TW201517910A - 黃體激素受體拮抗劑之劑型 - Google Patents
黃體激素受體拮抗劑之劑型 Download PDFInfo
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- TW201517910A TW201517910A TW103113485A TW103113485A TW201517910A TW 201517910 A TW201517910 A TW 201517910A TW 103113485 A TW103113485 A TW 103113485A TW 103113485 A TW103113485 A TW 103113485A TW 201517910 A TW201517910 A TW 201517910A
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Abstract
本發明係關於一種醫藥組合物，其包含劑量約0.5mg至5mg，且更特定言之2mg之黃體激素受體拮抗劑，亦即(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮。另外，本發明係關於該新穎醫藥組合物用於治療及/或預防婦科疾病(諸如：子宮之類纖維瘤(肌瘤、子宮平滑肌瘤)、子宮內膜異位或月經出血過量)之用途，及獲得該組合物及口服劑型之方法。
Description
本發明係關於一種醫藥組合物，其以約0.5mg至5mg，且更特定言之2mg之劑量包含黃體激素受體拮抗劑，亦即(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮。另外，本發明係關於該新穎醫藥組合物用於治療及/或預防婦科疾病之用途及獲得該組合物及口服劑型之方法，該等婦科疾病諸如為子宮之類纖維瘤(肌瘤、子宮平滑肌瘤)、子宮內膜異位或月經出血過量。
子宮平滑肌瘤(亦稱作類纖維瘤或肌瘤)為常見的子宮肌層之良性腫瘤，據報導其出現在所有生殖年齡女性之大致30-40%中。其可保持無症狀的，或視其數目、尺寸及位置而定引起出血異常及/或大部分相關的症狀。各種藥劑(例如組合的口服避孕藥、助孕素、鐵補充劑)用於微小疾病中之症狀導向型療法。對於短期療法及/或作為手術之前驅物而言，促性腺激素釋放的激素促效劑代表最有效的醫學治療。然而，由於低雌激素副作用，其使用受限制至6個月。對於有症狀的平滑肌瘤之確定治療而言，迄今為止治療選擇主要為外科的。
各種研究表明類纖維瘤生長之甾類依賴性，其中黃體激素具有關鍵作用。此係藉由事實支持，已顯示黃體激素受體(progesterone receptor，PR)拮抗劑(如米非司酮(mifepristone)(RU 486))減小類纖維瘤之尺寸且減輕相關症狀。因此，PR拮抗劑可能使用不存在臨床上相關副作用的口服有效試劑來提供滿足有症狀的類纖維瘤之醫學長期
治療之需求的有前景的治療替代物。米非司酮(RU 486)係揭示於EP57115中。另外的競爭性黃體激素受體調節劑顯示於下文。
(a)米非司酮(11β-4-二甲胺基苯基-17β-羥基-17α-丙炔基-4,9-雌甾二烯-3-酮)、(b)CDB-4124(17α-乙醯氧基-11β-[4-(N,N-二甲胺基)苯基]-21-甲氧基-19-去甲孕甾-4,9-二烯-3,20-二酮)、(c)CDB-2914(17α-乙醯氧基-11β-(4-N,N-二甲胺基苯基)-19-去甲孕甾-4,9-二烯-3,20-二酮)、(d)ZK-230211(11β-(4-乙醯基苯基)-17β-羥基-17α-(1,1,2,2,2-五氟乙基)-4,9-雌甾-二烯-3-酮)及(e)索普瑞尼(asoprisnil)(苯甲醛-4-[(11β,17β)-17-甲氧基-17-(甲氧基甲基)-3-氧雌甾-4,9-二烯-11-基]-1-肟)之結構組態。
來自Spitz等人，Current Opinion in Obstetrics and Gynecology,2009,21：318-324。
如上文所列的所有此等化合物在子宮類纖維瘤之治療中為有效的，伴隨有疼痛、出血之減少及生活品質之改善及類纖維瘤尺寸之減小。長期治療伴隨有基於超音波及子宮內膜中之組織學變化之子宮內膜變厚。諸如子宮內膜變厚之子宮內膜變化似乎與囊性腺膨脹相關聯(Spitz等人，Current Opinion in Obstetrics and Gynecology,2009,21：318-324.)。
具有經氟化的17α-側鏈之黃體激素受體拮抗劑公開在WO 98/34947及Fuhrmann等人，J.Med.Chem.43,5010-5016(2000)中。
在PEARL I及PEARL II試驗(N Engl J Med.2012；366：409-420)中，隨機向由於類纖維瘤之存在而患有子宮出血過量的女性提供醋酸烏利司他(ulipristal acetate)(每天口服一次5mg與10mg)與安慰劑或對其肌肉內注射醋酸亮丙立德(leuprolide acetate)長達13週。
得出結論，在使用大部分上文所引用之黃體激素受體拮抗劑治療期間觀測到子宮內膜變化。
出人意料地發現(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮為產生治療婦科疾病之替代方案的有效競爭性黃體激素受體拮抗劑。在用該化合物治療的健康個體中觀測到停經。(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮最初揭示於WO2011/009531A1中。此外，出人意料地發現約0.5mg至5mg之劑量，且更特定言之2mg之劑量的有效黃體激素受體拮抗劑(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮適用於治療某些婦科疾病，其中該婦科疾病較佳地以子宮出血過量為特徵。實際上，在以2mg之劑量投與該化合物的健康個體中觀測到92.5%停經(不出血)。停經對應於治療之主要目標，亦即控制子宮出血過量。
就本發明而言，在治療結束之後的恢復出血及子宮內膜厚度方面觀測到進一步改善。
本發明係關於一種包含約0.5mg至5mg之(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮之醫藥組合物及在有需要的病患中治療及/或預防婦科疾病，其中該婦科疾病較佳地以子宮出血過量為特徵。
本發明係關於一種包含約2mg之(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮之醫藥組合物及在有需
要的病患中治療及/或預防婦科疾病，其中該婦科疾病較佳地以子宮出血過量為特徵。
此外，本發明係關於一種包含約2mg之(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮之口服劑型及在有需要的病患中治療及/或預防婦科疾病，其中該婦科疾病較佳地以子宮出血過量為特徵。
最後，本發明係關於一種獲得該醫藥組合物或口服劑型之方法。
本發明之化合物定義為具有經良好確認的拮抗劑特性之選擇性黃體激素受體調節劑。
圖1係未出血比率之事後分佈-全訊息先驗(符合方案數據集)。
圖2係在治療期內最大子宮內膜厚度之盒鬚圖。
在第一態樣中，本發明係關於一種醫藥組合物，其包含約0.5mg至5mg之具有以下化學式之(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮
或其鹽。
較佳地，醫藥組合物彼此獨立地包含範圍為約0.7mg至5mg、0.7mg至4.5mg、1mg至4.5mg、1mg至4mg、1.5mg至3.5mg或1.5mg至3mg之上文提及的化合物或其鹽。更佳地，醫藥組合物彼此獨立地包含範圍為約0.7mg至5mg、1mg至4mg或1.5mg至3mg之上文提及的化合物或其鹽。甚至更佳地，醫藥組合物包含範圍為約1mg至
4mg之上文提及的化合物或其鹽。
較佳地，醫藥組合物包含0.5mg、0.7mg、1mg、2mg、3mg、4mg、或5mg之上文提及的化合物或其鹽。更佳地，醫藥組合物包含2mg、3mg或4mg之上文提及的化合物或其鹽。
甚至更佳地，本發明係關於一種醫藥組合物，其包含約2mg之具有以下化學式之(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮
或其鹽。
在第一實施例中，醫藥組合物另外包含醫藥學上可接受之賦形劑。
醫藥學上可接受之賦形劑定義為填充劑(諸如糖，諸如乳糖、蔗糖、右旋糖及葡萄糖結合劑；糖醇，諸如甘露醇、山梨醇及木糖醇；鹼土金屬之碳酸鹽及磷酸鹽，諸如碳酸鈣及磷酸鈣；纖維素，諸如粉末狀纖維素及微晶纖維素；膠態二氧化矽；二氧化鈦；高嶺土；滑石)或潤滑劑(諸如硬脂酸鎂)。
在第二實施例中，該醫藥組合物另外包含醫藥學上可接受之賦形劑及/或至少一種或多種其他活性物質，特定言之已知用於治療及/或預防前述疾病之活性物質。
對於治療子宮之類纖維瘤或子宮內膜異位而言，根據本發明之化合物可同時或依次組合使用促孕素或動情素與促孕素之組合。
黃體激素受體拮抗劑/促孕素療程揭示於WO 96/15794(Spicer等人，Balance Pharm.Inc.)、WO 96/03130(Stöckemann等人，Schering AG)及PCT/EP2009/003249(Möller等人，Bayer Schering Pharma AG)
中。可視情況重複之療程(其中投與黃體激素受體拮抗劑歷時兩個月至四個月，之後投與促孕素一週至四週)極適於治療子宮之類纖維瘤及子宮內膜異位。尤其適合投與黃體激素受體拮抗劑84天，之後投與促孕素14天(可視情況重複)。
根據本發明化合物可以例如：與SERM、SERD及動情素同時或連續投藥用於治療與停經相關之不適症狀。
選擇性雌激素受體調節劑(selective estrogen receptor modulators，SERM)為具組織選擇性且具有抗動情素或動情素作用之化合物，例如在子宮上其抑制動情素之作用，但在骨骼上其具有中性或類似動情素作用。實例為克羅米芬(clomifene)、雷洛昔芬(raloxifene)、他莫昔芬(tamoxifen)、托瑞米芬(torimifene)、巴多昔芬(bazedoxifene)、拉索昔芬(lasofoxifene)及奧美昔芬(ormeloxifene)。
選擇性雌激素受體去穩定劑(Selective estrogen receptor destabilizer，SERD)為完全拮抗動情素受體(『純抗動情素』，不含動情活性組分)且造成調降受體之藥劑(例如氟維司群(fulvestrant)、ZK-703及ZK-253(Hoffmann J等人，J Natl Cancer Inst 2004,96：210-218)及描述於WO 98/007740、WO 99/33855及WO 03/045972中之化合物)。抗動情素為完全拮抗動情素受體之化合物，例如氟維司群。
在本發明意義上，促孕素為天然黃體激素本身或合成的衍生物，其類似於黃體激素本身會結合至黃體激素受體，且在高於抑制排卵劑量之劑量下會抑制排卵。作為合成的衍生物之實例，吾人可提及屈螺酮(drospirenone)、孕二烯酮(gestodene)、左炔諾孕酮(levonorgestrel)、醋酸環丙孕酮(cyproterone acetate)、脫氧孕烯(desogestrel)及3-酮基去氧孕烯(3-ketodesogestrel)、煥諾酮(norethisterone)、醋酸煥諾酮(norethisterone acetate)及地諾孕素(dienogest)。
促孕素與動情素之組合為含在本身已知的口服避孕藥中之活性物質組合，例如優思明(Yasmin)、炔雌醇(Femovan)、特居樂(Triquilar)、馬富隆(Marvelon)、YAZ等。
本發明包涵所有鹽、溶劑合物或鹽之溶劑合物，其包括(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮之所有晶體變體。
醫藥組合物呈對於靜脈內(intravenous，i.v.)、肌肉內(intramuscular，i.m.)或經口投與而言合適的形式。較佳地，用於投與之口服形式為諸如錠劑膠囊或溶液之劑型。儘管如此，可能視情況必須背離規定的量，亦即視進行施用時之體重、投與途徑、對活性物質之個體反應、製備類型及時間點或時間間隔點而定。因此，在一些情況下使用少於前述最低量可能為適合的，而在其他情況下必須超過規定的上限。就投與較大量而言，在一整天中以若干單獨的劑量分配此等劑型可能為可取的。
在整個說明書內，(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮被識別為本發明化合物且引用為化合物1。
應理解劑量「約2mg」意謂1.5mg至2.5mg之化合物1之任何劑量。較佳地，劑量為2mg之化合物1。
根據本發明之化合物1顯示不可預見的、有價值的藥理學、藥物代謝動力學及藥力學作用特徵。
在第二態樣中，本發明係關於一種如第一態樣中所描述之適用於治療及/或預防婦科疾病之醫藥組合物。婦科疾病較佳地以子宮出血過量為特徵。更佳地，婦科疾病為子宮之類纖維瘤(肌瘤、子宮平滑肌瘤)、子宮內膜異位或月經出血過量。甚至更佳地，婦科疾病為子宮之類纖維瘤(肌瘤、子宮平滑肌瘤)。
換言之，本發明係關於一種治療及/或預防婦科疾病之方法，該方法向有需要的患者投與包含約0.5mg至5mg之(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮或其鹽之醫藥組合物。婦科疾病較佳地以子宮出血過量為特徵。更佳地，婦科疾病為子宮之類纖維瘤(肌瘤、子宮平滑肌瘤)、子宮內膜異位或月經出血過量。甚至更佳地，婦科疾病為子宮之類纖維瘤(肌瘤、子宮平滑肌瘤)。
較佳地，醫藥組合物彼此獨立地包含範圍為約0.7mg至5mg、0.7mg至4.5mg、1mg至4.5mg、1mg至4mg、1.5mg至3.5mg或1.5mg至3mg之上文提及的化合物或其鹽。更佳地，醫藥組合物彼此獨立地包含範圍為約0.7mg至5mg、1mg至4mg或1.5mg至3mg之上文提及的化合物或其鹽。甚至更佳地，醫藥組合物包含範圍為約1mg至4mg之上文提及的化合物或其鹽。
較佳地，醫藥組合物包含0.5mg、0.7mg、1mg、2mg、3mg、4mg或5mg之上文提及之化合物或其鹽。更佳地，醫藥組合物包含2mg、3mg或4mg之上文提及的化合物或其鹽。
更特定言之，本發明係關於一種治療及/或預防婦科疾病之方法，該方法向有需要的患者投與包含約2mg之(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮或其鹽之醫藥組合物。婦科疾病較佳為以子宮出血過量為特徵。更佳地，婦科疾病為子宮之類纖維瘤(肌瘤、子宮平滑肌瘤)、子宮內膜異位或月經出血過量。甚至更佳地，婦科疾病為子宮之類纖維瘤(肌瘤、子宮平滑肌瘤)。
在第三態樣中，本發明係關於一種口服劑型，其包含約0.5mg至5mg之具有以下化學式之(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮
或其鹽。
較佳地，醫藥組合物彼此獨立地包含範圍為約0.7mg至5mg、0.7mg至4.5mg、1mg至4.5mg、1mg至4mg、1.5mg至3.5mg或1.5mg至3mg之上文提及的化合物或其鹽。更佳地，醫藥組合物彼此獨立地包含範圍為約0.7mg至5mg、1mg至4mg或1.5mg至3mg之上文提及的化合物或其鹽。甚至更佳地，醫藥組合物包含範圍為約1mg至4mg之上文提及的化合物或其鹽。
較佳地，醫藥組合物包含0.5mg、0.7mg、1mg、2mg、3mg、4mg、或5mg之上文提及的化合物或其鹽。更佳地，醫藥組合物包含2mg、3mg或4mg之上文提及的化合物或其鹽。
更特定言之，本發明係關於一種口服劑型，其包含約2mg之具有以下化學式之(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮
或其鹽。
在第一實施例中，口服劑型另外包含醫藥學上可接受之賦形劑。
在第二實施例中，口服劑型另外包含醫藥學上可接受之賦形劑及/或至少一種或多種其他活性物質，尤其是已知的用於治療及/或預防前述疾病之活性物質。
在本文中包括如上文所描述之實施例及較佳特徵。
在第四態樣中，本發明係關於一種如第三態樣中所描述之用於治療及/或預防婦科疾病之口服劑型。婦科疾病較佳為以子宮出血過量為特徵。更佳地，婦科疾病為子宮之類纖維瘤(肌瘤、子宮平滑肌瘤)、子宮內膜異位或月經出血過量。甚至更佳地，婦科疾病為子宮之類纖維瘤(肌瘤、子宮平滑肌瘤)。
在本文中包括如上文所描述之實施例及較佳特徵。
在第五態樣中，本發明係關於一種獲得如上文所描述之該醫藥組合物或口服劑型之方法。
在本文中包括如上文所描述之實施例及較佳特徵。
適用於第一至第四態樣之定義及較佳特徵：
在本發明範疇內的鹽類較佳為根據本發明化合物之生理上無害的鹽類。然而，亦涵蓋本身不適合用於醫藥用途但可(例如)用於分離或純化根據本發明之化合物的鹽類。
根據本發明化合物之生理上無害的鹽類當含有鹼性官能基時，其包含與無機酸或有機酸形成之鹽，特定言之與礦物酸、羧酸及磺酸形成之鹽，例如與氫氯酸、氫溴酸、硫酸、磷酸、甲磺酸、乙磺酸、甲苯磺酸、苯磺酸、萘-二磺酸、乙酸、三氟乙酸、丙酸、乳酸、酒石酸、蘋果酸、檸檬酸、反丁烯二酸、順丁烯二酸及苯甲酸形成之鹽。
根據本發明化合物之生理上無害的鹽當含有酸性官能基時，其包含鹼金屬鹽、鹼土金屬鹽或銨鹽，諸如可藉由與對應的無機鹼或有機鹼反應而獲得者。吾人可能提及，舉例而言且較佳為鹼金屬鹽(例如鈉鹽及鉀鹽)、鹼土金屬鹽(例如鈣鹽及鎂鹽)及銨鹽(其衍生自氨或具有1至16個碳原子之有機胺，諸如，舉例而言及較佳為乙胺、二乙胺、三乙胺、乙基二異丙胺、單乙醇胺、二乙醇胺、三乙醇胺、雙環-己胺、二甲胺基-乙醇、普魯卡因(procaine)、二苄胺、N-甲基嗎啉、
精胺酸、離胺酸、乙二胺、N-甲基哌啶、N-甲基還原葡糖胺、D-甲基還原葡糖胺、乙基還原葡糖胺、1,6-己二胺、葡糖胺、N-甲基甘胺酸、2-胺基-1,3-丙二醇、參-羥甲基-胺基甲烷及1-胺基-2,3,4-丁三醇)。
彼等呈固態或液態形式之根據本發明化合物與溶劑分子形成之加合物在本發明之範疇內稱為溶劑合物。溶劑可依化學計量比例或甚至依非化學計量比例存在。就化學計量溶劑合物而言，其亦稱作半-(hemi-)、(半-)((semi-))、單-(mono-)、倍半-(sesqui-)、二-(di-)、三-(tri-)、四-(tetra-)、五-(penta-)，等等溶劑合物。水合物為其中與水進行配位之特殊溶劑合物形式。
可藉由根據本發明之化合物作為黃體激素受體拮抗劑之作用，且因此藉由其在黃體激素受體上之拮抗作用來解釋其醫藥功效。
本發明之另一目標為根據本發明之化合物用於治療及/或預防基於激素依賴性過度增殖過程的疾病之用途，較佳為治療及/或預防婦科疾病，特定言之子宮之類纖維瘤、子宮內膜異位或激素依賴性乳癌。
根據本發明之化合物可全身性及/或局部地起作用。為此目的，其可以適合之方式施用，例如藉由經口、子宮內、陰道內、非經腸、經肺、經鼻、舌下、經舌、頰內、經直腸、經皮、透皮、經結膜或經耳之途徑，或作為植入物或血管內支架。
子宮內尤其意謂藉助於子宮內體系(intrauterine system，IUS)或子宮內裝置(intrauterine device，IUD)之施用。除其他之外，陰道內施用可藉助於陰道內環/陰道環體系(intravaginal ring/vaginal ring system，IVR/VRS)來實現。
子宮內或陰道內施用之形式(參看例如WO 01/47490，尤其第1頁第10行至第5行、第13行及第7行、第19行至第58行、第6行，或對於
陰道環：WO 06/010097，尤其第10頁第22行至第14頁第28行)可含有根據本發明之化合物及非聚矽氧及/或聚矽氧聚合物，尤其亦含有基於矽氧烷之彈性體(參看WO 01/47490，尤其第7頁第19行-第15頁第15行)。
對於此等投與途徑而言，根據本發明之化合物可以適合的劑型投與。
根據先前技術起作用的快速釋放及/或緩釋劑型適合於經口投與，其含有呈結晶及/或非晶形及/或溶解形式之根據本發明之化合物，該等形式例如錠劑(未經包覆或經包覆之錠劑，例如具有控制根據本發明之化合物之釋放的腸溶包衣或延緩溶解包衣或不溶性包衣)、在口腔中快速崩解的錠劑或薄膜/粉片、薄膜/凍乾物、膠囊(例如硬明膠膠囊或軟明膠膠囊)、經包覆之錠劑、粒劑、丸劑、粉劑、乳劑、懸浮液、氣霧劑或溶液。
非經腸施用可在避免吸收步驟(例如靜脈內、動脈內、心內、脊椎內或腰內)或包括吸收(例如肌肉內、皮下、皮內、經皮或腹膜內)的情況下進行。除其他之外，呈溶液、懸浮液、乳劑、凍乾物或無菌粉劑形式之注射及輸液製劑適合作為非經腸投與之劑型。
對於其他投與途徑而言，以下為適合的，例如吸入劑型(包括粉末吸入劑、噴霧劑)、經鼻滴劑、溶液及噴霧劑；用於經舌、舌下或頰內投與之錠劑，薄膜/粉片或膠囊，栓劑，耳或眼製劑，陰道膠囊，水狀懸浮液(洗劑、搖晃混合物)，親脂性懸浮液，軟膏，乳膏，經皮治療體系(例如貼劑)，乳狀物，糊劑，泡沫劑，敷粉，植入物或血管內支架。
可將根據本發明之化合物轉化成前述劑型。此可以本身已知的方式進行，藉由與惰性的、無毒的、醫藥學上適合的賦形劑混合。除其他之外，此等賦形劑包括載劑物質(例如微晶纖維素、乳糖、甘露
醇)、溶劑(例如液態聚乙二醇)、乳化劑及分散劑或潤濕劑(例如十二烷基硫酸鈉、聚氧脫水山梨醇油酸鹽)、黏合劑(例如聚乙烯吡咯啶酮)、合成的及天然的聚合物(例如白蛋白)、穩定劑(例如抗氧化劑，例如抗壞血酸)、染色物質(例如無機顏料，例如氧化鐵)及味道及/或氣味矯味藥。
除非另外陳述，否則在以下測試及實例中，百分比為重量百分比；份為重量份。用於液體/液態溶液的溶劑、稀釋比率及濃度數字之比例始終係指體積。
以下實例用以解釋本發明而不以任何方式限制本發明。
將5g描述於實例1b)中之化合物溶解於140ml THF與140ml甲醇之混合物中。在0℃下緩慢逐滴添加20g Oxone®於94ml水中之溶液。隨後在0℃下將其攪拌另外3.5小時。隨後將水與二氯甲烷之混合物添加至反應混合物中。分隔相，且用二氯甲烷萃取水相若干次。用飽和氯化鈉水溶液洗滌經合併之有機相，經硫酸鈉乾燥，且在真空中濃縮。藉由矽膠層析來純化粗製產物。此得到3.8g標題化合物。
1H-NMR(300MHz,CDCl3)：δ=7.86 d(2H)；7.40 d(2H)；5.81 sbr(1H)；4.50 dbr(1H)；3.07 s(3H)；0.51 s(3H).
1. 健康女性個體，藉由小管結紮滅菌
2. 篩選年齡：18-45歲
3. 篩選的身體質量指數(Body mass index，BMI)：18且32kg/m2
4. 在根據個體之病史初次篩選檢查之前至少3次週期長度為24-35天的連續規律的月經週期
5. 在預治療子宮內膜生檢中不存在臨床上相關異常結果
6. 適當的靜脈通路(頻繁血液取樣)
在預治療週期之後個體必須在月經出血之第一或第二天開始攝取研究藥物。開始於個體在篩選檢查之後的月經出血之第一天的預治療週期已顯示個體對於進一步參與為合格的。在預治療週期之後開始治療。治療時段以化合物1之第一次攝取開始且以化合物1之最後一次攝取結束。在各攝取日，個體收到一個含有4粒錠劑的小瓶。服用的錠劑之數目及攝取時間必須記錄於日記中。
出血型式之評價係基於個體對出血強度之每天自評估。此等評估如下文所定義的來分類。以本土語言向個體提供類別之說明，且要
求其在其日記中相應地記錄出血強度(每天記錄一次)。
在84天期間投與化合物1(多劑量投與)。
出血型式之結果顯示於圖1中(未出血之事後分佈(符合方案數據集))。
在治療時段期間觀測到化合物1引起出血天數之顯著的及劑量依賴性的減少。在投與0.5mg之化合物1之後，十一(11)個個體中之三(3)個(27%)在84天之治療時段期間未進一步出血。在0.7mg之劑量下觀測到50%之劑量依賴性出血減少。明顯的停滯在大約2mg之劑量下出現且自2mg直至5mg之劑量下觀測到大約95%之飽和。
如實例2中所描述。
標記治療結束之後的第一天出血。
在84天期間用2mg之化合物1治療的研究個體顯示延緩的出血恢復，平均值為25天。對於個體，治療之後延緩的出血恢復產生每年更長的無出血時段。在治療之後一個個體顯示約52天的延緩的出血恢復。
所有結果均在下表3中。
如實例2中所描述。
使用經陰道超音波以中部矢狀部分作為雙層以毫米為單位量測子宮內膜厚度。
在84天期間用2mg之化合物1治療之研究個體與使用其他劑量的化合物1之研究個體相比顯示較小的子宮內膜之最大厚度。此外，觀測到的該組個體之結果比其他劑量組更為一致。
參見圖2(在治療期內最大子宮內膜厚度之盒鬚圖)。
Bay意謂化合物1。
方案：如上文實例2中所描述之健康女性個體之隨機研究人群。
自健康女性個體獲得血液樣品用於測定血清中之雌甾二醇(E2)、黃體激素(P)、促黃體素(luteinizing hormon，LH)及激濾泡素(follicle stimulating hormone，FSH)，且於預治療週期、治療及後續週期期間在與下文所列相同的時間點進行。
經陰道超音波(transvaginal ultrasound，TVU)用於在預治療(第9
及第21天)、治療(第7、14、21、28、35、42、49、56、63、70、77、84天)及後續週期(第9及第21天)期間監測卵巢卵泡生長。
表4顯示個體之數目與百分比，根據在治療時段期間最大卵泡尺寸及雌甾二醇(E2)及黃體激素(P)值歸類(個體之數目n=69)。
在治療期間，在所有治療組(包括安慰劑)之大部分個體中卵泡狀結構(Follicle-like structure，FLS)之最大直徑為13mm與30mm之間。
在84天的受試治療期間在大部分接受劑量0.5mg之化合物1的個體中未發生排卵(亦即黃體激素值<1.57μg/L)。
Claims (13)
- 一種醫藥組合物，其包含約0.5mg至5mg之具有以下化學式之(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮
- 如請求項1之醫藥組合物，其中該醫藥組合物包含約1mg至4mg之(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮。
- 如請求項1或2之醫藥組合物，其中該醫藥組合物包含約2mg之(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮。
- 如請求項1或2之醫藥組合物，其另外包含醫藥學上可接受之載劑。
- 如請求項1或2之醫藥組合物，其呈口服劑型，其中該劑型為錠劑或膠囊。
- 一種如請求項1至5中任一項之醫藥組合物之用途，其用於製造用於治療及/或預防婦科疾病之藥劑，該婦科疾病較佳地以子宮出血過量為特徵，諸如子宮之類纖維瘤(肌瘤、子宮平滑肌瘤)、子宮內膜異位或月經出血過量。
- 如請求項6之用途，其中該藥劑用於治療子宮之類纖維瘤(肌瘤、子宮平滑肌瘤)。
- 一種口服劑型，其包含約0.5mg至5mg之具有以下化學式之 (11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮
- 如請求項8之口服劑型，其包含約2mg之具有以下化學式之(11β,17β)-17-羥基-11-[4-(甲基磺醯基)苯基]-17-(五氟乙基)雌甾-4,9-二烯-3-酮
- 一種如請求項8或9之口服劑型之用途，其用於製造用於治療及/或預防婦科疾病之藥劑，該婦科疾病較佳地以子宮出血過量為特徵，諸如子宮之類纖維瘤(肌瘤、子宮平滑肌瘤)、子宮內膜異位或月經出血過量。
- 如請求項10之用途，其中該藥劑用於治療子宮之類纖維瘤(肌瘤、子宮平滑肌瘤)。
- 一種獲得如請求項1至7中任一項中所述的醫藥組合物的方法。
- 一種獲得如請求項8至11中任一項中所述的口服劑型的方法。
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| ??13163417.2 | 2013-04-11 | ||
| EP13163417 | 2013-04-11 |
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| TW201517910A true TW201517910A (zh) | 2015-05-16 |
| TWI672142B TWI672142B (zh) | 2019-09-21 |
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| TW103113485A TWI672142B (zh) | 2013-04-11 | 2014-04-11 | 黃體激素受體拮抗劑之劑型 |
| TW107141225A TW201932116A (zh) | 2013-04-11 | 2014-04-11 | 黃體激素受體拮抗劑之劑型 |
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| TW107141225A TW201932116A (zh) | 2013-04-11 | 2014-04-11 | 黃體激素受體拮抗劑之劑型 |
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| CN113797210A (zh) * | 2015-05-18 | 2021-12-17 | 拜耳医药股份有限公司 | 选择性孕酮受体调节剂(sprm)方案 |
| EP3214092A1 (en) * | 2016-03-04 | 2017-09-06 | Bayer Pharma Aktiengesellschaft | Prodrugs of the selective progesterone receptor modulator (sprm) (11.beta.,17.beta.)-17-hydroxy-11-[4-(methylsulphonyl)phenyl]-17-(pentafluoroethyl)estra-4,9-dien-3-one |
| EP3384913A1 (en) * | 2017-04-03 | 2018-10-10 | Bayer Pharma Aktiengesellschaft | Selective progesterone receptor modulators and stabilized estrogen level in patient |
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| DE4426601A1 (de) | 1994-07-27 | 1996-02-01 | Schering Ag | Verwendung eines Kombinationsproduktes enthaltend einen kompetitiven Progesteronantagonisten und ein Gestagen zur Herstellung eines Arzneimittels zur Behandlung der Endometriose oder des Leiomyomata uteri |
| ES2218556T3 (es) | 1994-11-22 | 2004-11-16 | Balance Pharmaceuticals, Inc. | Metodos de contracepcion. |
| DE19635525A1 (de) | 1996-08-20 | 1998-02-26 | Schering Ag | 7alpha-(xi-Aminoalkyl)-estratriene, Verfahren zu deren Herstellung, pharmazeutische Präparate, die diese 7alpha(xi-Aminoalkyl-estratriene enthalten sowie deren Verwendung zur Herstellung von Arzneimitteln |
| DE19706061A1 (de) | 1997-02-07 | 1998-08-13 | Schering Ag | Antigestagen wirksame Steroide mit fluorierter 17alpha-Alkylkette |
| AR015500A1 (es) | 1997-12-23 | 2001-05-02 | Schering Ag | 11 BETA-HALoGENO-ESTRATRIENOS SUSTITUIDOS EN 7 ALFA, PROCEDIMIENTO PARA ELABORAR PREPARADOS FARMACEUTICOS QUE CONTIENEN TALES 11 BETA-HALOGENO-ESTRATRIENOSSUSTITUIDOS EN 7 ALFA, ASI COMO SU UTILIZACION EN LA ELABORACION DE MEDICAMENTOS. |
| US6476079B1 (en) | 1999-12-23 | 2002-11-05 | Leiras Oy | Devices for the delivery of drugs having antiprogestinic properties |
| DE10159217A1 (de) | 2001-11-27 | 2003-06-05 | Schering Ag | 17alpha-Alkyl-17ß-oxy-estratriene und Zwischenprodukte zu deren Herstellung, Verwendung der 17alpha-Alkyl-17ß-oxy-estratriene zur Herstellung von Arzneimitteln sowie pharmazeutische Präparate |
| US20040242551A1 (en) * | 2003-05-28 | 2004-12-02 | Schering Ag | Composition comprising antiprogestins and pure antiestrogens for prophylaxis and treatment of hormone-dependent diseases |
| US8088758B2 (en) * | 2003-11-12 | 2012-01-03 | Abbott Products Gmbh | 17β-hydroxysteroid dehydrogenase type I inhibitors |
| BRPI0513141A (pt) | 2004-07-09 | 2008-04-29 | Population Council Inc | composição para anel vaginal, e, processo de contracepção a longo prazo |
| DE102009034362A1 (de) * | 2009-07-20 | 2011-01-27 | Bayer Schering Pharma Aktiengesellschaft | 17-Hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-aryl-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung zur Behandlung von Krankheiten |
| DE102009034525A1 (de) * | 2009-07-21 | 2011-01-27 | Bayer Schering Pharma Aktiengesellschaft | 17-Hydroxy-17-pentafluorethyl-estra-4,9(10)-dien-11-aryl-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung zur Behandlung von Krankheiten |
| DE102010007722A1 (de) * | 2010-02-10 | 2011-08-11 | Bayer Schering Pharma Aktiengesellschaft, 13353 | Progesteronrezeptorantagonisten |
| DE102010007719A1 (de) * | 2010-02-10 | 2011-08-11 | Bayer Schering Pharma Aktiengesellschaft, 13353 | Progesteronrezeptorantagonisten |
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