘌呤或其治療活性鹽,其係用於製備供治療糖尿病前期或第二型糖尿病的藥劑,其中該DPP IV抑制劑在錠劑中係與二甲雙胍或格列酮或噻唑烷二酮,以自由組合形式或固定組合形式組合,該DPP IV抑制劑係以0.5mg至10mg之劑量經口投與。
- 如請求項45之用途,其中該DPP IV抑制劑係以2.5mg至 10mg之劑量經口投與。
- 如請求項45之用途,其中該DPP IV抑制劑係以2.5mg或5mg之劑量經口投與。
- 如請求項45之用途,其中該DPP IV抑制劑之日口服劑量為5mg。
- 如請求項45之用途,其中該格列酮為吡格列酮。
- 一種DPP IV抑制劑之用途,該DPP IV抑制劑係為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-哌啶-1-基)-黃嘌呤,或其治療活性鹽,其係用於製備供預防或減少在第二型糖尿病或糖尿病前期患者中之大血管併發症的藥劑,該DPP IV抑制劑視情況與另一種活性物質組合。
- 如請求項50之用途,其中該大血管併發症係選自心肌梗塞、急性冠狀動脈徵候群、不穩定型心絞痛、穩定型心絞痛、中風、周邊動脈阻塞性疾病、心肌病、心臟衰竭、心律異常及血管再狹窄。
- 如請求項50或51之用途,其中該患者係經1至6年之長時期治療。
- 一種DPP IV抑制劑之用途,該DPP IV抑制劑係為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-哌啶-1-基)-黃嘌呤,或其治療活性鹽,其係用於製備供治療第二型糖尿病的藥劑,該DPP IV抑制劑係以0.5mg至10mg之劑量經口投與。
- 如請求項53之用途,其中該DPP IV抑制劑係以2.5mg至 10mg之劑量經口投與。
- 如請求項53之用途,其中該DPP IV抑制劑係以2.5mg或5mg之劑量經口投與。
- 如請求項53之用途,其中該DPP IV抑制劑之日口服劑量為5mg。
- 一種DPP IV抑制劑之用途,該DPP IV抑制劑係為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-哌啶-1-基)-黃嘌呤,或其治療活性鹽,其係用於製備供治療患有第二型糖尿病或糖尿病前期或患有代謝症候群之患者的藥劑,其中該DPP IV抑制劑在錠劑中係與ACE-抑制劑、AT1-受體拮抗劑、β-阻斷劑或利尿劑,以自由組合形式或固定組合形式組合,該DPP IV抑制劑係以0.5mg至10mg之劑量經口投與。
- 如請求項57之用途,其中該DPP IV抑制劑係以2.5mg至10mg之劑量經口投與。
- 如請求項57之用途,其中該DPP IV抑制劑係以2.5mg或5mg之劑量經口投與。
- 如請求項57之用途,其中該DPP IV抑制劑之日口服劑量為5mg。
- 一種DPP IV抑制劑之用途,該DPP IV抑制劑係為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-哌啶-1-基)-黃嘌呤,或其治療活性鹽,其係用於製備供治療患有心臟衰竭之患者的藥劑,其中該DPP IV抑制劑在錠劑中可與ACE-抑制劑、AT1-受 體拮抗劑、β-阻斷劑、組合α/β-阻斷劑、利尿劑、鹽皮質激素受體拮抗劑;及/或B-型利尿鈉肽(BNP)、BNP衍生之肽或BNP-融合產物,以自由組合形式或固定組合形式組合,該DPP IV抑制劑係以0.5mg至10mg之劑量經口投與。
- 如請求項61之用途,其中該DPP IV抑制劑係以2.5mg至10mg之劑量經口投與。
- 如請求項61之用途,其中該DPP IV抑制劑係以2.5mg或5mg之劑量經口投與。
- 如請求項61之用途,其特徵為該DPP IV抑制劑之日口服劑量為5mg。
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TW200404542A (en) * | 2002-08-21 | 2004-04-01 | Boehringer Ingelheim Pharma | 8-[3-Amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
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