WO2023016551A1 - Composé hétéroaromatique à six chaînons de pyrrolo pour le traitement ou la prévention d'une maladie du greffon contre l'hôte - Google Patents

Composé hétéroaromatique à six chaînons de pyrrolo pour le traitement ou la prévention d'une maladie du greffon contre l'hôte Download PDF

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Publication number
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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WO
WIPO (PCT)
Prior art keywords
versus
host disease
graft
pharmaceutically acceptable
acceptable salt
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Application number
PCT/CN2022/112101
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English (en)
Chinese (zh)
Inventor
宋献民
邱慧颖
邹建军
张晓静
李华军
Original Assignee
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/fr

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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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Transplantation (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un composé hétéroaromatique à six chaînons de pyrrolo ou un sel pharmaceutiquement acceptable de celui-ci pour traiter ou prévenir une maladie du greffon contre l'hôte, la structure de ce composé étant telle que représentée par la formule suivante : La présente invention concerne spécifiquement l'utilisation du composé hétéroaromatique à six chaînons de pyrrolo dans la préparation d'un médicament pour le traitement ou la prévention d'une maladie du greffon contre l'hôte. Le composé hétéroaromatique à six chaînons de pyrrolo peut améliorer l'efficacité du traitement de la maladie du greffon contre l'hôte, améliorer la qualité de vie des patients et augmenter le taux de survie des patients.
PCT/CN2022/112101 2021-08-12 2022-08-12 Composé hétéroaromatique à six chaînons de pyrrolo pour le traitement ou la prévention d'une maladie du greffon contre l'hôte WO2023016551A1 (fr)

Priority Applications (1)

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CN202280054355.1A CN118043051A (zh) 2021-08-12 2022-08-12 用于治疗或预防抗宿主病的吡咯并六元杂芳物

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CN202111452126.9 2021-12-01

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105566327A (zh) * 2014-10-09 2016-05-11 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的i型结晶及其制备方法
US20180222912A1 (en) * 2011-12-21 2018-08-09 Jiangsu Hengrui Medicine Co., Ltd. Pyrrole heteroaryl ring derivative and method of use thereof
US20190308972A1 (en) * 2016-11-23 2019-10-10 Jiangsu Hengrui Medicine Co., Ltd. Preparation method for and intermediate of pyrrolo six-membered heteroaromatic ring derivative
US20200276109A1 (en) * 2017-11-20 2020-09-03 Jiangsu Hengrui Medicine Co., Ltd. Pharmaceutical composition for topical administration and preparation method therefor
WO2021097074A1 (fr) * 2019-11-13 2021-05-20 New York University Systèmes de co-culture d'organoïdes intestinaux et méthodes de traitement ou de prévention d'une maladie ou d'un trouble associé à une lésion tissulaire médiée par une réponse immunitaire
CN113440613A (zh) * 2020-03-26 2021-09-28 轶诺(浙江)药业有限公司 小檗碱类似物与jak抑制剂在胃肠道炎症性疾病治疗中的用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180222912A1 (en) * 2011-12-21 2018-08-09 Jiangsu Hengrui Medicine Co., Ltd. Pyrrole heteroaryl ring derivative and method of use thereof
CN105566327A (zh) * 2014-10-09 2016-05-11 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的i型结晶及其制备方法
US20190308972A1 (en) * 2016-11-23 2019-10-10 Jiangsu Hengrui Medicine Co., Ltd. Preparation method for and intermediate of pyrrolo six-membered heteroaromatic ring derivative
US20200276109A1 (en) * 2017-11-20 2020-09-03 Jiangsu Hengrui Medicine Co., Ltd. Pharmaceutical composition for topical administration and preparation method therefor
WO2021097074A1 (fr) * 2019-11-13 2021-05-20 New York University Systèmes de co-culture d'organoïdes intestinaux et méthodes de traitement ou de prévention d'une maladie ou d'un trouble associé à une lésion tissulaire médiée par une réponse immunitaire
CN113440613A (zh) * 2020-03-26 2021-09-28 轶诺(浙江)药业有限公司 小檗碱类似物与jak抑制剂在胃肠道炎症性疾病治疗中的用途

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TW202320788A (zh) 2023-06-01

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