CN109438388B - 具有降糖作用化合物的晶型及制备方法和含其的组合物 - Google Patents
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Abstract
本发明公开了一种具有降糖作用化合物的晶型及制备方法和含其的组合物。本发明具有降糖作用化合物的制备方法：将化合物Ⅰ溶于到3—4倍的9:1的二甲基甲酰胺/甲醇中，加热至回流，溶解后，然后冷却至20℃—25℃，保温静置9—11小时，析出结晶，过滤，室温真空度0.04‑0.07Mpa干燥10—12小时，得到上述化合物Ⅰ晶型。本发明该晶型活性强，稳定性好，具有一定的优越性，适合制剂工艺过程和长期储存。
Description
技术领域
本发明属于医药技术领域，更具体的说，是涉及一种具有降血糖作用的化合物的晶型及其制备方法和应用。
背景技术
目前在临床使用的抗糖尿病药物主要有胰岛素类、磺酰脲类、二甲双胍类及近来上市的α-葡糖苷酶抑制剂和胰岛素增敏剂噻唑烷二酮类药物等。这些药物具有良好的疗效，但仍存在药物长期使用而导致的不能维持长期疗效的缺点，并且容易引起低血糖、体重增加和产生肝毒性等诸多不良反应。
因此，寻找新的降糖药物是国内外医药界研究的热点之一。
中国发明专利201210575394.4(2015年3月11日授权)中公开了一类如下结构的磺胺类化合物：
其中：
X为S或O原子；
n＝1、2、3或4；
R1与R2同时或分别为氢或C1-C4烷基；
R3、R4与R5同时或分别为氢、C1-C6烷基、C1-C4烷氧基、卤素、单或多卤素取代C1-C4烷基、氰基、苯基、单卤代苯基、C1-C4烷氧基苯基、C1-C4烷基磺酰基、溴甲基羰基中的任一种。
当X为S原子；n＝2；R1与R2为氢，R3、R4与R5分别为氢、氟、氰基时，化学名为N-(3-(4-(苯并噻唑-2-基)哌嗪-1-基)丙基)-3-氰基-4-氟苯磺酰胺，即化合物Ⅰ，化学结构式：
化合物Ⅰ
化合物Ⅰ，白色固体，熔点178.0℃-179.2℃；具有良好的降糖活性。
发明内容
本发明的一个目的，公开了一种具有降糖作用化合物Ⅰ的新晶型。
本发明的另一个目的，公开了一种具有降糖作用化合物Ⅰ新晶型的制备方法。
本发明的又一个目的，公开了包含一种具有降糖作用化合物Ⅰ新晶型的药物组合物。
本发明还公开了一种具有降糖作用化合物Ⅰ新晶型在制造治疗降糖药物中的应用。
现结合本发明的目的对本发明内容进行具体描述。
本发明提供了一种具有降糖作用化合物Ⅰ的新晶型，该晶型X射线粉末衍射特征吸收峰(2θ)和D值见下表，误差为±0.2，见附图。
所有特征峰:
本发明中2θ值的测定使用光源，精度为±0.2°，因此代表上述所取的值允许有一定合理的误差范围，其误差范围为±0.2°。
新晶型为白色结晶性粉末，熔点151.7℃-152.5℃；纯度(HPLC法)99.5％。
本发明的另外一个目的，公开了新晶型的制备方法，其过程包括：将化合物Ⅰ在二甲基甲酰胺和甲醇混合溶液中加热溶解，通过保温静置得到新晶型的化合物Ⅰ。具体地，将化合物Ⅰ溶于到3—4倍的9:1的二甲基甲酰胺/甲醇中，加热至回流，溶解后，然后冷却至20℃—25℃，保温静置9—11小时，析出结晶，过滤，室温真空度0.04-0.07Mpa干燥10—12小时，得到上述化合物Ⅰ新晶型。这种操作是得到上述新晶型所必需的。
所用的化合物Ⅰ，根据中国发明专利201210575394.4提供的方法合成，化学结构质谱(Ms)确证，证明化学结构是正确的。
本发明的又一个目的，提供了包含化合物Ⅰ新晶型的药物组合物。本发明的药物组合物制备如下：使用标准和常规的技术，使本发明化合物与制剂学上可接受的固体载体结合，制成固体剂型，包括片剂、分散颗粒、胶囊、缓释片、缓释微丸等等。固体载体可以是至少一种物质，其可以充当稀释剂、香味剂、增溶剂、润滑剂、悬浮剂、粘合剂、崩解剂以及包裹剂。惰性固体载体包括磷酸镁、硬脂酸镁、滑粉糖、乳糖、果胶、丙二醇、聚山梨酯80、糊精、淀粉、明胶、纤维素类物质例如甲基纤维素、微晶纤维素、低熔点石蜡、聚乙二醇、甘露醇、可可脂等。
药物组合物以及单元剂型中含有的活性成份(本发明化合物)的量可以根据患者的病情、医生诊断的情况特定的加以应用，所用的化合物的量或浓度在一个较宽的范围内调节，活性化合物的量范围为组合物的1％～40％(重量)。
本发明还提供了化合物Ⅰ新晶型在制造治疗糖尿病药物中的应用。
降糖作用：小鼠体内口服糖耐量模型(oral glucose tolerance test，OGTT)测定，样品配置、给药量、实验过程与中国发明专利201210575394.4提供的方法一致。实验结果如下：
对小鼠血糖抑制作用
| 化合物 | 抑制率/％ |
| 空白对照组 | - |
| 新晶型的化合物Ⅰ | 87 |
| 盐酸二甲双胍 | 20 |
结果：新晶型的化合物Ⅰ的降糖活性大大增强，抑制率由66％提高到87％。
本发明该新晶型活性强，稳定性好，具有一定的优越性，适合制剂工艺过程和长期储存。
附图说明
图1为化合物Ⅰ新晶型的X-射线衍射图。
具体实施方式：
下面结合实施例对本发明做进一步的说明，使本领域专业技术人员更好的理解本发明。实施例仅为解释性的，决不意味着它以任何方式限制本发明的范围。
本发明中所用的化合物Ⅰ，即N-(3-(4-(苯并噻唑-2-基)哌嗪-1-基)丙基)-3-氰基-4-氟苯磺酰胺，根据中国发明专利201210575394.4提供的方法合成，白色固体，熔点178.0℃-179.2℃；纯度98.7％(HPLC归一化法)。
实施例1
在装有搅拌、温度计、冷凝器的500ml反应瓶中，加入50克化合物Ⅰ(纯度98.7％)、200ml9:1的二甲基甲酰胺/甲醇中，加热至回流，溶解后，然后冷却至20℃—25℃，保温静置10小时，析出结晶，过滤，室温真空度0.04-0.07Mpa干燥11小时，得到得到白色结晶性粉末，为新晶型的化合物Ⅰ，新晶型为白色结晶性粉末，熔点151.7℃-152.5℃，纯度(HPLC法)99.5％。
该结晶性粉末的X-射线衍射图见图1。仪器型号和测定条件：日本理学D/max 2500型衍射仪；CuKa 40Kv 100mA；2θ扫描范围：0－50°。
实施例2
用下述成分制备片剂：
将原辅料预先干燥，过100目筛备用。先将处方量的辅料淀粉、羧甲基淀粉钠盐、硬脂酸镁、滑石粉充分混匀。将原料药化合物Ⅰ-8以递增稀释法加到辅料中，每次加时充分混匀2－3次，保证原料药与辅料充分混匀，过20目筛，在55℃通风烘箱中干燥2h，干颗粒过16目筛整粒，测定中间体含量，混合均匀，在压片机上压片。
Claims (4)
1.一种具有降糖作用的化合物Ⅰ的晶型，
Ⅰ
其特征在于：用CuKa射线作为特征X射线粉末测定中，在下述2θ衍射角处具有特征峰，其图谱具有下列2θ衍射角和D值，2θ衍射角的误差为0.2；
化合物Ⅰ为白色结晶性粉末，熔点151.7℃-152.5℃。
2.一种权利要求1所述具有降糖作用的化合物Ⅰ的晶型的制备方法，其特征在于，按照下述步骤进行：将化合物Ⅰ溶于到3—4倍的体积比9:1的二甲基甲酰胺/甲醇中，加热至回流，溶解后，然后冷却至20℃-25℃，保温静置9-11小时，析出结晶，过滤，室温真空度0.04-0.07Mpa干燥10-12小时，得到上述化合物Ⅰ的晶型。
3.一种含有权利要求1所述的化合物Ⅰ晶型的组合物，其特征是，化合物Ⅰ与一种或多种药学上可接受的载体、赋形剂或稀释剂组成的组合物。
4.根据权利要求3所述的含有权利要求1所述的化合物Ⅰ晶型的组合物，其特征在于，该组合物用于制备口服制剂，用于制备治疗糖尿病药物。
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