CN115300513A - 一种包含杂环类shp2抑制剂的组合物及其用途 - Google Patents
一种包含杂环类shp2抑制剂的组合物及其用途 Download PDFInfo
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Abstract
本发明属于医药制剂领域,涉及一种包含杂环类SHP2抑制剂的组合物及其用途,具体涉及一种包含式(I)的(R)‑6‑氨基‑2‑(3‑氨基‑3H‑螺[苯并呋喃‑2,4’‑哌啶]‑1’‑基)‑3‑甲基‑5‑((2‑(三氟甲基)吡啶‑3‑基)硫基)嘧啶‑4(3H)‑酮或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物的药物组合物。本发明提供的药物组合物溶出完全,稳定性好,且吸收性质良好,相对生物利用度较高,
Description
技术领域
本发明属于医药制剂领域,涉及一种包含杂环类SHP2抑制剂的组合物及其用途,具体涉及一种包含(R)-6-氨基-2-(3-氨基-3H-螺[苯并呋喃-2,4’-哌啶]-1’-基)-3-甲基-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-4(3H)-酮或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物的药物组合物。
背景技术
SHP2磷酸酶是PTPN11基因编码的非受体PTP(protein tyrosine phosphatase)。其中包括了两个N端的SRC(肉瘤基因)同源结构域(SH2),一个PTP结构域和一个C端尾巴。X衍射结果表明SHP2通过N端的SH2与PTP结构域相互作用并阻断了ATP进入催化位点,该激酶处于一个自抑制的构型。一些可结合于SH2结构域的小肽或蛋白,可以激活该酶的磷酸化,促使癌症的发展。在细胞中,SHP2的功能与细胞质中下游的受体酪氨酸激酶有关,包括RAS-ERK,PI3K-AKT,JAK-STAT。首先,SHP2可结合于RAS并使RAS去磷酸化,从而增加效应蛋白RAF的作用而激活RAS/ERK/MAPK促进增殖的信号通路。其次,SHP2参与PD-1/PD-L1信号通路,并促进免疫逃逸。PD-1/SHP2/STAT1/T-bet信号轴介导了PD-1对Th1细胞的免疫抑制作用。因此,抑制PD-1或SHP2可以恢复Th1的免疫作用和T细胞的激活,解除肿瘤微环境中的免疫抑制。
SHP2与多种疾病的发生相关,如努南综合征(Noonan syndrome)、乳腺癌、黑色素瘤、胃癌、食道癌、肺癌、结肠癌、头癌、成神经细胞瘤、头颈的鳞状细胞癌、间变性大细胞淋巴瘤和成胶质细胞瘤等。
针对其催化位点的抑制剂一般选择性和成药性都较差,近年来,研究者发现通过变构位点抑制SHP2的活性可以提高活性和选择性,药物研究也取得了一些进展。不过,仍然需要开发更优异的SHP2抑制剂,以便获得活性优、药代性质更好的药物,从而用于治疗SHP2介导的相关疾病。
发明内容
本发明的发明人发现了一种SHP2抑制剂,该抑制剂的化合物结构如下式(I)所示,其化学名称为(R)-6-氨基-2-(3-氨基-3H-螺[苯并呋喃-2,4’-哌啶]-1’-基)-3-甲基-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-4(3H)-酮(以下简称“式(I)化合物”):
本发明的发明人研究发现,式(I)化合物或其水合物、溶剂合物或结晶对SHP2表现出了显著的抑制活性,非常有希望成为SHP2相关疾病的治疗剂。
至今尚未见报导包含式(I)化合物或其异构体或它们的药学可接受的盐的合适的制剂。本领域公知,在研究该类制剂的配制中面临许多问题,例如制剂的长期稳定性,有关物质的控制,药物的吸收以及生物利用度等。这些问题是由多种因素决定的,如许多因素影响药物的吸收,包括药物从制剂中的溶出或释放、药物在生理条件下的溶解以及在胃肠道的渗透性等。
因此,需要对式(I)化合物或其衍生物进行研究,以提供符合临床用药需求的适宜制剂。
本发明的发明人在前期研究中发现式(I)化合物在水中、乙醇、0.01mol/L盐酸溶液中几乎不溶。
本发明的一个目的是提供一种药物组合物,其包含(a)式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物;和(b)崩解剂,本发明的药物组合物制成制剂能够完全溶出,且生物利用度高。
本发明的另一个目的是提供含有本发明的药物组合物的药物制剂。
本发明的再一个目的是提供本发明的药物组合物在制备用于治疗和/或预防SHP2介导的的疾病的药物中的用途。
针对上述目的,本发明提供以下技术方案:
本发明一方面提供了一种药物组合物,其包含:
(a)式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物,
和(b)崩解剂。
在一些具体的实施方案中,本发明的药物组合物由式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、崩解剂、润滑剂和填充剂组成,其中基于式(I)化合物的量计,所述式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物占药物组合物总重的约0.1%至60%(重量/重量),优选为约0.5%至20%(重量/重量),更进一步优选为约0.5%至18%(重量/重量)。
在一些具体的实施方案中,本发明的药物组合物包含式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物和崩解剂,其中所述的崩解剂选自羧甲淀粉钠(简称:CMS-Na)、交联聚维酮、交联羧甲基纤维素钠(简称:CCNa)和低取代羟丙纤维素(简称:L-HPC)中的一种或多种,优选选自羧甲淀粉钠、交联羧甲基纤维素钠和低取代羟丙纤维素中的一种或多种,进一步优选选自交联羧甲基纤维素钠。本领域公知,在一定范围内,随着崩解剂量的增加,可以促进崩解和药物的溶出,但是,超过一定量后,其促崩解作用会逐渐减弱,甚至阻碍药物的溶出。因此,需要对崩解剂的含量及使用方法进行研究,以使崩解剂达到最好的崩解效果。在一些实施方案中,本发明提供的药物组合物中崩解剂占药物组合物总重的约1%至30%(重量/重量),优选为2%至15%(重量/重量),更优选为2%至10%(重量/重量)。本发明的发明人发现,使用含有上述崩解剂的本发明的药物组合物制得的制剂能够明显改善式(I)化合物的溶出度,并且制剂在高湿、高温、光照以及加速和长期试验条件下性质稳定,杂质少。
在一些实施方案中,本发明提供的药物组合物中进一步包含粘合剂,所述粘合剂选自海藻酸、羧甲基纤维素钙、羧甲基纤维素钠、羧甲基纤维素、粉状纤维素、明胶、硫酸镁铝、麦芽糖糊精、聚维酮、共聚维酮、羟丙甲纤维素、羟丙纤维素、羟乙纤维素、甲基纤维素、阿拉伯胶、海藻酸钠、瓜尔胶、淀粉、预胶化淀粉和蔗糖中的一种或多种。更优选地,所述粘合剂选自聚维酮、羟丙甲纤维素和羟丙纤维素中的一种或多种。本领域公知,处方中粘合剂的适量增加可以改善制粒后颗粒的硬度和流动性,但是,用量过多,一方面会使制粒工艺不易控制,颗粒容易过湿,另一方面,也会导致颗粒崩解困难,药物溶出缓慢,因此,需要对粘合剂的含量进行研究。在本发明中的一些实施方案中,本发明提供的药物组合物中粘合剂占制剂药物组合物总重的约0%至30%(重量/重量),优选为约5%至25%(重量/重量),进一步优选为约5%至20%(重量/重量)。
在一些实施方案中,本发明提供的药物组合物进一步包含润滑剂,其中所述的润滑剂选自硬脂酸镁、硬脂酸钙、硬脂酸、硬脂酸锌、硬脂富马酸钠、滑石粉、聚乙二醇、山嵛酸甘油酯、单硬脂酸甘油酯、硬脂酸棕榈酸甘油酯、月桂硫酸钠和氢化植物油中的一种或多种。更优选地,所述润滑剂选自硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸、聚乙二醇、滑石粉、硬脂富马酸钠和山嵛酸甘油酯的一种或多种。在本发明中的一些实施方案中,本发明提供的药物组合物中润滑剂占药物组合物总重的约0%至10%(重量/重量),优选为约0.5%至5%(重量/重量),进一步优选为约1%至2%(重量/重量)。
在一些实施方案中,本发明提供的药物组合物进一步包含填充剂,其中所述的填充剂选自微晶纤维素(简称:MCC)、粉状纤维素、碳酸镁、硫酸钙二水合物、预胶化淀粉、甘露醇(简称:MAN)、淀粉类、乳糖(简称:LAC)、糖类、纤维素类和无机盐中的一种或多种。本发明的发明人发现含有还原糖类如乳糖的药物组合物在加速条件30天时会产生新的未知杂质,而使用非还原糖类如甘露醇作为填充剂的处方在相同加速条件下则不会产生该杂质。此外,本发明的组合物中的填充剂仅为水溶性的甘露醇时,对润湿剂水的用量较为敏感,软材易过湿,在pH1.2和pH4.5介质中均未能完全溶出;填充剂仅为微晶纤维素时,颗粒的可压性较差,且片剂在pH4.5介质中未能完全溶出。在一些优选的实施方案中,本发明的药物组合物包含两种或更多种填充剂,其中一种选自微晶纤维素、粉状纤维素、碳酸镁、硫酸钙二水合物和预胶化淀粉,其他填充剂选自甘露醇、非还原糖类和无机盐类的一种或多种。更优选地,所述其他填充剂选自淀粉、糊精、山梨醇和甘露醇中的一种或多种。在本发明中的一些实施方案中,本发明提供的药物组合物中填充剂占药物组合物总重的约0%至95%(重量/重量),优选为约40%至90%(重量/重量),进一步优选为约50%至85%(重量/重量)。
在一些优选的实施方案中,本发明的药物组合物由式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、崩解剂、粘合剂、润滑剂和填充剂组成,其中基于式(I)化合物的量计,所述式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物占药物组合物总重的约0.1%至60%(重量/重量),所述崩解剂占药物组合物总重的约1%至30%(重量/重量),所述粘合剂占制剂药物组合物总重的约0%至30%(重量/重量),所述润滑剂占药物组合物总重的约0%至10%(重量/重量),所述填充剂占药物组合物总重的约0%至95%(重量/重量)。进一步优选地,本发明的药物组合物由式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、崩解剂、粘合剂、润滑剂和填充剂组成,其中基于式(I)化合物的量计,所述式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物占药物组合物总重的约0.5%至20%(重量/重量),所述崩解剂占药物组合物总重的约2%至15%(重量/重量),所述粘合剂占制剂药物组合物总重的约5%至25%(重量/重量),所述润滑剂占药物组合物总重的约0.5%至5%(重量/重量),所述填充剂占药物组合物总重的约40%至90%(重量/重量)。更进一步优选地,本发明的药物组合物由式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、崩解剂、粘合剂、润滑剂和填充剂组成,其中基于式(I)化合物的量计,所述式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物占制剂总重的约0.5%至18%(重量/重量),所述崩解剂占药物组合物总重的约2%至10%(重量/重量),所述粘合剂占制剂药物组合物总重的约5%至20%(重量/重量),所述润滑剂占药物组合物总重的约1%至2%(重量/重量),所述填充剂占药物组合物总重的约50%至85%(重量/重量)。
本发明还提供一种药物制剂,其包含本发明的药物组合物。
在一些优选的实施方案中,本发明的药物制剂为片剂、颗粒剂、散剂、缓释剂、丸剂、胶囊剂、锭剂或扁囊剂。在一个具体的实施方案中,所述缓释剂为缓释微丸。在一个具体的实施方案中,本发明的药物制剂为片剂、胶囊剂或颗粒剂。
在一些优选的实施方案中,本发明提供一种药物制剂,其包含本发明的药物组合物,所述药物组合物由式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、崩解剂、粘合剂、润滑剂和填充剂组成,其中基于式(I)化合物的量计,所述式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物占药物组合物总重的约0.1%至60%(重量/重量),所述崩解剂占药物组合物总重的约1%至30%(重量/重量),所述粘合剂占制剂药物组合物总重的约0%至30%(重量/重量),所述润滑剂占药物组合物总重的约0%至10%(重量/重量),所述填充剂占药物组合物总重的约0%至95%(重量/重量)。进一步优选地,本发明的药物组合物由式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、崩解剂、粘合剂、润滑剂和填充剂组成,其中基于式(I)化合物的量计,所述式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物占药物组合物总重的约0.5%至20%(重量/重量),所述崩解剂占药物组合物总重的约2%至15%(重量/重量),所述粘合剂占制剂药物组合物总重的约5%至25%(重量/重量),所述润滑剂占药物组合物总重的约0.5%至5%(重量/重量),所述填充剂占药物组合物总重的约40%至90%(重量/重量)。更进一步优选地,本发明的药物组合物由式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、崩解剂、粘合剂、润滑剂和填充剂组成,其中基于式(I)化合物的量计,所述式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物占制剂总重的约0.5%至18%(重量/重量),所述崩解剂占药物组合物总重的约2%至10%(重量/重量),所述粘合剂占制剂药物组合物总重的约5%至20%(重量/重量),所述润滑剂占药物组合物总重的约1%至2%(重量/重量),所述填充剂占药物组合物总重的约50%至85%(重量/重量)
本发明另一方面提供了本发明的组合物的制备方法,包括将本发明的药物组合物中各组分混合。
在一些实施方案中,本发明提供本发明的药物制剂的制备方法,所述制剂包含式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物和崩解剂,所述方法包括:将式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物和崩解剂混合,然后制粒的步骤。在一些具体的实施方案中,根据本发明的药物制剂的制备方法,所述崩解剂选自羧甲淀粉钠、交联聚维酮、交联羧甲基纤维素钠或低取代的羟丙纤维素中的一种或多种。
在一些优选的实施方案中,本发明提供本发明的药物制剂的制备方法,所述制剂包含式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、填充剂和崩解剂,所述方法包括:将式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物和填充剂、崩解剂混合,然后制粒的步骤。在一些具体的实施方案中,根据本发明的药物制剂的制备方法,所述填充剂选自微晶纤维素、粉状纤维素、碳酸镁、硫酸钙二水合物、预胶化淀粉、甘露醇、淀粉类、乳糖、糖类、纤维素类和无机盐中的一种或多种;所述崩解剂选自羧甲淀粉钠、交联聚维酮、交联羧甲基纤维素钠或低取代的羟丙纤维素中的一种或多种。
在一些优选的实施方案中,本发明提供本发明的药物制剂的制备方法,所述制剂包含式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、润滑剂和崩解剂,所述方法包括:将式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物和崩解剂、润滑剂混合,然后制粒的步骤。在一些具体的实施方案中,根据本发明的药物制剂的制备方法,所述润滑剂选自硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸、聚乙二醇、滑石粉、硬脂富马酸钠、山嵛酸甘油酯的一种或多种;所述崩解剂选自羧甲淀粉钠、交联聚维酮、交联羧甲基纤维素钠或低取代的羟丙纤维素中的一种或多种。
在另一些优选的实施方案中,本发明提供本发明的药物制剂的制备方法,所述制剂包含式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、填充剂、崩解剂和润滑剂,所述方法包括:将式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物和填充剂、崩解剂和润滑剂混合,制粒的步骤。在一些具体的实施方案中,根据本发明的药物制剂的制备方法,所述的填充剂选自微晶纤维素、粉状纤维素、碳酸镁、硫酸钙二水合物、预胶化淀粉、甘露醇、淀粉类、乳糖、糖类、纤维素类和无机盐中的一种或多种;所述崩解剂选自羧甲淀粉钠、交联聚维酮、交联羧甲基纤维素钠或低取代的羟丙纤维素中的一种或多种;所述润滑剂选自硬脂酸镁、硬脂酸钙、硬脂酸、硬脂酸锌、硬脂富马酸钠、滑石粉、聚乙二醇、山嵛酸甘油酯、单硬脂酸甘油酯、硬脂酸棕榈酸甘油酯、月桂硫酸钠和氢化植物油中的一种或多种。
在另一些优选的实施方案中,本发明提供本发明的药物制剂的制备方法,所述制剂包含式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、填充剂、崩解剂、润滑剂和粘合剂,所述方法包括:将式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物和填充剂、崩解剂、润滑剂和粘合剂混合,制粒的步骤。在一些具体的实施方案中,根据本发明的药物制剂的制备方法,所述的填充剂选自微晶纤维素、粉状纤维素、碳酸镁、硫酸钙二水合物、预胶化淀粉、甘露醇、淀粉类、乳糖、糖类、纤维素类和无机盐中的一种或多种;所述崩解剂选自羧甲淀粉钠、交联聚维酮、交联羧甲基纤维素钠或低取代的羟丙纤维素中的一种或多种;所述润滑剂选自硬脂酸镁、硬脂酸钙、硬脂酸、硬脂酸锌、硬脂富马酸钠、滑石粉、聚乙二醇、山嵛酸甘油酯、单硬脂酸甘油酯、硬脂酸棕榈酸甘油酯、月桂硫酸钠和氢化植物油中的一种或多种;所述粘合剂选自聚维酮、羟丙甲纤维素和羟丙纤维素中的一种或多种。
在另一些优选的实施方案中,本发明提供本发明的药物制剂的制备方法,所述制剂包含式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、填充剂、崩解剂、润滑剂、粘合剂和润湿剂,所述方法包括:将式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物和填充剂、崩解剂、润滑剂、粘合剂和润湿剂混合,制粒的步骤。在一些具体的实施方案中,根据本发明的药物制剂的制备方法,所述的填充剂选自微晶纤维素、粉状纤维素、碳酸镁、硫酸钙二水合物、预胶化淀粉、甘露醇、淀粉类、乳糖、糖类、纤维素类和无机盐中的一种或多种;所述崩解剂选自羧甲淀粉钠、交联聚维酮、交联羧甲基纤维素钠或低取代的羟丙纤维素中的一种或多种;所述润滑剂选自硬脂酸镁、硬脂酸钙、硬脂酸、硬脂酸锌、硬脂富马酸钠、滑石粉、聚乙二醇、山嵛酸甘油酯、单硬脂酸甘油酯、硬脂酸棕榈酸甘油酯、月桂硫酸钠和氢化植物油中的一种或多种;所述粘合剂选自聚维酮、羟丙甲纤维素和羟丙纤维素中的一种或多种;所述润湿剂为水。
在另一些优选的实施方案中,本发明提供本发明的药物制剂的制备方法,所述方法包括:将式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物和填充剂、崩解剂、润滑剂、粘合剂和润湿剂充分混合,制粒,胶囊填充的步骤。
在另一些优选的实施方案中,本发明提供本发明的药物制剂的制备方法,所述方法包括:将式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物和填充剂、崩解剂、润滑剂、粘合剂和润湿剂充分混合,制粒,压片制成片剂的步骤。
在另一些优选的实施方案中,本发明提供本发明的药物制剂的制备方法,所述方法包括:根据需要向式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物中加入填充剂、崩解剂、润滑剂、粘合剂和润湿剂等进行搅拌制粒、挤出制粒、转动制粒、喷雾一步制粒等来制造,或者直接干法制粒亦可。此外,也可采用微丸上药方式制备。此外,也可根据需要进行整粒、粉碎。进而,可根据需要进行压片制成片剂或者直接灌胶囊;也可进一步向上述颗粒剂中选择性加入崩解剂、填充剂、润滑剂、粘合剂、抗氧剂、着色剂等进行压片制成片剂或者直接灌胶囊。
在一些具体的实施方案中,本发明提供本发明的药物制剂的制备方法,所述方法包括:
(1)将式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、崩解剂和任选的粘合剂、填充剂、润滑剂混合均匀;
(2)任选将适量的润湿剂加入步骤(1)的混合物料中进行湿法制粒;
(3)将步骤(2)的颗粒干燥,整粒;
(4)任选地,将步骤(3)的颗粒和崩解剂、润滑剂混合均匀;
(5)将步骤(4)的混合物料制成制剂。
在一些具体的实施方案中,本发明提供本发明的药物制剂的制备方法,所述方法包括:
(1)将式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、崩解剂和任选的粘合剂、填充剂、润滑剂过筛,按处方量加入湿法制粒机中混合均匀;
(2)将适量的润湿剂加入步骤(1)的混合物料中进行湿法制粒;
(3)将步骤(2)的颗粒在干燥装置中干燥;
(4)任选地,将步骤(3)的颗粒、崩解剂和润滑剂加入可换桶混合机中混合均匀;
(5)将步骤(4)的混合物料倒入胶囊充填机中填充胶囊。
在一些具体的实施方案中,本发明提供本发明的药物制剂的制备方法,所述方法包括:
(1)将式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、崩解剂和任选的粘合剂、填充剂、润滑剂过筛,按处方量加入湿法制粒机中混合均匀;
(2)将适量的润湿剂加入步骤(1)的混合物料中进行湿法制粒;
(3)将步骤(2)的颗粒在干燥装置中干燥;
(4)任选地,将步骤(3)的颗粒、崩解剂和润滑剂加入可换桶混合机中混合均匀;
(5)将步骤(4)的混合物料倒入压片机中压制成片剂。
本发明的再一个方面提供了本发明的组合物或药物制剂用于治疗和/或预防SHP2介导的的疾病的方法以及在制备用于治疗和/或预防SHP2介导的的疾病的药物中的用途,其中所述的SHP2介导的疾病包括但不限于:增殖性疾病、代谢疾病或血液疾病。在一些实施方案中,本发明所述的SHP2介导的疾病为癌症。
在一些实施方案中,本发明所述的SHP2介导的疾病包括但不限于:听神经瘤、腺癌、肾上腺癌、肛门癌、血管肉瘤(例如,淋巴管肉瘤、淋巴管内皮肉瘤、血管肉瘤)、附件癌、良性单克隆性丙种球蛋白病、胆癌(例如,胆管癌)、膀胱癌、乳癌(例如,乳房腺癌、乳房乳头状癌、乳腺癌、乳房髓样癌、三阴性乳腺癌)、脑癌(例如,脑膜瘤;神经胶质瘤,例如星形细胞瘤、少突神经胶质瘤;成神经管细胞瘤)、支气管癌、类癌瘤、宫颈癌(例如宫颈腺癌)、绒毛膜癌、脊索瘤、颅咽管瘤、结肠直肠癌(例如,结肠癌、直肠癌、结肠直肠腺癌)、上皮癌、室管膜瘤、内皮肉瘤(例如,卡波西氏肉瘤(Kaposi's sarcoma)、多发性特发性出血性肉瘤)、子宫内膜癌(例如,子宫癌、子宫肉瘤)、食道癌(例如,食道腺癌、巴瑞特氏腺癌(Barrett’sadenocarinoma))、尤因肉瘤(Ewing sarcoma)、眼癌(例如,眼内黑素瘤、成视网膜细胞瘤)、家族性嗜酸性粒细胞增多症、胆囊癌、胃癌(例如,胃腺癌)、胃肠道间质瘤(GIST)、头颈部癌(例如,头颈部鳞状细胞癌、口腔癌(例如,口腔鳞状细胞癌(OSCC)、咽喉癌(例如,喉癌、咽癌、鼻咽癌、口咽癌))、造血系统癌(例如,白血病如急性淋巴细胞性白血病(ALL)(例如,B-细胞ALL、T-细胞ALL)、急性髓细胞性白血病(AML)(例如,B-细胞AML、T-细胞AML)、慢性粒细胞性白血病(CML)(例如,B-细胞CML、T-细胞CML)以及慢性淋巴细胞性白血病(CLL)(例如,B-细胞CLL、T-细胞CLL);淋巴瘤如霍奇金淋巴瘤(HL)(例如,B-细胞HL、T-细胞HL)以及非霍奇金淋巴瘤(NHL)(例如,B-细胞NHL如弥漫性大细胞淋巴瘤(DLCL)(例如,弥漫性大B-细胞淋巴瘤(DLBCL))、滤泡性淋巴瘤、慢性淋巴细胞性白血病/小淋巴细胞性淋巴瘤(CLL/SLL)、套细胞淋巴瘤(MCL)、边缘带B-细胞淋巴瘤(例如,粘膜相关淋巴样组织(MALT)淋巴瘤、结节边缘带B-细胞淋巴瘤、脾边缘带B-细胞淋巴瘤)、原发性纵隔B-细胞淋巴瘤、伯基特淋巴瘤(Burkittlymphoma)、淋巴浆细胞淋巴瘤(即,“沃尔丹斯特伦巨球蛋白血症(macroglobulinemia)”)、毛细胞白血病(HCL)、免疫母细胞性大细胞淋巴瘤、前体B-成淋巴细胞性淋巴瘤以及原发性中枢神经系统(CNS)淋巴瘤;以及T-细胞NHL如前体T-成淋巴细胞性淋巴瘤/白血病、外周T-细胞淋巴瘤(PTCL)(例如,皮肤T-细胞淋巴瘤(CTCL)(例如,蕈样真菌病(mycosis fungiodes)、西泽里综合征(Sezary syndrome))、血管免疫母细胞性T-细胞淋巴瘤、结节外天然杀伤T-细胞淋巴瘤、肠病类型T-细胞淋巴瘤、皮下脂膜炎样T-细胞淋巴瘤、间变性大细胞淋巴瘤);如上所描述的一种或多种白血病/淋巴瘤的混合物;以及多发性骨髓瘤(MM))、重链病(例如,α链病、γ链病、μ链病)、成血管细胞瘤、炎性肌纤维母细胞瘤、免疫细胞淀粉样变性、肾癌(例如,肾母细胞瘤又称韦尔姆斯氏瘤(Wilms’tumor)、肾细胞癌)、肝癌(例如,肝细胞癌(HCC)、恶性肝细胞瘤)、肺癌(例如,支气管癌、小细胞肺癌(SCLC)、非小细胞肺癌(NSCLC)、肺腺癌)、平滑肌肉瘤(LMS)、肥大细胞增多症(例如,全身性肥大细胞增多症)、骨髓发育不良综合征(MDS)、间皮瘤、骨髓增殖性疾病(MPD)(例如,真性红细胞增多症(PV)、特发性血小板增多症(ET)、特发性骨髓外化生(AMM)又称为骨髓纤维变性(MF)、慢性特发性骨髓纤维变性、慢性骨髓性白血病(CML)、慢性嗜中性白血病(CNL)、嗜酸性白细胞增多综合征(HES))、成神经细胞瘤、神经纤维瘤(例如,1型或2型多发性神经纤维瘤(NF)、施旺细胞瘤病(schwannomatosis))、神经内分泌癌(例如,胃肠胰腺神经内分泌肿瘤(GEP-NET)、类癌瘤)、骨肉瘤、卵巢癌(例如,囊腺癌、卵巢胚胎性癌、卵巢腺癌、卵巢透明细胞癌、卵巢浆液性囊腺癌、)、乳头状腺癌、胰腺癌(例如,胰腺腺癌、管内乳头状粘液瘤(IPMN)、胰岛细胞肿瘤)、阴茎癌(例如,阴茎和阴囊佩吉特氏病(Paget’s disease))、松果体瘤、原发性神经外胚层瘤(PNT)、前列腺癌(例如,前列腺腺癌)、直肠癌、横纹肌肉瘤、唾液管癌、皮肤癌(例如,鳞状细胞癌(SCC)、角化棘皮瘤(KA)、黑素瘤、基底细胞癌(BCC))、小肠癌(例如,附件癌)、软组织肉瘤(例如,恶性纤维组织细胞瘤(MFH)、脂肪肉瘤、恶性外周神经鞘瘤(MPNST)、软骨肉瘤、纤维肉瘤、粘液肉瘤)、皮脂腺癌、汗腺癌、滑膜瘤、睾丸癌(例如,精原细胞瘤、睾丸胚胎性癌)、甲状腺癌(例如,甲状腺乳头状癌、乳头状甲状腺癌(PTC)、髓样甲状腺癌)、尿道癌、阴道癌以及外阴癌(例如,外阴佩吉特氏病)、髓母细胞瘤、腺样囊性癌、黑色素瘤、胶质母细胞癌。
在一些优选的实施方案中,本发明提供本发明的药物组合物或药物制剂用于治疗SHP2介导的疾病的方法以及在制备治疗SHP2介导的疾病的药物中的用途,其中所述的SHP2介导的疾病包括但不限于:非小细胞肺癌、乳腺癌、食道癌、膀胱癌、肺癌、造血系统癌、淋巴瘤、髓母细胞瘤、成神经管细胞瘤、直肠腺癌、结肠癌、胃癌、胰腺癌、肝癌、腺样囊性癌、前列腺癌、肺癌、头颈部鳞状细胞癌、脑癌、肝细胞癌、黑色素瘤、少突神经胶质瘤、胶质母细胞癌、睾丸癌、卵巢透明细胞癌、卵巢浆液性囊腺癌、甲状腺癌、多发性骨髓瘤(AML)、肾细胞癌、套细胞淋巴瘤、三阴性乳腺癌、血红蛋白病、糖尿病和肥胖症。
在本发明的药物组合物或药物制剂中,可以采用式(I)化合物的任意形态或无定型物,获得的制剂具有非常好的稳定性。在另一些实施方案中,使用式(I)化合物的晶型形式来制备本发明的药物组合物。
本发明提供的药物组合物或药物制剂在体外能够溶出完全,杂质少,稳定性好,能简化贮藏和运输条件等。
术语说明
除非另外定义,本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。
本发明的“盐”可以是任何盐,尤其是指药学上可接受的盐。在本文中,“药学上可接受的盐”是指本发明所述的化合物与本发明的“酸”或“酸性试剂”形成的药学上可接受的盐,本发明的“酸”或“酸性试剂”可选自盐酸、氢溴酸、磷酸、氨基磺酸、硝酸、对甲基苯磺酸、苯磺酸、对氨基苯磺酸、硫酸、乙酸、乙二酸、苯乙酸、丙酸、丙二酸、三氟乙酸、琥珀酸、乙醇酸、硬脂酸、抗坏血酸、双羟萘酸、羟基马来酸、谷氨酸、苯甲酸、水杨酸、2-乙酰氧基苯甲酸、反丁烯二酸、乙烷二磺酸、草酸、羟乙磺酸、柠檬酸、D-葡萄糖酸、乳酸、L-苹果酸、琥珀酸、L-酒石酸、富马酸、α-酮戊二酸、马尿酸、马来酸、D-酒石酸、甲烷磺酸或其类似物。本发明化合物的“药学上可接受的盐”能由包含酸性或碱性部分的本发明化合物经常规的化学方法合成,通常,碱性化合物的盐类能通过例子交换色谱法制备,或将游离碱与化学计量或过量的所期望的成盐无机或有机酸在适宜的溶剂或溶剂的各种组合中进行反应来制备。类似的,酸性化合物的盐类可通过与适宜的无机或有机碱进行反应来形成。
术语“溶剂合物”是指通过与溶剂分子配位形成固态或液态的配合物的本发明化合物的形式,包括水合物、乙醇合物、乙腈合物等。
术语“结晶”是指本发明所述的化合物形成的各种固体形态,包括晶型、无定型。本发明化合物中的“氢”、“碳”、“氧”包括其所有同位素。同位素应理解为包括具有相同原子数但具有不同质量数的那些原子。举例来说,氢的同位素包括氕、氚和氘,碳的同位素包括13C和14C,氧的同位素包括16O和18O等。
术语“API”是指(R)-6-氨基-2-(3-氨基-3H-螺[苯并呋喃-2,4’-哌啶]-1’-基)-3-甲基-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-4(3H)-酮。
附图说明
图1为本发明实施例3-12的制剂的溶出曲线;
图2为本发明实施例13-21的制剂的溶出曲线。
具体实施方式
下面代表性的实施例是为了更好地说明本发明,而非用于限制本发明的保护范围。以下实施例中使用的材料如无特殊说明均为商购获得。
实施例1(R)-6-氨基-2-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-3-甲基-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-4(3H)-酮的制备
步骤1:(R)-N-((R)-1'-(4-氨基-5-溴-1-甲基-6-氧代-1,6-二氢嘧啶-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺的制备
在50L玻璃反应釜中加入N,N-二甲基甲酰胺(DMF,9.45kg),室温下开启搅拌,然后加入(R)-2-甲基-N-((R)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)丙烷-2-亚磺酰胺(1.0kg,3.24mol)和6-氨基-5-溴-3-甲基嘧啶-2,4(1H,3H)-二酮(0.71kg,3.23mol),搅拌均匀。将1,8-二氮杂二环十一碳-7-烯(DBU,2.47kg,14.6mol)缓慢加入到反应釜中,将苯并三唑-1-三(三甲氨基)-六氟磷酸酯(BOP试剂,2.16kg,4.89mol)分成4份,每份0.4~0.6kg,加入至反应液,每隔10-15min加入一次。反应完毕,室温下向100L的玻璃反应釜中加入乙酸乙酯(15.0kg),开启搅拌,然后将上述反应液投入到搅拌的乙酸乙酯中,加入纯化水(50.0kg),搅拌10min。分出有机相,减压浓缩,干燥,得0.93kg标题化合物,收率56.2%
步骤2:(R)-N-((R)-1'-(4-氨基-1-甲基-6-氧代-5-((2-(三氟甲基)吡啶-3-基)硫基)-1,6-二氢嘧啶-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺的制备
取1,4-二氧六环(19.0kg)加入到50L玻璃反应釜中,开启搅拌,加入(R)-N-((R)-1'-(4-氨基-5-溴-1-甲基-6-氧代-1,6-二氢嘧啶-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺(0.92kg,1.8mol)、2-(三氟甲基)哌啶-3-硫醇钠(0.51kg,2.52mol)和乙酸(0.11kg,1.8mol),升温,维持反应液温度60~70℃反应。将反应液抽滤,减压浓缩,得标题化合物粗品1.07kg,收率97.5%
步骤3:(R)-6-氨基-2-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-3-甲基-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-4(3H)-酮粗品的制备
称取二氯甲烷(30.0kg)加入到50L玻璃反应釜中,开启搅拌,加入(R)-N-((R)-1'-(4-氨基-1-甲基-6-氧代-5-((2-(三氟甲基)吡啶-3-基)硫基)-1,6-二氢嘧啶-2-基)-3H-螺[苯并呋喃-2,4'-哌啶]-3-基)-2-甲基丙烷-2-亚磺酰胺(1.07kg),降温,保持反应液温度15~25℃,滴加氯化氢-二氧六环溶液(2.63L),搅拌2-3小时。离心。
然后在20~30℃下缓慢加NaOH水溶液(氢氧化钠0.3kg,纯化水0.6kg)调节体系pH8-9,继续搅拌2-4小时。将物料离心,纯化水淋洗,收集得到的游离碱固体转移至50L玻璃反应釜中,加入纯化水/无水乙醇(20:1)溶液(3.37kg),打浆。将物料离心,固体依次用纯化水和无水乙醇洗涤。干燥,得0.51kg标题化合物粗品,收率57.5%。
步骤4:(R)-6-氨基-2-(3-氨基-3H-螺[苯并呋喃-2,4'-哌啶]-1'-基)-3-甲基-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-4(3H)-酮精品的制备
在50L玻璃反应釜中加入二甲基亚砜(3.37kg),开启搅拌,然后加入上述反应中制得的粗品(0.51kg),升温至75~85℃搅拌溶清,保温0.5~1.0小时,滴加无水乙醇(1.58kg)析出晶体,关闭加热,自然降温至60℃左右时继续滴加无水乙醇(2.04kg),并控制反应温度在40~60℃。加入完毕后自然降至室温20~30℃继续搅拌析晶1-2小时。抽滤,用无水乙醇(0.76kg)洗涤固体,干燥,得0.37kg固体,收率72.5%。1H NMR(400MHz,DMSO-d6)δ8.40(d,J=4.0Hz,1H),7.52-7.50(m,1H),7.43(d,J=8.5Hz,1H),7.33(d,J=7.5Hz,1H),7.14(t,J=7.5Hz,1H),6.87(t,J=7.5Hz,1H),6.77(d,J=8.0Hz,1H),4.12(s,1H),3.63-3.53(m,2H),3.31-3.24(m,5H),2.09-2.03(m,1H),1.92-1.89(m,2H),1.86-1.82(m,2H),1.77-1.74(m,1H)。ESI-MS m/z:505.2[M+H]+。
实施例2-21
表1至表3所示的实施例2-21为使用本发明实施例1制备的式(I)化合物(简称API)和不同的崩解剂、粘合剂、填充剂、润湿剂、润滑剂等制成的制剂。
表1
表2
表3
“/”表示未添加
实施例2-21的制备方法如下:
(1)辅料预处理及原辅料称量:按表1-3所示的实施例2-21的处方量分别称取API、乳糖、甘露醇、微晶纤维素、预胶化淀粉、交联羧甲基纤维素钠、交联羧甲基淀粉钠、低取代羟丙基纤维素、交联聚维酮、硬脂酸镁、硬脂富马酸钠,分别过60目筛,振摇混合进行预混;
(2)将适量的润湿剂加入步骤(1)的混合物料中,进行湿法制粒;
(3)将步骤(2)的颗粒在60℃温度的烘箱中干燥,干颗粒过筛网进行整粒;
(4)将步骤(3)的颗粒和表1-3所示的实施例2-21的处方量交联羧甲基纤维素钠、硬脂酸镁、硬脂富马酸钠加入可换桶混合机中混合均匀;
(5)将步骤(4)的混合物料倒入压片机中压制成片剂。
比较例1
参照WO2018/172984(PCT/IB2018/051973)中化合物45公开的方法制备下式代表的化合物(化合物A),并通过氢谱和质谱鉴定,
实验例1:实施例3~21的溶出性检测
溶出度测定法检查方法:
色谱柱:十八烷基硅烷键合硅胶为填充剂(Waters Symmetry C18,4.6×100mm,3.5μm或效能相当色谱柱);
流动相:0.1%甲酸水溶液-乙腈(76:24);
检测波长:285nm,柱温:30℃,流速:1.0mL/min,进样体积:50μL;
溶出介质:pH4.5醋酸盐缓冲液(三水合醋酸钠+冰醋酸);
溶出条件:桨法,转速50rpm;介质体积:900mL;取样体积5mL。溶出度见图1-2。实验结果表明:在pH4.5醋酸盐缓冲液的溶出介质中,实施例3-21制得的制剂,大部分均能充分溶出。
实验例2:稳定性
将以上实施例16、21制得的制剂在加速条件(40℃±2℃、75%RH±5%RH)、高湿条件(75%±5%、90%±5%)、高温条件(40℃、60℃)下放置,进行检测,检测结果显示本发明的制剂性质稳定,杂质少,各项指标未见明显变化。
从以上的实验结果,可以看出,本发明的含有崩解剂的(R)-6-氨基-2-(3-氨基-3H-螺[苯并呋喃-2,4’-哌啶]-1’-基)-3-甲基-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-4(3H)-酮制剂,溶出完全,稳定性好,符合临床用药需求;此外,制备的式(I)化合物吸收性质良好,相对生物利用度较高。
实验例3:细胞增殖抑制实验
1.实验材料
受试化合物:本发明式(I)的化合物和比较例制备的化合物A,每个化合物用DMSO配制成20mM。作用于NCI-H358细胞的化合物浓度依次为100μM、25μM、6.25μM、1.56μM、0.391μM、0.098μM、0.024μM、0.006μM、0.0015μM、0.00038μM;
人非小细胞肺癌细胞NCI-H358购于美国典型培养物保藏中心(ATCC)。
试剂:CCK-8增殖抑制检测试剂盒,购自于中国江苏凯基生物技术股份有限公司仪器:CKX41倒置显微镜,购自于日本Olympus公司;多功能读板机,购自于美国MolecularDevices公司;细胞培养箱,购自于美国Thermo公司。
2.实验方法
2.1细胞培养:
细胞复苏:从液氮罐中取出NCI-H358细胞冻存管置于37℃水浴锅中,轻轻摇动使其尽快解冻。解冻后取出冻存管,用酒精棉球消毒后旋开盖子,吸出细胞液注入离心管,并加入1mL含血清的完全培养基,混匀后置于离心机中,1000rpm,离心5min。之后弃上清液,加入完全培养基反复吹打至细胞完全吹散、重悬。以适宜浓度接种于培养皿中。置37℃,5%CO2、95%潮湿空气的CO2培养箱中培养。
细胞传代:细胞生长至约80-90%融合,吸弃原有培养液(1640培养基+10%FBS+1%青链霉素+1mM丙酮酸钠),加入1mL的PBS将残余培养基洗净后吸弃,加入1mL胰蛋白酶消化液,消化1-2min,镜下观察细胞伪足回缩变圆但细胞还未成片脱落,此时吸弃胰酶并用1-2mL完全培养基终止消化,轻轻吹打并收集细胞悬液,1000rpm,离心5min。去除上清,用完全培养基重悬细胞,按所需密度接种于培养皿中,置于37℃、5%CO2、95%潮湿空气的CO2培养箱中培养,视细胞生长情况每2-3天换一次培养液或进行传代。
2.2实验步骤:
NCI-H358细胞传代后用新鲜培养基(1640培养基+3%FBS+1%青链霉素+1mM丙酮酸钠)重悬,细胞计数之后按照1.5X104个细胞/mL的密度接种到96孔细胞培养板中,每孔加入100μL(即为1.5X103个细胞/孔)。24h后,在原有旧培养基的基础上,加入100μL含不同浓度(2×)药物的新鲜培养基。化合物终浓度分别为100μM、25μM、6.25μM、1.56μM、0.391μM、0.098μM、0.024μM、0.006μM、0.0015μM、0.00038μM,每个浓度组设置两个复孔。继续放入培养箱培养168h后吸弃孔内培养基,尽量吸干,加入100μL已加入CCK-8的培养基(CCK-8:培养基=1:10)。继续放入培养箱培养一定时间后,将96孔板从培养箱中取出,置于室温中平衡5min,置于多功能读板机中,检测450nm处的吸光度(OD值),并计算细胞增殖抑制率。计算公式为Inhibition(%)=100-(OD实验孔-OD空白孔)/(OD溶剂对照孔-OD空白孔)*100,根据不同药物浓度及其所对应的抑制率,使用GraghPad 5.0软件进行IC50曲线绘制,分析数据,得出最终IC50值。实验结果见表4。
表4
从以上实验可以看出,本发明的式(I)化合物对NCI-H358细胞表现出了良好的抑制活性,非常有希望成为非小细胞肺癌治疗剂。
实验例4:药物动力学实验
1.实验材料
化合物:本发明式(I)的化合物。药物溶媒为Captisol/50mM sodium acetate,pH4.6(10%/90%,w/v%)。口服药物配制成0.5mg/mL,透明溶液;静脉药物配置成0.1mg/mL,透明溶液。
动物:雄性BALB/c小鼠,SPF级,购自上海西普尔-必凯实验动物有限公司;18-20g。实验前给予2~3天适应期。
仪器:美国AB公司API4500型三重四级杆液质联用仪,配有电喷雾离子源(ESI),LC-30AD双泵;SIL-30AC自动进样器;CTO-30AC柱温箱;DGU-20A3R脱气机;AnalystQSA01.01色谱工作站;Milli-Q超纯水器(Millipore Inc);QilinbeierVortex-5振荡器;HITACHICF16R Ⅹ Ⅱ台式高速冷冻离心机。
2.实验方法
(1)每组3只小鼠。灌胃(I.G.)给予本发明式(I)的化合物10mg/kg,静脉(IV)给予本发明式(I)的化合物1mg/kg;
(2)灌胃及静脉给药后于5min、15min、30min、1h、2h、6h、10h、24h自眼眶静脉丛采血于肝素化EP管(0.6ML)中,8000rpm/min离心5min后取上层血浆,-20℃冻存,LC-MS/MS分析;
(3)根据上述步骤所得的血药浓度数据绘制血药浓度-时间曲线图,采用WinNonlin软件求算药代动力学参数。实验结果见表5。
表5
使用实验例4的方法测定比较例的化合物A的药物动力学。实验结果显示化合物A的生物利用度(F)为51.2%,明显低于本发明的式(I)化合物。
实验结果表明,本发明的化合物具有较好的半衰期T1/2、曲线下面积AUC、生物利用度F,口服吸收暴露好,适于成药。
尽管以上已经对本发明作了详细描述,但是本领域技术人员理解,在不偏离本发明的精神和范围的前提下可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作的详细描述,而应归属于权利要求。
Claims (10)
2.根据权利要求1的药物组合物,其中所述式(I)化合物为晶型或无定型物。
3.根据权利要求1或2的药物组合物,其中所述崩解剂为羧甲淀粉钠、交联聚维酮、交联羧甲基纤维素钠和低取代羟丙纤维素中的一种或多种。
4.根据权利要求1-3之任一项的药物组合物,其进一步包含粘合剂,优选地,所述粘合剂选自聚维酮、羟丙甲纤维素和羟丙纤维素中的一种或多种。
5.根据权利要求1-4之任一项的药物组合物,其进一步包含润滑剂,优选地,所述的润滑剂选自硬脂酸镁、硬脂酸钙、硬脂酸、硬脂酸锌、硬脂富马酸钠、滑石粉、聚乙二醇、山嵛酸甘油酯、单硬脂酸甘油酯、硬脂酸棕榈酸甘油酯、月桂硫酸钠和氢化植物油中的一种或多种。
6.根据权利要求1-5之任一项的药物组合物,其进一步包含填充剂,优选地,所述填充剂选自微晶纤维素、粉状纤维素、碳酸镁、硫酸钙二水合物、预胶化淀粉、甘露醇、淀粉类、乳糖、糖类、纤维素类和无机盐中的一种或多种。
7.根据权利要求1-6之任一项的药物组合物,其由式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、崩解剂、粘合剂、润滑剂和填充剂组成,其中基于式(I)化合物的量计,所述式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物占药物组合物总重的约0.1%至60%(重量/重量),所述崩解剂占药物组合物总重的约1%至30%(重量/重量),所述粘合剂占制剂药物组合物总重的约0%至30%(重量/重量),所述润滑剂占药物组合物总重的约0%至10%(重量/重量),所述填充剂占药物组合物总重的约0%至95%(重量/重量)。
8.一种药物制剂,其包含权利要求1-7之任一项的药物组合物,优选地,所述的药物制剂为片剂、颗粒剂、散剂、缓释剂、丸剂、胶囊剂、锭剂或扁囊剂。
9.一种权利要求8所述的药物制剂的制备方法,所述方法包括:
(1)将式(I)化合物或其药学可接受的盐、水合物、溶剂合物、结晶或无定型物、崩解剂和任选的粘合剂、填充剂、润滑剂混合均匀;
(2)任选将适量的润湿剂加入步骤(1)的混合物料中进行湿法制粒;
(3)将步骤(2)的颗粒干燥;
(4)任选地,将步骤(3)的颗粒和填充剂、润滑剂混合均匀;
(5)将步骤(4)的混合物料制成制剂。
10.权利要求1-7之任一项的药物组合物或权利要求8所述的药物制剂用于治疗和/或预防SHP2介导的的疾病的方法以及在制备用于治疗和/或预防SHP2介导的疾病的药物中的用途。
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