WO2017088790A1 - 噻二唑衍生物类dpp-iv抑制剂的结晶及其用途 - Google Patents

噻二唑衍生物类dpp-iv抑制剂的结晶及其用途 Download PDF

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WO2017088790A1
WO2017088790A1 PCT/CN2016/107076 CN2016107076W WO2017088790A1 WO 2017088790 A1 WO2017088790 A1 WO 2017088790A1 CN 2016107076 W CN2016107076 W CN 2016107076W WO 2017088790 A1 WO2017088790 A1 WO 2017088790A1
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crystal
type
formula
compound
dpp
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PCT/CN2016/107076
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French (fr)
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彭岩
刘飞
陈智林
张亚羽
胡中元
江金凤
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正大天晴药业集团股份有限公司
北京赛林泰医药技术有限公司
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Priority to CN201680064181.1A priority Critical patent/CN108350000A/zh
Priority to US15/779,420 priority patent/US10450328B2/en
Priority to EP16868013.0A priority patent/EP3381922B1/en
Priority to JP2018526804A priority patent/JP2018535231A/ja
Publication of WO2017088790A1 publication Critical patent/WO2017088790A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the invention belongs to the field of medical chemistry, and particularly relates to a crystallization, crystallization composition, pharmaceutical composition, preparation method and use thereof of a thiadiazole derivative DPP-IV inhibitor.
  • DPP-IV (dipeptidyl peptidase IV) is a serine protease that is expressed in various tissues in the body (eg liver, lung, intestine, kidney, etc.) and is responsible for endogenous peptides in vivo (GLP-1 (7) -36)) Metabolic cleavage.
  • GLP-1 (7-36) has a variety of beneficial effects in the body, including stimulating insulin secretion, inhibiting glucagon secretion, promoting satiety, and delaying gastric emptying. Therefore, inhibition of DPP-IV can be used to prevent and/or treat diabetes, especially type II diabetes.
  • a variety of DPP-IV inhibitors have been marketed, such as alogliptin, sitagliptin, saxagliptin, vildagliptin, linagliptin, and the like.
  • Cispheral Patent Application No. CN102807568 discloses a thiadiazole derivative DPP-IV inhibitor as shown in Formula I or Formula II, which has a very good DPP-IV inhibitory activity.
  • Compound 7 has a very good level of in vivo metabolism and a very suitable half-life in vivo, and is particularly suitable as a DPP-IV inhibitor.
  • drug developers attempt to provide a suitable form of active molecule with properties as a drug (eg, processing, preparation, storage stability, etc.). Therefore, finding a form with the desired properties is also critical to drug development.
  • the invention provides Form A crystals of a compound of Formula 7:
  • the type A crystal using Cu-K ⁇ radiation, has a diffraction peak at an angle of 2 ⁇ of about 6.54, 8.27, and 11.68 in an X-ray powder diffraction (XRD) pattern; typically, the degree of 2 ⁇ is about 6.54, 8.27, 8.67, 9.16, 9.55, 11.68, 12.17, 12.98, 16.23, 18.15, 18.91 have diffraction peaks; further typically at 2 ⁇ degrees are about 6.54, 8.27, 8.67, 9.16, 9.55, 10.80, 11.68, 12.17, 12.98, 14.35, There are diffraction peaks at 15.05, 15.64, 16.23, 16.73, 17.31, 18.15, 18.91, 19.43, 20.23, 20.79, 21.36, 23.25, 23.96, 24.53, 25.05, 26.54, 28.43, 29.63, 30.19.
  • the XRD pattern of the Form A crystal of the compound of Formula 7 has the following characteristics:
  • the Form A crystal of the compound of Formula 7 has substantially a powder X-ray diffraction pattern as shown in FIG.
  • a process for the preparation of a type A crystal of a compound represented by Formula 7, which comprises the steps of: a) dissolving an amorphous compound of formula 7 in an appropriate amount of ethanol and heating to 75- Dissolve at 80 ° C, add appropriate amount of activated carbon, stir for 1-2 hours and then filter; b) gradually reduce the temperature at 5 ° C per hour until 10-20 ° C, then continue to stir for 5-7 hours; c) filter, filter cake Dry at 45-55 ° C for 5-7 hours under vacuum.
  • Another aspect of the present invention provides a Form B crystal of a compound of Formula 7, using Cu-K ⁇ radiation in an X-ray powder diffraction (XRD) pattern at a degree of 2 ⁇ of about 4.86, 6.24, 7.88,
  • XRD X-ray powder diffraction
  • the XRD pattern of the Form B crystal of the compound of Formula 7 has the following characteristics:
  • the Form B crystal of the compound of Formula 7 has substantially a powder X-ray diffraction pattern as shown in FIG.
  • a process for the preparation of a Form B crystal of a compound of Formula 7, which comprises the steps of: a) dissolving an amorphous compound of formula 7 in an appropriate amount of ethyl acetate, isopropanol Or isopropyl ether, heated to 70-80 ° C, stirred for 1-2 hours; b) gradually cooled at a rate of 5 ° C per hour until 10-20 ° C, then continued stirring for 5-7 hours; c) filtration, will The filter cake was dried under vacuum at 45-55 ° C for 5-7 hours.
  • the present invention provides a crystalline composition of the above-described A-type crystal or B-type crystal.
  • the crystal composition of the type A crystal means that the type A crystal in the composition accounts for 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more, of the composition.
  • Other crystals or amorphous materials which may contain minor amounts of the compound of formula 7, for example, include, but are not limited to, Form B crystals or amorphous forms of the compound of Formula 7.
  • the crystalline composition of the B-form crystal means that the B-form crystal in the composition accounts for 50% or more, preferably 80% or more, more preferably 90% or more, and most preferably 95% or more, of the composition.
  • Other crystals or amorphous materials which may contain minor amounts of a compound of formula 7, for example, include, but are not limited to, a type A crystal or amorphous form of a compound of formula 7.
  • the present invention provides a pharmaceutical composition comprising the above crystalline or crystalline composition.
  • the pharmaceutical composition may also include a pharmaceutically acceptable adjuvant.
  • Pharmaceutically acceptable excipients are well known to those skilled in the art, for example, see the commonly used excipients listed in the 6th edition of Pharmacy, edited by Trifford.
  • the invention provides a method of inhibiting DPP-IV, the method comprising contacting DPP-IV with a Form A crystal, a Type B crystal, a crystalline composition or a pharmaceutical composition of the invention.
  • the present invention provides a method of treating a disease that benefits from inhibition of DPP-IV, the method comprising administering to a subject in need thereof a Form A crystal, a Form B crystal, a crystalline composition or a pharmaceutical composition according to the invention.
  • the disease is selected from the group consisting of diabetes. More preferably, the disease is selected from the group consisting of type 2 diabetes.
  • the term "individual” includes humans and animals, for example, mammals (eg, primates, cows, horses, pigs, dogs, cats, mice, rats, rabbits, goats, sheep, birds, etc.).
  • the present invention provides the use of the above-described Form A crystal, Form B crystal, crystalline composition or pharmaceutical composition for the preparation of a medicament for the treatment of a disease which benefits from inhibition of DPP-IV.
  • the disease is selected from the group consisting of diabetes. More preferably, the disease is selected from the group consisting of type 2 diabetes.
  • the present invention provides a Type A crystal, a Form B crystal, a crystalline composition or a pharmaceutical composition of the present invention for inhibiting DPP-IV.
  • the invention provides a Form A crystal, Form B crystal, crystalline composition or pharmaceutical composition of the invention for use in the treatment of a disease that benefits from inhibition of DPP-IV.
  • Both the type A crystal and the type B crystal of the present invention have excellent stability. For example, under high temperature, high humidity or light test conditions, the content of the related substance of the crystal of the compound of the formula 7 does not change significantly.
  • the type A crystal and the type B crystal of the present invention also have good powder fluidity, and meet the requirements for drug preparation and production.
  • Figure 1 X-ray powder diffraction pattern of Form A crystal of the compound of Formula 7.
  • Figure 2 X-ray powder diffraction pattern of Form B crystal of the compound of Formula 7.
  • Figure 3 X-ray powder diffraction pattern of the amorphous form of the compound of formula 7.
  • the amorphous form of the compound of formula 7 can be prepared by the method described in Example 7 of CN102807568A.
  • the amorphous form of the compound of formula 7 can also be prepared as follows:
  • the filtrate was evaporated to dryness under reduced pressure at 45 ⁇ 5°C, dissolved in 5 L of dichloromethane, washed with 5 L of purified water; 5 L of purified water was added, 288 g of citric acid was extracted, 2.5 L of purified water was used to extract the organic phase, and the aqueous phase was combined; Washing with methyl chloride and 10 L of ethanol; adding 5 L of dichloromethane, the temperature is not more than 30 degrees, slowly adding sodium hydroxide solution, extracting and separating; the organic phase is washed with 5 L of purified water; and the organic phase is dried over anhydrous sodium sulfate. Filtration and evaporation of the filtrate to a solid under reduced pressure of 30 ⁇ 5 ° C afforded 372 g of the compound of formula 7 as an amorphous form.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

本发明属于药物结晶领域，涉及噻二唑衍生物类DPP-IV抑制剂的结晶，具体涉及如式7所示的化合物的A型和B型结晶。本发明的结晶具有优异的稳定性，例如在高温、高湿或者光照试验条件下，式7化合物的结晶的有关物质含量并未发生明显变化。此外，本发明的结晶还具有很好的粉体流动性，满足药物制备、生产的要求。

Description

噻二唑衍生物类DPP-IV抑制剂的结晶及其用途
相关申请的交叉引用
本申请要求于2015年11月27日向中国国家知识产权局提交的第201510845342.8号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本发明属于医药化学领域，具体涉及噻二唑衍生物类DPP-IV抑制剂的结晶、结晶组合物、药物组合物、及其制备方法和用途。
背景技术
DPP-IV(二肽基肽酶IV)是一种丝氨酸蛋白酶，其在体内多种组织(例如肝、肺、肠、肾等)都有表达，负责体内内源性肽(GLP-1(7-36))的代谢性裂解。然而，GLP-1(7-36)在体内具有多种有利的作用，包括刺激胰岛素分泌、抑制高血糖素分泌、促进饱满感和延缓胃排空等。因此，抑制DPP-IV可用于预防和/或治疗糖尿病，尤其是II型糖尿病。目前已有多种DPP-IV抑制剂上市，例如阿格列汀、西他列汀、沙格列汀、维格列汀、利拉列汀等。
中国专利申请CN102807568公开了如通式I或通式II所示的噻二唑衍生物类DPP-IV抑制剂，所述通式化合物(尤其是化合物7)具有非常好的DPP-IV抑制活性。此外，化合物7还具有非常好的体内代谢水平和非常合适的体内半衰期，特别适合作为DPP-IV抑制剂类药物。
Figure PCTCN2016107076-appb-000001
除了治疗效力外，药物研发者试图提供具有作为药物的性质(例如加工、制备、储存稳定性等)的活性分子的合适形式。因此，发现具有所需性质的形式对药物研发也是至关重要的。
发明内容
本发明一方面提供了如式7所示的化合物的A型结晶：
Figure PCTCN2016107076-appb-000002
所述A型结晶，使用Cu-Kα辐射，在X-射线粉末衍射(XRD)图谱中，在2θ度数约为6.54、8.27、11.68处有衍射峰；典型地在2θ度数约为6.54、8.27、8.67、9.16、9.55、11.68、12.17、12.98、16.23、18.15、18.91处有衍射峰；进一步典型地在2θ度数约为6.54、8.27、8.67、9.16、9.55、10.80、11.68、12.17、12.98、14.35、15.05、15.64、16.23、16.73、17.31、18.15、18.91、19.43、20.23、20.79、21.36、23.25、23.96、24.53、25.05、26.54、28.43、29.63、30.19处有衍射峰。
在本发明的一个具体实施方案中，如式7所示的化合物的A型结晶的XRD图谱具有如下特征：
编号 2θ(度) 相对强度(％) 编号 2θ(度) 相对强度(％)
1 6.54 73 16 18.15 21
2 8.27 68 17 18.91 23
3 8.67 21 18 19.43 14
4 9.16 23 19 20.23 24
5 9.55 24 20 20.79 21
6 10.80 16 21 21.36 21
7 11.68 100 22 23.25 34
8 12.17 26 23 23.96 55
9 12.98 33 24 24.53 30
10 14.35 7 25 25.05 20
11 15.05 10 26 26.54 30
12 15.64 18 27 28.43 28
13 16.23 21 28 29.63 15
14 16.73 14 29 30.19 8
15 17.31 14      
在本发明的一个具体实施方案中，如式7所示的化合物的A型结晶基本上具有如图1所示的粉末X-射线衍射图谱。
本发明再一方面提供了一种如式7所示的化合物的A型结晶的制备方法，所述方法包括如下步骤：a)将无定形的式7化合物溶解在适量乙醇中，加热至75-80℃溶清，加入适量活性炭，搅拌1-2小时后过滤；b)以每小时5℃的速度逐渐降温，直至10-20℃，随后持续搅拌5-7小时；c)过滤，将滤饼在45-55℃真空干燥5-7小时。
本发明的另一方面提供了如式7所示的化合物的B型结晶，使用Cu-Kα辐射，其在X-射线粉末衍射(XRD)图谱中，在2θ度数约为4.86、6.24、7.88、10.54、12.16、15.82、23.70处有衍射峰；典型地在2θ度数约为4.86、6.24、7.88、9.48、10.54、12.16、15.82、17.16、17.76、20.94、23.70处有衍射峰；进一步典型地在2θ度数约为4.86、6.24、7.88、9.48、10.54、12.16、12.54、14.00、14.68、15.30、15.82、17.16、17.76、18.16、19.16、19.58、20.94、22.96、23.70、24.76、25.70、26.44、28.02、28.96、29.38处有衍射峰。
在本发明的一个具体实施方案中，如式7所示的化合物的B型结晶的XRD图谱具有如下特征：
编号 2θ(度) 相对强度(％) 编号 2θ(度) 相对强度(％)
1 4.86 20 14 18.16 15
2 6.24 100 15 19.16 25
3 7.88 23 16 19.58 25
4 9.48 13 17 20.94 19
5 10.54 36 18 22.96 40
6 12.16 28 19 23.70 84
7 12.54 14 20 24.76 32
8 14.00 23 21 25.70 35
9 14.68 13 22 26.44 23
10 15.30 23 23 28.02 33
11 15.82 48 24 28.96 16
12 17.16 25 25 29.38 26
13 17.76 23      
在本发明的一个具体实施方案中，如式7所示的化合物的B型结晶基本上具有如图2所示的粉末X-射线衍射图谱。
本发明再一方面提供了一种如式7所示的化合物的B型结晶的制备方法，所述方法包括如下步骤：a)将无定形的式7化合物溶解在适量乙酸乙酯、异丙醇或异丙醚中，加热至70-80℃，搅拌1-2小时；b)以每小时5℃的速度逐渐降温，直至10-20℃，随后持续搅拌5-7小时；c)过滤，将滤饼在45-55℃真空干燥5-7小时。
又一方面，本发明提供了上述A型结晶或B型结晶的结晶组合物。
其中A型结晶的结晶组合物是指，组合物中A型结晶占组合物重量的50％以上，优选在80％以上，更优选在90％以上，最优选在95％以上，该组合物中可含有少量式7化合物的其他结晶或无定形物，例如，包括但不限于式7化合物的B型结晶或无定形物。
其中B型结晶的结晶组合物是指，组合物中B型结晶占组合物重量的50％以上，优选在80％以上，更优选在90％以上，最优选在95％以上，该组合物中可含有少量式7化合物的其他结晶或无定形物，例如，包括但不限于式7化合物的A型结晶或无定形物。
再一方面，本发明提供了一种药物组合物，其包含上述结晶或结晶组合物。任选的，所述药物组合物还可包括药学上可接受的辅料。药学上可接受的辅料是本领域技术人员所公知的，例如参见崔福德主编的《药剂学》第6版里面所列举的常用辅料。
另一方面，本发明提供了抑制DPP-IV的方法，所述方法包括使DPP-IV与本发明所述的A型结晶、B型结晶、结晶组合物或药物组合物接触。
又一方面，本发明提供了治疗受益于DPP-IV的抑制的疾病的方法，所述方法包括给予有需要的个体本发明所述的A型结晶、B型结晶、结晶组合物或药物组合物。优选的，所述疾病选自糖尿病。更优选的，所述疾病选自II型糖尿病。术语“个体”包括人和动物，例如，哺乳动物(如灵长类动物，牛，马，猪，狗，猫，小鼠，大鼠，兔，山羊，绵羊以及禽类等)。
还一方面，本发明提供了上述A型结晶、B型结晶、结晶组合物或药物组合物在制备治疗受益于DPP-IV的抑制的疾病的药物中的用途。优选的，所述疾病选自糖尿病。更优选的，所述疾病选自II型糖尿病。再一方面，本发明提供了用于抑制DPP-IV的本发明所述的A型结晶、B型结晶、结晶组合物或药物组合物。
另一方面，本发明提供了用于治疗受益于DPP-IV的抑制的疾病的本发明所述的A型结晶、B型结晶、结晶组合物或药物组合物。
本发明的A型结晶和B型结晶均具有优异的稳定性，例如在高温、高湿或者光照试验条件下，式7化合物的结晶的有关物质含量并未发生明显变化。此外，本发明的A型结晶和B型结晶还具有很好的粉体流动性，满足药物制备、生产的要求。
附图说明
图1：式7化合物的A型结晶的X-射线粉末衍射图谱。
图2：式7化合物的B型结晶的X-射线粉末衍射图谱。
图3：式7化合物的无定形形式的X-射线粉末衍射图谱。
具体实施方式
下面将结合实施例对本发明作进一步的说明，可以使本领域技术人员更全面地理解本发明，它们不应该被认为是对本发明范围的限制，而只是本发明的示例性说明和典型代表。
实施例1 式7化合物的无定形形式的制备
式7化合物的无定形形式可参照CN102807568A实施例7所述的方法进行制备。
式7化合物的无定形形式也可按照下述方法进行制备：
Figure PCTCN2016107076-appb-000003
氮气保护下，向30L玻璃反应釜中加入5.5L乙醇，550g中间体1，256g(R)3-氨基哌啶二盐酸盐，414g碳酸氢钠，搅拌，加热升温，控温75℃～80℃，搅拌反应4h。TLC(254nm紫外灯显色，甲醇∶二氯甲烷∶氨水＝1∶10∶0.1，Rf中间体1＝0.7，Rf产物＝0.5)监控至中间体1反应完全，过滤，乙醇洗涤滤饼。滤液45±5℃减压蒸干，加入5L二氯甲烷溶解，5L纯化水洗涤；加入5L纯化水，288g柠檬酸萃取分液，2.5L纯化水反萃有机相，合并水相；加入5L二氯甲烷和10L乙醇洗涤；加入5L二氯甲烷，控温不超过30度，缓慢加入氢氧化钠溶液，萃取分液；有机相用5L纯化水洗涤；无水硫酸钠干燥有机相。过滤，滤液30±5℃减压蒸干至固体，得372g式7化合物，为无定形形式。
式7化合物的无定形形式的X-射线粉末衍射图谱参见图3。
实施例2 式7化合物的A型结晶的制备
向2.5L三口烧瓶中加入250g无定形形式的式7化合物和1.25L乙醇，加热至75-80℃溶清，加入12.5g活性炭，搅拌1h，压滤至2.5L三口烧瓶中。以每小时5℃的速度逐渐降温，控温10-20℃搅拌6h。过滤，滤饼于50±5℃真空干燥6h，得151g黄色粉末，HPLC：98.5％，收率60.4％。
式7化合物的A型结晶的X-射线粉末衍射图谱参见图1。
实施例3 式7化合物的B型结晶的制备
向2.5L三口烧瓶中加入250g无定形形式的式7化合物和2.5L乙酸乙酯，加热至70℃，搅拌2h。以每小时5℃的速度逐渐降温，控温10-20℃搅拌6h。过滤，滤饼于50±5℃真空干燥6h，得137g黄色粉末，HPLC：98.5％，收率55％。
式7化合物的B型结晶的X-射线粉末衍射图谱参见图2。
实施例4 稳定性实验
参照中国药典2010年版二部附录的方法，取适量实施例2所得的A型结晶、实施例3所得的B型结晶，进行影响因素实验。
结果参见表1和表2。
表1： 式7化合物的A型结晶的影响因素实验
Figure PCTCN2016107076-appb-000004
表2： 式7化合物的B型结晶的影响因素实验
Figure PCTCN2016107076-appb-000005

Claims (15)

  1. 如式7所示的化合物的A型结晶，其在X-射线粉末衍射图谱中，在2θ度数约为6.54、8.27、11.68处有衍射峰
    Figure PCTCN2016107076-appb-100001
  2. 如权利要求1所述的A型结晶，其在2θ度数约为6.54、8.27、8.67、9.16、9.55、11.68、12.17、12.98、16.23、18.15、18.91处有衍射峰。
  3. 如权利要求2所述的A型结晶，其在2θ度数约为6.54、8.27、8.67、9.16、9.55、10.80、11.68、12.17、12.98、14.35、15.05、15.64、16.23、16.73、17.31、18.15、18.91、19.43、20.23、20.79、21.36、23.25、23.96、24.53、25.05、26.54、28.43、29.63、30.19处有衍射峰。
  4. 如权利要求1所述的A型结晶，其具有基本上如图1所示的粉末X-射线衍射图谱。
  5. 如式7所示的化合物的B型结晶，其在X-射线粉末衍射图谱中，在2θ度数约为4.86、6.24、7.88、10.54、12.16、15.82、23.70处有衍射峰
    Figure PCTCN2016107076-appb-100002
  6. 如权利要求5所述的B型结晶，其在2θ度数约为4.86、6.24、7.88、9.48、10.54、12.16、15.82、17.16、17.76、20.94、23.70处有衍射峰。
  7. 如权利要求6所述的B型结晶，其在2θ度数约为4.86、6.24、7.88、9.48、10.54、12.16、12.54、14.00、14.68、15.30、15.82、17.16、17.76、18.16、19.16、19.58、20.94、22.96、23.70、24.76、25.70、26.44、28.02、28.96、29.38处有衍射峰。
  8. 如权利要求5所述的B型结晶，其具有基本上如图2所示的粉末X-射线衍射图谱。
  9. 一种结晶组合物，其中权利要求1-4中任一项所述的A型结晶或权利要求5-8中任一项所述的B型结晶占所述结晶组合物重量的50％以上，优选在80％以上，更优选在90％以上，最优选在95％以上。
  10. 一种药物组合物，其包含权利要求1-4中任一项所述的A型结晶或权利要求5-8中任一项所述的B型结晶或权利要求9所述的结晶组合物，以及药学上可接受的辅料。
  11. 权利要求1-4中任一项所述的A型结晶、权利要求5-8中任一项所述的B型结晶、权利要求9所述的结晶组合物或权利要求10所述的药物组合物在制备治疗受益于DPP-IV的抑制的疾病的药物中的用途，优选所述疾病为糖尿病。
  12. 抑制DPP-IV的方法，所述方法包括使DPP-IV与权利要求1-4中任一项所述的A型结晶、权利要求5-8中任一项所述的B型结晶、权利要求9所述的结晶组合物或权利要求10所述的药物组合物接触。
  13. 治疗受益于DPP-IV的抑制的疾病的方法，所述方法包括给予有需要的个体权利要求1-4中任一项所述的A型结晶、权利要求5-8中任一项所述的B型结晶、权利要求9所述的结晶组合物或权利要求10所述的药物组合物，优选所述疾病为糖尿病。
  14. 用于抑制DPP-IV的权利要求1-4中任一项所述的A型结晶、权利要求5-8中任一项所述的B型结晶、权利要求9所述的结晶组合物或权利要求10所述的药物组合物。
  15. 用于治疗受益于DPP-IV的抑制的疾病的权利要求1-4中任一项所述的A型结晶、权利要求5-8中任一项所述的B型结晶、权利要求9所述的结晶组合物或权利要求10所述的药物组合物。
PCT/CN2016/107076 2015-11-27 2016-11-24 噻二唑衍生物类dpp-iv抑制剂的结晶及其用途 WO2017088790A1 (zh)

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