CN102482235B - 苯并噁嗪酮化合物的结晶 - Google Patents
苯并噁嗪酮化合物的结晶 Download PDFInfo
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- C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本发明提供作为肥胖症等的预防剂或治疗剂有用的2-十六烷氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮的结晶。本发明涉及2-十六烷氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮的结晶,该结晶具有在粉末X射线衍射的晶面间距(d)为16.54±0.2、13.26±0.2、4.70±0.2、4.38±0.2、3.67±0.2埃的附近出现特征峰的粉末X射线衍射图谱。
Description
技术领域
本发明涉及作为肥胖症的预防剂或治疗剂有用的苯并噁嗪酮化合物的结晶。
发明背景
美国专利第6624161号说明书中报告了具有脂肪酶抑制作用、作为肥胖症等的预防剂或治疗剂有用的2-十六烷氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮。
发明内容
人们一直期望一种有效性和安全性优良的肥胖症的预防剂或治疗剂。本发明的目的在于提供作为肥胖症的预防剂或治疗剂有用的2-十六烷氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮的新的结晶。
本发明人进行认真的探索,结果成功地将2-十六烷氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮(新利司他,Cetilistat)制成稳定性高的结晶,并发现该结晶是能充分满足作为药品的结晶,基于这些发现完成了本发明。
即,本发明涉及以下发明:
(1)一种2-十六烷氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮的结晶,上述结晶具有在粉末X射线衍射的晶面间距(d)为16.54±0.2、13.26±0.2、4.70±0.2、4.38±0.2、3.67±0.2埃的附近出现特征峰的粉末X射线衍射图谱;
(2)含有上述(1)所述的结晶而形成的药品;
(3)作为肥胖症的预防剂或治疗剂的上述(2)所述的药品等。
发明的效果
本发明的结晶(例如,下述的A型结晶、B型结晶)具有优良的脂肪酶抑制作用、脂肪吸收抑制作用等,而且由于毒性低,因此可用作药品。
附图的简单说明
图1表示实施例1的B型结晶的粉末X射线衍射图谱。
图2表示参考例1的A型结晶的粉末X射线衍射图谱。
(发明的详细说明)
本发明的2-十六烷氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮(以下,也简称为“苯并噁嗪酮化合物”)的结晶可以是水合物等溶剂合物,也可以是非溶剂合物。
作为上述“水合物”,可例举0.5水合物至5.0水合物。其中,优选0.5水合物、1.0水合物、1.5水合物、2.0水合物、2.5水合物。特别优选0.5水合物、1.0水合物、1.5水合物。
本发明的苯并噁嗪酮化合物或其水合物也可以是氘取代物(日语:重水素変換体)。
此外,本发明的苯并噁嗪酮化合物的结晶也可以是水合物以外的溶剂合物。
作为苯并噁嗪酮化合物的溶剂合物结晶,可例举例如甲醇合物结晶、乙醇合物结晶等醇合物结晶(优选C1-6醇合物结晶)或者附加了水和有机溶剂的有机溶剂·水合物结晶(例如,甲醇·水合物、乙醇·水合物等醇·水合物结晶,优选C1-6醇·水合物结晶)等。
本发明的结晶可通过使非晶态的苯并噁嗪酮化合物或者苯并噁嗪酮化合物的其它结晶进行结晶转变来制造。
结晶转变是在超过某个温度或者压力时结晶结构发生变化的现象。
作为“结晶转变法”,可例举其本身公知的方法,可例举例如自溶液的结晶化(例如,浓缩法、除冷法、反应法(扩散法、电解法)、水热育成法、熔剂法等)、自蒸气的结晶化(例如,气化法(密封管法、气流法)、气相反应法、化学输送法)、自熔融体的结晶化(正常凝固法(直拉法、温度梯度法、布里奇曼法(Bridgman method))、带熔融法(区熔匀化、浮区法)、特殊生长法(气液固反应法(VLS法)、液相外延法))、泻流法(将结晶溶于溶剂,过滤后在大气条件下使溶剂蒸发)、淤浆法(向溶剂中添加结晶使过量的固体剩余以制成悬浊液,在大气温度、加热或冷却下搅拌后,滤集固体)、减压干燥、磨碎、粉碎、加压等。
为获得本发明的结晶,上述的方法中特别优选淤浆法。特别优选向溶剂中添加苯并噁嗪酮化合物的结晶使过量的固体剩余以制成悬浊液,搅拌后滤集固体的方法。作为使用的溶剂,可例举例如芳香族烃类(例如,苯、甲苯、二甲苯等)、卤代烃类(例如,二氯甲烷、三氯甲烷等)、饱和烃类(例如,己烷、庚烷、环己烷等)、醚类(例如,二乙醚、二异丙醚、四氢呋喃、二噁烷等)、腈类(例如,乙腈等)、酮类(例如,丙酮等)、亚砜类(例如,二甲亚砜等)、酰胺类(N,N-二甲基甲酰胺等)、酯类(例如,乙酸乙酯等)、醇类(例如,甲醇、乙醇、异丙醇等)、水等。这些溶剂可单独使用,也可以将两种以上溶剂以合适的比例(例如,1∶1至1∶100)混合后使用。优选芳香族烃类(例如,二甲苯等)、醚类(例如,四氢呋喃等),更加优选醚类(例如,四氢呋喃等)。
相对于1g苯并噁嗪酮化合物的结晶,溶剂的使用量通常约为2.5mL~约10mL,优选为约2.5mL~约3mL。
优选悬浊液在大气温度下搅拌后,在冷却下再进行搅拌。本说明书中,室温、大气温度是指约15℃~约30℃。在大气温度下的搅拌时间通常为约2小时~约24小时,优选为约15小时~约24小时。冷却温度通常为约0℃~约10℃,优选为约℃~约5℃。冷却下的搅拌时间通常为约4小时~约24小时,优选为约16小时~约24小时。悬浊液中的结晶可通过过滤等其自身公知的方法进行分离。过滤温度通常为约0℃~约10℃,优选为约0℃~约5℃。
或者,也可以在大气温度下将悬浊液搅拌后,在大气温度下滤集结晶。在大气温度下的搅拌时间通常为约2小时~约24小时,优选为约15小时~约24小时。
通过用其自身公知的方法使获得的结晶干燥,可获得本发明的结晶。干燥也可以通过减压干燥或者通风来进行。由于本发明的结晶在25℃~40℃下稳定,因此干燥温度优选在40℃以下,更加优选为约35℃~约40℃。干燥时间通常为约3小时~约24小时,优选为约15小时~约24小时。
非晶态的苯并噁嗪酮化合物或者苯并噁嗪酮化合物的其它结晶可按照例如美国专利第6624161号公报中记载的方法或者基于其的方法来制造。
作为获得的结晶的分析方法,通常是利用X射线衍射的结晶分析的方法。还有,作为确定结晶取向的方法,还可例举机械的方法或者光学的方法(例如,FT-拉曼光谱、固体NMR谱)等。
根据上述分析方法得到的谱图的峰在其性质上必然会产生一定的测定误差。谱图的峰的数值在该误差范围内的结晶也都包含在本发明的结晶中。例如,粉末X射线衍射的晶面间距(d)中的“±0.2”表示该误差是可允许的。
作为2-十六烷氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮的结晶,可例举:
具有在粉末X射线衍射的晶面间距(d)为20.07±0.2、6.86±0.2、4.79±0.2、4.34±0.2、3.72±0.2埃处出现特征峰的粉末X射线衍射图谱的结晶,优选具有在粉末X射线衍射的晶面间距(d)为22.52±0.2、20.07±0.2、9.99±0.2、7.18±0.2、6.86±0.2、4.79±0.2、4.34±0.2、3.72±0.2、3.51±0.2、3.36±0.2埃处出现特征峰的粉末X射线衍射图谱的结晶(以下,称为“A型结晶”);
具有在粉末X射线衍射的晶面间距(d)为16.54±0.2、13.26±0.2、4.70±0.2、4.38±0.2、3.67±0.2埃处出现特征峰的粉末X射线衍射图谱的结晶,优选具有在粉末X射线衍射的晶面间距(d)为16.54±0.2、13.26±0.2、8.22±0.2、6.61±0.2、6.49±0.2、4.70±0.2、4.38±0.2、3.75±0.2、3.67±0.2、3.14±0.2埃处出现特征峰的粉末X射线衍射图谱的结晶(以下,称为“B型结晶”)。
优选A型结晶或者B型结晶。
这样获得的2-十六烷氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮的结晶具有优良的脂肪酶抑制作用、脂肪吸收抑制作用等,且毒性低,因此可用作药品。而且,由于本发明的结晶稳定性优良,因此操作容易,可再现性良好地制造固体的药品组合物。
本发明的结晶对于哺乳动物(例如,人、大鼠、小鼠、猫、狗、兔、牛、猪、仓鼠、羊、猴)能用作例如肥胖症、高血脂症(例如,高甘油三酯血症、高胆固醇血症、低高密度脂蛋白血症、食后高血脂血症)、高血糖症(2型糖尿病、耐糖量异常(Impaired Glucose Tolerance))、高血压、心血管疾病、中风、消化器疾病等各种疾病或者这些疾病的并发症(例如,2型糖尿病并发肥胖症、高血脂症并发肥胖症、代谢综合征)的安全的预防剂或治疗剂。
本发明的结晶的毒性低,能直接或者按照其自身公知的方法制成与药理学上允许的载体混合的药品组合物,例如,片剂(包括糖衣片、覆膜片)、散剂、颗粒剂、胶囊剂(包括软胶囊)、口腔内崩解片、口腔内崩解膜、液剂、注射剂、栓剂、缓释剂、贴剂等,以口服或非口服(例如,局部、直肠、静脉给药等)的方式安全地给药。
本发明的结晶在药品组合物中的给药量为组合物整体的约0.01至100重量%。该给药量因给药对象、给药途径、疾病等而异,但在例如作为脂肪酶抑制剂对患有肥胖症或其并发症(例如,2型糖尿病并发肥胖症、高血脂症并发肥胖症)的成人患者(体重:60kg)进行口服投药时,以有效成分计约1~500mg/天,优选为约5~250mg/天,更加优选为约5~100mg/天。本发明的结晶也可1天1次或者分2~3次给药。
作为可用于制造本发明的药品组合物的药理学上允许的载体,可例举作为制剂原材料惯用的各种有机或者无机载体物质,例如可例举固体制剂中的赋形剂、润滑剂、粘合剂、崩解剂、水溶性高分子;液体制剂中的溶剂、助溶剂、悬浮剂、等渗剂、缓冲剂、无痛剂等。此外,根据需要还可使用通常的防腐剂、抗氧化剂、着色剂、甜味剂、酸味剂、发泡剂、香料等添加物。
作为“赋形剂”,可例举例如乳糖、白糖、D-甘露糖醇、淀粉、玉米淀粉、结晶纤维素、轻质硅酸酐、氧化钛等。
作为“润滑剂”,可例举例如硬脂酸镁、蔗糖脂肪酸酯、聚乙二醇、滑石、硬脂酸等。
作为“粘合剂”,可例举例如羟丙基纤维素、羟丙基甲基纤维素、结晶纤维素、α淀粉、聚乙烯吡咯烷酮、阿拉伯胶粉末、明胶、支链淀粉、低取代率羟丙基纤维素等。
作为“崩解剂”,可例举(1)交聚维酮(日语:クロスポビドン)、(2)交联羧甲基纤维素钠(FMC-旭化成)、羧甲基纤维素钙(五德药品)等称为“超级崩解剂”的崩解剂、(3)羧甲基淀粉钠(例如,松谷化学工业株式会社(松谷化学(株)))、(4)低取代率羟丙基纤维素(例如,信越化学工业株式会社(信越化学(株)))、(5)玉米淀粉等。作为“交聚维酮”,可以是交联聚乙烯吡咯烷酮(PVPP)、包括称为“1-乙烯基-2-吡咯烷酮均聚物(1-ビニル-2-ピロリジノンホモポリマ一)”的化合物在内的化学名为“1-乙烯基-2-吡咯烷酮均聚物”的交联的聚合物中的任一个,作为具体例子,有科利当CL(コリドンCL(KollidonCL))(巴斯夫公司(BASF社))、交联聚维酮XL(ポリプラスドンXL)(国际特品公司(ISP社))、交联聚维酮XL-10(ポリプラスドンXL-10)(国际特品公司)、交联聚维酮INF-10(ポリプラスドンINF-10)(国际特品公司)等。
作为“水溶性高分子”,可例举例如乙醇可溶性水溶性高分子(例如,羟丙基纤维素(以下,也记为“HPC”)等纤维素衍生物、聚乙烯吡咯烷酮等)、乙醇不溶性水溶性高分子(例如,羟丙基甲基纤维素(以下,也记为“HPMC”)、甲基纤维素、羧甲基纤维素钠等纤维素衍生物、聚丙烯酸钠、聚乙烯醇、海藻酸钠、瓜尔胶等)等。
作为“溶剂”,可例举例如注射用水、醇、丙二醇、聚乙二醇(日语:マクロゴ一ル(Macrogol))、芝麻油、玉米油、橄榄油等。
作为“助溶剂”,可例举例如聚乙二醇、聚丙二醇、D-甘露糖醇、苯甲酸苯甲酯、乙醇、三羟甲基氨基甲烷、胆固醇、三乙醇胺、碳酸钠、柠檬酸钠等。
作为“悬浮剂”,可例举例如硬脂酰基三乙醇胺、十二烷基硫酸钠、十二烷基丙氨酸、卵磷脂、苯扎氯铵、苄索氯铵、单硬脂酸甘油酯等表面活性剂;例如聚乙烯醇、聚乙烯吡咯烷酮、羧甲基纤维素钠、甲基纤维素、羟甲基纤维素、羟乙基纤维素、羟丙基纤维素等亲水性高分子等。
作为“等渗剂”,可例举例如葡萄糖、D-山梨糖醇、氯化钠、甘油、D-甘露糖醇等。
作为“缓冲剂”,可例举例如磷酸盐、醋酸盐、碳酸盐、柠檬酸盐等的缓冲液等。
作为“无痛剂”,可例举例如苄醇等。
作为“防腐剂”,可例举例如对羟基苯甲酸酯类、氯丁醇、苄醇、苯乙醇、脱氢乙酸、山梨酸等。
作为“抗氧化剂”,可例举例如亚硫酸盐、抗坏血酸、α-生育酚等。
作为“着色剂”,可例举例如食用黄色5号、食用红色2号、食用蓝色2号等食用色素;食用色淀色素、氧化铁红等。
作为“甜味剂”,可例举例如糖精钠、甘草酸二钾、阿司巴甜、甜菊糖、甜味蛋白等。
作为“酸味剂”,可例举例如柠檬酸(无水柠檬酸)、酒石酸、苹果酸等。
作为“发泡剂”,可例举例如碳酸氢钠等。
作为“香料”,可以是合成物和天然物中的任一种,可例举例如柠檬、酸橙、柑橘、薄荷醇、草莓等。
本发明的结晶可按照其自身的方法,例如添加赋形剂、崩解剂、粘合剂或者润滑剂等进行压缩成形,接着根据需要,为了遮掩味道、肠溶性或者持续性的目的,通过使用其自身公知的方法进行覆膜以制成口服给药制剂。作为肠溶性被覆层,可例举例如邻苯二甲酸醋酸纤维素(CAP)、羟丙基甲基纤维素邻苯二甲酸酯、羟甲基纤维素醋酸邻苯二甲酸酯、甲基丙烯酸共聚物(例如,Eudragit(オイドラギツト)L30D-55(商品名;莱姆公司(レ一ム社))、Kollicoat(コリコ一ト)MAE30DP(商品名;巴斯夫公司)、Polyquid(ポリキツド)PA30(商品名;三洋化成工业株式会社(三洋化成社))等)、羧甲基乙基纤维素、虫胶等水系肠溶性高分子基剂;甲基丙烯酸共聚物(例如,EudragitNE30D(商品名)、Eudragit RL30D(商品名)、Eudragit RS30D(商品名)等)等缓释性基剂;水溶性高分子;柠檬酸三乙酯、聚乙二醇、乙酰化单甘油酯、三醋精、蓖麻油等增塑剂等的一种或者两种以上的混合物等。
本发明的结晶可按照例如WO2006/132440号公报中记载的方法制成片剂等固体制剂。
本发明的结晶也可与其它药物并用。作为可与本发明的结晶并用的药物(以下,简记为“并用药物”),可使用例如以下的药物。
(1)糖尿病治疗剂
胰岛素制剂(例如,从牛、猪等的胰腺提取出的动物胰岛素制剂;使用大肠杆菌、酵母菌,以基因工程的方法合成的胰岛素制剂;锌胰岛素;鱼精蛋白锌胰岛素;胰岛素片段或衍生物(例如,INS-1);口服胰岛素制剂);胰岛素耐性改善剂(例如,吡格列酮或其盐(优选盐酸盐)、罗格列酮或其盐(优选马来酸盐)、Reglixane、萘格列酮(Netoglitazone)、FK-614、利格列酮(Rivoglitazone)、DRF-2593、依格列宗(Edaglitazone)(BM-13.1258)、R-119702、WO01/38325中记载的化合物、替格列扎(Tesaglitazar)、拉格列扎(Ragaglitazar)、莫格列扎(Muraglitazar)、ONO-5816、LM-4156、Metaglidasen(MBX-102)、那格列扎(Naveglitazar)(LY-519818)、MX-6054、LY-510929、巴格列酮(Balaglitazone)、T-131或其盐、THR-0921);α-葡萄糖苷酶抑制剂(例如,伏格列波糖、阿卡波糖、米格列醇、乙格列酯);双胍类制剂(例如,苯乙福明、甲福明、丁福明或它们的盐(例如,盐酸盐、富马酸盐、琥珀酸盐));胰岛素分泌促进剂(磺酰脲类制剂(例如,甲苯磺丁脲、格列本脲、甲磺吡脲、氯磺吡脲、甲磺氮卓脲、醋磺己脲、氯磺丙脲、谷胱甘肽、格列吡嗪、格列丁唑)、瑞格列奈、色那列奈、那格列奈、米格列奈或其钙盐水合物);GPR40激动剂;GLP-1受体激动剂(例如,GLP-1、GLP-1MR剂、NN-2211、AC-2993(艾塞那肽-4(exendin-4))、BIM-51077、Aib(8,35)hGLP-1(7,37)NH2、CJC-1131);二肽基肽酶IV抑制剂(例如,NVP-DPP-278、PT-100、P32/98、维格列汀(Vildagliptin)(LAF-237)、P93/01、TS-021、磷酸西他列汀(Sitagliptin phosphate)(MK-431)、沙格列汀(Saxagliptin)(BMS-477118)、E-3024、T-6666(TA-6666)、823093、825964、815541);β3受体激动剂(例如,AJ-9677);胰淀素激动剂(Amylin Agonist)(例如,普兰林肽);磷酸酪氨酸磷酸酶抑制剂(例如,钒酸钠);糖异生抑制剂(例如,糖原磷酸化酶抑制剂、葡糖-6-磷酸酯酶抑制剂、胰高血糖素拮抗剂);SGLT(钠-葡萄糖协同转运蛋白)抑制剂(例如,T-1095);11β-HSD1抑制剂(例如,BVT-3489);脂联素或其激动剂;IKK抑制剂(例如,AS-2868);瘦素耐性改善药;生长抑素受体激动剂(例如,WO01/25228、WO03/42204、WO98/44921、WO98/45285、WO99/22735中记载的化合物);葡萄糖激酶激活剂药物(例如,Ro-28-1675)等。
(2)糖尿病并发症治疗剂
醛糖还原酶抑制剂(例如,托瑞司他、依帕司他、折那司他、唑泊司他、非达司他、米那司他、雷尼司他、CT-112);神经营养因子及其增加药物(例如,NGF、NT-3、BDNF、WO01/14372中记载的神经营养蛋白的产生、分泌促进剂(例如,4-(4-氯苯基)-2-(2-甲基-1-咪唑基)-5-[3-(2-甲基苯氧基)-丙基]噁唑));神经再生促进药(例如,Y-128、VX853、Prosaptide);PKC抑制剂(例如,甲磺酸索拉非尼(Ruboxistaurin mesylate));AGE抑制剂(例如,ALT-945、匹马吉定、溴化-N-苯乙酰噻唑鎓(ALT-766)、EXO-226、ALT-711、吡多胺(Pyridorin)、吡多胺(Pyridoxamine));活性氧清除药物(例如,硫辛酸);脑血管扩张剂(例如,泰必利);生长抑素受体激动剂(例如,BIM23190);细胞凋亡信号调节激酶-1(ASK-1)抑制剂等。
(3)抗高血脂症药剂
HMG-CoA还原酶抑制剂(例如,普伐他汀、辛伐他汀、洛伐他汀、阿托伐他汀、氟伐他汀、匹伐他汀、瑞舒伐他汀或它们的盐(例如,钠盐、钙盐));角鲨烯合成酶抑制剂(例如,WO97/10224中记载的化合物,例如,N-[[(3R,5S)-1-(3-乙酰氧基-2,2-二甲基丙基)-7-氯-5-(2,3-二甲氧基苯基)-2-氧代-1,2,3,5-四氢-4,1-苯并氧氮杂卓-3-基]乙酰基]哌啶-4-乙酸);贝特类化合物(例如,苯扎贝特、氯贝特、双贝特、克里贝特);ACAT抑制剂(例如,阿伐麦布(Avasimibe)、依鲁麦布(Eflucimibe));阴离子交换树脂(例如,考来烯胺);普罗布考;烟碱酸类药物(例如,尼克莫尔(Nicomol)、戊四烟酯(Niceritrol));二十碳五烯酸乙酯;植物甾醇(例如,大豆甾醇(Soysterol)、伽玛谷维素(γ-oryzanol))等。
(4)降压剂
血管紧张素转换酶抑制剂(例如卡托普利、依那普利、地拉普利、赖诺普利);血管紧张素Ⅱ拮抗剂(例如氯沙坦、坎地沙坦西酯、依普沙坦、缬沙坦、替米沙坦、厄贝沙坦、他索沙坦、1-[[2’-(2,5-二氢-5-氧代-4H-1,2,4-噁二唑-3-基)联苯-4-基]甲基]-2-乙氧基-1H-苯并咪唑-7-羧酸);钙拮抗剂(例如,马尼地平、硝苯地平、氨氯地平、依福地平、尼卡地平);钾通道开放剂(例如,左色满卡林、L-27152、AL 0671、NIP-121);α1阻滞剂(例如,盐酸哌唑嗪、盐酸特拉唑嗪、盐酸布那唑嗪);β阻滞剂(例如,盐酸普萘洛尔、吲哚洛尔、阿替洛尔、盐酸塞利洛尔、酒石酸美托洛尔);α1、β阻滞剂(例如,盐酸拉贝洛尔、卡维地洛、盐酸布尼洛尔);可乐定等。
(5)抗肥胖剂
中枢性抗肥胖药(例如,右芬氟拉明、芬氟拉明、芬特明、西布曲明、安非拉酮、右苯丙胺、马吲哚、苯丙醇胺、氯苄雷司;MCH受体拮抗剂(例如,SB-568849;SNAP-7941;WO01/82925及WO01/87834中记载的化合物);神经肽Y拮抗剂(例如,CP-422935);大麻素受体拮抗剂(例如,SR-141716、SR-147778);生长素拮抗剂);β3激动剂(例如AJ-9677);肽类食欲抑制药(例如,瘦素、CNTF(睫状神经营养因子));胆囊收缩素激动剂(例如,林替曲特、FPL-15849);食欲抑制药(例如,P-57)等。
(6)利尿剂
黄嘌呤衍生物(例如,可可碱水杨酸钠、可可碱水杨酸钙);噻嗪类制剂(例如,乙噻嗪、环戊噻嗪、三氯甲噻嗪、氢氯噻嗪、氢氟噻嗪、苄氢氯噻嗪、戊氟噻嗪、泊利噻嗪、甲氯噻嗪);抗醛固酮制剂(例如,螺内酯、氨苯喋啶);碳酸酐酶抑制剂(例如,乙酰唑胺);氯苯磺酰胺类制剂(例如,氯噻酮、美呋西特、吲达帕胺);阿佐塞米;异山梨醇;依他尼醇;吡咯他尼;布美他尼;呋塞米;美替克仑等。
(7)化学疗法药剂
烷基化剂(例如,环磷酰胺、异环磷酰胺);代谢拮抗剂(例如,甲氨蝶呤、5-氟脲嘧啶或其衍生物(例如,氟铁龙、新氟铁龙));抗癌性抗生素(例如,丝裂霉素、阿霉素);植物来源的抗癌药剂(例如,长春新碱、长春地辛、紫杉醇);顺铂、卡铂、依托泊苷等。
(8)免疫疗法药剂
微生物或细菌成分(例如,胞壁酰二肽衍生物、溶链菌);具有免疫增强活性的多糖类(例如,香菇多糖、西佐喃、云芝多糖);通过基因工程方法获得的细胞因子(例如,干扰素、白细胞介素(例如,IL-1、IL-2、IL-12));集落刺激因子(例如,粒细胞集落刺激因子、红细胞生长素)等。
(9)抗血栓剂
肝素(例如,肝素钠、肝素钙、达肝素钠(Dalteparin sodium));华法林(例如,华法林钾);抗凝血酶药(例如,阿加曲班(Argatroban));血栓溶解剂(例如,尿激酶(Urokinase)、组织型纤维蛋白溶酶原激活剂(Tisokinase)、阿替普酶(Alteplase)、那替普酶(Nateplase)、孟替普酶(Monteplase)、帕替普酶(Pamiteplase));血小板聚集抑制剂(例如,盐酸噻氯匹定(Ticlopidinehydrochloride);西洛他唑(Cilostazol);二十碳五烯酸乙酯;贝前列素钠(Beraprost sodium);盐酸沙格雷酯(Sarpogrelate hydrochloride))等。
(10)恶液质改善剂
黄体酮衍生物(例如,甲地孕酮磺酸酯);甲氧氯普胺类药剂;四氢大麻酚类药剂;脂肪代谢改善剂(例如,二十碳五烯酸);生长激素;IGF-1;或者针对作为诱导恶液质的因子的TNF-α、LIF、IL-6、抑瘤素M的抗体等。
(11)消炎剂
类固醇(例如,地塞米松);透明质酸钠;环氧合酶抑制剂(例如,吲哚美辛、酮洛芬、洛索洛芬、美洛昔康、安吡昔康、塞来昔布、罗非昔布)等。
(12)其它
糖化抑制剂(例如,ALT-711);抗抑郁药(例如,地昔帕明、阿米替林、丙咪嗪、氟西汀、帕罗西汀、多塞平);抗癫痫药(例如,拉莫三嗪、卡马西平);抗心律失常药(例如,美西律);乙酰胆碱受体配体(例如,ABT-594);内皮素受体拮抗剂(例如,ABT-627);单胺摄取抑制剂(例如,曲马多);吲哚胺摄取抑制剂(例如,氟西汀、帕罗西汀);麻醉镇痛药(例如,吗啡);GABA受体激动剂(例如,加巴喷丁);GABA摄取抑制剂(例如,噻加宾);α2受体激动剂(例如,可乐定);局部镇痛药(例如,辣椒素);抗焦虑剂(例如,苯二氮类);磷酸二酯酶抑制剂(例如,西地那非);多巴胺受体激动剂(例如,阿朴吗啡);多巴胺受体拮抗剂(例如,氟哌啶醇);血清素受体激动剂(例如,枸橼酸坦度螺酮、舒马普坦);血清素受体拮抗剂(例如,盐酸赛庚啶、昂丹司琼);血清素摄取抑制剂(例如,马来酸氟伏沙明、氟西汀、帕罗西汀);催眠剂(例如,三唑仑、唑吡坦);抗胆碱剂;α1受体阻滞剂(例如,坦索罗辛);肌肉松弛剂(例如,巴氯芬);阿尔茨海默氏病的预防或治疗药(例如,多奈哌齐、卡巴拉汀、加兰他敏);帕金森病的治疗药(例如,左旋多巴);多发性硬化症的预防或治疗药(例如,干扰素β-1a);组胺H1受体抑制剂(例如,盐酸异丙嗪);质子泵抑制剂(例如,兰索拉唑、奥美拉唑、雷贝拉唑或其盐(例如,钠盐));NK-2受体拮抗剂;HIV感染症治疗药(例如,沙奎那韦、齐多夫定、拉米夫定、奈韦拉平);慢性阻塞性肺疾病的治疗药(例如,沙美特罗、噻托溴铵、西洛司特)等。
作为抗胆碱剂,可使用例如阿托品、东莨菪碱、后马托品、托吡卡胺、环喷托酯、溴丁东莨菪碱、溴丙胺太林、溴甲贝那替秦、溴美喷酯、黄酮哌酯、哌仑西平、溴化异丙阿托品、苯海索、奥昔布宁、丙哌维林、达非那新、托特罗定、替米维林、曲司氯铵或其盐(例如,硫酸阿托品、氢溴酸东莨菪碱、氢溴酸后马托品、盐酸环喷托酯、盐酸黄酮哌酯、盐酸哌仑西平、盐酸苯海索、盐酸奥昔布宁、酒石酸托特罗定)等,其中,优选奥昔布宁、丙哌维林、达非那新、托特罗定、替米维林、曲司氯铵或其盐(例如,盐酸奥昔布宁、酒石酸托特罗定)。此外,也可使用乙酰胆碱酯酶抑制剂(例如,溴地斯的明)等。
作为NK-2受体拮抗剂,可例举例如GR159897、GR149861、SR48968(沙瑞度坦(saredutant))、SR144190、YM35375、YM38336、ZD7944、L-743986、MDL105212A、ZD6021、MDL105172A、SCH205528、SCH62373、R-113281等哌啶衍生物;RPR-106145等异吲哚衍生物;SB-414240等喹啉衍生物;ZM-253270等吡咯并嘧啶衍生物;MEN11420(奈帕坦特(Nepadutant))、SCH217048、L-659877、PD-147714(CAM-2291)、MEN10376、S16474等伪肽衍生物;其它的GR100679、DNK333、GR94800、UK-224671、MEN10376、MEN10627,或它们的盐等。
作为并用药物,优选胰岛素制剂、胰岛素耐性改善剂(优选吡格列酮或其盐(优选盐酸盐))、α-葡萄糖苷酶抑制剂(优选伏格列波糖)、双胍类制剂(优选甲福明)、胰岛素分泌促进剂(优选磺酰脲类制剂、米格列奈或其钙盐水合物)、HMG-CoA还原酶抑制剂(优选辛伐他汀、阿托伐他汀)等。
在掺合或并用本发明的结晶和并用药物的本发明的药品中,包含(1)将含有本发明的结晶和并用药物的药品组合物单独制剂化的药品、(2)将含有本发明的结晶的药品组合物和并用药物分别制剂化的药品中的任一种。以下,将它们统称、简记为“本发明的并用剂”。
本发明的并用剂可通过将本发明的结晶及并用药物的有效成分分别或者同时直接混合、或者与药学上允许的载体等混合,用与上述的本发明的固体制剂相同的方法制成制剂。
本发明的并用剂的一天的给药量随症状、人种、给药对象的年龄、性别、体重、给药形态、有效成分的种类等而不同,但只要是在不引起副作用的问题的范围内,则无特别限定。在例如口服给药的情况下,以本发明的结晶与并用药物的合计给药量计,本发明的并用剂的一天的给药量通常为哺乳动物每1kg体重约0.005~100mg,优选约0.05~50mg,更加优选约0.2~30mg,该给药量通常1天分为1~3次给药。
在将本发明的并用剂给药时,可将本发明的结晶和并用药物同时给药,也可以将并用药物先给药,然后将本发明的结晶给药,也可以将本发明的结晶先给药,然后将并用药物给药。在隔有时间差进行给药时,时间差随给药的有效成分、剂型、给药方法而不同,举例如,将并用药物先给药的情况下,可例举在将并用药物给药后1分钟~3天以内、优选10分钟~1天之内、更加优选15分钟~1小时以内将本发明的结晶给药的方法。在将本发明的结晶先给药的情况下,可例举在将本发明的结晶给药后1分钟~1天以内、优选10分钟~6小时以内、更加优选15分钟至1小时以内将并用药物给药的方法。
本发明的并用剂中,相对于并用剂整体,本发明的结晶的含量随并用剂的形态而不同,但通常在0.1重量%~65重量%、优选0.3重量%~50重量%、更加优选0.5重量%~20重量%的程度。
实施例
以下,例举实施例和参考例对本发明进行更详细的说明,但本发明并不限定于此。
以下的实施例及参考例中,室温是指约15℃~约30℃。
使用Rigaku RINT2500V(Cu-Kα射线:λ=1.5418埃;管电压:40kV;管电流:400mA;累积次数:16次)进行粉末X射线衍射的测定。
实施例1
2-十六烷氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮的结晶(B型结晶)
将用参考例1中记载的方法获得的A型结晶(100g)在室温下悬浮于四氢呋喃(250mL)中,于室温下搅拌3小时以上。搅拌后,将悬浊液冷却至0~10℃,在相同温度下搅拌4小时以上。搅拌后,将悬浊液冷却至0~10℃,在相同温度下滤集结晶,获得湿结晶(日语:ウエツト結晶)。将获得的湿结晶于35~40℃下减压干燥,获得B型结晶(收率约94%)。将粉末X射线衍射的测定结果示于下表。
[表1]
粉末X射线衍射的数据(B型结晶)
实施例2
2-十六烷氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮的结晶(B型结晶)
将用参考例1中记载的方法获得的A型结晶(3g)在室温下悬浮于对二甲苯(10mL)中,于室温下搅拌17小时以上。搅拌后,在相同温度下滤集结晶,获得湿结晶。将获得的湿结晶于35~40℃下减压干燥,获得B型结晶(收率约41%)。
参考例1
2-十六烷氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮的结晶(A型结晶)
将按照美国专利第6624161号公报的实施例4中记载的方法制造的粗制2-十六烷氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮(10g)悬浮于正庚烷(90mL)中,然后升温至50~55℃使其溶解。确认溶解后,添加活性炭(白鹭(白鷺,注册商标)A,日本环境化学株式会社(日本エンバイロケミカルズ株式会社))(0.5g),于50~55℃下搅拌30分钟。搅拌后,趁热将炭过滤,用正庚烷(10mL)洗涤。将滤液及洗涤液冷却至室温,接着在室温下滴入乙醇(40mL)。滴完后,冷却至0~10℃,在相同温度下搅拌1小时。搅拌后,滤集结晶,用乙醇(20mL)洗涤后,获得湿结晶。将获得的湿结晶于40~50℃下减压干燥,获得A型结晶(收率约93%)。将粉末X射线衍射的测定结果示于下表。
[表2]
粉末X射线衍射的数据(A型结晶)
本申请以在日本提出申请的日本专利特愿2009-106606为基础,引用其全部内容纳入本说明书中。
Claims (4)
1.一种2-十六烷氧基-6-甲基-4H-3,1-苯并噁嗪-4-酮的结晶,所述结晶具有在粉末X射线衍射的晶面间距d为16.54±0.2、13.26±0.2、8.22±0.2、6.61±0.2、6.49±0.2、4.70±0.2、4.38±0.2、3.75±0.2、3.67±0.2、3.14±0.2埃的附近出现特征峰的粉末X射线衍射图谱。
2.一种药品组合物,其特征在于,包括权利要求1所述的结晶和药理学上允许的载体。
3.如权利要求1所述的结晶在制备预防或治疗肥胖症的药物中的用途。
4.如权利要求2所述的药品组合物在制备预防或治疗肥胖症的药物中的用途。
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JP2009-106606 | 2009-04-24 | ||
JP2009106606A JP2010254623A (ja) | 2009-04-24 | 2009-04-24 | ベンゾオキサジノン化合物の結晶 |
PCT/JP2010/057110 WO2010123047A1 (ja) | 2009-04-24 | 2010-04-22 | ベンゾオキサジノン化合物の結晶 |
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WO2013092786A1 (en) * | 2011-12-23 | 2013-06-27 | Norgine B.V. | Compositions comprising cetilistat |
GB201122213D0 (en) * | 2011-12-23 | 2012-02-01 | Norgine Bv | Compositions |
NL2009995C2 (en) * | 2011-12-23 | 2013-09-18 | Norgine Bv | Compositions. |
DE202012104963U1 (de) | 2012-12-19 | 2013-01-14 | Norgine B.V. | Cetilistat aufweisende Zusammensetzungen |
CN106032364A (zh) * | 2015-03-18 | 2016-10-19 | 北京万生药业有限责任公司 | 新利司他晶体 |
CN106032363A (zh) * | 2015-03-18 | 2016-10-19 | 北京万生药业有限责任公司 | 新利司他晶体 |
CN106310287B (zh) * | 2015-06-25 | 2019-03-19 | 山东省药学科学院 | 新利司他药用组合物及其制备方法 |
CN105111162A (zh) * | 2015-09-28 | 2015-12-02 | 济南康和医药科技有限公司 | 一种赛利司他新晶型及其制备方法 |
CN111789819B (zh) * | 2020-07-14 | 2023-01-31 | 南京海纳医药科技股份有限公司 | 一种含有新利司他的片剂及其制备方法 |
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WO2010123047A1 (ja) | 2010-10-28 |
EP2423203A4 (en) | 2012-10-31 |
EP2423203A1 (en) | 2012-02-29 |
US20120101090A1 (en) | 2012-04-26 |
US8883780B2 (en) | 2014-11-11 |
CN102482235A (zh) | 2012-05-30 |
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