TWI850199B - 做為腺苷受體拮抗劑之噻唑并吡啶衍生物 - Google Patents
做為腺苷受體拮抗劑之噻唑并吡啶衍生物 Download PDFInfo
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Abstract
本發明係關於通式I之噻唑并吡啶衍生物,
Description
本發明係關於通式I之噻唑并吡啶衍生物,及本發明之化合物用於治療及/或預防哺乳動物、尤其人類之過度增殖性或傳染性疾病及病症之用途,以及含有此等化合物之醫藥組合物。
腺苷係普遍存在之多種生理活性之調節劑,尤其在心血管、神經及免疫系統內。腺苷在結構及代謝二者上與生物活性核苷酸三磷酸腺苷(ATP)、二磷酸腺苷(ADP)、單磷酸腺苷(AMP)及環狀單磷酸腺苷(cAMP)相關、與生物化學甲基化劑S-腺苷基-L-甲硫胺酸(SAM)相關且在結構上與輔酶NAD、FAD及輔酶A相關且與RNA相關。
經由細胞表面受體,腺苷調節多種生理功能,包括誘導鎮靜、血管舒張、阻抑心率及收縮性、抑制血小板聚集性、刺激糖質新生且抑制脂類分解。研究顯示,腺苷能夠活化腺苷酸環化酶、開放鉀通道、降低通過鈣通道之通量且藉助受體介導之機制抑制或刺激磷酸肌醇轉換(Muller C. E.及Stein B.,Current Pharmaceutical Design, 2: 501, 1996;Muller C. E.,Exp. Opin. Ther. Patents, 7(5): 419, 1997)。
腺苷受體屬G蛋白偶合受體(GPCR)超家族。腺苷受體之四種主要亞型已在藥理學、結構及功能上予以表徵(Fredholm等人,Pharm. Rev., 46: 143-156, 1994),且稱為A1
、A2A
、A2B
及A3
。儘管相同腺苷受體可偶合至不同G蛋白,但腺苷A1
及A3
受體通常偶合至抑制性G蛋白(稱為Gi
及G0
),該等抑制性G蛋白抑制腺苷酸環化酶且下調細胞cAMP含量。相比之下,腺苷A2A
及A2B
受體偶合至刺激性G蛋白(稱為GS
),該等刺激性G蛋白活化腺苷酸環化酶且增加cAMP之細胞內含量(Linden J.,Annu. Rev. Pharmacol. Toxicol., 41:775-87 2001)。
根據本發明,「腺苷-受體-選擇性配體」係選擇性結合至腺苷受體之一或多種亞型,由此模擬腺苷之作用(腺苷激動劑)或阻斷其作用(腺苷拮抗劑)之物質。根據其受體選擇性,可將腺苷-受體-選擇性配體分成不同類別,例如選擇性結合至A1
或A2
受體之配體,且在A2
受體情形下亦為例如選擇性結合至A2A
或A2B
受體之彼等配體。亦可能為選擇性結合至腺苷受體之複數種亞型之腺苷受體配體,例如選擇性結合至A1
及A2
但不結合至A3
受體之配體。以上所提及之受體選擇性可藉由物質對細胞系之效應來測定,該等細胞系在經相應cDNA穩定轉染後,表現所討論之受體亞型(Olah, M. E.等人,J. Biol. Chem., 267: 10764-10770, 1992)。物質對此等細胞系之效應可藉由細胞內信使cAMP之生物化學量測來監測(Klotz, K. N.等人,Naunyn Schmiedebergs Arch. Pharmacol. 357: 1-9, 1998)。
已知A1
受體系統包括磷脂酶C之活化及鉀及鈣離子通道二者之調節。A3
亞型除與腺苷酸環化酶締合以外,亦刺激磷脂酶C且因此活化鈣離子通道。
A1
受體(326-328個胺基酸)係自各種物種(犬、人類、大鼠、狗、小雞、牛、天竺鼠)選殖,其中哺乳動物物種間具有90-95%序列一致性。A2A
受體(409-412個胺基酸)係自犬、大鼠、人類、天竺鼠及小鼠選殖。A2B
受體(332個胺基酸)係自人類及小鼠選殖,其中人類A2B
與人類A1
及A2A
受體具有45%同源性。A3
受體(317-320個胺基酸)係自人類、大鼠、狗、兔及綿羊選殖。
提出A1
及A2A
受體亞型在腺苷之能量供應調控中起補充作用。腺苷係ATP之代謝產物,其自細胞擴散且在局部起作用以使腺苷受體活化來降低需氧量(A1
及A3
)或增加供氧量(A2A
),且因此恢復組織內之能量供應/需求平衡。兩種亞型之作用係增加至組織之可用氧之量並保護細胞免受由短期氧不平衡所造成之損害。內源性腺苷之重要功能之一係防止創傷期間之損害,例如低氧、缺血、低血壓及癲癇發作。此外,已知腺苷受體激動劑與表現大鼠A3
受體之肥胖細胞之結合導致三磷酸肌醇及細胞內鈣濃度增加,此增強抗原誘導之發炎介質之分泌。因此,A3
受體在介導氣喘發作及其他過敏反應方面起作用。
該等腺苷受體係由不同基因編碼且根據其對腺苷類似物及甲基黃嘌呤拮抗劑之親和力進行分類(Klinger等人,Cell Signal., 14 (2): 99-108, 2002)。
關於腺苷對神經系統之作用,首先觀察在所有精神作用藥物中最廣泛使用之咖啡因之效應。實際上,咖啡因係眾所周知之能夠增強哺乳動物之意識及學習能力之腺苷受體拮抗劑。腺苷A2A
受體路徑產生該等效應(Fredholm等人,Pharmacol. Rev., 51 (1): 83-133, 1999;Huang等人,Nat Neurosci., 8 (7): 858-9, 2005),且咖啡因對腺苷A2A
受體信號傳導路徑之效應促進對高度特異性及強效腺苷A2A
拮抗劑之研究。
在哺乳動物中,腺苷A2A
受體在腦中具有有限分佈且在紋狀體、嗅結節及依核中有發現(Dixon等人,Br. J. Pharmacol., 118 (6): 1461-8, 1996)。在免疫細胞、心臟、肺及血管中可觀察到高及中等程度之表現。在外周系統中,G3
似乎係與腺苷A2A
受體締合之主要G蛋白,但在紋狀體中,已顯示紋狀體腺苷A2A
受體藉助活化稱為Go
if之G蛋白來介導其效應(KuIl等人,MoI. Pharmacol., 58 (4): 772-7, 2000),該G蛋白與G3
類似且亦偶合至腺苷酸環化酶。
迄今為止,對基因修飾小鼠及藥理學分析之研究表明,A2A
受體係有希望之用於治療諸如帕金森氏病(Parkinson's disease)、亨庭頓氏病(Huntington's disease)、注意力缺失過動病症(ADHD)、中風(缺血性腦損傷)及阿茲海默氏病(Alzheimer's disease)等中樞神經系統(CNS)病症及疾病之治療靶標(Fredholm等人,Annu. Rev. Pharmacol. Toxicol., 45: 385-412, 2005;Higgins等人;Behav. Brain Res. 185: 32-42, 2007;DaIl' Igna等人,Exp. Neurol., 203 (1): 241-5, 2007;Arendash等人,Neuroscience, 142 (4): 941-52, 2006;Trends in Neurosci., 29 (11), 647-654, 2006;Expert Opinion Ther. Patents,17, 979-991, 2007;Exp. Neurol., 184 (1), 285-284, 2003;Prog. Brain Res, 183, 183-208, 2010;J. Alzheimer Dis., 增刊1, 1 17-126, 2010;J. Neurosci., 29 (47), 14741-14751, 2009;Neuroscience, 166 (2), 590-603, 2010;J. Pharmacol. Exp. Ther., 330 (1), 294-303, 2009;Frontiers Biosci., 13, 2614-2632, 2008),且亦適用於各種器質性起源之精神病(Weiss等人,Neurology, 61 (11增刊6): 88-93, 2003)。
使用腺苷A2A
受體剔除小鼠已顯示腺苷A2A
受體不活化保護免於由缺血(Chen等人,J. Neurosci., 19 (21): 9192-200, 1999及Monopoli等人,Neuroreport, 9 (17): 3955-9, 1998)及粒線體毒素3-NP (Blum等人,J. Neurosci., 23 (12): 5361-9, 2003)誘導之神經元細胞死亡。彼等結果為利用腺苷A2A
拮抗劑治療缺血及亨庭頓氏病提供基礎。腺苷A2A
受體之阻斷亦具有抗抑鬱藥效應(El Yacoubi等人,Neuropharmacology, 40 (3): 424-32, 2001)。最終,此阻斷預防記憶功能障礙(Cunha等人,Exp. Neurol., 210 (2): 776-81, 2008;Takahashi等人,Front. Biosci., 13: 2614-32, 2008),且此可係有希望之用於治療及/或預防阿茲海默氏病之治療途徑。
關於涉及A2A
腺苷受體之綜述,參見(例如) Moreau等人,(Brain Res. Reviews 31: 65-82, 1999)及Svenningsson等人,(Progress in Neurobiology 59: 355-396, 1999)。
迄今為止,若干種腺苷A2A
受體拮抗劑已顯示有希望之用於治療帕金森氏病之潛能。做為實例,KW-6002 (伊曲茶鹼(Istradefylline))在證實其在緩和該疾病之症狀方面之效能之研究後,在美國完成III期臨床試驗(Bara-Himenez等人,Neurology, 61 (3): 293-6, 2003及Hauser等人,Neurology, 61 (3): 297-303, 2003)。SCH420814 (普瑞丁奈(Preladenant))現在美國處於II期臨床試驗中且在帕金森氏病之動物模型(Neustadt等人,Bioorg. Med. Chem. Lett., 17 (5): 1376-80, 2001)且亦在人類患者(Hunter J. C,poster Boston 2006 - http://www.a2apd.org/Speaker abstracts/Hunter.pdf)中產生運動功能改良。
除A2A
受體拮抗劑治療神經退化疾病之受歡迎效用以外,已考慮將彼等化合物用於互補症狀性適應症。該等係基於以下證據:A2A
受體活化可導致一系列神經精神病症及功能障礙(例如抑鬱症、過度日間睡眠、不寧腿症候群、注意力缺失過動病症及認知疲勞)之病理生理學(Neurology, 61 (增刊6), 82-87, 2003;Behav. Pharmacol., 20 (2), 134-145, 2009;CNS Drug Discov., 2 (1), 1-21, 2007)。
一些作者提出施加A2A
拮抗劑用於治療糖尿病(WO1999035147;WO2001002400)。其他研究表明A2A
腺苷受體涉及傷口癒合或心房震顫(Am. J. Path., 6, 1774- 1778, 2007;Arthritis & Rheumatism, 54 (8), 2632-2642, 2006)。
製藥公司過去發現之一些強效腺苷A2A
拮抗劑已進展至臨床試驗,其顯示陽性結果且證實此化合物類用於治療神經退化病症(如帕金森氏病、亨庭頓氏病或阿茲海默氏病)亦及其他CNS相關疾病(如抑鬱症、不寧症候群、睡眠及焦慮症)之潛能(Clin. Neuropharmacol., 33, 55-60, 2010;J. Neurosci., 30 (48), 2010), 16284-16292;Parkinson Relat. Disord., 16 (6), 423-426, 2010;Expert Opinion Ther. Patents, 20(8), 987-1005, 2010;Current Opinion in Drug Discovery & Development, 13 (4), 466-480 ,2010及其中之參考文獻;Mov. Disorders 25 (2), S305, 2010)。
已知之A2A
抑制劑係伊曲茶鹼(KW-6002)、普瑞丁奈(SCH420814)、SCH58261、CGS15943、托紮丁奈(Tozadenant)、維帕丁奈(Vipadenant)(V-2006)、V-81444 (CPI-444、HTL-1071、PBF-509、Medi-9447、PNQ-370、ZM-241385、ASO-5854、ST-1535、ST-4206、DT1133及DT-0926,在大多數情形下其係為帕金森氏病而開發。
腺苷A2B
受體係採用標準聚合酶鏈式反應技術與經設計以識別大多數G蛋白偶合受體之保守區之簡並寡核苷酸引子自大鼠下視丘(Rivkees及Reppert,1992)、人類海馬體(Pierce等人,1992)及小鼠肥胖細胞(Marquardt等人,1994)來選殖。人類A2B
受體與大鼠及小鼠A2B
受體共有86%至87%之胺基酸序列同源性(Rivkees及Reppert,1992;Pierce等人,1992;Marquardt等人,1994)且與人類A1
及A2A
受體共有45%之胺基酸序列同源性。如對於緊密相關物種所預期,大鼠及小鼠A2B
受體共有96%之胺基酸序列同源性。藉由對比,來自各種物種之A1
受體之間的總體胺基酸一致性為87% (Palmer及Stiles,1995)。A2A
受體在物種之間共有90%之同源性(Ongini及Fredholm,1996),大多數差異發生在第2個細胞外環及長C末端結構域(Palmer及Stiles,1995)。對於A3
受體序列觀察到物種之間的最低(72%)一致性程度(Palmer及Stiles,1995)。
腺苷類似物NECA仍為最強效之A2B
激動劑(Bruns,1981;Feoktistov及Biaggioni,1993, 1997;Brackett及Daly,1994),其產生刺激腺苷酸環化酶之半最大效應(EC50
)之濃度為大約2 µM。然而,其係非選擇性的且以甚至更高之親和力活化其他腺苷受體,其EC50
在低奈莫耳(A1
及A2A
)或高奈莫耳(A3
)範圍內。因此,對A2B
受體之表徵通常依賴於做為其他受體類型之強效及選擇性激動劑之化合物缺乏有效性。已藉由排除法(即,藉由缺乏對其他受體具有特異性之激動劑之效能)來表徵A2B
受體。舉例而言,A2A
選擇性激動劑CGS-21680 (Webb等人,1992)已用於區別A2A
與A2B
腺苷受體(Hide等人,1992;Chern等人,1993;Feoktistov及Biaggioni,1995;van der Ploeg等人,1996)。兩種受體均正偶合至腺苷酸環化酶並由非選擇性激動劑NECA活化。CGS-21680對A2B
受體幾乎無效,但在活化A2A
受體方面與NECA一樣強效,兩種激動劑之EC50
均在低奈莫耳範圍內(Jarvis等人,1989;Nakane及Chiba,1990;Webb等人,1992;Hide等人,1992;Feoktistov及Biaggioni,1993;Alexander等人,1996)。A2B
受體對A1
選擇性激動劑R-PIA (Feoktistov及Biaggioni,1993;Brackett及Daly,1994)以及對A3
選擇性激動劑N6
-(3-碘苄基)-N-甲基-5′-胺甲醯基腺苷(IB-MECA) (Feoktistov及Biaggioni,1997)亦具有極低親和力。在人類紅血球性白血病(HEL)細胞中經測定,A2B
介導之cAMP累積之激動劑概況為NECA > R-PIA = IB-MECA > CGS-21680。NECA與其餘激動劑之EC50
之間的差異為大約2個數量級。因此,由NECA在低微莫耳範圍(1-10 μM)之濃度下引發而非由R-PIA、IB-MECA或CGS-21680引發之反應係A2B
受體之特徵。
儘管與其他受體亞型相比,A2B
受體通常對激動劑具有較低之親和力,但對於拮抗劑則不然。腺苷拮抗劑對A2B
受體之結構活性關係尚未完全表徵,但至少一些黃嘌呤做為A2B
受體亞型之強效拮抗劑或係較其他亞型更強效之拮抗劑。具體而言,DPSPX (1,3-二丙基-8-磺基苯基黃嘌呤)、DPCPX (1,3-二丙基-8-環戊基黃嘌呤)、DPX (1,3二乙基苯基黃嘌呤)、抗氣喘藥物恩丙茶鹼(enprofylline)(3-正丙基黃嘌呤)及非黃嘌呤化合物2,4-二側氧基苯并喋啶(咯嗪)在中等至高nM範圍內具有親和力。
其他已知之A2B
抑制劑係ATL801、PSB-605、PSB-1115、ISAM-140、GS6201、MRS1706及MRS1754。
本文揭示腺苷受體藉由充當生理「STOP」(終止機制)而在活體內發炎下調方面起非冗餘作用,其可限制免疫反應且藉此保護正常組織在不同疾病之發病機制期間免受過度免疫損害。
A2A
受體拮抗劑藉由降低T細胞介導之對抗原性刺激之耐受性、增強記憶T細胞之誘導且增強被動抗體投與以用於治療癌症及傳染病之效能來提供免疫反應之長期增強,而A2A
受體激動劑藉由增強T細胞介導之對抗原性刺激之耐受性來提供免疫反應之長期降低,尤其在某些條件下降低免疫抑制劑之使用。
免疫調節係治療多種疾病及病症之關鍵方面。T細胞尤其在對抗感染方面起至關重要之作用,且具有識別並破壞癌細胞之能力。增強T細胞介導之反應係增強對治療劑之反應之關鍵組成部分。然而,在免疫調節中,免疫反應之任何增強與預防自體免疫性以及慢性發炎之需求相平衡至關重要。慢性發炎及T細胞之自我識別係諸如類風濕性關節炎、多發性硬化及全身性紅斑狼瘡等全身性病症之發病機制之主要原因。此外,在預防移植器官或移植物之排斥方面需要長期免疫抑制。
腫瘤誘導之免疫抑制係當前癌症療法效能之主要障礙。由於其針對更廣泛範圍癌症之顯著臨床效能,最近利用免疫檢查點阻斷抑制劑(例如抗CTLA-4及抗PD-1/PDL1)獲得之成功正在使癌症治療發生變革。
腺苷係臨床前研究中揭示之新的有希望之免疫抑制靶標之一。此代謝物由宿主抑制細胞及腫瘤細胞上表現之胞外酶CD73產生。CD73之表現增加與患有多種癌症之患者之不良預後相關,該等癌症包括結腸直腸癌(Liu等人,J. Surgical Oncol, 2012)、胃癌(Lu等人,World J. Gastroenterol., 2013)、膽囊癌(Xiong等人,Cell and Tissue Res., 2014)。臨床前研究證實,CD73之親腫瘤(protumor)效應可(至少部分地)由腺苷介導之免疫抑制驅動。如上文所揭示,腺苷結合至四種已知之受體A1
、A2A
、A2B
及A3
,其中已知A2A
及A2B
受體之活化抑制許多免疫細胞之效應功能,即A2A
及A2B
受體誘導cAMP之腺苷酸環化酶依賴性累積,從而導致免疫抑制。由於拮抗A1
及A3
將抵消期望效應且A1
及A3
激動劑用作潛在心臟保護劑,因此需要達成對A1
及A3
之選擇性(Antonioli等人,Nat. rev. Cancer, 2013,Thiel等人,Microbes and Infection, 2003)。在腫瘤微環境中,已證實A2A
及A2B
受體二者之活化均抑制抗腫瘤免疫性且增加CD73腫瘤之擴散。另外,用小分子拮抗劑對A2A
或A2B
進行阻斷可降低腫瘤轉移。已發現,阻斷A2A
受體可克服腫瘤逃逸機制(包括腫瘤細胞引起之無反應性及調節性T細胞誘導二者)且引起對治療之長期腫瘤易感性。Ohta等人證實,與正常小鼠中之無排斥相比,在A2A
受體缺陷小鼠中大約60%之已確立CL8-1黑色素瘤受排斥(Ohta等人;PNAS 103 (35): 13132-7, 2006)。與此一致,研究者亦展示在用A2A
受體拮抗劑治療之後,抗腫瘤T細胞對腫瘤生長之抑制、轉移之破壞及新血管形成之阻止均有改良。
已顯示,腫瘤藉助抑制B7-CD28及TNF家族中之共刺激因子阻礙T細胞活化以及藉由吸引抑制抗腫瘤T細胞反應之調節性T細胞來逃避免疫破壞(Wang,Cancer. Semin. Cancer. Biol. 16: 73-79, 2006;Greenwald等人,Ann. Rev. Immunol. 23: 515-48, 2005;Watts,Ann. Rev. Immunol. 23: 23-68, 2005;Sadum等人,Clin. Cane. Res. 13 (13): 4016-4025, 2007)。由於活化後淋巴球中A2A
受體表現增加,因此釋放淋巴球效應反應之療法(例如抗CTLA-4及抗PD-1)亦可增加A2A
介導之免疫抑制之效應。免疫檢查點阻斷與A2A
或雙重A2A/2B
拮抗劑之組合增加對腫瘤及轉移之免疫反應之量級。因此,A2A
抑制與抗PD-1療法之組合增強與MC38腫瘤細胞共培養之T細胞之IFN-γ產生,改良4T1乳房腫瘤模型中之小鼠存活且降低AT-3ovadim
CD73+
腫瘤中之腫瘤生長(Beavis等人,Cancer Immunol. Res., 2015;Mittal等人,Cancer Res., 2014)。
此外,臨床前研究證實,A2B
抑制使得路易斯肺癌(Lewis lung carcinoma)、MB49膀胱癌、正位4T1乳癌模型中之腫瘤生長降低且小鼠存活延長(Ryzhov等人,2009,Cekic等人,2012),且A2B
抑制與抗PD-1療法之組合降低B16-F10黑色素瘤之肺轉移且改良4T1乳房腫瘤模型中之小鼠存活。
WO 03/050241闡述增加對抗原之免疫反應、增加疫苗效能或增加對腫瘤抗原之免疫反應或免疫細胞介導之腫瘤破壞之方法,其係藉由投與抑制細胞外腺苷或抑制腺苷受體之藥劑來實施。
WO 2004/089942、WO 2005/000842及WO 2006/008041揭示做為用於治療帕金森氏病之A2A
抑制劑之苯并噻唑衍生物(包括托紮丁奈)。WO 2004/092171及WO 2005/028484揭示亦做為用於治療帕金森氏病之A2A
抑制劑之類似噻唑并吡啶及吡唑并嘧啶衍生物。然而,該等化合物不顯示顯著之A2B
抑制活性,且僅在大鼠(帕金森氏病動物模型)中顯示良好之藥物動力學性質,但在小鼠(癌症動物模型)中則不顯示良好之藥物動力學性質。此外,該等化合物不顯示其能夠防止免疫抑制,且因此不能支持抗腫瘤T細胞誘導之對腫瘤生長之抑制、轉移之降低或破壞及新血管形成之阻止。
因此,業內仍需要能夠長期增強對特定抗原之免疫反應、尤其用於治療及預防過度增殖性及傳染性疾病及病症之療法,且因此本發明之目標係提供容許簡化之治療方案並增強針對某些抗原之免疫反應之治療方法。本發明之具體目標係提供改良之預防或治療宿主之過度增殖性及傳染性疾病及病症之方法,尤其提供用於治療及預防此等疾病之有效A2A
或雙重A2A/2B
拮抗劑。
令人驚訝的是,已發現,根據本發明之噻唑并吡啶衍生物係A2A
腺苷受體或A2A
及A2B
腺苷受體二者之高度有效抑制劑,且同時對A1
及A3
腺苷受體具有高選擇性,且因此本發明之化合物可用於治療過度增殖性疾病及病症(例如癌症)以及傳染性疾病及病症。
具體而言,與已知之腺苷A2A
受體拮抗劑托紮丁奈及類似苯并噻唑衍生物相比,本發明之化合物令人驚訝地顯示A2A
/A2B
雙重活性,此對於治療及/或預防如上文所揭示之過度增殖性及傳染性疾病及病症較佳,或本發明之化合物至少顯示高A2A
抑制活性以及本文所揭示之在治療及/或預防過度增殖性及傳染性疾病及病症中產生高效能之其他令人驚訝之優點。
另外,與已知之腺苷A2A
受體拮抗劑托紮丁奈及類似苯并噻唑衍生物相比,本發明之化合物在做為癌症相關動物模型之小鼠中令人驚訝地顯示較佳藥物動力學性質,此對於治療及/或預防如上文所揭示之過度增殖性及傳染性疾病及病症較佳。
此外,如上文所論述,腫瘤微環境中之腺苷可藉助經由A2A
受體進行信號傳導來抑制T細胞活性並抑制T細胞之細胞介素分泌。與腺苷類似,A2A
特異性激動劑(如CGS-21680)抑制活體外及活體內之T細胞細胞介素分泌。相比之下,潛在A2A
拮抗劑或A2A
/A2B
雙重拮抗劑可拯救T細胞免於此抑制。與已知之腺苷A2A
受體拮抗劑托紮丁奈相比,本發明之化合物顯示其能夠拯救T細胞免受抑制且能夠防止對如由腺苷或A2A
特異性激動劑(如CGS-2168)誘導之細胞介素分泌之抑制,此對於治療及/或預防如上文所揭示之過度增殖性及傳染性疾病及病症較佳。因此,令人驚訝地,本發明之化合物能夠防止免疫抑制且因此能夠支持抗腫瘤T細胞誘導之對腫瘤生長之抑制、轉移之降低或破壞及新血管形成之阻止。
本發明係關於通式I之噻唑并吡啶衍生物,其中 R1
係具有1至10個C原子之直鏈或具支鏈烷基,其未經取代或經R5
單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2
、NH、NCH3
、-OCO-、-NHCONH-、-NHCO-、-NR6
SO2
R7
-、-COO-、-CONH-、-NCH3
CO-、-CONCH3
-、-C≡C-基團及/或-CH=CH-基團替代及/或另外1至10個H原子可經F及/或Cl替代;或具有3至7個C原子之單環或二環環狀烷基,其未經取代或經R5
單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2
、NH、NCH3
、-OCO-、-NHCONH-、-NHCO-、-NR6
SO2
R7
-、-COO-、-CONH-、-NCH3
CO-、-CONCH3
-、-C≡C-基團及/或-CH=CH-基團替代及/或另外1至10個H原子可經F及/或Cl替代;或含有3至14個碳原子及0至4個獨立地選自N、O及S之雜原子之單環或二環雜芳基、雜環基、芳基或環狀烷基芳基,其未經取代或經R5
單取代、二取代或三取代, R2
係具有1至10個C原子之直鏈或具支鏈烷基,其未經取代或經R5
單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2
、NH、NCH3
、-OCO-、-NHCONH-、-NHCO-、-NR6
SO2
R7
-、-COO-、-CONH-、-NCH3
CO-、-CONCH3
-、-C≡C-基團及/或-CH=CH-基團替代及/或另外1至10個H原子可經F及/或Cl替代;或具有3至7個C原子之環狀烷基,其未經取代或經R5
單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2
、NH、NCH3
、-OCO-、-NHCONH-、-NHCO-、-NR6
SO2
R7
-、-COO-、-CONH-、-NCH3
CO-、-CONCH3
-、-C≡C-基團及/或-CH=CH-基團替代及/或另外1至11個H原子可經F及/或Cl替代;或含有3至14個碳原子及0至4個獨立地選自N、O及S之雜原子之單環或二環雜芳基、雜環基、芳基或環狀烷基芳基,其未經取代或經R5
單取代、二取代或三取代, R3
係具有1至6個C原子之直鏈或具支鏈烷基或O-烷基或具有3至6個C原子之環狀烷基,其未經取代或經以下單取代、二取代或三取代:H、=S、=NH、=O、OH、具有3至6個C原子之環狀烷基、COOH、Hal、NH2
、SO2
CH3
、SO2
NH2
、CN、CONH2
、NHCOCH3
、NHCONH2
或NO2
, R4
係H、D、具有1至6個C原子之直鏈或具支鏈烷基或Hal, R5
係H、R6
、=S、=NR6
、=O、OH、COOH、Hal、NH2
、SO2
CH3
、SO2
NH2
、CN、CONH2
、NHCOCH3
、NHCONH2
、NO2
或具有1至10個C原子之直鏈或具支鏈烷基,其未經取代或經R6
單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2
、NH、NCH3
、-OCO-、-NHCONH-、-NHCO-、-NR6
SO2
R7
-、-COO-、-CONH-、-NCH3
CO-、-CONCH3
-、-C≡C-基團及/或-CH=CH-基團替代及/或另外1至10個H原子可經F及/或Cl替代;或具有3至7個C原子之單環或二環環狀烷基,其未經取代或經R6
單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2
、NH、NCH3
、-OCO-、-NHCONH-、-NHCO-、-NR6
SO2
R7
-、-COO-、-CONH-、-NCH3
CO-、-CONCH3
-、-C≡C-基團及/或-CH=CH-基團替代及/或另外1至10個H原子可經F及/或Cl替代;或含有3至14個碳原子及0至4個獨立地選自N、O及S之雜原子之單環或二環雜芳基、雜環基、芳基或環狀烷基芳基,其未經取代或經R6
單取代、二取代或三取代, R6
、R7
彼此獨立地選自由以下組成之群:H、=S、=NH、=O、OH、COOH、Hal、NH2
、SO2
CH3
、SO2
NH2
、CN、CONH2
、NHCOCH3
、NHCONH2
、NO2
及具有1至10個C原子之直鏈或具支鏈烷基,其中1至4個C原子可彼此獨立地經O、S、SO、SO2
、NH、NCH3
、-OCO-、-NHCONH-、-NHCO-、-COO-、-CONH-、-NCH3
CO-、-CONCH3
-、-C≡C-基團及/或-CH=CH-基團替代及/或另外1至10個H原子可經F及/或Cl替代, Hal 係F、Cl、Br或I, D 係氘 及其生理上可接受之鹽、衍生物、溶劑合物、前藥及立體異構物,包括其所有比率之混合物。
本發明較佳係關於式I化合物,其中 R1
係具有1至10個C原子之直鏈或具支鏈烷基,其未經取代或經R4
單取代、二取代或三取代且其中1至4個C原子可彼此獨立地經O、S、SO、SO2
、NH、NCH3
、-OCO-、-NHCONH-、-NHCO-、-NR5
SO2
R6
-、-COO-、-CONH-、-NCH3
CO-、-CONCH3
-、-C≡C-基團及/或-CH=CH-基團替代及/或另外1至10個H原子可經F及/或Cl替代;或以下結構中之一者:其未經取代或經R5
單取代、二取代或三取代 且其中R2
、R3
、R4
、R5
、R6
及R7
具有如上文所揭示之含義。
本發明尤佳係關於式I化合物,其中 R1
係以下結構中之一者:且其中R2
、R3
、R4
、R5
、R6
及R7
具有如上文所揭示之含義。
本發明較佳係關於式I化合物,其中 R1
係苯基、甲基吡唑或二氫吡喃 且R2
、R3
、R4
、R5
、R6
及R7
具有如上文所揭示之含義。
本發明尤佳係關於式I化合物,其中R2
係以下結構中之一者:其未經取代或經R6
單取代、二取代或三取代 且其中R1
、R3
、R4
、R5
、R6
及R7
具有如上文所揭示之含義。
本發明尤佳係關於式I化合物,其中 R2
係以下結構中之一者: 且其中R1
、R3
、R4
、R5
、R6
及R7
具有如上文所揭示之含義。
本發明較佳係關於式I化合物,其中 R3
係以下結構中之一者:且R1
、R2
、R4
、R5
、R6
及R7
具有如上文所揭示之含義。
本發明較佳係關於式I化合物,其中 R3
係具有1至6個C原子之O-烷基,其未經取代或經F單取代、二取代或三取代 且R1
、R2
、R4
、R5
、R6
及R7
具有如上文所揭示之含義。
本發明較佳係關於式I化合物,其中 R3
係OMe 且R1
、R2
、R4
、R5
、R6
及R7
具有如上文所揭示之含義。
本發明尤佳係關於式I化合物,其中 R1
係苯基、甲基吡唑或二氫吡喃, R3
係OMe 且R2
、R4
、R5
、R6
及R7
具有如上文所揭示之含義。
本發明較佳係關於式I化合物,其中 R4
係H、D、甲基、乙基、F、Br或Cl 且其中R1
、R2
、R3
、R5
、R6
及R7
具有如上文所揭示之含義。
本發明較佳係關於式I化合物,其中 R4
係H、D、甲基、F、Br或Cl 且其中R1
、R2
、R3
、R5
、R6
及R7
具有如上文所揭示之含義。
本發明較佳係關於式I化合物,其中 R4
係H 且其中R1
、R2
、R3
、R5
、R6
及R7
具有如上文所揭示之含義。
本發明尤佳係關於選自由以下組成之群之化合物:
及其生理上可接受之鹽、衍生物、溶劑合物、前藥及立體異構物,包括其所有比率之混合物。
式I化合物之以上基團之所有上文所提及之較佳、尤佳及極佳含義應以此一方式理解,即該等較佳、尤佳及極佳含義或實施例可以任何可能的組合彼此組合以獲得式I化合物,且在此同樣地明確揭示較佳、尤佳及極佳之此類型之式I化合物。
Hal表示氟、氯、溴或碘,尤其氟、溴或氯。
D或2
H表示氘。
−(C=O)−或=O表示羰基氧且代表或氧原子藉助雙鍵與碳原子鍵結。
烷基係飽和無支鏈(直鏈)或具支鏈烴鏈,且具有1、2、3、4、5、6、7、8、9或10個C原子。烷基較佳表示烯基甲基,此外表示乙基、丙基、異丙基、丁基、異丁基、第二丁基或第三丁基,此外亦表示戊基、1-、2-或3-甲基丁基、1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基,直鏈或具支鏈庚基、辛基、壬基或癸基,此外較佳表示(例如)三氟甲基。
環狀烷基或環烷基係飽和環狀烴鏈且具有3至10個、較佳3至7個C原子且較佳表示環丙基、環丁基、環戊基、環己基或環庚基。環烷基亦表示部分不飽和環狀烷基,例如環己烯基或環己炔基。
烯基表示不飽和無支鏈(直鏈)或具支鏈烴鏈,且具有1、2、3、4、5、6、7、8、9或10個C原子。
O-烷基或OA表示具有1至6個C原子之直鏈或具支鏈烷氧基,且較佳係甲氧基,此外亦表示(例如)乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第二丁氧基或第三丁氧基。
烷基氧基羰基係指本發明之羧酸衍生物之直鏈或具支鏈酯,即甲基氧基羰基(MeOCO-)、乙基氧基羰基或丁基氧基羰基。
烷基羰基係指直鏈或具支鏈烷基及羧酸基團。
芳基、Ar或芳香族環表示單環或多環芳香族或完全不飽和環狀烴鏈,例如未經取代之苯基、萘基或聯苯基,此外較佳地苯基、萘基或聯苯基、其每一者經(例如)以下單取代、二取代或三取代:A、氟、氯、溴、碘、羥基、甲氧基、乙氧基、丙氧基、丁氧基、戊基氧基、己氧基、硝基、氰基、甲醯基、乙醯基、丙醯基、三氟甲基、胺基、甲基胺基、乙基胺基、二甲基胺基、二乙基胺基、苄基氧基、磺醯胺基、甲基磺醯胺基、乙基磺醯胺基、丙基磺醯胺基、丁基磺醯胺基、二甲基磺醯胺基、苯基磺醯胺基、羧基、甲氧基羰基、乙氧基羰基、胺基羰基。
雜環及雜環基係指飽和或不飽和非芳香族環或環系統,其含有至少一個選自O、S及N之雜原子,進一步包括硫之氧化形式,即SO及SO2
。雜環之實例包括四氫呋喃(THF)、二氫呋喃、1,4-二噁烷、嗎啉、1,4-二噻烷、六氫吡嗪、六氫吡啶、1,3-二氧雜環戊烷、咪唑啶、咪唑啉、吡咯啉、吡咯啶、四氫吡喃、二氫吡喃、氧硫雜環戊烷、二硫雜環戊烷、1,3-二噁烷、1,3-二噻烷、氧硫雜環己烷、硫嗎啉及諸如此類。
雜芳基意指含有至少一個選自O、S及N之環雜原子之芳香族或部分芳香族雜環。因此,雜芳基包括與其他類型之環(例如芳基、環烷基及不係芳香族之雜環)稠合之雜芳基。雜芳基之實例包括: 吡咯基、異噁唑基、異噻唑基、吡唑基、吡啶基、噁唑基、噁二唑基、噻二唑基、噻唑基、咪唑基、三唑基、四唑基、呋喃基、三嗪基、噻吩基、嘧啶基、苯并異噁唑基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、二氫苯并呋喃基、吲哚啉基、嗒嗪基、吲唑基、異噁唑基、異吲哚基、二氫苯并噻吩基、吲嗪基、㖕啉基、酞嗪基、喹唑啉基、萘啶基、咔唑基、苯并二氧雜環己烯基、苯并二氧雜環戊烯基、喹喏啉基、嘌呤基、呋呫基、噻吩基、異苄基呋喃基、苯并咪唑基、苯并呋喃基、苯并噻吩基、喹啉基、吲哚基、異喹啉基、二苯并呋喃基及諸如此類。對於雜環基及雜芳基,包括含有3至15個原子之環及環系統,從而形成1至3個環。
單環或二環飽和、不飽和或芳香族雜環較佳表示未經取代或經單取代、二取代或三取代之2-或3-呋喃基、2-或3-噻吩基、1-、2-或3-吡咯基、1-、2、4-或5-咪唑基、1-、3-、4-或5-吡唑基、2-、4-或5-噁唑基、3-、4-或5-異噁唑基、2-、4-或5-噻唑基、3-、4-或5-異噻唑基、2-、3-或4-吡啶基、2-、4-、5-或6-嘧啶基,此外較佳表示1,2,3-三唑-1-、-4-或-5-基、1,2,4-三唑-1-、-3-或5-基、1-或5-四唑基、1,2,3-噁二唑-4-或-5-基、1,2,4-噁二唑-3-或-5-基、1,3,4-噻二唑-2-或-5-基、1,2,4-噻二唑-3-或-5-基、1,2,3-噻二唑-4-或-5-基、3-或4-嗒嗪基、吡嗪基、1-、2-、3-、4-、5-、6-或7-吲哚基、4-或5-異吲哚基、1-、2-、4-或5-苯并咪唑基、1-、3-、4-、5-、6-或7-苯并吡唑基、2-、4-、5-、6-或7-苯并噁唑基、3-、4-、5-、6-或7-苯并異噁唑基、2-、4-、5-、6-或7-苯并噻唑基、2-、4-、5-、6-或7-苯并異噻唑基、4-、5-、6-或7-苯并-2,1,3-噁二唑基、2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-異喹啉基、3-、4-、5-、6-、7-或8-㖕啉基、2-、4-、5-、6-、7-或8-喹唑啉基、5-或6-喹喏啉基、2-、3-、5-、6-、7-或8-2H-苯并-1,4-噁嗪基,此外較佳表示1,3-苯并二氧雜環戊烯-5-基、1,4-苯并二噁烷-6-基、2,1,3-苯并噻二唑-4-或-5-基或2,1,3-苯并噁二唑-5-基。
雜環基團亦可部分或完全地氫化且亦表示(例如) 2,3-二氫-2-、-3-、-4-或-5-呋喃基、2,5-二氫-2-、-3-、-4-或5-呋喃基、四氫-2-或-3-呋喃基、1,3-二氧戊環-4-基、四氫-2-或-3-噻吩基、2,3-二氫-1-、-2-、-3-、-4-或-5-吡咯基、2,5-二氫-1-、-2-、-3-、-4-或-5-吡咯基、1-、2-或3-吡咯啶基、四氫-1-、-2-或-4-咪唑基、2,3-二氫-1-、-2-、-3-、-4-或-5-吡唑基、四氫-1-、-3-或-4-吡唑基、1,4-二氫-1-、-2-、-3-或-4-吡啶基、1,2,3,4-四氫-1-、-2-、-3-、-4-、-5-或-6-吡啶基、1-、2-、3-或4-六氫吡啶基、2-、3-或4-嗎啉基、四氫-2-、-3-或-4-吡喃基、1,4-二噁烷基、1,3-二噁烷-2-、-4-或-5-基、六氫-1-、-3-或-4-嗒嗪基、六氫-1-、-2-、-4-或-5-嘧啶基、1-、2-或3-六氫吡嗪基、1,2,3,4-四氫-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-喹啉基、1,2,3,4-四氫-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-異喹啉基、2-、3-、5-、6-、7-或8-3,4-二氫-2H-苯并-1,4-噁嗪基,此外較佳表示2,3-亞甲基二氧基苯基、3,4-亞甲基二氧基苯基、2,3-伸乙基二氧基苯基、3,4-伸乙基二氧基苯基、3,4-(二氟亞甲基二氧基)苯基、2,3-二氫苯并呋喃-5-或6-基、2,3-(2-側氧基亞甲基二氧基)苯基或亦3,4-二氫-2H-1,5-苯并二氧呯-6-或-7-基,此外較佳表示2,3-二氫苯并呋喃基或2,3-二氫-2-側氧基呋喃基。
雜環此外表示(例如) 2-側氧基六氫吡啶-1-基、2-側氧基吡咯啶-1-基、2-側氧基-1H
-吡啶-1-基、3-側氧基嗎啉-4-基、4-側氧基-1H
-吡啶-1-基、2,6-二側氧基六氫吡啶1-基、2-側氧基六氫吡嗪-1-基、2,6-二側氧基六氫吡嗪-1-基、2,5-二側氧基吡咯啶-1-基、2-側氧基-1,3-噁唑啶-3-基、3-側氧基-2H
-嗒嗪-2-基、2-己內醯胺-1-基(=2-側氧基氮雜環庚烷-1-基)、2-羥基-6-側氧基六氫吡嗪-1-基、2-甲氧基-6-側氧基六氫吡嗪-1-基或2-氮雜二環[2.2.2]辛-3-酮-2-基。
此處雜環烷基表示完全氫化或飽和之雜環,雜環烯基(一或多個雙鍵)或雜環炔基(一或多個三鍵)表示部分或不完全氫化或不飽和之雜環,雜芳基表示芳香族或完全不飽和之雜環。
與本發明相關之環狀烷基芳基意味著一或兩個芳香族環Ar縮合至未經取代或經單取代或二取代之環狀烷基上,其中一或兩個CH2
基團及/或另外1至11個H原子可經(例如)以下所繪示之基團替代:及
此外,以下縮寫具有以下含義: Boc 第三丁氧基羰基 CBZ 苄基氧基羰基 DNP 2,4-二硝基苯基 FMOC 9-茀基甲氧基羰基 imi-DNP 咪唑環之1位中之2,4-二硝基苯基 OMe 甲基酯 POA 苯氧基乙醯基 DCCI 二環已基碳化二亞胺 HOBt 1-羥基苯并三唑
因此本發明係關於醫藥製劑,其包含本發明之化合物及/或其生理上可接受之鹽、衍生物、溶劑合物、前藥及立體異構物中之一者,包括其所有比率之混合物。
本發明亦係關於此類型之本發明之醫藥製劑,其包含其他賦形劑及/或佐劑。
另外,本發明係關於根據本發明之以上醫藥製劑,其包含至少一種其他藥劑活性化合物。
醫藥上或生理上可接受之衍生物意指(例如)本發明化合物之鹽,亦及所謂的前藥化合物。前藥化合物意指本發明化合物之衍生物,其已藉助(例如)烷基或醯基(亦參見下文之胺基及羥基保護基團)、糖或寡肽進行修飾且其在生物體中快速裂解或釋放以形成有效分子。該等亦包括本發明化合物之生物可降解之聚合物衍生物,如(例如) Int. J. Pharm. 115 (1995), 61-67中所闡述。
本發明之化合物可以其最終非鹽形式使用。另一方面,本發明亦涵蓋呈其醫藥上可接受之鹽形式之胃酶抑素(pepstatin)之用途,其可藉由業內已知之程序自各種有機及無機鹼衍生。胃酶抑素之醫藥上可接受之鹽形式在極大程度上係藉由習用方法來製備。若本發明之化合物含有羧基,則其適宜鹽中之一者可藉由使本發明之化合物與適宜鹼反應以獲得相應鹼加成鹽來形成。此等鹼係(例如)鹼金屬氫氧化物,包括氫氧化鉀、氫氧化鈉及氫氧化鋰;鹼土金屬氫氧化物,例如氫氧化鋇及氫氧化鈣;鹼金屬醇鹽,例如乙醇鉀及丙醇鈉;及各種有機鹼,例如六氫吡啶、二乙醇胺及N-甲基麩醯胺酸。同樣地包括胃酶抑素之鋁鹽。
此外,本發明化合物之鹼式鹽包括鋁、銨、鈣、銅、鐵(III)、鐵(II)、鋰、鎂、錳(III)、錳(II)、鉀、鈉及鋅鹽,但此並不意欲代表具有限制性。
在以上所提及之鹽中,較佳者係銨;鹼金屬鹽鈉及鉀,及鹼土金屬鹽鈣及鎂。自醫藥上可接受之有機無毒性鹼衍生之本發明化合物之鹽包括以下之鹽:一級、二級及三級胺、經取代胺(亦包括天然經取代胺)、環狀胺及鹼性離子交換樹脂,例如精胺酸、甜菜鹼、咖啡因、氯普魯卡因(chloroprocaine)、膽鹼、N,N'-二苄基乙二胺(苄星青黴素(benzathine))、二環己基胺、二乙醇胺、二乙胺、2-二乙基胺基乙醇、2-二甲基胺基乙醇、乙醇胺、乙二胺、N-乙基嗎啉、N-乙基六氫吡啶、葡萄糖胺、葡糖胺、組胺酸、哈胺(hydrabamine)、異丙胺、利多卡因(lidocaine)、離胺酸、葡甲胺、N-甲基-D-葡萄糖胺、嗎啉、六氫吡嗪、六氫吡啶、多胺樹脂、普魯卡因、嘌呤、可可鹼、三乙醇胺、三乙胺、三甲胺、三丙胺及參(羥基甲基)甲胺(胺丁三醇),但此並不意欲代表具有限制性。
如所提及,胃酶抑素之醫藥上可接受之鹼加成鹽係利用金屬或胺(例如鹼金屬及鹼土金屬或有機胺)形成。較佳金屬係鈉、鉀、鎂及鈣。較佳有機胺係N,N’-二苄基乙二胺、氯普魯卡因、膽鹼、二乙醇胺、乙二胺、N-甲基-D-葡萄糖胺及普魯卡因。
本發明化合物之鹼加成鹽係藉由使游離酸形式與足量期望鹼接觸,從而以習用方式引起形成鹽來製備。游離酸可藉由使鹽形式與酸接觸並以習用方式分離游離酸來再生。游離酸形式在某一方面關於某些物理性質(例如於極性溶劑中之溶解度)不同於其相應鹽形式;然而,出於本發明之目的,鹽原本對應於其各別游離酸形式。
就上文所述內容而言,可見術語「醫藥上可接受之鹽」在本發明上下文中意指活性化合物,其包含呈其鹽中之一者形式之本發明化合物,尤其若此鹽形式與該活性化合物之游離形式或先前所用活性化合物之任一其他鹽形式相比,賦予該活性化合物改良之藥物動力學性質時。活性化合物之醫藥上可接受之鹽形式亦可提供初次具有期望藥物動力學性質之此活性化合物,該活性化合物先前並不具有該期望藥物動力學性質且關於其在體內之治療效能方面,該期望藥物動力學性質對此活性化合物可甚至具有積極影響。
本發明化合物之溶劑合物意指惰性溶劑分子胃酶抑素之加合物,其係由於其相互引力而形成。溶劑合物係(例如)水合物,例如一水合物或二水合物,或醇化物,即與醇(例如與甲醇或乙醇)之加成化合物。
該等化合物之所有生理上可接受之鹽、衍生物、溶劑合物及立體異構物(包括其所有比率之混合物)亦符合本發明。
通式I之化合物可含有一或多個手性中心,從而使得本發明亦主張通式I化合物之所有立體異構物、鏡像異構物、非鏡像異構物等。
本發明亦係關於該等化合物之光學活性形式(立體異構物)、鏡像異構物、外消旋物、非鏡像異構物以及水合物及溶劑合物。
根據本發明之式I化合物由於其分子結構可係手性的,且可因此以各種鏡像異構形式存在。因此,其可呈外消旋或光學活性形式。由於本發明化合物之外消旋物或立體異構物之醫藥效能可有所不同,因此可期望使用鏡像異構物。在該等情形下,終產物以及甚至中間體均可藉由熟習此項技術者已知之化學或物理方式分離成鏡像異構化合物或已在合成中原樣採用。
醫藥上或生理上可接受之衍生物意指(例如)本發明化合物之鹽,亦及所謂的前藥化合物。前藥化合物意指式I化合物,其已經(例如)烷基或醯基(亦參見下文之胺基保護基團及羥基保護基團)、糖或寡肽修飾且其在生物體中快速裂解或釋放以形成本發明之有效化合物。該等亦包括本發明化合物之生物可降解之聚合物衍生物,如(例如) Int. J. Pharm. 115 (1995), 61-67中所闡述。
適宜酸加成鹽係所有生理或藥理學上可接受之酸之無機或有機鹽,例如鹵化物、尤其鹽酸鹽或氫溴酸鹽、乳酸鹽、硫酸鹽、檸檬酸鹽、酒石酸鹽、馬來酸鹽、富馬酸鹽、草酸鹽、乙酸鹽、磷酸鹽、甲基磺酸鹽或對甲苯磺酸鹽。
極尤佳者係本發明化合物之鹽酸鹽、三氟乙酸鹽或雙三氟乙酸鹽。
式I化合物之溶劑合物意指式I化合物上之惰性溶劑分子之加合物,其係由於其相互引力而形成。溶劑合物係(例如)水合物,例如一水合物或二水合物,或醇化物,即與醇(例如與甲醇或乙醇)之加成化合物。
此外,式I化合物意欲包括其同位素標記形式。除化合物之一或多個原子經原子質量或質量數不同於通常天然存在之原子質量或質量數之原子替代的事實外,式I化合物之同位素標記形式與此化合物相同。易於商業購得且可藉由熟知方法併入至式I化合物中之同位素之實例包括氫、碳、氮、氧、磷、氟及氯之同位素,例如分別為2
H、3
H、13
C、14
C、15
N、18
O、17
O、31
P、32
P、35
S、18
F及36
Cl。含有以上所提及同位素及/或其他原子之其他同位素中之一或多者之式I化合物、其前藥或醫藥上可接受之鹽意欲為本發明之一部分。同位素標記之式I化合物可以多種有益方式使用。舉例而言,併入(例如)放射性同位素(例如3
H或14
C)之同位素標記之式I化合物適於藥劑及/或受質組織分佈分析。該等放射性同位素(即氚(3
H)及碳-14 (14
C))由於其製備簡單且可檢測性優良而尤佳。併入式I化合物中之較重同位素(例如氘(2
H))由於此同位素標記之化合物之較高代謝穩定性而具有治療優勢。較高代謝穩定性直接轉變為增加之活體內半衰期或較低劑量,此在大多數情況下將代表本發明之較佳實施例。同位素標記之式I化合物通常可藉由實施合成方案及相關說明、本文中之實例部分及製備部分中所揭示之程序用易於獲得之同位素標記之反應物替代無同位素標記之反應物來製備。
為藉助一級動力學同位素效應操控化合物之氧化代謝,亦可將氘(2
H)併入至式I化合物中。一級動力學同位素效應係由於同位素核之交換所致化學反應速率之變化,而同位素核之交換係由此同位素交換之後共價鍵形成所需基態能量之變化所引起。較重同位素之交換通常導致化學鍵之基態能量降低且由此引起限制速率之鍵斷裂速率降低。若在鞍點區域中或在其附近沿多產物反應之坐標發生鍵斷裂,則可實質上改變產物分佈比。關於解釋:若氘在不可交換之位置處鍵結至碳原子,則kM
/kD
= 2-7之速率差係典型的。若此速率差成功地適於易於氧化之式I化合物,則此化合物之活體內特徵可顯著經修飾且使得藥物動力學性質改良。
在發現並開發治療劑時,熟習此項技術者試圖優化藥物動力學參數,同時保留合意之活體外性質。合理地假定,許多藥物動力學特徵較差之化合物易於氧化代謝。目前可用之活體外肝微粒體分析提供關於此類型之氧化代謝過程之有價值之資訊,此進而允許合理設計經由抵抗此氧化代謝而具有改良穩定性之式I之氘化化合物。藉此獲得式I化合物之藥物動力學特徵之顯著改良,且該等改良可針對活體內半衰期(T/2)、最大治療效應下之濃度(C最大
)、劑量反應曲線下面積(AUC)及F增加以及針對降低之清除率、劑量及材料成本定量地表示。
下文意欲說明上文:製備對氧化代謝具有多個潛在攻擊位點(例如苄基氫原子及鍵結至氮原子之氫原子)之式I化合物做為一系列類似物,其中氫原子之不同組合由氘原子替代,從而使得一些、大部分或所有該等氫原子由氘原子替代。半衰期測定使得能夠有利且精確地測定對氧化代謝抗性改良之改良程度。以此方式,確定由於此類型之氘-氫交換,母體化合物之半衰期可延長高達100%。
在式I化合物中用氘替代氫亦可用於達成起始化合物之代謝物譜之有利修飾,以減少或消除不期望之毒性代謝物。舉例而言,若經由氧化性碳-氫(C-H)鍵裂解產生毒性代謝物,則可合理地假定,氘化類似物將大大減少或消除不期望代謝物之產生,即使特定氧化並非決定速率之步驟。關於氘-氫交換之現有技術之其他資訊於(例如)以下中給出:Hanzlik等人,J. Org. Chem. 55, 3992-3997, 1990、Reider等人,J. Org. Chem. 52, 3326-3334, 1987, Foster, Adv.Drug Res. 14, 1-40, 1985、Gillette等人,Biochemistry 33(10), 2927-2937, 1994及Jarman等人,Carcinogenesis 16(4), 683-688, 1993。
本發明亦係關於根據本發明之式I化合物之混合物,例如,兩種非鏡像異構物之比率為(例如) 1:1、1:2、1:3、1:4、1:5、1:10、1:100或1:1000之混合物。該等混合物係兩種立體異構化合物之尤佳混合物。然而,較佳者亦係兩種或更多種式I化合物之混合物。
另外,本發明係關於製備式I化合物之製程,其特徵在於 a) 式II化合物經歷還原得到式III化合物,式III化合物與式IV化合物在升高溫度下反應得到式V化合物,式V化合物採用觸媒及鹼轉化成式VI化合物,式VI化合物藉由溴化轉化成式VII化合物,式VII化合物在基本上鹼性之條件下轉化成式VIII化合物且式VIII化合物與式IX化合物在標準醯胺化或碳醯胺形成條件下反應得到式I化合物,b) 式V化合物與式X化合物在鈴木型(Suzuki-type)反應條件下反應得到式VI化合物,式VI化合物藉由溴化轉化成式VII化合物,式VII化合物在基本上鹼性之條件下轉化成式VIII化合物且式VIII化合物與式IX化合物在標準醯胺化或碳醯胺形成條件下反應得到式I化合物,c) 式XII化合物經碘化得到式XIII化合物,式XIII化合物藉由經鹼及親電子劑處理轉化成式XIV化合物,式XIV化合物藉由還原轉化成式XV化合物,式XV化合物與式IV化合物在升高溫度下反應得到式XVI化合物,式XVI化合物在催化條件下轉化成式XVII化合物,式XVII化合物在鹼性條件下轉化成式VIII化合物且式VIII化合物與式IX化合物在標準醯胺化或碳醯胺形成條件下反應得到式I化合物,d) 式I化合物之鹼藉由經酸處理轉化成其鹽中之一者,或 e) 式I化合物之酸藉由經鹼處理轉化成其鹽中之一者。
亦可在每一情形下逐步實施反應且可修改構建組元之連接反應之順序以與保護基團概念相適應。
起始材料或起始化合物通常已知。若其係新穎化合物,則其可藉由本身已知之方法來製備。
若期望,則起始材料亦可不與反應混合物分離而原位形成,進而立即進一步轉化成式I化合物。
式I化合物較佳藉由溶劑分解、尤其藉由水解或藉由氫解自其功能性衍生物釋放出而獲得。用於溶劑分解或氫解之較佳起始材料係含有相應保護胺基、羧基及/或羥基而非一或多個游離胺基、羧基及/或羥基之彼等、較佳攜帶胺基保護基團而非連結至N原子之H原子之彼等。此外,較佳者係攜帶羥基保護基團而非羥基H原子之起始材料。較佳者亦係攜帶保護羧基而非游離羧基之起始材料。亦可在起始材料之分子中存在複數個相同或不同之保護胺基、羧基及/或羥基。若所存在之保護基團彼此不同,則其在許多情形下可選擇性地裂解。
術語「胺基保護基團」通常已知且係指如下基團:其適於保護(阻斷)胺基免於化學反應,但可在分子中之其他地方實施期望化學反應之後容易地去除。典型之此等基團尤其係未經取代或經取代之醯基、此外未經取代或經取代之芳基(例如2,4-二硝基苯基)或芳烷基(例如苄基、4-硝基苄基、三苯基甲基)。由於胺基保護基團在期望反應或反應順序之後去除,故其類型及大小亦無關緊要;然而,較佳者係具有1-20個、尤其1-8個C原子之彼等。術語「醯基」應結合本發明製程以最廣泛意義理解。其涵蓋衍生自脂肪族、芳脂族、芳香族或雜環羧酸或磺酸及尤其烷氧基羰基、芳基氧基羰基及尤其芳烷氧基羰基之醯基。此等醯基之實例係烷醯基,例如乙醯基、丙醯基、丁醯基;芳烷醯基,例如苯基乙醯基;芳醯基,例如苯甲醯基或甲苯醯基;芳基氧基烷醯基,例如苯氧基乙醯基;烷基氧基羰基,例如甲氧基羰基、乙氧基羰基、2,2,2-三氯乙氧基羰基、BOC、2-碘乙氧基羰基;芳烷氧基羰基,例如CBZ、4-甲氧基苄基氧基羰基或FMOC。較佳醯基係CBZ、FMOC、苄基及乙醯基。
術語「酸保護基團」或「羧基保護基團」同樣通常已知且係指如下基團:其適於保護-COOH基團免於化學反應,但可在分子中之其他地方實施期望化學反應之後容易地去除。通常使用酯而非游離酸,例如使用經取代及未經取代之烷基酯(例如甲基、乙基、第三丁基及其經取代之衍生物)、經取代及未經取代之苄基酯或矽基酯。酸保護基團之類型及大小無關緊要,但較佳者係具有1-20個、尤其1至10個C原子之彼等。
術語「羥基保護基團」同樣通常已知且係指如下基團:其適於保護羥基免於化學反應,但在分子中之其他地方實施期望化學反應之後可容易地去除。典型之此等基團係上文所提及之未經取代或經取代之芳基、芳烷基或醯基,此外亦係烷基。羥基保護基團之其類型及大小無關緊要,但較佳者係具有1-20個、尤其1至10個C原子之彼等。羥基保護基團之實例係尤其苄基、對硝基苯甲醯基、對甲苯磺醯基及乙醯基,其中苄基及乙醯基較佳。
胺基、酸及羥基保護基團之其他典型實例參見(例如) 「Greene’s Protective Groups in Organic Synthesis」,第四版,Wiley-Interscience, 2007。
欲用作起始材料之式I化合物之功能性衍生物可藉由胺基酸及肽合成之已知方法來製備,如(例如)該等權威著作及專利申請案中所闡述。
取決於所使用之保護基團,例如借助強酸、有利地使用三氟乙酸或過氯酸,但亦使用其他強無機酸(例如鹽酸或硫酸)、強有機酸(例如三氯乙酸)或磺酸(例如苯甲醯基甲苯磺酸或對甲苯磺酸)自其功能性衍生物釋放式I化合物。可存在其他惰性溶劑及/或觸媒,但並非總是需要。
端視於各別合成途徑而定,起始材料可視情況在惰性溶劑存在下反應。
適宜惰性溶劑係(例如)庚烷、己烷、石油醚、DMSO、苯、甲苯、二甲苯、三氯乙烯、1,2-二氯乙烷四氯化碳、氯仿或二氯甲烷;醇,例如甲醇、乙醇、異丙醇、正丙醇、正丁醇或第三丁醇;醚,例如二乙醚、二異丙基醚(較佳在吲哚氮上取代)、四氫呋喃(THF)或二噁烷;二醇醚,例如乙二醇單甲基或單乙基醚、乙二醇二甲基醚(二甘二甲醚);酮,例如丙酮或丁酮;醯胺,例如乙醯胺、二甲基乙醯胺、N-甲基吡咯啶酮(NMP)或二甲基甲醯胺(DMF);腈,例如乙腈;酯,例如乙酸乙酯;羧酸或酸酐,例如乙酸或乙酸酐;硝基化合物,例如硝基甲烷或硝基苯,視情況亦及該等溶劑彼此之混合物或與水之混合物。
溶劑之量無關緊要;每g欲反應之式I化合物可較佳添加10 g至500 g溶劑。
可有利地添加酸結合劑,例如鹼金屬或鹼土金屬氫氧化物、碳酸鹽或碳酸氫鹽或弱酸之其他鹼金屬或鹼土金屬鹽,較佳鉀、鈉或鈣鹽,或添加有機鹼,例如三乙胺、二甲胺、吡啶或喹啉或過量之胺組分。
根據本發明之所得化合物可自其中製備其之相應溶液分離(例如藉由離心及洗滌),且可在分離後儲存在另一組合物中,或其可直接保留在製備溶液中。根據本發明之所得化合物亦可於用於特定用途之期望溶劑中溶解。
反應持續時間取決於所選擇之反應條件。一般而言,反應持續時間為0.5小時至10天、較佳地1至24小時。在使用微波時,反應時間可降低至1至60分鐘之值。
另外,式I化合物亦及用於其製備之起始材料係藉由如文獻(例如在權威著作中,例如Houben-Weyl,Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart)中所闡述之已知方法,例如在已知且適用於該等反應之反應條件下來製備。此處亦可使用本身已知之變化形式,其在此處不再更詳細地闡述。
習用後處理步驟(例如向反應混合物添加水並萃取)使得能夠在將溶劑去除後獲得化合物。對於產物之進一步純化,可有利地在此之後進行蒸餾或結晶或實施層析純化。
可使用鹼將式I之酸轉化成相關之加成鹽,例如藉由使等量之酸與鹼於惰性溶劑(例如乙醇)中反應並包括蒸發來實施。用於此反應之適宜鹼係尤其產生生理上可接受之鹽之彼等鹼。因此,可使用鹼(例如氫氧化鈉、氫氧化鉀、碳酸鈉或碳酸鉀)將式I之酸轉化成相應金屬鹽、尤其鹼金屬或鹼土金屬鹽或轉化成相應銨鹽。產生生理上可接受之鹽之有機鹼(例如乙醇胺)亦適用於此反應。
另一方面,可使用酸將式I之鹼轉化成相關酸加成鹽,例如藉由使等量之鹼與酸於惰性溶劑(例如乙醇)中反應,隨後蒸發來實施。用於此反應之適宜酸係尤其產生生理上可接受之鹽之彼等酸。因此,可使用無機酸,例如硫酸、硝酸、氫鹵酸(例如鹽酸或氫溴酸)、磷酸(例如正磷酸)、磺胺酸,此外可使用有機酸、尤其脂肪族、脂環族、芳脂族、芳香族或雜環、單或多元羧酸、磺酸或硫酸,例如甲酸、乙酸、丙酸、特戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富馬酸、馬來酸、乳酸、酒石酸、蘋果酸、檸檬酸、葡萄糖酸、抗壞血酸、菸鹼酸、異菸鹼酸、甲磺酸或乙磺酸、乙二磺酸、2-羥基磺酸、苯磺酸、對甲苯磺酸、萘單磺酸及萘二磺酸或月桂基硫酸。與生理上不可接受之酸之鹽(例如苦味酸鹽)可用於式I化合物之分離及/或純化。
已發現,式I化合物耐受性良好且具有有價值之藥理學性質。
由於腺苷受體(例如A2A
及A2B
)顯示在發炎期間下調免疫反應並保護組織免受免疫損害,因此抑制經由腺苷受體進行之信號傳導可用於加強並延長免疫反應。
本文提供增加免疫反應之方法。在一實例中,該方法增加合意且靶向之組織損害,例如腫瘤(例如癌症)之損害。本文揭示抑制一或多種有助於細胞外腺苷產生及腺苷觸發之經由腺苷受體進行信號傳導之過程之方法。舉例而言,免疫反應、局部組織發炎及靶向組織破壞之增強係藉由以下來完成: 抑制或降低產生腺苷之局部組織低氧;降解累積之細胞外腺苷(或使其無活性);防止或減少免疫細胞上腺苷受體之表現;及/或抑制/拮抗腺苷配體經由腺苷受體之信號傳導。本文所揭示之結果證實,藉由活體內投與破壞患有各種疾病(例如癌症及敗血症)之個體中之「低氧->腺苷累積->免疫抑制腺苷受體信號傳導至免疫細胞」路徑之藥劑可活體內治療腫瘤或改良免疫。
在一實例中,該方法包括投與細胞外腺苷之一或多種抑制劑及/或腺苷受體抑制劑(例如腺苷受體拮抗劑)。為增加疫苗之效能,可將一或多種腺苷受體抑制劑及/或細胞外腺苷抑制劑與疫苗結合投與。在一實例中,投與一或多種腺苷受體抑制劑或細胞外腺苷抑制劑以增加免疫反應/發炎。在另一實例中,提供達成靶向組織損害(例如用於腫瘤破壞)之方法。
因此此外,本發明係關於本發明化合物之用途,其用於製備用於治療及/或預防由腺苷或其他A2A
及/或A2B
受體激動劑引起、促進及/或傳播之疾病之藥劑。
因此,本發明亦尤其係關於包含以下之藥劑:至少一種本發明之化合物及/或其生理上可接受之鹽、衍生物、溶劑合物、前藥及立體異構物中之一者(包括其所有比率之混合物),該藥劑用於治療及/或預防生理及/或病理生理狀態。
尤佳者尤其係與腺苷A2A
及/或A2B
受體相關之生理及/或病理生理狀態。
生理及/或病理生理狀態意指醫學上相關之生理及/或病理生理狀態,例如疾病(diseases or illnesses)及醫學病症、病痛、症狀或併發症及諸如此類、尤其疾病。
此外,本發明係關於包含以下之藥劑:至少一種本發明之化合物及/或其生理上可接受之鹽、衍生物、溶劑合物、前藥及立體異構物中之一者(包括其所有比率之混合物),該藥劑用於治療及/或預防選自由過度增殖性及傳染性疾病及病症組成之群之生理及/或病理生理狀態。
本發明進一步係關於包含以下之藥劑:至少一種本發明之化合物及/或其生理上可接受之鹽、衍生物、溶劑合物、前藥及立體異構物中之一者(包括其所有比率之混合物),該藥劑用於治療及/或預防選自由過度增殖性及傳染性疾病及病症組成之群之生理及/或病理生理狀態,其中該過度增殖性疾病或病症係癌症。
因此,本發明尤佳係關於包含以下之藥劑:至少一種本發明之化合物及/或其生理上可接受之鹽、衍生物、溶劑合物、前藥及立體異構物中之一者(包括其所有比率之混合物),其中癌症係選自由以下組成之群:急性淋巴球性白血病、急性顆粒球性白血病、腎上腺皮質癌、膀胱癌、腦癌、乳癌、子宮頸癌、頸椎增生、絨毛膜癌、慢性顆粒球性白血病、慢性淋巴球性白血病、結腸癌、子宮內膜膜、食管癌、原發性血小板增多症、泌尿道癌、神經膠質瘤、神經膠母細胞瘤、毛細胞白血病、頭頸癌、霍奇金氏病(Hodgkin's disease)、卡波西氏肉瘤(Kaposi's sarcoma)、肺癌、淋巴瘤、惡性類癌、惡性高鈣血症、惡性黑色素瘤、惡性胰臟胰島素瘤、甲狀腺髓樣癌、黑色素瘤、多發性骨髓瘤、蕈樣真菌病、骨髓性及淋巴球性白血病、神經胚細胞瘤、非霍奇金氏淋巴瘤、非小細胞肺癌、骨原性肉瘤、卵巢癌、胰臟癌、真性多血症、原發性腦癌、原發性巨球蛋白血症、前列腺癌、腎細胞癌、橫紋肌肉瘤、皮膚癌、小細胞肺癌、軟組織肉瘤、鱗狀細胞癌、胃癌、睪丸癌、甲狀腺癌及威爾姆氏瘤(Wilms' tumor)。
本發明進一步較佳係關於包含以下之藥劑:至少一種本發明之化合物及/或其生理上可接受之鹽、衍生物、溶劑合物、前藥及立體異構物中之一者(包括其所有比率之混合物),該藥劑用於治療及/或預防選自由過度增殖性及傳染性疾病及病症組成之群之生理及/或病理生理狀態,其中該過度增殖性疾病或病症選自由以下組成之群:年齡相關性黃斑退化、克隆氏病(Crohn's disease)、硬化、慢性發炎性相關病症、增殖性糖尿病視網膜病變、增殖性玻璃體視網膜病變、早產兒視網膜病變、肉芽腫、與器官或組織移植相關之免疫過度增殖及選自由以下組成之群之免疫增殖疾病或病症:發炎性腸病、牛皮癬、類風濕性關節炎、全身性紅斑狼瘡(SLE)、繼發於視網膜低氧之血管過度增殖及血管炎。
本發明進一步較佳係關於包含以下之藥劑:至少一種本發明之化合物及/或其生理上可接受之鹽、衍生物、溶劑合物、前藥及立體異構物中之一者(包括其所有比率之混合物),該藥劑用於治療及/或預防選自由過度增殖性及傳染性疾病及病症組成之群之生理及/或病理生理狀態,其中該傳染性疾病或病症係選自由以下組成之群: a) 病毒誘導之傳染病,其係由反轉錄病毒、嗜肝病毒(hepadnavirus)、疱疹病毒、黃病毒科(flaviviridae)及/或腺病毒引起,其中該等反轉錄病毒係選自慢病毒(lentivirus)或致癌反轉錄病毒,其中該慢病毒係選自由以下組成之群:HIV-1、HIV-2、FIV、BIV、SIV、SHIV、CAEV、VMV及EIAV且該致癌反轉錄病毒係選自由以下組成之群:HTLV-I、HTLV-II及BLV,該嗜肝病毒係選自由以下組成之群:HBV、GSHV及WHV,該疱疹病毒係選自由以下組成之群:HSV I、HSV II、EBV、VZV、HCMV或HHV 8且該黃病毒科選自由以下組成之群:HCV、西尼羅病毒(West nile)及黃熱病, b) 由革蘭氏陽性(Gram-positive)細菌引起之細菌性傳染病,其中該等革蘭氏陽性細菌係選自由以下組成之群:甲氧西林(methicillin)敏感及甲氧西林抗性葡萄球菌(staphylococci)(包括金黃色葡萄球菌(Staphylococcus aureus)、表皮葡萄球菌(Staphylococcus epidermidis)、溶血性葡萄球菌(Staphylococcus haemolyticus)、人葡萄球菌(Staphylococcus hominis)、腐生葡萄球菌(Staphylococcus saprophyticus)及凝固酶陰性葡萄球菌)、對醣肽類中度敏感之金黃色葡萄球菌(GISA)、青黴素敏感及青黴素抗性鏈球菌(streptococci)(包括肺炎鏈球菌(Streptococcus pneumoniae)、釀膿鏈球菌(Streptococcus pyogenes)、無乳鏈球菌(Streptococcus agalactiae)、鳥鏈球菌(Streptococcus avium)、牛鏈球菌(Streptococcus bovis)、乳酸鏈球菌(Streptococcus lactis)、血鏈球菌(Streptococcus sanguis)及C組鏈球菌(GCS)、G組鏈球菌(GGS)及草綠色鏈球菌(viridans streptococci))、腸球菌(enterococci)(包括萬古黴素(vancomycin)敏感及萬古黴素抗性菌株,例如糞腸球菌(Enterococcus faecalis)及屎腸球菌(Enterococcus faecium))、難養芽胞梭菌(Clostridium difficile)、單核球增多性李斯特菌(Listeria monocytogenes)、傑氏棒狀桿菌(Corynebacterium jeikeium)、披衣菌屬(Chlamydia spp)(包括肺炎披衣菌(C. pneumoniae))及結核分枝桿菌(Mycobacterium tuberculosis), c) 由革蘭氏陰性細菌引起之細菌性傳染病,其中該等革蘭氏陰性細菌係選自由腸桿菌屬(Genus Enterobacteriacae)組成之群,包括埃希氏菌屬(Escherichia spp.) (包括大腸桿菌(Escherichia coli))、克雷伯氏菌屬(Klebsiella spp.)、腸桿菌屬(Enterobacter spp.)、檸檬酸桿菌屬(Citrobacter spp.)、沙雷氏菌屬(Serratia spp.)、變形桿菌屬(Proteus spp.)、普羅威登斯菌屬(Providencia spp.)、沙門桿菌屬(Salmonella spp.)、志賀桿菌屬(Shigella spp.)、假單胞菌屬(Pseudomonas)(包括綠膿桿菌(P. aeruginosa))、莫拉菌屬(Moraxella spp.) (包括卡他莫拉菌(M. catarrhalis))、嗜血桿菌屬(Haemophilus spp.)及奈瑟菌屬(Neisseria spp.), d) 由細胞內活性寄生蟲誘導之傳染病,該等寄生蟲係選自由以下組成之群:頂複門(Apicomplexa)或肉質鞭毛蟲門(Sarcomastigophora)(包括錐蟲屬(Trypanosoma)、瘧原蟲屬(Plasmodia)、利什曼蟲屬(Leishmania)、巴貝蟲屬(Babesia)或泰勒蟲屬(Theileria))、隱孢子蟲(Cryptosporidia)、肉孢子蟲(Sacrocystida)、變形蟲(Amoebia)、球蟲(Coccidia)及毛滴蟲(Trichomonadia)。
上文所揭示之藥劑意欲包括本發明化合物用於製備用於治療及/或預防以上生理及/或病理生理狀態之藥劑之相應用途。
另外,上文所揭示之藥劑意欲包括治療及/或預防以上生理及/或病理生理狀態之相應方法,其中向需要此一治療之患者投與至少一種本發明之化合物。
本發明之化合物較佳展現有利之生物學活性,其可容易地在如實例中所闡述之酶分析及動物實驗中證實。在此等基於酶之分析中,本發明之化合物較佳展現並引起抑制效應,其通常由在適宜範圍、較佳微莫耳範圍及更佳奈莫耳範圍內之IC50
值記錄。
本發明之化合物可向人類或動物、尤其哺乳動物(例如猿、狗、貓、大鼠或小鼠)投與,且可用於人類或動物身體之治療性治療及對抗上文所提及之疾病中。此外,其可用作診斷劑或用作試劑。
此外,本發明之化合物可用於腺苷A2A
及/或A2B
受體之分離及其活性或表現之研究。另外,其尤其適用於與擾亂之腺苷A2A
及/或A2B
受體活性相關之疾病之診斷方法中。因此此外,本發明係關於本發明化合物之用途,其用於腺苷A2A
及/或A2B
受體之分離及其活性或表現之研究或作為腺苷A2A
及/或A2B
受體之結合劑及抑制劑。
出於診斷目的,本發明之化合物可(例如)經放射性標記。放射性標記之實例係3
H、14
C、231
I及125
I。較佳之標記方法係iodogen方法(Fraker等人,1978)。另外,本發明之化合物可經酶、螢光團及化學發色團(chemophore)標記。酶之實例係鹼性磷酸酶、β-半乳糖苷酶及葡萄糖氧化酶,螢光團之實例係螢光黃,化學發色團之實例係發光胺,且自動化檢測系統(例如針對螢光著色)闡述於(例如) US 4,125,828及US 4,207,554中。
本發明進一步係關於含有本發明化合物之醫藥組合物及其用於治療及/或預防其中腺苷A2A
及/或A2B
受體之部分或完全不活化可有益之疾病及病症之用途。
式I化合物可用於製備醫藥製劑,尤其藉由非化學方法。在此情形中,將其與至少一種固體、液體及/或半液體賦形劑或佐劑一起及視情況與一或多種其他活性化合物組合製成適宜劑型。
因此此外,本發明係關於醫藥製劑,其包含至少一種式I化合物及/或其生理上可接受之鹽、衍生物、溶劑合物及立體異構物,包括其所有比率之混合物。具體而言,本發明亦係關於包含其他賦形劑及/或佐劑之醫藥製劑,且亦係關於包含至少一種其他藥劑活性化合物之醫藥製劑。
具體而言,本發明亦係關於用於製備醫藥製劑之製程,其特徵在於將式I化合物及/或其生理上可接受之鹽、衍生物、溶劑合物及立體異構物中之一者(包括其所有比率之混合物)與固體、液體或半液體賦形劑或佐劑及視情況與另一藥劑活性化合物一起製成適宜劑型。
本發明之醫藥製劑可用作人類或獸醫學中之藥劑。患者或宿主可屬任何哺乳動物物種,例如靈長類動物物種,具體而言人類;齧齒類動物,包括小鼠、大鼠及倉鼠;兔;馬;牛;狗;貓等。實驗研究對動物模型感興趣,其中其為治療人類疾病提供模型。
適宜載劑物質係適於經腸(例如經口)、非經腸或局部投與且不與新穎化合物反應之有機或無機物質,例如水、植物油(例如葵花油或鱈魚肝油)、苄醇、聚乙二醇、明膠、碳水化合物(例如乳糖或澱粉)、硬脂酸鎂、滑石、羊毛脂或凡士林。熟習此項技術者因其專業知識而熟悉適用於期望藥劑調配物之佐劑。除溶劑(例如水、生理鹽水溶液或醇(例如乙醇、丙醇或甘油)、糖溶液(例如葡萄糖或甘露醇溶液)或該等溶劑之混合物)、凝膠形成劑、錠劑助劑及其他活性成分載劑以外,亦可使用(例如)潤滑劑、穩定劑及/或潤濕劑、乳化劑、用於影響滲透壓之鹽、抗氧化劑、分散劑、消泡劑、緩衝物質、調味劑及/或芳香或矯味劑、防腐劑、增溶劑或染料。若期望,本發明之製劑或藥劑可包含一或多種其他活性化合物,例如一或多種維生素。
若期望,本發明之製劑或藥劑可包含一或多種其他活性化合物及/或一或多種作用增強劑(佐劑)。
出於本發明之目的,術語「醫藥調配物」及「醫藥製劑」係做為同義詞使用。
如本文所使用,「醫藥上耐受」係指藥劑、沈澱試劑、賦形劑、佐劑、穩定劑、溶劑及其他藥劑有助於將自其獲得之醫藥製劑投與哺乳動物而無不期望之生理副作用(例如噁心、眩暈、消化問題或諸如此類)。
在用於非經腸投與之醫藥製劑中,對調配物(低毒性)、所採用佐劑及一級包裝之等滲性、水合狀態以及耐受性及安全性有要求。令人驚訝的是,本發明之化合物較佳具有以下優點:可直接使用,且因此在醫藥調配物中使用本發明化合物之前不需要進行用於去除毒物學上不可接受之藥劑(例如高濃度之有機溶劑)或其他毒物學上不可接受之佐劑之進一步純化步驟。
本發明尤佳亦係關於醫藥製劑,其包含至少一種呈沈澱非結晶、沈澱結晶或呈溶解或懸浮形式之本發明之化合物,及視情況賦形劑及/或佐劑及/或其他醫藥活性化合物。
本發明之化合物較佳使得能夠製備高度濃縮之調配物,而不發生本發明化合物之不利、不期望之聚集。因此,可借助於本發明之化合物利用水性溶劑或於水性介質中製備具有高活性成分含量之即用型溶液。
亦可將化合物及/或其生理上可接受之鹽及溶劑合物凍乾並使用所得凍乾物(例如)用於製備注射製劑。
可藉由將本發明之化合物溶解或懸浮於水溶液中且視情況添加佐劑來製備水性製劑。為此,有利地將包含界定濃度之該等其他佐劑之界定體積之原液添加至具有界定濃度之本發明化合物之溶液或懸浮液中,且視情況將混合物用水稀釋至預先計算之濃度。或者,佐劑可以固體形式添加。可將在每一情形下所需量之原液及/或水隨後添加至所獲得之水溶液或懸浮液。亦可有利地將本發明之化合物直接溶解或懸浮於包含所有其他佐劑之溶液中。
可有利地製備包含本發明之化合物且pH為4至10、較佳pH為5至9且滲透重量莫耳濃度為250 mOsmol/kg至350 mOsmol/kg之溶液或懸浮液。因此,醫藥製劑可以靜脈內、動脈內、關節內、皮下或經皮方式實質上無疼痛地直接投與。另外,亦可將製劑添加至亦可含有其他活性化合物之輸注溶液(例如葡萄糖溶液、等滲鹽水溶液或林格氏溶液(Ringer’s solution)),因此亦使得能夠投與相對大量之活性化合物。
本發明之醫藥製劑亦可包含複數種本發明化合物之混合物。
本發明之製劑在生理上耐受性良好,易於製備,可精確分配且較佳在整個儲存及運輸中且在多次冷凍及解凍製程期間關於分析、分解產物及聚集物較為穩定。其可較佳在冰箱溫度(2-8℃)及室溫(23-27℃)及60%相對大氣濕度(R.H.)下以穩定方式儲存至少3個月至2年之時期。
舉例而言,本發明之化合物可藉由乾燥以穩定方式儲存,且在必要時可藉由溶解或懸浮轉化成即用型醫藥製劑。舉例而言,可能之乾燥方法係(但不限於該等實例):氮氣乾燥、真空烘箱乾燥、凍乾、利用有機溶劑洗滌且隨後風乾、液體床乾燥、流化床乾燥、噴霧乾燥、輥筒式乾燥、層式乾燥、室溫下風乾及其他方法。
術語「有效量」表示(例如)研究者或醫師尋求或期望在組織、系統、動物或人類中引起生物學或醫學反應之藥劑或醫藥活性化合物之量。
另外,術語「治療有效量」表示與未接受此量之相應個體相比具有以下結果之量: 改良之對疾病、症候群、疾病狀態、病狀、病症之治療、治癒、預防或消除或對副作用之預防或亦降低疾病、病痛或病症之進展。術語「治療有效量」亦涵蓋有效增加正常生理功能之量。
在使用本發明之製劑或藥劑時,本發明之化合物及/或其生理上可接受之鹽及溶劑合物通常係以與已知、市售製劑或藥劑類似之方式使用,較佳劑量為每使用單位介於0.1 mg與500 mg、尤其5 mg與300 mg之間。日劑量較佳介於0.001 mg/kg體重與250 mg/kg體重、尤其0.01 mg/kg體重與100 mg/kg體重之間。製劑可每天投與一或多次,例如每天兩次、三次或四次。然而,用於患者之個別劑量取決於多種個別因素,例如所使用特定化合物之效能、年齡、體重、一般健康狀況、性別、營養、投與時間及方法、排泄速率、與其他藥劑之組合及特定疾病之嚴重程度及持續時間。
在生物體中攝取藥劑活性化合物之量度係其生物利用度。若藥劑活性化合物係以注射溶液之形式靜脈內遞送至生物體,則其絕對生物利用度(即以未改變之形式到達全身血液(即主要循環)之醫藥之比例)係100%。在經口投與治療活性化合物之情形下,活性化合物通常在調配物中呈固體形式且因此必須首先溶解以使得其能夠克服進入障壁(例如胃腸道、口腔黏膜、鼻黏膜或皮膚,尤其角質層),或可由身體吸收。關於藥物動力學(即關於生物利用度)之數據可以與J. Shaffer等人,J. Pharm. Sciences, 88 (1999), 313-318之方法類似之方式獲得。
此外,此類型之藥劑可藉助醫藥領域中通常已知製程中之一者來製備。
藥劑可適合經由任一期望適宜途徑投與,例如藉由經口(包括經頰或舌下)、經直腸、經肺、經鼻、經局部(包括經頰、舌下或經皮)、經陰道或非經腸(包括皮下、肌內、靜脈內、真皮內及尤其關節內)途徑。此類型之藥劑可藉助醫藥領域中已知之所有製程來製備,例如,將活性化合物與一或多種賦形劑或一或多種佐劑組合。
非經腸投與較佳適於投與本發明之藥劑。在非經腸投與之情形下,關節內投與尤佳。
因此,本發明較佳亦係關於本發明之醫藥製劑之用途,其用於在治療及/或預防選自由以下組成之群之生理及/或病理生理狀態中關節內投與:骨關節炎、創傷性軟骨損傷、關節炎、疼痛、觸摸痛或痛覺過敏。
關節內投與具有以下優點:本發明之化合物可直接投與至關節軟骨附近之滑液中且亦能夠自此擴散至軟骨組織中。因此,本發明之醫藥製劑亦可直接注射至關節間隙中,且由此直接在如所預期之作用部位處發揮其作用。本發明之化合物亦適於製備非經腸投與且具有緩慢、持續及/或控制釋放之活性化合物之藥劑。因此,其亦適於製備延遲釋放調配物,該等延遲釋放調配物對患者係有利的,此乃因投與僅需以相對較大之時間間隔來進行。
適於非經腸投與之藥劑包括水性及非水性無菌注射溶液,其包含抗氧化劑、緩衝劑、抑菌劑及溶質(藉助其使調配物與欲治療接受者之血液或滑液等滲);以及水性及非水性無菌懸浮液,其可包含懸浮介質及增稠劑。調配物可以單劑量或多劑量容器(例如密封安瓿及小瓶)遞送,並以冷凍乾燥(凍乾)狀態儲存,從而使得在即將使用前僅需要添加無菌載劑液體(例如注射用水)。依照調配物製備之注射溶液及懸浮液可自無菌粉末、顆粒劑及錠劑製備。
本發明之化合物亦可以脂質體遞送系統形式(例如小單室囊泡、大單室囊泡及多室囊泡)投與。脂質體可自各種磷脂(例如膽固醇、硬脂基胺或磷脂醯膽鹼)形成。
本發明之化合物亦可做為靶向藥劑賦形劑偶合至可溶性聚合物。此等聚合物可涵蓋經棕櫚醯基取代之聚乙烯基吡咯啶酮、吡喃共聚物、聚羥基丙基甲基丙烯醯胺基酚、聚羥基乙基天冬醯胺基酚或聚氧化乙烯聚離胺酸。此外,本發明之化合物可偶合至一類適於達成藥劑之緩慢釋放之生物可降解聚合物,例如聚乳酸、聚-ε-己內酯、聚羥基丁酸、聚原酸酯、聚縮醛、聚二羥基吡喃、聚氰基丙烯酸酯、聚乳酸共-乙醇酸、聚合物(例如聚葡萄糖與甲基丙烯酸酯之間的偶聯物、聚磷酸酯、各種多醣及多胺以及聚-e-己內酯)、白蛋白、幾丁聚醣、膠原或改質明膠及水凝膠之交聯或兩親性嵌段共聚物。
適於經腸投與(經口或直腸)者尤其係錠劑、糖衣錠、膠囊、糖漿、汁液、滴劑或栓劑,且適於局部使用者係軟膏劑、霜劑、糊劑、洗劑、凝膠、噴霧、泡沫、氣溶膠、溶液(例如於醇(例如乙醇或異丙醇)、乙腈、DMF、二甲基乙醯胺、1,2-丙二醇或其彼此之混合物及/或與水之混合物中之溶液)或粉末。亦尤其適於局部使用者係脂質體製劑。
在調配以得到軟膏劑之情形中,活性化合物可與石蠟或水可混溶性霜劑基質一起使用。或者,活性化合物可與水包油型霜劑基質或油包水型基質一起調配成霜劑。
適於經皮投與之藥劑可做為獨立硬膏劑遞送以與接受者之表皮長期密切接觸。因此,舉例而言,活性化合物可藉助離子電滲自硬膏劑供應,如Pharmaceutical Research, 3(6), 318 (1986)之通用術語中所闡述。
不言而喻,除上文所具體提及之成分以外,本發明之藥劑亦可包含關於特定類型之醫藥調配物業內常用之其他試劑。
本發明亦係關於由以下之單獨包裝組成之套件(套組) a) 有效量之式I化合物及/或其生理上可接受之鹽、衍生物、溶劑合物、前藥及立體異構物(包括其所有比率之混合物),及 b) 有效量之另一藥劑活性化合物。
該套件包含適宜容器,例如盒或紙板箱、個別瓶、袋或安瓿。該套件可(例如)包含單獨安瓿,該等單獨安瓿各自含有有效量之式I化合物及/或其醫藥上可接受之鹽、衍生物、溶劑合物、前藥及立體異構物(包括其所有比率之混合物),以及有效量之呈溶解或凍乾形式之另一藥劑活性化合物。
此外,本發明之藥劑可用於在某些已知療法中提供加性或協同效應及/或可用於恢復某些現有療法之效能。
除本發明之化合物以外,本發明之醫藥製劑亦可包含其他藥劑活性化合物,例如其他抗腫瘤藥劑以用於治療癌症。為治療所提及之其他疾病,除本發明之化合物以外,本發明之醫藥製劑亦可包含熟習此項技術者已知之用於其治療之其他藥劑活性化合物。
在一個主要實施例中,提供在有需要之宿主中增強免疫反應之方法。免疫反應可藉由降低T細胞耐受性來增強,包括藉由增加IFN-γ釋放、藉由減少調節性T細胞產生或活化或藉由增加宿主中之抗原特異性記憶T細胞產生。在一個實施例中,該方法包含將本發明之化合物與抗體組合或交替投與宿主。在特定子實施例中,抗體係治療性抗體。在一特定實施例中,提供增強被動抗體療法之效能之方法,其包含將本發明之化合物與一或多種被動抗體組合或交替投與。此方法可增強用於治療異常細胞增殖性病症(例如癌症)之抗體療法之效能,或可增強療法在治療或預防傳染病中之效能。可將本發明之化合物與諸如利妥昔單抗(rituximab)、賀癌平(herceptin)或爾必得舒(erbitux)等抗體組合或交替投與。
在另一主要實施例中,提供治療或預防異常細胞增殖之方法,其包含在實質上不存在另一抗癌劑之情形下向有需要之宿主投與本發明之化合物。
在另一主要實施例中,提供治療或預防有需要之宿主中異常細胞增殖之方法,其包含向該宿主投與本發明之第一化合物與第一抗癌劑之實質性組合且隨後投與第二A2A
及/或A2B
受體拮抗劑。在一個子實施例中,該第二拮抗劑係在實質上不存在另一抗癌劑之情形下投與。在另一主要實施例中,提供治療或預防有需要之宿主中異常細胞增殖之方法,其包含向該宿主投與本發明之化合物與第一抗癌劑之實質性組合且隨後在不存在拮抗劑之情形下投與第二抗癌劑。
因此,本文所揭示之癌症治療可作為利用本發明之化合物或與手術、輻射或化學療法組合之療法實施。此類型之化學療法可包括使用以下抗腫瘤活性化合物類別之一或多種活性化合物: (i) 如內科腫瘤學中所使用之抗增殖/抗瘤/DNA損害活性化合物及其組合,例如烷基化活性化合物(例如順鉑、帕鉑(parboplatin)、環磷醯胺、氮芥、美法侖(melphalan)、氮芥苯丁酸、白消安(busulphan)及亞硝基脲);抗代謝物(例如抗葉酸劑,例如氟嘧啶(例如5-氟尿嘧啶及替加氟(tegafur))、雷替曲塞(raltitrexed)、胺甲喋呤(methotrexate)、胞嘧啶阿拉伯糖苷、羥基脲及吉西他濱(gemcitabine));抗腫瘤抗生素(例如蒽環,例如阿德力黴素(adriamycin)、博來黴素(bleomycin)、多柔比星(doxorubicin)、道諾黴素(daunomycin)、泛艾黴素(epirubicin)、伊達比星(idarubicin)、絲裂黴素-C (mitomycin-C)、放線菌素D (dactinomycin)及光輝黴素(mithramycin));抗有絲分裂活性化合物(例如長春花生物鹼,例如長春新鹼(vincristine)、長春鹼(vinblastine)、長春地辛(vindesine)及長春瑞濱(vinorelbine)及類紫杉醇,例如紫杉醇及剋癌易(taxotere));拓樸異構酶抑制劑(例如表鬼臼毒素(epipodophyllotoxin),例如依託泊苷(etoposide)及替尼泊苷(teniposide)、安吖啶(amsacrine)、托泊替康(topotecan)、伊立替康(irinotecan)及喜樹鹼(camptothecin))以及細胞分化活性化合物(例如全反式-視黃酸、13-順式-視黃酸及芬維A胺(fenretinide)); (ii) 細胞生長抑制活性化合物,例如抗雌激素(例如他莫昔芬(tamoxifen)、托瑞米芬(toremifene)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)及艾多昔芬(iodoxyfene))、雌激素受體調節劑(例如氟維司群(fulvestrant))、抗雄激素(例如比卡魯胺(bicalutamide)、氟他胺(flutamide)、尼魯米特(nilutamide)及乙酸環丙孕酮)、LHRH拮抗劑或LHRH激動劑(例如戈舍瑞林(goserelin)、亮丙瑞林(leuprorelin)及布舍瑞林(buserelin))、助孕酮(例如乙酸甲地孕酮)、芳香酶抑制劑(例如阿那曲唑(anastrozole)、來曲唑(letrozole)、伏氯唑(vorazole)及依西美坦(exemestane)以及5a-還原酶之抑制劑,例如非那雄胺(finasteride); (iii) 抑制癌症侵襲之活性化合物,包括(例如)金屬蛋白酶抑制劑,如馬立馬司他(marimastat),及尿激酶纖維蛋白溶酶原活化劑受體功能之抑制劑; (iv) 生長因子功能之抑制劑,例如生長因子抗體、生長因子受體抗體(例如抗erbb2抗體曲妥珠單抗(trastuzumab)[HerceptinTM
]及抗erbbl抗體西妥昔單抗(cetuximab)[C225]));法尼基轉移酶抑制劑;酪胺酸激酶抑制劑及絲胺酸/蘇胺酸激酶抑制劑,例如表皮生長因子家族之抑制劑(例如EGFR家族酪胺酸激酶抑制劑,例如N-(3-氯-4-氟苯基)-7-甲氧基-6-(3-嗎啉基丙氧基)喹唑啉-4-胺(吉非替尼(gefitinib),AZD1839)、N-(3-乙炔基苯基)-6,7-雙(2-甲氧基乙氧基)喹唑啉-4-胺(厄洛替尼(erlotinib),OSI-774)及6-丙烯醯胺基-N-(3-氯-4-氟苯基)-7-(3-嗎啉基丙氧基)喹唑啉-4-胺(CI 1033));例如血小板源生長因子家族之抑制劑及例如肝細胞生長因子家族之抑制劑; (v) 抗血管生成活性化合物,例如貝伐珠單抗(bevacizumab)、血管抑素、內皮抑素、利諾胺(linomide)、巴馬司他(batimastat)、卡托普利(captopril)、軟骨源抑制劑、金雀異黃酮(genistein)、介白素12、薰草菌素(lavendustin)、乙酸甲羥基孕酮、重組人類血小板因子4、替康蘭(tecogalan)、凝血酶敏感蛋白、TNP-470、抗VEGF單株抗體、可溶性VEGF-受體嵌合蛋白、抗VEGF受體抗體、抗PDGF受體、整聯蛋白抑制劑、酪胺酸激酶抑制劑、絲胺酸/蘇胺酸激酶抑制劑、反義寡核苷酸、反義寡去氧核苷酸、siRNA、抗VEGF適配體、色素上皮源因子及國際專利申請案WO 97/22596、WO 97/30035、WO 97/32856及WO 98/13354中已公開之化合物); (vi) 血管破壞劑,例如考布他汀A4 (combretastatin A4)及國際專利申請案WO 99/02166、WO 00/40529、WO 00/41669、WO 01/92224、WO 02/04434及WO 02/08213中已公開之化合物; (vii) 反義療法,例如針對上文所提及靶標之彼等,例如ISIS 2503,即抗Ras反義; (viii) 基因療法方法,包括(例如)替代異常經修飾基因(例如異常p53或異常BRCA1或BRCA2)之方法;GDEPT方法(基因導向酶前藥療法),例如使用胞嘧啶去胺酶、胸苷激酶或細菌硝基還原酶之彼等方法;及增加患者對化學療法或放射療法(例如多抗藥性療法)之耐受性之方法;及 (ix) 免疫療法方法,包括(例如)增加患者腫瘤細胞之免疫原性之離體及活體內方法,例如用諸如介白素2、介白素4或顆粒球巨噬細胞群落刺激因子等細胞介素轉染;降低T細胞無反應性之方法;使用經轉染之免疫細胞(例如經細胞介素轉染之樹突細胞)之方法;使用經細胞介素轉染之腫瘤細胞之方法;及使用抗個體遺傳型抗體之方法 (x) 化學治療劑,包括(例如)阿巴瑞克(abarelix)、阿地介白素(aldesleukin)、阿倫單抗(alemtuzumab)、阿曲諾英(alitretinoin)、別嘌呤醇、六甲蜜胺(altretamine)、阿米福汀(amifostine)、阿那曲唑、三氧化二砷、天冬醯胺酶、活BCG、貝伐珠單抗、貝沙羅汀(bexarotene)、博來黴素、硼替佐米(bortezomib)、白消安、卡普睪酮(calusterone)、喜樹鹼、卡培他濱(capecitabine)、卡鉑(carboplatin)、卡莫司汀(carmustine)、塞來昔布(carmustine)、西妥昔單抗、氮芥苯丁酸、西那卡塞(cinacalcet)、順鉑、克拉屈濱(cladribine)、環磷醯胺、阿糖胞苷、達卡巴嗪(dacarbazine)、放線菌素D、阿法達伯汀(darbepoetin alfa)、道諾黴素、地尼白介素(denileukin diftitox)、右雷佐生(dexrazoxane)、多西他賽(docetaxel)、多柔比星、屈他雄酮(dromostanolone)、泛艾黴素、阿法依泊汀(epoetin alfa)、雌氮芥、依託泊苷、依西美坦、非格司亭(filgrastim)、氟尿苷、氟達拉濱(fludarabine)、氟尿嘧啶、氟維司群及吉西他濱。
來自表1之藥劑可較佳(但非排他地)與式I化合物組合。
即使無其他實施例,亦可假定,熟習此項技術者將能夠以最寬範疇使用以上描述。因此,較佳實施例僅應視為決不以任何方式進行限制之描述性揭示內容。
因此,以下實例意欲解釋本發明而非對其加以限制。除非另有指示,否則百分比數據表示重量百分比。所有溫度均係以攝氏度指示。「習用後處理」:若需要,添加水,若需要,將pH調整至介於2與10之間的值,此取決於終產物之構成,用乙酸乙酯或二氯甲烷萃取混合物,分離各相,使有機相經硫酸鈉乾燥,過濾並蒸發,且產物藉由於矽膠上之層析及/或藉由結晶進行純化。
矽膠上之Rf值;質譜: EI (電子碰撞電離):M+
,FAB (快速原子轟擊):(M+H)+
,THF (四氫呋喃),NMP (N-甲基吡咯啶酮),DMSO (二甲基亞碸),EA (乙酸乙酯),MeOH (甲醇),TLC (薄層層析)
縮寫列表
AUC 血漿藥物濃度-時間曲線下之面積 C最大
最大血漿濃度 CL 清除率 CV 變異係數 CYP 細胞色素P450 DMSO 二甲基亞碸 F 生物利用度 fa
吸收分數 iv 靜脈內 LC-MS/MS 液相層析串聯質譜 LLOQ 量化下限 NC 未計算 ND 未測定 PEG 聚乙二醇 Pgp 滲透性醣蛋白 PK 藥物動力學 po 口服(經口) t1/2
半衰期 t最大
達到藥物之最大血漿濃度之時間 UPLC 超高效液相層析 Vss
分佈體積(在穩態下) v/v 體積對體積
實例 1 : 本發明化合物之實例
本發明尤其係關於表2之化合物及其生理上可接受之鹽、衍生物、溶劑合物、前藥及立體異構物,包括其所有比率之混合物。表 2 - 本發明化合物之實例 表 3 - 本發明化合物之 NMR 譜
本文所列舉之編號對應於表2中所揭示化合物之編號。
實例 2 :本發明化合物之製備及分析方法
所使用之所有溶劑均可商業購得且不經進一步純化即使用。反應通常使用無水溶劑在惰性氮氣氛下運行。急速管柱層析通常使用矽膠60 (0.035-0.070 mm粒徑)來實施。
所有NMR實驗均記錄在配備有在400 MHz下用於質子NMR之Bruker 400 BBFO探針之Bruker Mercury Plus 400 NMR光譜儀或配備有在300 MHz下用於質子NMR之Bruker 300 BBFO探針之Bruker Mercury Plus 300 NMR光譜儀上。所有氘化溶劑通常均含有0.03%至0.05% v/v之四甲基矽烷,其用作參考信號(對於1
H及13
C二者,設置為d = 0.00)。
LC-MS分析係在由UFLC 20-AD系統及LCMS 2020 MS檢測器組成之SHIMADZU LC-MS機器上實施。所使用之管柱係Shim-pack XR-ODS, 2.2 µm, 3.0 × 50 mm。施加線性梯度,以95% A (A:於水中之0.05% TFA)開始且以100% B (B: 於乙腈中之0.05% TFA)經2.2 min結束,總運行時間為3.6 min。管柱溫度為40℃,且流速為1.0 mL/min。二極體陣列檢測器在200-400 nm間掃描。質譜儀配備有以正或負模式操作之電噴霧離子源(ES)。質譜儀在m/z
90-900間掃描,且掃描時間為0.6 s。
1.N
-[4-
甲氧基
-7-(
嗎啉
-4-
基
)-[1,3]
噻唑并
[4,5-c]
吡啶
-2-
基
]-1-(2-
甲氧基乙基
)-1H-
吡唑
-4-
甲醯胺,
4
a. 1-(2- 甲氧基乙基 )-1H- 吡唑 -4- 甲酸乙基酯
在室溫下向1H-吡唑-4-甲酸乙基酯(950 mg, 6.78 mmol)於N,N-二甲基甲醯胺(18 ml)中之溶液添加1-溴-2-甲氧基乙烷(1.14 g, 8.20 mmol)、碳酸鉀(1.80 g, 13.8 mmol)。用微波輻射在160℃下將反應混合物輻照2 h。在反應完成時,將固體過濾出。然後將濾液在真空下濃縮,產生呈淺黃色液體之1-(2-甲氧基乙基)-1H-吡唑-4-甲酸乙基酯(1.50 g,粗製)。MS:m/z
= 199.2 [M+H]+
。
b. 1-(2- 甲氧基乙基 )-1H- 吡唑 -4- 甲酸
在室溫下向1-(2-甲氧基乙基)-1H-吡唑-4-甲酸乙基酯(1.50 g,粗製)於四氫呋喃(10 ml) 中之溶液添加LiOH水溶液(20 ml, 32 mmol, 1.6 M)。將所得混合物在室溫下攪拌3 h。在反應完成時,用H2
O (10 ml)使其淬滅。用二氯甲烷(100 ml × 3)萃取所得混合物且將有機相合併,用鹽水洗滌並經無水Na2
SO4
乾燥。將溶劑在減壓下去除且藉由急速層析用於DCM中之MeOH (0%至70%梯度)溶析來純化殘餘物,產生呈白色固體之1-(2-甲氧基乙基)-1H-吡唑-4-甲酸(600 mg,2個步驟為52%)。MS:m/z
= 171.2 [M+H]+
。
c. 5- 溴 -4- 氯吡啶 -3- 胺
在室溫下向3-溴-4-氯-5-硝基吡啶(9.50 g, 40.01 mmol)於EtOH (500 mL)中之溶液添加NH4
Cl (13.27 g, 248 mmol)、水(50 ml)及Fe (22.39 g, 401 mmol)。將所得混合物在80℃下攪拌2 h。在反應完成時,將固體過濾出。將所得混合物在減壓下濃縮且藉由急速層析用於石油醚中之0%至60% EtOAc溶析來純化殘餘物,產生呈黃色油狀物之5-溴-4-氯吡啶-3-胺(5.94 g, 72%)。MS:m/z
= 209.2 [M+H]+
。
d.N
-[7- 溴 -[1,3] 噻唑并 [4,5-c] 吡啶 -2- 基 ] 苯甲醯胺
在室溫下向5-溴-4-氯吡啶-3-胺(2.97 g, 14.3 mmol)於丙酮(64 mL)中之溶液添加異硫氰酸苯甲醯基酯(4.47 g, 27.4 mmol)。將所得混合物在50℃下攪拌16 h。在反應完成時,藉由過濾收集固體,產生呈黃色固體之N-[7-溴-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲醯胺(3.36 g, 70%)。MS:m/z
= 333.8 [M+H]+
。
e.N
-[7-( 嗎啉 -4- 基 )-[1,3] 噻唑并 [4,5-c] 吡啶 -2- 基 ] 苯甲醯胺
在室溫下向N-[7-溴-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲醯胺(336 mg, 1.01 mmol)於二噁烷(12 ml)中之溶液添加嗎啉(7 ml)、第2代RuPhos前觸媒(88 mg, 0.11 mmol)、RuPhos (104 mg, 0.22 mmol)、t-BuOK (380 mg, 3.39 mmol)。在三次真空/氮吹掃循環後,用微波輻射將反應混合物在160℃下輻照2 h。將固體過濾出。將濾液在減壓下濃縮且藉由急速層析用於石油醚中之EtOAc (0%至66%梯度)溶析來純化殘餘物,產生呈白色固體之N-[7-(嗎啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲醯胺(99 mg, 29%)。MS:m/z
= 341.0 [M+H]+
。
f.N
-[4- 溴 -7-( 嗎啉 -4- 基 )-[1,3] 噻唑并 [4,5-c] 吡啶 -2- 基 ] 苯甲醯胺
在70℃下,在4 h時期內向N-[7-(嗎啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲醯胺(653 mg, 1.92 mmol)於N,N-二甲基甲醯胺(55 ml)中之溶液逐滴添加NBS (410 mg, 2.30 mmol)於N,N-二甲基甲醯胺(15 ml)中之溶液並攪拌。在添加結束時,將所得混合物在70℃下攪拌10 min。將所得混合物在真空下濃縮以產生粗產物,將粗產物用熱EA (100 ml × 3)洗滌,產生呈淺黃色固體之N-[4-溴-7-(嗎啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲醯胺(437 mg, 53%)。MS:m/z
= 418.8 [M+H]+
。1
H NMR (400 MHz, DMSO-d 6
) δ 8.23-8.15 (m, 2 H), 7.72 (s, 1 H), 7.60-7.46 (m, 3 H), 3.86-3.78 (m, 4 H), 3.25-3.18 (m, 4 H)。
g. 4- 甲氧基 -7-( 嗎啉 -4- 基 )-[1,3] 噻唑并 [4,5-c] 吡啶 -2- 胺
在室溫下向N-[4-溴-7-(嗎啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲醯胺(388 mg, 0.94 mmol)於甲醇(20 ml)中之溶液添加於MeOH中之MeONa (7.9 mL, 42 mmol, 5.4 M)。用微波輻射將反應混合物在140℃下輻照2 h。在反應完成時,用H2
O (6 ml)使其淬滅。用二氯甲烷(50 ml × 3)萃取所得混合物且將有機相合併,用鹽水洗滌並經Na2
SO4
乾燥。將溶劑在減壓下去除且藉由急速層析用於DCM中之MeOH (0%至5%梯度)溶析來純化殘餘物,產生呈淺黃色固體之4-甲氧基-7-(嗎啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-胺(150 mg, 60%)。MS:m/z
= 267.0 [M+H]+
。
h.N
-[4- 甲氧基 -7-( 嗎啉 -4- 基 )-[1,3] 噻唑并 [4,5-c] 吡啶 -2- 基 ]-1-(2- 甲氧基乙基 )-1H- 吡唑 -4- 甲醯胺
於30-mL密封管中,在N2
氣氛下向1-(2-甲氧基乙基)-1H-吡唑-4-甲酸(143 mg, 0.84 mmol)於THF (10 ml)中之溶液添加HATU (353 mg, 0.93 mmol)、4-甲基嗎啉(170 mg, 1.68 mmol)。將反應在50℃下攪拌16 h,且然後添加4-甲氧基-7-(嗎啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-胺(75 mg, 0.28 mmol)。將所得溶液於油浴中在90℃下再攪拌16 h。在反應完成時,藉由添加水(10 ml)使反應淬滅。用DCM (30 ml × 3)萃取所得溶液。將有機相合併,用鹽水洗滌且經Na2
SO4
乾燥。將溶劑在減壓下去除且藉由製備型HPLC在以下條件下來純化殘餘物: 管柱,XBridge Prep C18 OBD管柱,19 × 150mm 5um;於水(含10 mmol/L NH4
HCO3
)中之MeCN,8 min內22%至40%梯度;檢測器,UV 254/220 nm,得到呈白色固體之N-[4-甲氧基-7-(嗎啉-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]-1-(2-甲氧基乙基)-1H-吡唑-4-甲醯胺(54 mg, 45%)。HPLC: 98.8%純度,RT = 4.216 min. MS:m/z
= 419.1 [M+H]+
。1
H NMR (400 MHz, DMSO-d 6
) δ 12.87 (s, 1 H), 8.52 (s, 1 H), 8.21 (s, 1 H), 7.64 (s, 1 H), 4.35 (t,J
= 5.1 Hz, 2 H), 3.98 (s, 3 H), 3.84-3.76 (m, 4 H), 3.71 (t,J
= 5.1 Hz, 2 H), 3.25 (s, 3 H), 3.14-3.06 (m, 4 H)。
2. N-[4-
甲氧基
-7-(1-
甲基
-1H-
吡唑
-4-
基
)-[1,3]
噻唑并
[4,5-c]
吡啶
-2-
基
]-4-(
甲氧基甲基
)
苯甲醯胺,
14
i. N-[7-(1- 甲基 -1H- 吡唑 -4- 基 )-[1,3] 噻唑并 [4,5-c] 吡啶 -2- 基 ] 苯甲醯胺
在室溫下向N
-[7-溴-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲醯胺(2.94 g, 8.80 mmol)於二噁烷(112 mL)中之溶液添加1-甲基-4-(四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吡唑(2.19 g, 10.6 mmol)、Pd(dppf)Cl2CH2Cl2 (359 mg, 0.44 mmol)、碳酸鈉(3.27 g, 30.8 mmol)、水(23 ml)。在三次真空/氮吹掃循環後,將所得混合物在80℃下攪拌16 h。在反應完成時,將固體過濾出。將濾液在減壓下濃縮且藉由急速層析用於石油醚中之EtOAc (0%至100%梯度)溶析來純化殘餘物,產生呈灰白色固體之N-[7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲醯胺(2.54 g, 86%)。MS:m/z = 336.2 [M+H]+。
j. N-[4- 溴 -7-(1- 甲基 -1H- 吡唑 -4- 基 )-[1,3] 噻唑并 [4,5-c] 吡啶 -2- 基 ] 苯甲醯胺
在50℃下,在1 h時期內向N-[7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲醯胺(960 mg, 2.86 mmol)於N,N-二甲基甲醯胺(150 ml)中之溶液逐滴添加於N,N-二甲基甲醯胺(30 mL)中之NBS (662 mg, 3.72 mmol)並攪拌。然後將所得溶液在50℃下攪拌1 h。在反應完成時,用H2O (100 ml)使其淬滅。用二氯甲烷(150 ml × 3)萃取所得混合物且將有機相合併,用鹽水洗滌且經無水Na2SO4乾燥。將溶劑在減壓下去除且藉由急速層析用於石油醚中之EtOAc (0%至60%梯度)溶析來純化殘餘物,產生呈白色固體之N-[4-溴-7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲醯胺(675 mg, 57%)。MS:m/z = 414.1 [M+H]+。1H NMR (400 MHz,氯仿-d) δ 9.92 (s, 1 H), 8.41 (s, 1 H), 8.03 (d, J = 7.7 Hz, 2 H), 7.98 (s, 1 H), 7.92 (s, 1 H), 7.76-7.68 (m, 1 H), 7.66-7.58 (m, 2 H), 4.07 (s, 3 H)。
k. 4- 甲氧基 -7-(1- 甲基 -1H- 吡唑 -4- 基 ) 噻唑并 [4,5-c] 吡啶 -2- 胺
在室溫下向N-[4-溴-7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲醯胺(338 mg, 0.81 mmol)於甲醇(12 ml)中之溶液添加於MeOH中之MeONa (5.5 ml, 29.7 mmol, 5.4 M)。用微波輻射將反應混合物在140℃下輻照2 h。在反應完成時,用冰水(20 mL)使其淬滅。用二氯甲烷(50 ml × 3)萃取所得混合物且將有機相合併,用鹽水洗滌並經Na2
SO4
乾燥。將溶劑在減壓下去除且藉由急速層析用於DCM中之MeOH (0%至9%梯度)溶析來純化殘餘物,產生呈淺黃色固體之4-甲氧基-7-(1-甲基-1H-吡唑-4-基)噻唑并[4,5-c]吡啶-2-胺(33 mg, 11%)。MS:m/z = 382.2 [M+H]+。
l. N-[4- 甲氧基 -7-(1- 甲基 -1H- 吡唑 -4- 基 )-[1,3] 噻唑并 [4,5-c] 吡啶 -2- 基 ]-4-( 甲氧基甲基 ) 苯甲醯胺, 14
在室溫下向4-(甲氧基甲基)苯甲酸(53 mg, 0.32 mmol)於四氫呋喃(5 ml)中之溶液添加4-甲基嗎啉(65 mg, 0.64 mmol)、HATU (135 mg, 0.35 mmol)。將所得混合物在50℃下攪拌8 h。向以上所提及之反應混合物添加4-甲氧基-7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-胺(28 mg, 0.11 mmol),且將所得混合物在90℃下攪拌16 h。在反應完成時,藉由添加水(10 ml)使其淬滅。用DCM (30 ml × 3)萃取所得混合物。將有機相合併,用鹽水洗滌且經Na2
SO4
乾燥。將溶劑在減壓下去除且藉由製備型HPLC在以下條件下來純化殘餘物: 管柱,XBridge Shield RP18 OBD管柱,19 × 150mm 5um;於水(含10 mmol/l NH4
HCO3
+ 0.1% NH3.
H2
O)中之MeCN,於7 min內30%至52%梯度;檢測器,UV 254/220 nm。呈白色固體之N-[4-甲氧基-7-(1-甲基-1H-吡唑-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]-4-(甲氧基甲基)苯甲醯胺(18 mg, 40%)。HPLC: 99.4%純度,RT = 5.40 min. MS:m/z = 410.1 [M+H]+
。1H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1 H), 8.25-8.13 (m, 4 H), 7.94 (s, 1 H), 7.50 (d, J = 8.0 Hz, 2 H), 4.53 (s, 2 H), 4.05 (s, 3 H), 3.97 (s, 3 H), 3.35 (s, 3 H)。
3.N
-[4-
甲氧基
-7-(1-
甲基
-1H-
吡唑
-4-
基
)-[1,3]
噻唑并
[4,5-c]
吡啶
-2-
基
]-4-(
甲氧基甲基
)
苯甲醯胺,
30
m. 4- 氯 -5- 碘 -3- 硝基吡啶 -2- 醇
在室溫下向4-氯-3-硝基吡啶-2-醇(40.00 g, 229.22 mmol)於CH3
CN (500 ml)中之溶液添加NIS (56.72 g, 252.14 mmol)。將所得混合物在80℃下攪拌12 h。當反應完成時,將溶劑在減壓下去除。藉由急速層析用於PE中之EtOAc (0%至100%梯度)溶析來純化殘餘物,產生呈黃色固體之4-氯-5-碘-3-硝基吡啶-2-醇(46.43 g, 63%)。MS:m/z = 301.0 [M+H]+
。
n. 4- 氯 -5- 碘 -2- 甲氧基 -3- 硝基吡啶
在室溫下向4-氯-5-碘-3-硝基吡啶-2-醇(34.00 g, 112.00 mmol)於甲苯(700 ml)中之溶液添加Ag2
CO3
(30.88 g, 112.0 mmol)、CH3
I (31.81 g, 224.2 mmol)。將所得混合物在80℃下攪拌16 h。在反應完成時,將固體過濾出。將濾液在減壓下濃縮且藉由急速層析用於PE中之EtOAc (0%至20%梯度)溶析來純化殘餘物,產生呈淺黃色固體之4-氯-5-碘-2-甲氧基-3-硝基吡啶(19.50 g, 91%)。1
H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1 H), 4.00 (s, 3 H)。
o. 4- 氯 -5- 碘 -2- 甲氧基吡啶 -3- 胺
在室溫下向4-氯-5-碘-2-甲氧基-3-硝基吡啶(20.00 g, 63.59 mmol)於EtOH (1 l)中之溶液添加NH4
Cl (61.26 g, 1145 mmol)、水(180 ml)、Fe (53.42 g, 953.85 mmol)。將所得混合物在80℃下攪拌10 h。在反應完成時,將固體過濾出。將濾液在減壓下濃縮且將殘餘物於H2
O (1.5 L)中稀釋。用二氯甲烷(1.5 l × 3)萃取所得溶液且將合併之有機層用鹽水洗滌,經無水Na2
SO4
乾燥並過濾。將濾液在減壓下濃縮且藉由急速層析用於PE中之EtOAc (0%至100%梯度)溶析來純化殘餘物,產生呈淺黃色固體之4-氯-5-碘-2-甲氧基吡啶-3-胺(17.36 g, 96%)。MS:m/z = 284.8 [M+H]+
。
p. N
-(7- 碘 -4- 甲氧基噻唑并 [4,5-c] 吡啶 -2- 基 ) 苯甲醯胺
向4-氯-5-碘-2-甲氧基吡啶-3-胺(11.13 g, 39.13 mmol)於丙酮(293 ml)中之溶液添加異硫氰酸苯甲醯基酯(9.58 g, 58.70 mmol)。將所得混合物在50℃下攪拌16 h。在反應完成時,將溶劑在減壓下去除且藉由急速層析用於PE中之EtOAc (0%至100%梯度)溶析來純化殘餘物,產生呈淺黃色固體之N
-(7-碘-4-甲氧基噻唑并[4,5-c]吡啶-2-基)苯甲醯胺(16.00 g, 99%)。MS:m/z = 412.0 [M+H]+
。
q.N
-(7-(3,6- 二氫 -2H- 吡喃 -4- 基 )-4- 甲氧基噻唑并 [4,5-c] 吡啶 -2- 基 ) 苯甲醯胺
在室溫下向N
-[7-碘-4-甲氧基-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲醯胺(2.85 g, 6.93 mmol)於二噁烷(120 ml)中之溶液添加2-(3,6-二氫-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(2.18 g, 10.40 mmol)、Pd(dppf)Cl2CH2Cl2 (566 mg, 0.69 mmol)、氫氧化鈉(1.05 g, 26.34 mmol)及水(30 ml)。在三次真空/氮吹掃循環後,將所得混合物在100℃下攪拌16 h。在反應完成時,將固體過濾出。將濾液在減壓下濃縮且藉由急速層析用於DCM中之MeOH (0%至10%梯度)溶析來純化殘餘物,產生呈灰白色固體之N
-(7-(3,6-二氫-2H-吡喃-4-基)-4-甲氧基噻唑并[4,5-c]吡啶-2-基)苯甲醯胺(702 mg, 28%)。MS:m/z = 368.2 [M+H]+
。
r.N
-(4- 甲氧基 -7-( 四氫 -2H- 吡喃 -4- 基 ) 噻唑并 [4,5-c] 吡啶 -2- 基 ) 苯甲醯胺
在氮氣氛下向N
-[7-(3,6-二氫-2H-吡喃-4-基)-4-甲氧基-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲醯胺(702 mg, 1.91 mmol)於MeOH (30 ml)中之溶液添加Pd/C (10%, 500 mg)。在三次真空/氫吹掃循環後,使用氫氣囊在氫氣氛下將反應混合物在50℃下氫化16 h。在反應完成時,經由矽藻土墊過濾所得混合物。將濾液在減壓下濃縮且藉由急速層析用於DCM中之MeOH (0%至10%梯度)溶析來純化殘餘物,產生呈白色固體之N
-(4-甲氧基-7-(四氫-2H-吡喃-4-基)噻唑并[4,5-c]吡啶-2-基)苯甲醯胺(330 mg, 47%)。MS:m/z = 370.3 [M+H]+
。
s. 4- 甲氧基 -7-( 四氫 -2H- 吡喃 -4- 基 ) 噻唑并 [4,5-c] 吡啶 -2- 胺
在室溫下向N
-[4-甲氧基-7-(氧雜環己-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]苯甲醯胺(330 mg, 0.89 mmol)於甲醇(10 ml)中之溶液添加水(10 ml)、氫氧化鈉(357 mg, 8.93 mmol)。將所得混合物在90℃下攪拌16 h。在反應完成時,將甲醇在減壓下去除。將水(30 ml)添加至殘餘物並用二氯甲烷(30 ml × 3)萃取。將合併之有機相用鹽水洗滌,經Na2
SO4
乾燥且過濾。將濾液在減壓下濃縮且藉由急速層析用於DCM中之MeOH (0%至10%梯度)溶析來純化殘餘物,產生呈白色固體之4-甲氧基-7-(四氫-2H-吡喃-4-基)噻唑并[4,5-c]吡啶-2-胺(106 mg, 42%)。MS:m/z = 266.0 [M+H]+
。
t. (4- 甲氧基 -7-( 四氫 -2H- 吡喃 -4- 基 ) 噻唑并 [4,5-c] 吡啶 -2- 基 ) 胺基甲酸苯基酯
在室溫下向4-甲氧基-7-(氧雜環己-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-胺(87 mg, 0.33 mmol)於THF (20 ml)中之溶液添加碳酸鉀(136 mg, 0.98 mmol)、氯甲酸苯基酯(308 mg, 1.97 mmol)及吡啶(78 mg, 0.98 mmol)。將所得混合物在50℃下攪拌8 h。在反應完成時,將溶劑在減壓下去除。將所得混合物用水(30 ml)稀釋且用二氯甲烷(30 mL × 3)萃取。將合併之有機相用鹽水洗滌,經Na2
SO4
乾燥且過濾。將濾液在減壓下濃縮,產生呈橙色油狀物之(4-甲氧基-7-(四氫-2H-吡喃-4-基)噻唑并[4,5-c]吡啶-2-基)胺基甲酸苯基酯(88 mg, 70%),其不經進一步純化即用於下一步驟中。MS:m/z = 386.3 [M+H]+
。
u.N
-[4- 甲氧基 -7-(1- 甲基 -1H- 吡唑 -4- 基 )-[1,3] 噻唑并 [4,5-c] 吡啶 -2- 基 ]-4-( 甲氧基甲基 ) 苯并 - 醯胺, 30
在室溫下向N
-[4-甲氧基-7-(氧雜環己-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]胺基甲酸苯基酯(88 mg, 0.23 mmol)及4-甲基六氫吡啶-4-醇(79 mg, 0.68 mmol)於THF (10 ml)中之溶液添加 DIPEA (177 mg, 1.37 mmol)。將所得混合物在50℃下攪拌16 h。在反應完成時,將溶劑在減壓下去除且藉由製備型HPLC在以下條件下來純化殘餘物: 管柱,XBridge Prep OBD C18管柱,30 × 150 mm 5 um;移動相,水(含10 mmol/l NH4
HCO3
+ 0.1% NH3.
H2
O)及ACN (8 min內13.0% ACN直至40.0%);檢測器,UV 220nm。獲得呈白色固體之標題化合物4-羥基-N-[4-甲氧基-7-(氧雜環己-4-基)-[1,3]噻唑并[4,5-c]吡啶-2-基]-4-甲基六氫吡啶-1-甲醯胺(30 mg, 32%)。HPLC: 99.7%純度,RT = 3.13 min. MS:m/z = 407.3 [M+H]+。1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1 H), 7.79 (s, 1 H), 4.41 (s, 1 H), 4.02-3.92 (m, 5 H), 3.84 (d, J = 13.2 Hz, 2 H), 3.54-3.44 (m, 2 H), 3.29-3.21 (m, 2 H), 3.03-2.84 (m, 1 H), 1.93-1.68 (m, 4 H), 1.56-1.36 (m, 4 H), 1.14 (s, 3 H)。
實例 3 : 測試本發明之化合物對重組細胞中人類腺苷受體之抑制活性。
藉由量化cAMP (其係腺苷受體之第二傳訊者)來測定人類A2A
、A2B
、A1
及A3
受體之功能活性。 出於此目的,將表現人類A2A
或A2B
受體(二者均經Gs偶合)之重組HEK293細胞接種至394孔微量滴定板中,添加測試化合物及激動劑(NECA)。培育15 min後,添加HTRF試劑(cAMP dynamic 2, Cis Bio),且使用ENVISION (Perkin Elmer)讀板儀來測定細胞cAMP含量。
對於人類A1
及A3
受體,使用表現A1
或A3受體之重組CHO細胞。由於兩種受體均偶合至Gi蛋白,因此將分析方案改為: 將細胞接種至384孔板中,添加毛喉素、測試化合物及激動劑(對於A1
受體為CPA且對於A3
受體為IB-MECA)。培育30 min後,添加HTRF試劑(cAMP dynamic 2, Cis Bio),且使用ENVISION (Perkin Elmer)讀板儀測定細胞cAMP含量。
將所獲得之原始數據針對抑制劑對照及中性對照(DMSO)進行正規化,且使用GeneData軟體將正規化之數據擬合。
本發明之化合物顯示對腺苷A2A
及A2B
受體之選擇性高於腺苷A1
及A3
受體(例如,參見表4中本發明化合物之一些實例之數據) 具體而言,與已知之腺苷A2A
受體拮抗劑托紮丁奈及類似苯并噻唑衍生物相比,本發明之化合物令人驚訝地顯示A2A
/A2B
雙重活性(參見表4),此對於治療及/或預防如上文所揭示之過度增殖性及傳染性疾病及病症較佳,或本發明之化合物至少顯示高A2A
抑制活性以及本文所揭示之在治療及/或預防過度增殖性及傳染性疾病及病症中產生高效能之其他令人驚訝之優點。表 4
A意味著IC50
值< 10 nM,B意味著IC50
值< 100 nM,C意味著IC50
值< 1 µM,D意味著IC50
值> 1 µM。
實例 4 :測試本發明之化合物對內源性人類 A2A 受體之效應
在T細胞中量測Gs偶合人類A2A
受體之內源性功能活性,此受體在T細胞中高度表現。藉由量化cAMP (其係腺苷受體之第二傳訊者)進行受體活性之測定。
簡言之,自源自新鮮全血之人類PBMC (MACS全T細胞分離套組,Miltenyi Biotec)分離人類全T細胞。將T細胞接種於384孔微量滴定板中並用測試化合物處理。在室溫下培育10 min後,添加A2A
腺苷受體激動劑CGS-21680,並將板再培育45 min。最後,將HTRF試劑(cAMP Femto套組,CisBio)添加至孔,且在1 h後使用ENVISION (Perkin Elmer)讀板儀測定細胞cAMP含量。
將所獲得之原始數據針對抑制劑對照及中性對照(DMSO)進行正規化,且使用Genedata Screener軟體將正規化之數據擬合。
本發明之化合物顯示,其能夠抑制與A2A
腺苷受體激動劑CGS-21680一起培育之人類T細胞中表現之A2A
受體(如藉由量化cAMP所量測),此對於治療及/或預防如上文所揭示之過度增殖性及傳染性疾病及病症較佳。因此,令人驚訝地,本發明之化合物能夠防止免疫抑制且因此能夠支持抗腫瘤T細胞誘導之對腫瘤生長之抑制、轉移之降低或破壞及新血管形成之阻止。
實例 5 :測試本發明之化合物在大鼠及小鼠中之藥物動力學性質
本研究之目標係獲得關於在單次靜脈內及經口投與後,本發明之化合物在雌性Wistar大鼠/小鼠中之藥物動力學性質之資訊。
材料及方法: 動物實驗(存活期) 雌性Wistar大鼠/小鼠(n=6)接受單次靜脈內(濃注)注射或經口投與(藉由胃管灌食)測試化合物。分別靜脈內及口服給予(每種化合物) 0,2 mg/kg及10 mg/kg之劑量,其做為於DMSO (0.2%)/PEG 200 (40%)/水中之溶液用於iv投與且做為於Methocel (0.5%)/Tween 20 (0.25%)(於水中)之懸浮液用於經口投用。在0.1 h (僅iv)、0.25 h (僅po)、0.5 h、1 h、2 h、4 h、6 h及24 h後,每種投與途徑在異氟醚吸入下自3隻動物取連續血液樣品且進一步處理以獲得血漿。此外,在0-24 h之時間間隔內每種投與途徑收集3隻大鼠之尿液及糞便樣品且合併用於分析。
生物分析: 使用UPLC方法利用先前在「藥物代謝及藥物動力學研究所(Institute of Drug Metabolism and Pharmacokinetics)」開發出之串聯質譜檢測(LC-MS/MS)對血漿、糞便中之化合物濃度進行量化。該LC-MS/MS系統係由耦合至AB Sciex質譜儀API 5500 Q-trap之Waters Acquity UPLC組成。在反相管柱(HSS T3, 1.8 µM, 2.1 ´ 50 mm)上使用移動相梯度以0.1%甲酸及乙腈做為溶析液來實施UPLC分離。使用正電離模式之多反應監測進行化合物之檢測。向血漿樣品摻加內標準品(20 µl),且使用第三丁基甲醚(tBME)自基質萃取分析物。在氮流下將有機相蒸發至乾燥。將殘餘物溶解於乙腈/0.1%甲酸中以供LC-MS/MS分析。用4倍其體積之乙醇/水混合物(4:1, v/v)使糞便樣品勻漿化。向水性-醇性萃取物之等分試樣摻加內標準品,用乙腈/水(1:1, v/v)稀釋且直接注射至LC-MS/MS系統中。
藥物動力學評估: 藥物動力學參數C最大
及t最大
取自所觀察到之數據。曲線下面積(AUC)、清除率(CL)、體積(V)、半衰期(t1/2
)、F及所有劑量正規化之值均使用定製軟體「DDS-TOX」來計算。評估若干種化合物之「DDS-TOX」值且顯示與由經驗證之軟體WinNonLin給出之值相當。藉由非房室性分析使用線性上升/對數下降(linear up/log down)方法計算AUC值。將平均血漿濃度及導出之藥物動力學參數之數值數據舍入至3位有效數位以用於呈現。經口生物利用度及排泄數據(以劑量%表示)係使用2位有效數位來展現。
與已知之腺苷A2A
受體拮抗劑托紮丁奈及類似苯并噻唑衍生物相比,本發明之化合物令人驚訝地在做為癌症相關動物模型之小鼠中顯示更佳之藥物動力學性質(參見表6),此對於治療及/或預防如上文所揭示之過度增殖性及傳染性疾病及病症較佳。表 6
實例 6 :測試本發明之化合物對小鼠 T 細胞之效應
背景: 腫瘤微環境中之腺苷(Ado)可藉由經由A2A
受體之信號傳導抑制T細胞活性並抑制T細胞之細胞介素分泌。A2A
特異性激動劑(如CGS-21680)在活體外及活體內具有抑制T細胞細胞介素分泌之類似作用。潛在A2A
拮抗劑或A2A
/A2B
雙重拮抗劑可拯救T細胞免於此抑制。在本文中,吾人闡述使用來自小鼠脾之全T細胞建立之活體外系統以篩選潛在A2A
拮抗劑或A2A
/A2B
雙重拮抗劑之其活性。所闡述之方法涉及使用CD3/CD28預包覆珠粒來刺激自小鼠脾細胞純化之全T細胞,與添加A2A
激動劑以及潛在A2A
或A2A
/A2B
雙重拮抗劑組合來評估T細胞細胞介素產生之增強。
分析闡述: 簡言之,根據製造商之方案,使用全T細胞分離套組Mouse II (MACS Miltenyi biotech,目錄號訂單號130-095-130)自BALB/c小鼠之脾純化小鼠全T細胞。於Nunc™ 96孔聚苯乙烯圓底微孔板中將經純化之T細胞接種於含有10%熱不活化胎牛血清之RPMI培養基中。將細胞在37℃下靜置1 h,之後用CD3/CD28預包覆珠粒(Dynabeads™小鼠T-活化劑CD3/CD28;目錄號11456D)活化。30 min後,用不同劑量之測試拮抗劑處理細胞。將細胞在37℃下再培育30 min,之後用A2A
激動劑CGS-21680 (1 μM)或中性對照(DMSO)處理。根據製造商之方案(R&D systems,目錄號DY402 (IL-2);DY485 (IFN-γ)),藉由ELISA量測培育24 h後上清液中之IL-2含量及培育48 h後上清液中之IFN-γ含量。濃度計算出後,計算DMSO對照與單獨之激動劑對照之細胞介素濃度差(稱為Δ),並藉由使用Microsoft Excel計算每一濃度之拮抗劑之拯救百分比。在GraphPad Prism軟體中繪製該等以拮抗劑之劑量依賴性方式之細胞介素拯救百分比並計算IC50
。
與已知之腺苷A2A
受體拮抗劑托紮丁奈相比,本發明之化合物顯示其能夠拯救T細胞免受抑制且能夠防止對如由腺苷或A2A
特異性激動劑(如CGS-2168)誘導之細胞介素分泌之抑制(參見表7),此對於治療及/或預防如上文所揭示之過度增殖性及傳染性疾病及病症較佳。因此,令人驚訝地,本發明之化合物能夠防止免疫抑制且因此能夠支持抗腫瘤T細胞誘導之對腫瘤生長之抑制、轉移之降低或破壞及新血管形成之阻止。表 7
實例 7 : 注射小瓶
使用2 N鹽酸將100 g本發明之化合物及5 g磷酸氫二鈉於3 l重蒸餾水中之溶液調整至pH 6.5,在無菌條件下過濾,轉移至注射小瓶中,在無菌條件下凍乾並在無菌條件下密封。每一注射小瓶含有5 mg本發明之化合物。
實例 8 :溶液
於940 ml重蒸餾水中自1 g本發明之化合物、9.38 g NaH2
PO4
2 H2
O、28.48 g Na2
HPO4
12 H2
O及0.1 g苯紮氯銨製備溶液。將pH調整至6.8且將該溶液補足至1 l並藉由輻照滅菌。
實例 9 :安瓿
將1 kg本發明之化合物於60 l重蒸餾水中之溶液在無菌條件下過濾,轉移至安瓿中,在無菌條件下凍乾並在無菌條件下密封。每一安瓿含有10 mg本發明之化合物。
Claims (21)
- 如請求項1之化合物,其中R1係苯基、甲基吡唑或二氫吡喃,且R2、R3及R4具有如請求項1中之含義,及其生理上可接受之鹽、水合物及立體異構物,包括其所有比率之混合物。
- 如請求項1或2之化合物,其中R3係OMe且R1、R2及R4具有如請求項1中所揭示之含義,及其生理上可接受之鹽、水合物及立體異構物,包括其所有比率之混合物。
- 如請求項1或2之化合物,其中R1係苯基、甲基吡唑或二氫吡喃,R3係OMe且R2及R4具有如請求項1中所揭示之含義,及其生理上可接受之鹽、水合物及立體異構物,包括其所有比率之混合物。
- 如請求項1或2之化合物,其中R4係H,且其中R1、R2及R3具有如請求項1中所揭示之含義,及其生理上可接受之鹽、水合物及立體異構物,包括其所有比率之混合物。
- 一種用於製備如請求項1之式I化合物之方法,其特徵在於a)式II化合物經歷還原得到式III化合物,式III化合物與式IV化合物在升高溫度下反應得到式V化合物,式V化合物採用觸媒及鹼轉化成式VI化合物,式VI化合物藉由溴化轉化成式VII化合物,式VII化合物在鹼性之條件下轉化成式VIII化合物且式VIII化合物與式IX化合物在醯胺化或碳醯胺形成條件下反應得到式I化合物,
- 一種醫藥製劑,其包含至少一種如請求項1至6中任一項之化合物及/或其生理上可接受之鹽、水合物及立體異構物,包括其所有比率之混合物。
- 如請求項8之醫藥製劑,其包含其他賦形劑及/或佐劑。
- 一種醫藥製劑,其包含至少一種如請求項1至6中任一項之化合物及/或其生理上可接受之鹽、水合物及立體異構物,包括其所有比率之混合物,及至少一種其他藥劑活性化合物,該其他藥劑活性化合物為抗腫瘤藥劑。
- 一種用於製備醫藥製劑之方法,其特徵在於將如請求項1至6中任一項之化合物及/或其生理上可接受之鹽、水合物及立體異構物中之一者、包括其所有比率之混合物與固體、液體或半液體賦形劑或佐劑一起製成適宜劑型。
- 一種至少一種如請求項1至6中任一項之化合物及/或其生理上可接受之鹽、水合物及立體異構物中之一者、包括其所有比率之混合物用於製備藥劑之用途,其中該藥劑係用於治療及/或預防生理及/或病理生理狀態。
- 一種至少一種如請求項1至6中任一項之化合物及/或其生理上可接受之鹽、水合物及立體異構物中之一者、包括其所有比率之混合物用於製備藥劑之用途,其中該藥劑係用於治療及/或預防選自由過度增殖性及傳染性疾病及病症組成之群之生理及/或病理生理狀態。
- 如請求項13之用途,其中該過度增殖性疾病或病症係癌症。
- 如請求項14之用途,其中該癌症係選自由以下組成之群:急性顆粒球性白血病、腎上腺皮質癌、膀胱癌、腦癌、乳癌、子宮頸癌、頸椎增生、絨毛膜癌、慢性顆粒球性白血病、結腸癌、子宮內膜癌、食管癌、原發性血小板增多症、泌尿道癌、神經膠質瘤、神經膠母細胞瘤、毛細胞白血病、頭頸癌、霍奇金氏病(Hodgkin's disease)、卡波西氏肉瘤(Kaposi's sarcoma)、肺癌、淋巴瘤、惡性類癌、惡性高鈣血症、惡性胰臟胰島素瘤、甲狀腺髓樣癌、黑色素瘤、多發性骨髓瘤、蕈樣真菌病、骨髓性及淋巴球性白血病、神經胚細胞瘤、非霍奇金氏淋巴瘤、骨原性肉瘤、卵巢癌、胰臟癌、真性多血症、原發性腦癌、原發性巨球蛋白血症、前列腺癌、腎細胞癌、橫紋肌肉瘤、皮膚癌、軟組織肉瘤、鱗狀細胞癌、胃癌、睪丸癌、甲狀腺癌及威爾姆氏瘤(Wilms' tumor)。
- 如請求項14之用途,其中該癌症係選自由以下組成之群:非小細胞肺癌、小細胞肺癌、惡性黑色素瘤及急性或慢性淋巴球性白血病。
- 如請求項13之用途,其中該過度增殖性疾病或病症係選自由以下組成之群:年齡相關性黃斑退化、克隆氏病(Crohn's disease)、硬化、慢性發炎性相關病症、增殖性糖尿病視網膜病變、增殖性玻璃體視網膜病變、早產兒視網膜病變、肉芽腫、與器官或組織移植相關之免疫過度增殖及選自由以下組成之群之免疫增殖疾病或病症:發炎性腸病、牛皮癬、類風濕性關節炎、全身性紅斑狼瘡(SLE)、繼發於視網膜低氧之血管過度增殖及血管炎。
- 如請求項13之用途,其中該傳染性疾病或病症係選自由以下組成之群:a)病毒誘導之傳染病,其係由反轉錄病毒、嗜肝病毒(hepadnavirus)、疱疹病毒、黃病毒科(flaviviridae)及/或腺病毒引起,其中該等反轉錄病毒係選自慢病毒(lentivirus)或致癌反轉錄病毒,其中該慢病毒係選自由以下組成之群:HIV-1、HIV-2、FIV、BIV、SIV、SHIV、CAEV、VMV及EIAV且該致癌反轉錄病毒係選自由以下組成之群:HTLV-I、HTLV-II及BLV,該嗜肝病毒係選自由以下組成之群:HBV、GSHV及WHV,該疱疹病毒係選自由以下組成之群:HSV I、HSV II、EBV、VZV、HCMV或HHV 8且該黃病毒科選自由以下組成之群:HCV、西尼羅病毒(West nile)及黃熱病,b)由革蘭氏陽性(Gram-positive)細菌引起之細菌性傳染病,其中該等革蘭氏陽性細菌係選自由以下組成之群:甲氧西林(methicillin)敏感及甲氧西林抗性葡萄球菌(staphylococci)、對醣肽類中度敏感之金黃色葡萄球菌(GISA)、青黴素敏感及青黴素抗性鏈球菌(streptococci)、萬古黴素(vancomycin)敏感及萬古黴素抗性腸球菌(enterococci)、難養芽胞梭菌(Clostridium difficile)、單核球增多性李斯特菌(Listeria monocytogenes)、傑氏棒狀桿菌(Corynebacterium jeikeium)、披衣菌屬(Chlamydia spp)及結核分枝桿菌(Mycobacterium tuberculosis),c)由革蘭氏陰性細菌引起之細菌性傳染病,其中該革蘭氏陰性細菌係選自由腸桿菌屬(Genus Enterobacteriacae)組成之群,d)由細胞內活性寄生蟲誘導之傳染病,該等寄生蟲係選自由以下組成之群:頂複門(Apicomplexa)或肉質鞭毛蟲門(Sarcomastigophora)、 隱孢子蟲(Cryptosporidia)、肉孢子蟲(Sacrocystida)、變形蟲(Amoebia)、球蟲(Coccidia)及毛滴蟲(Trichomonadia)。
- 如請求項18之用途,其中該甲氧西林敏感及甲氧西林抗性葡萄球菌包括金黃色葡萄球菌(Staphylococcus aureus)、表皮葡萄球菌(Staphylococcus epidermidis)、溶血性葡萄球菌(Staphylococcus haemolyticus)、人葡萄球菌(Staphylococcus hominis)、腐生葡萄球菌(Staphylococcus saprophyticus)或凝固酶陰性葡萄球菌;該青黴素敏感及青黴素抗性鏈球菌包括肺炎鏈球菌(Streptococcus pneumoniae)、釀膿鏈球菌(Streptococcus pyogenes)、無乳鏈球菌(Streptococcus agalactiae)、鳥鏈球菌(Streptococcus avium)、牛鏈球菌(Streptococcus bovis)、乳酸鏈球菌(Streptococcus lactis)、血鏈球菌(Streptococcus sanguis)及C組鏈球菌(GCS)、G組鏈球菌(GGS)或草綠色鏈球菌(viridans streptococci);該萬古黴素敏感及萬古黴素抗性腸球菌包括糞腸球菌(Enterococcus faecalis)或屎腸球菌(Enterococcus faecium);以及該披衣菌屬包括肺炎披衣菌(C.pneumoniae);其中該腸桿菌屬包括埃希氏菌屬(Escherichia spp.)、克雷伯氏菌屬(Klebsiella spp.)、腸桿菌屬(Enterobacter spp.)、檸檬酸桿菌屬(Citrobacter spp.)、沙雷氏菌屬(Serratia spp.)、變形桿菌屬(Proteus spp.)、普羅威登斯菌屬(Providencia spp.)、沙門桿菌屬(Salmonella spp.)、志賀桿菌屬(Shigella spp.)、假單胞菌屬(Pseudomonas)、莫拉菌屬(Moraxella spp.)、嗜血桿菌屬(Haemophilus spp.)或奈瑟菌屬(Neisseria spp.);以及 其中該頂複門或肉質鞭毛蟲門包括錐蟲屬(Trypanosoma)、瘧原蟲屬(Plasmodia)、利什曼蟲屬(Leishmania)、巴貝蟲屬(Babesia)或泰勒蟲屬(Theileria)。
- 如請求項19之用途,其中該埃希氏菌屬包括大腸桿菌(Escherichia coli);該假單胞菌屬包括綠膿桿菌(P.aeruginosa);或該莫拉菌屬包括卡他莫拉菌(M.catarrhalis)。
- 一種套件,其係由以下之單獨包裝組成:a)有效量之如請求項1至6中任一項之化合物及/或其生理上可接受之鹽、水合物及立體異構物,包括其所有比率之混合物,及b)有效量之另一藥劑活性化合物,其為抗腫瘤藥劑。
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