TWI508965B - 有機化合物的鹽形式 - Google Patents
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Description
本發明係關於一種黃嘌呤素衍生物之特定鹽形式,即醫藥活性化合物1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素之特定鹽形式,包括其非晶體及晶體形式(包括溶劑化物及水合物形式),及其製造方法,以及其於醫藥組合物中之用途。亦涵蓋藉由如本文定義之此等化合物,視情況與一或多種其他活性物質組合來治療及/或預防與酵素二肽基肽酶IV(DPP-4)有關之疾病,如(例如)代謝疾病,尤其糖尿病(尤其2型糖尿病)及與其相關之疾病之方法。
一般而言,指定物質之鹽、溶劑化物、水合物、多晶型物、結晶及非晶體形式通常係於晶體外貌及/或結晶固態特性上不同,因此其等可具有不同物理及醫藥特性,如(例如)形狀、密度、硬度、可變形性、穩定性、純度、吸濕性、流動性、緊密性、溶解度及/或溶解特性等,該等特性會受(例如)其等可製造性、可加工性、藥物動力學概況(例如生物利用率)、藥物穩定性(貯藏期限)、可投藥性及/或可調配性等,如,例如:其等作為固體、半固體或液體醫藥劑型(例如,如錠劑、膠囊、分散液、溶液、栓劑或其他醫藥劑型(包括例如,持續釋放調配物或包含其他活性成份之組合製備物))的影響。
於先前技藝中已知作為DPP-4抑制劑之許多種黃嘌呤素衍生物。
亦已知作為CD26之酵素DPP-4(二肽基肽酶IV)係一種已知會導致許多種N末端上具有脯胺酸或丙胺酸殘基之蛋白質之N-末端裂解產生二肽之絲胺酸蛋白酶。由於此特性,故DPP-4抑制劑會干擾包括肽GLP-1之生物活性肽血漿濃度,被認為可用於治療糖尿病之可靠藥物。
例如,DPP-4抑制劑及其等用途,尤其其等於代謝性(尤其糖尿性)疾病之用途係描述於WO 2002/068420、WO 2004/018467、WO 2004/018468、WO 2004/018469、WO 2004/041820、WO 2004/046148、WO 2005/051950、WO 2005/082906、WO 2005/063750、WO 2005/085246、WO 2006/027204、WO 2006/029769或WO 2007/014886;或於WO 2004/050658、WO 2004/111051、WO 2005/058901或WO 2005/097798中;或於WO 2006/068163、WO 2007/071738或WO 2008/017670中;或於WO 2007/128721或WO 2007/128761中。
化合物1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素係一種具有用於治療2型糖尿病、肥胖症及相關疾病之治療價值之經口活性DPP-4抑制劑。
現已發現1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素之某些鹽具有出乎意料及可用之特性。
因此,本發明係關於一種化合物,其係1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素之酸加成鹽,尤其醫藥可接受無機或有機酸加成鹽。可特別提及與常用於藥物學中之無機或有機酸(如(例如)以下所述之彼等無機或有機酸中之任一者)形成之醫藥可接受鹽。該等鹽包括水不可溶及尤其係水可溶鹽。
常用於形成醫藥可接受酸加成鹽之無機酸包括(以舉例但非限制方式)氫氯酸、氫溴酸、磷酸、硝酸、硫酸等。
常用於形成醫藥可接受酸加成鹽之有機酸包括(以舉例但非限制之方式)醋酸、2,2-二氯醋酸、己二酸、抗壞血酸(其D-或L型,尤其係其L型)、天冬胺酸(其D-或L型,尤其係其L型)、苯磺酸、苯甲酸、4-乙醯胺基-苯甲酸、樟腦酸(其(+)或(-)形式,尤其係其(+)形式)、樟腦基-10-磺酸(其(+)或(-)形式,尤其係其(+)形式)、癸酸(十碳烷酸)、己酸(六碳烷酸)、辛酸(八碳烷酸)、碳酸、肉桂酸、檸檬酸、環己基胺基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羥基-乙磺酸、甲酸、反丁烯二酸、半乳糖二酸、龍膽酸、葡庚醣酸(其D-或L-形式,尤其係其D-形式)、葡糖酸(其D-或L-形式,尤其係其D-形式)、葡糖醛酸(其D-或L-形式,尤其係其D-形式)、穀胺酸、戊二酸、2-側氧基-戊二酸、甘油磷酸、乙醇酸、馬尿酸、異丁酸、乳酸(其D-或L-形式)、乳糖酸、月桂酸、順二丁烯酸、蘋果酸(其D-或L-形式)、丙二酸、扁桃酸(其D-或L-形式)、甲磺酸、萘-1,5-二磺酸、萘-2-磺酸、1-羥基-2-萘甲酸、菸鹼酸、油酸、乳清酸、草酸、棕櫚酸、雙羥萘酸(恩貝酸(embonic acid))、丙酸、焦穀胺酸(其D-或L-形式,尤其其L-形式)、水楊酸、4-胺基水楊酸、癸二酸、硬脂酸、琥珀酸、酒石酸(其D-或L-形式)、硫氰酸、甲苯磺酸(尤其係其對位-異構體)、十一碳烯酸等。
上述有機酸之一類包括羧酸衍生物。上述有機酸之另一類包括磺酸衍生物。
該等酸可係一元酸或多元酸,示例性多元酸係二元酸或三元酸。此等多元酸根據其等特性,實質上可經一次、兩次或三次去質子化,一般而言其等實質上經一次去質子化。
例如,於羧酸鹽中,該酸可為分別具有一個或兩個或更多個羧酸基團之單-或多元羧酸。就多元羧酸鹽之第一子類而言,此等鹽中之多元羧酸可實質上經一次去質子化,如(例如)在1:1化學計量比之游離化合物與二元羧酸之二元羧酸鹽的情況。就多元羧酸鹽之第二子類而言,在不考慮酸中之羧酸基團數下,多元羧酸與游離化合物可呈實質上1:1化學計量比。
上述無機或有機酸之子群包括(以舉例但非限制之方式)醋酸、己二酸、L-抗壞血酸、癸酸、碳酸、檸檬酸、反丁烯二酸、半乳糖二酸、D-葡庚醣酸、D-葡糖酸、D-葡糖醛酸、穀胺酸、戊二酸、甘油磷酸、馬尿酸、氫氯酸、D-或L-乳酸、月桂酸、順丁烯二酸、(-)-L-蘋果酸、磷酸、癸二酸、琥珀酸、硫酸、(+)-L-酒石酸及硫氰酸。
上述無機或有機酸之另一子群包括(以舉例但非限制之形式)海藻酸、苯磺酸、苯甲酸、(+)-樟腦酸、辛酸、環己基胺基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羥基-乙磺酸、龍膽酸、2-側氧基-戊二酸、異丁酸、乳糖酸、丙二酸、甲磺酸、萘-1,5-二磺酸、萘-2-磺酸、1-羥基-2-萘甲酸、菸鹼酸、十八烯酸、乳清酸、草酸、雙羥萘酸、丙酸、(-)-L-焦穀胺酸及對-甲苯磺酸。
根據考量單-或多元酸及根據所期望為哪一種鹽,該等酸係以等莫耳定量比或與其不同之比例應用於鹽製備中。
因此,在本發明之酸加成鹽內,該酸與游離化合物可呈實質上1:1化學計量比或與其不同之比,如(例如)約1:2至約2:1化學計量比。亦可能係非整數化學計量比,如(例如)1:1.5或1.5:1。
與無機或有機酸形成之酸加成鹽之特定子群包括(以舉例但非限制之形式)氫氯酸鹽、甲磺酸鹽、氫溴酸鹽、醋酸鹽、反丁烯二酸鹽、硫酸鹽、琥珀酸鹽、檸檬酸鹽、磷酸鹽、順丁烯二酸鹽、酒石酸鹽、乳酸鹽、苯甲酸鹽及碳酸鹽。
與無機或有機酸形成之酸加成鹽之另一特定子群包括(以舉例但非限制之形式)氫氯酸鹽、硫酸鹽、酒石酸鹽、順丁烯二酸鹽、檸檬酸鹽、磷酸鹽、醋酸鹽、乳酸鹽及反丁烯二酸鹽。
本發明亦包括鹽混合物。
此外,本文所指定之任何鹽傾向於包括其互變異構體、水合物、溶劑化物、結晶、非晶體及多晶型物形式,以及其等混合物。
熟習本項技藝者將瞭解,有機化合物可與溶劑分子一起結合後單離,或可與於其中反應、自其中沉澱、結晶或單離之溶劑形成錯合物。根據專家之認知,當以固體形式單離時,根據本發明之某些鹽可含有(例如)變化或固定量之溶劑(包括水性及/或非水性溶劑)。因此,於本發明範圍內包括根據本發明之鹽的溶劑化物(包括水合物、有機溶劑化物及水合物/有機溶劑化物混合物)。根據本發明鹽形式之溶劑化物包括化學計量及非化學計量溶劑化物。較佳地,使用之溶劑係醫藥可接受溶劑,例如,水及/或乙醇等。本發明同時包括非溶劑化物及所有溶劑化物形式。同樣地,本發明包括所有水合、無水、吸濕及/或非吸濕形式。
於另一態樣中,本發明係關於一種根據本發明之鹽之溶劑化物的化合物,該溶劑化物或係呈單純形式,如(例如)僅包含一種有機溶劑或水之溶劑化物;或係呈混合形式,如(例如)包含至少一種有機溶劑,如(例如)低分子量脂肪族醇與水之混合溶劑化物(例如混合水合物/溶劑化物),或包含依任何混合比之至少兩種不同的帶水或不帶水有機溶劑之混合溶劑化物,包括同溶劑化物(其中僅有一類溶劑之溶劑化物)及雜合溶劑化物(其中有兩種或更多種不同類溶劑之溶劑化物)。
就更詳細實例而言,根據本發明鹽之溶劑化物包括水合物及醇化物(與醇,如(例如)乙醇形成之溶劑化物)以及其等混合物(包括混合之水合物/醇化物)。
該一或多種溶劑可依非化學計量比之量或依化學計量比之量存在,如(例如)基於非溶劑化物鹽量之0.5:1、1:1、1.5:1、2:1、3:1、或4:1莫耳比。若結晶形式經溶劑化時,其可含有(例如)至多4分子之溶劑,更一般為至多2或3分子,例如,1分子或2分子之溶劑。非化學計量比溶劑化物之形成法亦可為:每一分子化合物中,所存在溶劑之分子數小於1或於其他情況係非整數,如(例如)每一化合物中有小於1分子之溶劑存在,亦可有(例如)0.4、或0.5、或0.6、或0.7、或0.8、或0.9分子之溶劑存在。例如,根據本發明鹽之溶劑化物或水合物分別包括(不限於)半-、單-、倍半-、二-、三-及四-溶劑化物或水合物。此等水合物與一或多種有機溶劑(如,例如,醇,尤其乙醇)依任何混合比例形成之化學計量或非化學計量混合溶劑化物亦涵蓋於本發明中。
某些實施例中,本發明係關於本發明鹽之水合物、與乙醇形成之溶劑化物(乙醇化物)及混合水合物/乙醇化物。
於本發明之溶劑化物中,溶劑分子可併入固態結構(如(例如)其可於單離時埋入晶體內)或不然(如(例如)其可保留於晶體表面)。當溶劑或水強力鍵結時(如,例如,於獨立位點溶劑化物中),錯合物通常具有不受濕度影響之界定完整之化學計量比。然而,當溶劑或水之鍵結弱時(如(例如)通道溶劑化物及吸濕性化合物),水/溶劑含量通常取決於濕度及/或乾燥條件,且通常係非化學計量比。
例如,於工業規模製造期間作為過程產物獲得之醫藥不可接受鹽(包括其等溶劑化物及水合物)可藉由熟習本項技藝者已知之方法,例如藉由鹽及/或溶劑化物交換或置換,或經由非鹽及/或非溶劑化物化合物(經單離或未經單離)而轉化為醫藥可接受鹽(包括其等溶劑化物及水合物)。
不適用於醫藥用途但可用於,例如,單離或純化游離化合物1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素或其等醫藥可接受鹽(包括溶劑化物、水合物及/或其他形式)之鹽(包括溶劑化物、水合物及/或其他形式)亦包括於本發明中。
本發明之一項具體實施例係關於一種選自由如下物質組成之群之1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素之酸加成鹽:苯磺酸鹽、氫溴酸鹽、苯甲酸鹽、乙磺酸鹽、反丁烯二酸鹽、甲磺酸鹽、水楊酸鹽、甲苯磺酸鹽、氫氯酸鹽、乙醇酸鹽、丙二酸鹽及龍膽酸鹽,以及其等溶劑化物,尤其係有機溶劑化物、水合物及混合有機溶劑化物/水合物。
本發明之鹽(包括其等溶劑化物、水合物及/或其他形式)可藉由熟習該項技術者已知用於製造酸加成鹽之方法獲得,例如,此等鹽可於游離化合物(或前藥、前驅體或受保護化合物)之最後反應、脫除保護基、單離、純化及/或進一步處理期間,或藉由使該游離化合物與所需酸或適用的陰離子交換劑反應,如(例如)藉由包含本文所述一或多個步驟之方法而製得(例如,於原位製備)。一般而言,該游離化合物可與所需酸組合,例如藉由在加熱或不加熱下(例如,於周溫或加溫(如,例如,約30℃至70℃或40℃至60℃)或所使用溶劑之沸騰溫度下進行溶解、混合及/或反應,例如可應用高達100℃之溫度以形成溶液),將該游離化合物溶於、分散或漿化於含有所需酸之適用溶劑或溶劑混合物中,或隨後添加所需酸(視情況溶於適合溶劑或溶劑混合物),或反之亦然。該加成鹽可經過例如:過濾、結晶、沉澱(例如:使用針對該加成鹽之反溶劑)或藉由冷卻,或藉由濃縮(例如藉由加熱、移除或蒸發溶劑)來單離,且若須要時,藉由(例如)自適宜的再結晶溶劑或溶劑混合物中再結晶,並藉由熟習本項技術者習知方法(例如,如上述般相似或相同地)純化,及/或,若須要時,該方法進一步包含:在合適製程時移除或分離任何非所需物質或雜質,並最終(視情況)清洗及/或乾燥該等鹽。
一般而言,於本發明中熟練技術者所考慮之溶劑可包括(但不限於)有機、非水性或水性、質子性或非質子性、極性或非極性溶劑,如(例如)酮類如(例如)丙酮、甲基乙基酮、甲基丙基酮、甲基第三-或異-丁基酮等;內酯如(例如)戊內酯;醚類如(例如)乙醚、二異丙醚、乙二醇二甲基醚、四氫呋喃、二噁烷等;烴類如(例如)甲苯、己烷等;氯化烴如(例如)二氯甲烷、氯仿等;低分子量脂族醇如(例如)甲醇、乙醇、1-丙醇、異丙醇、丁醇等;酯類如(例如)醋酸低碳數烷基酯(例如醋酸乙酯)等;醯胺或內醯胺類如(例如)N,N-二甲基甲醯胺、N-甲基-2-吡咯啶酮等;腈類如(例如)乙腈等;或亞碸如(例如)DMSO等;或水;或其等混合物。
合適的溶劑或反溶劑可於各種溶劑中測定溶解度來確定。
於本發明之意義內,當述及以可完全或部份水可混溶之有機溶劑(如(例如)適用於鹽之形成及/或結晶之溶劑)作為具體溶劑時,係指低分子量脂肪族醇,例如乙醇,並視情況與水組合。
於另一態樣中,本發明係關於一種製備本發明鹽,尤其呈結晶形式鹽之方法,其包含如下一或多個步驟:
i) 形成包含1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素與一種酸(如(例如)本文所述醫藥可接受酸中之任一者,尤其以舉例方式於以下實例所述酸中之任一者)之溶液;
ii) 誘發該鹽(例如)自溶液中結晶;及
iii) 回收該結晶1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素鹽。
於此方法之一項實施例中,1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素與該酸係呈1:1化學計量比。
於此方法之另一實施例中,可於醇(尤其乙醇)中,視情況於水存在下進行反應及/或(再)結晶。
可藉由與合適酸之反應或藉由適用的離子交換方法,使所製備之鹽轉化為另一種鹽。同樣地,可將所獲得之鹽轉化為游離化合物(例如藉由適用鹼經由中和,並單離或不單離該游離鹼,例如藉由萃取),該游離化合物可藉由酸化再次轉化為鹽。於此方式中,可轉化生理不可接受鹽形成生理可接受鹽。
於另一態樣中,本發明係關於呈固體形式,包括非晶體、半非晶體、多晶型、半結晶及結晶形式以及其等混合物之本發明鹽(包括其溶劑化物與水合物)。
就更詳盡實例而言,本發明涉及呈部份結晶形式(如,例如,約5至20%結晶)以及呈實質上結晶形式(如,例如大於約20、30、40、50、50、70、80、90或95%結晶之任一者)之本發明鹽(包括其等混合與否之溶劑化物及水合物)。
結晶形式之存在及結晶程度(%)係由熟練技術者利用X-射線粉末繞射(XRPD)來確定。亦可使用其他技術,如固態NMR、FT-IR、Raman光譜法、差示掃描量熱法(DSC)及微熱量測定法。
本發明鹽之結晶形式及多晶型之特徵在於如下文實例所顯示之其等熔點(例如,藉由DSC方法獲得)或其等各別的x-射線粉末繞射光譜數據或包含主峰之圖案(例如相對強度大於或等於約10%、20%或25%等)。如(例如)本發明氫氯酸鹽之結晶形式具有實質上如表10定義及/或實質上如圖9定義之X-射線粉末繞射圖案。
結晶形式及多晶型係可藉由本發明化合物之結晶方法製備。可將各種結晶技術用於形成及單離晶體化合物及多晶型物,如(例如)本文所述之任一彼等晶體形成方法,如(例如)自合適溶劑或溶劑混合物中結晶或沉澱、攪拌懸浮液(相平衡)、漿化、溶劑蒸發、自然或強制冷卻至適宜溫度以引發結晶、於結晶期間在極快至極慢之冷卻速率範圍內選用適宜冷卻模式、施加適宜壓力、施加晶種、再結晶、過濾、清洗(例如於結晶溶劑中)及/或乾燥(例如減壓及/或加溫下)。
結晶形式亦可藉由加熱或熔化所得形式,接著在常速或快速冷卻下獲得;依此方式,多晶型或結晶形式可相互轉換。
於另一態樣中,本發明係關於實質上呈純化形式(例如實質上不含雜質及/或其他形式),例如,各別形式具有約>80%、>85%、>90%、>95%、>98%、或>99%純度之本發明鹽(包括其等溶劑化物、水合物、多晶型物、結晶及非晶體形式)。
於另一態樣中,本發明係關於實質上呈純化形式之本發明鹽(包括其等溶劑化物、水合物、多晶型物、結晶及非晶體形式),其意指(例如)各別形式包含小於20重量%、小於10重量%、小於5重量%、小於3重量%或小於1重量%之任何雜質或其他物理形式。
本發明另係關於一種用於治療及/或預防糖尿病,尤其2型糖尿病之如本文所述鹽。
本發明另係關於一種如本文所述鹽之用途,其係用於製造用於治療及/或預防糖尿病,尤其2型糖尿病之藥物。
本發明另係關於一種用於治療及/或預防糖尿病,尤其2型糖尿病之醫藥組合物,其中該醫藥組合物包含如本文所述鹽及視情況選用之一或多種醫藥可接受載體及/或稀釋劑。
本發明另係關於一種用於治療及/或預防糖尿病,尤其2型糖尿病中使用之包含組份套組之固定或非固定組合物,其中該組合物包含如本文所述鹽及視情況選用之一或多種其他活性物質,例如本文所述活性物質中之任一者。
本發明另係關於以如本文所述之鹽與一或多種其他活性物質(如(例如)本文所提及活性物質中之任一者)之組合之用途,其係用於製造治療及/或預防糖尿病,尤其2型糖尿病之醫藥組合物。
本發明另係關於一種用於治療及/或預防糖尿病,尤其2型糖尿病之醫藥組合物,該醫藥組合物包含如本文所述鹽及視情況選用之一或多種其他活性物質,如(例如)本文所述活性物質中之任一者。
本發明另係關於一種治療及/或預防糖尿病,尤其2型糖尿病之方法,該方法包括將有效量之如本文所述鹽,視情況獨立、依序、同時、並行或依時序交替,與有效量之一或多種其他活性物質(如(例如)本文所述活性物質中之任一者)投與有此需求之個體(尤其人類病患)。
此外,如本文所述鹽係可用於如下方法中之一或多者:
- 用於糖尿病之預防、減緩進程、延遲、或治療;
- 用於改善血糖控制及/或降低空腹血漿葡萄糖、餐後血漿葡萄糖及/或糖化血紅素HbAlc;
- 用於預防、減緩、延遲或逆轉葡萄糖耐受異常、胰島素抵抗及/或代謝症候群至2型糖尿病之進程;
- 用於預防選自由糖尿病併發症組成之群之病況或病變、減緩其進程、延遲或治療該病況或病變;
- 用於減輕體重或防止體重增加或促進體重減輕;
- 用於預防或治療胰腺β細胞變異及/或用於改良及/或恢復胰腺β細胞功能及/或激發及/或恢復胰島素分泌功能;及/或
- 用於維持及/或改良胰島素敏感性及/或用於治療或預防高胰島素血症及/或胰島素抗性。
可藉由本發明療法治愈之此等糖尿病或病變之實例包括,不限於,1型糖尿病、2型糖尿病、葡萄糖耐受性不當、胰島素抗性、高血糖症、高血脂症、高膽固醇血症、血脂異常、代謝症候群X、肥胖症、高血壓、慢性全身性炎症、視網膜病變、神經病變、動脈粥樣硬化、內皮功能障礙及骨質疏鬆症。
1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素(參見WO 2004/018468,實例2(142)),其亦稱為BI 1356,具有下式:
用於合成1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素之方法係為熟練技術者所已知。1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素宜利用文獻所述之方法製備。因此,例如,其可如WO 2002/068420、WO 2004/018468或WO 2006/048427所述般獲得,該等文獻內容已併入本文。
用於溫血脊椎動物,尤其人類之醫藥用途時,可採用之一般活性成份劑量為0.001至100mg/kg體重,較佳係0.1至15mg/kg,其分別每日投與1至4次。就此目的而言,該等化合物(視情況與其他活性物質組合)可與一或多種惰性習知載體及/或稀釋劑,例如,與玉米澱粉、乳糖、葡萄糖、微晶纖維素、硬脂酸鎂、聚乙烯吡咯啶酮、檸檬酸、酒石酸、水、水/乙醇、水/甘油、水/山梨醇、水/聚乙二醇、丙二醇、鯨蠟基硬脂基醇、羧甲基纖維素或諸如硬脂肪之脂肪物質或其等適宜混合物一起併入諸如無包衣或有包衣之錠劑、膠囊、粉末、懸浮液或栓劑之習知蓋倫製劑中。
常見液體或固體載體不僅係無機載體,而且亦可為有機載體物質。因此(例如)乳糖、玉米澱粉或其衍生物、滑石、硬脂酸或其鹽可作為錠劑、包衣錠劑、糖衣藥丸及硬明膠囊之載體物質使用。用於軟明膠囊之典型載體物質係例如,植物油、蠟、脂肪及半固體及固體多元醇(然而,視活性成份之特性而定,軟明膠囊並不需要載劑)。用於製造溶液及糖漿之典型載體物質係例如,水、多元醇、蔗糖、轉化糖等。用於注射溶液之典型載體物質係例如,水、醇類、多元醇、甘油及植物油。用於栓劑之典型載體物質係例如,天然或硬化油類、蠟、脂肪及半液體或液體多元醇。
因此,包含如本文所定義鹽之根據本發明醫藥組合物可由習此相關技藝之人士使用相關技藝所說明之醫藥可接受調配賦形劑,如(例如)上文及下文所述之合適類型賦形劑,(例如)用於所需調配物及所需投與模式中之賦形劑製備。活性化合物含量適宜在0.1至95重量%(最終劑型之重量百分比),尤其係1至60重量%。藉由適當選擇賦形劑,可能獲得適於活性成份及/或所需效用起始及/或持續時間之醫藥投與形式。此等賦形劑之實例包括,不限制於,習慣上用於固體醫藥形式(如錠劑)之賦形劑,如(例如)稀釋劑、填充劑、黏結劑、載體、潤滑劑、崩解劑、流動促進劑、助流劑及/或包衣劑,常用於液體口服形式之賦形劑(例如糖漿或酏劑),如(例如)成凝膠劑、潤濕劑、消泡劑、著色劑、吸附劑、增稠劑、矯味劑及/或甜味劑,常用於注射溶液或輸液之賦形劑,如(例如)分散劑、乳化劑、防腐劑、增溶劑、緩衝物質及/或等滲調節物質,及其他輔助賦形劑,如(例如)穩定劑及/或溶劑。
本發明之一實施例係關於用於本發明化合物之經口投與劑型。錠劑、包衣錠劑、糖衣藥丸、丸劑、扁囊劑、膠囊、膜衣錠、顆粒、溶液、乳液及分散液係(例如)適用於經口投與。固體經口劑型可特別提及如(例如)膠囊、錠劑、丸劑、粉末或顆粒。
若須要,此等調配物亦可適於呈現(例如)腸溶性形式、即釋形式、緩釋形式、重複劑量釋放形式、長期時效釋放形式或持續釋放形式。該等形式可藉由(例如)包覆錠劑、基質技術、將錠劑分割成(例如其核心及/或包衣)數個隔層,可藉由不同條件(例如pH條件)下之分層崩解而分離,或藉由將本發明化合物與生物可降解聚合物偶合而獲得。
於特定實施例中,本發明化合物較佳係呈錠劑形式。此錠劑一般包含活性成份與一或多種稀釋劑、填充劑及/或載體,及視情況選用之一或多種黏結劑、一或多種潤滑劑、一或多種崩解劑、及/或一或多種助流劑,及(若須要時)膜塗層。
此錠劑可藉由(例如)使該活性物質與已知賦形劑,例如選自上述賦形劑者混合而製得。
包衣錠劑可藉由一般用於錠劑包衣之物質(例如成膜劑、增塑劑、助流劑及/或顏料)包覆其核心(類似錠劑製法)而製得。
該錠劑(包括其核心及塗層)亦可包含數層(例如單-、雙-或三層),例如,以獲得延遲釋放或防止不相容性。
一般而言,通常可考慮使用甘露醇、乳糖、蔗糖、麥芽糖糊精、山梨醇、木糖醇、纖維素粉末、微晶纖維素、羧甲基纖維素、羧乙基纖維素、甲基纖維素、乙基纖維素、羥乙基纖維素、羥丙基纖維素、甲基羥乙基纖維素、澱粉、羥基乙酸澱粉鈉、預糊化澱粉、磷酸鈣、金屬碳酸鹽、金屬氧化物或金屬鋁矽酸鹽中之一或多者作為稀釋劑/填充劑。
一般而言,通常可考慮使用聚乙烯吡咯啶酮、共聚維酮、羥丙基纖維素、羥丙基甲基纖維素、交聯聚(丙烯酸)、阿拉伯膠、金合歡樹膠、黃著膠、卵磷脂、酪蛋白、聚乙烯醇、明膠、高嶺土、纖維素、甲基纖維素、羥甲基纖維素、羧甲基纖維素、羧甲基纖維素鈣、羧甲基纖維素鈉、羥丙基纖維素、羥丙基甲基纖維素、鄰苯二甲酸酯、羥乙基纖維素、甲基羥乙基纖維素、矽化微晶纖維素、澱粉、麥芽糖糊精、糊精、微晶纖維素或山梨醇中之一或多者作為黏結劑。
一般而言,通常可考慮使用交聯羧甲纖維素鈉、羧甲纖維素鈣、交聯聚維酮、海藻酸、海藻酸鈉、海藻酸鉀、海藻酸鈣、離子交換樹脂、基於食物酸及鹼性碳酸鹽組份之泡騰系統、黏土、滑石、澱粉、預糊化澱粉、羥基乙酸澱粉鈉、纖維素粉末(cellulose floe)、羧甲基纖維素、羥丙基纖維素、矽酸鈣、金屬碳酸鹽、碳酸氫鈉、檸檬酸鈣或磷酸鈣中之一或多者作為崩解劑。
一般而言,通常可考慮使用硬脂酸、金屬硬脂酸鹽、富馬酸硬脂鈉、脂肪酸、脂肪醇、脂肪酸酯、甘油山萮酸酯、礦物油、植物油、石蠟、白胺酸、矽石、矽酸、滑石、丙二醇脂肪酸酯、聚乙二醇、聚丙二醇、聚伸烷二醇或氯化鈉中之一或多者作為潤滑劑。
若須要,亦可考慮使用混合物及/或組份之直接壓縮或造粒,其可藉由熟習此項技術者已知之習知造粒技術完成。例如,乾式造粒技術包括,但不限於,於高溫下藉由滾筒壓製或於重載壓錠機中之「壓錠」,壓縮混合粉末。濕式造粒技術包括,但不限於,高剪切造粒、單槽處理、頂部噴霧造粒、底部噴霧造粒、流化噴霧造粒、擠壓/球粒化、及滾筒造粒。
適用於本發明化合物之稀釋劑實例包括纖維素粉末、磷酸氫鈣、赤蘚糖醇、低取代羥丙基纖維素、甘露醇、預糊化澱粉或木糖醇。
適用於本發明化合物之潤滑劑實例可包括滑石、聚乙二醇、山萮酸鈣、硬脂酸鈣、氫化蓖麻油或硬脂酸鎂。
適用於本發明化合物之黏結劑實例可包括聚維酮(乙烯吡咯烷酮與其他乙烯衍生物之共聚鹽)、羥丙基甲基纖維素(HPMC)、羥丙基纖維素(HPC)、聚乙烯吡咯烷酮(聚維酮)、預糊化澱粉、或低取代羥丙基纖維素(L-HPC)。
適用於本發明化合物之崩解劑實例可包括玉米澱粉或交聯聚維酮。
製備本發明化合物之醫藥調配物之適用方法可係:
‧ 由活性物質於含有合適壓錠賦形劑之粉末混合物中直接壓錠;
‧ 藉由合適賦形劑造粒,及隨後與適用賦形劑混合並隨後壓錠,及包覆膜衣;或
‧ 將粉末混合物或顆粒封入膠囊中。
適用造粒方法可為:
‧ 於強力混合器中濕式造粒,接著藉由流化床乾燥;
‧ 一鍋式造粒;
‧ 流化床造粒;或
‧ 藉由合適賦形劑進行乾式造粒(例如,藉由滾筒壓製)並隨後壓錠或封裝入膠囊內。
具體調配物及其等製備係描述於專利申請案WO 2007/128724中,為了所有目的,該案之全文係以引用之方式併入本文中。
於本發明中,當經靜脈投與時所需劑量一般係0.1mg至10mg,較佳係0.25mg至5mg,及當經口投與時,其係0.5mg至100mg,較佳係2.5mg至50mg或0.5mg至10mg,更佳係2.5mg至10mg或1mg至5mg活性成份,且於每一情況中皆以每日投與1至4次。因此,當經口投與時,每一病患每日之1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素劑量係(例如)0.5mg至10mg,較佳2.5mg至10mg或1mg至5mg。
由包含如本文所述鹽之醫藥組合物製備之劑型含有0.1至100mg劑量範圍之該活性成份。因此,例如,1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素之具體劑量強度係0.5mg、1mg、2.5mg、5mg及10mg。
本發明一項特別具體實施例係關於彼等在低劑量強度下經口投與之DPP-4抑制劑,其劑量強度係例如每病患每日<100mg或<70mg,較佳係每病患每日<50mg,更佳<30mg或<20mg,甚佳係1mg至10mg,尤其係1mg至5mg(更尤其5mg)之活性成份,且較佳係每日一次,更佳為在一日內任一時間點,伴隨或不伴隨食物投與。
就活性物質,尤其本文所述者之劑型、調配物及投藥的細節而言,可參考相關科學文獻及/或已公開專利文獻,尤其本文所引用者。
因不同代謝功能病變經常同時發生,故經常將許多種不同活性成份彼此組合投與。因此,依照所診斷之功能病變,若將DPP-4抑制劑與習用於相關病變之活性物質,如(例如)選自其他抗糖尿病物質(尤其降低血液中之血糖濃度或脂質、提高血液中之HDL濃度、降低血壓或於動脈粥樣硬化或肥胖症治療中投與之活性物質)組合,則可獲得改善之治療結果。
除在單方療法中使用外,本發明化合物亦與其他活性物質一起使用,藉以獲得改善之治療結果。此組合治療可呈物質自由組合或呈固定組合形式,例如呈錠劑或膠囊之形式提供。於此所需之組合搭配物之醫藥調配物可呈醫藥組合物自商品購置或藉由熟練技術者利用習知方法調配。可自商品呈醫藥組合物取得之活性物質描述於先前技術之多處,例如,每年出版之藥物列表,醫藥工業聯邦協會之「Rote Liste」(the "Rote Liste" of the federal association of the pharmaceutical industry),或於每年更新一次稱為「Physicians' Desk Reference」之關於處方藥之製造商信息彙編。
抗糖尿病組合搭配物之實例係二甲雙胍;磺醯脲類如格列本脲(glibenclamide)、甲苯磺丁脲(tolbutamide)、格列美脲(glimepiride)、格列吡嗪(glipizide)、格列喹酮(gliquidon)、格列波脲(glibornuride)及格列齊特(gliclazide);那替格列(nateglinide);瑞格列萘(repaglinide);噻唑烷二酮類如梵帝雅(rosiglitazone)及吡格列酮(pioglitazone);PPAR-γ調節劑如第二代胰島素增敏劑(metaglidases);PPAR-γ激動劑如GI 262570;PPAR-γ拮抗劑;PPAR-γ/α調節劑如替格列扎(tesaglitazar)、莫格列扎(muraglitazar)及KRP297;PPAR-γ/α/β調節劑;AMPK-活化劑如AICAR;乙醯-CoA羧化酶(ACC1及ACC2)抑制劑;二醯基甘油-乙醯基轉移酶(DGAT)抑制劑;胰β細胞GCRP激動劑如SMT3-受體-激動劑及GPR119;11β-HSD-抑制劑;FGF19激動劑或類似物;α-配醣酶阻斷劑如醣祿(acarbose)、伏格列波(voglibose)及米格列醇(miglitol);α2-拮抗劑;胰島素及胰島素類似物如人胰島素、離脯胰島素(insulin lispro)、麩胺胰島素(insulin glusilin)、r-DNA-門冬胰島素(r-DNA-insulinaspart)、NPH胰島素、地特胰島素(insulin detemir)、胰島素鋅懸浮液及甘精胰島素(insulin glargin);胃抑制肽(GIP);普蘭林肽(pramlintide);胰澱素或GLP-1及GLP-1類似物如腸促胰島素類似物-4;SGLT2-抑制劑如KGT-1251;蛋白質酪胺酸-磷酸酶抑制劑;葡萄糖-6-磷酸酶抑制劑;果糖-1,6-二磷酸酶調節劑;肝糖磷解酶調節劑;胰高血糖素受體拮抗劑;磷酸烯醇丙酮羧酸激酶(PEPCK)抑制劑;丙酮酸脫氫酶激酶(PDK)抑制劑;酪胺酸激酶抑制劑(50mg至600mg)如PDGF受體激酶(參見EP-A-564409、WO 98/35958、US 5093330、WO 2004/005281、及WO 2006/041976);葡萄糖激酶/調節蛋白調節劑,包括葡萄糖激酶活化劑;肝糖合成酶激酶抑制劑;含SH-2功能部位之肌醇-5-磷酸酶2型(SHIP2)抑制劑;IKK抑制劑如高劑量水楊酸鹽;JNK1抑制劑;蛋白質激酶C-θ抑制劑;β3激動劑如瑞比葛榮(ritobegron)、YM 178、沙列葛榮(solabegron)、塔里貝葛榮(talibegron)、N-5984、GRC-1087、瑞弗貝葛榮(rafabegron)、FMP825;醛糖還原酶抑制劑如AS 3201、折那司他(zenarestat)、非達司他(fidarestat)、依帕司他(epalrestat)、雷尼司他(ranirestat)、NZ-314、CP-744809、及CT112;SGLT-1或SGLT-2抑制劑;KV1.3通道抑制劑;GPR40調節劑;SCD-1抑制劑;CCR-2拮抗劑;及其他DPPIV抑制劑。
二甲雙胍一般係依每日約500mg至2000mg及至高2500mg內變化之劑量投與,其係使用約100mg至500mg或200mg至850mg(每日1至3次)或約300mg至1000mg(每日1或2次)之各種投藥療程,或約100mg至1000mg或較佳500mg至1000mg(每日1或2次)或約500mg至2000mg(每日1次)劑量之緩釋二甲雙胍。具體劑量強度可為250、500、625、750、850及1000mg二甲雙胍氫氯酸鹽。
吡格列酮之劑量一般係約1至10mg、15mg、30mg、或45mg(每日1次),例如呈吡格列酮氫氯酸鹽使用。
格列本脲(glyburide)一般係以每日1(或2)次2.5至20mg之劑量(典型劑量強度係1.25、2.5及5mg),或以每日1次0.75至12mg劑量之微粉化格列本脲投與(典型劑量強度係1.5、3、4.5及6mg)。
格列吡嗪一般係以每日1(或2)次2.5至40mg之劑量(典型劑量強度係5及10mg),或以每日1次5至20mg劑量之緩型格列吡嗪投與(典型劑量強度係2.5、5及10mg)。
格列美脲一般係以每日1次1至8mg之劑量投與(典型劑量強度係1、2及4mg)。
格列本脲/二甲雙胍之雙組合物一般係以每日1次1.25/250mg至每日兩次10/1000mg之劑量投與。
格列吡嗪/二甲雙胍之雙組合物一般係以每日2次2.5/250至10/1000mg之劑量投與。
格列美脲/二甲雙胍之雙組合物一般係以每日2次1/250至4/1000mg之劑量投與。
梵帝雅/格列美脲之雙組合物一般係以每日1或2次4/1mg至每日2次4/2mg之劑量投與。
吡格列酮/格列美脲之雙組合物一般係以每日1次30/2至30/4mg之劑量投與。
梵帝雅/二甲雙胍之雙組合物一般係以每日2次1/500至4/1000mg之劑量投與。
吡格列酮/二甲雙胍之雙組合物一般係以每日1或2次15/500至每日3次15/850mg之劑量投與。
非磺醯脲類胰島素促分泌素那替格列一般係以60至120mg劑量伴隨進餐投與;瑞格列萘一般係以0.5至4mg劑量伴隨進餐投與。
醣祿一般係以25至100mg劑量伴隨進餐投與。米格列醇一般係以25至100mg劑量伴隨進餐投與。
降低血液中脂質濃度之組合搭配物實例係HMG-CoA-還原酶抑制劑如辛伐他汀(simvastatin)、阿伐他汀(atorvastatin)、洛伐他汀(lovastatin)、氟伐他汀(fluvastatin)、普伐他汀(pravastatin)及羅素他汀(rosuvastatin);纖維酸酯類如苯扎貝特(bezafibrate)、非諾貝特(fenofibrate)、降固醇酸(clofibrate)、吉非洛齊(gemfibrozil)、依託貝特(etofibrate)及益多酯(etofyllineclofibrate);菸鹼酸及其衍生物如阿西莫司(acipimox);PPAR-α激動劑;PPAR-δ激動劑;乙醯輔酶A:膽固醇醯基轉移酶抑制劑(ACAT;EC 2.3.1.26)如阿伐麥布(avasimibe);膽固醇再吸收抑制劑如愛西提米(ezetimib);結合膽酸之物質,如消膽胺(cholestyramine)、考來替泊(colestipol)及考來維綸(colesevelam);膽酸轉運抑制劑;HDL調節活性物質如D4F、反向D4F、LXR調節活性物質及FXR調節活性物質;CETP抑制劑如特西托比(torcetrapib)、JTT-705或來自WO 2007/005572之化合物12;LDL受體調節劑;及ApoB100反義RNA。
阿伐他汀之劑量一般係每日1次1mg至40mg或10mg至80mg。
降低血壓之組合搭配物實例係β-阻斷劑,如阿替洛爾(atenolol)、比索洛爾(bisoprolol)、塞利洛爾(celiprolol)、美托洛爾(metoprolol)及卡維地洛(carvedilol);利尿劑,如氫氯噻嗪(hydrochlorothiazide)、氯噻酮(chlortalidon)、希帕胺(xipamide)、呋塞米(furosemide)、吡咯他尼(piretanide)、托拉塞米(torasemide)、螺內酯(spironolactone)、依普利酮(eplerenone)、阿米洛利(amiloride)及胺苯蝶啶(triamterene);鈣通道阻斷劑如阿洛地平(amlodipine)、硝苯地平(nifedipine)、尼群地平(nitrendipine)、尼索地平(nisoldipine)、尼卡地平(nicardipine)、非洛地平(felodipine)、拉西地平(lacidipine)、樂卡地平(lercanidipine)、馬尼地平(manidipine)、伊拉地平(isradipine)、尼伐地平(nilvadipine)、維拉帕米(verapamil)、戈洛帕米(gallopamil)及地爾硫卓(diltiazem);ACE抑制劑如雷米普利(ramipril)、賴諾普利(lisinopril)、西拉普利(cilazapril)、喹那普利(quinapril)、卡托普利(captopril)、依那普利(enalapril)、貝那普利(benazepril)、培哚普利(perindopril)、福辛普利(fosinopril)及群多普利(trandolapril);以及血管緊縮素II受體阻斷劑(ARB)如替米沙坦(telmisartan)、坎地沙坦(candesartan)、纈沙坦(valsartan)、氯沙坦(losartan)、厄貝沙坦(irbesartan)、奧美沙坦(olmesartan)及伊普羅沙坦(eprosartan)。
替米沙坦之劑量一般係每日20mg至320mg或40mg至160mg。
提高血液中之HDL濃度之組合搭配物實例係膽固基酯轉移蛋白(CETP)抑制劑;內皮肽脂酶抑制劑;ABC1調節劑;LXR-α拮抗劑;LXR-β激動劑;PPAR-δ激動劑;LXR-α/β調節劑、及提高載脂蛋白A-I之表現及/或血漿濃度之物質。
用於治療肥胖症之組合搭配物實例係西布曲明(sibutramine);四氫利潑斯汀(tetrahydrolipstatin)(奧利司他(orlistat));阿利西米(alizyme);右旋芬氟拉明(dexfenfluramine);阿索開(axokine);類大麻受體1拮抗劑,如CB1拮抗劑利莫那班(rimonobant);MCH-1受體拮抗劑;MC4受體激動劑;NPY5以及NPY2拮抗劑;β3-AR激動劑,如SB-418790及AD-9677;5HT2c受體激動劑,如APD 356;肌肉抑制素抑制劑;Acrp30及脂聯素;硬脂醯CoA去飽和酶(SCD1)抑制劑;脂肪酸合成酶(FAS)抑制劑;CCK受體激動劑;多肽格那啉(Ghrelin)受體調節劑;Pyy 3至36;食慾素受體拮抗劑;及特索芬辛(tesofensine)。
用於治療動脈粥樣硬化之組合搭配物實例係磷脂酶A2抑制劑;酪胺酸激酶抑制劑(50mg至600mg),如PDGF受體激酶(參見EP-A-564409、WO 98/35958、US 5093330、WO 2004/005281、及WO 2006/041976);oxLDL抗體及oxLDL疫苗;apoA-1 Milano;ASA;及VCAM-1抑制劑。
應瞭解本文所述作為本發明鹽之組合搭配物之其他活性物質亦包含其等醫藥可接受鹽以及水合物、溶劑化物及其多晶型物形式。
本發明不限於本文所述具體實施例之範圍。除了本文所述外,習此相關技藝之人士由本揭示內容即了解,可對本發明進行各種修改。此等修改仍在附錄之申請專利範圍領域內。
為避免任何疑惑,本文所引用之文獻及專利申請案任一者之內容係以引用全文之方式特定併入本文中。
本發明之其他實施例、特徵及優勢將藉由以下實例明瞭。以下實例係用於說明(以實例方式)本發明之原理而非加以限制。
於室溫下將0.5g BI 1356游離鹼懸浮於4ml EtOH中。於回流下加熱該懸浮液直至獲得澄清溶液,其一般係於數分鐘後獲得。將溶於EtOH或水之1mol當量各對應酸(參見表1)加入BI 1356熱溶液中。然後停止加熱,並緩慢冷卻該溶液及於室溫下放置過夜。若出現沉澱時,藉由過濾移除所獲得晶體,及隨後於周圍條件下乾燥過夜。若未出現沉澱時,部份蒸發該溶液(約50%)並隨後於冰箱(4℃)中再放置一晚。亦藉由過濾移除沉澱之晶體,隨後於周圍條件下乾燥過夜。藉由偏振光顯微鏡、X-射線粉末繞射及熱分析法來分析所獲得晶體。
STOE Stadi P X-射線粉末繞射儀,其具有以傳輸模式工作且具有彎晶鍺(Germanium)(111)主單色器之位置感測器;所使用波長:CuKα1
mit λ=1.540598;X-射線管之功率設定:40kV,40mA;2θ範圍:3至40°。
可取得單晶結構數據之X-射線粉末圖案之指標可採用程式TREOR,其係STOE Stadi P套裝軟體之一部份。表2至13顯示特徵X-射線峰,包括以2θ表示之至高達30°之校正後強度。對應XRPD-圖顯示於附錄中圖1至12。
使用來自Fa. Mettler Toldeo之DSC 822。應用以下標準參數:加熱速率:10K/min;坩堝類型:針孔型鋁坩堝;氣體氛圍:N2
,80ml/min流動速率;一般稱重量:3至10mg。
使用與Nicolet FT-IR 4700光譜儀偶聯之來自Mettler Toledo之TGA/SDTA 851(用於分析揮發性物質)。應用以下標準參數:加熱速率:10K/min;坩堝類型:敞口式氧化鋁坩堝;氣體氛圍:N2
,20ml/min流動速率;一般稱重量:15至25mg。
藉由DSC測定之熔點(=Tfus
)顯示於表1。
圖1至12顯示BI 1356鹽形式之對應X-射線繞射圖。
(無元件符號說明)
Claims (30)
- 一種呈1:1化學計量比之1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素與醫藥可接受酸之固體鹽,其中該酸係選自苯甲酸、水楊酸、反丁烯二酸、乙醇酸或龍膽酸。
- 一種1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素與選自以下酸之固體酸加成鹽:苯甲酸、龍膽酸、乙醇酸、水楊酸,或其溶劑化物、水合物或其等混合物。
- 如請求項1或2之鹽,其係選自下列組成之群:苯甲酸鹽、水楊酸鹽、乙醇酸鹽及龍膽酸鹽,或其有機溶劑化物、水合物或混合水合物/有機溶劑化物,或其任一晶體形式。
- 如請求項1或2之鹽,其係呈溶劑化物之形式。
- 如請求項1或2之鹽,其係呈有機溶劑化物之形式。
- 如請求項5之鹽,其係呈乙醇化物之形式。
- 如請求項1或2之鹽,其係呈水合物之形式。
- 如請求項1或2之鹽,其係呈混合水合物/有機溶劑化物之形式。
- 如請求項8之鹽,其係呈混合水合物/乙醇化物之形式。
- 如請求項1或2之鹽,其係呈結晶、部份結晶、非晶體或多晶型物形式。
- 一種醫藥組合物,其包含如請求項1至10中任一項之鹽。
- 如請求項11之醫藥組合物,其包含一或多種醫藥可接受 載體及/或稀釋劑。
- 如請求項11或12之醫藥組合物,其進一步包含一或多種其他活性物質。
- 一種製造醫藥組合物之方法,其包含混合如請求項1至10中任一項之鹽與一或多種醫藥可接受賦形劑。
- 如請求項14之方法,其包含混合如請求項1至10中任一項之鹽與一或多種醫藥可接受賦形劑及一或多種其他活性物質混合。
- 一種如請求項1至10中任一項之鹽之用途,其係用於製造一種用於治療及/或預防藉由酵素DPP-4調控之疾病、病變或病況之藥物。
- 如請求項16之用途,其中該藥物包含一或多種其他治療活性劑,或該藥物係供與一或多種其他治療活性劑組合使用。
- 如請求項16或17之用途,其中由該酵素DPP-4調控之該疾病、病變或病況係2型糖尿病。
- 一種用於製備如請求項1至10中任一項之鹽之方法,其包含以下步驟之一或多者:i)形成一種包含1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素與酸之溶液;ii)誘發該鹽結晶;及iii)回收該結晶1-[(4-甲基-喹唑啉-2-基)甲基]-3-甲基-7-(2-丁炔-1-基)-8-(3-(R)-胺基-哌啶-1-基)-黃嘌呤素鹽。
- 如請求項19之方法,其中該溶液之溶劑係乙醇。
- 如請求項20之方法,其中該溶劑含有水。
- 一種有機溶液,其包含如請求項1至10中任一項之鹽。
- 如請求項22之溶液,該溶液為醇溶液。
- 如請求項22或23之溶液,該溶液另包含水。
- 如請求項22或23之溶液,其中該溶液之溶劑係乙醇。
- 如請求項25之溶液,其中該溶劑含有水。
- 如請求項3之鹽,其為苯甲酸鹽。
- 如請求項3之鹽,其為水楊酸鹽。
- 如請求項3之鹽,其為乙醇酸鹽。
- 如請求項3之鹽,其為龍膽酸鹽。
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Families Citing this family (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US7501426B2 (en) | 2004-02-18 | 2009-03-10 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
DE102004054054A1 (de) | 2004-11-05 | 2006-05-11 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Herstellung chiraler 8-(3-Amino-piperidin-1-yl)-xanthine |
DE102005035891A1 (de) | 2005-07-30 | 2007-02-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
EA015687B1 (ru) | 2006-05-04 | 2011-10-31 | Бёрингер Ингельхайм Интернациональ Гмбх | Полиморфы |
PE20110235A1 (es) | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | Combinaciones farmaceuticas que comprenden linagliptina y metmorfina |
EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
PE20090938A1 (es) | 2007-08-16 | 2009-08-08 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un derivado de benceno sustituido con glucopiranosilo |
PE20091730A1 (es) | 2008-04-03 | 2009-12-10 | Boehringer Ingelheim Int | Formulaciones que comprenden un inhibidor de dpp4 |
EP2146210A1 (en) | 2008-04-07 | 2010-01-20 | Arena Pharmaceuticals, Inc. | Methods of using A G protein-coupled receptor to identify peptide YY (PYY) secretagogues and compounds useful in the treatment of conditions modulated by PYY |
KR20200118243A (ko) | 2008-08-06 | 2020-10-14 | 베링거 인겔하임 인터내셔날 게엠베하 | 메트포르민 요법이 부적합한 환자에서의 당뇨병 치료 |
UY32030A (es) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "tratamiento para diabetes en pacientes inapropiados para terapia con metformina" |
MX2011002558A (es) | 2008-09-10 | 2011-04-26 | Boehringer Ingelheim Int | Terapia de combinacion para el tratamiento de diabetes y estados relacionados. |
US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
CA2745037C (en) | 2008-12-23 | 2020-06-23 | Boehringer Ingelheim International Gmbh | Salt forms of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8(3-(r)-amino-piperidin-1-yl)-xanthine |
TW201036975A (en) | 2009-01-07 | 2010-10-16 | Boehringer Ingelheim Int | Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy |
CN102307577A (zh) | 2009-02-13 | 2012-01-04 | 贝林格尔.英格海姆国际有限公司 | 包含sglt2抑制剂、dpp-iv抑制剂和任选的另一种抗糖尿病药的药物组合物及其用途 |
CN107115530A (zh) | 2009-11-27 | 2017-09-01 | 勃林格殷格翰国际有限公司 | 基因型糖尿病患者利用dpp‑iv抑制剂例如利拉利汀的治疗 |
WO2011132435A1 (ja) | 2010-04-22 | 2011-10-27 | 学校法人日本大学 | 脳機能障害予防・改善用の薬剤及び飲食物 |
AU2011249722B2 (en) | 2010-05-05 | 2015-09-17 | Boehringer Ingelheim International Gmbh | Combination therapy |
KR20220025926A (ko) | 2010-06-24 | 2022-03-03 | 베링거 인겔하임 인터내셔날 게엠베하 | 당뇨병 요법 |
EP2407469A1 (en) * | 2010-07-13 | 2012-01-18 | Chemo Ibérica, S.A. | Salt of sitagliptin |
AR083878A1 (es) | 2010-11-15 | 2013-03-27 | Boehringer Ingelheim Int | Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento |
UY33937A (es) | 2011-03-07 | 2012-09-28 | Boehringer Ingelheim Int | Composiciones farmacéuticas que contienen inhibidores de dpp-4 y/o sglt-2 y metformina |
CA2835332C (en) * | 2011-05-10 | 2019-03-26 | Sandoz Ag | Polymorph of linagliptin benzoate |
KR101985384B1 (ko) | 2011-07-15 | 2019-06-03 | 베링거 인겔하임 인터내셔날 게엠베하 | 치환된 퀴나졸린, 이의 제조 및 약제학적 조성물에서의 이의 용도 |
WO2013074817A1 (en) * | 2011-11-16 | 2013-05-23 | Assia Chemical Industries Ltd. | Solid state forms of linagliptin |
WO2013098775A1 (en) * | 2011-12-28 | 2013-07-04 | Dr. Reddy's Laboratories Limited | Improved process for preparation of pure linagliptin |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
EP2849755A1 (en) | 2012-05-14 | 2015-03-25 | Boehringer Ingelheim International GmbH | A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome |
WO2013174767A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in modifying food intake and regulating food preference |
US9867829B2 (en) | 2012-08-13 | 2018-01-16 | Sandoz Ag | Stable pharmaceutical composition containing 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione or a pharmaceutically acceptable salt thereof |
ES2663389T3 (es) | 2012-08-17 | 2018-04-12 | Glenmark Pharmaceuticals Limited | Procedimiento de preparación de los inhibidores de dipeptidilpeptidasa |
WO2014083554A1 (en) | 2012-11-30 | 2014-06-05 | Ranbaxy Laboratories Limited | Stable amorphous form of linagliptin |
US11813275B2 (en) | 2013-04-05 | 2023-11-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
PT2981271T (pt) | 2013-04-05 | 2019-02-19 | Boehringer Ingelheim Int | Utilizações terapêuticas de empagliflozina |
US20140303097A1 (en) | 2013-04-05 | 2014-10-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
PL2986304T3 (pl) | 2013-04-18 | 2022-05-02 | Boehringer Ingelheim International Gmbh | Kompozycja farmaceutyczna, sposoby leczenia i jej zastosowania |
JP6615109B2 (ja) | 2014-02-28 | 2019-12-04 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Dpp−4阻害薬の医学的使用 |
CN105712995B (zh) * | 2014-12-05 | 2017-11-03 | 浙江京新药业股份有限公司 | 一种利格列汀的纯化方法 |
MX2017011392A (es) * | 2015-03-27 | 2018-01-15 | Jiangsu Hengrui Medicine Co | P-toluensulfonato para inhibidor de mek cinasa, y su forma de cristal y su metodo de preparacion. |
WO2016186844A1 (en) * | 2015-05-15 | 2016-11-24 | Mayo Foundation For Medical Education And Research | Methods and materials for treating peripheral artery disease |
KR102442536B1 (ko) * | 2015-09-17 | 2022-09-13 | 한미정밀화학주식회사 | 리나글립틴 결정형 및 이의 제조방법 |
CA2998982A1 (en) | 2015-10-09 | 2017-04-13 | Hexal Ag | Pharmaceutical composition containing 8-[(3r)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[4-methyl-2-quinazolinyl)methyl]-1h-purine-2,6-dione or a pharmaceutically acceptable salt thereof |
WO2017142002A1 (ja) * | 2016-02-17 | 2017-08-24 | 大正製薬株式会社 | C-4"位置換マクロライド化合物フリー体及び塩の結晶形並びにそれらの製造方法 |
CN107216339B (zh) * | 2016-03-22 | 2021-05-04 | 中国科学院上海药物研究所 | 一种dppiv抑制剂马来酸盐的多晶型及其制备方法 |
CN107216340B (zh) * | 2016-03-22 | 2021-05-04 | 中国科学院上海药物研究所 | 一种dppiv抑制剂的盐型及其制备方法 |
CA3022202A1 (en) | 2016-06-10 | 2017-12-14 | Boehringer Ingelheim International Gmbh | Combinations of linagliptin and metformin |
CN106543180B (zh) * | 2016-10-28 | 2018-03-30 | 南京正大天晴制药有限公司 | 苯甲酸利格列汀晶型及其制备方法 |
IL301470A (en) | 2016-11-29 | 2023-05-01 | Ptc Therapeutics Mp Inc | Polymorphs of spiafatrin and its salts |
US11459328B2 (en) * | 2017-07-24 | 2022-10-04 | Achieve Pharma Uk Limited | Cytisine salts |
JP2020532535A (ja) | 2017-09-01 | 2020-11-12 | ピーティーシー セラピューティクス エムピー,インコーポレイテッド | セピアプテリンを含む医薬組成物及びその使用 |
KR102208009B1 (ko) | 2018-04-26 | 2021-01-28 | 주식회사 경보제약 | 신규한 리나글립틴 염 화합물, 이의 제조 방법 및 신규한 리나글립틴 염 화합물로부터 제조된 리나글립틴 |
IT201800005383A1 (it) | 2018-05-15 | 2019-11-15 | Intermedi e processi per la preparazione di linagliptin e suoi sali | |
US20210269443A1 (en) * | 2018-05-30 | 2021-09-02 | Ptc Therapeutics Mp, Inc. | Pharmaceutically acceptable salts of sepiapterin |
CN113292511B (zh) * | 2021-06-01 | 2022-11-25 | 天津大学 | 依帕司他-二甲双胍盐乙醇水双溶剂化物及制备方法和应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004018468A2 (de) * | 2002-08-21 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthine, deren herstellung und deren verwendung als arzneimittel |
CN101048409A (zh) * | 2004-11-05 | 2007-10-03 | 贝林格尔·英格海姆国际有限公司 | 手性8-(3-氨基-哌啶-1-基)-黄嘌呤的制备方法 |
TW200812591A (en) * | 2006-05-04 | 2008-03-16 | Boehringer Ingelheim Int | Polymorphs |
Family Cites Families (358)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2056046A (en) | 1933-05-19 | 1936-09-29 | Rhone Poulenc Sa | Manufacture of bases derived from benz-dioxane |
US2375138A (en) | 1942-05-01 | 1945-05-01 | American Cyanamid Co | Alkamine esters of aryloxymethyl benzoic acid |
US2629736A (en) | 1951-02-24 | 1953-02-24 | Searle & Co | Basically substituted n-alkyl derivatives of alpha, beta, beta-triarylpropionamides |
US2730544A (en) | 1952-07-23 | 1956-01-10 | Sahyun Lab | Alkylaminoalkyl esters of hydroxycyclohexylbenzoic acid |
US2750387A (en) | 1953-11-25 | 1956-06-12 | Searle & Co | Basically substituted derivatives of diarylaminobenzamides |
DE1211359B (de) | 1955-11-29 | 1966-02-24 | Oreal | Oxydationsmittelfreies Kaltfaerbemittel fuer menschliches Haar |
US2928833A (en) | 1959-03-03 | 1960-03-15 | S E Massengill Company | Theophylline derivatives |
US3174901A (en) | 1963-01-31 | 1965-03-23 | Jan Marcel Didier Aron Samuel | Process for the oral treatment of diabetes |
US3454635A (en) | 1965-07-27 | 1969-07-08 | Hoechst Ag | Benzenesulfonyl-ureas and process for their manufacture |
US3673241A (en) | 1968-04-04 | 1972-06-27 | Ciba Geigy Corp | Substituted benzaldehyde guanylhydrazones |
ES385302A1 (es) | 1970-10-22 | 1973-04-16 | Miquel S A Lab | Procedimiento para la obtencion de derivados trisubstitui- dos de etilendiamina. |
DE2205815A1 (de) | 1972-02-08 | 1973-08-16 | Hoechst Ag | Piperazinderivate und verfahren zu ihrer herstellung |
JPS5512435B2 (zh) | 1972-07-01 | 1980-04-02 | ||
US4005208A (en) | 1975-05-16 | 1977-01-25 | Smithkline Corporation | N-Heterocyclic-9-xanthenylamines |
US4061753A (en) | 1976-02-06 | 1977-12-06 | Interx Research Corporation | Treating psoriasis with transient pro-drug forms of xanthine derivatives |
DE2758025A1 (de) | 1977-12-24 | 1979-07-12 | Bayer Ag | Neue derivate von 3,4,5-trihydroxypiperidin, verfahren zu ihrer herstellung und ihre verwendung |
NO154918C (no) | 1977-08-27 | 1987-01-14 | Bayer Ag | Analogifremgangsmaate til fremstilling av terapeutisk aktive derivater av 3,4,5-trihydroksypiperidin. |
DE2929596A1 (de) | 1979-07-21 | 1981-02-05 | Hoechst Ag | Verfahren zur herstellung von oxoalkyl-xanthinen |
GB2084580B (en) | 1980-10-01 | 1984-07-04 | Glaxo Group Ltd | Aminoalkyl furan derivative |
US4382091A (en) | 1981-04-30 | 1983-05-03 | Syntex (U.S.A.) Inc. | Stabilization of 1-substituted imidazole derivatives in talc |
FR2558162B1 (fr) | 1984-01-17 | 1986-04-25 | Adir | Nouveaux derives de la xanthine, leurs procedes de preparation et les compositions pharmaceutiques les renfermant |
FI79107C (fi) | 1984-06-25 | 1989-11-10 | Orion Yhtymae Oy | Foerfarande foer framstaellning av stabil -form av prazosinhydroklorid. |
AR240698A1 (es) | 1985-01-19 | 1990-09-28 | Takeda Chemical Industries Ltd | Procedimiento para preparar compuestos de 5-(4-(2-(5-etil-2-piridil)-etoxi)benzil)-2,4-tiazolidindiona y sus sales |
US5258380A (en) | 1985-06-24 | 1993-11-02 | Janssen Pharmaceutica N.V. | (4-piperidinylmethyl and -hetero)purines |
GB8515934D0 (en) | 1985-06-24 | 1985-07-24 | Janssen Pharmaceutica Nv | (4-piperidinomethyl and-hetero)purines |
EP0223403B1 (en) | 1985-10-25 | 1993-08-04 | Beecham Group Plc | Piperidine derivative, its preparation, and its use as medicament |
US5433959A (en) | 1986-02-13 | 1995-07-18 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
EP0237608B1 (de) | 1986-03-21 | 1992-01-29 | HEUMANN PHARMA GMBH & CO | Kristalline, wasserfreie Sigma -Form von 2-[4-(2-Furoyl-(2-piperazin)-1-yl]-4-amino-6,7-dimethoxychinazolinhydrochlorid und Verfahren zu ihrer Herstellung |
AU619444B2 (en) | 1986-06-02 | 1992-01-30 | Nippon Chemiphar Co. Ltd. | 2-(2-aminobenzylsulfinyl)- benzimidazole derivatives |
US4968672A (en) | 1987-01-02 | 1990-11-06 | The United States Of America As Represented By The Department Of Health And Human Services | Adenosine receptor prodrugs |
US4743450A (en) | 1987-02-24 | 1988-05-10 | Warner-Lambert Company | Stabilized compositions |
US5093330A (en) | 1987-06-15 | 1992-03-03 | Ciba-Geigy Corporation | Staurosporine derivatives substituted at methylamino nitrogen |
JPS6440433A (en) | 1987-08-05 | 1989-02-10 | Green Cross Corp | Aqueous liquid composition of thrombin |
US5329025A (en) | 1988-09-21 | 1994-07-12 | G. D. Searle & Co. | 3-azido compound |
US5234897A (en) | 1989-03-15 | 1993-08-10 | Bayer Aktiengesellschaft | Herbicidal 3-amino-5-aminocarbonyl-1,2,4-triazoles |
DE3926119A1 (de) | 1989-08-08 | 1991-02-14 | Bayer Ag | 3-amino-5-aminocarbonyl-1,2,4-triazol-derivate |
GB8906792D0 (en) | 1989-03-23 | 1989-05-10 | Beecham Wuelfing Gmbh & Co Kg | Treatment and compounds |
DE3916430A1 (de) | 1989-05-20 | 1990-11-22 | Bayer Ag | Verfahren zur herstellung von 3-amino-5-aminocarbonyl-1,2,4-triazol-derivaten |
US5332744A (en) | 1989-05-30 | 1994-07-26 | Merck & Co., Inc. | Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists |
US5223499A (en) | 1989-05-30 | 1993-06-29 | Merck & Co., Inc. | 6-amino substituted imidazo[4,5-bipyridines as angiotensin II antagonists |
IL94390A (en) | 1989-05-30 | 1996-03-31 | Merck & Co Inc | The 6-membered trans-nitrogen-containing heterocycles are compressed with imidazo and pharmaceutical preparations containing them |
FI94339C (fi) | 1989-07-21 | 1995-08-25 | Warner Lambert Co | Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi |
HU208115B (en) | 1989-10-03 | 1993-08-30 | Biochemie Gmbh | New process for producting pleuromutilin derivatives |
FR2654935B1 (fr) | 1989-11-28 | 1994-07-01 | Lvmh Rech | Utilisation de xanthines, eventuellement incorporees dans des liposomes, pour favoriser la pigmentation de la peau ou des cheveux. |
DE19675036I2 (de) | 1990-02-19 | 2004-10-21 | Novartis Ag | Acylverbindungen. |
KR930000861B1 (ko) | 1990-02-27 | 1993-02-08 | 한미약품공업 주식회사 | 오메프라졸 직장투여 조성물 |
DE69104453T2 (de) | 1990-09-13 | 1995-03-16 | Akzo Nv | Stabilisierte feste chemische Zusammensetzungen. |
GB9020959D0 (en) | 1990-09-26 | 1990-11-07 | Beecham Group Plc | Novel compounds |
US5084460A (en) | 1990-12-24 | 1992-01-28 | A. H. Robins Company, Incorporated | Methods of therapeutic treatment with N-(3-ouinuclidinyl)-2-hydroxybenzamides and thiobenzamides |
US5594003A (en) | 1991-02-06 | 1997-01-14 | Dr. Karl Thomae Gmbh | Tetrahydroimidazo[1,2-a]pyridin-2-yl-(benzimidazol-1-yl)-methyl-biphenyls useful as angiotensin-II antagonists |
US5614519A (en) | 1991-02-06 | 1997-03-25 | Karl Thomae Gmbh | (1-(2,3 or 4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls useful as angiotensin-II antagonists |
US5602127A (en) | 1991-02-06 | 1997-02-11 | Karl Thomae Gmbh | (Alkanesultam-1-yl)-benzimidazol-1-yl)-1yl)-methyl-biphenyls useful as angiotensin-II antagonists |
GB9109862D0 (en) | 1991-05-08 | 1991-07-03 | Beecham Lab Sa | Pharmaceutical formulations |
DE4124150A1 (de) | 1991-07-20 | 1993-01-21 | Bayer Ag | Substituierte triazole |
TW225528B (zh) | 1992-04-03 | 1994-06-21 | Ciba Geigy Ag | |
US5300298A (en) | 1992-05-06 | 1994-04-05 | The Pennsylvania Research Corporation | Methods of treating obesity with purine related compounds |
GB9215633D0 (en) | 1992-07-23 | 1992-09-09 | Smithkline Beecham Plc | Novel treatment |
ATE165360T1 (de) | 1992-07-31 | 1998-05-15 | Shionogi & Co | Triazolylthiomethylthiocephalosporin- hydrochlorid, sein kristallines hydrat und seine herstellung |
TW252044B (zh) | 1992-08-10 | 1995-07-21 | Boehringer Ingelheim Kg | |
DE4242459A1 (de) | 1992-12-16 | 1994-06-23 | Merck Patent Gmbh | Imidazopyridine |
FR2707641B1 (fr) | 1993-07-16 | 1995-08-25 | Fournier Ind & Sante | Composés de l'imidazol-5-carboxamide, leur procédé de préparation leurs intermédiaires et leur utilisation en thérapeutique. |
DE4339868A1 (de) | 1993-11-23 | 1995-05-24 | Merck Patent Gmbh | Imidazopyridazine |
DE4404183A1 (de) | 1994-02-10 | 1995-08-17 | Merck Patent Gmbh | 4-Amino-1-piperidylbenzoylguanidine |
US5545745A (en) | 1994-05-23 | 1996-08-13 | Sepracor, Inc. | Enantioselective preparation of optically pure albuterol |
CO4410191A1 (es) | 1994-09-19 | 1997-01-09 | Lilly Co Eli | SINTESIS DE 3-[4-(2-AMINOETOXI)BENZOIL]-2-ARIL-6- HIDROXIBENZO [b] TIOFENOS |
WO1996011917A1 (en) | 1994-10-12 | 1996-04-25 | Euro-Celtique, S.A. | Novel benzoxazoles |
GB9501178D0 (en) | 1995-01-20 | 1995-03-08 | Wellcome Found | Guanine derivative |
US5821366A (en) | 1995-05-19 | 1998-10-13 | Chiroscience Limited | Xanthines and their therapeutic use |
DE19543478A1 (de) | 1995-11-22 | 1997-05-28 | Bayer Ag | Kristallines Hydrochlorid von {(R)-(-)-2- N-[4-(1,1-Dioxido-3-oxo-2,3-dihydrobenzisothiazol-2-yl)-buytl]-aminomethyl}-chroman |
FR2742751B1 (fr) | 1995-12-22 | 1998-01-30 | Rhone Poulenc Rorer Sa | Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent |
PT888293E (pt) | 1995-12-26 | 2002-07-31 | Alteon Inc | N-acilaminoalquilhidrazinocarboximidamidas |
DE19616486C5 (de) | 1996-04-25 | 2016-06-30 | Royalty Pharma Collection Trust | Verfahren zur Senkung des Blutglukosespiegels in Säugern |
US5965555A (en) | 1996-06-07 | 1999-10-12 | Hoechst Aktiengesellschaft | Xanthine compounds having terminally animated alkynol side chains |
WO1997046526A1 (en) | 1996-06-07 | 1997-12-11 | Eisai Co., Ltd. | Stable polymorphs of donepezil (1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]methylpiperidine) hydrochloride and process for production |
US5958951A (en) | 1996-06-14 | 1999-09-28 | Novo Nordiskials | Modified form of the R(-)-N-(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid hydrochloride |
US5753635A (en) | 1996-08-16 | 1998-05-19 | Berlex Laboratories, Inc. | Purine derivatives and their use as anti-coagulants |
WO1998011893A1 (en) | 1996-09-23 | 1998-03-26 | Eli Lilly And Company | Olanzapine dihydrate d |
EP0937056A1 (en) | 1996-10-28 | 1999-08-25 | Novo Nordisk A/S | A process for the preparation of (-)-3,4-trans-diarylchromans |
GB9623859D0 (en) | 1996-11-15 | 1997-01-08 | Chiroscience Ltd | Novel compounds |
PT948358E (pt) | 1996-12-24 | 2004-10-29 | Biogen Idec Inc | Formulacoes de interferao liquidas e estaveis |
CO4950519A1 (es) | 1997-02-13 | 2000-09-01 | Novartis Ag | Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion |
US6011049A (en) | 1997-02-19 | 2000-01-04 | Warner-Lambert Company | Combinations for diabetes |
ZA982155B (en) | 1997-03-13 | 1998-12-01 | Hexal Ag | Stabilization of acid sensitive benzimidazoles with amino acid/cyclodextrin combinations |
US5972332A (en) | 1997-04-16 | 1999-10-26 | The Regents Of The University Of Michigan | Wound treatment with keratinocytes on a solid support enclosed in a porous material |
PE79099A1 (es) | 1997-06-13 | 1999-08-24 | Lilly Co Eli | Formulaciones de insulina estables |
EE200000318A (et) | 1997-12-05 | 2001-08-15 | Astrazeneca Uk Limited | Uudsed ühendid |
JPH11193270A (ja) | 1997-12-26 | 1999-07-21 | Koei Chem Co Ltd | 光学活性1−メチル−3−ピペリジンメタノールの製造方法 |
DE69815554T2 (de) | 1998-01-05 | 2004-05-06 | Eisai Co., Ltd. | Purinderivate und antagonisten des adenosin-a2-rezeptors, welche zur vorsorge oder heilung von diabetes dienen |
IL138521A0 (en) | 1998-03-31 | 2001-10-31 | Nissan Chemical Ind Ltd | Pyridazinone hydrochloride compound and method for producing the same |
CA2268621A1 (en) | 1998-04-13 | 1999-10-13 | Takeda Chemical Industries, Ltd. | 2-pipirazinone-1-acetic acid derivative, production and use thereof |
US6207207B1 (en) | 1998-05-01 | 2001-03-27 | Mars, Incorporated | Coated confectionery having a crispy starch based center and method of preparation |
DE19823831A1 (de) | 1998-05-28 | 1999-12-02 | Probiodrug Ges Fuer Arzneim | Neue pharmazeutische Verwendung von Isoleucyl Thiazolidid und seinen Salzen |
DE19828114A1 (de) | 1998-06-24 | 2000-01-27 | Probiodrug Ges Fuer Arzneim | Produgs instabiler Inhibitoren der Dipeptidyl Peptidase IV |
CO5150173A1 (es) | 1998-12-10 | 2002-04-29 | Novartis Ag | Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv |
IT1312018B1 (it) | 1999-03-19 | 2002-04-04 | Fassi Aldo | Procedimento migliorato per la produzione di sali non igroscopicidella l(-)-carnitina. |
US6545002B1 (en) | 1999-06-01 | 2003-04-08 | University Of Virginia Patent Foundation | Substituted 8-phenylxanthines useful as antagonists of A2B adenosine receptors |
UA71976C2 (en) | 1999-06-21 | 2005-01-17 | Boehringer Ingelheim Pharma | Bicyclic heterocycles and a medicament based thereon |
ES2166270B1 (es) | 1999-07-27 | 2003-04-01 | Almirall Prodesfarma Sa | Derivados de 8-fenil-6,9-dihidro-(1,2,4,)triazolo(3,4-i)purin-5-ona. |
US6515117B2 (en) | 1999-10-12 | 2003-02-04 | Bristol-Myers Squibb Company | C-aryl glucoside SGLT2 inhibitors and method |
GB9928330D0 (en) | 1999-11-30 | 2000-01-26 | Ferring Bv | Novel antidiabetic agents |
MXPA02006660A (es) | 2000-01-07 | 2002-12-13 | Transform Pharmaceuticals Inc | Formacion, identificacion y analisis de diversas formas solidas de alto rendimiento. |
US6362172B2 (en) | 2000-01-20 | 2002-03-26 | Bristol-Myers Squibb Company | Water soluble prodrugs of azole compounds |
JP2003520226A (ja) | 2000-01-21 | 2003-07-02 | ノバルティス アクチエンゲゼルシャフト | ジペプチジルペプチダーゼ−iv阻害剤および抗糖尿病薬剤を含む組合せ物 |
JP4621326B2 (ja) | 2000-02-01 | 2011-01-26 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | テプレノンの安定化組成物 |
WO2001056993A2 (en) | 2000-02-05 | 2001-08-09 | Vertex Pharmaceuticals Incorporated | Pyrazole compositions useful as inhibitors of erk |
EP1132389A1 (en) | 2000-03-06 | 2001-09-12 | Vernalis Research Limited | New aza-indolyl derivatives for the treatment of obesity |
US6395767B2 (en) | 2000-03-10 | 2002-05-28 | Bristol-Myers Squibb Company | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
GB0006133D0 (en) | 2000-03-14 | 2000-05-03 | Smithkline Beecham Plc | Novel pharmaceutical |
JP2001278812A (ja) | 2000-03-27 | 2001-10-10 | Kyoto Pharmaceutical Industries Ltd | 錠剤用崩壊剤及びこれを用いた錠剤 |
ATE419036T1 (de) | 2000-03-31 | 2009-01-15 | Prosidion Ltd | Verbesserung der aktivität der inselzellen bei diabetes mellitus und dessen prävention |
GB0008694D0 (en) | 2000-04-07 | 2000-05-31 | Novartis Ag | Organic compounds |
US6962998B2 (en) | 2000-06-14 | 2005-11-08 | Toray Industries, Inc. | Processes for producing racemic piperidine derivative and for producing optically active piperidine derivative |
GB0014969D0 (en) | 2000-06-19 | 2000-08-09 | Smithkline Beecham Plc | Novel method of treatment |
US7078397B2 (en) | 2000-06-19 | 2006-07-18 | Smithkline Beecham Corporation | Combinations of dipeptidyl peptidase IV inhibitors and other antidiabetic agents for the treatment of diabetes mellitus |
AU2001268958B2 (en) | 2000-07-04 | 2006-03-09 | Novo Nordisk A/S | Heterocyclic compounds, which are inhibitors of the enzyme dpp-iv |
EP1950199B1 (en) | 2000-08-10 | 2009-12-02 | Mitsubishi Tanabe Pharma Corporation | Proline derivatives and use thereof as drugs |
US6821978B2 (en) | 2000-09-19 | 2004-11-23 | Schering Corporation | Xanthine phosphodiesterase V inhibitors |
US20060034922A1 (en) | 2000-11-03 | 2006-02-16 | Andrx Labs, Llc | Controlled release metformin compositions |
US20040180925A1 (en) | 2000-12-27 | 2004-09-16 | Kenji Matsuno | Dipeptidylpeptidase-IV inhibitor |
FR2819254B1 (fr) | 2001-01-08 | 2003-04-18 | Fournier Lab Sa | Nouveaux composes de la n-(phenylsulfonyl) glycine, leur procede de preparation et leur utilisation pour obtenir des compostions pharmaceutiques |
DE10117803A1 (de) | 2001-04-10 | 2002-10-24 | Boehringer Ingelheim Pharma | Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel |
DE10109021A1 (de) | 2001-02-24 | 2002-09-05 | Boehringer Ingelheim Pharma | Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel |
PT1953162E (pt) | 2001-02-24 | 2012-07-13 | Boehringer Ingelheim Pharma | Derivados de xantina, sua preparação e sua utilização como produto farmacêutico |
US6936590B2 (en) | 2001-03-13 | 2005-08-30 | Bristol Myers Squibb Company | C-aryl glucoside SGLT2 inhibitors and method |
US6693094B2 (en) | 2001-03-22 | 2004-02-17 | Chrono Rx Llc | Biguanide and sulfonylurea formulations for the prevention and treatment of insulin resistance and type 2 diabetes mellitus |
JP2002348279A (ja) | 2001-05-25 | 2002-12-04 | Nippon Kayaku Co Ltd | 光学活性ピリジルケトン誘導体の製造方法並びに光学活性ピリジルケトン誘導体 |
DE10130371A1 (de) | 2001-06-23 | 2003-01-02 | Boehringer Ingelheim Pharma | Neue Arzneimittelkompositionen auf der Basis von Anticholinergika, Corticosteroiden und Betamimetika |
CN1990469A (zh) | 2001-06-27 | 2007-07-04 | 史密丝克莱恩比彻姆公司 | 作为二肽酶抑制剂的氟代吡咯烷 |
US6869947B2 (en) | 2001-07-03 | 2005-03-22 | Novo Nordisk A/S | Heterocyclic compounds that are inhibitors of the enzyme DPP-IV |
ATE388951T1 (de) | 2001-07-03 | 2008-03-15 | Novo Nordisk As | Dpp-iv-inhibierende purin-derivative zur behandlung von diabetes |
UA74912C2 (en) | 2001-07-06 | 2006-02-15 | Merck & Co Inc | Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes |
US7638522B2 (en) | 2001-08-13 | 2009-12-29 | Janssen Pharmaceutica N.V. | Salt of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino] benzonitrile |
EP1463727A2 (en) | 2001-09-19 | 2004-10-06 | Novo Nordisk A/S | Heterocyclic compounds that are inhibitors of the enzyme dpp-iv |
DE10294792D2 (de) | 2001-10-15 | 2004-09-16 | Hemoteq Gmbh | Beschichtung von Stents zur Verhinderung von Restenose |
DE10151296A1 (de) | 2001-10-17 | 2003-04-30 | Boehringer Ingelheim Pharma | Keratinozyten verwendbar als biologisch aktive Substanz bei der Behandlung von Wunden |
US6861440B2 (en) | 2001-10-26 | 2005-03-01 | Hoffmann-La Roche Inc. | DPP IV inhibitors |
US20030083354A1 (en) | 2001-10-26 | 2003-05-01 | Pediamed Pharmaceuticals, Inc. | Phenylephrine tannate and pyrilamine tannate salts in pharmaceutical compositions |
CA2363053C (en) | 2001-11-09 | 2011-01-25 | Bernard Charles Sherman | Clopidogrel bisulfate tablet formulation |
WO2003053929A1 (fr) | 2001-12-21 | 2003-07-03 | Toray Fine Chemicals Co., Ltd. | Procede de production de derives de cis-piperidine optiquement actifs |
US6727261B2 (en) | 2001-12-27 | 2004-04-27 | Hoffman-La Roche Inc. | Pyrido[2,1-A]Isoquinoline derivatives |
AU2003201274A1 (en) | 2002-01-11 | 2003-07-24 | Novo Nordisk A/S | Compositions comprising inhibitors of dpp-iv and nep enzymes for the treatment of diabetes |
EP1333033A1 (en) | 2002-01-30 | 2003-08-06 | Boehringer Ingelheim Pharma GmbH & Co.KG | FAP-activated anti-tumor compounds |
JP2005517690A (ja) | 2002-02-01 | 2005-06-16 | ファイザー・プロダクツ・インク | 固体薬物分散物を含有する即時放出剤形 |
US7610153B2 (en) | 2002-02-13 | 2009-10-27 | Virginia Commonwealth University | Multi-drug titration and evaluation |
EP1338595B1 (en) | 2002-02-25 | 2006-05-03 | Eisai Co., Ltd. | Xanthine derivatives as DPP-IV inhibitors |
JP4298212B2 (ja) | 2002-03-29 | 2009-07-15 | 大日本印刷株式会社 | 塩酸エピナスチン高融点型結晶の製造法 |
JP2003300977A (ja) | 2002-04-10 | 2003-10-21 | Sumitomo Pharmaceut Co Ltd | キサンチン誘導体 |
EP1496982A4 (en) | 2002-04-16 | 2006-07-19 | Merck & Co Inc | SOLID FORMS OF SALTS WITH TYROSINE KINASE EFFECT |
AU2003231517A1 (en) | 2002-04-26 | 2003-11-10 | Ajinomoto Co., Inc. | Preventive/remedy for diabetes |
WO2003094909A2 (en) | 2002-05-09 | 2003-11-20 | Enos Pharmaceuticals, Inc. | Methods and compositions for the treatment and prevention of intermittent claudication or alzheimer's disease |
GB0212412D0 (en) | 2002-05-29 | 2002-07-10 | Novartis Ag | Combination of organic compounds |
DE60307628T2 (de) | 2002-05-31 | 2007-08-09 | Schering Corporation | Verfahren zur herstellung von xanthin phosphodiesterase v inhibitoren und deren vorstufen |
BR0311697A (pt) | 2002-06-06 | 2005-03-22 | Eisai Co Ltd | Novos derivados condensados de imidazol |
FR2840897B1 (fr) | 2002-06-14 | 2004-09-10 | Fournier Lab Sa | Nouveaux derives d'arylsulfonamides et leur utilisation en therapeutique |
US20040002615A1 (en) | 2002-06-28 | 2004-01-01 | Allen David Robert | Preparation of chiral amino-nitriles |
GB0215676D0 (en) | 2002-07-05 | 2002-08-14 | Novartis Ag | Organic compounds |
US20040023981A1 (en) | 2002-07-24 | 2004-02-05 | Yu Ren | Salt forms with tyrosine kinase activity |
TW200409746A (en) | 2002-07-26 | 2004-06-16 | Theravance Inc | Crystalline β2 adrenergic receptor agonist |
TW200404796A (en) | 2002-08-19 | 2004-04-01 | Ono Pharmaceutical Co | Nitrogen-containing compound |
DE10238243A1 (de) | 2002-08-21 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-Amino-piperidin-1-yl]-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US7495005B2 (en) | 2002-08-22 | 2009-02-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, their preparation and their use in pharmaceutical compositions |
DE10238470A1 (de) | 2002-08-22 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel |
US7569574B2 (en) | 2002-08-22 | 2009-08-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Purine derivatives, the preparation thereof and their use as pharmaceutical compositions |
DE10238477A1 (de) | 2002-08-22 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Purinderivate, deren Herstellung und deren Verwendung als Arzneimittel |
DE10238723A1 (de) | 2002-08-23 | 2004-03-11 | Bayer Ag | Phenyl-substituierte Pyrazolyprimidine |
DE10238724A1 (de) | 2002-08-23 | 2004-03-04 | Bayer Ag | Alkyl-substituierte Pyrazolpyrimidine |
EP1537880A4 (en) | 2002-09-11 | 2009-07-01 | Takeda Pharmaceutical | PREPARATION FOR PROLONGED RELEASE |
EP1545474A1 (en) | 2002-09-16 | 2005-06-29 | Wyeth | Delayed release formulations for oral administration of a polypeptide therapeutic agent and methods of using same |
BR0314655A (pt) | 2002-09-26 | 2005-08-02 | Eisai Co Ltd | Droga de combinação |
WO2004033455A2 (en) | 2002-10-08 | 2004-04-22 | Novo Nordisk A/S | Hemisuccinate salts of heterocyclic dpp-iv inhibitors |
US20040122048A1 (en) | 2002-10-11 | 2004-06-24 | Wyeth Holdings Corporation | Stabilized pharmaceutical composition containing basic excipients |
US6861526B2 (en) | 2002-10-16 | 2005-03-01 | Pfizer Inc. | Process for the preparation of (S,S)-cis-2-benzhydryl-3-benzylaminoquinuclidine |
JP2004161749A (ja) | 2002-10-24 | 2004-06-10 | Toray Fine Chemicals Co Ltd | 光学活性含窒素化合物の製造方法 |
WO2004048379A1 (ja) | 2002-11-01 | 2004-06-10 | Sumitomo Pharmaceuticals Co., Ltd. | キサンチン化合物 |
DE10251927A1 (de) | 2002-11-08 | 2004-05-19 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel |
US7482337B2 (en) | 2002-11-08 | 2009-01-27 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions |
DE10254304A1 (de) | 2002-11-21 | 2004-06-03 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Xanthinderivate, deren Herstellung und deren Verwendung als Arzneimittel |
US7109192B2 (en) | 2002-12-03 | 2006-09-19 | Boehringer Ingelheim Pharma Gmbh & Co Kg | Substituted imidazo-pyridinones and imidazo-pyridazinones, the preparation thereof and their use as pharmaceutical compositions |
UY28103A1 (es) | 2002-12-03 | 2004-06-30 | Boehringer Ingelheim Pharma | Nuevas imidazo-piridinonas sustituidas, su preparación y su empleo como medicacmentos |
PT1572196E (pt) | 2002-12-10 | 2008-11-20 | Novartis Ag | Combinação de um inibidor da dpp-iv e um composto ppar alfa |
US20040152720A1 (en) | 2002-12-20 | 2004-08-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Powdered medicaments containing a tiotropium salt and salmeterol xinafoate |
DE10351663A1 (de) | 2002-12-20 | 2004-07-01 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pulverförmige Arzneimittel enthaltend ein Tiotropiumsalz und Salmeterolxinafoat |
US20040224886A1 (en) | 2003-01-08 | 2004-11-11 | Chiron Corporation | Stabilized compositions comprising tissue factor pathway inhibitor protein or tissue factor pathway inhibitor variant proteins |
ATE374766T1 (de) | 2003-01-14 | 2007-10-15 | Arena Pharm Inc | 1,2,3-trisubstituierte aryl- und heteroarylderivate als modulatoren des metabolismus zur vorbeugung und behandlung von metabolismus-bedingten krankheiten wie diabetes oder hyperglykämie |
DE10335027A1 (de) | 2003-07-31 | 2005-02-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von Angiotensin II Rezeptor Antagonisten |
PE20040950A1 (es) | 2003-02-14 | 2005-01-01 | Theravance Inc | DERIVADOS DE BIFENILO COMO AGONISTAS DE LOS RECEPTORES ADRENERGICOS ß2 Y COMO ANTAGONISTAS DE LOS RECEPTORES MUSCARINICOS |
JP2004250336A (ja) | 2003-02-18 | 2004-09-09 | Kao Corp | コーティング錠及び糖衣錠の製造法 |
US7135575B2 (en) | 2003-03-03 | 2006-11-14 | Array Biopharma, Inc. | P38 inhibitors and methods of use thereof |
JP2006519852A (ja) | 2003-03-12 | 2006-08-31 | アリゾナ ボード オブ リージェンツ オン ビハーフ オブ ザ ユニバーシティー オブ アリゾナ | 弱塩基の塩 |
NZ541516A (en) | 2003-03-18 | 2008-05-30 | Novartis Ag | Compositions comprising fatty acids and amino acids |
WO2004096806A1 (ja) | 2003-04-30 | 2004-11-11 | Sumitomo Pharmaceuticals Co. Ltd. | 縮合イミダゾール誘導体 |
US20040220186A1 (en) | 2003-04-30 | 2004-11-04 | Pfizer Inc. | PDE9 inhibitors for treating type 2 diabetes,metabolic syndrome, and cardiovascular disease |
TW200510277A (en) | 2003-05-27 | 2005-03-16 | Theravance Inc | Crystalline form of β2-adrenergic receptor agonist |
AU2003902828A0 (en) | 2003-06-05 | 2003-06-26 | Fujisawa Pharmaceutical Co., Ltd. | Dpp-iv inhibitor |
US7566707B2 (en) | 2003-06-18 | 2009-07-28 | Boehringer Ingelheim International Gmbh | Imidazopyridazinone and imidazopyridone derivatives, the preparation thereof and their use as pharmaceutical compositions |
DE10327439A1 (de) | 2003-06-18 | 2005-01-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Imidazopyridazinon- und Imidazopyridonderivate, deren Herstellung und deren Verwendung als Arzneimittel |
ES2355105T3 (es) | 2003-06-20 | 2011-03-22 | F. Hoffmann-La Roche Ag | Pirido(2,1-a)isoquinolina como inhibidores de la dpp-iv. |
RU2339636C2 (ru) | 2003-06-20 | 2008-11-27 | Ф.Хоффманн-Ля Рош Аг | Гексагидропиридоизохинолины в качестве ингибиторов дипептидилпептидазы iv (dpp-iv) |
JO2625B1 (en) | 2003-06-24 | 2011-11-01 | ميرك شارب اند دوم كوربوريشن | Phosphoric acid salts of dipeptidyl betidase inhibitor 4 |
AR045047A1 (es) | 2003-07-11 | 2005-10-12 | Arena Pharm Inc | Derivados arilo y heteroarilo trisustituidos como moduladores del metabolismo y de la profilaxis y tratamiento de desordenes relacionados con los mismos |
MXPA06000554A (es) | 2003-07-14 | 2006-07-03 | Arena Pharm Inc | Derivados arilo y heteroarilo fusionados como moduladores del metabolismo y la profilaxis y tratamiento de trastornos relacionados con los mismos. |
ATE457166T1 (de) | 2003-07-24 | 2010-02-15 | Wockhardt Ltd | Orale zusammensetzungen zur behandlung von diabetes |
RU2355687C2 (ru) | 2003-08-01 | 2009-05-20 | Дженелэбс Текнолоджиз, Инк | Бициклические производные имидазола в качестве средства против вирусов семейства flaviviridae |
US6995183B2 (en) | 2003-08-01 | 2006-02-07 | Bristol Myers Squibb Company | Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods |
WO2005023179A2 (en) | 2003-08-29 | 2005-03-17 | Aton Pharma, Inc. | Combination methods of treating cancer |
US7790734B2 (en) | 2003-09-08 | 2010-09-07 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
ATE534404T1 (de) | 2003-10-03 | 2011-12-15 | Takeda Pharmaceutical | Dipeptidylpeptidase-iv-inhibitoren zur behandlung von diabetes-patienten mit sekundärversagen durch sulfonylharnstoffe |
KR20140089408A (ko) | 2003-11-17 | 2014-07-14 | 노파르티스 아게 | 디펩티딜 펩티다제 ⅳ 억제제의 용도 |
DE10355304A1 (de) | 2003-11-27 | 2005-06-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 8-(Piperazin-1-yl)-und 8-([1,4]Diazepan-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
US20070219178A1 (en) | 2003-12-04 | 2007-09-20 | Eisai Co., Ltd. | Preventive or therapeutic agents for multiple sclerosis |
DE10359098A1 (de) | 2003-12-17 | 2005-07-28 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 2-(Piperazin-1-yl)- und 2-([1,4]Diazepan-1-yl)-imidazo[4,5-d]pyridazin-4-one, deren Herstellung und deren Verwendung als Arzneimittel |
US7217711B2 (en) | 2003-12-17 | 2007-05-15 | Boehringer Ingelheim International Gmbh | Piperazin-1-yl and 2-([1,4]diazepan-1-yl)-imidazo[4,5-d]-pyridazin-4-ones, the preparation thereof and their use as pharmaceutical compositions |
RU2381224C2 (ru) | 2003-12-18 | 2010-02-10 | Тиботек Фармасьютикалз Лтд. | Пиперидинаминобензимидазольные производные как ингибиторы репликации респираторного синцитиального вируса |
DE10360835A1 (de) | 2003-12-23 | 2005-07-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bicyclische Imidazolverbindungen, deren Herstellung und deren Verwendung als Arzneimittel |
CN1898235A (zh) | 2003-12-24 | 2007-01-17 | 普罗西迪恩有限公司 | 作为gpcr受体激动剂的杂环衍生物 |
PL1758905T3 (pl) | 2004-02-18 | 2009-10-30 | Boehringer Ingelheim Int | 8-[3-Aminopiperydyn-1-ylo]-ksantyna, jej wytwarzanie i jej zastosowanie jako inhibitora DPP-IV |
US7501426B2 (en) | 2004-02-18 | 2009-03-10 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
DE102004019540A1 (de) | 2004-04-22 | 2005-11-10 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Arzneimittelkombinationen zur Behandlung von Atemwegserkrankungen |
DE102004009039A1 (de) | 2004-02-23 | 2005-09-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-Amino-piperidin-1-yl]-xanthine, deren Herstellung und Verwendung als Arzneimittel |
EP1593671A1 (en) | 2004-03-05 | 2005-11-09 | Graffinity Pharmaceuticals AG | DPP-IV inhibitors |
US7393847B2 (en) | 2004-03-13 | 2008-07-01 | Boehringer Ingleheim International Gmbh | Imidazopyridazinediones, their preparation and their use as pharmaceutical compositions |
GEP20094679B (en) | 2004-03-15 | 2009-05-10 | Takeda Pharmaceuticals Co | Dipeptidyl peptidase inhibitors |
EP2295422A3 (de) | 2004-03-16 | 2012-01-04 | Boehringer Ingelheim International GmbH | Glucopyranosylsubstituierte Benzolderivate, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
EP1577306A1 (de) | 2004-03-17 | 2005-09-21 | Boehringer Ingelheim Pharma GmbH & Co.KG | Neue Benzoxazinonderivate als langwirksame Betamimetika zur Behandlung von Atemwegserkrankungen |
EP1740589A1 (de) | 2004-04-10 | 2007-01-10 | Boehringer Ingelheim International GmbH | Neue 2-amino-imidazo[4,5-d]pyridazin-4-one und 2-amino-imidazo[4,5-c]pyridin-4-one, deren herstellung und deren verwendung als arzneimittel |
US7179809B2 (en) | 2004-04-10 | 2007-02-20 | Boehringer Ingelheim International Gmbh | 2-Amino-imidazo[4,5-d]pyridazin-4-ones, their preparation and their use as pharmaceutical compositions |
US20050239778A1 (en) | 2004-04-22 | 2005-10-27 | Boehringer Ingelheim International Gmbh | Novel medicament combinations for the treatment of respiratory diseases |
US20050244502A1 (en) | 2004-04-28 | 2005-11-03 | Mathias Neil R | Composition for enhancing absorption of a drug and method |
US7439370B2 (en) | 2004-05-10 | 2008-10-21 | Boehringer Ingelheim International Gmbh | Imidazole derivatives, their preparation and their use as intermediates for the preparation of pharmaceutical compositions and pesticides |
RS51106B (sr) | 2004-05-12 | 2010-10-31 | Pfizer Products Inc. | Derivati prolina i njihova upotreba kao inhibitora dipeptidil peptidaze iv |
DE102004024454A1 (de) | 2004-05-14 | 2005-12-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Enantiomerenreine Betaagonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel |
PE20060315A1 (es) | 2004-05-24 | 2006-05-15 | Irm Llc | Compuestos de tiazol como moduladores de ppar |
TWI415635B (zh) | 2004-05-28 | 2013-11-21 | 必治妥施貴寶公司 | 加衣錠片調製物及製備彼之方法 |
MXPA06014079A (es) | 2004-06-01 | 2007-02-15 | Ares Trading Sa | Metodo para estabilizar proteinas. |
WO2005117861A1 (en) | 2004-06-04 | 2005-12-15 | Novartis Ag | Use of organic compounds |
WO2005120576A2 (en) | 2004-06-09 | 2005-12-22 | Yasoo Health | Composition and method for improving pancreatic islet cell survival |
DE102004030502A1 (de) | 2004-06-24 | 2006-01-12 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Imidazole und Triazole, deren Herstellung und Verwendung als Arzneimittel |
BRPI0513384A (pt) | 2004-07-14 | 2008-05-06 | Novartis Ag | combinação de inibidores de dpp-iv e compostos que modulam receptores de 5-ht3 e/ou 5-ht4 |
JP2006045156A (ja) | 2004-08-06 | 2006-02-16 | Sumitomo Pharmaceut Co Ltd | 縮合ピラゾール誘導体 |
TW200613275A (en) | 2004-08-24 | 2006-05-01 | Recordati Ireland Ltd | Lercanidipine salts |
EP1782832A4 (en) | 2004-08-26 | 2009-08-26 | Takeda Pharmaceutical | MEANS FOR THE TREATMENT OF DIABETES |
DE102004043944A1 (de) | 2004-09-11 | 2006-03-30 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 8-(3-Amino-piperidin-1-yl)-7-(but-2-inyl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
DE102004044221A1 (de) | 2004-09-14 | 2006-03-16 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue 3-Methyl-7-butinyl-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
CN1759834B (zh) | 2004-09-17 | 2010-06-23 | 中国医学科学院医药生物技术研究所 | 黄连素或其与辛伐他汀联合在制备用于预防或治疗与血脂有关疾病或症状的产品中用途 |
AU2005289881A1 (en) | 2004-09-23 | 2006-04-06 | Amgen Inc. | Substituted sulfonamidopropionamides and methods of use |
KR20070099527A (ko) | 2004-10-08 | 2007-10-09 | 노파르티스 아게 | 유기 화합물의 조합물 |
NZ554515A (en) | 2004-10-12 | 2009-12-24 | Glenmark Pharmaceuticals Sa | Novel dipeptidyl peptidase IV inhibitors, pharmaceutical compositions containing them, and process for their preparation |
JP2008517921A (ja) | 2004-10-25 | 2008-05-29 | ノバルティス アクチエンゲゼルシャフト | Dpp−iv阻害剤、ppar抗糖尿病薬およびメトホルミンの組合わせ剤 |
DE102005013967A1 (de) | 2004-11-05 | 2006-10-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Bradykinin-B1-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
TW200635930A (en) | 2004-12-24 | 2006-10-16 | Dainippon Sumitomo Pharma Co | Bicyclic pyrrole derivatives |
KR100760430B1 (ko) | 2004-12-31 | 2007-10-04 | 한미약품 주식회사 | 당뇨병 치료제의 경구 투여용 서방성 복합 제제 및 이의제조 방법 |
DOP2006000008A (es) | 2005-01-10 | 2006-08-31 | Arena Pharm Inc | Terapia combinada para el tratamiento de la diabetes y afecciones relacionadas y para el tratamiento de afecciones que mejoran mediante un incremento de la concentración sanguínea de glp-1 |
MY148521A (en) | 2005-01-10 | 2013-04-30 | Arena Pharm Inc | Substituted pyridinyl and pyrimidinyl derivatives as modulators of metabolism and the treatment of disorders related thereto |
MX2007011453A (es) | 2005-04-22 | 2008-02-12 | Alantos Pharmaceuticals Holding Inc | Inhibidores de la dipeptidil peptidasa-iv. |
JP2008545688A (ja) | 2005-05-25 | 2008-12-18 | ワイス | 置換3−シアノキノリン並びにその中間体を合成する方法 |
GT200600218A (es) | 2005-06-10 | 2007-03-28 | Formulación y proceso de compresión directa | |
EA016397B1 (ru) | 2005-06-20 | 2012-04-30 | Декоуд Дженетикс Ехф. | Генетические варианты гена tcf7l2 как диагностические маркеры риска возникновения сахарного диабета ii типа |
EP1901741B1 (en) | 2005-07-01 | 2015-09-16 | Merck Sharp & Dohme Corp. | Process for synthesizing a cetp inhibitor |
DE602006017373D1 (de) | 2005-07-08 | 2010-11-18 | Pfizer Ltd | Madcam-antikörper |
UY29694A1 (es) | 2005-07-28 | 2007-02-28 | Boehringer Ingelheim Int | Metodos para prevenir y tratar trastornos metabolicos y nuevos derivados de pirazol-o-glucosido |
DE102005035891A1 (de) | 2005-07-30 | 2007-02-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-(3-Amino-piperidin-1-yl)-xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
CN101232873A (zh) | 2005-08-11 | 2008-07-30 | 霍夫曼-拉罗奇有限公司 | 含有dpp-iv抑制剂的药物组合物 |
EP1760076A1 (en) | 2005-09-02 | 2007-03-07 | Ferring B.V. | FAP Inhibitors |
RS52110B2 (sr) | 2005-09-14 | 2018-05-31 | Takeda Pharmaceuticals Co | Inhibitori dipeptidil peptidaze za lečenje dijabetesa |
DE602006006461D1 (de) | 2005-09-16 | 2009-06-04 | Arena Pharm Inc | Stoffwechselmodulatoren und behandlung damit verbundener erkrankungen |
US8143217B2 (en) | 2005-09-20 | 2012-03-27 | Novartis Ag | Use of DPP-IV inhibitor to reduce hypoglycemic events |
JOP20180109A1 (ar) | 2005-09-29 | 2019-01-30 | Novartis Ag | تركيبة جديدة |
WO2007052964A1 (en) * | 2005-11-04 | 2007-05-10 | Ls Cable Ltd. | Synthesis of mdh-polymer hybrid particles |
EP1962827A4 (en) | 2005-12-16 | 2011-02-16 | Merck Sharp & Dohme | PHARMACEUTICAL COMPOSITIONS OF COMBINATIONS OF DIPEPTIDYL-PEPTIDASE-4-INHIBITORS WITH METFORMIN |
GB0526291D0 (en) | 2005-12-23 | 2006-02-01 | Prosidion Ltd | Therapeutic method |
WO2007071738A1 (en) | 2005-12-23 | 2007-06-28 | Novartis Ag | Condensed heterocyclic compounds useful as dpp-iv inhibitors |
CA2635399A1 (en) | 2006-01-06 | 2007-10-25 | Novartis Ag | Use.of vildagliptin for the treatment of diabetes |
US7745414B2 (en) | 2006-02-15 | 2010-06-29 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture |
WO2007099345A1 (en) | 2006-03-02 | 2007-09-07 | Betagenon Ab | Medical use of bmp-2 and/ or bmp-4 |
PE20071221A1 (es) | 2006-04-11 | 2007-12-14 | Arena Pharm Inc | Agonistas del receptor gpr119 en metodos para aumentar la masa osea y para tratar la osteoporosis y otras afecciones caracterizadas por masa osea baja, y la terapia combinada relacionada a estos agonistas |
US8455435B2 (en) | 2006-04-19 | 2013-06-04 | Ludwig-Maximilians-Universitat Munchen | Remedies for ischemia |
EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
PE20110235A1 (es) | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | Combinaciones farmaceuticas que comprenden linagliptina y metmorfina |
KR20070111099A (ko) | 2006-05-16 | 2007-11-21 | 영진약품공업주식회사 | 시타글립틴 염산염의 신규 결정형, 이의 제조 방법과 이를포함하는 약학적 조성물 |
ATE534377T1 (de) | 2006-05-16 | 2011-12-15 | Gilead Sciences Inc | Verfahren und zusammensetzungen zur behandlung von hämatologischen erkrankungen |
WO2007137107A2 (en) | 2006-05-19 | 2007-11-29 | Abbott Laboratories | Inhibitors of diacylglycerol o-acyltransferase type 1 enzyme |
WO2007149797A2 (en) | 2006-06-19 | 2007-12-27 | Novartis Ag | Use of organic compounds |
WO2007148185A2 (en) | 2006-06-21 | 2007-12-27 | Pfizer Products Inc. | Substituted 3 -amino- pyrrolidino-4 -lactams as dpp inhibitors |
AT503443B1 (de) | 2006-06-23 | 2007-10-15 | Leopold Franzens Uni Innsbruck | Verfahren zur herstellung einer eisfläche für eissportbahnen |
TW200811147A (en) | 2006-07-06 | 2008-03-01 | Arena Pharm Inc | Modulators of metabolism and the treatment of disorders related thereto |
TW200811140A (en) | 2006-07-06 | 2008-03-01 | Arena Pharm Inc | Modulators of metabolism and the treatment of disorders related thereto |
EP2057160A1 (en) | 2006-08-08 | 2009-05-13 | Boehringer Ingelheim International GmbH | Pyrrolo [3, 2 -d]pyrimidines as dpp-iv inhibitors for the treatment of diabetes mellitus |
EP2054426A1 (en) | 2006-08-15 | 2009-05-06 | Boehringer Ingelheim International GmbH | Glucopyranosyl-substituted cyclopropylbenzene derivatives, pharmaceutical compositions containing such compounds, their use as sglt inhibitors and process for their manufacture |
CA2661293A1 (en) | 2006-08-17 | 2008-02-21 | Wellstat Therapeutics Corporation | Combination treatment for metabolic disorders |
DE102006042586B4 (de) | 2006-09-11 | 2014-01-16 | Betanie B.V. International Trading | Verfahren zum mikropartikulären Beladen von hochpolymeren Kohlenhydraten mit hydrophoben Wirkflüssigkeiten |
US7879806B2 (en) | 2006-11-06 | 2011-02-01 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzyl-benzonitrile derivates, medicaments containing such compounds, their use and process for their manufacture |
US7956201B2 (en) | 2006-11-06 | 2011-06-07 | Hoffman-La Roche Inc. | Process for the preparation of (S)-4-fluoromethyl-dihydro-furan-2-one |
NZ598778A (en) | 2006-11-09 | 2013-09-27 | Boehringer Ingelheim Int | Combination therapy with SGLT-2 inhibitors and their pharmaceutical compositions |
MX2009005935A (es) | 2006-12-06 | 2009-06-30 | Smithkline Beecham Corp | Compuestos biciclicos y su uso como anti-diabeticos. |
US7638541B2 (en) | 2006-12-28 | 2009-12-29 | Metabolex Inc. | 5-ethyl-2-{4-[4-(4-tetrazol-1-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-1-yl}-pyrimidine |
CL2008000017A1 (es) | 2007-01-04 | 2008-08-01 | Prosidion Ltd | Compuestos derivados de heterociclos de nitrogeno y oxigeno, agonistas de gpcr; composicion farmaceutica que comprende a dicho compuesto; y uso del compuesto para el tratamiento de la obesidad, diabetes, sindrome metabolico, hiperlipidemia, toleranci |
CL2008000133A1 (es) | 2007-01-19 | 2008-05-23 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un compuesto derivado de pirazol-o-glucosido combinado con al menos un segundo agente terapeutico; y uso de la composicion para el tratamiento de diabetes mellitus, cataratas, neuropatia, infarto de miocardio, e |
DE602008003522D1 (de) | 2007-02-01 | 2010-12-30 | Takeda Pharmaceutical | Feste zubereitung mit alogliptin und pioglitazon |
EP2124901B1 (en) | 2007-02-01 | 2017-07-19 | Takeda Pharmaceutical Company Limited | Tablet preparation without causing a tableting trouble |
CA2681092A1 (en) | 2007-03-15 | 2008-09-18 | Nectid, Inc. | Anti-diabetic combinations comprising a slow release biguanide composition and an immediate release dipeptidyl peptidase iv inhibitor composition |
KR101361427B1 (ko) | 2007-04-03 | 2014-02-10 | 미쓰비시 타나베 파마 코퍼레이션 | 디펩티딜 펩티다아제 4 저해 화합물과 감미료와의 병용 |
EP2508141A1 (en) | 2007-04-16 | 2012-10-10 | Smith & Nephew, Inc. | Powered surgical system |
PE20090696A1 (es) | 2007-04-20 | 2009-06-20 | Bristol Myers Squibb Co | Formas cristalinas de saxagliptina y procesos para preparar las mismas |
CN101668756A (zh) | 2007-05-04 | 2010-03-10 | 百时美施贵宝公司 | [6,6]和[6,7]-双环gpr119 g蛋白偶合受体激动剂 |
EP2178493B2 (en) | 2007-07-09 | 2015-12-09 | Symrise AG | Stable soluble salts of phenylbenzimidazole sulfonic acid at pH 6.0 to below 6.8 |
NZ583346A (en) | 2007-07-19 | 2012-02-24 | Takeda Pharmaceutical | Solid preparation comprising alogliptin and metformin hydrochloride |
PE20090987A1 (es) | 2007-08-16 | 2009-08-14 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un derivado de pirazol-o-glucosido |
PE20090603A1 (es) | 2007-08-16 | 2009-06-11 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un inhibidor de sglt2 y un inhibidor de dpp iv |
UY31291A1 (es) | 2007-08-16 | 2009-03-31 | Composicion farmacéutica que comprende un derivado de pirazol-0-glucosido | |
PE20090938A1 (es) | 2007-08-16 | 2009-08-08 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un derivado de benceno sustituido con glucopiranosilo |
US20110112069A1 (en) | 2007-08-17 | 2011-05-12 | Boehringer Ingelheim International Gmbh | Purin derivatives for use in the treatment of fab-related diseases |
PL2597103T3 (pl) | 2007-11-16 | 2017-04-28 | Novo Nordisk A/S | Stabilne kompozycje farmaceutyczne zawierające liraglutyd i degludec |
CN101234105A (zh) | 2008-01-09 | 2008-08-06 | 北京润德康医药技术有限公司 | 一种含有二甲双胍和维格列汀的药用组合物及其制备方法 |
US20090186086A1 (en) | 2008-01-17 | 2009-07-23 | Par Pharmaceutical, Inc. | Solid multilayer oral dosage forms |
TW200936136A (en) | 2008-01-28 | 2009-09-01 | Sanofi Aventis | Tetrahydroquinoxaline urea derivatives, their preparation and their therapeutic application |
AU2009210641A1 (en) | 2008-02-05 | 2009-08-13 | Merck Sharp & Dohme Corp. | Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-IV inhibitor |
AU2009220615B2 (en) | 2008-03-05 | 2013-12-19 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
US8551524B2 (en) | 2008-03-14 | 2013-10-08 | Iycus, Llc | Anti-diabetic combinations |
KR20100134659A (ko) | 2008-03-31 | 2010-12-23 | 메타볼렉스, 인코포레이티드 | 옥시메틸렌 아릴 화합물 및 그것의 사용 |
PE20091730A1 (es) | 2008-04-03 | 2009-12-10 | Boehringer Ingelheim Int | Formulaciones que comprenden un inhibidor de dpp4 |
PE20100156A1 (es) | 2008-06-03 | 2010-02-23 | Boehringer Ingelheim Int | Tratamiento de nafld |
UY32030A (es) | 2008-08-06 | 2010-03-26 | Boehringer Ingelheim Int | "tratamiento para diabetes en pacientes inapropiados para terapia con metformina" |
MX2011001525A (es) | 2008-08-15 | 2011-03-29 | Boehringer Ingelheim Int | Derivados de purina para su uso en el tratamiento de enfermedades relacionadas con fab. |
JP2010053576A (ja) | 2008-08-27 | 2010-03-11 | Sumitomo Forestry Co Ltd | 舗装用マット |
MX2011002558A (es) | 2008-09-10 | 2011-04-26 | Boehringer Ingelheim Int | Terapia de combinacion para el tratamiento de diabetes y estados relacionados. |
UY32177A (es) | 2008-10-16 | 2010-05-31 | Boehringer Ingelheim Int | Tratamiento de diabetes en pacientes con control glucémico insuficiente a pesar de la terapia con fármaco, oral o no, antidiabético |
WO2010045656A2 (en) | 2008-10-17 | 2010-04-22 | Nectid, Inc. | Novel sglt2 inhibitor dosage forms |
CA2745037C (en) | 2008-12-23 | 2020-06-23 | Boehringer Ingelheim International Gmbh | Salt forms of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8(3-(r)-amino-piperidin-1-yl)-xanthine |
TW201036975A (en) | 2009-01-07 | 2010-10-16 | Boehringer Ingelheim Int | Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy |
AR075204A1 (es) | 2009-01-29 | 2011-03-16 | Boehringer Ingelheim Int | Inhibidores de dpp-4 y composiciones farmaceuticas que los comprenden, utiles para tratar enfermedades metabolicas en pacientes pediatricos, particularmente diabetes mellitus tipo 2 |
US20120094894A1 (en) | 2009-02-13 | 2012-04-19 | Boehringer Ingelheim International Gmbh | Antidiabetic medications comprising a dpp-4 inhibitor (linagliptin) optionally in combination with other antidiabetics |
UY32427A (es) | 2009-02-13 | 2010-09-30 | Boheringer Ingelheim Internat Gmbh | Composicion farmaceutica, forma farmaceutica, procedimiento para su preparacion, metodos de tratamiento y usos de la misma |
CN102307577A (zh) | 2009-02-13 | 2012-01-04 | 贝林格尔.英格海姆国际有限公司 | 包含sglt2抑制剂、dpp-iv抑制剂和任选的另一种抗糖尿病药的药物组合物及其用途 |
TW201031661A (en) | 2009-02-17 | 2010-09-01 | Targacept Inc | Fused benzazepines as neuronal nicotinic acetylcholine receptor ligands |
WO2010106457A2 (en) | 2009-03-20 | 2010-09-23 | Pfizer Inc. | 3-oxa-7-azabicyclo[3.3.1]nonanes |
US8815292B2 (en) | 2009-04-27 | 2014-08-26 | Revalesio Corporation | Compositions and methods for treating insulin resistance and diabetes mellitus |
US20120059011A1 (en) | 2009-06-15 | 2012-03-08 | Nicholas Birringer | Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with pioglitazone |
AU2010276242B2 (en) | 2009-07-21 | 2014-05-29 | Keryx Biopharmaceuticals, Inc. | Ferric citrate dosage forms |
US10610489B2 (en) | 2009-10-02 | 2020-04-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof |
ES2942185T3 (es) | 2009-10-02 | 2023-05-30 | Boehringer Ingelheim Int | Composiciones farmacéuticas que comprenden BI-1356 y metformina |
CN107115530A (zh) | 2009-11-27 | 2017-09-01 | 勃林格殷格翰国际有限公司 | 基因型糖尿病患者利用dpp‑iv抑制剂例如利拉利汀的治疗 |
JP2010070576A (ja) | 2009-12-28 | 2010-04-02 | Sato Pharmaceutical Co Ltd | 速溶解性錠剤 |
EP2547339A1 (en) | 2010-03-18 | 2013-01-23 | Boehringer Ingelheim International GmbH | Combination of a gpr119 agonist and the dpp-iv inhibitor linagliptin for use in the treatment of diabetes and related conditions |
AR082091A1 (es) | 2010-05-05 | 2012-11-14 | Boehringer Ingelheim Int | Composiciones farmaceuticas que comprenden pioglitazona y linagliptina y procedimiento de preparacion |
AU2011249722B2 (en) | 2010-05-05 | 2015-09-17 | Boehringer Ingelheim International Gmbh | Combination therapy |
KR20220025926A (ko) | 2010-06-24 | 2022-03-03 | 베링거 인겔하임 인터내셔날 게엠베하 | 당뇨병 요법 |
US20130224296A1 (en) | 2010-09-03 | 2013-08-29 | Bristol-Myers Squibb Company | Drug Formulations Using Water Soluble Antioxidants |
AR083878A1 (es) | 2010-11-15 | 2013-03-27 | Boehringer Ingelheim Int | Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento |
JP2014504639A (ja) | 2011-02-01 | 2014-02-24 | ブリストル−マイヤーズ スクイブ カンパニー | アミン化合物を含む医薬製剤 |
UY33937A (es) | 2011-03-07 | 2012-09-28 | Boehringer Ingelheim Int | Composiciones farmacéuticas que contienen inhibidores de dpp-4 y/o sglt-2 y metformina |
CA2835332C (en) | 2011-05-10 | 2019-03-26 | Sandoz Ag | Polymorph of linagliptin benzoate |
KR101985384B1 (ko) | 2011-07-15 | 2019-06-03 | 베링거 인겔하임 인터내셔날 게엠베하 | 치환된 퀴나졸린, 이의 제조 및 약제학적 조성물에서의 이의 용도 |
US20130172244A1 (en) | 2011-12-29 | 2013-07-04 | Thomas Klein | Subcutaneous therapeutic use of dpp-4 inhibitor |
US9139802B2 (en) | 2012-01-04 | 2015-09-22 | The Procter & Gamble Company | Active containing fibrous structures with multiple regions |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
EP2849755A1 (en) | 2012-05-14 | 2015-03-25 | Boehringer Ingelheim International GmbH | A xanthine derivative as dpp -4 inhibitor for use in the treatment of podocytes related disorders and/or nephrotic syndrome |
WO2013174768A1 (en) | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in the treatment of autoimmune diabetes, particularly lada |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004018468A2 (de) * | 2002-08-21 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthine, deren herstellung und deren verwendung als arzneimittel |
CN101048409A (zh) * | 2004-11-05 | 2007-10-03 | 贝林格尔·英格海姆国际有限公司 | 手性8-(3-氨基-哌啶-1-基)-黄嘌呤的制备方法 |
TW200812591A (en) * | 2006-05-04 | 2008-03-16 | Boehringer Ingelheim Int | Polymorphs |
Non-Patent Citations (1)
Title |
---|
ECKHARDT M ET AL: "8-(3-(R)-aminopiperidin-1-yl)-7-but-2-yny l-3-methyl-1-(4-methyl-quina zolin- 2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes" 27 December 2007 (2007-12-27), JOURNAL OF MEDICINAL CHEMISTRY 20071227 US, VOL. 50, NR. 26, PAGE(S) 6450 - 6453 * |
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Publication number | Publication date |
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CN102256976A (zh) | 2011-11-23 |
EA201100969A1 (ru) | 2012-01-30 |
IL212604A0 (en) | 2011-07-31 |
JP2012512848A (ja) | 2012-06-07 |
WO2010072776A1 (en) | 2010-07-01 |
CA2745037A1 (en) | 2010-07-01 |
US20140303194A1 (en) | 2014-10-09 |
AR074879A1 (es) | 2011-02-16 |
US9212183B2 (en) | 2015-12-15 |
JP6169524B2 (ja) | 2017-07-26 |
KR20110103968A (ko) | 2011-09-21 |
BRPI0923121A2 (pt) | 2015-08-11 |
CA2745037C (en) | 2020-06-23 |
AU2009331471B2 (en) | 2015-09-03 |
CN107011345A (zh) | 2017-08-04 |
US8865729B2 (en) | 2014-10-21 |
AU2009331471A1 (en) | 2010-07-01 |
EA022310B1 (ru) | 2015-12-30 |
CL2011001182A1 (es) | 2011-09-30 |
NZ592924A (en) | 2014-05-30 |
US20120129874A1 (en) | 2012-05-24 |
TW201033208A (en) | 2010-09-16 |
JP2014167007A (ja) | 2014-09-11 |
EP2382216A1 (en) | 2011-11-02 |
MX2011006713A (es) | 2011-07-13 |
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