WO2022268158A1 - Utilisation d'un composé comme inhibiteur de la kinase c-met pour le traitement de la neurofibromatose de type i - Google Patents

Utilisation d'un composé comme inhibiteur de la kinase c-met pour le traitement de la neurofibromatose de type i Download PDF

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Publication number
WO2022268158A1
WO2022268158A1 PCT/CN2022/100720 CN2022100720W WO2022268158A1 WO 2022268158 A1 WO2022268158 A1 WO 2022268158A1 CN 2022100720 W CN2022100720 W CN 2022100720W WO 2022268158 A1 WO2022268158 A1 WO 2022268158A1
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compound
formula
pharmaceutically acceptable
acceptable salt
type
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PCT/CN2022/100720
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English (en)
Chinese (zh)
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万晓婧
张喜全
王训强
于鼎
梁洪铭
刘雯雯
胡雯雯
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正大天晴药业集团股份有限公司
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Priority to CN202280041587.3A priority Critical patent/CN117460509A/zh
Publication of WO2022268158A1 publication Critical patent/WO2022268158A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the disclosure belongs to the field of medical technology, and relates to the use of compounds as c-Met kinase inhibitors in the treatment of type I neurofibromatosis, in particular to N-(4-((7-((1-(cyclopentylamino)cyclo Propyl)methoxy)-6-methoxyquinolin-4-yl)oxy)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dimethyl Uses and methods of amides for the treatment of neurofibromatosis.
  • NF Neurofibromatosis
  • NF1 neurofibromatosis type I
  • NF2 neurofibromatosis type II
  • schwannomatosis schwannomatosis 3
  • the NF1 gene is located at 17q11.2, and its full length is about 350kb, including 60 exons, which can be transcribed to form 11-13kb mRNA, encoding a protein of 2818 amino acids, that is, neurofibromin.
  • Neurofibromin is a tumor suppressor, and its main functional domain is GAP-related domains (GRD), which is encoded by exons 21-27a and is related to the GTPase-activating protein family.
  • GAP-related domains GAP-related domains (GRD)
  • GTPase-activating protein family GTPase-activating protein family.
  • Homology which activates Ras-GTPase in vivo, is a negative regulator of Ras signaling.
  • Gene mutations lead to the disappearance of the negative regulatory effect of neurofibromin, which leads to increased activity of Ras, mainly manifested in the abnormal activation of the two pathways downstream of Ras, Raf-MEK-ERK and PI3K-AKT-mTOR, and ultimately leads to abnormal cell hyperplasia and tumor growth.
  • NF1 neurofibromatosis
  • PN plexiform neurofibroma
  • Neurofibromatosis has multiple lesions and is difficult to cure.
  • its treatment has mainly been symptomatic treatment and surgical resection of the tumor.
  • many patients are not suitable for surgery. Therefore, the existence of this disease is still highly unknown.
  • seeking effective chemotherapy drugs is still an urgent problem to be solved clinically.
  • WO2012034055 discloses N-(4-((7-((1-(cyclopentylamino)cyclopropyl)methoxy)-6-methoxyquinolin-4 as c-Met kinase inhibitor -yl) oxygen group)-3-fluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (hereinafter referred to as formula (I) compound) and its inhibitory tyrosine kinase activity the use of.
  • the compound of formula (I) is a new class of compounds with excellent pharmacological properties, which can inhibit the activity of various protein tyrosine kinases, such as c-Met, VEGFr, EGFr, c-kit, PDGF, FGF, SRC , Ron, Tie2, etc.
  • the present disclosure relates to the treatment of neurofibromatosis type I with compounds of formula (I).
  • the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of neurofibromatosis type I:
  • the present disclosure provides a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of neurofibromatosis type I.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of neurofibromatosis type I.
  • the present disclosure provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of neurofibromatosis type I.
  • the present disclosure provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of neurofibromatosis type I.
  • the pharmaceutical composition further contains pharmaceutically acceptable excipients.
  • the present disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of neurofibromatosis type I.
  • the present disclosure provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of neurofibromatosis type I.
  • the pharmaceutical composition further contains pharmaceutically acceptable excipients.
  • the present disclosure provides a method of treating neurofibromatosis type I comprising administering to a patient a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides methods of treating neurofibromatosis type I comprising administering to a patient a pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating neurofibromatosis type I comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a method of treating neurofibromatosis type I comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof thing.
  • the pharmaceutical composition further contains pharmaceutically acceptable excipients.
  • a compound of Formula (I) of the present disclosure is used as the single active agent.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present disclosure may be in the form of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, for example, may be in a form comprising A therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the form of a pharmaceutical composition.
  • the present disclosure provides a kit for treating neurofibromatosis type I, the kit comprising: a) a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (I) a pharmaceutical composition of the compound or a pharmaceutically acceptable salt thereof; and b) instructions for use.
  • the kit may comprise single or multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof things.
  • the treatment of neurofibromatosis type I is carried out with 28 days as a treatment cycle.
  • the neurofibromatosis type I is selected from benign neurofibromatosis type I or malignant neurofibromatosis type I.
  • the neurofibromatosis type I is selected from neurofibromas or malignant peripheral nerve sheath tumors (MPNSTs).
  • the neurofibroma is a benign neurofibroma.
  • the neurofibromatosis type I is selected from benign neurofibromatosis type I or malignant peripheral nerve sheath tumors (MPNSTs).
  • the neurofibromatosis type I is selected from cutaneous neurofibroma (cNF) or plexiform neurofibroma (pNF).
  • the neurofibromatosis type I is selected from cutaneous neurofibroma, plexiform neurofibroma (benign), or malignant peripheral nerve sheath tumor.
  • the neurofibromatosis type I is selected from the group consisting of milky spots of the skin, axillary or inguinal freckles, optic gliomas, Lisch nodes (hamartomas of the iris), characteristic bony lesions such as sphenoid development Dysplasia or cortical hypoplasia or thinning of long bones), plexiform neurofibromas, or malignant peripheral nerve sheath tumors.
  • the neurofibromatosis type I is selected from milky spot of the skin, plexiform neurofibroma, or malignant peripheral nerve sheath tumor.
  • the neurofibromatosis type I is selected from neurofibromatosis type I cutaneous type, neurofibromatosis type I plexiform neurofibroma (benign), or malignant peripheral nerve sheath tumor.
  • the patient with neurofibromatosis type I meets at least two of the following diagnostic criteria: a) greater than or equal to 6 cafe-au-lait macules (prepubertal patients greater than or equal to 0.5 cm, greater than or equal to 1.5 cm in postpubertal patients); b) axillary or inguinal freckles; c) greater than or equal to 2 neurofibromas of any type, or greater than or equal to 1 plexiform neurofibroma; d) optic nerve Glioma; e) two or more Lisch nodules (iris hamartoma); f) characteristic bone lesion (sphenoid bone dysplasia or long bone cortical dysplasia or thinning); g) first-degree relative diagnosed as NF1.
  • the neurofibromatosis type I is genetically mutated neurofibromatosis type I.
  • the neurofibromatosis type I is neurofibromatosis type I with a mutation in the nf1 gene.
  • the nf1 gene mutation type includes but is not limited to base substitution, insertion mutation, missense mutation, nonsense mutation, gene large fragment deletion and splicing mutation, frameshift mutation (or deletion mutation) or duplication mutation.
  • the nf1 gene mutations include but are not limited to c.168C>T, c.601T>A, c.702G>A, c.871G>T, c.1009G>T, c.1318C>T , c.1448A>G, c.2033dup, c.2033del, c.2034G>A, c.3443_3444delCA, c.3619delA, c.3721C>T, c.3822delC, c.3975-2A>T, c.4084C >T, c.4600C>T, c.6852_6855del, c.7348C>T, or c.7909C>T mutations.
  • the neurofibromatosis type I is neurofibromatosis type I that cannot be completely surgically removed and requires systemic therapy.
  • the neurofibromatosis type I is neurofibromatosis type I that has previously been treated with surgery, chemotherapy, and/or radiation. In some embodiments, the neurofibromatosis type I is neurofibromatosis type I that has failed surgery, chemotherapy, and/or radiation therapy.
  • the subject with neurofibromatosis type I relapses or relapses after complete remission or partial remission following surgery, chemotherapy, and/or radiation therapy. In some embodiments, the subject with neurofibromatosis type I is not in complete remission or in partial remission following surgery, chemotherapy, and/or radiation therapy.
  • the type I neurofibromatosis previously treated with chemotherapy and/or radiation is cutaneous neurofibroma, plexiform neurofibroma, or malignant peripheral nerve sheath tumor.
  • the chemotherapy comprises ifosfamide plus doxorubicin regimen, or pirarubicin plus ifosfamide regimen.
  • the chemotherapy includes ifosfamide, doxorubicin, and/or mesna.
  • the chemotherapy includes ifosfamide in combination with doxorubicin, or ifosfamide in combination with doxorubicin and mesna.
  • the neurofibromatosis type I is neurofibromatosis type I that has previously been treated with surgery and/or ifosfamide plus doxorubicin regimen (eg, treatment failure). In some embodiments, the neurofibromatosis type I is neurofibromatosis type I that has previously been treated with surgery and/or ifosfamide combined with doxorubicin and mesna regimen (eg, treatment failure).
  • the neurofibromatosis type I was previously treated with ifosfamide, doxorubicin, and/or anlotinib (eg, treatment failure).
  • the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 2-6 weeks. In some embodiments, the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks or the range formed by any value above. In some embodiments, the administration period of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 3 weeks or 4 weeks.
  • the administration cycle of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 6-10 cycles or more. In some embodiments, the administration cycle of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be selected from at least 6 cycles, at least 7 cycles, at least 8 cycles, at least 9 cycles or at least 10 cycles. In some embodiments, the administration cycle of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be at least 8 cycles.
  • the dosage regimen of the compound of formula (I) or a pharmaceutically acceptable salt thereof is once a day to three times a day, or once every two days. In some embodiments, the dosing regimen of the compound of formula (I) or a pharmaceutically acceptable salt thereof is once, twice or three times a day. In some embodiments, the dosing regimen of the compound of formula (I) or a pharmaceutically acceptable salt thereof is once a day.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 20-180 mg. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 20-40 mg, 20-60 mg, 20-90 mg, 20-120 mg, 20-150 mg, 40-60 mg , 40-90mg, 40-120mg, 40-150mg, 40-180mg, 60-90mg, 60-120mg, 60-150mg, 60-180mg, 90-120mg, 90-150mg, 90-180mg, 120-150mg, 120 - 180mg or 150-180mg.
  • the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 90-120 mg, 90-150 mg, 90-180 mg, 120-150 mg, 120-180 mg or 150-180 mg . In some embodiments, the daily dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 90 mg, 120 mg, 150 mg or 180 mg. In some embodiments, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 120 mg or 150 mg.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is in single or multiple doses. In some embodiments multiple doses.
  • the pharmaceutical composition is a single dose of 30-60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a single dose of 30 mg or 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is a multi-dose pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the multi-dose may consist of a single dose of 30 mg or 60 mg of the compound of formula (I) or The composition of the pharmaceutical composition of its pharmaceutically acceptable salt.
  • the pharmaceutical composition is a pharmaceutical composition of multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the multiple doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • the salt is 90mg, 120mg, 150mg or 180mg.
  • the multiple doses of the compound of formula (I) or a pharmaceutically acceptable salt thereof are 120 mg or 150 mg.
  • the content of the compound of formula (I) or a pharmaceutically acceptable salt thereof is once a day, and the multi-dose consists of a single dose of 30 mg or 60 mg of the compound of formula (I) ) compound or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered by administering to a subject a daily dose of 90 mg, 120 mg, 150 mg or 180 mg of the formula ( I)
  • the compound or a pharmaceutically acceptable salt thereof is administered continuously every day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered in the following manner: with 28 days as a treatment cycle, the daily dose is 90 mg, 120 mg, 150 mg or 180 mg was administered once a day.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof can be administered by various routes, including but not limited to oral administration. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is orally administered on an empty stomach before breakfast.
  • the administration method is as follows: administer the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the administration dose is 90 mg, 120 mg, 150 mg or 180 mg, daily Take it orally on an empty stomach, once a day, for 28 consecutive days.
  • the treatment cycles described above are repeated as long as the disease remains under control and the regimen is clinically tolerable.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is prepared to be suitable for administering 90 mg-180 mg, or 90 mg-150 mg once a day for 28 consecutive days to a patient each time A single dose or multiple dose form.
  • the compound of formula (I) in the present disclosure can be administered in the form of its free base or in the form of its pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts of compounds of formula (I) can be generated from various organic and inorganic acids according to methods well known in the art.
  • the compound of formula (I) is administered in its free base form.
  • the "compound of formula (I) or a pharmaceutically acceptable salt thereof” described in the present disclosure may be in the form of a “pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof".
  • the method of administration can be comprehensively determined according to the activity, toxicity and patient tolerance of the drug.
  • the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof further contains pharmaceutically acceptable excipients.
  • compositions of compounds of formula (I) or pharmaceutically acceptable salts thereof may be suitable for oral administration.
  • the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition.
  • the preparation form of the solid pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule.
  • the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of capsules, with specifications of 30 mg and 60 mg.
  • the "compound of formula (I) or a pharmaceutically acceptable salt thereof” described in the present disclosure may be in the form of a "pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof".
  • the method of administration can be comprehensively determined according to the activity, toxicity and patient tolerance of the drug.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof further comprises pharmaceutically acceptable excipients.
  • compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be adapted for oral administration.
  • the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition.
  • the formulation form of a solid pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof is a capsule.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of capsules, and the specifications are 30 mg and 60 mg.
  • composition of the present disclosure comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof can be produced by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, grinding method, emulsification method, freeze-drying method, etc.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and then processing the mixture into granules to obtain capsules, The core of the tablet or dragee.
  • Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be a capsule, which contains a compound of formula (I) or a pharmaceutically acceptable salt thereof, corn starch, carboxymethyl Cellulose calcium, hypromellose and magnesium stearate.
  • the pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof can be a capsule, which contains the compound of formula (I) or a pharmaceutically acceptable salt thereof, lactose, microcrystalline cellulose Sodium starch glycolate, sodium starch glycolate and magnesium stearate.
  • the compound of formula (I) or its pharmaceutically acceptable salt, or its pharmaceutical composition of the present disclosure has good safety and antitumor activity.
  • the treatment scheme disclosed in the present disclosure has a good curative effect in the treatment of type I neurofibromatosis.
  • the compound of formula (I) or its pharmaceutically acceptable salt, or the pharmaceutical composition comprising the compound of formula (I) or its pharmaceutically acceptable salt is at least in objective response rate (ORR), disease control rate (DCR) , disease response time (DOR), progression-free survival (PFS), overall survival (OS), tolerance or side effects have excellent effects.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof has a good objective remission rate and/or disease control rate in the treatment of neurofibromatosis type I.
  • the doses and ranges of the compound of formula (I) or its pharmaceutically acceptable salts provided herein are calculated based on the molecular weight of the free base of the compound of formula (I).
  • pharmaceutically acceptable means its use in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes its use in human pharmaceutical use. acceptable.
  • treatment generally refers to obtaining desired pharmacological and/or physiological effects, including partial or complete stabilization or cure of a disease and/or effects resulting from a disease.
  • treatment encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, ie arresting its development; or (b) relieving the symptoms of the disease, ie causing regression of the disease or symptoms.
  • an effective amount means an amount of a compound of the disclosure that (i) treats a particular disease, condition or disorder, or (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder.
  • the amount of a compound of the present disclosure that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art according to its own knowledge and this disclosure.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • administration means the physical introduction into a subject of a composition comprising an active compound using any of a variety of methods and delivery systems known to those skilled in the art. In certain embodiments, the administration is orally.
  • daily dose refers to the dose administered to a patient for one day.
  • patient or subject or subject are used interchangeably herein and refer to mammals such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats and transgenic non-human animals.
  • the patient or subject or subject is a human.
  • single dose refers to the smallest packaging unit containing a certain amount of medicine.
  • a box of medicine has seven capsules, and each capsule is a single dose; for example, a box of medicine has seven medicines, and each medicine is a single dose.
  • multiple dose consists of a number of single doses.
  • composition refers to a mixture of one or more active ingredients of the present disclosure and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to a subject.
  • day refers to the time within a calendar day beginning at midnight and ending at midnight the next following.
  • first degree relative refers to immediate family members.
  • Embodiment 1 clinical trial
  • NF1 patients with measurable lesions including patients with malignant peripheral nerve sheath tumors who are judged by the investigator to be incomplete surgical resection, need systemic treatment, and have measurable lesions;
  • the diagnostic criteria for NF1 is to meet at least one of the following:
  • WBC White blood cell count
  • TBIL Total bilirubin
  • ALT Alanine-based transferase
  • AST aspartate-based transferase
  • Thyroid function tests must meet the following criteria:
  • Thyroid-stimulating hormone (TSH) ⁇ ULN Thyroid-stimulating hormone (TSH) ⁇ ULN; if abnormal, T3 and T4 levels should be investigated, and T3 and T4 levels can be selected if normal.
  • LVEF left ventricular ejection fraction
  • Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, contraceptives or condoms) during the study period and within 6 months after the end of the study; serum pregnancy test within 7 days before study enrollment Negative, and must be non-lactating subjects; male subjects should agree to use contraceptive measures during the study period and within 6 months after the end of the study period;
  • contraceptive measures such as intrauterine devices, contraceptives or condoms
  • Patients enrolled in the cohort expansion stage need to be confirmed by pathology to be enrolled in cohort 1 (patients with NF1 skin type), cohort 2 (patients with NF1 plexiform neurofibroma (benign)) or cohort 3 (patients with MPNST).
  • Test drug capsules of the compound of formula (I), with specifications of 30 mg and 60 mg.
  • the compound of formula (I) is prepared according to the method disclosed in WO2012034055.
  • Dosing method Oral administration, once a day, 28 consecutive days as a cycle, until the study termination standard.
  • the daily dose is 120mg or 150mg.
  • ORR Objective Response Rate
  • PFS Progression-free survival
  • DOR Duration of Disease Response
  • DCR Disease control rate
  • PFS>12m Proportion of subjects alive without disease progression from first dose to 12 months (estimated using Kaplan-Meier).
  • the patients have received surgical treatment or chemotherapy (such as ifosfamide+doxorubicin, or ifosfamide+doxorubicin+mesna) in the past.
  • the median treatment time of the experimental drug is about 8 months, including 1 patient with cutaneous neurofibroma (120mg dose group), and 3 patients with plexiform neurofibroma (1 patient with 120mg dose group, 2 patients with 150mg dose group) and 2 patients with malignant peripheral nerve sheath tumors (1 case in the 120mg dose group and 1 case in the 150mg dose group), the best curative effect of the 6 patients was SD, and the volume of target lesions was reduced to varying degrees, and the patients had clinical benefits.

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Abstract

L'invention concerne l'utilisation d'un composé en tant qu'inhibiteur de la kinase c-Met dans la préparation d'un médicament pour le traitement de la neurofibromatose de type I, et plus précisément, l'utilisation de N-(4-((7-((1-(cyclopentylamino)cyclopropyle)méthoxy)-6-méthoxyquinolin-4-yl)oxy)-3-fluorophényl)-N-(4-fluorophényl)cyclopropane-1,1-dicarboxamide, dans la préparation d'un médicament pour le traitement de la neurofibromatose de type I, ainsi qu'un procédé associé.
PCT/CN2022/100720 2021-06-23 2022-06-23 Utilisation d'un composé comme inhibiteur de la kinase c-met pour le traitement de la neurofibromatose de type i WO2022268158A1 (fr)

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CN202280041587.3A CN117460509A (zh) 2021-06-23 2022-06-23 作为c-Met激酶抑制剂的化合物治疗I型神经纤维瘤病的用途

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