CN105566327A - 一种jak激酶抑制剂的硫酸氢盐的i型结晶及其制备方法 - Google Patents
一种jak激酶抑制剂的硫酸氢盐的i型结晶及其制备方法 Download PDFInfo
- Publication number
- CN105566327A CN105566327A CN201410529863.8A CN201410529863A CN105566327A CN 105566327 A CN105566327 A CN 105566327A CN 201410529863 A CN201410529863 A CN 201410529863A CN 105566327 A CN105566327 A CN 105566327A
- Authority
- CN
- China
- Prior art keywords
- methyl
- pyrrolo
- amino
- thiadiazoles
- pyrroles
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229940043355 kinase inhibitor Drugs 0.000 title abstract description 5
- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 5
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 title abstract 2
- 238000002425 crystallisation Methods 0.000 claims abstract description 31
- 230000008025 crystallization Effects 0.000 claims abstract description 31
- 239000007787 solid Substances 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 229910002483 Cu Ka Inorganic materials 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- 108091000080 Phosphotransferase Proteins 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 102000020233 phosphotransferase Human genes 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 27
- 239000000126 substance Substances 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 239000000047 product Substances 0.000 description 7
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 5
- 239000004012 Tofacitinib Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 229960001350 tofacitinib Drugs 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005286 illumination Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002917 arthritic effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- DNBCBAXDWNDRNO-FOSCPWQOSA-N (3aS,6aR)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxamide Chemical compound COC1=NSC(NC(=O)N2C[C@H]3CC(C[C@H]3C2)N(C)C=2C=3C=CNC=3N=CN=2)=N1 DNBCBAXDWNDRNO-FOSCPWQOSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 206010060820 Joint injury Diseases 0.000 description 1
- 206010039361 Sacroiliitis Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940126397 ivarmacitinib Drugs 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Rheumatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明涉及一种JAK激酶抑制剂的硫酸氢盐的I型结晶及其制备方法。具体地，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。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。本发明所得到式(I)化合物的I型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
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(rheumatoidarthritis)治疗的首创药物(first-in-classdrug)。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)。
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。
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：MettlerToledoDSC1StareeSystem
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
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％。
MSm/z(ESI):415.1651[M+1].
1HNMR(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
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 (6)
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。
6.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。
Priority Applications (17)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410529863.8A CN105566327A (zh) | 2014-10-09 | 2014-10-09 | 一种jak激酶抑制剂的硫酸氢盐的i型结晶及其制备方法 |
| BR112017005564A BR112017005564A2 (pt) | 2014-10-09 | 2015-09-09 | forma de cristal de bissulfato de inibidor de jak e método de preparação do mesmo |
| KR1020177011477A KR20170057441A (ko) | 2014-10-09 | 2015-09-09 | Jak 억제제의 바이설페이트의 결정형 및 이의 제조방법 |
| CN201580008157.1A CN105980389B (zh) | 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 |
| 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 |
| PL15849469.0T PL3205653T3 (pl) | 2014-10-09 | 2015-09-09 | Krystaliczna postać wodorosiarczanu inhibitora jak i sposób jej przygotowania |
| PCT/CN2015/089223 WO2016054959A1 (zh) | 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 |
| US15/516,529 US10150770B2 (en) | 2014-10-09 | 2015-09-09 | Crystal form of bisulfate of JAK inhibitor and preparation method therefor |
| EP15849469.0A EP3205653B1 (en) | 2014-10-09 | 2015-09-09 | Crystal form of bisulfate of jak inhibitor and preparation method therefor |
| AU2015330554A AU2015330554B2 (en) | 2014-10-09 | 2015-09-09 | Crystal form of bisulfate of JAK inhibitor and preparation method therefor |
| HUE15849469A HUE052924T2 (hu) | 2014-10-09 | 2015-09-09 | A JAK gátló biszulfátjának kristályos formája és annak elõkészítési eljárása |
| ES15849469T ES2836100T3 (es) | 2014-10-09 | 2015-09-09 | Forma cristalina de bisulfato de inhibidor de JAK y método de preparación de la misma |
| CA2963581A CA2963581C (en) | 2014-10-09 | 2015-09-09 | Crystal form of bisulfate of jak inhibitor and preparation method therefor |
| RU2017114689A RU2704795C2 (ru) | 2014-10-09 | 2015-09-09 | Кристаллическая форма бисульфата ингибитора jak и способ ее получения |
| PT158494690T PT3205653T (pt) | 2014-10-09 | 2015-09-09 | Forma cristalina de bissulfato do inibidor da jak e seu método de preparação |
| DK15849469.0T DK3205653T3 (da) | 2014-10-09 | 2015-09-09 | Krystalform af bisulfat af jak-hæmmer og fremgangsmåde til fremstilling deraf |
| TW104130773A TWI675839B (zh) | 2014-10-09 | 2015-09-17 | 一種ｊａｋ激酶抑制劑的硫酸氫鹽的結晶形式及其製備方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410529863.8A CN105566327A (zh) | 2014-10-09 | 2014-10-09 | 一种jak激酶抑制剂的硫酸氢盐的i型结晶及其制备方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105566327A true CN105566327A (zh) | 2016-05-11 |
Family
ID=55652569
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410529863.8A Pending CN105566327A (zh) | 2014-10-09 | 2014-10-09 | 一种jak激酶抑制剂的硫酸氢盐的i型结晶及其制备方法 |
| CN201580008157.1A Active CN105980389B (zh) | 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 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201580008157.1A Active CN105980389B (zh) | 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 |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US10150770B2 (zh) |
| EP (1) | EP3205653B1 (zh) |
| JP (1) | JP6830888B2 (zh) |
| KR (1) | KR20170057441A (zh) |
| CN (2) | CN105566327A (zh) |
| AU (1) | AU2015330554B2 (zh) |
| BR (1) | BR112017005564A2 (zh) |
| CA (1) | CA2963581C (zh) |
| DK (1) | DK3205653T3 (zh) |
| ES (1) | ES2836100T3 (zh) |
| HU (1) | HUE052924T2 (zh) |
| PL (1) | PL3205653T3 (zh) |
| PT (1) | PT3205653T (zh) |
| RU (1) | RU2704795C2 (zh) |
| TW (1) | TWI675839B (zh) |
| WO (1) | WO2016054959A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10023577B2 (en) | 2014-11-05 | 2018-07-17 | Jiangsu Hengrui Co., Ltd. | Crystalline form of JAK kinase inhibitor bisulfate and a preparation method thereof |
| WO2023016551A1 (zh) * | 2021-08-12 | 2023-02-16 | 江苏恒瑞医药股份有限公司 | 用于治疗或预防抗宿主病的吡咯并六元杂芳物 |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3417861B1 (en) | 2016-02-19 | 2020-09-23 | Jiangsu Hengrui Medicine Co., Ltd. | Pharmaceutical composition containing jak kinase inhibitor or pharmaceutically acceptable salt thereof |
| DK3511333T3 (da) * | 2016-11-23 | 2021-08-02 | Wuxi Fortune Pharmaceutical Co Ltd | Krystalform og saltform af 7h-pyrrolo[2,3-d]pyrimidinforbindelse og fremgangsmåde til fremstilling deraf |
| CN108779122B (zh) * | 2017-01-20 | 2021-01-15 | 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 |
| 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 |
| US11730740B2 (en) | 2020-07-28 | 2023-08-22 | Arcutis Biotherapeutics, Inc. | Laureth-4 containing topical formulations |
| MX2023005763A (es) | 2020-11-17 | 2023-05-29 | Arcutis Biotherapeutics Inc | Composiciones y metodos para la administracion dermica profunda de farmacos. |
| US12161643B2 (en) | 2021-12-15 | 2024-12-10 | Arcutis Biotherapeutics, Inc. | Stable formulations of SHR0302 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100351253C (zh) * | 2000-06-26 | 2007-11-28 | 辉瑞产品公司 | 作为免疫抑制剂的吡咯并[2,3－d]嘧啶化合物 |
| GB0307856D0 (en) * | 2003-04-04 | 2003-05-14 | Novartis Ag | Organic compounds |
| 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 |
| 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 |
-
2014
- 2014-10-09 CN CN201410529863.8A patent/CN105566327A/zh active Pending
-
2015
- 2015-09-09 RU RU2017114689A patent/RU2704795C2/ru active
- 2015-09-09 PT PT158494690T patent/PT3205653T/pt unknown
- 2015-09-09 CA CA2963581A patent/CA2963581C/en active Active
- 2015-09-09 WO PCT/CN2015/089223 patent/WO2016054959A1/zh active Application Filing
- 2015-09-09 PL PL15849469.0T patent/PL3205653T3/pl unknown
- 2015-09-09 US US15/516,529 patent/US10150770B2/en active Active
- 2015-09-09 CN CN201580008157.1A patent/CN105980389B/zh active Active
- 2015-09-09 BR BR112017005564A patent/BR112017005564A2/pt not_active Application Discontinuation
- 2015-09-09 EP EP15849469.0A patent/EP3205653B1/en active Active
- 2015-09-09 KR KR1020177011477A patent/KR20170057441A/ko active Pending
- 2015-09-09 JP JP2017517304A patent/JP6830888B2/ja not_active Expired - Fee Related
- 2015-09-09 AU AU2015330554A patent/AU2015330554B2/en not_active Ceased
- 2015-09-09 DK DK15849469.0T patent/DK3205653T3/da active
- 2015-09-09 ES ES15849469T patent/ES2836100T3/es active Active
- 2015-09-09 HU HUE15849469A patent/HUE052924T2/hu unknown
- 2015-09-17 TW TW104130773A patent/TWI675839B/zh not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10023577B2 (en) | 2014-11-05 | 2018-07-17 | Jiangsu Hengrui Co., Ltd. | Crystalline form of JAK kinase inhibitor bisulfate and a preparation method thereof |
| WO2023016551A1 (zh) * | 2021-08-12 | 2023-02-16 | 江苏恒瑞医药股份有限公司 | 用于治疗或预防抗宿主病的吡咯并六元杂芳物 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3205653A4 (en) | 2018-06-20 |
| CA2963581A1 (en) | 2016-04-14 |
| WO2016054959A1 (zh) | 2016-04-14 |
| KR20170057441A (ko) | 2017-05-24 |
| RU2017114689A3 (zh) | 2019-01-22 |
| CA2963581C (en) | 2022-07-12 |
| PL3205653T3 (pl) | 2021-03-22 |
| ES2836100T3 (es) | 2021-06-24 |
| AU2015330554B2 (en) | 2020-01-02 |
| JP2017530146A (ja) | 2017-10-12 |
| RU2017114689A (ru) | 2018-11-14 |
| EP3205653B1 (en) | 2020-11-25 |
| DK3205653T3 (da) | 2021-01-11 |
| JP6830888B2 (ja) | 2021-02-17 |
| RU2704795C2 (ru) | 2019-10-31 |
| CN105980389B (zh) | 2017-12-19 |
| US10150770B2 (en) | 2018-12-11 |
| CN105980389A (zh) | 2016-09-28 |
| TWI675839B (zh) | 2019-11-01 |
| AU2015330554A1 (en) | 2017-04-27 |
| TW201613931A (en) | 2016-04-16 |
| EP3205653A1 (en) | 2017-08-16 |
| BR112017005564A2 (pt) | 2017-12-12 |
| US20180237438A1 (en) | 2018-08-23 |
| PT3205653T (pt) | 2020-12-15 |
| HUE052924T2 (hu) | 2021-06-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105566327A (zh) | 一种jak激酶抑制剂的硫酸氢盐的i型结晶及其制备方法 | |
| CN101243056B (zh) | 苯基丙氨酸衍生物的结晶、其制备方法及其应用 | |
| CN103974949B (zh) | 一种酪氨酸激酶抑制剂的二马来酸盐的i型结晶及制备方法 | |
| CN102985416B (zh) | 制备凝血酶特异性抑制剂的方法 | |
| JP6151453B2 (ja) | １−［（２−ブロモフェニル）スルホニル］−５−メトキシ−３−［（４−メチル−１−ピペラジニル）メチル］−１ｈ−インドールジメシラート一水和物の大規模合成法 | |
| CN103965114A (zh) | 氘代的苯基氨基嘧啶化合物以及包含该化合物的药物组合物 | |
| TWI672305B (zh) | 一種ｊａｋ激酶抑制劑的硫酸氫鹽的結晶形式及其製備方法 | |
| RU2720810C2 (ru) | Соли производного хиназолина и способ их получения | |
| CN103313985A (zh) | 嘧啶并[6,1-a]异喹啉-4-酮化合物的结晶型 | |
| BR112021014563A2 (pt) | Dispersão sólida amorfa, complexo da fórmula (i), formas cristalina de composto 1, cristal isolado, métodos de preparação da dispersão sólida amorfa, de tratamento ou prevenção de doenças, de preparação de compostos da fórmula i, composto da fórmula ia | |
| AU2016274961A1 (en) | Adipate forms and compositions of biaryl inhibitors of Bruton's tyrosine kinase | |
| JP2022520629A (ja) | 固体形態のｆｇｆｒ阻害剤化合物およびその製造方法 | |
| EA036964B1 (ru) | Способ получения производных диаминопиримидина и их промежуточные соединения | |
| CN106795159A (zh) | 一种周期素依赖性蛋白激酶抑制剂的结晶形式及其制备方法 | |
| US9085607B2 (en) | ACH-0142684 sodium salt polymorph, composition including the same, and method of manufacture thereof | |
| WO2019228171A1 (zh) | 一种稠环嘧啶类化合物的盐、晶型及其制备方法和应用 | |
| TWI820182B (zh) | 四氫哌喃基胺基－吡咯并嘧啶酮化合物的固體形式 | |
| CN106065016B (zh) | 一种周期素依赖性蛋白激酶抑制剂的结晶形式及其制备方法 | |
| CN109153652A (zh) | 1-(芳基甲基)喹唑啉-2,4(1h,3h)-二酮的制备工艺 | |
| CN105906553B (zh) | 一种n-苄基-4-甲基哌啶-3-酮盐酸盐的合成方法 | |
| CN105294698A (zh) | N-甲基-n-((3r,4r)-4-甲基-1-苄基-3-哌啶基)-7h-吡咯并[2,3-d]嘧啶-4-胺的一种结晶形式 | |
| CN106397407A (zh) | 新型抗肿瘤药物azd9291衍生物及其制备方法和应用 | |
| EP3004104A1 (en) | Crystalline form of n,n-dicyclopropyl-4-(1,5-dimethyl-1 h-pyrazol-3-ylamino)-6-ethyl-1 -methyl-1,6-dihyrdroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders | |
| CN105037341A (zh) | 阿齐沙坦醇铵晶型及其制备方法 | |
| JP7710449B2 (ja) | 複素環化合物およびその製造方法と使用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20160511 |
|
| WD01 | Invention patent application deemed withdrawn after publication |