TW201331202A - ［１，２，４］三唑并吡啶及其作為磷酸二酯酶抑制劑之用途 - Google Patents
［１，２，４］三唑并吡啶及其作為磷酸二酯酶抑制劑之用途 Download PDFInfo
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Abstract
本發明係關於具有磷酸二酯酶抑制活性之新穎[1,2,4]三唑并吡啶化合物，及其等作為發炎疾病及病況治療中之治療劑之用途。
Description
本發明係關於具有磷酸二酯酶抑制活性之新穎[1,2,4]三唑并吡啶化合物，及其等作為發炎疾病及病況治療中之治療劑之用途。
磷酸二酯酶係分別將細胞中之環狀AMP及/或環狀GMP催化水解為5-AMP及5-GMP之酶，及因此其等對於cAMP或cGMP濃度之細胞調控至為關鍵。在至今識別之11種磷酸二酯酶中，磷酸二酯酶(PDE)4、PDE7及PDE8係用於cAMP。PDE4係表現在諸如嗜中性白血球、巨噬細胞及T-淋巴細胞之免疫及炎症細胞中之cAMP之最重要調控劑(Z.Huang and J.A.Mancini,Current Med.Chem.13,2006,pp.3253-3262)。由於cAMP係炎症反應調控中之關鍵第二信使，故發現PDE4透過調控諸如TNF-α、IL-2、IFN-γ、GM-CSF及LTB4之促發炎細胞介素以調控炎症細胞之炎症反應。因此，PDE4抑制已成為發炎疾病(如哮喘、慢性阻塞性肺病(COPD)、類風濕性關節炎、異位性皮膚炎、發炎性腸病(如克隆氏病)等)療法之受關注目標(M.D.Houslay等人，Drug Discovery Today 10(22),2005,pp.1503-1519)。由於異位性皮膚炎(AD)病患具有增大之PDE-活性，故PDE-4抑制亦成為有價值之AD治療手段(Journal of Investigative Dermatology(1986),87(3),372-6)。
PDE4基因家族由至少四種基因A、B、C及D組成，其等
具有高度同源性(V.Boswell Smith and D.Spina,Curr.Opinion Investig.Drugs 6(11),2006,pp.1136-1141)。該四種PDE4同功異型物以不同方式表現在不同組織及細胞類型中。因此，PDE4B主要表現在單核球及嗜中性白血球中，但不在皮質及上皮細胞中，而PDE4D表現在肺、皮質、小腦及T-細胞中(C.Kroegel and M.Foerster,Exp.Opinion Investig.Drugs 16(1),2007,pp.109-124)。已推測在大腦中之PDE4D抑制係與當臨床投與PDE4抑制劑時所引起之不良作用(主要係噁心及嘔吐)有關，而PDE4B抑制係與抗發炎作用有關(B.Lipworth,Lancet 365,2005,pp.167-175)。然而，據信至今仍未開發出對四種PDE4同功異型物中之任一者特異之PDE抑制劑。
已研究過許多PDE4抑制劑對發炎疾病(主要係哮喘及COPD)之治療作用。
此等抑制劑中之第一種，茶鹼(theophylline)係低效、非選擇性磷酸二酯酶抑制劑，其用於治療呼吸道疾病，如哮喘及COPD。然而，採用茶鹼之治療可引起輕度及嚴重不良作用，例如心律失常及驚厥，此限制茶鹼之臨床實用性(Kroegel and Foerster，如上所述)。由於磷酸二酯酶仍係抗發炎療法之受關注目標，故在臨床配置中已開發及研究數種其他更具選擇性之PDE4抑制劑。許多第一代PDE4抑制劑(如咯利普蘭(rolipram))之臨床開發因劑量相關副作用(主要係噁心及嘔吐)而中斷。然而，羅氟司特(roflumilast)在將劑量相關副作用(噁心、腹瀉及頭痛)減至最低後於
2010年經核准用於與慢性支氣管炎相關之嚴重COPD。具有顯然較少明顯不良作用之第二代PDE4抑制劑現正處於臨床試驗中(Houslay，如上所述)。PDE4抑制劑揭示於例如EP 0771794及EP 0943613中。
WO 2008/125111，LEO Pharma A/S，揭示具有強力PDE4抑制活性之三唑并吡啶化合物。此等化合物包括連接子，其包含位於雙環、雜環系統與單環系統之間之羰基。在相關化合物吡拉米特(piclamilast)中已發現該連接子對單環之定位至關重要，因此其可與PDE4酶相互作用(Card G.L.等人，「Structural basis for the activity of drugs that inhibit phosphodiesterases」,Structure 2004 Dec；12(12)；2233-47)以產生所需之抑制作用。
WO 2010/069322,LEO Pharma A/S揭示不具有位於雙環與單環系統之間之羰基連接子之三唑并吡啶化合物。已發現該等化合物展現PDE4抑制活性。
仍需開發具有更合適治療範圍(即較少不良作用)同時維持其等治療抗發炎作用之新穎PDE4抑制劑。
本發明之一目的係提供新穎化合物，該等化合物係在生物組織中具有穩定性概況之強力PDE4抑制劑，此意指在例如局部投與時僅觀察到該等化合物之極低全身性曝露。更准確而言，本發明之化合物在人類肝微粒體中具有高清除率。其等在人類全血中快速水解但同時對於在人類角質細胞中之酶促水解展現穩定性。
在一態樣中，本發明提供一種如式(I)之化合物
其中R係如下定義。
在另一態樣中，本發明提供醫藥組成物，其包含如上定義之如通式(I)之化合物及醫藥可接受媒劑或賦形劑或醫藥可接受載劑，視需要與一或多種其他治療活性化合物。
在另一態樣中，本發明提供本發明化合物之用途，其用於製造醫藥組成物以預防、治療、防止或改善對PDE4抑制活性呈反應性之疾病、病症或病況。
在另一態樣中，本發明提供一種預防、治療、防止或改善對PDE4抑制活性呈反應性之疾病、病症或病況之方法，及該方法包含對活動物軀體投與治療有效量之本發明式(I)化合物之步驟。
熟習本項技術者將自以下詳細敘述及實例瞭解本發明之其他目的。
在一態樣中，本發明提供如式(I)之化合物
其立體異構體中之任一者或其立體異構體之任何混合物或其醫藥可接受鹽，其中R係支化丁基。
在本發明之一實施例中，R係1-甲基丙基、2-甲基丙基或第三丁基。
在另一實施例中，R係1-甲基丙基。
在另一實施例中，R係2-甲基丙基。
在另一實施例中，R係第三丁基。
式(I)化合物之具體實例可選自由以下化合物組成之群：1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸[(1S)-1-甲基丙基]酯；1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸[(1R)-1-甲基丙基]酯；1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸[2-甲基丙基]酯；1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸第三丁基酯；或其等醫藥可接受鹽。
如本說明書全文及附接申請專利範圍中所使用，以下術語具有所指示含義：
如本文中所使用，術語「治療」意指管理及照料病患，目的在於打擊疾病、病症或病況。該術語意欲包括疾病、病症或病況進程之延遲、症狀及併發症之減輕或緩解，及/或疾病、病症或病況之治愈或消除。計劃治療之病患較佳係哺乳動物，特定言之，人類。
如本文中所使用，術語「疾病」、「病況」及「病症」可交換使用以指明病患之狀態(即非正常人類生理狀態)。
如本文中所使用，術語「藥劑」意指適合將醫藥活性化合物投與給病患之醫藥組成物。
如本文中所使用，術語「醫藥可接受」意指適合正常醫藥應用，即，不在病患中引起不良事件等。
術語「醫藥可接受鹽」意指透過使式I化合物與合適無機或有機酸(如鹽酸、氫溴酸、氫碘酸、硫酸、硝酸、磷酸、甲酸、乙酸、2,2-二氯乙酸、己二酸、抗壞血酸、L-天冬胺酸、L-榖胺酸、半乳糖二酸、乳酸、馬來酸、L-蘋果酸、鄰苯二甲酸、檸檬酸、丙酸、苯甲酸、戊二酸、葡萄糖酸、D-葡糖醛酸、甲烷磺酸、水楊酸、琥珀酸、丙二酸、酒石酸、苯磺酸、乙烷-1,2-二磺酸、2-羥基乙烷磺酸、甲苯磺酸、胺基磺酸或富馬酸)反應而製備之鹽。
本發明之化合物可直接透過自有機溶劑濃縮或透過自有機溶劑或該溶劑與共溶劑(可為有機或無機物，如水)之混合物結晶或再結晶而以結晶形式獲得。該等晶體可以實質
上無溶劑形式或以溶劑化物形式(如水合物)單離。本發明涵蓋所有結晶變體及形式亦及其等混合物。
式(I)化合物可或可不包含致使異構形式(例如對映異構體)存在之不對稱取代(對掌性)碳原子。本發明係關於呈純形式或其等混合物(例如消旋物)形式之所有此等異構體。本發明化合物及中間物之純立體異構形式可透過應用本技藝已知之製程獲得。各種異構形式可藉由物理分離方法分離，如選擇性結晶及層析技術，例如使用對掌性固定相之液相層析。該等純立體異構形式亦可自合適起始材料之對應純立體異構形式衍生，條件係反應依照立體選擇或立體特異方式發生。較佳，若需要某一具體立體異構體，則該化合物將透過立體選擇性或立體特異性製備方法合成。此等方法宜採用對掌性純起始材料。
由於本發明化合物展現PDE4抑制活性，故該等化合物可作為治療劑用於發炎性過敏性疾病，如支氣管哮喘、COPD、過敏性鼻炎、及腎炎；自體免疫疾病，如類風濕性關節炎、多發性硬化、克隆氏病及全身性紅斑狼瘡；急性或慢性皮膚損傷病；中樞神經系統疾病，如抑鬱、健忘症及癡呆；與心力衰竭所導致之缺血性回流相關之器官病、休克及腦血管病，及類似者；胰島素抵抗糖尿病；外傷；AIDS及類似者。
在一實施例中，本發明之化合物可用於治療、防止或改善皮膚疾病或病況。
在另一實施例中，本發明之化合物可用於治療、防止或改善選自由以下疾病組成之群之皮膚疾病或病況：增生性及發炎性皮膚病、皮膚炎、異位性皮膚炎、脂溢性皮膚炎、接觸性皮膚炎、牛皮癬、癌症、上皮發炎、禿頭症、皮膚萎縮、類固醇誘發之皮膚萎縮、皮膚老化、光致皮膚老化、痤瘡、蕁麻疹、瘙癢及濕疹。
在另一實施例中，本發明化合物可用於治療或改善特異性皮膚炎。
在另一實施例中，本發明化合物可用於治療或改善牛皮癬。
視需要與其他活性化合物組合之本發明化合物可用於治療皮膚疾病或病況，特定言之，治療增生性及發炎性皮膚病、皮膚炎、異位性皮膚炎、脂溢性皮膚炎、接觸性皮膚炎、牛皮癬、癌症、上皮發炎、禿頭症、皮膚萎縮、類固醇誘發之皮膚萎縮、皮膚老化、光致皮膚老化、痤瘡、蕁麻疹、瘙癢及濕疹。
除可用於人類治療外，本發明化合物亦可用於動物之獸醫學治療，該等動物包括哺乳動物，如馬、牛、羊、豬、犬及貓。
就治療用途而言，本發明化合物一般係呈醫藥組成物之形式。因此，本發明係關於一種醫藥組成物，其包含式(I)化合物、及視需要一或多種其他治療活性化合物，及醫藥可接受賦形劑或媒劑。該賦形劑應為「可接受」，即與組成物之其他成分可相容且不毒害其接受者。
在劑量單元之形式下，該化合物可在一天內以合適間隔分一或多次投與，但通常取決於病患情況，及依照主治醫師處方進行。合宜地，局部調配物之劑量單元含有0.1 mg與1000 mg之間，較佳1 mg與100 mg之間，如5至50 mg之式(I)化合物。
本發明化合物之合適劑量尤其取決於病患年齡及狀況、計劃治療疾病之嚴重性及主治醫師所熟知之其他因素。該化合物可經口、經腸外或局部，依照不同投藥方案(例如每日或以週為間隔)投與。基本上，單劑量係於0.001至10 mg/kg體重之範圍內，例如在0.01至1 mg/kg體重之範圍內。該化合物可以大丸劑形式投與(即一次性投與整個日劑量)或在一天內分兩或更多次投與。
就局部治療而言，其更適宜稱為「用量單元」，表示整體，即，可投與給病患及可輕易操作及包裝之單劑量，其仍為物理及化學穩定單位劑量，包含所描述之活性材料或其與固體或液體醫藥稀釋劑或載劑之混合物。「用量單元」可以0.1 mg至50 mg及較佳0.2 mg至5 mg受關注最終調配物/平方厘米皮膚之用量經局部投與給病患。
在某些治療方案中，亦假設以更長間隔投與，例如合宜者為每隔一天、每週或甚至更長間隔。
若治療涉及投與另一種治療活性化合物，則建議查閱Goodman & Gilman所著之The Pharmacological Basis of Therapeutics,9th Ed.,J.G.Hardman and L.E.Limbird(Eds.),McGraw-Hill 1995，以求該等化合物可用劑量。
本發明化合物與一或多種其他活性化合物可相伴或依序投與。
調配物包括例如，適合經口(包括延長或延時釋放)、經直腸、經腸外(包括皮下、腹膜內、肌肉內、動脈內及靜脈內)、經皮、經眼、經局部、經表皮、經鼻或經口含投與之形式之彼等物。特別適合經局部投與本發明調配物。
該等調配物可合宜地以單位劑型存在及可藉由醫藥技藝熟知方法中之任一者製備，例如，如Remington,The Science and Practice of Pharmacy,20th ed.,2000中所揭示般來製備。所有方法包括將活性成分與載劑(構成一或多種輔助成分)締合之步驟。基本上而言，該等調配物係透過將活性成分與液體載劑或微細固體載劑或兩者均勻且緊密締合，及隨後，若需要，將產物成形為所需調配物之方式製備。
適合經口投與之本發明調配物可呈離散單位之形式，如膠囊、藥囊、錠劑或口含錠，各者含有預確定量之活性成分；呈粉末或顆粒形式；呈在水性液體或非水性液體(如乙醇或甘油)中之溶液或懸浮液之形式；或呈水包油乳化液或油包水乳化液之形式。此等油可為食用油，如，例如棉籽油、芝麻油、椰子油或花生油。用於水性懸浮液之合適分散或懸浮劑包括合成或天然樹膠，如黃蓍膠、藻酸鹽、阿拉伯膠、葡聚糖、羧甲基纖維素鈉、明膠、甲基纖維素、羥丙基甲基纖維素、羥丙基纖維素、卡波姆(carbomer)及聚乙烯吡咯啶酮。活性成分亦可以大丸劑、
舐劑或糊膏形式投與。
錠劑可透過將活性成分與視需要之一或多種輔助成分一起壓縮或模製而製成。壓縮錠劑可透過在合適機器中壓縮呈自由流動形式之活性成分(如粉末或顆粒)，視需要藉由黏合劑(如，例如乳糖、葡萄糖、澱粉、明膠、阿拉伯膠、黃蓍膠、藻酸鈉、羧甲基纖維素、甲基纖維素、羥丙基甲基纖維素、聚乙二醇、石蠟或類似者)；潤滑劑(如例如油酸鈉、硬脂酸鈉、硬脂酸鎂、苯甲酸鈉、乙酸鈉、氯化鈉或類似者)；崩解劑(如，例如澱粉、甲基纖維素、瓊脂、膨潤土、交聯羧甲纖維素鈉、澱粉乙醇酸鈉、交聚維酮或類似者)或分散劑(如聚山梨醇酯80)混合而製備。模製錠劑可透過在合適機器中模塑粉末狀活性成分與利用惰性液體稀釋劑潤濕之合適載體之混合物而製成。
用於經直腸投與之調配物可呈栓劑之形式，其中本發明化合物係與低熔點水可溶或不可溶固體(如可可油、氫化植物油、聚乙二醇或聚乙二醇之脂肪酸酯)混合，而酒劑則可利用棕櫚酸肉豆蔻酯製備。
適合經腸外投與之調配物宜包含活性成分之無菌油性或水性製劑，其較佳與接受者之血液等滲，例如等滲鹽水、等滲葡萄糖溶液或緩衝溶液。該調配物可合宜地藉由例如阻菌過濾器過濾、將滅菌劑添加至調配物、輻射調配物或加熱調配物來滅菌。在例如Encyclopedia of Pharmaceutical Technology,vol.9,1994中所揭示之脂質體調配物亦適合經腸外投與。
或者，式(I)化合物可以無菌固體製劑(例如凍乾粉末)形式提供，其可在使用前才溶於無菌溶劑中。
經皮調配物可呈石膏或貼片之形成。
適合經眼投與之調配物可呈活性成分之無菌水性製劑形式，可呈微晶形式，例如，呈水性微晶懸浮液形式。例如，在Encyclopedia of Pharmaceutical Technology,vol.2,1989中所揭示之脂質體調配物或生物可降解聚合物系統亦可用於提供經眼投與之活性成分。
適合經局部或經眼投與之調配物包括液體或半液體製劑，如擦劑、乳液、凝膠、塗劑、水包油或油包水乳化液(如乳霜、軟膏或糊膏)；或溶液或懸浮液，如滴液。用於眼部治療之組成物可較佳額外含有環糊精。
就局部投與而言，式(I)化合物一般可以該組成物之0.01至5重量%，例如該組成物之0.01%至1重量%之量存在。
適合經鼻或經口含投與之調配物包括粉末、自推進及噴撒調配物，如氣霧劑及噴霧。此等調配物更詳細揭示在例如Modern Pharmaceutics,2nd ed.,G.S.Banker and C.T.Rhodes(Eds.)，第427-432頁，Marcel Dekker,New York；Modern Pharmaceutics,3th ed.,G.S.Banker and C.T.Rhodes(Eds.)，第618-619及718-721頁，Marcel Dekker,New York；及Encyclopedia of Pharmaceutical Technology,vol.10,J.Swarbrick and J.C.Boylan(Eds)，第191-221頁，Marcel Dekker,New York中。
除上述成分外，式(I)化合物之調配物可包括一或多種額
外成分，如稀釋劑、緩衝劑、調味劑、著色劑、表面活性劑、增稠劑、防腐劑(例如羥基苯甲酸甲酯)(包括抗氧化劑)、乳化劑及類似者。
醫藥組成物可額外包含習知用於治療皮膚疾病或病況之一或多種其他活性組分，例如，選自由以下組成之群：糖皮質激素、維生素D及維生素D類似物、抗組織胺、血小板活化因子(PAF)拮抗劑、抗膽鹼劑、甲基黃嘌呤、β-腎上腺素激導劑、COX-2抑制劑、水楊酸鹽、吲哚美辛(indomethacin)、氟芬那酸(flufenamate)、萘普生(naproxen)、替美加定(timegadine)、金鹽(gold salts)、青黴胺(penicillamine)、血清膽固醇降低劑、視黃醛、鋅鹽、柳醯偶氮磺胺吡啶(salicylazosulfapyridine)及鈣依賴磷酸酶抑制劑。
本發明之化合物可以熟習合成技藝者熟知之許多方式製備。式(I)化合物可例如利用下文出示之反應及技術，結合合成有機化學技藝中已知之方法，或熟習本項技術者已知之其等變形製備。較佳方法包括，但不限於，下文所描述之彼等方法。反應係於適合所採用之試劑及材料且適用於計劃實施之轉變之溶劑中進行。此外，在下文所描述之合成方法中，應理解所有推薦反應條件，包括溶劑、反應環境、反應溫度、實驗時間及處理製程之選擇，係經選擇為用於彼反應之標準條件，該條件應可由熟習有機合成技藝者輕易知曉。屬於指定類別之所有化合物並非均可與在所
描述之一些方法中所要求的一些反應條件相容。熟習本項技術者將輕易知曉對可與反應條件相容之取代物之限制，且可使用替代方法。
起始材料為已知或市售化合物或可透過熟習本項技術者熟知之常規合成方法製備。
在Waters LCT Premier MS儀器及Waters Aquity UPLC上實施品質檢查。
管柱：Waters Aquity UPLC HSS T3 1.8 μm，2.1×50 mm，在40℃下。
溶劑：A=10 mM乙酸銨+0.1% HCOOH，B=MeCN+0.1% HCOOH。
流速：0.7 ml/分鐘。注射體積2 μl。UV偵測範圍240至400 nm。
藉由OpenLynx摘錄及檢查MW確認及純度。
在400或600 MHz下記錄1H核磁共振(NMR)頻譜。引用在
指定溶劑中相對於內部四甲基矽烷(δ=0.00)或氯仿(δ=7.25)標準之化學位移值(δ，ppm)。除非另外引用範圍，否則出示在接近中點處之經定義(雙重峰(d)、三重峰(t)、四重峰(q))或未經定義(m)之多重峰之值。(bs)指示寬單重峰。所使用之有機溶劑通常係酐。在Merck矽膠60(0.040至0.063 mm)上實施層析。除非另外說明，否則所指出之溶劑比係指體積比。
在全文使用以下縮寫：
Pet. 石油
本發明化合物可例如依照以下非限制性基本方法及實例製備。R係如上文針對式(I)化合物所定義：
羥基胺基甲酸第三丁酯
在0℃下，在15分鐘內將二碳酸二第三丁酯(308 g，1.41 mmol)在二乙醚(600 ml)中之溶液緩慢添加至羥基胺．HCl(150 g，2.17 mol)及K2CO3(150 g，1.09 mol)在二乙醚(940 ml)及水(30 ml)中之攪拌懸浮液。添加完成後，將反應混合物在RT下攪拌2小時。過濾反應混合物及藉由無水Na2SO4乾燥濾液並濃縮。藉由環己烷(50 ml×3)清洗所獲得之粗產物及乾燥以得到標題化合物(150 g，52%，白色固體)。1H NMR(400 MHz，CDCl3)：δ=7.18(br,2H),1.47(s,9H)ppm。
4-硝基苯甲醯氧基胺基甲酸第三丁酯
在0℃下將三乙胺(174 ml，1.24 mol)添加至羥基胺基甲酸第三丁酯(150 g，1.128 mol)在二氯甲烷(2 L)中之攪拌溶液，接著分數個等份添加4-硝基苯甲醯氯(205 g，1.105 mol)。添加完成後，將反應混合物在RT下攪拌1小時。藉由水(500 ml)淬冷反應混合物及萃取。藉由鹽水(200 ml)清洗分離得到之二氯甲烷層，藉由無水Na2SO4乾燥及濃縮。藉由己烷(100 ml×2)清洗所獲得之粗產物及乾燥以得到標
題化合物(300 g，94%，黃色固體)。1H NMR(400 MHz,CDCl3)：δ=8.34-8.27(m,4H),2.97-2.92(m,1H),1.53(s,9H)ppm。
O-(4-硝基苯甲醯基)羥基胺
在0℃下將甲烷磺酸(69 ml，1.06 mol)緩慢添加至4-硝基苯甲醯氧基胺基甲酸第三丁酯(300 g，1.06 mol)在二氯甲烷(2 L)中之攪拌溶液。添加完成後，將反應混合物在RT下攪拌16小時。藉由二氯甲烷(1 L)稀釋反應混合物，藉由10% aq NaHCO3(300 ml)、水(200 ml)、鹽水(200 ml)清洗，藉由無水Na2SO4乾燥及濃縮。藉由己烷(100 ml×2)清洗所獲得之粗產物及乾燥以得到標題化合物(150 g，77%，淺黃色固體)。1H NMR(400 MHz,CDCl3)：δ=8.33-8.30(m,2H),8.22-8.19(m,2H),6.73(brs,2H)ppm。
1-羥甲基-環丙烷甲酸乙酯
在RT下，將三第三丁氧基氫化鋰鋁(38.76 ml，38.76 mmol，1.0 M THF溶液)緩慢添加至環丙烷-1,1-二甲酸二乙酯(2.13 g，11.4 mmol)在THF(80 ml)中之攪拌溶液。添加完成後，將反應混合物在RT下攪拌18小時。藉由乙酸乙酯
(100 ml)稀釋反應混合物，藉由1N aq HCl(20 ml)、水(20 ml)、5% aq.NaHCO3(25 ml)、鹽水(20 ml)清洗反應混合物，藉由無水Na2SO4乾燥，過濾及濃縮以得到標題化合物(1.3 g，79%，黃色油)。1H NMR(400 MHz,CDCl3)：δ=4.20-4.13(m,2H),3.62(m,2H),2.61(m,1H),1.29-1.24(m,5H),0.88-0.85(m,2H)ppm。
1-甲醯基-環丙烷甲酸乙酯
將NaHCO3(2.5 g，29.76 mmol)及戴斯-馬丁高碘烷(Dess-Martin periodinane)(6.46 g，15.23 mmol)添加至1-羥甲基-環丙烷甲酸乙酯(1.1 g，7.63 mmol)在二氯甲烷(45 ml)中之攪拌溶液。隨後將懸浮液在RT下攪拌30分鐘。藉由10% aq.Na2S2O3與10% aq.NaHCO3(20 ml)之1：1溶液淬冷反應混合物，維持溫度低於20℃，攪拌30分鐘。隨後藉由二氯甲烷(100 ml)稀釋反應混合物及萃取。藉由鹽水(30 ml)清洗有機層，藉由無水Na2SO4乾燥，過濾及濃縮。藉由矽膠柱層析(0至10% EtOAc-pet醚作為溶離劑)純化粗產物以得到標題化合物(800 mg，76%，黃色油)。1H NMR(400 MHz,CDCl3)：δ=10.40(s,1H),4.25(m,2H),1.68-1.65(m,2H),1.62-1.59(m,2H),1.33-1.26(m,3H)ppm。
3-甲氧基-吡啶-2-基胺
在par氫化器(H2，40 psi壓力)中，在RT下將3-甲氧基-2-硝基吡啶(30 g，194.8 mmol)及10% Pd/C(10 g)在乙醇(1 L)中之懸浮液氫化4小時。使反應混合物經矽藻土過濾及濃縮濾液以得到標題化合物(22 g，91%，棕色固體)。1H NMR(400 MHz,CDCl3)：δ=7.66(d,J=5.2 Hz；1H),6.91(d,J=7.6 Hz,1H),6.63-6.60(m,1H),4.65(br,2H),3.84(s,3H)ppm。
4-硝基苯甲酸之1,2-二胺基-3-甲氧基-吡啶鎓鹽
在10℃下將O-(4-硝基苯甲醯基)羥基胺(13.2 g，214.2 mmol)添加至3-甲氧基-吡啶-2-基胺(30 g，164.8 mmol)在二氯甲烷(400 ml)中之攪拌溶液。添加完成後，將反應混合物在RT下攪拌16小時。過濾所生成之沉澱物，藉由二氯甲烷(25 ml×2)清洗及乾燥以得到標題化合物(40 g，91%，棕色固體)(注意：該鹽熱不穩定)。1H NMR(400 MHz,DMSO)：δ=8.53(br,2H),8.12(d,J=8 Hz；2H),8.01(d,J=8.8 Hz；2H),7.73(d,J=6.4 Hz；1H),7.33(d,J=7.2 Hz；1H),7.17(br,2H),6.77(t,J=6.8 Hz；1H),3.93(s,3H)
ppm。
1-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-環丙烷甲酸乙酯
在0℃下將DBU(2.1 ml)添加至4-硝基苯甲酸之二胺基-3-甲氧基-吡啶鎓鹽(1 g，7.14 mmol)在乙醇(10 ml)中之攪拌溶液，接著添加1-甲醯基-環丙烷甲酸乙酯(1.5 g，10.71 mmol)。添加完成後，將反應混合物在RT下攪拌2小時。濃縮反應混合物，藉由EtOAc(100 ml)稀釋所獲得之殘餘物，藉由水(20 ml×2)、鹽水(20 ml)清洗，藉由無水Na2SO4乾燥，過濾及濃縮。藉由矽膠柱層析(將0至15% EtOAc-CH2Cl2溶液用作溶離劑)純化粗產物以得到標題化合物(800 mg，53%，白色固體)。1H NMR(400 MHz,CDCl3)：δ=8.18-8.16(d,J=6.4 Hz；1H),6.89(t,J=7.2 Hz,1H),6.76(d,J=8Hz；1H),4.20-4.14(m,2H),4.03(s,3H),1.73-1.70(m,2H),1.59-1.56(m,2H),1.20(t,J=6.8 Hz；3H)ppm。
1-(5-溴-8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-環丙烷甲酸乙酯
在RT下將N-溴琥珀醯亞胺(34 g，191.5 mmol)逐份添加至1-(8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)-環丙烷甲酸乙酯(25 g，95.7 mmol)在乙腈(300 ml)中之攪拌溶液。添加完成後，將反應混合物在RT下攪拌6小時。藉由EtOAc(600 ml)稀釋反應混合物，藉由水(100 ml×2)、鹽水(50 ml)清洗，藉由無水Na2SO4乾燥，過濾及濃縮。藉由矽膠柱層析(將0至10% EtOAc在二氯己烷中之溶液用作溶離劑)純化粗產物以得到標題化合物(25 g，77%，無色固體)。1H NMR(400 MHz,DMSO)：δ=7.44(d,J=8.4 Hz；1H),7.07(d,J=8 Hz；1H),4.13-4.08(m,2H),3.97(s,3H),1.60-1.57(m,2H),1.48-1.45(m,2H),1.13(t,J=7.4 Hz；3H)ppm。
1-(5-溴-8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)環丙烷甲酸
將LiOH之1M水溶液(25 ml)添加至1-(5-溴-8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)環丙烷甲酸乙酯(3.00 g，8.82 mmol)在THF(25 ml)中之溶液。將混合物在80℃下攪拌30分鐘，冷卻至室溫及藉由EtOAc(50 ml)及水(50 ml)稀
釋。藉由0.1M NaOH水溶液(25 ml)萃取有機相及藉由濃HCl將合併之水相酸化至pH0-1，及藉由DCM(30 ml)萃取四次。蒸乾合併之有機相，得到標題化合物(2.54 g，94%)。1H NMR(DMSO,400 MHz)：δ=12.61(s,1H),7.42(d,1H,J=8.3 Hz),7.06(d,1H,J=8.3 Hz),3.97(s,3H),1.53(q,2H,J=3.9 Hz),1.40(q,2H,J=3.9 Hz)ppm。
1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸
將1-(5-溴-8-甲氧基-[1,2,4]三唑并[1,5-a]吡啶-2-基)環丙烷甲酸(1.00 g，3.20 mmol)及5-(4,4,5,5-四甲基-1,3,2-二氧雜硼烷-2-基)-3H-異苯并呋喃-1-酮(硼酸鹽之製備描述在WO2011/134468中)(1.67 g，6.40 mmol)溶於脫氣二噁烷(16 ml)中。將Pd2(dba)3(29 mg，32 μmol)、PCy3(18 mg，64 μmol)及K3PO4(2.38 g，11.2 mmol)混合在脫氣水(10 ml)中。混合兩種溶液及隨後在微波爐中加熱至110℃，維持10分鐘，冷卻至室溫及藉由EtOAc(40 ml)稀釋。藉由水(25 ml)及0.1 M NaOH水溶液(25 ml)萃取有機相及藉由濃HCl將合併之水相酸化至pH0-1，及藉由DCM(30 ml×4)萃取。
蒸發合併之有機相後，結晶出標題化合物(746 mg，64%)。HPLC-滯留時間(XE Metode 7 CM)：1.97分鐘。測得之「M+1」-質量：366.11。計得「M+1」-質量：366.11。1H NMR(DMSO,300 MHz)：δ=8.25-8.20(m,1H),8.13(dd,1H,J=8.2,1.4 Hz),8.00(d,1H,J=8.0 Hz),7.40(d,1H,J=8.2 Hz),7.24(d,1H,J=8.3 Hz),5.51(s,2H),4.04(s,3H),1.58-1.48(m,2H),1.48-1.39(m,2H)ppm。
1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸[(1S)-1-甲基丙基]酯(化合物1)
在密封小瓶中將1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸(10 mg，27 μmol)、(1S)-1-甲基丙醇(10 μL，108 μmol)、DMAP(6.7 mg，54 μmol)及EDCI．HCl(10.5 mg，54 μmol)在DCM(0.5 ml)中之溶液在RT下攪拌過夜，然後添加更多(1S)-1-甲基丙醇(10 μL，108 μmol)及DMAP(6.7 mg，54 μmol)及將混合物加熱至50℃，維持3小時。蒸乾及酸性製備型HPLC純
化得到標題化合物。HPLC-滯留時間(XE Metode 7 CM)：2.35分鐘。測得「M+1」-質量：422.16。計得「M+1」-質量：422.17。1H NMR(DMSO,600 MHz)：δ=8.25-8.21(m,1H),8.14(dd,1H,J=8.0,1.2 Hz),8.01-7.97(m,1H),7.41(d,1H,J=8.2 Hz),7.23(d,1H,J=8.2 Hz),5.51(s,2H),4.78(h,1H,J=6.3 Hz),4.04(s,3H),1.61-1.40(m,6H),1.13(d,3H,J=6.2 Hz),0.78(t,3H,J=7.4 Hz)ppm。
1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸[(1R)-1-甲基丙基]酯(化合物2)
將1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸(400 mg，1.095 mmol)、(2R)-丁-2-醇(122 mg，1.64 mmol)、DMAP(147 mg，1.20 mmol)及EDCI．HCl(231 mg，1.20 mmol)在DCM(10 ml)中之溶液在RT下攪拌過夜，然後蒸乾。柱層析(梯度0至5% MeOH在DCM中之溶液)，接著在EtOH中再結晶及凍乾，得到呈無色粉末形式之標題化合物(138 mg，30%)。HPLC-滯留時間(XE Metode 7 CM)：2.33分
鐘。測得「M+1」-質量：422.15。計得「M+1」-質量：422.17。1H NMR(DMSO,400 MHz)：δ=8.23(br s,1H),8.14(dd,1H,J=8.0,1.6 Hz),7.99(d,1H,J=8.0 Hz),7.41(d,1H,J=8.2 Hz),7.24(d,1H,J=8.2 Hz),5.51(s,2H),4.87(h,1H,J=6.3 Hz),4.04(s,3H),1.62-1.38(m,6H),1.13(d,3H,J=6.3 Hz),0.78(t,3H,J=7.4 Hz)ppm。
1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸[2-甲基丙基]酯(化合物3)
在密封小瓶中將1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸(250 mg，685 μmol)、異丁醇(100 μl，1.37 mmol)、DMAP(250 mg，2.05 mmol)及EDCI．HCl(262 mg，1.37 mmol)在DCM(14 ml)中之混合物在50℃下攪拌2小時，然後藉由DCM(80 ml)稀釋，藉由1M HCl水溶液(40 ml)清洗及蒸乾。將粗混合物再溶於MeCN(~2 ml)中及在添加水(~2 ml)後結晶出粗產物。柱層析(梯度EtOAc 20至100% pet.醚溶液)及隨後在MeCN及水中再結晶，得到呈無色晶體形式之標題化合物(178 mg，62%)。HPLC-滯留時間(XE Metode 7
CM)：2.34分鐘。測得「M+1」-質量：422.16。計得「M+1」-質量：422.17。1H NMR(DMSO,600 MHz)：δ=8.22(br s,1H),8.13(dd,1H,J=8.1 Hz,1.5 Hz),8.00(d,1H,J=8.0 Hz),7.40(d,1H,J=8.2 Hz),7.24(d,1H,J=8.2 Hz),5.51(s,2H),4.04(s,3H),3.84(d,2H,J=6.5 Hz),1.79(m,1H),1.61-1.54(m,2H),1.54-1.46(m,2H),0.78(d,6H,J=6.7 Hz)ppm。
1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸第三丁基酯(化合物4)
將1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸(30 mg，83 μmol)及氯化苄基三乙基銨(19 mg，83 μmol)在DMF(1.0 ml)中之懸浮液溫和加熱直至其變為溶液。添加第三丁基溴(297 μL，2.64 mmol)及K2CO3(171 mg，1.24 mmol)及將混合物在55℃下攪拌三天。額外添加第三丁基溴(139 μL，1.24 mmol)及K2CO3(171 mg，1.24 mmol)及將混合物在55℃下再攪拌一天。製備型HPLC純化得到標題化合物。HPLC-滯留時間(XE Metode 7 CM)：2.29分鐘。測得「M+1」-質
量：422.18。計得「M+1」-質量：422.17。1H NMR(DMSO,300 MHz)：δ=8.27-8.22(m,1H),8.16(dd,1H,J=8.0,1.5 Hz),8.00(d,1H,J=8.2 Hz),7.40(d,1H,J=8.2 Hz),7.22(d,1H,J=8.3 Hz),5.51(s,2H),4.04(s,3H),1.54-1.40(m,4H),1.38(s,9H)ppm。
試驗
PDE4試驗
將人類重組PDE4(Genbank寄存號NM_006203)與濃度高達10 μM之測試化合物、cAMP(1×10-5 M)及少量(0.021 MBq)放射活性標記cAMP一起培養1小時。在培養結束時，透過AMP產物對SPA球(當結合至放射活性示蹤物時產生化學發光)之結合評價基質裂解。AMP產物抑制放射活性示蹤物對球粒之結合，及阻礙發光信號。
將該等結果計算為使基質裂解相較於對照樣品發生50%抑制之莫耳濃度，及表示為IC50範圍(nM)。
在PDE4試驗中測試本發明之化合物。
化合物1、2、3及4均具有小於50 nM之IC50值。
TNF-α釋放
自白血球層單離人類周邊血液單核細胞(PBMC)。將血液與鹽水以1：1之比混合，及利用Lymphoprep tubesTM(Nycomed,Norway)單離PBMC。將PBMC懸浮在含有0.5%人類血清白蛋白、pen/strep及2 mM L-榖胺醯胺之RPMI1640中，達到5×105 c/ml之濃度。將細胞與測試化合物一起在96孔組織培養皿中預培養30分鐘及利用脂多糖1
mg/ml(Sigma)刺激18小時。利用均相時差式螢光共振(TR-FRET)測量上清液中之TNF-α濃度。透過測量在665 nm下之螢光度(與TNF-α濃度成比例)及在620 nm(對照)下之螢光度量化該試驗。將結果表示為IC50值，其係自將LPS刺激孔中之分泌用作正對照及將未經刺激孔中之分泌用作負對照之抑制曲線計得。
在TNF-α釋放試驗中測試本發明之化合物。
化合物1、2、3及4均具有小於50 nM之IC50值。
HLM(人類肝微粒體)試驗
將藉由0.5 μM磷酸鹽緩衝液pH7.4稀釋之測試化合物-DMSO溶液與人類肝微粒體(0.5 mg/ml)一起培養。在培養液中之有機溶劑之百分比為1%。將人類肝微粒體在磷酸鹽緩衝液中之懸浮液與NADPH(1 mM)混合及預熱至37℃，然後添加測試化合物。在0、5、10、20及30分鐘時取出分液，及藉由添加含有分析內標準品(IS)之甲醇終止反應。
將結果表示為表觀清除率(Clapp)(ml/分鐘/kg)及肝提取率(Eh)(%)(自測試化合物消耗速率常量(k)(min-1)計得)。
在HLM試驗中測試本發明之實例。
化合物1、2、3及4均具有大於90%之HLM Eh值。
人類全血(WB)試驗
將藉由1 μM磷酸鹽緩衝液pH 7.4稀釋之測試化合物-DMSO溶液與人類全血一起培養。在培養液中之有機溶劑之百分比為1%。以0、15、30、60及120分鐘時所取之分
液在37℃下實施培養，及藉由添加含分析內標準品(IS)之甲醇終止反應。
將結果表示為半週期(T½)(分鐘)，自測試化合物消耗速率常量(k)(min-1)計得。
在WB試驗中測試本發明之實例。
化合物1、2、3及4均展現小於30分鐘之T½值。
角質細胞穩定性(KC)試驗
將藉由1 μM生長培養基pH~7.4稀釋之測試化合物-DMSO溶液與塗佈人類角質細胞一起培養。在培養液中之有機溶劑之百分比為0.5%。以0、60、120、240及1440分鐘時所取之分液在37℃下實施培養，及藉由添加含分析內標準品(IS)之甲醇終止反應。
將結果表示為半週期(T½)(分鐘)，自測試化合物消耗速率常量(k)(min-1)計得。
在KC試驗中測試本發明之實例。
化合物1、2、3及4均展現大於720分鐘之T½值。
Claims (19)
- 一種如通式(I)之化合物
- 如請求項1之化合物，其立體異構體中之任一者或其立體異構體之任何混合物或其醫藥可接受鹽，其中R係1-甲基丙基、2-甲基丙基或第三丁基。
- 如請求項1之化合物，其係1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸[(1S)-1-甲基丙基]酯游離鹼。
- 如請求項1之化合物，其係1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸[(1R)-1-甲基丙基]酯游離鹼。
- 如請求項1之化合物，其係1-[8-甲氧基-5-(1-氧基-3H-異苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸[2-甲基丙基]酯游離鹼。
- 如請求項1之化合物，其係1-[8-甲氧基-5-(1-氧基-3H-異 苯并呋喃-5-基)-[1,2,4]三唑并[1,5-a]吡啶-2-基]環丙烷甲酸第三丁基酯游離鹼。
- 一種醫藥組成物，其包含如請求項1至6中任一項之化合物與醫藥可接受媒劑或賦形劑或醫藥可接受載劑。
- 如請求項7之醫藥組成物，其進一步包含一或多種其他治療活性化合物。
- 一種如請求項1至6中任一項之化合物之用途，其用於製造醫藥組成物。
- 如請求項9之化合物用途，其用於製造供治療或改善對PDE4抑制活性呈反應性之疾病、病症或病況用之醫藥組成物。
- 如請求項10之用途，其中該疾病、病症或病況係皮膚疾病或病況。
- 如請求項11之用途，其中該疾病、病症或病況係增生性及發炎性皮膚病、皮膚炎、異位性皮膚炎、脂溢性皮膚炎、接觸性皮膚炎、牛皮癬、癌症、上皮發炎、禿頭症、皮膚萎縮、類固醇誘發之皮膚萎縮、皮膚老化、光致皮膚老化、痤瘡、蕁麻疹、瘙癢及濕疹。
- 如請求項1至6中任一項之化合物，其用作藥劑。
- 如請求項13之化合物，其用於治療或改善對PDE4抑制活性呈反應性之疾病、病症或病況。
- 如請求項13之化合物，其用於治療或改善皮膚疾病或病況。
- 如請求項13之化合物，其用於治療增生性及發炎性皮膚 病、皮膚炎、異位性皮膚炎、脂溢性皮膚炎、接觸性皮膚炎、牛皮癬、癌症、上皮發炎、禿頭症、皮膚萎縮、類固醇誘發之皮膚萎縮、皮膚老化、光致皮膚老化、痤瘡、蕁麻疹、瘙癢及濕疹。
- 一種如請求項1至6中任一項之化合物之用途，其用於製造供治療或減輕對PDE4抑制活性呈反應性之疾病或病症或病況用之藥劑。
- 一種如請求項1至6中任一項之化合物之用途，其用於製造供治療或改善皮膚疾病或病況用之藥劑，其中該藥劑視需要包含醫藥可接受載劑或一或多種賦形劑且視需要與其他治療活性化合物組合。
- 如請求項18之用途，其中該皮膚疾病或病況選自由以下組成之群：增生性及發炎性皮膚病、皮膚炎、異位性皮膚炎、脂溢性皮膚炎、接觸性皮膚炎、牛皮癬、癌症、上皮發炎、禿頭症、皮膚萎縮、類固醇誘發之皮膚萎縮、皮膚老化、光致皮膚老化、痤瘡、蕁麻疹、瘙癢及濕疹。
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| WO2013092739A1 (en) | 2013-06-27 |
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| PL2794603T3 (pl) | 2017-08-31 |
| US20150105420A1 (en) | 2015-04-16 |
| JP2015502381A (ja) | 2015-01-22 |
| CN104011048B (zh) | 2017-03-15 |
| CA2858123A1 (en) | 2013-06-27 |
| EP2794603B1 (en) | 2016-06-15 |
| ES2583478T3 (es) | 2016-09-21 |
| US20140329853A1 (en) | 2014-11-06 |
| NZ625849A (en) | 2016-06-24 |
| IL232712A0 (en) | 2014-08-03 |
| BR112014014802A2 (pt) | 2017-06-13 |
| RU2014129514A (ru) | 2016-02-10 |
| SG11201402424PA (en) | 2014-09-26 |
| CN104011048A (zh) | 2014-08-27 |
| US9181248B2 (en) | 2015-11-10 |
| AU2012357106A1 (en) | 2014-06-05 |
| EP2794603A1 (en) | 2014-10-29 |
| JP6138150B2 (ja) | 2017-05-31 |
| ZA201403649B (en) | 2016-05-25 |
| US8940761B2 (en) | 2015-01-27 |
| KR20140105598A (ko) | 2014-09-01 |
| MX2014006812A (es) | 2014-10-13 |
| HK1200815A1 (zh) | 2015-08-14 |
| RU2630699C2 (ru) | 2017-09-12 |
| PT2794603T (pt) | 2016-07-26 |
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