WO2017101777A1 - 吡咯并嘧啶化合物的盐 - Google Patents

吡咯并嘧啶化合物的盐 Download PDF

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WO2017101777A1
WO2017101777A1 PCT/CN2016/109835 CN2016109835W WO2017101777A1 WO 2017101777 A1 WO2017101777 A1 WO 2017101777A1 CN 2016109835 W CN2016109835 W CN 2016109835W WO 2017101777 A1 WO2017101777 A1 WO 2017101777A1
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compound
formula
hydrochloride salt
hydrochloride
pharmaceutical composition
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PCT/CN2016/109835
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English (en)
French (fr)
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祝力
戴丽光
韩永信
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北京赛林泰医药技术有限公司
正大天晴药业集团股份有限公司
连云港润众制药有限公司
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Priority to CN201680072397.2A priority Critical patent/CN108368115B/zh
Publication of WO2017101777A1 publication Critical patent/WO2017101777A1/zh

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    • 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
    • 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

Definitions

  • the present application belongs to the field of medicinal chemistry, in particular, the present application relates to (3R)-3-[3-amino-4-(7H-pyrrole[2,3-d]pyrimidin-4-yl)-1H-pyrazole- A hydrochloride salt of 1-yl]-3-cyclopentylpropionitrile, a process for preparing the hydrochloride salt, a pharmaceutical composition comprising the hydrochloride salt, and a pharmaceutical use of the hydrochloride salt.
  • Protein kinases also known as protein phosphakinase, are a class of enzymes that catalyze the phosphorylation of proteins.
  • a subgroup of oncoprotein kinases of protein kinases can cause tumor formation and growth when dysregulated, and further lead to tumor metastasis and progression.
  • oncogenic protein kinases are one of the most important targets for the treatment of cancer diseases.
  • Protein kinases can be divided into receptor type and non-receptor type.
  • Janus kinase is a type of non-receptor tyrosine kinase (PTK) that is present in cells and transmits cytokine stimulation signals through the JAK-STAT pathway.
  • the JAK-STAT pathway transmits extracellular chemical signals through the cell membrane into the gene promoter located on the DNA in the nucleus, ultimately affecting the changes in DNA transcription and activity levels in the cell.
  • the JAK family plays a role in cell proliferation and functional cytokine-dependent regulation involving immune responses.
  • the present application provides the hydrochloride salt of a compound of Formula I.
  • the application provides a hydrochloride salt of a compound of formula I:
  • the application provides a pharmaceutical composition comprising the hydrochloride salt of a compound of formula I.
  • the application provides the use of a hydrochloride salt of a compound of formula I for the manufacture of a medicament for the treatment of a dihedral kinase mediated disease.
  • the application provides a method for treating a disease mediated by diphtheria kinase, the method comprising administering to a patient a therapeutically effective amount of a hydrochloride salt of a compound of formula I.
  • the application provides a hydrochloride salt of a compound of formula I for use in the treatment of a dihedral kinase mediated disease, and the above pharmaceutical composition.
  • the application provides a hydrochloride salt of a compound of formula I:
  • the ratio of the amount of the compound of formula I to the amount of HCl in the hydrochloride salt of the compound of formula I is from 1:0.5 to 3, preferably 1:1.
  • the hydrochloride salt of the compound of formula I described herein may exist in a variety of solid forms, may exist as an amorphous form, or may exist as a crystalline form, the amorphous or crystalline form being not limited to one, A variety of forms of amorphous and crystalline forms can be included.
  • the amorphous or crystalline form can be characterized by powder X-ray diffraction (XRD), Raman spectroscopy, differential scanning calorimetry (DSC) or thermogravimetric analysis (TGA).
  • hydrochloride salt of the compound of formula I described herein may exist in unsolvated as well as solvated forms, including hydrated forms.
  • the present application also provides a process for the preparation of the hydrochloride salt of the compound of formula I which comprises precipitating the hydrochloride salt of the compound of formula I from a solvent such as acetonitrile.
  • the preparation of the hydrochloride salt of the compound of formula I described herein can be prepared by known techniques. For example, by contacting the free base compound with an acid containing an anion of the desired salt form in solution, the salt product is then separated from the reaction solution. Salts described herein can also be obtained using other salt preparation techniques.
  • the application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a hydrochloride salt of a compound of formula I, which comprises a therapeutically effective amount of the hydrochloride salt of a compound of formula I.
  • the pharmaceutical compositions may or may not contain pharmaceutically acceptable carriers, excipients and/or vehicles.
  • compositions of the present invention comprising the hydrochloride salt of the compound of formula I may be administered by typical routes including, but not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, Sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • compositions comprising a hydrochloride salt of a compound of formula I as described herein can be carried out by any acceptable mode of administration that provides a similarly useful agent.
  • the pharmaceutical composition of the present application can be obtained by administering the hydrochloride of the compound of formula I of the present application.
  • the salts are prepared in combination with a suitable pharmaceutically acceptable carrier, diluent or excipient and can be formulated into solid, semi-solid, liquid or gaseous preparations such as tablets, pills, capsules, powders, granules, Ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, and the like.
  • the application provides the use of a hydrochloride salt of a compound of formula I for the manufacture of a medicament for the treatment of a dihedral kinase mediated disease.
  • the application provides a method for treating a disease mediated by diphtheria kinase, the method comprising administering to a patient a therapeutically effective amount of a hydrochloride salt of a compound of formula I.
  • the application provides a hydrochloride salt of the compound of formula I or a pharmaceutical composition as described above for use in the treatment of a dihedral kinase mediated disease.
  • the two-faced kinases mediated by the present application include, but are not limited to, tumors (eg, lymphoma, leukemia).
  • Lymphomas as described herein may include, but are not limited to, Hodgkins disease or Non-Hodgkins leukemia, including but not limited to B-cell lymphocytes B-celllymphoma or T-cell lymphoma.
  • Leukemias as described herein include, but are not limited to, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, and chronic myelocytic leukemia.
  • the therapeutic dose of the hydrochloride salt of the compound of formula I described herein can be determined, for example, according to the particular use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the pharmaceutical compositions of the present invention comprising the hydrochloride salt of the compound of Formula I may not be fixed, depending on a variety of factors including dosage, chemical characteristics (e.g., hydrophobicity) and route of administration.
  • the compound of the present application can be provided for parenteral administration by a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound.
  • Some typical dosages range from about 1 [mu]g/kg to about 1 g/kg body weight per day. In certain embodiments, the dosage ranges from about 0.01 mg/kg to about 100 mg/kg body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or condition, the general state of health of the particular patient, the relative biological effectiveness of the selected compound, the excipient formulation, and the route of administration thereof.
  • An effective dose can be obtained by extrapolation from a dose-response curve derived from an in vitro or animal model test system.
  • patient refers to any animal, including a mammal, preferably a mouse, rat, other rodent, rabbit, dog, cat, pig, cow, sheep, horse, or primate. Most preferred is a person.
  • Treatment as described herein may be the effect of modulating activity upon contact with JAK based on the hydrochloride salt of a compound of formula I as described herein.
  • modulate is meant the ability to increase or decrease the activity of one or more members of the JAK family.
  • the treatment includes, but is not limited to, one or more of the following:
  • Prevention of disease for example, prevention of a disease, disorder or condition in an individual who is susceptible to a disease, disorder or condition but has not experienced or developed a pathology or symptom of the disease;
  • inhibiting a disease for example, inhibiting a disease, disorder or condition (ie preventing further progression of pathology and/or symptoms) in an individual who is experiencing or developing a pathology or symptom of a disease, disorder or condition;
  • Relieving a disease for example, alleviating a disease, disorder, or condition (ie, reversing pathology and/or symptoms) in an individual who is experiencing or developing a pathology or symptom of a disease, disorder, or condition.
  • an effective amount or “therapeutically effective amount” refers to an active compound that causes a biological or medical response to be sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, individual, or human. The amount of the drug.
  • hydrochloride salt of the compound of the formula I described herein exhibits excellent stability, pharmacokinetic properties and pharmacodynamic properties, and is easy to prepare, and can be used for the preparation of a medicament for treating a disease mediated by diphtheria kinase.
  • the stability of the hydrochloride salt of the compound of formula I described herein can be determined according to the "Guidelines for the Stability Test of APIs and Pharmaceutical Preparations", and the hydrochloride salt of the compound of formula I of the present application is examined under accelerated test conditions. Stability.
  • the hydrochloride salt of the compound of Formula I prepared herein is placed in a light environment (eg, 5000 Lx ⁇ 500 Lx), a high temperature environment (eg, 60 ° C ⁇ 2 ° C), and a high humidity environment (eg, 75%). Stability tests were carried out under RH ⁇ 5% RH), and samples were taken on days 5, 10, and 30, respectively. The appearance traits, moisture content, and total impurities of the samples were compared with the initial data.
  • the pharmacokinetic properties of the hydrochloride salt of the compound of formula I described herein can be determined by animal experiments (e.g., rats, dogs). By administering, for example, by oral or injection, blood is collected at the time of design after administration, and blood samples are analyzed for blood samples and pharmacokinetic parameters are calculated to obtain property results.
  • the pharmacodynamic properties of the hydrochloride salt of the compound of formula I described herein can be determined by in vitro enzymatic activity assays, cell viability assays or animal experiments.
  • the tumor volume was randomly divided into small groups, and adjusted appropriately so that the average body weight of each group of animals was also at the same level.
  • the 5 groups were negative control group, positive control group, low, medium and high dose groups, 5 mice in each group, and started to be administered on the day of grouping, 2 times a day for 14 days, and the tumor was measured every week. Volume and weight 2 times.
  • the mice were sacrificed, the spleens were isolated and weighed.
  • TGI(%) 100% ⁇ (1-(T t -T 0 )/(V t -V 0 )), T t is the average tumor volume measured per treatment group, T 0 treatment group The mean tumor volume at the time, V t is the average tumor volume measured per control group, and V 0 is the average tumor volume at the time of grouping of the control group.
  • the tumor inhibitory effect of the hydrochloride salt of the compound of Example 1 in the animal was determined in the Ba/F3-JAK2 V617F tumor-bearing mouse model, and it was found that the dose of Ba/F3-JAK2 V617F tumor growth was dosed.
  • the inhibitory effect of dependence and the antitumor effect are very significant.
  • the inhibition rate (TGI) against tumor growth reached 85.8%, while the positive control of the same standard, Ruxolitinib (100 mg/kg).
  • the tumor growth inhibition rate (TGI) was only 64.5%.
  • the tumor suppressing effect of the hydrochloride salt of the compound of Example 1 at 50 mg/kg was also remarkable, and the TGI reached 68.4%, which was comparable to the tumor suppressing effect of the 100 mg/kg positive control product Ruxolitinib, indicating that the hydrochloride salt of the compound of Example 1 has a very remarkable Tumor inhibition and significantly better than Ruxolitinib.
  • Healthy adult female SD rats were obtained from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the rats were divided into two groups, three in each group, and the suspension of the test sample (30 mg/kg) was administered orally by a single oral administration. Animals were fasted overnight before the experiment, and the fasting time was from 10 hours before administration to 4 hours after administration. Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. After anesthesia with a small animal anesthesia machine, 0.4 mL whole blood was taken through the fundus venous plexus and placed in a heparin anticoagulant tube.
  • the sample was centrifuged at 4200 rpm for 5 min at 4 ° C, and the plasma was transferred to a centrifuge tube and placed in -80. °C is saved until analysis. Samples in plasma were extracted using protein precipitation and the extracts were analyzed by LC/MS/MS.
  • PK pharmacokinetics

Abstract

本申请提供了一种吡咯并嘧啶化合物的盐。具体而言，本申请涉及式Ⅰ所示化合物的盐酸盐，该盐酸盐的制备方法、包含该盐酸盐的药物组合物以及该盐酸盐的医药用途。本申请的式Ⅰ所示化合物的盐酸盐有利于开发有效的药物，可用于制备预防或治疗两面神激酶介导的疾病的药物。

Description

吡咯并嘧啶化合物的盐
相关申请的交叉引用
本申请要求于2015年12月15日向中国国家知识产权局提交的第201510932786.5号中国专利申请的优先权和权益，所述专利申请公开的内容通过引用整体并入本文中。
技术领域
本申请属于药物化学领域，具体而言，本申请涉及(3R)-3-[3-氨基-4-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]-3-环戊基丙腈的盐酸盐、所述盐酸盐的制备方法、包含所述盐酸盐的药物组合物以及所述盐酸盐的医药用途。
背景技术
蛋白激酶(Protein kinases，PK)又称蛋白质磷酸化酶(Protein phosphakinase)，是一类催化蛋白质磷酸化反应的酶。蛋白激酶的一个亚组致癌蛋白激酶在失调时可引起肿瘤的形成和生长，并进一步导致肿瘤转移和发展。迄今，致癌蛋白激酶是癌症疾病治疗最重要的靶标之一。
蛋白激酶可分为受体型和非受体型。两面神激酶(Janus kinase，JAK)是一类非受体型酪氨酸激酶(PTK)，其存在于细胞内，通过JAK-STAT通路传导细胞因子刺激信号。JAK-STAT通路将细胞外的化学信号经细胞膜传导入位于细胞核内DNA上的基因启动子上，最终影响细胞中DNA转录与活性水平发生改变。JAK家族在涉及免疫应答的细胞增殖和功能性细胞因子依赖性调节中产生作用。
目前，已有多种两面神激酶的抑制剂的报道，其中申请日为2014年12月16日、申请号为201410784461.2的中国专利申请中公开了多个JAK抑制剂(该专利申请通过引用全文并入本文中)，包括如下式I所示的(3R)-3-[3-氨基-4-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]-3-环戊基丙腈化合物：
Figure PCTCN2016109835-appb-000001
为了提供新的式I所示化合物的改进形式，以更好地开发有效的药物，本申请提供了式I所示化合物的盐酸盐。
发明概述
本申请一方面提供了式Ⅰ所示化合物的盐酸盐：
Figure PCTCN2016109835-appb-000002
另一方面，本申请提供了一种药物组合物，其包含式Ⅰ所示化合物的盐酸盐。
再一方面，本申请提供了式Ⅰ所示化合物的盐酸盐在制备治疗两面神激酶介导的疾病的药物中的用途。
又一方面，本申请提供了一种用于治疗两面神激酶介导的疾病的方法，所述方法包括给予患者治疗有效量的式Ⅰ所示化合物的盐酸盐。
再一方面，本申请提供了用于治疗两面神激酶介导的疾病的式Ⅰ所示化合物的盐酸盐以及上述药物组合物。
发明详述
本申请一方面提供了式Ⅰ所示化合物的盐酸盐：
Figure PCTCN2016109835-appb-000003
在本申请的某些实施方案中，式Ⅰ所示化合物的盐酸盐中式Ⅰ所示化合物与HCl的物质的量之比为1:0.5～3，优选为1:1。
本申请所述的式Ⅰ所示化合物的盐酸盐可以以多种固体形式存在，可以作为无定形形式存在，也可以作为晶型形式存在，所述无定形或晶型不局限于一种，可以包括多种形式的无定形和晶型。所述无定形或晶型可以通过粉末X-射线衍射(XRD)、拉曼光谱、差示扫描量热法(DSC)或热重分析(TGA)等方式进行表征。
本申请所述的式Ⅰ所示化合物的盐酸盐可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。
本申请还提供了所述式Ⅰ所示化合物的盐酸盐的制备方法，该方法包括使式Ⅰ所示化合物的盐酸盐从溶剂(例如，乙腈)中析出。
本申请所述的式Ⅰ所示化合物的盐酸盐的制备方法可用已知技术制备得到。例如，通过在溶液中，使游离碱化合物与含有所需盐形式的阴离子的酸接触，然后从反应溶液中分离盐产物。也可以用其他的盐制备技术得到本申请所述的盐。
另一方面，本申请提供了包含式Ⅰ所示化合物的盐酸盐的药物组合物，该药物组合物中包含治疗有效量的式Ⅰ所示化合物的盐酸盐。此外，该药物组合物还可以含有或不含有药学上可接受的载体、赋形剂和/或介质。
本申请所述的包含式Ⅰ所示化合物的盐酸盐的药物组合物可以通过典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。
本申请所述的包含式Ⅰ所示化合物的盐酸盐的药物组合物可通过提供类似用途的药剂的任何可接受给药模式来进行。本申请的药物组合物可通过将本申请的式Ⅰ所示化合物的盐酸 盐与适宜的药学上可接受的载剂、稀释剂或赋形剂组合而制备，且可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等等。
再一方面，本申请提供了式Ⅰ所示化合物的盐酸盐在制备治疗两面神激酶介导的疾病的药物中的用途。
又一方面，本申请提供了一种用于治疗两面神激酶介导的疾病的方法，所述方法包括给予患者治疗有效量的式Ⅰ所示化合物的盐酸盐。
再一方面，本申请提供了用于治疗两面神激酶介导的疾病的式Ⅰ所示化合物的盐酸盐或上述药物组合物。
本申请所述的两面神激酶介导的疾病包括但不限于肿瘤(例如，淋巴瘤、白血病)。本申请所述的淋巴瘤可以包括但不限于霍奇金病(Hodgkins disease)或非霍奇金淋巴瘤(Non-Hodgkins leukemia)，所述非霍奇金淋巴瘤包括但不限于B-细胞淋巴瘤(B-celllymphoma)或T-细胞淋巴瘤(T-cell lymphoma)。本申请所述的白血病包括但不限于急性淋巴细胞白血病(Acute lymphoblastic leukemia)、慢性淋巴细胞白血病(Chronic lymphocyticleukemia)、急性粒细胞白血病(Acute myeloid leukemia)、慢性粒细胞白血病(Chronic myelocytic leukemia)。
本申请所述的式Ⅰ所示化合物的盐酸盐的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本申请所述的包含式Ⅰ所示化合物的盐酸盐的药物组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供本申请化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验***导出的剂量-反应曲线外推，得到有效剂量。
本申请所述的“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。
本申请所述的“治疗”可以是基于本申请所述的式Ⅰ所示化合物的盐酸盐与JAK接触后调节活性产生的作用。所述“调节”意指提高或降低JAK家族的一种或多种成员的活性的能力。所述治疗包括但不仅限于以下一项或多项：
(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症；
(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)；
(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。
本申请所述的“有效量”或“治疗有效量”是指研究人员、兽医、医师或其它临床医师正在组织、***、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量。
本申请所述的式Ⅰ所示化合物的盐酸盐展现出优良的稳定性、药代动力学性质和药效学性质，同时易于制备，可用于制备治疗两面神激酶介导的疾病的药物。
本申请所述的式Ⅰ所示化合物的盐酸盐的稳定性可以依据《原料药与药物制剂稳定性试验指导原则》，考察本申请的式Ⅰ所示化合物的盐酸盐在加速试验条件下的稳定性。例如但不限于，将本申请制得的式Ⅰ所示化合物的盐酸盐分别置于光照环境(例如5000Lx±500Lx)、高温环境(例如60℃±2℃)和高湿环境(例如75％RH±5％RH)下进行稳定性测试，分别于第5天、第10天和第30天取样，所取样品记录外观性状、水分含量、相关物质总杂与初始数据比较。
本申请所述的式Ⅰ所示化合物的盐酸盐的药代动力学性质可以通过动物实验(例如大鼠、狗)测定。通过采用例如口服或注射的方式给药，给药后于设计的时间点采血，对血液样本检测分析血药浓度并计算药代动力学参数以得到性质结果。
本申请所述的式Ⅰ所示化合物的盐酸盐的药效学性质可以通过体外酶学活性实验、细胞活性实验或动物实验测定。
具体实施方式
为了更好地理解本申请的内容，下面结合具体实施例来做进一步的说明，但具体的实施方式并不是对本申请的内容所做的限制。
实施例1(3R)-3-[3-氨基-4-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]-3-环戊基丙腈盐酸盐
Figure PCTCN2016109835-appb-000004
室温下，浓盐酸(12M，0.52mL，6.223mmol，1.0eq.)滴加到(3R)-3-[3-氨基-4-(7H-吡咯[2,3-d]嘧啶-4-基)-1H-吡唑-1-基]-3-环戊基丙腈(2.0g，6.223mmol，1.0eq.)的乙腈溶液中。反应液60℃搅拌1小时直到溶液澄清，室温下搅拌冷却析出固体。减压浓缩，再加入二氯甲烷，浓缩两次，得深黄色固体粗品2.3g。向粗品中加入乙酸乙酯12mL，60℃加热下搅拌1小时，冷却至室温搅拌，浅黄色絮状固体过滤，乙酸乙酯洗涤，抽干，得浅黄色固体(2.2g，收率99.6％，纯度99.82％，ee值大于99.0％)。m/z＝322[M+1]+。1H NMR(400MHz,DMSO-d6)δ12.35(s,1H),8.71(s,1H),8.69(s,1H),7.64(s,1H),6.98(s,1H),4.27-4.33(m,1H),4.40(brs,3H),3.14(d,J＝7.2Hz,2H),2.32-2.38(m,1H),1.75-1.83(m,1H),1.41-1.67(m,4H),1.17-1.37(m,3H)。
生物活性实验
在小鼠皮下异种移植瘤模型中有效性的测定
SPF级Balb/c裸鼠，雌性，5-6周龄。将无血清培养基混悬的Ba/F3-JAK2V617F细胞悬液0.1mL(含1×107cells，50％MatriGel)皮下注射于每只小鼠右侧面。待平均肿瘤体积达到约500mm3时，处死荷瘤鼠，无菌摘取肿瘤组织，剪成小块，植入Balb/c裸鼠左右两侧皮下，待平均肿瘤体积达到约100mm3时，将各鼠按流水号标记，分别测量其肿瘤大小及体重，按肿瘤体积从小到大随机分组，并适当调整使各组动物的平均体重亦处于同一水平。5组分别为阴性对照组、阳性对照组、低、中及高剂量组，每组5只小鼠，分组当天开始给药，每天给药2次，连续给药14天，期间每周测量肿瘤体积及体重2次。实验结束时处死小鼠，分离脾脏并称重。
试验过程中测量肿瘤最长径(L)和垂直方向的最大横径(W)，计算肿瘤体积(V)，V(mm3)＝L×W2/2。肿瘤生长抑制率TGI(％)＝100％×(1-(Tt-T0)/(Vt-V0))，Tt为治疗组每次测量的平均肿瘤体积，T0治疗组分组时的平均肿瘤体积，Vt为对照组每次测量的平均肿瘤体积，V0为对照组分组时的平均肿瘤体积。
结果如下表所示：
Figure PCTCN2016109835-appb-000005
PO：口服；BID：每天两次。
由表中数据可见，在Ba/F3-JAK2V617F荷瘤小鼠模型中，测定了实施例1化合物盐酸盐在动物体内的肿瘤抑制效果，发现其对Ba/F3-JAK2V617F肿瘤生长呈现剂量依赖性的抑制作用，抑瘤效果非常显著。口服每天两次给药实施例1化合物盐酸盐(100mg/kg)14天之后，对肿瘤生长的抑制率(TGI)达到85.8％，而同等条件下的阳性对照品Ruxolitinib(100mg/kg)对肿瘤生长的抑制率(TGI)仅为64.5％。50mg/kg的实施例1化合物盐酸盐肿瘤抑制效果也很明显，TGI达到68.4％，与100mg/kg的阳性对照品Ruxolitinib的肿瘤抑制效果相当，说明实施例1化合物盐酸盐具有非常显著的肿瘤抑制作用且明显优于Ruxolitinib。
药代动力学实验
成年雌性SD大鼠中药代动力学的测定
健康成年雌性SD大鼠来源于北京维通利华实验动物技术有限公司，将大鼠分2组，每组3只，分别口服单次灌胃给予待测样品混悬液(30mg/kg)。动物在实验前禁食过夜，禁食时间从给药前10小时至给药后4小时。给药后0.25、0.5、1、2、4、6、8、和24小时采血。使用小动物麻醉机经异氟烷麻醉后通过眼底静脉丛采取0.4mL全血，放于肝素抗凝管中，样品于4℃、4200rpm离心5min，血浆转移至离心管中，并放于-80℃保存直到分析。血浆中样品使用蛋白质沉淀法萃取，萃取液通过LC/MS/MS分析。
Figure PCTCN2016109835-appb-000006
附注：a.数据来自于美国食品药品监督管理局FDA公开的药理学综述。
大鼠(30mg/kg PO)的药代动力学(PK)显示，实施例1化合物盐酸盐的数据优于Ruxolitinib。

Claims (13)

  1. 式Ⅰ所示化合物的盐酸盐：
    Figure PCTCN2016109835-appb-100001
  2. 如权利要求1所述的式Ⅰ所示化合物的盐酸盐，其中式Ⅰ所示化合物与HCl的物质的量之比为1:0.5～3。
  3. 如权利要求2所述的式Ⅰ所示化合物的盐酸盐，其中式Ⅰ所示化合物与HCl的物质的量之比为1:1。
  4. 一种药物组合物，其包含权利要求1-3中任一项所述的式Ⅰ所示化合物的盐酸盐。
  5. 权利要求1-3中任一项所述的式Ⅰ所示化合物的盐酸盐在制备治疗两面神激酶介导的疾病的药物中的用途。
  6. 一种用于治疗两面神激酶介导的疾病的方法，包括给予患者治疗有效量的权利要求1-3中任一项所述的式Ⅰ所示化合物的盐酸盐。
  7. 用于治疗两面神激酶介导的疾病的权利要求1-3中任一项所述的式I所示化合物的盐酸盐。
  8. 用于治疗两面神激酶介导的疾病的权利要求4所述的药物组合物。
  9. 如权利要求5所述的用途，如权利要求6所述的方法，如权利要求7所述的盐酸盐或如权利要求8所述的药物组合物，其中所述两面神激酶介导的疾病为肿瘤。
  10. 如权利要求9所述的用途、方法、盐酸盐或药物组合物，其中所述肿瘤选自淋巴瘤或白血病。
  11. 如权利要求10所述的用途、方法、盐酸盐或药物组合物，其中所述淋巴瘤选自霍奇金病或非霍奇金淋巴瘤。
  12. 如权利要求11所述的用途、方法、盐酸盐或药物组合物，其中所述非霍奇金淋巴瘤选自 B-细胞淋巴瘤或T-细胞淋巴瘤。
  13. 如权利要求10所述的用途、方法、盐酸盐或药物组合物，其中所述白血病选自急性淋巴细胞白血病、慢性淋巴细胞白血病、急性粒细胞白血病或慢性粒细胞白血病。
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WO2021180093A1 (zh) * 2020-03-09 2021-09-16 正大天晴药业集团股份有限公司 吡咯并嘧啶化合物的治疗噬血细胞综合征的用途
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WO2020135401A1 (zh) 2018-12-24 2020-07-02 正大天晴药业集团股份有限公司 吡咯并嘧啶化合物的治疗用途及其固体药物组合物
CN113242859A (zh) * 2018-12-24 2021-08-10 正大天晴药业集团股份有限公司 吡咯并嘧啶化合物的治疗用途及其固体药物组合物
RU2810112C2 (ru) * 2018-12-24 2023-12-21 Чиа Тай Тянцин Фармасьютикал Груп Ко., Лтд. Лечебное применение пирролопиримидинового соединения и твердая фармацевтическая композиция пирролопиримидинового соединения
WO2021180093A1 (zh) * 2020-03-09 2021-09-16 正大天晴药业集团股份有限公司 吡咯并嘧啶化合物的治疗噬血细胞综合征的用途
CN114981272A (zh) * 2020-03-09 2022-08-30 正大天晴药业集团股份有限公司 吡咯并嘧啶化合物的治疗噬血细胞综合征的用途
WO2022268083A1 (zh) * 2021-06-21 2022-12-29 正大天晴药业集团股份有限公司 吡咯并嘧啶化合物及其药物组合物治疗慢性移植物抗宿主病的用途
WO2023179547A1 (zh) * 2022-03-21 2023-09-28 正大天晴药业集团股份有限公司 吡咯并嘧啶化合物治疗中高危骨髓纤维化的用途

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