WO2023016551A1 - 用于治疗或预防抗宿主病的吡咯并六元杂芳物 - Google Patents

用于治疗或预防抗宿主病的吡咯并六元杂芳物 Download PDF

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WO2023016551A1
WO2023016551A1 PCT/CN2022/112101 CN2022112101W WO2023016551A1 WO 2023016551 A1 WO2023016551 A1 WO 2023016551A1 CN 2022112101 W CN2022112101 W CN 2022112101W WO 2023016551 A1 WO2023016551 A1 WO 2023016551A1
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versus
host disease
graft
pharmaceutically acceptable
acceptable salt
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PCT/CN2022/112101
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English (en)
French (fr)
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宋献民
邱慧颖
邹建军
张晓静
李华军
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江苏恒瑞医药股份有限公司
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Priority to CN202280054355.1A priority Critical patent/CN118043051A/zh
Publication of WO2023016551A1 publication Critical patent/WO2023016551A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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 disclosure relates to a pyrrolo six-membered heteroaryl compound for treating or preventing anti-host disease.
  • GVHD graft-versus-host disease
  • aGVHD acute graft-versus-host disease
  • cGVHD chronic graft-versus-host disease
  • corticosteroids have become the first-line regimen for the treatment of cGvHD, ie, prednisone (starting dose 1 mg/kg/d) or equivalent doses of methylprednisolone for systemic immunosuppressive therapy.
  • the drugs used for the second-line treatment of cGVHD include: mTOR inhibitors, mycophenolate mofetil, rituximab, alemtuzumab, thalidomide, imatinib, spray Sistatin and methotrexate, etc. These drugs can relieve some patients, but due to the strong immunosuppression of the drugs, the incidence of fungal, viral, bacterial and other infections increases significantly; and long-term use of glucocorticoids can lead to diabetes, Osteoporosis, negative nitrogen balance, malnutrition.
  • JAK inhibitors play an important role in the inflammatory response and tissue damage of GVHD.
  • JAK inhibitors can block the JAK-STAT molecular pathway and reduce the level of inflammatory cytokines, even in patients with negative JAK mutations.
  • Ruxolitinib, Baricitinib, etc. have some clinical experience in some GVHD patients, among which Ruxolitinib is approved for the treatment of steroid-refractory acute GVHD in adults and children aged 12 and over.
  • (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidine -4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide is a class of JAK kinase inhibitor compounds with in vivo and in vitro activity and high absorption
  • the disclosure provides the use of the compound represented by formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing graft-versus-host disease,
  • the graft versus host disease is chronic graft versus host disease. According to the 2014 NIH chronic graft-versus-host disease diagnosis and curative effect grading standards, it is graded, including mild graft-versus-host disease, moderate graft-versus-host disease and severe graft-versus-host disease. In some embodiments, the graft versus host disease is moderate graft versus host disease. In some embodiments, the graft-versus-host disease is more than moderate graft-versus-host disease. In some embodiments, the graft versus host disease is moderate-severe graft versus host disease. In some embodiments, the graft versus host disease is severe graft versus host disease.
  • a patient with graft-versus-host disease in the present disclosure is one who has undergone cell transplantation.
  • the patient with graft versus host disease has undergone allogeneic bone marrow or hematopoietic stem cell transplantation.
  • administration is based on the patient's body weight, and the dosage of the compound of formula I or its pharmaceutically acceptable salt in mammals is 0.1-10.0 mg/kg, specifically 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4mg/kg, 0.5mg/kg, 0.6mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.2mg/kg, 1.4mg/kg, 1.6 mg/kg, 1.8mg/kg, 2.0mg/kg, 2.2mg/kg, 2.4mg/kg, 2.6mg/kg, 2.8mg/kg, 3.0mg/kg, 3.2mg/kg, 3.4mg/kg, 3.6 mg/kg, 3.8mg/kg, 4.0mg/kg, 4.2mg/kg, 4.4mg/kg, 4.6mg/kg, 4.8mg/kg, 5.0mg/kg, 5.2mg/kg,
  • the dose of the compound of formula I or a pharmaceutically acceptable salt thereof in mammals is 0.1-5.0 mg/kg. In other embodiments, the dose of the compound of formula I or its pharmaceutically acceptable salt in mammals is 1.0-5.0 mg/kg. In other embodiments, the dose of the compound of formula I or its pharmaceutically acceptable salt in mammals is 4.0-6.0 mg/kg. In other embodiments, the dosage of the compound of formula I or its pharmaceutically acceptable salt in mammals is 5.0-6.0 mg/kg.
  • the dosage of the compound of formula I or its pharmaceutically acceptable salt in mammals is 1-50 mg, specifically 1.0 mg, 1.2 mg, 1.4 mg, 1.6 mg, 1.8 mg, 2.0 mg, 2.2 mg , 2.4mg, 2.6mg, 2.8mg, 3.0mg, 3.2mg, 3.4mg, 3.6mg, 3.8mg, 4.0mg, 4.2mg, 4.4mg, 4.6mg, 4.8mg, 5.0mg, 5.2mg, 5.4mg, 5.6 mg, 5.8mg, 6.0mg, 6.2mg, 6.4mg, 6.6mg, 6.8mg, 7.0mg, 7.2mg, 7.4mg, 7.6mg, 7.8mg, 8.0mg, 8.2mg, 8.4mg, 8.6mg, 8.8mg, 9.0mg, 9.2mg, 9.4mg, 9.6mg, 9.8mg, 10.0mg, 15mg, 20m
  • the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in mammals is 2-10 mg. In certain embodiments, the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in mammals is 2-5 mg. In certain embodiments, the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof in mammals is 4-8 mg.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition in the form of a 2 mg dosage.
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition in the form of a 4 mg dosage.
  • the compound of Formula I, or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition in an 8 mg dosage form.
  • the additional therapeutic agent is a corticosteroid (including but not limited to prednisone, methylprednisone, hydrocortisone, dexamethasone, betamethasone, or beclomethasone dipropionate). In certain embodiments, the additional therapeutic agent is prednisone or methylprednisone.
  • the additional therapeutic agent such as a corticosteroid
  • the additional therapeutic agent is administered in a mammalian human at a dose of 0.1-10.0 mg/kg.
  • the additional therapeutic agent, such as a corticosteroid is administered in a mammalian human at a dose of 1.0-2.0 mg/kg.
  • the additional therapeutic agent, such as a corticosteroid is administered in a mammalian human at a dose of 0.1-2.0 mg/kg.
  • the additional therapeutic agent, such as a corticosteroid is administered in a mammalian human at a dose of 0.1-1.0 mg/kg.
  • a GVHD patient of the present disclosure is not one who has received or is currently receiving systemic therapy for GVHD, except for corticosteroid therapy within 72 hours.
  • GVHD patients of the present disclosure are naive or not receiving systemic therapy for GVHD, except for corticosteroid therapy within 72 hours.
  • a patient with GVHD of the present disclosure is naive to systemic treatment for GVHD, or is treated with a corticosteroid within 72 hours.
  • the administration frequency of the compound of formula I or its pharmaceutically acceptable salt in the use of the present disclosure is once a day, twice a day, once every two days, once every three days, once every four days, once every five days, once every six days, Once a week, three days a week, once a day, four days a week, once a day, or five days a week, once a day.
  • the dosage of the compound of formula I and its pharmaceutically acceptable salt is 2-50 mg in mammals and humans, and the administration frequency is twice a day.
  • the corticosteroid is selected from prednisone, methylprednisone, betamethasone, hydrocortisone, dexamethasone, or combinations thereof.
  • a compound of Formula I, or a pharmaceutically acceptable salt thereof is administered in combination with an additional therapeutic agent.
  • the additional therapeutic agent is selected from a corticosteroid (including without limitation corticotropin, glucocorticoid, or mineralocorticoid), cyclosporine, mycophenolate mofetil, or combinations thereof .
  • Another aspect of the present disclosure also provides a method for treating or preventing graft-versus-host disease, which comprises administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient with graft-versus-host disease.
  • the dose of the compound of formula I or a pharmaceutically acceptable salt thereof in mammals is 2-50 mg.
  • the method of treating or preventing graft-versus-host disease comprises administering to a patient with graft-versus-host disease an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof in combination with another therapeutic agent.
  • the additional therapeutic agent is a corticosteroid (including but not limited to prednisone, methylprednisone, hydrocortisone, dexamethasone, betamethasone, or beclomethasone dipropionate). In certain embodiments, the additional therapeutic agent is prednisone or methylprednisone.
  • “Combination” or “joint use” or “combined administration” in the present disclosure refers to a mode of administration, which refers to the administration of at least one dose of a compound of formula I or a pharmaceutically acceptable salt thereof and at least one dose within a certain period of time.
  • the time period can be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent may be administered simultaneously or sequentially.
  • This period includes treatments wherein the compound of formula I, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered by the same route of administration or by different routes of administration.
  • the administration mode of the combination described in the present application is selected from simultaneous administration, independent formulation and co-administration or independent formulation and sequential administration.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. agent.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • Partial remission The measurable disease indicators in the affected organs of chronic GVHD are improved or improved by more than 50%, and there is no disease progression in any affected organ or part, and lasts for more than 3 weeks.
  • Treatment failure refers to intolerable side effects, disease progression during treatment, no improvement or recurrence after treatment.
  • the research population selected patients aged 18 to 70 who received allogeneic peripheral blood hematopoietic stem cell transplantation due to blood system diseases, and were diagnosed with moderate-severe chronic GVHD according to the 2014 chronic GVHD NIH grading criteria;
  • Patients may be receiving other immunosuppressants for the prevention or treatment of acute GVHD, but if the subject is receiving prednisone for the prevention or treatment of acute GVHD, it must be ⁇ 0.5mg/kg/d or equivalent dose of other glucocorticoids;
  • Drug A (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3- d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide hydrogen sulfate, tablet (specification: 1mg/tablet, 2mg/tablet, 4mg/tablet) orally, continuous Take orally for at least 4 weeks; unless the disease progresses during treatment, the primary tumor relapses or cannot tolerate the treatment of drug A, the total course of treatment is not less than 6 months; the specific dosage regimen is as follows:
  • Drug B prednisone, starting dose 1 mg/kg/day or equivalent dose of methylprednisolone orally once in the morning (maximum adult dose of prednisone 100 mg/day); oral prednisone 1 mg/kg/day if present Intolerance or inappropriate conditions, such as uncontrollable hyperglycemia, hypertension, aseptic necrosis, osteoporosis, severe emotional disorders, etc., the initial dose is 0.5mg/kg/day.
  • the overall effective rate (CR+PR) for 28 days of medication is 94.4% (17/18), of which the effective rate of 1mg/day dose group is 66.7%, 2mg/day, 4mg/day, 6mg/day, 8mg/day
  • the /daily dose group was 100%; the overall effective rate (CR+PR) was 93.5% (15/16) after 24 weeks of medication.
  • the effective rate (about 50%) is higher than the current first-line treatment (glucocorticoid combined with or without calmodulin inhibitor).
  • grade ⁇ 3 drug A-related AEs In terms of safety, the incidence of grade ⁇ 3 drug A-related AEs in this study was 22.2%, including 16.7% decrease in platelet count and 5.6% anemia. The short-term drug safety was relatively high, and no new safety risks were added. Compared with similar drug ruxolitinib (the incidence of cGVHD ⁇ grade 3 AE in the treatment of ruxolitinib was 57%, the most common ⁇ grade 3 AE were thrombocytopenia 15.2% and anemia 12.7%), the hematological toxicity was lower. On the other hand, first-line standard therapy for cGVHD had a 56% incidence of grade ⁇ 3 AEs and a 37% incidence of life-threatening/fatal infections.

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Abstract

一种用于治疗或预防抗宿主病的吡咯并六元杂芳物或其可药用盐，该化合物结构为：(I)，并具体涉及其在制备用于治疗或预防抗宿主病的药物中的用途，能够改善抗宿主病治疗的有效率，改善患者生命质量，提高患者生存率。

Description

用于治疗或预防抗宿主病的吡咯并六元杂芳物
本申请要求申请日为2021年8月12日的中国专利申请2021109254357和申请日为2021年12月1日的中国专利申请2021114521269的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开涉及一种用于治疗或预防抗宿主病的吡咯并六元杂芳物。
背景技术
移植物抗宿主病(GVHD)通常以发生时间和临床表现分为急性移植物抗宿主病(aGVHD)和慢性移植物抗宿主病(cGVHD)。
在过去的40年中，皮质类固醇已成为治疗cGvHD的一线方案，即，***(起始剂量1mg/kg/d)或者等效剂量的甲泼尼龙全身免疫抑制治疗。
仅约40％的cGVHD患者对一线治疗有效(包括完全缓解和部分缓解)，无反应患者非复发死亡率高出有反应患者约2.5倍。同时研究显示在***基础上增加钙调素抑制剂(环孢素、普乐可复等)、霉酚酸酯、沙利度胺等药物不能提高一线治疗有效率。
另外，目前还没有标准的二线疗法，用于cGVHD二线治疗的药物包括：mTOR抑制剂、霉酚酸酯、利妥昔单抗、阿仑单抗、沙利度胺、伊马替尼、喷司他丁及甲氨蝶呤等，这些药物可以使部分患者获得缓解，但由于药物强烈的免疫抑制导致真菌、病毒、细菌等感染的发生率明显增加；而且长期应用糖皮质激素会导致糖尿病、骨质疏松、负氮平衡、营养不良。例如，mTOR抑制剂西罗莫司与他克莫司和皮质类固醇激素联合用药，有效率可达63％，但肾毒性值得关注。如何提高中重度cGVHD的一线治疗成功率成为提高移 植后患者生存率的关键因素。
cGVHD的发病机制仍然在不断地探索中，过去的研究基础表明由于持久存在同种异体反应性T细胞，产生针对宿主抗原的自身或同种抗体的B细胞，以及供体抗原呈递细胞(APC)的作用替代宿主APC，从而导致同种异体抗原的间接呈递，造成皮肤、胃肠道及肝脏等靶器官的损害。cGVHD过程中，T淋巴细胞、树突状细胞、NK细胞、巨噬细胞等作为主要的效应细胞活化、增殖，并且释放大量的炎症细胞因子诱导靶器官细胞凋亡，导致靶器官组织的损伤。而移植后免疫缺陷所致的并发症和长期应用免疫抑制剂又会加重这种紊乱状态，所以其相互作用机制仍需进一步研究。
已有研究证实，JAK抑制剂在GVHD发生的炎症反应及组织损伤中发挥了重要作用。同时JAK抑制剂能够阻断JAK-STAT分子通路，降低炎症细胞因子的水平，即使在JAK突变阴性的患者中也有效果。
例如，Ruxolitinib、Baricitinib等在部分GVHD患者中已有一些临床经验，其中Ruxolitinib被批准用于治疗12岁及以上成人和儿童患者的类固醇难治性急性GVHD。一项研究中回顾性分析了Ruxolitinib在41例甾体难治性慢性GVHD患者中的使用情况：慢性GVHD患者总反应率为85％，中位反应时间为3周，GVHD的靶器官有所改善。
(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)-甲酰胺为一类具有体内、外活性，高吸收的JAK激酶抑制剂化合物，
Figure PCTCN2022112101-appb-000001
然而未见该分子能有效用于治疗或预防移 植物宿主病的临床报道。
发明内容
本公开(The disclosure)提供了式I所示化合物或其可药用盐在制备用于治疗或预防移植物抗宿主病的药物中的用途，
Figure PCTCN2022112101-appb-000002
在一些实施方案中，所述移植物抗宿主病为慢性移植物抗宿主病。参照2014年NIH慢性移植物抗宿主病的诊断和疗效分级标准进行分级，包括轻度移植物抗宿主病、中度移植物抗宿主病和重度移植物抗宿主病。在一些实施方案中，所述移植物抗宿主病为中度移植物抗宿主病。在一些实施方案中，所述移植物抗宿主病为中度以上移植物抗宿主病。在一些实施方案中，所述移植物抗宿主病为中度-重度移植物抗宿主病。在一些实施方案中，所述移植物抗宿主病为重度移植物抗宿主病。
另一方面，本公开中移植物抗宿主病患者为已经接受细胞移植的。在某一些实施方案中，移植物抗宿主病患者为异基因骨髓或造血干细胞移植的。
在一些实施方案中，根据患者体重给药，式I化合物或其可药用盐在哺乳动物人中的施用剂量为0.1～10.0mg/kg，具体为0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、 3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg、10.0mg/kg或任意两数值间任意值。
在另一些实施方案中，式I化合物或其可药用盐在哺乳动物人中的施用剂量为0.1～5.0mg/kg。在另一些实施方案中，式I化合物或其可药用盐在哺乳动物人中的施用剂量为1.0～5.0mg/kg。在另一些实施方案中，式I化合物或其可药用盐在哺乳动物人中的施用剂量为4.0～6.0mg/kg。在另一些实施方案中，式I化合物或其可药用盐在哺乳动物人中的施用剂量为5.0～6.0mg/kg。
在一些实施方案中，式I化合物或其可药用盐在哺乳动物人中的施用剂量为1～50mg，具体为1.0mg、1.2mg、1.4mg、1.6mg、1.8mg、2.0mg、2.2mg、2.4mg、2.6mg、2.8mg、3.0mg、3.2mg、3.4mg、3.6mg、3.8mg、4.0mg、4.2mg、4.4mg、4.6mg、4.8mg、5.0mg、5.2mg、5.4mg、5.6mg、5.8mg、6.0mg、6.2mg、6.4mg、6.6mg、6.8mg、7.0mg、7.2mg、7.4mg、7.6mg、7.8mg、8.0mg、8.2mg、8.4mg、8.6mg、8.8mg、9.0mg、9.2mg、9.4mg、9.6mg、9.8mg、10.0mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg或任意两数值间任意值，优选2mg、4mg、6mg或10mg。
在某些实施方案中，式I化合物或其可药用盐在哺乳动物人中的日施用剂量为2～10mg。在某些实施方案中，式I化合物或其可药用盐在哺乳动物人中的日施用剂量为2～5mg。在某些实施方案中，式I化合物或其可药用盐在哺乳动物人中的日施用剂量为4～8mg。
在另一些实施方案中，式I化合物或其可药用盐以药物组合物形式给药，所述组合物为1mg剂量形式。
在一些实施方案中，式I化合物或其可药用盐以药物组合物形式给药， 所述组合物为2mg剂量形式。
在一些实施方案中，式I化合物或其可药用盐以药物组合物形式给药，所述组合物为4mg剂量形式。
在一些实施方案中，式I化合物或其可药用盐以药物组合物形式给药，所述组合物为6mg剂量形式。
在一些实施方案中，式I化合物或其可药用盐以药物组合物形式给药，所述组合物为8mg剂量形式。
在另一些实施方案中，给药剂量、施用剂量或单位剂量以游离碱计。
在一些实施方案中，所述药物组合物包含式I化合物或其可药用盐以及一种或多种可药用的赋形剂、稀释剂或载体。
另一方面，本公开的用途中所述式I化合物或其可药用盐与一种或多种另外的治疗剂组合施用。
在一些实施方案中，另外的治疗剂选自皮质类激素(包括不限于促肾上腺皮质激素、糖皮质激素或盐皮质激素)、环孢菌素、霉酚酸吗啉乙酯或其组合。
在某些实施方案中，另外的治疗剂为皮质类激素(包括但不限于***、甲基***、氢化可的松、***、倍他米松或丙酸倍氯米松)。在某些实施方案中，另外的治疗剂为***或甲基***。
进一步地，所述式I化合物或其可药用盐联合另外的治疗剂具有协同药效作用。能有效降低式I化合物或其可药用盐单独施用剂量，减少药物如甲基***或***的不良反应。
在一些实施方案中，另外的治疗剂如皮质激素，根据患者体重给药，在哺乳动物人中的施用剂量为0.1～10.0mg/kg，具体为0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.6mg/kg、0.7mg/kg、0.8mg/kg、0.9mg/kg、1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、 2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg、10.0mg/kg或任意两数值间任意值。
在另一些实施方案中，另外的治疗剂如皮质激素在哺乳动物人中的施用剂量为0.1～10.0mg/kg。在另一些实施方案中，另外的治疗剂如皮质激素在哺乳动物人中的施用剂量为1.0～2.0mg/kg。在另一些实施方案中，另外的治疗剂如皮质激素在哺乳动物人中的施用剂量为0.1～2.0mg/kg。在另一些实施方案中，另外的治疗剂如皮质激素在哺乳动物人中的施用剂量为0.1～1.0mg/kg。
在一些实施方案中，本公开移植物抗宿主病患者不为已接受过或正在接受对移植物抗宿主病全身治疗的，除了在72小时内接受皮质类激素治疗的。
在另一些实施方案中，本公开移植物抗宿主病患者为未接受过或没有正在接受对移植物抗宿主病全身治疗的，除了在72小时内接受皮质类激素治疗的。
在某些实施方案中，本公开移植物抗宿主病患者为未接受过对移植物抗宿主病全身治疗的，或者在72小时内接受皮质类激素治疗的。
另一方面，本公开用途中式I化合物或其可药用盐的给药频率为一日一次，一日两次，两天一次，三天一次，四天一次，五天一次，六天一次，一周一次，每周给药三天、一天一次，每周给药四天、一天一次，或者每周给药五天、一天一次。
在一些实施方案中，式I化合物其可药用盐在哺乳动物人中的施用剂量为2～50mg，给药频率为一日一次。
在一些实施方案中，式I化合物其可药用盐在哺乳动物人中的施用剂量为2～50mg，给药频率为一日二次。
在一些实施方案中，式I化合物其可药用盐在哺乳动物人中的施用剂量为4mg，给药频率为一日一次。
在一些实施方案中，式I化合物其可药用盐在哺乳动物人中的施用剂量为4mg，给药频率为一日二次。
本公开另一方面还提供了式I所示化合物或其可药用盐与皮质类激素在制备用于治疗或预防移植物抗宿主病的药物中的用途，
Figure PCTCN2022112101-appb-000003
在一些实施方案中，所述皮质类激素选自***、甲基***、倍他米松、氢化可的松、***或其组合。
本公开另一方面还提供了用于治疗或预防移植物抗宿主病的式I化合物或其可药用盐，
Figure PCTCN2022112101-appb-000004
在一些实施方案中，式I化合物或其可药用盐与另外的治疗剂组合施用。在某些实施方案中，所述另外治疗剂选自皮质类激素(包括不限于促肾上腺皮质激素、糖皮质激素或盐皮质激素)、环孢菌素、霉酚酸吗啉乙酯或其组 合。
本公开另一方面还提供一种治疗或预防移植物抗宿主病的方法，其包括向移植物抗宿主病患者施用有效量的式I化合物或其可药用盐。在一些实施方案中，式I化合物或其可药用盐在哺乳动物人中的施用剂量为2～50mg。
在另一些实施方案中，治疗或预防移植物抗宿主病的方法包括向移植物抗宿主病患者组合施用有效量的式I化合物或其可药用盐与另外的治疗剂。
在某些实施方案中，另外的治疗剂为皮质类激素(包括但不限于***、甲基***、氢化可的松、***、倍他米松或丙酸倍氯米松)。在某些实施方案中，另外的治疗剂为***或甲基***。
在一些实施方案中，本公开式I化合物的可药用盐包括但不限于硫酸氢盐或硫酸盐。
本公开还提供一种用于治疗移植物抗宿主病的药物组合，其包含有效治疗量的式I化合物或其可药用盐。进一步地，所述药物组合还包括另外的治疗剂。
如无相反解释，本公开中术语具有如下含义：
本公开关于“联合”或“联用”或“组合施用”是一种给药方式，是指在一定时间期限内给予至少一种剂量的式I化合物或其可药用盐和至少一种剂量的另外的治疗剂，其中两种物质都显示药理学作用。所述的时间期限可以是一个给药周期内，优选4周内，3周内，2周内，1周内，或24小时以内，更优选12小时以内。可以同时或依次给予式I化合物或其可药用盐和另外的治疗剂。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予式I化合物或其可药用盐和另外的治疗剂。本申请所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药 用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本公开中所述“有效量”或“有效治疗量”包含足以改善或预防医学病症的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
完全缓解(CR)：慢性GVHD的症状完全消失，且持续3周以上。
部分缓解(PR)：慢性GVHD受累器官中可测量的疾病指标改善或好转50％以上，没有任一受累器官或部位疾病进展，且持续3周以上。
治疗无效：慢性GVHD的症状无改善，任一器官的严重程度加重至少一个级别，新出现某个器官的慢性GVHD，需要加用其他药物治疗慢性GVHD。
治疗失败：是指毒副作用不可耐受、治疗过程中疾病进展、无改善或治疗结束后复发。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制本公开的范围。
实施例1
研究人群选取18岁至70岁、因血液***疾病接受异基因外周血造血干细胞移植的患者，依据2014慢性GVHD NIH分级标准评估，诊断为中度-重度的慢性GVHD；
已经开始激素治疗的慢性GVHD时间不超过72小时；
患者可能正在接受其他免疫抑制剂预防或治疗急性GVHD，但如果受试者接受***预防或治疗急性GVHD，则必须＜0.5mg/kg/d或等效剂量其他糖皮质激素；
且排除接受任何对cGVHD的全身治疗，除了在签署知情同意书前72h内给予治疗cGVHD的皮质类固醇。
给药方案：
药物A：(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，片剂(规格：1mg/片、2mg/片、4mg/片)口服，连续口服至少4周；除非治疗过程中疾病进展、原发肿瘤复发或不能耐受药物A治疗，总疗程不少于6月；具体给药方案如下：
组别 剂量/日
1 1mg/日
2 2mg/日
3 4mg/日
4 6mg/日
5 8mg/日
药物物B：***，起始剂量1mg/kg/日或等效剂量甲泼尼龙早上一次口服(强的松成人最大剂量100mg/日)；如果患者存在口服***1mg/kg/日不耐受或不适当情况，如难以控制的高血糖、高血压、无菌性坏死、骨质疏松、严重情感障碍等，起始剂量0.5mg/kg/日。
结论：基于可评价患者，用药28天总体有效率(CR+PR)94.4％(17/18)，其中1mg/日剂量组有效率66.7％，2mg/日、4mg/日、6mg/日、8mg/日剂量组均为100％；用药24周总体有效率(CR+PR)93.5％(15/16)。高于目前一 线治疗(糖皮质激素联合或不联合钙调神经蛋白抑制剂)的有效率(约为50％)。
安全性方面，本研究≥3级与药物A相关AE发生率22.2％，其中血小板计数降低16.7％、贫血5.6％，短期用药安全性较高，未增加新的安全性风险。与同类药物芦可替尼(芦可替尼治疗cGVHD≥3级AE发生率57％，最常见≥3级AE为血小板减少15.2％和贫血12.7％)相比，血液学毒性更低。另一方面，cGVHD一线标准治疗≥3级AE发生率56％，危及生命/致命的感染发生率37％。

Claims (15)

  1. 式I所示化合物或其可药用盐在制备用于治疗或预防移植物抗宿主病的药物中的用途，
    Figure PCTCN2022112101-appb-100001
  2. 根据权利要求1所述的用途，其中所述移植物抗宿主病为慢性移植物抗宿主病。
  3. 根据权利要求1或2所述的用途，其中所述移植物抗宿主病为中度-重度移植物抗宿主病，优选中度-重度慢性移植物抗宿主病。
  4. 根据权利要求1-3任一项所述的用途，其中患者为已经接受细胞移植的，所述细胞移植优选异基因骨髓或造血干细胞移植的。
  5. 根据权利要求1-4任一项所述的用途，其中所述式I化合物或其可药用盐在哺乳动物人中的施用剂量选自1～50mg，优选2mg、4mg、6mg或10mg。
  6. 根据权利要求1-5任一项所述的用途，其中所述式I化合物或其可药用盐给药方式为一日一次或一日两次。
  7. 根据权利要求1-6任一项所述的用途，其中所述式I化合物或其可药用盐与一种或多种另外的治疗剂组合施用。
  8. 根据权利要求7所述的用途，其中所述另外的治疗剂选自皮质类激素、环孢菌素、霉酚酸吗啉乙酯或其组合，优选皮质类激素，更优选***或甲基***。
  9. 根据权利要求1-8任一项所述的用途，其中移植物抗宿主病患者不为已接受过或正在接受对移植物抗宿主病全身治疗的，除非在72小时内接受皮质类激素治疗的。
  10. 根据权利要求1-8任一项所述的用途，其中移植物抗宿主病患者为未接受过对移植物抗宿主病全身治疗的，或者接受皮质类激素治疗不超过72小时的。
  11. 式I所示化合物或其可药用盐与皮质类激素联合在制备用于治疗或预防移植物抗宿主病的药物中的用途，
    Figure PCTCN2022112101-appb-100002
  12. 根据权利要求11所述的用途，其中所述皮质类激素选自***、 甲基***、倍他米松、氢化可的松、***或其组合。
  13. 根据权利要求1或11所述的用途，其中式I所示化合物的可药用盐为硫酸氢盐或硫酸盐。
  14. 一种用于治疗或预防移植物抗宿主病的式I化合物或其可药用盐，
    Figure PCTCN2022112101-appb-100003
  15. 根据权利要求14所述的式I化合物或其可药用盐，其与一种或多种另外的治疗剂组合施用。
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