WO2020143593A1 - 双环取代吡唑酮偶氮类衍生物的给药方案 - Google Patents

双环取代吡唑酮偶氮类衍生物的给药方案 Download PDF

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WO2020143593A1
WO2020143593A1 PCT/CN2020/070579 CN2020070579W WO2020143593A1 WO 2020143593 A1 WO2020143593 A1 WO 2020143593A1 CN 2020070579 W CN2020070579 W CN 2020070579W WO 2020143593 A1 WO2020143593 A1 WO 2020143593A1
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salt
administration
formula
pharmaceutically acceptable
compound
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沈艳聪
阳国平
黄洁
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Jiangsu Hengrui Medicine Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
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Priority to AU2020206903A priority Critical patent/AU2020206903A1/en
Priority to JP2021539651A priority patent/JP2022517211A/ja
Priority to US17/420,791 priority patent/US20220071961A1/en
Priority to EP20738156.7A priority patent/EP3909645A4/en
Priority to CN202080007449.4A priority patent/CN113226463A/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

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  • the present disclosure belongs to the field of medicine and relates to the administration scheme of bicyclic substituted pyrazolone azo derivatives.
  • Thrombopoietin also known as megakaryocyte growth and development factor (MGDF)
  • MGDF megakaryocyte growth and development factor
  • Platelets are necessary for blood coagulation. When its number is very low, the patient is at risk of bleeding and death. Therefore, TPO has been used to treat a variety of blood diseases.
  • CN101679286A discloses a series of bicyclic substituted pyrazolone azo derivatives.
  • the preferred compound is represented by formula I, which is a thrombopoietin (TPO) receptor agonist, which can increase platelet production and is used to treat various blood diseases, such as diseases caused by platelet defects. It can also be used for the treatment of thrombocytopenia, especially in the treatment of cancer and lymphoma, which results in thrombocytopenia during chemotherapy, radiotherapy and bone marrow transplantation.
  • TPO thrombopoietin
  • CN102159217A discloses pharmaceutically acceptable salts of compounds of formula I.
  • the present disclosure provides an improved dosing scheme for bicyclic substituted pyrazolone azo derivatives, which enhances the therapeutic effect of drugs.
  • the present disclosure provides a method for treating a disease, comprising administering to a patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the interval between administration and eating is at least 2 hours, preferably at least 2 hours before a meal Administration.
  • the disease is selected from one or more of thrombocytopenia, thrombocytopenic purpura, and anemia.
  • the thrombocytopenia is selected from chemotherapy-induced thrombocytopenia or immune thrombocytopenia.
  • Thrombocytopenia caused by chemotherapy is preferably thrombocytopenia caused by chemotherapy of malignant tumors.
  • the immune thrombocytopenia is preferably primary immune thrombocytopenia, and may be, for example, chronic primary immune thrombocytopenia.
  • the anemia is preferably aplastic anemia, and more preferably severe aplastic anemia.
  • the thrombocytopenic purpura is preferably idiopathic thrombocytopenic purpura, for example, it may be chronic idiopathic thrombocytopenic purpura.
  • Another aspect of the present disclosure provides a method for enhancing platelet production, comprising administering to a patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the interval between administration and eating is at least 2 hours, preferably at least before a meal Dosing for 2 hours.
  • Another aspect of the present disclosure provides a method of agonizing a TPO receptor, comprising administering to a patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the interval between administration and eating is at least 2 hours, preferably at least a meal Dosing for the first 2 hours.
  • the interval of at least 2 hours between administration and eating in the present disclosure means that the compound of formula I or a pharmaceutically acceptable salt thereof is administered at least 2 hours before a meal or at least 2 hours after a meal.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is administered 2 hours before a meal or 2 hours after a meal.
  • the dosage range of the compound of Formula I or a pharmaceutically acceptable salt thereof according to the present disclosure is selected from 1-20 mg, for example, it can be 2.5 mg, 3.75 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15mg.
  • the compound of formula I or its pharmaceutically acceptable salt of the present disclosure is administered once a day, once a day, twice a day, or three times a day.
  • the dosage of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 2.5 mg, 3.75 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg, and the frequency of administration is once a day.
  • the pharmaceutically acceptable salts of the drugs described in this disclosure can be sodium, lithium, potassium, calcium, magnesium, arginine, lysine, methylamine, dimethylamine, trimethylamine, Ethylamine salt, diethylamine salt, triethylamine salt, ethanolamine salt, piperazine salt, dibenzylethylenediamine salt, meglumine, tromethamine salt, tetramethyl quaternary ammonium salt, tetraethyl quaternary
  • the ammonium salt or choline salt is preferably a diethylamine salt, ethanolamine salt, choline salt, piperazine salt, meglumine salt or tromethamine salt, more preferably an ethanolamine salt, and most preferably a diethanolamine salt.
  • the route of administration of the drug described in the present disclosure may be oral administration, parenteral administration, and transdermal administration.
  • the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection.
  • the patient described in this disclosure is a human.
  • the administration optionally further includes other components, including but not limited to colony stimulating factors, cytokines, chemokines, interleukins or cytokine receptors Agonists or antagonists, soluble receptors, receptor agonist or antagonist antibodies, or one or more peptides or small molecules with the same mechanism of action as the drug.
  • other components including but not limited to colony stimulating factors, cytokines, chemokines, interleukins or cytokine receptors Agonists or antagonists, soluble receptors, receptor agonist or antagonist antibodies, or one or more peptides or small molecules with the same mechanism of action as the drug.
  • the present disclosure avoids the influence of food on treatment by ensuring a long time interval between administration and eating, and ensures the therapeutic effect of the medicine.
  • FIG. 1 is a time curve of the average blood concentration of the compound of formula I in the plasma of the subject after oral administration of the compound of formula I with ethanolamine tablets;
  • FIG. 2 is a time curve of the median blood drug concentration of the compound of formula I.
  • Example 1 Study on the effects of different administration and feeding intervals on the pharmacokinetic parameters of the compound of formula I
  • the diethanolamine salt tablet of the compound represented by formula I has a specification of 2.5 mg/tablet and 5 mg/tablet.
  • Group A A single oral fasting test preparation (T1, 2.5 mg/tablet; T2, 5 mg/tablet) was taken on the morning of the test, and 240 mL of room temperature water was taken. Do not eat breakfast after administration. Drinking water is prohibited before and within 1 hour after taking the medicine, and water can be consumed as needed during the rest of the time.
  • Group B A single oral fasting test preparation (T1, 2.5 mg/tablet; T2, 5 mg/tablet) was taken on the morning of the test, and 240 mL of room temperature water was taken. Eat a high-fat, high-calorie standard meal 1 hour after administration, stagger the time of blood sample collection when eating breakfast, and breakfast should be finished within 30 minutes. Drinking water is prohibited before and within 1 hour after taking the medicine, and water can be consumed as needed during the rest of the time.
  • Group C A single oral fasting test preparation (T1, 2.5 mg/tablet; T2, 5 mg/tablet) was taken on the morning of the test day, and 240 mL of room temperature water was taken. Eat a high-fat, high-calorie standard meal 2 hours after administration, stagger the time of blood sample collection when eating breakfast, and breakfast should be finished within 30 minutes. Drinking water is prohibited before and within 1 hour after taking the medicine, and water can be consumed as needed during the rest of the time.
  • High-fat meal calories 800-1000kcal, composed of 150kcal protein, 250kcal carbohydrates and 500-600kcal fat, of which about 50% of the calories come from fat, each test cycle should ensure that the standard meal formula is consistent and the ratio must be consistent. See the table below for the order of administration. By collecting blood and measuring vital signs before and at a fixed time after dosing, the effect of food on the drug was analyzed.
  • T max median of 7.00h
  • T max median of 2.00h
  • group C (2h after administration Eating high-fat and high-calorie standard meals)
  • the median value of T max is 5.01h, which indicates that the peak time of the compound of formula I is advanced after eating, and the shorter the interval between eating, the more obvious this advancement trend is.
  • the average C max A group of 39.2461ng / mL, the mean C max group B and group C are 21.0785ng / mL and 28.5985ng / mL; mean AUC 0-t A group of 1040.5777h * ng / mL, B
  • the average AUC 0-t of group A and group C were 314.2101h*ng/mL and 546.7709h*ng/mL, the average AUC 0- ⁇ of group A was 1110.4290h*ng/mL, and the average AUC of group B and group C 0- ⁇ were 347.0549h*ng/mL and 590.9489h*ng/mL, respectively, indicating that food reduced the absorption of the compound represented by formula I, and this change tended to be more obvious as the time between administration and feeding shortened.
  • the average CL/F of group A was 10.4506L/h
  • the average CL/F of groups B and C were 52.4396L/h and 42.1126L/h, respectively
  • the average t 1/2 of group A was 29.26h
  • B The average t 1/2 of group C and group C were 13.09h and 18.58h respectively, which indicated that eating accelerated the elimination of the compound represented by formula I, and this change tended to increase with the shortening of the interval between meals.
  • GeoLSM is the geometric mean square method.

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Abstract

一种双环取代吡唑酮偶氮类衍生物的给药方案。具体涉及一种疾病的治疗方法，包括给予患者有效量的式I所示化合物或其可药用盐，其中，给药与进食的间隔为至少2小时。

Description

双环取代吡唑酮偶氮类衍生物的给药方案
本申请要求申请日为2019年1月8日的中国专利申请CN201910016024.9的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开属于医药领域，涉及双环取代吡唑酮偶氮类衍生物的给药方案。
背景技术
血小板生成素(Thrombopoietin，TPO)，又称为巨核细胞生长发育因子(megakaryocyte growth and development factor，MGDF)，是一种332-氨基酸糖基化多肽，在调节巨核细胞生成和由骨髓巨核细胞产生血小板的过程中起着关键的作用(Kuter et al.，Proc.Nat.Acad.Sci.USA 91：11104-11108(1994)；Barley et al.，Cell 77：1117-1124(1994)；Kaushansky et al.，Nature369：568-571(1994)；Wendling et al.，Nature 369：571-574(1994)；and Sauvageet al.，Nature 369：533-538(1994))。
血小板是血液凝固必需的，当它的数量非常低时，病人就有出血死亡的危险。因此，TPO已经被用于治疗多种血液疾病。
CN101679286A公开了一系列双环取代吡唑酮偶氮类衍生物。其中，优选的化合物如式I所示，其为一种血小板生成素(TPO)受体激动剂，能增加血小板产生，用于治疗多种血液疾病，如由血小板缺陷引起的疾病。同时也可以用于治疗血小板减少症，尤其是在治疗癌症和淋巴瘤而进行化疗、放疗和骨髓移植过程中导致血小板减少的情况。CN102159217A公开了式I所示化合物的可药用盐。
Figure PCTCN2020070579-appb-000001
本公开提供了一种改进的双环取代吡唑酮偶氮类衍生物的给药方案，该方案增强药物的治疗效果。
发明内容
本公开一方面提供了一种疾病的治疗方法，包括给予患者有效量的式I所示化合物或其可药用盐，其中，给药与进食的间隔为至少2小时，优选至少餐前2小时给药。
在某些实施方式中，所述的疾病选自血小板减少症、血小板减少性紫癜和贫血中的一种或多种。
在某些实施方式中，所述的血小板减少症选自化疗所致的血小板减少症或免疫性血小板减少症。化疗所致的血小板减少症优选恶性肿瘤化疗所致的血小板减少症。免疫性血小板减少症优选原发免疫性血小板减少症，例如可以是慢性原发免疫性血小板减少症。
在某些实施方式中，所述的贫血优选再生障碍性贫血，更优选重型再生障碍性贫血。
在某些实施方式中，所述的血小板减少性紫癜优选特发性血小板减少性紫癜，例如可以是慢性特发性血小板减少性紫癜。
本公开另一方面提供了一种增强血小板生成的方法，包括给予患者有效量的式I所示化合物或其可药用盐，其中，给药与进食的间隔为至少2小时，优选至少餐前2小时给药。
本公开另一方面提供了一种激动TPO受体的方法，包括给予患者有效量的式I所示化合物或其可药用盐，其中，给药与进食的间隔为至少2小时，优选至少餐前2小时给药。
本公开所述的给药与进食的间隔至少2小时是指，在餐前至少2小时或餐后至少2小时给予式I所示化合物或其可药用盐。例如，在餐前2小时或餐后2小时给予式I所示化合物或其可药用盐。
在某些实施方式中，本公开所述式I所示化合物或其可药用盐的剂量范围选自1-20mg，例如可以是2.5mg、3.75mg、5mg、7.5mg、10mg、12.5mg、15mg。
在某些实施方式中，本公开所述式I所示化合物或其可药用盐的给药频次为二日一次、一日一次、一日二次、一日三次。
在某些实施方式中，所述式I所示化合物或其可药用盐的剂量选自2.5mg、3.75mg、5mg、7.5mg、10mg、12.5mg、15mg，给药频次为一日一次。
本公开所述药物的可药用盐可以是钠盐、锂盐、钾盐、钙盐、镁盐、精氨酸盐、赖氨酸盐、甲胺盐、二甲胺盐、三甲胺盐、乙胺盐、二乙胺盐、三乙胺盐、乙醇胺盐、哌嗪盐、二苄基乙二胺盐、葡甲胺、氨丁三醇盐、四甲基季铵盐、四乙基季铵盐或胆碱盐，优选为二乙胺盐、乙醇胺盐、胆碱盐、哌嗪盐、葡甲胺盐或氨丁三醇盐，更优选为乙醇胺盐，最优选为二乙醇胺盐。
本公开所述的药物的给药途径可以是经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射。
在某些实施方式中，本公开所述的患者为人。
本公开所述的方案中，所述的给药任选的还包含其他组分，所述其他组分包括但不限于集落刺激因子、细胞因子、趋化因子、白细胞介素或细胞因子受体激动剂或拮抗剂、可溶的受体、受体激动剂或拮抗剂抗体或与一个或多个与所述药物具有相同的作用机理的肽或小分子类物质。
本公开通过将给药与进食间隔较长时间，避免了食物对治疗的影响，保 证了药物的治疗效果。
附图说明
图1为受试者口服式I所示化合物乙醇胺片后血浆中式I所示化合物平均血药浓度时间曲线；
图2为式I所示化合物中位血药浓度时间曲线。
具体实施方式
实施例1：不同给药与进食间隔时间对式I所示化合物的药代动力学参数影响研究
1、试验药物
式I所示化合物的二乙醇胺盐片剂，规格为2.5mg/片，5mg/片。
2、给药方案
本研究入组15例健康成年男性受试者。随机分为三个试验组，对应ABC、BCA、CAB三种给药序列。清洗期为10天。
A组：试验当天早上单次空腹口服受试制剂(T1，2.5mg/片；T2，5mg/片)各一片，240mL常温水送服。给药后不进食早餐。除服药前及服药后1h内禁止饮水，其余时间可按需饮水。
B组：试验当天早上单次空腹口服受试制剂(T1，2.5mg/片；T2，5mg/片)各一片，240mL常温水送服。给药后1h进食高脂高热量标准餐，进食早餐时应错开血样采集时间点，早餐需在30min内吃完。除服药前及服药后1h内禁止饮水，其余时间可按需饮水。
C组：试验当天早上单次空腹口服受试制剂(T1，2.5mg/片；T2，5mg/片)各一片，240mL常温水送服。给药后2h进食高脂高热量标准餐，进食早餐时应错开血样采集时间点，早餐需在30min内吃完。除服药前及服药后1h内禁止饮水，其余时间可按需饮水。
高脂餐：热量800-1000kcal，由150kcal蛋白质、250kcal碳水化合物和500-600kcal脂肪组成，其中约50％的热量来自于脂肪，各试验周期应保证标准餐的配方一致配比须一致。给药顺序详见下表。通过在给药前和给药后固定时间采集血液以及测量生命体征，分析食物对药物的影响。
表1三个试验组的给药顺序
Figure PCTCN2020070579-appb-000002
3、试验结果
本研究分为A组(给药后不进食早餐)、B组(给药后1h进食高脂高热量标准餐)和C组(给药后2h进食高脂高热量标准餐)三个试验组，对应ABC、BCA、CAB三种给药序列。根据实际采样时间使用WinNonlin 7.0版本的非房室模型(NCA)计算PK参数，采用SAS 9.4版本软件对PK参数进行列表和描述性统计。不同给药与进食间隔时间组(A组、B组和C组)中受试者的式I所示化合物的PK参数描述性统计分析结果见表2。
表2式I所示化合物的PK参数汇总表(PK参数分析集)
Figure PCTCN2020070579-appb-000003
Figure PCTCN2020070579-appb-000004
受试者单次口服7.5mg式I所示化合物乙醇胺片后，食物及给药与进食间隔时间长短对PK参数有明显影响。A组(给药后不进食早餐)T max中位值为7.00h；B组(给药后1h进食高脂高热量标准餐)T max中位值为2.00h；C组(给药后2h进食高脂高热量标准餐)T max中位值为5.01h，说明进食后式I所示化 合物的达峰时间提前，且进食间隔时间越短这种提前趋势越明显。A组的平均C max为39.2461ng/mL，B组与C组的平均C max分别为21.0785ng/mL和28.5985ng/mL；A组的平均AUC 0-t为1040.5777h*ng/mL，B组与C组的平均AUC 0-t分别为314.2101h*ng/mL和546.7096h*ng/mL，A组的平均AUC 0-∞为1110.4290h*ng/mL，B组与C组的平均AUC 0-∞分别为347.0549h*ng/mL和590.9489h*ng/mL，说明食物使式I所示化合物的吸收程度降低，且这一变化随着给药进食间隔时间的缩短趋于明显。另外，A组的平均CL/F为10.4506L/h，B组和C组的平均CL/F分别为52.4396L/h和42.1126L/h；A组的平均t 1/2为29.26h，B组和C组的平均t 1/2分别为13.09h和18.58h，这说明进食使式I所示化合物的消除加快，且这一变化随着进食间隔时间的缩短有增加的趋势。
采用SAS 9.4版本软件，用混合效应模型(Mixed-effects model)对自然对数转换后的不同给药与进食间隔时间组的受试者PK参数(C max、AUC 0-t和AUC 0-∞)进行方差分析(ANOVA)
表3给药与进食间隔时间对式I所示化合物PK的影响(PK参数分析集)
Figure PCTCN2020070579-appb-000005
Figure PCTCN2020070579-appb-000006
注：GeoLSM为几何最小二乘均值。
食物及给药与进食间隔时间长短对式I所示化合物的暴露水平有明显影响。受试者单次口服7.5mg式I所示化合物乙醇胺片后1h进食(B组)与给药后不进食(A组)的C max和AUC 0-∞的几何均值比值及其90％CI分别为44.01％(29.83％，64.92％)和25.37％(16.56％，38.86％)，说明给药后1h进食较给药后不进食式I所示化合物的C max和AUC 0-∞分别降低了约56％和75％；而受试者单次口服7.5mg式I所示化合物乙醇胺片后2h进食(C组)与给药后不进食(A组)的C max和AUC 0-∞的几何均值比值及其90％CI分别为56.33％(38.19％，83.11％)和38.57％(25.18％，59.10％)，说明给药后2h进食较给药后不进食式I所示化合物的C max和AUC 0-∞分别降低了约44％和61％；另外，给药后1h进食(B组)与给药后2h进食(C组)C max和AUC 0-∞的几何均值比值及其90％CI分别为78.12％(52.78％，115.63％)和65.76％(42.79％，101.08％)，给药后 1h进食较给药后2h进食式I所示化合物的C max和AUC 0-∞分别降低了约22％和34％。
综上所述，进食使式I所示化合物的血浆暴露水平降低，且给药与进食间隔时间越短，降低的程度越明显。前期PK/PD相关性分析结果显示，单次给药后受试者血小板计数最大变化百分比和Cmax存在具有统计学意义的相关性(相关系数和P值分别为r＝0.84，p<0.0001)。为保证给药后达到预期峰浓度，保证升血小板效应，并结合临床实际用药中患者的依从性，推荐的给药方式为给药与进食至少间隔2小时。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (9)

  1. 一种疾病的治疗方法，其包括给予患者有效量的式I所示化合物或其可药用盐，其中，给药与进食的间隔为至少2小时，优选至少餐前2小时给药，
    Figure PCTCN2020070579-appb-100001
  2. 根据权利要求1所述的方法，所述的疾病选自血小板减少症、血小板减少性紫癜和贫血中的一种或多种，所述的血小板减少症优选化疗所致的血小板减少症或免疫性血小板减少症，所述的贫血优选再生障碍性贫血，所述的血小板减少性紫癜优选特发性血小板减少性紫癜。
  3. 一种增强血小板生成的方法，其包括给予患者有效量的式I所示化合物或其可药用盐，其中，给药与进食的间隔为至少2小时，优选至少餐前2小时给药，
    Figure PCTCN2020070579-appb-100002
  4. 一种激动TPO受体的方法，其包括给予患者有效量的式I所示化合物或其可药用盐，其中，给药与进食的间隔为至少2小时，优选至少餐前2小时给药，
    Figure PCTCN2020070579-appb-100003
  5. 根据权利要求1-4任意一项所述的方法，所述式I所示化合物或其可药用盐的剂量范围选自1-20mg，优选2.5mg、3.75mg、5mg、7.5mg、10mg、12.5mg、15mg。
  6. 根据权利要求1-4任意一项所述的方法，所述式I所示化合物或其可药用盐的给药频次为二日一次、一日一次、一日二次、一日三次。
  7. 根据权利要求1-4任意一项所述的方法，其中所述式I所示化合物的可药用盐可以是钠盐、锂盐、钾盐、钙盐、镁盐、精氨酸盐、赖氨酸盐、甲胺盐、二甲胺盐、三甲胺盐、乙胺盐、二乙胺盐、三乙胺盐、乙醇胺盐、哌嗪盐、二苄基乙二胺盐、葡甲胺、氨丁三醇盐、四甲基季铵盐、四乙基季铵盐或胆碱盐，优选为二乙胺盐、乙醇胺盐、胆碱盐、哌嗪盐、葡甲胺盐或氨丁三醇盐，更优选为乙醇胺盐，最优选为二乙醇胺盐。
  8. 根据权利要求1-4任意一项所述的方法，所述的给药还包含其他组分，所述其他组分包括但不限于集落刺激因子、细胞因子、趋化因子、白细胞介素或细胞因子受体激动剂或拮抗剂、可溶的受体、受体激动剂或拮抗剂抗体或与一个或多个与所述药物具有相同的作用机理的肽或小分子类物质。
  9. 根据权利要求1-8任意一项所述的方法，其中所述的患者为人。
PCT/CN2020/070579 2019-01-08 2020-01-07 双环取代吡唑酮偶氮类衍生物的给药方案 Ceased WO2020143593A1 (zh)

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