TW201806941A - 經醯胺-取代的吡啶基三唑衍生物及其用途 - Google Patents
經醯胺-取代的吡啶基三唑衍生物及其用途 Download PDFInfo
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- TW201806941A TW201806941A TW106114432A TW106114432A TW201806941A TW 201806941 A TW201806941 A TW 201806941A TW 106114432 A TW106114432 A TW 106114432A TW 106114432 A TW106114432 A TW 106114432A TW 201806941 A TW201806941 A TW 201806941A
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Abstract
本發明係有關新穎之5-(羧醯胺)-1-吡啶基-1,2,4-三唑衍生物、用於製備此類化合物之方法、含有此類化合物之醫藥組成物、及此類化合物或組成物用於治療及/或預防疾病之用途,特別是用於治療及/或預防腎臟與心血管疾病。
Description
本發明係有關新穎之5-(羧醯胺)-1-吡啶基-1,2,4-三唑衍生物、用於製備此類化合物之方法、含有此類化合物之醫藥組成物、及此類化合物或組成物用於治療及/或預防疾病之用途,特別是用於治療及/或預防腎臟與心血管疾病。
血管加壓素為一神經激素,其基本上能調節水分恆定與血管緊張性。其係於第三腦室(下丘腦)壁中核上層(Nucleus supraopticus)與左室旁(N.paraventricularis)特化之內分泌神經元中產生,且由該處沿著髓突(neural processes)轉移至腦下垂體(神經垂體)後葉。於該處,激素釋放至血液中以響應不同生理與病理生理刺激。神經激素調節紊亂基本上會表現出交感神經緊張性升高及腎素-血管緊張素-醛固酮系統(RAAS)的不適當活化。儘管彼等組分一方面利用β受體阻斷劑抑制且另一方面利用ACE抑制劑或血管緊張素受體阻斷劑抑制的方式現為心血管疾病藥理學治療之固有部分,但目前尚無法充分治療血管加壓素分泌之不適當升高。
血管加壓素主要經由結合至三受體而發揮其作用,其係分類為V1a、V1b及V2受體,且其屬於G蛋白偶聯受體家族。
V2受體位於遠端腎小管上皮及腎集液管上皮。其活化使彼
等上皮可滲透水分。此現像係因水孔蛋白(aquaporins)(特殊水通道)併入上皮細胞腔膜。其結果為,血管加壓素對V2受體作用的藥理學抑制導致尿液排泄增加。因此,具有V2拮抗活性的藥物特別適用於治療與體內水分超載相關之所有疾病狀況。
V1b受體(亦稱作V3受體)主要出現在中樞神經系統。連同促皮質素釋放激素(CRH),血管加壓素經由V1b受體調節促腎上腺皮質激素(ACTH)之基礎與壓力誘發性分泌。
V1a受體主要位於血管平滑肌細胞(VSMC),但亦位於心肌細胞、纖維母細胞及特化之腎細胞,如腎小球膜細胞或控制腎素釋放的緻密斑(macula densa)細胞[Wasilewski MA,Myers VD,Recchia FA,Feldman AM,Tilley DG,Cell Signal.,28(3),224-233,(2016)]。利用血管加壓素活化VSMC V1a受體,引起細胞內鈣釋放及血管收縮。因此,刺激VSMC V1a受體引起血管阻力升高及心臟後負荷(afterload)增加。心臟輸出受到V1a介導之血管收縮的不良影響。後負荷的增加及V1a受體對心肌細胞的直接刺激可導致心臟肥大與重塑(remodeling),包括纖維化。心臟特異性過度表現V1a受體之小鼠會引起心臟肥大,其導致擴張與左心室功能障礙,顯示V1a受體於心臟衰竭發展中扮演重要角色[Li X,Chan TO,Myers V,Chowdhury I,Zhang XQ,Song J,Zhang J,Andrel J,Funakoshi H,Robbins J,Koch WJ,Hyslop T,Cheung JY,Feldman AM,Circulation.;124,572-581(2011)]。
V1a受體亦於腎皮質與髓質脈管系統中表現,其介導腎血管收縮且影響整個腎血流量。因此,活化V1a受體可減少腎髓質血流,誘發進一步病理過程,如組織缺氧、氧氣減少,從而導致腎小管轉運過程的能量供應,以及腎小球膜和緻密斑細胞的直接損傷。因此,活化V1a受體可減少腎髓質血流,導致進一步的病理過程,如組織缺氧、氧氣減少,從而導致
腎小管轉運過程的能量供應,以及腎小球膜與緻密斑細胞的直接損傷。現已證實,腎小球膜V1a受體活化可介導TGFβ傳訊且導致膠原IV產量增加。儘管此傳訊有助於腎臟之細胞外基質累積與重塑,但類似的傳訊途徑據信發生於心臟細胞,特別是在心肌梗塞之後,其強調V1a受體在發展增生與纖維化過程中響應病理生理上升高之血管加壓素濃度的中心角色[Wasilewski MA,Myers VD,Recchia FA,Feldman AM,Tilley DG.Arginine vasopressin receptor signaling and functional outcomes in heart failure.Cell Signal.,28(3),224-233(2016)]。
由於V1a受體主要表現在VSMCs,因此參與血管功能,可想像其聯結血管疾病如周邊動脈疾病(PAD),包括跛行(claudication)與關鍵胺體缺血,以及冠狀動脈微血管官能不良(CMD)。
除此之外,V1a受體亦表現於人類血小板與肝臟。血小板V1a受體之意義尚未釐清,儘管血管加壓素經由V1a受體,於體外以高濃度誘發人類血小板聚集。因此,利用V1a受體拮抗劑抑制血管加壓素誘發之血小板凝集,為適用之藥理學體外試驗,其係使用內源性表現V1a受體之人體組織[Thibonnier M,Roberts JM,J Clin Invest.;76:1857-1864,(1985)]。
血管加壓素經由活化肝臟V1a受體刺激糖質新生(gluconeogenesis)及肝醣分解(glycogenolysis)。動物實驗顯示,血管加壓素損害葡萄糖耐受性,其可受V1a受體拮抗劑抑制,從而提供血管加壓素受體V1a與糖尿病的聯結[Taveau C,Chollet C,Waeckel L,Desposito D,Bichet DG,Arthus MF,Magnan C,Philippe E,Paradis V,Foufelle F,Hainault I,Enhorning S,Velho G,Roussel R,Bankir L,Melander O,Bouby N.Vasopressin and hydration play a major role in the development of glucose intolerance and hepatic steatosis in obese rats.Diabetologia,58(5),1081-1090,
(2015)]。於動物模式中顯示,血管加壓素與蛋白尿和糖尿病誘發性腎病變之發展有關,其與人類流行病學的發現一致。
近來發現,血管加壓素似乎亦於子癇前症(preeclampsia)之發展中扮演因果作用。於小鼠懷孕期間,慢性輸注血管加壓素足以誘發與人類子癇前症相關聯之所有主要母體與胎兒表型,包括妊娠特異性高血壓[Santillan MK,Santillan DA,Scroggins SM,Min JY,Sandgren JA,Pearson NA,Leslie KK,Hunter SK,Zamba GK,Gibson-Corley KN,Grobe JL.Vasopressin in preeclampsia:a novel very early human pregnancy biomarker and clinically relevant mouse model.Hypertension.64(4),852-859,(2014)]。
若婦女於月經期間有痛經(婦科疾病,其特徵為周期性痙攣性骨盆疼痛),則血管加壓素濃度升高,此似乎增加子宮肌層平滑肌收縮。近來發現,一選擇性血管加壓素V1a受體拮抗劑(瑞考伐普坦(relcovaptan)/SR-49059)可減少血管加壓素引起的子宮內收縮。
由於彼等原因,抑制血管加壓素作用於V1a受體之藥劑似乎適用於治療幾種心血管疾病。具體而言,抑制血管加壓素選擇性作用於V1a受體之藥劑提供了尤其理想的治療方法,以治療其他正常血容量病患(normovolemic patients),亦即彼等不符合利用如高劑量循環利尿劑或V2拮抗劑緩解充血(decongestion)者,且其中不希望經由V2抑制引發除水(aquaresis)。
特定4-苯基-1,2,4-三唑-3-基衍生物描述於WO 2005/063754-A1與WO 2005/105779-A1,以作為血管加壓素V1a受體拮抗劑,其適用於治療婦科疾病,特別是月經失調如痛經。
於WO 2011/104322-A1中,一特定基團之雙芳基鍵接之1,2,4-三唑-3-酮類,包括其5-苯基-1,2,4-三唑-3-基與1-苯基-1,2,3-三唑-4-基衍
生物,經揭示可作為血管加壓素V2及/或V1a受體之拮抗劑,用於治療及/或預防心血管疾病。然而,所述化合物對V1a受體未顯示足夠選擇性,且主要顯示對血管加壓素V1a與V2受體的結合活性。然而,如上所述,對V1a受體的高親和力與選擇性為治療疾病狀況的理想先決條件且其中毋須除水,以及可導致體液恆定失調,包括正常血容量個體之血漿滲透壓降低。
於WO 2016/071212-A1中,揭示了特定5-(羥基烷基)-1-苯基-1,2,4-三唑衍生物,其可作為血管加壓素V1a與V2受體之強力拮抗劑,此外,其於口服施加後,顯示體內除水效力顯著提高。該化合物據稱適用於治療及/或預防心血管與腎臟疾病。然而,如上所述,對V1a受體的高親和力與選擇性為治療疾病狀況的理想先決條件且其中毋須除水,以及可導致體液恆定失調,包括正常血容量個體之血漿滲透壓降低。
對V1a受體具有高選擇性的活性輪廓,其造成非期望之相關副作用的機率低,且亦有助於降低欲達成與保持所需治療效果之物質量,因此侷限了高風險患者(如急性或慢性心臟與腎臟疾病)治療期間無法接受之副作用及/或不期望之藥物間相互作用的潛力。
因此,本發明欲解決之技術問題在於鑑定與提供新穎化合物,以作為血管加壓素V1a受體之有效拮抗劑。本發明之進一步目的在於鑑定及提供針對血管加壓素V1a受體之高親和力與選擇性的新化合物。該化合物旨在避免經由V2抑制而誘發除水。該化合物進一步旨在相比於先前技術之習知化合物,具有相似或改進之治療輪廓,如關於其體內性質,例如其藥物動力學與藥效動力學特徵及/或其代謝輪廓及/或其劑量活性關係。
令人驚訝的是,現已發現,特定5-(羧醯胺)-1-吡啶基-1,2,4-三唑衍生物可作為V1a受體之高效力與選擇性拮抗劑。此特殊特徵使得本發
明化合物適於治療及/或預防與V1a受體活化相關的疾病。本發明化合物具體適用於治療及/或預防未患有液體過載之腎臟與心血管疾病個體,因此其不會水痢。
本發明化合物具有有價值之藥理學性質,且可用於預防及/或治療人類與其他哺乳類動物之各疾病及疾病誘發狀態。
於一態樣,本發明係有關通式(I)之5-(羧醯胺)-1-吡啶基-1,2,4-三唑衍生物
其中R1代表式
或之基團,其中#1代表氮原子之連接點,Ar代表式
或之基團,其中#2代表氮原子之連接點,R2A代表一基團,其係選自於氯原子、溴原子、三氟甲基、三氟甲氧基、乙氧基羰基、及-C(=O)NH2,
R2B代表一基團,其係選自於氯原子、三氟甲基、及乙氧基羰基。
本發明化合物亦可以其鹽類、溶劑合物、及/或鹽類之溶劑合物形式存在。
當「包含」乙詞用於說明書時涵蓋「組成自」。
若本文中任何項目用於指稱「如本文所述」,則意指其可於本文中任何一處提及。
本文中所提及術語具有下列意義:
「C1-C4烷基」乙詞意指具有1、2、3、或4個碳原子之直鏈或支鏈、飽和、單價烴基,如甲基、乙基、丙基、異丙基、丁基、二級丁基、異丁基、三級丁基、或其異構物。具體而言,該基團具有1、2、3、或4個碳原子(「C1-C4烷基」),如甲基、乙基、丙基、異丙基、丁基、二級丁基、異丁基、三級丁基,更具體而言,1、2、或3個碳原子(「C1-C3烷基」),如甲基、乙基、正丙基、或異丙基,甚而更具體而言,甲基。
通式(I)化合物可能以同位素變體存在。因此,本發明包括一或多個通式(I)化合物之同位素變體,具體而言為通式(I)之含氘化合物。
化合物或試劑之「同位素變體」乙詞係定義為化合物呈現一非天然比例之一或多個同位素,以構成此一化合物。
「通式(I)化合物之同位素變體」乙詞係定義為通式(I)化合物呈現一非天然比例之一或多個同位素,以構成此一化合物。
「非天然比例」之表示意指此同位素之比例高於其天然豐度。本文中應用之同位素天然豐度係描述於“Isotopic Compositions of the Elements 1997”,Pure Appl.Chem.,70(1),217-235,1998。
此類同位素之實例包括氫、碳、氮、氧、磷、硫、氟、氯、溴、及碘之安定性與放射性同位素,如分別為2H(氘)、3H(氚)、11C、13C、
14C、15N、17O、18O、32P、33P、33S、34S、35S、36S、18F、36Cl、82Br、123I、124I、125I、129I、及131I。
關於治療及/或預防本文規定之病症,通式(I)化合物之同位素變體較佳地含有氘(「通式(I)之含氘化合物」)。通式(I)化合物之同位素變體,其中併入一或多個放射性同位素,如3H或14C,係適用於如藥物及/或受質之組織分佈研究。彼等同位素具體較佳係易於其併入與可檢測性。正子發射同位素,如18F或11C,可併入通式(I)化合物。彼等通式(I)化合物之同位素變體係適於體內造影應用。通式(I)之含氘及含13C化合物可用於前臨床或臨床研究之質譜分析。
通式(I)化合物之同位素變體通常可利用本領域技術人員習知之方法製備,如彼等描述於本文流程圖及/或實例者,利用試劑之同位素變體取代該試劑,較佳地為含氘試劑。取決於所需之氘化位點,在一些情況下,D2O之氘可直接併入化合物或併入用於合成此類化合物之試劑。氘氣亦為將氘併入分子之適用試劑。烯烴鍵與炔屬鍵之催化氘化為併入氘之直接途徑。金屬觸媒(亦即,Pd、Pt、及Rh)可於氘氣存在下將含烴官能基之氫直接交換為氘。各種氘化試劑及合成結構單元可由公司商購,如C/D/NIsotopes,Quebec,Canada;Cambridge Isotope Laboratories Inc.,Andover,MA,USA;以及CombiPhos Catalysts,Inc.,Princeton,NJ,USA。
「通式(I)之含氘化合物」乙詞係定義為通式(I)化合物中之一或多個氫原子係以一或多個氘原子取代,且其中通式(I)化合物各氘化位置氘之豐度係高於氘之天然豐度,其係約0.015%。具體而言,於通式(I)之含氘化合物中,通式(I)化合物各氘化位置氘之豐度係高於該位置10%、20%、30%、40%、50%、60%、70%、或80%,較佳地高於90%、95%、96%、或97%,甚而更佳地高於98%或99%。應理解的是,各氘化位置氘之豐度係獨
立於其他氘化位置氘之豐度。
選擇性併入一或多個氘原子至通式(I)化合物可改變該分子之物化性質(例如,酸度[C.L.Perrin,et al.,J.Am.Chem.Soc.,2007,129,4490]、鹼度[C.L.Perrin et al.,J.Am.Chem.Soc.,2005,127,9641]、親油性[B.Testa et al.,Int.J.Pharm.,1984,19(3),271])、及/或代謝特徵,且可造成母體化合物與代謝物之比率或所形成代謝物量的改變。此類改變可造成特定治療優勢,因此在一些情況下可為較佳。有報導指出,代謝速率與代謝轉化率下降,其中代謝物比率改變(A.E.Mutlib et al.,Toxicol.Appl.Pharmacol.,2000,169,102)。彼等暴露於母體藥物與代謝物之改變,對通式(I)之含氘化合物的藥效動力學、耐受性、及功效具有重要影響。在一些情況下,氘取代作用可減少或消除非期望或有毒代謝物形成,並增進所需代謝物之形成(例如,Nevirapine:A.M.Sharma et al.,Chem.Res.Toxicol.,2013,26,410;Efavirenz:A.E.Mutlib et al.,Toxicol.Appl.Pharmacol.,2000,169,102)。在其他情況下,氘化之主要作用為降低全身清除率。其結果為,化合物之生物半衰期增加。潛在之臨床益處將包括維持類似全身性暴露之能力,伴隨降低峰值(peak)濃度及增加谷值(trough)濃度。此可導致較低之副作用且增進功效,取決於特定化合物之藥物動力學/藥效動力學關係。ML-337(C.J.Wenthur et al.,J.Med.Chem.,2013,56,5208)與奧當卡替(Odanacatib)(K.Kassahun et al.,WO2012/112363)為此氘作用之實例。仍有其他案例報導,其中降低代謝率導致藥物曝露增加,而不改變全身清除率之速率(例如,Rofecoxib:F.Schneider et al.,Arzneim.Forsch./Drug.Res.,2006,56,295;Telaprevir:F.Maltais et al.,J.Med.Chem.,2009,52,7993)。具備此類作用之氘化藥物可減少劑量需求(例如,更低劑量數或更低劑量以達到所需功效)及/或可產生更低代謝物負荷。
通式(I)化合物可具多個潛在代謝攻擊位點。欲最適化上述對物化性質與代謝特徵之影響,可選擇具有一特定型態之一或多個氘氫交換的通式(I)含氘化合物。具體而言,通式(I)含氘化合物之氘原子係連接至碳原子及/或位於通式(I)化合物之彼等位置,其係代謝酵素(如細胞色素P450)之攻擊位點。
本文中使用的複數形式字詞,如化合物、鹽類、多形體、水合物、溶劑合物、及其類似物,亦指單一化合物、鹽類、多形體、異構物、水合物、溶劑合物、及其類似物。
「安定性化合物」或「安定性結構」意指化合物穩健性足夠,以便從反應混合物中分離出有用之純度,且配製成有效之治療劑。
本發明化合物任意地含有一不對稱中心,其取決於所需各取代基之位置與本質。一不對稱碳原子可存在(R)或(S)組態,其可產生外消旋混合物。在特定情況下,由於一給定鍵之旋轉受限,如中心鍵鄰接所指定化合物之二經取代芳環,其亦可存在不對稱性。較佳之化合物係彼等產生更所需之生物活性者。本發明化合物之經分離、純的或部分純化之異構物與立體異構物或外消旋混合物亦涵蓋於本發明之範疇內。利用本領域習知之標準技術,可完成此類材料之純化與分離。
光學異構物之取得可利用常規方法分離外消旋混合物,例如利用光學上活性酸或鹼形成非鏡像異構物鹽類或形成共價非鏡像異構物。適用酸之實例為酒石酸、二乙醯基酒石酸、二甲苯甲醯基酒石酸、及樟腦磺酸。非鏡像異構物之混合物可依據其物理及/或化學差異以本領域習知方法分離成其個別非鏡像異構物,例如利用色譜法或分段結晶法。接著,將光學上活性鹼或酸從分離之非鏡像異構物鹽類中釋出。一不同之光學異構物分離方法係涉及使用手性層析法(如,採用手性相HPLC管柱),其具或不
具常規衍生化,為最大化鏡像異構物分離之最佳選擇。適用之手性相HPLC管柱係可商購,如彼等Daicel製造者,例如Chiracel OD與Chiracel OJ等,皆為常規之選擇。具或不具衍生化之酵素分離方法亦適用。本發明光學上活性化合物同樣地可利用手性合成方法取得,其係使用光學上活性起始原料。欲區別不同類型之異構物,可參考IUPAC Rules Section E(Pure Appl Chem 45,11-30,1976)。
本發明包括本發明化合物所有可能之立體異構物,其係單一立體異構物,或任何比率之該立體異構物之任何混合物,如(R)-或(S)-異構物。利用本領域方法之任何合適狀態,如層析法,尤其是手性層析法,可達到分離本發明化合物之單一立體異構物,如單一鏡像異構物或單一非鏡像異構物。
此外,本發明化合物可能以互變異構物存在。本發明包括本發明化合物所有可能之互變異構物,其係單一互變異構物,或任何比率之該互變異構物之任何混合物。
此外,本發明化合物可以N-氧化物存在,其定義為本發明化合物之至少一氮經氧化。本發明包括所有此類可能的N-氧化物。
本發明亦涉及本發明化合物之有用形式,如代謝物、水合物、溶劑合物、鹽類,具體而言醫藥上可接受鹽類、及/或共沈澱物。
本發明化合物可以水合物或溶劑合物形式存在,其中本發明化合物含有極性溶劑,具體而言,如水、甲醇、或乙醇,其係作為化合物晶格之結構元件。可能的是,極性溶劑(具體而言為水)之量係以化學計量或非化學計量比率存在。在化學計量溶劑合物之情況中,例如,水合物、半-、(半-)、單-、一倍半-、二-、三-、四-、五-等溶劑合物或水合物是可能的。本發明包括所有此類水合物或溶劑合物。在本發明全文中,水合物係較佳
之溶劑合物。
具體而言,本發明式(I-B)之3,3,3-三氟-2-氧基丙基衍生物(酮形式)亦可能存在3,3,3-三氟-2,2-二羥基丙基形式(I-B)'(水合物形式)(參見下列流程圖I);本發明明確包含兩形式。
此外,本發明的化合物可以游離形式存在,例如,為游離鹼,或游離酸,或兩性離子,或以鹽類形式存在。所述鹽可以是任何鹽類,有機或無機加成鹽類,特別是任何醫藥上可接受的有機或無機加成鹽,其通常用於製藥,或用於分離或純化本發明化合物。
術語「醫藥上可接受鹽類」是指本發明化合物的無機或有機酸加成鹽,例如參見S.M.Berge,et al.“Pharmaceutical Salts,”J.Pharm.Sci.1977,66,1-19.
適用於本發明化合物的醫藥上可接受鹽類可為如本發明化合物在直鏈或環上帶有氮原子的酸加成鹽,其具有足夠鹼性,例如與無機酸或「礦物酸」例如氫氯酸、氫溴酸、氫碘酸、硫酸、氨基磺酸、雙硫、磷酸或硝酸,或與有機酸如甲酸、乙酸、乙醯乙酸、丙酮酸、三氟醋酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水楊酸、2-(4-羥基苯甲醯基)-苯甲酸、樟腦酸、肉桂酸、環戊烷丙酸、二葡萄糖酸、3-羥基-2-萘酸、菸鹼酸、樸酸、果膠酯酸、3-苯基丙酸、三甲基乙酸、2-羥基乙磺酸、衣康酸、三氟甲磺酸、十二烷基磺酸、乙磺酸、苯磺酸、對甲苯磺酸、
甲磺酸、2-萘磺酸、萘二磺酸、樟腦磺酸、檸檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、蘋果酸、己二酸、海藻酸、馬來酸、富馬酸、D-葡萄糖酸、扁桃酸、抗壞血酸、葡庚糖酸、甘油磷酸、天冬胺酸、磺基水楊酸或硫氰酸,形成的酸加成鹽類。
此外,本發明化合物具足夠酸性的另一適當醫藥上可接受鹽類為鹼金屬鹽如鈉鹽或鉀鹽、鹼土金屬鹽如鈣、鎂或鍶鹽,或鋁或鋅鹽,或衍生自氨基的銨鹽,或具有1至20個碳原子的有機一級、二級或三級胺,如乙胺、二乙胺、三乙胺、乙基二異丙基胺、單乙醇胺、二乙醇胺、三乙醇胺、二環己基胺、二甲基胺基乙醇、二乙基胺基乙醇、三(羥基甲基)胺基甲烷、普魯卡因、二芐基胺、N-甲基嗎啉、精胺酸、離胺酸、1,2-乙二胺、N-甲基哌啶、N-甲基-葡萄糖胺、N、N-二甲基-葡萄糖胺、N-乙基-葡萄糖胺、1,6-己二胺、葡糖胺、肌胺酸、絲胺醇、2-胺基-1,3-丙二醇、3-胺基-1,2-丙二醇、4-胺基-1,2,3-丁三醇,或具有1至20個碳原子的四級銨鹽類,如四甲基銨、四乙基銨、四(正丙基)銨、四(正丁基)銨、N-芐基-N,N,N-三甲基銨、膽鹼或苯扎銨。
本領域技術人員將進一步認識到,所申明化合物的酸加成鹽類可經由多種習知方法,將該化合物與合適的無機或有機酸進行反應而製備。或者,本發明酸性化合物的鹼金屬和鹼土金屬鹽類,可經由各種習知方法,由本發明化合物與適當的鹼反應而製備。
本發明包括本發明化合物所有可能的鹽類,可為單一鹽類的,或以任何比例形成的該鹽類的任何混合物。
在本文中,尤其是實驗部分,為了合成本發明的中間化合物和實施例,當化合物以與相對應的鹼或酸形成的鹽類形式提及時,該鹽類形式的精確化學計量組成,如同經由各製備及/或純化方法獲得者,在大多
數情況下是未知的。
除非另有說明,否則與鹽類有關的化學名稱或結構式的後綴,例如「氯化氫」、「三氟醋酸」、「鈉鹽」,或「x HCl」、「x CF3COOH」、「x Na+」,係指一種鹽類形式,而該鹽類形式之精確化學計量並未特定指出。
這可類似地用於該製備及/或純化方法獲得的合成中間化合物或實例化合物或其鹽類的情況,作為溶劑合物,如水合物,具有(如果有定義)未知的化學計量組成。
此外,本發明包括本發明化合物的所有可能結晶形式或多晶形物,不論是單一多晶形物,或作為多於一種多晶形物的混合物,以任何比例。
在一特定實施例中,本發明相關於式(I)化合物,其中R1代表式
其中#1 代表氮原子之連接點,Ar 代表式
其中#2 代表氮原子之連接點,R2A 代表一基團,其係選自於氯原子、溴原子、三氟甲基、三氟甲氧基、乙氧基碳基、及-C(=O)NH2,
或醫藥上可接受鹽類、其水合物及/或溶劑合物。
在一較佳實施例中,本發明相關於式(I)化合物,其中R1 代表式
其中#1 代表氮原子之連接點,Ar 代表式
其中#2 代表氮原子之連接點,R2A 代表一基團,其係選自於氯原子、三氟甲基與三氟甲氧基,或醫藥上可接受鹽類、其水合物及/或溶劑合物。
依據另一較佳實施例,本發明涵蓋通式(I)化合物,其中R1 代表(2S)-3,3,3-三氟-2-羥基丙基
其中#1 代表氮原子之連接點,或醫藥上可接受鹽類、其水合物及/或溶劑合物.R1 代表(2R)-3,3,3-三氟-2-羥基丙基
其中#1 代表氮原子之連接點,或醫藥上可接受鹽類、其水合物及/或溶劑合物。
在第一態樣之另一實施例中,本發明涵蓋二或多個上述實施例,標題為「本發明第一態樣之其他實施例」。
本發明涵蓋通式(I)化合物的本發明的任何實施方案或態樣的任何子組合。
本發明涵蓋通式(II)、(III)、(IV)、(V)、(VI)與(VIII)、(VIII)的中間化合物的任何實施例或態樣的任何子組合。本發明涵蓋通式(I)的化合物,其在下文的實例部分中公開。
依據第二態樣,本發明涵蓋製備通式(I)化合物之方法,該方法包含之步驟為[A]容許式(II)中間化合物:
其中R1係如申請專利範圍第1至3項中任一項之通式(I)化合物之定義,R3 代表(C1-C4)烷基,具體而言甲基,以在一第一步驟之鹼基存在下,且任意地銅鹽,與通式(III)化合物反應(III):
其中
R4 代表(C1-C4)烷基,具體而言甲基,以得一中間化合物,其之後容許在一第二步驟之鹼基存在下與通式(IV)聯胺化合物或其個別鹽類反應
其中Ar係如申請專利範圍第1至3項中任一項之通式(I)化合物之定義,從而得通式(V)化合物:
其中R1與Ar係如申請專利範圍第1至3項中任一項之通式(I)化合物之定義,以及R4代表(C1-C4)烷基,具體而言甲基,隨後為後續步驟[B]容許步驟[A]取得之式(V)化合物與氨反應,從而得通式(I)化合物:
其中R1與Ar係如申請專利範圍第1至3項中任一項之通式(I)化合物之定義,任意地隨後為步驟[C]將通式(I-A)之醇類:
其中Ar係如申請專利範圍第1至3項中任一項之通式(I)化合物之定義,轉化為通式(I-B)之酮類:
其中Ar係如申請專利範圍第1至3項中任一項之通式(I)化合物之定義,其係使用習知之氧化方法,於適當情況下,[A]、[B]、及[C]之每一者任意地隨後為(i)將所得式(I)化合物分離成其個別之鏡像異構物,及/或(ii)將式(I)化合物轉化成其個別之水合物、溶劑合物、鹽類、及/或該鹽類之水合物或溶劑合物,其係藉由處理相應之溶劑及/或酸或鹼。
本發明涵蓋製備本發明通式(I)化合物之方法,該方法包含描述於實驗部分之步驟。
下文描述的流程和步驟說明本發明通式(I)化合物的合成途徑,而非用於限制。對於本領域技術人員顯而易見的是,可以各種方式修改方案2、3、4、5、6和7中所示的轉換順序。因此,彼等方案中所示的轉換順序並不受限。此外,,R1、R2、R3、R4與Ar任一取代基之間的轉化,可以該示例性轉化之前及/或之後進行。彼等修飾可為保護基導入、保護基
切割、官能基還原或氧化、鹵化、金屬化、取代或其他本領域技術人員習知的反應。彼等轉換包括引入允許取代基進一步互相轉換的官能基。合適的保護基及其引入和切割是本領域技術人員公知的(請見如T.W.Greene and P.G.M.Wuts in Protective Groups in Organic Synthesis,3rd edition,Wiley 1999)。具體實例描述於後續段落中。
多成分環化(II)→(V)係於鹼存在下,首先將式(Ⅱ)亞胺酸酯與式(Ⅲ)醯氯反應,形成中間化合物,其在後續步驟與式(IV)芳基聯胺化合物反應。通常形成的中間化合物不分離,且二步驟反應在一鍋中進行。式(I)芳基聯胺化合物也可以其鹽類形式使用,例如氫氯酸鹽或甲苯磺酸鹽。在鹼性反應條件下,聯胺鹽將再轉化為游離鹼形式。然後可在這方面調整添加鹼的量。較加在第二步驟中添加銅或鋅鹽,如硫酸銅(II)、氯化銅(II)、硫酸鋅(II)和氯化鋅(II),通常且較佳使用硫酸銅(II)和硫酸鋅(II)。
該二步驟的合適鹼通常皆為三級胺鹼,例如N,N-二異丙基乙基胺(DIPEA)、三乙基胺、三異丙胺、N-甲基咪唑、N-甲基嗎啉、吡啶和4-(N,N-二甲基胺基)吡啶。較佳使用N,N-二異丙基乙胺(DIPEA)作為鹼。反應在惰性有機溶劑如二氯甲烷、1,2-二氯乙烷、甲基三級丁醚、四氫呋喃、1,4-二噁烷、1,2-二甲氧基乙烷、甲苯,吡啶、乙酸乙酯,乙腈或N,N-二甲基甲醯胺,或彼等溶劑的混合物中進行。較佳使用四氫呋喃或二噁烷或其混合物作為溶劑。第一步通常在-10℃至+120℃,較佳0℃的溫度下進行。第二步通常在+20℃至+120℃的溫度範圍內進行,較佳在室溫下進行。伴隨微波照射亦可對該反應有助益,在+60℃至+150℃範圍內的溫度下,較佳在+120℃。
胺基裂解反應(V)→(I)通常在氨溶液中進行。適用於此步驟的氨溶液是飽和的氨溶液,具體而言是氨於甲醇、乙醇、異丙醇、四氫呋喃、二噁烷或水或其混合物中的溶液。較佳使用甲醇性氨溶液。反應較佳
於任何其他反應溶劑不存在的情況下,直接在氨溶液中進行。該步驟通常在+20℃至+120℃的溫度範圍內進行,較佳在室溫下進行。伴隨微波照射亦可對該反應有助益,在+60℃至+150℃範圍內的溫度下,較佳在+120℃。
氧化反應(I-A)→(I-B)係使用文獻上習知的一般氧化方法進行[如JOC,1983,48,4155(Dess Martin氧化反應);Tet Lett,1994,35,3485(IBX氧化反應);JOC,1970,35,3589(酸性重鉻酸鹽氧化反應);Tet Lett,1979,399(PDC氧化反應);Tetrahedron,1978,34,1651(Swern氧化反應)]。因此,通式(I-A)化合物中的醇基較佳使用Dess-Martin過碘烷(DMP)氧化。在典型方法中,反應在二氯甲烷中,於0℃下進行,隨後升溫至室溫。
通式(II)化合物如定義,可使用包含下步驟之方法製備[a]容許式(VI)中間化合物:
其中R1如通式(I)化合物所定義,與通式(VII)腈化合物反應,
其中X代表離去基,如氯、溴、碘、甲磺酸酯或甲苯磺酸酯,具體而言為氯或溴,因此得到通式(VIII)化合物
其中R1如通式(I)化合物所定義,隨後為後續步驟[b]容許步驟[a]取得之式(VIII)化合物與鹼性醇化物反應,較佳為甲醇鈉,由此得到通式(II)化合物,
其中R1如通式(I)化合物所定義,R3代表(C1-C4)烷基,具體而言甲基。
N-烷基化反應(VI)+(VII)→(VIII)(步驟[a])通常於鹼存在下進行。典型和示例性鹼類包括碳酸鈉、碳酸鉀、碳酸銫、N,N-二異丙基乙基胺、三乙胺、三級丁酸鈉或三級丁酸鉀之乙腈溶液、甲基異丁酮、二噁烷、二甲基甲醯胺、二甲基乙醯胺、N-甲基吡咯烷酮、二甲基亞碸和環丁碸,較佳為碳酸鉀之甲基異丁基酮或乙腈溶液。反應較佳可任選地加入烷基化催化劑,例如溴化鋰、碘化鈉、碘化鋰、四-正丁基-溴化銨、四-正丁基-碘化銨,或芐基三乙基氯化銨。反應通常在+40℃至+120℃,較佳+60℃至+80℃的溫度範圍內進行。反應可以在大氣壓下、在較高或較低的壓力下進行(如0.5至5巴);通常反應在大氣壓下進行。緩慢地在更長的時間內加入烷基化劑(VII)可能有利。
可經由本領域技術人員習知的標準反應流程(步驟[b]:(VIII)→(II))實現通式(II)的醯亞胺化轉化。反應通常在鹼性反應條件下,與鹼性醇化物反應而進行。典型的鹼可以是甲醇鈉、乙醇鈉、丙醇鈉、異丙醇鈉、三級丁基鈉或三級丁基鉀之甲醇、乙醇、正丙醇、異丙醇、正丁醇、異丁醇與第三-丁醇溶液。較佳為甲醇中的甲醇鈉。反應通常在+20℃至+80℃,較佳+20℃至+40℃的溫度範圍內進行轉化。
或者,通式(VIII)腈化合物可任意地如下列流程2製備:
TFAA=三氟醋酸酐
醯胺偶聯(IX)→(X)可直接在縮合劑或活化劑協助下,在鹼存在下進行,或經由醯氯或羧酸咪唑物進行兩步以上的反應。在方法步驟(IX)→(X)中用於醯胺形成的典型的縮合和活化劑包括例如碳二亞醯胺,如N,N'-二乙基-、N,N'-二丙基-、N,N'-二異丙基-N,N'-二環己基碳二亞醯胺(DCC)或N-(3-二甲基胺基異丙基)-N'-乙基二碳二亞醯胺鹽酸鹽(EDC)、光氣衍生物如N,N'-羰基二咪唑(CDI)、1,2-噁唑鎓化合物如2-乙基-5-苯基-1,2-噁唑鎓-3-硫酸酯或2-三級丁基-5-甲基-異噁唑過氯酸鹽、醯基胺基化合物如2-乙氧基-1-乙氧基羰基-1,2-二氫喹啉或氯甲酸異丁酯、丙烷膦酸酐、氰基膦酸二乙酯、雙(2-側氧-3-噁唑啶)氯化磷、苯並三唑-1-基氧基三(二甲基胺基)鏻六氟磷酸鹽(PyBOP)、O-(苯並三唑-1-基)-N,N,N',N'-四甲基脲四氟硼酸鹽(TBTU)、O-(苯並三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸鹽(HBTU)、2-(2-
側氧-1-(2H)-吡啶基)-1,1,3,3-四甲基脲四氟硼酸鹽(TPTU)、O-(7-氮雜苯並三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸鹽(HATU)或O-(1H-6-氯-苯並三唑-1-基)-1,1,3,3-四甲基脲四氟硼酸鹽(TCTU),任選地與其他添加劑如1-羥基苯並三唑(HOBt)或N-羥基琥珀亞醯胺(HOSu)組合。醯氯通常以亞硫醯氯或草醯氯,在惰性溶劑如二氯甲烷或N,N-二甲基甲醯胺中製備。也可以使用所述溶劑的混合物。
典型和示例性鹼包括碳酸鈉、碳酸鉀、碳酸銫、N,N-二異丙基乙胺、三乙胺、三級丁酸鈉或三級丁基酯之乙腈溶液、甲基異丁酮、二噁烷、二甲基甲醯胺、二甲基乙醯胺、N-甲基吡咯烷酮、二甲基亞碸和環丁碸,較佳為碳酸鉀之甲基-異丁基酮或乙腈溶液。反應較佳可任選地加入烷基化催化劑,如溴化鋰、碘化鈉、碘化鋰、四-正丁基-溴化銨、四-正丁基-碘化銨或芐基三乙基氯化銨。腈(X)→(XI)之轉化可在脫水劑的幫助下進行。典型的脫水劑包括三氟乙酸酐、五氧化二磷(P4O10)、磷醯氯(POCl3)、五氯化磷(PCl5)、CCl4-PPh3(Appel試劑)、六甲基磷醯胺(HMPA);甲基N-(三乙基-N-磺醯基)胺基甲酸酯(Burgess試劑)、(氯亞甲基)二甲基氯化銨(Vilsmeier試劑)、草醯氯/DMSO和亞硫醯氯(SOCl2)。
步驟(IX)→(X)與(X)→(XI)的典型和示例性溶劑包括例如醚類如二乙醚、二噁烷、四氫呋喃、乙二醇二甲醚或二乙二醇二甲醚、烴類如苯、甲苯、二甲苯、己烷、環己烷或礦物油、餾分、鹵化烴類如二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷、三氯乙烯或氯苯,或其他溶劑如丙酮、乙酸乙酯、乙腈、吡啶、二甲基亞碸、N,N-二甲基甲醯胺、N,N'-二甲基丙烯脲(DMPU)或N-甲基吡咯烷酮(NMP)。也可以使用所述溶劑的混合物。
在典型和較佳流程中,羧酸(IX)首先與新戊醯氯反應,在吡
啶存在下,形成中間化合物,其在隨後的步驟中與氨反應。通常形成的中間化合物不分離,且兩個步驟反應在一鍋中進行。適用於第一步驟的鹼較佳為吡啶、4-(N,N-二甲基胺基)吡啶或N,N-二異丙基乙胺(DIPEA)。之後進行甲醯胺(X)轉化成腈(VIII),通常藉由與三氟乙酸酐反應來進行。二反應均在惰性有機溶劑,較佳為四氫呋喃中進行。
式(VI)與(IX)化合物可經由國際專利申請案號WO 2010/105770與WO 2011/104322中所描述之流程合成(亦請見下列合成流程3與4)。
式(III)、(IV)和(VII)化合物是商業上可獲得、文獻中習知,或可由容易獲得的原料,採用文獻中所述的標準方法製備。製備起始材料的詳細流程和文獻參考資料,也可以在實驗部分的起始物材料和中間化合物製備部分中找到。
本發明化合物之製備可由下列合成說明:
流程3
[參見國際專利申請號WO 2011/104322-A1].
本發明通式(I)化合物可以本領域技術人員習知的任何方法轉化為任何鹽類,較佳為醫藥上可接受鹽類。類似地,本發明通式(I)化合物的任何鹽類可以本領域技術人員習知的任何方法轉化為游離化合物。
本發明化合物具珍貴的藥理學性質,可用於預防及/或治療
人類和其他哺乳動物中各種疾病與疾病誘發狀態。本發明通式(I)化合物表現出珍貴的藥理作用光譜和藥物動力學特徵,兩者皆無法預測。令人驚奇地發現,本發明化合物可有效抑制血管加壓素V1a受體,因此該化合物可用於治療及/或預防人類與動物的疾病,較佳為腎臟和心血管疾病。
在本發明的上下文中,術語「治療(treatment)」或「治療(treating)」包括抑制、延遲、緩和,減輕、阻止、減少,或導致疾病、病症、狀況或狀態,其發展及/或進展,及/或其症狀的消退。術語「預防(prevention)」或「預防(preventing)」包括減少疾病、病症、狀況或狀態,其發展及/或進展,及/或其症狀的風險。術語預防(prevention)包括預防(prophylaxis)。病症、疾病、狀況或狀態的治療或預防可能是部分或完全的。
在本文中,為了簡單起見,較偏好使用單數語言而非複數語言,但通常意在包括複數語言,如果不是另外說明的話。例如,「一種治療患者疾病的方法,包括投予一患者一有效量的式(I)化合物」意在包括同時治療多種疾病,以及投予大於一式(I)化合物。
本發明的化合物具高藥效,特別是血管加壓素V1a受體的選擇性拮抗劑。因此,預期本發明化合物可作為用於治療及/或預防疾病的高效治療劑,尤其是用於治療及/或預防腎臟和心血管疾病。
本文所用的術語「血管加壓素V1a受體拮抗劑」是指藉由抑制(部分或完全)或阻斷血管加壓素V1a受體而發揮作用的化合物,因而阻止血管加壓素活化受體。
在一具體實施例中,本文所述的化合物對V1a受體具活性。在另一具體實施例中,依據B-1研究顯示,本文所述化合物具V1a受體抑制性,IC50<100nM。在另一具體實施例中,依據B-1研究顯示,本文所述化合物具V1a受體抑制性,IC50<20nM。在另一具體實施例中,依據B-1研究顯
示,本文所述化合物具V1a受體抑制性,IC50<10nM。在另一具體實施例中,依據B-1研究顯示,本文所述化合物具V1a受體抑制性,IC50<5nM。在另一具體實施例中,依據B-1研究顯示,本文所述化合物具V1a受體抑制性,IC50<2nM。
在另一具體實施例中,本文所述的化合物在V1a受體上具選擇性活性,並且對其他血管加壓素受體,例如V1b及/或V2亞型,活性較低、明顯較低及/或無活性。在另一具體實施例中,依據B-1研究顯示,與V2受體相較,本文所述的化合物對於V1a受體具至少10倍的選擇性。在另一具體實施例中,依據B-1研究顯示,與V2受體相較,本文所述的化合物對於V1a受體具至少15倍的選擇性。在另一具體實施例中,依據B-1研究顯示,與V2受體相較,本文所述的化合物對於V1a受體具至少20倍的選擇性。在另一具體實施例中,依據B-1研究顯示,與V2受體相較,本文所述的化合物對於V1a受體具至少30倍的選擇性。
本發明化合物適用於治療及/或預防腎臟疾病,具體而言為急性與慢性腎臟疾病、糖尿病性腎病、急性和慢性腎功能衰竭。一般術語「腎臟疾病(renal disease)」或「腎臟疾病(kidney disease)」描述某一類病症,其中腎臟無法從血液中過濾和移除廢物。腎臟疾病有兩種主要形式:急性腎臟疾病(急性腎損傷,AKI)和慢性腎臟疾病(CKD)。本發明化合物亦可用於治療及/或預防多發性損傷引起的急性腎損傷後遺症,例如缺血再灌注損傷、放射線對照性投予、心肺分流手術、休克和敗血症。在本發明的意義上,術語腎衰竭或腎功能不全包括腎功能不全的急性和慢性表現,以及潛在的或相關的腎臟疾病,例如腎低灌流、體內低血壓、尿路阻塞、腎小球病、IgA腎病、腎性腎炎、急性腎小球腎炎、腎小球硬化、腎小管間質性疾病、腎病如原發性和先天性腎病、腎炎、艾伯特症候群(Alport’s syndrome)、
腎臟發炎、免疫性腎臟疾病如腎移植排斥、免疫複合物誘導的腎臟疾病、由毒性物質引起的腎病、造影劑誘導的腎病;血小板變性腎小球性腎炎(脂質性);膜性腎小球性腎炎;局灶性節段性腎小球硬化症(FSGS);溶血性尿毒症症候群(HUS)、澱粉樣變性、古德帕斯特症候群(Goodpasture's syndrome)、韋格納肉芽腫病(Wegener's granulomatosi)、紫癜Schönlein-Henoch、糖尿病和非糖尿病性腎病、腎盂腎炎、腎囊腫、腎硬化、高血壓性腎硬化和腎病症候群,其可以診斷鑑定,如通過異常降低的肌酐及/或水分排泄、尿素、硝基、鉀及/或肌酸酐血液濃度異常增加、腎臟酵素活性的改變,例如穀醯胺合成酶、尿滲透壓或尿量改變、微量白蛋白尿增加、大量尿蛋白、腎小球和小動脈損傷、管狀擴張、高磷酸血症及/或需要透析。本發明亦包括使用本發明化合物治療及/或預防腎功能不全的後遺症,例如肺水腫、心臟衰竭、尿血症、貧血、電解質紊亂(例如高鉀血症、低鈉血症)和骨骼與碳水化合物代謝紊亂。本發明化合物也適用於治療及/或預防多囊腎病(PCKD)和ADH分泌不足症候群(SIADH)。
在本文中,可以本發明化合物治療及/或預處理的心血管疾病包括但不限於以下:急性和慢性心臟衰竭,包括惡化的慢性心臟衰竭(或心臟衰竭住院治療),並包括充血性心臟衰竭、動脈性高血壓、耐藥性高血壓、動脈血壓升高、冠心病、穩定型和不穩定型心絞痛、心房和心律失常、心律失常室性節律和傳導障礙,如I-III級房室傳導阻斷(AVB I-III)、室上性快速性心律失常、心房顫動、心房撲動、心室顫動、心室撲動、室性快速性心律失常、定位心動過速、心房和心室前收縮、AV結結外收、病竇症候群、暈厥、AV結節再入性心動過速和Wolff-Parkinson-White症候群、急性冠狀動脈綜合徵(ACS)、自體免疫性心臟病(心包炎、心內膜炎、瓣膜炎、主動脈炎、心肌病)、休克如心源性休克、膿毒性休克和消化性休克、動脈
瘤、拳擊手心肌病(過早的心室收縮)、進一步的血栓栓塞性疾病和局部缺血,如周圍灌注紊亂、再灌注損傷、動脈和靜脈血栓形成、心肌功能不全、內皮功能障礙、微與大血管損傷(血管炎),和預防再狹窄如溶栓治療後、經皮腔內血管成形術(PTA)、經皮腔內冠狀動脈血管成形術(PTCA)、心臟轉移和分流手術、動脈硬化、脂質代謝紊亂、低膽固醇蛋白癡呆、血脂異常、高三酸甘油酯血症、高脂血症和聯合高脂血症、高膽固醇血症、腹水脂蛋白血症、豆固醇血症、黃瘤病、丹吉爾病(Tangier disease)、脂肪過多、肥胖症、代謝症候群、轉移性和缺血性發作、中風、發炎性心血管疾病、周圍和心臟血管疾病、周圍循環障礙、冠狀動脈和周圍動脈痙攣,和水腫,例如肺水腫、腦水腫、腎水腫和心臟衰竭相關性水腫。
在本發明的意義上,術語心臟衰竭尚包括更具體或相關的疾病形式,例如右心衰竭、左心衰竭、全身功能不全、缺血性心肌病、擴張型心肌病、先天性心臟病、心臟瓣膜缺損、心臟瓣膜缺損之心臟衰竭、二尖瓣狹窄、二尖瓣功能不全、主動脈瓣狹窄、主動脈瓣關閉不全、三尖瓣狹窄、三尖瓣關閉不全、肺動脈瓣狹窄、肺動脈瓣關閉不全、合併性心臟瓣膜缺損、心肌發炎(心肌炎)、慢性心肌炎、急性心肌炎、病毒性心肌炎、糖尿病性心臟衰竭、酒精中毒性心肌病、心臟儲存疾病、正常收縮分率之心臟衰竭(HFpEF或舒張性心臟衰竭)和低收縮分率之心臟衰竭(HFrEF或收縮性心臟衰竭)。
本發明化合物可特別用於治療及/或預防心腎症後群(CRS)及其各種亞型。此術語包括心臟和腎臟的特定病症,其中一個器官的急性或慢性功能障礙,可能誘發另一器官的急性或慢性功能障礙。
此外,本發明化合物可用於治療及/或預防周圍動脈疾病(PAD),包括跛行,包括臨界肢體缺血、冠狀動脈微血管功能障礙(CMD)
包括CMD 1-4型、原發性和繼發性雷諾現象(Raynaud's phenomenon)、微循環障礙、周邊和自主神經病變、糖尿病性微血管病、糖尿病性視網膜病變、糖尿病性肢體潰瘍、壞疽、CREST症候群、紅斑性疾病、風濕性疾病和促進傷口癒合。
此外,本發明化合物適用於治療泌尿系統疾病和男性與女性泌尿生殖系統疾病,例如良性前列腺症後群(BPS)、良性前列腺增生(BPH)、良性前列腺擴大(BPE)、膀胱出口阻塞(BOO)、下尿路症後群(LUTS)、神經源性膀胱過度活動症(OAB)、間質性膀胱炎(IC)、尿失禁(UI)例如混合性、促進性、應力性和溢流性蕁麻疹(MUI、UUI、SUI、OUI)、骨盆腔疼痛、勃起功能障礙、痛經和子宮內膜異位症。
依據本發明的化合物還可用於治療及/或預防發炎性疾病、氣喘病、慢性阻塞性肺病(COPD)、急性呼吸窘迫症候群(ARDS)、急性肺損傷(ALI)α-1-抗胰蛋白酶缺乏症(AATD)、肺纖維化、肺氣腫(例如吸煙引起的肺氣腫)和囊性纖維化(CF)。此外,本發明的化合物可用於治療及/或預防肺動脈高壓(PAH)和其他形式的肺動脈高壓(PH),包括與左心室疾病相關的肺動脈高壓、HIV感染、鐮狀細胞性貧血、血栓栓塞(CTEPH)、結節病、慢性阻塞性肺病(COPD)或肺纖維化。
此外,本發明化合物可用於治療及/或預防肝硬化、腹水、糖尿病和糖尿病併發症,例如神經性疾病和腎臟病。
此外,本發明化合物適用於治療及/或預防中樞神經障礙,例如焦慮狀態、抑鬱症、青光眼、癌症,特別是肺腫瘤、以及晝夜節律失調,例如時差和輪班。
此外,本發明化合物可用於治療及/或預防疼痛症狀、腎上腺疾病,例如肝細胞瘤和腎上腺中風、腸病例如克羅恩病(Crohn's disease)
和腹瀉、月經紊亂例如痛經、子宮內膜異位症、早產、及分娩。
由於其活性和選擇性,本發明化合物被認為是特別適合治療及/或預防急性與慢性腎臟疾病,包括糖尿病腎病、急性與慢性心臟衰竭、子癎前症、周邊動脈疾病(PAD)、冠狀動脈微血管功能障礙(CMD)、雷諾氏症、及痛經。
上述疾病已於人類中良好鑑定出,但在其他哺乳動物中也存在可比擬之病因,並可用本發明化合物和方法進行治療。
因此,本發明亦涉及本發明化合物用於治療及/或預防疾病,特別是上述疾病的用途。
本發明亦涉及以本發明化合物製備用於治療及/或預防疾病,特別是上述疾病的醫藥組成物之用途。
本發明亦涉及在治療及/或預防疾病,特別是上述疾病的方法中,使用本發明化合物。
本發明亦涉及一治療及/或預防疾病,特別是上述疾病的方法,藉由使用有效量的至少一本發明化合物達成。
依據另一態樣,本發明涵蓋醫藥組成物,具體而言包含至少一本發明通式(I)的化合物和至少一或多個其他活性成分之藥物,具體而言其用於治療及/或預防疾病,特別是上述疾病。
具體而言,本發明涵蓋一醫藥組成物,其包含:●一或多個第一活性成分,具體而言為如上述定義之通式(I)化合物●一或多個其他活性成分,具體而言可治療及/或預防疾病,特別是上述疾病。
本發明中的術語「組合」如本領域技術人員所知使用,該組合可以是固定組合、非固定組合或試劑盒(kit-of-parts)。
本發明中的「固定組合」係以本領域技術人員習知者使用,且被定義為例如其中第一活性成分,如一或多個通式(I)化合物,與其他活性成分,共同存在於一單位劑量或依單一整體中之組合。「固定組合」的一個實例是一醫藥組成物,其中第一活性成分和其他活性成分以混合物的形式存在,用於同時投予,例如置於一製劑中。「固定組合」的另一實例為一醫藥組合,其中第一活性成分和其他活性成分存在於一單位中而非混合物形式。
本發明中的非固定組合或「試劑盒(kit-of-parts)」係以如本領域技術人員習知者使用,且被定義為其中第一活性成分和其他活性成分存在於大於一個單元中的組合。非固定組合或試劑盒之一實例是其中第一活性成分和其他活性成分分開存在的組合。非固定組合或試劑盒(kit-of-parts)的各組件可分開、依序、一起、同時、或按時間順序交錯進行投予。
本發明化合物可作為唯一的藥劑或與一或多個其他醫藥活性成分組合投予,其中該組合不會引起無法接受之不良反應。本發明亦涵蓋此類醫藥組成物。舉例而言,本發明化合物可組合用於治療及/或預防疾病(特別是上述疾病)之習知藥劑。
具體而言,本發明化合物可與下列物質,以固定或分開組合一起使用
●抗血栓形成劑,例如且較佳來自血小板聚集劑抑制劑、抗凝血劑和抗纖維蛋白溶解物質;●降血壓試劑,例如且較佳選自於鈣拮抗劑、血壓收縮素AII拮抗劑、ACE抑制劑、NEP抑制劑、血管肽酶抑制劑、內皮素拮抗劑、腎素抑制劑、α-阻斷劑、β-阻斷劑、鹽皮質素受體拮抗劑和利尿劑之群組;
●抗糖尿病試劑(降血糖或抗高血糖藥),例如且較佳為胰島素和衍生物、磺醯脲類、雙胍類、噻唑烷二酮類、阿卡波糖、DPP4抑制劑、GLP-1類似物或SGLT抑制劑(格列黴素(gliflozins))。
●有機硝化物與一氧化氮供體,如硝普鈉、硝酸甘油、單硝酸異山梨酯、二硝酸異山梨酯、嗎多明(molsidomine)或SIN-1,與吸入式一氧化氮;●抑制環鳥嘌呤單磷酸(cGMP)降解的化合物,如磷酸二酯酶(PDE)1、2、5及/或9抑制劑,具體而言PDE-5抑制劑如西地那非(sildenafil)、伐地那非(vardenafil)、他達拉非(tadalafil)、烏丹那非(udenafil)、丹薩他非(dasantafil)、艾凡那非(avanafil)、米羅奈非(mirodenafil)、洛德那非(lodenafil)、CTP-499或PF-00489791;●利鈉肽如心房利鈉肽(ANP,阿拉里肽)、B型利鈉肽或腦利鈉肽(BNP,奈西瑞肽(nesiritide))、C型利鈉肽(CNP)或尿嘧啶;●鈣敏化劑,例如且較佳為左西孟旦(levosimendan);●鳥苷酸環化酶(sGC)之一氧化氮與血紅素非依賴性活化劑,例如且較佳為描述於WO 01/19355、WO 01/19776、WO 01/19778、WO 01/19780、WO 02/070462與WO 02/070510中者;●鳥苷酸環化酶(sGC)之一氧化氮非依賴性但血紅素依賴性刺激劑,例如且較佳為描述於WO 00/06568、WO 00/06569、WO 02/42301、WO 03/095451、WO 2011/147809、WO 2012/004258、WO 2012/028647與WO 2012/059549中者;●可刺激cGMP合成之試劑,例如且較佳為sGC調節劑,例如且較佳為瑞西國(riociguat)、西那西國(cinaciguat)、凡瑞西國(vericiguat)或BAY 1101042;
●人類嗜中性粒細胞彈性蛋白酶(HNE)抑制劑,如西為雷斯特(sivelestat)或DX-890(瑞傳(reltran));●抑制訊息傳遞級聯的化合物,具體而言為酪胺酸及/或絲胺酸/蘇胺酸激酶抑制劑,例如奈丹替尼(nintedanib)、達沙替尼(dasatinib)、尼洛西坦(nilotinib)、波蘇替尼(bosutinib)、瑞格分(regorafenfen)、索拉分(sorafenfen)、舒尼替尼(sunitinib)、西地平(cediranib)、舒尼替尼(axitinib)、特拉替尼(telatinib)、依馬替尼(imatitinib)、瑞華替尼(brivanib)、帕索盤尼(pazopanib)、維它拉尼(vatalanib)、吉非替尼(gefitinib)、厄洛替尼(erlotinib)、拉帕替尼(lapatinib)、卡諾替尼(canertinib)、雷托替尼(lestaurtinib)、佩利替尼(pelitinib)、西美沙尼(semaxannib)或潭度替尼(tandutinib);●影響心臟能量代謝的化合物,例如且較佳為依托莫昔(etomoxir)、二氯乙酸鹽、雷諾嗪(ranolazine)或曲美他嗪(trimetazidine),或全部或部分腺苷A1受體協同劑,如GS-9667(舊稱為CVT-3619),卡帕諾生(capadenoson)和尼拉多所(neladenoson bialanate)(BAY 1067197);●影響心率的化合物,例如且較佳為伊伐布雷定(ivabradine);●心肌肌球蛋白活化劑,例如且較佳為奧美卡莫司他啶(omecamtiv mecarbil)(CK-1827452);●抗發炎藥物如非類固醇抗發炎藥物(NSAIDs),包括乙醯水楊酸(阿司匹林)、布洛芬(ibuprofen)和萘普生(naproxen)、糖皮質激素例如且較佳為潑尼松龍(prednison)、甲基潑尼松龍、曲安奈德(triamcinolon)、地塞米松(dexamethason)、倍氯米松(beclomethason)、倍他米松(betamethason)、氟尼松(flunisolid)、布地奈德(budesonid)或氟替卡松(fluticason)、5-胺基
水楊酸衍生物、白三烯拮抗劑、TNF-α抑制劑和趨化因子受體拮抗劑如CCR1、2、及/或5抑制劑;●脂肪代謝改變劑,例如且較佳來自甲狀腺受體協同劑、膽固醇合成抑制劑,例如且較佳為HMG-CoA還原酶或角鯊烯合成抑制劑、ACAT抑制劑、CETP抑制劑、MTP抑制劑、PPAR-α、PPAR-γ及/或PPAR-δ協同劑、膽固醇吸收抑制劑、脂肪酶抑制劑、聚膽汁酸吸附劑、膽汁酸再吸收抑制劑和脂蛋白(a)拮抗劑。
抗血栓劑較佳理解為來自血小板凝集抑制劑、抗凝血劑和纖維蛋白溶解物質之群組。
在本發明較佳具體實施例中,本發明化合物與血小板凝集抑制劑係組合投予,例如且較佳為阿司匹林(aspirin)、氯吡格雷(clopi-dogrel)、噻氯匹定(ticlopidine)或雙嘧達莫(dipyridamole)。
在本發明較佳具體實施例中,本發明化合物與血栓抑制劑組合投予,例如且較佳為西美加群(ximelagatran)、達比加群(dabigatran)、米拉群坦(melagatran)、比伐盧定(bivalirudin)、或依諾肝素(enoxaparin)。
在本發明較佳具體實施例中,本發明化合物與GPIIb/IIIa拮抗劑組合投予,例如且較佳為替羅法班(tirofiban)或阿昔單抗(abcixi-mab)。
在本發明較佳具體實施例中,本發明化合物與因子Xa抑制劑組合投予,例如且較佳為利伐沙班(rivaroxaban)、阿哌沙班(apixaban)、奧他他濱(otamixaban)、依諾沙班(fidexaban)、拉扎沙班(razaxaban)、芳達帕瑞(fondaparinux)、衣達帕瑞(idraparinux)、DU-176b、PMD-3112、YM-150、KFA-1982、EMD-503982、MCM-17、MLN-1021、DX 9065a、DPC 906、JTV 803、SSR-126512或SSR-128428。
在本發明較佳具體實施例中,本發明化合物與肝素或低分子量(LMW)肝素衍生物組合投予。
在本發明較佳具體實施例中,本發明化合物與維生素K組合投予,例如且較佳為香豆素(coumarin)。
降血壓劑較佳理解為選自於鈣拮抗劑、血管收縮素AII拮抗劑、ACE抑制劑、NEP抑制劑、血管肽酶抑制劑、內皮素拮抗劑、腎素抑制劑、α-阻斷劑、β-阻斷劑、鹽皮質素受體拮抗劑與利尿劑群組之化合物。
在本發明較佳具體實施例中,本發明化合物與鈣拮抗劑組合投予,較佳為硝苯地平(nifedipine)、氨氯地平(amlodipine)、維拉帕米(verapamil)、或地爾硫卓(diltiazem)。
在本發明較佳具體實施例中,本發明化合物與α-1-受體阻斷劑組合投予,較佳為哌唑嗪(prazosin)或替莫西林(tamsulosin)。
在本發明較佳具體實施例中,本發明化合物與β-阻斷劑組合投予,例如且較佳為普萘洛爾(propranolol)、阿替洛爾(atenolol)、替莫洛爾(timolol)、吲哚洛爾(pindolol)、阿普洛爾(alprenolol)、歐平洛爾(oxprenolol)、潘布洛爾(penbutolol)、苯丙酮酸(bupranolol)、美替洛爾(metipranolol)、奈多洛爾(nadolol)、甲氧吲哚(mepindolol)、卡羅洛爾(carazolol)、索他洛爾(sotalol)、美托洛爾(metoprolol)、倍他洛爾(betaxolol)、塞羅洛爾(celiprolol)、比索洛爾(bisoprolol)、卡替洛爾(carteolol)、艾司洛爾(esmolol)、拉貝洛爾(labetalol)、卡維地洛(carvedilol)、阿德洛爾(adaprolol)、蘭諾洛爾(landiolol)、奈必洛爾(nebivolol)、依諾洛爾(epanolol)或布可洛爾(bucindolol)。
在本發明較佳具體實施例中,本發明化合物與血管收縮素
AII受體拮抗劑組合投予,例如且較佳為洛沙坦(losartan)、坎地沙坦(candesartan)、纈沙坦(valsartan)、替米沙坦(telmisartan)、厄貝沙坦(irbesartan)、奧美沙坦(olmesartan)、依普羅沙坦(eprosartan)、奧沙沙坦(embursartan)或阿齊沙坦(azilsartan)。
在本發明較佳具體實施例中,本發明化合物與血管肽酶抑制劑或中性肽鏈內切酶(NEP)抑制劑組合投予,例如且較佳為薩庫必妥(sacubitril)、歐瑪帕妥(omapatrilat)、或AVE-7688。
在本發明較佳具體實施例中,本發明化合物與雙重血管收縮素AII受體拮抗劑/NEP抑制劑(ARNI)組合投予,例如且較佳為LCZ696。
在本發明較佳具體實施例中,本發明化合物與ACE抑制劑組合投予,例如且較佳為依那普利(enalapril)、卡托普利(captopril)、賴諾普利(lisinopril)、雷米普利(ramipril)、達美普利(delapril)、福斯普利(fosinopril)、奎諾普(quinopril)、培哚普利(perindopril)、貝那普利(benazepril)或群多普利(trandopril)。
在本發明較佳具體實施例中,本發明化合物與內皮素拮抗劑組合投予,例如且較佳為波生坦(bosentan)、丹參酮(darusentan)、安立生坦(ambrisentan)、替佐生坦(tezosentan)、西他生坦(sitaxsentan)、阿泊生坦(avosentan)、麥考坦(macitentan)、或阿曲他汀(atrasentan)。
在本發明較佳具體實施例中,本發明化合物與腎素抑制劑組合投予,例如且較佳為阿利吉崙(aliskiren)、SPP-600、或SPP-800。
在本發明較佳具體實施例中,本發明化合物與鹽皮質激素受體拮抗劑組合投予,例如且較佳為精細酮(finerenone)、螺內酯(spironolactone)、卡內酮(canrenone)、卡內酮鉀(potassium canrenoate)、依普利酮(eplerenone)、西沙酮(esaxerenone)(CS-3150)、或阿撲可隆
(apararenone)(MT-3995)。
在本發明較佳具體實施例中,本發明化合物與利尿劑組合投予,例如且較佳為呋塞米(furosemide)、布美他尼(bumetanide)、哌替尼(piretanide)、托塞米特(torsemide)、彎氟噻嗪(bendroflumethiazide)、氯噻嗪(chlorothiazide)、氫氯噻嗪(hydrochlorothiazide)、昔帕胺(xipamide)、吲達帕胺(indapamide)、氫氟噻嗪(hydroflumethiazide)、甲基噻嗪(methyclothiazide)、聚噻嗪(polythiazide)、三氯甲嘧啶(trichloromethiazide)、氯噻酮(chlorothalidone)、美托拉宗(metolazone)、喹硫酮(quinethazone)、乙醯唑胺(acetazolamide)、二氯苯醯胺(dichlorophenamide)、甲基咪唑醯胺(methazolamide)、甘油、異山梨醇、甘露醇、阿米洛利(amiloride)、或三安泰林(triamterene)。
脂肪代謝改變劑較佳理解為源自CETP抑制劑、甲狀腺受體協同劑、膽固醇合成抑制劑如HMG-CoA-還原酶或角鯊烯合成抑制劑、ACAT抑制劑、MTP抑制劑、PPAR-α、PPAR-γ及/或PPAR-δ協同劑、膽固醇吸收抑制劑、聚合膽酸吸附劑、膽酸再吸收抑制劑、脂肪酶抑制劑、及脂蛋白(a)拮抗劑之群組。
在本發明較佳具體實施例中,本發明化合物與CETP抑制劑組合投予,例如且較佳為達西它埤(dalcetrapib)、安西他埤(anacetrapib)、BAY 60-5521、或CETP-疫苗(Avant)。
在本發明較佳具體實施例中,本發明化合物與甲狀腺受體協同劑組合投予,例如且較佳為D-甲狀腺素、3,5,3'-三碘甲狀腺原氨酸(T3)、CGS 23425、或安西替隆(axitirome)(CGS 26214)。
在本發明較佳具體實施例中,本發明化合物與他汀(statin)類的HMG-CoA還原酶抑制劑組合投予,例如且較佳為洛伐他汀
(lovastatin)、辛伐他汀(simvastatin)、普伐他汀(pravastatin)、氟伐他汀(fluvastatin)、阿托伐他汀(atorvastatin)、羅蘇伐他汀(rosuvastatin)、或皮託他汀(pitavastatin)。
在本發明較佳具體實施例中,本發明化合物與角鯊烯合成抑制劑組合施用,例如且較佳為BMS-188494或TAK-475。
在本發明較佳具體實施例中,本發明化合物與ACAT抑制劑組合投予,例如且較佳為阿伐西密(avasimibe)、蜜胺醯胺(melinamide)、佩克替米(pactimibe)、依芙替米(eflucimibe)、或SMP-797。
在本發明較佳具體實施例中,本發明化合物與MTP抑制劑組合投予,例如且較佳為印里它埤(implitapide)、R-103757、BMS-201038、或JTT-130。
在本發明較佳具體實施例中,本發明化合物與PPAR-γ協同劑組合投予,例如且較佳為吡格列酮(pioglitazone)或羅格列酮(rosiglitazone)。
在本發明較佳具體實施例中,本發明化合物與PPAR-δ協同劑組合投予,例如且較佳為GW 501516或BAY 68-5042。
在本發明較佳具體實施例中,本發明化合物與膽固醇吸收抑制劑組合投予,例如且較佳為依澤替米貝(ezetimibe)、替奎斯(tiqueside)、或帕馬斯(pamaqueside)。
在本發明較佳具體實施例中,本發明化合物與脂肪酶抑制劑組合投予,例如且較佳為奧利斯他(orlistat)。
在本發明較佳具體實施例中,本發明化合物與聚合膽汁酸吸附劑組合投予,例如且較佳為考來烯胺(colesolvam)、考來斯塔凝膠(CholestaGel)、或考來斯替米(colestimide)。
在本發明較佳具體實施例中,本發明化合物與膽酸再吸收抑制劑組合投予,例如且較佳為ASBT(=IBAT)抑制劑,如AZD-7806、S-8921、AK-105、BARI-1741、SC-435、或SC-635。
在本發明較佳具體實施例中,本發明化合物與脂蛋白(a)拮抗劑組合投予,例如且較佳為吉卡濱鈣(gemcabene calcium)(CI-1027)或菸鹼酸。
在本發明較佳具體實施例中,本發明化合物與TGFB拮抗劑組合投予,例如且較佳為吡非尼酮(pirfenidone)或佛索林瑪(fresolimumab)。
在本發明較佳具體實施例中,本發明化合物與HIF-PH抑制劑組合投予,例如且較佳為莫利達斯他(molidustat)或羅沙達斯他(roxadustat)。
在本發明較佳具體實施例中,本發明化合物與CCR2拮抗劑組合投予,例如且較佳為CCX-140。
在本發明較佳具體實施例中,本發明化合物與TNFα拮抗劑組合投予,例如且較佳為阿達木單抗(adalimumab)。
在本發明較佳具體實施例中,本發明化合物與半乳糖凝集素-3抑制劑組合投予,例如且較佳為GCS-100。
在本發明較佳具體實施例中,本發明化合物與BMP-7協同劑組合投予,例如且較佳為THR-184。
在本發明較佳具體實施例中,本發明化合物與NOX1/4抑制劑組合投予,例如且較佳為GKT-137831。
在本發明較佳具體實施例中,本發明化合物與影響維生素D代謝的藥物組合投予,例如且較佳為膽鈣化醇或帕立骨化醇
(paracalcitol)。
在本發明較佳具體實施例中,本發明化合物與細胞生長抑制劑組合投予,例如且較佳為環磷醯胺。
在本發明較佳具體實施例中,本發明化合物與免疫抑制劑組合投予,例如且較佳為環孢素(ciclosporin)。
在本發明較佳具體實施例中,本發明化合物與磷酸鹽結合劑組合投予,例如且較佳為賽維默(sevelamer)或碳酸鑭。
在本發明較佳具體實施例中,本發明化合物與用於治療副甲狀腺功能亢進的擬鈣劑(calcimimetic)組合投予。
在本發明較佳具體實施例中,本發明化合物與缺鐵治療試劑組合投予,例如且較佳為鐵產物。
在本發明較佳具體實施例中,本發明化合物與高尿酸血症治療試劑組合投予,例如且較佳為別嘌醇(allopurinol)或拉布力酶(rasburicase)。
在本發明較佳具體實施例中,本發明化合物與用於治療貧血的醣蛋白激素組合投予。
在本發明較佳具體實施例中,本發明化合物與免疫治療生物物質製劑組合投予,例如且較佳為阿巴西普(abatacept)、利妥昔單抗(rituximab)、厄庫珠單抗(eculizumab)、或貝立姆單抗(belimumab)。
在本發明較佳具體實施例中,本發明化合物與Jak抑制劑組合投予,例如且較佳為魯索替尼(ruxolitinib)、托伐菌素(tofacitinib)、巴利司定(baricitinib)、CYT387、GSK2586184、雷司他丁(lestaurtinib)、紫杉醇(pacritinib)(SB1518)、或TG101348。
在本發明較佳具體實施例中,本發明化合物與用於治療微
血栓的前列環素類似物組合投予。
在本發明較佳具體實施例中,本發明化合物與鹼治療組合投予,例如且較佳為碳酸氫鈉。
在本發明較佳具體實施例中,本發明化合物與mTOR抑制劑組合投予,例如且較佳為依維莫司(everolimus)或雷帕黴素(rapamycin)。
在本發明較佳具體實施例中,本發明化合物與NHE3抑制劑組合投予,例如且較佳為AZD1722。
在本發明較佳具體實施例中,本發明化合物與eNOS調節劑組合投予,例如且較佳為沙丙蝶呤(sapropterin)。
在本發明較佳具體實施例中,本發明化合物與CTGF抑制劑組合投予,例如且較佳為FG-3019。
在本發明較佳具體實施例中,本發明化合物與抗糖尿病藥(降血糖或抗高血糖試劑)組合投予,例如且較佳為胰島素和衍生物、磺醯脲類如甲苯磺丁脲(tolbutamide)、碳尿酸(carbutamide)、乙醯己醯胺(acetohexamide)、氯丙醯胺(chlorpropamide)、格列吡嗪(glipizide)、格列齊特(gliclazide)、格列本脲(glibenclamide)、格列本脲(glyburide)、格列波脲(glibornuride)、格列酮(gliquidone)、格列派特(glisoxepide)、格吡瑞胺(glyclopyramide)、格列衛(glimepiride)、JB253和JB558、二甲雙胍如瑞格列奈(repaglinide)與那格列奈(nateglinide)、雙胍如二甲雙胍(metformin)、丁福明(buformin)、噻唑烷二酮如羅格列酮(rosiglitazone)與吡格列酮(pioglitazone)、α-葡萄糖苷酶抑制劑如米格列醇(miglitol)、阿卡波糖(acarbose)和伏格列波糖(voglibose)、DPP4抑制劑如維格列汀(vildagliptin)、西他列汀(sitagliptin)、沙格列汀(saxagliptin)、利格列汀(linagliptin)、阿格列汀(alogliptin)、腎上腺素(septagliptin)與替奈米汀
(teneligliptin)、GLP-1類似物如艾塞那肽(exenatide)(亦稱作艾塞丁-4(exendin-4)、利拉魯肽(liraglutide)、利西沙星(lixisenatide)和塔斯格除(taspoglutide)、或SGLT抑制劑(格列淨(gliflozins)),如卡納格列淨(canagliflozin)、達帕格列淨(dapagliflozin)、及恩格列淨(empagliflozin)。
在本發明較佳具體實施例中,本發明化合物與一或多個額外治療試劑組合投予,選自於由利尿劑、血管收縮素AII拮抗劑、ACE抑制劑、β-受體阻斷劑、鹽皮質素受體拮抗劑、抗糖尿病藥、有機硝酸鹽與NO供應物、可溶性鳥苷酸環化酶(sGC)活化劑與刺激劑、及正性肌力藥組成之群組。
在本發明較佳具體實施例中,本發明化合物與一或多個額外治療試劑組合投予,其係選自於由利尿劑、血管收縮素AII拮抗劑、ACE抑制劑、β受體阻斷劑、鹽皮質素受體拮抗劑、抗糖尿病藥、有機硝酸鹽與NO供體、可溶性鳥苷酸環化酶(sGC)活化劑與刺激劑、抗發炎劑、免疫抑制劑、磷酸鹽結合劑、及/或調控維生素D代謝之化合物組成之群組。因此,在另一具體實施例中,本發明涉及包含至少一本發明化合物及一或多個額外治療劑之醫藥組成物,用於治療及/或預防疾病,特別是上述疾病。
此外,本發明化合物可本身或以組成物方式用於本領域習知之研究與診斷或分析參考標準及其類似技術。
當本發明化合物以藥物形式投予至人類和其他哺乳動物中時,其本身或以醫藥組成物方式,其含有如0.1%至99.5%(更佳地0.5%至90%)之活性成分,與一或多個醫藥上可接受賦形劑組合。
因此,在另一態樣中,本發明有關醫藥組成物,其包含本發明至少一化合物,且常規上伴隨一或多個惰性、無毒之醫藥上可接受賦形劑,及其作為治療及/或預防疾病之用途,特別是上述疾病。
本發明化合物可具全身及/或局部活性。為此,其可以合適之方式投予,例如經由口服、胃腸外、肺、鼻、舌下、舌、口腔、直腸、陰道、皮膚、透皮、結膜、耳部途徑、或作為植入物或支架。
針對彼等投予途徑,本發明化合物可以合適的投予形式投予。
針對口服投予,可將本發明化合物配製成本領域習知以快速及/或以改良方式遞送本發明化合物的劑型,例如藥錠(未包衣或包衣藥錠,如具有用於延遲溶解或不溶性的腸溶或控制釋放包衣)、口服崩解藥錠、薄膜/薄片、薄膜/凍乾物、膠囊(如硬質或軟明膠膠囊)、糖衣藥錠、顆粒劑、丸劑、粉末、乳劑、懸浮液、氣溶膠、或溶液。本發明化合物可以晶形及/或非晶形及/或溶解形式併入該劑型。
腸胃外投予可避免吸收步驟(如靜脈內、動脈內、心內、脊柱內或腹膜內)或吸收包含(如肌內、皮下、皮內、經皮或腹膜內)的影響。適用於腸胃外投予的投予形式為溶液、懸浮液、乳液、凍乾物、或無菌粉末形式的注射與輸注製備物。
適用於其他投予途徑的實例為用於吸入之藥物形式[特別是粉末吸入器、噴霧器]、滴鼻劑、鼻溶液、鼻噴霧劑;用於舌、舌下或口腔投予藥錠/膜劑/片劑/膠囊;栓劑;滴眼劑、眼軟膏、眼浴、眼部插入物、滴耳劑、耳朵噴霧劑、耳用粉末、耳部潤洗劑、耳塞;陰道膠囊、水性懸浮液(乳液、混合攪拌物)、親脂性懸浮液、乳劑、軟膏、霜劑、透皮治療系統(例如貼片)、乳狀物、糊劑、泡沫、粉劑、植入物、或支架。
本發明化合物可加入上述之投予形式中。此可以本身習知之方式混合醫藥上合適之賦形劑而實現。醫藥上合適之賦形劑包括:
●填充劑與載體(如纖維素、微結晶纖維素(如Avicel®)、乳糖、甘露糖醇、澱粉、磷酸鈣(如Di-Cafos®)),●油膏基底(如石油、石蠟、三酸甘油酯、蠟、羊毛蠟、羊毛蠟醇類、羊毛脂、親水性軟膏、聚乙二醇),●栓劑基底(如聚乙二醇、可可油、硬脂肪),●溶劑(如水、乙醇、異丙醇、甘油、丙二醇、中鏈長度三酸甘油酯脂肪油、液體聚乙二醇、石蠟),●表面活性劑、乳化劑、分散劑或潤濕劑(如十二烷基硫酸鈉)、卵磷脂、磷脂質、脂肪醇類(如Lanette®)、水山梨糖醇脂肪酸酯(如Span®)、聚氧乙烯山梨醇脂肪酸酯(如Tween®)、聚氧乙烯脂肪酸甘油酯(如Cremophor®)、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、甘油脂肪酸酯、泊洛沙姆(如Pluronic®),●緩衝劑、酸與鹼(如磷酸鹽、碳酸鹽、檸檬酸、乙酸、氫氯酸、氫氧化鈉溶液、碳酸銨、氨丁三醇、三乙醇胺),●等滲劑(如葡萄糖、氯化鈉),●吸附劑(如高分散二氧化矽),●黏度增加劑、凝膠形成劑、增稠劑、及/或黏合劑(如聚乙烯吡咯烷酮、甲基纖維素、羥基丙基甲基纖維素、羥基丙基纖維素、羧基甲基纖維素鈉、澱粉、卡波姆(carbomers)、聚丙烯酸(例如Carbopol®)、藻酸鹽、明膠),●崩解劑(如修飾澱粉、羧基甲基纖維素鈉、羥基乙酸澱粉鈉(如Explotab®)、交聯聚乙烯吡咯烷酮、交聯羧甲基纖維素鈉(如AcDiSol®)),
●流動調節劑、潤滑劑、助流劑、及脫模劑(例如硬脂酸鎂、硬脂酸、滑石、高分散二氧化矽(如Aerosil®)),●塗料(如糖、紫膠)與薄膜或擴散膜之成膜劑,其可快速溶解或為修飾形式(如聚乙烯吡咯烷酮(如Kollidon®)、聚乙烯醇、羥基丙基甲基纖維素、羥基丙基纖維素、乙基纖維素、羥基丙基甲基纖維素鄰苯二甲酸酯、醋酸纖維素、醋酸鄰苯二甲酸纖維素、聚丙烯酸酯、聚甲基丙烯酸酯如Eudragit®)),●膠囊材料(如明膠、羥基丙基甲基纖維素),●合成聚合物(如聚交酯、聚乙交酯、聚丙烯酸酯、聚甲基丙烯酸酯(如Eudragit®)、聚乙烯吡咯烷酮(如Kollidon®)、聚乙烯醇類、聚乙酸乙烯酯、聚乙烯氧化物、聚乙二醇、及其共聚物與嵌段共聚物),●增塑劑(如聚乙二醇、丙二醇、甘油、三醋酸、檸檬酸三乙醯酯、鄰苯二甲酸二丁酯),●滲透增強劑,●安定劑(如抗氧化劑,如抗壞血酸、抗壞血酸棕櫚酸酯、抗壞血酸鈉、丁基羥基苯甲醚、丁基羥基甲苯、沒食子酸丙酯),●防腐劑(如對羥基苯甲酸酯、山梨酸、硫柳汞、苯扎氯銨、乙酸氯己定(chlorhexidine)、苯甲酸鈉),●著色劑(如無機顏料,如氧化鐵、二氧化鈦),●調味劑、甜味劑、香料、及/或氣味掩蔽劑。
本發明亦有關一醫藥組成物,其包含至少一本發明化合物,與常規上一或多個醫藥上合適之賦形劑,以及其於本發明之用途。
基於習知用於評價心血管與腎臟疾病治療化合物之標準實驗室技術,通過標準毒性試驗與標準藥理學試驗,測定上述哺乳動物所
辨識出的病症,且通過比較彼等結果與使用治療該些病症之習知活性成分或藥物的結果,可易於確定本發明化合物用於治療各所需適應症之有效劑量。投予治療彼等病症之一時施用的活性成分量,可因所使用之具體化合物與劑量單位、投予方式、治療時間、患者年齡與性別、及待治療症狀之性質與程度等因素而廣泛變化。
所投予的活性成分總量通常為每日約0.001毫克/公斤至約200毫克/公斤體重,較佳為每日約0.01毫克/公斤至約20毫克/公斤體重。臨床上有用的投予時程為每日一至三次投予至每四週投予一次。另外,患者在一定時間內未服用藥物的「藥物假期」,可能有利於藥理作用和耐受性之間的整體平衡。單位劑量可含有約0.5毫克至約1500毫克活性成分,且可每日一次或多次或每日少於一次投予。注射投予,包括靜脈內、肌內、皮下與腸胃外注射以及使用輸注技術的平均日劑量較佳為0.01至200毫克/公斤總體重。如所示,本發明化合物可以約0.001毫克/公斤至約10毫克/公斤,較佳約0.01毫克/公斤至約1毫克/公斤體重的劑量腸胃外投予。在口服投予中,示例性劑量範圍為約0.01至100毫克/公斤,較佳約0.01至20毫克/公斤,更佳約0.1至10毫克/公斤體重。中間值至上述值之範圍亦包含於本發明之一部分。
當然,每位患者具體之初始與持續劑量處方,將依據主治醫生診定的病情性質和嚴重程度、所使用的具體化合物活性、患者的年齡和一般症狀、投予時間、投予途徑、藥物排出速度、藥物組合及類似因素而變。本領域技術人員可使用常規治療試驗,以確定本發明化合物或醫藥上可接受鹽類或其酯類或組成物所需之治療模式與劑量數。
以下示例性具體實施例係說明本發明。本發明不侷限於彼等實例。
除非另有說明,以下試驗與實例中的重量百分比皆為分重(parts are by weight)。液體/液體溶液所報導之溶劑比率、稀釋比率、及濃度皆以體積為主。
NMR尖峰形式如其於光譜中所示,尚未考慮可能的高階效應。化學名稱係以ACD/Labs的ACD/命名軟體產生。在特定情況下,以普遍可接受的市售試劑名稱代替ACD/命名軟體產生的名稱。
下表1列出了本段落及實例部分中所使用的縮寫,其在本文中未解釋。其他縮寫具有本領域技術人員習知的含義。
本申請案所述各態樣係以下列實例說明,且彼等實例不以任何方式侷限本發明。
本文所述示例性測試實驗係用於說明本發明,且本發明不侷限於給定之實例。
實驗部分-一般部分
所有試劑,其未於實驗部分中描述合成方法者,可為市售或習知化合物,也可由習知化合物羥由本領域技術人員以習知之方法形成。
依據本發明方法產生的化合物和中間化合物可能需要純化。有機化合物的純化是本領域技術人員習知,且同一化合物可能有多個純化方法。在特定情況下,純化為非必要。在特定情況下,化合物可以通
過結晶進行純化。在特定情況下,可以使用合適溶劑攪拌出雜質。在特定情況下,化合物可以通過層析法,特別是快速管柱層析法純化,例如使用於預填充矽膠柱,如Biotage SNAP柱KP-Sil®或KP-NH®,與Biotage自動純化系統(SP4®或Isolera One®)組合,溶析液如己烷/乙酸乙酯或二氯甲烷/甲醇梯度。在特定情況下,化合物可通過製備級HPLC純化,使用Waters自動純化裝置,其配備二極體陣列偵測器及/或串聯電灑離子化質譜儀,與合適的預充填逆相管柱和溶析液如水和乙腈梯度,其可含有三氟乙酸、甲酸或氨水等添加劑。
在特定情況下,上述純化方法可提供具有足夠鹼性或酸性官能度之本發明化合物鹽類形式,例如在本發明化合物案例中,例如,其為具足夠鹼性的三氟乙酸鹽或甲酸鹽,或者在本發明化合物案例中,例如,其為具足夠酸性的銨鹽。此種鹽類可以通過本領域技術人員習知的各方法,分別轉化成其游離鹼或游離酸形式,或者可以在隨後的生物試驗中使用作為鹽類。應理解到,本文所述之本發明化合物具體形式(如鹽,游離鹼等),如單離形式與此述形式,不一定為唯一形式,其中該化合物可應用於生物試驗中,以定量特定生物活性。
UPLC-MS標準流程
方法1(LC/MS):
儀器:Agilent MS Quad 6150;HPLC:Agilent 1290;管柱:Waters Acquity UPLC HSS T3 1.8μ 50 x 2.1毫米;溶析液A:1公升水+0.25毫升99%甲酸,溶析液B:1公升乙腈+0.25毫升99%甲酸;梯度:0.0分鐘90% A→0.3分鐘90% A→1.7分鐘5% A→3.0分鐘5% A,烘箱:50℃;流速:1,20毫升/分鐘;UV-偵測:205-305奈米。
方法2(LC/MS):
儀器:Waters ACQUITY SQD UPLC系統;管柱:Waters Acquity UPLC HSS T3 1.8μ 50 x 1毫米;溶析液A:1公升水+0.25毫升99%甲酸,溶析液B:1公升乙腈+0.25毫升99%甲酸;梯度:0.0分鐘90% A→1.2分鐘5% A→2.0分鐘5% A,烘箱:50℃;流速:0.40毫升/分鐘;UV-偵測:208-400奈米。
方法3(LC/MS):
儀器MS:Thermo Scientific FT-MS;Gerätetyp UHPLC+:Thermo Scientific UltiMate 3000;管柱:Waters,HSST3,2.1 x 75毫米,C18 1.8微米;溶析液A:1公升水+0.01%甲酸;溶析液B:1l乙腈+0.01%甲酸;梯度:0.0分鐘10% B→2.5分鐘95% B→3.5分鐘95% B;烘箱:50℃;流速:0.90毫升/分鐘;UV-偵測:210奈米/Optimum Integration Path 210-300奈米。
方法4(LC/MS):
儀器:Waters ACQUITY SQD UPLC系統;管柱:Waters Acquity UPLC HSS T3 1.8μ 50 x 1毫米;溶析液A:1公升水+0.25毫升99%甲酸,溶析液B:1l乙腈+0.25毫升99%甲酸;梯度:0.0分鐘95% A→6.0分鐘5% A→7.5分鐘5% A,烘箱:50℃;流速:0.35毫升/分鐘;UV-偵測210-400奈米。
方法5(製備級HPLC):
管柱:Chromatorex或Reprosil C18 10μm;125 x 30毫米,流速:75毫升/分鐘,操作時間:20分鐘,於210奈米偵測,溶析液A:水+0.1%甲酸,溶析液B:乙腈+0.1%甲酸;梯度:3分鐘10% B;17.5分鐘:95% B;19.5分鐘100% B,20分鐘10% B。
實驗部分-起始材料與中間化合物
實施例1A
5-(4-氯化苯基)-4-[(2R)-3,3,3-三氟-2-羥基丙基]-2,4-二氫-3H-1,2,4-三唑-3-酮
5-(4-氯化苯基)-4-(3,3,3-三氟-2,2-二羥基丙基)-2,4-二氫-3H-1,2,4-三唑-3-酮(合成描述於WO 2010/105770-A1之實施例4A)(10.0克,30.9毫莫耳)、N-[(1R,2R)-2-胺基-1,2-二苯基乙基]-4-甲基苯磺醯胺(56.6毫克,154微莫耳)與1-甲基-4-(丙-2-基)苯-二氯化釕(47.3毫克,77.2微莫耳)之乙酸乙酯溶液,係經三乙基胺處理(8.6毫升,62毫莫耳),之後加入甲酸(5.8毫升,150毫莫耳)。所得混合物回流加熱3小時,之後冷卻至室溫。反應混合物以氫氯酸(70毫升,1N)稀釋。有機相以氫氯酸(1N)清洗二次。水相以乙酸乙酯萃取二次。合併之有機相進行蒸發。殘餘物重新溶於甲醇中(22.5毫升),所得懸浮液加熱至60℃,直至固體完全溶解。加入氫氯酸(22.5毫升,1N),所得懸浮液於78℃加熱10分鐘,並冷卻至室溫。固體過濾出,並於真空下乾燥。固體重新溶於氫氯酸(30毫升,1N)中,於35℃加熱。所得懸浮液以甲醇處理(30毫升),於35℃加熱4小時,並於35℃過濾。濾液蒸發,得4.9克(ee=99.6%,51%理論值)之5-(4-氯化苯基)-4-[(2R)-3,3,3-三氟-2-羥基丙基]-2,4-二氫-3H-1,2,4-三唑-3-酮。
LC-MS(方法3):Rt=1.40分鐘;MS(ESIpos):m/z=308[M+H]+
1H-NMR(400MHz,DMSO):δ[ppm]=12.10(s,1H),7.52-7.79(m,4H),
6.84(d,1H),3.54-4.52(m,3H)。
實施例2A
{3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙腈
於2公升反應瓶中,將100克(273毫莫耳)之{3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}醋酸(合成描述於WO 2010/105770-A1之實施例8A)、43.3克(547毫莫耳)吡啶與33毫克(0.3毫莫耳)之4-二甲基胺基吡啶溶於300毫升THF中。所得溶液於5℃下以52.8克(438毫莫耳)之2,2-二甲基丙醯基氯處理15分鐘,所得混合物於室溫下攪拌2.5小時。冷卻至0℃後,加入183毫升之28%氨水溶液,歷時1小時,同時溶液溫度維持於10℃至20℃間,所得混合物於5℃下額外攪拌1小時。之後加入500毫升甲基三級丁醚與300毫升20%檸檬酸水溶液,同時維持內部溫度於10℃至20℃間。各相分離,有機相以300毫升之20%檸檬酸水溶液清洗,之後以300毫升飽和碳酸氫鈉水溶液清洗,最後以300毫升之10%氯化鈉水溶液清洗。有機相於60℃下減壓蒸發,直至得到油狀殘餘物。之後加入300毫升THF,溶液再次蒸發,直至獲得油狀溶液。此操作再重複一次。油狀殘餘物重新溶於360毫升THF中,並以172克(820毫莫耳)三氟醋酸酐處理20分鐘,於溫度10℃至20℃間。之後所得溶液於室溫下攪拌1小時。加入720毫升4-甲基-2-戊酮與650毫升7.5%氫氧化鈉水溶
液,於溫度10℃至20℃間。最後使用7.5%氫氧化鈉水溶液將pH值調整至pH=9.5。各相分離後,有機相以450毫升10%氯化鈉水溶液清洗二次。有機相於溫度80℃下減壓蒸發,同時加入1200毫升正庚烷。所形成之懸浮液冷卻至20℃並形成固體,其過濾出,並以200毫升正庚烷清洗,之後減壓乾燥(50℃,30毫巴),得88克(93%理論值)之{3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙腈,為固體。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=7.78(d,2H),7.55(d,2H),6.91(d,1H),5.17(s,2 H),4.34-4.23(m,1 H),3.98(dd,1H),3.81(dd,1H)。
實施例3A
{3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙腈
40克(130毫莫耳)之5-(4-氯化苯基)-4-[(2R)-3,3,3-三氟-2-羥基丙基]-2,4-二氫-3H-1,2,4-三唑-3-酮(實施例1A)之400毫升甲基異丁酮溶液,係以17.9克(143毫莫耳)溴化乙腈與53.9克(390毫莫耳)碳酸鉀處理,並於60℃下攪拌4小時。冷卻至20℃後,加入200毫升水,混合物攪拌10分鐘。各相分離後,有機相以200毫升水清洗。有機相於80℃下減壓蒸發,同時加入300毫升正庚烷。所形成之懸浮液冷卻至20℃,將形成之固體過濾出,並以50毫升正庚烷清洗,之後減壓乾燥(50℃,30毫巴),得25.2克(56%理
論值)之{3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙腈。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=7.78(d,2H),7.65(d,2H),6.91(d,1H),5.17(s,2 H),4.34-4.23(m,1 H),3.98(dd,1H),3.81(dd,1H)。
實施例4A
甲基-2-{3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯
在4公升反應瓶中,200克(576.9毫莫耳)之{3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙腈(實施例2A)之1600毫升甲醇溶液,係以5.2克(28毫莫耳)甲醇鈉(30%甲醇溶液),所得混合物於50℃下攪拌2.5小時。之後溶液於50℃下減壓蒸發,直至獲得油狀溶液。加入2000毫升甲基三級丁醚,溶液濃縮,直至體積達到800毫升。之後加入3000毫升正庚烷並形成懸浮液。於20℃下冷卻,固體過濾出,並以500毫升正庚烷清洗,之後減壓乾燥(50℃,30毫巴),得175克(80%理論值)之甲基2-{3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯,為固體。
1H-NMR(400MHz,DMSO-d6):δ[ppm]=8.01(s,1H),7.78(d,2H),7.62(d,2H),6.93(br.s,1H),4.50(s,2 H),4.35-4.23(m,1 H),3.96(dd,1H),3.81(dd,1H),3.67(s,3 H)。
實施例5A
甲基-2-{3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯
8.58克(24.7毫莫耳)之{3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙腈(實施例3A)之甲醇溶液(43毫升),係以229微升(1.24毫莫耳)甲醇鈉溶液(30%甲醇溶液)處理。所得混合物於室溫下攪拌整夜,之後蒸發,得9.31克(99%理論值)如標題化合物。
1H NMR(DMSO-d6,400MHz):δ[ppm]=8.01(s,1H),7.81-7.58(m,4H),7.00-6.84(m,1H),4.50(s,2H),4.40-4.23(m,1H),4.04-3.74(m,2H),3.66(s,3H)。
實施例6A
甲基3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-(3-氯化吡啶-2-基)-1H-1,2,4-三唑-5-羧酸酯
150毫克之甲基-2-{3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三
氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯(實施例4A)(26.4毫莫耳)之3毫升THF溶液,冷卻至0℃,之後以58.2毫克(0.48毫莫耳)甲基氯化側氧醋酸酯與275微升(1.58毫莫耳)N,N-二異丙基乙胺處理。所得混合物回溫至室溫,並攪拌1小時,再次冷卻至0℃。之後加入62.6毫克(0.436毫莫耳)3-氯-2-肼吡啶,反應混合物回溫至室溫,之後攪拌1小時,然後於120℃下,在密封的小瓶中微波照射1小時。粗產物以製備級HPLC純化(方法5)。冷凍乾燥含有產物的分液,得25.3毫克(11%理論值)如標題產物。
LC-MS(方法3):Rt=1.82分鐘;MS(ESIpos):m/z=558.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.70-8.24(m,2H),7.89-7.56(m,5H),6.92(d,1H),5.22(s,2H),4.46-4.20(m,1H),3.79(s,5H)。
實施例7A
甲基3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-5-羧酸酯
1.0克之甲基-2-{3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯(實施例4A)(2.64毫莫耳)之20毫升1,4-二噁烷溶液係冷卻至10℃,之後以388毫克(3.17毫莫耳)甲基氯化側氧醋酸酯與0.55毫升(3.18毫莫耳)N,N-二異丙基乙胺處理。之後所得混合物攪拌30分鐘。加入1.10克(3.17毫莫耳)2-肼-3-(三氟甲基)吡啶
(4-甲基苯磺酸鹽1:1)、0.65毫升(3.72毫莫耳)之N,N-二異丙基乙胺與506毫克(3.19毫莫耳)無水硫酸銅(II)之10毫升的1,4-二噁烷之預攪拌溶液至反應混合物中,所得混合物之後於室溫下攪拌整夜。之後加入水,水相以乙酸乙酯萃取,合併之有機相以氯化鈉水溶液清洗,以硫酸鎂除水,並真空蒸發,得777毫克(50%理論值)如標題產物,為固體。
LC-MS(方法2):Rt=1.00分鐘;MS(ESIpos):m/z=592.6[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.93(d,1H),8.60(dd,1H),7.98(dd,1H),7.75(d,2H),7.67-7.57(m,2H),6.91(d,1H),5.22(s,2H),4.37-4.22(m,1H),4.10-3.97(m,1H),3.85(dd,1H),3.77(s,3H)。
實施例8A
甲基3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲氧基)吡啶-2-基]-1H-1,2,4-三唑-5-羧酸酯
150毫克之甲基-2-{3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯(實施例4A)(0.40毫莫耳)之3毫升THF溶液,冷卻至0℃,並以58毫克(0.48毫莫耳)甲基氯化側氧醋酸酯與275微升(1.58毫莫耳)之N,N-二異丙基乙胺。所得混合物回溫至室溫,之後攪拌1小時,之後再次冷卻至0℃。之後加入159毫克(0.44毫莫耳)2-肼-3-(三氟甲氧基)吡啶(4-甲基苯磺酸鹽1:1),之後反應混合物回溫
至室溫,並攪拌1小時,然後於120℃下,在密封的小瓶中微波照射1小時。粗產物以製備級HPLC(方法5)純化。冷凍乾燥含有產物的分液,得51.5毫克(21%理論值)如標題產物。
LC-MS(方法2):Rt=1.02分鐘;MS(ESIpos):m/z=608.1[M+H]+。
實施例9A
甲基1-(3-溴化吡啶-2-基)-3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1H-1,2,4-三唑-5-羧酸酯
1.0克之甲基-2-{3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯(實施例4A)(2.64毫莫耳)之20毫升1,4-二噁烷冷卻至10℃,之後以388毫克(3.17毫莫耳)甲基氯化側氧醋酸酯與0.55毫升(3.18毫莫耳)之N,N-二異丙基乙胺處理。所得混合物攪拌30分鐘。595毫克(3.17毫莫耳)之3-溴-2-肼吡啶與506毫克(3.19毫莫耳)無水硫酸銅(II)之10毫升的1,4-二噁烷預攪拌溶液,之後加至反應混合物中,所得混合物之後於室溫下攪拌整夜。之後加入水,水相以乙酸乙酯萃取,合併之有機相以氯化鈉水溶液清洗,以硫酸鎂除水,並真空蒸發。粗產物經管柱層析法純化(矽膠,環己烷/EtOAc 12%→100%),得696毫克(44%理論值)如標題產物。
LC-MS(方法3):Rt=1.82分鐘;MS(ESIpos):m/z=602.0[M+H]+。
1H NMR(DMSO-d6,400MHz):δ=8.63(dd,1H),8.45(dd,1H),7.76(d,
2H),7.66(dd,1H),7.62(d,2H),6.92(d,1H),5.22(s,2H),4.38-4.25(m,1H),4.09-3.96(m,1H),3.85(dd,1H),3.79(s,3H)。
實施例10A
乙基2-[3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-5-(甲氧基羰基)-1H-1,2,4-三唑-1-基]菸鹼酸酯
2.35克之甲基-2-{3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯(實施例4A)(26.19毫莫耳)之47毫升1,4-二噁烷溶液冷卻至10℃,之後以910毫克(7.41毫莫耳)甲基氯化側氧醋酸酯與1.20毫升(7.41毫莫耳)N,N-二異丙基乙胺處理。所得混合物之後攪拌30分鐘。1.87克(7.41毫莫耳)乙基2-肼菸鹼酸酯與1.45毫克(9.10毫莫耳)無水硫酸銅(II)之23毫升1,4-二噁烷預攪拌溶液之後加入反應混合物中,所得混合物於室溫下攪拌96小時。溶劑真空移除,粗產物經管柱層析法純化(矽膠,二氯甲烷/甲醇,92/8),得833毫克(23%理論值)如標題產物,為固體。
LC-MS(方法2):Rt=0.98分鐘;MS(ESIpos):m/z=596.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.82(dd,1H),8.51(dd,1H),7.85(dd,1H),7.75(d,2H),7.65-7.57(m,2H),6.91(d,1H),5.17(s,2H),4.38-4.24(m,1H),4.13-3.96(m,3H),3.85(dd,1H),3.77(s,3H),0.97(t,3H)。
實施例11A
甲基3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-(4-氯化吡啶-3-基)-1H-1,2,4-三唑-5-羧酸酯
1.0克之甲基-2-{3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯(實施例4A)(2.64毫莫耳)之18毫升THF溶液冷卻至0℃,並以388毫克(3.17毫莫耳)之甲基氯化側氧醋酸酯與1.06毫升(6.07毫莫耳)之N,N-二異丙基乙胺處理。所得混合物回溫至室溫,之後攪拌1小時,並再次冷卻至0℃。加入523毫克(2.90毫莫耳)4-氯-3-肼吡啶(氯化氫鹽1:1),反應混合物回溫至室溫,之後攪拌1小時,然後於120℃下,在密封的小瓶中微波照射1小時。粗產物經管柱層析法純化(矽膠,環己烷/EtOAc,梯度),得1.03克(66%理論值)如標題產物,為固體。
LC-MS(方法2):Rt=1.00分鐘;MS(ESIpos):m/z=558.2[M+H]+
1H NMR(DMSO-d6,400MHz):δ=9.00-8.62(m,2H),7.96-7.55(m,5H),6.91(d,1H),5.21(s,2H),4.42-4.21(m,1H),4.11-3.66(m,5H)。
實施例12A
甲基3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-[4-(三氟甲基)吡啶-3-基]-1H-1,2,4-三唑-5-羧酸酯
150毫克之甲基-2-{3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯(實施例4A)(0.40毫莫耳)之3毫升THF溶液,係冷卻至0℃,並以53毫克(0.44毫莫耳)甲基氯化側氧醋酸酯與75微升(0.44毫莫耳)N,N-二異丙基乙胺處理。所得混合物於0℃下攪拌30分鐘。加入77毫克(0.44毫莫耳)3-肼-4-(三氟甲基)吡啶,反應混合物之後回溫至室溫並攪拌1小時,然後於100℃下,在密封的小瓶中微波照射1小時。粗產物經製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得104毫克(41%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.84分鐘;MS(ESIpos):m/z=592.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=9.12-9.04(m,2H),8.07(d,1H),7.75(d,2H),7.63(d,2H),6.91(d,1H),5.20(d,2H),4.39-4.20(br m,1H),4.05-3.98(m,1H),3.86(dd,1H),3.77(s,3H)。
實施例13A
乙基3-[3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-5-(甲氧基羰基)-1H-1,2,4-三唑-1-基]異菸鹼酸酯
500毫克之甲基-2-{3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯(實施例4A)(1.32毫莫耳)之10毫升THF溶液冷卻至0℃,並以178毫克(1.45毫莫耳)甲基氯化側氧醋酸酯與252微升(1.45毫莫耳)N,N-二異丙基乙胺處理。所得混合物於0℃下攪拌30分鐘。之後加入309毫克(1.45毫莫耳)乙基3-肼異菸鹼酸酯,反應混合物回溫至室溫,之後攪拌16小時,之後加熱回流16小時。粗產物經製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得416毫克(26%理論值)如標題產物。
LC-MS(方法3):Rt=1.83分鐘;MS(ESIpos):m/z=596.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=9.00-8.90(m,2H),7.96(d,1H),7.75(d,2H),7.67-7.60(m,2H),6.91(d,1H),5.17(s,2H),4.37-4.22(m,1H),4.09-3,97(m,3H),3.86(dd,1H),3.76(s,3H),0.93(t,3H)。
實施例14A
甲基3-({3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-l,2,4-三唑-1-基}甲基)-1-(3-氯化吡啶-2-基)-1H-1,2,4-三唑-5-羧酸酯
546毫克之甲基-2-{3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯(實施例5A)(1.44毫莫耳)之10毫升THF溶液冷卻至0℃,並以194毫克(1.59毫莫耳)甲基氯化側氧醋酸酯與277微升(1.59毫莫耳)N,N-二異丙基乙胺處理。所得混合物於0℃下攪拌30分鐘。之後加入227毫克(1.59毫莫耳)3-氯-2-肼吡啶,反應混合物回溫至室溫,之後攪拌1小時,然後於120℃下,在密封的小瓶中微波照射1小時,之後於室溫下繼續進行36小時。反應混合物之後以甲醇/水處理,並經製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得121毫克(14%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.85分鐘;MS(ESIpos):m/z=558.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.81-8.18(m,2H),7.92-7.48(m,5H),6.91(d,1H),5.22(s,2H),4.44-4.16(m,1H),3.79(s,5H)。
實施例15A
甲基3-({3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-5-羧酸酯
340毫克之甲基-2-{3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯(實施例5A)(898微莫耳)之8毫升1,4-二噁烷溶液係冷卻至10℃,並以132毫克(1.08毫莫耳)
甲基氯化側氧醋酸酯與305微升(2.33毫莫耳)N,N-二異丙基乙胺處理。所得混合物攪拌30分鐘。376毫克(1.08毫莫耳)2-肼-3-(三氟甲基)吡啶(4-甲基苯磺酸鹽1:1)與172毫克(1.08毫莫耳)無水硫酸銅(II)之4毫升1,4-二噁烷預攪拌溶液,之後加入反應混合物中,所得混合物於室溫下攪拌16小時。溶劑真空移除,粗產物溶於EtOAc中,並以10%EDTA之水溶液清洗(重複四次),之後以水與飽和氯化鈉水溶液清洗。以硫酸鎂除水後,揮發物移除,所得粗產物經製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得167毫克(31%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.88分鐘;MS(ESIpos):m/z=592.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.93(d,1H),8.60(dd,1H),7.98(dd,1H),7.80-7.67(m,2H),7.67-7.58(m,2H),6.91(d,1H),5.28-5.13(m,2H),4.37-4.24(m,1H),4.06-3.95(m,1H),3.85(dd,1H),3.77(s,3H)。
實施例16A
甲基3-({3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-(4-氯化吡啶-3-基)-1H-1,2,4-三唑-5-羧酸酯
330毫克之甲基-2-{3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯(實施例5A)(871微莫耳)之6.6毫升THF溶液冷卻至0℃,並以117毫克(958微莫耳)甲基氯化側氧醋酸酯與166微升(958微莫耳)N,N-二異丙基乙胺處理。所得混合物之
後於0℃下攪拌30分鐘。加入166微升(958微莫耳)N,N-二異丙基乙胺與172毫克(958微莫耳)4-氯-3-肼吡啶(氯化氫鹽類1:1),所得反應混合物回溫至室溫,之後攪拌16小時,然後於100℃下,在密封的小瓶中微波照射1小時。粗產物經製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得126毫克(26%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.75分鐘;MS(ESIpos):m/z=558.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.86(s,1H),8.75(d,1H),7.89(d,1H),7.80-7.73(m,2H),7.65-7.60(m,2H),6.91(d,1H),5.21(s,2H),4.36-4.24(m,1H),4.08-3.99(m,1H),3.86(dd,1H),3.79(s,3H)。
實施例17A
甲基3-({3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-[4-(三氟甲基)吡啶-3-基]-1H-1,2,4-三唑-5-羧酸酯
350毫克之甲基-2-{3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}乙亞醯胺酯(實施例5A)(0.924毫莫耳)之7.0毫升THF溶液冷卻至0℃,並以124毫克(1.02毫莫耳)甲基氯化側氧醋酸酯與177微升(1.102毫莫耳)N,N-二異丙基乙胺處理。所得混合物於0℃下攪拌30分鐘。加入180毫克(1.02毫莫耳)3-肼-4-(三氟甲基)吡啶,反應混合物回溫至室溫並攪拌16小時,然後於100℃下,在密封
的小瓶中微波照射1小時。粗產物經製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得125毫克(23%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.85分鐘;MS(ESIpos):m/z=592.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=9.09(d,1H),9.07(s,1H),8.07(d,1H),7.77-7.73(m,2H),7.65-7.61(m,2H),6.91(d,1H),5.20(d,2H),4.39-4.20(br m,1H),4.04-3.98(m,1H),3.86(dd,1H),3.77(s,3H)。
實例部分-實施例
實施例1
3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-(3-氯化吡啶-2-基)-1H-1,2,4-三唑-5-甲醯胺
5.1克甲基3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-(3-氯化吡啶-2-基)-1H-1,2,4-三唑-5-羧酸酯(實施例6A,9.134毫莫耳)溶於42.5毫升之氨水溶液(7N於甲醇中,297毫莫耳)。所得混合物於室溫下攪拌2小時。之後該混合物倒至冰上,混合物攪拌10分鐘。沉澱物過濾出,並以水清洗,得3.5克粗產物。水相以乙酸乙酯萃取。有機相以硫酸鎂除水、過濾並真空移除溶劑。粗產物用快速層析法純化(矽膠,二氯甲烷/甲醇,97/3),得4.00克(81%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.62分鐘;MS(ESIpos):m/z=543.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.55(dd,1H),8.39(s,1H),8.25(dd,1H),8.00(s,1H),7.76(d,2H),7.69(dd,1H),7.62(d,2H),6.90(d,1H),5.18(d,2H),4.36-4.23(m,1H),4.06-3.97(m,1H),3.85(dd,1H)。
實施例2
3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-5-甲醯胺
1.80克甲基3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-5-羧酸酯(實施例7A,3.04毫莫耳)溶於10.0毫升氨水溶液中(7N於甲醇中,70.0毫莫耳)。所得混合物於室溫下攪拌1小時。真空移除溶劑,粗產物以製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得1.49克(85%理論值)如標題產物,為固體。
LC-MS(方法1):Rt=1.20分鐘;MS(ESIpos):m/z=577[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.87(d,1H),8.51(d,1H),8.39(s,1H),7.99(s,1H),7.90(dd,1H),7.82-7.68(m,2H),7.63(d,2H),6.90(s,1H),5.22-5.07(m,2H),4.39-4.20(br m,1H),4.16-3.94(m,1H),3.85(dd,1H)。
實施例3
3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲氧基)吡啶-2-基]-1H-1,2,4-三唑-5-
甲醯胺
51.0毫克甲基3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲氧基)吡啶-2-基]-1H-1,2,4-三唑-5-羧酸酯(實施例8A,84微莫耳)溶於5.0毫升氨水溶液(7N於甲醇中,35.0毫莫耳)。所得混合物於室溫下攪拌1小時。真空移除溶劑,粗產物以製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得44.2毫克(89%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.69分鐘;MS(ESIpos):m/z=593.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.71-7.53(m,9H),6.90(d,1H),5.17(d,2H),4.42-4.17(m,1H),4.08-3.73(m,2H)。
實施例4
1-(3-溴化吡啶-2-基)-3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1H-1,2,4-三唑-5-甲醯胺
100毫克甲基1-(3-溴化吡啶-2-基)-3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1H-1,2,4-三唑-5-羧酸酯(實施例9A,0.166毫莫耳)溶於10.0毫升氨水溶
液中(7N於甲醇中,70.0毫莫耳)。所得混合物於室溫下攪拌1小時。真空移除溶劑,粗產物以製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得83.1毫克(85%理論值)如標題產物,為固體。
LC-MS(方法2):Rt=0.91分鐘;MS(ESIpos):m/z=587.0[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.57(dd,1H),8.36(dd,2H),7.98(s,1H),7.80-7.73(m,2H),7.62(d,2H),7.60-7.56(m,1H),6.92(d,1H),5.17(d,2H),4.41-4.19(m,1H),4.11-3.95(m,1H),3.85(dd,1H)。
實施例5
乙基2-[5-胺甲醯基-3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1H-1,2,4-三唑-1-基]菸鹼酸酯
50.0毫克實例10A(84微莫耳)溶於1.25毫升氨水溶液中(7N於甲醇中,0.175毫莫耳)。所得混合物於室溫下攪拌1小時。真空移除溶劑,粗產物以製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得27.8毫克(57%理論值)如標題產物,為固體。
LC-MS(方法1):Rt=1.16分鐘;MS(ESIpos):m/z=581.0[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.76(dd,1H),8.46(dd,1H),8.29(s,1H),7.90(s,1H),7.83-7.77(m,1H),7.77-7.70(m,2H),7.68-7.57(m,2H),6.90(d,1H),5.14(s,2H),4.35-4.23(m,1H),4.06-3.97(m,3H),3.85(dd,1H),0.97(t,3H)。
實施例6
3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-(4-氯化吡啶-3-基)-1H-1,2,4-三唑-5-甲醯胺
100毫克實施例11A(0.179毫莫耳)溶於1.0毫升氨水溶液(7N於甲醇中,7.09毫莫耳)。所得混合物於室溫下攪拌16小時。真空移除溶劑,粗產物以製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得76.7毫克(79%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.55分鐘;MS(ESIpos):m/z=543.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.91-7.52(m,9H),6.90(d,1H),5.17(d,2H),4.40-4.18(m,1H),4.07-3.72(m,2H)。
實施例7
3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-[4-(三氟甲基)吡啶-3-基]-1H-1,2,4-三唑-5-甲醯胺
78.5毫克實施例12A(0.133毫莫耳)溶於8.0毫升氨水溶液
(7N於甲醇中,1.14毫莫耳)。所得混合物於室溫下攪拌1小時。真空移除溶劑,粗產物以製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得49.7毫克(77%理論值)如標題產物,為固體。
LC-MS(方法2):Rt=0.93分鐘;MS(ESIpos):m/z=577.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=9.03(d,1H),8.97(s,1H),8.36(s,1H),8.00(d,2H),7.86-7.70(m,2H),7.69-7.58(m,2H),6.90(d,1H),5.17(d,2H),4.39-4.20(br m,1H),4.06-3.94(m,1H),3.86(dd,1H)。
實施例8
乙基3-[5-胺甲醯基-3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1H-1,2,4-三唑-1-基]異菸鹼酸酯
100毫克實施例13A(151微莫耳)溶於1.0毫升NH3之EtOH溶液(2.00毫莫耳,2N)。所得混合物於室溫下攪拌16小時,繼續加入1.0毫升氨水溶液(7N於甲醇中,2.00毫莫耳),並繼續於室溫下攪拌16小時。真空移除溶劑,粗產物以製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得46.0毫克(49%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.63分鐘;MS(ESIpos):m/z=581.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.89(d,1H),8.83(s,1H),8.28(s,1H),7.94(s,1H),7.90(d,1H),7.78-7.72(m,2H),7.69-7.58(m,2H),6.89(d,1H),5.14(d,2H),4.40-4.24(m,1H),4.10-3.96(m,3H),3.86(dd,1H),0.95(t,
3H)。
實施例9
2-[5-胺甲醯基-3-({3-(4-氯化苯基)-5-側氧-4-[(2S)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1H-1,2,4-三唑-1-基]菸鹼醯胺
80毫克實施例10A(134微莫耳)溶於10毫升氨水溶液(7N於甲醇中,70.0毫莫耳)。所得混合物於70℃下攪拌10分鐘,真空移除溶劑,殘餘物溶於10毫升氨水溶液(7N於甲醇中,70.0毫莫耳),並於120℃下微波下攪拌3小時。真空移除溶劑,粗產物以製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得22.0毫克(28%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.31分鐘;MS(ESIpos):m/z=552.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.61(dd,1H),8.24-8.14(m,2H),7.90-7.83(m,1H),7.86(br d,1H),7.79-7.74(m,2H),7.69(dd,1H),7.65-7.60(m,2H),7.49(s,1H),6.92(d,1H),5.10(d,2H),4.39-4.21(br m,1H),4.06-3.93(m,1H),3.84(dd,1H)。
實施例10
3-({3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-(3-氯化吡啶-2-基)-1H-1,2,4-三唑-5-甲醯胺
110毫克實施例14A(0.197毫莫耳)溶於1.0毫升氨水溶液(7N於甲醇中,7.09毫莫耳)。所得混合物於室溫下攪拌1小時。真空移除溶劑,粗產物以製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得92.0毫克(86%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.60分鐘;MS(ESIpos):m/z=543.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.69-7.48(m,9H),6.90(d,1H),5.18(d,2H),4.47-4.16(m,1H),4.08-3.71(m,2H)。
實施例11
3-({3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-5-甲醯胺
160毫克實施例15A(270微莫耳)溶於5.0毫升氨水溶液(7N於甲醇中,2.00毫莫耳)。所得混合物於室溫下攪拌1.5小時。真空移除溶劑,粗產物以製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得162.1毫克(定量)如標題產物,為固體。
LC-MS(方法4):Rt=2.73分鐘;MS(ESIpos):m/z=577.3[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.90-8.81(m,1H),8.51(dd,1H),8.39(s,1H),7.99(s,1H),7.90(dd,1H),7.80-7.70(m,2H),7.66-7.59(m,2H),6.90(d,1H),5.25-5.12(m,2H),4.40-4.20(br m,1H),4.03-3.96(m,1H),3.85(dd,1H)。
實施例12
3-({3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-(4-氯化吡啶-3-基)-1H-1,2,4-三唑-5-甲醯胺
118毫克實施例16A(211微莫耳)溶於5.0毫升氨水溶液(7N於甲醇中,35.0毫莫耳)。所得混合物於室溫下攪拌1小時。真空移除溶劑,粗產物以製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得111毫克(97%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.53分鐘;MS(ESIpos):m/z=543.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=8.78(s,1H),8.69(d,1H),8.35(s,1H),8.01(s,1H),7.82(d,1H),7.79-7.73(m,2H),7.66-7.58(m,2H),6.90(d,1H),5.17(d,2H),4.39-4.20(br m,1H),4.07-3.95(m,1H),3.85(dd,1H)。
實施例13
3-({3-(4-氯化苯基)-5-側氧-4-[(2R)-3,3,3-三氟-2-羥基丙基]-4,5-二氫-1H-1,2,4-三唑-1-基}甲基)-1-[4-(三氟甲基)吡啶-3-基]-1H-1,2,4-三唑-5-甲醯胺
118毫克實施例17A(199微莫耳)溶於5.0毫升氨水溶液(7N於甲醇中,2.00毫莫耳)。所得混合物於室溫下攪拌20分鐘。真空移除溶劑,粗產物以製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得99.5毫克(87%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.63分鐘;MS(ESIpos):m/z=577.1[M+H]+
1H NMR(DMSO-d6,400MHz):δ=9.03(d,1H),8.96(s,1H),8.36(s,1H),8.00(d,2H),7.77-7.70(m,2H),7.68-7.59(m,2H),6.89(d,1H),5.28-5.05(m,2H),4.39-4.20(br m,1H),4.05-3.96(m,1H),3.85(dd,1H)。
實施例14
3-{[3-(4-氯化苯基)-5-側氧-4-(3,3,3-三氟-2-側氧丙基)-4,5-二氫-1H-1,2,4-三唑-1-基]甲基}-1-(3-氯化吡啶-2-基)-1H-1,2,4-三唑-5-甲醯胺(丙酮形式)或3-{[3-(4-氯化苯基)-5-側氧-4-(3,3,3-三氟-2,2-二羥基丙基)-4,5-二氫-1H-1,2,4-三唑-1-基]甲基}-1-[2-(三氟甲基)苯基]-1H-1,2,4-三唑-5-甲醯胺(水合物形式)
250毫克實施例1(460微莫耳)之5.0毫升二氯甲烷溶液係冷
卻至0℃,加入780毫克(1.84毫莫耳)之Dess-Martin過碘烷與9.0微升水(506毫莫耳)。所得混合物於室溫下攪拌1小時。於反應混合物中加入5毫升飽和硫代硫酸鈉水溶液與5毫升飽和碳酸氫鈉水溶液,將所得混合物攪拌10分鐘。各相分離,水層以乙酸乙酯萃取(10毫升,重複三次),合併之有機相以硫酸鎂除水,並蒸發。粗產物以製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得230毫克(87%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.57分鐘;MS(ESIpos):m/z=541.0[M+H]+(丙酮形式)。
1H NMR(DMSO-d6,400MHz):δ=8.54(dd,1H),8.40(s,1H),8.25(dd,1H),8.00(s,1H),7.76-7.63(m,3H),7.62-7.53(m,2H),7.44(s,2H),5.19(s,2H),4.05(s,2H))(水合物形式)。
實施例15
1-(3-溴化吡啶-2-基)-3-{[3-(4-氯化苯基)-5-側氧-4-(3,3,3-三氟-2-側氧丙基)-4,5-二氫-1H-1,2,4-三唑-1-基]甲基}-1H-1,2,4-三唑-5-甲醯胺(丙酮形式)或1-(3-溴化吡啶-2-基)-3-{[3-(4-氯化苯基)-5-側氧-4-(3,3,3-三氟-2,2-二羥基丙基)-4,5-二氫-1H-1,2,4-三唑-1-基]甲基}-1H-1,2,4-三唑-5-甲醯胺(水合物形式)
68.0毫克實施例4(116微莫耳)之1.3毫升二氯甲烷溶液冷卻至0℃,並加入196毫克(463毫莫耳)之Dess-Martin過碘烷與2.3微升水(127毫莫耳)。所得混合物於室溫下攪拌1小時。於反應混合物中加入1.3毫升飽
和硫代硫酸鈉水溶液與1.3毫升飽和碳酸氫鈉水溶液,將混合物攪拌10分鐘。各相分離,水層以乙酸乙酯萃取(3 x 10毫升),合併之有機相以硫酸鎂除水,並蒸發。粗產物以製備級HPLC純化(方法5)。含產物分液冷凍乾燥,得30.1毫克(42%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.58分鐘;MS(ESIpos):m/z=585.0[M+H]+(丙酮形式)。
1H NMR(DMSO-d6,400MHz):δ=8.57(dd,1H),8.40-8.34(m,2H),7.98(s,1H),7.72(s,1H),7.70(s,1H),7.58(d,3H),7.44(s,2H),5.20-5.16(m,2H),4.05(s,2H)(水合物形式)。
實施例16
3-{[3-(4-氯化苯基)-5-側氧-4-(3,3,3-三氟-2-側氧丙基)-4,5-二氫-1H-1,2,4-三唑-1-基]甲基}-1-(4-氯化吡啶-3-基)-1H-1,2,4-三唑-5-甲醯胺(丙酮形式)或3-{[3-(4-氯化苯基)-5-側氧-4-(3,3,3-三氟-2,2-二羥基丙基)-4,5-二氫-1H-1,2,4-三唑-1-基]甲基}-1-(4-氯化吡啶-3-基)-1H-1,2,4-三唑-5-甲醯胺(水合物形式)
120毫克之實施例6(221微莫耳)與4.3微升水(243毫莫耳)之2.4毫升二氯甲烷溶液冷卻至0℃,之後加入140.5毫克(331毫莫耳)Dess-Martin過碘烷。所得混合物回溫至室溫,之後攪拌2小時。在懸浮液中加入5毫升THF,於4℃下延長攪拌至72小時,之後於室溫下攪拌3小時,在反應混合物中加入2毫升飽和硫代硫酸鈉水溶液與2毫升飽和碳酸氫鈉
水溶液,然後將混合物攪拌10分鐘。各相分離,水層以二氯甲烷萃取(10毫升,重複四次),合併之有機層以水、飽和氯化鈉水溶液清洗,以硫酸鎂除水,並蒸發。粗產物以快速層析法(矽膠,環己烷/乙酸乙酯1:1→乙酸乙酯)純化。含產物分液蒸發,得8.0毫克(7%理論值)如標題產物,為固體。
LC-MS(方法4):Rt=2.43分鐘;MS(ESIpos):m/z=541.2[M+H]+(丙酮形式)。
1H NMR(DMSO-d6,400MHz):δ=8.78(s,1H),8.69(d,1H),8.36(s,1H),8.00(s,1H),7.82(d,1H),7.71(d,2H),7.58(d,2H),7.43(s,2H),5.19(s,2H),4.06(s,2H)(水合物形式)。
實施例17
3-{[3-(4-氯化苯基)-5-側氧-4-(3,3,3-三氟-2-側氧丙基)-4,5-二氫-1H-1,2,4-三唑-1-基]甲基}-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-5-甲醯胺(丙酮形式)或3-{[3-(4-氯化苯基)-5-側氧-4-(3,3,3-三氟-2,2-二羥基丙基)-4,5-二氫-1H-1,2,4-三唑-1-基]甲基}-1-[3-(三氟甲基)吡啶-2-基]-1H-1,2,4-三唑-5-甲醯胺(水合物形式)
100毫克實施例2(173微莫耳)之1.9毫升二氯甲烷溶液冷卻至0℃,之後加入294毫克(693毫莫耳)Dess-Martin過碘烷與3.5微升水(191毫莫耳)。所得混合物於室溫下攪拌1小時。於反應混合物中加入2毫升飽和硫代硫酸鈉水溶液與2毫升飽和碳酸氫鈉水溶液,將所得混合物攪拌10
分鐘。水層以二氯甲烷萃取(10毫升,重複四次),合併之有機層以水與飽和氯化鈉水溶液清洗,以硫酸鎂除水,並蒸發。粗產物以HPLC(方法5)純化。含產物分液冷凍乾燥,得18.4毫克(19%理論值)如標題產物,為固體。
LC-MS(方法3):Rt=1.64分鐘;MS(ESIpos):m/z=575.0[M+H]+(丙酮形式)。
1H NMR(DMSO-d6,400MHz):δ=8.88-8.85(m,1H),8.51(dd,1H),8.40(s,1H),7.98(s,1H),7.90(dd,1H),7.73-7.67(m,2H),7.58(d,2H),7.43(s,2H),5.18(s,2H),4.05(s,2H)(水合物形式)。
實驗部分-生物試驗
縮寫與首字母縮寫:
各實例係於選定之生物試驗中進行一或多次測試。當多次測試時,數據以平均值或中位數報導,其中●平均值,亦稱作算術平均值,表示獲得值總和除以測試次數,以及●中位數代表以升序或降序排列的值組中間數字。若數據組個數為奇數,則中位數為中間值。若數據組個數為偶數,則中位數為二中間值之算術平均值。
實施例係合成一或多次。當多次合成時,來自生物試驗的數據代表由一或多個合成批次測試獲得的數據組計算之平均值或中位數。
本發明化合物之活性證實可通過本領域熟知之體外、離體、及體內試驗完成。舉例而言,欲證實本發明化合物的活性,可使用以下試驗。
B-1. 以細胞體外試驗測定血管加壓素受體活性
源自人、大鼠、及犬之V1a與V2血管加壓素受體的協同劑和拮抗劑的辨識,以及本發明化合物的活性定量,係以重組細胞株進行。彼等細胞株最初源自倉鼠卵巢上皮細胞(中國倉鼠卵巢,CHO K1,ATCC:American Type Culture Collection,Manassas,VA 20108,USA)。測試細胞株組成性表現人、大鼠、或犬V1a或V2受體。於Gαq-偶聯V1a受體之情況,細胞亦穩定轉染鈣敏感光蛋白質水母發光蛋白之修飾形式(人和大鼠V1a)或螅蛋白(obelin)(犬V1a),在與腔腸素(coelenterazine)輔助因子重組後,其會在游離鈣濃度增加時發光[Rizzuto R,Simpson AW,Brini M,Pozzan T,Nature 358,325-327(1992);Illarionov BA,Bondar VS,Illarionova VA,Vysotski ES,Gene 153(2),273-274(1995)]。所產生的血管加壓素受體細胞會通過鈣離子的細胞內釋放,對重組性表現之V1a受體刺激起反應,其可通過所得光蛋白螢光進行定量。將Gs-偶聯之V2受體穩定轉染至表現螢火蟲螢光素酶基因之細胞株,其係於CRE反應性啟動子控制下進行。V2受體之活化會通過cAMP增加而誘發CRE反應性啟動子的活化,從而誘發螢火蟲螢光素酶表現。由V1a細胞株光蛋白發出之光,以及V2細胞株螢火蟲螢光素酶發出之光,皆對應於各血管加壓素受體之活化或抑制。以合適的發光計偵測各細胞株的生物螢光[Milligan G,Marshall F,Rees S,Trends in Pharmacological Sciences 17,235-237(1996)]。
測試流程:
血管加壓素V1a受體細胞株:
在試驗前一天,將細胞接種在培養液(DMEM/F12,2% FCS,2毫米榖胺醯胺,10毫米HEPES,5微克/毫升腔腸素(coelenterazine)),置於384孔微滴定盤,並保存於細胞培養箱(96%濕度,5% v/v CO2,37℃)。在試驗當日,將各種濃度測試化合物置於微量滴定盤各孔中10分鐘,在加入EC50濃度的協同劑[Arg8]-加壓素之前。立即以發光計測量所得到光訊號。
血管加壓素V2受體細胞株:
在測試前一天,將細胞接種在培養液中(DMEM/F12,2% FCS,2毫莫耳濃度榖胺醯胺,10毫莫耳濃度HEPES),置於384孔微滴定盤,並保存於細胞培養箱(96%濕度,5% v/v CO2,37℃)。在試驗當日,將各種濃度的測試化合物與EC50濃度的協同劑[Arg8]-加壓素,一同加入各孔中,該盤於細胞培養箱中靜置3小時。在加入細胞裂解試劑TritonTM與受質螢光素後,以發光計測量螢火蟲螢光素酶發出的光。
下表1A列出本發明化合物(包括外消旋混合物及單離鏡像異構物)的各IC50值,其係取自人類V1a或V2受體轉染細胞株:
表1A列出的IC50數據表明本發明化合物可作為具選擇性和有效的血管加壓素V1a受體拮抗劑。
針對比較目的,挑選出的苯基-三唑衍生物被認為是最接近先前技術者(參見國際專利申請案WO 2011/104322-A1和其中描述的示例化合物),其亦於上述V1a和V2細胞試驗中測試。由人類V1a或V2受體轉染細胞株獲得之彼等化合物IC50值列於下表1B:
針對比較目的,挑選出的苯基-三唑衍生物被認為是最接近先前技術者(參見國際專利申請案WO 2016/071212-A1和其中描述的示例化合物),其亦於上述V1a和V2細胞試驗中測試。由人類V1a或V2受體轉染細胞株獲得之彼等化合物IC50值列於下表1C:
B-2. 放射性結合試驗
IC50與Ki可在放射性結合測定中測定,其係使用分別表現人類血管加壓素V1a和V2受體之重組人類胚胎腎細胞株293(HEK293)和CHO-K1細胞系的膜部分。
利用標準技術,表現於HEK293細胞中的人類重組型血管加壓素V1a受體,係在50毫莫耳濃度Tris-HCl緩衝液,pH 7.4、5毫莫耳濃度MgCl2,0.1% BSA中使用。於25℃,將製備的膜等分試樣與不同濃度的測試化合物,以二重複方式,與0.03奈莫耳濃度[125I]苯基乙醯基-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2一同靜置120分鐘。在1微莫耳濃度[Arg8]血管加壓素存在下預估非特異性結合。受體經過濾和洗滌,
然後將濾液計數,測定特異性結合之[125I]苯基乙醯基-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2。
以編碼人類血管加壓素V2受體之質體穩定轉染CHO-K1細胞,係用於以標準技術製備膜,置於50毫莫耳濃度Tris-HCl緩衝液,pH 7.4、10毫莫耳濃度MgCl2、0.1% BSA。於25℃下,將製備的膜等分試樣與不同濃度的測試化合物,以二重複方式,與4奈莫耳濃度[3H](Arg8)-血管加壓素一起靜置120分鐘。在1毫莫耳濃度(Arg8)血管加壓素存在下預估非特異性結合。膜經過濾和洗滌3次,將濾液計數,測定特異性結合之[3H](Arg8)-血管加壓素。
IC50值係以非線性、最小平方回歸分析決定,使用MathIQTM(ID Business Solutions Ltd.,UK)。抑制常數Ki係使用Cheng與Prusoff(Cheng,Y.,Prusoff,W.H.,Biochem.Pharmacol.22:3099-3108,1973)之方程式計算。
B-3. 以細胞體外試驗檢測血管加壓素V1a受體拮抗劑對促纖維化基因之調節作用
細胞株H9C2(American Type Culture Collection ATCC No.CRL-1446),據描述係從大鼠心臟組織分離的心肌細胞類型,以高拷貝數內源性表現血管加壓素V1a受體AVPR1A,但未偵測到AVPR2表現。同樣地,從大鼠腎組織分離的細胞株NRK49F(ATCC No.CRL1570),表現出高程度AVPR1A mRNA和低程度AVPR2等相似表現模式。針對以受體拮抗劑檢測對AVPR1A受體依賴性調節基因表現抑制之細胞試驗,程序如下:
將H9C2細胞或NRK49F細胞種植於6孔微滴定盤以進行細胞培養,細胞密度為50 000細胞/孔,培養液為2.0毫升Opti-MEM(Invitrogen Corp.,Carlsbad,CA,USA,Cat.No.11058-021),並培養於細胞培養箱中
(96%濕度,8% v/v CO2,37℃)。於24小時後,每組三孔(三重複)注入載劑溶液(陰性控制組)與血管加壓素溶液([Arg8]-血管加壓素乙酸鹽,Sigma,Cat.No.V9879),或測試化合物(溶於載劑中:具有20% v/v乙醇之水)與血管加壓素溶液。在細胞培養物中,最終血管加壓素濃度為1奈莫耳濃度。測試化合物溶液以小體積加入細胞培養物中,使得細胞試驗之最終濃度不超過0.03%乙醇。靜置5小時後,抽吸出培養上清液,附著之細胞裂解於350微升之RLT緩衝液中(Qiagen,Cat.No.79216),RNA自裂解液中單離出,使用RNeasy套組(Qiagen,Cat.No.74104)。之後進行DNAse切割(Invitrogen,Cat.No.18068-015)、cDNA合成(Promaga,ImProm-II Reverse Transcription System,Cat.No.A3800),與反轉錄聚合酶鏈反應(RTPCR)(pPCR MasterMix RT-QP2X-03-075,Eurogentec,Seraing,Belgium)。所有程序均按照試劑製造商的工作流程進行。RTPCR的引子組係依據mRNA基因序列選擇(NCBI GenBank Entrez Nucleotide Data Base),使用Primer3Plus程式,6-FAM TAMRA-標記探針。用於測定各試驗批次中細胞之相對mRNA表現量之RTPCR,係使用Applied Biosystems ABI Prism 7700 Sequence Detector進行,使用384孔微滴定盤模式,依據儀器操作指示。相對基因表現係以delta-delta Ct值代表[Applied Biosystems,User Bulletin No.2 ABI Prism 7700 SDS,December 11,1997(更新至10/2001)],參考值為核糖體蛋白L-32基因(GenBank Acc.No.NM_013226)之表現量,且Ct閾值為Ct=35。
B-4. 血管加壓素誘發之人類血小板凝集之抑制
人類血小板內源性表現V1a受體。發現相對高的血管加壓素濃度(約50-100奈莫耳濃度)會刺激體外血小板凝集。因此,由人類血液富集的血小板可作為V1a的表現組織,用於藥物研究,具相對應的高濃度
血管加壓素拮抗劑。
通過靜脈穿刺從非吸煙健康志願者(n=4-8)中採集人類血液,其至少一週未服藥,將人類血液收集在10毫莫耳濃度檸檬酸三鈉溶液中。血小板富集血漿(PRP)係將血液樣本於4℃下,140g離心20分鐘而得。將得到的沉澱物進一步離心(每分鐘轉速15.000,2分鐘),以產生無血小板血漿(PPP)。使用凝集計(APACT 4)以比濁法測量血小板凝集。反應之後監測178微升PRP等分試樣的光透射變化,在37℃下連續攪拌下,相對於PPP控制組。在加入20微升Arg-血管加壓素(最終濃度為100奈莫耳濃度)之前,將各濃度的血管加壓素拮抗劑(2微升)加入到PRP中5分鐘。化合物的抑制作用,係測量源自形狀變化底部的聚集波高度而定,與對照組反應相較。IC50值係以迭代非線性回歸程式,由劑量-反應抑制曲線計算而得。
B-5. 對分離大鼠血管環收縮之影響
隔離主動脈
可從內源性表現V1a受體的雄性Wistar大鼠分離出的主動脈環上研究測試化合物。將雄性Wistar大鼠以二氧化碳安樂死。將主動脈取出並置於具有以下組成的冰冷Krebs-Henseleit緩衝液中(單位為毫末耳/升):NaCl 112、KCl 5.9、CaCl2 2.0、MgCl2 1.2、NaH2PO4 1.2、NaHCO3 25、葡萄糖11.5。將主動脈切成3毫米環,並轉移到含於95% O2、5% CO2、37°C平衡的Krebs-Henseleit溶液之20毫升器官浴。欲記錄等張張力,環安裝在兩個鉤之間。將靜止張力調節至3克。平衡一段期間後,將製備物暴露於K+(50毫莫耳濃度)Krebs-Henseleit溶液中而開始每個實驗。主動脈環之後使用1奈莫耳/升之Arg-血管加壓素進行預收縮。建立穩定的收縮後,構建測試化合物的累積劑量反應曲線。Arg-加壓素引起的穩定收縮定義為100%張力。鬆弛度以張力百分比表示。
分離腎臟
將雄性Wistar大鼠(200-250克)以二氧化碳安樂死。將腎臟取出並置於具有以下組成的冰冷Krebs-Henseleit緩衝液(單位為毫莫耳/升):NaCl 112、KCl 5.9、CaCl2 2.0、MgCl2 1.2、NaH2PO4 1.2、NaHCO3 25、葡萄糖11.5。欲記錄等張張力,2毫米長之環片段安裝在小血管腔肌成像儀中(Danish Myo Technology A/S,Denmark),使用固定在安裝夾爪上的兩根鎢絲。一個安裝爪連接到千分尺上,以此控制血管周長。另一個安裝爪連接到用於測量張力顯影的力傳感器上。將整個製備物保持於具有生理食鹽水溶液的37℃室中,打入氧氣起泡。在30分鐘平衡期後,將血管拉伸到其最佳內腔直徑,用於主動張力顯影,其以內圓周壁張力比為基礎決定。若血管暴露在相當於100毫米汞柱的透壁壓力產生的被動張力下,此時的內圓周設定為血管內圓周的90%。
之後,血管以Krebs-Henseleit緩衝液清洗三次,並平衡30分鐘。之後藉由二倍暴露於高K+溶液(50毫莫耳/升KCl)中測試收縮度。以Krebs-Henseleit緩衝液清洗血管後,血管使用1奈莫耳/升Arg-血管加壓素進行預收縮。建立穩定的收縮後,構建測試化合物的累積劑量反應曲線。Arg-加壓素引起的穩定收縮定義為100%張力。鬆弛度以張力百分比表示。
B-6. 以體內試驗檢測心血管作用:麻醉大鼠血壓測量(血管加壓素「刺激」模型)
在氯胺酮/甲苯噻嗪/戊巴比妥注射麻醉下使用雄性Sprague-Dawley大鼠(體重250-350克)。聚乙烯管(PE-50,Intramedic®),預填充有含肝素(500國際單位/毫升)等張氯化鈉溶液,導入頸靜脈和股靜脈,然後連接。Arg-血管加壓素(SIGMA)經由靜脈通路注射,其借助於注射器;受試經由第二靜脈通路投予。欲確定收縮壓,將壓力導管(Millar
SPR-320 2F)連接至頸動脈。動脈導管連接到壓力傳感器,該壓力傳感器將其信號饋送到配備有合適記錄軟體的記錄電腦中。在典型實驗中,實驗動物以10-15分鐘間隔連續3-4次全劑量注射(bolus injections),在等張氯化鈉溶液中使用定義量的Arg-血管加壓素(30奈克/公斤)。當血壓再次達到初始量時,受試以全劑量(bolus)投予,隨後以合適溶劑連續輸注。之後,於定義的間隔(10-15分鐘),再次施用如起始時相同量的Arg-血管加壓素。依據血壓值,確定受試對抗Arg-血管加壓素的高血壓作用程度。對照組動物只接受溶劑而無受試。
於靜脈投予後,相較於溶劑對照組,本發明化合物致使抑制由Arg-血管加壓素引起的血壓升高。
B-7. 以體內試驗檢測保護性腎臟作用:鼠科急性缺血/再灌流損傷模型
實驗室培育之雄性6-8週大C57Bl/6J小鼠係購自Taconic Biosciences,且雄性6-8週大Sprague Dawley®大鼠係購自Charles River。大鼠與小鼠皆保持在標準實驗室條件,採取12小時照光與黑暗循環,且自行獲取正常食物與飲水。針對缺血再灌流損傷模型實驗,各對照組與實驗組共使用10-12隻大鼠或小鼠。
以連續吸入異氟烷進行動物麻醉。於兩側腎缺血實驗前7天,通過右側切口進行右腎切除術。在腎缺血方面,完成一左側切口。進行左腎蒂(left renal pedicle)解剖以暴露腎血管。在45分鐘(大鼠)或25分鐘(小鼠)缺血期間,以非創傷性血管鉗停止血流(動脈與靜脈)。移除夾鉗以進行再灌流。腹腔壁(肌肉層與皮膚)以5.0聚丙烯縫線縫合。以Temgesic®(丁丙諾啡(Buprenorphin),0.025毫克/公斤皮下注射)作為止痛劑。
於缺血實驗後24小時且犧牲前,收集代謝籠中每隻動物之隔夜尿液。於犧牲時,在終端麻醉下取得血液樣本。於血液樣本離心後,
分離血清。以臨床生化分析儀(Pentra 400)測定血清肌酸酐與血清尿素。在評估血清與尿腎損傷生物標記物方面(嗜中性球明膠酶相關載脂蛋白[NGAL]、腎損傷分子-1[KIM-1]、及骨橋蛋白(Osteopontin)),依據製造商之方法進行EL1SA。測定尿液肌酸酐與白蛋白,以取得白蛋白/肌酸酐比率。
從RNA分離總RNA。於犧牲時以液態氮迅速冷凍左腎。隨後,將腎組織均質化並取得RNA。將總RNA轉錄成cDNA。利用TaqMan即時PCR,分析全腎組織中之腎NGAL、骨橋蛋白、KIM-1、腎病蛋白(Nephrin)、及足蛋白(Podocin)mRNA的表現。
組間差異係以單因子ANOVA分析並配合Dunnett氏校正以進行多重比較。統計上差異係定義為p<0.05。所有統計分析係以GraphPad Prism 6進行。
B-8. 以體內試驗檢測心血管作用:麻醉犬之血液動力學研究
以戊巴比妥(30毫克/公斤靜脈注射,Narcoren®,Merial,Germany)麻醉重量10至15公斤間之雄性米格魯犬(Beagle,Marshall BioResources,USA),以進行外科手術及血液動力學與終端功能研究。泮庫溴銨(Pancuroniumbromide)(Pancuronium Inresa,Inresa,Germany,2-4毫克/動物靜脈注射)額外作為肌肉鬆弛劑。該犬以氧氣/環境空氣混合物(30/70%)(約2.5-4公升/分鐘)插管及通氣。以GE Healthcare(Avance,Germany)呼吸機進行通氣,並以二氧化碳分析儀(-Datex Ohmeda)監測。持續輸注戊巴比妥(50微克/公斤/分鐘)維持麻醉;以芬太尼(fentanyl)作為止痛劑(10微克/公斤/小時)。
於預備實驗時,該犬配備心律調節器。實驗開始時,將購自Biotronik(德國Logos®)之心律調節器植入皮下皮膚空腔內,其經由調節器電極(SielloS60®,Biotronik,Germany)與心臟接觸,其通過頸外靜脈(伴
隨照明)進入右心室。
隨後,移除麻醉設備,使犬自然清醒。再過7天後,啟動上述心律調節器,並以每分鐘220次之頻率刺激心臟。
實際之藥物測試實驗係於啟動心律調節器刺激28天後進行,並使用下列儀器:
˙導入膀胱導尿管,以緩解膀胱及測量尿流量。
˙連接心電圖(ECG),使肢體配合心電圖測量。
˙將充滿氯化鈉溶液之鞘導引器導入股動脈。該管連接壓力感測器(Braun Melsungen,Melsungen,Germany)以測量全身血壓。
˙經由固定於頸動脈之端口導入Millar Tip導管(350PC型,Millar Instruments,Houston,USA),以測量心臟血液動力學。
˙經由頸靜脈將Swan-Ganz導管(CCOmbo 7.5F,Edwards,Irvine,USA)導入肺動脈,以測量心輸出量、氧飽和度、肺動脈壓、及中央靜脈壓。
˙將靜脈導管安置於頭靜脈,以輸注戊巴比妥、置換液體、及採血(測定血漿中物質濃度或其他臨床血液值)。
˙將靜脈導管安置於隱靜脈,以輸注芬太尼及投予物質。
˙輸注劑量漸增之血管加壓素(Sigma),最高劑量為4毫單位/公斤/分鐘。接著,以此劑量測試藥理學物質。
視需要,放大主信號(ACQ7700,Data Sciences International,USA或Edwards-Vigilance-Monitor,Edwards,Irvine,USA),隨後投入Ponemah系統(Data Sciences International,USA)以進行評估。於整個實驗期間持續記錄信號,並進一步以該軟體進行數位處理,平均約30秒。
B-9.於靜脈注射與口服投予後測定藥物動力學參數
測定本發明化合物於雄性C57b16小鼠、雄性Wistar大鼠、雌性米格魯犬、及雌性石蟹彌猴中之藥物動力學參數。在靜脈注射投予方面,於小鼠與大鼠之情況,利用物種特異性血漿/DMSO配方進行,於犬與猴子之情況,則利用水/PEG400/乙醇配方進行。於所有物種中,經由胃管灌食法(gavage)進行口服投予溶解物質,其係以水/PEG400/乙醇配方為主。於物質投予前,將矽膠導管插入右頸靜脈外側(Vena jugularis externa)以簡化大鼠的血液採集。在使用的實驗前至少一天進行手術,並施用鎮痛藥(阿托品/抗抑制素(3/1),0.1毫升)。手術係於異氟烷麻醉劑實驗的至少前一天進行,並投予止痛劑(阿托品/力莫敵(Rimadyl)(3/1)0.1毫升皮下注射)。於時間窗內(通常至少10個時間點)進行採血,包括物質投予後之終端時間點至少24至最多72小時。當取得血液後,將其送入肝素管。隨後,離心取得血漿,並任意地保存在20℃下直到進一步處理。
將內標準品(其亦可為化學上非相關物質)加入本發明化合物、校正樣本、及限定劑(qualifiers)之樣品中,並以過量之乙腈進行蛋白質沉澱。加入與LC條件相匹配之緩衝溶液,隨後渦旋,然後以1000g離心。上清液以LC-MS/MS分析,其使用C18或聯苯逆相管柱及可變移動相混合物。物質以特定選擇之離子監測實驗所提取離子層析圖之尖峰高度或面積進行定量。
經測定之血漿濃度/時間圖係用於計算藥物動力學參數,如AUC(曲線下面積)、Cmax(最大濃度)、t1/2(終端半衰期)、F(生物可利用率)、MRT(平均滯留時間)、及CL(清除率),其係使用經驗證之藥物動力學計算程式。
由於物質定量係於血漿中進行,需要測定物質之血液/血漿分佈,以便能相應地調整藥物動力學參數。為此目的,將一定義量之物質
培養於待釐清之肝素化全血中,並於滾動之混合物中進行20分鐘。於1000g離心後,測量血漿濃度(利用LC-MS/MS;參見前述),並計算全血濃度對血漿濃度(C血液/C血漿數值)之比率以確定。
B-10. 代謝研究
欲確定本發明化合物之代謝特徵,將其與各動物物種(如大鼠、犬、猴)及人源之重組型人類細胞色素P450(CYP)酵素、肝臟微粒體、或初代新鮮肝細胞一起培養,以取得及比較關於實質上完整之肝臟第I相與第II相代謝,以及相關涉及代謝之酵素等訊息。
本發明化合物係以約0.1-10μM之濃度培養。為此,製備在乙腈中具有0.01-1mM濃度之本發明化合物儲液,隨後以1:100稀釋倍率移液成培養混合物。肝臟微粒體與重組型酵素係於37℃下培養於50mM磷酸鉀緩衝液(pH7.4),內含或不含菸鹼醯胺腺嘌呤二核苷酸磷酸(NADPH)生成系統,其係由1mM NADP+、10mM葡萄糖-6-磷酸、及1單位之葡萄糖6-磷酸脫氫酶組成。將初代肝細胞培養於Williams E培養基懸液,同樣地於37℃下進行。於培養時間0-4小時後,以乙腈(最終濃度約30%)終止培養混合物,並以約15000xg離心分離蛋白質。經終止反應之樣品可直接分析或保存於-20℃下直到分析。
以高效能液態度層析術搭配紫外光與質譜檢測(HPLC-UV-MS/MS)進行分析。為此,所培養樣本之上清液以適用之C18逆相管柱及乙腈與10mM甲酸銨水溶液或0.05%甲酸之可變移動相混合物進行層析分離。以紫外光層析圖結合質譜數據用於代謝物之鑑定、結構闡明、及定量估計,以及用於本發明化合物在培養混合物中之定量代謝評估。
B-11. Caco-2滲透性試驗
受試物質之滲透性可藉助Caco-2細胞株測定,其係既定之
腸胃屏障滲透性預測之體外模型(Artursson,P.and Karlsson,J.(1991).Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial(Caco-2)cells.Biochem.Biophys.175(3),880-885)。將CaCo-2細胞(ACC No.169,DSMZ,Deutsche Sammlung von Mikroorganismen und Zellkulturen,Braunschweig,Germany)接種於凹槽型24孔培養盤中,並培養14至16天。在滲透性研究方面,將受試物質溶於DMSO,並以運輸緩衝液(Hanks緩衝鹽液,Gibco/Invitrogen,內含19.9mM葡萄糖與9.8mM HEPES)稀釋至最終測試濃度。欲確定受試物質從頂端至基底外側之滲透性(PappA-B),將包含受試物質之溶液置於Caco-2細胞單層之頂端側,並將輸送緩衝液置於基底外側。欲確定受試物質從基底外側至頂端之滲透性(PappB-A),將包含受試物質之溶液置於Caco-2細胞單層之基底外側,並將輸送緩衝液置於頂端側。於實驗開始時,從個別供體室取出樣本,以計算其後之質量平衡。於37℃下培養2小時後,從該二隔室中取出樣本。利用LC-MS/MS分析樣本,並計算表觀滲透係數(Papp)。針對各細胞單層,測定路西法黃色(Lucifer Yellow)之滲透性,以確保細胞層完整性。於每回試驗中,阿替洛爾(低滲透性標記)與柳氮磺胺吡啶(主動分泌標記)之滲透性皆視為品管依據。
C)醫藥組成物之工作例
本發明物質可轉化成醫藥製備物,如下:
片劑:
組成物:
100毫克實施例1化合物、50毫克乳糖(單水合物)、50毫克玉米澱粉、10毫克聚乙烯吡咯烷酮(PVP 25)(購自BASF,Germany)、及2毫克硬脂酸鎂。
片劑重212毫克。直徑8毫米,曲率半徑12毫米。
生產:
將實施例1化合物、乳糖、及澱粉之混合物與5%強度溶液(m/m)進行粒化,其係含PVP之水溶液。乾燥後,將顆粒與硬脂酸鎂混合5分鐘。此混合物係於常規壓片機中壓縮(參見上方片劑規格)。
口服懸液:
組成物:
1000毫克實施例1化合物、1000毫克乙醇(96%)、400毫克Rhodigel(黃原膠)(購自FMC,USA)、及99克水。
10毫升口服懸液相當於100毫克單一劑量之本發明化合物。
生產:
將Rhodigel懸浮於乙醇,並將實施例1化合物加入懸液。於攪拌時加入水。將混合物攪拌約6小時,直到Rhodigel完全膨脹。
無菌靜脈注射液:
本發明化合物係以低於飽和溶解度之濃度溶解於生理學上可接受溶劑中(例如,等滲氯化鈉溶液、5%葡萄糖溶液、及/或30%PEG400溶液)。溶液以過濾法除菌,並裝入無菌與無熱原之注射容器。
儘管本發明參考具體實施例而揭示,但應理解到,本領域技術人員可設計本發明之其他具體實施例與變化,而不脫離本發明之實際精神與範疇。申請專利範圍係旨在理解為涵蓋所有此類具體實施例與等同之變化。
Claims (11)
- 一種通式(I)化合物,
- 如申請專利範圍第1項之通式(I)化合物,其中R1代表式 之基團,其中#1代表氮原子之連接點,Ar代表式 之基團,其中#2代表氮原子之連接點,R2A代表選自於氯原子、溴原子、三氟甲基、三氟甲氧基、乙氧基羰基及-C(=O)NH2之基團,或其醫藥上可接受鹽類、水合物及/或溶劑合物。
- 如申請專利範圍第1或2項之通式(I)化合物,其中R1代表式 之基團,其中#1代表氮原子之連接點,Ar代表式 之基團,其中#2代表氮原子之連接點, R2A代表選自於氯原子、三氟甲基及三氟甲氧基之基團,或其醫藥上可接受鹽類、水合物及/或溶劑合物。
- 一種製備如申請專利範圍第1至3項中任一項之通式(I)化合物之方法,該方法包含之步驟為:[A]容許式(II)中間化合物:
- 如申請專利範圍第1至3項中任一項之化合物,其係用於治療及/或預防疾病。
- 如申請專利範圍第1至3項中任一項之化合物,其係用於一方法中,以治療及/或預防急性與慢性腎臟疾病,包括糖尿病腎病變、急性與慢性心臟衰竭、子癎前症、周邊動脈疾病(PAD)、冠狀動脈微血管功能障礙(CMD)、雷諾氏症、及痛經。
- 一種如申請專利範圍第1至3項中任一項所定義化合物之用途,其係用於製造醫藥組成物,以治療及/或預防急性與慢性腎臟疾病,包括糖尿病腎病變、急性與慢性心臟衰竭、子癎前症、周邊動脈疾病(PAD)、冠狀動脈微血管功能障礙(CMD)、雷諾氏症、及痛經。
- 一種醫藥組成物,其包含如申請專利範圍第1至3項中任一項定義之化合物及一或多個醫藥上可接受賦形劑。
- 如申請專利範圍第8項之醫藥組成物,其包含一或多個第一活性成分, 特別是如申請專利範圍第1至4項中任一項之通式(I)化合物,及一或多個進一步活性成分,特別是一或多個額外治療劑,其係選自於由利尿劑、血管收縮素AII拮抗劑、ACE抑制劑、β受體阻斷劑、鹽皮質素(mineralcorticoid)受體拮抗劑、抗糖尿病藥、有機硝酸鹽與NO供體、可溶性鳥苷酸環化酶(sGC)的活化劑與刺激劑、抗發炎劑、免疫抑制劑、磷酸鹽結合劑、及/或調控維生素D代謝之化合物組成之群組。
- 如申請專利範圍第8或9項之醫藥組成物,其用於治療及/或預防急性與慢性腎臟疾病,包括糖尿病腎病變、急性與慢性心臟衰竭、子癎前症、周邊動脈疾病(PAD)、冠狀動脈微血管功能障礙(CMD)、雷諾氏症、及痛經。
- 一種用於治療及/或預防人類或其他哺乳類動物之急性與慢性腎臟疾病之方法,該疾病包括糖尿病腎病變、急性與慢性心臟衰竭、子癎前症、周邊動脈疾病(PAD)、冠狀動脈微血管功能障礙(CMD)、雷諾氏症、及痛經,該方法包含投予有需求之人類或其他哺乳類動物一治療上有效量之如申請專利範圍第1至3項中任一項定義之一或多個化合物,或如申請專利範圍第8至10項中任一項定義之醫藥組成物。
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