TWI424848B - 新穎鹽類 - Google Patents
新穎鹽類 Download PDFInfo
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- TWI424848B TWI424848B TW097148921A TW97148921A TWI424848B TW I424848 B TWI424848 B TW I424848B TW 097148921 A TW097148921 A TW 097148921A TW 97148921 A TW97148921 A TW 97148921A TW I424848 B TWI424848 B TW I424848B
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Description
本發明係關於一種8-側氧腺嘌呤衍生物之鹽類、包含其之醫藥組成物及其在治療上的用途。
在已公告的國際專利申請案案號WO 2005/092893之實施例2-37中,特別揭示出(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯作為經由托耳樣(Toll-like)受體7(TLR7)作用之免疫調節化合物。
在藥物物質之調配物中,重要的是該藥物物質(活性化合物)呈可經合宜地處理及加工的形式。不僅從獲得商業可實行的藥物物質其自身之製造方法的觀點來看此重要,而且從隨後製造出包含該活性化合物與合適的賦形劑之醫藥調配物的觀點來看亦此重要。在此關聯中,該活性化合物的化學穩定性及物理穩定性為重要因素。該活性化合物及包含其之調配物必需能有效地貯存超過明顯的時間週期,而沒有在該活性化合物的物理化學特徵(例如,化學組成物、密度、吸濕性及溶解度)上顯示出任何明顯改變。
再者,若該活性化合物欲併入用於肺給藥(例如,經由乾粉吸入器(諸如,都保好啦(Turbuhaler)裝置))的調配物中時,想要該活性化合物可容易地被微粒化,以產生一具有好的流動性質且包含高細顆粒粒度組成(即,該活性化合物顆粒具有少於或等於10微米之質量中數粒徑(MMD)的粒度組成)之粉末。此粒度組成能被深深地攜入肺中而導致較快且增加的活性化合物吸收。
熟知此技藝者將察知,典型來說,若一藥物物質可容易地以穩定形式(諸如,穩定的結晶形式)獲得時,其可就容易處理、容易製備及延長合適的醫藥調配物之閑置壽命、及更可信賴的溶解度曲線來提供優點。
現在已驚人地發現,可製備出具有改良的物理化學性質(與游離態基礎化合物比較)之(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯的某些鹽類,其能配製成用於肺給藥之乾粉調配物。
(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯之結構顯示在下列:
因此,根據本發明已提供(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯之氫氯酸、氫溴酸或順丁烯二酸鹽(於此之後指為“氫氯酸、氫溴酸或順丁烯二酸鹽”)。
在另一個觀點中,本發明提供(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯的氫氯酸、氫溴酸或順丁烯二酸鹽,其具有各別顯示在表A、B或C中(參見於此之後的實施例4)之X射線粉末繞射波峰特徵(以2θ度表示)。
本發明亦提供該氫氯酸、氫溴酸或順丁烯二酸鹽的溶劑化物(包括水合物)。但是,該氫氯酸、氫溴酸或順丁烯二酸鹽無水較佳及呈未溶劑化形式較佳。
在本發明的具體實例中,該氫氯酸、氫溴酸或順丁烯二酸鹽或其溶劑化物具有結晶性質且至少50%結晶較佳,至少60%結晶更佳,至少70%結晶又更佳及至少80%結晶最佳。該結晶性可藉由習知的X射線繞射技術來估計。
在本發明的另一個具體實例中,該氫氯酸、氫溴酸或順丁烯二酸鹽或其溶劑化物具有50%、60%、70%、80%或90%至95%、96%、97%、98%、99%或100%結晶。
(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯之製備描述在已公告的國際專利申請案案號WO 2005/092893中。可根據已知技術來製備此化合物的氫氯酸、氫溴酸及順丁烯二酸鹽(包括溶劑化形式)。但是,將由熟知此技藝者明瞭的是,將有其它可能的途徑來製得此化合物及其鹽類。
根據本發明之鹽類(包括溶劑化形式)有用作為TLR7活性的調節劑,因此可給藥至哺乳動物(包括人類)來治療下列症狀或疾病:
1.呼吸道:氣道的阻塞性疾病,包括:氣喘,包括支氣管性、過敏性、內因性、外因性、運動引起、藥物引起(包括阿斯匹靈及NSAID引起)及粉塵引起的氣喘(間歇性及持續性二者及全部的嚴重性),及其它呼吸道過度反應性之原因;慢性阻塞性肺疾(COPD);支氣管炎,包括感染性及嗜伊紅血球性支氣管炎;肺氣腫;支氣管擴張;囊性纖維變性;肉狀瘤病;農夫肺及相關的疾病;過敏性肺炎;肺纖維變性,包括隱性纖維化肺泡炎、自發性間質性肺炎、纖維變性併發的抗腫瘤治療及慢性感染,包括結核病及麴菌病及其它黴菌感染;肺移殖的併發症;肺血管分布的血管炎及栓塞性病症,及肺動脈高血壓;止咳活性,包括與氣道的炎性及分泌症狀相關的慢性咳嗽之治療,及醫生引起的咳嗽;急性及慢性鼻炎,包括藥物性鼻炎及血管運動性鼻炎;終年性及季節性過敏性鼻炎,包括神經性鼻炎(花粉症);鼻息肉病;急性病毒感染,包括普通感冒,及由於呼吸道融合瘤病毒、流行性感冒、冠狀病毒(包括SARS)及腺病毒的感染;
2.皮膚:牛皮癬、異位性皮膚炎、接觸性皮膚炎或其它濕疹性皮膚病、及延遲型式的過敏性反應;植物及光照性皮膚炎;脂溢性皮膚炎、疱疹樣皮炎、扁平苔癬、硬化萎縮性苔癬、壞疽性膿皮病、皮膚類肉瘤、盤狀紅斑性狼瘡、天疱瘡、類天疱瘡、大泡性表皮鬆懈、蕁痲疹、血管性水腫、系統性血管炎(vasculitides)、毒物性紅斑、皮膚型嗜伊紅血球增多、簇圓禿、雄性禿髮型態、史威特氏(Sweet’s)症候群、韋伯-克麗斯啼安(Weber-Christian)症候群、多形性紅斑;蜂窩組織炎,感染性及非感染性二者;脂層炎;皮膚淋巴瘤、非黑腫瘤皮膚癌及其它發育不全病灶;藥物引起的病症,包括固定型藥疹;
3.眼睛:眼瞼炎;結膜炎,包括終年性及春季性過敏性結膜炎;虹膜炎;前及後葡萄膜炎;脈絡膜炎;影響視網膜之自體免疫性、變性或炎性病症;眼炎,包括交感性眼炎;肉狀瘤病;感染,包括病毒、黴菌及細菌;
4.生殖泌尿:腎炎,包括間質性及腎絲球腎炎;腎病變症候群;膀胱炎,包括急性及慢性(間質性)膀胱炎及哈納氏(Hunner’s)潰瘍;急性及慢性尿道炎、前列腺炎、附睪炎、卵巢炎及輸卵管炎;陰唇陰道炎;佩洛尼氏(Peyronie’s)疾病;勃起障礙(雄性及雌性二者);
5.同種異體移植排斥:急性及慢性,在例如腎臟、心臟、肝、肺、骨髓、皮膚或角膜移殖後或在輸血後;或慢性移植對宿主疾病;
6.其它自體免疫及過敏性疾病,包括類風濕性關節炎、腸過敏症候群、全身性紅斑狼瘡、多發性硬化、橋本氏(Hashimoto’s)甲狀腺炎、格雷夫司氏(Graves’)症、愛迪生氏(Addison’s)症、糖尿病、特發性血小板減少性紫瘢症、嗜伊紅性肌膜炎、高IgE症候群、抗磷脂症候群及沙拉里(Sazary)症候群;
7.腫瘤學:一般癌的治療,包括前列腺、乳房、肺、卵巢、胰、腸及結腸、胃、皮膚及腦腫瘤及侵襲骨髓的惡性腫瘤(包括白血病)及淋巴增生系統,諸如霍吉金氏(Hodgkin’s)及非霍吉金氏淋巴瘤;包括轉移性疾病及腫瘤復發,及腫瘤旁症候群之預防及治療;及
8.傳染性疾病:病毒疾病,諸如生殖器疣、尋常性疣、蹠疣、B型肝炎、C型肝炎、單純疱疹病毒、觸染性軟疣、痘、人類免疫缺陷病毒(HIV)、人乳頭瘤病毒(HPV)、巨細胞病毒(CMV)、水痘帶狀疱疹病毒(VZV)、鼻病毒、腺病毒、冠狀病毒、流行性感冒、副流行性感冒;細菌性疾病,諸如結核病及禽型分枝桿菌、痳瘋;其它傳染性疾病,諸如黴菌疾病、衣原體、念珠菌、麴菌、囊球菌性腦膜炎、卡氏肺囊蟲、隱孢子蟲病、組織漿菌病、毒漿體原蟲病、錐蟲感染及利什曼病(leishmaniasis)。
因此,本發明提供(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯的氫氯酸、氫溴酸或順丁烯二酸鹽或該鹽之溶劑化物,其可使用在治療。
在進一步觀點中,本發明提供(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯的氫氯酸、氫溴酸或順丁烯二酸鹽或該鹽的溶劑化物之用途,其使用來製造使用於治療的藥劑。
在本專利說明書的上下文中,名稱“治療”亦包括“預防”,除非有相反的特定指出。名稱“治療的”及“治療地”亦應該因此解釋。
已預計預防特別與已遭遇所討論的疾病或症狀之先前發作或其它方面視為風險增加的人士之治療有關聯。在發展出特別疾病或症狀的風險下之人士通常包括具有家族歷史疾病或症狀的那些人士,或已由基因測試或篩選鑑定為特別易受影響而會發展出該疾病或症狀的那些人士。
特別是,根據本發明之鹽類(包括溶劑化形式)可使用來治療氣喘、COPD、過敏性鼻炎、過敏性結膜炎、異位性皮膚炎、癌、B型肝炎、C型肝炎、HIV、HPV、細菌感染及皮膚病。
因此,本發明提供一種治療罹患炎性疾病或在該疾病風險下之患者的方法,其包括將一治療有效量之(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯的氫氯酸、氫溴酸或順丁烯二酸鹽或該鹽之溶劑化物給藥至該患者。
本發明亦提供一種治療罹患氣道疾病(例如,可逆性阻塞性氣道疾病,諸如氣喘)或在該疾病的風險下之患者的方法,其包括將一治療有效量之(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯的氫氯酸、氫溴酸或順丁烯二酸鹽或該鹽之溶劑化物給藥至該患者。
本發明仍然進一步提供一種治療包含或由異常的細胞生長(例如,癌)所引起之疾病或症狀或減低其風險的方法,該方法包括將一治療有效量之(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯的氫氯酸、氫溴酸或順丁烯二酸鹽或該鹽之溶劑化物給藥至需要其之患者。
對上述提及的治療用途來說,所給藥之劑量當然將隨著所使用的鹽、給藥模式、想要之治療及所指出的病症而變化。例如,該(溶劑化的)氫氯酸、氫溴酸或順丁烯二酸鹽之每日劑量(若吸入時)範圍可從每公斤體重0.05微克(微克/公斤)至每公斤體重100微克(微克/公斤)。再者,若口服給藥該(溶劑化的)氫氯酸、氫溴酸或順丁烯二酸鹽時,則每日劑量的範圍可從每公斤體重0.01微克(微克/公斤)至每公斤體重100毫克(毫克/公斤)。
根據本發明之氫氯酸、氫溴酸或順丁烯二酸鹽或其溶劑化物可獨立地使用,但是通常將以一醫藥組成物形式給藥,其中該醫藥組成物為將該氫氯酸、氫溴酸或順丁烯二酸鹽或其溶劑化物(活性成分)與一醫藥上可接受的佐藥、稀釋劑或載劑結合。用來選擇及製備合適的醫藥調配物之習知程序描述在例如“藥物-劑形設計科學(Pharmaceuticals-The Science of Dosage Form Designs)”(M.E.歐吞(Aulton),邱吉爾李文斯頓(Churchill Livingstone),1988)中。
依給藥模式而定,該醫藥組成物可包含從0.05至99重量%(重量百分比)的活性成分,從0.05至80重量%更佳,從0.10至70重量%又更佳及從0.10至50重量%甚至更佳,全部的重量百分比皆以全部的組成物為準。
本發明亦提供一種醫藥組成物,其包含(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯的氫氯酸、氫溴酸或順丁烯二酸鹽或該鹽之溶劑化物與一醫藥上可接受的佐藥、稀釋劑或載劑之結合。
本發明進一步提供一種用來製備本發明之醫藥組成物的方法,其包括混合(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯的氫氯酸、氫溴酸或順丁烯二酸鹽或該鹽之溶劑化物與一醫藥上可接受的佐藥、稀釋劑或載劑。
該醫藥組成物可以例如乳膏、溶液、懸浮液、七氟烷(HFA)氣霧劑及乾粉調配物(例如,在已知為都保好啦的吸入器裝置中之調配物)形式來局部給藥(例如至皮膚或至肺及/或氣道);或全身性給藥,例如以錠劑、膠囊、糖漿、粉末或顆粒形式口服給藥;或以溶液或懸浮液形式非經腸式給藥;或藉由皮下給藥;或以栓劑形式直腸給藥;或經皮膚給藥。
在本發明的具體實例中,該醫藥組成物藉由吸入(口或鼻)給藥。
在進一步具體實例中,該醫藥組成物藉由乾粉吸入器(DPI)給藥。
該DPI可“被動”或呼吸驅動、或“主動”(其中該粉末藉由除了患者吸入外的某些機制(例如,內部供應的壓縮空氣)分散)。目前,可獲得三種型式的被動式乾粉吸入器:單一劑量、多單位劑量或多劑量(貯存器)吸入器。在單一劑量裝置中,通常以凝膠膠囊提供各別劑量且其必需在使用前負載至吸入器中,其實施例包括史賓侯勒(Spinhaler)(阿文帝斯(Aventis))、羅塔侯勒(Rotahaler)(葛蘭素史克(GlaxoSmithKline))、艾羅里蛇(Aeroliser)TM
(諾伐帝斯(Novartis))、因侯拉特(Inhalator)(百靈格(Boehringer))及伊克麗普斯(Eclipse)(阿文帝斯)裝置。多單位劑量吸入器包括數個各別包裝的劑量(以多凝膠膠囊或在泡殼中),其實施例包括狄斯克侯勒(Diskhaler)(葛蘭素史克)、狄斯克斯(Diskus)(葛蘭素史克)及艾若侯勒(Aerohaler)(百靈格)裝置。在多劑量裝置中,藥物貯存在巨大粉末貯存器中且從其中計量供應出各別劑量,其實施例包括都保好啦(阿斯錯忍內卡(AstraZeneca))、伊日侯勒(Easyhaler)(歐里翁(Orion))、諾弗里惹(Novolizer)(阿斯塔美狄卡(ASTA Medica))、克里克侯勒(Clickhaler)(因諾伐塔拜歐美德(Innovata Biomed))及普爾文諾(Pulvinal)(奇葉西(Chiesi))裝置。
可藉由混合經細微分開的活性成分(具有質量中數粒徑通常等於或少於10微米,等於或少於5微米較佳)與一載劑物質(例如,單、二或多糖類、糖醇或另一種多元醇)來製備使用於DPI的可吸入性醫藥組成物或乾粉調配物。合適的載劑有糖類,例如,乳糖、葡萄糖、蜜三糖、落葉松糖、乳糖醇、麥芽糖醇、漏蘆糖、蔗糖、甘露醇;及澱粉。然後,如需要的話,該粉末混合物可配藥至硬質凝膠膠囊中,其中每個膠囊皆包含想要的劑量之活性成分。
再者,可藉由將經細微分開的粉末(例如,由細微分開的活性成分與細微分開的載劑顆粒組成)加工成球形(其將在吸入程序期間打散)來製備可吸入的醫藥組成物。將此團成球狀的粉末填入多劑量吸入器(例如,其已知為都保好啦,其中該劑量單位可計量給藥出想要的劑量)之藥物貯存器中,然後由患者吸入此粉末。
因此,本發明亦提供一種包含本發明之可吸入性醫藥組成物的乾粉吸入器,特別是多單位劑量乾粉吸入器。
根據本發明之氫氯酸、氫溴酸或順丁烯二酸鹽或其溶劑化物亦可與使用來治療上述症狀的相關其它化合物給藥。
因此,本發明進一步關於一種治療組合,其中可同時或相繼地給藥根據本發明之氫氯酸、氫溴酸或順丁烯二酸鹽或其溶劑化物,或一包含根據本發明之氫氯酸、氫溴酸或順丁烯二酸鹽或其溶劑化物的醫藥組成物,或如為含有另一種治療藥物的結合製劑,來治療一或多種所編列的症狀。
第1圖顯示出(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)-醋酸甲酯單氫氯酸之X射線粉末繞射圖案。
第2圖顯示出(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)-醋酸甲酯單氫溴酸之X射線粉末繞射圖案。
第3圖顯示出(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)-醋酸甲酯二順丁烯二酸鹽之X射線粉末繞射圖案。
現在,將藉由參考至下列闡明實施例進一步解釋本發明。
在298K下,於瓦里安優尼弟因諾瓦(Varian Unity Inova)400MHz(軟體:VNMR 6.1C及VNMRJ 1.1D;探針:奈羅瑞克(Nalorac)5毫米DG400-5AT)或瓦里安水星-VX 300MHz(軟體:VNMR6.1C;探針:瓦里安5毫米AutoSW PFG)裝置上記錄1
H NMR光譜。使用丙酮-d6
或二甲基亞碸(DMSO)-d6
的中央波峰作為內部參考。
對LC/MS分析使用下列方法:
MS裝置:安捷侖(Agilent)1100系列,其配備有APCI介面
LC裝置:安捷侖1100系列,其配備有UV偵測器VWD、自動取樣器ALS、二元幫浦及除氣機
LC-管柱:克羅莫里斯史德(Chromolith Speed)ROD,RP-C18,Φ4.6×50毫米
沖提液:溶劑A:水+0.1%三氟醋酸(TFA);溶劑B:乙腈+0.1%TFA
條件:LC:流動2.5毫升/分鐘;梯度5至95%的B;進行時間3.6分鐘;UV 220奈米
MS:正偵測;毛細管電壓3千伏
(a)將(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯(40毫克,0.07毫莫耳)溶解在醋酸乙酯(5毫升)中,及加入3.28M的HCl/乙醇溶液(21微升,0.07毫莫耳)。藉由蒸發移除溶劑及在真空中乾燥殘餘物,以獲得(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯單氫氯酸,如為最後產物。
(b)在室溫下,將80mM在甲醇(65.0微升,5.2微莫耳)中的氫氯酸溶液加入至已溶解在甲醇(1.5毫升)中的(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯(3.0毫克,5.3微莫耳)溶液。在60℃下搖晃該溶液一小時,然後將其冷卻至5℃。在30分鐘後,留下的溶劑在5℃下慢慢蒸發,以獲得(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯單氫氯酸,如為最後產物。
藉由下列方法製備進一步量的該單氫氯酸鹽:
(c)在5℃下,將化學計量的量在甲醇中之氫氯酸溶液(2.4重量比率,WR)加入至(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯在甲醇中的懸浮液(4.0WR)。在攪拌10分鐘後,該白色懸浮液已經溶解而獲得一透明溶液。將三級丁基甲基醚(5.1WR)逐滴加入至該溶液,接著加入如在上述(a)中所描述般所製備的(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}-苯基)醋酸甲酯單氫氯酸種晶,以形成白色沉澱。在攪拌5分鐘後,加入三級丁基甲基醚(11.2WR)及在5℃下攪拌該懸浮液1小時。過濾出沉澱物且以三級丁基甲基醚(3.7WR)清洗,以獲得(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯單氫氯酸,如為固體(產率90%)。
由NMR證實為1:1的鹼對酸之化學計量。
(a)將1.55M在乙醇中的氫溴酸溶液(34微升,53微莫耳)加入至在甲醇(0.3毫升)中之(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯(30毫克,0.053毫莫耳)溶液。在室溫下,將該溶液滴入三級丁基甲基醚(0.9毫升)中。將該透明溶液留在-10℃下1星期,在此時間之後沉澱出結晶物質。過濾及乾燥該結晶物質,(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯單氫溴酸。
藉由下列方法製備進一步量的單氫溴酸鹽:
(b)在室溫下,將化學計量的量之在甲醇中的氫溴酸溶液(水溶液,48%)(0.8WR)加入至在甲醇中之(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯懸浮液(11.9WR)。在攪拌10分鐘後,該白色懸浮液已經溶解而獲得一透明溶液。加入如在上述(a)中所描述般所製備的(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯單氫溴酸種晶。然後,將三級丁基甲基醚(11.3WR)逐滴加入至該溶液以獲得白色沉澱。將該懸浮液冷卻至3℃及攪拌1小時。過濾出沉澱物且以三級丁基甲基醚(3.7WR)清洗,以獲得(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯單氫溴酸,如為固體(產率87.7-89.4%)。
由NMR證實為1:1之鹼對酸的化學計量。
(a)在室溫下,將27mM在1,4-二中之順丁烯二酸溶液(0.5毫升,13.5微莫耳)加入至在1,4-二中的(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯(4毫克,7微莫耳)溶液(0.75毫升),及將該混合物留下靜置過夜。隔天,將該溶液加熱至40℃且搖晃一小時,之後讓其冷卻至室溫。在室溫下蒸發溶劑,以獲得(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯二順丁烯二酸酯,如為最後產物。
藉由下列方法來製備進一步量的二順丁烯二酸鹽:
(b)將順丁烯二酸(0.9克,7.8毫莫耳)加入至在甲醇(20毫升)與異丙基醇(20毫升)中的(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}-苯基)醋酸甲酯(2.2克,3.9毫莫耳)混合物,且將該混合物加熱至50℃直到獲得一透明溶液。讓該溶液冷卻至室溫,然後播種如在上述(a)中所描述般所製備之(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}-苯基)醋酸甲酯二順丁烯二酸酯結晶。在16小時後,過濾出固體及於高真空中在50℃下乾燥72小時。產率2.96克,95%。
1
H NMR(DMSO-d6
);69.88(s,1H),7.32-7.22(m,4H),6.43(s,2H),6.11(s,4H),4.12(t,2H),3.95(s,2H),3.71(brs,6H),3.68(s,2H),3.60(s,3H),2.94-2.75(m,10H),1.99-1.94(m,2H),1.90-1.80(m,2H),1.65-1.58(m,2H),1.41-1.32(m,2H),0.90(t,3H)。
LC-MS m/z 570 APCI+ve
由NMR證實為1:2之鹼對酸的化學計量。
可在根據標準方法所製備的樣品上進行X射線粉末繞射(XRPD)分析(參見例如,吉阿夠伐肉(Giacovazzo)等人編輯,基礎結晶學(Fundamentals of Crystallography),牛津大學出版社(Oxford University Press)(1992);珍金斯及史尼德(Jenkins & Snyder)編輯,X射線粉末繞射儀入門(Introduction to X-ray Powder Diffractometry),約翰威利及宋斯(John Wiley & Sons),紐約(1996);邦(Bunn)編輯,化學結晶學(Chemical Crystallography),克雷倫登出版社(Clarendon Press),倫敦(1948);及克拉格及阿雷山德(Klug & Alexander)編輯,X射線繞射程序(X-ray Diffraction Procedures),約翰威利及宋斯,紐約(1974))。
如在下列描述般獲得於上述實施例1至3中所描述的鹽類(呈無水形式)之X射線粉末繞射圖案:
使用一使用單色CuKα輻射(45千伏及40毫安)的布拉格布蘭塔諾(Bragg-Brentano)拋物面聚焦粉末X射線繞射儀來分析。一級光學物件包括索勒(Soller)隙縫及自動分歧隙縫。在零背景板(其於測量期間旋轉)上製備平坦樣品。二級光學物件包括索勒隙縫、自動抗散射隙縫、接收隙縫及單色器。以正比填充氙的偵測器來偵測繞射訊號。使用具有步繼尺寸0.016°2θ的連續掃描模式,在每分鐘4°2θ的速率下收集在2°≦2θ≦40°間之繞射圖案。電子性貯存原始資料。在原始或經平滑化的繞射圖案上進行鑑定。
對上述提及的測量使用反射模式之帕奈萊帝扣(Panalytical)X’Pert PRO MPD θ-θ繞射儀。熟知此技藝者可設定用於粉末X射線繞射儀的儀器參數,以便可收集可與已存在的資料比較之繞射資料。所獲得的結果顯示在第1圖、第2圖及第3圖中。下列表A、B及C每個列出2θ值(準確性:+/-0.1° 2Φ)、d-間隔及各別顯示在第1、2及3圖的X射線繞射圖案中之波峰的相對強度。
使用標準方法(例如,描述在侯內(Hohne)G.W.H.等人(1996)的示差掃描卡計(史普林爵(Springer),柏林(Berlin))中的那些),使用TA裝置Q1000調節溫度示差掃描卡計(MTDSC),使用±0.50℃的調變,在40秒區間及每分鐘5℃的跳躍速率下調查測試樣品對增加溫度之熱量反應。在氮環境下,將大約1至5毫克的測試樣品放置在含有蓋子(無打摺)的鋁杯中。
已熟知DSC開始及波峰溫度可由於樣品的純度及儀器參數(特別是溫度掃描速率)而變化。熟知此技藝者可使用例行的最佳化/校正來設定用於示差掃描卡計之儀器參數,以便可收集可與顯現於本文的資料比較之資料。
在實施例1(c)中所獲得的無水單氫氯酸鹽之典型樣品的熔化溫度實測為144℃±3℃(開始)。
在實施例2(b)中所獲得的無水單氫溴酸鹽之典型樣品的熔化溫度實測為150℃±3℃(開始)。
在實施例3(b)中所獲得的無水二順丁烯二酸鹽之典型樣品的熔化溫度實測為150℃±3℃(開始)。
使用2”螺旋噴射粉碎機(SJM),在下列三種測試物質上進行顆粒尺寸減低:根據實施例1的單氫氯酸鹽(發明鹽)、根據實施例3的二順丁烯二酸鹽(發明鹽)及游離態基礎化合物,(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯(比較化合物)。
經由文托利(Venturi)進料系統,藉由振動式進料器,將經篩選的測試物質配料進料進入噴射粉碎機室中。藉由強迫通過有角度的噴嘴之壓縮氣體(氮)在噴射粉碎機室中引起顆粒碰撞達成微粒化。不同尺寸的顆粒將發展出不同速度及動量,且當顆粒尺寸減低時,該顆粒將螺旋朝向噴射粉碎機中心及經由排出口引出而進入收集容器中。控制顆粒尺寸的製程參數除了欲微粒化之化合物的固有性質外,尚有進料速率、研磨壓力及文托利壓力,且這些總整理在下列表I中。
由於比較化合物會在排出口中積聚而讓磨粉機變堵塞。研磨/文托利壓力從2/5巴降低至1/4巴,在此方面中無明顯有益的效應。因此,在僅已負載想要的7克之1.7克後即放棄該比較化合物的顆粒尺寸減低。
相較之下,單氫氯酸與二順丁烯二酸鹽容易微粒化,且在加工期間無明顯磨粉機積聚或阻礙。
根據下列一系列的步驟來進行FPF之測量(從當接收時的物質開始):
1.減低所接收的物質之顆粒尺寸(微粒化)。
2.使用雷射繞射裝置測量顆粒尺寸(在尺寸減低後)。
3.手動負載樣品。
4.在串級式衝擊式破碎機中去聚集粉末及收集浮質。
5.使用高壓液相層析法(HPLC)來定量及計算FPF。
測試三種物質:根據實施例1的單氫氯酸鹽(發明鹽)、根據實施例2的單氫溴酸鹽(發明鹽)及游離態基礎化合物,(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯(比較化合物)。
在噴射粉碎機中進行顆粒尺寸減低(微粒化),其中使用加壓氣體來造成物質顆粒高速碰撞以達成顆粒尺寸減低。
使用馬爾文蛇若扣(Malvern Scirocco)裝置,以雷射繞射來進行顆粒尺寸測量。所獲得的結果顯現在下列表1中。
手動稱重1-2毫克的劑量(沒有擦除)至原型吸入器的腔中(參見下列)。對每種測試物質進行二次實驗且在每個實驗中使用二種劑量,因此,在實驗中每種測試物質使用總共四種劑量。在進行實驗前,於氮氣環境中乾燥該樣品過夜。
使用次代衝擊式破碎機(Next Generation Impactor,NGI)來進行細微顆粒的評估。此串級式衝擊式破碎機已在藥典中有描述,諸如USP(一般章節<601>氣霧劑、鼻腔噴霧劑、計量供應劑量的吸入器及乾粉吸入器,裝置5)及歐洲藥典(Eur. Pharmacopoeia)(5.8節2.9.18吸入用製劑:細微顆粒的空氣動力學評估,裝置E),其中關於如何設定、操作及校正該衝擊式破碎機以使用於不同流速已有詳細說明。使用二種NGI衝擊式破碎機,每個實驗使用一種。
使用由一包含垂直構件與水平構件之L形圓柱管道所組成的簡單原型吸入器來測試。該原型吸入器經由USP輸入口安裝至該NGI衝擊式破碎機。該經微粒化的粉末經由垂直管道傳遞進入該原型吸入器的彎曲部(即,該L形管道的彎曲部)中。
使用氣流60升/分鐘2秒可獲得每次劑量1-2毫克的粉末(在吸入口的入口處測量),以輸送該位於彎曲部中的粉末,之後,使用氣霧劑將該粉末移動通過該管道的水平構件、通過螺旋口及進入NGI衝擊式破碎機中。在吸入口中及在八個杯中收集該藥物粉末(參見上述提供的參考資料)。
在具有相對溼度低於2%的分隔(手套)箱中進行藥物粉末的移開及收集。
然後,使用高壓液相層析法來定量吸入口及在八個杯中的藥物粉末含量,如描述在表2中。
使用於FPF計算、如從HPLC分析獲得的關鍵資料顯現在表3中。如在上述藥典參考資料中所定義般計算FPF。
第1圖顯示出(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)-醋酸甲酯單氫氯酸之X射線粉末繞射圖案。
第2圖顯示出(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)-醋酸甲酯單氫溴酸之X射線粉末繞射圖案。
第3圖顯示出(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)-醋酸甲酯二順丁烯二酸鹽之X射線粉末繞射圖案。
Claims (12)
- 一種(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]-甲基}苯基)醋酸甲酯的氫氯酸、氫溴酸或順丁烯二酸鹽。
- 一種(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯單氫氯酸鹽。
- 一種(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯單氫溴酸鹽。
- 一種(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯二順丁烯二酸鹽。
- 如申請專利範圍第1至4項之任一項之鹽,其至少70%係結晶。
- 一種醫藥組成物,其包含如申請專利範圍第1至5項之任一項之鹽與一醫藥上可接受的佐藥、稀釋劑或載劑之組合。
- 如申請專利範圍第6項之醫藥組成物,其呈使用於吸入治療的乾粉調配物形式。
- 一種用來製備如申請專利範圍第6或7項之醫藥組成物的方法,其包括混合(3-{[[3-(6-胺基-2-丁氧基-8-側氧-7,8-二氫-9H-嘌呤-9-基)丙基](3-嗎福啉-4-基丙基)胺基]甲基}苯基)醋酸甲酯的氫氯酸、氫溴酸或順丁烯二酸鹽 或該鹽之溶劑化物與一醫藥上可接受的佐藥、稀釋劑或載劑。
- 一種如申請專利範圍第1至5項之任何一項的鹽或如申請專利範圍第6或7項之醫藥組成物,其使用於治療。
- 一種如申請專利範圍第1至5項之任何一項的鹽或如申請專利範圍第6或7項的醫藥組成物之用途,其使用來製造用於治療氣喘、COPD、過敏性鼻炎、過敏性結膜炎、異位性皮膚炎、癌、B型肝炎、C型肝炎、HIV、HPV或細菌感染的藥劑。
- 一種如申請專利範圍第1至5項之任何一項的鹽或如申請專利範圍第6或7項的醫藥組成物之用途,其使用來製造用於治療可逆性阻塞性氣道疾病的藥劑。
- 一種如申請專利範圍第1至5項之任何一項的鹽或如申請專利範圍第6或7項的醫藥組成物之用途,其使用來製造用於治療氣喘的藥劑。
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