CN112402385B - 4-羟甲基-1h-吲哚类化合物药物制剂及其制备方法 - Google Patents
4-羟甲基-1h-吲哚类化合物药物制剂及其制备方法 Download PDFInfo
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- CN112402385B CN112402385B CN202011366824.2A CN202011366824A CN112402385B CN 112402385 B CN112402385 B CN 112402385B CN 202011366824 A CN202011366824 A CN 202011366824A CN 112402385 B CN112402385 B CN 112402385B
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Abstract
本发明涉及4‑羟甲基‑1H‑吲哚类化合物药物制剂及其制备方法,所述4‑羟甲基‑1H‑吲哚类化合物具有如式Ι所示的结构:其中,R1和R2一起构建2‑氧代‑8‑氮杂螺[4.5]癸烷‑8‑基、1,8‑二氮杂螺[4.5]癸烷‑8‑基、2,8‑二氮杂螺[4.5]癸烷‑8‑基、4‑氨基‑4‑甲基哌啶‑1‑基、3,5‑二甲基哌嗪‑1‑基中的一种;R3代表2‑氯‑6‑氟苯基、3‑氯吡啶‑4‑基、2‑氯‑6‑甲氧基苯基、2,6‑二氯苯基、2,3‑二氯苯基中的一种。所述4‑羟甲基‑1H‑吲哚类化合物药物制剂由4‑羟甲基‑1H‑吲哚类化合物、填充剂、崩解剂、粘合剂、润滑剂组成。该4‑羟甲基‑1H‑吲哚类化合物药物制剂的溶出效果好,能够作为SHP2抑制剂应用在制备治疗或预防肿瘤的药物制剂中。
Description
技术领域
本发明涉及4-羟甲基-1H-吲哚类化合物药物制剂及其制备方法,属于化学医药制剂技术领域。
背景技术
癌症是威胁人类健康的重大疾病之一,目前癌症的主要治疗方式有药物治疗、手术治疗和放射治疗,其中,药物治疗是最常用的治疗方式之一。传统的抗肿瘤药物无法区分肿瘤细胞和正常细胞,常导致严重的副作用,而靶向药物以肿瘤细胞做为特异性靶点,能准确的作用于肿瘤,极大的提高了治疗水平并降低不良反应率。
在多种恶性肿瘤中均存在蛋白酪氨酸激酶或蛋白酪氨酸磷酸激酶的突变,抑制蛋白酪氨酸激酶的活性已经成为肿瘤靶向治疗最常用的策略之一,迄今为止已有几十种蛋白酪氨酸激酶抑制剂被批准用于临床使用。然而蛋白酪氨酸磷酸激酶作为抗肿瘤靶点的药物研发进展最快的化合物也仅处于II期临床。
蛋白酪氨酸磷酸酶(SHP2)是由PTPN11基因编码的非受体酪氨酸磷酸酶,包含一个保守的酪氨酸磷酸酶结构域,两个N-端的SH2结构域、一个C端尾巴,两个SH2结构域决定了SHP2的亚细胞定位及功能调节。在非活化状态下,N-端的SH2结构域会与PTP结构域结合并使之失去活性,当SHP2结构域与受体或者接头蛋白上的特定酪氨酸残基结合时,PTP结构域会被释放出来,例如,通过细胞因子和生长因子的刺激导致催化位点的暴露从而引起SHP2的活化。
SHP2表达广泛,且参与到多条细胞信号过程中,比如RAS-ERk、JAK-STAT、FGFR、EGFR等通络,在细胞增殖、分化、细胞周期和迁移中起重要作用。
SHP2活化与多种疾病发生相关,比如B细胞急性淋巴细胞白血病和急性骨髓性白血病等,另外,PTPN1的活化突变也在实体瘤中发现,如肺癌、肝癌、结肠癌等,因此,研究和发现新的SHP2小分子抑制剂具有重要意义。
发明内容
本发明提供了4-羟甲基-1H-吲哚类化合物药物制剂及其制备方法,具体技术方案如下:
4-羟甲基-1H-吲哚类化合物药物制剂包括以下质量份的组分:
所述4-羟甲基-1H-吲哚类化合物具有如式Ι所示的结构:
其中,R1和R2一起构建2-氧代-8-氮杂螺[4.5]癸烷-8-基、1,8-二氮杂螺[4.5]癸烷-8-基、2,8-二氮杂螺[4.5]癸烷-8-基、4-氨基-4-甲基哌啶-1-基、3,5-二甲基哌嗪-1-基中的一种;
R3代表2-氯-6-氟苯基、3-氯吡啶-4-基、2-氯-6-甲氧基苯基、2,6-二氯苯基、2,3-二氯苯基中的一种。
作为上述技术方案的改进,所述4-羟甲基-1H-吲哚类化合物选自下述式1~式23中的任一化合物,结构式如下:
作为上述技术方案的改进,所述填充剂为淀粉、微晶纤维素、甘露醇、乳糖中的一种或数种。
作为上述技术方案的改进,所述崩解剂为羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素中的一种或数种。
作为上述技术方案的改进,所述粘合剂为羟丙基纤维素、羟丙甲纤维素、聚维酮、预胶化淀粉、明胶中的一种或数种。
作为上述技术方案的改进,所述润滑剂为硬脂富马酸钠、硬脂酸镁、微粉硅胶、滑石粉中的一种或数种。
所述4-羟甲基-1H-吲哚类化合物药物制剂的制备方法,包括以下步骤:
步骤1、取4-羟甲基-1H-吲哚类化合物原料过筛后,备用;
步骤2、按照处方量称取粘合剂并将其与水配置成粘合剂溶液,称取4-羟甲基-1H-吲哚类化合物、填充剂、崩解剂和粘合剂溶液,混合后制备出湿颗粒;
步骤3、将制备的湿颗粒进行干燥,控制水分2-4%,然后进行整粒;
步骤4、将整粒后的颗粒加入润滑剂,采用三维混合机进行混合;
步骤5、将混合后的颗粒制成片剂、颗粒剂或胶囊剂。
所述4-羟甲基-1H-吲哚类化合物药物制剂作为SHP2抑制剂能够应用在制备治疗或预防肿瘤的药物中,所述肿瘤为皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、直肠癌、食管癌、舌癌、肾癌、肾实质癌、宫颈癌、子宫体癌、子宫内膜癌、睾丸癌、泌尿癌、黑素癌、星型细胞癌、脑膜瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病、慢性粒细胞白血病、成人T细胞白血病淋巴瘤、肝细胞癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、精原细胞瘤、软骨肉瘤、肌肉瘤、纤维肉瘤、食管鳞癌中的任一种。
本发明的有益效果:
1)、本发明所述4-羟甲基-1H-吲哚类化合物药物制剂通过抑制SHP2活性达到治疗肿瘤目的。
2)、本发明所述4-羟甲基-1H-吲哚类化合物药物制剂,其溶出度好,制剂的溶出效果好,有利于提高药物的生物利用度。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
实施例1
如式1所示的化合物:(1-(2,3-二氯苯基)-5-((3S,5R)-3,5-二甲基哌啶-1-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
第一步:
将化合物1a(25.3g,100.0mmol)、化合物1b(25.7g,120.0mmol)、碳酸铯(48.9g,150.0mmol)、醋酸钯(2.2g,10.0mmol)、BINAP(12.4g,20.0mmol)溶于DMF(200mL)中,升温至80℃保温反应10小时,薄层色谱(Thin Layer Chromatography,简写为TLC)监测反应,反应完毕后加水(200mL)淬灭反应,用乙酸乙酯萃取(200mL×2),有机层干燥,柱层析分离得到26.3g化合物1c,收率68.0%,化合物1c为类白色固体。
第二步:
将上述得到的化合物1c(26.0g,61.2mmol)溶于甲醇(200mL)中,冰浴下加入硼氢化钠(10.2g,268.7mmol),加完后升温至25℃,搅拌反应4小时,TLC监测反应,反应完毕后加水淬灭反应,用乙酸乙酯(200mL×2)提取,有机层干燥,过滤、浓缩,柱层析分离得到18.5g化合物1d,收率为84.2%,化合物1d为类白色固体。
第三步:
将化合物1d(3.6g,10.0mmol)、化合物1e(2.2g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,无水硫酸钠干燥、过滤,柱层析分离得到2.5g化合物1f,收率为49.7%,化合物1f为类白色固体。第四步:
将化合物1f(503mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到198mg的化合物1,收率为49.1%,ESI(+)m/z=404.1,化合物1为白色固体。
实施例2
如式2所示的化合物:(1-(2,6-二氯苯基)-5-((3S,5R)-3,5-二甲基哌啶-1-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物1d(3.6g,10.0mmol)、化合物2a(2.2g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到3.1g化合物2b,收率为61.6%,化合物2b为类白色固体。
将化合物2b(503mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到225mg的化合物2,收率为55.7%,ESI(+)m/z=404.1,化合物2为白色固体。
实施例3
如式3所示的化合物:(1-(2-氯-6-甲氧基苯基)-5-((3S,5R)-3,5-二甲基哌啶-1-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物1d(3.6g,10.0mmol)、化合物3a(2.2g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到2.3g化合物3b,收率为46.1%,化合物3b为类白色固体。
将化合物3b(499mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到231mg的化合物3,收率为57.9%,ESI(+)m/z=400.2,化合物3为白色固体。
实施例4
如式4所示的化合物:(1-(2-氯-6-氟苯基)-5-((3S,5R)-3,5-二甲基哌啶-1-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物1d(3.6g,10.0mmol)、化合物4a(2.1g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥,、过滤,柱层析分离得到3.3g化合物4b,收率为67.8%,化合物4b为类白色固体。
将化合物4b(487mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到255mg的化合物4,收率为65.9%,ESI(+)m/z=388.2,化合物4为白色固体。
实施例5
如式5所示的化合物:(1-(3-氯吡啶-4-基)-5-((3S,5R)-3,5-二甲基哌啶-1-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物1d(3.6g,10.0mmol)、化合物5a(1.9g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到1.8g化合物5b,收率为38.3%,化合物5b为类白色固体。
将化合物5b(470mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC检测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到279mg的化合物5,收率为75.4%,ESI(+)m/z=371.2,化合物5为白色固体。
实施例6
如式6所示的化合物:(5-(4-氨基-4-甲基哌啶-1-基)-1-(2,3-二氯苯基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
第一步:
将化合物1a(25.3g,100.0mmol)、化合物6a(25.7g,120.0mmol)、碳酸铯(48.9g,150.0mmol)、醋酸钯(2.2g,10.0mmol)、BINAP(12.4g,20.0mmol)溶于DMF(200mL)中,升温至80℃保温反应10小时,TLC监测反应,反应完毕后加水(200mL)淬灭反应,用乙酸乙酯萃取(200mL×2),有机层干燥,柱层析分离得到23.3g化合物6b,收率60.2%,化合物6b为类白色固体。
第二步:
将上述得到化合物6b(23.0g,59.4mmol)溶于甲醇(200mL)中,冰浴下加入硼氢化钠(9.0g,237.7mmol),加完后升温至30℃,搅拌反应4小时,TLC监测反应,反应完毕后加水淬灭反应,用乙酸乙酯(200mL×2)提取,有机层干燥,过滤、浓缩,柱层析分离得到16.1g化合物6c,收率为75.5%,化合物6c为类白色固体。
第三步:
将化合物6c(3.6g,10.0mmol)、化合物1e(2.2g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到2.9g化合物6d,收率为57.7%,化合物6d为类白色固体。
第四步:
将化合物6d(503mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到255mg的化合物6,收率为63.3%,ESI(+)m/z=404.1,化合物6为白色固体。
实施例7
如式7所示的化合物:(5-(4-氨基-4-甲基哌啶-1-基)-1-(2,6-二氯苯基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物6c(3.6g,10.0mmol)、化合物2a(2.2g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到3.0g化合物7a,收率为59.6%,化合物7a为类白色固体。
将化合物7a(503mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到288mg的化合物7,收率为71.5%,ESI(+)m/z=404.1,化合物7为白色固体。
实施例8
如式8所示的化合物:(5-(4-氨基-4-甲基哌啶-1-基)-1-(2-氯-6-甲氧基苯基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物6c(3.6g,10.0mmol)、化合物3a(2.2g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到2.5g化合物8a,收率为50.2%,化合物8a为类白色固体。
将化合物8a(499mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到268mg的化合物8,收率为67.2%,ESI(+)m/z=400.2,化合物8为白色固体。
实施例9
如式9所示的化合物:(5-(4-氨基-4-甲基哌啶-1-基)-1-(2-氯-6-氟苯基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物6c(3.6g,10.0mmol)、化合物4a(2.1g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到2.9g化合物9a,收率为59.5%,化合物9a为类白色固体。
将化合物9a(487mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到302mg的化合物9,收率为78.0%,ESI(+)m/z=388.1,化合物9为白色固体。
实施例10
如式10所示的化合物:(5-(4-氨基-4-甲基哌啶-1-基)-1-(3-氯吡啶-4-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物6c(3.6g,10.0mmol)、化合物5a(1.9g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到3.5g化合物10a,收率为74.5%,化合物10a为类白色固体。
将化合物10a(470mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到278mg的化合物10,收率为75.1%,ESI(+)m/z=371.1,化合物10为白色固体。
实施例11
如式11所示的化合物:(1-(2,3-二氯苯基)-5-(2,8-二氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
第一步:
将化合物1a(25.3g,100.0mmol)、化合物11a(28.8g,120.0mmol)、碳酸铯(48.9g,150.0mmol)、醋酸钯(2.2g,10.0mmol)、BINAP(12.4g,20.0mmol)溶于DMF(200mL)中,升温至80℃保温反应10小时,TLC检测反应,反应完毕后加水(200mL)淬灭反应,用乙酸乙酯萃取(200mL×2),有机层干燥,柱层析分离得到24.9g化合物11b,收率60.3%,化合物11b为类白色固体。
第二步:
将上述得到化合物11b(24.0g,58.1mmol)溶于甲醇(200mL)中,冰浴下加入硼氢化钠(8.8g,232.4mmol),加完后升温至25℃,搅拌反应5小时,TLC检测反应,反应完毕后加水淬灭反应,用乙酸乙酯(200mL×2)提取,有机层干燥,过滤、浓缩,柱层析分离得到16.5g化合物11c,收率为73.8%,化合物11c为类白色固体。
第三步:
将化合物1c(3.9g,10.0mmol)、化合物1e(2.2g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到3.6g化合物11d,收率为69.1%,化合物11d为类白色固体。
第四步:
将化合物11d(529mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC检测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到301mg的化合物11,收率为70.2%,ESI(+)m/z=430.1,化合物11为白色固体。
实施例12
如式12所示的化合物:(1-(2,6-二氯苯基)-5-(2,8-二氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物11c(3.9g,10.0mmol)、化合物2a(2.2g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到3.2g化合物12a,收率为60.5%,化合物12a为类白色固体。
将化合物12a(529mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到255mg的化合物12,收率为59.4%,ESI(+)m/z=430.1,化合物12为白色固体。
实施例13
如式13所示的化合物:(1-(2-氯-6-甲氧基苯基)-5-(2,8-二氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物11c(3.9g,10.0mmol)、化合物3a(2.2g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到2.7g化合物13a,收率为51.4%,化合物13a为类白色固体。
将化合物13a(525mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到312mg的化合物13,收率为73.4%,ESI(+)m/z=426.2,化合物13为白色固体。
实施例14
如式14所示的化合物:(1-(2-氯-6-氟苯基)-5-(2,8-二氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物11c(3.9g,10.0mmol)、化合物4a(2.1g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到3.2g化合物14a,收率为62.4%,化合物14a为类白色固体。
将化合物14a(513mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到334mg的化合物14,收率为80.9%,ESI(+)m/z=414.2,化合物14为白色固体。
实施例15
如式15所示的化合物:(1-(3-氯吡啶-4-基)-5-(2,8-二氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物11c(3.9g,10.0mmol)、化合物5a(1.9g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到2.6g化合物15a,收率为52.4%,化合物15a为类白色固体。
将化合物15a(496mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到298mg的化合物15,收率为75.3%,ESI(+)m/z=397.2,化合物15为白色固体。
实施例16
如式16所示的化合物:(1-(2,3-二氯苯基)-5-(1,8-二氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
第一步:
将化合物1a(25.3g,100.0mmol)、化合物16a(24.0g,120.0mmol)、碳酸铯(48.9g,150.0mmol)、醋酸钯(2.2g,10.0mmol)、BINAP(12.4g,20.0mmol)溶于DMF(200mL)中,升温至80℃保温反应10小时,TLC检测反应,反应完毕后加水(200mL)淬灭反应,用乙酸乙酯萃取(200mL×2),有机层干燥,柱层析分离得到25.5g化合物16b,收率61.7%,化合物16b为类白色固体。
第二步:
将上述得到的化合物16b(25.0g,60.5mmol)溶于甲醇(200mL)中,冰浴下加入硼氢化钠(9.2g,242.1mmol),加完后升温至25℃,搅拌反应3小时,TLC检测反应,反应完毕后加水淬灭反应,用乙酸乙酯(200mL×2)提取,有机层干燥,过滤、浓缩,柱层析分离得到13.8g化合物16c,收率为59.3%,化合物16c为类白色固体。
第三步:
将化合物16c(3.9g,10.0mmol)、化合物1e(2.2g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥,过滤,柱层析分离得到3.4g化合物16d,收率为64.3%,化合物16d为类白色固体。
第四步:
将化合物16d(529mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到318mg的化合物16,收率为74.1%,ESI(+)m/z=430.1,化合物16为白色固体。
实施例17
如式17所示的化合物:(1-(2,6-二氯苯基)-5-(1,8-二氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物16c(3.9g,10.0mmol)、化合物2a(2.2g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到2.7g化合物17a,收率为51.0%,化合物17a为类白色固体。
将化合物17a(529mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到296mg的化合物17,收率为69.0%,ESI(+)m/z=430.1,化合物17为白色固体。
实施例18
如式18所示的化合物:(1-(2-氯-6-甲氧基苯基)-5-(1,8-二氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物16c(3.9g,10.0mmol)、化合物3a(2.2g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到3.1g化合物18a,收率为59.0%,化合物18a为类白色固体。
将化合物18a(525mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到311mg的化合物18,收率为73.2%,ESI(+)m/z=426.1,化合物18为白色固体。
实施例19
如式19所示的化合物:(1-(2-氯-6-氟苯基)-5-(1,8-二氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物16c(3.9g,10.0mmol)、化合物4a(2.1g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到3.5g化合物19a,收率为68.2%,化合物19a为类白色固体。
将化合物19a(513mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到325mg的化合物19,收率为78.7%,ESI(+)m/z=414.2,化合物19为白色固体。
实施例20
如式20所示的化合物:(1-(3-氯吡啶-4-基)-5-(1,8-二氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物16c(3.9g,10.0mmol)、化合物5a(1.9g,10.0mmol)、碳酸钾(2.8g,20.0mmol)、碘化亚铜(380mg,2.0mmol)、L-Proline(460mg,4.0mmol)溶于DMSO(300mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到3.6g化合物20a,收率为72.6%,化合物20a为类白色固体。
将化合物20a(496mg,1.0mmol)溶于二氯甲烷(10mL)中,室温下加入三氟乙酸(4mL),室温搅拌反应6小时,TLC监测反应,反应完毕后,旋蒸除去溶剂,加入饱和碳酸氢钠溶液(10mL),用乙酸乙酯(50mL×2)萃取,有机层干燥,过滤、浓缩,柱层析分离得到308mg的化合物20,收率为77.8%,ESI(+)m/z=397.2,化合物20为白色固体。
实施例21
如式21所示的化合物:(1-(2,3-二氯苯基)-5-(2-噁唑-8-氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
第一步:
将化合物1a(25.3g,100.0mmol)、化合物21a(14.1g,100.0mmol)、碳酸铯(48.9g,150.0mmol)、醋酸钯(2.2g,10.0mmol)、BINAP(12.4g,20.0mmol)溶于DMF(200mL)中,升温至80℃保温反应10小时,TLC监测反应,反应完毕后加水(200mL)淬灭反应,用乙酸乙酯萃取(200mL×2),有机层干燥,柱层析分离得到20.3g化合物21b,收率64.6%,化合物21b为类白色固体。
第二步:
将上述得到的化合物21b(20.0g,63.7mmol)溶于甲醇(200mL)中,冰浴下加入硼氢化钠(9.7g,254.8mmol),加完后升温至25℃,搅拌反应5小时,TLC监测反应,反应完毕后加水淬灭反应,用乙酸乙酯(200mL×2)提取,有机层干燥,过滤、浓缩,柱层析分离得到15.1g化合物21c,收率为83.0%,化合物21c为类白色固体。
第三步:
将化合物21c(286mg,1.0mmol)、化合物1e(224mg,1.0mmol)、碳酸钾(276mg,2.0mmol)、碘化亚铜(38mg,0.2mmol)、L-Proline(46mg,0.4mmol)溶于DMSO(20mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到198mg的化合物21,收率为46.0%,ESI(+)m/z=431.1,化合物21为类白色固体。
实施例22
如式22所示的化合物:(1-(2,6-二氯苯基)-5-(2-噁唑-8-氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物21c(286mg,1.0mmol)、化合物2a(224mg,1.0mmol)、碳酸钾(276mg,2.0mmol)、碘化亚铜(38mg,0.2mmol)、L-Proline(46mg,0.4mmol)溶于DMSO(20mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到211mg的化合物22,收率为49.1%,ESI(+)m/z=431.1,化合物22为类白色固体。
实施例23
如式23所示的化合物:(1-(2-氯-6-甲氧基苯基)-5-(2-噁唑-8-氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇的制备方法,反应式如下:
将化合物21c(286mg,1.0mmol)、化合物3a(220mg,1.0mmol)、碳酸钾(276mg,2.0mmol)、碘化亚铜(38mg,0.2mmol)、L-Proline(46mg,0.4mmol)溶于DMSO(20mL)中,升温至100℃搅拌反应6小时,反应完毕后用稀盐酸淬灭反应,用乙酸乙酯(50mL×2)提取,合并有机层,干燥、过滤,柱层析分离得到238mg的化合物23,收率为55.9%,ESI(+)m/z=427.2,化合物23为类白色固体。
实施例24
生物学评价实验
24.1、磷酸酶活性试验(IC50)
采用6,8-二氟-4-甲基伞型酮磷酸盐(DiFMUP)作为反应底物,SHP2酶溶液(反应液稀释至0.5nm)与dPEG8肽在反应液(60mM 4-羟乙基呱嗪乙磺酸(HEPES),pH=7.2,75mMNaCl,75Mm KCl,1mM EDTA,0.05%Tween 20,2mM二硫苏糖醇(DTT))共同孵育30分钟以活化PTP,DMSO(0.5%(V/V))或化合物(浓度0.3nM~1μM)加入混合液中,继续在室温孵育30分钟,加入DiFMUP(12μM,反应液总体积为100μL),开始反应,室温下避光孵育30分钟,通过检测反应液荧光强度(激发光340nm,发射光450nm)以获得如式1-23所示化合物对应的SHP2抑制活性,IC50见下表1:(需要说明的是:表1中的如式1所示化合物对应的IC50为B挡,以此类推。)
表1
化合物结构式 | IC<sub>50</sub> | 化合物结构式 | IC<sub>50</sub> |
式1 | B | 式13 | A |
式2 | A | 式14 | A |
式3 | A | 式15 | A |
式4 | A | 式16 | B |
式5 | C | 式17 | C |
式6 | B | 式18 | B |
式7 | B | 式19 | B |
式8 | C | 式20 | A |
式9 | C | 式21 | C |
式10 | C | 式22 | B |
式11 | A | 式23 | A |
式12 | B |
其中,A<100nM,100nM≤B≤1000nM,1000nM≤C。
在该实施例中,含有如式1-23所示化合物作为活性成分的药物组合物作为SHP2抑制剂用于治疗肿瘤。其中,处于A挡和B挡所对应的化合物,其用作SHP2抑制剂,活性良好;尤其是A挡所对应的化合物,其活性最好。
如式1-23所示化合物作为活性成分的药物组合物用作SHP2抑制剂,在肿瘤药物临床试验研究中具有极大地指导价值。
所述肿瘤为皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、直肠癌、食管癌、舌癌、肾癌、肾实质癌、宫颈癌、子宫体癌、子宫内膜癌、睾丸癌、泌尿癌、黑素癌、星型细胞癌、脑膜瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病、慢性粒细胞白血病、成人T细胞白血病淋巴瘤、肝细胞癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、精原细胞瘤、软骨肉瘤、肌肉瘤、纤维肉瘤、食管鳞癌中的任一种。
24.2、人食管鳞癌细胞增殖试验
将KYSE-520细胞,用3%胎牛血清的RPMI-1640培养液调整浓度,接种于96孔板中,培养24小时后,加入含3%胎牛血清培养液配置的不同浓度的化合物孵育,第6天,每孔加入50μLMTS/PMS的混合液,按照说明书(Promega)检测吸光值,如式1-23所示化合物对应的IC50值如表2所示:
表2
化合物结构式 | IC<sub>50</sub>(μM) | 化合物 | IC<sub>50</sub>(μM) |
式2 | 11.5 | 式13 | 25.6 |
式3 | 20.6 | 式14 | 15.5 |
式4 | 16.4 | 式15 | 16.7 |
式11 | 12.8 | 式20 | 9.0 |
通过表2可知:在对含有如式2、3、4、11、13、14、15、20所示化合物作为活性成分的药物组合物用作SHP2抑制剂,在用于抑制人食管鳞癌细胞增值的试验中,其IC50值远小于100μM,说明含有如式2、3、4、11、13、14、15、20所示化合物作为SHP2抑制剂能够显著抑制人食管鳞癌细胞的增殖。
实施例25
配方1(各组分以wt%计)
4-羟甲基-1H-吲哚类化合物药物片剂的制备方法包括以下步骤:
步骤1、取4-羟甲基-1H-吲哚类化合物原料过筛后,备用,此处选择实施例2的产物(1-(2,6-二氯苯基)-5-((3S,5R)-3,5-二甲基哌啶-1-基)-1H-吲哚-4-基)甲醇作为4-羟甲基-1H-吲哚类化合物。
步骤2、按照配方1的处方量称取羟丙基纤维素并将其与水配置成羟丙基纤维素溶液,该羟丙基纤维素溶液的质量分数为5%;称取4-羟甲基-1H-吲哚类化合物、微晶纤维素、羧甲基淀粉钠和羟丙基纤维素溶液,混合后制备出湿颗粒。
步骤3、将制备的湿颗粒通过流化床进行干燥,控制水分2~3%,然后进行整粒。
步骤4、将整粒后的颗粒加入硬脂酸镁,采用三维混合机进行混合。
步骤5、将混合后的颗粒,采用旋转压片机压制素片。
步骤6、将素片采用高效包衣机进行包衣,控制包衣增重为2-3%。其中,包衣剂采用欧巴代包衣粉。
实施例26
配方2(各组分以wt%计)
4-羟甲基-1H-吲哚类化合物药物胶囊剂的制备方法包括以下步骤:
步骤1、取4-羟甲基-1H-吲哚类化合物原料过筛后,备用,此处选择实施例11的产物(1-(2,3-二氯苯基)-5-(2,8-二氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇作为4-羟甲基-1H-吲哚类化合物。
步骤2、按照配方2的处方量称取羟丙甲纤维素并将其与水配置成羟丙甲纤维素溶液,该羟丙甲纤维素溶液的质量分数为5%;称取4-羟甲基-1H-吲哚类化合物、淀粉、交联羧甲基纤维素钠和羟丙甲纤维素溶液,混合后制备出湿颗粒。
步骤3、将制备的湿颗粒通过流化床进行干燥,控制水分2~4%,然后进行整粒。
步骤4、将整粒后的颗粒加入滑石粉,采用三维混合机进行混合。
步骤5、将混合后的颗粒投入胶囊填充剂机中进行灌装得到胶囊。
步骤6、将填充好的胶囊采用铝塑包装。
实施例27
配方3(各组分以wt%计)
4-羟甲基-1H-吲哚类化合物药物颗粒剂的制备方法包括以下步骤:
步骤1、取4-羟甲基-1H-吲哚类化合物原料过筛后,备用,此处选择实施例20的产物(1-(3-氯吡啶-4-基)-5-(1,8-二氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇作为4-羟甲基-1H-吲哚类化合物。
步骤2、按照配方3的处方量称取聚维酮并将其与水配置成聚维酮溶液,该聚维酮溶液的质量分数为8%;称取4-羟甲基-1H-吲哚类化合物、乳糖、羧甲基淀粉钠和聚维酮溶液,混合后制备出湿颗粒。
步骤3、将制备的湿颗粒通过流化床进行干燥,控制水分2~4%,然后进行整粒。
步骤4、将整粒后的颗粒加入硬脂酸镁,采用三维混合机进行混合。
步骤5、将混合后的颗粒采用颗粒包装机进行分装。
实施例28
配方4(各组分以wt%计)
4-羟甲基-1H-吲哚类化合物药物片剂的制备方法包括以下步骤:
步骤1、取4-羟甲基-1H-吲哚类化合物原料过筛后,备用,此处选择实施例14的产物(1-(2-氯-6-氟苯基)-5-(2,8-二氮杂螺[4.5]癸烷-8-基)-1H-吲哚-4-基)甲醇作为4-羟甲基-1H-吲哚类化合物。
步骤2、按照配方4的处方量称取预胶化淀粉并将其与水配置成预胶化淀粉溶液,该预胶化淀粉溶液的质量分数为5%;称取4-羟甲基-1H-吲哚类化合物、甘露醇、交联聚维酮和预胶化淀粉溶液,混合后制备出湿颗粒。
步骤3、将制备的湿颗粒通过流化床进行干燥,控制水分2~4%,然后进行整粒。
步骤4、将整粒后的颗粒加入滑石粉,采用三维混合机进行混合。
步骤5、将混合后的颗粒投入胶囊填充剂机中进行灌装得到胶囊。
步骤6、将填充好的胶囊采用铝塑包装。
实施例29
配方5(各组分以wt%计)
4-羟甲基-1H-吲哚类化合物药物片剂的制备方法包括以下步骤:
步骤1、取4-羟甲基-1H-吲哚类化合物原料过筛后,备用,此处选择实施例4的产物(1-(2-氯-6-氟苯基)-5-((3S,5R)-3,5-二甲基哌啶-1-基)-1H-吲哚-4-基)甲醇作为4-羟甲基-1H-吲哚类化合物。
步骤2、按照配方5的处方量称取明胶并将其与水配置成明胶溶液,该明胶溶液的质量分数为3.5%;称取4-羟甲基-1H-吲哚类化合物、微晶纤维素、低取代羟丙基纤维素和明胶溶液,混合后制备出湿颗粒。
步骤3、将制备的湿颗粒通过流化床进行干燥,控制水分2~3%,然后进行整粒。
步骤4、将整粒后的颗粒加入硬脂酸镁,采用三维混合机进行混合。
步骤5、将混合后的颗粒,采用旋转压片机压制素片。
步骤6、将素片采用高效包衣机进行包衣,控制包衣增重为2%-3%。其中,包衣剂采用欧巴代包衣粉。
实施例30
对实施例25-29中对应的制剂进行溶出度测试实验。
溶出度参照溶出度与释放度测定法(中国药典2020年版四部通则0931第二法)测定。
仪器:紫外分光光度计和溶出度测定仪。
溶出介质:pH=4.5的醋酸盐缓冲溶液。
溶出介质体积:900mL,转速:50转/min。
取样时间:5min、10min、15min、30min。
取实施例25-29中对应的制剂,按照溶出度与释放度测定法,以pH=4.5的醋酸盐缓冲溶液为溶出介质,转速为每分钟50转,依法操作,根据取样时间取溶液测定。
实施例25-29和参比制剂在pH=4.5的醋酸盐缓冲溶液介质中的溶出曲线结果如表3所示:
表3
根据表3可知:采用所述4-羟甲基-1H-吲哚类化合物制备的对应的片剂、颗粒剂或胶囊剂,均具有优良的溶出效果,溶出速率高,因此,采用此配方和方法得到的4-羟甲基-1H-吲哚类化合物药物制剂具有较高的质量和生物利用度。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (8)
4.根据权利要求2所述的4-羟甲基-1H-吲哚类化合物药物制剂,其特征在于,所述填充剂为淀粉、微晶纤维素、甘露醇、乳糖中的一种或数种。
5.根据权利要求2所述的4-羟甲基-1H-吲哚类化合物药物制剂,其特征在于,所述崩解剂为羧甲基淀粉钠、交联羧甲基纤维素钠、交联聚维酮、低取代羟丙基纤维素中的一种或数种。
6.根据权利要求2所述的4-羟甲基-1H-吲哚类化合物药物制剂,其特征在于,所述粘合剂为羟丙基纤维素、羟丙甲纤维素、聚维酮、预胶化淀粉、明胶中的一种或数种。
7.根据权利要求2所述的4-羟甲基-1H-吲哚类化合物药物制剂,其特征在于,所述润滑剂为硬脂富马酸钠、硬脂酸镁、微粉硅胶、滑石粉中的一种或数种。
8.如权利要求2所述的4-羟甲基-1H-吲哚类化合物药物制剂的制备方法,其特征在于包括以下步骤:
步骤1、取4-羟甲基-1H-吲哚类化合物原料过筛后,备用;
步骤2、按照处方量称取粘合剂并将其与水配置成粘合剂溶液,称取4-羟甲基-1H-吲哚类化合物、填充剂、崩解剂和粘合剂溶液,混合后制备出湿颗粒;
步骤3、将制备的湿颗粒进行干燥,控制水分2-4%,然后进行整粒;
步骤4、将整粒后的颗粒加入润滑剂,采用三维混合机进行混合;
步骤5、将混合后的颗粒制成片剂、颗粒剂或胶囊剂。
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