TW201625247A - 用於治療傳染性疾病之醫藥組合物 - Google Patents
用於治療傳染性疾病之醫藥組合物 Download PDFInfo
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- TW201625247A TW201625247A TW104114803A TW104114803A TW201625247A TW 201625247 A TW201625247 A TW 201625247A TW 104114803 A TW104114803 A TW 104114803A TW 104114803 A TW104114803 A TW 104114803A TW 201625247 A TW201625247 A TW 201625247A
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Abstract
本發明提供化合物及其醫藥上可接受的鹽以及化合物組合、其等醫藥組合物、其等製備方法及其等用於治療或預防傳染性疾病之方法。
Description
此係專利合作條約申請案,且主張2014年5月12日申請之美國臨時專利申請案第61/991,754號;2015年4月20日申請之美國臨時專利申請案第62/149,893號;及2015年4月22日申請之美國臨時專利申請案第62/151,013號之權益;其等全部係以其全文引用方式併入本文中。
本發明係關於某些用於治療傳染性疾病(諸如病毒及細菌感染)之化合物、方法及醫藥組合物。亦揭示製備此等化合物之方法及使用該等化合物之方法。特定言之,揭示(諸如)彼等由副黏液病毒科(Paramyxoviridae)、正黏液病毒科(Orthomyxoviridae)、黃熱病毒科(Flaviviridae)、小核糖核酸病毒科(Picornaviridae)及冠狀病毒科(Coronaviridae)引起之病毒感染之療法。
CXCR2係一種趨化因子受體,其在嗜中性白血球高度表現,且透過此受體之信號傳遞導致炎性細胞募集至受傷組織(1-2)。例如,已注意到,經RSV-感染的嬰兒肺中之嗜中性白血球升高(3-6)。此外,使CXCR2配體(IL-8)之生成增加之遺傳單核苷酸多型性(SNP)與RSV細支氣管炎及喘鳴相關聯(7、8)。嗜中性白血球亦係一種在流感病毒感
染期間募集至肺之突出細胞類型,且在小鼠流感感染期間CXCR2的清除可顯著減少嗜中性白血球浸潤至肺中(9、10)。
已知,RSV感染期間過度生成黏液對嬰兒有害,因為其阻塞狹小的肺呼吸道,並阻礙正常氧氣交換。在RSV感染之小鼠模型中,經由CXCR2之信號傳遞有助於過度生成黏液及呼吸道高反應性。用抗CXCR2抗體進行免疫中和,則CXCR2-/-小鼠顯示顯著減少在RSV感染後肺中的黏液(11)。亦據報導,用CXCR2配體抗體(MIP-2)治療經流感感染小鼠可減少肺嗜中性白血球計數,同時改良肺病理,而不會影響病毒複製及清除(12)。總之,已顯示,CXCR2及其一些配體(例如,IL-8)在人類呼吸道感染期間顯著上調。
因此,可結合至CXCR2受體及抑制CXCR2配體(例如,IL-8)結合之化合物可幫助治療與CXCR2配體生成增加相關聯之病狀。因此,此等化合物可治療與CXCR2配體誘導之嗜中性白血球趨化性相關聯之發炎病症。急性病毒及細菌肺感染引起明顯免疫炎症及黏液生成,其通常導致呼吸道阻塞、呼吸困難及住院。在症狀開始後不久投與時,當前抗病毒療法及抗生素作用可取得不同程度的成功。雖然傳染性因子在疾病及致病性方面起作用,但針對感染的免疫反應過度積極亦係顯著促進嚴重呼吸道疾病之病因。
流感病毒係全球性的健康問題,自1900年以來,其係已殺死全世界範圍內超過五千萬人的第三大流行病之原因。最近,世界衛生組織(World Health Organization)估計,每年有三至五百萬嚴重流感病例,且此等個體中每年有多達五十萬因併發症而死亡。參見WHO,Fact sheet N°211,(2009)。流感之特徵為突發高燒、咳嗽、頭痛、肌肉及關節痛、嚴重不適、咽喉炎及流鼻涕。據信,此等症狀係免疫系統的過度或非特異性反應的結果。大多數人無需就醫便可在一週內自發燒及其他症狀痊愈。然而,流感可導致高風險人之嚴重疾病或死
亡。同上。實際上,年紀小於兩歲的兒童、年齡為65歲或更年長的成年人及患有某些醫學病症(諸如慢性心臟、肺(亦即COPD及哮喘)、腎臟、肝臟、血液或代謝疾病(亦即糖尿病))之任何年齡的人或彼等具有弱化免疫系統者中出現併發症的風險最高。
當前針對各種流感病毒感染的治療劑聚焦在干擾神經胺糖酸苷酶之作用。在流感病毒可傳播至其他細胞之前,需藉助病毒蛋白神經胺糖酸苷酶清除細胞表面上的唾液酸。Tamiflu®(磷酸奧司他韋(oseltamivir phosphate))係一種經口投與之神經胺糖酸苷酶抑制劑,且Relenza®(扎那米韋(zanamivir))係一種由口吸入之神經胺糖酸苷酶抑制劑。其他獲批的治療劑(如阿曼他丁(amantadine)及金剛乙胺(rimantadine))是靶向病毒離子通道(M2蛋白)及抑制病毒脫殼。不幸的是,已報導,Tamiflu®具有嚴重副作用,包括噁心、嘔吐及神經或精神系統紊亂。而且,亦報導耐Tamiflu®病毒及耐阿曼他丁病毒的爆發,包括出現耐藥性病毒之人際(human-to-human)傳播。事實上,美國CDC建議,不再開立阿曼他丁及金剛乙胺處方來治療流感,因為最近如此高比例之季節性菌株已顯示出對其等作用之耐藥性。許多此等治療劑之另一缺點係,若未在症狀開始四十八小時內開始治療,則效果要小很多。雖然可預防性地服用針對某些流感菌株之疫苗,但美國CDC及疫苗製造商必須精確地預測在即將到來的季節將傳播的特定菌株,該預測係難以實施。
因此,需要有益地靶向呼吸道感染之多個態樣(包括例如過度生成黏液、呼吸道高反應性)且亦可抑制潛在傳染性因子複製之其他醫療療法。
根據本發明之一實施例,提供一種治療罹患呼吸道感染之個體之呼吸道感染之新穎方法,其包括向該個體投與式(I)化合物,
或者其醫藥上可接受的鹽,
其係單獨投與或與抗微生物劑或其醫藥上可接受的鹽組合投與。該式(I)化合物與抗微生物劑(諸如,例如任何神經胺糖酸苷酶抑制劑)之此等「組合」可作為在相同劑量中之固定劑量組合投與至罹患呼吸道感染之個體,或者此等組合可以多個獨立劑量投與。
亦提供一種組合物,其包含式(I)化合物:
及神經胺糖酸苷酶抑制劑化合物。
亦提供一種組合物,其包含式(I)化合物:式(I)
及利巴韋林(ribavirin)。
亦提供包含醫藥上可接受的載劑或賦形劑及該式(I)化合物或其醫藥上可接受的鹽以及抗微生物劑或其醫藥上可接受的鹽之醫藥組合物。
亦提供一種預防個體之呼吸道感染之方法,其包括向具有患呼吸道感染風險或易感染呼吸道感染、獲呼吸道感染之個體投與該式(I)化合物或其醫藥上可接受的鹽,其係單獨投與或與抗微生物劑或其醫藥上可接受的鹽組合投與。
亦提供包含醫藥上可接受的載劑或賦形劑及僅該式(I)化合物或其醫藥上可接受的鹽或者其與抗微生物劑或其醫藥上可接受的鹽組合之醫藥組合物。
亦提供製備該式(I)化合物或其醫藥上可接受的鹽與抗微生物劑之組合及其組合物之方法以及該組合之治療用途。
在整篇申請案中,參考關於化合物、組合物及方法之各種實施例。所述各種實施例意在提供各種說明性實例,且不應視為描述替代
性物質。確切而言,應注意,本文所提供各種實施例之描述之範圍可重疊。本文所述實施例僅具說明性,且意不在於限制本發明之範圍。
應理解,本文所用之術語之目的僅在於描述特定實施例,而意不在於限制本發明之範圍。在本申請案及後面的申請專利範圍中,將參考許多應經定義以具有以下含義之術語。
如本文所使用,「抗微生物劑」係指會殺死微生物或抑制其生長或預防或阻礙其致病作用之製劑,呈化合物或生物實體。抗微生物劑可根據主要作用之微生物分類,諸如抗病毒劑或抗細菌劑。
如本文所使用之「化合物(compound)」、「化合物(compounds)」、「化學品(chemical)」及「化學化合物(chemical compounds)」係指本文所揭示通式、彼等通式之任何亞屬所涵蓋之化合物及通式及亞通式內之任何形式化合物,包括該化合物之外消旋物、立體異構體及互變異構體。
「外消旋物」係指對映異構體混合物。在本發明之一實施例中,式(I)化合物或其醫藥上可接受的鹽係經一種對映異構體而對映體上強化,其中所有提及的對掌性碳均係呈一種構型。一般而言,提及對映體上強化的化合物或鹽亦在表明指定的對映異構體將佔該化合物或鹽之所有對映異構體總重之超過50重量%。
化合物之「溶劑化物」係指結合至化學計量或非化學計量之溶劑之彼等如上所定義之化合物。化合物之溶劑化物包括該化合物所有形式之溶劑化物。在某些實施例中,溶劑係揮發性、無毒及/或可接受以微量投與至人類。適宜的溶劑化物包含水,其中該溶劑化物係水合物。
「立體異構體」係指一或多個立體中心之對掌性不同之化合物。立體異構體包括對映異構體及非對映異構體。
「互變異構體」係指質子位置不同之化合物之替代形式,諸如
烯醇-酮及亞胺-烯胺互變異構體,或者含同時附接至環的-NH-部分及環的=N-部分之環原子的雜芳基之互變異構形式,諸如吡唑、咪唑、苯并咪唑、三唑及四唑。
「醫藥上可接受的鹽」係指衍生自此項技術中熟知之各種有機及無機抗衡離子之醫藥上可接受的鹽,且包括(僅舉例而言)鈉鹽、鉀鹽、鈣鹽、鎂鹽、銨鹽及四烷銨鹽,及當分子包含鹼性官能度時之有機酸或無機酸之鹽,諸如鹽酸鹽、氫溴酸鹽、酒石酸鹽、甲磺酸鹽、乙酸鹽、馬來酸鹽及草酸鹽。適宜的鹽包括彼等P.Heinrich Stahl,Camille G.Wermuth(編輯),Handbook of Pharmaceutical Salts Properties,Selection,and Use;2002中所述者。
在一實施例中,該醫藥上可接受的鹽為式(I)化合物之氫溴酸鹽。
「患者」或「個體」係指哺乳動物,且包括人類及非人類哺乳動物。
「治療」患者之疾病係指1)預防易感染或尚未顯示該疾病症狀之患者出現該疾病;2)抑制該疾病或阻止其發展;或3)改善該疾病或使之消退。
根據本發明之一實施例,提供一種針對呼吸道系統之傳染性疾病之藥物療法。在一實施例中,本發明可用於治療由病毒感染所引起之症狀,該病毒包括(但不限於)流感病毒、人類鼻病毒、其他腸道病毒、呼吸道融合病毒、副流行性感冒病毒、偏肺病毒、冠狀病毒、疱疹病毒或腺病毒。亦應注意,本文治療之呼吸道病毒感染亦可與後續繼發性細菌感染相關聯。
CXCR2係一種趨化因子受體,其在嗜中性白血球高度表現,且透過此受體之信號傳遞導致炎性細胞募集至受傷組織。預期,細胞因子信號傳遞以減少嗜中性白血球趨化性之化學拮抗作用可藉由減少嗜
中性白血球浸潤來控制、減少及減輕許多最終症狀而使罹患呼吸道感染之個體受益。因此,本發明提供一種新穎療法,其僅包括與CXCR2受體拮抗之式(I)化合物或其與抗微生物劑組合。例如,預期本發明可減少病原體效價,及防止炎性細胞反復發送信號並浸潤感染患者之肺,其可減輕疾病症狀及肺病理。本發明亦提供減少過度炎症免疫反應及病毒或細菌複製之治療組合物及方法。
在一實施例中,預期CXCR2拮抗劑化合物(例如,式I化合物)與抗微生物劑之組合療法可靶向病毒/細菌及疾病之免疫態樣,從而加速疾病恢復及消退,速度可能快於單獨採用的任一療法。
在其他實施例中,可向CXCR2拮抗劑式I化合物與抗微生物劑之組合療法添加其他製劑。此等其他製劑可包括可有效減少一或多種症狀(包括例如高燒、咳嗽、頭痛、肌肉及關節痛、不適、咽喉炎及流鼻涕)之任何其他呼吸道感染療法。
式I化合物亦可與抗微生物劑組合使用,以治療人類因細菌引起之感染(特定言之呼吸道感染)症狀。具體的細菌包括(但不限於)細菌性肺炎之病原體(causative agent),諸如肺炎鏈球菌(Streptococcus pneumoniae)、金黃色葡萄球菌(Staphylococcus aureus)、流感嗜血桿菌(Haemophilus influenza)、克留氏肺炎桿菌(Klebsiella pneumoniae)、嗜肺性退伍軍人桿菌(Legionella pneumophila)、齒齦卟啉菌(Porphyromonas gingivalis)及鮑曼不動桿菌(Acinetobacter baumanii)。此外,本發明係關於會加劇潛在慢性病症之呼吸道感染(諸如哮喘、慢性支氣管炎、慢性阻塞性肺病、中耳炎及竇炎)。在此情形下,感染可起到引發病情惡化之作用,且用本發明控制症狀將減少出現惡化的可能性。
按照本發明,已發現,藉由向個體單獨投與式(I)化合物或其與一或多種抗微生物劑之組合可治療及預防該個體之傳染性疾病及傳染
性疾病相關併發症。出於本發明之目的,包含式(I)化合物與至少一種抗微生物劑之組合之新穎組合療法亦可用於預防及治療需要此預防或治療之個體之傳染性疾病及傳染性疾病相關併發症。因此,本發明組合療法將可用於(例如)減少罹患此等症狀之個體之此等傳染性疾病症狀,如(例如)咳嗽、鼻漏、呼吸困難、呼吸短促、疼痛、炎症、眼睛瘙癢及/或流淚、流鼻涕、鼻充血、面部壓力、打噴嚏、咽喉炎、咳嗽、頭痛、發燒、不適、疲勞、虛弱、及/或肌肉疼痛。本發明組合療法將亦可用於預防出現此等症狀。
本發明方法及組合物亦可用於減少罹患傳染性疾病之個體之住院數量,或預防或延遲個體發展出與傳染性疾病相關聯之併發症,其最終可由患上慢性或復發性傳染性疾病而引起。式(I)化合物與抗微生物劑之組合療法亦可用於降低所需獨立劑型之數量,因而可能提高患者順服性。投與式(I)化合物以預防及治療傳染性疾病及傳染性疾病相關併發症係意外有效的療法及預防性療法。此投與有效改良傳染性疾病及傳染性疾病相關併發症之症狀,同時避免或減少當前療法之某些缺點。此外,投與式(I)化合物與抗微生物劑之組合可有效治療傳染性疾病或傳染性疾病相關併發症或症狀,且在一些實施例中,可優於單獨使用任一製劑。例如,組合療法可有效降低抗微生物劑作為單一療法通常所開處方之劑量。投與較低劑量之習知治療劑可減少此等習知製劑相應之副作用。包含式(I)化合物及抗微生物劑之組合療法不僅可用於改良傳染性疾病症狀及縮短恢復時間,而且亦可減少抗微生物劑通常所需之劑量。
如本文所使用,當指組合使用式(I)化合物與抗微生物劑時,片語「組合療法」、「共投與(co-administration)」、「共投與(co-administering)」、「與...一起投與(administration with)」、「投與」、「組合」或「協同療法(co-therapy)」意欲包括在將提供藥物組合之有益效
果之方案中以依次方式投與各製劑,且亦意欲包括以實質上同時的方式共同投與此等製劑。因此,式(I)化合物及抗微生物劑可以一個治療劑型投與,諸如呈單一膠囊、錠劑、注射劑或輸注劑,或以兩個獨立治療劑型投與,諸如呈獨立膠囊、錠劑、注射劑或輸注劑。在其他實施例中,當式(I)化合物以相對於抗微生物劑之獨立劑型投與時,此獨立用藥可在類似或不同時間框內進行,端視患者之治療需求而定。熟習此項技術者將理解如何適宜地確定此等獨立用藥時期。
依次投與此等療法涵蓋投與本方法各藥物間之相對短及相對長時間。然而,在本發明之一些實施例中,在第一藥物仍對個體具有有效效果時投與第二藥物。因此,在一實施例中,本發明利用個體中同時存在式(I)化合物與抗微生物劑之組合之事實而具有大於單獨投與任一製劑之臨床療效。或者,在本發明之一些實施例中,在第一藥物已對個體沒有有效效果時投與第二藥物。
在一實施例中,兩種藥物之第二者欲在欲投與之第一藥物之治療反應時間內投與至個體。例如,本發明涵蓋向個體投與式(I)化合物,及隨後投與抗微生物劑,只要在式(I)化合物仍以一定濃度存在於個體中時投與抗微生物劑至該固體,該一定濃度與抗微生物劑之濃度組合具有治療效果,且反之亦然。
如本文所使用,術語「治療反應時間」意指化合物在個體體內以治療濃度存在或可檢測到治療濃度之持續時間。
如本文所使用,術語「單一療法」意欲包括向罹患傳染性疾病或傳染性疾病相關併發症之個體呈單一治療處理投與式(I)化合物,而無包含抗微生物劑之另一治療處理。然而,式(I)化合物仍可以多個劑型投與。因此,式(I)化合物可以一個治療劑型投與,諸如呈單一膠囊、錠劑、注射劑或輸注劑,或以兩個獨立治療劑型投與,諸如呈獨立膠囊、錠劑、注射劑或輸注劑。
本文所述之式(I)化合物或其鹽及其他醫藥活性劑之量以及相對投與時序將經選擇,以達到所需組合療效。
在其他實施例中,本發明化合物可與一或多種可用於預防或治療病毒性疾病或相關聯病理生理之抗微生物劑組合使用。因此,本發明化合物及其鹽、溶劑化物或其醫藥上可接受的其他衍生物可單獨使用或與其他抗微生物劑組合使用。本發明化合物及任何其他醫藥活性劑可一起或分開投與,且當分開投與時可同時或以任何次序依次進行投與。本發明化合物其他醫藥活性劑之量以及相對投與時序將經選擇,以達到所需組合療效。本發明化合物及其鹽、溶劑化物或其他醫藥上可接受的衍生物與其他治療劑之組合投與可以如下組合同時投與:(1)包含兩種化合物之整體醫藥組合物;或(2)各包含其中一種化合物之獨立醫藥組合物。或者,該組合可以依次方式分開投與,其中先投與一種治療劑,然後投與另一第二治療劑,或反之亦然。此依次投與之時間間隔可較接近或較遠。
在一實施例中,本發明涵蓋一種預防個體之傳染性疾病之方法,該方法包括向該個體單獨投與式(I)化合物或其與抗微生物劑之組合。
如本文所使用,術語「以預防(to prevent)」、「預防(preventing)」或「預防(prevention)」係指個體發展出傳染性疾病或傳染性疾病相關併發症之傾向或風險之任何程度下降,無論該程度多麼輕微。出於本發明之目的,該個體係任何個體,且較佳係具有發展出傳染性疾病或傳染性疾病相關併發症之風險或傾向之個體。術語「預防」包括在具風險個體中完全預防臨床上明顯傳染性疾病發作,或預防臨床前明顯傳染性疾病發作
在另一實施例中,本發明涵蓋一種治療個體之傳染性疾病或傳染性疾病相關併發症之方法,該方法包括向該個體單獨投與式(I)化合物或其與抗微生物劑之組合。
如本文所使用,術語「治療(treating)」、「治療(treatment)」、「治療(treated)」或「以治療(to treat)」意指減輕症狀、暫時或永久地消除病因、或改變或減緩症狀出現或症狀惡化。此等術語亦包括減輕或消除與本文所述任何傳染性疾病或傳染性疾病相關併發症相關聯(但不限於)之症狀起因。此等術語亦包括減少個體之傳染性疾病或傳染性疾病相關併發症之持續時間。
不受此或任何其他理論之限制,據信包含式(I)化合物之療法可有效削弱呼吸道感染期間肺內之炎症進程,從而預防或治療傳染性疾病症狀及因而預防或治療傳染性疾病相關併發症。此外,在較佳實施例中,式(I)化合物與抗微生物劑之組合可提供協同效果,其可減少與傳染性疾病及傳染性疾病相關併發症相關聯之症狀,其減少程度大於單獨使用任一者所能預期之程度。
術語「協同」係指式(I)化合物與抗微生物劑之組合作為組合療法之預防及治療傳染性疾病之療效可大於其各自效果之總和。本發明組合療法之某些實施例之協同效果可涵蓋治療及預防傳染性疾病之其他意外優勢。此等其他優勢可包括(但不限於)降低抗微生物劑所需劑量、減少抗微生物劑副作用及使彼等製劑對經歷傳染性疾病療法之個體耐受性更強。
而且,本發明單一療法及組合療法可藉由治療自身潛在的呼吸道傳染性疾病來治療或預防可由患上呼吸道傳染性疾病間接引起之傳染性疾病相關併發症。例如,若個體罹患病毒性呼吸道疾病相關併發症(諸如繼發性呼吸道細菌感染(例如肺炎)),則藉由本發明方法及組合物治療潛在病毒性傳染性疾病(諸如病毒性流感)可預防出現相關聯之細菌性感染併發症及其症狀。本發明係關於一種預防或治療有此預防或治療需要之個體之傳染性疾病及傳染性疾病相關併發症之新穎方法,其包括向該個體投與式(I)化合物。本發明亦係關於一種預防或治療
有此預防或治療需要之個體之傳染性疾病及傳染性疾病相關併發症之新穎方法,其包括向該個體投與式(I)化合物及一或多種抗微生物劑。
根據本發明之一實施例,提供一種具有式I結構之化合物:
在其他實施例中,式(I)化合物亦可以所示其立體化學結構描繪。因此,式(I)化合物亦係具有以下結構之對掌性化合物:
式(I)化合物係用於慢性阻塞性肺病(COPD)之CXCR2抑制劑,其當前處在美國2期臨床試驗,且稱為「黛力新」,且化學名為:N-[4-氯-2-羥基-3-(3-哌啶基磺醯基)-苯基]-N'-(3-氟-2-甲基苯基)脲,全部名稱在本文中可互換。式(I)化合物係描述於美國專利案第7,893,089號中,該專利案之全文以引用的方式併入本文中。
在一替代性實施例中,亦提供呈氫溴酸鹽形式之式(I)化合物作為獨立新穎化合物。此外,式(I)化合物之此氫溴酸鹽可與本發明新穎療法及組合一起使用。
在本發明之另一實施例中,提供一種包含式(I)與抗微生物劑之組合之組合療法或預防療法。在本發明之一實施例中,該抗微生物劑為神經胺糖酸苷酶抑制劑。在本發明之另一實施例中,該抗微生物劑係選自由扎那米韋、奧司他韋、拉尼米韋(laninamivir)及帕拉米韋(peramivir)組成之群。在本發明之另一實施例中,該抗微生物劑為扎那米韋。在本發明之另一實施例中,該抗微生物劑為奧司他韋。在本發明之一實施例中,該抗微生物劑為利巴韋林。
扎那米韋係一種面世的流感病毒神經胺糖酸苷酶抑制劑,稱為Relenza®,且被美國FDA批准用於治療及預防流感。參見Ryan,D.M.等人,Antimicrob.Agents Chemother.1994,38,2270。扎那米韋係作為用於DiskhalerTM裝置中之吸入粉末以5mg強度投與至患者。隨後扎那米韋結合至流感神經胺糖酸苷酶活性位點,從而使得流感病毒無法逃離其宿主細胞並感染其他細胞。儘管如此,本發明涵蓋扎那米韋之替代性投與模式及替代性劑量,諸如例如靜脈內用藥。
扎那米韋具有如下化學結構:
在其他實施例中,扎那米韋亦可以所示其真實立體化學結構描
繪。此立體化學結構指示扎那米韋係具有以下結構之對掌性化合物:
扎那米韋係描述在von Izstein等人之美國專利案第5,360,817號;美國專利案第5,597,933號;美國專利案第5,495,027號;及美國專利案第6,156,544號中,該等專利案之全文以引用的方式併入本文中。除此等專利案之揭示內容以外,已報導另一種製造扎那米韋之合成途徑。參見Zhu等人,Tetrahedron,68(8),2041-2044(2012)。
奧司他韋係一種面世的流感病毒神經胺糖酸苷酶抑制劑,稱為Tamiflu®,且被美國FDA批准用於治療及預防流感。參見Lew等人,Curr.Med.Chem.,7(6):663-72(2000)。
奧司他韋係作為膠囊(含98.5mg磷酸奧司他韋,相當於75mg奧司他韋)及作為口服懸浮劑之粉末(磷酸奧司他韋相當於奧司他韋,6mg/ml)投與至患者。隨後奧司他韋結合至流感神經胺糖酸苷酶活性位點,從而使得流感病毒無法逃離其宿主細胞並感染其他細胞。Tamiflu®亦可以含30mg或45mg奧司他韋之膠囊購得。
奧司他韋具有如下化學結構:
在其他實施例中,奧司他韋亦可以所示其真實立體化學結構描繪。此立體化學結構指示奧司他韋係具有以下結構之對掌性化合物:
奧司他韋係描述於美國專利案第5,763,483號;第5,866,601號及第5,952,375號中;該等專利案之全文以引用的方式併入本文中。除此等專利案之揭示內容以外,已報導另一種製造奧司他韋之合成途徑。參見Ishikawa等人,Angew.Chem.Int.Ed.,48:1304-1307(2009)。
因此,根據本發明之一實施例,提供一種用於呼吸道感染之新穎組合治療療法。
本發明亦提供一種包含式(I)化合物與扎那米韋之組合之新穎組合物。在另一實施例中,本發明提供一種包含式(I)化合物與奧司他韋之組合之新穎組合物。在另一實施例中,本發明提供一種包含式(I)化合物與拉尼米韋之組合之新穎組合物。在另一實施例中,本發明提供一種包含式(I)化合物與帕拉米韋之組合之新穎組合物。在另一實施例中,本發明提供一種包含式(I)化合物與法匹拉韋(T-705)之組合之新穎組合物。
另外提供一種治療罹患呼吸道感染之個體之呼吸道感染之新穎方法,其包括向該個體投與式(I)化合物或其醫藥上可接受的鹽及扎那米韋或其醫藥上可接受的鹽。式(I)化合物與扎那米韋之此等「組合」可作為相同劑量中之固定劑量組合投與至罹患呼吸道感染之個體,或者此等組合可以兩個獨立劑量投與。
亦提供包含醫藥上可接受的載劑或賦形劑及式(I)化合物或其醫
藥上可接受的鹽以及扎那米韋或其醫藥上可接受的鹽之醫藥組合物。
亦提供一種預防個體之呼吸道感染之方法,其包括向具有患上呼吸道感染風險或易感呼吸道感染、獲呼吸道感染之個體投與式(I)化合物或其醫藥上可接受的鹽與扎那米韋或其醫藥上可接受的鹽之組合。
另外提供一種治療罹患病毒性呼吸道感染之個體之病毒性呼吸道感染之新穎方法,其包括向該個體投與式(I)化合物或其醫藥上可接受的鹽與扎那米韋或其醫藥上可接受的鹽之組合。
另外提供一種治療罹患流感感染之個體之流感感染之新穎方法,其包括向該個體投與式(I)化合物或其醫藥上可接受的鹽與扎那米韋或其醫藥上可接受的鹽之組合。
另外提供一種用於治療罹患RSV感染之個體之RSV感染之新穎組合物及/或方法,其包括向該個體投與式(I)化合物或其醫藥上可接受的鹽與利巴韋林或其醫藥上可接受的鹽之組合。
本發明之此等化合物可以特定幾何或立體異構形式存在。本發明涵蓋所有此等化合物,包括順式-及反式-異構體、(-)-及(+)-對映異構體、(R)-及(S)-對映異構體、非對映異構體、(D)-異構體、(L)-異構體、其外消旋混合物及其其他混合物(諸如對映異構體或非對映異構體上強化的混合物),如同落入本發明範圍內一般。取代基(諸如烷基)中可存在其他不對稱碳原子。希望所有此等異構體及其混合物意欲包括在本發明中。
可使用對掌性合成子或對掌性試劑來製備或使用習知技術來解析光學活性(R)-及(S)-異構體以及d及I異構體。例如,若需要本發明化合物之特定對映異構體,則可藉由不對稱合成或藉由用對掌性助劑衍生化來製備,其中分離所得非對映異構體混合物,並切除助劑基團,以提供純淨所需對映異構體。或者,當分子包含鹼性官能團(諸
如胺基)或酸性官能團(諸如羧基)時,可用適宜光學活性酸或鹼形成非對映異構鹽,隨後藉由分段結晶或此項技術中已知之層析手段解析由此形成之非對映異構體,及隨後回收純淨對映異構體。此外,通常利用層析,使用對掌性固定相,視情況與化學衍生化(例如自胺形成胺基甲酸酯)分離對映異構體及非對映異構體。
在本發明之另一實施例中,提供式(I)化合物與抗微生物劑之組合,其中該化合物及抗微生物劑係用於製造用於治療人類之病毒感染之藥劑。
在本發明之另一實施例中,提供一種包含醫藥上可接受的稀釋劑及治療有效量之如式(I)所定義之化合物與抗微生物劑之組合之醫藥組合物。
在一實施例中,本發明係關於具有作為病毒感染之新穎治療及/或預防性療法效用之化合物、組合物及醫藥組合物。在另一實施例中,本發明係關於具有作為呼吸道病毒感染之新穎治療及/或預防性療法效用之化合物、組合物及醫藥組合物。在另一實施例中,本發明係關於具有作為細菌呼吸道感染之新穎治療及/或預防性療法效用之化合物、組合物及醫藥組合物。
病毒係藉由評估若干種特性(包括病毒基因組類型)分類。病毒基因組可由DNA或RNA組成,可為雙股或單股(其可進一步為正義或反義),且大小及基因組織形式可大不相同。
RNA病毒係具有RNA(核糖核酸)作為其遺傳物質之病毒。此核酸通常係單股RNA(ssRNA)。RNA病毒可根據其RNA之義(sense)或極性進一步分為反義及正義。正義病毒RNA類似於mRNA,且因此可由宿主細胞立即轉譯。反義病毒RNA與mRNA互補,且因此必須在轉譯前藉由RNA聚合酶轉化為正義RNA。因此,正義病毒之純化RNA可直接導致感染,但其傳染性可小於整個病毒粒子。反義病毒之純化RNA本
身不具傳染性,因其需要轉錄成正義RNA;各病毒粒子可轉錄成若干種正義RNA。
正義單股RNA病毒(「單股RNA病毒」)構成來自許多不同亞家族之病毒之大型超家族。此等病毒橫跨植物及動物界,引起介於輕度表現型至重度衰竭性疾病範圍內之病理。正義股RNA病毒聚合酶超群之組合物包括至少以下家族:輕小病毒、裸露核糖核酸病毒、小核糖核酸病毒、雙順反子病毒、海生病毒、伴生病毒、豇豆花葉病毒、馬鈴薯y病毒、杯狀病毒、星狀病毒、諾達病毒、四病毒、黃矮病毒、番茄叢矮病毒、冠狀病毒、動脈炎病毒、輪狀病毒(roni-)、黃病毒、披衣病毒、雀麥花葉病毒、蕪菁黃花葉病毒、線性病毒、彎曲病毒、塞科病毒、桿菌狀核糖核酸病毒、軟腐病病毒、溫州蜜柑矮縮病毒、櫻桃銼葉病毒、肝炎病毒、南方菜豆花葉病毒、幽影病毒、煙草花葉病毒、煙草脆裂病毒、大麥病毒、真菌傳桿狀病毒、馬鈴薯帚頂病毒、簇生病毒、甜菜壞死黃脈病毒、歐爾蜜病毒及懸鈎子病毒。
反義單股RNA病毒(「反義股RNA病毒」)必須藉由RNA-依賴性RNA聚合酶複製其基因組,以形成正義RNA。此意味著該病毒必須攜帶RNA複製酶。然後,正義RNA分子充當病毒mRNA,藉由宿主核糖體將其轉譯為蛋白質。所得蛋白質繼續引導合成新的病毒粒子,諸如衣殼蛋白及RNA複製酶,將其用於製造新的反義RNA分子。
反義單股RNA病毒群中識別出八個科,並將一些未指定的歸為特定科。
˙波納病毒(Bornaviridae)科-波納(Borna)病病毒
˙絲狀病毒(Filoviridae)科-包括埃博拉(Ebola)病毒、馬爾堡(Marburg)病毒
˙副黏液病毒科-包括麻疹(Measles)病毒、腮腺炎(Mumps)病
毒、尼帕(Nipah)病毒、亨德拉(Hendra)病毒
˙炮彈病毒(Rhabdoviridae)科-包括狂犬病(Rabies)病毒
˙沙粒病毒(Areaaviridae)科-包括賴薩(Lassa)病毒
˙布尼亞病毒(Bunyaviridae)科-包括漢坦病毒(Hantavirus)、克里米亞-剛果(Crimean-Congo)出血熱
˙蛇形病毒(Ophioviridae)科
˙正黏液病毒(Orthomyxoviridae)科-包括流感病毒
˙δ病毒(Deltavirus)屬-包括肝炎病毒
˙戴可哈病毒(Dichorhavirus)屬
˙歐洲花楸環斑病毒(Emaravirus)屬
˙尼亞病毒(Nyavirus)屬-包括尼亞瑪尼(Nyamanini)及米德偉(Midway)病毒
˙纖細病毒(Tenuivirus)屬
˙葉脈曲張病毒(Varicosavirus)屬
塔斯楚普(Taastrup)病毒
因此,希望本發明可涵蓋治療或預防本文所引用之任何病毒或者病毒科或屬以及本文未引用但將為熟習此項技術者所知之其他病毒。
在本發明之一實施例中,本文所述化合物可用於預防或治療個體中由單股RNA病毒所引起之病毒感染。
在本發明之一實施例中,本文所述化合物可用於預防或治療個體中由正義單股RNA病毒所引起之病毒感染。
在本發明之一實施例中,本文所述化合物可用於預防或治療個
體中由反義單股RNA病毒所引起之病毒感染。
在一些實施例中,提供一種治療個體中至少部分由尼多病毒目(Nidovirale)、小核糖核酸病毒目(picornavirale)、蕪菁黃花葉病毒目(tymovirale)、單股反鏈病毒目(mononegavirale)、呼腸孤病毒科(reoviridae)、派可皮核醣核酸病毒(pycobirnaviridae)、小DNA病毒科(parvoviridae)、腺病毒科(adenoviridae)、痘病毒科(poxviridae)、多瘤病毒科(polyomaviridae)、皰疹病毒科(herpesviridae)、副黏液病毒科之病毒介導之病毒感染之方法,其包括向該個體投與包含任一式(I)化合物與抗微生物劑之組合之組合物。
一種治療罹患病毒感染之個體之病毒感染之方法,其包括向該個體投與式(I)化合物與抗微生物劑之組合。
一種預防個體之病毒感染之方法,其包括向該個體投與任一式(I)化合物與抗微生物劑之組合。
在其他實施例中,本文所述化合物可用於預防或治療個體之病毒感染,其中該感染係由屬於以下家族之病毒所引起:輕小病毒、裸露核糖核酸病毒、小核糖核酸病毒、雙順反子病毒、海生病毒、伴生病毒、豇豆花葉病毒、馬鈴薯y病毒、杯狀病毒、星狀病毒、諾達病毒、四病毒、黃矮病毒、番茄叢矮病毒、冠狀病毒、動脈炎病毒、輪狀病毒、黃病毒、披衣病毒、雀麥花葉病毒、蕪菁黃花葉病毒、線性病毒、彎曲病毒、塞科病毒、桿菌狀核糖核酸病毒、軟腐病病毒、溫州蜜柑矮縮病毒、櫻桃銼葉病毒、肝炎病毒、南方菜豆花葉病毒、幽影病毒、煙草花葉病毒、煙草脆裂病毒、大麥病毒、真菌傳桿狀病毒、馬鈴薯帚頂病毒、簇生病毒、甜菜壞死黃脈病毒、歐爾蜜病毒及懸鈎子病毒。
本發明揭示化合物、方法及醫藥組合物,其用於藉由向罹患該病毒感染之個體單獨投與式(I)化合物或其與本文所述抗微生物劑之組
合來治療呼吸道病毒感染。本發明亦揭示製備此等化合物之方法及使用該等化合物及其醫藥組合物之方法。特定言之,揭示(諸如)彼等由RNA或DNA病毒所引起之病毒感染之治療及預防。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由屬於小核糖核酸病毒科、絲狀病毒(filoviridae)科、副黏液病毒或冠狀病毒科之病毒所引起。在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由屬於小核糖核酸病毒科之病毒所引起。在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由屬於冠狀病毒科之病毒所引起。
在其他實施例中,本文所述化合物可用於預防或治療個體之病毒感染,其中該感染係由任一種或多種選自以下組成之群之病毒所引起:脊髓灰質炎病毒(poliovirus)、鼻病毒(rhinovirus)、柯薩奇病毒(coxsackievirus)、A型流感病毒、B型流感病毒、腺病毒、冠狀病毒、A型肝炎病毒、B型肝炎病毒、C型肝炎病毒、E型肝炎病毒、埃博拉病毒、馬爾堡病毒、嚴重急性呼吸道症候群(SARS)病毒、沙粒病毒(arenavirus)、裂谷熱病毒(Rift Valley Fever virus)、黃熱病毒、呼吸道合胞體病毒(RSV)、丙型肝炎病毒(hepacivirus)、西尼羅河病毒(west nile virus)、登革熱病毒(Dengue fever virus)、愛知病毒(Aichi virus)、腸病毒、風疹病毒、小鼠腦脊髓炎病毒、副流感病毒、偏肺病毒、口蹄疫病毒、禽流感病毒及中東呼吸道症候群(MERS)。
在其他實施例中,本文所述化合物可用於預防或治療由下表1中所列任何種系發生(phylogenetic)目、屬、科或特定種所引起之病毒感染。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由屬於副黏液病毒科、小核糖核酸病毒科或黃熱病毒科之病毒所引起。在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由屬於副黏液病毒科之病毒所引起。在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由屬於黃熱病毒科之病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感
染,其中該感染係由屬於小核糖核酸病毒科之病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由任一種或多種選自以下組成之群之病毒所引起:脊髓灰質炎病毒、鼻病毒、柯薩奇病毒、A型流感病毒、B型流感病毒、C型流感病毒、腺病毒、冠狀病毒、A型肝炎病毒、B型肝炎病毒、C型肝炎病毒、E型肝炎病毒、埃博拉病毒、馬爾堡病毒、嚴重急性呼吸道症候群(SARS)病毒、沙粒病毒、裂谷熱病毒、黃熱病毒、呼吸道合胞體病毒(RSV)、西尼羅河病毒、登革熱病毒、愛知病毒、腸病毒、風疹病毒、泰萊(Theiler)氏小鼠腦脊髓炎病毒(TMEV)、口蹄疫病毒(FMDV)、人類免疫缺乏病毒(HIV)、呼吸道合胞體病毒(RSV)、副流感病毒(PIV)、人類PIV、人類偏肺病毒(hMPV)、禽流感病毒及中東呼吸道症候群(MERS)。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由人類腸道病毒A至D中任一者所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由腸道病毒A71所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由人類鼻病毒A至C中任一者所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由人類鼻病毒A所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由人類鼻病毒B所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由人類鼻病毒C所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由人類呼吸道融合病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由人類呼吸道融合病毒A所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由人類呼吸道融合病毒B所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由愛知病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由脊髓灰質炎病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由柯薩奇病毒(coxackievirus)所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由埃可病毒(echovirus)所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由A型肝炎病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由嚴重急性呼吸道症候群病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由胡寧病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由猴痘病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由裂谷熱病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由B型肝炎病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由C型肝炎病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由人類免疫缺乏病毒(HIV)所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由流感病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由A型流感病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由B型流感病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由C型流感病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由冠狀病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由屬於絲狀毒科之病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由屬於沙狀病毒(arenaviriade)科之病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由屬於布尼亞病毒科之病毒所引起。
在其他實施例中,本文所述化合物可用於治療個體之病毒感染,其中該感染係由人類免疫缺乏病毒1及/或人類免疫缺乏病毒2所引起。
合成式(I)化合物
以下實例旨在更完整地描述製造式(I)化合物之方式。熟習此項技術者在閱讀美國專利案第7,893,089號後將知曉如何合成式(I)化合物,該案以引用的方式完全併入本文中。
應理解,此實例絕不在於限制本發明之真實範圍,而是出於說
明目的提供。
若需要,可藉由任何合適分離或純化程序,諸如例如,過濾、萃取、結晶、管柱層析、薄層層析或厚層層析、製備型低或高壓液相層析或此等程序之組合來單離及純化本文中所描述之化學實體及中間物。可藉由參考下文實例獲得合適分離及單離程序之具體說明。然而,亦可使用其他等效分離或單離程序。
在需要時,(R)-及(S)-異構體可藉由熟習此項技術者所知之方法解析,例如藉由形成可(例如)藉由結晶分離之非對映異構體鹽或複合物;經由形成可(例如)藉由結晶、氣-液或液相層析分離之非對映異構體衍生物;選擇性地使一種對映異構體與對映異構體特異性試劑反應(例如酶促氧化或還原),隨後使改質及未改質對映異構體分離;或在對掌性環境(例如在對掌性載體(諸如具有結合對掌性配體之矽石)上或在對掌性溶劑存在下)中進行氣-液或液相層析。或者,可藉由不對稱合成,使用光學活性試劑、受質、觸媒或溶劑,或藉由不對稱轉換將一種對映異構體轉化為另一種來合成特定對映異構體。
此等實例意不在於限制本發明之範圍,而是為熟練技術人員製備及使用本發明化合物、組合物及方法提供指導。雖然已描述本發明之特定實施例,但熟練技術人員將暸解,可在不脫離本發明精髓及範圍下作出各種改變及修改。
所有提及醚之情形係指乙醚;鹽水係指飽和NaCl水溶液,DCM係指二氯甲烷,THF係指四氫呋喃,EtOAc係指乙酸乙酯,Hex及Hx係指己烷,IMS係指工業用甲醇變性酒精,TBME係指第三丁基甲基醚,DMF係指二甲基甲醯胺,BOC及Boc係指第三丁氧羰基。除非另有指示,否則所有溫度係以℃(攝氏度)表示。除非另有指明,否則所有反應係在室溫惰性氣氛下進行。
1H NMR光譜係在Jeol Delta2(300MHz)光譜儀上記錄。化學位移
係以百萬分率(ppm,δ單位)表示。裂分圖譜描述表觀多重性,且命名為s(單態)、d(雙重態)、t(三重態)、q(四重態)、quint(五重態)、m(多重態)、br(寬態)。
除非另有說明,否則「急驟層析(flash)」及「管柱層析」係指在矽膠上使用所述溶劑系統進行之急驟管柱層析。LC-MS資料係在與Shimadzu LC系統(SCL-10A控制器及雙波長UV偵測器)組合之PE Sciex單四級桿質譜儀(Single Quadrupole)LC/MS API-150或與Waters 2695分離模組組合之Waters micromass ZQ上獲得。
起始物質1:
N-(3,4-二氯苯基)-2,2-二甲基丙醯胺:
將3,4-二氯苯胺(150g)溶解於1.0L TBME中,並將溶液冷卻至10℃。在機械攪拌下添加氫氧化鈉(140.7g之30%水溶液)。逐滴添加新戊醯氯(125.9mL),同時將內部溫度保持在35℃以下。添加後,將反應溫度維持在30至35℃下再持續30min。然後使反應混合物冷卻至室溫,隨後在0至5℃下維持1h。過濾所得沈澱物,並先後用600mL水/MeOH(90/10)及900mL水清洗。在55℃真空烘箱中乾燥所得固體4天。產量:162g。1H-NMR(DMSO-d6)δ 9.46(s,1H),8.04(d,J=2.4Hz,1H),7.65(dd,J=9.0.2.4Hz,1H),7.54(d,J=9.0Hz,1H),1.22(9H,s)。
起始物質2:
6-氯-2-(1,1-二甲基乙基)-1,3-苯并噁唑-7-磺醯氯:
將N-(3,4-二氯苯基)-2,2-二甲基丙醯胺(121g)溶解於720mL THF中,並將溶液冷卻至-50℃。添加丁基鋰(433mL,2.5N含於hex),同時將內部溫度維持在-45℃與-35℃之間。(最終溫度:-35℃)。在-25℃下維持40min。以HPLC檢查反應混合物,結果顯示殘留5至10%起始物質。在-30℃下又添加35mL丁基鋰,並在-30至-25℃下另外反應
30min(HPLC:無明顯變化)。將反應混合物冷卻至-45℃,並使SO2鼓泡通過溶液,直至表現出達到飽和。隨後,在-10至0℃下攪拌反應混合物45min。使氬氣(2倍氣球體積)鼓泡通過溶液,隨後將反應混合物冷卻至-5℃。添加硫醯氯(58.8mL),同時將溫度保持在22℃以下。隨後,將反應混合物維持在10至15℃下1h(HPLC:完全)。添加EtOAc,並濃縮混合物,用水、飽和碳酸氫納水溶液及鹽水清洗,在MgSO4上乾燥,並在真空中蒸發溶劑。結晶出粗物質,並用熱己烷濕磨。產量:87.2g。1H-NMR(DMSO-d6)δ 7.60(d,J=8.4Hz,1H),7.34(d,J=8.4Hz,1H),1.43(9H,s)。
中間物1:
在氬氣氛下將起始物質1 N-(3,4-二氯苯基)-2,2-二甲基丙醯胺(根據WO01/68033A2製備,該案以引用的方式併入本文中,引用程度係其教示亦在上文描述之起始物質1之合成法)溶解於無水THF(400mL)中,然後冷卻至-75℃)。逐滴添加n-BuLi(160mL,2.5M含於己烷,5eq.),同時將溫度維持在-60℃以下。添加所有n-BuLi後,在-5℃下攪拌反應1.5h,然後冷卻至-70℃,並添加硫磺(「硫花」)(13g),隨後在-70℃至室溫下攪拌過夜。在-10℃下攪拌反應混合物後,溶液顏色從黃色變為棕色/橙色。將反應混合物冷卻至0℃,然後用2N HCl溶液(200mL)驟冷,並攪拌10min。分離有機層,並用2N NaOH溶液鹼化至pH 12至13,然後用EtOAc清洗。用2M HCl溶液再次使水層酸化至約pH 1,並用二氯甲烷萃取(2X),用水清洗,在Na2SO4上乾燥並濃縮。藉由管柱層析使用1:5(EtOAc/Hex)純化粗產物。產量:6g(30%,橙色油)。1H-NMR(CDCl3)δ 7.39-7.30(m,2H),4.08(s,1H),1.50(9H,s)。
或者以如下方式製備中間物1:將三苯基膦(89g)溶解於DCM(200ml)及DMF(2.2ml)中。溶液在冰/甲醇浴中冷卻至-1℃。歷時30分鐘向此溶液添加6-氯-2-(1,1-二甲基乙基)-1,3-苯并噁唑-7-磺醯氯(起始材料2)(根據WO01/68033A2製備,該案以引用的方式併入本文中,引用程度係其教示亦在上文描述之起始物質2之合成法)(35g)含於DCM(100ml)之溶液,將溫度保持在15℃以下。在室溫下,在氮氣下攪拌反應混合物18小時。用2N鹽酸(200ml)使反應混合物驟冷。分離各相並在真空中蒸發有機層。將殘餘物懸浮於2N氫氧化鈉(400ml)中,並快速攪拌3小時。藉由過濾移除固體,並用水清洗。在冰/水浴中使合併濾液及洗出液冷卻,並用5N鹽酸酸化至約pH 1。使用TBME(400ml)萃取此混合物。在硫酸鎂上乾燥有機相,並在真空中蒸發得到呈棕色固體之中間物1(22.85g)。
中間物2:(一般程序A)
在0℃下向(R)-(+)-3-羥基哌啶鹽酸鹽(1g)含於DCM(20mL)之懸浮液先後添加Et3N(3.04mL)及BOC2O(1.75g),使其度過週末。添加水(50mL),並用DCM(100mL)萃取。先後用水(2 x 50mL)及鹽水(50mL)清洗合併有機物,乾燥(Na2SO4)並濃縮。對殘餘物進行管柱層析(急驟層析,用0至10% MeOH/DCM之梯度溶離)。產量:1.55g。1H-NMR(CDCl3)δ 3.74-3.69(2H,m),3.56-3.48(1H,m),3.18-3.03(2H,m),1.92-1.83(1H,m),1.79-1.71(2H,m),1.55-1.45(1H,m),1.43(9H,s)。
中間物3:(一般程序B)
在0℃下向中間物2(1g)含於DCM(10mL)之溶液先後逐滴添加Et3N(1.38mL)及MsCl(0.46mL)。在0℃下攪拌1小時後,將反應溫至室溫,用水(10mL)驟冷並分離。以DCM(2×20mL)萃取水層。用水(40mL)清洗合併有機物,添加矽石刮刀,乾燥(Na2SO4)並濃縮。產量:1.4148g。1H-NMR(CDCl3)δ 4.71(1H,br s),3.62(2H,br d),3.49-3.27(2H,m),3.04(3H,s),2.01-1.76(3H,m),1.79-1.71(2H,m),1.55-1.45(1H,m),1.45(9H,s)。
中間物4:(一般程序C)
向NaH(0.30g)含於THF(20mL)之懸浮液逐滴添加中間物1(使用起始物質1)(1.22g)。攪拌1小時後,添加含於THF之中間物3(1.41g),並將反應加熱至80℃,並留其過夜。將反應混合物冷卻至室溫,然後用飽和NaHCO3水溶液(50mL)驟冷。以DCM(2×50mL)萃取反應混合物。用水(100mL)清洗合併之有機物,乾燥(Na2SO4)並濃縮。對殘餘物進行管柱層析(急驟層析,20% EtOAC/Hx,矽石)。產量:946.9mg。1H-NMR(CDCl3)δ 7.50(d,J=7.9Hz,1H),7.38(d,J=7.9Hz,1H),3.82(d,J=13.4Hz,1H),3.55-3.45(m,1H),3.00-2.80(m,2H)。
中間物5:(一般程序D)
在-10℃下向中間物4(946.9mg)含於DCM(10mL)之溶液添加含
於DCM(10mL)之mCPBA(2.31g)。在-10℃下攪拌反應1h,然後溫至室溫。先後用飽和NaHCO3水溶液(50mL)及DCM(2 x 70mL)使反應混合物驟冷。用水(50mL)清洗合併之有機物,乾燥(Na2SO4)並濃縮。對殘餘物進行管柱層析(急驟層析,30% EtOAc/Hx,矽石)。產量353.6mg(35%,黃色油)。MS(m/z,ES+,M+H):457.08。
中間物6:(一般程序E)
向中間物5(353mg)含於IMS(5mL)之溶液添加濃HCl水溶液(5mL)。然後將反應加熱至80℃,並留其過夜。將反應混合物冷卻至室溫,並濃縮以移除IMS。用飽和NaOH水溶液將殘餘物鹼化至pH 12,在0℃下添加EtOAc(30mL)、BOC2O(1eq.,0.17g)並留其過夜。分離反應混合物,並以EtOAc(2×30mL)萃取水層。(用Na2SO4)乾燥合併之有機物並濃縮。對殘餘物進行管柱層析(急驟層析,用10%至30% EA/Hx之梯度溶離)。產量:單離兩種含產物的溶離份:58.0mg及180.9mg。MS(m/z,ES+,M+H):291.01。
中間物7:(一般程序F)
在氬氣氛下,在室溫下將3-氟-2-甲基苯胺(7.4g)溶解於DCM(220mL)中。冷卻至0℃後,先後添加飽和NaHCO3水溶液(220mL)及三光氣(5.85g)。使反應在0℃下攪拌1h。此後,以DCM(2×50mL)萃取產物。合併有機溶離份,在MgSO4上乾燥,並在真空中移除溶劑,得到
黃色油。添加己烷,沈澱出白色鹽,將其過濾。在真空中移除己烷,得到黃色油(7.69g,86%)。1H-NMR(CDCl3)δ 7.09(dd,1H),6.92-6.85(m,2H),2.24(s,3H)。
中間物8:(一般程序G)
向中間物6(60mg)含於DCM(3mL)之溶液添加中間物7(70mg),並使反應度過週末。濃縮反應混合物,並對殘餘物進行管柱層析(急驟層析,用20%至30% EtOAc/Hx之梯度溶離)。產量:56.2mg。MS(m/z,ES+,M+H):542.01。
實例1
N-{4-氯-2-羥基-3-[(3S)-3-哌啶基磺醯基]苯基}-N'-(3-氟-2-甲基苯基)脲。(一般程序H)
在室溫下一起攪拌中間物8(56.2mg)及4N HCl/二噁烷(3mL),並留其過夜。如上所述製備中間物6、5、4、3及2。使用起始物質1製備中間物1,以合成實例1。濃縮反應混合物,並將殘餘物溶解於最少量MeOH中,並添加Et2O。固體析出(crashed out),過濾並乾燥。粗物質產量:28.4mg。將粗產物溶解於最少量MeOH中,並添加Et2O。固體析出,傾倒出溶劑並乾燥固體。產量:18.8mg。MS(m/z,ES+,
M+H):441.98。NMR(MeOD)δ 8.40(1H,d,ArH),7.46(1H,d,ArH),7.19-7.15(2H,m,ArH),6.85(1H,t,ArH),4.14(1H,dt,CH),3.66(1H,dd,CH),3.37(2H,d,CH 2),3.04(1H,dt,CH),2.19(3H,S,ArCH 3),2.14-1.69(4H,m,2xCH 2)。
本發明之一實施例涵蓋僅包含式(I)化合物及/或其與一或多種其他治療劑之組合之組合。例如,在一實施例中,本發明涵蓋包含式(I)化合物與一或多種選自彼等在表2、表3及/或表4中製劑之抗微生物劑之組合之組合。在一實施例中,該抗微生物劑係選自彼等見於表2中之抗病毒劑。
在本發明之其他實施例中,該抗病毒劑係選自阿昔洛韋(acyclovir)、更昔洛韋(gancyclovir)、干擾素、硫汞(thimerasol)、碘苷(idoxuridine)、阿糖腺苷(vidarabine)、曲氟尿苷(trifluridine)、泛昔洛韋(famciclovir)、伐昔洛韋(valacyclovir)、噴昔洛韋(penciclovir)、更昔洛韋、雙嘧達莫(dipyridamole)、依姆帕辛(impulsin)、普利康那利(pleconaril)、膦甲酸(foscarnet)、西多福韋(cidofovir)、(ICI 130,685)、纈更昔洛韋(valganciclovir)、阿昔洛韋、碘苷、阿糖腺苷或伐昔洛韋。
在本發明之一實施例中,該抗微生物劑為扎那米韋。
扎那米韋係一種面世的強效流感病毒神經胺糖酸苷酶抑制劑,稱為Relenza®,且被美國FDA批准用於治療及預防流感。
扎那米韋之合成法係描述在von Izstein等人之美國專利案第5,360,817號之實例3中,該專利案之全文以引用的方式併入本文中。
例如,該文中將扎那米韋之製備方法描述為:用三氟化硼合乙醚選擇性地使式(II)之5-乙醯胺基-4-乙醯氧基-6-(1,2,3-三乙醯氧基丙基)-5,6-二氫-4H-哌喃-2-甲酸酯脫乙醯基,得到式(III)之5-乙醯胺基-4-羥基-6-(1,2,3-三乙醯氧基丙基)-5,6-二氫-4H-哌喃-2-甲酸酯,進一步用三氟甲磺酸酐及疊氮化鈉處理,得到式(IV)之5-乙醯胺基-4-疊氮基-6-(1,2,3-三乙醯氧基丙基)-5,6-二氫-4H-哌喃-2-甲酸酯。在吡啶中用硫化氫使式(IV)之中間化合物還原,得到相應的式(V)之5-乙醯胺基-4-胺基-6-(1,2,3-三乙醯氧基丙基)-5,6-二氫-4H-哌喃-2-甲酸酯中間物,最後與S-甲基異硫脲在水中縮合,並透過Dowex 50W在氫氧化銨水溶液中皂化得到扎那米韋。
在本發明之其他實施例中,該抗微生物劑為抗生素。出於本發明之目的,式(I)化合物與抗微生物劑(諸如抗生素)之組合為罹患呼吸道細菌傳染性疾病之個體提供有效治療療法。本文可互換使用之術語「抗細菌劑」或「抗生素」意指具有殺死或抑制或阻止生物細胞生長效果之天然或合成化合物。本發明組合方法及組合物所涵蓋之抗細菌劑之實例包括彼等在下表3中所列之抗生素及抗生素類別。參見Todar,K.,Todar之Textbook of Bacteriology,University of Wisconsin-Madison,Department of Bacteriology(2002)及The Merck Manual,Sec.13.章節153.,「Antibacterial Drugs,」第17版(1999)。
在其他實施例中,本發明涵蓋包含式(I)化合物與一或多種選自彼等在表2、表3及/或表4中製劑之抗微生物劑組合及視情況亦與一或多種其他習知呼吸道治療劑組合之組合。
如本文所使用,術語「習知呼吸道治療劑」包含治療或緩和(無論程度如何輕微)由患有呼吸道傳染性疾病引起之任何症狀,而並非式(I)化合物或抗微生物劑之任何此等呼吸道傳染性疾病治療。
出於本發明之目的,適宜的習知呼吸道治療劑可包括一或多種選自消炎劑(例如,Cox-2抑制劑、Cox-2/Cox-1抑制劑、NSAID)、抗組織胺、抗膽鹼藥(特別係M1/M2/M3受體拮抗劑)、β2-腎上腺素能受體促效劑、類固醇(例如,腎上腺皮質類固醇)、PDE4抑制劑(例如,羅氟斯特(Roflumilast))、解除充血劑之製劑。
在本文中可互換使用之術語「環氧合酶-2抑制劑」或「Cox-2抑
制劑」包括抑制Cox-2酶之化合物,無論對Cox-1酶之抑制程度如何,且包括彼等化合物之醫藥上可接受的鹽。因此,出於本發明之目的,將一種化合物視為Cox-2抑制劑,不論該化合物抑制Cox-2酶之程度是否等於、大於或小於Cox-1酶。在本發明之一實施例中,Cox-2抑制劑較佳係非類固醇抗炎症藥劑(NSAID)。因此,可充當本發明Cox-2抑制劑之較佳物質包括非類固醇抗炎症藥劑化合物、其醫藥上可接受的鹽或其純(-)或(+)光學異構形式。
消炎劑之實例包括非類固醇抗炎症藥劑(NSAID)。可用於本發明之適宜NSAID化合物包括阿西美辛(acemetacin)、乙醯水楊酸、阿氯酚酸(alclofenac)、胺普芬(alminoprofen)、阿扎丙酮(azapropazone)、苯樂來(benorylate)、苯惡洛芬(benoxaprofen)、布氯酸、卡洛芬(carprofen)、三水楊酸膽鹼鎂、環氯茚酸(clidanac)、氯吡酸(clopinac)、胺苯碸(dapsone)、雙氯芬酸(diclofenac)、雙氟尼酸(diflunisal)、屈昔康(droxicam)、依託度酸(etodolac)、非諾洛芬(fenoprofen)、苯布芬(fenbufen)、芬氯芬尼克(fenclofenec)、芬替酸(fentiazac)、夫洛非寧(floctafenine)、氟苯柳(flufenisal)、氟比洛芬(flurbiprofen)、(r)-氟比洛芬、(s)-氟比洛芬、呋羅芬酸(furofenac)、非普拉宗(feprazone)、氟芬那酸(flufenamic acid)、氟洛芬(fluprofen)、異丁芬酸(ibufenac)、伊布洛芬(ibuprofen)、吲哚美辛(indometacin)、吲哚美辛(indomethacin)、吲哚布洛芬(indoprofen)、伊索克酸(isoxepac)、伊索昔康(isoxicam)、酮基布洛芬(ketoprofen)、酮洛酸(ketorolac)、咪洛芬(miroprofen)、吡羅昔康(piroxicam)、美儂西康(meloxicam)、滅芬草(mefenamic)、甲滅酸(mefenamic acid)、甲氯芬那酸(meclofenamic acid)、甲氯芬(meclofen)、萘丁美酮(nabumetone)、萘普生(naproxen)、尼氟酸(niflumic acid)、奧沙普秦(oxaprozin)、奧昔平酸(oxipinac)、羥基保泰松(oxyphenbutazone)、苯
基丁氮酮(苯基butazone)、鬼臼素(podophyllotoxin)衍生物、丙谷美辛(proglumetacin)、皮普洛芬(piprofen)、吡洛布洛芬(pirprofen)、普拉洛芬(prapoprofen)、水楊酸、水楊酸酯、舒多昔康(sudoxicam)、舒洛芬(suprofen)、舒林酸(sulindac)、替諾昔康(tenoxicam)、噻洛芬酸(tiaprofenic acid)、硫平酸(tiopinac)、硫噁洛芬(tioxaprofen)、托芬那酸(tolfenamic acid)、托美丁(tolmetin)、齊多美辛(zidometacin)、佐美酸(zomepirac)及2-氟-a-甲基[1,1'-聯苯]-4-乙酸4-(硝基氧基)丁酯。
其他適宜的NSAID化合物包括伊布洛芬、萘普生、舒林酸、酮洛芬(ketoporfen)、非諾洛芬、噻洛芬酸、舒洛芬、依託度酸、卡洛芬、酮洛酸(ketrolac)、皮普洛芬、吲哚布洛芬、水楊酸及氟比洛芬。
在一實施例中,本發明涵蓋含式(I)化合物與β2-腎上腺素能受體促效劑之組合。
β2-腎上腺素能受體促效劑之實例包括維蘭特羅(vilanterol)、沙美特羅(salmeterol)(其可為外消旋物或單一對映異構體,諸如R-對映異構體)、沙丁胺醇(salbutamol)(其可為外消旋物或單一對映異構體,諸如R-對映異構體)、福莫特羅(formoterol)(其可為外消旋物或單一對映異構體,諸如R,R-非對映異構體)、沙甲胺醇(salmefamol)、非諾特羅(fenoterol)、卡莫特羅(carmoterol)、依坦特羅(etanterol)、那明特羅(naminterol)、克倫特羅(clenbuterol)、吡布特羅(pirbuterol)、氟丁特羅(flerbuterol)、瑞普特羅(reproterol)、班布特羅(bambuterol)、茚達特羅(indacaterol)、特布他林(terbutaline)及其鹽,例如沙美特羅之羥萘甲酸(1-羥基-2-萘甲酸鹽)鹽、沙丁胺醇之硫酸鹽或游離鹼或福莫特羅之富馬酸鹽。在一實施例中,β2-腎上腺素能受體促效劑係長效β2-腎上腺素能受體促效劑,例如可有效擴張支氣管約12小時或更長時間之化合物。
其他β2-腎上腺素能受體促效劑包括彼等WO2002/066422、
WO2002/070490、WO2002/076933、WO2003/024439、WO2003/072539、WO2003/091204、WO2004/016578、WO2004/022547、WO2004/037807、WO2004/037773、WO2004/037768、WO2004/039762、WO2004/039766、WO2001/42193及WO2003/042160中所述者。
β2-腎上腺素能受體促效劑之其他實例包括:3-(4-{[6-({(2R)-2-羥基-2-[4-羥基-3-(羥甲基)苯基]乙基}胺基)己基]氧基}丁基)苯磺醯胺;3-(3-{[7-({(2R)-2-羥基-2-[4-羥基-3-羥甲基)苯基]乙基}-胺基)庚基]氧基}丙基)苯磺醯胺;4-{(1R)-2-[(6-{2-[(2,6-二氯苄基)氧基]乙氧基}己基)胺基]-1-羥乙基}-2-(羥甲基)苯酚;4-{(1R)-2-[(6-{4-[3-(環戊基磺醯基)苯基]丁氧基}己基)胺基]-1-羥乙基}-2-(羥甲基)苯酚;N-[2-羥基-5-[(1R)-1-羥基-2-[[2-4-[[(2R)-2-羥基-2-苯基乙基]胺基]苯基]乙基]胺基]乙基]苯基]甲醯胺;N-2{2-[4-(3-苯基-4-甲氧基苯基)胺基苯基]乙基}-2-羥基-2-(8-羥基-2(1H)-喹啉酮-5-基)乙胺;及5-[(R)-2-(2-{4-[4-(2-胺基-2-甲基-丙氧基)-苯基胺基]-苯基}-乙基胺基)-1-羥基-乙基]-8-羥基-1H-喹啉-2-酮。
β2-腎上腺素能受體促效劑可呈與選自以下之醫藥上可接受的酸所形成之鹽形式:硫酸、鹽酸、富馬酸、羥基萘甲酸(例如1-或3-羥基-2-萘甲酸)、肉桂酸、經取代的肉桂酸、三苯基乙酸、胺基磺酸、磺胺酸、萘丙烯酸、苯甲酸、4-甲氧基苯甲酸、2-或4-羥基苯甲酸、4-氯苯甲酸及4-苯基苯甲酸。
適宜的消炎劑包括皮質類固醇。可與本發明式I化合物組合使用
之皮質類固醇實例為彼等口服及吸入皮質類固醇及其具有消炎活性之前藥。實例包括甲基潑尼松龍(prednisolone)、潑尼松龍、地塞米松(dexamethasone)、氟替卡松丙酸酯(fluticasone propionate)、6α,9α-二氟-11β-羥基-16α-甲基-17α-[(4-甲基-1,3-噻唑-5-羰基)氧基]-3-側氧基-雄甾-1,4-二烯-17β-羧硫代酸S-氟甲酯、6α,9α-二氟-17α-[(2-呋喃甲醯基)氧基]-11β-羥基-16α-甲基-3-側氧基-雄甾-1,4-二烯-17β-羧硫代酸S-氟甲酯(糠酸氟替卡松)、6α,9α-二氟-11β-羥基-16α-甲基-3-側氧基-17α-丙醯氧基-雄甾-1,4-二烯-17β-羧硫代酸S-(2-側氧基-四氫-呋喃-3S-基)酯、6α,9α-二氟-11β-羥基-16α-甲基-3-側氧基-17α-(2,2,3,3-四甲基環丙基羰基)氧基-雄甾-1,4-二烯-17β-甲酸氰基甲酯及6α,9α-二氟-11β-羥基-16α-甲基-17α-(1-甲基環丙基羰基)氧基-3-側氧基-雄甾-1,4-二烯-17β-羧硫代酸S-氟甲酯、倍氯米松(beclomethasone)酯(例如17-丙酸酯或17,21-二丙酸酯)、布地奈德(budesonide)、氟尼縮松(flunisolide)、莫米他松(mometasone)酯(例如糠酸莫米他松)、曲安奈德(triamcinolone acetonide)、羅氟奈德(rofleponide)、環索奈德(ciclesonide)(16α,17-[[(R)-環己亞甲基]雙(氧基)]-11β,21-二羥基-孕甾-1,4-二烯-3,20-二酮)、丙酸布替可特(butixocort)、RPR-106541及ST-126。在一實施例中,皮質類固醇包括氟替卡松丙酸酯、6α,9α-二氟-11β-羥基-16α-甲基-17α-[(4-甲基-1,3-噻唑-5-羰基)氧基]-3-側氧基-雄甾-1,4-二烯-17β-羧硫代酸S-氟甲酯、6α,9α-二氟-17α-[(2-呋喃甲醯基)氧基]-11β-羥基-16α-甲基-3-側氧基-雄甾-1,4-二烯-17β-羧硫代酸S-氟甲酯、6α,9α-二氟-11β-羥基-16α-甲基-3-側氧基-17α-(2,2,3,3-四甲基環丙基羰基)氧基-雄甾-1,4-二烯-17β-甲酸氰基甲酯及6α,9α-二氟-11β-羥基-16α-甲基-17α-(1-甲基環丙基羰基)氧基-3-側氧基-雄甾-1,4-二烯-17β-羧硫代酸S-氟甲酯。在一實施例中,皮質類固醇為6α,9α-二氟-17α-[(2-呋喃甲醯基)氧基]-11β-羥基-16α-甲基-3-側氧基-雄甾-1,4-
二烯-17β-羧硫代酸S-氟甲酯。
皮質類固醇之實例可包括彼等描述在WO2002/088167、WO2002/100879、WO2002/12265、WO2002/12266、WO2005/005451、WO2005/005452、WO2006/072599及WO2006/072600中者。
對轉錄抑制之選擇性強於轉錄激活且可用於組合療法中之具有糖皮質激素促效作用之非類固醇化合物包括彼等以下公開專利申請案及專利案中所涵蓋者:WO1998/54159、WO2000/66590、WO2001/16128、WO2002/02565、WO2003/059899、WO2003/061651、WO2003/082280、WO2003/082787、WO2003/082827、WO2003/086294、WO2003/101932、WO2003/104195、WO2004/005229、WO2004/009017、WO2004/018429、WO2004/026248、WO2006/000398、WO2006/000401、WO2006/015870、WO2006/108699、WO2007/000334、WO2007/054294、WO2007/122165、WO2007/144327及WO2008/000777。
在一實施例中,本發明使用式(I)化合物與磷酸二酯酶4(PDE4)抑制劑之組合,例如在適用於吸入之調配物情形下。可用於本發明之此態樣之PDE4抑制劑可為已知或發現可充當PDE4抑制劑(例如充當PDE4B及/或PDE4D之抑制劑)之任何化合物。
PDE4抑制劑化合物包括順式-4-氰基-4-(3-環戊氧基-4-甲氧基苯基)環己-1-甲酸、2-甲氧甲醯基-4-氰基-4-(3-環丙基甲氧基-4-二氟甲氧基苯基)環己-1-酮及順式-[4-氰基-4-(3-環丙基甲氧基-4-二氟甲氧基苯基)環己-1-醇]。還有,1996年9月3日頒發之美國專利案5,552,438中所述之順式-4-氰基-4-[3-(環戊氧基)-4-甲氧基苯基]環己-1-甲酸(亦稱為西洛司特(cilomilast))及其鹽、酯、前藥或物理形式;此專利案及
其所揭示之化合物全部以引用的方式併入本文中。
其他PDE4抑制化合物包括AWD-12-281(N-(3,5-二氯-4-吡啶基)-1-[4-氟苯基)甲基]-5-羥基-α-側氧基-1H-吲哚-3-乙醯胺),來自Elbion(Hofgen,N.等人.15th EFMC Int Symp Med Chem(9月6日至10日,Edinburgh)1998,Abst P.98;CAS索引號247584020-9);命名為NCS-613之9-苄基腺嘌呤衍生物(INSERM);來自Chiroscience and Schering-Plough之D-4418;確定為CI-1018且歸屬於Pfizer之苯并二氮呯PDE4抑制劑(PD-168787);Kyowa Hakko在WO99/16766中揭示之苯并二噁唑衍生物;來自Kyowa Hakko之K-34;V-11294A來自Napp(Landells,L.J.等人Eur Resp J[Annu Cong Eur Resp Soc(9月19日至23日,Geneva)1998]1998,12(增刊28):Abst P.2393);羅氟斯特(3-(環丙基甲氧基)-N-(3,5-二氯-4-吡啶基)-4-(二氟甲氧基)苯甲醯胺)(參見Byk Gulden Lomberg之EP 0 706 513 B1,例如參見其實例5);來自Byk-Gulden之雜環聚芳醚(WO1999/47505);普馬芬群(Pumafentrine),(-)-p-[(4aR*,10bS*)-9-乙氧基-1,2,3,4,4a,10b-六氫-8-甲氧基-2-甲基苯并[c][1,6]萘啶-6-基]-N,N-二異丙基苯甲醯胺,其係由Byk-Gulden(現為Altana)製備及公開之混合PDE3/PDE4抑制劑;Almirall-Prodesfarma正在研發之阿羅茶鹼(arofylline);來自Vernalis之VM554/UM565;或T-440(Tanabe Seiyaku;Fuji,K.等人,J Pharmacol Exp Ther,1998,284(1):162)及T2585。
其他PDE4抑制化合物揭示在公開的國際專利申請案WO2004/024728、WO2004/056823、WO2004/103998(例如本文所揭示之實例399或544)、WO2005/058892、WO2005/090348、WO2005/090353及WO2005/090354,全部在Glaxo Group Limited名下。
抗膽鹼藥之實例係彼等充當蕈毒鹼受體之拮抗劑之化合物,特
定言之彼等作為M1或M3受體之拮抗劑、M1/M3或M2/M3受體之雙重拮抗劑或M1/M2/M3受體之泛拮抗劑之化合物經由吸入投與之示例性化合物包括異丙托銨(ipratropium)(例如,呈溴化物形式,CAS 22254-24-6,以Atrovent之名銷售)、氧托溴銨(oxitropium)(例如,呈溴化物形式,CAS 30286-75-0)及噻托溴銨(tiotropium)(例如,呈溴化物形式,CAS 136310-93-5,以Spiriva之名銷售)。亦受到關注的是瑞伐托酯(revatropate)(例如,呈氫溴化物形式,CAS 262586-79-8)及WO2001/04118中所揭示之LAS-34273。用於口服投與之示例性化合物包括派侖西平(pirenzepine)(CAS 28797-61-7)、達非那新(darifenacin)(CAS 133099-04-4或對應以Enablex之名銷售之氫溴化物之CAS 133099-07-7)、奧昔布寧(oxybutynin)(CAS 5633-20-5,以Ditropan之名銷售)、特羅地林(terodiline)(CAS 15793-40-5)、托特羅定(tolterodine)(CAS 124937-51-5或對應以Detrol之名銷售之酒石酸鹽之CAS 124937-52-6)、奧替溴銨(otilonium)(例如,作為溴化物,CAS 26095-59-0,以Spasmomen之名銷售)、托司氯銨(trospium chloride)(CAS 10405-02-4)及索利那新(solifenacin)(CAS 242478-37-1或對應亦稱為YM-905並以Vesicare之名銷售之針對琥珀酸鹽之CAS 242478-38-2)。
其他化合物揭示在WO 2005/037280、WO 2005/046586及WO 2005/104745中,該等案以引用的方式併入本文中。本發明組合包括(但不限於):(3-內)-3-(2,2-二-2-噻吩基乙烯基)-8,8-二甲基-8-氮鎓二環[3.2.1]辛烷碘化物;(3-內)-3-(2-氰基-2,2-二苯基乙基)-8,8-二甲基-8-氮鎓二環[3.2.1]辛烷溴化物;4-[羥基(二苯基)甲基]-1-{2-[(苯基甲基)氧基]乙基}-1-氮鎓二環
[2.2.2]辛烷溴化物;及(1R,5S)-3-(2-氰基-2,2-二苯基乙基)-8-甲基-8-{2-[(苯基甲基)氧基]乙基}-8-氮鎓二環[3.2.1]辛烷溴化物。
在一實施例中,本發明提供一種包含式(I)化合物或其醫藥上可接受的鹽與抗組織胺(諸如H1拮抗劑)之組合。適宜H1拮抗劑之實例包括(但不限於)苯海拉明(diphenhydramine)、胺來佔諾(amelexanox)、阿司咪唑(astemizole)、阿扎他啶(azatadine)、氮卓斯汀(azelastine)、阿伐斯汀(acrivastine)、溴苯那敏(brompheniramine)、西替利嗪(cetirizine)、左旋西替利嗪(levocetirizine)、乙氟利嗪(efletirizine)、氯苯那敏(chlorpheniramine)、克立馬丁(clemastine)、賽克力嗪(cyclizine)、卡瑞斯汀(carebastine)、賽庚啶(cyproheptadine)、卡比沙明(carbinoxamine)、去羧乙氧基氯雷他定(descarboethoxyloratadine)、多西拉敏(doxylamine)、二甲茚定(dimethindene)、依巴斯汀(ebastine)、依匹斯汀(epinastine)、乙氟利嗪、非索非那定(fexofenadine)、羥嗪、酮替芬(ketotifen)、氯雷他定(loratadine)、左卡巴斯汀(levocabastine)、咪唑斯汀(mizolastine)、美喹他嗪(mequitazine)、米安色林(mianserin)、諾白拉斯啶(noberastine)、氯苯甲嗪(meclizine)、諾阿司咪唑(norastemizole)、奧洛他定(olopatadine)、哌香豆司特(picumast)、吡拉明(pyrilamine)、異丙嗪(promethazine)、特非那定(terfenadine)、曲吡那敏(tripelennamine)、泰美拉斯(temelastine)、異丁嗪(trimeprazine)及曲普利啶(triprolidine),尤其係氮卓斯汀、西替利嗪、左旋西替利嗪、(乙氟利嗪)及(非索非那定)。
在另一實施例中,本發明提供一種包含式(I)化合物或其醫藥上可接受的鹽與H3拮抗劑(及/或反向促效劑)之組合。H3拮抗劑之實例包括(例如)彼等揭示在WO2004/035556、WO2006/045416、
WO2006/090142、WO2006/125665、WO2007/009739及WO2007/009741中之化合物。在另一實施例中,本發明提供一種包含式(I)化合物或其醫藥上可接受的鹽與H1/H3雙重拮抗劑(及/或反向促效劑)之組合。H1/H3雙重拮抗劑之實例包括(例如)彼等揭示在WO2004/035556、WO2007/071691、WO2007/122156及WO2007/135081中之化合物。在另一實施例中,本發明提供一種包含式(I)化合物或其醫藥上可接受的鹽與選自3-(4-{[4-(4-{[3-(3,3-二甲基-1-哌啶基)丙基]氧基}苯基)-1-哌啶基]羰基}-1-萘基)丙酸及4-[(4-氯苯基)甲基]-2-({(2R)-1-[4-(4-{[3-(六氫-1H-氮呯基-1-基)丙基]氧基}苯基)丁基]-2-吡咯啶基}甲基)-1(2H)-雜環聚芳醚之H1/H3雙重拮抗劑之組合。可與本發明化合物組合使用之其他組織胺受體拮抗劑包括H4受體之拮抗劑(及/或反向促效劑),例如揭示在Jablonowski等人,J.Med.Chem.46:3957-3960(2003)中之化合物。
其他適宜的習知呼吸道治療劑包括色甘酸鈉、奈多羅米(nedocromil)鈉、磷酸二酯酶(PDE)抑制劑(例如,茶鹼、PDE4抑制劑或混合PDE3/PDE4抑制劑)、白三烯拮抗劑、白三烯合成抑制劑(例如孟魯司特(montelukast))、iNOS抑制劑、類胰蛋白酶及彈性蛋白酶抑制劑、β-2整合酶拮抗劑及腺苷受體促效劑或拮抗劑(例如腺苷2a促效劑)、細胞因子拮抗劑(例如趨化激素拮抗劑,諸如CCR3拮抗劑)或細胞因子合成抑制劑或者5-脂氧化酶抑制劑。在一實施例中,本發明涵蓋口服投與之iNOS(誘導型一氧化氮合成酶)抑制劑。iNOS抑制劑之實例包括彼等揭示在WO1993/13055、WO1998/30537、WO2002/50021、WO1995/34534及WO1999/62875中者。CCR3抑制劑之實例包括彼等揭示在WO2002/26722中。
在本發明之其他實施例中,習知呼吸道治療劑可選自由下列組成之群:芬那酯(fenamate)、吡咯燒酸(pyrrolealkanoic acid)、吡唑啉
酮衍生物、昔康類、普莫卡因(pramoxine)、(阿扎他啶)、氯苯甲嗪、異丙嗪溴苯海拉明、溴苯那敏、馬來酸溴苯那敏、卡比沙明、氯苯那敏、右旋氯苯那敏(dexchlorpheniramine)、苯海拉明、多西拉敏、苯茚胺(phenindamine)、非尼拉敏(pheniramine)、(苯基toloxamine)、吡拉明、曲普利啶、克立馬丁、茶苯海明(dimenhydrinate)、西替利嗪、特非那定、阿司咪唑、氯雷他定、阿伐斯汀、羥嗪、美克洛嗪(meclozine)、丙氯拉嗪(compazine)、丙咪嗪(imipramine)、多昔平(doxopin)、阿米替林(amitryptoline)、曲吡那敏、非索非那定、阿扎他啶、麻黃鹼(ephedrine)、腎上腺素(ephinephrine)、左旋脫氧麻黃鹼(levodesoxyephedrine)、羥甲唑啉(oxymetazoline)、萘甲唑啉(naphazoline)、苯福林(phenylephrine)、苯丙醇胺(phenylpropanolamine)、環己丙甲胺(propylhexedrine)、假麻黃鹼(pseudoephedrine)、丁苄唑啉(xylometazoline)、氯己定(chlorhexidine)、紅溴汞(mercurochrome)、聚維酮碘(povidone iodine)、聚羥碘(polyhyroxine iodine)、甲酚鹽(cresylate)、氫化可的松(hydrocortisone)、強的松(prednisone)、氟潑尼龍(fluprednisolone)、地塞米松、倍他米松(betamethasone)、戊酸倍他米松、甲潑尼龍(methylprednisolone)、氟輕鬆(fluocinolone acetonide)、丙酮縮氟氫羥龍(flurandrenolone acetonide)、氟米龍(fluorometholone)、可的松(cortisone)、潑尼松龍(prednisolone)、阿氯米松(alclometasone)、安西奈德(amcinonide)、倍他米松、氯倍他索(clobetasol)、氯可托龍(clocortolone)、地奈德(desonide)、去羥米松(desoximetasone)、雙氟拉松(diflorasone)、氟輕鬆醋酸酯(fluocinonide)、氟氫縮松(flurandrenolide)、氟替卡松、哈西奈德(halcinonide)、烏倍他索(halobetasol)、莫米他松、氟甲松(flumethasone)、潑尼卡酯(prednicarbate)、曲安西龍(triamcinolone)、
(clotrimazole)、灰黃黴素(griseofulvin)、十一碳烯(undecylenic)、益康唑(econazole)、咪康唑(miconazole)、酮康唑(ketaconazole)、硫康唑(sulconazole)、奧昔康唑(oxiconazole)、氟康唑(fluconazole)、伊曲康唑(itraconazole)、制黴菌素(nystatin)、奈替芬(naftifine)、特比萘芬(terbinafine)、環匹羅司(ciclopirox)、布替萘芬(butenafine)、鹵普羅近(haloprogin)、托萘酯(tolnaftate)、妥布黴素加地塞米松、乙酸間甲苯酯、雙-(2-吡啶基-1-氧化物)二硫化物、乙醯胺酚、磺胺米隆及其混合物。
因此,在本發明之一實施例中,提供一種包含黛力新與神經胺糖酸苷酶抑制劑化合物之組合之組合物。
在本發明之另一實施例中,提供一種包含黛力新與扎那米韋之組合之組合物。
在本發明之另一實施例中,提供一種包含黛力新與奧司他韋之組合之組合物。
在本發明之另一實施例中,提供一種包含黛力新與利巴韋林之組合之組合物。
在本發明之另一實施例中,提供一種包含黛力新與法匹拉韋之組合之組合物。
在本發明之另一實施例中,提供一種包含黛力新與一或多種選自表4之抗微生物劑之組合之組合物。
在本發明之另一實施例中,提供一種包含黛力新與神經胺糖酸苷酶抑制劑化合物之組合及醫藥上可接受的賦形劑之醫藥組合物。
在本發明之另一實施例中,提供一種包含黛力新與扎那米韋之組合及醫藥上可接受的賦形劑之醫藥組合物。
在本發明之另一實施例中,提供一種包含黛力新與奧司他韋之組合及醫藥上可接受的賦形劑之醫藥組合物。
在本發明之另一實施例中,提供一種包含黛力新與利巴韋林之組合及醫藥上可接受的賦形劑之醫藥組合物。
在本發明之另一實施例中,提供一種包含黛力新與一或多種選自表4之抗微生物劑之組合及醫藥上可接受的賦形劑之組合物。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與神經胺糖酸苷酶抑制劑化合物之組合。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與扎那米韋之組合。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與奧司他韋之組合。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與利巴韋林之組合。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與法匹拉韋之組合。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與一或多種選自表4之抗微生物劑之組合。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與神經胺糖酸苷酶抑制劑化合物之組合,其中該呼吸道傳染性疾病為流感。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與神經胺糖酸苷酶抑制劑化合物之組合,其中該黛力新與神經胺糖酸苷酶抑制劑化合物之組合係以相同劑型投與。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與神經胺糖酸苷酶抑制劑化合物之組合,其中該黛力新與神經胺糖酸苷酶抑制劑化合物之組合係同時投與。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與神經胺糖酸苷酶抑制劑化合物之組合,其中該黛力新與神經胺糖酸苷酶抑制劑化合物之組合係分開投與。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與神經胺糖酸苷酶抑制劑化合物之組合,其中該黛力新與神經胺糖酸苷酶抑制劑化合物之組合係以相同劑型投與。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與神經胺糖酸苷酶抑制劑化合物之組合,其中該黛力新化合物與神經胺糖酸苷酶抑制劑化合物之組合係同時投與。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與利巴韋林之組合。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與利巴韋林之組合,其中該黛力新化合物與利巴韋林之組合係同時投
與。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與利巴韋林之組合,其中該黛力新與利巴韋林之組合係以相同劑型投與。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與利巴韋林之組合,其中該黛力新化合物與利巴韋林之組合係同時投與。
在本發明之另一實施例中,提供一種治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與黛力新與利巴韋林之組合,其中該黛力新與利巴韋林之組合係分開投與。
一種用於治療個體之流感之方法,該方法包括向罹患流感之個體投與黛力新。
一種用於治療個體之RSV之方法,該方法包括向罹患RSV之個體投與黛力新。
一種用於靜脈內投與之醫藥組合物,其包含:水溶液中呈氫溴酸鹽形式之黛力新。
一種用於靜脈內投與之醫藥組合物,其包含:水溶液中呈氫溴酸鹽形式之黛力新及醫藥上可接受的賦形劑。
一種用於靜脈內投與之醫藥組合物,其包含:水溶液中呈氫溴酸鹽形式之黛力新及醫藥上可接受的賦形劑,其中該醫藥上可接受的賦形劑包括環糊精。
一種用於靜脈內投與之醫藥組合物,其包含:水溶液中呈氫溴酸鹽形式之黛力新及醫藥上可接受的賦形劑,其中該醫藥上可接受的賦形劑包括β-環糊精。
一種用於靜脈內投與之醫藥組合物,其包含:水溶液中呈氫溴酸鹽形式之黛力新及醫藥上可接受的賦形劑,其中該醫藥上可接受的賦形劑包括磺基丁醚。
一種用於靜脈內投與之醫藥組合物,其包含:水溶液中呈氫溴酸鹽形式之黛力新及醫藥上可接受的賦形劑,其中該醫藥上可接受的賦形劑包括β-環糊精及磺基丁醚。
一種用於靜脈內投與之醫藥組合物,其包含:水溶液中呈氫溴酸鹽形式之黛力新及醫藥上可接受的賦形劑,其中該醫藥上可接受的賦形劑包括Captisol®。
一種用於治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與靜脈內投與醫藥組合物,其包含:水溶液中呈氫溴酸鹽形式之黛力新及醫藥上可接受的賦形劑。
一種用於治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與靜脈內投與醫藥組合物,其包含:水溶液中呈氫溴酸鹽形式之黛力新及醫藥上可接受的賦形劑,其中該醫藥上可接受的賦形劑包括環糊精。
一種用於治療個體之呼吸道傳染性疾病之方法,該方法包括向罹患呼吸道傳染性疾病之個體投與靜脈內投與醫藥組合物,其包含:水溶液中呈氫溴酸鹽形式之黛力新及醫藥上可接受的賦形劑,其中該醫藥上可接受的賦形劑包括β-環糊精。
投與及調配物
在另一實施例中,提供一種僅包含醫藥上可接受的稀釋劑以及治療有效量之式(I)化合物或其醫藥上可接受的鹽或者其與抗微生物劑及/或習知呼吸道治療劑之組合之醫藥組合物。
本發明化合物可以醫藥上可接受的鹽形式提供。術語「醫藥上可接受的鹽」係指自醫藥上可接受的無機及有機酸及鹼製備之鹽。因
此,語境「化合物或其醫藥上可接受的鹽」中之詞語「或」應理解為係指化合物或其醫藥上可接受的鹽(或者)或化合物或其醫藥上可接受的鹽(組合地)。
如本文所使用,術語「醫藥上可接受的」係指彼等在合理範圍的醫藥判斷下適於與人類及動物組織接觸而無過度毒性、刺激性或其他問題或併發症之化合物、物質、組合物及劑型。熟練技術人員將暸解,可製備式I、II或III化合物之醫藥上可接受的鹽。此等醫藥上可接受的鹽可在分離及純化化合物期間原地製備,或藉由分別使呈游離酸或游離鹼形式之純化化合物分別與適宜鹼或酸反應製備。
本發明化合物之說明性醫藥上可接受的酸式鹽可由以下酸製得,包括(但不限於)甲酸、乙酸、丙酸、苯甲酸、琥珀酸、乙醇酸、葡萄糖酸、乳酸、馬來酸、蘋果酸、酒石酸、檸檬酸、檸檬酸、硝酸、抗壞血酸、葡糖醛酸、馬來酸、富馬酸、丙酮酸、天冬胺酸、麩胺酸、苯甲酸、鹽酸、氫溴酸、氫碘酸、異檸檬酸、三氟乙酸、雙羥萘酸、丙酸、鄰胺基苯甲酸、甲磺酸(mesylic)、草醯乙酸、油酸、硬脂酸、水楊酸、對羥基苯甲酸、菸鹼酸、苯乙酸、扁桃酸、恩貝酸(雙羥萘酸)、甲基磺酸、磷酸、膦酸、乙基磺酸、苯磺酸、泛酸、甲苯磺酸、2-羥乙磺酸、磺胺酸、硫酸、水楊酸、環己胺基磺酸、海藻酸(algenic)、β-羥基丁酸、黏酸及半乳糖醛酸。較佳的醫藥上可接受的鹽包括鹽酸及三氟乙酸之鹽。
本發明化合物之說明性醫藥上可接受的無機鹼式鹽包括金屬離子。更佳的金屬離子包括(但不限於)適宜鹼金屬鹽、鹼土金屬鹽及其他生理上可接受的金屬離子。衍生自無機鹼之鹽包括呈其常見價態之鋁鹽、銨鹽、鈣鹽、銅鹽、三價鐵鹽、二價鐵鹽、鋰鹽、鎂鹽、三價錳鹽、二價錳鹽、鉀鹽、鈉鹽、鋅鹽及類似物。示例性鹼式鹽包括鋁鹽、鈣鹽、鋰鹽、鎂鹽、鉀鹽、鈉鹽及鋅鹽。其他示例性鹼式鹽包括
銨鹽、鈣鹽、鎂鹽、鉀鹽及鈉鹽。還有其他示例性鹼式鹽包括(例如)氫氧化物、碳酸鹽、氫化物、及醇鹽,包括NaOH、KOH、Na2CO3、K2CO3、NaH及第三丁醇鉀。
衍生自醫藥上可接受的有機無毒性鹼之鹽包括以下物質之鹽:一級、二級、及三級胺(部分包括三甲胺、二乙胺、N,N'-二苄基乙二胺、氯普魯卡因(chloroprocaine)、膽鹼、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)及普魯卡因);經取代之胺(包括天然存在之經取代之胺);環狀胺;四級銨陽離子;及鹼性離子交換樹脂,諸如精胺酸、甜菜鹼、咖啡因、膽鹼、N,N-二苄基乙二胺、二乙胺、2-二乙胺基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基嗎啉、N-乙基哌啶、葡醣胺、葡萄糖胺、組胺酸、海巴明(hydrabamine)、異丙胺、離胺酸、甲基葡糖胺、嗎啉、哌嗪、哌啶、聚胺樹脂、普魯卡因、嘌呤、可可鹼(theobromine)、三乙胺、三甲胺、三丙胺、緩血酸胺(tromethamine)、及類似物。
以上所有鹽均可由熟習此項技術者藉由習知方式自本發明相應化合物製得。例如,可藉由習知化學方法自含鹼性或酸性部分之母體化合物合成本發明之醫藥上可接受的鹽。通常,此等鹽可藉由使此等化合物之游離酸或鹼形式與化學計量之適宜鹼或酸在水或有機溶劑或者二者之混合物中反應而製得;通常,以非水性介質如醚、乙酸乙酯、乙醇。異丙醇或乙腈較佳。鹽可自溶液中沈澱出,且可藉由過濾收集或可藉由蒸發溶劑回收。鹽中之電離度可從完全電離變化至幾乎不電離。適宜鹽之清單可見於Remington's Pharmaceutical Sciences,第17版,Mack Publishing Company,Easton,Pa.,1985,第1418頁中,僅將其關於適宜鹽之清單之揭示內容以引用的方式併入本文中。
本發明化合物可以非溶劑化及溶劑化形式存在。本文使用術語
「溶劑化物」來描述一種含本發明化合物及一或多種醫藥上可接受的溶劑分子(例如乙醇)之分子複合物。當該溶劑為水時採用術語「水合物」。醫藥上可接受之溶劑化物包括水合物及其他溶劑化物,其中結晶溶劑可經同位素取代,例如D2O、d6-丙酮、d6-DMSO。
含一或多個不對稱碳原子之式(I)化合物可以兩種或更多種立體異構體存在。當式(I)化合物(或抗微生物劑及/或習知呼吸道治療劑)包含烯基或伸烯基或環烷基時,可能存在幾何順式/反式(或Z/E)異構體。當該化合物包含(例如)酮基或肟基或芳族部分時,可出現互變異構現象(「互變異構性」)。其符合單一化合物可呈現超過一種異構性。
本發明範圍內包括式(I)化合物(或抗微生物劑及/或習知呼吸道治療劑)(包括呈現超過一種異構性之化合物及其中一或多者之混合物)之所有立體異構體、幾何異構體及互變異構體形式。亦包括酸加成鹽或鹼式鹽,其中抗衡離子係具有光學活性之(例如)D-乳酸根或L-離胺酸根,或外消旋(例如)DL-酒石酸根或DL-精胺酸根。
順式/反式異構體可藉由熟習此項技術者所熟知之習知技術分離,例如層析或分段結晶。
用於製備/單離個別對映異構體之習知技術包括自適宜光學純淨前驅體進行對掌性合成或者使用(例如)對掌性高壓液相層析(HPLC)解析外消旋物(或者鹽或衍生物之外消旋物)。
本發明對掌性化合物(及其對掌性前驅體)可以對映體上強化的形式獲得,方式為使用層析(通常為HPLC)在具有不對稱固定相及由含0至50%異丙醇(通常2至20%)及0至5%烷胺(通常0.1%二乙胺)之烴(通常為庚烷或己烷)組成之移動相之樹脂上進行。濃縮溶離液得到強化混合物。
可藉由熟習此項技術者所知之習知技術分離立體異構體混合
物。[參見例如E L Eliel之「Stereochemistry of Organic Compounds」(Wiley,New York,1994)]。
本發明包括所有醫藥上可接受的經同位素標記的化合物,其中一或多個原子可經具有相同原子序數,但原子質量或質量數不同於常見於自然界之原子質量或質量數之原子置換。
適合包含在本發明化合物中之同位素實例包括以下元素之同位素:氫(諸如2H及3H)、碳(諸如11C、13C及14C)、氯(諸如36Cl)、氟(諸如18F)、碘(諸如123I及125I)、氮(諸如13N及15N)、氧(諸如15O、17O及18O)、磷(諸如32P)及硫(諸如35S)。
包括本發明之某些經同位素標記之化合物,包括(例如)彼等含放射性同位素者,其等可用於藥物及/或受質組織分佈研究。鑑於併入便利性及已有的偵測方式,放射活性同位素氚(即3H)及碳-14(即14C)特別可用於此目的。
經較重同位素(諸如氘(即2H))取代可提供源自更大代謝安定性(例如活體內半衰期增加或劑量要求降低)的一些治療優點,且因此在一些情形下可係較佳。
通常,可藉由熟習此項技術者已知的習知技術或藉由與彼等本文所述者類似的方法使用適當同位素標記反應試劑代替先前使用的非標記反應試劑來製備同位素標記化合物。
本發明化合物可作為前藥投與。因此,當投與至人體時,本發明化合物之某些衍生物(其本身可具有極小或無藥理活性)可(例如)藉由水解裂解轉化為具有所需活性之化合物。此等衍生物稱為「前藥」。
一般而言,本發明組合物係由至少一種本文所述化學實體與至少一種醫藥上可接受的賦形劑之組合組成。可接受的賦形劑係無毒,有助於投與,且不會不利地影響該至少一種本文所述化學實體之治療
效益。此賦形劑可為任何固體、液體、半固體或(在氣霧劑組合物之情形下之)氣態賦形劑,熟習此項技術者通常可獲得氣態賦形劑。
本文之化合物、其醫藥上可接受的鹽及包含其之醫藥組合物可便利地藉由任何習知用於藥物投與之途徑進行投與。本文之化合物可以根據習知程序將式(I)化合物與標準醫藥載劑組合在一起製得之習知劑型投與。本文之化合物亦可以習知劑量與已知的第二治療活性化合物組合投與。
本文所述化學實體可經由任何對起到類似效用之製劑而言可接受的投與模式投與,包括(但不限於)經口、全身(例如,經皮、鼻內或經栓劑)或非經腸(例如,肌肉內、靜脈內或皮下)、舌下、局部、腹膜內、肺內、陰道內、直腸或眼內。在一些實施例中,式(I)化合物係經口非經腸投與。在其他實施例中,式(I)化合物係經肺內途徑投與。在其他實施例中,抗微生物劑係經肺內途徑投與。
在其他實施例中,式(I)化合物係經靜脈內投與。在一實施例中,式(I)化合物係作為含0.1至10mg/mL呈游離鹼之式(I)化合物且包含β環糊精及磺基丁醚之注射用水溶液進行靜脈內投與。在另一實施例中,式(I)化合物係作為含2mg/mL呈游離鹼之式(I)化合物且包含β環糊精及磺基丁醚之注射用水溶液進行靜脈內投與。在其他實施例中,式(I)化合物係作為含2mg/mL呈游離鹼之式(I)化合物且包含β環糊精及磺基丁醚之注射用水溶液進行靜脈內投與,且其中每小瓶式(I)化合物之靜脈輸液含13mL之2mg/mL式(I)化合物。
醫藥組合物或調配物包括固體、半固體、液體及氣霧劑劑型,諸如例如,錠劑、膠囊、粉劑、液體、懸浮液、栓劑、氣霧劑等。化學實體亦可以緩釋或控制釋放劑型投與,包括以預定速率長時間及/或定時脈衝式投與之儲積注射液、滲透活性泵、丸劑、經皮(包括電遷移)貼片等。在某些實施例中,該等組合物係以適合單次投與精確
劑量之單位劑型提供。
本文所述化學實體可單獨投與或更通常與習知載劑、賦形劑等(例如,甘露糖醇、乳糖、澱粉、硬脂酸鎂、糖精鈉、滑石、纖維素、交聯羧甲基纖維素鈉、葡萄糖、明膠、蔗糖、碳酸鎂等)組合投與。若需要,醫藥組合物亦可包含少量無毒輔助物質,諸如潤濕劑、乳化劑、增溶劑、pH緩衝劑等(例如,乙酸鈉、檸檬酸鈉、環糊精(cyclodextrin)、環式糊精(cyclodextrine)、環糊精衍生物及環式糊精衍生物、山梨糖醇單月桂酸酯、三乙醇胺乙酸酯、三乙醇胺油酸酯)。通常,依據預期投與模式,醫藥組合物將包含約0.005重量%至95重量%;在某些實施例中,約0.5重量%至50重量%之化學實體。熟習此項技術者知道或將知曉製備此等劑型之實際方法;例如參見Remington's Pharmaceutical Sciences,Mack Publishing Company,Easton,Pennsylvania。
在某些實施例中,組合物將採取丸劑或錠劑之形式,且因此該組合物將連同活性成分包含稀釋劑,諸如乳糖、蔗糖、磷酸二鈣等;潤滑劑,諸如硬脂酸鎂等;及黏合劑,諸如澱粉、阿拉伯樹膠、聚乙烯基吡咯啶、明膠、纖維素、纖維素衍生物等。在另一固體劑型中,將粉末、顆粒(marume)、溶液或懸浮液(例如,在碳酸丙烯酯、植物油或甘油三酯)囊封在明膠膠囊中。
液體醫藥投與組合物可(例如)如下製備:藉由將至少一種化學實體及可選醫藥佐劑溶解、分散於載劑(例如,水、鹽水、右旋糖水溶液、甘油、二醇、乙醇等)中,以形成溶液或懸浮液。注射液可製備成習知形式,製備成液體溶液或懸浮液、製備成乳液或製備成適合於注射之前溶解或懸浮於液體中之固體形式。此非經腸組合物中所含化學實體之百分比高度依賴其具體性質以及及化學實體之活性及個體需求。然而,可採用活性成分百分比為溶液中之0.01%至10%,且若組
合物係隨後將稀釋至上述百分比之固體,則百分比將更高。在某些實施例中,組合物將包括溶液中約0.2至2%活性劑。
本文所述化學實體之醫藥組合物亦可作為噴霧器用噴霧劑或溶液、或作為吸入用微細粉末投與至呼吸道,其係單獨投與或與惰性載劑(諸如)乳糖組合投與。在此情形下,醫藥組合物顆粒具有小於50微米,在某些實施例中,小於10微米之直徑。
此等程序可涉及根據所需製備物混合、粒化及壓縮或溶解成分。應暸解,醫藥上可接受的載劑或稀釋劑之形式及特性係由欲與其組合之活性成分之量、投與途徑及其他熟知變量決定。該(等)載劑必須在與調配物之其他成分相容之意義上來說是「可接受」且對其接受者不會造成傷害。
所用醫藥載劑可為(例如)固體或液體。固體載劑之實例為乳糖、白土、蔗糖、滑石、明膠、瓊脂、果膠、阿拉伯膠、硬脂酸鎂、硬脂酸等。液體載劑之實例為糖漿、花生油、橄欖油、水等。類似地,載劑或稀釋劑可包括此項技術所熟知之延時材料,諸如僅有甘油單硬脂酸酯或甘油二硬脂酸酯或者與蠟一起。可採用眾多醫藥形式。因此,若使用固體載劑,可將製備物壓制成粉末或九粒形式或者片劑或口含錠形式,置於硬質明膠膠囊中。固體載劑之量將大不相同,但較佳為約25mg至約1g。當使用液體載劑時,製備物將呈糖漿、乳液、軟明膠膠囊、無菌注射液(諸如安瓿劑)或非水性液體懸浮液。
一般而言,所提供的化學實體將藉由任何對起到類似效用之製劑而言可接受的投與模式以治療有效量投與。化學實體(亦即活性成分)之實際用量將取決於許多因素,諸如待治療疾病之嚴重性、個體之年齡及相對健康、所用化學實體之效力、投與途徑及形式及其他因素。藥物可一天投與超過一次,諸如一天一次或兩次。
本文所述化學實體之治療有效量可介於約0.01至200mg/千克接
受者體重/天之範圍內;諸如約0.01至100mg/kg/天,例如約0.1至50mg/kg/天。因此,就投與至70kg的人而言,劑量範圍可為約1至2000mg/天。
投與所提供化學實體之另一方式係吸入。調配物之選擇取決於各種因素,諸如藥物投與模式及原料藥之生物利用率。就經由吸入遞送而言,化學實體可調配成液體溶液、懸浮液、氣霧劑推進劑或乾燥粉末,並裝載在適宜的投與用分配器中。有若干種醫藥吸入裝置-噴霧吸入器、定劑量吸入器(MDI)及乾粉吸入器(DPI)。噴霧裝置產生高速空氣流,其導致治療劑(調配成液體形式)作為攜帶進入患者呼吸道之霧噴出。MDI通常為封裝有壓縮氣體之調配物。致動時,裝置藉由壓縮氣體釋放出一定量治療劑,從而得到一種投與固定量製劑之可靠方法。DPI分配呈自由流動粉末形式之治療劑,其可在患者呼吸期間藉由該裝置分配於吸氣氣流。為得到自由流動粉末,用諸如乳糖之賦形劑調配治療劑。以膠囊形式儲存一定量治療劑,並藉助每次致動進行分配。
本文之化合物可局部投與,即所謂非全身性投與。此包括將式(I)化合物施加至表皮或頰腔及將此化合物滴注於耳部、眼部及鼻部,以使得該化合物不會明顯進入血流。相比之下,全身性投與係指經口、靜脈內、腹膜內及肌肉內投與。適合局部投與之調配物包括適合透過皮膚滲透至發炎位置之液體或半液體製備物,諸如擦劑、洗劑、乳膏、油膏或糊膏及適合投與至眼部、耳部或鼻部之滴劑。就局部投與而言,活性成分可佔調配物之0.001重量%至10重量%,例如1重量%至2重量%。然而,其可佔調配物之多達10重量%,但較佳將佔小於5重量%,更佳0.1重量%至1重量%。
根據本發明之洗劑包括彼等適合施加至皮膚或眼部者。眼用洗劑可包括視情況含殺菌劑之無菌水溶液,且可藉由類似於彼等用於製
備滴劑之方法製備。用於施加至皮膚之洗劑或擦劑亦可包含加速乾燥及冷卻皮膚之製劑(諸如酒精或丙酮)及/或保濕劑(諸如甘油)或油(諸如蓖麻油或花生油)。
根據本發明之乳膏、油膏或糊膏係活性成分之外用半固體調配物。其等可如下製備:藉助具有油脂性或非油脂性基質之適宜機器,在水性或非水性液體中混合僅呈細分散或粉末形式之活性成分或者呈溶液或懸浮液之活性成分。該基質可包括烴,諸如硬、軟或液體石蠟、甘油、蜂臘、金屬皂;黏質;天然油,諸如杏仁油、玉米油、花生油、蓖麻油或橄欖油;羊毛脂或其衍生物或脂肪酸,諸如硬脂酸或油酸;以及醇(諸如丙二醇)或大粒凝膠。調配物可包含任何適宜表面活性劑,諸如陰離子、陽離子或非離子表面活性劑,諸如山梨糖醇酯或其聚氧乙烯衍生物。亦可包括懸浮劑(諸如天然膠)、纖維素衍生物或無機材料(諸如火成矽石(silicaceous silicas))及其他成分(諸如羊毛脂)。
根據本發明之滴劑可包含無菌水溶液或油性溶液或懸浮液,且可藉由將活性成分溶解於適宜殺菌及/或殺真菌劑及/或任何適宜保存劑之水溶液中製得,且較佳包括表面活性劑。然後藉由過濾使所得溶液澄清,轉移至適宜容器中,隨後將其密封並藉由熱壓處理或維持在98至100℃半小時滅菌。或者,溶液可藉由過濾滅菌,並藉由無菌操作技術轉移至容器中。適合包含在滴劑中之殺菌劑及殺真菌劑之實例為硝酸苯汞或乙酸苯汞(0.002%)、氯化苄二甲烴銨(0.01%)及乙酸氯己定(0.01%)。適合用於製備油性溶液之溶劑包括甘油、稀酒精及丙二醇。
本文所述化合物亦可藉由吸入投與,亦即藉由鼻內及經口吸入投與。對應此種投與方式之適宜劑型(諸如氣霧劑調配物或定劑量吸入劑)可藉由習知技術製備。在本發明之一實施例中,本發明製劑係
經由經口吸入或鼻內投與遞送。對應此種投與方式之適宜劑型(諸如氣霧劑調配物或定劑量吸入劑)可藉由習知技術製備。
就藉由吸入投與而言,化合物可藉助使用適宜推進劑(例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、氫氟烷(諸如四氟乙烷或六氟丙烷)、二氧化碳或其他適宜氣體)以噴霧劑呈現形式自加壓包或噴霧器遞送。在加壓氣霧劑之情形下,劑量單位可藉由提供遞送計量之閥確定。用於吸入器或吹入器之(例如)明膠之膠囊及濾筒可經調配,以包含本發明化合物及適宜粉末基質(諸如乳糖或澱粉)之粉末混合物。
用於藉由吸入局部遞送至肺之乾粉組合物可(例如)存在於用於吸入器或吹入器之(例如)明膠之膠囊及濾筒或者(例如)層壓鋁箔之泡罩(blister)中。粉末混合調配物通常包含本發明化合物及適宜粉末基質(載劑/稀釋劑/賦形劑物質)(諸如單糖、二糖或多糖(例如乳糖或澱粉))之吸入粉末混合物。較佳使用乳糖。
各膠囊或濾筒通常可包含20μg至1000mg式(I)化合物,視情況與另一治療活性劑(抗微生物劑)組合。或者,本發明化合物可在無賦形劑下存在。適宜地,包裝/藥劑分配器係一類選自由以下之群者:貯存乾粉吸入器(RDPI)、多劑量粉末吸入器(MDPI)及定劑量吸入器(MDI)。所謂貯存乾粉吸入器(RDPI),其意指具有適用於包含多劑(非定劑量)呈乾粉形式之藥劑之貯存形式包裝,且包括用於將計量藥劑劑量自貯存器運至遞送位置之構件之吸入器。計量構件可(例如)包括計量杯,其可自該計量杯可自貯存器填充藥劑之第一位置移動至患者可吸入計量藥劑劑量之第二位置。所謂多劑量乾粉吸入器(MDPI)意指適合分配呈乾粉形式之藥劑之吸入器,其中該藥劑係包含在含(或以其他方式攜帶)多個確定劑量(或其部分)藥劑之多劑量包裝內。在一較佳態樣中,載劑具有泡罩包裝形式,但其亦可(例如)包含膠囊基包裝形式或其上已藉由任何適宜方法(包括印刷、噴塗及真空嚙合)施加
藥劑之載劑。
在多劑量遞送之情形下,該調配物可預先計量(例如,如在乾粉吸入器(Diskus)中,參見美國專利案第6,632,666號、第5,860,419號、第5,873,360號、第5,622,166號及第5,590,645號,或在蝶式吸入器(Diskhaler)中,參見美國專利案第4,627,432號、第4,778,054號、第4,811,731號、第5,035,237號,該等案之揭示內容以引用的方式併入本文中)或在使用時計量(例如,如在都保(Turbuhaler)中,參見US 4,524,769,或在美國專利案6,321,747中所述裝置中,該等案之揭示內容以引用的方式併入本文中)。單位劑量裝置之實例為旋轉吸入器(Rotahaler)(參見美國專利案第4,353,656號及第5,724,959號,該等案之揭示內容以引用的方式併入本文中)。
Diskus吸入裝置包括由具有複數個沿著其長度間隔開之凹穴之基片形成之細長條帶以及氣密性地但可剝離地密封至細長條帶,以定義複數個容器之蓋片,各容器內具有含式(I)化合物(較佳與乳糖組合)之可吸入調配物。較佳地,該條帶具有足夠可撓性,以繞成一卷。該蓋片及基片較佳將具有未彼此密封之引導端部分,且該等引導端部分中之至少一者經結構化,以附接至纒繞構件。還有,較佳地,基片與蓋片間之氣密性密封件延伸越過其完整寬度。該蓋片較佳可在長度方向上由該基片之第一端自該基片剝離。在一態樣中,多劑量包裝係泡罩包裝,其包括多個用於密封呈乾粉形式之藥劑之泡罩。泡罩通常係以規則方式排列,以易於自其釋放藥劑。在一態樣中,多劑量泡罩包裝包括複數個通常以環形方式排列在盤形泡罩包裝上之泡罩。在另一態樣中,多劑量泡罩包裝係細長形式,例如包括條帶或膠帶。在一態樣中,多劑量泡罩包裝係界定在兩個以可剝離方式彼此固定之膜之間。美國專利案第5,860,419號、第5,873,360號及第5,590,645號描述此一般類型之藥劑泡罩。在此態樣中,該裝置通常具有開放平台,其包括
用於分開部件以接觸各藥劑劑量之剝離構件。適宜地,該裝置適合用於可剝離部件係細長片材之情形,細長片材界定複數個沿著其長度間隔開之藥劑容器,該裝置具有用於輪流指引各容器之指引構件。更佳地,該裝置適合用於其中一個片材係其內具有複數個口袋之基片,且另一個片材係蓋片之情形,各口袋及蓋片之相鄰部分界定各個容器,該裝置包括用於在開放平台上使蓋片與基片分開之驅動構件。
所謂定劑量吸入器(MDI)意指適合分配呈氣霧劑形式之藥劑之藥劑分配器,其中該藥劑包含在適用於容納推進劑基氣霧劑藥劑調配物之氣霧劑容器中。該氣霧劑容器通常具有用於將氣霧劑形式藥劑調配物釋放至患者之計量閥,例如滑閥。該氣霧劑容器通常經設計,以在每次藉助閥致動時遞送預定劑量之藥劑,其可藉由在容器保持靜止時降低閥或者在閥保持靜止時降低容器開放。當該藥劑容器為氣霧劑容器時,閥通常包括具有藥劑噴霧劑調配物可透過其進入閥本體之入口埠、氣霧劑可透過其離開該閥本體之出口埠之閥本體、及可藉以控制流過該出口埠之流之開放/關閉機制。該閥可為滑閥,其中該開放/關閉機制包括密封環及可為該密封環所接受之具有分配通道之閥桿,該閥桿可在該環內自閥關閉位置滑移至閥開放位置,其中該閥本體之內部與經由該分配通道與該閥本體之外部連通。
通常該閥係計量閥。計量體積通常為10至100μl,諸如25μl、50μl或63μl。適宜地,該閥體界定用於計量藥劑調配物之量之計量室及可藉以控制透過入口埠流至該計量室之流之開放/關閉機制。較佳地,該閥本體具有經由第二入口埠與該計量室連通之取樣室,該入口埠可藉助該開放/關閉機制控制,從而調節進入該計量室之藥劑調配物流。
該閥亦可包括「自由流動氣霧劑閥」,其具有室及延伸進入該室,並可相對於該室在分配與非分配位置間移動之閥桿。該閥桿具有一定結構,且該室具有內部結構,以使得在其間界定計量體積,且使
得在其間移動期間係非分配及分配位置,該閥桿依次:(i)容許氣霧劑調配物自由流動至該室中,(ii)在該閥桿外表面與該室內表面之間為加壓氣霧劑調配物界定密閉計量體積,及(iii)隨著該室內之該密閉計量體積移動而不會減少該密閉計量體積之體積,直至該劑量體積與出口通道連通,從而允許分配該計量體積之加壓氣霧劑調配物。美國專利案第5,772,085號中描述此類閥。此外,本發明化合物可有效進行鼻內遞送。
為調配有效醫藥鼻用組合物,藥劑必須容易地遞送至鼻腔之其發揮其藥理功能之所有部分(目標組織)。此外,藥劑應保持與目標組織接觸相對長時間段。藥劑與目標組織保持接觸時間越長,藥劑必須可抵抗鼻道內彼等起到移除鼻子顆粒作用之力。此等力(稱為「黏液纖毛清除」)被認為在快速移除鼻子之顆粒方面極其有效,例如,在自顆粒進入鼻子時間開始10至30分鐘內。
鼻用組合物之其他所需特性在於,其必須不含致使使用者不適之成分,其具有令人滿意的穩定性及儲藏壽命性質,及其不含視為對環境有害之成分,例如臭氧耗竭劑。當投與至鼻子時,就患者而言,本發明調配物之適宜給藥方案將係在清潔鼻腔後深深吸氣。在吸入過程中,調配物將施加至一個鼻孔,同時用手壓著另一個。然後將對另一鼻孔重複此程序。一種用於將本發明調配物施加至鼻腔之方式係使用預壓泵。更佳地,該預壓泵將係由Valois SA製造之VP7型號。此泵係有益的,因為其將確保調配物直到施加足夠力時才釋放,否則可施加較小劑量。預壓泵之另一優勢在於可確保噴射物之霧化,因為其直到達到使噴射物有效霧化之閾值壓力時才釋放調配物。通常,VP7型號可與可容納10至50ml調配物之瓶子一起使用。每次噴射通常將遞送50至100μl此調配物;因此,VP7型號可提供至少100個計量劑量。
用於藉由吸入局部遞送至肺之噴霧組合物可(例如)調配成藉助使
用適宜液化推劑劑自加壓包(諸如定劑量吸入器)遞送之水溶液或懸浮液或者氣霧劑。適合吸入之氣霧劑組合物可為懸浮液或溶液,且通常包含視情況與另一種治療活性成分組合之式(I)化合物及適宜推進劑,諸如氟碳化物或含氫之氟氯碳化物或者其組合,特定言之氫氟烷,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷,特別係1,1,1,2-四氟乙烷、1,1,1,2,3,3,3-七氟正丙烷或其混合物。二氧化碳或其他適宜氣體亦可用作推進劑。該氣霧劑組合物可不含賦形劑或可視情況包含此項技術中所熟知之其他調配物毒性,諸如表面活性劑(例如油酸或卵磷脂)及共溶劑(乙醇)。加壓調配物通常將保存在以閥(例如計量閥)密封,並裝入具有噴嘴之致動器中之藥罐(例如鋁罐)中。用於藉由吸入投與之藥劑宜具有受控粒度。用於吸入支氣管系統之最適粒度通常為1至10μm,較佳2至5μm。當吸入到達小呼吸道時,尺寸大於20μm之顆粒通常過大。為達到此等粒度,所生產的活性成分顆粒可藉由習知方式(例如藉由微粒化)減小尺寸。所需部分可藉由風選或篩分分離。適宜地,顆粒將呈結晶形式。當使用賦形劑如乳糖時,賦形劑之粒度通常將遠大於本發明之吸入藥劑。當賦形劑係乳糖時,其通常將作為濕磨乳糖提供,其中不超過85%之乳糖顆粒將具有60至90μm之MMD,且不少於15%的將具有小於15μm之MMD。鼻內噴霧劑可使用水性或非水性媒劑,藉由添加諸如增稠劑、調節pH之緩衝鹽或酸或鹼、滲透性調節劑或抗氧化劑之試劑進行調配。
用於藉由噴霧法吸入之溶液可用水性媒劑,藉由添加諸如酸或鹼、緩衝鹽、滲透性調節劑或抗氧化劑之試劑進行調配。其等可藉由過濾或在高壓釜中滅菌或作為未滅菌產品提供。適宜地,藉由吸入投與較佳可靶向呼吸道疾病所涉及的器官,亦即肺,且藉此可減少需遞送至患者之有效劑量。此外,藉由吸入投與可減少全身接觸該化合物,因而避免該化合物在肺以外的效應。
最近,基於可藉由增加表面積(亦即減小粒度)來提高生物利用率之原則,已為顯示較差生物利用率之藥物開發出醫藥組合物。例如,美國專利案第4,107,288號描述一種具有尺寸介於10至1,000nm範圍內之顆粒之醫藥調配物,其中活性物質係負載於大分子之交聯基質上。美國專利案第5,145,684號描述醫藥組合物之製法,其中原料藥在表面改質劑存在下碎成奈米顆粒(平均粒度為400nm),然後分散於液體介質中,以得到呈現極高生物利用率之醫藥調配物。
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Claims (39)
- 一種包含黛力新(danirixin)及神經胺糖酸苷酶抑制劑化合物之組合,二者係呈相同或獨立劑型。
- 一種包含黛力新及扎那米韋(zanamivir)之組合,二者係呈相同或獨立劑型。
- 一種包含黛力新及奧司他韋(oseltamivir)之組合,二者係呈相同或獨立劑型。
- 一種包含黛力新及利巴韋林(ribavirin)之組合,二者係呈相同或獨立劑型。
- 一種包含黛力新及法匹拉韋(favipiravir)之組合,二者係呈相同或獨立劑型。
- 一種包含黛力新及一或多種選自表4之抗微生物劑之組合,其等係呈相同或獨立劑型。
- 一種醫藥組合物,其包含黛力新及神經胺糖酸苷酶抑制劑化合物以及醫藥上可接受的賦形劑。
- 一種醫藥組合物,其包含黛力新及扎那米韋以及醫藥上可接受的賦形劑。
- 一種醫藥組合物,其包含黛力新及奧司他韋以及醫藥上可接受的賦形劑。
- 一種醫藥組合物,其包含黛力新及利巴韋林以及醫藥上可接受的賦形劑。
- 一種醫藥組合物,其包含黛力新及法匹拉韋以及醫藥上可接受的賦形劑。
- 一種醫藥組合物,其包含黛力新及一或多種選自表4之抗微生物劑以及醫藥上可接受的賦形劑。
- 一種如請求項1至6中任一項之組合或如請求項7至12中任一項之醫藥組合物之用途,其係用於製造用於治療個體之呼吸道傳染性疾病之藥劑。
- 如請求項13之用途,其中該呼吸道傳染性疾病係流感。
- 如請求項13之用途,其中該呼吸道傳染性疾病係RSV。
- 如請求項13至15中任一項之用途,其中該藥劑包含呈相同劑型之黛力新及神經胺糖酸苷酶抑制劑化合物。
- 如請求項13至15中任一項之用途,其中該藥劑包含用於同時投與之黛力新及神經胺糖酸苷酶抑制劑化合物。
- 如請求項13至15中任一項之用途,其中該藥劑包含呈獨立劑型之黛力新及神經胺糖酸苷酶抑制劑化合物。
- 如請求項13至15中任一項之用途,其中該藥劑包含用於單獨投與之黛力新及神經胺糖酸苷酶抑制劑化合物。
- 如請求項13至15中任一項之用途,其中該藥劑包含呈相同劑型之黛力新及利巴韋林。
- 如請求項13至15中任一項之用途,其中該藥劑包含用於同時投與之黛力新及利巴韋林。
- 如請求項13至15中任一項之用途,其中該藥劑包含呈獨立劑型之黛力新及利巴韋林。
- 如請求項13至15中任一項之用途,其中該藥劑包含用於單獨投與之黛力新及利巴韋林。
- 一種黛力新之用途,其係用於製造用於治療個體之流感之藥劑。
- 一種黛力新之用途,其係用於製造用於治療個體之RSV之藥劑。
- 一種用於靜脈內投與之醫藥組合物,其包含:水溶液中呈氫溴酸鹽形式之黛力新。
- 一種用於靜脈內投與之醫藥組合物,其包含:水溶液中呈氫溴酸鹽形式之黛力新及醫藥上可接受的賦形劑。
- 如請求項27之醫藥組合物,其中該醫藥上可接受的賦形劑包含β-環糊精。
- 如請求項27之醫藥組合物,其中該醫藥上可接受的賦形劑包含磺基丁醚。
- 如請求項27之醫藥組合物,其中該醫藥上可接受的賦形劑包含β-環糊精及磺基丁醚。
- 如請求項27之醫藥組合物,其中該醫藥上可接受的賦形劑包含Captisol®。
- 一種如請求項26至31中任一項之醫藥組合物之用途,其係用於製造用於治療個體之呼吸道傳染性疾病之藥劑。
- 一種如請求項26至31中任一項之醫藥組合物之用途,其係用於製造用於治療個體之RSV之藥劑。
- 一種如請求項26至31中任一項之醫藥組合物之用途,其係用於製造用於治療個體之流感之藥劑。
- 一種黛力新及帕利珠單抗(Palivizumab)之組合之用途,其係用於製造用於治療個體之RSV之藥劑。
- 如請求項35之用途,其中該藥劑包含呈相同劑型之黛力新及帕利珠單抗。
- 如請求項35之用途,其中該藥劑包含用於同時投與之黛力新及帕利珠單抗。
- 如請求項35之用途,其中該藥劑包含呈獨立劑型之黛力新及帕利珠單抗。
- 如請求項35之用途,其中該藥劑包含用於單獨投與之黛力新及帕利珠單抗。
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-
2015
- 2015-05-08 WO PCT/IB2015/053373 patent/WO2015173701A2/en active Application Filing
- 2015-05-08 EA EA201692111A patent/EA201692111A1/ru unknown
- 2015-05-08 AU AU2015260841A patent/AU2015260841A1/en not_active Abandoned
- 2015-05-08 UY UY0001036117A patent/UY36117A/es not_active Application Discontinuation
- 2015-05-08 CA CA2948441A patent/CA2948441A1/en not_active Abandoned
- 2015-05-08 US US15/310,592 patent/US20170100385A1/en not_active Abandoned
- 2015-05-08 CN CN201580038007.5A patent/CN107072976A/zh active Pending
- 2015-05-08 JP JP2016567399A patent/JP2017515840A/ja active Pending
- 2015-05-08 EP EP15721878.5A patent/EP3142694A2/en not_active Withdrawn
- 2015-05-08 MX MX2016014859A patent/MX2016014859A/es unknown
- 2015-05-08 PE PE2016002229A patent/PE20170185A1/es not_active Application Discontinuation
- 2015-05-08 CR CR20160529A patent/CR20160529A/es unknown
- 2015-05-08 KR KR1020167034634A patent/KR20170003673A/ko unknown
- 2015-05-08 SG SG11201609276RA patent/SG11201609276RA/en unknown
- 2015-05-08 TW TW104114803A patent/TW201625247A/zh unknown
-
2016
- 2016-11-06 IL IL248779A patent/IL248779A0/en unknown
- 2016-11-09 ZA ZA2016/07729A patent/ZA201607729B/en unknown
- 2016-11-11 DO DO2016000297A patent/DOP2016000297A/es unknown
- 2016-11-11 CL CL2016002879A patent/CL2016002879A1/es unknown
- 2016-11-11 PH PH12016502243A patent/PH12016502243A1/en unknown
-
2018
- 2018-03-19 US US15/924,952 patent/US20180207145A1/en not_active Abandoned
- 2018-06-04 AU AU2018203911A patent/AU2018203911A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
AU2018203911A1 (en) | 2018-06-21 |
CN107072976A (zh) | 2017-08-18 |
WO2015173701A3 (en) | 2016-02-18 |
EP3142694A2 (en) | 2017-03-22 |
CA2948441A1 (en) | 2015-11-19 |
SG11201609276RA (en) | 2016-12-29 |
DOP2016000297A (es) | 2016-12-31 |
UY36117A (es) | 2016-01-08 |
EA201692111A1 (ru) | 2017-08-31 |
WO2015173701A2 (en) | 2015-11-19 |
ZA201607729B (en) | 2018-11-28 |
PH12016502243A1 (en) | 2017-01-09 |
JP2017515840A (ja) | 2017-06-15 |
MX2016014859A (es) | 2017-06-27 |
KR20170003673A (ko) | 2017-01-09 |
IL248779A0 (en) | 2017-01-31 |
CL2016002879A1 (es) | 2017-02-24 |
US20180207145A1 (en) | 2018-07-26 |
US20170100385A1 (en) | 2017-04-13 |
PE20170185A1 (es) | 2017-04-01 |
CR20160529A (es) | 2017-01-02 |
AU2015260841A1 (en) | 2016-12-01 |
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