TW201619153A - 唑苯衍生物之結晶 - Google Patents
唑苯衍生物之結晶 Download PDFInfo
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- TW201619153A TW201619153A TW104124555A TW104124555A TW201619153A TW 201619153 A TW201619153 A TW 201619153A TW 104124555 A TW104124555 A TW 104124555A TW 104124555 A TW104124555 A TW 104124555A TW 201619153 A TW201619153 A TW 201619153A
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- crystal
- dimethylpropoxy
- methyl
- acid
- activity
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Abstract
本發明係提供一種有用於作為痛風、高尿酸血症等的治療藥或預防藥的2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸之結晶。
Description
本發明係有關於一種有用於作為痛風、高尿酸血症、腫瘤溶解症候群、尿路結石、高血壓、異常血脂症、糖尿病、動脈硬化症或心臟機能不全等的心血管疾病、糖尿病腎病等的腎疾病、慢性阻塞性肺疾病等的呼吸道疾病、發炎性腸道疾病或自體免疫性疾病等黃嘌呤氧化酶所參與之疾病的治療藥或預防藥的新穎唑苯衍生物之結晶。
黃嘌呤氧化酶係一種在核酸代謝中，催化次黃嘌呤轉化為黃嘌呤，進而轉化為尿酸的酵素。
對於黃嘌呤氧化酶的作用，黃嘌呤氧化酶抑制劑係藉由抑制尿酸合成來降低血中尿酸值。亦即，對高尿酸血症及其所引起的各種疾病的治療係屬有效。另一方面，作為高尿酸血症惡化而沉積尿酸鹽結晶之結果所引起的病症，有稱為「痛風」的痛風關節炎、痛風結節。又，高尿酸血症係作為肥胖、高血壓、異常血脂症及糖尿病等相關之生活型態疾病或代謝症候群的因子備受重視；近年來，根據
疫學調查，逐漸闡明其為腎損害、尿路結石、心血管疾病的危險因子(日本痛風‧核酸代謝學會指南改訂委員會編，「高尿酸血症‧痛風的治療指南 第2版」，Medical Review公司，2010)。而且，黃嘌呤氧化酶抑制劑藉由其活性氧分子產生抑制活性，可望發揮對活性氧分子所參與之疾病之治療的有用性，例如透過血管機能改善作用之對心血管疾病治療的有用性(Circulation.2006；114：2508-2516)。
臨床上，作為高尿酸血症的治療藥，係使用異嘌呤醇、非布索坦，惟異嘌呤醇被報導有史蒂芬強生症候群、毒性表皮壞死鬆解症、肝損害、腎機能損害等的副作用(Nippon Rinsho,2003；61,Suppul.1：197-201)。
作為具有黃嘌呤氧化酶抑制活性的化合物，有人報導例如2-苯基噻唑衍生物(專利文獻1~3)。
另一方面，專利文獻4及專利文獻5中報導一種中央具有苯環的二噻唑羧酸衍生物。又，專利文獻6及專利文獻7中報導一種聯苯噻唑羧酸衍生物。
[專利文獻1]國際公開第92/09279號
[專利文獻2]日本特開2002-105067號
[專利文獻3]國際公開第96/31211號
[專利文獻4]國際公開第2011/139886號
[專利文獻5]國際公開第2011/101867號
[專利文獻6]國際公開第2010/018458號
[專利文獻7]國際公開第2010/128163號
本發明之目的在於提供一種有用於作為痛風、高尿酸血症、腫瘤溶解症候群、尿路結石、高血壓、異常血脂症、糖尿病、動脈硬化症或心臟機能不全等的心血管疾病、糖尿病腎病等的腎疾病、慢性阻塞性肺疾病等的呼吸道疾病、發炎性腸道疾病或自體免疫性疾病等黃嘌呤氧化酶所參與之疾病的治療藥或預防藥的新穎化合物之結晶。
本案發明人等依上述目的而致力進行研究的結果發現，2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸(以下亦有表示為化合物(I))可結晶化、及存在有至少1種的結晶多形體。
亦即，本發明係：[1]一種2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸之結晶；
[2]如[1]之結晶，其係A晶；[3]如[2]之結晶，其中在粉末X射線繞射光譜中，於繞射角2θ=7.2°、11.3°、15.9°、17.9°、20.8°、22.3°、23.1°、23.8°、24.3°、及28.6°處具有特徵峰；[4]如[2]之結晶，其中粉末X射線繞射光譜係具有第1圖所示之圖形；[5]如[2]之結晶，其中熱重量測定‧示差熱分析中的放熱峰為232℃；[6]一種醫藥組成物，其係包含如[1]~[5]中任一項之結晶、及製藥學上可容許的載體；[7]一種黃嘌呤氧化酶抑制劑，其係含有如[1]~[5]中任一項之結晶作為有效成分；及[8]一種選自由痛風、高尿酸血症、腫瘤溶解症候群、尿路結石、高血壓、異常血脂症、糖尿病、心血管疾病、腎疾病、呼吸道疾病、發炎性腸道疾病及自體免疫性疾病所成之群中的一種以上之疾病的治療藥或預防藥，其係含有如[1]~[5]中任一項之結晶作為有效成分。
根據本發明，可提供一種有用於作為痛風、高尿酸血症、腫瘤溶解症候群、尿路結石、高血壓、異常血脂症、糖尿病、動脈硬化症或心臟機能不全等的心血管疾病、糖尿病腎病等的腎疾病、慢性阻塞性肺疾病等的呼吸道疾病、發炎性腸道疾病或自體免疫性疾病等黃嘌呤氧
化酶所參與之疾病的治療藥或預防藥的唑苯衍生物之結晶。該結晶可作為醫藥品製造用原體使用。
第1圖為A晶的粉末X射線繞射光譜。
「黃嘌呤氧化酶」一般而言係以「催化次黃嘌呤至黃嘌呤，進而至尿酸之氧化反應的酵素」之廣義、及「作為催化該反應的酵素之一的氧化酶型黃嘌呤氧化還原酶」之狹義使用，於本發明中，所稱「黃嘌呤氧化酶」，若非合先敘明，則意指催化次黃嘌呤至黃嘌呤，進而至尿酸之氧化反應的酵素之總稱。參與該反應的黃嘌呤氧化還原酶存在有氧化酶型與脫氫酶型此兩型，惟任一型均包含於本發明之黃嘌呤氧化酶中。就「黃嘌呤氧化酶抑制活性」、「黃嘌昤氧化酶抑制劑」等而言，若非合先敘明，則「黃嘌呤氧化酶」亦具有與上述定義相同之意義。
本發明之結晶係藉由粉末X射線繞射光譜及/或熱重量測定‧示差熱分析(TG/DTA)等來表徵。本發明之結晶的粉末X射線繞射(XRD)光譜顯示出獨特的圖形，具有特殊的繞射角2θ值。又，本發明之結晶，在熱重量測定‧示差熱分析(TG/DTA)中，亦分別顯示出獨特的熱行為。
本發明之A晶，在粉末X射線繞射光譜中，
於繞射角2θ=7.2°、11.3°、15.9°、17.9°、20.8°、22.3°、23.1°、23.8°、24.3°、及28.6°處具有特徵峰。又，本發明之A晶，在粉末X射線繞射光譜中具有第1圖所示之圖形。在熱重量測定‧示差熱分析(TG/DTA)下，於232℃具有放熱峰。A晶為無水物晶體。
此處所稱「特徵峰」，係指在各結晶多形的粉末X射線繞射光譜中主要可辨識的峰及固有的峰之意。本發明之以繞射角所判定的結晶，亦包含辨識出上述之特徵峰以外的峰者。
由於粉末X射線繞射光譜中的繞射角2θ的位置及相對強度可能會隨著測定條件而些微變動，因此，當2θ僅有些微差異時，仍應適當參照光譜全體的圖形來認定結晶形的同一性，且所述誤差範圍之結晶亦包含於本發明內。就2θ的誤差而言，係認定為例如±0.5°、±0.2°。亦即，以上述繞射角所判定的結晶亦包括誤差介於±0.5°至±0.2°的範圍而與各繞射角位置相符者。
熱重量測定‧示差熱分析(TG/DTA)中，「放熱峰」及「吸熱峰」為峰的起始點的溫度，係指藉由外插所求得的放熱及吸熱起始溫度。TG/DTA中的吸熱及放熱峰亦可能隨著測定條件而些微變動。就誤差而言，係認定為例如±5℃、±2℃的範圍。亦即，以上述峰所判定的結晶亦包括誤差介於±5℃至±2℃的範圍而與各峰位置相符者。
更且，就粉末X射線繞射光譜、TG/DTA任
一者而言，結晶的標準品，例如依本案實施例記載之方法所得之各結晶的實測值、與本案記載之數值的差均可容許作為測定誤差。亦即，在依據所述方法所算出的誤差範圍內，繞射角或吸熱及放熱峰相符的結晶亦包含於本發明之結晶。
2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸之A晶能以例如以下的方法合成。
(式中，Y1及Y2表示離去基。)
作為Y1及Y2所示之離去基可舉出鹵素原子、甲磺醯氧基、對甲苯磺醯氧基、三氟甲磺醯氧基等。本反應係藉由在鹼的存在下使新戊醇與化合物(A-1)中的離去基Y2反應來合成化合物(A-2)的方法。作為所使用的鹼，可使用氫化鈉、氫氧化鈉、氫氧化鉀、氫氧化鋰、碳酸鈉、碳酸鉀、碳酸銫等的無機鹽、乙醇鈉、甲醇鈉、三級丁醇鉀等的金屬烷氧化物、三乙胺、吡啶、4-胺
基吡啶、N-乙基-N,N-二異丙基胺(DIPEA)、1,8-二氮雜雙環[5.4.0]-7-十一烯(DBU)等的有機胺。本反應係藉由在0℃~140℃下，在對反應呈惰性的溶媒中，使等量或者少許過量的鹼、及等量或者過量的新戊醇與化合物(A-1)反應後，添加化合物(A-1)，通常使其反應0.5~16小時來進行。本反應較佳在氮氣等的惰性氣體環境下進行。於此，作為溶媒不特別限定，可舉出例如苯、甲苯、二甲苯等的芳香族烴類、二乙醚、四氫呋喃(THF)、1,4-二噁烷、1,2-二甲氧基乙烷、1,2-二乙氧基乙烷等的醚類、二氯甲烷、1,2-二氯乙烷、氯仿等的鹵化烴類、N,N-二甲基甲醯胺(DMF)、N-甲基吡咯啶酮、二甲基亞碸(DMSO)、水或此等的混合溶媒等。
(式中，R表示碳數1~6之烷基。)
本合成法係藉由使化合物(A-2)與(A-3)偶合，來合成化合物(A-4)的方法。作為Y1所示之離去基可舉出鹵素原子、甲磺醯氧基、對甲苯磺醯氧基、三氟
甲磺醯氧基等。本反應係藉由使化合物(A-2)與(A-3)，以等量、或者過量地使用其中一者，在對反應呈惰性的溶媒中、鹼及過渡金屬觸媒存在下，視情況添加配基、羧酸及銅(I價或II價)鹽，在室溫~加熱回流下，通常反應0.5小時~2日來進行。本反應較佳在氮氣等的惰性氣體環境下進行。於此，作為溶媒不特別限定，可舉出例如苯、甲苯、二甲苯等的芳香族烴類、二乙醚、四氫呋喃(THF)、1,4-二噁烷、1,2-二甲氧基乙烷、1,2-二乙氧基乙烷等的醚類、二氯甲烷、1,2-二氯乙烷、氯仿等的鹵化烴類、甲醇、乙醇、2-丙醇、丁醇等的醇類、N,N-二甲基甲醯胺(DMF)、N-甲基吡咯啶酮、二甲基亞碸(DMSO)、水或此等的混合溶媒等。作為鹼，可舉出氫化鋰、氫化鈉、氫化鉀、氫氧化鈉、氫氧化鉀、碳酸鈉、碳酸鉀、碳酸銫、氟化鉀、氟化銫、磷酸三鉀、乙酸鈉、乙酸鉀等、碳數1~6之烷氧化物的金屬鹽(鋰鹽、鈉鹽、鉀鹽、鎂鹽)、碳數1~6之烷基陰離子的金屬鹽(鋰鹽、鈉鹽、鉀鹽、鎂鹽)、四(碳數1~4之烷基)銨鹽(氟化鹽、氯化鹽、溴化鹽)、二異丙基乙基胺、三丁基胺、N-甲基嗎啉、二氮雜雙環十一烯、二氮雜雙環辛烷、或咪唑等。作為過渡金屬觸媒，可舉出銅、鈀、鈷、鐵、銠、釕、及銥等。作為配基，可舉出三(三級丁基)膦、三(環己基)膦、三級丁基二環己基膦、二(三級丁基)環己基膦、或二(三級丁基)甲基膦等。作為銅(I價或II價)鹽，可舉出氯化銅(I)、溴化銅(I)、碘化
銅(I)、乙酸銅(I)、氟化銅(II)、氯化銅(II)、溴化銅(II)、碘化銅(II)、乙酸銅(II)及此等的水合物、以及此等的混合物等。作為羧酸，可舉出甲酸、乙酸、丙酸、正丁酸、異丁酸、戊酸、異戊酸、特戊酸、及三氟乙酸等。
(式中，R表示碳數1~6之烷基。)
本合成法係藉由將化合物(A-4)的硝基還原，來合成化合物(A-5)的方法。本反應係藉由使化合物(A-4)，在對反應呈惰性的溶媒中、過渡金屬觸媒存在下、氫氣環境下、室溫~加熱回流下通常反應0.5小時~2日來進行。於此，作為溶媒不特別限定，可舉出例如苯、甲苯、二甲苯等的芳香族烴類、二乙醚、四氫呋喃(THF)、1,4-二噁烷、1,2-二甲氧基乙烷、1,2-二乙氧基乙烷等的醚類、二氯甲烷、1,2-二氯乙烷、氯仿等的鹵化烴類、甲醇、乙醇、2-丙醇、丁醇等的醇類、N,N-二甲基甲醯胺(DMF)、N-甲基吡咯啶酮、二甲基亞碸
(DMSO)、乙酸乙酯或此等的混合溶媒等。作為過渡金屬觸媒，較佳為鈀-碳、氫氧化鈀、鈀黑、鉑-碳、雷氏鎳等。
(式中，R及R1獨立地表示碳數1~6之烷基。)
本合成法係使化合物(A-5)與原甲酸酯與疊氮化合物反應來合成四唑環的方法。本反應係使化合物(A-5)、原甲酸酯與疊氮化合物以等量、或者過量地使用任一者，在對反應呈惰性的溶媒中、酸存在下、室溫~加熱回流下通常反應0.5小時~2日來進行。本反應較佳在氮氣等的惰性氣體環境下進行。作為原甲酸酯，可舉出原甲酸三甲酯及原甲酸三乙酯等。又，作為疊氮化合物，可舉出疊氮化鈉、三甲基矽烷基疊氮等。作為所使用的酸可舉出甲酸、乙酸等的有機酸、鹽酸、硫酸等的無機酸、
三氟甲磺酸銦、三氟甲磺酸鐿、三氟甲磺酸鋅、三氯銦等的路易士酸。作為此等反應所使用的溶媒不特別限定，可舉出例如苯、甲苯、二氯甲烷、二氯乙烷、氯仿、四氯化碳、二乙醚、四氫呋喃(THF)、1,4-二噁烷、1,2-二甲氧基乙烷、1,2-二乙氧基乙烷、N,N-二甲基甲醯胺(DMF)、N-甲基吡咯啶酮、二甲基亞碸(DMSO)或此等的混合溶媒等，亦可將乙酸等的酸作為溶媒使用。
(式中，R表示碳數1~6之烷基。)
化合物(I)之A晶可根據包含將化合物(A-7)懸浮於溶媒，並添加鹼的水溶液進行水解的步驟、及將反應物中和的步驟的方法來製造。又，在前述方法中，可包含對中和物添加水的步驟，其次將反應溶液攪拌的步驟。作為供懸浮化合物(A-7)的溶媒，可舉出例如苯、甲苯、二甲苯等的芳香族烴類、二乙醚、四氫呋喃
(THF)、1,4-二噁烷、1,2-二甲氧基乙烷、1,2-二乙氧基乙烷等的醚類、二氯甲烷、1,2-二氯乙烷、氯仿等的鹵化烴類、甲醇、乙醇、2-丙醇、丁醇等的醇類、N,N-二甲基甲醯胺(DMF)、N-甲基吡咯啶酮、二甲基亞碸(DMSO)、乙酸乙酯或此等的混合溶媒等。較佳為醚類或者醇類、水或此等的混合溶媒。
化合物(A-7)中，R較佳為碳數1~6之烷基，更佳為乙基。於此，烷基係指直鏈或支鏈之脂肪族飽和烴基。作為碳數1~6之烷基，可舉出甲基、乙基、丙基、異丙基、丁基、異丁基、三級丁基、戊基、異戊基、己基等作為具體實例。
由化合物(A-7)向化合物(I)的水解反應，係藉由使化合物(A-7)懸浮於上述溶媒(例如化合物(A-7)的15倍量)後，使等量、或者少許過量的鹼與化合物(A-7)反應來進行。作為較佳的鹼，可舉出氫氧化鈉、氫氧化鉀、氫氧化鋰。本反應係於0℃至100℃進行，較佳為20-30℃。水解反應後，藉由使所使用的鹼與等量、或者少許過量的酸反應來進行中和。作為較佳的酸，可舉出鹽酸。中和反應係於0℃至100℃進行，較佳為0-30℃。
其次，對經過中和的反應物添加水(例如化合物(A-7)的5倍量)，攪拌1小時後，濾取析出物，加以乾燥而得到結晶。溶媒量、水的添加量、攪拌條件、分離過濾之間的時間不特別限定，但由於此等條件會影響
結晶的產率、化學純度、粒徑、粒度分布等，因此較佳視目的而定加以組合、設定。濾取可採用一般的方法，例如自然過濾、加壓過濾、減壓過濾、或離心分離。乾燥可採用一般的方法，例如自然乾燥、減壓乾燥、加熱乾燥、減壓加熱乾燥。上述反應的中間體化合物，在合成過程中，若有需要時，可藉由再結晶、再沉澱或各種層析法等的常見方法加以精製。
本發明之結晶可藉由獨特的粉末X射線繞射光譜或熱重量測定‧示差熱分析(TG/DTA)來識別，惟，若有其他的結晶形存在時，無須論及其混入率。單獨獲得特定之結晶時，若有至少無法藉由此等測定方法檢測出之程度的混入則可被容許。又，作為醫藥，將特定之結晶作為原體使用時，其意旨亦不在於不容許含有其他結晶。
本發明之結晶可作為醫藥的有效成分使用。又，若有其他的結晶形存在時，非僅可使用單獨之結晶，亦能以2種以上的混合物使用。
於本發明中，藉由獲得2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸之結晶，相較於非呈結晶者，製造時的處理或再現性、穩定性、且保存穩定性等更為有利。
可使用本發明之結晶、及醫藥上可容許的載體調成醫藥組成物。
含有本發明之結晶的製劑，通常使用製劑化所使用的
添加劑調製而成。作為此等添加劑，若為固態製劑時，可舉出乳糖、白糖、葡萄糖、玉米澱粉、馬鈴薯澱粉、結晶纖維素、輕質無水矽酸、合成矽酸鋁、鎂鋁矽酸鹽、及磷酸氫鈣等的賦形劑；結晶纖維素、羧甲基纖維素、羥丙基纖維素、羧甲基纖維素鈉、及聚乙烯吡咯啶酮等的黏合劑；澱粉、羧甲基纖維素鈉、羧甲基纖維素鈣、交聯羧甲基纖維素鈉、及羧甲基澱粉鈉等的崩解劑；滑石、及硬脂酸類等的潤滑劑；羥甲基丙基纖維素、羥丙基甲基纖維素鄰苯二甲酸酯、及乙基纖維素等的塗佈劑；著色劑；若為半固態製劑時，可舉出白色凡士林等的基劑；若為液狀製劑時，可舉出乙醇等的溶劑、乙醇等的溶解助劑、對羥基苯甲酸酯類等的保存劑、葡萄糖等的等滲壓劑、檸檬酸類等的緩衝劑、L-抗壞血酸等的抗氧化劑、EDTA等的螯合劑、及聚山梨酸酯80等的懸浮劑‧乳化劑等。
本發明之結晶係固態製劑、半固態製劑、及液狀製劑等的任一種劑形、口服劑及非口服劑(注射劑、經皮劑、洗眼劑、塞劑、滴鼻劑、及吸入劑等)的任一種適用製劑，均可加以使用。
含有本發明之結晶作為有效成分的醫藥組成物可作為黃嘌呤氧化酶抑制劑、或者痛風、高尿酸血症、腫瘤溶解症候群、尿路結石、高血壓、異常血脂症、糖尿病、動脈硬化症或心臟機能不全等的心血管疾病、糖尿病腎病等的腎疾病、慢性阻塞性肺疾病等的呼吸道疾病、發炎性腸道疾病或自體免疫性疾病等、黃嘌昤氧化酶所參與
之疾病的治療藥或預防藥使用。於此，「預防」指的是，針對尚未罹患或發病的個體，防範罹患或發病於未然；「治療」指的是，針對既已罹患或發病的個體，治癒、抑制或改善疾病或症狀。
本發明之結晶的粉末X線繞射係依以下條件測定。
裝置：Bruker AXS製D8 DISCOVER With GADDS CS
射線源：Cu‧Kα，波長：1.541838(10-10m)、40kv-40mA、入射側平板石墨單色器、準直儀 300μm、二維PSPC檢測器、掃描3~40°
本發明之結晶的熱重量測定.示差熱分析(TG/DTA)係依以下條件測定。
裝置：Rigaku製TG8120
升溫速度：每分鐘10℃、氣體環境：氮氣、試樣秤盤：鋁、參考物：氧化鋁、採樣：1.0秒、測定溫度範圍：25~300℃
測定1H NMR光譜(400MHz、DMSO-d6或CDCl3)後，示出其化學位移(δ：ppm)及偶合常數(J：Hz)。以下之縮寫係分別表示下者：裝置：JEOL製JMTC-400/54/SS s=singlet、d=doublet、t=triplet、q=quartet、brs=broad
sing1et、m=multiplet
(1)使1.06g新戊醇懸浮於40.0mL甲苯中，在氮氣環境下使其冷卻至0℃後，添加1.35g三級丁醇鉀，於0℃下攪拌30分鐘。其次在0℃下添加2.20g的4-溴-1-氟-2-硝基苯後，予以升溫至室溫，在室溫下攪拌2小時。對反應混合液添加水，以乙酸乙酯進行萃取。以食鹽水清洗有機層後，進行乾燥、減壓濃縮，而得到3.12g的4-溴-1-(2,2-二甲基丙氧基)-2-硝基苯。
(2)對4.18g的4-溴-1-(2,2-二甲基丙氧基)-2-硝基苯添加3.04g碳酸氫化鉀、63mg氯化鈀(II)、297mg溴化銅(I)，使其懸浮於45mL甲苯中。其後加入2.97g的4-甲基-1,3-噻唑-5-羧酸乙酯、133μL異丁酸及333μL二-三級丁基環己基膦，在氮氣環境下、120℃下加熱14小時。將反應混合液進行矽藻土過濾而去除不溶物，對濾液添加水，以乙酸乙酯進行萃取。以食鹽水清洗有機層後，進行乾燥、減壓濃縮後根據常見方法進行精製，得到5.13g的2-[4-(2,2-二甲基丙氧基)-3-硝基苯基]-4-甲基-1,3-噻唑-5-羧酸乙酯。
1H-NMR(400Mz,CDCl3)δ：1.08(9H,s),1.39(3H,t,J=6.8Hz),2.77(3H,s),3.79(2H,s),4.36
(2H,q,J=6.8Hz),7.12(1H,d,J=8.8Hz),8.10(1H,dd,J=2.0,8.8Hz),8.45(1H,d,J=2.0Hz)
(3)使5.13g的2-[4-(2,2-二甲基丙氧基)-3-硝基苯基]-4-甲基-1,3-噻唑-5-羧酸乙酯懸浮於50mL乙醇中，添加500mg鈀/碳(10%wt)後，在氫氣環境下、50℃下攪拌20小時。藉由將反應混合液過濾，並對濾液進行減壓濃縮，而得到2-[3-胺基-4-(2,2-二甲基丙氧基)苯基]-4-甲基-1,3-噻唑-5-羧酸乙酯4.66g。
(4)使2.58g的2-[3-胺基-4-(2,2-二甲基丙氧基)苯基]-4-甲基-1,3-噻唑-5-羧酸乙酯懸浮於30mL乙酸後，加入962mg疊氮化鈉、2.19g原甲酸三乙酯，在氮氣環境下、70℃下加熱2小時。使其冷卻至室溫後對反應混合液添加20mL水，根據常見方法進行精製，而得到2.78g的2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸乙酯。
1H-NMR(400Mz,CDCl3)δ：1.00(9H,s),1.39(3H,t,J=6.8Hz),2.78(3H,s),3.82(2H,s),4.36(2H,q,J=6.8Hz),7.18(1H,d,J=8.8Hz),8.08(1H,dd,J=2.4,8.8Hz),8.42(1H,d,J=2.4Hz),9.19(1H,s)
將2.58g的2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸乙酯溶解於四氫呋喃/甲醇=1/1的混合溶液30.0L中，添加2M氫氧化鈉水溶液6.50mL，於20-30℃攪拌3小時。一面於20-30℃攪拌一面對反應混合液緩緩添加2M鹽酸6.50mL，進而緩緩添加水17.0mL。將反應溶液於20-30℃攪拌1小時後，濾取結晶。以甲醇/水=1/1的混合溶媒7.0mL及水7.0mL清洗所得之結晶。對結晶在50℃下進行減壓乾燥，而得到2.25g的2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸之結晶。將所得之結晶的XRD示於第1圖。於繞射角2θ=7.2°、11.3°、15.9°、17.9°、20.8°、22.3°、23.1°、23.8°、24.3°、及28.6°處觀測到譜峰。又，熱重量測定‧示差熱分析(TG/DTA)中的放熱峰為232℃。
1H-NMR(400Mz,DMSO-d6)δ：0.83(9H,s),2.66(3H,s),3.83(2H,s),7.47(1H,d,J=8.8Hz),8.18(1H,dd,J=2.4,8.8Hz),8.27(1H,d,J=2.0Hz),9.78(1H,s),13.40(1H,s)
將307mg的2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸乙酯溶
解於四氫呋喃/甲醇=1/1的混合溶液8.0mL，添加2M氫氧化鈉水溶液1.0mL，在室溫下攪拌3小時。對反應混合液添加2M鹽酸1.0mL並加以攪拌後，添加6.0mL的水，根據常見方法進行精製，而得到244mg的2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸。
1H-NMR(DMSO-d6)δ：0.83(9H,s),2.66(3H,s),3.83(2H,s),7.47(1H,d,J=8.8Hz),8.18(1H,dd,J=2.4,8.8Hz),8.27(1H,d,J=2.0Hz),9.78(1H,s),13.40(1H,s)
將2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸溶解於DMSO(SIGMA公司製)使其成濃度20mM後，調製成使用時的目標濃度來使用。
將文獻記載之方法(Method Enzymatic Analysis,1,521-522,1974)的一部分改變來實施2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸的黃嘌呤氧化酶抑制活性評定。本評定係依據氧
化酶型之黃嘌呤氧化還原酶活性的測定來進行。亦即，將事先以20mM氫氧化鈉溶液調製成10mM的黃嘌呤(SIGMA公司製)溶液使用100mM磷酸緩衝液調製成30μM，對96孔平板按75μL/孔逐一添加。將以DMSO稀釋成最終濃度的100倍的試驗化合物按1.5μL/孔逐一添加，混合後以微盤分析儀SPECTRA max Plus384(MOLECULAR DEVICES公司製)測定290nm的吸光度。接著將氧化酶型黃嘌呤氧化還原酶(取自酪漿；Calbiochem公司製)使用100mM磷酸緩衝液調製成30.6mU/mL，按73.5μL/孔逐一添加。混合後迅速測定290nm下的吸光度變化達5分鐘。設替代試驗化合物溶液而添加DMSO時的酵素活性為100%，計算試驗化合物的抑制率，對用量響應曲線進行擬合而算出相對於氧化酶型黃嘌呤氧化還原酶的50%抑制濃度。
2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸係顯示出1.0nM≦IC50<5.0nM的黃嘌呤氧化酶抑制活性。
茲確認2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸的降血中尿酸作用。對8~9週大的Sprague-Dawley系公大鼠(日本Charles River股份有限公司)使用餵食管強制投予懸浮於
0.5%甲基纖維素液的試驗化合物。於投予後2小時由尾靜脈抽血後，分離出血漿。血中尿酸值係使用尿酸測定套組(L type Wako UA‧F：和光純藥工業)，以尿酸酶法，利用吸光度計來測定，依下式求出尿酸下降率：尿酸下降率(%)=(對照動物的尿酸值-投予試驗化合物之動物的尿酸值)×100/對照動物的尿酸值
2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸，在10mg/kg、1mg/kg的任一種用量下均顯示尿酸下降率50%以上。
由此結果顯示，2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸具有強力的降血中尿酸效果。
以與參考例4同樣的方法對Sprague-Dawley系公大鼠投予2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸。於投予後24小時由尾靜脈抽血後，分離出血漿。血中尿酸值係使用尿酸測定套組(L type Wako UA‧F：和光純藥工業)，以尿酸酶法，利用吸光度計來測定，依下式求出尿酸下降率：尿酸下降率(%)=(對照動物的尿酸值-投予試驗化合物之動物的尿酸值)×100/對照動物的尿酸值
2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-
基)苯基]-4-甲基-1,3-噻唑-5-羧酸，於投予後24小時，以10mg/kg的用量顯示尿酸下降率50%以上，以3mg/kg的用量顯示尿酸下降率40%以上。
由此結果顯示，2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸具有長期的持續性降血中尿酸效果。
取2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸，確認米格魯犬的降血中尿酸作用。對米格魯犬(KITAYAMA LABES)強制口服投予懸浮於0.5%甲基纖維素液的試驗化合物。於投予後8小時由橈側皮靜脈抽血後分離出血漿。血中尿酸值係採用LC-MS/MS法來測定，依下式求出尿酸下降率：
尿酸下降率(%)=(對照動物的尿酸值-投予試驗化合物之動物的尿酸值)×100/對照動物的尿酸值
2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸，以10mg/kg的用量，於投予後8小時顯示尿酸下降率80%以上。
由此結果顯示，本發明之化合物對犬具有強力的降血中尿酸效果。
就本發明之「黃嘌呤氧化酶」，限於本實施例，為了區別氧化酶型之黃嘌呤氧化還原酶所參與的氧化反應觸媒活性、及氧化酶型與脫氫酶型兩者之黃嘌呤氧化還原酶所參與的氧化反應觸媒活性，而將前者稱為「XO活性」、將後者稱為「XOR活性」。對於「組織XO活性」、「血漿XO活性」、「組織XO抑制活性」、「組織XOR抑制活性」等，「XO活性」及「XOR活性」亦具有同樣意義。「組織」係包括肝臟、腎臟、脂肪組織、腸、血管。此外，茲認為本試驗中的同一試樣的XOR活性抑制率與XO活性抑制率係為同程度之數值者。
取2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸，確認組織XO活性、組織XOR活性及血漿XO活性。對7~9週大的Sprague-Dawley系公大鼠(日本Charles River股份有限公司)使用餵食管強制投予懸浮於0.5%甲基纖維素液的試驗化合物。於投予後24小時或27小時後由腹大動脈進行抽血及進行組織的採樣。得到的血液經過離心分離，採取血漿。
組織XO活性、組織XOR活性及血漿XO活性係利用pterin被各型之黃嘌呤氧化還原酶氧化而生成屬螢光物質之isoxanthopterin的反應來測定。將組織以含有1m MEDTA及蛋白酶抑制劑之pH7.4的磷酸鉀溶液均質化，使各組織濃度成為肝臟：25mg/mL、腎臟：25
mg/mL、脂肪：5mg/mL、腸：5mg/mL、血管：30mg/mL，以4℃、12000rpm進行離心15分鐘。XO活性的測定時係將組織均漿的上清液或血漿與含有50μM pterin的溶液混合，使其在37℃下反應。XOR活性的測定時係將組織均漿的上清液與含有50μM pterin及50μM Methylene Blue的溶液混合，使其在37℃下反應。作為控制組係使含有氧化酶型黃嘌呤氧化還原酶(取自酪漿；Calbiochem公司製)與50μM pterin的溶液以同樣的方法反應。測定生成之isoxanthopterin的螢光強度，以控制組的酵素活性及蛋白質濃度校正而作為XO或XOR活性算出。
XO抑制活性及XOR抑制活性係依下式求得。
XO抑制活性(%)=(對照動物的XO活性或XOR活性-投予試驗化合物之動物的XO活性或XOR活性)×100/對照動物的XO活性或XOR活性
將投予約27小時後的組織及血漿XO抑制活性示於下表。
2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸，在10mg/kg的用量下，將投予後27小時之肝臟的XO活性與對照動物相比抑制了80%以上，將投予後27小時之腎臟的XO活性與對照動物相比抑制了70%以上，將投予後27小時之血漿的XO活性與對照動物相比抑制了40%以上。
2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸，在1mg/kg的用量下，將投予後27小時之肝臟的XO活性與對照動物相比抑制了80%以上，將投予後27小時之腎臟的XO活性與對照動物相比抑制了60%以上，將投予後27小時之血漿的XO活性與對照動物相比抑制了25%以上。
又，將投予24小時後的組織XOR抑制活性示於下表。
2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸在10mg/kg的用量下，將投予後24小時之肝臟的XOR活性與對照動物相
比抑制了80%以上，將投予後24小時之血管的XOR活性與對照動物相比抑制了50%以上。
又，在1mg/kg的用量下，將投予後24小時之肝臟的XOR活性與對照動物相比抑制了80%以上，將投予後24小時的血管XOR活性與對照動物相比抑制了30%以上。
由以上結果顯示，本發明之化合物對於各組織具有長期的持續性XO活性、XOR活性抑制作用。
本發明之2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸之結晶可作為醫藥品使用。再者，該結晶可作為醫藥品製造用原體使用。
Claims (8)
- 一種2-[4-(2,2-二甲基丙氧基)-3-(1H-1,2,3,4-四唑-1-基)苯基]-4-甲基-1,3-噻唑-5-羧酸之結晶。
- 如請求項1之結晶，其係A晶。
- 如請求項2之結晶，其中在粉末X射線繞射光譜中，於繞射角2θ=7.2°、11.3°、15.9°、17.9°、20.8°、22.3°、23.1°、23.8°、24.3°、及28.6°處具有特徵峰。
- 如請求項2之結晶，其中粉末X射線繞射光譜係具有第1圖所示之圖形。
- 如請求項2之結晶，其中熱重量測定‧示差熱分析中的放熱峰為232℃。
- 一種醫藥組成物，其係包含如請求項1~5中任一項之結晶、及製藥學上可容許的載體。
- 一種黃嘌呤氧化酶抑制劑，其係含有如請求項1~5中任一項之結晶作為有效成分。
- 一種選自由痛風、高尿酸血症、腫瘤溶解症候群、尿路結石、高血壓、異常血脂症、糖尿病、心血管疾病、腎疾病、呼吸道疾病、發炎性腸道疾病及自體免疫性疾病所成之群中的一種以上之疾病的治療藥或預防藥，其係含有如請求項1~5中任一項之結晶作為有效成分。
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| CN101282936B (zh) * | 2005-10-07 | 2012-05-16 | 橘生药品工业株式会社 | 氮化杂环化合物及包含其的药物组合物 |
| WO2008126770A1 (ja) * | 2007-04-05 | 2008-10-23 | Astellas Pharma Inc. | トリアリールカルボン酸誘導体の製造方法 |
| CN101679244B (zh) * | 2007-04-11 | 2014-01-01 | 橘生药品工业株式会社 | 5元杂环衍生物及其医药用途 |
| WO2010018458A2 (en) | 2008-08-12 | 2010-02-18 | Crystalgenomics, Inc. | Phenol derivatives and methods of use thereof |
| WO2010128163A2 (en) | 2009-05-08 | 2010-11-11 | Pike Pharma Gmbh | Small molecule inhibitors of influenza a and b virus and respiratory syncytial virus replication |
| US20130190366A1 (en) | 2010-02-19 | 2013-07-25 | Cadila Healthcare Limited | Substantially pure salts of febuxostat and processes for preparation thereof |
| US8969582B2 (en) | 2010-04-29 | 2015-03-03 | Dr. Reddy's Laboratories Ltd. | Preparation of febuxostat |
| TWI606048B (zh) * | 2013-01-31 | 2017-11-21 | 帝人製藥股份有限公司 | 唑苯衍生物 |
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