WO2016054959A1 - 一种jak激酶抑制剂的硫酸氢盐的结晶形式及其制备方法 - Google Patents

一种jak激酶抑制剂的硫酸氢盐的结晶形式及其制备方法 Download PDF

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WO2016054959A1
WO2016054959A1 PCT/CN2015/089223 CN2015089223W WO2016054959A1 WO 2016054959 A1 WO2016054959 A1 WO 2016054959A1 CN 2015089223 W CN2015089223 W CN 2015089223W WO 2016054959 A1 WO2016054959 A1 WO 2016054959A1
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crystal
hexahydrocyclopenta
pyrrolo
pyrrole
amino
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PCT/CN2015/089223
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English (en)
French (fr)
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孙飘扬
武乖利
高晓晖
陈永江
沈灵佳
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江苏恒瑞医药股份有限公司
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Priority to CN201580008157.1A priority Critical patent/CN105980389B/zh
Priority to EP15849469.0A priority patent/EP3205653B1/en
Priority to DK15849469.0T priority patent/DK3205653T3/da
Priority to ES15849469T priority patent/ES2836100T3/es
Priority to JP2017517304A priority patent/JP6830888B2/ja
Priority to CA2963581A priority patent/CA2963581C/en
Priority to BR112017005564A priority patent/BR112017005564A2/pt
Priority to RU2017114689A priority patent/RU2704795C2/ru
Priority to US15/516,529 priority patent/US10150770B2/en
Priority to KR1020177011477A priority patent/KR20170057441A/ko
Priority to AU2015330554A priority patent/AU2015330554B2/en
Publication of WO2016054959A1 publication Critical patent/WO2016054959A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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 present invention relates to (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3- Form I crystal of d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide hydrogensulfate, and a preparation method and use thereof.
  • the compounds of formula (I) obtained according to the process of the invention are useful in the treatment of arthritis.
  • Tofacitinib (CP-690550) is a new oral JAK pathway inhibitor developed by Pfizer Inc. Tofacitinib is the first-in-class drug developed for the treatment of rheumatoid arthritis. Since the birth of tofacitinib in Pfizer's own laboratory, the drug has been placed on the high hopes of heavy drugs, the success of the drug will also be a major victory for Pfizer's highly criticized R & D business, after the results of the clinical phase III trial, Pfizer tofacitinib is significantly more effective than methotrexate.
  • the crystal structure of the pharmaceutically active ingredient often affects the chemical stability of the drug, and the difference in crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the formation of other forms of crystal form.
  • amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, and poor fluidity. Therefore, it is necessary to improve the various aspects of the above products. We need to study in depth to find new crystal forms with high purity and good chemical stability.
  • the form of the compound of the formula (I) which can be used as a raw material is not particularly limited, and any crystal form or amorphous solid can be used, and the type I crystal of the compound of the formula (I) of the present invention
  • the preparation method is:
  • alcohols having a carbon number of 3 or less are preferred.
  • more preferably methanol is used as a recrystallization solvent for the compound of the formula (I).
  • the method for preparing Form I crystals of the compound of formula (I) provided by the present invention comprises the steps of:
  • the organic solvent is selected from the group consisting of alcohols having a carbon number of 3 or less, and further preferably the organic solvent is methanol.
  • the method of recrystallization differs from the usual recrystallization operation method. After the compound of the formula (I) in any form is heated and dissolved in an organic solvent, a part of the solvent is removed by atmospheric distillation, and after completion of the crystallization, it is dried by filtration to obtain a desired crystal.
  • the crystals to be collected are usually dried under vacuum at a temperature of about 30 to 100 ° C, preferably 40 to 60 ° C, to obtain an effect of removing the recrystallization solvent.
  • the crystal form of the type I crystal of the obtained compound of the formula (I) was examined by differential scanning calorimetry (DSC) and X-ray diffraction pattern measurement, and the solvent residue of the obtained crystal was examined.
  • the type I crystal of the compound of the formula (I) prepared according to the process of the present invention does not contain or contains only a relatively low amount of residual solvent, and meets the requirements of the national pharmacopoeia for the residual solvent of the pharmaceutical product, so that the crystal of the present invention can be better.
  • the ground is used as a pharmaceutically active ingredient.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form I of the compound of formula (I), said composition further comprising at least one pharmaceutically acceptable carrier, said pharmaceutically acceptable carrier It may be selected from at least one of lactose, mannitol, microcrystalline cellulose, croscarmellose sodium, sodium carboxymethyl starch, hydroxypropylmethylcellulose, povidone, and magnesium stearate.
  • the content of the type I crystal in the pharmaceutical composition provided by the present invention is from 0.5 mg to 200 mg.
  • Another aspect of the invention relates to the use of a compound of the formula (I) of the invention, Form I, or a pharmaceutical composition of the invention, for the manufacture of a medicament for the treatment of a disease associated with JAK kinase.
  • the disease is preferably rheumatoid and rheumatoid arthritis.
  • Figure 1 shows an X-ray powder diffraction pattern of a type I crystal of a compound of formula (I) (represented by the code SHR0302 in the figure).
  • Figure 2 shows a DSC pattern of the Form I crystal of the compound of formula (I).
  • Figure 3 shows an X-ray powder diffraction pattern of an amorphous solid of the compound of formula (I).
  • Figure 4 shows a DSC pattern of an amorphous solid of the compound of formula (I).
  • Example 1 A sample of the compound of formula (I) was prepared according to the method of Example 2 of the patent (PCT Application No. PCT/CN2014/076794).
  • Example 2 the crystal form of the sample of the measurement example 1 was measured.
  • the X-ray diffraction spectrum of the solid sample prepared in Example 1 is shown in Fig. 3, and the characteristic peak of the amorphous form is shown.
  • the DSC spectrum is shown in Fig. 4, and no melting characteristic absorption peak is observed below 300 ° C, and the product is determined as follows. Amorphous solid.
  • the crystals are at about 6.38 (13.85), 10.38 (8.51), 10.75 (8.23), 14.49 (6.11), 15.07 (5.88), 15.58 (5.69), 16.23 (5.46), 17.84 (4.97), 18.81 (4.72), 19.97. (4.44), 20.77 (4.27), 22.12 (4.02), 23.19 (3.83), 24.12 (3.69), 25.51 (3.49), 26.62 (3.35), 27.38 (3.26), 28.56 (3.12), 29.91 (2.99) Characteristic peaks.
  • the DSC spectrum is shown in Fig. 2, which has a sharp melting endothermic peak of 220.23 ° C, and this crystal form is defined as the I crystal form.
  • Example 1 The amorphous sample prepared in Example 1 and the Form I crystalline product obtained in Example 3 were separately placed in an open position, and examined under illumination (4,500 Lux), heated (40 ° C, 60 ° C), and high humidity (RH 75%, Stability of the sample under RH90%) conditions.
  • the sampling time was 5 days and 10 days, and the purity of HPLC was shown in Table 1.
  • the stability study showed that the compound of formula (I) type I crystal and amorphous sample were open. Under the condition of mouth placement, the stability under light, high temperature and high humidity conditions showed that high humidity had little effect on the two, but under the conditions of light and high temperature, the stability of type I crystal was significantly better than none. Stereotype the sample.

Abstract

提供一种式(I)所示JAK激酶抑制剂(3aR, 5s, 6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的I型结晶及其制备方法。所述制备方法包括将任意晶型或无定型的式(I)化合物固体在单一的有机溶剂中结晶得到I型结晶，该结晶具备良好的晶型稳定性和化学稳定性，并且所用结晶溶剂低毒低残留，可更好地用于临床治疗。

Description

一种JAK激酶抑制剂的硫酸氢盐的结晶形式及其制备方法 技术领域
本发明涉及(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的I型结晶及其制备方法和用途。根据本发明的方法制备获得的式(I)化合物可用于关节炎的治疗。
背景技术
关节炎是全世界最常见的慢性疾病，导致关节炎的原因很多，引起关节损伤也各有不同。目前，Tofacitinib(CP-690550)是辉瑞公司研发的一种新型口服JAK通路抑制剂，Tofacitinib是开发用于类风湿性关节炎(rheumatoid arthritis)治疗的首创药物(first-in-class drug)。自从tofacitinib在辉瑞自己的试验室诞生以来，该药就被寄予了重磅药物的厚望，该药的成功也将为辉瑞公司备受诟病的研发业务迎来重大胜利，经临床三期试验结果，辉瑞tofacitinib药物药效明显优于甲氨蝶呤(methotrexate)。
Figure PCTCN2015089223-appb-000001
基于tofacitinib的结构，已开发出一系列具有体内、外活性，高吸收的JAK激酶抑制剂化合物，参见WO2013091539。根据WO2013091539中化合物筛选后并制备成盐得到了式(I)示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐，其制备方法参见申请人在先提交的PCT专利申请PCT/CN2014/076794，式(I) 化合物有望成为JAK激酶抑制剂的优选化合物，对于治疗风湿及类风湿性关节炎方面，具有重要的研究意义。
药用活性成分的晶型结构往往影响到该药物的化学稳定性，结晶条件及储存条件的不同有可能导致化合物的晶型结构的变化，有时还会伴随着产生其他形态的晶型。一般来说，无定型的药物产品没有规则的晶型结构，往往具有其它缺陷，比如产物稳定性较差，析晶较细，过滤较难，易结块，流动性差等。因此，改善上述产物的各方面性质是很有必要的，我们需要深入研究找到晶型纯度较高并且具备良好化学稳定的新晶型。
发明内容
本发明的目的是提供一种式(I)化合物的稳定晶型以及制备该晶型的方法。
我们考察了式(I)化合物在不同结晶条件下得到的一系列结晶产物，对所得结晶产物进行了X-衍射及DSC检测，发现式(I)化合物在常规的结晶条件下，可以得到一种稳定性良好的晶型，我们称其为I型结晶。本申请中的I型结晶的DSC图谱显示在220℃附近有熔融吸热峰，X-射线粉末衍射图谱如图1所示，使用Cu-Ka辐射，以2θ角度和晶面间距(d值)表示的X-射线粉末衍射图谱，其中在6.38(13.85)，10.38(8.51)，10.75(8.23)，14.49(6.11)，15.07(5.88)，15.58(5.69)，16.23(5.46)，17.84(4.97)，18.81(4.72)，19.97(4.44)，20.77(4.27)，22.12(4.02)，23.19(3.83)，24.12(3.69)，25.51(3.49)，26.62(3.35)，27.38(3.26)，28.56(3.12)，29.91(2.99)有特征峰。
本发明制备I型结晶的方法中，可作为原料使用的式(I)化合物的存在形态没有特别限定，可以使用任意晶型或无定型固体，本发明的式(I)化合物的I型结晶的制备方法为：
用某些低级有机溶剂，优选碳原子数小于等于3的醇类；更优选为甲醇作为式(I)化合物的重结晶溶剂。
具体的，本发明提供的制备式(I)化合物的I型结晶的方法包括以下步骤：
(1)将任意形态的式(I)化合物固体加热溶解于适量的有机溶剂 中，蒸馏除去部分溶剂；
(2)过滤、洗涤、干燥。
在本发明优选的实施方案中，步骤(1)中，有机溶剂选自碳原子数小于等于3的醇类，进一步优选有机溶剂为甲醇。
重结晶的方法与通常的重结晶操作方法有所不同。可以用任意形态的式(I)化合物在有机溶剂中加热溶解后，常压蒸馏除去部分溶剂，结晶完成后，经过滤干燥，即可得到所需要的结晶。所滤取的结晶体通常在30～100℃左右，优选40～60℃的加热条件下进行真空干燥，就能达到去除重结晶溶剂的效果。
通过差示扫描热分析(DSC)、X－衍射图谱测定，对得到的式(I)化合物的I型结晶体进行了晶型研究，同时对所得结晶的溶剂残留进行了检测。
按照本发明的方法制备的式(I)化合物的I型结晶不含有或仅含有较低含量的残留溶剂，符合国家药典规定的有关医药产品残留溶剂的限量要求，因而本发明的结晶可以较好地作为医药活性成分使用。
另一方面，本发明还提供了一种含有式(I)化合物I型结晶的药用组合物，所述组合物还包含至少一种药学上可接受的载体，所述药学上可接受的载体可以选自乳糖、甘露醇、微晶纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠、羟丙基甲基纤维素、聚维酮和硬脂酸镁中的至少一种。本发明提供的药物组合物中I型结晶的含量为0.5mg～200mg。
本发明另一方面涉及本发明的式(I)化合物I型结晶或本发明的药物组合物在制备治疗与JAK激酶有关的疾病的药物中的用途。所述疾病优选为风湿及类风湿性关节炎。
附图说明
图1示出式(I)化合物(图中以代号SHR0302表示)I型结晶的X-射线粉末衍射图谱。
图2示出式(I)化合物I型结晶的DSC图谱。
图3示出式(I)化合物无定型固体的X-射线粉末衍射图谱。
图4示出式(I)化合物无定型固体的DSC图谱。
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
实验所用的测试仪器
1、DSC谱
仪器型号：Mettler Toledo DSC 1 Staree System
吹扫气：氮气
升温速率：10.0℃/min
温度范围：40-300℃
2、X-射线衍射谱
仪器型号：D/Max-RA日本RigakuX-射线粉末衍射仪
射线：单色Cu-Kα射线
Figure PCTCN2015089223-appb-000002
扫描方式：θ/2θ，扫描范围：2－40°
电压：40KV电流：40mA
实施例1、按专利(PCT申请号：PCT/CN2014/076794)实施例2的方法制备式(I)化合物的样品。
(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的制备(式I)
在10L反应瓶中投入(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺140g(0.34mol)，加入无水甲醇350g，二氯甲烷2.0kg，悬浮搅拌，室温下缓慢滴加硫酸34.8g(0.36mol)，反应液溶清，搅拌反应30min。过滤除去不溶物，滤液减压浓缩干，干燥，得目标产物135g～168g，产率：80～90％。
MS m/z(ESI):415.1651[M+1].
1H NMR(400MHz,DMSO-d6):δ12.75(s,1H),11.04(s,1H),8.37(s,1H),7.41-7.42(t,1H),6.89(s,1H),5.15-5.19(m,1H),3.89(s,3H),3.68-3.70(m,2H),3.38-3.40(m,2H),3.29(s,3H),2.95(s,2H),2.09-2.16(m,2H),1.92-1.97(m,2H)
实施例2、测定实施例1样品的晶型
将实施例1中制得的固体样品X-射线衍射谱图见图3，显示无晶型特征吸收峰，DSC谱图见4，在300℃以下未见熔融特征吸收峰，据此确定产物为无定型固体。
实施例3
取(1.0g，2.4mmol)式(I)化合物(按实施例1制备方法所得)加入到250ml单口瓶中，加入100ml甲醇，加热回流溶清，继续回流10min，常压蒸馏掉约90ml甲醇，有大量白色固体析出，趁热过滤，干燥得白色固体784mg，收率为78.4％。该结晶样品的X-射线衍射谱图见图1。该结晶在约6.38(13.85)，10.38(8.51)，10.75(8.23)，14.49(6.11)，15.07(5.88)，15.58(5.69)，16.23(5.46)，17.84(4.97)，18.81(4.72)，19.97(4.44)，20.77(4.27)，22.12(4.02)，23.19(3.83)，24.12(3.69)，25.51(3.49)，26.62(3.35)，27.38(3.26)，28.56(3.12)，29.91(2.99)处有特征峰。DSC谱图见图2，有尖锐熔融吸热峰220.23℃，将此晶型定义为I晶型。
实施例4
将实施例1制得的无定型的样品与实施例3所得的I型结晶产物分别敞口平摊放置，考察在光照(4500Lux)，加热(40℃，60℃)，高湿(RH75％，RH90％)条件下样品的稳定性。考察取样时间为5天和10天，HPLC检测纯度见表1。
表1、式(I)化合物I型结晶和无定型样品的稳定性比较
Figure PCTCN2015089223-appb-000003
稳定性考察结果表明，式(I)化合物I型结晶和无定型样品在敞 口放置的条件下，经光照、高温和高湿条件下的稳定性比较发现，高湿对两者的影响不大，但是在光照、高温的条件下，I型结晶的稳定性显著好于无定型样品。

Claims (8)

  1. 一种(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的I型结晶，其特征在于使用Cu-Ka辐射，得到以2θ角度和晶面间距表示的X-射线粉末衍射图谱，所述结晶具有如图1所示的X-射线粉末衍射图谱，其中在约6.38(13.85)，10.38(8.51)，10.75(8.23)，14.49(6.11)，15.07(5.88)，15.58(5.69)，16.23(5.46)，17.84(4.97)，18.81(4.72)，19.97(4.44)，20.77(4.27)，22.12(4.02)，23.19(3.83)，24.12(3.69)，25.51(3.49)，26.62(3.35)，27.38(3.26)，28.56(3.12)，29.91(2.99)有特征峰。
  2. 一种制备如权利要求1所述的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的I型结晶的方法，所述方法包括下述步骤：
    1)将任意晶型或无定型的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐固体加热溶解于适量的有机溶剂中，常压蒸除部分溶剂，析出固体，所述有机溶剂选自碳原子数小于等于3的醇类；
    2)过滤，洗涤，干燥。
  3. 根据权利要求2所述的制备方法，其特征在于在步骤1)中所述的有机溶剂为甲醇。
  4. 一种药物组合物，其含有如权利要求1所述的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的I型结晶以及药学上可接受的载体。
  5. 根据权利要求4所述的药物组合物，其特征在于其 (3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的I型结晶的含量为0.5mg～200mg。
  6. 根据权利要求4所述的药物组合物，其特征在于，所述药学上可接受的载体选自乳糖、甘露醇、微晶纤维素、交联羧甲基纤维素钠、羧甲基淀粉钠、羟丙基甲基纤维素、聚维酮和硬脂酸镁中的至少一种。
  7. 根据权利要求1所述的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的I型结晶或根据权利要求4所述的药物组合物在制备治疗与JAK激酶有关的疾病的药物中的用途。
  8. 根据权利要求1所述的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的I型结晶或根据权利要求4所述的药物组合物在制备治疗风湿及类风湿性关节炎的药物中的用途。
PCT/CN2015/089223 2014-10-09 2015-09-09 一种jak激酶抑制剂的硫酸氢盐的结晶形式及其制备方法 WO2016054959A1 (zh)

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EP15849469.0A EP3205653B1 (en) 2014-10-09 2015-09-09 Crystal form of bisulfate of jak inhibitor and preparation method therefor
DK15849469.0T DK3205653T3 (da) 2014-10-09 2015-09-09 Krystalform af bisulfat af jak-hæmmer og fremgangsmåde til fremstilling deraf
ES15849469T ES2836100T3 (es) 2014-10-09 2015-09-09 Forma cristalina de bisulfato de inhibidor de JAK y método de preparación de la misma
JP2017517304A JP6830888B2 (ja) 2014-10-09 2015-09-09 Ｊａｋ阻害剤の硫酸水素塩の結晶形およびその製造方法
CA2963581A CA2963581C (en) 2014-10-09 2015-09-09 Crystal form of bisulfate of jak inhibitor and preparation method therefor
BR112017005564A BR112017005564A2 (pt) 2014-10-09 2015-09-09 forma de cristal de bissulfato de inibidor de jak e método de preparação do mesmo
RU2017114689A RU2704795C2 (ru) 2014-10-09 2015-09-09 Кристаллическая форма бисульфата ингибитора jak и способ ее получения
US15/516,529 US10150770B2 (en) 2014-10-09 2015-09-09 Crystal form of bisulfate of JAK inhibitor and preparation method therefor
KR1020177011477A KR20170057441A (ko) 2014-10-09 2015-09-09 Jak 억제제의 바이설페이트의 결정형 및 이의 제조방법
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018133823A1 (zh) * 2017-01-20 2018-07-26 江苏恒瑞医药股份有限公司 一种jak激酶抑制剂的硫酸氢盐的晶型及其制备方法
CN109563097A (zh) * 2016-11-23 2019-04-02 无锡福祈制药有限公司 一种7H-吡咯并[2,3-d]嘧啶类化合物的晶型、盐型及其制备方法
CN111205290A (zh) * 2018-11-22 2020-05-29 江苏恒瑞医药股份有限公司 一种jak激酶抑制剂的结晶形式及其制备方法
US10786507B2 (en) 2016-02-19 2020-09-29 Jiangsu Hengrui Medicine Co., Ltd. Pharmaceutical composition containing JAK kinase inhibitor or pharmaceutically acceptable salt thereof

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3216790B1 (en) 2014-11-05 2019-10-02 Jiangsu Hengrui Medicine Co., Ltd. Crystalline form of jak kinase inhibitor bisulfate and a preparation method thereof
AU2021318201A1 (en) 2020-07-28 2023-02-02 Arcutis Biotherapeutics, Inc. Topical formulation containing jak inhibitor and laureth-4
JP2023550363A (ja) 2020-11-17 2023-12-01 アーキュティス・バイオセラピューティクス・インコーポレーテッド 深部皮膚薬物送達のための組成物および方法
TW202320788A (zh) * 2021-08-12 2023-06-01 大陸商江蘇恒瑞醫藥股份有限公司 用於治療或預防抗宿主病的吡咯并六元雜芳物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1439010A (zh) * 2000-06-26 2003-08-27 辉瑞产品公司 吡咯并[2,3－d]嘧啶化合物作为免疫抑制剂
CN1798559A (zh) * 2003-04-04 2006-07-05 诺瓦提斯公司 用于治疗气管疾病的喹啉－2－酮衍生物
WO2013091539A1 (zh) * 2011-12-21 2013-06-27 江苏恒瑞医药股份有限公司 吡咯并六元杂芳环类衍生物、其制备方法及其在医药上的应用
WO2014194741A1 (zh) * 2013-06-07 2014-12-11 江苏恒瑞医药股份有限公司 一种jak激酶抑制剂的硫酸氢盐及其制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004057195A1 (de) * 2004-11-26 2006-06-01 Wilex Ag Kristalline Modifikationen von N-Alpha-(2,4,6-Triisopropylphenylsulfonyl)-3-hydroxyamidino-(L)-phenylalanin-4-ethoxycarbonylpiperazid und/oder Salzen davon
US7432398B2 (en) * 2005-01-06 2008-10-07 Cj Corporation Inorganic acid salts of sibutramine
TWI405756B (zh) * 2005-12-21 2013-08-21 Array Biopharma Inc 新穎硫酸氫鹽
EP2691395B1 (en) * 2011-03-28 2017-08-30 ratiopharm GmbH Processes for preparing tofacitinib salts

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1439010A (zh) * 2000-06-26 2003-08-27 辉瑞产品公司 吡咯并[2,3－d]嘧啶化合物作为免疫抑制剂
CN1798559A (zh) * 2003-04-04 2006-07-05 诺瓦提斯公司 用于治疗气管疾病的喹啉－2－酮衍生物
WO2013091539A1 (zh) * 2011-12-21 2013-06-27 江苏恒瑞医药股份有限公司 吡咯并六元杂芳环类衍生物、其制备方法及其在医药上的应用
WO2014194741A1 (zh) * 2013-06-07 2014-12-11 江苏恒瑞医药股份有限公司 一种jak激酶抑制剂的硫酸氢盐及其制备方法

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10786507B2 (en) 2016-02-19 2020-09-29 Jiangsu Hengrui Medicine Co., Ltd. Pharmaceutical composition containing JAK kinase inhibitor or pharmaceutically acceptable salt thereof
CN109563097A (zh) * 2016-11-23 2019-04-02 无锡福祈制药有限公司 一种7H-吡咯并[2,3-d]嘧啶类化合物的晶型、盐型及其制备方法
JP2019535771A (ja) * 2016-11-23 2019-12-12 无▲錫▼福祈制▲薬▼有限公司Ｗｕｘｉ Ｆｏｒｔｕｎｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．，Ｌｔｄ ７Ｈ−ピロロ［２、３−ｄ］ピリミジン化合物の結晶形、塩型並びにその製造方法
CN109563097B (zh) * 2016-11-23 2021-05-14 无锡福祈制药有限公司 一种7H-吡咯并[2,3-d]嘧啶类化合物的晶型、盐型及其制备方法
WO2018133823A1 (zh) * 2017-01-20 2018-07-26 江苏恒瑞医药股份有限公司 一种jak激酶抑制剂的硫酸氢盐的晶型及其制备方法
CN108779122A (zh) * 2017-01-20 2018-11-09 江苏恒瑞医药股份有限公司 一种jak激酶抑制剂的硫酸氢盐的晶型及其制备方法
CN111205290A (zh) * 2018-11-22 2020-05-29 江苏恒瑞医药股份有限公司 一种jak激酶抑制剂的结晶形式及其制备方法
CN111205290B (zh) * 2018-11-22 2021-10-08 江苏恒瑞医药股份有限公司 一种jak激酶抑制剂的结晶形式及其制备方法

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