CN117126175A - 噻吩并嘧啶类化合物的共晶及其用途 - Google Patents
噻吩并嘧啶类化合物的共晶及其用途 Download PDFInfo
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Abstract
本发明涉及噻吩并嘧啶类化合物的共晶及其用途。具体地,本发明涉及2‑[1‑[(2R)‑2‑[[(3aR,6aR)‑3,3a,4,5,6,6a‑六氢化‑1H‑环戊二烯并[c]呋喃‑5‑基]氧基]‑2‑(2‑甲氧基苯基)乙基]‑5‑甲基‑6‑噁唑‑2‑基‑2,4‑二氧代‑噻吩并[2,3‑d]嘧啶‑3‑基]‑2‑甲基‑丙酸和哌嗪形成的共晶及包含所述的共晶的药物组合物,进一步涉及它们在制备用于治疗和预防由乙酰辅酶A羧化酶调节的疾病的药物中的用途。
Description
技术领域
本发明属于医药技术领域,涉及噻吩并嘧啶类化合物的共晶及其用途,具体涉及2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸和哌嗪形成的共晶以及包含所述的共晶的药物组合物,进一步涉及它们在制备用于治疗和预防由乙酰辅酶A羧化酶调节的疾病的药物中的用途。
背景技术
乙酰辅酶A羧化酶(Acetyl-CoA carboxylase,ACC)是脂肪酸合成代谢第一步反应的限速酶,在ATP供能、Mg2+存在下,以HCO3 -为羧基供体,将乙酰辅酶A羧化生成丙二酸单酰辅酶A,是生物素依赖性酶。
在人类和其他哺乳动物中该酶属于组织特异性酶,存在两种亚型,ACC1和ACC2,两者在组织分布及功能上有所差别;ACC1通常在所有组织中表达,但在脂肪生成的组织(例如肝脏和脂肪组织)中表达最多,ACC2在骨骼肌和心脏中高度表达,在肝脏组织中表达较少。ACC1催化长链脂肪酸的生物合成,如果乙酰辅酶A不被羧化以形成丙二酸单酰辅酶A时,则其通过柠檬酸循环(Krebs cycle)进行代谢;ACC2催化在线粒体的胞质表面产生丙二酸单酰辅酶A,且通过抑制肉碱棕榈酰基转移酶-1(carnitine palmityl transferase,CPT-1)调节用于β-氧化的脂肪酸的量。
研究表明,ACC抑制剂抑制ACC1能够减少脂肪酸的合成,抑制ACC2则可以促进肝脏中脂肪酸的氧化,从而减少脂质在体内的累积,可有效治疗与肥胖、高血压、糖尿病、肿瘤、血脂异常和高血脂症有关的疾病以及由于脂质在肝的累积引起肝脏胰岛素抗性且导致的II型糖尿病、非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪性肝炎(NASH)。
非酒精性脂肪性肝炎(NASH)是一种肝内脂肪积聚而导致的慢性进展性肝病,可导致肝硬化、肝衰竭及肝细胞癌。诱发NASH的原因有很多,比如年龄、肥胖、身体质量指数(Body Mass Index,BMI),胰岛素敏感性、血脂异常、高血压以及肝功相关酶(比如丙氨酸转氨酶(ALT)或天冬氨酸转氨酶(AST))的异常活性等等。据报道,出现代谢综合征表现的患者(主要为向心性肥胖、高血压、胰岛素抵抗、高甘油三酯和低高密度脂蛋白)与NASH的发生风险正相关。在大于50岁的糖尿病或肥胖的患者中,66%肝活检提示NASH伴有严重的纤维化。在美国,约有12%的人们深受这种疾病的影响,在患有糖尿病的人群中比例会升高到22%,更值得注意的是NASH患者中约有15~25%的病人会发展成肝硬化,这是一种仅次于病毒性肝炎和酒精性肝炎的另一种导致肝癌的原因。肝硬化是因肝脏疾病导致死亡的主要原因,其直接导致了肝脏失代偿及每年将近4%的死亡率。
国际申请WO2021000242 A1公开了化合物2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(式(I)所示化合物),其可以治疗或减轻由乙酰辅酶A羧化酶调节的疾病,如非酒精性脂肪肝炎等。该化合物存在溶解性差,动物体内吸收不理想以及稳定性差等问题,这些缺陷给后续的制剂开发带来诸多不便。
“药物共晶”是药物活性组分(API)和药学上可接受的配体(CCF)通过分子识别,在不破坏API自身化学键的前提下,通过分子间作用力(氢键、卤键、π堆积作用和范德华力)形成特定的晶体结构。对于药物活性成分,其结晶态的形式可以影响诸多物理化学性质,这些性质会对其加工和/或制备药物和相应的最终剂型的能力具有直接的影响,例如,共晶可以改善原料药的溶解性、吸湿性、稳定性及其生产制造(如可压性、流动性、过滤性),还会影响药品稳定性、溶出度和生物利用度。共晶可影响药物的质量、安全性和药效。药物共晶的形成能够提供一种更好的改变药物活性成分理化性质的手段,通过形成API和共结晶剂(配体)的共晶而实现特定API的期望性质。当活性化合物与合适的配体形成共晶之后,结晶性质得到改善,更易结晶,并且所获得的共晶具备非常好的稳定性。
发明内容
本发明提供了式(I)所示化合物与哌嗪的共晶。具体地,本发明提供了式(I)所示化合物与哌嗪的共晶晶型I,可以明显改善了化合物的稳定性和药代动力学等性质,从而具有更优良的成药性。
具体而言,本发明涉及式(I)所示化合物的共晶,以及包含所述共晶的药物组合物,还涉及它们在制备用于治疗或预防由乙酰辅酶A羧化酶调节的疾病的药物中的用途。
一方面,本发明提供了一种式(I)所示化合物与哌嗪的共晶,
在一些实施方案中,本发明所述的式(I)所示化合物与哌嗪的共晶为共晶晶型I。
在一些实施方案中,本发明所述的共晶,其特征在于,所述共晶晶型I的X射线粉末衍射图谱包含下列2θ角处的衍射峰:9.46°±0.2°,11.33°±0.2°,15.55°±0.2°,18.20°±0.2°,25.66°±0.2°,26.47°±0.2°。
在一些实施方案中,本发明所述的共晶,其特征在于,所述共晶晶型I的X射线粉末衍射图谱包含下列2θ角处的衍射峰:9.46°±0.2°,10.56°±0.2°,11.33°±0.2°,15.55°±0.2°,16.06°±0.2°,16.59°±0.2°,18.20°±0.2°,19.04°±0.2°,24.05°±0.2°,25.66°±0.2°,26.47°±0.2°。
在另一些实施方案中,本发明所述的共晶,其特征在于,所述共晶晶型I的X射线粉末衍射图谱包含下列2θ角处的衍射峰:4.68°±0.2°,9.46°±0.2°,10.56°±0.2°,11.19°±0.2°,11.33°±0.2°,11.66°±0.2°,12.03°±0.2°,13.17°±0.2°,13.91°±0.2°,14.32°±0.2°,15.07°±0.2°,15.55°±0.2°,16.06°±0.2°,16.59°±0.2°,16.75°±0.2°,17.48°±0.2°,18.20°±0.2°,18.50°±0.2°,19.04°±0.2°,19.96°±0.2°,20.24°±0.2°,20.85°±0.2°,21.11°±0.2°,21.70°±0.2°,22.07°±0.2°,22.53°±0.2°,23.33°±0.2°,24.05°±0.2°,24.36°±0.2°,24.99°±0.2°,25.35°±0.2°,25.66°±0.2°,25.96°±0.2°,26.47°±0.2°,27.30°±0.2°,27.56°±0.2°,27.86°±0.2°,28.08°±0.2°,28.95°±0.2°,29.19°±0.2°,29.63°±0.2°,29.96°±0.2°,30.36°±0.2°,30.90°±0.2°,31.49°±0.2°,32.16°±0.2°,32.74°±0.2°,33.17°±0.2°,33.43°±0.2°,33.71°±0.2°,35.88°±0.2°,36.77°±0.2°,37.51°±0.2°,38.14°±0.2°,38.71°±0.2°,39.02°±0.2°,40.28°±0.2°,41.02°±0.2°,41.39°±0.2°,42.22°±0.2°,42.99°±0.2°,43.86°±0.2°,45.43°±0.2°,45.80°±0.2°,47.28°±0.2°,49.44°±0.2°,51.43°±0.2°,53.17°±0.2°,54.48°±0.2°,56.23°±0.2°,58.44°±0.2°。
在一些实施方案中,本发明所述的共晶晶型I,其特征在于,所述共晶晶型I具有基本上如图1所示的X射线粉末衍射图。
在一些实施方案中,本发明所述的共晶晶型I,其特征在于,所述共晶晶型I的差示扫描量热图包含165.78℃±3℃的吸热峰。
在一些实施方案中,本发明所述的共晶晶型I,其特征在于,所述共晶晶型I具有基本上如图2所示的差示扫描量热图。
在一些实施方案中,本发明所述的共晶晶型I,其特征在于,所述共晶晶型I加热到150℃左右时,失重约为0.4716%,存在±0.1%的误差容限。
另一方面,本发明涉及一种药物组合物,其包含本发明所述的共晶,和药学上可接受的载体、赋形剂、稀释剂、辅剂或它们的组合。
一方面,本发明涉及所述的共晶或所述的药物组合物在制备药物中的用途,所述药物用于预防、治疗或减轻由乙酰辅酶A羧化酶调节的疾病。
在一些实施方案中,本发明所述的乙酰辅酶A羧化酶调节的疾病为代谢性疾病和肿瘤。
另一方面,本发明涉及所述的共晶或所述的药物组合物在制备药物中的用途,所述药物用于预防、治疗或减轻患者至少部分由乙酰辅酶A羧化酶调节的疾病。
在一些实施方案中,本发明所述代谢性疾病包括胰岛素抵抗、肥胖症、血脂异常、代谢综合征、II型糖尿病、非酒精性脂肪性肝病、非酒精性脂肪肝炎、肝脏脂肪变性、大泡性脂肪变性、晚期纤维化或肝硬化;所述肿瘤包括肝癌、肾癌、肺癌、乳腺癌、黑色素瘤、***状甲状腺肿瘤、胆管癌、结肠癌、卵巢癌、恶性淋巴肿瘤、膀胱癌、***癌、胰腺癌、皮肤癌或复发性实体瘤。
本发明一方面涉及预防、治疗或减轻由乙酰辅酶A羧化酶调节的疾病的方法,包括使用本发明所述的共晶或所述的药物组合物药学上可接受的有效剂量对患者进行给药。
另一方面,本发明还涉及式(I)所示化合物的共晶的制备方法。
本发明所述的共晶的制备方法中所使用的溶剂没有特别限制,任何在程度上能溶解起始原料并且不影响其性质的溶剂均包含在本发明中。另外,本领域的许多类似改动,等同替换,或等同于本发明所描述的溶剂,溶剂组合,及溶剂组合的不同比例,均视为本发明的包含范围。本发明给出了各反应步骤所使用的较佳的溶剂。
本发明所述的共晶的制备实验将在实施例部分进行了详细描述。同时,本发明提供了所述共晶的药理测试实验(如药代动力学实验)和稳定性实验等。经实验证明,本发明所述的共晶具有良好的稳定性和药代性质。
定义和一般术语
除非另有说明,本发明使用的所有技术和科学术语与本发明所属领域的普通技术人员所通常理解的具有相同含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。尽管在本发明的实践或者测试中可以使用与本发明所述相似或者相同的任何方法和物质,但是本发明中描述的是优选的方法、设备和物质。
“晶型”或“结晶形式”是指具有高度规则化学结构的固体,包括,但不限于,单组分或者多组分晶体,和/或化合物的多晶型物、溶剂化物、水合物、包合物、共晶、盐、盐的溶剂化物、盐的水合物。物质的结晶形式可通过本领域已知的许多方法得到。这种方法包括,但不限于,熔体结晶、熔体冷却、溶剂结晶、在限定的空间中结晶,例如,在纳米孔或者毛细管中,在表面或者模板上结晶,例如,在聚合物上,在添加剂如共结晶反分子的存在下结晶、去溶剂、脱水、快速蒸发、快速冷却、缓慢冷却、蒸气扩散、升华、反应结晶、反溶剂添加、研磨和溶剂滴研磨等。
“共晶”是由两个或以上的不同分子形成的结晶物质,典型的共晶体是药物和配体在同一晶格内形成的晶体物质。
“溶剂”是指一种物质(典型地是一种液体),该物质能够完全地或部分地溶解另一种物质(典型地是一种固体)。用于本发明实施的溶剂包括但并不限于,水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、吡啶、四氢呋喃、甲苯、二甲苯、它们的混合物等等。
“反溶剂”是指促进产物(或产物前体)从溶剂中沉淀的流体。反溶剂可以包括冷气体、或通过化学反应促进沉淀的流体、或降低产物在溶剂中的溶解度的流体;其可以是与溶剂相同的液体但是处于不同温度,或者它可以是与溶剂不同的液体。
“溶剂化物”是指在表面上、在晶格中或者在表面上和在晶格中具有溶剂的化合物,所述溶剂可以是水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、甲基吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、吡啶、四氢呋喃、甲苯、二甲苯以及它们的混合物等等。溶剂化物的一个具体例子是水合物,其中在表面上、在晶格中或者在表面上和在晶格中的溶剂是水。在物质的表面上、在晶格中或者在表面上和在晶格中,水合物可以具有或者不具有除了水以外的其它溶剂。
晶型可以通过多种技术手段进行鉴别,例如X射线粉末衍射(XRPD)、红外吸收光谱法(IR)、熔点法、差示扫描量热法(DSC)、热重分析法(TGA)、核磁共振法、拉曼光谱、X射线单晶衍射、溶解量热法、扫描电子显微镜(SEM)、定量分析、溶解度和溶解速度等等。
X射线粉末衍射(XRPD)可检测晶型的变化、结晶度、晶构状态等信息,是鉴别晶型的常用手段。XRPD图谱的峰位置主要取决于晶型的结构,对实验细节相对不敏感,而其相对峰高取决于与样品制备和仪器几何形状有关的许多因素。因此,在一些实施方案中,本发明的晶型的特征在于具有某些峰位置的XRPD图,其基本上如本发明附图中提供的XRPD图所示。同时,XRPD图谱的2θ的量度可以有实验误差,不同仪器以及不同样品之间,XRPD图谱的2θ的量度可能会略有差别,因此所述2θ的数值不能视为绝对的。根据本试验所用仪器状况,衍射峰存在±0.2°的误差容限。
差示扫描量热(DSC)是在程序控制下,通过不断加热或降温,测量样品与惰性参比物(常用α-Al2O3)之间的能量差随温度变化的一种技术。DSC曲线的吸热峰高取决于与样品制备和仪器几何形状有关的许多因素,而峰位置对实验细节相对不敏感。因此,在一些实施方案中,本发明所述晶型的特征在于具有特征峰位置的DSC图,其基本上如本发明附图中提供的DSC图所示。同时,DSC图谱可以有实验误差,不同仪器以及不同样品之间,DSC图谱的峰位置和峰值可能会略有差别,因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。根据本试验所用仪器状况,吸热峰存在±3°的误差容限。
热重分析(TGA)是在程序控制下,测定物质的质量随温度变化的一种技术,适用于检查晶体中溶剂的丧失或样品升华、分解的过程,可推测晶体中含结晶水或结晶溶剂的情况。TGA曲线显示的质量变化取决于样品制备和仪器等许多因素;不同仪器以及不同样品之间,TGA检测的质量变化略有差别。根据本试验所用的仪器状况,质量变化存在±0.1%的误差容限。
在本发明的上下文中,X-射线粉末衍射图中的2θ值均以度(°)为单位。
术语“基本上如图所示”是指X-射线粉末衍射图或DSC图或拉曼光谱图或红外光谱图中至少50%,或至少60%,或至少70%,或至少80%,或至少90%,或至少95%,或至少99%的峰显示在其图中。
当提及谱图或/和出现在图中的数据时,“峰”指本领域技术人员能够识别的不会归属于背景噪音的一个特征。
本发明涉及所述2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸的共晶,例如,哌嗪共晶晶型I,它们以基本上纯净的结晶形态存在。
“基本上纯净的”是指一种晶型基本上不含另外一种或多种晶型,即晶型的纯度至少80%,或至少85%,或至少90%,或至少93%,或至少95%,或至少98%,或至少99%,或至少99.5%,或至少99.6%,或至少99.7%,或至少99.8%,或至少99.9%,或晶型中含有其它晶型,所述其它晶型在晶型的总体积或总重量中的百分比少于20%,或少于10%,或少于5%,或少于3%,或少于1%,或少于0.5%,或少于0.1%,或少于0.01%。
“基本上不含”是指一种或多种其它晶型在晶型的总体积或总重量中的百分比少于20%,或少于10%,或少于5%,或少于4%,或少于3%,或少于2%,或少于1%,或少于0.5%,或少于0.1%,或少于0.01%。
XRPD图中的“相对强度”(或“相对峰高”)是指X-射线粉末衍射图(XRPD)的所有衍射峰中第一强峰的强度为100%时,其它峰的强度与第一强峰的强度的比值。
在本发明的上下文中,当使用或者无论是否使用“大约”或“约”等字眼时,表示在给定的值或范围的10%以内,适当地在5%以内,特别是在1%以内。或者,对于本领域普通技术人员而言,术语“大约”或“约”表示在平均值的可接受的标准误差范围内。每当公开一个具有N值的数字时,任何具有N+/-1%,N+/-2%,N+/-3%,N+/-5%,N+/-7%,N+/-8%或N+/-10%值以内的数字会被明确地公开,其中“+/-”是指加或减。
本发明中“室温”指的是温度由大约10℃到大约40℃。在一些实施例中,“室温”指的是温度由大约20℃到大约30℃;在另外一些实施例中,“室温”指的是20℃,22.5℃,25℃,27.5℃等等。
本发明所述化合物的共晶的药物组合物,制剂,给药和用途
本发明的药物组合物的特点包括式(I)所示化合物的共晶和药学上可接受的载体,辅剂,或赋形剂。本发明的药物组合物中化合物的共晶的量能有效地可探测地治疗或减轻由乙酰辅酶A羧化酶调节的疾病。
像本发明所描述的,本发明药学上可接受的组合物进一步包含药学上可接受的载体,辅剂,或赋形剂,这些像本发明所应用的,包括任何溶剂,稀释剂,或其他液体赋形剂,分散剂或悬浮剂,表面活性剂,等渗剂,增稠剂,乳化剂,防腐剂,固体粘合剂或润滑剂,等等,适合于特有的目标剂型。如以下文献所描述的:In Remington:The Science and Practiceof Pharmacy,21st edition,2005,ed.D.B.Troy,Lippincott Williams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrickand J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容,表明不同的载体可应用于药学上可接-受的组合物的制剂和它们公知的制备方法。除了任何常规的载体媒介与本发明的共晶或其晶型不相容的范围,例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用,它们的用途也是本发明所考虑的范围。
可作为药学上可接受载体的物质包括,但并不限于,离子交换剂;铝;硬脂酸铝;卵磷脂;血清蛋白,如人血清蛋白;缓冲物质如磷酸盐;甘氨酸;山梨酸;山梨酸钾;饱和植物脂肪酸的部分甘油酯混合物;水;盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐;胶体硅;三硅酸镁;聚乙烯吡咯烷酮;聚丙烯酸脂;蜡;聚乙烯-聚氧丙烯-阻断聚合体;羊毛脂;糖,如乳糖,葡萄糖和蔗糖;淀粉如玉米淀粉和土豆淀粉;纤维素和它的衍生物如羧甲基纤维素钠,乙基纤维素和乙酸纤维素;树胶粉;麦芽;明胶;滑石粉;辅料如可可豆脂和栓剂蜡状物;油如花生油,棉子油,红花油,麻油,橄榄油,玉米油和豆油;二醇类化合物,如丙二醇和聚乙二醇;酯类如乙基油酸酯和乙基月桂酸酯;琼脂;缓冲剂如氢氧化镁和氢氧化铝;海藻酸;无热原的水;等渗盐;林格(氏)溶液;乙醇;磷酸缓冲溶液;和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁;着色剂;释放剂;包衣衣料;甜味剂;调味剂;香料;防腐剂和抗氧化剂。
本发明的药物组合物可以是胶囊,片剂,丸剂,粉剂,粒剂和水制悬浮液或溶液;可以通过如下途径给药:口服给药,注射给药,喷雾吸入法,局部给药,经直肠给药,经鼻给药,含服给药,***给药或通过植入性药盒给药。
口服给药可以用如下形式给药:片剂、丸剂、胶囊、可分散的粉末、颗粒或悬浮液、糖浆、和酏剂等;外用方式给药可以通过如下形式给药:软膏剂、凝胶、含药胶布等。
本发明的共晶或其晶型优选地按制剂配方制备成剂量单位型以减轻给药量和剂量的均匀性。术语“剂量单位型”在此处是指患者得到适当治疗所需药物的物理分散单位。然而,应了解本发明式(I)化合物的共晶或其晶型、或本发明的药物组合物每日总的用法将通过主治医生根据可靠的医学范围判断来确定。具体的有效剂量水平对于任何一个特殊的患者或有机体将取决于许多因素包括被治疗的病症和病症的严重性,具体化合物的共晶的活性,所用的具体组合物,患者的年龄、体重、健康状况、性别和饮食习惯,给药时间,给药途径和所用具体化合物的共晶或晶型的***速率,治疗的持续时间,药物应用于联合用药或与有特效的化合物的盐或其晶型联用,以及其他一些药学领域公知的因素。
所用的活性成分的有效剂量可随所用的化合物的共晶或其晶型、给药的模式和待治疗的疾病的严重程度而变化。然而,通常当本发明的化合物的共晶或其晶型每天以约0.25-1000mg/kg动物体重的剂量给予时,能得到令人满意的效果,较佳地每天以2-4次分开的剂量给予,或以缓释形式给药。可调节此剂量方案以提供最佳治疗应答。另外,由于治疗状况的不同,可每天给予若干次分开的剂量,或将剂量按比例减少。
本发明涉及的化合物的共晶或其晶型、本发明的药物组合物可用于抑制乙酰辅酶A羧化酶的活性,从而调节乙酰辅酶A羧化酶的稳定性和/或活性。所述化合物的共晶或所述的药物组合物可用于对乙酰辅酶A羧化酶相关的病症进行治疗、预治疗或延迟其发作或发展的方法中,所述疾病包括但不限于非酒精性脂肪肝炎。
具体地,本发明涉及的化合物的共晶或其晶型可用于抑制乙酰辅酶A羧化酶的活性。可施以所述化合物的共晶或其晶型来预防、预治疗或治疗由乙酰辅酶A羧化酶调节的病症,包括例如胰岛素抵抗、肥胖症、血脂异常、代谢综合征、II型糖尿病、非酒精性脂肪性肝病、非酒精性脂肪肝炎、肝脏脂肪变性、大泡性脂肪变性、晚期纤维化或肝硬化;所述肿瘤包括肝癌、肾癌、肺癌、乳腺癌、黑色素瘤、***状甲状腺肿瘤、胆管癌、结肠癌、卵巢癌、恶性淋巴肿瘤、膀胱癌、***癌、胰腺癌、皮肤癌或复发性实体瘤。
附图说明
图1为式(I)所示化合物与哌嗪共晶的晶型I的X射线粉末衍射(XRPD)图。
图2为式(I)所示化合物与哌嗪共晶的晶型I的差示扫描量热(DSC)图。
图3为式(I)所示化合物与哌嗪共晶的晶型I的热失重(TGA)分析图。
一般制备和检测方法
下面通过实施例的方式进一步说明本发明,并不因此将本发明限制在所述的实施例范围之中。
本发明所用X射线粉末衍射分析方法为:Empyrean衍射仪,使用Cu-Kα辐射(45KV,40mA)获得X射线粉末衍射图。在单晶硅样品架上将粉末状样品制备成薄层,放在旋转样品台上,在3°-40°的范围内以0.0168°步长进行分析。使用Data Collector软件收集数据,HighScore Plus软件处理数据,Data Viewer软件读取数据。
本发明所用差示扫描量热(DSC)分析方法为:使用带有热分析控制器的TA Q2000模件进行差示扫描量热。收集数据并使用TA Instruments Thermal Solutions软件进行分析。将约1-5mg样品准确地称重到带有盖子的特制铝坩埚中,使用10℃/分钟的线形加热装置,从室温至大约300℃进行样品分析。在使用期间,将DSC小室用干燥氮气吹扫。
本发明所用热失重(TGA)分析方法为:使用带有热分析控制器的TA Q500模件进行热失重。收集数据并使用TA Instruments Thermal Solutions软件进行分析。将约10mg样品准确地称重到铂金样品盘中,使用10℃/分钟的线形加热装置,从室温至大约300℃进行样品分析。在使用期间,将TGA炉室用干燥氮气吹扫。
具体实施方法
式(I)所示化合物2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸的具体合成方法参照国际申请WO2021000242A1中的实施例1)。
实施例
实施例1哌嗪共晶的晶型I
1.哌嗪共晶的晶型I的制备
方法一:将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(1.01g)悬浮于丙酮(3.0mL)和乙酸乙酯(1.0mL)混合溶剂中,加入哌嗪(0.29g),室温搅拌溶解,过夜,析出较多固体,抽滤,滤饼用异丙醚洗涤(6.0mL),抽至近干,室温真空干燥过夜,得到白色固体粉末(0.84g,收率72.6%)。
方法二:将2-[1-[(2R)-2-[[(3aR,6aR)-3,3a,4,5,6,6a-六氢化-1H-环戊二烯并[c]呋喃-5-基]氧基]-2-(2-甲氧基苯基)乙基]-5-甲基-6-噁唑-2-基-2,4-二氧代-噻吩并[2,3-d]嘧啶-3-基]-2-甲基-丙酸(1.01g)悬浮于丙酮(3.0mL)中,加入哌嗪(0.29g),补加乙酸乙酯(3.0mL),室温搅拌溶解,过夜,析出较多固体,抽滤,用乙酸乙酯洗涤滤饼(5.0mL),抽至近干,室温真空干燥过夜,得到白色固体(0.71g,收率61.6%)。
2.哌嗪共晶的晶型I的鉴定
(1)通过Empyrean X射线粉末衍射(XRPD)分析鉴定:使用Cu-Kα辐射,具有下列以角度2θ表示的特征峰:4.68°,9.46°,10.56°,11.19°,11.33°,11.66°,12.03°,13.17°,13.91°,14.32°,15.07°,15.55°,16.06°,16.59°,16.75°,17.48°,18.20°,18.50°,19.04°,19.96°,20.24°,20.85°,21.11°,21.70°,22.07°,22.53°,23.33°,24.05°,24.36°,24.99°,25.35°,25.66°,25.96°,26.47°,27.30°,27.56°,27.86°,28.08°,28.95°,29.19°,29.63°,29.96°,30.36°,30.90°,31.49°,32.16°,32.74°,33.17°,33.43°,33.71°,35.88°,36.77°,37.51°,38.14°,38.71°,39.02°,40.28°,41.02°,41.39°,42.22°,42.99°,43.86°,45.43°,45.80°,47.28°,49.44°,51.43°,53.17°,54.48°,56.23°,58.44°,存在±0.2°的误差容限。
(2)通过TA Q2000差示扫描量热(DSC)分析鉴定:扫描速度为10℃/分钟,所得DSC曲线如图2所示,其包含165.78℃的吸热峰,存在±3℃的误差容限。
(3)通过TA Q500进行热失重(TGA)分析鉴定:升温速率为10℃/分钟,所得TGA曲线如图3所示,其包含0.4716%的重量损失,存在±0.1%的误差容限。
实施例2本发明所述共晶的药代动力学实验
将本发明所述的式(I)所示化合物的共晶灌装胶囊,用于口服给药。
取8-12kg雄性比格犬,3只为一组,口服给予装有供试样品的胶囊,剂量为5mg/kg,按时间点0.25,0.5,1.0,2.0,4.0,6.0,8.0和24h采血。根据样品浓度建立合适范围的标准曲线,使用AB SCIEX API4000型LC-MS/MS,在MRM模式下测定血浆样品中供试样品的浓度,并进行定量分析。根据药物浓度-时间曲线,采用WinNonLin 6.3软件非房室模型法计算药动学参数。实验结果如表1所示。
表1本发明所述共晶的药代动力学数据
结论:本发明所述的哌嗪共晶在比格犬体内的暴露量较高,具有较好的药代动力学性质。
实施例3本发明所述共晶的稳定性实验
(1)高温实验:取一批供试品适量放入扁形称量瓶中,摊成≤3mm厚的薄层,分别于60℃、40℃两个温度下放置30天,于第5、10、30天取样,观察样品颜色变化,HPLC检测样品纯度,X射线粉末衍射分析结构。
(2)高湿实验:取一批供试品适量放入扁形称量瓶中,摊成≤3mm厚的薄层,分别于25℃,RH 90%±5%和25℃,RH 75%±5%两个条件下放置30天,于第5、10、30天取样,观察样品颜色变化,HPLC检测样品纯度,X射线粉末衍射分析结构。
(3)光照实验:取一批供试品适量放入扁形称量瓶中,摊成≤3mm厚的薄层,敞口置于光照箱内(带紫外),于照度4500±500lx、紫外光≥0.7w/m2条件下放置30天,于第5、10、30天取样,观察样品颜色变化,HPLC检测样品纯度,X射线粉末衍射分析结构。
(4)长期稳定性试验:考察样品在单层PE内包装,铝箔袋外包装,内置KD-20脱氧剂,并抽真空充氮气后热封口包装条件下,低温5℃±3℃长期试验条件,观察样品颜色变化,HPLC检测样品纯度。
由实验结果可知,本发明所述的哌嗪共晶在高温高湿条件下稳定;在长期稳定性试验条件下,本发明所述哌嗪共晶的外观、纯度和水含量均无明显变化。
综上,本发明所述哌嗪共晶的稳定性较好,适合制药用途。
以上所述内容仅为本发明构思下的基本说明,而依据本发明的技术方案所作的任何等效变换,均应属于本发明的保护范围。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (10)
1.一种式(I)所示化合物与哌嗪的共晶,其中,所述的共晶为共晶晶型I,
2.根据权利要求1所述的共晶,其特征在于,所述共晶晶型I的X射线粉末衍射图谱包含下列2θ角处的衍射峰:9.46°±0.2°,11.33°±0.2°,15.55°±0.2°,18.20°±0.2°,25.66°±0.2°,26.47°±0.2°。
3.根据权利要求1或2所述的共晶,其特征在于,所述共晶晶型I的X射线粉末衍射图谱包含下列2θ角处的衍射峰:9.46°±0.2°,10.56°±0.2°,11.33°±0.2°,15.55°±0.2°,16.06°±0.2°,16.59°±0.2°,18.20°±0.2°,19.04°±0.2°,24.05°±0.2°,25.66°±0.2°,26.47°±0.2°。
4.根据权利要求1-3任意一项所述的共晶,其特征在于,所述共晶晶型I的X射线粉末衍射图谱包含下列2θ角处的衍射峰:4.68°±0.2°,9.46°±0.2°,10.56°±0.2°,11.19°±0.2°,11.33°±0.2°,11.66°±0.2°,12.03°±0.2°,13.17°±0.2°,13.91°±0.2°,14.32°±0.2°,15.07°±0.2°,15.55°±0.2°,16.06°±0.2°,16.59°±0.2°,16.75°±0.2°,17.48°±0.2°,18.20°±0.2°,18.50°±0.2°,19.04°±0.2°,19.96°±0.2°,20.24°±0.2°,20.85°±0.2°,21.11°±0.2°,21.70°±0.2°,22.07°±0.2°,22.53°±0.2°,23.33°±0.2°,24.05°±0.2°,24.36°±0.2°,24.99°±0.2°,25.35°±0.2°,25.66°±0.2°,25.96°±0.2°,26.47°±0.2°,27.30°±0.2°,27.56°±0.2°,27.86°±0.2°,28.08°±0.2°,28.95°±0.2°,29.19°±0.2°,29.63°±0.2°,29.96°±0.2°,30.36°±0.2°,30.90°±0.2°,31.49°±0.2°,32.16°±0.2°,32.74°±0.2°,33.17°±0.2°,33.43°±0.2°,33.71°±0.2°,35.88°±0.2°,36.77°±0.2°,37.51°±0.2°,38.14°±0.2°,38.71°±0.2°,39.02°±0.2°,40.28°±0.2°,41.02°±0.2°,41.39°±0.2°,42.22°±0.2°,42.99°±0.2°,43.86°±0.2°,45.43°±0.2°,45.80°±0.2°,47.28°±0.2°,49.44°±0.2°,51.43°±0.2°,53.17°±0.2°,54.48°±0.2°,56.23°±0.2°,58.44°±0.2°。
5.根据权利要求1-4任意一项所述的共晶,其特征在于,所述共晶晶型I具有基本上如图1所示的X射线粉末衍射图。
6.根据权利要求1-5任意一项所述的共晶,其特征在于,所述共晶晶型I的差示扫描量热图包含165.78℃±3℃的吸热峰。
7.根据权利要求1-6任意一项所述的共晶,其特征在于,所述共晶晶型I具有基本上如图2所示的差示扫描量热图。
8.一种药物组合物,其包含权利要求1-7任意一项所述的共晶,和药学上可接受的载体、赋形剂、稀释剂、辅剂或它们的组合。
9.权利要求1-7任意一项所述的共晶或权利要求8所述的药物组合物在制备药物中的用途,所述药物用于预防、治疗或减轻由乙酰辅酶A羧化酶调节的疾病。
10.根据权利要求9所述的用途,其中,所述由乙酰辅酶A羧化酶调节的疾病为代谢性疾病和肿瘤;
所述代谢性疾病包括胰岛素抵抗、肥胖症、血脂异常、代谢综合征、II型糖尿病、非酒精性脂肪性肝病、非酒精性脂肪肝炎、肝脏脂肪变性、大泡性脂肪变性、晚期纤维化或肝硬化;所述肿瘤包括肝癌、肾癌、肺癌、乳腺癌、黑色素瘤、***状甲状腺肿瘤、胆管癌、结肠癌、卵巢癌、恶性淋巴肿瘤、膀胱癌、***癌、胰腺癌、皮肤癌或复发性实体瘤。
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