TW201836615A - 治療貓冠狀病毒感染之方法 - Google Patents
治療貓冠狀病毒感染之方法 Download PDFInfo
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- TW201836615A TW201836615A TW107108464A TW107108464A TW201836615A TW 201836615 A TW201836615 A TW 201836615A TW 107108464 A TW107108464 A TW 107108464A TW 107108464 A TW107108464 A TW 107108464A TW 201836615 A TW201836615 A TW 201836615A
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Abstract
本發明提供治療貓冠狀病毒感染之方法，其包含投與治療有效量之化合物1至化合物9之化合物或其醫藥上可接受之鹽。
Description
本發明概言之係關於用於治療貓冠狀病毒感染之方法及化合物、具體而言用於治療貓傳染性腹膜炎病毒(FIPV)之方法。
貓冠狀病毒(FCoV)屬冠狀病毒科(Coronaviridae family)(一組有套膜之正鏈RNA病毒)，通常在貓中發現。在自然界中，FCoV作為兩種不同生物型存在：貓腸內冠狀病毒(FECV)及貓傳染性腹膜炎病毒(FIPV)(FECV之突變形式)。 FECV感染在貓中極為普遍，其中估計全世界40-80%之貓脫落該病毒。FECV慢性感染貓之胃腸道上皮細胞且通常藉助糞-口途徑(fecal-oral route)傳播。FECV在貓中之感染大部分係無症狀的，其中一些貓經歷腹瀉、嘔吐、食欲不振及發燒。 FIPV生物型係在單核苷酸多型性或使FECV中之病毒3c蛋白酶基因不活化之缺失後出現，但亦可涉及病毒突起蛋白內之突變。3c蛋白酶之不活化改變細胞向性，使得病毒在巨噬細胞內複製，此促進FIPV之全身播散及貓傳染性腹膜炎(FIP)之發作。 FIP係貓中之進行性免疫相關疾病。FIP疾病可呈「濕性」或「乾性」FIP之形式。濕性FIP與內臟漿膜及網膜之發炎相關聯，其導致流體滲出至腹腔及/或胸腔中。乾性FIP之特徵在於實質性器官(例如肝、中樞神經系統或眼睛)之肉芽腫侵襲。濕性或乾性形式之FIP之發展均係致命的。 FIP係具有大的貓密度之環境(例如多貓家庭、貓舍、收容所及貓救難設備)中之主要問題。由於較高程度之複製FECV，故疾病最常見於較年幼的貓(＜ 3歲)且具體而言小貓中，此增加FIPV生物型突變之可能性以及降低之對具有彼等突變之病毒的抗性。FIP係2歲以下貓之致死病因且估計在全世界殺死0.3%與1%之間的貓。 目前，業內沒有用於治療FIP之經批准疫苗或有效抗病毒療法。因此，業內存在開發用於治療貓之FIP的化合物之重要需求。不欲被束縛，假設治療FCoV或FIPV將預防或治療FIP。
在一些實施例中，本發明提供治療貓冠狀病毒感染之方法，其包含投與治療有效量之以下化合物： 或； 或其醫藥上可接受之鹽。 提供治療貓冠狀病毒感染之方法，其包含投與治療有效量之或其醫藥上可接受之鹽。
相關申請案之交叉參考 本申請案主張對2017年3月14日提出申請之美國臨時申請案第62/470,944號之優先權，其整體出於所有目的併入本文中。I. 定義
除非另外陳述，否則本文所用之下列術語及片語意欲具有下列含義： 除非另外指示，否則本文所用之術語「治療(treating, treatment)」意指逆轉、緩解、抑制該術語所應用之病症或病狀或該病症或病狀之一或多種症狀之進展或加以預防。 如本文所用，術語「治療有效量」係本文所述組合物中存在之化合物1或其醫藥上可接受之鹽在藉由所選投與途徑投與組合物時在欲治療個體之氣道及肺之分泌物及組織中或者在血流中提供期望量之藥物以給出預期生理反應或期望生物效應所需之量。精確量將取決於多種因素，例如組合物之特定活性、所採用之遞送裝置、組合物之物理特徵、其期望用途以及動物之考慮因素(例如疾病狀態之嚴重程度、獸醫合作等)，且可容易地由熟習此項技術者基於本文提供之資訊來確定。 對本文所述化合物1、或化合物2至9之提及亦可包括對其醫藥上可接受之鹽之提及。醫藥上可接受之鹽之實例包括源自適宜鹼之鹽，例如鹼金屬或鹼土金屬(例如，Na+
、Li+
、K+
、Ca+2
及Mg+2
)、銨及NR4 +
(其中R係如本文所定義)。氮原子或胺基之醫藥上可接受之鹽包括(a)與無機酸形成之酸加成鹽，例如鹽酸、氫溴酸、硫酸、磺胺酸、磷酸、硝酸及諸如此類；(b)與有機酸形成之鹽，例如乙酸、草酸、酒石酸、琥珀酸、馬來酸、富馬酸、葡萄糖酸、檸檬酸、蘋果酸、抗壞血酸、苯甲酸、羥乙磺酸、乳糖酸、單寧酸、棕櫚酸、海藻酸、聚麩胺酸、萘磺酸、甲磺酸、對甲苯磺酸、苯磺酸、萘二磺酸、聚半乳糖醛酸、丙二酸、磺基柳酸、乙醇酸、2-羥基-3-萘甲酸鹽、雙羥萘酸鹽、柳酸、硬脂酸、苯二甲酸、苦杏仁酸、乳酸、乙磺酸、離胺酸、精胺酸、麩胺酸、甘胺酸、絲胺酸、蘇胺酸、丙胺酸、異白胺酸、白胺酸及諸如此類；及(c) 自元素陰離子形成之鹽，例如氯、溴及碘。羥基化合物之醫藥上可接受之鹽包括該化合物之陰離子與適宜陽離子(例如Na+
及NR4 +
)之組合。 化合物1及化合物2至9或其醫藥上可接受之鹽可作為不同多晶型或擬態多晶型存在。如本文所用，結晶多型性意指結晶化合物以不同晶體結構存在之能力。結晶多型性可源自晶體堆積之差別(堆積多型性)或同一分子之不同構形異構物之間堆積之差別(構形多型性)。如本文所用，結晶擬態多晶型意指化合物之水合物或溶劑合物以不同晶體結構存在之能力。本發明之擬態多晶型可係由於晶體堆積之差別(堆積擬態多型性)或由於同一分子之不同構形異構物之間堆積之差別(構形擬態多型性)而存在。本發明包含化合物1或其醫藥上可接受之鹽之所有多晶型及擬態多晶型。 化合物1及化合物2至9及其醫藥上可接受之鹽亦可以非晶形固體存在。如本文所用，非晶形固體係在固體中不存在原子位置之長程有序之固體。當晶體大小為2奈米或以下時，此定義同樣適用。添加劑(包括溶劑)可用於產生本發明之非晶型。在一些實施例中，本發明包含化合物1或其醫藥上可接受之鹽之所有非晶型。 在一些實施例中，化合物1及化合物2至9或其醫藥上可接受之鹽亦欲代表化合物之未經標記之形式以及經同位素標記之形式。經同位素標記之化合物具有本文所給式繪示之結構，惟一或多個原子經具有所選原子質量或質量數之原子替代。可納入本發明化合物之同位素之實例包括氫、碳、氮、氧、磷、氟及氯之同位素，例如(但不限於)2
H (氘，D)、3
H (氚)、11
C、13
C、14
C、15
N、18
F、31
P、32
P、35
S、36
Cl及125
I。多種經同位素標記之本發明化合物係例如納入放射性同位素(例如3
H、13
C及14
C)者。該等經同位素標記之化合物可用於代謝研究、反應動力學研究、檢測或成像技術(例如正電子發射斷層掃描術(PET)或單光子發射電腦斷層掃描術(SPECT)，包括藥物或基質組織分佈分析)或用於放射性治療。 本發明亦包括其中1至n個連接至碳原子之氫經氘替代之化合物1及化合物2至9，其中n係分子中氫之數量。該等化合物展現增加之代謝抗性，且因此可在投與哺乳動物時用於增加化合物1之半衰期。參見例如Foster, 「Deuterium Isotope Effects in Studies of Drug Metabolism」, Trends Pharmacol. Sci. 5(12):524-527 (1984)。該等化合物係藉由業內所熟知之方式、例如藉由採用其中一或多個氫已經氘替代之起始材料來合成。 本發明經氘標記或取代之治療化合物可具有與分佈、代謝及排泄(ADME)相關之改良DMPK (藥物代謝及藥物動力學)性質。用較重同位素(例如氘)取代可提供由較高代謝穩定性產生之某些治療優點，例如增加之活體內半衰期、降低之劑量需求及/或治療指數之改良。經18
F標記之化合物可用於PET或SPECT研究。經同位素標記之本發明化合物及其前藥通常可藉由實施下文所述之反應圖中或實例及製備中所揭示之程序藉由輕易可得之經同位素標記之試劑取代未經同位素標記之試劑來製備。 此一較重同位素、特定而言氘之濃度可藉由同位素富集係數來定義。在本發明之化合物中，未明確指定為具體同位素之任何原子意欲代表彼原子之任何穩定同位素。除非另外陳述，否則當一位置特定指定為「H」或「氫」時，則該位置應理解為具有處於其天然豐度同位素組成之氫。II. 治療貓冠狀病毒
現將詳細地提及某些實施例，其實例在所附描述、結構及式中說明。儘管將結合枚舉之實施例闡述本發明，但應理解，並不意欲將本發明限制於彼等實施例。與此相反，本發明意欲涵蓋所有替代、修改及等效物，該等可包括在本發明之範圍內。A. 化合物
可用於本發明方法中之化合物包括以下：
在一些實施例中，可用於本發明方法中之化合物係：(2R,3R,4S,5R)-2-(4- 胺基吡咯并 [2,1-f][1,2,4] 三嗪 -7- 基 )-3,4- 二羥基 -5-( 羥基甲基 ) 四氫呋喃 -2- 甲腈
上文所提供之化合物名稱係使用ChemBioDraw Ultra命名且熟習此項技術者瞭解，化合物結構可使用其他普遍認可之命名系統及符號來命名或鑑別。舉例而言，可利用常用名、系統性或非系統性名稱來命名或鑑別化合物。化學領域中普遍認可之命名系統及符號包括(但不限於)化學摘要服務社(Chemical Abstract Service, CAS)及國際純化學和應用化學聯合會(International Union of Pure and Applied Chemistry, IUPAC)。因此，化合物1：化合物1 可根據IUPAC命名或鑑別為(2R,3R,4S,5R)-2-(4-胺基吡咯并[2,1-f][1,2,4]三嗪-7-基)-3,4-二羥基-5-(羥基甲基)四氫呋喃-2-甲腈。 在一些實施例中，可用於本發明方法中之化合物係化合物2：化合物2 化合物2可命名或鑑別為雙(2,2-二甲基硫代丙酸) ((((2R,3S,4R,5R)-5-(4-胺基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羥基四氫呋喃-2-基)甲氧基) (S,S'-(((羥基磷醯基)雙(氧基))雙(乙烷-2,1-二基)))酯。 在一些實施例中，可用於本發明方法中之化合物係化合物3：化合物3 化合物3可根據IUPAC命名或鑑別為((((2R,3S,4R,5R)-5-(4-胺基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羥基四氫呋喃-2-基)甲氧基)(苯氧基)磷醯基)-L-丙胺酸2-乙基丁基酯。 在一些實施例中，可用於本發明方法中之化合物係化合物4：化合物4 化合物4可根據IUPAC命名或鑑別為(2R,3R,4R,5S)-5-(4-胺基吡咯并[2,1-f][1,2,4]三嗪-7-基)-4-氟-3-羥基-2-(羥基甲基)四氫呋喃-2-甲腈。 在一些實施例中，可用於本發明方法中之化合物係化合物5：化合物5 化合物5可根據IUPAC命名或鑑別為(2R,3S,4R,5S)-5-(4-胺基吡咯并[2,1-f][1,2,4]三嗪-7-基)-3,4-二羥基-2-(羥基甲基)四氫呋喃-2-甲腈。 在一些實施例中，可用於本發明方法中之化合物係化合物6：化合物6 化合物6可命名或鑑別為雙(2,2-二甲基硫代丙酸) ((((2R,3S,4R,5R)-5-(4-胺基吡咯并[2,1-f][1,2,4]三嗪-7-基)-2-氰基-3,4-二羥基四氫呋喃-2-基)甲氧基)(S,S'-(((羥基磷醯基)雙(氧基))雙(乙烷-2,1-二基)))酯。 在一些實施例中，可用於本發明方法中之化合物係化合物7：化合物7 化合物7可根據IUPAC命名或鑑別為((((2R,3S,4R,5S)-5-(4-胺基吡咯并[2,1-f][1,2,4]三嗪-7-基)-2-氰基-3,4-二羥基四氫呋喃-2-基)甲氧基)(苯氧基)磷醯基)-L-丙胺酸2-乙基丁基酯。 在一些實施例中，可用於本發明方法中之化合物係化合物8：化合物8 化合物8可命名或鑑別為((2R,3S,4R,5R)-5-(4-胺基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羥基四氫呋喃-2-基)甲基磷醯二胺雙(L-丙胺酸2-乙基丁基酯)。 在一些實施例中，可用於本發明方法中之化合物係化合物9：化合物9 化合物9可根據IUPAC命名或鑑別為((((2R,3S,4R,5R)-5-(4-胺基吡咯并[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羥基四氫呋喃-2-基)甲氧基)(苯氧基)磷醯基)-D-丙胺酸2-乙基丁基酯。B. 方法
本發明提供治療貓冠狀病毒感染之方法，其包含投與治療有效量之化合物1至化合物9之化合物或其醫藥上可接受之鹽。 藥物動力學證據證實貓具有不同於其他物種(例如狗或人類)之藥物代謝輪廓。舉例而言，貓可由於缺乏許多藥物偶聯酶(包括涉及葡萄糖醛酸化(CYP)、甲基化(TPMT)基乙醯化(NAT1及NAT2)之彼等)或其表現降低而具有較緩慢之藥物清除速率。因此，人類藥物代謝及清除與在貓中所觀察到之情形的關聯性較差(Vet Clin Small Anim 2013
, 43, 1039-1054)。 在一些實施例中，本發明提供治療貓冠狀病毒感染之方法，其包含投與治療有效量之以下化合物：或； 或其醫藥上可接受之鹽。 提供治療貓冠狀病毒感染之方法，其包含投與治療有效量之或其醫藥上可接受之鹽。 在一些實施例中，冠狀病毒係貓腸內冠狀病毒(FECV)或貓傳染性腹膜炎病毒(FIPV)。 提供治療貓冠狀病毒感染之方法，其包含投與治療有效量之或其醫藥上可接受之鹽。 在一些實施例中，冠狀病毒係貓腸內冠狀病毒(FECV)或貓傳染性腹膜炎病毒(FIPV)。 在一些實施例中，本發明提供治療貓腸內冠狀病毒(FECV)感染之方法，其包含投與治療有效量之以下化合物：或； 或其醫藥上可接受之鹽。 在一些實施例中，治療貓腸內冠狀病毒(FECV)感染之方法包含投與治療有效量之或其醫藥上可接受之鹽。 在一些實施例中，本發明提供治療貓傳染性腹膜炎病毒(FIPV)感染之方法，其包含投與治療有效量之以下化合物：或； 或其醫藥上可接受之鹽。 在一些實施例中，治療貓傳染性腹膜炎病毒(FIPV)感染之方法包含投與治療有效量之或其醫藥上可接受之鹽。 在一些實施例中，本發明提供治療貓傳染性腹膜炎(FIP)之方法，其包含投與治療有效量之以下化合物： 或； 或其醫藥上可接受之鹽。 在一些實施例中，治療貓傳染性腹膜炎(FIP)之方法包含投與治療有效量之或其醫藥上可接受之鹽。 本發明化合物可藉由熟習此項技術者已知之方法製備。舉例而言，本發明化合物可根據美國專利第8,008,264號及第7,973,013號以及PCT公開案第WO2012/012776號及第WO 2015/069939中所述之方法製備。III. 醫藥調配物
本發明化合物係利用習用載劑及賦形劑調配，該等載劑及賦形劑將根據常規選擇。錠劑將含有賦形劑、助流劑、填充劑、黏合劑及諸如此類。水性調配物係以無菌形式製備，且當預期藉由經口投與以外之方式遞送時，通常應係等滲的。所有調配物將視情況含有賦形劑，例如在「Handbook of Pharmaceutical Excipients」 (1986)中所述者。賦形劑包括抗壞血酸及其他抗氧化劑、螯合劑(例如EDTA)、碳水化合物(例如聚葡萄糖)、羥基烷基纖維素、羥基烷基甲基纖維素、硬脂酸及諸如此類。調配物之pH在約3至約11之範圍內，但通常約7至10。在一些實施例中，調配物之pH在約2至約5之範圍內，但通常約3至4。 儘管可單獨投與活性成分，但其較佳可以醫藥調配物存在。獸醫調配物可包含至少一種如上所定義之活性成分連同一或多種其可接受載劑及視情況其他治療成分、特別是本文所討論之其他治療成分。載劑必須係「可接受的」，其意為與調配物之其他成分相容且對其接受者生理上無害。 調配物包括適於上述投與途徑者。調配物可方便地以單位劑型呈遞且可藉由製藥業內熟知之任何方法製備。技術及調配物通常可發現於Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA)。該等方法包括使活性成分與構成一或多種輔助成分之載劑結合之步驟。一般而言，調配物係藉由使活性成分與液體載劑或細碎固體載劑或二者均勻且充分結合，然後(若需要)使產物成形來製備。 本發明適於經口投與之調配物可呈現為個別單元，例如膠囊、扁囊劑(cachets)或錠劑，各含有預定量的活性成分；呈粉末或顆粒；呈於水性或非水性液體中之溶液或懸浮液；或呈水包油液體乳液或油包水液體乳液。亦可以濃注(bolus)、舐劑或膏糊投與活性成分。 可藉由視情況與一或多種輔助成分一起壓縮或模製來製備錠劑。壓製錠劑可藉由在適宜機器中壓製呈自由流動形式(例如粉末或顆粒)之活性成分來製得，該活性成分視情況與黏合劑、潤滑劑、惰性稀釋劑、防腐劑、表面活性劑或分散劑混合。模製錠劑可藉由在適宜機器中模製經惰性液體稀釋劑潤濕之粉末狀活性成分之混合物來製備。錠劑可視情況經塗覆或刻痕且視情況經調配以提供活性成分自其之緩慢或受控釋放。 對於眼睛或其他外部組織(例如口腔及皮膚)之感染，調配物較佳作為含有活性成分之局部軟膏劑或乳膏施加，該(等)活性成分之量為(例如) 0.075% w/w至20% w/w (包括以0.1% w/w之增量在0.1%與20%之間之範圍內、例如0.6% w/w、0.7% w/w等之活性成分)、較佳0.2% w/w至15% w/w且最佳0.5% w/w至10% w/w。當調配於軟膏劑中時，活性成分可與石蠟或水混溶性軟膏基一起使用。或者，活性成分可利用水包油乳膏基調配於乳膏中。 若期望，乳膏基之水相可包括(例如)至少30% w/w多元醇，即具有兩個或更多個羥基之醇，例如丙二醇、丁烷1,3-二醇、甘露醇、山梨醇、甘油及聚乙二醇(包括PEG 400)及其混合物。局部調配物可期望地包括增強活性成分穿過皮膚或其他受影響區域之吸收或滲透的化合物。該等經皮滲透促進劑之實例包括二甲亞碸及相關類似物。 本發明乳液之油相可以已知方式自已知成分構成。儘管該相可僅包含乳化劑(emulsifier)(亦稱為乳化劑(emulgent))，但其可期望地包含至少一種乳化劑與脂肪或油或者與脂肪及油二者之混合物。較佳地，包括親水性乳化劑以及用作穩定劑之親脂性乳化劑。亦較佳包括油及脂肪二者。同時，乳化劑在有或沒有穩定劑之情況下形成所謂的乳化蠟，且該蠟與油及脂肪一起形成所謂的乳化軟膏基質，其形成乳膏調配物之油性分散相。 適用於本發明調配物之乳化劑及乳液穩定劑包括Tween®
60、Span®
80、鯨蠟硬脂醇、苄醇、肉豆蔻醇、單硬脂酸甘油基酯及月桂基硫酸鈉。適用於本發明調配物之其他乳化劑及乳液穩定劑包括包括Tween®
80。 用於調配物之適宜油或脂肪之選擇係基於達成期望化妝品性質。乳膏較佳為具有適宜稠度以避免自管或其他容器洩漏之不油膩、不染色且可洗產品。可使用直鏈或具支鏈單或二烷基酯，例如二異己二酸酯、硬脂酸異鯨蠟基酯、椰子脂肪酸之丙二醇二酯、肉豆蔻酸異丙基酯、油酸癸基酯、棕櫚酸異丙基酯、硬脂酸丁基酯、棕櫚酸2-乙基己基酯或具支鏈酯之摻合物(稱為Crodamol CAP)，後三者係較佳酯。該等端視所需之性質，該等可單獨或組合使用。或者，使用高熔點液體，例如白軟石蠟及/或液體石蠟或其他礦物油。 本發明之醫藥調配物包含根據本發明連同一或多種醫藥上可接受之載劑或賦形劑及視情況其他治療劑之組合。含有活性成分之醫藥調配物可呈適於期望投與方法之任何形式。舉例而言，當用於經口使用時，可製備錠劑、糖錠劑、菱形錠劑、水性或油性懸浮液、可分散粉末或顆粒、乳液、硬或軟膠囊、糖漿或酏劑。意欲用於經口使用之組合物可根據用於製造醫藥組合物之技術中已知之任何方法製備且該等組合物可含有一或多種試劑(包括甜味劑、矯味劑、著色劑及防腐劑)，以提供適口的製劑。含有活性成分與適於製造錠劑之醫藥上可接受之無毒賦形劑的混合物的錠劑係可接受的。該等賦形劑可為(例如)惰性稀釋劑，例如碳酸鈣或碳酸鈉、乳糖、磷酸鈣或磷酸鈉；製粒劑及崩解劑，例如玉米澱粉或海藻酸；黏合劑，例如澱粉、明膠或阿拉伯樹膠；及潤滑劑，例如硬脂酸鎂、硬脂酸或滑石粉。錠劑可無包衣或其可藉由已知技術(包括微膠囊化)包衣以延遲在胃腸道中之崩解及吸收並由此在較長時期內提供持續作用。舉例而言，諸如單硬脂酸甘油基酯或二硬脂酸甘油基酯等延時材料可單獨或與蠟一起採用。 用於經口使用之調配物亦可呈現為硬明膠膠囊形式，其中將活性成分與惰性固體稀釋劑(例如，磷酸鈣或高嶺土)混合；或作為軟明膠膠囊，其中將活性成分與水或油介質(例如，花生油、液體石蠟或橄欖油)混合。 本發明之水性懸浮液含有活性材料與適於製造水性懸浮液之賦形劑之混合物。該等賦形劑包括懸浮劑，例如羧甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、海藻酸鈉、聚乙烯基吡咯啶酮、黃蓍膠及阿拉伯樹膠；及分散劑或潤濕劑，例如天然磷脂(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)、環氧乙烷與長鏈脂肪族醇之縮合產物(例如十七伸乙基氧基鯨蠟醇)、環氧乙烷與衍生自脂肪酸及己醣醇酸酐之部分酯之縮合產物(例如聚氧乙烯山梨糖醇酐單油酸酯)。水性懸浮液亦可含有一或多種防腐劑，例如對羥基苯甲酸乙基酯或對羥基苯甲酸正丙基酯、一或多種著色劑、一或多種矯味劑及一或多種甜味劑(例如蔗糖或糖精)。懸浮劑之其他非限制性實例包括環糊精及Captisol (=磺丁基醚β-環糊精；SEB-β-CD)。 油性懸浮液可藉由將活性成分懸浮於植物油(例如花生油、橄欖油、芝麻油或椰子油)或礦物油(例如液體石蠟)中來調配。該等口服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(例如，彼等上文所述者)及矯味劑以提供適口經口製劑。該等組合物可藉由添加抗氧化劑(例如抗壞血酸)保存。 適於藉由添加水來製備水性懸浮液之本發明之可分散粉末及顆粒提供活性成分與分散劑或潤濕劑、懸浮劑及一或多種防腐劑之混合物。適宜分散劑或潤濕劑以及懸浮劑由彼等上文揭示者例示。亦可存在其他賦形劑，例如，甜味劑、矯味劑及著色劑。 本發明之醫藥組合物亦可呈水包油乳液形式。油相可為植物油(例如橄欖油或花生油)、礦物油(例如液體石蠟)或該等之混合物。適宜乳化劑包括天然樹膠(例如阿拉伯樹膠及黃蓍膠)、天然磷脂(例如大豆卵磷脂)、衍生自脂肪酸及己醣醇酸酐之酯或部分酯(例如山梨糖醇酐單油酸酯)及該等部分酯與環氧乙烷之縮合產物(例如聚氧乙烯山梨糖醇酐單油酸酯)。乳液亦可含有甜味劑及矯味劑。糖漿及酏劑可使用甜味劑(例如，甘油、山梨糖醇或蔗糖)調配。該等調配物亦可含有緩和劑、防腐劑、矯味劑或著色劑。 本發明之醫藥組合物可呈無菌可注射製劑形式，例如無菌可注射水性或油性懸浮液。此懸浮液可根據已知技術使用彼等上文已提及之適宜分散劑或潤濕劑及懸浮劑來調配。無菌可注射製劑可為於無毒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1,3-丁二醇中之溶液)或可自凍乾粉劑製備。可採用之可接受媒劑及溶劑尤其係水、林格氏溶液(Ringer's solution)及等滲氯化鈉溶液。另外，傳統上可採用無菌不揮發油作為溶劑或懸浮介質。出於此目的，可採用任何溫和不揮發油，包括合成甘油單酯或甘油二酯。另外，諸如油酸等脂肪酸亦可用於製備可注射劑。可採用之可接受媒劑及溶劑係水、林格氏溶液、等滲氯化鈉溶液及高滲氯化鈉溶液。 可與載劑材料組合以產生單一劑型之活性成分之量可隨所治療之主體及具體投與模式而變。舉例而言，預期經口投與給貓之時間釋放調配物可含有大約1至1000 mg活性材料，該活性材料與可在總組合物之約5%至約95% (重量:重量)變化之適當且方便量之載劑材料複合。醫藥組合物可經製備以提供對於投與而言易於量測量。舉例而言，預期靜脈內輸注之水溶液可含有每毫升溶液約3 mg至500 mg活性成分，以可以約30 mL/hr之速率輸注適宜體積。 適於局部投與至眼睛之調配物亦包括滴眼劑，其中活性成分溶解或懸浮於適宜載劑中、尤其用於活性成分之水性溶劑。活性成分較佳以0.5%至20%、有利地0.5%至10%且具體地約1.5% w/w之濃度存在於該等調配物中。 適於口腔中局部投與之調配物包括於矯味基質(通常為蔗糖及阿拉伯膠或黃蓍膠)中包含活性成分之菱形錠劑、於惰性基質(例如明膠及甘油、或蔗糖及阿拉伯膠)中包含活性成分之糖錠；及於適宜液體載劑中包含活性成分之漱口劑。 直腸投與之調配物可利用包含(例如)可可脂或柳酸酯之適宜基質呈現為栓劑。 適於肺內或經鼻投與之調配物具有(例如)在0.1微米至500微米(例如0.5、1、30、35等)之粒徑，其藉由快速吸入穿過鼻道或藉由吸入穿過口腔以到達肺泡囊來投與。適宜調配物包括活性成分之水性或油性溶液。適用於氣溶膠或乾燥粉末投與之調配物可根據習用方法製備且可與其他治療劑(例如，如下文所述迄今為止用於治療或預防冠狀病毒感染之化合物)一起遞送。 適用於陰道遞送之調配物可呈現為子宮托、棉塞、乳膏、凝膠、膏糊、泡沫或噴霧調配物，該等調配物除活性成分外亦含有如此項技術中已知適當之載劑。 適於非經腸投與之調配物包括水性及非水性無菌注射溶液，其可含有抗氧化劑、緩衝劑、抑菌劑及可使調配物與預期接受者之血液等滲的溶質；及水性及非水性無菌懸浮液，其可包括懸浮劑及增稠劑。 該等組合物可存在於單位劑量或多劑量容器(例如，密封安瓿及小瓶)中，且可儲存於冷凍乾燥(凍乾)條件下，僅需在即將使用前添加無菌液體載劑(例如，注射用水)。製備臨時注射用溶液及懸浮液可自先前所述種類之無菌粉劑、顆粒及錠劑製備。較佳單位劑量調配物係彼等含有如本文上文所列舉之日劑量或單位日亞劑量(unit daily sub-dose)或其適當份數之活性成分者。 應理解，除上文具體體積之成分以外，本發明之調配物可包括在關於所討論調配物類型之領域中習用之其他試劑，例如適於經口投與之彼等可包括矯味劑。 本發明進一步提供包含至少一種如上所定義之活性成分連同其獸用載劑之獸用組合物。 獸用載劑係可用於投與組合物之目的的材料且可為在獸醫領域中原本惰性或可接受的且與活性成分相容之固體、液體或氣體材料。該等獸用組合物可經口、非經腸或藉由任何其他期望途徑投與。 本發明化合物用於提供含有一或多種本發明化合物作為活性成份之控制釋放醫藥調配物(「控制釋放調配物」)，其中活性成分之釋放經控制及調節以允許較小頻率投藥或以改良既定活性成分之藥物動力學或毒性輪廓。IV . 投與途徑
一或多種本發明化合物(在本文中稱為活性成分)係藉由適於欲治療病狀之任何途徑投與。適宜途徑包括經口、經直腸、經鼻、經肺、局部(包括經頰及舌下)、經陰道及非經腸(包括皮下、肌內、靜脈內、真皮內、鞘內及硬膜外)及諸如此類。應瞭解，較佳途徑可隨(例如)接受者之病狀而變。 在本發明用於治療冠狀病毒感染之方法，本發明化合物可在任何時間投與給可能與遭受冠狀病毒感染之其他貓接觸或已經遭受冠狀病毒感染的貓。在一些實施例中，本發明化合物可預防性地投與給與遭受冠狀病毒感染之其他貓接觸的貓。在一些實施例中，本發明化合物可投與給針對冠狀病毒感染測試呈陽性但尚未顯示冠狀病毒感染症狀之貓。在一些實施例中，本發明化合物可在冠狀病毒感染之症狀開始時投與給貓。 活性成分之有效量至少取決於所治療病狀之性質、毒性、是否已預防性地(較低劑量)或針對活動性病毒感染使用化合物、遞送方法及醫藥調配物，且將由臨床醫師使用習用劑量遞增研究進行確定。其預期可為約0.0001至約100 mg/kg體重/天；通常，約0.01至約10 mg/kg體重/天；更通常，約.01至約5 mg/kg體重/天；最通常，約.05至約0.5 mg/kg體重/天。 本發明化合物用於治療冠狀病毒感染之有效劑量可取決於該劑量係欲預防性地使用還是治療已遭受冠狀病毒感染之貓。此外，劑量可取決於遭受冠狀病毒感染之貓係尚未顯示冠狀病毒感染之症狀還是已經顯示症狀。與接受預防性治療之貓相比，用於治療針對冠狀病毒感染測試呈陽性的貓及顯示冠狀病毒感染症狀之貓可需要較大劑量。 涵蓋投與本發明化合物之任何適宜時期。舉例而言，投與可持續1天至100天，包括2、3、4、5、6、7、8、9、10、15、20、25、30、40、50、60、70、80或90天。投與亦可持續1週至15週，包括2、3、4、5、6、7、8、9、10、11、12、13或14週。亦涵蓋較長之投與時期。投與時間可取決於化合物係預防性地投與還是治療遭受冠狀病毒感染之貓。舉例而言，預防性投與可持續在貓頻繁接觸遭受冠狀病毒感染之其他貓時之時期且在與冠狀病毒感染之貓最後一次接觸之後持續適宜時期。對於已經遭受冠狀病毒感染之貓，投與之時期可為治療動物所需之任何時間長度及在冠狀病毒感染之陰性測試以確保冠狀病毒感染不會返回之適宜時期。V. 實例 實例 1 . 治療貓冠狀病毒
在活體外分析中針對抗貓冠狀病毒之活性對化合物1進行篩選。將化合物1之連續稀釋液與2.5 × 104
拷貝之貓冠狀病毒混合並一式六份添加至具有預接種CRFK細胞之96孔板中。將板培育72小時，隨後用結晶紫使細胞培養單層染色。病毒誘導之細胞病變效應之程度係視覺上及使用讀板儀量化。陽性對照孔包含無化合物1之病毒。陰性對照孔缺少病毒及化合物1二者。藉由回歸分析計算EC50
。化合物1之EC50
顯示於表1中。 表1
在未感染CRFK細胞中使用市售CellTox Green細胞毒性分析(Promega)針對細胞毒性對化合物1進行篩選。分析係在96孔板格式中使用化合物1之連續稀釋液一式六份實施。在72小時培育之後藉由回歸分析計算與50%細胞毒性相關之化合物濃度(CC50
)。化合物1之CC50
顯示於表2中。參見圖1。 表2 實例 2 . 治療分析
在克蘭德爾裡斯貓腎(Crandell Rees Feline Kidney, CRFK)細胞中針對抗貓傳染性腹膜炎病毒(FIPV)之抗病毒活性測試化合物。將化合物之連續稀釋液混入10至100 TCID50
之FIPV並添加至含有預接種CRFK細胞之96孔板。將板在37℃培育48小時。培育後，使用結晶紫對CRFK細胞單層進行染色並使用吸光度讀板儀量化FIPV誘導之細胞病變效應。使用非線性回歸分析測定EC50
。參見圖1至圖15。本文上文所引用之所有出版物、專利及專利文件均以引用的方式併入本文中，如同個別地以引用方式併入一般。 已參照各種特定及較佳實施例及技術闡述本發明。然而，熟習此項技術者應瞭解，可作出許多改變及修改，同時保持在本發明之精神及範圍內。 儘管出於清晰理解之目的已藉助說明及實例相當詳細地闡述了上述發明，但熟習此項技術者應瞭解，可在隨附申請專利範圍之範圍內實踐某些變化及修改。另外，本文所提供之每一參考文獻均以整體引用的方式併入，併入程度如同每一參考文獻個別地以引用方式併入一般。若本申請案與本文提供之參考文獻之間存在衝突，則以本申請案為準。
圖1顯示CRFK細胞中之貓冠狀病毒利用化合物1之抑制，其中在3、2及1 µM接近100%抑制；EC50為0.75 µM。 圖2顯示化合物1對抗CRFK細胞中之FIPV之抗病毒活性。 圖3顯示化合物1對抗CRFK細胞中之FIPV之抗病毒活性。 圖4顯示化合物2對抗CRFK細胞中之FIPV之抗病毒活性。 圖5顯示化合物9對抗CRFK細胞中之FIPV之抗病毒活性。 圖6顯示化合物3對抗CRFK細胞中之FIPV之抗病毒活性。 圖7顯示化合物6對抗CRFK細胞中之FIPV之抗病毒活性。 圖8顯示化合物1對抗CRFK細胞中之FIPV之抗病毒活性。 圖9顯示化合物4對抗CRFK細胞中之FIPV之抗病毒活性。 圖10顯示化合物5對抗CRFK細胞中之FIPV之抗病毒活性。 圖11顯示化合物3對抗CRFK細胞中之FIPV之抗病毒活性。 圖12顯示化合物2對抗CRFK細胞中之FIPV之抗病毒活性。 圖13顯示化合物7對抗CRFK細胞中之FIPV之抗病毒活性。 圖14顯示化合物8對抗CRFK細胞中之FIPV之抗病毒活性。 圖15顯示化合物9對抗CRFK細胞中之FIPV之抗病毒活性。
Claims (10)
- 一種化合物或其醫藥上可接受之鹽在製造用於治療貓冠狀病毒感染之藥劑之用途，其中該化合物係：或。
- 如請求項1之用途，其中該冠狀病毒係貓腸內冠狀病毒(FECV)或貓傳染性腹膜炎病毒(FIPV)。
- 一種化合物或其醫藥上可接受之鹽在製造用於治療貓冠狀病毒感染之藥劑之用途，其中該化合物係。
- 如請求項3之用途，其中該冠狀病毒係貓腸內冠狀病毒(FECV)或貓傳染性腹膜炎病毒(FIPV)。
- 一種化合物或其醫藥上可接受之鹽在製造用於治療貓腸內冠狀病毒(FECV)感染之藥劑之用途，其中該化合物係： 或。
- 一種化合物或其醫藥上可接受之鹽在製造用於治療貓腸內冠狀病毒(FECV)感染之藥劑之用途，其中該化合物係。
- 一種化合物或其醫藥上可接受之鹽在製造用於治療貓傳染性腹膜炎病毒(FIPV)感染之藥劑之用途，其中該化合物係： 或。
- 一種化合物或其醫藥上可接受之鹽在製造用於治療貓傳染性腹膜炎病毒(FIPV)感染之藥劑之用途，其中該化合物係。
- 一種化合物或其醫藥上可接受之鹽在製造用於治療貓傳染性腹膜炎(FIP)之藥劑之用途，其中該化合物係：或。
- 一種化合物或其醫藥上可接受之鹽在製造用於治療貓傳染性腹膜炎(FIP)之藥劑之用途，其中該化合物係。
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| EP3595672B1 (en) | 2023-09-06 |
| KR20210130267A (ko) | 2021-10-29 |
| AU2018235754A1 (en) | 2019-10-24 |
| US10682368B2 (en) | 2020-06-16 |
| US20200376014A1 (en) | 2020-12-03 |
| CA3056072A1 (en) | 2018-09-20 |
| ES2961460T3 (es) | 2024-03-12 |
| EP4331677A2 (en) | 2024-03-06 |
| CN116036112A (zh) | 2023-05-02 |
| CA3056072C (en) | 2022-08-23 |
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