WO2022268158A1 - 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 - Google Patents

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 Download PDF

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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)
French (fr)
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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/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
    • A61K31/435—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.

Abstract

c-Met激酶抑制剂的化合物制备治疗I型神经纤维瘤病药物的用途，具体涉及N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺制备治疗I型神经纤维瘤病药物的用途和方法。

Description

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
相关申请的引用
本公开要求于2021年06月23日向中华人民共和国国家知识产权局提交的第202110696200.5号中国专利申请的优先权和权益，在此将其全部内容以援引的方式整体并入文本中。
技术领域
本公开属于医药技术领域，涉及作为c-Met激酶抑制剂的化合物治疗I型神经纤维瘤病的用途，具体涉及N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺治疗神经纤维瘤病的用途和方法。
背景技术
神经纤维瘤病(Neurofibromatosis，NF)是一种由基因突变导致的神经***遗传肿瘤，通常可分为I型神经纤维瘤病(NF1)、II型神经纤维瘤病(NF2)和神经鞘瘤病(Schwannomatosis，NF3)三种类型。其中，NF1基因定位于17q11.2，其全长约350kb，包含60个外显子，可以转录形成11～13kb的mRNA，编码2818个氨基酸的蛋白，即神经纤维瘤素。神经纤维瘤素是一种肿瘤抑制物，其主要功能区为三磷酸鸟苷激活蛋白相关区域(GAP-related domains，GRD)，由第21～27a外显子编码，与GTP酶激活蛋白家族有同源性，能够激活体内的Ras-GTPase，是Ras信号转导的一种负性调节因子。基因突变导致神经纤维瘤素的负性调节作用消失，从而引起Ras的活性增高，主要表现为Ras下游的两条通路Raf-MEK-ERK和PI3K-AKT-mTOR的异常活化，最终导致异常的细胞增生和肿瘤生长。
我国目前约有55万神经纤维瘤患者，其中NF1是神经纤维瘤病中最常见的类型，约占90％。在NF1患者中，约20～50％有丛状神经纤维瘤(Plexiform neurofibroma，PN)，可沿神经的长轴生长，或延伸至周围的结构，导致剧痛和骨骼的破坏，带来严重的并发症并且存在恶变的可能。神经纤维瘤病为多发病灶，难以根治，一直以来，其治疗方式主要是对症处理及手术切除肿瘤，但由于肿瘤的位置或体积，许多患者并不适合进行手术，因此，该疾病存在高度仍未被满足的医疗需求，寻求有效的化疗药物仍是临床上亟待解决的问题。
WO2012034055公开了作为c-Met激酶抑制剂的N-(4-((7-((1-(环戊烷基氨基)环丙烷基)甲氧基)-6-甲氧基喹诺林-4-基)氧基)-3-氟苯基)-N-(4-氟苯基)环丙烷-1,1-二甲酰胺(下称式(I)化合物)及其抑制酪氨酸激酶活性的用途。式(I)化合物是一类新的具有优良药理学性质的化合物，该化合物可抑制多种蛋白酪氨酸激酶的活性，例如c-Met、VEGFr、EGFr、c-kit、PDGF、FGF、SRC、Ron、Tie2等。本公开涉及式(I)化合物对I型神经纤维瘤病的治疗。
Figure PCTCN2022100720-appb-000001
发明内容
一方面，本公开提供用于治疗I型神经纤维瘤病的式(I)化合物或其药学上可接受的盐：
Figure PCTCN2022100720-appb-000002
另一方面，本公开提供用于治疗I型神经纤维瘤病的式(I)化合物或其药学上可接受的盐的药物组合物。
另一方面，本公开提供用于治疗I型神经纤维瘤病的包含式(I)化合物或其药学上可接受的盐的药物组合物。
另一方面，本公开提供式(I)化合物、或其药学上可接受的盐在制备用于治疗I型神经纤维瘤病的药物中的用途。
在一些实施方案中，本公开提供包含式(I)化合物或其药学上可接受的盐的药物组合物在制备用于治疗I型神经纤维瘤病的药物中的用途。在一些实施方案中，所述药物组合物还含有药学上可接受的辅料。
另一方面，本公开提供式(I)化合物或其药学上可接受的盐在治疗I型神经纤维瘤病中的用途。
在一些实施方案中，本公开提供包含式(I)化合物或其药学上可接受的盐的药物组合物在治疗I型神经纤维瘤病中的用途。在一些实施方案中，所述药物组合物还含有药学上可接受的辅料。
另一方面，本公开提供治疗I型神经纤维瘤病的方法，所述方法包括向患者给予式(I)化合物或其药学上可接受的盐。
在一些实施方案中，本公开提供治疗I型神经纤维瘤病的方法，所述方法包括向患者给予式(I)化合物或其药学上可接受的盐的药物组合物。
另一方面，本公开提供治疗I型神经纤维瘤病的方法，所述方法包括向有需要的患者给予治疗有效量的式(I)化合物或其药学上可接受的盐。
在一些实施方案中，本公开提供治疗I型神经纤维瘤病的方法，所述方法包括向有需要的患者给予治疗有效量的包含式(I)化合物或其药学上可接受的盐的药物组合物。在一些实施方案中，所述药物组合物还含有药学上可接受的辅料。
在一些实施方案中，本公开的式(I)化合物或其药学上可接受的盐是作为单一活性剂使用。
在一些实施方案中，本公开的式(I)化合物或其药学上可接受的盐可以处于包含式(I)化合物或其药学上可接受的盐的药物组合物的形式，例如，可以处于包含治疗有效量的式(I)化合物或其药学上可接受的盐的药物组合物的形式。
在一个方面，本公开提供一种用于治疗I型神经纤维瘤病的试剂盒，所述试剂盒包含：a)式(I)化合物或其药学上可接受的盐，或者包含式(I)化合物或其药学上可接受的盐的药物组合物；以及b)使用说明。
在一些实施方案中，所述试剂盒可包含单剂量或多剂量的式(I)化合物或其药学上可接受的盐，或者包含式(I)化合物或其药学上可接受的盐的药物组合物。在所述使用说明中，以28天为一个治疗周期来进行I型神经纤维瘤病的治疗。
发明详述
I型神经纤维瘤病
在一些实施方案中，所述I型神经纤维瘤病选自良性的I型神经纤维瘤病或恶性的I型神经纤维瘤病。
在一些实施方案中，所述I型神经纤维瘤病选自神经纤维瘤或恶性外周神经鞘膜瘤(malignant peripheral nerve sheath tumors,MPNSTs)。
在一些实施方案中，所述神经纤维瘤是指良性神经纤维瘤。
在一些实施方案中，所述I型神经纤维瘤病选自良性的I型神经纤维瘤病或恶性外周神经鞘膜瘤(MPNSTs)。
在一些实施方案中，所述I型神经纤维瘤病选自多发性皮肤型神经纤维瘤(cutaneous neurofibroma,cNF)或丛状型神经纤维瘤(plexiform neurofibroma,pNF)。
在一些实施方案中，所述I型神经纤维瘤病选自皮肤型神经纤维瘤、丛状型神经纤维瘤(良性)或恶性外周神经鞘膜瘤。
在一些实施方案中，所述I型神经纤维瘤病选自皮肤牛奶斑、腋窝或腹股沟雀斑、视神经胶质瘤、Lisch结节(虹膜错构瘤)、特征性的骨病变(例如蝶骨发育不良或长骨皮质发育不良或变薄)、丛状型神经纤维瘤或恶性外周神经鞘膜瘤。
在一些实施方案中，所述I型神经纤维瘤病选自皮肤牛奶斑、丛状型神经纤维瘤或恶性外周神经鞘膜瘤。
在一些实施方案中，所述I型神经纤维瘤病选自I型神经纤维瘤病皮肤型、I型神经纤维瘤病丛状型神经纤维瘤(良性)或恶性外周神经鞘膜瘤。
在一些实施方案中，所述I型神经纤维瘤病患者至少满足以下诊断标准中的2项：a)大于或等于6个牛奶咖啡斑(cafe-au-lait macules)(***前患者大于或等于0.5cm，***后患者大于或等于1.5cm)；b)腋窝或腹股沟雀斑；c)大于或等于2个任何类型的神经纤维瘤，或大于或等于1个丛状型神经纤维瘤；d)视神经胶质瘤；e)两个或多个Lisch结节(虹膜错构瘤)；f)特征性的骨病变(蝶骨发育不良或长骨皮质发育不良或变薄)；g)一级亲属诊断为NF1。
在一些实施方案中，所述I型神经纤维瘤病为基因突变的I型神经纤维瘤病。
在一些实施方案中，所述I型神经纤维瘤病为nf1基因突变的I型神经纤维瘤病。在一些实施方案中，所述nf1基因突变类型包括但不限于碱基置换、***突变、错义突变、无义突变、基因大片段缺失与剪切突变、移码突变(或缺失突变)或重复突变。
在一些实施方案中，所述nf1基因突变包括但不限于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或c.7909C>T突变。
在一些实施方案中，所述I型神经纤维瘤病为不能完全手术切除，且需要全身治疗的I型神经纤维瘤病。
在一些实施方案中，所述I型神经纤维瘤病为既往接受过手术治疗、化疗和/或放射治疗的I型神经纤维瘤病。在一些实施方式中，所述I型神经纤维瘤病为手术治疗、化疗和/或放射治疗失败的I型神经纤维瘤病。
在一些实施方案中，所述I型神经纤维瘤病的主体经手术治疗、化疗和/或放射治疗后获完全缓解或部分缓解后再次出现疾病进展或复发。在一些实施方案中，所述I型神经纤维瘤病的主体经手术治疗、化疗和/或放射治疗后未能完全缓解或未能部分缓解。
在一些实施方案中，所述既往接受过化疗和/或放射治疗的I型神经纤维瘤病为皮肤型神经纤维瘤、丛状型神经纤维瘤或恶性外周神经鞘膜瘤。
在一些实施方案中，所述化疗包括异环磷酰胺联合多柔比星方案、或吡柔比星联合异环磷酰胺方案。
在一些实施方案中，所述化疗包括异环磷酰胺、多柔比星和/或美司钠。例如，所述化疗包括异环磷酰胺联合多柔比星，或者异环磷酰胺联合多柔比星和美司钠。
在一些实施方案中，所述I型神经纤维瘤病为既往接受过手术治疗和/或异环磷酰胺联合多柔比星方案治疗(例如治疗失败)的I型神经纤维瘤病。在一些实施方案中，所述I型神经纤维瘤病为既往接受过手术治疗和/或异环磷酰胺联合多柔比星和美司钠方案治疗(例如治疗失败)的I型神经纤维瘤病。
在一些实施方案中，所述I型神经纤维瘤病为既往接受过异环磷酰胺、多柔比星和/或安罗替尼的治疗 (例如治疗失败)。
给药方案
在一些实施方案中，所述给予式(I)化合物或其药学上可接受的盐的给药周期是2-6周。在一些实施方案中，所述给予式(I)化合物或其药学上可接受的盐的给药周期是2周、3周、4周、5周、6周或上述任意值形成的范围。在一些实施方案中，所述给予式(I)化合物或其药学上可接受的盐的给药周期是3周或4周。
在一些实施方案中，所述给予式(I)化合物或其药学上可接受的盐的给药周期为6-10个周期或以上。在一些实施方案中，所述给予式(I)化合物或其药学上可接受的盐的给药周期可选自至少6个周期、至少7个周期、至少8个周期、至少9个周期或至少10个周期。在一些实施方案中，所述给予式(I)化合物或其药学上可接受的盐的给药周期可为至少8个周期。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的给药方案是每日给药1次到每日给药3次，或每两日给药1次。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的给药方案是每日给药1次、2次或3次。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的给药方案是每日给药1次。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的每日剂量选自20-180mg。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的每日剂量选自20-40mg、20-60mg、20-90mg、20-120mg、20-150mg、40-60mg、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或150-180mg。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的每日剂量选自90-120mg、90-150mg、90-180mg、120-150mg、120-180mg或150-180mg。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的每日剂量选自90mg、120mg、150mg或180mg。在一些实施方案中，所述式(I)化合物或其药学上可接受的盐的每日剂量选自120mg或150mg。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐以包含式(I)化合物或其药学上可接受的盐的药物组合物形式给药。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物为单剂量或多剂量。在一些实施方案中为多剂量。
在一些实施方案中，所述药物组合物为单剂量为30-60mg的式(I)化合物或其药学上可接受的盐的药物组合物。在一些实施方案中，所述药物组合物为单剂量为30mg或60mg的式(I)化合物或其药学上可接受的盐的药物组合物。
在一些实施方案中，所述药物组合物为式(I)化合物或其药学上可接受的盐的多剂量药物组合物，所述多剂量可由单剂量为30mg或60mg的式(I)化合物或其药学上可接受的盐的药物组合物组成。
在一些实施方案中，所述药物组合物为多剂量的式(I)化合物或其药学上可接受的盐的药物组合物，其中所述多剂量的式(I)化合物或其药学上可接受的盐为90mg、120mg、150mg或180mg。在一些实施方案中，其中所述多剂量的式(I)化合物或其药学上可接受的盐为120mg或150mg。在一些实施方案中，在多剂量药物组合物中，式(I)化合物或其药学上可接受的盐的含量为一日一次剂量，所述多剂量由单剂量为30mg或60mg的式(I)化合物或其药学上可接受的盐的药物组合物组成。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：给予受试者每日剂量为90mg、120mg、150mg或者180mg的式(I)化合物或其药学上可接受的盐，连续每天给药。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物通过如下方式给药：以28天为一个治疗周期，每日剂量为90mg、120mg、150mg或者180mg进行给予，每日一次。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物可通过多种途径给药，所述途径包括但不限于口服给药。在一些实施方案中，式(I)化合物或其药学上可接受的盐在早餐前空腹口服。
在一些实施方案中，以28天为一个治疗周期，给药方式如下：给予式(I)化合物或其药学上可接受的盐， 其中，给药剂量为90mg、120mg、150mg或者180mg，每日空腹口服，每日1次，连续服用28天。
本公开的实施方案中，只要疾病仍处于控制之下和方案具有临床耐受性，就重复上述治疗周期。
在一些实施方案中，所述式(I)化合物或其药学上可接受的盐或其药物组合物被制备为适合连续28天每天1次并且每次向患者给予90mg-180mg、或者90mg-150mg、或者90mg-120mg、或者120mg-150mg、或者120mg-180mg、或者150mg-180mg、或者90mg、或者120mg、或者150mg、或者180mg的式(I)化合物或其药学上可接受的盐的单剂量或多剂量形式。
式(I)化合物或其药学上可接受的盐
本公开式(I)化合物可以以其游离碱形式给药，也可以以其药学上可接受的盐的形式给药。例如，式(I)化合物的药学上可接受的盐可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐。在本公开的一些实施方案中，式(I)化合物以其游离碱形式给药。
药物组合物
本公开所述的“式(I)化合物或其药学上可接受的盐”可处于“式(I)化合物或其药学上可接受的盐的药物组合物”的形式。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的药物组合物还含有药学上可接受的辅料。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的药物组合物可适于口服给药。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的药物组合物为固体药物组合物。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的固体药用组合物的制剂形式为胶囊。
在一些实施方案中，式(I)化合物或其药学上可接受的盐的药物组合物为胶囊形式，规格为30mg和60mg。
本公开所述的“式(I)化合物或其药学上可接受的盐”可处于“包含式(I)化合物或其药学上可接受的盐的药物组合物”的形式。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。
在一些实施方案中，包含式(I)化合物或其药学上可接受的盐的药物组合物还含有药学上可接受的辅料。
在一些实施方案中，包含式(I)化合物或其药学上可接受的盐的药物组合物可适于口服给药。
在一些实施方案中，包含式(I)化合物或其药学上可接受的盐的药物组合物为固体药物组合物。
在一些实施方案中，包含式(I)化合物或其药学上可接受的盐的固体药用组合物的制剂形式为胶囊。
在一些实施方案中，包含式(I)化合物或其药学上可接受的盐的药物组合物为胶囊形式，规格为30mg和60mg。
本公开的包含式(I)化合物或其药学上可接受的盐的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了胶囊、片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。
在一些实施方案中，包含式(I)化合物或其药学上可接受的盐的药物组合物可为胶囊，其含有式(I)化合物或其药学上可接受的盐、玉米淀粉、羧甲基纤维素钙、羟丙甲纤维素和硬脂酸镁。
在另一些实施方案中，包含式(I)化合物或其药学上可接受的盐的药物组合物可为胶囊，其含有式(I)化合物或其药学上可接受的盐、乳糖、微晶纤维素、羧甲淀粉钠和硬脂酸镁。
技术效果
本公开的式(I)化合物或其药物上可接受的盐、或其药物组合物具有良好的安全性以及抗肿瘤活性。
本公开的治疗方案在治疗I型神经纤维瘤病中具有较好的疗效。其中，式(I)化合物或其药物上可接受的盐、或包含式(I)化合物或其药物上可接受的盐的药物组合物至少在客观缓解率(ORR)、疾病控制率(DCR)、疾病缓解时间(DOR)、无进展生存期(PFS)、总生存时间(OS)、耐受性或副作用中的至少一个方面具有优异的效果。
在本公开的一些实施方案中，式(I)化合物或其药物上可接受的盐、或其药物组合物在治疗I型神经纤维瘤病中具有良好的客观缓解率和/或疾病控制率。
定义和说明
除非另有说明，为本公开的目的，本说明书和权利要求书中所用的下列术语应具有下述含义。
本公开中，除非另有说明，这里提供的涉及式(I)化合物或其药学上可接受的盐的剂量及其范围，均是基于式(I)化合物游离碱的分子量计算的。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
除非另外特别说明，否则单数术语涵盖复数术语，并且复数术语涵盖单数术语。除非另外特别说明，否则词语“一个”或“一种”意指“至少一个”或“至少一种”。除非另外说明，否则“或”的使用意指“和/或”。
术语“药学上可接受的”是指其用于制备药物组合物，该药物组合物通常是安全、无毒的并且既不在生物学上或其它方面不合乎需要，并且包括其对于人类药物使用是可接受的。
术语“治疗”一般是指获得需要的药理和/或生理效应，包括部分或完全稳定或治愈疾病和/或由于疾病产生的作用。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。
术语“有效量”意指(i)治疗特定疾病、病况或障碍，或(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状的本公开化合物的用量。构成“治疗有效量”的本公开化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
术语“施用”或“给药”或“给予”表示，使用本领域技术人员已知的多种方法和递送***中的任一种，向主体物理引入包含活性化合物的组合物。在某些实施方案中，口服施用。
术语“每日剂量”是指施用给患者一日的剂量。
术语“患者”或“受试者”或“主体”在本文中可互换使用，指哺乳动物，如人、狗、牛、马、猪、绵羊、山羊、猫、小鼠、兔、大鼠和转基因非人动物。在部分实施方案中，所述患者或受试者或主体是人。
术语“单剂量”是指含有一定量药品的最小包装单元，例如一盒药有七粒胶囊，则每个胶囊为单剂量；例如一盒药有七片药品，则每片药为单剂量。
术语“多剂量”由多个单剂量组成。
术语“药物组合物”是指一种或多种本公开的活性成分与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对受试者给予本公开的化合物。
涉及给药方案时，术语“天(日)”、“每天(每日)”等指一个日历日内的时间，开始于午夜且终止于下一个午夜。
术语“一级亲属”是指直系亲属。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
具体实施方式
下面的具体实施例的目的是使本领域的技术人员能更清楚地理解和实施本公开。它们不应该被认为是对本公开范围的限制，而只是本公开的示例性说明和典型代表。
实施例1临床试验
1.1入选标准：
(1)受试者自愿加入本研究，签署知情同意书；
(2)年龄：[18～75]周岁(签署知情同意书时)；ECOG PS评分：≤2分；外周恶性神经鞘膜瘤患者预计生存期≥12周；
(3)经研究者判断为不能完全手术切除，需要全身治疗，且有可测量病灶的NF1患者(包含恶性外周神经鞘膜瘤患者)；
注：NF1诊断标准为满足以下至少一条：
1)基因检查确认：即在经过CLIA认证的实验室检测NF1胚系突变阳性(NF1胚系突变阳性需经本项目中心实验室确认，或者有CLIA认证的实验室出具的NF1突变检测报告)；
2)临床和影像学检查确认：根据临床NIH共识标准，至少满足以下7条中的2条NF1诊断标准：
a.≥6个牛奶咖啡斑(cafe-au-lait macules)(***前患者大于或等于0.5cm，***后患者大于或等于1.5cm)；
b.腋窝或腹股沟雀斑；
c.≥2个任何类型的神经纤维瘤，或≥1个丛状型神经纤维瘤；
d.视神经胶质瘤；
e.两个或多个Lisch结节(虹膜错构瘤)；
f.特征性的骨病变(蝶骨发育不良或长骨皮质发育不良或变薄)；
g.一级亲属诊断为NF1；
(4)通过直接测量或根据RECIST 1.1标准证实，具有至少一个可评估病灶，且病灶直径＞3cm，连续三个切面都可见该病灶；
(5)主要器官功能良好，符合下列标准：
1)血常规检查标准(检查前7天内未输血、未使用造血刺激因子类药物纠正)：
a.白细胞计数(WBC)≥3.5×10 9/L；
b.血红蛋白(HGB)≥90g/L；
c.中性粒细胞绝对值(NEUT)≥1.5×10 9/L；
d.血小板计数(PLT)≥100×10 9/L；
2)生化检查需符合以下标准：
a.白蛋白(ALB)≥35g/L；
b.总胆红素(TBIL)≤1.5倍正常值上限(ULN)，具有Gilbert综合征的患者为≤2.5倍正常值上限(ULN)；
c.丙氨酸基转移酶(ALT)和天门冬氨酸基转移酶(AST)≤2.5×ULN；
d.血清肌酐(CR)≤1.5×ULN或肌酐清除率(CCR)≥50mL/min(应用标准的Cockcroft-Gault公式)。
3)凝血功能检查需符合以下标准：
国际标准化比值(INR)≤1.5×ULN(未接受过抗凝治疗)；
4)甲状腺功能检查需符合以下标准：
促甲状腺激素(TSH)≤ULN；如果异常应考察T3和T4水平，T3和T4水平正常则可以入选。
5)心脏彩超评估：左室射血分数(LVEF)≥50％。
(6)育龄女性受试者应同意在研究期间和研究结束后6个月内必须采用避孕措施(如宫内节育器、避孕药或避孕套)；在研究入组前的7天内血清妊娠试验阴性，且必须为非哺乳期受试者；男性受试者应同意在研究期间和研究期结束后6个月内必须采用避育措施；
(7)队列扩展阶段入组患者需经病理证实入组队列一(NF1皮肤型患者)、队列二(NF1丛状型神经纤维瘤患者(良性))或队列三(MPNST患者)。
1.2给药方案
试验药物：式(I)化合物胶囊，规格为30mg和60mg。
其中，式(I)化合物根据WO2012034055中公开的方法进行制备。
给药方法：口服给药，每日1次，连续服药28天为一个周期，直至研究终止标准。
给药剂量：每日剂量为120mg或150mg。
1.3评价标准
有效性评价：采用直接测量方法或RECIST1.1标准评价疗效。
安全性评价：采用CTCAE v5.0标准判断不良事件严重程度。
1.4疗效评估
客观缓解率(ORR)：研究者依据直接测量结果或RECIST 1.1确定的完全(CR)或部分缓解(PR)受试者所占百分比例。
无进展生存期(PFS)：从首次用药开始至出现疾病客观进展或复发或各种原因导致的死亡(以先出现的为准)之间的时间。
疾病缓解时间(DOR)：对于最佳缓解为完全缓解(CR)或部分缓解(PR)的受试者，定义为从首次记录肿瘤缓解的日期到首次记录疾病进展或复发的日期或因任何原因死亡的日期(以先出现的为准)。
疾病控制率(DCR)：肿瘤缩小或稳定且保持一定时间的受试者比例，包含CR、PR和SD(疾病稳定)的病例。
1年无进展生存率(PFS>12m)：从首次用药开始至12个月时未发生疾病进展且存活的受试者比例(使用Kaplan-Meier估计)。
生存期(OS)：从首次用药开始至各种原因导致的死亡之间的时间。
对受试者疼痛的影响。
对受试者健康相关生活质量(HRQoL)的影响。
对受试者相关症状的影响。
不良事件发生率。
1.5试验结果
目前可进行疗效评估的患者共有6例，患者既往接受过手术治疗或化疗(例如异环磷酰胺+多柔比星，或异环磷酰胺+多柔比星+美司钠)，给予本发明的试验药物的中位治疗时间约8个月，其中皮肤型神经纤维瘤患者1例(120mg剂量组)、丛状型神经纤维瘤患者3例(120mg剂量组1例，150mg剂量组2例)和恶性外周神经鞘膜瘤患者2例(120mg剂量组1例，150mg剂量组1例)，6例患者最佳疗效均为SD，靶病灶体积出现不同程度缩小，患者临床有收益。

Claims (15)

  1. 用于治疗I型神经纤维瘤病的式(I)化合物或其药学上可接受的盐：
    Figure PCTCN2022100720-appb-100001
  2. 根据权利要求1所述的式(I)化合物或其药学上可接受的盐，其中所述I型神经纤维瘤病选自良性的I型神经纤维瘤病或恶性外周神经鞘膜瘤。
  3. 根据权利要求1所述的式(I)化合物或其药学上可接受的盐，其中所述I型神经纤维瘤病选自多发性皮肤型神经纤维瘤或丛状型神经纤维瘤。
  4. 根据权利要求1所述的式(I)化合物或其药学上可接受的盐，其中所述I型神经纤维瘤病选自I型神经纤维瘤病皮肤型、I型神经纤维瘤病丛状型神经纤维瘤(良性)或恶性外周神经鞘膜瘤。
  5. 根据权利要求1所述的式(I)化合物或其药学上可接受的盐，其中所述I型神经纤维瘤病为基因突变的I型神经纤维瘤病。
  6. 根据权利要求1所述的式(I)化合物或其药学上可接受的盐，其中所述I型神经纤维瘤病为不能完全手术切除，且需要全身治疗的I型神经纤维瘤病；或者，所述I型神经纤维瘤病为既往接受过手术治疗、化疗和/或放射治疗的I型神经纤维瘤病。
  7. 根据权利要求1-6任一项所述的式(I)化合物或其药学上可接受的盐，其中所述治疗I型神经纤维瘤病的给药周期为2-6周。
  8. 根据权利要求1-7任一项所述的式(I)化合物或其药学上可接受的盐，其中所述治疗I型神经纤维瘤病的给药方案是每日给药1次到每日给药3次，或每两日给药1次。
  9. 根据权利要求1-8任一项所述的式(I)化合物或其药学上可接受的盐，其中所述治疗I型神经纤维瘤病的每日剂量选自20-180mg、20-40mg、20-60mg、20-90mg、20-120mg、20-150mg、40-60mg、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或150-180mg。
  10. 一种用于治疗I型神经纤维瘤病的药物组合物，所述药物组合物包含式(I)化合物或其药学上可接受的盐，
    Figure PCTCN2022100720-appb-100002
  11. 根据权利要求10所述的药物组合物，其中所述药物组合物为单剂量为30-60mg的式(I)化合物或其药学上可接受的盐的药物组合物。
  12. 根据权利要求1-9任一项所述的式(I)化合物或其药学上可接受的盐，或权利要求10或11所述的药物组合物，其中所述治疗I型神经纤维瘤病以28天为一个治疗周期。
  13. 一种用于治疗I型神经纤维瘤病的试剂盒，所述试剂盒包含：a)式(I)化合物或其药学上可接受的盐，或者包含式(I)化合物或其药学上可接受的盐的药物组合物；以及b)使用说明，
    Figure PCTCN2022100720-appb-100003
  14. 式(I)化合物或其药学上可接受的盐或包含所述式(I)化合物或其药学上可接受的盐的药物组合物在制备用于治疗I型神经纤维瘤病的药物中的用途，
    Figure PCTCN2022100720-appb-100004
  15. 一种治疗I型神经纤维瘤病的方法，所述方法包括向有需要的患者给予治疗有效量的式(I)化合物或其药学上可接受的盐、或包含所述式(I)化合物或其药学上可接受的盐的药物组合物，
    Figure PCTCN2022100720-appb-100005
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