TWI774683B - sGC刺激劑之固體形式 - Google Patents
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Abstract
本發明係關於可溶性鳥苷酸環化酶(soluble guanylate cyclase；sGC)刺激劑(化合物I)之結晶固體形式。本發明亦提供用於製備此等固體形式之方法。本發明亦係關於包含此等固體形式之醫藥調配物及劑型以及其單獨或結合一或多種其他藥劑用於治療及/或預防多種疾病或病症的用途；此等疾病或病症為受益於sGC刺激或氧化氮(NO)及/或環單磷酸鳥苷(cGMP)之濃度增加的疾病或病症。
Description
本發明係關於可溶性鳥苷酸環化酶(sGC)刺激劑之固體形式。本發明亦提供用於製備此等固體形式之方法。本發明亦係關於包含此等固體形式之醫藥調配物及劑型以及其單獨或結合一或多種其他藥劑用於治療及/或預防多種疾病或病症的用途；此等疾病或病症為受益於sGC刺激或氧化氮(NO)及/或環單磷酸鳥苷(cGMP)之濃度增加的疾病或病症。
sGC為活體內NO之初級受體。sGC可經由NO依賴性機制及NO非依賴性機制兩者活化。為回應此活化，sGC會將鳥苷-5'-三磷酸酯(GTP)轉化成第二信使cGMP。cGMP之含量增加反過來調節包括蛋白激酶、磷酸二酯酶(PDE)及離子通道之下游效應子的活性。
在體內，NO係由精胺酸及氧氣利用多種氧化氮合成酶(NOS)酶類及利用無機硝酸鹽之連續還原而合成。已鑑別NOS之三種不同的同功異型物：發現於經活化巨噬細胞中之誘導性NOS(iNOS或NOS II)；涉及神經傳遞及長期增益之組成性神經元NOS(nNOS或NOS I)；以及調節平滑肌鬆弛及血壓之組成性內皮NOS(eNOS或NOS III)。實驗及臨床跡象顯示，NO之濃度或生物可用性減小及/或對內源性產生之NO的反應性減弱會促成疾病發展。
NO非依賴性、血紅素依賴性之sGC刺激劑在與sGC活化劑相比時，已展示若干重要的區分特徵，包括針對其活性對於減小輔助血紅素部分的存在的關鍵依賴性、當與NO組合時較強的協同酶活化，及由不依賴於NO、sGC之直接刺激對cGMP之合成的刺激。苯甲基吲唑化合物YC-1是第一個經鑑別之sGC刺激劑。因此已研發具有改良之效能及針對sGC之特異性的其他sGC刺激劑。
以NO非依賴性方式刺激sGC之化合物提供優於靶向異常NO路徑之其他現用替代性治療劑的可觀優勢。有需要研發新穎性的良好表徵之sGC刺激劑。化合物I為sGC刺激劑，在臨床前模型中已證實可有效治療多種NO相關病症。化合物I先前在WO2014144100(實例1)中描述為淺橙色固體。化合物I可以多種結晶形式存在且亦可形成若干醫藥學上可接受之鹽。
與固體作為藥物之功效相關的其特性可視固體之形式而定。舉例而言，在藥物物質中，固體形式之變體會導致諸如以下特性差異：溶解度及溶解速率、表面特性(例如，可濕性)、粉末特性(流動、內聚力、體密度、混合行為、可壓縮性、靜態等)、錠劑特性(硬度、均質性、易脆性、崩解、熱及濕度之穩定性等)、口服吸收、生物可用性、儲存特性(結塊、吸濕性)、毒理學結果及臨床試驗結果。
多晶型物之特徵適用於避免在臨床試驗及/或藥物之商業化期間產生某些問題，例如以避免藥物物質與產品之不一致性(例如，批次與批次之不一致)、水合物之水合作用或脫水作用、化學分解、藥物產品中之非晶化或多晶型轉換。若多晶型物相比於化合物之另一多晶型物或其非晶形式改良溶解度及/或生物可用性，則其亦可為較佳的。由於其賦予增大的物理或化學穩定性，其提供較高的熔點(產生改良之機械特性)，其具有更多
可接受之口味或氣味、或更中性的pH等等，所以其亦可為較佳的。
在一個態樣中，本發明係關於下文所描繪之化合物I之結晶固體形式：
出於本發明之目的，除非另外特別說明，否則「化合物I」係指游離鹼或指上文所指代之結構的鹽酸鹽。呈其結晶游離鹼形式之化合物I為高度多晶型且已知具有七種結晶形式(形式A、形式B、形式D、形式E、形式F、形式G及形式H)以及多種溶劑合物。化合物I先前在WO2014144100(實例1)中描述為淺橙色固體。
在一個實施例中，此處所揭示之化合物I之結晶固體形式為游離鹼之多晶型物。在另一實施例中，化合物I之結晶固體形式為鹽酸鹽。在一個實施例中，化合物I之多晶型物為結晶游離鹼形式。在另一實施例中，其為溶劑合物。
在另一態樣中，本文亦提供用於製備化合物I之上文所描述之結晶游離形式及鹽的方法。
在另一態樣中，本發明係關於包含本文所揭示之化合物I之多晶型物、或化合物I之鹽酸鹽中之一或多者，及至少一種醫藥學上可接受之賦形劑或載劑之醫藥組合物。在另一實施例中，本發明係關於包含該等醫藥
組合物之醫藥劑型。
在另一實施例中，本發明係關於一種治療有需要個體之疾病、健康狀況或病症的方法，該方法包含單獨或結合療法向個體投與治療有效量之本文所揭示之化合物I之多晶型物，或其多晶型物之混合物或其鹽酸鹽；其中該疾病或病症為受益於sGC刺激或NO及/或cGMP之濃度增加的疾病或病症。
圖1：展示化合物I非晶形形式之XRPD圖案。
圖2：展示在5至45之2θ刻度範圍中之形式A、形式B、形式D及形式E之(自底部至頂部，按比例調整，具有偏移)疊置XRPD圖案。
圖3A：展示在5至45之2θ刻度範圍中之形式A之XRPD圖案。
圖3B：展示形式A在儲存之前及儲存14個月之後的XRPD圖案。
圖3C：展示在3至40之2θ刻度範圍中之形式A之XRPD圖案。
圖4A：展示在5至45之2θ刻度範圍中形式B之XRPD圖案。
圖4B：展示形式B在儲存之前及儲存14個月之後之XRPD圖案。
圖4C：展示在3至40之2θ刻度範圍中之形式B之XRPD圖案。
圖5A：展示在5至45之2θ刻度範圍中之形式D之XRPD圖案。
圖5B：展示形式D在儲存之前及儲存14個月之後之XRPD圖案。
圖5C：展示在3至40之2θ刻度範圍中之形式D之XRPD圖案。
圖6：展示在5至45之2θ刻度範圍中形式E之XRPD圖案。
圖7：展示在3至40之2θ刻度範圍中之形式F之XRPD圖案。
圖8：展示在3至40之2θ刻度範圍中之形式G之XRPD圖案。
圖9：展示在3至40之2θ刻度範圍中之形式H之XRPD圖案。
圖10：展示在自1800cm-1至200cm-1之波數範圍中的形式A、形式B、形式D及形式E之(自底部至頂部，按比例調整，具有偏移)疊置FT-拉曼光譜(FT-Raman spectra)。
圖11：展示在0至40之2θ刻度範圍中之化合物I之HCl鹽的XRPD圖案。
圖12：展示在粗化合物I、多晶型物形式A、形式B、形式D、形式E、形式F、形式G及形式H之間的關係。
該等圖以實例方式提供且不意欲限制本發明之範疇。
現將詳細參考本發明之某些實施例，其實例在隨附結構及式中說明。雖然本發明將結合所列舉之實施例描述，但應瞭解其不意欲將本發明限於彼等實施例。確切而言，本發明意欲涵蓋可包括於如申請專利範圍所界定之本發明之範疇內之所有替代方案、修改及等效物。本發明不限於本文所描述之方法及材料但包括類似或等效於可用於本發明之實踐的本文所描述之彼等的任何方法及材料。在所併入之參考文獻、專利及類似材料中之一或多者不同於本申請案(包括(但不限於)所定義之術語、術語用法、所描述之技術或其類似物)或與其矛盾之情況下，以本申請案為準。
定義及一般術語
出於本發明之目的，根據元素週期表，CAS版及Handbook of Chemistry and Physics，第75版，1994來鑑別化學元素。此外，有機化學之一般原理描述於「Organic Chemistry」,Thomas Sorrell,University Science Books,Sausalito：1999及「March's Advanced Organic Chemistry」，第5版，Smith,M.B.及March,J.編，John Wiley & Sons,
New York：2001，其全部內容以引用之方式併入本文中。
本發明亦包括經同位素標記之化合物，其等同於本文所述之彼等物質，但實際上一或多個原子經具有與通常在自然界中發現之原子質量或質量數不同之原子質量或質量數的原子置換。如所指定之任何特定原子或元素之所有同位素皆涵蓋於本發明之化合物之範疇及其用途內。可併入至本發明之化合物中之例示性同位素包括氫、碳、氮、氧、磷、硫、氟、氯及碘之同位素，分別諸如2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、32P、33P、35S、18F、36Cl、123I及125I。本發明之某些經同位素標記之化合物(例如，經3H或14C標記之彼等化合物)適用於化合物及/或受質組織分佈分析。氚化(亦即，3H)及碳-14(亦即，14C)同位素因其易於製備及可檢測性而適用。另外，經較重同位素(諸如氘(亦即，2H))取代可提供由較大代謝穩定性產生之某些治療優勢(例如，活體內半衰期增加或劑量要求減小)且因此可在某些情況下為較佳的。諸如15O、13N、11C及18F之正電子發射同位素適用於正電子發射斷層攝影法(PET)研究以檢查受質受體佔有率。本發明之經同位素標記化合物一般可藉由遵循與下文流程及/或實例中所揭示之彼等類似的程序，藉由用經同位素標記之試劑取代未經同位素標記之試劑來製備。
如本文所使用，化合物I之「固體形式」特徵在於或係指該化合物之特定固相晶格結構(在單位晶胞級下)。
諸如化合物I之化合物可以其「純形式」或「游離鹼形式」存在，且該游離鹼形式可為結晶形或非晶形。化合物之游離鹼形式僅由該化合物之分子形成。
如本文所使用，「非晶形」或「非晶形式」為長程分子無序之固體形
式，因此，其不具有獨特的X射線粉末繞射圖案(XRPD)。
「晶體」或「結晶形式」為由原子、離子或分子之重複三維圖案形成之均相固體，其在組成成分之間具有固定的距離。術語「晶體」亦可用於指定此圖案之單位晶胞。
如本文所使用「結晶」為導致由溶液、熔融劑、蒸氣、不同的固相形成固體晶體或更罕見地由氣體直接沈積的過程。結晶可為自然或人造過程。結晶亦為一種化學的固液分離技術，其中發生自液體溶液至純固體結晶相之溶質的質量傳遞。
如本文所使用，「多形現象」為化合物(例如，化合物I)以超過一種結晶形式存在，或以不同晶體結構結晶的能力。「多晶型物」為化合物(例如，化合物I)之不同晶體結構中之各者。多晶型物為化合物之自由形式(亦即，結晶自由形式)或其溶劑合物(亦即，「多組分結晶形式」)的晶體結構，其中該化合物(例如，化合物I)與溶劑結晶。在一些實施例中，當結晶之溶劑為水時，溶劑合物為水合物。
如本文所使用，「溶劑合物」係指一或多種溶劑分子(在室溫下為液體之物質的分子)與呈結晶形式之化合物(例如，化合物I)的結合物或錯合物，從而產生新特徵的結晶固體。本發明描述化合物I之游離鹼形式之若干「非溶劑合物」(亦即，為結晶自由形式且不為溶劑合物之化合物I之固體形式)。
存在可形成的其他類型之固體形式。舉例而言，當呈多組分結晶形式之兩種化合物將在室溫下存在時獨立地為固體時，所得固體形式稱為「共晶體」。
當呈固體形式之組分中之一者已清晰地將質子傳遞至其他組分，且
多組分結晶形式之所得組分為離子時，所得固體形式稱為「鹽」。
在共晶體中，在固體形式之不同組分之間不進行離子傳遞，使得所得組分以非離子形式存在。在共晶體中，多組分結晶形式之兩種(或更多種)組分為固體且在室溫下彼此獨立地存在的非離子。
在混合兩種物質時係形成鹽抑或共晶體將由該兩種組分之pKa之間的差值為多大來決定。
本發明描述為鹽(鹽酸鹽)之化合物I之一種固體形式。
存在使得熟習此項技術者獲得結晶材料之多種可用結晶技術。對於溶液發生結晶，該溶液必須「過飽和」。此意謂，溶液必須含有比其在熱力學平衡條件(「飽和溶液」)下將含有的更多的經溶解之溶質實體(分子或離子)。此可利用多種方法來達成，例如：1)「冷卻結晶」；2)添加第二溶劑以減小溶質之溶解度(稱為「反溶劑結晶」之技術)；3)化學反應；4)pH改變；以及5)有機及/或水性溶劑系統中的漿液轉化，該等方法為工業實踐中使用的最常見方法。亦可使用其他方法，諸如「溶劑蒸發結晶」。如本文所使用，「過飽和」為溶液之濃度(C)與在相同溫度下處於平衡之濃度(C*)之間的差值。其以濃度單位量測。
表徵化合物I之固體形式(例如，多晶型物或鹽)之術語「化學上穩定」指示，當其在經歷指定條件(例如，40℃/75%相對濕度)持續特定時間段(例如1天、2天、3天、1週、2週、1個月、2個月、3個月、6個月、12個月、18個月、24個月或更長)時並不分解成一或多種新的不同的化合物。在一些實施例中，小於25%之化合物I之多晶型物分解；在一些實施例中，小於20%、小於15%、小於10%、小於5%、小於3%、小於1%或小於0.5%之化合物I之多晶型物在指定條件下分解。在一些實施例中，無可
偵測量之化合物I之既定多晶型物在指定條件下某一時間段之後分解(如藉由所使用之分析技術之最低偵測極限所測定)。
表徵化合物I之結晶固體形式(例如，多晶型物或鹽)之術語「物理上穩定」意謂，結晶固體形式不改變成化合物I之一或多種不同的結晶固體形式(例如，多晶型物改變成化合物I之不同多晶型物，如利用分析技術(諸如XRPD等)所量測)或當其經歷特定條件(例如，40℃/75%相對濕度)持續特定時間段(例如，1天、2天、3天、1週、2週、1個月、2個月、3個月、6個月、12個月、18個月、24個月或更長)時改變成非晶形式。在一些實施例中，小於25%之化合物I之結晶固體形式在經歷指定條件時改變成一或多種不同的固體形式(另一結晶固體形式或非晶形式)。在一些實施例中，小於20%、小於15%、小於10%、小於5%、小於3%、小於1%，或小於0.5%之化合物I之結晶固體形式在經歷指定條件時改變成化合物I之一或多種不同的結晶固體或非晶形式。在一些實施例中，無可偵測量之化合物I之既定固體形式在指定條件下改變成化合物I之一或多種不同的固體形式。
術語「大體上純」在指代化合物I之指定結晶固體形式(例如，本文所描述之化合物I之多晶型物或鹽)時意謂，該指定結晶固體形式含有小於20%(按重量計)之殘餘組分(諸如化合物I之替代性多晶型物，或非晶形形式或其他溶劑分子或雜質)。在其他實施例中，化合物I之大體上純結晶固體含有小於10%(按重量計)之化合物I之替代性多晶型物，或非晶形形式或其他溶劑分子或雜質。在其他實施例中，其含有小於5%(按重量計)之化合物I之替代性多晶型物，或非晶形形式或其他溶劑分子或雜質。在另其他實施例中，其含有小於1%(按重量計)之化合物I之替代性多晶型物、
或非晶形形式或其他溶劑分子或雜質。
如本文所使用之術語「大體上類似」在指代化合物I之指定固體形式(例如，本文所描述之化合物I之多晶型物或鹽)之光譜、跡線、熱量曲線等特徵時，意謂光譜、跡線、熱量曲線等係指含有少於10%之峰，該等峰不同於如本說明書中之圖式所展示及正論述之化合物I之特定固體形式指配之光譜、跡線或曲線的峰。在其他實施例中，其含有少於5%的不同的峰。在另其他實施例中，其含有少於1%的不同的峰。
當比較XRPD光譜時，光譜將「大體上類似」於針對化合物I之特定固體形式在本發明中所展示之一者，其中該光譜中之特徵峰在本發明之圖式中所展示之彼等相同的°2θ值，或在來自該圖式中所展示之彼等峰之°2θ+0.5單位或-0.5單位的範圍內量測。若該固體形式之XRPD在該某些條件下在該某一時間長度前後「大體上類似」，則將認為化合物I之固體形式之XRPD在某些條件下在某一時間長度之後「基本上不變」。
本發明通常係關於評估本文所揭示之化學、物理或生物參數。熟習此項技術者將理解，此類參數可由其他化學、物理或生物參數取代，儘管該等參數未揭示於本文中，但在鑑別固體形式方面基本上類似。
在一個態樣中，本發明係關於下文所描繪之化合物I之結晶固體形式：
化合物I。
化合物I為在臨床前模型中已證實治療多種NO相關病症之功效的sGC刺激劑。化合物I可以多種晶體形式或多晶型物存在。此等多晶型物中之一些為結晶游離鹼形式。其他為溶劑合物。在一些實施例中，溶劑合物為水合物。化合物I亦可形成若干醫藥學上可接受之鹽，包括其鹽酸鹽。
在一個實施例中，本文所揭示之化合物I之固體形式為多晶型物。在另一實施例中，化合物I之固體形式為其鹽酸鹽。化合物I至少以七種純多晶型物或結晶自由形式存在：形式A、形式B、形式D、形式E、形式F、形式G及形式H。化合物I先前在WO2014144100(實例1)中描述為淺橙色固體。
在一個實施例中，化合物I之結晶固體形式為多晶型物形式E。當如實例部分中所描述製備之粗化合物I在>60℃(例如，>70℃)下溶解於MeOH中以獲得溶液，接著過濾，在>60℃下加熱濾液，添加水且冷卻至室溫(rt)，接著過濾且在80℃下在真空下乾燥超過72小時時，形成形式E。
在另一實施例中，化合物I之結晶固體形式為多晶型物形式A。當化合物I在>70℃下溶解於乙酸乙酯中以獲得溶液，接著過濾，在20℃至25℃下額外攪拌濾液超過16小時以得到漿液，在真空下濃縮該漿液，添加庚烷，進一步濃縮所得漿液，過濾且在100℃下在真空下乾燥超過3小時時，形成形式A。
在另一實施例中，當多晶型物形式E在>70℃下溶解於乙酸乙酯中以獲得溶液，接著過濾，在20℃至25℃下額外攪拌濾液超過16小時以得到漿液，在真空下濃縮該漿液，添加庚烷，進一步濃縮所得漿液，過濾且在
100℃下在真空下乾燥超過3小時時，形成多晶型物形式A。
在另一實施例中，可由粗化合物I藉由在高於60℃下在DMSO中加熱，接著添加水以形成漿液且過濾該漿液來直接獲得多晶型物形式A。
在另一實施例中，當粗化合物I在室溫下在溶劑中漿化且允許攪拌14小時至30小時時，亦分離出多晶型物形式A。在一些實施例中，溶劑係選自庚烷、乙酸異丙酯(IPAC)、乙醇、乙酸乙酯或癸烷或其混合物。隨後過濾漿液且在真空下乾燥。
在另一實施例中，化合物I之固體形式為多晶型物形式D。當如上文所描述製備之形式E與正癸烷在145℃至155℃下混合45分鐘以獲得漿液，接著歷經1小時將該漿液冷卻至20℃至30℃，過濾且在80℃下在真空下乾燥超過72小時時，形成形式D。
在另一實施例中，形式D可藉由在180℃下加熱純的(在無溶劑存在下)多晶型物形式(形式E、形式B、形式F、形式G或形式H)中之任一者或其混合物來形成。
在另一實施例中，化合物I之固體形式為多晶型物形式B。當如實例部分中所描述製備之粗化合物I與乙腈在70℃至75℃下混合以形成溶液，接著過濾，在70℃至75℃下額外加熱濾液，添加水，冷卻至52℃至62℃以形成漿液，歷經超過4小時將該漿液冷卻至0℃至5℃，過濾且在90℃至100℃下在真空下乾燥超過最小30小時時，形成形式B。
在另一實施例中，化合物I之固體形式為多晶型物形式F。當如實例章節中所描述，在160℃下加熱純的形式A時，可獲得形式F。
在另一實施例中，化合物I之固體形式為多晶型物形式G。當如實例部分中所描述製備之粗化合物I在環境溫度下在丙酮中漿化2小時，接著過
濾且在30℃至40℃下在真空下乾燥時，獲得形式G。在另一實施例中，當多晶型物形式H在rt(室溫)下在丙酮中攪拌，接著過濾且在30℃至40℃下在真空下乾燥時，獲得多晶型物形式G。
在另一實施例中，化合物I之固體形式為多晶型物形式H。當如實例部分中所描述製備之粗化合物I與丙酮在45℃至50℃下混合以形成溶液，接著過濾，冷卻至室溫以形成漿液，隨後在室溫下攪拌5小時，接著過濾且在30℃至40℃下在真空下乾燥時，獲得形式H。
在一個態樣中，化合物I之固體形式為多晶型物形式A。
在一些實施例中，形式A特徵在於FT-拉曼光譜大體上類似於圖10中所展示之FT-拉曼光譜。
在一些實施例中，形式A特性在於其IR光譜在1730cm-1處呈現頻帶最大值。
在一些實施例中，形式A特徵在於XRPD光譜大體上類似於圖2或圖3A中所展示之XRPD光譜。
在其他實施例中，形式A特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：6.0、18.3、19.3、20.2及22.0。
在其他實施例中，形式A之特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：6.0、8.5、9.5、12.4至12.9、13.4、17.1、18.3、19.3、20.2、22.0、30.1及34.1。
在其他實施例中，形式A特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：6.0、6.7、8.5、9.5、10.9、12.4至12.9、13.4、16.2、17.1、18.3、19.3、20.2、22.0、23.0、24.1至24.8、25.8、30.1及34.1。
在一些實施例中，形式A特徵在於XRPD光譜大體上類似於圖3C中所
展示之XRPD光譜。
在其他實施例中，形式A特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：6.1(80.81%相對強度(relative intensity或rel int))、18.4(53.57%)、19.4(100.00%)、20.3(57.01%)及22.0(56.64%)。
在其他實施例中，形式A特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：6.1(80.81%相對強度)、9.6(40.35%)、12.6(41.26%)、13.6(43.19%)、18.4(53.57%)、19.4(100.00%)、20.3(57.01%)及22.0(56.64%)。
在其他實施例中，形式A特徵在於當其在40℃及75%相對濕度之穩定條件下儲存14個月時顯示基本上不變的XRPD跡線。形式A在彼等條件下儲存前後之XRPD跡線展示於圖3B中。
在一個態樣中，化合物I之固體形式為多晶型物形式B。
在一些實施例中，形式B特徵在於FT-拉曼光譜大體上類似於圖10中所展示之FT-拉曼光譜。
在一些實施例中，形式B特性在於其IR光譜在1200cm-1處呈現峰最大值。
在一些實施例中，形式B特徵在於XRPD光譜大體上類似於圖2或圖4A中所展示之XRPD光譜。
在其他實施例中，形式B特徵在於XRPD光譜中之以下°2θ之一或多個峰：18.8至19.1。
在另一實施例中，形式B特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：8.8、16.4、17.2、18.8至19.1、20.1及21.1至21.6。
在另一實施例中，形式B特徵在於選自XRPD光譜中之以下°2θ之一
或多個峰：8.8、10.6、12.6至13.0、14.6、16.4、17.2、18.8至19.1、20.1、21.1至21.6、24.5、25.3、27.0至27.5、28.9、29.8及30.5。
在一些實施例中，形式B特徵在於XRPD光譜大體上類似於圖4C中所展示之XRPD光譜。
在其他實施例中，形式B特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：8.9(76.55%相對強度)、17.4(57.67%)、19.1(100.00%)及25.5(52.26%)。
在其他實施例中，形式B特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：7.0(44.44%相對強度)、8.9(76.55%)、17.4(57.67%)、19.1(100.00%)、20.3(49.78%)、21.8(36.16%)及25.5(52.26%)。
在其他實施例中，形式B特徵在於當其在40℃及75%相對濕度之穩定條件下儲存14個月時顯示基本上不變的XRPD跡線。形式B在彼等條件下儲存前後之XRPD跡線展示於圖4B中。
在一個態樣中，化合物I之固體形式為多晶型物形式D。
在一些實施例中，形式D特徵在於FT-拉曼光譜大體上類似於圖10中所展示之FT-拉曼光譜。
在一些實施例中，形式D特徵在於其IR光譜在1665cm-1、1639cm-1及968cm-1處呈現頻帶最大值。在一些實施例中，形式D特徵在於其IR光譜在1665cm-1處呈現頻帶最大值。在其他實施例中，形式D特徵在於其IR光譜在1639cm-1處呈現頻帶最大值。在其他實施例中，形式D特徵在於其IR光譜在968cm-1處呈現頻帶最大值。
在一些實施例中，形式D特徵在於XRPD光譜大體上類似於圖2或圖5A中所展示之XRPD光譜。
在其他實施例中，形式D特徵在於當其在40℃及75%相對濕度之穩定條件下儲存14個月時顯示基本上不變的XRPD跡線。形式D在彼等條件下儲存前後之XRPD跡線展示於圖5B中。
在其他實施例中，形式D特徵在於XRPD光譜中之18.8 °2θ處之峰。
在另一實施例中，形式D特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：17.1、18.1、18.8及25.0。
在另一實施例中，形式D特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：8.8、17.1、18.1、18.8及25.0。
在一些實施例中，形式D特徵在於XRPD光譜大體上類似於圖5C中所展示之XRPD光譜。
在其他實施例中，形式D特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：4.7(97.11%相對強度)、18.1(80.97%)、18.6(100.00%)及26.8(65.25%)。
在其他實施例中，形式D之特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：4.7(97.11%相對強度)、8.3(64.04%)、18.1(80.97%)、18.6(100.00%)及26.8(65.25%)。
在一個態樣中，化合物I之固體形式為多晶型物形式E。
在一些實施例中，形式E特徵在於FT-拉曼光譜大體上類似於圖10中所展示之FT-拉曼光譜。
在一些實施例中，形式E特徵在於其IR光譜在1690cm-1及1515cm-1處呈現頻帶最大值。在一些實施例中，形式E特徵在於其IR光譜在1690cm-1處呈現峰最大值。在一些實施例中，形式E特徵在於其IR光譜在1515cm-1處呈現峰最大值。
在一些實施例中，形式E特徵在於XRPD光譜大體上類似於圖2或圖6中所展示之XRPD光譜。
在其他實施例中，形式E特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：7.4、18.8至19.3、21.1、24.8及25.5。
在其他實施例中，形式E特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：7.4、13.9、15.1、16.3、17.6、18.8至19.3、21.1、22.3至22.5、24.8、25.5及27.1。
在一個態樣中，化合物I之固體形式為多晶型物形式F。
在一些實施例中，形式F特徵在於XRPD光譜大體上類似於圖7中所展示之XRPD光譜。
在其他實施例中，形式F特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：5.3(100.00%相對強度)、8.6(58.80%)及16.4(62.95%)。
在其他實施例中，形式F特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：5.3(100.00%相對強度)、8.6(58.80%)、16.4(62.95%)及19.0(48.51%)。
在一個態樣中，化合物I之固體形式為多晶型物形式G。
在一些實施例中，形式G特徵在於XRPD光譜大體上類似於圖8中所展示之XRPD光譜。
在其他實施例中，形式G特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：10.7(55.47%相對強度)及18.33(100.00%)。
在另一實施例中，形式G特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：10.7(55.47%相對強度)、13.9(42.47%)、18.33(100.00% %)及21.6(40.73%)。
在一個態樣中，化合物I之固體形式為多晶型物形式H。
在一些實施例中，形式H特徵在於XRPD光譜大體上類似於圖9中所展示之XRPD光譜。
在其他實施例中，形式H特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：5.77(89.22%相對強度)、6.39(100.00% %)、9.1(84.17%)及18.5(67.04%)。
在其他實施例中，形式H特徵在於選自XRPD光譜中之以下°2θ之一或多個峰：5.77(89.22%相對強度)、6.39(100.00% %)、9.1(84.17%)、18.5(67.04%)及18.83(67.04%)。
本發明之醫藥學上可接受之鹽。
如本文所使用之片語「醫藥學上可接受之鹽」係指化合物I之醫藥學上可接受之有機鹽或無機鹽。化合物I之醫藥學上可接受之鹽可用於藥物中。然而，不為醫藥學上可接受之鹽類可在製備化合物I之其他固體形式時適用作中間物。
醫藥學上可接受之鹽包括充當相對離子之另一原子或分子的包含物。相對離子可為使母體化合物上之電荷穩定的任何有機或無機部分。此外，醫藥學上可接受之鹽的結構中可具有超過一個帶電原子。其中多個帶電原子為醫藥學上可接受之鹽的一部分的情況可具有多個相對離子。在一些情況下，相對離子可為相同的。在其他情況下，對於各帶電原子，其可不同。因此，醫藥學上可接受之鹽可具有一或多個帶電原子及/或一或多個相對離子。
本文所描述之醫藥學上可接受之鹽及其他典型的醫藥學上可接受之鹽之製備更全面地描述於Berg等人之「Pharmaceutical Salts」，J.Pharm.
Sci.,1977：66：1-19中，其以全文引用之方式併入本文。
在一個實施例中，化合物I之醫藥學上可接受之鹽為化合物I之鹽酸鹽。
化合物I之鹽酸鹽可藉由將呈如上文所描述製備之其多晶型物形式D的化合物I懸浮於1M HCl中，使其與異PrOH混合，以40℃/h之加熱速率及5℃/h之冷卻速率在20℃與40℃之間循壞的溫度下攪拌來製備。
化合物I之鹽酸鹽特徵在於256℃之熔點。
化合物I之鹽酸鹽特徵在於在pH 1.4下的0.5mg/mL之水溶解度。在飽和溶液之pH下測定水溶解度。在25℃下將鹽於水中震盪24小時。在過濾之後，在1.4之pH下利用HPLC測定濃度為0.5mg/mL。
化合物I之鹽酸鹽特徵在於XRPD圖案大體上類似於圖11中所展示之XRPD圖案。
醫藥組合物及投與方法。
本文所揭示之結晶固體形式可調配為醫藥組合物或「調配物」。
典型調配物係藉由將化合物I之結晶固體形式與載劑、稀釋劑或賦形劑混合製備。適合載劑、稀釋劑及賦形劑為熟習此項技術者所熟知，且包括諸如碳水化合物、蠟、水溶性及/或膨脹性聚合物、親水性或疏水性物質、明膠、油、溶劑、水及其類似物之物質。所使用之特定載劑、稀釋劑或賦形劑將視化合物I之多晶型物或醫藥學上可接受之鹽經調配之方法及目的而定。溶劑一般基於熟習此項技術者認識之安全(GRAS-公認安全)投與哺乳動物之溶劑來選擇。一般而言，安全溶劑為無毒水性溶劑，諸如水及可溶於水或可混溶於水之其他無毒溶劑。適合的水性溶劑包括水、乙醇、丙二醇、聚乙二醇(例如，PEG400、PEG300)等，及其混合物。調配
物亦可包括其他類型之賦形劑，諸如一或多種緩衝液、穩定劑、抗黏劑、界面活性劑、潤濕劑、潤滑劑、乳化劑、黏合劑、懸浮劑、崩解劑、填充劑、吸附劑、包衣(例如，腸溶性或緩慢釋放)防腐劑、抗氧化劑、避光劑、滑動劑、加工助劑、著色劑、甜味劑、芳香劑、調味劑及其他已知添加劑，以提供藥物之優美呈現或有助於製造醫藥產品(亦即，藥物)。
調配物可使用習知溶解及混合程序製備。舉例而言，在存在上文所描述之賦形劑中之一或多者的情況下，將原料藥物物質(亦即，化合物I之多晶型物或醫藥學上可接受之鹽)溶解於適合溶劑中。具有所需純度之化合物視情況與呈凍乾調配物形式、經研磨之粉末或水性溶液形式之醫藥學上可接受之稀釋劑、載劑、賦形劑或穩定劑混合。調配物可藉由在環境溫度下在適當pH下及在所需純度下，與生理學上可接受之載劑混合來實施。調配物之pH主要視化合物之特定用途及濃度而定，但可在約3至約8之範圍內。當本文所描述之調配物為利用溶劑處理所形成之固體非晶形分散液時，添加劑可在形成混合物時直接添加至噴霧乾燥溶液，諸如添加劑溶解或懸浮於溶液中作為漿液，該漿液可隨後經噴霧乾燥。替代地，添加劑可在噴霧乾燥處理之後添加以有助於形成最終調配產物。
化合物I之多晶型物或醫藥學上可接受之鹽通常調配成醫藥劑型以提供可容易控制劑量之藥物且使患者能夠順應處方療法。可製備用於多種途徑及投與類型的化合物I之多晶型物或醫藥學上可接受之鹽之醫藥調配物。相同化合物可存在多種劑型，此係由於不同醫學病況可保證不同的投與途徑。
可結合載劑材料產生單一劑型之活性成分之量將視所治療之個體及特定投與模式而變化。舉例而言，欲用於向人類經口投與之時間釋放調配
物可含有與適當且適宜量之載劑材料複合之約1mg至1000mg活性材料，該載劑材料之量可在總組合物之約5%至約95%(重量：重量)範圍內變化。可製備醫藥組合物以提供可易於量測之投與量。舉例而言，欲用於靜脈內輸注之水溶液每毫升溶液可含有約3μg至500μg活性成分，以便可在約30mL/hr之速率下進行適合體積之輸注。作為一般建議，所投與之抑制劑的每劑量之初始醫藥學上有效量將在約0.01mg/kg至100mg/kg範圍內，亦即每天約0.1mg/kg至20mg/kg患者體重範圍內，其中所用化合物之典型初始範圍為0.3毫克/公斤/天至15毫克/公斤/天。
如本文所使用之術語「治療有效量」意謂，在組織、系統、動物或人類中引起研究人員、獸醫、醫生或其他臨床醫師所尋求之生物或藥物反應之活性化合物或醫藥劑的量。待投與之化合物之治療上或醫藥學上之有效量將利用此類考慮因子來控制，且為改善、治癒或治療疾病或病症或其症狀中之一或多者所必需的最小量。
化合物I之多晶型物或醫藥學上可接受之鹽之醫藥組合物將以以下方式調配、給藥及投與：符合良好醫學實踐之亦即，量、濃度、時程、療程、媒劑及投與途徑。在此上下文中考慮之因子包括被治療之特定病症、被治療之特定哺乳動物、個別患者之臨床病況、病症之病因、藥劑之傳送部位、投與方法、投與時程，及醫學從業者已知之其他因子，諸如個別患者之年齡、體重及反應。
術語「預防有效量」係指在罹患疾病或病症之前預防或大體上減少罹患疾病或病症之可能性或有效地減輕疾病或病症之嚴重程度的量，或在症狀發展之前有效地降低其症狀中之一或多者之嚴重度中的量。粗略地，在初級預防(預防疾病之發展)與二級預防(其中疾病已經發展且保護患者
以免此過程惡化)之間劃分預防性措施。
可接受之稀釋劑、載劑、賦形劑及穩定劑為在所採用之劑量及濃度下對接受者無毒性之彼等，且包括緩衝液，諸如磷酸鹽、檸檬酸鹽及其他有機酸；抗氧化劑，包括抗壞血酸及甲硫胺酸；防腐劑(諸如十八烷基二甲基苯甲基氯化銨、氯化六羥季銨、苯紮氯銨、苄索氯銨、酚、丁基醇或苯甲醇、諸如對羥苯甲酸甲酯或對羥基苯甲酸丙酯之烷基對羥苯甲酸酯、兒茶酚(catechol)、間苯二酚(resorcinol)、環己醇、3-戊醇及間甲酚)；蛋白質，諸如血清白蛋白、明膠或免疫球蛋白；親水性聚合物，諸如聚乙烯吡咯啶酮；胺基酸，諸如甘胺酸、麩醯胺酸、天冬醯胺、組胺酸、精胺酸或離胺酸；單糖、雙糖及其他碳水化合物，包括葡萄糖、甘露糖或糊精；螯合劑，諸如EDTA；糖，諸如蔗糖、甘露醇、海藻糖或山梨醇；成鹽相對離子，諸如鈉；金屬錯合物(例如，鋅-蛋白質錯合物)；及/或非離子型界面活性劑，諸如TWEENTM、PLURONICSTM或聚乙二醇(PEG)。活性醫藥成分亦可包覆在例如利用凝聚技術或利用界面聚合製備之微膠囊中，分別例如羥基甲基纖維素或明膠-微膠囊及聚-(丙烯酸甲甲酯)微膠囊；在膠狀藥物傳送系統(例如，脂質體、白蛋白微粒、微乳劑、奈米顆粒及奈米膠囊)中或在巨乳液中。此類技術揭示於Remington's：The Science and Practice of Pharmacy，第21版，University of the Sciences in Philadelphia編，2005(下文簡稱為「Remington's」)中。
關於本發明之固體形式、組合物或調配物之術語「投與(administer/administering或administration)」意謂將化合物引入至需要治療之動物之系統中。當以與一或多種其他活性劑之組合提供本發明之化合物時，「投與」及其變體各自理解為包括同時及/或依序引入化合物及其他
活性劑。
本文所描述之組合物可視被治療之疾病之嚴重度及類型而定全身性或局部投與，例如經口(例如，使用膠囊、粉劑、溶液、懸浮液、錠劑、舌下錠劑及類似者)、利用吸入(例如，用霧劑、氣體、吸入劑、霧化器或其類似物)、至耳(例如，使用滴耳劑)、經表皮(例如，使用乳膏、凝膠劑、擦劑、乳液、軟膏、糊劑、經皮貼片等)、經眼(例如，用滴眼劑、經眼凝膠劑、經眼軟膏)、經直腸(例如，使用灌腸劑或栓劑)、經鼻、經頰、經陰道(例如，使用灌洗器、子宮內器件、經陰道栓劑、陰道環或錠劑等)、經由植入式貯器或其類似物，或非經腸。
如本文所使用之術語「非經腸」包括(但不限於)皮下、靜脈內、肌肉內、關節內、滑液內、胸骨內、鞘內、肝內、病灶內及顱內注射或輸注技術。較佳地，組合物經口、腹膜內或靜脈內投與。
本文所描述之醫藥組合物可以任何經口可接受之劑型經口投與，該劑型包括(但不限於)膠囊、錠劑、水性懸浮液或溶液。用於經口投與之液體劑型包括(但不限於)醫藥學上可接受之乳液、微乳液、溶液、懸浮液、糖漿及酏劑。除活性化合物以外，液體劑型可含有此項技術中常用之惰性稀釋劑，諸如水或其他溶劑；增溶劑及乳化劑，諸如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、二甲基甲醯胺、油(尤其棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油及芝麻油)、甘油、四氫糠醇、聚乙二醇及脫水山梨糖醇之脂肪酸酯，及其混合物。除惰性稀釋劑以外，經口組合物亦可包括佐劑，諸如濕潤劑、乳化劑及懸浮劑、甜味劑、調味劑及芳香劑。
用於經口投與之固體劑型包括膠囊劑、錠劑、丸劑、粉劑及粒劑。
在此類固體劑型中，活性化合物與以下混合：至少一種惰性、醫藥學上可接受之賦形劑或載劑，諸如檸檬酸鈉或磷酸二鈣及/或a)填充劑或展劑，諸如澱粉、乳糖、蔗糖、葡萄糖、甘露醇及矽酸；b)黏合劑，諸如羧基甲基纖維素、褐藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖及阿拉伯膠；c)保濕劑，諸如甘油；d)崩解劑，諸如瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、褐藻酸、某些矽酸鹽及碳酸鈉；e)溶液阻滯劑，諸如烷烴；f)吸附加速劑，諸如四級銨化合物；g)潤濕劑，諸如十六基醇及甘油單硬脂酸酯；h)吸附劑，諸如高嶺土及膨潤土；以及i)潤滑劑，諸如滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、月桂基硫酸鈉；及其混合物。錠劑可未包覆包衣，或可利用包括微囊封裝之已知技術被包衣以掩蔽不適味道或延緩在胃腸道中之崩解及吸收且進而在更長時段內提供持續作用。舉例而言，可單獨或伴以蠟使用諸如單硬脂酸甘油酯或二硬脂酸甘油酯之時間延遲材料。可使用諸如羥丙基-甲基纖維素或羥丙基-纖維素之水溶性味覺掩蔽材料。
適用於經口投與的化合物I之多晶型物或化合物I之醫藥學上可接受之鹽之調配物可製備為離散單元，諸如錠劑、丸劑、糖衣錠、口含錠、水性或油性懸浮液、分散性粉劑或顆粒劑、乳化液、硬膠囊或軟膠囊(例如，明膠膠囊)、糖漿劑或酏劑。意欲用於經口使用的化合物之調配物可根據此項技術已知用於製備醫藥組合物之任何方法來製備。
用於經口使用之調配物亦可以硬明膠膠囊形式呈現，其中活性成分與惰性固體稀釋劑(例如碳酸鈣、磷酸鈣或高嶺土)混合；或以軟明膠膠囊形式呈現，其中活性成分與水水溶性載劑(諸如聚乙二醇或油狀介質，例如花生油、液體石蠟或橄欖油)混合。
活性固體形式亦可呈具有如上文所示之一或多種賦形劑之微膠囊化
形式。
當需要水性懸浮液用於經口使用時，使活性成分與乳化劑及懸浮劑組合。若需要，亦可添加某些甜味劑及/或調味劑。糖漿及酏劑可用例如甘油、丙二醇、山梨糖醇或蔗糖之甜味劑來調配。此類調配物亦可含有緩和劑、防腐劑、調味劑及著色劑以及抗氧化劑。
本文所描述之組合物之無菌可注射形式(例如，用於非經腸投與)可為水性或油性懸浮液。此等懸浮液可根據此項技術中已知之技術使用適合分散劑或濕潤劑及懸浮劑來調配。無菌可注射製劑亦可為於無毒性非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液或懸浮液，例如於1,3-丁二醇或PEG400中之溶液。在可接受之媒劑及溶劑中，可採用的為水、林格氏溶液(Ringer's solution)及等張氯化鈉溶液。此外，無菌不揮發性油習知地用作溶劑或懸浮介質。出於此目的，可使用任何溫和的不揮發性油，包括合成單甘油酯或二甘油酯。脂肪酸(諸如油酸及其甘油酯衍生物)適用於製備可注射劑，天然醫藥學上可接受之油(諸如橄欖油或蓖麻油，尤其其聚氧乙烯化形式)亦然。此等油溶液或懸浮液亦可含有長鏈醇稀釋劑或分散劑，諸如羧甲基纖維素或通常用於調配醫藥學上可接受之劑型(包括乳液及懸浮液)之類似分散劑。其他常用界面活性劑(諸如Tween、Span及其他乳化劑)或常用於製造醫藥學上可接受之固體、液體或其他劑型之生物可用性增進劑亦可用於可注射調配物之目的。
油性懸浮液可藉由將化合物I之多晶型物或其醫藥學上可接受之鹽懸浮於植物油(例如花生油、橄欖油、芝麻油或椰子油)中，或於礦物油(諸如液體石蠟)中來調配。油性懸浮液可含有增稠劑，例如蜂蠟、硬石蠟或鯨蠟醇。可添加甜味劑(諸如上述彼等甜味劑)及調味劑，以提供適口之經
口製劑。此等組合物可藉由添加抗氧化劑(諸如丁基化羥基大茴香醚或α-生育酚)來保存。
化合物I之多晶型物或化合物I之醫藥學上可接受之鹽之水性懸浮液含有與適用於製備水性懸浮液之賦形劑摻合的活性材料。此類賦形劑包括懸浮劑，諸如羧基甲基纖維素鈉、交聯羧甲纖維素、普維酮(povidone)、甲基纖維素、羥基丙基甲基纖維素、褐藻酸鈉、聚乙烯吡咯啶酮、膠狀黃蓍及阿拉伯膠；及分散劑或濕潤劑，諸如天然存在之磷脂(例如卵磷脂)、環氧烷與脂肪酸之縮合產物(例如聚氧乙烯硬脂酸酯)、環氧乙烷與長鏈脂族醇之縮合產物(例如十七伸乙氧基鯨蠟醇)、環氧乙烷與衍生自脂肪酸之偏酯及己糖醇酐之縮合產物(例如聚氧乙烯脫水山梨糖醇單油酸酯)。水性懸浮液亦可含有一或多種防腐劑，諸如對羥基苯甲酸乙酯或對羥基苯甲酸正丙酯；一或多種著色劑；一或多種調味劑及一或多種甜味劑，諸如蔗糖或糖精。
可例如藉由經由細菌保留過濾器過濾或藉由併入在使用之前可溶解或分散於無菌水或其他無菌可注射介質中之呈無菌固體組合物形式之滅菌劑來將可注射調配物滅菌。
可注射溶液或微乳劑可藉由局部快速注射引入至患者之血流中。替代地，以維持即溶化合物之恆定循環濃度的此方式投與溶液或微乳劑可為有利的。為維持此恆定濃度，可利用連續靜脈內傳送器件。此器件之實例為Deltec CADD-PLUSTM模型5400靜脈內泵。
用於經直腸或經陰道投與之組合物較佳為栓劑，其可藉由將本文所描述之固體形式與在環境溫度下為固體，但在體溫下為液體且因此在直腸或陰道腔中融化並釋放活性化合物之適合非刺激性賦形劑或載劑(諸如可
可脂、蜂蠟、聚乙二醇或栓劑蠟)混合來製備。適用於經陰道投與之其他調配物可呈現為子宮托、棉塞、乳膏、凝膠劑、糊劑、泡沫劑或噴霧劑。
本文所描述之醫藥組合物亦可表皮投與，尤其當治療標靶包括藉由表皮塗覆可容易達至之區域或器官時，該治療標靶包括眼、耳、皮膚或低位腸道之疾病。容易製備適合表皮調配物用於此等區域或器官中之各者。
用於經表皮或經皮投與本文所描述之化合物之劑型包括軟膏、糊劑、乳膏、洗劑、凝膠、粉劑、溶液、噴霧劑、吸入劑或貼片。活性組分在無菌條件下與醫藥學上可接受之載劑及如可為所需之任何所需防腐劑或緩衝劑摻合。亦預期眼用調配物、滴耳劑及滴眼劑屬於本發明之範疇內。另外，本發明預期使用經皮貼片，其具有向身體提供控制傳送化合物之附加優點。可藉由將化合物溶解或分配於適當介質中來製造此類劑型。亦可使用吸收增強劑來增加化合物通過皮膚之通量。速率可藉由提供速率控制膜或藉由將化合物分散於聚合物基質或凝膠中來控制。用於低位腸道之局部施用可以經直腸栓劑調配物(參見上文)形式或以適合的灌腸調配物形式實現。亦可使用局部經皮貼片。
為了經表皮塗覆，醫藥組合物可以含有懸浮或溶解於一或多種載劑中之活性組分之適合軟膏形式調配。用於經表皮投與本發明之固體形式的載劑包括(但不限於)礦物油、液體礦脂、白礦脂、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蠟及水。替代地，醫藥組合物可以含有懸浮或溶解於一或多種醫藥學上可接受之載劑中之活性組分之適合洗劑或乳膏形式調配。適合載劑包括(但不限於)礦物油、脫水山梨糖醇單硬脂酸酯、聚山梨醇酯60、十六酯蠟、十六醇十八醇、2-辛基十二醇、苯甲醇及水。
為了眼用用途，醫藥組合物可經調配為於等張pH值調節無菌生理食
鹽水中之微米尺寸化懸浮液，或較佳為於等張pH值調節無菌生理食鹽水中之溶液，其具有抑或不具有防腐劑(諸如氯苄烷銨)。替代地，為了眼用用途，醫藥組合物可以軟膏(諸如礦脂)形式調配。對於治療眼睛或其他外部組織(例如口部及皮膚)，調配物可以含有例如0.075% w/w至20% w/w之量之活性成分的表皮軟膏或乳膏形式塗覆。當調配成軟膏時，活性成分可與油基、石蠟或水可混溶性軟膏基質一起使用。
替代地，活性成分可與水包油乳膏基質一起調配成乳膏。必要時，乳膏基質之水相可包括多元醇，亦即具有兩個或更多個羥基之醇，諸如丙二醇、1,3-丁二醇、甘露糖醇、山梨糖醇、甘油及聚乙二醇(包括PEG 400)及其混合物。表面調配物可宜包括提高活性成分經由皮膚或其他受影響區域吸收或滲透之化合物。此類經皮穿透增強劑之實例包括二甲亞碸及相關類似物。
使用化合物I之多晶型物或化合物I之醫藥學上可接受之鹽製備之乳化液的油相可由已知成分以已知方式組成。儘管該相可僅包含乳化劑(或稱為利泄劑)，但其宜包含至少一種乳化劑與脂肪或油或與脂肪及油之混合物。親水性乳化劑可與充當穩定劑之親脂性乳化劑一起包括在內。在一些實施例中，乳化劑包括油及脂肪兩者。在存在或不存在穩定劑下，乳化劑一起構成所謂的乳化蠟，且蠟與油及脂肪一起構成所謂的乳化軟膏基質，其形成乳膏調配物之油性分散相。適用於化合物I之多晶型物或化合物I之醫藥學上可接受之鹽之調配物中的利泄劑及乳液穩定劑包括TweenTM-60、SpanTM-80、鯨蠟硬脂醇、苯甲醇、肉豆蔻基醇、單硬脂酸甘油酯及月桂基硫酸鈉。
醫藥組合物亦可藉由經鼻氣霧劑或藉由吸入投與。此類組合物係根
據醫藥調配技術中熟知之技術製備，且可採用苯甲醇或其他適合防腐劑、增強生物可用性之吸收促進劑、碳氟化合物及/或其他習知溶解劑或分散劑製備為於生理食鹽水中之溶液。適於肺內或經鼻投與之調配物具有粒徑例如在0.1微米至500微米範圍內(包括0.1微米至500微米範圍內諸如0.5微米、1微米、30微米、35微米等之增量微米數之粒徑)，其藉由經鼻腔快速吸入或藉由經口吸入從而到達肺泡小囊來投與。
可視所使用之藥物投與方法而定，以多種方式封裝供使用之醫藥組合物(或調配物)。一般而言，供分配用之物品包括其中存放有適當形式之醫藥調配物之容器。適合之容器為熟習此項技術者所熟知且包括諸如瓶子(塑膠及玻璃)、藥囊、安瓿、塑膠袋、金屬筒及其類似物之材料。容器亦可包括防干擾裝配以防止輕易獲取封裝之內含物。另外，容器上附有描述容器內含物之標籤。標籤亦可包括適當警告。
調配物可封裝於單位劑量或多劑量容器(例如密封安瓿及小瓶)中，且可儲存在經冷凍乾燥(凍乾)之條件下，其僅需要在臨使用之前添加無菌液體載劑(例如水)以供注射。由上文所描述種類之無菌粉劑、顆粒及錠劑製備即用型注射溶液及懸浮液。較佳單位劑量調配物為含有如上文中所述之日劑量或單位每日子劑量或其適當部分之活性成分的彼等。
在另一態樣中，化合物I之多晶型物或化合物I之醫藥學上可接受之鹽可調配在包含獸醫載劑之獸醫組合物中。獸醫載劑為適用於投與組合物之目的的材料且可為另外為惰性的或在獸醫領域中可接受且與活性成分相容的固體、液體或氣體材料。此等獸醫學組合物可以非經腸、經口或利用任何其他適宜途徑投與。
在另一態樣中，本發明係關於藉由在有需要之患者中單獨或組合使用本文所揭示之化合物I之結晶固體形式或包含其之醫藥組合物治療某些疾病。
本發明係關於化合物I之結晶固體形式及其醫藥調配物以及其單獨或結合一或多種額外藥劑用於治療及/或預防多種疾病之用途，其中NO濃度增加或cGMP濃度增加為合乎需要的。
在組織中之NO產量增加或cGMP濃度增加引起血管擴張、抑制血小板凝集及黏著、抗高血壓效果、抗重塑效果、抗纖維化、抗細胞凋亡效果、抗炎效果及神經元信號傳輸效果，以及其他效果。
在其他實施例中，本文所揭示之化合物I之結晶固體形式適用於預防及/或治療特徵在於生物系統(例如，在人體中)之NO的生物可用性及/或靈敏性不合需要的減小的疾病及病症，諸如與氧化應力或硝化應力之病況相關之彼等疾病及病症。
如本文所使用之術語「心血管疾病」(或「心血管病症」)係指基於諸如心臟、血管(動脈、毛細管及靜脈)或兩者之循環器官的異常症狀的疾病。該術語亦包括影響心血管系統之任何疾病，一般包括心臟疾病、大腦血管疾病、腎、肝及相關器官或肺之血管疾病，及周邊動脈疾病，以及其他。
「sGC相關之心血管疾病」為已知或懷疑涉及NO/sGC/cGMP系統的疾病且為可藉由sGC活化/刺激、藉由NO合成酶之活化，或藉由添加NO或NO供體或NO前驅物(諸如L-精胺酸或L-瓜胺酸)，或藉由抑制負責分解cGMP之PDE(磷酸二酯酶)酶，或結合以上方法中之任一者來治療或預防之心血管疾病。
如本文所使用之術語「血管擴張」係指血管之擴寬。其由血管壁內(尤其大靜脈、大動脈及較小動脈中之)之平滑肌細胞的鬆弛引起。本質上，該過程與使血管變窄之「血管收縮」相反。當血管擴張時，血流歸因於血管阻力減小而增大。因此，動脈血管(主要小動脈)之擴大減小血壓。反應可為固有的(歸因於周圍組織中之局部過程)或非固有的(歸因於激素或神經系統)。此外，反應對於特定器官可為局部的(當在費力運動期間，視特定組織之代謝需求而定)，或其可為全身性的(在整個全身循環中可見)。
如本文所使用之術語「血管收縮」係指歸因於肌肉收縮的血管變窄。血管收縮為身體調節且保持平均動脈壓(MAP)所利用之一種機制。廣義的血管收縮通常引起全身性血壓增加，但其亦可在特定組織中發生，從而致使血流局部減小。
如本文所使用，術語「支氣管收縮」用於定義歸因於周圍平滑肌之收緊，以及隨之而來的咳嗽、喘鳴及呼吸短促所引起的肺中之氣道的收縮。病況具有多個原因，最常見為哮喘。運動及過敏反應可在另外的無症狀個體中引起症狀。諸如慢性阻塞性肺病(COPD)之其他病況亦可呈現伴隨支氣管收縮。
貫穿本發明，術語「高血壓(hypertension)」、「動脈高血壓」或「高血壓(HBP)」可互換地使用且係指極其常見及高度可預防的慢性病況，其中動脈中之血壓(BP)高於正常或所需要的血壓。若未恰當地控制，則其代表若干嚴重的心血管及腎病況之顯著風險因子。高血壓可為原發性疾病，稱作「原發性高血壓」或「特發性高血壓」，或其可由其他疾病造成或與其他疾病相關，在此情況下將其歸類為「繼發性高血壓」。原發性高血壓
佔全部案例之90%至95%。
如本文所使用，術語「耐藥性高血壓」係指儘管同時使用屬於不同抗高血壓藥物類之三種抗高血壓劑，仍高於目標血壓(通常小於140/90mmHg，但對於伴隨共存糖尿病或腎病之患者而言，建議小於130/80mmHg之較低目標)之高血壓。需要四種或更多種藥物以控制其血壓之人亦視為患有耐藥性高血壓。高血壓為一種極其常見的糖尿病中的共存病況，其視肥胖、種族及年齡而定影響約20%至60%之患有糖尿病之患者。此類型之高血壓在本文稱作「糖尿病性高血壓」。在2型糖尿病中，高血壓通常呈現為胰島素抗性代謝症候群之部分，另外包括中心型肥胖及血脂異常。在1型糖尿病中，高血壓可反映糖尿病腎病變之發病。
如本文所使用之「肺高血壓(PH)」為特徵在於肺脈管(肺動脈、肺靜脈及肺毛細管)中之血壓持續升高的疾病，其引起右心肥大，最終導致右心衰竭及死亡。PH之常見症狀包括呼吸短促、眩暈及昏厥，其皆因運動加重。在不治療之情況下，診斷之後的中值預期壽命為2.8年。PH以多種不同形式存在，其根據其病因分類。類別包括肺動脈高血壓(PAH)、伴隨左側心臟病之PH、與肺病及/或低血氧相關之PH、歸因於慢性血栓性及/或栓塞疾病之PH及雜項PH。PAH在一般人群中為罕見的，但結合某些常見病況(諸如HIV感染、硬皮病及鐮刀型紅血球疾病)發病率增加。其他形式之PH一般比PAH更常見，且例如，特別關注PH與慢性阻塞性肺病(COPD)之結合。用於肺高血壓之當前治療視疾病之階段及機制而定。
術語「冠狀動脈疾病」係指供應至心臟肌肉之血液部分或完全地被阻塞(心臟肌肉或心肌之缺血)的病況。供應至心肌之血液減少會引起多種「急性心肌症候群」：胸痛(「絞痛」，亦稱作「心絞痛」，穩定型或不穩定
型)及不同類型之心臟病發作(「心肌梗塞」或MI)。冠狀動脈疾病之一個常見病因為「動脈粥樣硬化」，其係指動脈之硬化，此係歸因於脂肪沈積於動脈壁中，隨後漸進成經由動脈粥樣硬化斑之形成，而縮窄且最終阻塞血液流動至動脈。動脈粥樣硬化之此過程不僅影響心臟之彼等，同樣可影響其他動脈。血凝塊為動脈堵塞之最常見病因，通常動脈歸因於動脈粥樣硬化斑(動脈粥樣化)已經部分堵塞；動脈粥樣化會斷裂或撕裂，從而導致形成凝塊。間或，冠狀動脈疾病係由冠狀動脈之痙攣造成的，其可自發地發生或作為使用某些藥物(例如，可卡因、菸鹼)之結果。罕見地，冠狀動脈疾病之病因為先天缺陷、病毒感染(例如，川崎病(Kawasaki disease))、全身性紅斑性狼瘡症(狼瘡)、動脈炎症(動脈炎)、自心室行進至冠狀動脈中之一者的血凝塊或物理損傷(例如，來自受傷或放射治療)。
如本文所使用之「不穩定型心絞痛」係指包括延長或惡化心絞痛及新發作嚴重症狀的心絞痛症狀模式之改變。
MI(心肌梗塞)可歸類為兩種類型：「非ST段升高」MI及「ST段升高」MI。急性冠狀動脈症候群之併發症視多少冠狀動脈經堵塞、冠狀動脈經堵塞多長，及冠狀動脈經堵塞的地方而定。若堵塞影響大量心臟肌肉，則心臟將不能有效地泵送。若堵塞關閉至心臟之電力系統的血流，則心律可受到影響。當產生心臟病發作時，部分心肌死亡。死亡組織及代替其之瘢痕組織並不收縮。當心臟之剩餘部分嘗試收縮時，瘢痕組織有時甚至擴展或凸起。因此，存在較少肌肉泵送血液。若足夠的肌肉死亡，則心臟之泵送能力可因此減小，使得心臟不能滿足人體對於氧氣及血液之需求。隨後發展心臟衰竭、低血壓或兩者。若超過一半之心肌經損壞或死亡，則心臟一般不具有功能，且嚴重的殘疾或死亡係有可能的。
如本文所使用之「心臟衰竭」(HF)為在複雜臨床症候群中到達頂峰的左心室(LV)心肌重塑之進行性病症，其中減弱的心臟功能及循環充血為定義特徵，且導致血液及營養物質不充足的傳送至身體組織。當心臟受損或過度勞累且不能將自全身循環返回至其之全部血液泵送出時，發生病況。由於較少血液被泵送出，所以返回至心臟之血液退回且流體在身體之其他部分中積累。心臟衰竭亦損害腎分配鈉及水之能力，從而使流體保留進一步複雜化。心臟衰竭特徵在於自主功能障礙、神經激素活化及過度產生造成進行性循環衰竭之細胞介素。心臟衰竭之症狀包括：在運動或休息及在夜間醒來時歸因於突然氣喘(兩者均指示肺水腫)之呼吸困難(呼吸短促)；一般疲勞或虛弱；腳、腳踝及腿之水腫；體重快速增加；或慢性咳嗽，包括產生黏液或血液。視其臨床表現而定，心臟衰竭歸類為新生的、短暫的、急性的、急性後的或慢性的。急性心臟衰竭(亦即需要緊急治療之症狀的快速或漸進性發作)可發展成新生的或作為變為代償失調之慢性心臟衰竭的結果。術語「心臟衰竭」通常用於意謂「慢性心臟衰竭」。術語「充血性心臟衰竭(congestive heart failure(CHF)或congestive cardiac failure(CCF))」通常可與慢性心臟衰竭互換使用。心臟衰竭之常見原因包括包括以下之冠狀動脈疾病：陳舊性心肌梗塞(心臟病發作)、高血壓、心房顫動、心臟瓣膜病及心肌病。此等藉由改變心臟之結構或功能造成心臟衰竭。
存在兩種主要類型之心臟衰竭：「歸因於射血分數減小之心臟衰竭(HFREF)」，亦稱作「歸因於左心室收縮功能障礙之心臟衰竭」或「收縮性心臟衰竭」；及「伴隨保存射血分數之心臟衰竭(HFPEF)」，亦稱作「舒張性心臟衰竭」或「伴隨正常射血分數之心臟衰竭(HFNEF)」。射血分數
為在單次收縮期間自心臟泵送出之心臟中之血液的比例。其為百分比，其中正常的在50%與75%之間。
術語「急性」(如同「急性HF」)用於意謂快速發作，且「慢性」係指較長持續時間。慢性心臟衰竭為通常伴隨穩定的經治療症候學之長期情形。「急性代償失調」心臟衰竭為惡化或代償失調的心臟衰竭，涉及其中個人之特徵可為心臟衰竭跡象及症狀變化引起需要緊急治療或住院的事件。心臟衰竭亦可在高輸出之情形中出現(因而其被稱為「高輸出心臟衰竭」)，其中心室收縮功能正常但心臟不能處理重要的血量增強。
在心臟血管生理學中，術語「射血分數(EF)」定義為隨著每一次心跳或心臟循環泵送出之左側及右側心室中之血液分數。在醫學成像允許之有限數學中，EF應用於經由肺瓣噴射血液至肺循環中之右側心室或經由主動脈瓣噴射血液至大腦及全身性循環中之左側心室兩者。
術語「伴隨保存射血分數之心臟衰竭(HFPEF)」通常理解為係指具有大於55%之射血分數的心臟衰竭之跡象及症狀的表現。其特徵在於左心室順應性減小，從而導致左側心室中之壓力增大。由於左心室功能較差，所以在HFPEF之情況下通常看到左心房尺寸增大。充血性心臟衰竭、心房顫動及肺高血壓之風險增大。風險因子為高血壓、高脂質血症、糖尿病、抽菸及阻塞性睡眠呼吸暫停。在此類型之心臟衰竭中，心臟肌肉收縮良好但心室在鬆弛期並未良好填充有血液。
術語「伴隨射血分數減小之心臟衰竭(HFREF)」係指射血分數小於40%之心臟衰竭。
糖尿病為患有心臟衰竭之患者中的常見共病且與較差的結果以及潛在地損害治療功效相關。其他重要共病包括全身性高血壓、慢性氣流阻
塞、睡眠呼吸暫停、認識功能障礙、貧血症、慢性腎病及關節炎。慢性左側心臟衰竭常常與肺高血壓之發展相關。某些共病之出現率因性別而變化：在女性中，高血壓及甲狀腺疾病更常見，而男性更常患有慢性阻塞性肺病(COPD)、周邊血管疾病、冠狀動脈疾病及腎機能不全。抑鬱症為心臟衰竭之常見共病且兩個病況均可且通常使彼此複雜化。惡病體質長期被視為心臟衰竭之嚴重的且常見的併發症，影響高達15%的全部心臟衰竭患者且與較差預後相關。心臟惡病體質定義為在歷經六個月之時段，非水腫、非自發損失至少6%的體重。
如本文所使用之術語「心律不齊」，係指在超過90%的已患有心臟病發作之人類中發生之不正常心臟節律。有時，問題為觸發心跳之心臟的部分且心跳速率可能太慢；其他時間，問題可造成心臟跳動過快或跳動不規則地。有時，跳動之信號並不自心臟之一部分傳導至另一部分且心跳可能減慢或停止。此外，未死亡但具有較差血流之心肌區域可能易受刺激。此造成心律問題，諸如心室心動過速或心室性顫動。若心臟完全停止泵送，則此可導致心跳驟停。
「心包」為環繞心臟之袋或膜。「心包炎」或此膜之炎症可作為心臟病發作之結果發展且可導致發熱、心包積液、覆蓋肺(胸膜)之膜的炎症、肋膜積液及關節痛。在心臟病發作之後的其他併發症可包括二尖瓣膜功能障礙、心臟肌肉斷裂、心室壁凸出(心室動脈瘤)、血液凝塊及低血壓。
術語「心肌病」係指心臟腔室之肌肉壁之結構及功能的進行性障礙。主要類型之心肌病為擴張的、肥大的及限定性的。心肌病通常造成心臟衰竭之症狀，且其亦可造成胸痛、昏厥及猝死。
術語「二尖瓣回流(mitral valve regurgitation/mitral
regurgitation)」、「二尖瓣機能不全」或「二尖瓣關閉不全」係指心臟之二尖瓣不緊密地閉合，從而允許血液在心臟中回流的情形。因此，血液不能有效地穿過心臟或身體之剩餘部分，從而導致疲勞或呼吸短促。
術語「睡眠呼吸暫停」係指最常見的睡眠呼吸障礙症。其為特徵在於氣流之間歇性週期性減少或完全停止的病況，其可或可不涉及上呼吸道阻塞。存在三種類型之睡眠呼吸暫停：阻塞性睡眠呼吸暫停(最常見形式)、中樞性睡眠呼吸暫停及混合性睡眠呼吸暫停。
「中樞性睡眠呼吸暫停(CSA)」由大腦之正常呼吸信號的不正常造成，而非呼吸道之物理堵塞造成。呼吸努力的缺乏導致血液中之二氧化碳增加，此可喚醒患者。CSA在一般群體中為罕見的，但在患有收縮性心臟衰竭之患者中為相對常見的事件。
如本文所使用，術語「代謝症候群」、「胰島素抗性症候群」或「症候群X」係指一組或一集群之代謝病況(腹部肥胖、空腹葡萄糖升高、「血脂異常」(亦即，脂質水準升高)及血壓升高(HBP))，其一起發生比單獨偶然發生更常見且一起促使出現2型糖尿病及心血管疾病。代謝症候群特徵在於三酸甘油酯增大、高密度脂蛋白膽固醇(HDL-膽固醇)減少及在一些情況下低密度脂蛋白膽固醇(LDL-膽固醇)水準適度地升高的特定脂質特徵以及歸因於成分風險因子之壓力的「動脈粥樣硬化疾病」之進展加速。存在若干類型之血脂異常：「高膽固醇血症」係指膽固醇水準升高。家族性高膽固醇血症為歸因於染色體19(19p13.1-13.3)上之缺陷的一種特定形式之高膽固醇血症。「高甘油酯血症」係指甘油酯水準升高(例如，「高三酸甘油酯血症」涉及三酸甘油酯水準升高)。「高脂蛋白血症」係指脂蛋白水準升高(除非另外說明，否則通常為LDL)。
術語「脂肪變性」係指脂質在細胞內之異常保留。其通常反映合成及消除三酸甘油酯之正常過程的障礙。過量脂肪積聚在移置細胞之細胞質的囊泡中。在嚴重情況中，細胞可爆裂。通常在肝中觀測到脂肪變性，因為肝為與脂肪代謝最主要相關之器官。亦可在心臟、腎及肌肉組織中觀測到脂肪變性。
如本文所使用，通常亦稱作「周邊動脈疾病(PAD)」或「周邊動脈閉塞疾病(PAOD)」之術語「周邊血管疾病(PVD)」係指不在冠狀動脈、主動脈弧脈管或大腦內之大動脈阻塞。PVD可由動脈粥樣硬化、發炎過程產生，從而導致狹窄、栓塞、血栓形成或其他類型之閉塞。其造成急性或慢性「缺血(血液供應缺乏)」。通常PVD為用以指代在下肢中發現之動脈粥樣硬化堵塞的術語。PVD亦包括歸類為由動脈之間歇性變窄(例如，「雷諾氏現象(Raynaud's phenomenon)」)或其擴寬(紅斑性肢痛)(亦即，血管痙攣)所引起之微血管疾病的一子集之疾病。周邊動脈疾病包括閉塞血栓性脈管炎、周邊動脈閉塞疾病、雷諾氏疾病及雷諾氏症候群。常見症狀為腿冷或腳冷、間歇性跛行、下肢痛及嚴重肢體缺血(下肢潰瘍及壞死)。周邊動脈疾病之診斷及治療準則可見於Eur.J.Vasco Endovasc.Surg,2007,33(1),Sl中。
如本文所使用之術語「狹窄」係指血管或其他管狀器官或結構異常變窄。其有時亦稱作「狹窄(stricture)」(如同尿道狹窄)。術語「縮窄」為同義詞，但常常僅用於主動脈縮窄之情形下。術語「再狹窄」係指在一程序之後復發狹窄。
術語「血栓」係指血液凝塊(「血栓」)在血管內部之形成，從而阻塞經由循環系統之血流。當血管受損時，身體使用血小板(凝血細胞)及血纖
維蛋白以形成血液凝塊以預防失血。替代地，即使當血管不受損時，若自身出現恰當條件，則血液凝塊可在體內形成。若凝血過於嚴重且凝塊自由斷裂，則正在行進之凝塊現稱為「栓子」。術語「血栓栓塞」係指血栓形成與其主要併發症「栓塞」之組合。當血栓佔據動脈之內腔的超過75%之表面積時，供應至組織之血流減少至足以引起歸因於氧氣減少(低氧)及類似乳酸之代謝產物積聚(「痛風」)的症狀。超過90%阻塞可引起缺氧症、完全喪失氧及「梗塞」(一種細胞死亡模式)。
「栓塞」(複數個栓塞)為栓子(能夠在遠離其起點之部位堵塞動脈毛細管床之經脫離血管內物質)倒伏至動脈床之狹窄毛細血管中之現象，此引起身體遠端部分之阻塞(血管閉塞)。此並不與在起點部位阻塞之血栓混淆。形成栓塞之物質可具有多個不同來源：若物質為血液，則「栓子」稱為「血栓」；固體物質亦可包含脂肪、細菌殘餘物、感染組織等。
「缺血」為限制供應至組織之血液，造成用於細胞代謝所需之氧氣及葡萄糖不足(以保持組織存活)。缺血一般由血管問題、以及對組織所產生的損傷或組織之功能障礙造成。其亦意謂有時由充血(諸如血管收縮、血栓形成或栓塞)引起的身體之既定部分的局部貧血。若「缺血」發生在心臟肌肉(或「心肌」)中，則缺血稱為心肌缺血。其他類型之缺血為例如大腦缺血、嚴重肢體缺血及類似者。
「再灌注」發生在血液供應在缺血時段之後返回至組織時。一旦循環至組織恢復，則可發展發炎及氧化應力過程。此事件鏈之一個實例為與器官移植相關之缺血性再灌注。
「再灌注損傷」為當血液供應在缺血及炎症及接著發生的氧化損傷而非正常功能恢復時段之後返回至組織時所引起之組織損傷。缺血性問題
之再灌注通常與微血管損傷相關，尤其歸因於導致穿過組織之擴散及流體過濾增加的毛細管及小動脈滲透性增加。經活化內皮細胞在再灌注之後產生更多的反應性氧物種但更少的NO，且不平衡引起發炎性反應。利用最新返回之血流攜載至區域之白血球回應於組織損傷而釋放大量發炎因子及自由基。經恢復血流引入損害細胞蛋白質、DNA及質膜之氧氣。亦認為缺血性再灌注之此過程負責形成慢性傷口且未能治癒慢性傷口，(例如，壓瘡或糖尿病性潰瘍)。
如本文所使用之術語「血管病變」為血管(動脈、靜脈及毛細管)之疾病的通用術語。最常見及最普遍的血管病變為「糖尿病性血管病變」(一種慢性糖尿病之常見併發症)。另一常見類型之血管病變為「大腦澱粉樣血管病變(CAA)」，亦稱為嗜剛果紅血管病變(congophilic angiopathy)，其中澱粉樣蛋白沈積物在中樞神經系統之血管之壁中形成。因為澱粉樣蛋白之異常聚合之存在情況可藉由在施用稱作剛果紅(Congo red)之特定染色劑之後對大腦組織之微觀檢查來證實，所以使用術語嗜剛果紅。澱粉樣蛋白物質僅發現於大腦中且因此該疾病與其他形式之澱粉樣變性無關。
「中風」或腦血管事故(CVA)為歸因於供應至大腦之血液紊亂的對大腦功能之快速損耗。此可歸因於由阻塞(血栓形成、動脈栓塞、脂肪積聚或痙攣)或出血(血液滲漏)造成之「缺血」(缺乏血流，導致供應至組織之氧氣及葡萄糖不足)。因此，大腦之受影響區域不能起作用，此可引起在身體之一側上之一或多個肢體不能移動、不能理解或闡述語言，或不能看見視野之一側。中風之風險因子包括老年、高血壓、陳舊性中風或暫時性缺血性發作(TIA)、糖尿病、高膽固醇、吸菸及心房顫動。高血壓為中風之最重要的可更改風險因子。「缺血性中風」在醫院藉由血栓溶解(亦稱為
「凝塊破壞者」)經間或治療，且一些出血性中風受益於神經外科。預防復發可涉及投與諸如阿司匹林(aspirin)及雙嘧達莫(dipyridamole)之抗血小板藥物，控制且降低高血壓，以及使用士他汀(statin)。所選擇之患者受益於頸動脈內膜切除術及抗凝劑之使用。
「血管性癡呆」為老年人中之癡呆的第2最常見病因。其在男性中更常見且通常在70歲之後開始。其更常發生在具有血管風險因子(例如，高血壓、糖尿病、高脂質血症、吸菸)之人類及已有幾次中風之彼等人中。許多人均患有血管性癡呆及阿茲海默疾病(Alzheimer disease)。血管性癡呆通常發生在多發小腦梗塞(或有時出血)引起足夠神經元或軸突損耗以損害大腦功能時。血管性癡呆包括以下類型：多發性腔隙性梗塞(其中小血管受影響且梗塞發生在半球形白質及灰質內深部)；多梗塞性癡呆(其中中型血管受影響)；關鍵性單發性梗塞癡呆(其中單發性梗塞發生在大腦之關鍵區域中，諸如角形腦回或丘腦)；賓斯萬格式癡呆(Binswanger dementia)或皮層下動脈硬化腦病(其中小血管癡呆與重度控制不良的高血壓及全身性血管疾病相關且其引起軸突及髓鞘之彌漫性及不規律損耗，其伴隨有分佈廣泛的神經膠瘤病、歸因於梗塞之組織死亡，或供應至大腦之白質的血液損耗)。
術語「神經膠質瘤」係指開始於大腦或脊椎中之一種類型的腫瘤。因為其由神經膠質細胞引起，所以其稱作神經膠質瘤。神經膠質瘤之最常見部位為大腦。神經膠質瘤佔全部大腦及中樞神經系統腫瘤之約30%及全部惡性腦瘤之80%。
根據美國精神病學會(American Psychiatric Association)之精神病症診斷與統計手冊(Diagnostic and Statistical Manual of Mental
Disorders)，第四版(DSM-IV)，術語「性功能障礙」涵蓋「特徵在於性欲及與性反應週期相關之精神生理變化紊亂」的一系列病況；雖然此類型問題常見，但認為性功能障礙僅存在於該等問題造成患者之痛苦時。性功能障礙可為身體或心理病因。其可以原發性病況之形式存在，一般本質上為激素，但最通常其繼發於其他醫學病況或該等病況之藥物療法。全部類型之性功能障礙可進一步歸類為終身的、獲取的、情境性的或廣泛性(或其組合)。
DSM-IV-TR指定五個主要類別之「女性性功能障礙」：性欲/興趣障礙；「性喚起障礙(包括生殖器、主觀的及結合的)」；高潮障礙；性交困難及陰道痙攣；以及持久性性喚起障礙。
「女性性喚起障礙(FSAD)」定義為持久性或復發不能達到或維持性興奮的充足水準，從而致使個人痛苦。FSAD涵蓋缺乏主觀興奮感(亦即主觀性喚起障礙)及缺乏諸如潤滑及腫脹之身體反應(亦即，生殖器/生理性喚起障礙)兩者。FSAD可絕對地為心理病因，儘管其一般由醫學或生理性因子引起或併發。雌性激素過少為與FSAD相關之最常見生理病況，其導致泌尿生殖器萎縮及陰道潤滑降低。
如本文所使用，「勃起功能障礙(ED)」為特徵在於在性行為期間不能發展或維持陰莖勃起的男性性功能障礙。陰莖勃起為血液進入且保留在陰莖內之海綿狀物體中的液壓效果。當信號自大腦傳輸至陰莖中之神經時，通常作為性喚起之結果而起始該過程。在難以產生勃起時指示勃起功能障礙。最重要的有機病因為心血管疾病及糖尿病、神經問題(例如，來自前列腺切除手術之損失)、激素不足(性腺低能症)及藥物副效應。
在一個實施例中，本文所描述之化合物I之多晶型物及醫藥學上可接
受之鹽因而適用於預防及/或治療以下類型之與循環相關之心臟、肺部、周邊、肝臟、腎臟或大腦血管/內皮病症、病況及疾病：˙與高血壓及冠狀動脈血流減少相關之病症；急性及慢性冠狀動脈血壓升高；動脈高血壓；由心臟及腎併發症引起之血管病症；由心臟病、中風、大腦缺血或腎衰竭引起之血管病症；耐藥性高血壓；糖尿病性高血壓；原發性高血壓；繼發性高血壓；妊娠期高血壓；子癇前症；門靜脈高血壓；心肌梗塞；˙心臟衰竭、HFPEF、HFREF；急性及慢性HF；更特定形式之HF：急性代償失調HF、右心室衰竭、左心室衰竭、總HF、缺血性心肌病、擴張型心肌症、先天性心臟缺陷、伴隨瓣膜缺陷之HF、二尖瓣狹窄、二尖瓣關閉不全、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、肺瓣狹窄、肺瓣關閉不全、聯合瓣膜缺陷；糖尿病性心臟衰竭；酒精性心肌病或儲存型心肌病；舒張性HF、收縮性HF；現有慢性HF之急性期(惡化HF)；舒張或收縮功能障礙；冠狀動脈功能不全；心律不齊；心室預負載減小；心臟肥大；心臟衰竭/心腎症候群；門靜脈高血壓；內皮細胞功能障礙或損傷；心房及心室節律紊亂及傳導紊亂：房室阻塞度I-III(AVB I-III)、室上性快速性心律失常、心房顫動、心房撲動、心室震顫、心室撲動、心室快速性心律失常、扭轉型心動過速(torsade-de-pointes tachycardia)、心房及心室期外收縮、AV接合點期外收縮、病態竇房結症候群、暈厥、AV節點折返性心動過速；沃夫-帕金森-懷特症候群(Wolff-Parkinson-White syndrome)或急性冠狀動脈症候群；布克二心肌病(Boxer cardiomyopathy)；心室早發性收縮；心肌病；癌症誘發心肌病；化學治療誘發心臟毒性；
˙血栓栓塞病症及缺血症；心肌缺血；梗塞；心肌梗塞；心臟病發作；心肌功能不全；內皮細胞功能障礙；中風；短暫性缺血發作(TIA)；阻塞性脈管炎、穩定型或不穩定型心絞痛；冠狀動脈痙攣或周邊動脈痙攣；變異型心絞痛、普潤茲曼特心絞痛(Prinzmetal's angina)；心臟肥大；子癇前症；血栓形成病症；缺血性再灌注損傷；與器官移植相關之缺血性再灌注；與肺移植、肺部移植、心臟移植、靜脈移植物衰竭相關之缺血性再灌注；創傷患者中之血液替代品之保存；˙周邊血管疾病；周邊動脈疾病；周邊閉塞性動脈疾病；張力亢進；雷諾氏症候群或現象(Raynaud's syndrome or phenomenon)(原發性及繼發性)；雷諾氏疾病(Raynaud's disease)；嚴重肢體缺血；周邊栓塞症；間歇性跛行；血管閉塞危機；肌肉萎縮症、杜興氏肌肉萎縮症(Duchenne muscular dystrophy)、貝克爾肌肉萎縮症(Becker muscular dystrophy)、微循環異常、血管滲漏或滲透性控制；腰椎管狹窄；閉塞血栓性脈管炎；血栓性脈管炎；周邊灌注紊亂；動脈及靜脈血栓；微白蛋白尿；周邊及自主神經病變；糖尿病性神經痛；糖尿病性微血管病；肝臟血管閉塞病症；鐮刀型紅血球疾病中之血管閉塞危機；高血壓危機；˙水腫；歸因於心臟衰竭之腎水腫；˙阿茲海默氏症(Alzheimer's disease)；帕金森氏病(Parkinson's disease)；血管性癡呆；血管認知障礙；大腦血管痙攣；先天性重症肌無力症候群；蛛膜下出血；創傷性腦損傷；在諸如輕度認知障礙中發生之彼等的認識障礙、年齡相關之學習及記憶障礙、年齡相關之記憶損耗、血管性癡呆、頭部損傷、中風、中風後癡呆、創傷後頭部損傷、一般集中障礙及伴有學習及記憶問題之兒童的集中障礙；路易體性癡呆(Lewy body
dementia)；包括皮克氏症候群(Pick's syndrome)之伴有前額葉變性之癡呆；進行性細胞核麻痺；伴有皮質基底核退化症之癡呆；肌肉萎縮性側索硬化(Amyotrophic Lateral Sclerosis；ALS)；亨廷頓氏病(Huntington's disease)；髓鞘脫失；多發性硬化症；丘腦退化症；克羅伊茨費爾特-賈考伯癡呆(Creutzfeldt-Jakob dementia)；HIV-癡呆；伴有癡呆或柯薩可夫精神病(Korsakoff psychosis)之精神分裂症；多發性系統萎縮症及其他形式之帕金森氏症附加症候群(Parkinsonism Plus)；運動障礙；神經保護；焦慮、緊張及憂鬱或創傷後壓力症(PTSD)；躁鬱症、精神分裂症、CNS相關之性功能障礙及睡眠紊亂；病理性飲食障礙及使用奢侈食品及成癮藥物；控制大腦灌注；偏頭痛；預防及控制腦梗塞後果(大腦中風)；預防及控制中風後果、大腦缺血及頭部損傷；與CNS疾病相關之神經病；與MS相關之神經痛；化學治療誘發之神經痛；與帶狀疱疹相關之神經痛；與脊柱手術相關之神經痛；˙休克；心源性休克；敗血症；敗血性休克；過敏性休克；動脈瘤；控制白細胞活化；抑制或調節血小板凝集；多器官功能障礙症候群(multiple organ dysfunction syndrome；MODS)；多器官衰竭(multiple organ failure；MOF)；˙肺部/呼吸道病況：肺高血壓(pulmonary hypertension；PH)；肺部動脈高血壓(PAH)，及相關肺部血管重塑；呈局部血栓及右心臟肥大形式之血管重塑；肺部張力亢進；原發性肺高血壓；繼發性肺高血壓；家族性肺高血壓；偶發性肺高血壓；前毛細血管肺高血壓；特發性肺高血壓；其他形式之PH；與以下相關之PH：左心室疾病、HIV、SCD、血栓栓塞(CTEPH)類肉瘤病、COPD、肺纖維化、急性呼吸窘迫症候群(ARDS)、
急性肺損傷、α-1-抗胰蛋白酶不足(AATD)、肺氣腫、抽菸誘發之肺氣腫及囊腫性纖維化症(CF)；血栓性肺部動脈病；致叢性肺部動脈病；囊腫性纖維化症；支氣管收縮或肺部支氣管收縮；急性呼吸道症候群；肺纖維化；肺移植；哮喘疾病；˙與以下相關或有關之肺高血壓：左心室功能障礙、低氧血症、WHO I組、II組、III組、IV組及V組高血壓；二尖瓣膜疾病；縮窄性心包炎、主動脈瓣狹窄、心肌病、縱隔纖維化、肺纖維化、肺靜脈畸形引流、肺靜脈閉塞疾病、肺脈管炎、膠原蛋白血管疾病、先天性心臟病、肺靜脈高血壓、間質性肺病、睡眠呼吸障礙、睡眠呼吸暫停、肺泡換氣不足病症、長期暴露於高海拔、新生肺疾病、肺泡毛細血管發育異常、鐮刀型紅血球疾病、其他凝血病症、慢性血栓栓塞、肺栓塞；歸因於腫瘤、寄生蟲或外來材料之肺栓塞；結締組織疾病、狼瘡、狼瘡性腎炎、血吸蟲病、類肉瘤病、慢性阻塞性肺病、哮喘、肺氣腫、慢性支氣管炎、肺毛細血管瘤病、組織細胞增多病X、淋巴管瘤病、壓縮之肺脈管；歸因於淋巴結腫大、腫瘤或纖維性縱隔炎的壓縮肺脈管；˙動脈粥樣硬化疾病或病況：動脈粥樣硬化；與內皮損傷、血小板、及單核球黏附及聚集、平滑肌增生或遷移相關之動脈粥樣硬化；再狹窄；在血栓溶解療法、經皮腔內血管成形術(PTA)、經冠狀動脈腔內血管成形術(PTCA)、心臟移植、旁通操作或發炎過程之後發展之再狹窄；˙微血管及大血管損傷(脈管炎)；血纖維蛋白原含量增大及低密度DLD；纖維蛋白溶酶原活化劑抑制劑1(PA-1)濃度增大；˙代謝症候群；代謝疾病或與代謝症候群相關之疾病：肥胖；皮下脂肪過多；過度肥胖；糖尿病；高血壓；脂質相關病症、高血脂、血脂異
常、高膽固醇血症、高密度脂蛋白膽固醇(HDL-膽固醇)減少、低密度脂蛋白膽固醇(LDL-膽固醇)含量適度升高、高甘油三酯血症、高甘油酯血症、低脂蛋白血症、穀固醇血症、脂肪肝病、酒精性脂肪肝病(AFLD)、非酒精性脂肪肝病(NAFLD)、肝炎；子癇前症；多囊性腎病進展；肝脂肪變性或肝中之不正常脂質積聚；非酒精性脂肪變性肝炎(NASH)；心臟、腎或肌肉之脂肪變性；αβ脂蛋白血症；穀固醇血症；黃瘤症；丹吉爾病(Tangier disease)；高氨血症及相關疾病；肝腦病；其他有毒性腦病；急性腦病綜合症(Reye syndrome)；˙性病、婦科疾病及泌尿疾病或病況：勃起功能障礙；陽萎；早洩；女性性功能障礙；女性性喚起功能障礙；機能減退的性喚起障礙；陰道萎縮；性交困難；萎縮性陰道炎；良性前列腺增生(BPH)；前列腺肥大；前列腺增大；膀胱出口阻塞；膀胱疼痛綜合症(BPS)；間質性膀胱炎(IC)；膀胱過動症；神經性膀胱及失禁；糖尿病腎病變；原發性及繼發性痛經；下尿路症候群(LUTS)；子宮內膜異位；骨盆疼痛；男性及女性泌尿生殖器系統之器官之良性及惡性疾病；˙慢性腎病；急性及慢性腎機能不全；急性及慢性腎衰竭；狼瘡性腎炎；潛在或相關腎臟疾病：灌注不足、透析中低血壓、阻塞性尿路病、腎小球病、絲球體腎炎、急性絲球體腎炎、腎小球硬化、小管間質性疾病、腎病、原發性及先天性腎臟疾病、腎炎；特徵在於肌酐及/或水分泌非正常地減小的疾病；特徵在於脲、氮、鉀及/或肌酐之血液濃度非正常增大的疾病；特徵在於腎酶類活性改變的疾病、特徵在於麩胺醯基合成酶活性改變的疾病；特徵在於尿容積滲透濃度或尿體積改變的疾病；之特徵在於微白蛋白尿增大的疾病、特徵在於大量白蛋白尿的疾病；特徵在於腎小球
及小動脈病變、小管膨脹、高磷酸鹽血症及/或需要透析之疾病；腎機能不全後遺症；腎機能不全相關之肺灌腸；與HF相關之腎機能不全；與尿毒症或貧血症相關之腎機能不全；電解質紊亂(高鉀血症、低鈉血症)；骨骼及碳水化合物代謝紊亂；急性腎臟損傷；˙眼部疾病或病症，諸如青光眼、視網膜病變及糖尿病性視網膜病變。
術語「炎症」係指血管組織對有害刺激(諸如病原體、受損細胞或刺激物)之複雜的生物反應。急性炎症之經典跡象為疼痛、發熱、發紅、腫脹及功能缺失。炎症為生物移除有害刺激且起始治癒過程之保護性嘗試。炎症不為感染之同義詞，即使該兩者常常相關(前者通常為後者之結果)。炎症亦可在無感染之情況下發生，但此類型之炎症通常為適應不良的(諸如，動脈粥樣硬化)。炎症為刻板反應，且因此相比於對各病原體具有特異性之自適應免疫，將其視為一種固有免疫機制。組織在不存在炎症之情況下之進行性損壞將損害生物之存活。在另一方面，慢性炎症可導致大量疾病，諸如枯草熱、齒根骨膜炎、動脈粥樣硬化、類風濕性關節炎及甚至癌症(例如，膽囊癌)。出於彼原因，炎症通常由身體密切調節。炎症可歸類為急性或慢性。「急性炎症」為身體對有害刺激之起始反應且藉由增強血漿及白細胞(尤其粒細胞)自血液移動至受傷組織中來達成。生物化學事件之級聯傳播發炎反應且使其成熟，從而涉及局部血管系統、免疫系統及受傷組織內之多種細胞。稱為「慢性炎症」之長期炎症導致在發炎部位存在之細胞類型之進行性改變，且特徵在於自發炎過程同時損壞且治癒組織。
在另一實施例中，本文所描述之化合物I之多晶型物及醫藥學上可接
受之鹽因而適用於預防及/或治療可涉及炎症或發炎過程的以下類型之心臟、肺部、周邊、肝臟、腎臟、消化或中樞神經系統病症、病況及疾病：˙心臟肌肉炎症(心肌炎)；慢性心肌炎；急性心肌炎；病毒性心肌炎；˙脈管炎；胰臟炎；腹膜炎；類風濕性疾病；˙腎發炎性疾病；免疫性腎疾病：腎移植排斥、免疫複合物誘發之腎病、毒素誘發之腎病、對比介質誘發之腎病、糖尿病性及非糖尿病腎病變、腎盂腎炎、腎胞囊、腎硬化、高血壓腎硬化及腎病症候群；˙慢性間質性炎症、發炎性腸道疾病(IBD)、克羅恩氏病(Crohn's disease)、潰瘍性結腸炎(UC)；˙發炎性皮膚病；˙眼之發炎性疾病、瞼炎、乾眼症候群，及休格連氏症候群(Sjögren's Syndrome)；眼纖維化。
術語「傷口癒合」係指皮膚(或另一器官或組織)在損傷之後修復自身的錯綜複雜的過程。舉例而言，在正常皮膚中，表皮(最外層)及真皮(內層或較深層)存在穩態平衡，從而形成針對外部環境的保護性障壁。一旦該保護性障壁被打破，則傷口癒合的正常(生理)過程立即設定成活動狀態。傷口癒合之經典模型劃分成三個或四個連續又重疊的階段：(1)止血(一些作者不將其視為一個階段)、(2)炎症、(3)增生及(4)重塑。皮膚損傷後，一組複雜的生物化學事件以密切協同的級聯發生，以修復損傷。在損傷之後的前幾分鐘內，血小板黏著於損傷部位，變為活化的，且聚集(接合在一起)，接著活化在交聯血纖維蛋白網中形成經聚集血小板之凝塊的凝血級聯。此凝塊阻止活動性出血(「止血」)。在炎症階段期間，細菌及
細胞碎片經吞噬且由白血球自傷口移除。血小板衍生之生長因子(儲存在血小板之α細粒中)釋放至傷口中，該傷口在增生性階段期間引起細胞之遷移及分裂。增生階段特徵在於血管生成、膠原蛋白沈積、顆粒組織形成、上皮形成及傷口收縮在「血管生成」中，血管內皮細胞形成新的血管。在「纖維組織形成」及顆粒組織形成中，纖維母細胞生長且藉由分泌膠原蛋白及纖維結合蛋白形成新的臨時胞外基質(ECM)。同時，發生表皮之「上皮再形成」，其中上皮細胞增生且『爬』上傷口床，從而為新的組織提供保護層。在傷口收縮期間，肌纖維母細胞藉由夾持傷口邊緣且使用平滑肌細胞中類似的機制收縮來減小傷口之大小。當細胞之作用接近完成時，不需要的細胞進行細胞凋亡。在成熟及重塑期間，膠原蛋白經重塑且沿張力線再配向，且不再需要之細胞藉由細胞凋亡移除。然而，此過程不僅複雜而且易損壞，且易受到中斷或失敗，從而導致形成非癒合慢性傷口(一個實例包括糖尿病性傷口或潰瘍，及特定言之糖尿病性足潰瘍)。造成非癒合慢性傷口之因子為糖尿病、靜脈或動脈疾病、感染及老年代謝缺陷。
術語「骨癒合」或「骨折癒合」係指身體促使骨折之修復的增生性生理過程。在骨折癒合之過程中，恢復之若干階段有助於骨折及脫臼周圍之區域的增生及保護。過程之時長視損傷之程度而定，且對於大部分上體骨折之修復，給予兩週至三週之常見界限；對下體損傷給予大於四週。癒合過程主要由「骨膜」(覆蓋骨骼之結締組織膜)判定。骨膜為前驅細胞之一個來源，該等前驅細胞發育成為骨骼癒合必不可少的「軟骨母細胞」及骨母細胞。骨髓(若存在)、骨內膜、小血管及纖維母細胞為前驅細胞之其他來源。
在另一實施例中，本文所描述之化合物I之多晶型物及醫藥學上可接
受之鹽因而適用於治療以下類型之疾病、病症或病況，其中傷口或骨癒合過程之刺激將係合乎需要的：˙糖尿病患者中之傷口或潰瘍癒合；微血管灌注改良；損傷之後或抵抗手術期間護理中之發炎性反應的微血管灌注改良；肛裂；糖尿病性潰瘍；糖尿病性足潰瘍；骨骼癒合；破骨細胞性骨再吸收及重塑；以及新的骨骼形成。
術語「結締組織」(CT)係指支撐、連接身體之不同類型之組織及器官或將其隔開的一種動物組織。其為四種一般類別之動物組織中之一種，其他為上皮組織、肌肉組織及神經組織。在包括中樞神經系統之各處中發現結締組織。其位於其他組織之間。全部CT具有三種主要組分--基底物質、纖維及細胞--且全部此等組分浸沒在體液中。
術語「結締組織病症或病況」係指涉及身體之一或多個部分中之結締組織異常的任何病況。某些病症特徵在於免疫系統之過度活性伴隨引起炎症及對組織之系統性損傷，通常伴隨由結締組織替代正常組織(例如，某一器官之正常組織)。其他病症涉及結締組織本身之生物化學異常或結構缺陷。此等病症中之一些為遺傳性的，且一些為未知病源的。
當結締組織疾病為自體免疫性病因時，將其歸類為「風濕性病症」、「自體免疫性風濕性病症」或「自體免疫性膠原蛋白-血管病症」。
在「自體免疫性病症」中，由身體產生之抗體或其他細胞侵襲身體之自身組織。許多自體免疫性病症影響多種器官中之結締組織。在自體免疫性病症中，炎症及免疫反應可引起圍繞關節以及在其他組織(包括生命器官，諸如腎或胃腸道之器官)中的結締組織損傷。圍繞心臟之囊(心包膜)、覆蓋肺之膜(胸膜)、縱隔(胸部中之由疏鬆結締組織圍繞之含有心
臟、心臟之大血管、食道、氣管、膈神經、心臟神經、胸導管、胸腺、及中心胸之淋巴結的未描繪結構群)及甚至大腦可受影響。
如本文所使用之術語「纖維化」係指身體之某一器官或部分中之結締組織或纖維組織(瘢痕組織、膠原蛋白)的積聚。若纖維化由單細胞株引起，則將其稱作「纖維瘤」。當身體試圖修復且替換受損細胞時產生纖維化，且因此可為反應性、良性的或病理性狀態。生理性纖維化類似於瘢痕形成之過程。當所討論之組織反覆地且連續地受損時，發展病理性性狀態。單次損傷事件，即使嚴重，並不通常引起纖維化。若損傷為反覆或連續的(例如，當其發生在慢性肝炎中時)，則身體試圖修復損傷，但該等嘗試實際上產生瘢痕組織之過度積聚。瘢痕組織開始替換執行瘢痕組織不能執行之某些功能的器官之常規組織；其亦可干擾血流且限制供應至其他細胞之血液。因此，此等其他功能性細胞開始死亡且形成更多疤痕組織。當此發生在肝中時，將血液自腸道攜載至肝之靜脈(門靜脈)中的血壓增加，從而產生被稱為「門靜脈高血壓」之病況。
術語「硬化症」係指通常藉由結締組織替代正常器官特定組織而使一般為可撓性的組織或結構或器官的硬化或硬挺。
存在多種類型之纖維化或纖維性疾病，包括(但不限於)肺纖維化(特發性肺部纖維化、囊腫性纖維化)、肝纖維化(或「肝硬化」)、心內膜心肌纖維化、陳舊性心肌梗塞、心房纖維化、縱隔纖維化、骨髓纖維化(影響骨髓)、腹膜後纖維化、進行性大規模纖維化(影響肺)、腎源性纖維化(影響皮膚)、克羅恩氏病、關節纖維化、佩羅尼氏病(Peyronie's disease)(影響陰莖)、杜普宜特朗氏攣縮(Dupuytren's contracture)(影響手及手指)、某些形式之黏著性囊炎(影響肩部)。
存在多種類型之硬化症或「硬化性疾病」，包括(但不限於)肌肉萎縮性側索硬化(ALS)；動脈粥樣硬化；病灶性節段腎小球硬化及腎病症候群；海馬硬化症(影響大腦)；苔癬硬化(硬化陰道及陰莖之結締組織的疾病)；肝硬化症(肝硬化)；多發性硬化症或病灶性硬化(影響協調之疾病)；骨硬化(骨密度顯著減小之疾病)；耳硬化症(影響耳朵之疾病)；結節性硬化症(影響多個系統之罕見的遺傳性疾病)；原發性硬化性膽管炎(膽管之硬化)；原發性側索硬化(自發肌肉中之進行性肌肉無力)；以及瘢痕瘤。
術語「硬皮病」或「全身性硬化症」或「進行性全身性硬皮病」係指涉及關節、皮膚及內臟之瘢痕形成以及血管異常的病況。全身性硬化症有時可以限制形式發生，例如有時僅影響皮膚或主要僅影響皮膚之特定部分或呈CREST綜合症形式(其中涉及皮膚之周邊區域而非軀幹)。全身性硬化症之常見初始症狀為腫脹，接著變厚且繃緊手指末端之皮膚。手指突然且暫時變得非常蒼白及刺痛或變得麻木、疼痛或兩者之「雷諾氏現象(Raynaud's phenomenon)」為常見的。
術語「多發性肌炎」係指肌肉炎症。術語「皮肌炎」係指伴有皮膚炎症之肌肉炎症。術語「多軟骨炎」係指軟骨炎症。
術語「嗜酸性筋膜炎」係指嗜酸性免疫細胞經釋放且產生炎症且使為皮膚下方、肌肉頂部及肌肉之間的堅韌纖維組織層的「筋膜」硬化的罕見病症。筋膜變成疼痛地發炎且膨脹且逐漸硬化手臂及腿部。當手臂及腿部之皮膚進行性地硬化時，其變得難以移動。最終其變得卡在不常見的位置。有時，若涉及手臂，則個人可發展腕隧道症候群。
在另一實施例中，可藉由投與本文所描述之化合物I之多晶型物醫藥學上可接受之鹽來治療及/或預防之特異性疾病或病症包括(但不限於)涉及
炎症、自體免疫或纖維化(亦即，纖維化疾病)的以下類型之疾病：˙泌尿生殖器系統或腎病症：糖尿病性腎病變；由慢性腎疾病或功能障礙引起之腎纖維化及腎衰竭；歸因於積聚/沈積及組織損傷之腎纖維化及腎衰竭；腎硬化症；進行性硬化症；絲球體腎炎；病灶性節段性腎小球硬化；腎病症候群；前列腺肥大；腎纖維化；間質性腎纖維化；˙肺系統病症：肺纖維化；特發性肺部纖維化；囊腫性纖維化症；進行性纖維化；影響肺之進行性大塊纖維化；˙影響心臟之病症：心內膜心肌纖維化；陳舊性心肌梗塞；心房纖維化；心臟間質纖維化；心臟重塑及纖維化；心臟肥大；˙肝及相關器官之病症：肝硬化症或肝硬化；與慢性肝病相關之肝硬化；肝纖維化；肝臟星形細胞活化；NASH；肝纖維膠原蛋白及總膠原蛋白積聚；壞死炎症肝病及/或免疫源肝病；原發性膽汁性肝硬化；原發性硬化性膽管炎；其他膽汁鬱積性肝病：與肉芽腫性肝病相關之彼等、肝惡性腫瘤、妊娠肝內膽汁鬱積症、肝炎、敗血症、藥物或毒素、移植物抗宿主病、肝移植後、輸膽管結石、膽管腫瘤、胰腺癌、米瑞茲症候群(Mirizzi's syndrome)、AIDS膽管病或寄生蟲；血吸蟲病；肝細胞癌；˙消化疾病或病症：克羅恩氏病(Crohn's disease)；潰瘍性結腸炎；胃腸道硬化；弛緩不能；˙皮膚或眼睛之疾病：腎源性纖維化；增生性玻璃體視網膜病變；糖尿病性視網膜病變；眼纖維化；˙纖維化體表或皮膚病症或病況；真皮纖維化；硬皮病；皮膚纖維化；硬斑病；肥厚性瘢痕；痣；瘢痕瘤；肉狀瘤病；肉芽腫；˙影響神經系統之疾病：肌肉萎縮性側索硬化(ALS)；海馬硬化症；
多發性硬化症(MS)；病灶性硬化症；原發性側索硬化症；˙骨之疾病；骨硬化症；˙耳硬化症；其他聽力疾病或病症；聽力障礙；部分或全部聽力損失；部分或全部聾；耳鳴；噪聲性聽力損失；˙涉及自體免疫、炎症或纖維化之其他疾病：硬皮病；局部硬皮病或侷限性硬皮病；縱隔纖維化；纖維化縱隔炎；骨髓纖維化；腹膜後纖維化；關節纖維化；佩羅尼氏病(Peyronie's disease)；杜普宜特朗氏攣縮(Dupuytren's contracture)；苔癬硬化；某些形式之黏著性囊炎；動脈粥樣硬化；結節性硬化症；全身性硬化症；多發性肌炎；皮肌炎；多軟骨炎；嗜酸性筋膜炎；全身性紅斑性狼瘡症或狼瘡；骨髓纖維化；骨髓纖維化症或骨髓纖維化瘤；類肉瘤病；子宮肌瘤；子宮內膜異位。
在另一實施例中，可藉由投與本文所描述之化合物I之多晶型物或醫藥學上可接受之鹽來治療及/或預防之特異性疾病或病症包括(但不限於)：特定類型之癌症；鐮刀型紅血球疾病；鐮刀型紅血球貧血；癌轉移；骨質疏鬆；胃輕癱；機能性消化不良；糖尿病性併發症；禿頭症或脫髮；與內皮細胞功能障礙相關之疾病；與氧化氮產量減少相關之神經性病症；精胺琥珀酸尿症；神經肌肉疾病：杜興氏肌肉萎縮症(Duchenne muscular dystrophy；DMD)、貝克爾肌肉萎縮症(Becker muscular dystrophy；BMD)、肢帶型肌營養不良、末端型肌病、I型及II型肌緊張性營養不良、面肩肱型肌肉萎縮症、常染色體及X-性聯之艾美芮-德賴富斯肌肉萎縮症(X-linked Emery-Dreifuss muscular dystrophy)、眼咽型肌肉萎縮症、肌肉萎縮性側索硬化，以及脊髓性肌肉萎縮(SMA)。
在一些實施例中，本發明係關於一種治療個體之疾病、健康狀況或
病症的方法，其包含向有需要之個體投與治療有效量之本文所描述之化合物I之多晶型物或醫藥學上可接受之鹽，其中該疾病、健康狀況或病症係選自上文所列出之疾病中之一者。
在另一實施例中，本發明之固體形式可以植入器件(諸如支架)之形式傳送。支架為插入至中體內之固有通道/導管之網『管』以預防或抵抗疾病誘發之局部流量收縮。該術語亦可係指用於暫時固持此固有導管開口以允許手術進入之管。
藥物溶離支架(DES)為置放於較窄的、患病周邊或冠狀動脈中之緩慢釋放藥物以阻斷細胞增生(通常平滑肌細胞增生)的周邊或冠狀動脈支架(架構)。此預防與凝塊(血栓)一起可另外阻塞支架動脈(一種稱作再狹窄之過程)之纖維化。支架通常由介入性心臟病專家或介入性放射學家在血管成形術程序期間置放於周邊或冠狀動脈內。為阻斷細胞增生在DES中常用之藥物包括太平洋紫杉醇(paclitaxel)或雷帕黴素(rapamycin)類似物。
在本發明之一些實施例中，本發明之化合物I之多晶型物或醫藥學上可接受之鹽或其醫藥組合物可藉助於塗佈有固體形式或醫藥組合物之藥物溶離支架傳送。塗佈有本發明之化合物I之固體形式(或醫藥組合物)的藥物溶離支架可適用於在經皮冠狀動脈介入術期間預防支架再狹窄及血栓形成。塗佈有本發明之化合物I之固體形式(或醫藥組合物)的藥物溶離支架可能夠預防平滑細胞增生以及輔助血管再形成及插入支架之動脈的內皮組織之再生。
用於治療歸因於冠狀動脈閉塞疾病之難治性心絞痛的經皮冠狀動脈介入術的替代術為命名為冠狀動脈繞通移植術(CABG)之程序。CABG僅提供因移植物動脈粥樣硬化之快速發展而進一步複雜之進行過程的緩解。
隱靜脈移植物為CABG手術中最常用之導管。靜脈CABG之長期臨床成效受三個主要原因妨礙：移植物動脈粥樣硬化加速、不完全內皮化及血栓形成。
在一些實施例中，本發明之化合物I之固體形式可用於在CABG期間預防隱靜脈移植物失敗。本發明之固體形式可輔助內皮化過程且有助於預防血栓形成。在此指示中，化合物I之固體形式以凝膠形式局部傳送。
術語「疾病」、「病症」及「病況」在本文中可互換使用以係指sGC、cGMP及/或NO介導之醫學或病理性病況。
如本文所使用，術語「個體」及「患者」可互換地使用。術語「個體」及「患者」係指動物(例如，諸如雞、鵪鶉或火雞之鳥，或哺乳動物)，特定言之，包括非靈長類(例如，牛、豬、馬、羊、兔、天竺鼠、大鼠、貓、狗及小鼠)及靈長類(例如，猴、黑猩猩及人類)之「哺乳動物」，且更特定言之人類。在一些實施例中，個體為非人類動物，諸如農場動物(例如，馬、牛、豬或羊)或寵物(例如，狗、貓、天竺鼠或兔)。在一些實施例中，個體為人類。
本發明亦提供一種用於治療個體內之上述疾病、病況及病症中之一者的方法，其包含向需要治療之個體投與治療有效量之化合物I之多晶型物或醫藥學上可接受之鹽。替代地，本發明提供化合物I之多晶型物或醫藥學上可接受之鹽在治療需要治療之個體內的此等疾病、病況及病症中之一者中的用途。本發明進一步提供一種製備或製造適用於治療此等疾病、病況及病症中之一者之藥物的方法，該方法包含使用化合物I之多晶型物或醫藥學上可接受之鹽。
如本文所使用，術語「生物樣品」係指活體外或離體樣品，且包括
(但不限於)細胞培養物或其提取物；自哺乳動物或其提取物獲得之活檢材料；血液、唾液、尿、糞便、精液、淚液、淋巴液、眼內液、玻璃狀體，或其他體液或其提取物。
如本文所使用，術語「治療(treatment/treating)」可互換使用。此等術語係指獲得包括(但不限於)治療效益之有利的或所需結果的方法。治療效益包括根除或改善被治療之潛在病症；其亦包括根除或改善與潛在病症相關之症狀中之一或多者使得在患者中觀測到改良，儘管患者可仍罹患該潛在病症。
如本文所使用，術語「治療(treat/treatment/treating)」係指由投與一或多個療法(例如，一或多個治療劑，諸如本發明之化合物I之多晶型物或醫藥學上可接受之鹽或其組合物)引起的sGC、cGMP及/或NO介導之病況的進展、嚴重度及/或持續時間的減小或改善，或該病況之一或多個症狀(較佳地，一或多個可辨別的症狀)之改善(亦即，在未「治癒」該病況之情況下之「控制」)。在特定實施例中，術語「治療(treat/treatment/treating)」係指sGC、cGMP及/或NO介導之病況之至少一種可量測物理參數的改善。在其他實施例中，術語「治療(treat/treatment/treating)」係指在物理上藉由例如穩定可辨別症狀或在生理上藉由例如穩定物理參數或兩者來抑制sGC、cGMP及/或NO介導之病況之進展。
如本文所使用之術語「預防」係指預先投與藥物以避免或防止疾病或病症之一或多個症狀出現。醫學領域中之一般技術者認為術語「預防」不為絕對術語。應理解，在醫學領域中係指預防性投與藥物以大體上減小病況之可能性或嚴重性，或病況之症狀，且此為本發明中意欲之含義。醫
師之桌上參考(Physician's Desk Reference)(本領域中之標準文本)使用術語「預防」數百次。如本文中所使用，術語「預防(prevent/preventing/prevention)」關於病症或疾病係指在疾病或病症完全顯示自身之前避免疾病或病症之病因、作用、症狀或進展。
在一個實施例中，本發明之方法為對具有發展sGC、cGMP及/或NO相關之疾病、病症或症狀的傾向性(例如，遺傳傾向性)之患者(尤其人類)的預防性或「預先防範性」措施。
在其他實施例中，本發明之方法為對患有使其處於發展sGC、cGMP或NO相關之疾病、病症或症狀之風險下的疾病、病症或病狀之患者(尤其人類)的預防性或「預先防範性」措施。
本文所描述之固體形式及醫藥組合物可單獨或結合療法用於治療或預防受sGC、cGMP及/或NO介導、調節或影響之疾病或病症。
本文所揭示之固體形式及組合物亦適用於獸醫治療伴侶動物、外來動物及農畜，包含(但不限於)狗、貓、小鼠、大鼠、倉鼠、沙鼠、天竺鼠、兔、馬、豬及牛。
在其他實施例中，本發明提供一種刺激生物樣品中之sGC活性之方法，其包含將該生物樣品與本發明之固體形式或組合物接觸。sGC刺激劑在生物樣品中之用途適用於熟習此項技術者已知之多種目的。此類目的之實例包括(但不限於)生物分析法及生物標本儲存。
本文所描述之固體形式及醫藥組合物可用於與一或多種額外治療劑組合治療。對於與超過一種活性劑之組合治療，其中該等活性劑呈獨立劑型，該等活性劑可單獨地或結合投與。此外，可在投與其他藥劑之前、同
時或之後投與一種成分。
在與其他藥劑共同投與時，例如在與另一藥物共同投與時，第二藥劑之「有效量」將視所使用之藥物類型而定。適合劑量對於經審批通過之藥劑而言為已知的且可由熟習此項技術者根據個體之病況、被治療之病況類型及被使用之本文所描述之化合物之量來調整。在未明確地指出量之情況下，應採用有效量。舉例而言，本文所描述之固體形式可以介於以下之劑量範圍投與個體：約0.01毫克/公斤體重/天至約10,000毫克/公斤體重/天、約0.01毫克/公斤體重/天至約5000毫克/公斤體重/天、約0.01毫克/公斤體重/天至約3000毫克/公斤體重/天、約0.01毫克/公斤體重/天至約1000毫克/公斤體重/天、約0.01毫克/公斤體重/天至約500毫克/公斤體重/天、約0.01毫克/公斤體重/天至約300毫克/公斤體重/天、約0.01毫克/公斤體重/天至約100毫克/公斤體重/天。
當採用「組合療法」時，有效量可使用化合物I之多晶型物或醫藥學上可接受之鹽之第一量及額外適合治療劑之第二量來達成。
在本發明之一個實施例中，化合物I之多晶型物或醫藥學上可接受之鹽，及額外治療劑各自以有效量投與(亦即，若單獨投與，各者呈將為治療上有效的量)。在另一實施例中，化合物I之多晶型物或醫藥學上可接受之鹽及額外治療劑各自以單獨並不提供治療性效果之量(低於治療性劑量)投與。在又另一實施例中，化合物I之多晶型物或醫藥學上可接受之鹽可以有效量投與，而額外治療劑以低於治療性劑量投與。在再另一實施例中，化合物I之多晶型物或醫藥學上可接受之鹽可以低於治療性劑量投與，而額外治療劑(例如，適合之癌症治療劑)以有效量投與。
如本文所使用，術語「組合」或「共同投與」可互換地使用以係指
使用超過一種治療劑(例如，一或多種預防性及/或治療劑)。該等術語之使用不限定治療劑(例如，預防性及/或治療性劑)投與個體之順序。
共同投與涵蓋第一量及第二量之化合物以基本上同步的方式，諸如以單一醫藥組合物(例如具有第一量及第二量之固定比率之膠囊或錠劑)或對於各自以多個獨立膠囊或錠劑投與。此外，此共同投與亦涵蓋在任一順序中以依序方式使用各化合物。當共同投與涉及單獨投與第一量之化合物I之多晶型物或醫藥學上可接受之鹽及第二量之額外治療劑時，該等化合物在足夠接近時間內投與以具有所需治療性效果。舉例而言，可產生所需治療性效果之各投與之間的時間段可介於數分鐘至數小時範圍內，且可考量各化合物之特性(諸如效能、溶解度、生物可用性、血漿半衰期及動力學特徵曲線)來判定。舉例而言，化合物I之多晶型物或醫藥學上可接受之鹽及第二治療劑可在彼此之約24小時內、彼此之約16小時內、彼此之約8小時內、彼此之約4小時內、彼此之約1小時內或彼此之約30分鐘內以任何順序投與。
更特定言之，第一療法(例如，預防性量或治療量之本文所描述之化合物I之多晶型物或醫藥學上可接受之鹽)可在向個體投與第二療法(例如，預防劑或治療劑，諸如抗癌劑)之前(例如，5分鐘、15分鐘、30分鐘、45分鐘、1小時、2小時、4小時、6小時、12小時、24小時、48小時、72小時、96小時、1週、2週、3週、4週、5週、6週、8週或12週之前)、同時或之後(例如，5分鐘、15分鐘、30分鐘、45分鐘、1小時、2小時、4小時、6小時、12小時、24小時、48小時、72小時、96小時、1週、2週、3週、4週、5週、6週、8週或12週之後)投與。
可與化合物I之多晶型物或醫藥學上可接受之鹽組合、單獨投與或在
同一醫藥組合物中之其他治療劑之實例包括(但不限於)：
(1)內皮衍生之釋放因子(EDRF)；
(2)NO供體，諸如亞硝基硫醇、亞硝酸根、悉尼酮亞胺、NO親核複合體、N-亞硝基胺、N-羥基亞硝胺、亞硝亞胺、硝基酪胺酸、二氮雜環丁烯二氧化物、噁三唑5-亞胺、肟、羥胺、N-羥胍、羥基脲或抗氧化呋咱(antifuroxan)。此等類型之化合物之一些實例包括：三硝酸甘油酯(亦稱為GTN、硝化甘油、硝酸甘油酯及三硝酸甘油酯)(甘油之硝酸酯)；硝普化鈉(SNP)，其中氧化氮之分子與鐵金屬配位形成方形雙錐形錯合物；3-嗎啉悉尼酮亞胺(3-morpholinosydnonimine)(SIN-1)，藉由嗎啉與悉尼酮亞胺之組合所形成之兩性離子化合物；S-亞硝基-N-乙醯青黴胺(SNAP)(一種具有亞硝基硫醇官能基之N-乙醯化胺基酸衍生物)；二伸乙基三胺/NO(DETA/NO)(一種氧化氮與二伸乙基三胺共價連接之化合物)；以及NCX 4016(一種乙醯基柳酸之間硝醯甲基苯基酯)。此等類別之NO供體中之一些之更特定實例包括：典型的硝化血管擴張劑，諸如有機硝酸鹽及亞硝酸酯，包括硝化甘油、亞硝酸戊酯、異山梨醇二硝酸鹽、異山梨醇5-單硝酸鹽，及尼可地爾(nicorandil)；異山梨醇(Dilatrate®-SR、Imdur®、Ismo®、Isordil®、Isordil®、Titradose®、Monoket®)、FK 409(NOR-3)；FR 144420(NOR-4)；3-嗎啉悉尼酮亞胺；林西多明氫氯酸鹽(「SIN-1」)；S-亞硝基-N-乙醯青黴胺(「SNAP」)；AZD3582(CINOD主導化合物)、NCX 4016、NCX 701、NCX 1022、HCT 1026、NCX 1015、NCX 950、NCX 1000、NCX 1020、AZD 4717、NCX 1510/NCX 1512、NCX 2216及NCX 4040(全部購自NicOx S.A.)、S-亞硝基谷胱甘肽(GSNO)、硝普化鈉、S-亞硝基谷胱甘肽單-乙基-酯(GSNO-
酯)、6-(2-羥基-1-甲基-亞硝基肼基)-N-甲基-1-己胺(NOC-9)或二乙胺NO親核複合體。氧化氮供體亦揭示於美國專利第5,155,137號、第5,366,997號、第5,405,919號、第5,650,442號、第5,700,830號、第5,632,981號、第6,290,981號、第5,691,423號、第5,721,365號、第5,714,511號、第6,511,911號及第5,814,666號，Chrysselis等人(2002)J Med Chem.45：5406-9(諸如NO供體14及17)，及Nitric Oxide Donors for Pharmaceutical and Biological Research,Peng George Wang,Tingwei Bill Cai,Naoyuki Taniguchi,Wiley編，2005中；
(3)增加cGMP濃度之其他物質，諸如原卟啉IX、二十碳四烯酸及苯肼衍生物；
(4)氧化氮合成酶基質：例如，基於正羥胍之類似物，諸如N[G]-羥基-L-精胺酸(NOHA)、1-(3,4-二甲氧基-2-氯苯亞甲基胺基)-3-羥胍，及PR5(1-(3,4-二甲氧基-2-氯苯亞甲基胺基)-3-羥胍)；L-精胺酸衍生物(諸如高精胺酸、高NOHA、N-第三丁氧基-L-精胺酸及N-(3-甲基-2-丁烯基)氧基-L-精胺酸、刀豆胺酸(canavanine)、ε胍-己酸、胍丁胺、羥基-胍丁胺及L-酪胺醯基-L-精胺酸)；N-烷基-N'-羥胍(諸如N-環丙基-N'-羥胍及N-丁基-N'-羥胍)、N-芳基-N'-羥胍(諸如N-苯基-N'-羥胍及其分別攜有-F、-Cl、-甲基、-OH取代基的經對位取代之衍生物)；胍衍生物，諸如3-(三氟甲基)丙基胍；以及綜述於Cali等人(2005，Current Topics in Medicinal Chemistry 5：721-736)中且揭示於其中所引用之參考案中的其他化合物。
(5)增強eNOS轉錄之化合物：例如描述於WO 02/064146、WO 02/064545、WO 02/064546及WO 02/064565以及對應的專利文件，
諸如US2003/0008915、US2003/0022935、US2003/0022939及US2003/0055093中之彼等。包括描述於US20050101599中之彼等的其他eNOS轉錄增強劑(例如，2,2-二氟苯并[1,3]二氧雜環戊烯-5-羧酸茚滿-2-基醯胺，及4-氟-N-(茚滿-2-基)-苯甲醯胺)，及賽諾菲-安萬特(Sanofi-Aventis)化合物AVE3085及AVE9488(CA登記號916514-70-0；Schäfer等人，Journal of Thrombosis and Homeostasis 2005；第3卷，增刊1：摘要編號P1487)；
(6)NO非依賴性血紅素非依賴性之sGC活化劑，其包括(但不限於)：BAY 58-2667(參見專利公開案DE19943635)
(7)血紅素依賴性之sGC刺激劑，其包括(但不限於)：
YC-1(參見專利公開案EP667345及DE19744026)
瑞司瓜特(Riociguat)(BAY 63-2521，Adempas，商品化產品，描述於DE19834044中)
樂力司瓜特(Neliciguat)(BAY 60-4552，描述於WO 2003095451中)
衛瑞司瓜特(Vericiguat)(BAY 1021189，瑞司瓜特之臨床備份)，BAY 41-2272(描述於DE19834047及DE19942809中)
BAY 41-8543(描述於DE19834044中)
艾崔司瓜特(Etriciguat)(描述於WO 2003086407中)
CFM-1571(參見專利公開案WO2000027394)
A-344905，其丙烯醯胺類似物A-350619及胺基嘧啶類似物A-778935。
A350-619；
A-344905；
A-778935；
揭示於以下公開案中之一者中的化合物：US20090209556、US8455638、US20110118282(WO2009032249)、US20100292192、US20110201621、US7947664、US8053455(WO2009094242)、US20100216764、US8507512(WO2010099054)、US20110218202(WO2010065275)、US20130012511(WO2011119518)、US20130072492(WO2011149921)、US20130210798(WO2012058132)及揭示於Tetrahedron Letters(2003),44(48)：8661-8663中之其他化合物。
(8)抑制cGMP降解之化合物，諸如：PDE5抑制劑，諸如西地那非(Sildenafil)(Viagra®)；及其他相關藥劑，諸如阿伐那非(Avanafil)、羅地那非(Lodenafil)、米羅那非(Mirodenafil)、西地那非檸檬酸鹽(Sildenafil citrate)(Revatio®)、他達拉非(Tadalafil)(Cialis®或Adcirca®)、伐地那非(Vardenafil)(Levitra®)及烏地那非(Udenafil)；前列地爾(Alprostadil)；以及雙嘧達莫
(Dipyridamole)；PF-00489791 PDE9抑制劑，諸如PF-04447943；
(9)鈣通道阻斷劑，諸如：二氫吡啶鈣通道阻斷劑：胺氯地平(Amlodipine)(Norvasc)、阿軟地平(Aranidipine)(Sapresta)、阿則靈地平(Azelnidipine)(Calblock)、巴尼地平(Barnidipine)(HypoCa)、貝尼地平(Benidipine)(Coniel)、西尼地平(Cilnidipine)(Atelec、Cinalong、Siscard)、氯維地平(Clevidipine)(Cleviprex)、地爾硫卓(Diltiazem)、依福地平(Efonidipine)(Landel)、非洛地平(Felodipine)(Plendil)、拉西地平(Lacidipine)(Motens、Lacipil)、樂卡地平(Lercanidipine)(Zanidip)、馬尼地平(Manidipine)(Calslot、Madipine)、尼卡地平(Nicardipine)(Cardene、Carden SR)、硝苯地平(Nifedipine)(Procardia、Adalat)、尼伐地平(Nilvadipine)(Nivadil)、尼莫地平(Nimodipine)(Nimotop)、尼索地平(Nisoldipine)(Baymycard、Sular、Syscor)、尼群地平(Nitrendipine)(Cardif、Nitrepin、Baylotensin)、普瑞地平(Pranidipine)(Acalas)、伊拉地平(Isradipine)(Lomir)；苯基烷基胺鈣通道阻斷劑：維拉帕米(Verapamil)(Calan、Isoptin)
加洛帕米(Gallopamil)(Procorum、D600)；苯并硫氮雜：地爾硫卓(Diltiazem)(Cardizem)；
非選擇性鈣通道抑制劑，諸如：米貝地爾(mibefradil)、苄普地爾(bepridil)及氟斯必靈(fluspirilene)、芬地林(fendiline)；
(10)內皮素受體拮抗劑(ERA)：例如雙(ETA及ETB)內皮素受體拮抗劑波生坦(Bosentan)(以Tracleer®出售)；西他塞坦(Sitaxentan)，在商品名為Thelin®下出售；安立生坦(Ambrisentan)在美國以Letairis®出售；2008年進入臨床試驗之雙/非選擇性內皮素拮抗劑Actelion-1；
(11)前列環素衍生物或類似物：例如前列環素(前列腺素I2)、依前列醇(Epoprostenol)(合成性前列環素，以Flolan®出售)；曲前列環素(Treprostinil)(Remodulin®)、伊洛前列素(Iloprost)(Ilomedin®)、伊洛前列素(以Ventavis®出售)；正在研發之口服及吸入形式之Remodulin®；貝前列素(Beraprost)，一種在日本及南朝鮮可供使用之口服前列腺素；
(12)降高血脂藥，諸如：膽酸螯合劑(例如，消膽胺、考來替潑(Colestipol)、考來替蘭(Colestilan)及考來維侖(Colesevelam))；士他汀，諸如阿托伐他汀(Atorvastatin)、辛伐他汀(Simvastatin)、洛伐他汀(Lovastatin)、氟伐他汀(Fluvastatin)、匹伐他汀(Pitavastatin)、羅素他汀(Rosuvastatin)及普伐他汀(Pravastatin)；膽固醇吸附抑制劑，諸如依澤替米貝(Ezetimibe)；其他降脂藥劑，諸如二十碳五烯酸乙酯、ω-3-酸乙酯、瑞地可(Reducol)；纖維酸衍生物，諸如氯貝特(Clofibrate)、苯紮貝特(Bezafibrate)、克利貝特(Clinofibrate)、吉非羅齊(Gemfibrozil)、偌尼貝特(Ronifibrate)、比尼貝特(Binifibrate)、芬尼貝特(Fenofirate)、環丙貝
特(Ciprofibrate)、膽鹼非諾貝特(Choline fenofibrate)；菸鹼酸衍生物，諸如阿昔莫司(Acipimox)及菸酸；以及士他汀、菸酸、腸道膽固醇吸附抑制補充劑(依澤替米貝(ezetimibe)及其他)及纖維酸酯之組合；抗血小板治療劑，諸如氯吡格雷硫酸氫鹽；
(13)抗凝血劑，諸如以下類型：˙香豆素(維生素K拮抗劑)：在美國及英國最常使用之Warfarin®(苄丙酮香豆素鈉)；在其他國家主要使用之Acenocoumarol®及Phenprocoumon®；Phenindione®；˙肝素及衍生物質，諸如：肝素；低分子量肝素；方達珀魯(Fondaparinux)及艾卓肝素(Idraparinux)；˙直接凝血酶抑制劑，諸如：阿加曲班(Argatroban)、來匹盧定(Lepirudin)、比伐盧定(Bivalirudin)及達比加群(Dabigatran)；在美國未審批通過之希美加群(Ximelagatran)(Exanta®)；˙組織纖維蛋白溶酶原活化劑，其用於溶解凝塊且不阻塞動脈，諸如阿替普酶(Alteplase)；
(14)抗血小板藥物：例如噻吩并吡啶，諸如氯吡格雷(Lopidogrel)及噻氯匹定(Ticlopidine)；雙嘧達莫(Dipyridamole)；阿司匹林(Aspirin)；
(15)ACE抑制劑，例如以下類型：˙含有硫氫基之藥劑，諸如卡托普利(Captopril)(商標Capoten®)、第一ACE抑制劑及佐芬普利(Zofenopril)；˙含有二甲酸酯之藥劑，諸如依那普利(Enalapril)(Vasotec/Renitec®)；雷米普利(Ramipril)
(Altace/Tritace/Ramace/Ramiwin®)；喹那普利(Quinapril)(Accupril®)、培哚普利(Perindopril)(Coversyl/Aceon®)；賴諾普利(Lisinopril)(Lisodur/Lopril/Novatec/Prinivil/Zestril®)及貝那普利(Benazepril)(Lotensin®)；˙含有膦酸酯之藥劑，諸如福辛普利(Fosinopril)；˙天然存在之ACE抑制劑，諸如：酪激肽(Casokinin)及乳激肽(lactokinin)，其為在攝入乳製品(尤其醱酵牛奶)之後自然產生的酪蛋白及乳清之分解產物；藉由益生菌瑞士乳桿菌(Lactobacillus helveticus)製備或來源於酪蛋白之乳清三肽(Lactotripeptide)Val-Pro-Pro及Ile-Pro-Pro亦具有ACE抑制及抗高血壓功能；˙其他ACE抑制劑，諸如阿拉普利(Alacepril)、地拉普利(Delapril)、西拉普利(Cilazapril)、咪達普利(Imidapril)、群多普利(Trandolapril)、替莫普利(Temocapril)、莫西普利(Moexipril)、螺普利(Spirapril)，
(16)補充氧療法；
(17)β阻斷劑，諸如以下類型：˙非選擇性藥劑：Alprenolol®、Bucindolol®、Carteolol®、Carvedilol®(具有額外的α-阻斷活性)、Labetalol®(具有額外的α阻斷活性)、Nadolol®、Penbutolol®(具有固有的擬交感神經活性)、Pindolol®(具有固有的擬交感神經活性)、沃克普洛爾(Oxprenonol)、醋丁洛爾(Acebutolol)、索他洛爾(Sotalol)、甲吲洛爾(Mepindolol)、塞利洛爾(Celiprolol)、阿羅洛爾(Arotinolol)、特他洛爾(Tertatolol)、胺磺洛爾(Amosulalol)、尼普地洛(Nipradilol)、Propranolol®及Timolol®；
˙β1選擇性藥劑：Acebutolol®(具有固有的擬交感神經活性)、Atenolol®、Betaxolol®、Bisoprolol®、Celiprolol®、鹽酸多巴酚丁胺(Dobutamine hydrochloride)、伊索拉定順丁烯二酸酯(Irsogladine maleate)、卡維地洛(Carvedilol)、他力洛爾(Talinolol)、Esmolol®、Metoprolol®及Nebivolol®；˙β2選擇性藥劑：Butaxamine®(微弱的α腎上腺素促效活性)；
(18)抗心律失常藥劑，諸如以下類型：˙I型(鈉通道阻斷劑)：奎尼丁(Quinidine)、利多卡因(Lidocaine)、苯妥英(Phenytoin)、普羅帕酮(Propafenone)˙III型(鉀通道阻斷劑)：胺碘酮(Amiodarone)、多非利特(Dofetilide)、索他洛爾(Sotalol)˙V型：腺苷(Adenosine)、地高辛(Digoxin)
(19)利尿劑，諸如：噻嗪化物利尿劑，例如氯噻嗪、氯噻酮及氫氯噻嗪、苄氟甲噻嗪、環戊噻嗪、甲氯噻嗪、多噻嗪、喹乙唑酮、希伯胺(Xipamide)、美托拉宗(Metolazone)、吲達帕胺(Indapamide)、西氯他丁(Cicletanine)；環形利尿劑，諸如呋喃苯胺酸(Furosemide)及特瑞胺(Toresamide)；留鉀利尿劑，諸如胺氯吡脒(Amiloride)、螺內酯(Spironolactone)、坎利酸鉀、(Canrenoate potassium)、依普利酮(Eplerenone)及胺苯喋啶(Triamterene)；此等藥劑之組合；其他利尿劑，諸如乙醯唑胺(Acetazolamid)及卡培立肽(Carperitide)
(20a)直接起作用之血管擴張劑，諸如肼酞嗪氫氯化物、二氮嗪、硝普化鈉、卡屈嗪(Cadralazine)；其他血管擴張劑，諸如異山梨醇二硝酸鹽及異山梨醇5-單硝酸鹽；
(20b)外源性血管擴張劑，諸如：˙Adenocard®，一種腺苷促效劑，主要用作抗心律不齊；˙α阻斷劑(其阻斷腎上腺素之血管收縮效果)：α-1-腎上腺素受體拮抗劑，諸如哌唑嗪(Prazosin)、吲哚拉明(Indoramin)、烏拉地爾(Urapidil)、布那唑嗪(Bunazosin)、特拉唑嗪(Terazosin)、多沙唑嗪(Doxazosin)˙心房利尿鈉肽(ANP)；˙乙醇；˙組織胺誘導劑，其補體蛋白質C3a、C4a及C5a藉由觸發自肥大細胞及嗜鹼性血球粒細胞釋放之組織胺來作用；˙四氫大麻酚(THC)，具有輕微血管舒張作用之大麻中的主要活性化學物質；˙罌粟鹼，一種鴉片罌粟花中發現之生物鹼；
(21)支氣管擴張劑：存在兩種主要類型之支氣管擴張劑，下文所例示之β 2促效劑及抗膽鹼激導性劑：˙β2促效劑：Salbutamol®或沙丁胺醇(albuterol)(常見品牌名稱：Ventolin)及Terbutaline®為快速緩解COPD症狀之短效β2促效劑。長效β 2促效劑(LABA)，諸如Salmeterol®及Formoterol®；˙抗膽鹼激導性劑：Ipratropium®為最廣泛地處方短效抗膽鹼激導性藥物。Tiotropium®為COPD之最常處方長效抗膽鹼激導性藥物；˙Theophylline®，一種支氣管擴張劑及磷酸二酯酶抑制劑；
(22)皮質類固醇：諸如倍氯米松(beclomethasone)、甲基潑尼龍(methylprednisolone)、倍他米松(betamethasone)、潑尼松(prednisone)、
潑尼龍(prenisolone)、曲安西龍(triamcinolone)、地塞米松(dexamethasone)、氟替卡松(fluticasone)、氟尼縮松(flunisolide)及氫化可體松(hydrocortisone)，及諸如布地奈德(budesonide)之皮質類固醇類似物；
(23)膳食補充劑，諸如：Ω-3油；葉酸；菸酸；鋅；銅；朝鮮紅參根、銀杏、松樹皮、蒺藜(Tribulus terrestris)、精胺酸、燕麥(Avena sativa)、淫羊藿、秘魯人參根、鐵青樹鹼(muira puama)、鋸棕櫚(saw palmetto)，及瑞典花粉(Swedish flower pollen)；維生素C、維生素E、維生素K2；睾固酮補充劑、睾固酮經皮貼片；克拉維酸(Zoraxel)、納曲酮(Naltrexone)、布雷默浪肽(Bremelanotide)(先前為PT-141)、美拉諾坦II(Melanotan II)、hMaxi-K；碧蘿芷(Prelox)：一種天然存在成分(L-精胺酸天冬氨酸鹽及碧容健(Pycnogenol))之專屬混合/組合；
(24)PGD2受體拮抗劑，其包括(但不限於)：在美國公開申請案US20020022218、US20010051624及US20030055077、PCT公開申請案W09700853、W09825919、WO03066046、WO03066047、WO03101961、WO03101981、WO04007451、WO0178697、WO04032848、WO03097042、WO03097598、WO03022814、WO03022813及WO04058164、歐洲專利申請案EP945450及EP944614中描述為具有PGD2拮抗活性之化合物，及在Torisu等人，2004 Bioorg Med Chem Lett 14：4557，Torisu等人.2004 Bioorg Med Chem Lett 2004 14：4891及Torisu等人.2004 Bioorg & Med Chem 2004 12：4685中所列出之彼等化合物；
(25)免疫抑制劑，諸如環孢靈(cyclosporine)(環孢靈A、
Sandimmune®、Neoral®)、他克莫司(tacrolimus)(FK-506、Prograf®)、雷帕黴素(rapamycin)(西羅莫司(sirolimus)、Rapamune®)及其他FK-506型免疫抑制劑，及黴酚酸酯(mycophenolate)，例如黴酚酸嗎啉乙酯(CellCept®)；
(26)非類固醇抗氣喘劑，諸如β2-促效劑(例如，間羥叔丁腎上腺素(terbutaline)、間羥異丙腎上腺素(metaproterenol)、非諾特羅(fenoterol)、異他林(isoetharine)、沙丁胺醇(albuterol)、沙美特羅(salmeterol)、比托特羅(bitolterol)及吡布特羅(pirbuterol))及β2促效劑-皮質類固醇組合(例如，沙美特羅-氟替卡松(Advair®)、福莫特羅(formoterol)-布地奈德(budesonid)(Symbicort®))、茶鹼(theophylline)、色甘酸(cromolyn)、色甘酸鈉(cromolyn sodium)、奈多羅米(nedocromil)、阿托品(atropine)、異丙托銨(ipratropium)、異丙托溴銨(ipratropium bromide)、白三烯(leukotriene)生物合成抑制劑(齊留通(zileuton)、BAY1005)；
(27)非類固醇消炎劑(NSAID)，諸如丙酸衍生物(例如，阿明洛芬(alminoprofen)、苯惡洛芬(benoxaprofen)、布氯酸(bucloxic acid)、卡洛芬(carprofen)、芬布芬(fenbufen)、非諾洛芬(fenoprofen)、氟洛芬(fluprofen)、氟比洛芬(flurbiprofen)、布洛芬(ibuprofen)、吲哚洛芬(indoprofen)、酮基布洛芬(ketoprofen)、咪洛芬(miroprofen)、萘普生(naproxen)、奧沙普嗪(oxaprozin)、吡洛芬(pirprofen)、普拉洛芬(pranoprofen)、舒洛芬(suprofen)、噻洛芬酸(tiaprofenic acid)及硫惡洛芬(tioxaprofen))、乙酸衍生物(例如，吲哚美辛(indomethacin)、阿西美辛(acemetacin)、阿氯芬酸(alclofenac)、環氯茚酸(clidanac)、雙氯芬酸
(diclofenac)、芬氯酸(fenclofenac)、芬克洛酸(fenclozic acid)、芬替酸(fentiazac)、呋羅芬酸(furofenac)、異丁芬酸(ibufenac)、伊索克酸(isoxepac)、噁平酸(oxpinac)、舒林酸(sulindac)、硫平酸(tiopinac)、托美丁(tolmetin)、齊多美辛(zidometacin)及佐美酸(zomepirac))、芬那酸衍生物(例如，氟芬那酸(flufenamic acid)、甲氯芬那酸(meclofenamic acid)、甲芬那酸(mefenamic acid)、氟尼酸(niflumic acid)及托芬那酸(tolfenamic acid))、二苯基羧酸衍生物(例如，二氟尼柳(diflunisal)及氟苯柳(flufenisal))、昔康(oxicams)(例如，伊索昔康(isoxicam)、吡羅昔康(piroxicam)、舒多昔康(sudoxicam)及替諾昔康(tenoxican))、水楊酸酯(例如，乙醯水楊酸及柳氮磺胺吡啶)及吡唑啉酮(例如，阿帕宗(apazone)、苯哌隆(bezpiperylon)、非普拉宗(feprazone)、莫非布宗(mofebutazone)、羥布宗(oxyphenbutazone)及苯基丁氮酮(phenylbutazone))；
(28)環加氧酶-2(COX-2)抑制劑，諸如塞內昔布(celecoxib)(Celebrex®)、羅非昔布(rofecoxib)(Vioxx®)、伐地考昔(valdecoxib)、依他昔布(etoricoxib)、帕瑞昔布(parecoxib)及羅美昔布(lumiracoxib)；類鴉片鎮痛劑，諸如可待因(codeine)、芬太尼(fentanyl)、氫嗎啡酮(hydromorphone)、左啡諾(levorphanol)、麥啶(meperidine)、美沙酮(methadone)、嗎啡鹼(morphine)、羥考酮(oxycodone)、羥嗎啡酮(oxymorphone)、丙氧吩(propoxyphene)、丁基原啡因(buprenorphine)、布托啡諾(butorphanol)、地佐辛(dezocine)、納布啡(nalbuphine)及戊唑星(pentazocine)；及
(29)抗糖尿病劑，諸如胰島素及胰島素模擬物、磺醯脲(例如，格
列瑞得(Glyburide)、格列本脲(Glybenclamide)、格列吡嗪(Glipizide)、格列齊特(Gliclazide)、格列喹酮(Gliquidone)、格列美脲(Glimepiride)、麥格林那(Meglinatide)、甲苯磺丁脲(Tolbutamide)、氯磺丙脲(Chlorpropamide)、醋磺環已脲(Acetohexamide)、甲磺吖庚脲(Tolazamide))，雙胍(例如二甲雙胍(metformin)(Glucophage®))、α葡糖苷酶抑制劑(諸如阿卡波糖(Acarbose)、依帕司他(Epalrestat)、伏格列波糖(Voglibose)、米格列醇(Miglitol))，噻唑烷酮化合物，例如羅格列酮(rosiglitazone)(Avandia®)、曲格列酮(troglitazone)(Rezulin®)、環格列酮(ciglitazone)、吡格列酮(pioglitazone)(Actos®)及恩格列酮(englitazone)；胰島素敏化劑，諸如吡格列酮及羅格列酮；胰島素促分泌物，諸如瑞格列奈(Repaglinide)、那格列奈(Nateglinide)及米格列奈(Mitiglinide)；促胰島素模擬物，諸如艾塞那肽(Exanatide)及利拉魯肽(Liraglutide)；澱粉素類似物，諸如普蘭林肽(Pramlintide)；降葡萄糖劑，諸如吡啶甲酸鉻(Chromium picolinate)(視情況可與生物素組合)；二肽基肽酶IV抑制劑，諸如西他列汀(Sitagliptin)、維格列汀(Vildagliptin)、沙格列汀(Saxagliptin)、阿格列汀(Alogliptin)及利格列汀(Linagliptin)；目前研發用於治療糖尿病之疫苗；AVE-0277、Alum-GAD、BHT-3021、IBC-VS01；用於治療糖尿病的研發中之細胞激素靶向治療劑，諸如阿那白滯素(Anakinra)、康納單抗(Canakinumab)、雙醋瑞因(Diacerein)、介維單抗(Gevokizumab)、LY-2189102、MABP-1、GIT-027；
(30)HDL膽固醇遞增劑，諸如安特普(Anacetrapib)、MK-524A、CER-001、DRL-17822、達塞曲匹(Dalcetrapib)、JTT-302、RVX-
000222、TA-8995；
(31)抗肥胖藥，諸如鹽酸甲基安非他明、鹽酸安非拉酮(Tenuate®)、苯丁胺(Ionamin®)、鹽酸苄非他明(Didrex®)、苯二甲嗎啉酒石酸鹽(Bontril®、Prelu-2®、Plegine®)、氯苯咪吲哚(Mazindol)(Sanorex®)、羅氏鮮(Orlistat)(Xenical®)、鹽酸諾美婷單水合物(Meridia®、Reductil®)、利莫那班(Rimonabant)(Acomplia®)、安非潑拉酮(Amfepramone)、吡啶甲酸鉻(Chromium picolinate)、RM-493、TZP-301；諸如苯丁胺/托吡酯、安非他酮/納曲酮、諾美婷/二甲雙胍、安非他酮SR/唑尼沙胺SR、沙美特羅、羥萘甲酸鹽/丙酸氟替卡松之組合；鹽酸氯卡色林、苯丁胺/托吡酯、安非他酮/納曲酮、賽利司他、艾塞那肽、KI-0803、利拉魯肽、鹽酸二甲雙胍、諾美婷/二甲雙胍、876167、ALS-L-1023、安非他酮SR/唑尼沙胺SR、CORT-108297、卡格列淨(Canagliflozin)、吡啶甲酸鉻、GSK-1521498、LY-377604、美曲普汀(Metreleptin)、奧尼匹肽(Obinepitide)、P-57AS3、PSN-821、羥萘甲酸沙美特羅/丙酸氟替卡松、鎢酸鈉、促生長激素(重組型)、TM-30339、TTP-435、替莫瑞林(Tesamorelin)、泰索酚辛(Tesofensine)、韋利貝特(Velneperit)、唑尼沙胺(Zonisamide)、BMS-830216、ALB-127158、AP-1030、ATHX-105、AZD-2820、AZD-8329、半草酸貝洛尼布、CP-404、HPP-404、ISIS-FGFR4Rx、胰島素促生素、KD-3010PF、05212389、PP-1420、PSN-842、肽YY3-36、白藜蘆醇(Resveratrol)、S-234462；S-234462、薩貝替揉(Sobetirome)、TM-38837、四氫次大麻酚、ZYO-1、β-拉帕酮；
(32)血管收縮素受體阻斷劑，諸如洛沙坦(Losartan)、纈沙坦
(Valsartan)、坎地沙坦酯(Candesartan cilexetil)、艾普薩瑞(Eprosaran)、依貝沙坦(Irbesartan)、替米沙坦(Telmisartan)、奧美沙坦(Olmesartran)美度米(medoxomil)、阿奇沙坦美度米；
(33)腎素抑制劑，諸如阿力克倫半富馬酸鹽(Aliskiren hemifumirate)；
(34)中樞作用α-2-腎上腺素受體促效劑，諸如甲基多巴(Methyldopa)、可樂定(Clonidine)、胍法新(Guanfacine)；
(35)腎上腺素神經元阻斷劑，諸如胍乙啶(Guanethidine)、胍那決爾(Guanadrel)；
(36)咪唑啉I-1受體促效劑，諸如利美尼定二氫磷酸鹽(Rimenidine dihydrogen phosphate)及鹽酸莫索尼定水合物(Moxonidine hydrochloride hydrate)；
(37)醛固酮拮抗劑，諸如螺內酯及依普利酮(Eplerenone)；
(38)鉀通道活化劑，諸如吡那地爾(Pinacidil)；
(39)多巴胺D1促效劑，諸如非諾多泮甲磺酸鹽(Fenoldopam mesilate)；其他多巴胺促效劑，諸如異波帕胺(Ibopamine)、多培沙明(Dopexamine)及多卡巴胺(Docarpamine)；
(40)5-HT2拮抗劑，諸如酮色林(Ketanserin)；
(42)血管加壓素拮抗劑，諸如托伐普坦(Tolvaptan)；
(43)鈣通道敏化劑，諸如左西孟旦(Levosimendan)，或鈣通道活化劑，諸如尼可地爾；
(44)PDE-3抑制劑，諸如氨利酮(Amrinone)、米利酮(Milrinone)、依諾昔酮(Enoximone)、維司力農(Vesnarinone)、匹莫苯(Pimobendan)、
奧普力農(Olprinone)；
(45)腺苷酸環化酶活化劑，諸如鹽酸考福斯達普酸鹽(Colforsin dapropate hydrochloride)；
(46)正性心肌收縮劑，諸如地高辛(Digoxin)及甲地高辛(Metildigoxin)；代謝強心劑，諸如泛癸利酮(Ubidecarenone)；腦促脲鈉排泄肽，諸如奈西立肽(Nesiritide)；
(47)用於治療勃起功能障礙之藥物，諸如前列地爾(Alprostadil)、阿肽地爾(Aviptadil)、甲磺酸芬托拉明(Phentolamine mesilate)、偉哥(Weige)、前列地爾；
(48)抗肥胖藥物：
(49)用於治療阿茲海默氏症之藥物：例如，針對輕度至中度阿茲海默氏症處方之膽鹼酯酶抑制劑，包括Razadyne®(加蘭他敏(galantamine))、Exelon®(雷斯替明(rivastigmine))及Aricept®(多奈哌齊(donepezil))、Cognex®(他可林(tacrine))；Namenda®(美金剛(memantine))(一種D-天冬氨酸N-甲酯(NMDA)拮抗劑)及Aricept®，處方以治療中度至重度的阿茲海默氏症；維生素E(一種抗氧化劑)。
(50)抗抑鬱劑：三環抗抑鬱劑，諸如阿米曲替林(amitriptyline)(Elavil®)、地昔帕明(desipramine)(Norpramin®)、丙咪嗪(imipramine)(Tofranil®)、阿莫沙平(amoxapine)(Asendin®)、去甲替林(nortriptyline)；選擇性血清素再攝取抑制劑(SSRI's)，諸如帕羅西汀(paroxetine)(Paxil®)、氟西汀(Prozac®)、舍曲林(sertraline)(Zoloft®)及西酞普蘭(citralopram)(Celexa®)；及其他，諸如多塞平(doxepin)(Sinequan®)及曲唑酮(trazodone)(Desyrel®)；SNRI(例如，文拉法辛(venlafaxine)及瑞波西汀(reboxetine))；多巴胺激導性抗抑鬱劑(例如，安非他酮(bupropion)及安咪奈丁(amineptine))。
(51)神經保護性藥劑：例如，美金剛、左旋多巴(L-dopa)、溴麥角環肽(bromocriptine)、培高利特(pergolide)、他利克索(talipexol)、普拉克索(pramipexol)、卡麥角林(cabergoline)、目前正在研究中之神經保護性藥劑(包括抗細胞凋亡藥物(CEP 1347及CTCT346))、拉紮洛依(lazaroids)、生物能學劑、抗谷胺酸能劑及多巴胺受體。其他臨床上評估之神經保護性藥劑為例如單胺氧化酶B抑制劑司來吉蘭(selegiline)及雷沙吉蘭(rasagiline)、多巴胺促效劑及複合物I粒線體強化劑輔酶Q10。
(52)抗精神病藥物：例如，齊拉西酮(ziprasidone)(GeodonTM)、利培酮(risperidone)(RisperdalTM)及奧氮平(olanzapine)(ZyprexaTM)。
(53)NEP抑制劑，諸如沙庫必曲(Sacubitril)、奧馬曲拉(Omapatrilat)。
(54)亞甲基藍(MB)。
本文所描述之固體形式及醫藥調配物可包含於套組中。套組可包括
各自單獨地封裝或調配之兩種或更多種藥劑之單劑量或多劑量，或以組合形式封裝或調配之兩種或更多種藥劑之單劑量或多劑量。因此，一或多種藥劑可存在於第一容器中，且套組可視情況包括第二容器中之一或多種藥劑。將一或多個容器置放於封裝內，且該封裝可視情況包括投藥或劑量說明。套組可包括諸如注射器之額外組件或用於投與藥劑以及稀釋劑之其他構件或用於調配之其他構件。因此，套組可包含：a)包含本文所描述之化合物及醫藥學上可接受之載劑、媒劑或稀釋劑的醫藥組合物；及b)容器或封裝。套組可視情況包含描述在本文所描述之方法(例如，預防或治療本文所描述之疾病及病症中之一或多者)中之一或多者中使用醫藥組合物之方法的說明。套組可視情況包含第二醫藥組合物，該第二醫藥組合物包含用於共同療法使用之本文所描述之一或多種額外藥劑、醫藥學上可接受之載劑、媒劑或稀釋劑。包含本文所描述之化合物及套組中含有之第二醫藥組合物的醫藥組合物可視情況組合在同一醫藥組合物中。
套組包括含有醫藥組合物之容器或封裝，且亦可包括分開的容器，諸如分開的瓶子或分開的箔片封包。容器可為例如紙盒或硬紙盒、玻璃或塑膠瓶子或罐、可再密封袋(例如，以固持錠劑「再填充」用於置放在不同容器中)，或用於根據治療時程自包裝按壓出之具有個別劑量的泡殼包裝。可行的係在單個封裝中一起使用超過一個容器以行銷單一劑型。舉例而言，錠劑可容納於瓶子中，再因此將瓶子容納於盒內。
套組之一個實例是所謂的泡殼包裝。泡殼包裝在封裝行業中為人所熟知，且廣泛用於封裝醫藥單位劑型(錠劑、膠囊及其類似劑型)。泡殼包裝一般係由用較透明塑膠材料之箔片覆蓋的相對剛性材料之薄片組成。在封裝過程期間，在塑膠箔片中形成凹槽。凹槽具有待封裝之個別錠劑或膠
囊之大小及形狀或可具有容納待封裝之多個錠劑及/或膠囊的大小及形狀。然後，將錠劑或膠囊相應地置放在凹槽中，且相對於塑膠箔片，在箔片上與形成凹槽之方向相反之一面密封相對剛性材料之薄片。因此，按需要，將錠劑或膠囊單獨地密封或集體地密封於塑膠箔片與薄片之間的凹槽中。較佳地，薄片之強度使得可藉由在凹槽上手動施加壓力，藉此在凹槽位置處的薄片中形成開口來自泡殼包裝移除錠劑或膠囊。錠劑或膠囊可隨後經由該開口來移除。
可能需要提供含有關於何時服用藥物之醫師、藥劑師或個體之信息及/或說明的書面記憶輔助物。「日劑量」為於指定日期待服用之單一錠劑或膠囊、或若干錠劑或膠囊。當套組含有獨立的組合物時，套組之一或多種組合物之日劑量可由一種錠劑或膠囊組成而套組之其他或更多組合物之日劑量可由若干錠劑或膠囊組成。套組可採取經設計以按其所希望之使用次序每次分配日劑量的分配器形式。分配器可配備有記憶輔助物，以便進一步促成與療程一致。此記憶輔助物之實例為指示已分配之日劑量之數目的機械計數器。此記憶輔助物之另一實例為與液晶讀數器或音頻提醒信號耦接的電池供電之微晶片記憶體，該液晶讀數器或音頻提示信號例如讀出服用上一日劑量之日期及/或提醒吾人何時服用下一劑量。
實例1：粗化合物I之製備
i)：化合物(1')與N,O-二甲基羥胺偶合以獲得N-甲氧基-N-甲基異噁唑-3-甲醯胺(2')
將異噁唑-3-羧酸((1')，241.6g，2137毫莫耳，1.0當量)、甲苯(1450mL)及DMF(7.8g，107毫莫耳，0.05當量)充添至配備有機械攪拌器及數位溫度計之適合反應容器中。將所得漿液加熱至45℃至50℃。隨後歷經2h時程將乙二醯氯(325g，2559毫莫耳，1.2當量)經由加料漏斗充添，同時使反應溫度維持在45℃至50℃之間且觀測到劇烈的氣體釋放。在添加之後獲得褐色混合物。歷經1h將褐色混合物加熱至87℃至92℃且在87℃至92℃下攪拌1h。如利用HPLC所展示完成反應。在加熱期間，褐色混合物變為深色溶液。藉由將部分反應混合物淬滅成哌啶且利用HPLC監測哌啶醯胺來監測反應。使深色混合物冷卻至20℃至25℃且隨後經由燒結玻璃漏斗過濾以移除任何不溶物。在減壓下將深色濾液濃縮至400mL體積之深色油狀物。
將碳酸鉀(413g，2988毫莫耳，1.4當量)及水(1000mL)充添至配備有機械攪拌器及數位溫度計之適合反應容器中。使反應溶液冷卻至-10℃至-5℃。將N,O-二甲基羥胺鹽酸鹽(229g，2348毫莫耳，1.1當量)充添至適合反應容器中且溶解於水(1000mL)中。隨後將N,O-二甲基羥胺溶液與二氯甲烷(2500mL)充添至碳酸鉀溶液中。
隨後經由加料漏斗緩慢充添上述深色油狀物(400mL)同時使反應溫度維持在-10℃至0℃。添加略微地發熱且在添加之後獲得褐色混合物。在0℃至5℃下攪拌混合物超過20min。且隨後升溫至20℃至25℃。收集底部有機層且用二氯甲烷(400mL)萃取頂部水層。經合併之有機層用15%氯化鈉溶液(1200mL)洗滌。有機層經硫酸鎂乾燥且隨後過濾。在減壓下濃縮濾液，以得到呈深色油狀之中間物(2')(261.9g，97wt%，76%產率，1H-NMR為3wt%甲苯，KF為0.04wt%含水量)。1H-NMR(500MHz,
CDCl3)δ ppm 8.48(s,1 H)；6.71(s,1 H)；3.78(s,3 H)；3.38(s,3 H)。
ii)：化合物(2')與丙炔酸乙酯之烷化以獲得4-(異噁唑-3-基)-2-(甲氧基(甲基)胺基)-4-側氧基丁-2-烯酸(E)-乙酯(3')
將中間物(2')(72.2g，96wt%，444毫莫耳，1.0當量)、丙炔酸乙酯(65.7g，670毫莫耳，1.5當量)及無水THF(650mL)充添至配備有機械攪拌器及數位溫度計之適合反應容器中。使溶液冷卻至-65℃至-55℃。隨後經由加料漏斗緩慢充添含雙(三甲基矽烷基)醯胺鈉之THF(1M，650mL,650毫莫耳，1.46當量)同時使反應溫度維持在-65℃至-55℃。在添加完成後，在低於-55℃下攪拌混合物超過10min。隨後充添1N HCl(650mL，650毫莫耳，1.46當量)以淬火反應同時使反應溫度維持在低於-20℃，之後緊接著添加乙酸乙酯(1500mL)及水(650mL)。收集頂部乙酸乙酯層且用乙酸乙酯(800mL)萃取底部水性層。經合併之有機層用10%檸檬酸(1000mL)及飽和氯化鈉溶液(650mL)洗滌。在減壓下濃縮有機層，以得到深色油狀物。
使深色油狀物溶解於二氯甲烷/乙酸乙酯/庚烷(150mL/100mL/100mL)之溶液中。將溶液裝載於矽石襯墊(410g)上且用乙酸乙酯/庚烷(1/1 v/v)溶離矽石襯墊。收集濾液(~3000mL)且隨後在減壓下將其濃縮至體積150mL，在靜置之後得到漿液。隨後將庚烷(200mL)添加至漿液中且在減壓下濃縮漿液至體積150mL。過濾所得漿液且用庚烷(150mL)洗滌
濾餅。隨後空氣乾燥濾餅隔夜以獲得呈褐色固體狀之中間物(3')(63.4g，56%產率，HPLC純度>99%)。1H-NMR(500MHz,CDCl3)δ ppm 8.42(d,J=1.53Hz,1 H)；6.76(d,J=1.53Hz,1 H)；6.18(s,1 H)；4.47(q,J=7.07Hz,2H)；3.75(s,3 H)；3.21(s,3 H)；1.41(t,J=7.17Hz,3 H)。
iii)：化合物3'與2-氟苯甲基肼之環化以獲得1-(2-氟苯甲基)-5-(異噁唑-3-基)-1H-吡唑-3-羧酸乙酯(4')
將中間物(3')(72.9g，287毫莫耳，1.0當量)及無水乙醇(730mL)充添至配備有機械攪拌器及數位溫度計之反應容器中將混合物冷卻至0℃至5℃。隨後將2-氟苯甲基肼(48.2g，344毫莫耳，1.2當量)充添至混合物中。在0℃至10℃下攪拌混合物超過1h且隨後升溫至20℃至25℃且在20℃至25℃下攪拌超過16h。利用HPLC完成反應。歷經1min將濃縮之HCl(33.9g，37wt%，344毫莫耳，1.2當量)充添至反應混合物且批料溫度自20℃發熱至38℃。獲得漿液。歷經1h使混合物冷卻至0℃至10℃且在0℃至10℃下攪拌1h。過濾所得漿液，且用乙醇(200mL)洗滌濾餅。在30℃至40℃下在真空下乾燥濾餅超過16h以獲得呈灰白色固體之中間物(4')(81.3g，90%產率，HPLC純度>99%)。1H-NMR(500MHz,CDCl3)δ ppm 8.47(d,J=1.68Hz,1 H)；7.15-7.26(m,2 H)；6.94-7.08(m,2H)；6.77-6.87(m,1 H)；6.55(d,J=1.68Hz,1 H)；5.95(s,2 H)；4.43(q,J=7.02Hz,2 H)；1.41(t,J=7.17Hz,3 H)。
iv)：化合物(4')之胺化以獲得1-(2-氟苯甲基)-5-(異噁唑-3-基)-1H-吡唑-3-甲脒氫氯化物(5'B)
將無水氯化銨(267g，4991毫莫耳，5.0當量)及甲苯(5400mL)充添至配備有機械攪拌器及數位溫度計之反應容器中。經由加料漏斗緩慢充添含三甲基鋁之甲苯(2M，2400mL，4800毫莫耳，4.8當量)同時使反應溫度維持在20℃至40℃(注意：在添加期間觀測到甲烷氣體釋放)。隨後歷經30min使混合物加熱至75℃至80℃且獲得透明白色溶液。在75℃至90℃下歷經1h將中間物(4')(315g，999毫莫耳，1.0當量)以四等份充添至反應混合物中。在80℃至90℃下攪拌反應物超過30min且隨後加熱至100℃至110℃並在100℃至110℃下攪拌超過3h。利用HPLC完成反應。使反應混合物冷卻至10℃至20℃且經由加料漏斗緩慢充添甲醇(461g，14.4莫耳，14.4當量)同時使反應溫度維持在10℃至40℃。注意淬滅係極其發熱的且觀測到大量氣體釋放。獲得濃稠的漿液。隨後經由加料漏斗緩慢充添3N HCl(6400mL，3N，19.2莫耳，19.2當量)同時使反應溫度維持在20℃至45℃下。將混合物加熱至80℃至85℃且在80℃至85℃下攪拌超過10min以獲得透明的兩相混合物。歷經3h使混合物冷卻至0℃至5℃且在0℃至5℃下攪拌超過1h。過濾所得漿液，且用水(3000mL)洗滌濾餅。在40℃至50℃下在真空下乾燥濾餅超過24h以獲得呈灰白色固體之中間物(5'B)(292g，91%產率，HPLC純度>99%)。1H-NMR(500MHz,
DMSO-d 6)δ ppm 9.52(s,2 H)；9.33(s,2 H)；9.18(d,J=1.53Hz,1 H)；7.88(s,1 H)；7.29-7.38(m,1 H)；7.19-7.25(m,1 H)；7.10-7.16(m,1 H)；7.03(d,J=1.53Hz,1 H)；6.92-6.98(m,1 H)；5.91(s,2 H)。M.P.180℃-185℃。
v)：化合物(5'B)與氟丙二酸二乙酯之環化以獲得5-氟-2-(1-(2-氟苯甲基)-5-(異噁唑-3-基)-1H-吡唑-3-基)嘧啶-4,6-二醇(6')
將中間物(5'B)(224.6g，698毫莫耳，1.0當量)、甲醇(2250mL)及氟丙二酸二乙酯(187g，1050毫莫耳，1.5當量)充添至配備有機械攪拌器及數位溫度計之適合反應容器中。隨後經由加料漏斗充添含甲醇鈉之甲醇溶液(567g，30wt%，3149毫莫耳，4.5當量)同時使反應溫度維持在20℃至35℃。在20℃至35℃下攪拌混合物超過30min且獲得淺色懸浮液。利用HPLC完成反應。經由加料漏斗歷經1h充添1.5N HCl溶液(2300mL，3450毫莫耳，4.9當量)同時使反應溫度維持在20℃至30℃。獲得白色懸浮液。反應混合物之pH經pH紙測定為~1。在20℃至30℃下攪拌漿液超過30min。過濾所得漿液，且用甲醇與水(500mL/500mL)之預混溶液，且隨後用水(1000mL)洗滌濾餅。在50℃至60℃下在真空下乾燥濾餅超過16h以獲得呈灰白色固體之中間物(6')(264g，97%產率，HPLC純度>99%)。1H-NMR(500MHz,DMSO-d 6)δ ppm 12.82(br.s.,1 H)；12.31(br.s.,
1 H)；9.14(d,J=1.53Hz,1 H)；7.55(s,1 H)；7.31-7.37(m,1 H)；7.18-7.25(m,1 H)；7.10-7.15(m,2 H)；6.97-7.02(t,J=7.55Hz,1 H)；5.88(s,2 H)。
vi)：化合物(6')之氯化以獲得3-(3-(4,6-二氯-5-氟嘧啶-2-基)-1-(2-氟苯甲基)-1H-吡唑-5-基)異噁唑(7')
將中間物(6')(264g，711毫莫耳，1.0當量)、乙腈(4000mL)及N,N-二甲基苯胺(138g，1137毫莫耳，1.6當量)充添至配備有機械攪拌器及數位溫度計之適合反應容器中。使漿液混合物加熱至70℃至80℃。隨後經由加料漏斗歷經1h充添氧氯化磷(655g，4270毫莫耳，6.0當量)同時使反應溫度維持在70℃至80℃。在75℃至80℃下攪拌混合物超過22h且獲得褐色溶液。利用HPLC完成反應。隨後使混合物冷卻至0℃與5℃之間且在25℃下沈澱出棉花狀固體。經由加料漏斗緩慢充添水(3000mL)同時使反應溫度維持在0℃至10℃。在0℃至10℃下攪拌漿液超過30min。過濾所得漿液，且用乙腈與水(500mL/500mL)之預混溶液洗滌濾餅。在35℃至45℃下在真空下乾燥濾餅超過16h以獲得呈灰白色固體狀之中間物(7')(283g，98%產率，HPLC純度>99%)。1H-NMR(500MHz,CDCl3)δ ppm 8.48(d,J=1.68Hz,1 H)；7.44(s,1 H)；7.19-7.25(m,1 H)；6.96-7.08(m,2 H)；6.81-6.88(m,1 H)；6.60(d,J=1.68Hz,1 H)；
6.03(s,2 H)。
vii)：化合物(7')經甲醇鹽取代以獲得3-(3-(4-氯-5-氟-6-甲氧基嘧啶-2-基)-1-(2-氟苯甲基)-1H-吡唑-5-基)異噁唑(8')
將甲醇(3400mL)及含甲醇鈉之甲醇(154mL，5.4M，832毫莫耳，1.2當量)充添至配備有機械攪拌器及數位溫度計之適合反應容器中。將反應混合物加熱至23℃至27℃。歷經40min將中間物(7')(283g，693毫莫耳，1.0當量)以小份(5g至10g各份)充添至混合物同時使反應溫度維持在23℃至27℃。在23℃至27℃下攪拌漿液超過30min。利用HPLC完成反應。過濾所得漿液，且用甲醇(850mL)且隨後水(850mL)洗滌濾餅。在35℃至45℃下在真空下乾燥濾餅超過16h以獲得呈灰白色固體之中間物(8')(277g，99%產率，HPLC純度為97%)。1H-NMR(500MHz,CDCl3)δ ppm 8.47(d,J=1.83Hz,1 H)；7.38(s,1 H)；7.18-7.25(m,1 H)；7.01-7.08(m,1 H)；6.94-7.00(m,1 H)；6.81-6.88(m,1 H)；6.60(d,J=1.68Hz,1 H)；6.00(s,2 H)；4.21(s,3 H)。
viii)：化合物(8')之氫化以獲得3-(3-(5-氟-4-甲氧基嘧啶-2-基)-1-(2-氟苯甲基)-1H-吡唑-5-基)異噁唑(9')
將中間物(8')(226g，560毫莫耳，1.0當量)、鈀(10%於活化碳上，標稱地50%水潤濕，22.6g，0.01莫耳，0.018當量)、四氫呋喃(3400mL)及三乙胺(91g，897毫莫耳，1.6當量)充添至配備有機械攪拌器及數位溫度計之適合反應容器中。在20℃至30℃下使氮氣經由鐵氟龍(teflon)導管歷經10min鼓泡至反應混合物中。隨後使混合物加熱至40℃至50℃且使氫氣經由鐵氟龍導管歷經6h鼓泡至反應混合物中同時使反應溫度維持在40℃至50℃。利用HPLC完成反應。隨後在40℃至50℃下使氮氣經由鐵氟龍導管歷經10min鼓泡至反應混合物中。使反應混合物經由Hypo SupercelTM熱過濾且用四氫呋喃(2000mL)洗滌濾餅。在減壓下濃縮濾液至體積~1300mL以獲得漿液。隨後在減壓下經由連續地饋入甲醇(3000mL)將四氫呋喃溶劑交換成甲醇。在溶劑交換之後的最終體積為1300mL。過濾所得漿液，且用甲醇(500mL)洗滌濾餅。在20℃至25℃下在真空下乾燥濾餅超過16h以獲得呈白色固體狀之中間物(9')(192g，93%產率，HPLC純度為98%)。1H-NMR(500MHz,CDCl3)δ ppm 8.47(d,J=1.68Hz,1 H)；8.41(d,J=2.59Hz,1 H)；7.36(s,1 H)；7.17-7.24(m,1 H)；6.95-7.07(m,2 H)；6.83-6.90(m,1 H)；6.60(d,J=1.68Hz,1 H)；5.99(s,2 H)；4.19(s,3 H)。
ix：化合物(9')之去甲基化以獲得5-氟-2-(1-(2-氟苯甲基)-5-(異噁唑-3-基)-
1H-吡唑-3-基)嘧啶-4-醇(10')
將中間物(9')(230g，623毫莫耳，1.0當量)、MeOH(3450mL)及濃HCl(307g，37wt%，3117毫莫耳，5.0當量)充添至配備有機械攪拌器及數位溫度計之適合反應容器中。使混合物加熱至60℃至65℃且獲得溶液。隨後在60℃至65℃下攪拌混合物超過17h且獲得漿液。利用HPLC完成反應。歷經2h使漿液冷卻至20℃至25℃且在20℃至25℃下攪拌超過30min。過濾所得漿液，且用甲醇(1000mL)洗滌濾餅。在35℃至45℃下在真空下乾燥濾餅超過16h以獲得呈白色固體狀之中間物(10')(214g，97%產率，HPLC純度>99%)。1H-NMR(500MHz,DMSO-d 6)δ ppm 12.90-13.61(br.s.,1 H)；9.11(d,J=1.68Hz,1 H)；8.16(s,1 H)；7.64(s,1 H)；7.29-7.42(m,1 H)；7.17-7.28(m,2 H)；7.08-7.15(m,1 H)；6.97(s,1 H)；5.91(s,3 H)。
x)：化合物(10')之氯化以獲得3-(3-(4-氯-5-氟嘧啶-2-基)-1-(2-氟苯甲基)-1H-吡唑-5-基)異噁唑(式IV)
將中間物(10')(214g，602毫莫耳，1.0當量)、乙腈(3000mL)及N,N-二甲基苯胺(109g，899毫莫耳，1.5當量)充添至配備有機械攪拌器及數位溫度計之適合反應容器中。使漿液混合物加熱至70℃至80℃。隨後經由加料漏斗歷經30min充添氧氯化磷(276g，1802毫莫耳，3.0當量)同時使反應溫度維持在70℃至80℃。在75℃至80℃下攪拌混合物超過2h且獲得綠色溶液。利用HPLC完成反應。隨後使混合物冷卻至0℃至5℃。經由加料漏斗緩慢充添水(1500mL)同時使反應溫度維持在0℃至10℃。在0℃至10℃下攪拌漿液超過30min。過濾所得漿液，且用乙腈與水(500mL/500mL)之預混溶液及水(500mL)洗滌濾餅。在30℃至40℃下在真空下乾燥濾餅超過16h以獲得呈灰白色至粉紅固體狀之式IV之中間物(214g，95%產率，HPLC純度>99%)。1H NMR(500MHz,CDCl3)δ ppm 8.65(s,1 H)；8.48(d,J=1.68Hz,1 H)；7.44(s,1 H)；7.21-7.25(m,1 H)；6.97-7.06(m,2 H)；6.83-6.87(m,1 H)；6.61(d,J=1.68Hz,1 H)；6.03(s,2 H)。
a)：中間物(15)之氯化以獲得2-(溴甲基)-3,3,3-三氟-2-((三甲基矽烷基)氧基)丙腈(16)
將三甲基矽烷甲腈(153g，1.54莫耳，0.97當量)及三乙胺(4.44mL，3.22g，0.032莫耳，0.02當量)充添至配備有機械攪拌器及數位溫度計之適合反應容器中。使混合物冷卻至5℃。歷經35min經由加料漏斗充添3-溴-1,1,1-三氟丙-2-酮((15)，304g，1.59莫耳，1.0當量)，同時使反應溫度維持在10℃至20℃之間。在添加之後在20℃至30℃下攪拌混合物超過3h以獲得呈緻密油狀之中間物(16)，其直接用於下一步驟。1H-NMR(500MHz,CDCl3)δ ppm 3.68(d,J=11.14Hz,1 H)；3.57(d,J=11.14Hz,1 H)；0.34-0.37(m,9 H)。
b)：腈化合物(16)轉化為醯胺以獲得2-(溴甲基)-3,3,3-三氟-2-羥基丙醯胺(17)
將濃硫酸(339mL，6.37莫耳，4.0當量)在配備有機械攪拌器、數位溫度計及加料漏斗之適合反應容器中攪拌。使硫酸加熱至45℃。歷經50min經由加料漏斗添加上述中間物(16)，同時使溫度保持低於75℃。在75℃下攪拌反應混合物2h且隨後使其冷卻至室溫。1H-NMR指示反應完成。使反應混合物冷卻至-15℃且經由加料漏斗歷經45min用乙酸乙酯(1824mL)稀釋(極其發熱的)，同時使溫度保持在-15℃至5℃之間。在-10℃至0℃之間經由加料漏斗緩慢添加水(1520mL)持續1h 20min(極其發
熱的)。分離各層且有機層用15%氯化鈉水溶液(1520mL)、25%碳酸鈉水溶液(911mL)接著15%氯化鈉水溶液(911mL)洗滌。過濾有機層且減壓濃縮以得到348g呈淡黃色油狀物之中間物(17)。將此油狀物溶解於甲醇(1200mL)中且濃縮以獲得380g中間物(17)。(296g調整重量，79%產率)。1H-NMR(500MHz,CDCl3)δ 6.61-6.94(m,1 H)；5.92-6.26(m,1 H)；3.93-4.00(m,1 H)；3.68(d,J=11.14Hz,1 H)。
c)：化合物(17)之N-烷化以獲得2-(胺甲基)-3,3,3-三氟-2-羥基丙醯胺(14)
將氨於甲醇中之7N溶液(600mL，4.28莫耳，10當量)充添至配備有機械攪拌器及數位溫度計之適合反應容器中。使溶液冷卻至0℃至5℃。隨後在0℃至5℃下經由加料漏斗歷經30min添加中間物(17)(102g，0.432莫耳，1當量)。使反應混合物歷經1h升溫至20℃至25℃並保持72h。利用HPLC完成反應。使反應混合物冷卻至0℃至5℃且歷經2min添加甲醇鈉(78mL，5.4M，0.421莫耳，0.97當量)。隨後使反應混合物在減壓下濃縮至體積300mL。添加2L乙酸乙酯且在減壓下繼續濃縮至體積700mL以得到漿液。將700mL乙酸乙酯添加至漿液以製得最終體積1400mL。添加102mL水且攪拌2min以得到兩相溶液。分離各層。在減壓下濃縮乙酸乙酯層至體積600mL。隨後使乙酸乙酯層加熱至>60℃且在55℃至60℃之間緩慢添加庚烷(600mL)。使混合物冷卻至15℃至20℃，以得到漿液。在15℃至20℃下攪拌漿液2h並過濾。在25℃下在真空下乾燥固體16h以獲得呈白色固體狀之胺(14)(48g，64%產率)。1H-NMR(500MHz,MeOH-d4)δ ppm 2.94(d,J=13.73Hz,1H)；3.24(d,J=13.58Hz,
1H)。
d)：在(R)-2,2-二甲基-5-(三氟甲基)噁唑啶-5-甲醯胺(R)-2-羥基丁二酸酯(18A)與(D)-蘋果酸之1：1鹽下對胺(14)進行對掌性離析
將胺(14)(105g，0.608莫耳，1.0當量)、(D)-蘋果酸(82g，0.608莫耳，1.0當量)及丙酮(1571mL)充添至配備有機械攪拌器及數位溫度計之適合反應容器中。在20℃至25℃下攪拌反應混合物16h。過濾所得漿液，且用丙酮(300mL)洗滌濕濾餅。將濕濾餅充添回至反應容器，且充添丙酮(625mL)。使漿液加熱至53℃並保持6h。使漿液冷卻至20℃至25℃且在此溫度下保持16h。過濾漿液，且用丙酮(200mL)洗滌濕濾餅。在40℃下在真空下乾燥濕濾餅4h以獲得82.4g呈白色固體狀之(18A)與(D)-蘋果酸之1：1鹽(82.4g，39%產率，97% ee)。1H-NMR(500MHz,D2O)δ ppm 4.33(br,s,1H)；3.61(br,d,J=13.58Hz,1H)；3.40-3.47(m,1H)；2.76(br,d,J=15.87Hz,1H)；2.53-2.63(m,1H)；2.16(br,s,4H)。
e)：使中間物(18A)之1：1(D)-蘋果酸鹽與式IV偶合以獲得(R)-3,3,3-三氟-2-(((5-氟-2-(1-(2-氟苯甲基)-5-(異噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-基)胺基)甲基)-2-羥基丙醯胺(化合物I)
將中間物(18A)與(D)-蘋果酸之1：1鹽(74.1g，0.214莫耳，2.5當量)及水(44.8mL)充添至配備有機械攪拌器及數位溫度計之適合反應容器中。將反應混合物加熱至70℃且攪拌20min。藉由氮氣吹氣移除在反應期間生成之丙酮。使反應混合物冷卻至30℃至40℃，且充添式IV(32g，0.086莫耳，1.0當量)、DMSO(448mL)及惠寧氏鹼(Hunig's base)(44.7mL，0.257莫耳，3.0當量)。將反應混合物加熱至90℃並在90℃下攪拌超過17h。利用HPLC完成反應。隨後使混合物冷卻至60℃。在55℃至62℃下充添另一部分之惠寧氏鹼(104mL，0.599莫耳，7.0當量)，接著水(224mL)。在55℃至60℃下攪拌反應混合物15min，以形成種床。在55℃至62℃下歷經30min時程經由加料漏斗添加水(320mL)，且在55℃至60℃下攪拌所產生的漿液1h。過濾所得漿液，且用甲醇與水(320mL/320mL)之預混溶液接著水(640mL)洗滌濾餅。隨後在40℃下在真空下乾燥濾餅超過16h以獲得呈灰白色固體狀之化合物I(40g，92%產率，HPLC純度為99%，98% ee)。1H-NMR(500MHz,DMSO-d 6)δ ppm 9.10(s,1 H)；8.33(d,J=2.90Hz,1 H)；7.93(s,br,1 H)；7.90(s,1 H)；7.78(s,br,1 H)；7.69(s,br,1 H)；7.52(s,1 H)；7.33(q,J=7.02Hz,1 H)；7.17-7.25(m,1 H)；7.17-7.25(m,1 H)；7.10(t,J=7.48Hz,1 H)；6.98(t,J=7.55Hz,1 H)；5.90(s,2 H)；3.92-4.05(m,2 H)。
粗化合物I與其多晶型形式形式A、形式B、形式D、形式E、形式F、形式G及形式H之間的相互關係說明於圖12中。
實例2：粗(R)-3,3,3-三氟-2-(((5-氟-2-(1-(2-氟苯甲基)-5-(異噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-基)胺基)甲基)-2-羥基丙醯胺(粗化合物I)再結晶成多晶型物形式B
將粗化合物I(0.68kg，1.33mol)及乙腈(20.4L)充添至30L夾套反應容器中。以低速攪拌反應混合物且將其加熱至70℃至75℃直至大部分固體溶解。將30L夾套反應容器中之溶液經由氣體分散管(粗糙玻璃料)線過濾至100L夾套反應容器中。隨後將反應混合物加熱至70℃至75℃且充添水(20.4L)同時使批料溫度維持在>65℃超過1h。使反應混合物冷卻至52℃至62℃且在52℃至62℃下攪拌超過最少1h，以形成種床。歷經最少4h將所得漿液冷卻至0℃至5℃並在0℃至5℃下保持超過最少1h。過濾漿液且用乙腈與水(3.4L/3.4L)之預混溶液洗滌濾餅。隨後在90℃至100℃下在真空下乾燥濾餅超過最少30h以獲得呈白色固體狀之呈多晶型物形式B的化合物I(0.58kg，85%產率)。1H-NMR(500MHz,DMSO-d 6)δ ppm 9.10(s,1 H)；8.33(d,J=2.90Hz,1 H)；7.93(s,br,1 H)；7.90(s,1 H)；7.78(s,br,1 H)；7.69(s,br,1 H)；7.52(s,1 H)；7.33(q,J=7.02Hz,1 H)；7.17-7.25(m,1 H)；7.17-7.25(m,1 H)；7.10(t,J=7.48Hz,1 H)；6.98(t,J=7.55Hz,1 H)；5.90(s,2 H)；3.92-4.05(m,2 H)。
實例3：粗(R)-3,3,3-三氟-2-(((5-氟-2-(1-(2-氟苯甲基)-5-(異噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-基)胺基)甲基)-2-羥基丙醯胺(化合物I)再結晶成多晶型物形式E
向配備有機械攪拌器、冷凝器、滴液漏斗、氮氣入口-出口、熱電偶
及加熱-冷卻能力之5L 4頸圓底燒瓶中，充添粗化合物I(67.4g，132mmol)及甲醇(2500mL)。將混合物加熱至>60℃(例如，高於70℃)以獲得溶液。過濾溶液且將濾液加熱至>60℃。將水(1500mL)添加至混合物中同時維持溫度在>60℃。歷經1h使混合物冷卻至室溫並且在此溫度下保持超過1h。過濾漿液且用甲醇/水(600mL，1/1 v/v)沖洗濾餅。收集濾餅，且在80℃下在真空下乾燥超過72h，以得到呈白色固體狀之呈多晶型物形式E的化合物I(59.5g，88%產率)。
實例4A：(R)-3,3,3-三氟-2-(((5-氟-2-(1-(2-氟苯甲基)-5-(異噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-基)胺基)甲基)-2-羥基丙醯胺之多晶型物形式E再結晶成多晶型物形式A
向配備有機械攪拌器、冷凝器、滴液漏斗、氮氣入口-出口、熱電偶及加熱-冷卻能力之1L 4頸圓底燒瓶中充添呈多晶型物形式E之化合物I(19.3g，38mmol)及乙酸乙酯(600mL)。使混合物加熱至>70℃以獲得溶液。過濾溶液且在20℃至25℃下攪拌濾液超過16h，以得到漿液。在真空下濃縮漿液至最終體積~150mL。歷經20min將庚烷(300mL)添加至漿液中且在真空下濃縮混合物至最終體積~350mL。過濾漿液且用庚烷(50mL)沖洗濾餅。收集濾餅，且在100℃下在真空下乾燥超過3h，以得到呈白色固體狀之多晶型物形式A(19.1g，99%產率)。
實例4B：粗(R)-3,3,3-三氟-2-(((5-氟-2-(1-(2-氟苯甲基)-5-(異噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-基)胺基)甲基)-2-羥基丙醯胺(化合物I)再結晶成多晶型物形式A
亦直接自粗化合物I來獲得多晶型物形式A，該粗化合物I使用粗化合物I而非形式E作為起始物質，藉由利用類似於實例4A中所描述之過程自
乙酸乙酯來分離。
亦直接自粗化合物I來獲得多晶型物形式A，該粗化合物I藉由在高於60℃下加熱之後自DMSO/水來分離。
當粗化合物I在室溫下在溶劑庚烷、(乙酸異丙酯)IPAC、乙醇、乙酸乙酯或癸烷中之任一者中漿化且使其攪拌14小時至30小時時，亦分離出多晶型物形式A。過濾樣品且利用XRPD分析殘餘固體。
實例5A：(R)-3,3,3-三氟-2-(((5-氟基-2-(1-(2-氟苯甲基)-5-(異噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-基)胺基)甲基)-2-羥基丙醯胺之多晶型物形式E再結晶成多晶型物形式D
向配備有機械攪拌器、冷凝器、滴液漏斗、氮氣入口-出口、熱電偶及加熱-冷卻能力之2L 4頸圓底燒瓶中，充添呈多晶型物形式E之化合物I(14.0g，28mmol)及正癸烷(560mL)。使混合物加熱至145℃至155℃並在145℃至155℃下保持45min。歷經1h使所得漿液冷卻至20℃至30℃且隨後過濾。用庚烷(280mL)沖洗濾餅。收集濾餅，且在80℃下在真空下乾燥超過72h，以得到呈白色固體狀之呈形式D的化合物I(12.9g，92%產率)。
實例5B：獲得多晶型物形式D之其他方法
亦藉由在180℃下加熱多種其他多晶型形式(純的)可獲得多晶型物形式D，如圖12中所彙總及下文所描述。在一些實施例中，加熱化合物I以獲得多晶型物形式D。在一些實施例中，加熱多晶型物形式F以獲得多晶型物形式D。在一些實施例中，加熱多晶型物形式B以獲得多晶型物形式D。在一些實施例中，加熱多晶型物形式E以獲得多晶型物形式D。在一些實施例中，加熱多晶型物形式G以獲得多晶型物形式D。在一些實施例
中，加熱多晶型物形式H以獲得多晶型物形式D。
使100mL圓底燒瓶充添有化合物I、形式F、形式B、形式E、形式G或形式H(5g)。將固體加熱至180℃並在180℃下保持超過5min。使全部化合物I固體緩慢融化且再固化，以得到固體。用研缽及研杵磨碎固體，以得到約4.8g粉末。HPLC展示99.8%純度。XRPD展示其為形式D。DSC在196℃下展示銳峰。
實例6：形式F之製備
在160℃下，加熱純的形式A可獲得新的多晶型物形式F。此形式在室溫下顯得不穩定且尚未分離純淨。
實例7：粗(R)-3,3,3-三氟-2-(((5-氟-2-(1-(2-氟苯甲基)-5-(異噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-基)胺基)甲基)-2-羥基丙醯胺(化合物I)再結晶成多晶型物形式G
向配備有攪拌棒之燒瓶中充添粗化合物I(2.0g)及丙酮(15.0mL)。在室溫(22℃至25℃)下攪拌混合物兩小時。隨後過濾所得漿液。用丙酮(5mL)沖洗濾餅。收集濾餅，且在40℃下在真空下乾燥超過15h，以得到呈白色固體狀之多晶型物形式G。
亦藉由在室溫下將如下文所描述獲得之多晶型物形式H攪拌在丙酮中，接著過濾且在30℃至40℃下在真空下乾燥，來獲得多晶型物形式G。
實例8：粗(R)-3,3,3-三氟-2-(((5-氟-2-(1-(2-氟苯甲基)-5-(異噁唑-3-基)-1H-吡唑-3-基)嘧啶-4-基)胺基)甲基)-2-羥基丙醯胺再結晶成多晶型物形式H
向配備有攪拌棒之燒瓶中充添粗化合物I(2.0g)及丙酮(15.0mL)。使混合物加熱至45℃至50℃且攪拌直至形成溶液。隨後過濾熱溶液
且在攪拌時緩慢冷卻至室溫。攪拌額外15小時且隨後過濾所得漿液。用丙酮(5mL)沖洗濾餅。收集濾餅，且在40℃下在真空下乾燥超過15h，以得到呈白色固體狀之多晶型物形式H。
實例9：多晶型物特徵
X射線粉末繞射(XRPD)：
使用D8先進布魯克設備(Bruker apparatus)，使用兩種方法中之一者來獲得X射線粉末繞射跡線：
掃描5°2θ至45°2θ，0.02°步長，1秒/步；或掃描3°2θ至40°2θ，0.037°步長，1.5秒/步
傅里葉變換紅外光譜(Fourier Transform Infrared Spectroscopy；FTIR)：
使用來自ThermoFisher Scientific Nicolet iS10 FTIR設備來獲得FTIR跡線
方法：利用具有32個掃描衰減總反射及在具有在各量測之前獲得之背景之525cm-1至4000cm-1之波數範圍中的4的解析度來分析
實例10：HCl鹽製備
方案1：將50.5mg化合物I(呈其多晶型物形式D)及98.2mL 1M HCl懸浮於2mL異PrOH中。在循環於20℃與40℃之間的溫度下攪拌懸浮液。使用40℃/h之加熱速率及5℃/h之冷卻速率。在8天之後，過濾懸浮液且在真空下(大致5毫巴，1h)乾燥固體。
方案2：將299.9mg化合物I(呈其多晶型物形式D)及上文獲得之鹽酸鹽之少量晶體(來自方案1)懸浮於5mL異PrOH中。隨後添加589mL 1M HCl及5mL異PrOH，且在循環於20℃與40℃之間的溫度下攪拌懸浮液。
使用40℃/h之加熱速率及5℃/h之冷卻速率。在6天之後，過濾懸浮液且在真空下(大致5毫巴，1h)乾燥固體。
實例11：HCl鹽特徵
化合物I之HCl鹽特徵在於圖11之XRPD圖案。
化合物I之HCl鹽特徵在於元素分析，從而得出針對下表中所顯示之1：1比率(形式D：HCl)的量測值及計算值：
本文中所使用的術語僅出於描述特定實施例的目的且並不意欲限制本發明。如本文中所使用，除非上下文另有清晰地指示，否則單數形式「一(a/an)」及「該」意欲亦包括複數形式。將進一步理解，術語「包含(comprise)」(及包含(comprise)之任何形式，諸如「comprises」及「comprising」)、「具有」(have)」(及具有(have)之任何形式，諸如「has」及「having」)、「包括(include)」(及包括(include)之任何形式，諸如「includes」及「including」)、「含有(contain)」(及含有(contain)之任何形式，諸如「contains」及「containing」)及其任何其他文法變體為開放式連結動詞。因此，「包含」、「具有」、「包括」或「含有」一或多個步驟或元件之方法或器件擁有一或多個步驟或元件，但不限於僅具有彼等一或多個步驟或元件。同樣地，「包含」、「具有」、「包括」或「含有」一或多個特徵之方法之步驟或器件之元件擁有彼等一或多個特徵，但不限於僅擁有彼等一或多個特徵。此外，以某一方式經組態之器件或結構以至少
該方式組態，但亦可以未列出之方式組態。
如本文中所使用，術語「包含」、「具有」、「包括」、「含有」及其其他文法變體涵蓋術語「由......組成(consisting of)」及「基本上由......組成(consisting essentially of)」。
片語「基本上由......組成」或其文法變體當在本文中使用時應視為指定所陳述特徵、整體、步驟或組件，但不排除添加一或多個額外特徵、整體、步驟、組件或其群組，但僅當額外特徵、整體、步驟、組件或其群組並不實質上更改所主張組合物、器件或方法之基本及新穎特性時。
在本說明書中引用之所有公開案在本文中以引用之方式併入，如同各個別公開案經特定且個別地指示為如同充分闡明般地以引用之方式併入本文中。
除非另有明確指示，否則以引用之方式併入的主題不應視為對任何申請專利範圍限制之替代。
在貫穿本說明書參考一或多個範圍之情況下，各範圍意欲為用於呈現資訊之簡寫格式，其中該範圍應理解為涵蓋在該範圍內之各離散點，如同在本文中充分闡明。
雖然已在本文中描述及描繪本發明之若干態樣及實施例，但可由熟習此項技術者實現替代性態樣及實施例以實現相同目標。因此，本發明及隨附申請專利範圍意欲涵蓋如在本發明之真實精神及範疇內的所有此等另外及替代性態樣及實施例。
Claims (24)
- 一種化合物I之結晶游離形式形式E，
- 如請求項1之結晶游離形式形式E，其特徵在於XRPD光譜中在7.4、18.8至19.3、21.1、24.8及25.5°2θ的峰。
- 一種化合物I之結晶游離形式形式A，
- 如請求項3之結晶游離形式形式A，其特徵在於XRPD光譜中在6.0、18.3、19.3、20.2及22.0°2θ的峰。
- 一種化合物I之結晶游離形式形式D，
- 如請求項5之結晶游離形式形式D，其特徵在於XRPD光譜中在17.1、18.1、18.8及25.0°2θ的峰。
- 一種化合物I之結晶游離形式形式B，
- 如請求項7之結晶游離形式形式B，其特徵在於XRPD光譜中在8.8、16.4、17.2、18.8至19.1、20.1及21.1至21.6°2θ的峰。
- 一種化合物I之結晶游離形式形式F，
- 如請求項9之結晶游離形式形式F，其特徵在於XRPD光譜中在5.3(100.00%相對強度)、8.6(58.80%)、16.4(62.95%)及19.0(48.51%)°2θ的峰。
- 一種化合物I之結晶游離形式形式G，
- 如請求項11之結晶游離形式形式G，其特徵在於XRPD光譜中在10.7(55.47%相對強度)、13.9(42.47%)、18.33(100.00% %)及21.6(40.73%)°2θ的峰。
- 一種化合物I之結晶游離形式形式H，
- 如請求項13之結晶游離形式形式H，其特徵在於XRPD光譜中在5.77(89.22%相對強度)、6.39(100.00% %)、9.1(84.17%)及18.5(67.04%)°2θ的峰。
- 一種用於製備如請求項1或2之化合物I之結晶游離形式形式E的方法，其包含： a.在最低60℃下將粗化合物I溶解於MeOH中以獲得溶液；b.過濾該溶液且在最低60℃下加熱濾液；c.添加水至該濾液以形成水溶液且將該水溶液冷卻至室溫(rt)；d.過濾該水溶液且在真空下乾燥該濾液。
- 一種用於製備如請求項3或4化合物I之結晶游離形式形式A的方法，其包含：(i)以下步驟：a.在最低70℃下將如請求項1或2之結晶游離形式形式E溶解於乙酸乙酯中以獲得溶液；b.過濾該溶液且在20℃至25℃下攪拌所得濾液16小時以形成漿液；c.濃縮且過濾，且在真空下乾燥該漿液；或(ii)以下步驟：a.在最低70℃下將粗化合物I溶解於乙酸乙酯中以獲得溶液；b.過濾該溶液且在20℃至25℃下攪拌所得濾液16小時形成漿液；c.濃縮且過濾，且在真空下乾燥該漿液；或(iii)以下步驟：a.在最低60℃下加熱在DMSO中之粗化合物I，以形成溶液；b.添加水以形成漿液，以及c.過濾該漿液以分離如請求項3或4之結晶游離形式形式A；或(iv)以下步驟：a.將粗化合物I在選自以下之溶劑中漿化：庚烷、IPAC、乙醇、乙酸乙酯或癸烷或其混合物； b.在室溫下攪拌14小時至30小時；以及c.過濾該漿液且在真空下乾燥。
- 一種用於製備如請求項5或6化合物I之結晶游離形式形式D的方法，其包含：(i)以下步驟：a.在145℃至155℃下將如請求項1或2之結晶游離形式形式E與正癸烷混合以獲得漿液；b.經1小時將該漿液冷卻至20℃至30℃；以及c.過濾該漿液且在真空下乾燥；或(ii)在180℃下，加熱如請求項9或10之結晶游離形式形式F、如請求項7或8之結晶游離形式形式B、如請求項1或2之結晶游離形式形式E、如請求項11或12之結晶游離形式形式G或如請求項13或14之結晶游離形式形式H中之任一者或其混合物。
- 一種用於製備如請求項7或8之化合物I之結晶游離形式形式B的方法，其包含：a.將粗化合物I與乙腈混合以形成溶液；b.過濾該溶液以形成濾液且在70℃至75℃下加熱該濾液；c.添加水至該經加熱濾液；d.冷卻至52℃至62℃以形成漿液；e.進一步冷卻該漿液至0℃至5℃，持續至少4小時；以及f.過濾該經冷卻之漿液且在真空下乾燥所得濾液。
- 一種用於製備如請求項9或10化合物I之結晶游離形式形式F的方法，其包含在160℃下加熱純的如請求項3或4之結晶游離形式形式A。
- 一種用於製備如請求項11或12之化合物I之結晶游離形式形式G的方法，其包含：(i)以下步驟：a.在室溫下將粗化合物I混合於丙酮中約2小時以形成漿液；及b.過濾該漿液且在真空下乾燥；或(ii)以下步驟：a.在室溫下攪拌在丙酮中之如請求項13或14之結晶游離形式形式H約2小時以形成漿液；以及b.過濾該漿液且在真空下乾燥。
- 一種用於製備如請求項13或14之化合物I之結晶游離形式形式H的方法，其包含：a.在45℃至50℃下將粗化合物I與丙酮混合以獲得溶液；b.過濾且冷卻以形成漿液；以及c.攪拌且過濾該漿液且在真空下乾燥。
- 一種醫藥組合物，其包含如請求項1至14中任一項之化合物I之結晶游離形式，及至少一種醫藥學上可接受之賦形劑或載劑。
- 一種醫藥組合物，其包含如請求項1至14中任一項之化合物I之結晶游離形式，其用於需要治療的病患中以治療疾病、健康狀況或病症，其中該疾病、健康狀況或病症係選自：與高血壓及冠狀動脈血流減少相關之病症；急性及慢性冠狀動脈血壓升高；動脈高血壓；由心臟及腎併發症引起之血管病症；由心臟病、中風、大腦缺血或腎衰竭引起之血管病症；耐藥性高血壓；糖尿病性高血壓；原發性高血壓；繼發性高血壓；妊娠期高血壓；子癇前症；門靜脈高血壓；心肌梗塞；心臟衰竭、HFPEF、HFREF；急性及慢性HF；更特定形式之HF：急性代償失調HF、右心室衰竭、左心室衰竭、總HF、缺血性心肌病、擴張型心肌症、先天性心臟缺陷、伴隨瓣膜缺陷之HF、二尖瓣狹窄、二尖瓣關閉不全、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、肺瓣狹窄、肺瓣關閉不全、聯合瓣膜缺陷；糖尿病性心臟衰竭；酒精性心肌病或儲存型心肌病；舒張性HF、收縮性HF；既有慢性HF之急性期(惡化HF)；舒張或收縮功能障礙；冠狀動脈功能不全；心律不齊；心室預負載減小；心臟肥大；心臟衰竭/心腎症候群；門靜脈高血壓；內皮細胞功能障礙或損傷；心房及心室節律紊亂及傳導紊亂：房室阻塞度I-III(AVB I-III)、室上性快速性心律失常、心房顫動、心房撲動、心室震顫、心室撲動、心室快速性心律失常、扭轉型心動過速(torsade-de-pointes tachycardia)、心房及心室期外收縮、AV接合點期外收縮、病態竇房結症候群、暈厥、AV節點折返性心動過速；沃夫-帕金森-懷特症候群(Wolff-Parkinson-White syndrome)或急性冠狀動脈症候群；布克二心肌病(Boxer cardiomyopathy)；心室早發性收縮；心肌病；癌症誘發心肌 病；化學治療誘發的心臟毒性；血栓栓塞病症及缺血症；心肌缺血；梗塞；心肌梗塞；心臟病發作；心肌功能不全；內皮細胞功能障礙；中風；短暫性缺血發作(TIA)；阻塞性脈管炎、穩定型或不穩定型心絞痛；冠狀動脈痙攣或周邊動脈痙攣；變異型心絞痛、普潤茲曼特心絞痛(Prinzmetal's angina)；心臟肥大；子癇前症；血栓形成病症；缺血性再灌注損傷；與器官移植相關之缺血性再灌注；與肺移植、肺部移植、心臟移植、靜脈移植物衰竭相關之缺血性再灌注；創傷患者中之血液替代品之保存；周邊血管疾病；周邊動脈疾病；周邊閉塞性動脈疾病；張力亢進；雷諾氏症候群或現象(Raynaud's syndrome or phenomenon)(原發性及繼發性)；雷諾氏疾病(Raynaud's disease)；嚴重肢體缺血；周邊栓塞症；間歇性跛行；血管閉塞危機；肌肉萎縮症、杜興氏肌肉萎縮症(Duchenne muscular dystrophy)、貝克爾肌肉萎縮症(Becker muscular dystrophy)、微循環異常、血管滲漏或滲透性控制；腰椎管狹窄；閉塞血栓性脈管炎；血栓性脈管炎；周邊灌注紊亂；動脈及靜脈血栓；微白蛋白尿；周邊及自主神經病變；糖尿病性神經痛；糖尿病性微血管病；肝臟血管閉塞病症；鐮刀型紅血球疾病中之血管閉塞危機；高血壓危機；水腫；歸因於心臟衰竭之腎水腫；阿茲海默氏病(Alzheimer's disease)；帕金森氏病(Parkinson's disease)；血管性癡呆；血管認知障礙；大腦血管痙攣；先天性重症肌無力症候群；蛛膜下出血；創傷性腦損傷；在諸如輕度認知障礙中發生之彼等的認識障礙、年齡相關之學習及記憶障礙、年齡相關之記憶損耗、血管性癡呆、頭部損傷、中風、中風後癡呆、創傷後頭部損傷、一般集中障礙 及伴有學習及記憶問題之兒童的集中障礙；路易體性癡呆(Lewy body dementia)；包括皮克氏症候群(Pick's syndrome)之伴有前額葉變性之癡呆；進行性細胞核麻痺；伴有皮質基底核退化症之癡呆；肌肉萎縮性側索硬化(Amyotrophic Lateral Sclerosis；ALS)；亨廷頓氏病(Huntington's disease)；髓鞘脫失；多發性硬化症；丘腦退化症；克羅伊茨費爾特-賈考伯癡呆(Creutzfeldt-Jakob dementia)；HIV-癡呆；伴有癡呆或柯薩可夫精神病(Korsakoff psychosis)之精神分裂症；多發性系統萎縮症及其他形式之帕金森氏症附加症候群(Parkinsonism Plus)；運動障礙；神經保護；焦慮、緊張及憂鬱或創傷後壓力症(PTSD)；躁鬱症、精神分裂症、CNS相關之性功能障礙及睡眠紊亂；病理性飲食障礙及使用奢侈食品及成癮藥物；控制大腦灌注；偏頭痛；預防及控制腦梗塞後果(大腦中風)；預防及控制中風後果、大腦缺血及頭部損傷；與CNS疾病相關之神經病變；與MS相關之神經痛；化學治療誘發之神經痛；與帶狀疱疹相關之神經痛；與脊柱手術相關之神經痛；休克；心源性休克；敗血症；敗血性休克；過敏性休克；動脈瘤；控制白細胞活化；抑制或調節血小板凝集；多器官功能障礙症候群(multiple organ dysfunction syndrome；MODS)；多器官衰竭(multiple organ failure；MOF)；肺部/呼吸道病況：肺高血壓(pulmonary hypertension；PH)；肺部動脈高血壓(PAH)，及相關肺部血管重塑；呈局部血栓及右心臟肥大形式之血管重塑；肺部張力亢進；原發性肺高血壓；繼發性肺高血壓；家族性肺高血壓；偶發性肺高血壓；前毛細血管肺高血壓；特發性肺高血壓；其他形式之PH；與以下相關之PH：左心室疾病、HIV、SCD、血栓栓塞 (CTEPH)、類肉瘤病、COPD、肺纖維化、急性呼吸窘迫症候群(ARDS)、急性肺損傷、α-1-抗胰蛋白酶不足(AATD)、肺氣腫、抽菸誘發之肺氣腫及囊腫性纖維化症(CF)；血栓性肺部動脈病變；致叢性肺部動脈病變；囊腫性纖維化症；支氣管收縮或肺部支氣管收縮；急性呼吸道症候群；肺纖維化；肺移植；哮喘疾病；與以下相關或有關之肺高血壓：左心室功能障礙、低氧血症、WHO I組、II組、III組、IV組及V組高血壓；二尖瓣膜疾病；縮窄性心包炎、主動脈瓣狹窄、心肌病、縱隔纖維化、肺纖維化、肺靜脈畸形引流、肺靜脈閉塞疾病、肺脈管炎、膠原蛋白血管疾病、先天性心臟病、肺靜脈高血壓、間質性肺病、睡眠呼吸障礙、睡眠呼吸暫停、肺泡換氣不足病症、長期暴露於高海拔、新生肺疾病、肺泡毛細血管發育異常、鐮刀型紅血球疾病、其他凝血病症、慢性血栓栓塞、肺栓塞；歸因於腫瘤、寄生蟲或外來材料之肺栓塞；結締組織疾病、狼瘡、狼瘡性腎炎、血吸蟲病、類肉瘤病、慢性阻塞性肺病、哮喘、肺氣腫、慢性支氣管炎、肺毛細血管瘤病、組織細胞增多病X、淋巴管瘤病、壓縮之肺脈管；歸因於淋巴結腫大、腫瘤或纖維性縱隔炎的壓縮肺脈管；動脈粥樣硬化疾病或病況：動脈粥樣硬化；與內皮損傷、血小板及單核球黏附及聚集、平滑肌增生或遷移相關之動脈粥樣硬化；再狹窄；在血栓溶解療法、經皮腔內血管成形術(PTA)、經冠狀動脈腔內血管成形術(PTCA)、心臟移植、旁通操作或發炎過程之後發展之再狹窄；微血管及大血管損傷(脈管炎)；血纖維蛋白原含量增大及低密度DLD；纖維蛋白溶酶原活化劑抑制劑1(PA-1)濃度增大；代謝症候群；代謝疾病或與代謝症候群相關之疾病：肥胖；皮下脂 肪過多；過度肥胖；糖尿病；高血壓；脂質相關病症、高血脂、血脂異常、高膽固醇血症、高密度脂蛋白膽固醇(HDL-膽固醇)減少、低密度脂蛋白膽固醇(LDL-膽固醇)含量適度升高、高甘油三酯血症、高甘油酯血症、低脂蛋白血症、穀固醇血症、脂肪肝病、酒精性脂肪肝病(AFLD)、非酒精性脂肪肝病(NAFLD)、肝炎；子癇前症；多囊性腎病進展；肝脂肪變性或肝中之不正常脂質積聚；非酒精性脂肪變性肝炎(NASH)；心臟、腎或肌肉之脂肪變性；αβ脂蛋白血症；穀固醇血症；黃瘤症；丹吉爾病(Tangier disease)；高氨血症及相關疾病；肝腦病；其他有毒性腦病；急性腦病綜合症(Reye syndrome)；性病、婦科疾病及泌尿疾病或病況：勃起功能障礙；陽萎；早洩；女性性功能障礙；女性性喚起功能障礙；機能減退的性喚起障礙；陰道萎縮；性交困難；萎縮性陰道炎；良性前列腺增生(BPH)；前列腺肥大；前列腺增大；膀胱出口阻塞；膀胱疼痛綜合症(BPS)；間質性膀胱炎(IC)；膀胱過動症；神經性膀胱及失禁；糖尿病性腎病變；原發性及繼發性痛經；下尿路症候群(LUTS)；子宮內膜異位；骨盆疼痛；男性及女性泌尿生殖器系統之器官之良性及惡性疾病；慢性腎病；急性及慢性腎機能不全；急性及慢性腎衰竭；狼瘡性腎炎；潛在或相關腎臟疾病：灌注不足、透析中低血壓、阻塞性尿路病變、腎小球病變、絲球體腎炎、急性絲球體腎炎、腎小球硬化、小管間質性疾病、腎病、原發性及先天性腎臟疾病、腎炎；特徵在於肌酐及/或水分泌非正常地減小的疾病；特徵在於脲、氮、鉀及/或肌酐之血液濃度異常升高的疾病；特徵在於腎酶類活性改變的疾病、特徵在於麩胺醯基合成酶活性改變的疾病；特徵在於尿容積滲透濃度或尿體積改變的疾病；特徵在於 微白蛋白尿增加的疾病、特徵在於大量白蛋白尿的疾病；特徵在於腎小球及小動脈病變、小管膨脹、高磷酸鹽血症及/或需要透析之疾病；腎機能不全後遺症；腎機能不全相關之肺灌腸；與HF相關之腎機能不全；與尿毒症或貧血症相關之腎機能不全；電解質紊亂(高鉀血症、低鈉血症)；骨骼及碳水化合物代謝紊亂；急性腎臟損傷；眼部疾病或病症，諸如青光眼、視網膜病變及糖尿病性視網膜病變；或者，其中該疾病、健康狀況或病症係選自：鐮刀型紅血球疾病，較佳地，鐮刀型紅血球貧血；或者，其中該疾病、健康狀況或病症係選自：血管閉塞危機，較佳地，鐮刀型紅血球疾病中之血管閉塞危機。
- 一種如請求項1至14中任一項之化合物I之結晶游離形式或如請求項22之醫藥組合物之用途，其係用於製備用於需要治療的病患中以治療疾病、健康狀況或病症之藥物，其中該疾病、健康狀況或病症係選自：與高血壓及冠狀動脈血流減少相關之病症；急性及慢性冠狀動脈血壓升高；動脈高血壓；由心臟及腎併發症引起之血管病症；由心臟病、中風、大腦缺血或腎衰竭引起之血管病症；耐藥性高血壓；糖尿病性高血壓；原發性高血壓；繼發性高血壓；妊娠期高血壓；子癇前症；門靜脈高血壓；心肌梗塞；心臟衰竭、HFPEF、HFREF；急性及慢性HF；更特定形式之HF：急性代償失調HF、右心室衰竭、左心室衰竭、總HF、缺血性心肌病、擴張型心肌症、先天性心臟缺陷、伴隨瓣膜缺陷之HF、二尖瓣狹窄、二尖 瓣關閉不全、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、肺瓣狹窄、肺瓣關閉不全、聯合瓣膜缺陷；糖尿病性心臟衰竭；酒精性心肌病或儲存型心肌病；舒張性HF、收縮性HF；既有慢性HF之急性期(惡化HF)；舒張或收縮功能障礙；冠狀動脈功能不全；心律不齊；心室預負載減小；心臟肥大；心臟衰竭/心腎症候群；門靜脈高血壓；內皮細胞功能障礙或損傷；心房及心室節律紊亂及傳導紊亂：房室阻塞度I-III(AVB I-III)、室上性快速性心律失常、心房顫動、心房撲動、心室震顫、心室撲動、心室快速性心律失常、扭轉型心動過速(torsade-de-pointes tachycardia)、心房及心室期外收縮、AV接合點期外收縮、病態竇房結症候群、暈厥、AV節點折返性心動過速；沃夫-帕金森-懷特症候群(Wolff-Parkinson-White syndrome)或急性冠狀動脈症候群；布克二心肌病(Boxer cardiomyopathy)；心室早發性收縮；心肌病；癌症誘發心肌病；化學治療誘發的心臟毒性；血栓栓塞病症及缺血症；心肌缺血；梗塞；心肌梗塞；心臟病發作；心肌功能不全；內皮細胞功能障礙；中風；短暫性缺血發作(TIA)；阻塞性脈管炎、穩定型或不穩定型心絞痛；冠狀動脈痙攣或周邊動脈痙攣；變異型心絞痛、普潤茲曼特心絞痛(Prinzmetal's angina)；心臟肥大；子癇前症；血栓形成病症；缺血性再灌注損傷；與器官移植相關之缺血性再灌注；與肺移植、肺部移植、心臟移植、靜脈移植物衰竭相關之缺血性再灌注；創傷患者中之血液替代品之保存；周邊血管疾病；周邊動脈疾病；周邊閉塞性動脈疾病；張力亢進；雷諾氏症候群或現象(Raynaud's syndrome or phenomenon)(原發性及繼發性)；雷諾氏疾病(Raynaud's disease)；嚴重肢體缺血；周邊栓塞症；間 歇性跛行；血管閉塞危機；肌肉萎縮症、杜興氏肌肉萎縮症(Duchenne muscular dystrophy)、貝克爾肌肉萎縮症(Becker muscular dystrophy)、微循環異常、血管滲漏或滲透性控制；腰椎管狹窄；閉塞血栓性脈管炎；血栓性脈管炎；周邊灌注紊亂；動脈及靜脈血栓；微白蛋白尿；周邊及自主神經病變；糖尿病性神經痛；糖尿病性微血管病；肝臟血管閉塞病症；鐮刀型紅血球疾病中之血管閉塞危機；高血壓危機；水腫；歸因於心臟衰竭之腎水腫；阿茲海默氏病(Alzheimer's disease)；帕金森氏病(Parkinson's disease)；血管性癡呆；血管認知障礙；大腦血管痙攣；先天性重症肌無力症候群；蛛膜下出血；創傷性腦損傷；在諸如輕度認知障礙中發生之彼等的認識障礙、年齡相關之學習及記憶障礙、年齡相關之記憶損耗、血管性癡呆、頭部損傷、中風、中風後癡呆、創傷後頭部損傷、一般集中障礙及伴有學習及記憶問題之兒童的集中障礙；路易體性癡呆(Lewy body dementia)；包括皮克氏症候群(Pick's syndrome)之伴有前額葉變性之癡呆；進行性細胞核麻痺；伴有皮質基底核退化症之癡呆；肌肉萎縮性側索硬化(Amyotrophic Lateral Sclerosis；ALS)；亨廷頓氏病(Huntington's disease)；髓鞘脫失；多發性硬化症；丘腦退化症；克羅伊茨費爾特-賈考伯癡呆(Creutzfeldt-Jakob dementia)；HIV-癡呆；伴有癡呆或柯薩可夫精神病(Korsakoff psychosis)之精神分裂症；多發性系統萎縮症及其他形式之帕金森氏症附加症候群(Parkinsonism Plus)；運動障礙；神經保護；焦慮、緊張及憂鬱或創傷後壓力症(PTSD)；躁鬱症、精神分裂症、CNS相關之性功能障礙及睡眠紊亂；病理性飲食障礙及使用奢侈食品及成癮藥物；控制大腦灌注；偏頭痛；預防及控制腦梗塞後果(大腦中風)；預防及 控制中風後果、大腦缺血及頭部損傷；與CNS疾病相關之神經病變；與MS相關之神經痛；化學治療誘發之神經痛；與帶狀疱疹相關之神經痛；與脊柱手術相關之神經痛；休克；心源性休克；敗血症；敗血性休克；過敏性休克；動脈瘤；控制白細胞活化；抑制或調節血小板凝集；多器官功能障礙症候群(multiple organ dysfunction syndrome；MODS)；多器官衰竭(multiple organ failure；MOF)；肺部/呼吸道病況：肺高血壓(pulmonary hypertension；PH)；肺部動脈高血壓(PAH)，及相關肺部血管重塑；呈局部血栓及右心臟肥大形式之血管重塑；肺部張力亢進；原發性肺高血壓；繼發性肺高血壓；家族性肺高血壓；偶發性肺高血壓；前毛細血管肺高血壓；特發性肺高血壓；其他形式之PH；與以下相關之PH：左心室疾病、HIV、SCD、血栓栓塞(CTEPH)、類肉瘤病、COPD、肺纖維化、急性呼吸窘迫症候群(ARDS)、急性肺損傷、α-1-抗胰蛋白酶不足(AATD)、肺氣腫、抽菸誘發之肺氣腫及囊腫性纖維化症(CF)；血栓性肺部動脈病變；致叢性肺部動脈病變；囊腫性纖維化症；支氣管收縮或肺部支氣管收縮；急性呼吸道症候群；肺纖維化；肺移植；哮喘疾病；與以下相關或有關之肺高血壓：左心室功能障礙、低氧血症、WHO I組、II組、III組、IV組及V組高血壓；二尖瓣膜疾病；縮窄性心包炎、主動脈瓣狹窄、心肌病、縱隔纖維化、肺纖維化、肺靜脈畸形引流、肺靜脈閉塞疾病、肺脈管炎、膠原蛋白血管疾病、先天性心臟病、肺靜脈高血壓、間質性肺病、睡眠呼吸障礙、睡眠呼吸暫停、肺泡換氣不足病症、長期暴露於高海拔、新生肺疾病、肺泡毛細血管發育異常、鐮刀型紅血球疾 病、其他凝血病症、慢性血栓栓塞、肺栓塞；歸因於腫瘤、寄生蟲或外來材料之肺栓塞；結締組織疾病、狼瘡、狼瘡性腎炎、血吸蟲病、類肉瘤病、慢性阻塞性肺病、哮喘、肺氣腫、慢性支氣管炎、肺毛細血管瘤病、組織細胞增多病X、淋巴管瘤病、壓縮之肺脈管；歸因於淋巴結腫大、腫瘤或纖維性縱隔炎的壓縮肺脈管；動脈粥樣硬化疾病或病況：動脈粥樣硬化；與內皮損傷、血小板及單核球黏附及聚集、平滑肌增生或遷移相關之動脈粥樣硬化；再狹窄；在血栓溶解療法、經皮腔內血管成形術(PTA)、經冠狀動脈腔內血管成形術(PTCA)、心臟移植、旁通操作或發炎過程之後發展之再狹窄；微血管及大血管損傷(脈管炎)；血纖維蛋白原含量增大及低密度DLD；纖維蛋白溶酶原活化劑抑制劑1(PA-1)濃度增大；代謝症候群；代謝疾病或與代謝症候群相關之疾病：肥胖；皮下脂肪過多；過度肥胖；糖尿病；高血壓；脂質相關病症、高血脂、血脂異常、高膽固醇血症、高密度脂蛋白膽固醇(HDL-膽固醇)減少、低密度脂蛋白膽固醇(LDL-膽固醇)含量適度升高、高甘油三酯血症、高甘油酯血症、低脂蛋白血症、穀固醇血症、脂肪肝病、酒精性脂肪肝病(AFLD)、非酒精性脂肪肝病(NAFLD)、肝炎；子癇前症；多囊性腎病進展；肝脂肪變性或肝中之不正常脂質積聚；非酒精性脂肪變性肝炎(NASH)；心臟、腎或肌肉之脂肪變性；αβ脂蛋白血症；穀固醇血症；黃瘤症；丹吉爾病(Tangier disease)；高氨血症及相關疾病；肝腦病；其他有毒性腦病；急性腦病綜合症(Reye syndrome)；性病、婦科疾病及泌尿疾病或病況：勃起功能障礙；陽萎；早洩；女性性功能障礙；女性性喚起功能障礙；機能減退的性喚起障礙；陰道萎 縮；性交困難；萎縮性陰道炎；良性前列腺增生(BPH)；前列腺肥大；前列腺增大；膀胱出口阻塞；膀胱疼痛綜合症(BPS)；間質性膀胱炎(IC)；膀胱過動症；神經性膀胱及失禁；糖尿病性腎病變；原發性及繼發性痛經；下尿路症候群(LUTS)；子宮內膜異位；骨盆疼痛；男性及女性泌尿生殖器系統之器官之良性及惡性疾病；慢性腎病；急性及慢性腎機能不全；急性及慢性腎衰竭；狼瘡性腎炎；潛在或相關腎臟疾病：灌注不足、透析中低血壓、阻塞性尿路病變、腎小球病變、絲球體腎炎、急性絲球體腎炎、腎小球硬化、小管間質性疾病、腎病、原發性及先天性腎臟疾病、腎炎；特徵在於肌酐及/或水分泌非正常地減小的疾病；特徵在於脲、氮、鉀及/或肌酐之血液濃度異常升高的疾病；特徵在於腎酶類活性改變的疾病、特徵在於麩胺醯基合成酶活性改變的疾病；特徵在於尿容積滲透濃度或尿體積改變的疾病；特徵在於微白蛋白尿增加的疾病、特徵在於大量白蛋白尿的疾病；特徵在於腎小球及小動脈病變、小管膨脹、高磷酸鹽血症及/或需要透析之疾病；腎機能不全後遺症；腎機能不全相關之肺灌腸；與HF相關之腎機能不全；與尿毒症或貧血症相關之腎機能不全；電解質紊亂(高鉀血症、低鈉血症)；骨骼及碳水化合物代謝紊亂；急性腎臟損傷；眼部疾病或病症，諸如青光眼、視網膜病變及糖尿病性視網膜病變；或者，其中該疾病、健康狀況或病症係選自：鐮刀型紅血球疾病，較佳地，鐮刀型紅血球貧血；或者，其中該疾病、健康狀況或病症係選自：血管閉塞危機，較佳地，鐮刀型紅血球疾病中之血管閉塞危機。
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| EP3481820B1 (en) * | 2016-07-07 | 2023-10-18 | Cyclerion Therapeutics, Inc. | Solid forms of an sgc stimulator |
| MA45603A (fr) * | 2016-07-07 | 2019-05-15 | Ironwood Pharmaceuticals Inc | Nouveaux procédés de préparation de stimulateurs de la guanylate cyclase soluble |
| WO2019161534A1 (en) * | 2018-02-22 | 2019-08-29 | Ironwood Pharmaceuticals, Inc. | Novel processes and intermediates for preparation of soluble guanylate cyclase stimulators |
| CN109503574B (zh) * | 2018-12-14 | 2021-07-06 | 中国人民解放军军事科学院军事医学研究院 | 抗肺动脉高压药物sgc-003的多晶型晶体变体及其制备方法 |
| CN110862424A (zh) * | 2019-12-03 | 2020-03-06 | 海南顿斯医药科技有限公司 | 一种硫酸阿米卡星化合物 |
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| WO2014144100A2 (en) * | 2013-03-15 | 2014-09-18 | Takashi Nakai | Sgc stimulators |
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| CN109563087A (zh) | 2019-04-02 |
| EA201990235A1 (ru) | 2019-07-31 |
| TW201805283A (zh) | 2018-02-16 |
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| EP3481820A1 (en) | 2019-05-15 |
| KR20190025989A (ko) | 2019-03-12 |
| WO2018009609A1 (en) | 2018-01-11 |
| CL2019000018A1 (es) | 2019-05-03 |
| MA45588A (fr) | 2019-05-15 |
| JP2022130689A (ja) | 2022-09-06 |
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| US20240059683A1 (en) | 2024-02-22 |
| EP3481820B1 (en) | 2023-10-18 |
| JOP20180127A1 (ar) | 2019-01-30 |
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