CN116898850A - 一种氧代哒嗪酰胺类衍生物的药物制剂及其制备方法与医药用途 - Google Patents
一种氧代哒嗪酰胺类衍生物的药物制剂及其制备方法与医药用途 Download PDFInfo
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Abstract
本发明属于药物制剂领域,具体涉及一种氧代哒嗪酰胺类衍生物的药物制剂及其制备方法与医药用途。
Description
技术领域
本发明属于药物制剂领域,具体涉及一种氧代哒嗪酰胺类衍生物的药物制剂及其制备方法与医药用途。
背景技术
由心脑血管疾病和糖尿病及其并发症引起的血栓问题,成为当今要解决的刻不容缓的问题。
人体血液凝固过程由内源性途径(intrinsic pathway)、外源性途径(extrinsicpathway)和共同通路组成(Annu.Rev.Med.2011.62:41–57),是通过多种酶原被顺序激活而过程不断得到加强和放大的一种连锁反应。凝血级联反应由内源性途径(又称接触激活途径)及外源性途径(又称组织因子途径)启动生成FXa,再经共同途径生成凝血酶(FIIa),最终形成纤维蛋白。
内源性途径是指由XII因子被激活形XIa-VIIIa-Ca2+-P L复合物、并激活X因子的过程,外源性凝血途径则是从组织因子(TF)释放到TF-VIIa-Ca2+复合物形成并激活因子Ⅹ的过程。共同通路是指因子Xa形成后,两条途径合二为一,激活凝血酶原并最终生成纤维蛋白的过程,其中FXI是维持内源性途径所必需的,而且在凝血级联反应放大过程中发挥关键作用。在凝血级联反应中,凝血酶可反馈激活FXI,活化的FXI(FXIa)又促使凝血酶的大量产生,从而使凝血级联反应放大。因此,FXI的拮抗剂被广泛开发,用于各种血栓的治疗。
传统的抗凝药物,如华法林、肝素、低分子量肝素(LMWH),以及近年上市的新药,如FXa抑制剂(利伐沙班、阿哌沙班等)和凝血酶抑制剂(达比加群酯、水蛭素等),对减少血栓形成均具有较好效果,以其显著有效性占据广大心脑血管市场,然而其副作用也越来越显著,其中“出血风险(bleeding risk)”是首当其冲最为严峻的问题之一(N Engl J Med1991;325:153-8、Blood.2003;101:4783-4788)。
研究发现,在血栓模型中,抑制FXIa因子可以有效抑制血栓的形成,但在更为严重的血栓情况下,FXIa的作用微乎其微(Blood.2010;116(19):3981-3989)。临床统计显示,提高FXIa的量会增加VTE的患病率(Blood 2009;114:2878-2883),而FXIa严重不足者其患有DVT的风险性减少(Thromb Haemost 2011;105:269–273)。
FXIa作为目前抑制血栓的新兴靶点,公开具有FXIa抑制活性的化合物的专利申请有WO9630396、WO9941276、WO2013093484、WO2004002405、WO2013056060、WO2017005725、WO2017/023992、WO2018041122等。
PCT/CN2020/117257公开了一种氧代哒嗪酰胺类衍生物,作为FXIa拮抗剂,可用于血栓栓塞等病症,通式和具体化合物如下式所示:
为了用于患者治疗相关疾病,需要进一步研究适宜的药物制剂。
发明内容
本发明提供了一种药物制剂,所述药物制剂含有活性成分化合物A或其可药用盐,
和载体材料,其中所述载体材料为:
(1)载体一:醋酸羟丙甲纤维素琥珀酸酯、羟丙甲纤维素、醋酸纤维素、丙烯酸树脂、羟丙纤维素、羟丙甲纤维素邻苯二甲酸酯、聚维酮或共聚维酮中的一种以上,
(2)载体二:聚乙二醇、山嵛酸甘油酯、硬脂酸、十六醇、十八醇、氢化植物油、脂肪酸甘油酯、聚氧乙烯蓖麻油、石蜡等。
作为本发明的一种优选技术方案,所述载体材料和活性成分的重量比为0.2:1~4:1,优选为0.4:1~3:1。考虑到载药量与生物利用度之间的平衡,本发明中载体材料与活性成分的重量比可以为0.4:1~3:1,可以为0.4:1、0.5:1、0.6:1、0.7:1、0.8:1、0.9:1、1:1、1.1:1、1.2:1、1.3:1、1.4:1、1.5:1、1.6:1、1.7:1、1.8:1、1.9:1、2:1、2.2:1、2.4:1、2.6:1、2.8:1、3:1等等。
作为本发明的一种优选技术方案,所述醋酸羟丙甲纤维素琥珀酸酯为HPMC-AS。
作为本发明的一种优选技术方案,所述醋酸羟丙甲纤维素琥珀酸酯为HPMC-AS选自HPMC-AS MG、HPMC-MF、HPMC-MP,聚维酮为K30,聚乙二醇为聚乙二醇6000。
作为本发明的一种优选技术方案,化合物:载体一:载体二=3:1:1~3:1:2。
作为本发明的一种优选技术方案,所述制剂的制备方法包括将载体材料与活性成分预混后,再进行熔融制粒。
本发明进一步提供了一种固体制剂,其包含前述的药物制剂,所述固体制剂选自片剂、丸剂、颗粒剂或胶囊剂。
所述胶囊剂包括:胃溶胶囊剂、肠溶胶囊剂、微型胶囊剂。
其中,胃溶型胶囊剂为最常见的胶囊剂,口服后,胶囊在胃中溶解,药物释放出来产生药效。
肠溶胶囊剂实际上就是硬胶囊剂或软胶囊剂中的一种,只是在囊壳中加入了特殊的药用高分子材料或经特殊处理,所以它在胃液中不溶解,仅在肠液中崩解溶化而释放出活性成分,达到一种肠溶的效果,故而称为肠溶胶囊剂。
微型胶囊剂是利用天然的或合成的高分子材料,将固体药物微粒或液体药物微滴包裹成直径1~500微米的微小胶囊剂。
作为本发明的一种优选技术方案,所述固体制剂还包含药学上可接受的赋形剂,所述赋形剂选自崩解剂、填充剂、粘合剂、助流剂、表面活性剂或润滑剂中的至少一种。
作为本发明的一种优选技术方案,所述崩解剂选自低取代羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、羧甲基纤维素钙、淀粉、预胶化淀粉、微晶纤维素、二氧化硅、泡腾成分或海藻酸中的至少一种,所述崩解剂的用量占固体制剂重量的1~50%;
所述填充剂选自糊精、乳糖、蔗糖、磷酸氢钙、淀粉、无水磷酸氢钙、磷酸氢钙、微晶纤维素、硅化微晶纤维素、微晶纤维素乳糖复合物、或甘露醇中的至少一种,所述填充剂的用量占固体制剂重量的30~90%;
所述粘合剂选自聚乙烯吡咯烷酮、淀粉、甲基纤维素、羧基纤维素、羟丙基纤维素、羟丙甲基纤维素、羧甲纤维素钠、或海藻酸盐中至少一种,所述粘合剂的用量占固体制剂重量的0.5~10%。
所述助流剂选自气相二氧化硅、三硅酸镁、粉状纤维素、淀粉或滑石粉中的至少一种,所述助流剂的用量占固体制剂重量的0.1~10%;
所述表面活性剂选自十二烷基苯磺酸钠、十二烷基硫酸钠、泊洛沙姆、多库酯钠中的至少一种,所述表面活性剂的用量占固体制剂重量的0.1~10%;
所述润滑剂选自硬脂酸镁、硬脂酸、棕榈酸、硬脂酸钙、滑石粉、巴西棕榈蜡或硬脂富马酸钠中的至少一种,所述润滑剂的用量占固体制剂重量的0.1~5%。
在可选实施方案中,本发明所述药物组合物还可进一步制备成固体制剂,所述固体制剂为片剂、丸剂、颗粒剂和胶囊剂等。
所述固体制剂中活性成分含量为5~60%,可以为5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、35、40、45、50、55或60%,优选为8~25%,以固体制剂重量计;在实施方案中,本发明所述活性成分的量(重量或质量)为10~500mg,可以为400mg、390mg、380mg、370mg、360mg、350mg、340mg、330mg、320mg、310mg、300mg、290mg、280mg、270mg、260mg、250mg、240mg、230mg、220mg、210mg、200mg、190mg、180mg、170mg、160mg、150mg、140mg、130mg、120mg、110mg、100mg、95mg、90mg、85mg、80mg、75mg、70mg、65mg、60mg、55mg、50mg、45mg、40mg、35mg、30mg、25mg、20mg、15mg或10mg。
进一步地,本发明所述固体制剂中还含药学上可接受的赋形剂,所述赋形剂为本领域技术人员所熟知或可以确定的,选自但不限于崩解剂、填充剂、粘合剂、助流剂、润滑剂中的至少一种。
本发明所述崩解剂为本领域技术人员所知或可以确认的,选自但不限于交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、羧甲纤维素钙、淀粉、预胶化淀粉、微晶纤维素、二氧化硅、泡腾成分或海藻酸中的至少一种;优选地,所述崩解剂的用量占固体制剂重量的1~50%,可以为1.0、1.5、2.0、2.5、3.0、3.5、4.0、4.5、5.0、5.5、6.0、6.5、7.0、7.5、8.0、8.5、9.0、9.5、10.0、10.5、11.0、11.5、12.0、12.5、13.0、13.5、14.0、14.5、15.0、15.5、16.0、16.5、17.0、17.5、18.0、18.5、19.0、19.5、20.0%,21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50,优选为5~50%,以固体制剂重量计。
本发明所述填充剂为本领域技术人员所知或可确定的,选自但不限于糊精、乳糖、蔗糖、磷酸氢钙、淀粉、无水磷酸氢钙、磷酸氢钙、微晶纤维素、硅化微晶纤维素、微晶纤维素乳糖复合物、或甘露醇中至少一种;优选地,所述填充剂的用量占固体制剂重量的30~90%,更优选35~60%,可以为35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60%,以固体制剂重量计。
本发明所述粘合剂为本领域技术人员所知或可以确认的,选自但不限于聚乙烯吡咯烷酮、淀粉、甲基纤维素、羧基纤维素、羟丙基纤维素、羟丙甲基纤维素、羧甲纤维素钠、或海藻酸盐中的至少一种,优选自聚乙烯吡咯烷酮(优选商品名K30的聚维酮)、羟丙基纤维素中的至少一种;优选所述粘合剂的用量占固体制剂重量的0.5~10%,可以为0.5、0.6、0.7、0.8、0.9、1.0、1.2、1.4、1.6、1.8、2.0、2.2、2.4、2.6、2.8、3.0、3.2、3.4、3.6、3.8、4.0、4.2、4.4、4.6、4.8、5.0、5.2、5.4、5.6、5.8、6.0、6.2、6.4、6.6、6.8、7.0、7.2、7.4、7.6、7.8、8.0、8.2、8.4、8.6、8.8、9.0、9.2、9.4、9.6、9.8或10.0%,以固体制剂重量计。
本发明所述助流剂为本领域技术人员所知或可以确认的,选自但不限于气相二氧化硅(例如Aerosil200)、三硅酸镁、粉状纤维素、淀粉、滑石粉中的至少一种,优选气相二氧化硅;所述助流剂的用量占固体制剂重量的0.5~10%,可以为0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、1.2、1.4、1.6、1.8、2.0、2.2、2.4、2.6、2.8、3.0、3.2、3.4、3.6、3.8、4.0、4.2、4.4、4.6、4.8、5.0、5.2、5.4、5.6、5.8、6.0、6.2、6.4、6.6、6.8、7.0、7.2、7.4、7.6、7.8、8.0、8.2、8.4、8.6、8.8、9.0、9.2、9.4、9.6、9.8或10.0%,以固体制剂重量计。
本发明所述表面活性剂为本领域技术人员所知或可以确认的,选自但不限于十二烷基苯磺酸钠、十二烷基硫酸钠、泊洛沙姆、多库酯钠的至少一种;优选地,本发明所述述表面活性剂的用量占固体制剂重量的0.1~10%,可以为0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9或5.0%,优选为0.1~2%,以固体制剂重量计。
本发明所述润滑剂为本领域技术人员所知或可以确认的,选自但不限于硬脂酸镁、硬脂酸、棕榈酸、硬脂酸钙、滑石粉、巴西棕榈蜡或硬脂富马酸钠中的至少一种;优选地,本发明所述润滑剂的用量占固体制剂重量的0.1~5%,可以为0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、1.1、1.2、1.3、1.4、1.5、1.6、1.7、1.8、1.9、2.0、2.1、2.2、2.3、2.4、2.5、2.6、2.7、2.8、2.9、3.0、3.1、3.2、3.3、3.4、3.5、3.6、3.7、3.8、3.9、4.0、4.1、4.2、4.3、4.4、4.5、4.6、4.7、4.8、4.9或5.0%,优选为0.1~2%,以固体制剂重量计。
本发明还提供了制备前述固体制剂的方法,该方法包括:先将化合物A或其可药用盐药物组合物经粉碎后,再与固体制剂成型所需的填充剂和/或崩解剂等混合均匀,加入粘合剂湿法制粒,或干法制粒,制备的颗粒干燥过筛整粒后与润滑剂混合均匀,制备丸剂或颗粒剂或压片或装胶囊;也可采用药物组合物加入适当辅料直接装胶囊或制剂压片的方法。根据需要,所的颗粒剂或素片或胶囊还可以进一步包衣等。
作为本发明的一种优选技术方案,所述固体制剂含有1)前述述的药物制剂,包含10mg~600mg重量的活性成分;
进一步任选含有以下组成的一种以上的赋形剂:
2)5~50%重量的崩解剂;
3)30~90%重量的填充剂;
4)0.5~10%重量的粘合剂;
5)0.1~10%重量的助流剂;
6)0.1~10%重量的表面活性剂;
7)0.1~5%重量的润滑剂;
固体制剂各组份之和为100%。
本发明固体制剂所述溶出实验通过“模拟空腹胃肠液转换的介质”条件进行,15min达到50%或更高,比如大于或等于70、71、72、73、74、75、76、77、78、79、80、81、82、83、84、85、86、87、88、89、90、91、92、93、94、95%。
本发明所述固体制剂在温度40℃±2℃、相对湿度75%±5%的条件下放置3个月以上(比如3个月、6个月、12个月、18个月、24个月等)均没有明显变化。
本发明所述化合物A可药用盐,选自但不限于钠盐、钾盐、葡甲胺盐、钙盐及胆碱盐等,优选钠盐和葡甲胺盐。
本发明所述的“以固体制剂的重量计”为不包含包衣剂的片芯重量计算活性成分或其他种类药用辅料的使用量数值范围。
本发明所述制剂设备和药物辅料或试剂均可来自商业途径获得。
具体实施方式
下面结合实施例对本发明作进一步详细的描述,但发明的实施方式不限于此。
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-III核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),内标为四甲基硅烷(TMS)。
MS的测定用ISQ EC质谱仪(生产商:Thermo,型号:ISQ EC)。
高效液相色谱法(HPLC)分析使用Thermo U3000 HPLC DAD高效液相色谱仪。
CombiFlash快速制备仪使用CombiFlash Rf+LUMEN(TELEDYNE ISCO)。
薄层层析硅胶板使用烟台银龙HSGF254或GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.17mm~0.23mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
硅胶柱色谱法一般使用乳山上邦硅胶100~200目硅胶为载体。
实施例1
合成(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸
具体合成路线如下:
步骤A:合成5-溴-6-羟基-2-(4-甲氧基苄基)哒嗪-3(2H)-酮
室温下,将溴马来酸酐(2.00克,11.3毫摩尔)和4-甲氧基苄基肼盐酸盐(2..13克,11.3毫摩尔)加入冰醋酸(50.0毫升)中,100℃反应3小时。
反应结束,冷却至室温,将反应液倒入水中,析出大量固体,搅拌一段时间后抽滤,滤饼用水洗,滤饼烘干得1.50克淡黄色固体5-溴-6-羟基-2-(4-甲氧基苄基)哒嗪-3(2H)-酮,无需纯化,直接用于下步反应。LCMS:RT=3.44min,[M+H]+=311.03。
步骤B:合成5-溴-6-甲氧基-2-(4-甲氧基苄基)哒嗪-3(2H)-酮
室温下,将5-溴-6-羟基-2-(4-甲氧基苄基)哒嗪-3(2H)-酮(1.50克,4.82毫摩尔)和碳酸钾(2.66克,19.29毫摩尔)加入N,N-二甲基甲酰胺(15.0毫升)中,80℃搅拌15分钟,在该温度下,加入碘甲烷(1.2毫升),继续反应30分钟。
反应结束,加水淬灭,混合液用乙酸乙酯(50毫升×3次)萃取,合并有机相,有机相先用饱和食盐水(50毫升×2次),然后用无水硫酸钠干燥,最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂:乙酸乙酯/正己烷=1/3)。得到1.10克白色固体5-溴-6-甲氧基-2-(4-甲氧基苄基)哒嗪-3(2H)-酮(收率:70.3%)。LCMS:RT=3.87min,[M+H]+=325.01。
步骤C:合成6-乙酰基-3-氯苯硼酸频哪醇酯
室温下,将2-溴-4-氯苯乙酮(5.00克,21.41毫摩尔)、联硼酸频哪醇酯(8.16克,32.12毫摩尔)和醋酸钾(4.20克,42.82毫摩尔)加入三颈瓶中,置换氮气,加入1,4-二氧六环(60.0毫升),置换氮气,加入1,1'-双二苯基膦二茂铁二氯化钯(1.75克,2.14毫摩尔),置换氮气,升温至80℃反应3小时。
反应结束,加水淬灭,垫硅藻土抽滤,乙酸乙酯洗涤滤饼,滤液用乙酸乙酯(80毫升×3次)萃取,合并有机相,有机相先用饱和食盐水(50毫升×2次),然后用无水硫酸钠干燥,最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂:乙酸乙酯/正己烷=1/50)。得到2.1克黄色固体6-乙酰基-3-氯苯硼酸频哪醇酯(收率:35.0%)。LCMS:RT=4.26min,[M-H]-=279.08。
步骤D:合成5-(2-乙酰基-5-氯苯基)-6-甲氧基-2-(4-甲氧基苄基)哒嗪-3(2H)-酮
室温下,将5-溴-6-甲氧基-2-(4-甲氧基苄基)哒嗪-3(2H)-酮(1.10克,3.39毫摩尔)、6-乙酰基-3-氯苯硼酸频哪醇酯(949毫克,3.39毫摩尔)和碳酸钠(718毫克,6.78毫摩尔)加入三颈瓶中,置换氮气,加入混合溶剂(10毫升,1,2-二甲氧基乙烷:乙醇:水=8:1:1),置换氮气,加入1,1'-双二苯基膦二茂铁二氯化钯(249毫克,0.34毫摩尔),置换氮气,升温至90℃反应1小时。
反应结束,加水淬灭,混合液用乙酸乙酯(50毫升×3次)萃取,合并有机相,有机相先用饱和食盐水(50毫升×2次),然后用无水硫酸钠干燥,最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂:乙酸乙酯/正己烷=1/2)。得到676毫克黄色固体5-(2-乙酰基-5-氯苯基)-6-甲氧基-2-(4-甲氧基苄基)哒嗪-3(2H)-酮(收率:50.2%)。LCMS:RT=3.99min,[M+H]+=399.07。
步骤E:合成5-(2-乙酰基-5-氯苯基)-6-甲氧基哒嗪-3(2H)-酮
0℃下,将5-(2-乙酰基-5-氯苯基)-6-甲氧基-2-(4-甲氧基苄基)哒嗪-3(2H)-酮(676毫克,1.70毫摩尔)加入混合溶剂(4毫升,乙腈:水=3:1)中,再缓慢加入硝酸铈铵(7.46克,13.60毫摩尔),加毕,室温下反应30分钟。
反应结束,加水淬灭,混合液用乙酸乙酯(30毫升×3次)萃取,合并有机相,有机相先用饱和食盐水(30毫升×2次),然后用无水硫酸钠干燥,最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂:乙酸乙酯/正己烷=1/1)。得到238毫克黄色固体5-(2-乙酰基-5-氯苯基)-6-甲氧基哒嗪-3(2H)-酮(收率:50.0%)。LCMS:RT=3.23min,[M+H]+=279.08。
步骤F:合成(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸叔丁酯)苯甲酸叔丁酯
室温下,将5-(2-乙酰基-5-氯苯基)-6-甲氧基哒嗪-3(2H)-酮(50毫克,0.18毫摩尔)、(R)-4-(2-(((4-硝基苯基)磺酰基)氧基)-3-苯基丙酰胺基)苯甲酸叔丁酯(113毫克,0.22毫摩尔)和碳酸钾(50毫克,0.36毫摩尔)加入N,N-二甲基甲酰胺(2.0毫升)中,室温反应过夜。
反应结束,加水淬灭,混合液用乙酸乙酯(10毫升×3次)萃取,合并有机相,有机相先用饱和食盐水(10毫升×2次),然后用无水硫酸钠干燥,最后减压浓缩。所得残余物用硅胶柱层析纯化(洗脱剂:乙酸乙酯/正己烷=1/2)。得到75毫克淡黄色固体(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸叔丁酯(收率:66.7%)。LCMS:RT=4.53min,[M+H]+=602.13。
步骤G:合成(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸
室温下,将(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸叔丁酯(75毫克,0.12毫摩尔)加入二氯甲烷(2.0毫升)中,滴加三氟乙酸(0.25毫升),室温反应3小时。
反应结束,蒸干二氯甲烷并用油泵抽干三氟乙酸,所得残余物用溶于二氯甲烷(1.0毫升)中,将其滴加入正己烷(10.0毫升)中,析出白色固体,抽滤,滤饼用正己烷洗涤,干燥得到50毫克白色固体(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸(收率:76.5%)。LCMS:RT=3.98min,[M-H]-=544.10。1HNMR(500MHz,DMSO)δ12.79(s,1H),10.52(s,1H),7.99(d,J=8.4Hz,1H),7.91(d,J=8.7Hz,2H),7.72(d,J=8.7Hz,2H),7.69(dd,J=8.3,2.1Hz,1H),7.50(d,J=2.1Hz,1H),7.37–7.23(m,4H),7.19(t,J=7.1Hz,1H),6.91(s,1H),5.74(dd,J=10.2,4.9Hz,1H),3.67(s,3H),3.52(dd,J=14.1,10.3Hz,1H),3.41(dd,J=14.1,4.7Hz,1H),2.53(s,3H)。
实施列2
(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸钠盐
将化合物A,(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸(7.5克,13.7毫摩尔)加入到纯化水(75.0毫升)中,开启搅拌。零摄氏度下,缓慢滴加预先配制的5%氢氧化钠溶液(氢氧化钠,0.55克,13.7毫摩尔;纯化水,10.0毫升),约30分钟滴加完毕。
滴加结束后,继续补加5%氢氧化钠溶液调节水溶液pH 8~9。升温至室温,搅拌30~60分钟,保证(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸溶解完全。过滤,水溶液低温冻干得7.5克(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸钠。
实施例3
(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸钾盐
零摄氏度下,向含有(S)-4-(2-(4-(2-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧并哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸(100.0毫克,0.18毫摩尔)的甲醇(10.0毫升)中,滴加氢氧化钾水溶液(氢氧化钾;10.3毫克,0.18毫摩尔;水:2.0毫升),保持该温度反应5小时。
反应结束,蒸除甲醇,所得水溶液低温冻干得到98.0毫克白色固体(S)-4-(2-(4-(2-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧并哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸钾盐(收率:93.4%)。LCMS:RT=2.00min,[M+H]+=546.22。1H NMR(400MHz,DMSO)δ10.23(s,1H),7.98(d,J=8.4Hz,1H),7.77(d,J=8.6Hz,2H),7.68(dd,J=8.3,2.2Hz,1H),7.50(d,J=2.1Hz,1H),7.46(d,J=8.5Hz,2H),7.38–7.24(m,4H),7.18(t,J=7.1Hz,1H),6.89(s,1H),5.75(dd,J=10.3,4.7Hz,1H),3.68(s,3H),3.56–3.41(m,2H),2.52(s,3H)。
实施列4
(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸葡甲胺盐
室温下,将(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸(60克,109.89毫摩尔)和葡甲胺(21.5g,109.89毫摩尔)加入到丙酮和纯化水的混合溶液中(丙酮,1000毫升;纯化水,100.0毫升)中,搅拌溶清。室温搅拌24小时以上。
反应结束后,减压浓缩除掉丙酮,所得水溶液低温冻干得80.0克(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸葡甲胺盐。
实施例5
(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸镁盐
零摄氏度下,向含有(S)-4-(2-(4-(2-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧并哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲钠(100.0毫克,0.18毫摩尔)的甲醇(10.0毫升)中,滴加氯化镁水溶液(氯化镁;16.8毫克,0.18毫摩尔;水:2.0毫升),保持该温度反应5小时。
反应结束,蒸除甲醇,析出白色固体,抽滤,干燥得到62.0毫克白色固体(S)-4-(2-(4-(2-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧并哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸镁盐(收率:30.9%)。LCMS:RT=2.00min,[M+H]+=546.20。1H NMR(500MHz,DMSO)δ10.33(s,1H),7.98(d,J=8.4Hz,1H),7.93(s,2H),7.67(dd,J=8.3,2.1Hz,1H),7.59(d,J=8.2Hz,2H),7.49(d,J=1.9Hz,1H),7.36–7.22(m,4H),7.17(t,J=7.2Hz,1H),6.88(s,1H),5.73(dd,J=10.2,4.8Hz,1H),3.66(s,3H),3.41(dd,J=14.3,4.7Hz,2H),2.51(s,3H)。
实施例6
(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸钙盐
零摄氏度下,向含有(S)-4-(2-(4-(2-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧并哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲钠(100.0毫克,0.18毫摩尔)的甲醇(10.0毫升)中,滴加氯化钙水溶液(氯化钙;20.0毫克,0.18毫摩尔;水:2.0毫升),保持该温度反应5小时。
反应结束,蒸除甲醇,析出白色固体,抽滤,水洗,干燥得到58.0毫克白色固体(S)-4-(2-(4-(2-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧并哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸钙盐(收率:28.5%)。LCMS:RT=2.00min,[M+H]+=546.17。
实施例7
(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸胆碱盐
将(S)-4-(2-(4-(2-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧并哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸和胆碱以1:1当量比加入丙酮中,在温度循环下(50℃~5℃,0.1℃/min,2循环)搅拌3天得到胶状样品,胶状样品在室温下真空干燥8小时得固体粉末(S)-4-(2-(4-(2-乙酰基-5-氯苯基)-3-甲氧基-6-氧代哒嗪-1(6H)-基)-3-苯基丙酰胺基)苯甲酸胆碱盐。
实施例8:本发明化合物的大鼠药代动力学研究
1、实验材料
SD大鼠:雄性,180-250g,购于北京维通利华实验动物技术有限公司。
试剂:生理盐水,肝素,乙腈,甲酸,普萘洛尔(内标)均为市售可得。
仪器:赛默飞LC-MS(U300 UPLC,TSQ QUANTUMN ULTRA三重四级杆质谱)。
2、实验方法
称取各化合物固体粉末(折算为游离酸重量约3.5mg),填充于9号ToRPAC胶囊内口服给药后,于15min、30min、1h、2h、5h、7h、24h采集静脉血200μL于肝素化EP管中,12000rpm离心2min,取血浆-80℃冻存待测。精密称取一定量供试品用DMSO溶解至2mg/mL,作为储备液。准确吸取适量的化合物储备液,加入乙腈稀释制成标准系列溶液。准确吸取上述标准系列溶液各20μL,加入空白血浆180μL,涡旋混匀,配制成相当于血浆浓度为0.3、1、3、10、30、100、300、1000、3000ng/mL的血浆样品,每一浓度进行双样本分析,建立标准曲线。取30μL血浆,加入内标普萘洛尔(50ng/mL)的乙腈溶液200μL,涡旋混匀后,加入100μL纯化水,再次涡旋混匀,4000rpm离心5min,取上清LC-MS/MS分析。LC-MS/MS检测条件如下:
色谱柱:赛默飞HYPERSIL GOLD C-18UPLC柱,100*2.1mm,1.7μm。
流动相:水(0.1%甲酸)-乙腈按下表进行梯度洗脱
时间(min) | 水(含0·1%甲酸) | 乙睛 |
0 | 90% | 10% |
0·6 | 90% | 10% |
1 | 10% | 90% |
2·6 | 10% | 90% |
2·61 | 90% | 10% |
4 | 90% | 10% |
3、数据处理
LC-MS/MS检测血药浓度后,采用WinNonlin 6.1软件,非房室模型法计算药动学参数,结果见下表十。
表十.本发明化合物盐及游离酸对大鼠药代动力学结果
从上述结果可见,采用胶囊制剂,在相同的口服崩解条件下化合物A葡甲胺盐、钠盐体内的暴露量明显优于化合物A游离酸,说明相对于化合物A游离酸有更好的吸收。
实施例9本发明化合物的药物制剂
物料名称 | 用量 |
API(化合物A葡甲胺盐) | 50mg(以游离酸计) |
聚维酮K30 | 22.6mg |
聚乙二醇6000 | 45.3mg |
将上述物料预混后,再进行熔融制粒,得到颗粒,灌装胶囊。
实施例10本发明化合物的药物制剂
将上述物料预混后,再进行熔融制粒,得到颗粒,灌装胶囊。
对比实施例1
物料名称 | 用量 |
API(化合物A葡甲胺盐) | 50mg(以游离酸计) |
硅化微晶纤维素 | 89mg |
交联聚维酮XL | 8.4mg |
硬脂酸镁 | 1.7mg |
将上述物料混合后,压片,控制崩解时限不高于5min。
本发明化合物的药物制剂的药效研究
1、实验材料
食蟹猴:雄性,2.5-5kg,来自于康龙化成(宁波)新药技术有限公司。
药物:API不同制剂。
仪器:Waters APITQ-XS LC/MS/MS、AB SCIEX API 5500 LC/MS/MS。
2、实验方法
每次采用6只食蟹猴交叉灌胃给药方式考察各制剂吸收情况,试验前动物禁食过夜,各制剂经口给药于药后0.5h、1h、2h、4h、6h、8h、24h采集静脉血离心制备成血浆,-80℃冻存待测。采用蛋白沉淀方式处理血浆样品,用空白血浆配制浓度为0.5、1、2、5、10、50、100、500、1000和2000ng/mL的血浆样品,每一浓度进行双样本分析,建立标准曲线检测血浆样品中药物浓度。液相条件如下:
色谱柱:Agilent Poroshell 120EC-C184μm(50×2.1mm)。
流动相:按下表进行梯度洗脱
3、数据处理
LC/MS/MS检测血药浓度后,采用非房室模型法计算药动学参数。
实施例11
将实施例9与对比实施例1分别开展食蟹猴PK试验,给药剂量50mg,试验结果表明,
实施例9的Cmax和AUClast明显优于对比实施例1(其中,AUClast提高了2.6倍,给药剂量50mg时:对比实施例1的AUClast为1860h*ng/mL),说明采用熔融制粒技术制备的样品与混粉直压工艺相比,能显著提高动物体内吸收,能较好解决难溶性药物的吸收问题。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
1.一种药物制剂,其特征在于,所述药物制剂含有活性成分化合物A或其可药用盐,
和载体材料,其中所述载体材料为:
(1)载体一:醋酸羟丙甲纤维素琥珀酸酯、羟丙甲纤维素、醋酸纤维素、丙烯酸树脂、羟丙纤维素、羟丙甲纤维素邻苯二甲酸酯、聚维酮或共聚维酮中的一种以上,
(2)载体二:聚乙二醇、山嵛酸甘油酯、硬脂酸、十六醇、十八醇、氢化植物油、脂肪酸甘油酯、聚氧乙烯蓖麻油、石蜡等。
2.根据权利要求1所述的药物制剂,其特征在于,所述载体材料和活性成分的重量比为0.2:1~4:1,优选为0.4:1~3:1。
3.根据权利要求1所述的药物制剂,其特征在于,所述醋酸羟丙甲纤维素琥珀酸酯为HPMCAS。
4.根据权利要求1所述的药物制剂,其特征在于,所述醋酸羟丙甲纤维素琥珀酸酯为HPMCAS选自HPMCAS-MG、HPMCAS-MF、HPMCAS-MP,聚维酮为K30,聚乙二醇为聚乙二醇6000。
5.根据权利要求1所述的药物制剂,其特征在于,化合物:载体一:载体二=3:1:1~3:1:2。
6.根据权利要求1所述的药物制剂,其特征在于,制备方法包括将载体材料与活性成分预混后,再进行熔融制粒。
7.一种固体制剂,其包含权利要求1-6任一项所述的药物制剂,所述固体制剂选自片剂、丸剂、颗粒剂或胶囊剂。
8.根据权利要求7所述的固体制剂,其特征在于所述固体制剂还包含药学上可接受的赋形剂,所述赋形剂选自崩解剂、填充剂、粘合剂、助流剂、表面活性剂或润滑剂中的至少一种。
9.根据权利要求8所述的固体制剂,其特征在于,
所述崩解剂选自低取代羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、羧甲基纤维素钙、淀粉、预胶化淀粉、微晶纤维素、二氧化硅、泡腾成分或海藻酸中的至少一种,所述崩解剂的用量占固体制剂重量的1~50%;
所述填充剂选自糊精、乳糖、蔗糖、磷酸氢钙、淀粉、无水磷酸氢钙、磷酸氢钙、微晶纤维素、硅化微晶纤维素、微晶纤维素乳糖复合物、或甘露醇中的至少一种,所述填充剂的用量占固体制剂重量的30~90%;
所述粘合剂选自聚乙烯吡咯烷酮、淀粉、甲基纤维素、羧基纤维素、羟丙基纤维素、羟丙甲基纤维素、羧甲纤维素钠、或海藻酸盐中至少一种,所述粘合剂的用量占固体制剂重量的0.5~10%。
所述助流剂选自气相二氧化硅、三硅酸镁、粉状纤维素、淀粉或滑石粉中的至少一种,所述助流剂的用量占固体制剂重量的0.1~10%;
所述表面活性剂选自十二烷基苯磺酸钠、十二烷基硫酸钠、泊洛沙姆、多库酯钠中的至少一种,所述表面活性剂的用量占固体制剂重量的0.1~10%;
所述润滑剂选自硬脂酸镁、硬脂酸、棕榈酸、硬脂酸钙、滑石粉、巴西棕榈蜡或硬脂富马酸钠中的至少一种,所述润滑剂的用量占固体制剂重量的0.1~5%。
10.根据权利要求7-9任一项所述的固体制剂,其特征在于所述固体制剂中含有:
1)权利要求1-6任一权利要求所述的药物制剂,包含10mg~600mg重量的活性成分;
进一步任选含有以下组成的一种以上的赋形剂:
2)5~50%重量的崩解剂;
3)30~90%重量的填充剂;
4)0.5~10%重量的粘合剂;
5)0.1~10%重量的助流剂;
6)0.1~10%重量的表面活性剂;
7)0.1~5%重量的润滑剂;
固体制剂各组份之和为100%。
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