TWI842924B - Gpr119致效劑及dpp-4抑制劑的藥物組合及藥物套組 - Google Patents
Gpr119致效劑及dpp-4抑制劑的藥物組合及藥物套組 Download PDFInfo
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- TWI842924B TWI842924B TW109122094A TW109122094A TWI842924B TW I842924 B TWI842924 B TW I842924B TW 109122094 A TW109122094 A TW 109122094A TW 109122094 A TW109122094 A TW 109122094A TW I842924 B TWI842924 B TW I842924B
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- dpp
- pharmaceutically acceptable
- combination
- inhibitor
- gpr119 agonist
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Abstract
本發明涉及GPR119受體致效劑與DPP-4抑制劑的組合及其在治療或預防心血管疾病及代謝疾病中的用途，所述疾病包括糖尿病、非酒精性脂肪肝病(non-alcoholic fatty liver disease,NAFLD)、NAFL、NASH、血脂異常以及與之相關的病症。
Description
本發明係關於GPR119致效劑與DPP-4抑制劑的組合，以及這些組合在治療及/或預防心血管疾病及代謝疾病，包括糖尿病、非酒精性脂肪肝病(non-alcoholic fatty liver disease,NAFLD)、NAFL、NASH、血脂異常以及與之相關的病症中的用途。
糖尿病是一種與生活方式有關的疾病，其係源於多種致病因子。它的特徵是在禁食狀態下或口服葡萄糖耐量試驗期間給予葡萄糖後，血漿葡萄糖(高血糖)濃度升高。有兩種公認的糖尿病形式：第1型及第2型糖尿病。胰島素是調節葡萄糖利用的激素，在第1型糖尿病或胰島素依賴型糖尿病(insulin-dependent diabetes mellitus,IDDM)中，患者產生的胰島素很少或根本不產生胰島素。在第2型糖尿病或非胰島素依賴型糖尿病(noninsulin-dependent diabetes mellitus,T2DM)中，人體中仍會產生胰島素，並且患者在主要的胰島素敏感組織(即肌肉、肝臟及脂肪組織)中表現出對胰島素刺激葡萄糖及脂質代謝的抗性。這些患者通常具有正常的胰島素濃度，並且可能患有高胰島素血症(血
漿胰島素濃度升高)，因為他們透過分泌增加量的胰島素來補償胰島素有效性下降。
糖尿病是眼後視網膜受損的主要原因之一，並增加了白內障及青光眼的風險。它也與神經損傷有關，尤其是腿及腳，其損害了感覺疼痛的能力並導致了嚴重的感染。糖尿病也與腎臟疾病、眼睛疾病及神經系統問題的發展有關。總體而言，糖尿病併發症是全世界死亡的主要原因之一。
肥胖是熱量攝入及能量消耗之間不平衡的結果。它與胰島素抗性及糖尿病高度相關。但是，涉及肥胖-糖尿病症候群的分子機制尚不清楚。
在肥胖症的早期發展期間，增加的胰島素分泌平衡了胰島素抗性並保護患者免受高血糖症的困擾，但是幾十年後，β細胞功能惡化，並且非胰島素依賴型糖尿病在約20%的肥胖人群中發展。因此，肥胖已成為糖尿病的主要危險因素，然而，目前仍未知使一部分患者易因脂肪積累而引起胰島素分泌改變的因素。肥胖也大大增加了發展出心血管疾病的風險。
非酒精性脂肪肝病(non-alcoholic fatty liver disease,NAFLD)包括幾種肝病，包括NAFL及NASH，這是全世界最常見的肝病，其係過重及代謝症候群(例如：T2DM)的臨床表現。
T2DM的治療通常從減肥、健康飲食及運動計劃開始。儘管這些因素對於解決與糖尿病有關的心血管疾病風險的增加特別重要，但它們通常對控制糖尿病本身無效。有許多可用於治療糖尿病的藥物，包括胰島素、二甲雙胍(metformin)、磺醯脲(sulfonylureas)、阿卡波糖(acarbose)、噻唑烷二酮(thiazolidinedione)、GLP-1類似物及DPP-4抑制劑。然而，與當前可用的治療相關的缺陷包括低血糖發作、體重增加、隨著時間的推移對治療的反應性下降、胃腸道問題及水腫。因此，對於在血糖控制、疾病改善特性、降低心血管疾病
發病率及死亡率，同時顯示改善的安全性方面具有良好功效的藥物組合，存在醫學上的未滿足需求。
儘管人類中存在許多受體類別，但迄今為止，最豐富且與治療相關的是G蛋白偶聯受體(G protein-coupled receptor,GPCR)類，據估計，大約4%的蛋白質編碼基因組編碼GPCR。GPCR也被稱為七跨膜結構域受體(seven-transmembrane domain receptors)，因為它們具有共同的結構模體(structural motif)，具有七個22至24個疏水胺基酸序列，形成七個α螺旋，每個螺旋橫跨膜。進一步地，人們對基於胰島的胰島素分泌有了新的關注，其受葡萄糖依賴性胰島素分泌(glucose-dependent insulin secretion,GDIS)控制。在這方面，最近已鑑定出幾種孤兒G蛋白偶聯受體(GPCR)，它們優先在β細胞中表現並與GDIS有關。
GPR119是一種細胞表面GPCR，在人(及囓齒動物)胰島以及胰島素分泌細胞株中高度表現。已證明GPR119的活化可刺激細胞內cAMP並導致葡萄糖依賴性GLP-1及胰島素分泌(T.Soga等人，Biochem.Biophys.Res.Commun.2005,326)。合成的GPR119致效劑僅在葡萄糖升高的條件下才增加從孤立的靜態小鼠胰島中釋放胰島素的程度，並改善糖尿病小鼠及飲食誘導的肥胖(diet-induced obese,DIO)C57/B6小鼠的葡萄糖耐量，而不會引起低血糖症。
進一步地，酶DPP-4(二肽基肽酶IV)也稱為CD26，是一種絲胺酸蛋白酶，已知可導致從許多在N末端具有脯胺酸或丙胺酸殘基的蛋白質的N末端切割二肽。由於該特性，DPP-4抑制劑干擾包括肽GLP-1的生物活性肽的血漿濃度，並且被認為是具有治療糖尿病的前景的藥物。
US 10,208,030 B2公開了作為GPR119受體致效劑的新型化合物，其透過引用整體併入本文。
PCT公開號WO 2006/076231、WO 2007/120702、WO 2010/029089、WO 2011/113947、WO 2010/029089及WO 2011/113947公開了可用於治療及預防代謝性疾病的藥物組合，包括糖尿病(I型及II型)以及與之相關的病症。
儘管從先前習知的參考文獻中已知各種組合，但是仍然需要使用GPR119致效劑及DPP-4抑制劑來治療或預防心血管及代謝疾病的藥物組合。式I的GPR119致效劑及DPP-4抑制劑的組合具有令人驚訝且特別有利的性質，這使得這些組合特別適用於治療及預防心血管疾病及代謝疾病，包括糖尿病以及與之相關的病症。
發明目的
本發明的目的是提供GPR119致效劑及DPP-4抑制劑的組合，以及這些組合在治療及預防心血管及代謝疾病中的用途，所述疾病包括糖尿病、非酒精性脂肪肝病(non-alcoholic fatty liver disease,NAFLD)、NAFL、NASH、血脂異常以及與之相關的病症。
發明概要
在一態樣中，本發明提供了GPR119致效劑及DPP-4抑制劑的藥物組合，其減緩了其進程、延遲或治療代謝疾病，特別是在改善患者的血糖控制中。這為治療及預防第2型糖尿病、過重、肥胖、糖尿病以及周圍的疾病狀態如NAFLD及NASH的併發症開闢了新的治療可能性。
在另一態樣中，本發明提供了治療有效量的式I的GPR119致效劑、互變異構物、立體異構物，其藥學上可接受的鹽及治療有效量的DPP-4抑制劑或其藥學上可接受的鹽的組合。
本文所用的術語「治療有效量」是指在患有第2型糖尿病、非酒精性脂肪肝疾病(non-alcoholic fatty liver disease,NAFLD)、NAFL、NASH、血脂異常以及與之相關的病症的特定患者(受試者)中有效產生所需治療反應的式I GPR119致效劑或DPP-4抑制劑的量。特別地，術語「治療有效量」包括治療劑的量，其在施用時將達到期望的治療效果。在本發明的上下文中，期望的治療效果包括部分或全部抑制、延遲或預防代謝疾病的進程，特別是在改善患者的血糖控制中。關於治療劑的治療量，即式I的GPR119致效劑或DPP-4抑制劑的治療量，還考慮用於治療對象的每種治療劑的量低至足以避免不期望的或嚴重的副作用。組合中所使用的式I的GPR119致效劑及DPP-4抑制劑中之每一種的治療有效量將隨著最終使用者的年齡及身體狀況、疾病的嚴重程度、治療的持續時間、任何其他並行治療的性質、用於治療的治療劑的具體類型、在包含治療劑的藥物組合物中使用的特定藥學上可接受的載體而變化。
因此，在另一態樣中，本發明提供了藥物組合，其包含式I的GPR119致效劑、互變異構物、立體異構物或其藥學上可接受的鹽及DPP-4抑制劑或其藥學上可接受的鹽，其中式I化合物表示為：
其中，X1、X2、X3、X4及X5各自獨立地為N、O、S或CH；以及
X4及X5可以選擇性地結合以形成包含一個或更多個各自獨立地選自N、O及S的雜原子的五元環，並且另外的五元環可以進一步選擇性地被選自F、Cl、Br、I、CF3及C1-6烷基的一個或更多個基團取代；R1及R2獨立地選自包含-H、-O、C1-6烷基、C1-6烷氧基、-(CH2)n、胺基、-CO、-CONH、-NH(烷基)、-N(烷基)2、-NH-芳烷基、-CH2O、-OCH(CH3)2、鹵素COOR3、-CONR3R4、NR3COR4的基團；R3及R4獨立地選自包含氫，或可以進一步被鹵素或C1-6烷基取代的C1-6直鏈或支鏈烷基的基團；n係為0、1、2或3，A係選自；
環‘B’係選自；
在另一態樣中，本發明提供了藥物組合，其包含式I的GPR119致效劑、互變異構物、立體異構物或其藥學上可接受的鹽及DPP-4抑制劑或其藥學上可接受的鹽，其中所述DPP-4抑制劑係選自包含西他列汀(sitagliptin)、維格列汀(vildagliptin)、沙格列汀(saxagliptin)、利拉列汀(linagliptin)、卡格列汀(carmegliptin)、戈格列汀(gosogliptin)、阿格列汀(alogliptin)、美格列汀(melogliptin)、吉格列汀(gemigliptin)、安奈格列汀(anagliptin)、特力列汀(teneligliptin)、曲格列汀(trelagliptin)、杜拓格列汀(dutogliptin)、依格列汀(evogliptin)、奧格列汀(omarigliptin)之群組。
在另一態樣，本發明提供了一種用於治療糖尿病以及與之相關的病症的方法，所述方法包括施用式I的GPR119致效劑、互變異構物、立體異構物或其藥學上可接受的鹽及DPP-4抑制劑或其藥學上可接受的鹽，其中GPR119致效劑及DPP-4抑制劑可以同時、一同、交替或依序施用。
在另一態樣，本發明提供了一種透過施用包含式I的GPR119致效劑、互變異構物、立體異構物或其藥學上可接受的鹽以及DPP-4抑制劑或其藥學上可接受的鹽方法來治療非酒精性脂肪肝病(non-alcoholic fatty liver disease,
NAFLD)、NAFL、NASH、血脂異常以及與之相關的病症的方法，其中GPR119致效劑及DPP-4抑制劑可以同時、一同、交替或依序施用。
在另一態樣中，本發明提供了藥物組合，其包含式I的GPR119致效劑、互變異構物、立體異構物或其藥學上可接受的鹽以及DPP-4抑制劑或其藥學上可接受的鹽，其中GPR119致效劑及DPP-4抑制劑存在於單一劑型或分開的劑型中。
在另一態樣中，本發明提供了藥物組合，其包含約0.001mg至約5000mg的GPR119及約1mg至約500mg的DPP-4抑制劑。
〔圖1〕表示1A單獨或與西他列汀組合對血糖AUC的影響，其中列舉諸如「*、**、***、#」，其分別表示，*與載體組相比具有顯著差異，#與式Ia的化合物(10mg/kg，口服)相比具有顯著差異，*P<0.05，**P<0.01&***P<0.001，#P<0.05，並且圖1示出了與單藥治療相比，組合組中觀察到的葡萄糖降低具有統計學意義；以及〔圖2〕表示1A單獨或與西他列汀組合對血漿活性GLP-1 AUC的影響，其中列舉諸如「*、***、###」，其分別表示，*與載體組相比具有顯著差異，#與式Ia的化合物(10mg/kg，口服)相比具有顯著差異，*P<0.05、$$$/***/###P<0.001，並且圖2示出了與單藥治療相比，組合組中觀察到的活性GLP-1分泌具有統計學意義。
在本發明的上下文中，術語「藥學上可接受的鹽」或「鹽」可互換使用。在本發明的上下文中使用的「藥學上可接受的鹽」或「鹽」是指無機酸，例如鹽酸、氫溴酸、硫酸、磷酸鹽、碳酸鹽；有機酸，例如琥珀酸、甲酸、乙酸、二苯乙酸、棕櫚酸、三苯乙酸、辛酸、二氯乙酸、三氟乙酸、丙酸、丁酸、乳酸、檸檬酸、葡萄糖酸、扁桃酸、酒石酸、蘋果酸、己二酸、天冬胺酸、延胡索酸、麩胺酸、馬來酸、丙二酸、苯甲酸、對氯苯甲酸、二苯甲醯基酒石酸、草酸、菸鹼酸、鄰羥基苯甲酸、對羥基苯甲酸、1-羥基萘-2-羧酸、羥基萘-2-羧酸、乙磺酸、乙烷1,2-二磺酸、2-羥基乙磺酸、甲磺酸、(+)-樟腦10磺酸、苯磺酸、萘-2-磺酸、對甲苯磺酸等。本文所用的術語「鹽」是指無機及/或有機酸，特別地，較佳係為藥學上可接受的(即，無毒的、生理上可接受的)鹽。
本發明涉及GPR119致效劑及DPP-4抑制劑的組合，以及這些組合在治療及預防心血管及代謝疾病中的用途，所述疾病包括糖尿病、非酒精性脂肪肝病(non-alcoholic fatty liver disease,NAFLD)、NAFL、NASH、血脂異常以及與之相關的病症。
因此，在第一實施方式中，本發明上下文中的GPR119致效劑是式(I)的任何GPR119致效劑。
其中，X1、X2、X3、X4及X5各自獨立地為N、O、S或CH；以及
X4及X5可以選擇性地結合以形成包含一個或更多個各自獨立地選自N、O及S的雜原子的五元環，並且另外的五元環可以進一步選擇性地被選自F、Cl、Br、I、CF3及C1-6烷基的一個或更多個基團取代；R1及R2獨立地選自包含-H、-O、C1-6烷基、C1-6烷氧基、-(CH2)n、胺基、-CO、-CONH、-NH(烷基)、-N(烷基)2、-NH-芳烷基、-CH2O、-OCH(CH3)2、鹵素COOR3、-CONR3R4、NR3COR4的基團；R3及R4獨立地選自包含氫，或可以進一步被鹵素或C1-6烷基取代的C1-6直鏈或支鏈烷基的基團；n係為0、1、2或3，A係選自；
B係選自；
式(I)的化合物可以涉及一種或多種實施方式。式(I)的化合物的實施方式包括如下文所述的式(II)的化合物。應當理解，下面的實施方式是本發明的示例，並不旨在將申請專利範圍限制於所例示的具體實施方式。還應理解，本文定義的實施方式可獨立使用或與本文定義的任何定義及任何其他實施方式結合使用。因此，本發明考慮了各種獨立描述的實施方式的所有可能的組合及排列。例如，本發明提供了如上定義的式(I)的化合物，其中，X4及X5可以結合以形成包含各自獨立地選自N或O的雜原子之一的環。
在另一個實施方式中，具體提供了GPR119致效劑的式(II)的化合物，其中，X4及X5可以結合形成五元環。
應當理解，式(I)及(II)在結構上涵蓋可以從本文所述類型的化學結構中考慮到的所有幾何異構物、立體異構物及藥學上可接受的鹽。
在主要實施方式中，本發明提供了藥物組合，其包含式I的GPR119、互變異構物、立體異構物或其藥學上可接受的鹽，以及至少一種DPP-4抑制劑或其藥學上可接受的鹽。
在另一個實施方式中，本發明提供了藥物組合，其包含至少一種式I的化合物，DPP-4抑制劑及至少一種藥學上可接受的賦形劑。
因此，在一個實施方式中，本發明提供了一種藥物組合，其包含：a)治療有效量的式I的GPR119致效劑；
其中，X1、X2、X3、X4及X5各自獨立地為N、O、S或CH；以及X4及X5可以選擇性地結合以形成包含一個或更多個各自獨立地選自N、O及S的雜原子的五元環，並且另外的五元環可以進一步選擇性地被選自F、Cl、Br、I、CF3及C1-6烷基的一個或更多個基團取代；R1及R2獨立地選自包含-H、-O、C1-6烷基、C1-6烷氧基、-(CH2)n、胺基、-CO、-CONH、-NH(烷基)、-N(烷基)2、-NH-芳烷基、-CH2O、-OCH(CH3)2、鹵素COOR3、-CONR3R4、NR3COR4的基團；R3及R4獨立地選自包含氫，或可以進一步被鹵素或C1-6烷基取代的C1-6直鏈或支鏈烷基的基團；n係為0、1、2或3，
A係選自；
環B係選自；
互變異構物、立體異構物或其藥學上可接受的鹽；b)治療有效量的DPP-4抑制劑，選自西他列汀(sitagliptin)、維格列汀(vildagliptin)、沙格列汀(saxagliptin)、卡格列汀(carmegliptin)、戈格列汀(gosogliptin)、阿格列汀(alogliptin)、利拉列汀(linagliptin)、美格列汀(melogliptin)、吉格列汀(gemigliptin)、安奈格列汀(anagliptin)、特力列汀
(teneligliptin)、曲格列汀(trelagliptin)、杜拓格列汀(dutogliptin)、依格列汀(evogliptin)、奧格列汀(omarigliptin)或其藥學上可接受的鹽；以及c)至少一種藥學上可接受的載體。
如本文所述，本發明的藥物組合包含治療有效量的式I的GPR119致效劑及DPP-4抑制劑，其中所述式I的化合物包括：
本發明的組合可以透過口服劑型(包括但不限於：錠劑、顆粒劑、細顆粒劑、散劑、膠囊劑、囊錠劑、軟膠囊劑、丸劑、口服溶液劑、糖漿劑、乾糖漿劑、咀嚼錠、口含錠、發泡錠、滴劑、混懸劑、速溶錠、口服速分散錠等)；腸胃外劑型(例如：肌內、腹膜內、靜脈內、ICV或輸注、皮下注射或植入)，透過吸入噴霧、鼻腔、陰道、直腸、舌下或局部施用途徑施用，可以在合適的劑量單位製劑中單獨或一起配製，即含有適合於每種施用途徑的常規無毒藥學上可接受的載體、佐劑及載體的劑型。所述組合可以採取諸如在油性或水性載體中的懸浮液、溶液或乳液的形式，並且可以包含配製劑，例如：懸浮劑、穩定劑或分散劑。或者，活性成分可以是透過無菌分離無菌固體或透過從溶液中冷凍乾燥獲得的粉末形式，其係用於在使用前與合適的載體(例如：無菌、無熱原的水)構成藥物。
在另一個實施方式中，本發明提供了一種藥物組合物，其包含：a)治療有效量的式I的GPR119致效劑或其異構物或其藥學上可接受的鹽；b)治療有效量的DPP-4抑制劑；以及c)至少一種藥學上可接受的賦形劑。
根據本發明的藥物組合可以包含(GPR119致效劑)及(DPP-4抑制劑)，例如以(GPR119致效劑)：(DPP-4抑制劑)的範圍自0.001：5000至300：1(w/w)的比例(w/w)，較佳自1：5至200：1，較佳自1：3至150：1，更佳自1：2至100：1。
本發明中使用的GPR119致效劑可以約0.001mg至約5000mg的劑量施用，方便地以單劑量呈現或以分開的劑量在適當的間隔施用。
本發明中使用的GPR119致效劑可以約0.001mg至約1000mg的劑量施用，方便地以單劑量呈現或以分開的劑量在適當的間隔施用。
DPP-4(也稱為DPP-IV)抑制劑是指抑制二肽基肽酶-4(DPP-4)/(DPP-IV)的一類化合物。
DPP-4抑制劑可以是抑制DPP-4酶的任何化合物。DPP-4抑制劑可以選自由西他列汀(sitagliptin)、維格列汀(vildagliptin)、沙格列汀(saxagliptin)、卡格列汀(carmegliptin)、戈格列汀(gosogliptin)、阿格列汀(alogliptin)、利拉列汀(linagliptin)、美格列汀(melogliptin)、吉格列汀(gemigliptin)、安奈格列汀(anagliptin)、特力列汀(teneligliptin)、曲格列汀(trelagliptin)、杜拓格列汀(dutogliptin)、依格列汀(evogliptin)、奧格列汀(omarigliptin)或其藥學上可接受的鹽所組成之群組，但不限於此。
本發明中使用的DPP-4抑制劑可以約1mg至約500mg的劑量施用。
西他列汀(sitagliptin)(MK-0431)係指(3R)-3-胺基-1-[3-(三氟甲基)-5,6,7,8-四氫-5H-[1,2,4]三唑-[4,3-a]吡嗪-7-基]-4-(2,4,5-三氟苯基)丁-1-酮((3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-5H-[1,2,4]triazolo-[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one)，也稱為(2R)-4-氧代-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((2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine)。在一個實施方式中，西他列汀是其磷酸二氫鹽，即磷酸西他列汀的形式。在另一個實施方式中，磷酸西他列汀呈結晶無水物或一水合物的形式。在一個較佳的實施方式中，西他列汀磷酸一水合物。西他列汀的劑量範圍為1-300mg。DPP-4抑制劑西他列汀的口服劑量強度通常在25至200mg的活性部分(active moiety)之間。
利拉列汀(linagliptin)(BI 1356)是指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(1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine)或其藥學上可接受的鹽。口服施用利拉列汀通常需要的劑量為每位患者每天0.5mg至10mg。
維格列汀(vildagliptin)(LAF-237)係指(2S)-{[((3-羥基金剛烷-1-基)胺基]乙醯基}吡咯烷-2-腈((2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}pyrrolidine-2-carbonitrile)，也稱為(S)-1-[(3-羥基-1-金剛烷基))胺基]乙醯基-2-氰基-吡咯烷((S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine)。DPP-4抑制劑維格列汀的口服劑量範圍通常為每天10至150mg。
沙格列汀(saxagliptin)(BMS-477118)指(1S,3S,5S)-2-{(2S)-2-胺基-2-(3-羥基金剛烷-1-基)乙醯基}-2-氮雜雙環[3.1.0]己烷-3-腈((1S,3S,5S)-2-{(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl}-2-azabicyclo[3.1.0]hexane-3-carbonitrile)，也稱為(S)-3-羥基金剛烷基甘胺酸-L-順式-4,5-甲基脯胺酸腈((S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile)或其藥學上可接受的鹽。沙格列汀可以每日口服劑量在2.5mg/天至100mg/天之間，選擇性地在2.5mg至50mg之間給予患者。
阿格列汀(alogliptin)(SYR-322)指2-({6-[(3R)-3-胺基哌啶-1-基]-3-甲基-2,4-二氧代-3,4-二氫-2H-嘧啶-1-基}甲基)芐腈(2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl}methyl)benzonitrile)或其藥學上可接受的鹽。阿格列汀可以每天5mg/天至250mg/天的口服劑量給予患者。
特力列汀(teneligliptin)是指3-{(2S,4S)-4-[4-(3-甲基-1-苯基-1H-吡唑-5-基)哌嗪-1-基]吡咯烷-2-基羰基}噻唑烷(3-{(2S,4S)-4-[4-(3-Methyl-1-phenyl-
1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl}thiazolidine)或其藥學上可接受的鹽。在成年人中，特力列汀的口服劑量為20mg每天一次，可增加至每天40mg。由於該藥物的代謝物透過腎臟及肝臟排泄而消除，因此腎功能不全患者無需調整劑量。
本文提及的組合包含GPR119致效劑及DPP-4抑制劑，其中所述GPR119致效劑及DPP-4抑制劑可以被視為它們的藥學上可接受的鹽及/或水合物、溶劑化物及多晶型形式。本發明化合物的所有立體異構物，例如由於不對稱碳而可能存在的立體異構物，包括鏡像異構物及非鏡像異構物形式，均涵蓋在本發明的範圍內。本發明的化合物可以其鏡像異構物純形式或其外消旋混合物存在。此外，本發明中的化合物可以是固體形式。
根據本發明的組合或組合用途設想了兩種活性成分的同時、依序、交替或分開施用。
根據本發明的藥物組合可以以單劑量或以適當的時間間隔施用的分劑量給予，例如：每天每位患者以二個、三個、四個或更多個次劑量給予(伴隨或不伴隨食物)。
本發明進一步提供了包含GPR119致效劑、DPP-4抑制劑及選擇性地一種或多種藥學上可接受的賦形劑的藥物組合。每種藥物可以單一劑型或分開的劑型施用，或者它們可以透過不同途徑施用。
如上所討論的，本發明提供了與DPP-4抑制劑組合的GPR119致效劑，其具有可用於治療或預防心血管及代謝疾病的生物學特性。在某些實施方式中，本發明提供了包含本文定義的DPP-4抑制劑及本文定義的GPR119致效劑的組合治療產品或藥物組合，用於同時或依序用於治療或預防心血管及代謝疾病，包括第2型糖尿病、非酒精性脂肪肝病(non-alcoholic fatty liver disease,NAFLD)、NAFL、NASH、血脂異常及其相關病症。
因此，在一個實施方式中，本發明提供了一種治療第2型糖尿病的方法，該方法包括施用，(a)治療有效量的式I的GPR119致效劑，
其中，X1、X2、X3、X4及X5各自獨立地為N、O、S或CH；以及X4及X5可以選擇性地結合以形成包含一個或更多個各自獨立地選自N、O及S的雜原子的五元環，並且另外的五元環可以進一步選擇性地被選自F、Cl、Br、I、CF3及C1-6烷基的一個或更多個基團取代；R1及R2獨立地選自包含-H、-O、C1-6烷基、C1-6烷氧基、-(CH2)n、胺基、-CO、-CONH、-NH(烷基)、-N(烷基)2、-NH-芳烷基、-CH2O、-OCH(CH3)2、鹵素COOR3、-CONR3R4、NR3COR4的基團；R3及R4獨立地選自包含氫，或可以進一步被鹵素或C1-6烷基取代的C1-6直鏈或支鏈烷基的基團；n係為0、1、2或3，A係選自；
環B係選自；
互變異構物、立體異構物或其藥學上可接受的鹽；b)治療有效量的DPP-4抑制劑或其藥學上可接受的鹽；以及c)至少一種藥學上可接受的載體。
根據本發明的組合可用於以下一種或多種方法中，以預防、減緩其進程、延緩或治療代謝疾病：用於改善血糖控制及/或降低空腹血糖、餐後
血漿葡萄糖及/或糖基化血紅蛋白HbA1c；用於預防、減緩、延遲或逆轉由糖耐量降低、胰島素抗性及/或從代謝症候群到第2型糖尿病的進程；用於預防、減緩、延緩或治療選自由糖尿病併發症所組成的群組的疾病或病症；用於減輕重量或防止重量增加或有利於減輕重量；用於預防或治療胰腺β細胞的變性及/或用於改善及/或恢復胰腺β細胞的功能及/或恢復胰腺胰島素分泌的功能；及/或用於維持及/或改善胰島素敏感性及/或用於治療或預防高胰島素血症及/或胰島素抗性。
因此，適於本發明治療的此類疾病或病症的實例包括但不限於第1型糖尿病、第2型糖尿病、葡萄糖耐量不足、胰島素抗性、高血糖症。
各種其他狀況可能與代謝疾病有關，例如：腹圍增加、肥胖、高血壓、肝臟疾病(例如：脂肪肝、非酒精性脂肪肝病(nonalcoholic fatty liver disease,NAFLD)、非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)、脂肪變性、肝硬化)、血脂異常(例如：高三酸甘油酯血症、高脂血症、高膽固醇血症、高脂蛋白血症及/或低HDL)、高凝血症、高尿酸血症、血栓形成、高凝血及血栓形成前狀態(動脈及靜脈)以及內皮功能障礙；心血管疾病，例如：慢性心臟衰竭、心肌梗塞、高血壓心臟病、心肌病及中風；微血管及大血管疾病，例如：視網膜病、動脈粥樣硬化、腎病、微量白蛋白尿、慢性全身性發炎及神經疾病；以骨量減少為特徵的骨相關疾病及病症，例如：骨質疏鬆症、類風濕關節炎及骨關節炎。
在某些實施方式中，本發明的組合可用於患有嚴重或高度胰島素抗性的糖尿病(特別是肥胖)患者的抗糖尿病治療或預防。
在一個較佳的實施方式中，本發明提供了包含GPR119致效劑、DPP-4抑制劑及選擇性地一種或多種藥學上可接受的賦形劑的藥物組合，其中所述組合顯示出對治療或預防包括糖尿病、非酒精性脂肪肝病(non-alcoholic
fatty liver disease,NAFLD)、NAFL、NASH、血脂異常以及與之相關的病症的心血管疾病及代謝疾病的協同作用。。
治療套組
在其他實施方式中，本發明涉及一種套組，其係用於方便及有效地實施根據本發明的方法。一般而言，藥物包裝或套組包括一個或更多個裝有本發明藥物組合物/組合(pharmaceutical compositions/combinations)的一種或多種成分的容器。這樣的套組特別適合於遞送固體口服形式，例如：錠劑或膠囊。這種套組較佳地包括許多單位劑量，並且還可以包括具有在它們的預期使用依序排列的劑量的卡片。如果需要，可以例如以數字、字母或其他標記的形式或帶有日曆插頁的形式提供記憶輔助，以指定可以在其中施用劑量的治療方案中的天數。或者，可以包括安慰劑劑量或鈣飲食補充劑(以類似於或不同於藥物組合物劑量的形式)，以提供每天服用一定劑量的套組。選擇性的，由政府機構規定的，規範藥品生產、使用或銷售的須知可以附在這樣的容器內，該須知反映了當局用於人類施用的生產、使用或銷售的核准。
在某些實施方式中，本發明的藥物組合物以單獨或多種劑型，較佳以套組的形式存在，可用於組合療法以靈活地適合患者的個體治療需要。
在另一個實施方式中，本發明提供了一種套組，其包括：(a)第一組分，其係包含包括式I的GPR119致效劑、其互變異構物、立體異構物或其藥學上可接受的鹽的劑型；(b)第二組分，其係包含包括DPP-4抑制劑或其藥學上可接受的鹽的劑型；及(c)選擇性地一種或多種藥學上可接受的載體。
GPR119是一種G蛋白偶聯受體，主要在胰腺β細胞及腸內分泌L細胞中表現。GPR119致效劑透過雙重作用機制起作用：1)活化胰腺β細胞中的GPR119受體導致直接刺激葡萄糖依賴性胰島素分泌，2)活化腸內分泌細胞中的GPR119導致刺激腸促胰島素釋放(GLP-1及GIP)，從而改善了急性葡萄糖耐量。因此，透過配體活化GPR119受體被認為是治療第2型糖尿病的可行策略。已經開發了幾種小分子GPR119致效劑並在臨床前模型中研究了其功效，而在第2型糖尿病的臨床研究中卻很少。
實施例
實施例1：口服葡萄糖耐量試驗(OGTT(oral glucose tolerance test)研究)
實驗：
OGTT研究在雄性Sprague dawley大鼠中進行。將8-10週大的動物禁食過夜(僅隨意提供水)。根據基礎葡萄糖值將八隻雄性大鼠隨機分為四個不同的組。向控制動物施用載體(0.5% Tween 80及99.5% NaCMC水溶液(0.5% w/v))，其餘各組分別口服以載體製備的測試化合物。在施用後立即採集血液樣品(在-30分鐘的時間點)。在施用30分鐘後(這是零分鐘的時間點)監測血糖。所有動物均口服2g/kg/10ml(20%)葡萄糖溶液。在施用葡萄糖後，分別在不同時間點(5、15、30、60及120分鐘)估算葡萄糖濃度。透過試紙法估算血糖濃度(Accu-Check活性血糖儀)。計算在各個時間點收集的樣品得血糖AUC。數據以平均值±SEM表示。進行單向ANOVA及Tukey的多重比較測試以了解所研究參數的統計學意義。
結果：
式IA的GPR119致效劑(10mg/kg)與載體相比顯示出葡萄糖降低了16%，而西他列汀3mg/kg與載體相比顯示出葡萄糖降低了15%。式IA化合物
(10mg/kg/wt)與加上西他列汀(3mg/kg/wt)的組合與載體控制組相比顯示葡萄糖降低了25%。如圖1所示，組合組中觀察到的葡萄糖降低與單藥治療相比具有統計學意義。
該研究結果表明，本發明的式I的GPR119致效劑及DPP-4抑制劑的組合以出乎意料的且高度協同的方式顯示了葡萄糖的降低。
實施例2：GLP-1估算
在雄性Sprague dawley大鼠中進行GLP-1估算。將8-10週大的動物禁食過夜(僅隨意提供水)。根據基礎葡萄糖值將八隻雄性大鼠隨機分為四個不同的組。向控制動物施用載體(0.5% Tween 80及99.5% NaCMC水溶液(0.5% w/v))，其餘各組分別口服以載體製備的測試化合物。
為了進行活性GLP-1估算，在異氟烷麻醉下透過眼眶後穿刺收集血液。在-30、0、5、15、30及60分鐘的時間點從收集的血漿中估算出活性GLP-1濃度。在異氟烷麻醉下，透過眼眶後穿刺，借助經DPP-4抑制劑(#DPP4-010，Merck-Millipore)沖洗的毛細血管來採血(約400-500μl)，並將其收集到預先塗布DPP-4抑制劑(10μl/ml血液)的微量離心管(Eppendorf)中。
結果：
式IA的GPR119致效劑10mg/kg/wt與載體相比，顯示出活性GLP-1分泌增加了123%，西他列汀3mg/kg/wt與載體相比，顯示出活性GLP-1分泌增加了253%。式IA化合物(10mg/kg/wt)加上西他列汀(3mg/kg/wt)的組合與載體控制組相比，顯示出活性GLP-1分泌增加了350%。如圖2所示，組合組中觀察到的活性GLP-1分泌與單藥治療相比具有統計學意義。
如上所示的結果證明了本發明的式I的GPR119致效劑及DPP-4抑制劑的組合對GLP-1分泌具有強大的協同作用，其中GLP-1分泌顯著地增加。
實施例3：
包含600mg活性物質的錠劑(即式I的GPR119致效劑(500mg)及磷酸西他列汀(100mg)的組合)
組成：
(1)活性物質600.0mg
(2)乳糖98.0mg
(3)玉米澱粉50.0mg
(4)硬脂酸鎂2.0mg
製備：
將活性物質、乳糖及玉米澱粉混合在一起並製成顆粒。將硬脂酸鎂添加到顆粒中。然後將顆粒壓製成錠劑。
實施例4：
包含550mg活性物質的錠劑(即式I的GPR119致效劑(500mg)及磷酸西他列汀(50mg)的組合)
組成：
(1)活性物質550.0mg
(2)乳糖98.0mg
(3)玉米澱粉50.0mg
(4)硬脂酸鎂2.0mg
製備：
將活性物質、乳糖及玉米澱粉混合在一起並製成顆粒。將硬脂酸鎂添加到顆粒中。然後將顆粒壓製成錠劑。
實施例5：
含500mg活性物質的錠劑(式I的GPR119致效劑(495mg)及利拉列汀(5mg)的組合)
組成：
(1)活性物質500.0mg
(2)乳糖136.0mg
(3)玉米澱粉80.0mg
(4)硬脂酸鎂2.0mg
製備：
將活性物質、乳糖及玉米澱粉混合在一起並製成顆粒。將硬脂酸鎂添加到顆粒中。然後將顆粒壓製成錠劑。
實施例6：
包含550mg活性物質的錠劑(即式I的GPR119致效劑(500mg)及維格列汀(50mg)的組合)
組成：
(1)活性物質550.0mg
(2)玉米乾澱粉58.0mg
(4)硬脂酸鎂2.0mg
製備：
將活性物質、乳糖及玉米澱粉混合在一起並製成顆粒。將硬脂酸鎂添加到顆粒中。然後將顆粒壓製成錠劑。
Claims (7)
- 一種藥物組合，包括：a)10mg/kg/wt的式IA的GPR119致效劑；
- 如請求項1所述的藥物組合，其中所述組合還包含至少一種藥學上可接受的載體。
- 如請求項1所述的藥物組合，其中所述GPR119致效劑及DPP-4抑制劑係以單一劑型存在。
- 如請求項1所述的藥物組合，其中所述GPR119致效劑及DPP-4抑制劑係各自以單獨的劑型存在。
- 如請求項1所述的藥物組合，其中所述GPR119致效劑及DPP-4抑制劑係同時或依序施用。
- 如請求項1所述的藥物組合，其中所述藥物組合被配製用於口服施用。
- 一種藥物套組，包括：(a)第一組分，其包含10mg/kg/wt的式IA的GPR119致效劑、互變異構物、立體異構物或其藥學上可接受的鹽；
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