WO2023025141A1 - Utilisation d'un composé macrocyclique contenant un acide aminé dans le traitement de tumeurs à médiation par kinase trk - Google Patents

Utilisation d'un composé macrocyclique contenant un acide aminé dans le traitement de tumeurs à médiation par kinase trk Download PDF

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WO2023025141A1
WO2023025141A1 PCT/CN2022/114215 CN2022114215W WO2023025141A1 WO 2023025141 A1 WO2023025141 A1 WO 2023025141A1 CN 2022114215 W CN2022114215 W CN 2022114215W WO 2023025141 A1 WO2023025141 A1 WO 2023025141A1
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WIPO (PCT)
Prior art keywords
fusion gene
ntrk1
mutant
ntrk3
compound
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PCT/CN2022/114215
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English (en)
Chinese (zh)
Inventor
万晓婧
张喜全
王训强
田心
于鼎
陈琴
郭方方
Original Assignee
正大天晴药业集团股份有限公司
首药控股(北京)股份有限公司
连云港润众制药有限公司
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Application filed by 正大天晴药业集团股份有限公司, 首药控股(北京)股份有限公司, 连云港润众制药有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN202280046303.XA priority Critical patent/CN117597128A/zh
Publication of WO2023025141A1 publication Critical patent/WO2023025141A1/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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the application belongs to the field of medicine and relates to the use of amino-containing macrocyclic compounds in the treatment of tumors mediated by TRK kinase.
  • TRK is a family of tyrosine kinases activated by nerve growth factor, including three subtypes, TRKA, TRKB and TRKC, encoded by NTRK1 (neurotrophic receptor tyrosine kinase 1), NTRK2 and NTRK3 genes, respectively.
  • the complete TRK kinase includes three parts: extracellular region, transmembrane region and intracellular region. After the extracellular receptor region of TRK kinase binds to the corresponding ligand, it can cause a change in the kinase configuration and form a dimer.
  • the intracellular kinase region is autophosphorylated to activate its own kinase activity, and further activate the downstream signal transduction.
  • NGF nerve growth factor
  • BDNF derived neurotrophic factor
  • TRKB TRKB
  • NT3 neurotrophic factor 3
  • TRK kinases play important physiological functions in the development of nerves, including the growth and function maintenance of neuronal axons, the occurrence and development of memory, and the protection of neurons from injury and so on.
  • TRK signal transduction pathways Activated TRK signaling proteins have been found in neurocytoma, prostate cancer, and breast cancer.
  • TRK fusion proteins have shown its biological function of promoting tumorigenesis. The earliest TPM3-TRKA fusion protein was found in colon cancer cells, with an incidence of about 1.5% in clinical patients tested.
  • TRK fusion proteins were found in different types of clinical tumor patient samples such as lung cancer, head and neck cancer, breast cancer, thyroid cancer, glioma, etc., such as CD74-NTRK1, MPRIP-NTRK1, QKI-NTRK2, ETV6 -NTRK3, BTB1-NTRK3, etc.
  • These different TRK fusion proteins are in a state of highly activated kinase activity without the need for ligand binding, so they can continuously phosphorylate downstream signaling pathways, induce cell proliferation, and promote the occurrence and development of tumors. Therefore, in recent years, TRK fusion protein has become an effective anti-cancer target and research hotspot.
  • WO2019037761A1 discloses macrocyclic compounds containing aminopyrazolopyrimidines such as (1 3 E, 1 4 E, 2 2 R, 2 4 S)-1 2 -amino-2 4 ,3 5 -difluoro-4-oxa -7-Aza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclooctane-8-one (compound of formula I), which has TRK kinase inhibitory activity, can be used for treating diseases mediated by TRK kinase.
  • aminopyrazolopyrimidines such as (1 3 E, 1 4 E, 2 2 R, 2 4 S)-1 2 -amino-2 4 ,3 5 -difluoro-4-oxa -7-Aza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidinecyclooctane-8-one (
  • the application provides a method for treating TRK kinase-mediated tumors, which comprises administering to a subject an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof
  • the present application provides a method for treating TRK kinase-mediated tumors, which comprises administering to a subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present application provides the use of the compound of formula I or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation of a medicament for treating tumors mediated by TRK kinase.
  • the present application also provides a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating TRK kinase-mediated tumors.
  • the present application also provides the use of the compound of formula I of the present application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating tumors mediated by TRK kinase.
  • the present application provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating TRK kinase-mediated tumors, wherein the medicament comprises, with Based on the weight of the compound of formula I, 0.5-100mg of the compound of formula I or its pharmaceutically acceptable salt or its pharmaceutical composition.
  • the compound of formula I of the present application is used as a single active agent.
  • the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is used as a single active agent in a single dose or a daily dose of 0.5-100 mg (based on the weight of the compound of formula I).
  • the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is used in a single dose or a daily dose of 0.5-100 mg (based on the weight of the compound of formula I).
  • the pharmaceutical composition described herein comprises 0.5-100 mg (based on the weight of the compound of formula I) of the compound of formula I or a pharmaceutically acceptable salt thereof as a single active agent.
  • the pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
  • the application provides a method for treating TRK kinase-mediated tumors, which comprises daily administration of 0.5-100 mg of a compound of formula I or its pharmaceutically acceptable A salt, or a pharmaceutical composition thereof (based on the weight of the compound of formula I).
  • the present application also provides a kit for treating TRK kinase-mediated tumors, comprising: a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient; optionally, Instructions for use of pharmaceutical compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is a single-dose pharmaceutical composition comprising 0.5-100 mg of the compound of formula I or a pharmaceutically acceptable salt thereof (based on the weight of the compound of formula I) as an active ingredient.
  • the method for treating tumor provided by the application comprises:
  • the subject is a primate, preferably a human.
  • the tumor is mediated by TRKA, and/or TRKB, and/or TRKC.
  • the tumor is mediated by wild-type (non-mutated) or mutated TRK. In some embodiments, the tumor is mediated by wild-type (non-mutated) or mutant TRKA, and/or TRKB, and/or TRKC.
  • the tumor is mediated by a mutant TRK comprising G667C, G595R, or G623R.
  • the tumor is mediated by mutant TRKA comprising G667C or G595R, and/or TRKB, and/or mutant TRKC comprising G623R.
  • the mutant is selected from TRKA G595R , TRKA G667C or TRKC G623R .
  • the tumor is selected from tumors with a TRK fusion protein.
  • the TRK kinase-mediated tumor is selected from tumors with non-mutated or mutated TRK fusion proteins.
  • the TRK fusion protein is selected from non-mutant or mutant TRKA fusion protein, and/or TRKB fusion protein, and/or TRKC fusion protein.
  • the TRK fusion protein is selected from non-mutated TRKA fusion protein, and/or TRKB fusion protein, and/or TRKC fusion protein.
  • the TRK fusion protein is selected from a mutant TRKA fusion protein, and/or TRKB fusion protein, and/or TRKC fusion protein.
  • the tumor is selected from tumors with an NTRK fusion gene.
  • the NTRK fusion gene is selected from non-mutated or mutant NTRK fusion genes.
  • the NTRK fusion gene is selected from an NTRK1 fusion gene, an NTRK2 fusion gene, and an NTRK3 fusion gene.
  • the NTRK fusion gene is selected from non-mutant or mutant NTRK1 fusion gene, and/or NTRK2 fusion gene, and/or NTRK3 fusion gene.
  • the NTRK fusion gene is selected from non-mutant or mutant NTRK1 fusion genes.
  • the NTRK fusion gene is selected from non-mutant or mutant NTRK2 fusion genes. In some embodiments, the NTRK fusion gene is selected from non-mutant or mutant NTRK3 fusion genes. In some embodiments, the NTRK fusion gene is selected from non-mutated NTRK1 fusion gene, and/or NTRK2 fusion gene, and/or NTRK3 fusion gene. In some embodiments, the NTRK fusion gene is selected from a mutant NTRK1 fusion gene, and/or NTRK2 fusion gene, and/or NTRK3 fusion gene.
  • the NTRK fusion gene can be a TPM3-NTRK1 fusion gene, an ETV6-NTRK3 fusion gene, and/or a CD74-NTRK1 fusion gene. In some embodiments, the NTRK fusion gene can be an ETV6-NTRK3 fusion gene.
  • the NTRK fusion gene expresses a TRK fusion protein in the tumor.
  • the NTRK fusion gene in the tumor, can express wild-type (ie, non-mutated) or mutant TRK fusion protein.
  • the NTRK1 fusion gene can express wild-type (ie, non-mutated) or mutant TRKA fusion protein in the tumor.
  • the NTRK2 fusion gene may express wild-type (ie, non-mutated) or mutant TRKB fusion protein in the tumor.
  • the NTRK3 fusion gene in the tumor, can express wild-type (ie, non-mutated) or mutant TRKC fusion protein.
  • the NTRK1 fusion gene in the tumor, can express wild-type (ie, non-mutated) or mutant TRKA fusion protein; and/or the NTRK2 fusion gene can express wild-type (ie, non-mutated) or mutant TRKB fusion protein; and/or NTRK3 fusion gene can express wild-type (ie, non-mutated) or mutant TRKC fusion protein.
  • the mutant NTRK fusion gene is selected from fusion genes with NTRK1 G595R , NTRK1 G667C and/or NTRK3 G623R .
  • the mutant NTRK fusion gene is selected from the CD74-NTRK1 G667C fusion gene and/or the ETV6-NTRK3 G623R fusion gene. In some embodiments, the mutant NTRK fusion gene is selected from the ETV6-NTRK3 G623R fusion gene.
  • the NTRK1 fusion gene is selected from a non-mutated TPM3-NTRK1 fusion gene, a non-mutated CD74-NTRK1 fusion gene, or a mutant NTRK1 fusion gene with NTRK1 G595R and/or NTRK1 G667C (e.g., with TPM3-NTRK1 fusion gene or CD74-NTRK1 fusion gene of NTRK1 G595R and/or NTRK1 G667C ).
  • the NTRK1 fusion gene is selected from a non-mutant TPM3-NTRK1 fusion gene, a mutant NTRK1 fusion gene with NTRK1 G595R , a non-mutant CD74-NTRK1 fusion gene, or a CD74-NTRK1 G667C fusion gene.
  • the NTRK3 fusion gene is selected from a non-mutant ETV6-NTRK3 fusion gene, or a mutant NTRK3 fusion gene with NTRK3 G623R (eg, an ETV6-NTRK3 fusion gene with NTRK3 G623R ). In some embodiments, the NTRK3 fusion gene is selected from a non-mutant ETV6-NTRK3 fusion gene, or an ETV6-NTRK3 G623R fusion gene.
  • the method for treating tumor provided by the application comprises:
  • the NTRK fusion gene is selected from non-mutated or mutant NTRK fusion genes. In some embodiments, the NTRK fusion gene is selected from an NTRK1 fusion gene, an NTRK2 fusion gene, and/or an NTRK3 fusion gene. In some embodiments, the NTRK fusion gene is selected from an NTRK1 fusion gene. In some embodiments, the NTRK fusion gene is selected from an NTRK2 fusion gene. In some embodiments, the NTRK fusion gene is selected from an NTRK3 fusion gene. In some embodiments, the NTRK fusion gene is selected from non-mutated NTRK fusion genes.
  • the NTRK fusion gene is selected from mutant NTRK fusion genes.
  • the mutation of the NTRK fusion gene is selected from an acquired mutation or a non-acquired mutation.
  • the mutant NTRK fusion gene is selected from a drug-resistant mutant NTRK fusion gene.
  • the NTRK fusion gene is selected from an NTRK1 fusion gene, an NTRK2 fusion gene, and/or an NTRK3 fusion gene.
  • the NTRK fusion gene is selected from a mutant NTRK1 fusion gene, NTRK2 fusion gene, and/or NTRK3 fusion gene.
  • the NTRK fusion gene can be selected from non-mutant or mutant TPM3-NTRK1 fusion gene, ETV6-NTRK3 fusion gene or CD74-NTRK1 fusion gene.
  • the NTRK fusion gene may be selected from a TPM3-NTRK1 fusion gene, an ETV6-NTRK3 fusion gene, or a CD74-NTRK1 fusion gene.
  • the NTRK fusion gene may be ETV6-NTRK3.
  • the mutant NTRK fusion gene is selected from fusion genes with NTRK1 G595R , NTRK1 G667C or NTRK3 G623R . In some embodiments, the mutant NTRK fusion gene is selected from fusion genes with NTRK3 G623R .
  • the TRK fusion protein is selected from wild-type (ie non-mutated) or mutant TRK fusion protein. In some embodiments, the TRK fusion protein is selected from TRKA fusion protein, TRKB fusion protein, and/or TRKC fusion protein. In some embodiments, the TRK fusion protein is selected from wild-type (ie non-mutant) or mutant TRKA fusion protein, wild-type (ie non-mutant) or mutant TRKB fusion protein, and/or wild-type (ie non-mutant) or mutant TRKC fusion protein.
  • the mutant TRK fusion protein is selected from mutant TRKA with G595R and/or G667C or mutant TRKC with G623R. In some embodiments, the mutant TRK fusion protein is selected from mutant TRKA with G595R, mutant TRKA with G667C, or mutant TRKC with G623R.
  • the mutant TRK fusion protein is selected from TRKA G595R , TRKA G667C or TRKC G623R .
  • the mutation of the mutant TRK fusion protein is selected from an acquired mutation or a non-acquired mutation. In some embodiments, the mutant TRK fusion protein is selected from a drug-resistant mutant TRK fusion protein. In some embodiments, the mutant TRK fusion protein is selected from acquired drug resistance mutant TRK fusion proteins.
  • the fusion gene described in the present application may contain a point mutation of NTRK gene or not contain a point mutation of NTRK gene. In some embodiments, the fusion gene described herein may contain a point mutation in the NTRK gene. In some embodiments, the fusion gene described in this application may not contain NTRK gene point mutation.
  • the tumors described herein may be from subjects and/or patients carrying NTRK1, NTRK2, or NTRK3 gene fusions without NTRK point mutations. In some embodiments, the tumors described herein may be from subjects and/or patients carrying NTRK1, NTRK2 or NTRK3 gene fusions and NTRK gene point mutations.
  • the methods provided herein include performing morphological diagnosis, or molecular testing, or a combination of both before administering the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the methods provided herein comprise assaying a tumor sample obtained from a subject to determine that the subject has a dysregulation of NTRK fusion gene, TRK protein, or expression or level thereof.
  • the methods provided herein include assaying a tumor sample obtained from a subject to determine that the subject has an NTRK fusion gene or/and a TRK fusion protein.
  • the assay method is selected from one or more of the following methods: denaturing gradient gel electrophoresis (DGGE), temperature gradient gel electrophoresis (TGGE), temperature gradient capillary electrophoresis, single-strand conformation multiple morphological assays, molecular beacon assays, kinetic hybridization assays, PCR-based assays, or denaturing high-performance liquid chromatography.
  • DGGE denaturing gradient gel electrophoresis
  • TGGE temperature gradient gel electrophoresis
  • TGGE temperature gradient capillary electrophoresis
  • single-strand conformation multiple morphological assays single-strand conformation multiple morphological assays
  • molecular beacon assays kinetic hybridization assays
  • PCR-based assays or denaturing high-performance liquid chromatography.
  • the mutants described herein are selected from G595R, G667C or G623R mutations. In some embodiments, the mutant is selected from a G595R-type mutation. In some embodiments, the mutant is selected from a G667C-type mutation. In some embodiments, the mutant is selected from a G623R-type mutation.
  • the fusion gene described herein is selected from non-mutant or mutant NTRK1, NTRK2 or NTRK3 gene fusions. In some embodiments, the fusion gene described herein is selected from a non-mutant or mutant NTRK1 gene fusion. In some embodiments, the fusion gene described herein is selected from a non-mutant or mutant NTRK2 gene fusion. In some embodiments, the fusion gene described herein is selected from a non-mutant or mutant NTRK3 gene fusion.
  • the NTRK fusion gene described herein can be selected from non-mutant or mutant TPM3-NTRK1, ETV6-NTRK3 or CD74-NTRK1. In some embodiments, the NTRK fusion gene described herein can be selected from non-mutant or mutant TPM3-NTRK1. In some embodiments, the NTRK fusion gene described herein can be selected from non-mutant or mutant ETV6-NTRK3. In some embodiments, the NTRK fusion gene described herein can be selected from non-mutated or mutant CD74-NTRK1.
  • the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at a weight of 0.0001 mg/kg to 20 mg/kg (calculated by the weight of the compound of formula I) per administration.
  • the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 0.5-100 mg, 0.5-25 mg or 2.5-25 mg (calculated by the weight of the compound of formula I) per administration. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 0.5-20 mg (calculated by the weight of the compound of formula I) for each administration. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 0.5-15 mg (calculated by the weight of the compound of formula I) for each administration.
  • the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 2.5-10 mg (calculated by the weight of the compound of formula I) for each administration. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 5-10 mg (calculated by the weight of the compound of formula I) for each administration.
  • the daily dosage of the compound of formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof (based on the weight of the compound of formula I) is selected from 0.5-100 mg, 0.5-25 mg or 2.5-25 mg.
  • the daily dose (by weight of the compound of formula I) of the compound of formula I or its pharmaceutically acceptable salt or pharmaceutical composition thereof is selected from 0.5 mg, or 1 mg, or 1.5 mg, or 2 mg, or 2.5mg, or 3mg, or 3.5mg, or 4mg, or 4.5mg, or 5mg, or 5.5mg, or 6mg, or 6.5mg, or 7mg, or 7.5mg, or 8mg, or 8.5mg, or 9mg, or 9.5 mg, or 10mg, or 10.5mg, or 11mg, or 11.5mg, or 12mg, or 12.5mg, or 13mg, or 13.5mg, or 14mg, or 14.5mg, or 15mg, or 15.5m
  • the daily dose (based on the weight of the compound of formula I) of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 0.5 mg-20 mg. In some schemes, the daily dose (based on the weight of the compound of formula I) of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 0.5 mg-15 mg. In some schemes, the daily dose (based on the weight of the compound of formula I) of the compound of formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof is selected from 2.5 mg-10 mg.
  • the daily dose (based on the weight of the compound of formula I) of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is selected from 5 mg-10 mg.
  • the administration frequency of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may be 3 times a day, 2 times a day, 1 time a day, 1 time every two days, Once every three days, once every four days, once every five days, once every six days, three times a week, twice a week, once a week, once every two weeks, or once every three weeks Second-rate.
  • the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may be administered once a day.
  • the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof may be administered twice a day.
  • the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered with a specification dose of 2-20 mg each time, such as a specification dose of 2.5 mg, 5 mg or 10 mg (weight of the compound of formula I calculate).
  • the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered at a weight of 0.0001 to 20 mg/kg (calculated by the weight of the compound of formula I) each time.
  • the administration cycle of the compound of formula I or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof is 1-6 cycles. In some embodiments, the administration cycle of the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is 1, 2, 3, 4, 5, 6 cycles or the range formed by any value above.
  • 8-32 days is used as a dosing cycle, for example, 8-28 days, 8-21 days, 8-15 days, 15-28 days, 15-21 days, 21-28 days , 21-32 days, 28-32 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, or 32 days constitute one administration cycle.
  • 28 days or 32 days are used as one administration cycle.
  • 28-32 days is taken as one administration cycle.
  • administering an effective amount of the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a subject is continuous administration.
  • the compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is administered in single or multiple doses.
  • the subject is selected from subjects with advanced malignant solid tumors diagnosed pathologically and/or cytologically, and/or subjects who lack conventional effective treatment methods or fail or relapse after conventional treatment. tester.
  • the tumor is selected from tumor patients with or without prior treatment. In some embodiments, the tumor is selected from patients with previously treated tumors.
  • the subject is selected from subjects who have or have not previously received treatment with a TRK inhibitor.
  • the subject is selected from subjects who have previously been treated with one or more TRK inhibitors.
  • the TRK inhibitor is selected from larotrectinib, TL118 and/or SIM1803.
  • the subject is selected from subjects who have not previously received TRK inhibitor treatment.
  • the aforementioned tumor is selected from solid tumors.
  • the aforementioned tumor is selected from advanced malignant solid tumors.
  • the aforementioned tumor is selected from adult advanced malignant solid tumors.
  • the aforementioned tumor is selected from glioma, central nervous system tumor, sarcoma, peripheral primitive neuroectodermal tumor, Wilms tumor, lung cancer, thyroid cancer, colorectal cancer, salivary gland cancer, biliary tract cancer, brain cancer , breast cancer, breast ductal carcinoma, head and neck cancer, cell carcinoma, pancreatic cancer, male and female reproductive system tumors, kidney cancer, bile duct cancer, gastric cancer, bronchial cancer, chest cancer, neuroendocrine tumor, lymphoma or melanoma.
  • the aforementioned tumor is selected from soft tissue sarcoma, salivary adenoma, thyroid cancer, lung cancer, melanoma, colorectal cancer, gastric cancer, stromal tumor, cholangiocarcinoma, breast cancer, or pancreatic cancer.
  • the aforementioned tumor is selected from lung cancer, adenocarcinoma or oral cancer.
  • the aforementioned lung cancer is selected from lung adenocarcinoma; the adenocarcinoma is selected from parotid gland carcinoma or lung adenocarcinoma; and the oral cavity cancer is selected from mouth floor cancer.
  • the aforementioned tumor is selected from lung adenocarcinoma, parotid gland carcinoma, floor of the mouth carcinoma, acinar cell carcinoma, or intestinal carcinoma.
  • the compound of formula I in the present application can be administered in the form of its free base, and can also be administered in the form of its pharmaceutically acceptable salt, hydrate and prodrug, and the prodrug can be converted into the free base form of the compound of formula I in vivo.
  • the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is selected from solid pharmaceutical compositions, preferably tablets or capsules.
  • the compound of formula I or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition, wherein, based on the weight of the compound of formula I, the pharmaceutical composition is a single dose of 0.5-100 mg, preferably 0.5 mg- 25 mg of the pharmaceutical composition, preferably from a single dose of 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg , 8.5mg, 9mg, 9.5mg, 10mg, 10.5mg, 11mg, 11.5mg, 12mg, 12.5mg, 13mg, 13.5mg, 14mg, 14.5mg, 15mg, 15.5mg, 16mg, 16.5mg, 17mg, 17.5mg, 18mg , 18.5mg, 19mg, 19.5mg, 20mg, 20.5mg, 21mg, 21.5m
  • the pharmaceutical composition of the present application is administered orally.
  • each pharmaceutical composition of the present application is a solid pharmaceutical composition.
  • the preparation form of the solid pharmaceutical composition of the present application is a tablet.
  • TRKA TRKB and TRKC, it is encoded by the genes NTRK1, NTRK2 and NTRK3, respectively.
  • administration refers to the physical introduction of a therapeutic agent or a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art.
  • administration or “administration” or “administration” are used interchangeably herein.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the 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.
  • the term "effective amount” means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying the The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder described in .
  • the amount of a compound of the present application 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 a person skilled in the art according to its own knowledge and this disclosure.
  • subject refers to an animal, preferably a mammal, preferably a primate, including humans and non-humans, who has been the subject of treatment, observation or experimentation Primates (such as apes, monkeys, orangutans, and chimpanzees, such as cynomolgus monkeys, spider monkeys, and macaques, such as rhesus monkeys), most preferably humans.
  • the subject has experienced and/or exhibited at least one symptom of the disease or condition to be treated and/or prevented.
  • the term "individual” may be a mammal, preferably a primate, most preferably a human.
  • the compound of formula I or a pharmaceutically acceptable salt thereof may be administered by any suitable route and method, such as orally or parenterally (eg, intravenously).
  • pharmaceutical composition refers to a mixture of one or more compounds of the present application or a pharmaceutical combination or salt thereof and pharmaceutically acceptable auxiliary materials.
  • the purpose of the pharmaceutical composition is to facilitate administration of a compound of the present application, or a pharmaceutical combination thereof, to a subject.
  • 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.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid preparations such as tablets, pills, capsules and the like.
  • the pharmaceutical composition of the present application can be produced by methods well known in the art, such as conventional mixing methods, dissolving methods, granulating methods, dragee-making methods, pulverizing methods, emulsifying methods, freeze-drying methods and the like.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive Toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • Solid oral pharmaceutical compositions can be prepared by conventional mixing, filling or tabletting methods. 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 processing the mixture into granules to obtain tablets or the core of a capsule or dragee.
  • suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
  • pharmaceutically acceptable salt or “pharmaceutically acceptable salt” refers to a salt of a compound of the present application that falls within the definition of "pharmaceutically acceptable”.
  • 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; or each bottle of injection is a single dose.
  • multiple dose consists of a number of single doses.
  • the pharmaceutical combination of the present application can be formulated as a pharmaceutical composition suitable for single or multiple administrations. In one embodiment, the pharmaceutical combination of the present application can be a single-dose or multi-dose pharmaceutical composition.
  • ORR Objective Response Rate
  • DCR disease control rate
  • progression-free survival the time from the first medication to disease progression (PD) or death before PD; if there is no PD or death before PD, the date of the last imaging assessment is used as the cut-off date.
  • Term “Duration of Response (DOR)” In subjects with CR or PR, the time between when the tumor was first assessed as CR or PR and death before PD or PD; if the subjects with CR or PR did not develop PD or died before PD, the date of the last imaging assessment was used as the cut-off date.
  • AE Adverse Event
  • NCI-CTC AE v5.0 Common Toxic Reaction Criteria
  • Moderate Significantly affects the patient's daily life.
  • OS refers to the overall survival time of cancer patients.
  • DFS refers to the disease-free survival period of cancer patients.
  • TTP refers to the time to disease progression of a tumor patient.
  • the treatment plan of the present application has a good curative effect on the treatment of TRK-mediated tumors.
  • the compound of formula I described in the application or its pharmaceutically acceptable salt, or its pharmaceutical composition is at least in survival efficacy evaluation (such as OS, median survival period); in tumor response efficacy evaluation (such as DFS, median DFS, PFS, At least one of TTP, ORR, DCR, DOR) has an excellent effect, such as ORR.
  • the compound of formula I described in the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition has a low onset dose, good patient tolerance, and small side effects (for example, little impact on the respiratory system and central nervous system, etc.), Few adverse events; no obvious accumulation in the body; excellent exposure level. It shows that the compound of formula I of the present application or its pharmaceutically acceptable salt, or its pharmaceutical composition has good pharmaceutical value.
  • the compound of formula I can be prepared by referring to the method disclosed in Example 14 of WO2019037761A1.
  • the Mobility shift assay method was used to detect the effect of the compound of formula I on the levels of TRKA, TRKB and TRKC kinases, as well as TRKA G595R , TRKA G667C and TRKC G623R kinases (the kinases were from Sandia Pharmaceutical Technology (Shanghai) Co., Ltd.).
  • the inhibition rate was calculated according to the measured fluorescence value and the IC 50 was obtained. The specific values are shown in Table 1.
  • KM12 tumor cells inoculate 7200 KM12 tumor cells per well in a 96-well transparent culture plate, compound of formula I (0.7812-200 ⁇ M, 2-fold dilution, three duplicate wells for each concentration) acts on the cells for 72 hours, discard the culture medium, Add pre-cooled 10% trichloroacetic acid (TCA) solution to each well to fix the cells, place in a refrigerator at 4°C for 2 hours, wash each well of the culture plate with deionized water 5 times to remove the TCA solution, and dry each well Add the SRB solution (4mg/mL) prepared by 1% acetic acid, let it stand at room temperature for 20 minutes, discard the liquid in each well and wash it with 1% acetic acid for 5 times, wash the unbound SRB dye and air-dry it, add appropriate amount to each well Volume of 10mM Tris-base (trishydroxymethylaminomethane) solution was dissolved, and after complete dissolution, the absorbance OD value was measured at a wavelength of 515nm with
  • CD74-NTRK1 G595R /3T3 tumor cells inoculate 3600/well CD74-NTRK1 G595R /3T3 tumor cells in a 96-well transparent culture plate, compound of formula I (0.3125-20 ⁇ M, 2-fold dilution, three replicate wells for each concentration) After acting on the cells for 72 h, the culture medium was discarded, and pre-cooled 10% trichloroacetic acid (TCA) solution was added to each well to fix the cells, and placed in a refrigerator at 4°C for 2 h, and each well of the culture plate was washed 5 times with deionized water, and Remove the trichloroacetic acid solution, add SRB solution (4mg/mL) prepared by 1% acetic acid to each well after drying, place at room temperature for 20 minutes, discard the liquid in each well and wash 5 times with 1% acetic acid to wash away unbound After the SRB dye was air-dried, an appropriate volume of 10 mM Tris-base (tris
  • ETV6-NTRK3 G623R /BaF3 tumor cells Inoculate 3000 ETV6-NTRK3 G623R /BaF3 tumor cells per well in a 96-well transparent culture plate, compound of formula I (0.03125-8nM, 2-fold dilution, three duplicate holes for each concentration) After acting on the cells for 72 hours, add the prepared 5 mg/mL MTT solution 4 hours before acting on the cells for 72 hours, continue to incubate for 4 hours, centrifuge at 1500 rpm for 5 minutes, discard the supernatant, add 200 ⁇ L DMSO to each well, and shake to dissolve Afterwards, the absorbance OD value was measured at a wavelength of 570 nm with a microplate reader.
  • ETV6-NTRK3 G623R /BaF3 cells are suspension cells, IC 50 is determined by MTT method
  • Table 2 formula I compound is to the proliferation inhibitory effect of TRK high expression cell line
  • CD74-NTRK1 G595R /3T3 cells were planted in 6-well culture plates and cultured in a 37°C, 5% CO 2 incubator.
  • the cells were treated with compounds of formula I at concentrations of 1.25 ⁇ M, 2.5 ⁇ M, and 5 ⁇ M for 24 hours and 48 hours, the cells were digested and collected, and protein samples were lysed to prepare protein samples.
  • the expression levels of proteins TRK, PLC ⁇ 1, AKT and Erk were detected by Western Blot. The results show that the compound of formula I can inhibit the activation of TRK receptor and its downstream PLC ⁇ 1, AKT and Erk signaling pathways at 24 and 48 hours, and inhibit the level of its phosphorylated protein, thereby exerting the effect of inhibiting tumor cell proliferation.
  • Embodiment 3 experiment in vivo
  • KM12 cells 5 ⁇ 10 6 human colon cancer cells KM12 were injected into the left armpit of SPF-grade female nude mice (Jiangsu Jicui Yaokang Biotechnology Co., Ltd.). After the tumor grew to an average volume of about 100 mm 3 , the animals were pressed The tumor volume was randomized and then administered. 3 mg/kg, 10 mg/kg, and 30 mg/kg of the compound of formula I were administered orally, once a day, and the tumor volume was weighed and measured twice a week. The administration cycle was 11 days, and the body weight and tumor volume were measured on the 12th day After the volume, the relative tumor volume (RTV) and relative tumor proliferation rate (T/C) were calculated. On the 12th day, the mice were sacrificed, the tumor was dissected, the tumor weight was weighed, and the inhibition rate (IR) was calculated for statistical analysis. .
  • RTV relative tumor volume
  • T/C relative tumor proliferation rate
  • CD74-NTRK1 G595R /3T3 Inject 5 ⁇ 106 mouse embryonic fibroblasts CD74-NTRK1 G595R /3T3 into the left armpit of SPF female nude mice (Jiangsu Jicui Yaokang Biotechnology Co., Ltd.), and treat the tumor After growing to an average volume of 50-100 mm 3 , animals were randomly divided into groups according to tumor volume and administered. Oral administration of 0.8mg/kg, 2.4mg/kg, 8mg/kg of the compound of formula I, 2 times a day; oral administration of 2mg/kg of the compound of formula I, once a day; weekly weighing and measurement of tumor volume 2 times , the administration cycle was 8 days or 20 days.
  • the relative tumor volume (RTV) and relative tumor proliferation rate (T/C) were calculated, and on the 8th or 21st day.
  • the mice were sacrificed, the tumors were dissected, the tumor weights were weighed, and the IR was calculated for statistical analysis.
  • ETV6-NTRK3 G623R /BaF3 Inject 5 ⁇ 106 mouse primary B cells ETV6-NTRK3 G623R /BaF3 into the left armpit of nude mice (Jiangsu Jicui Yaokang Biotechnology Co., Ltd.), and wait until the tumor grows to the average volume After about 100 mm 3 , the animals were randomly divided into groups according to the tumor volume and administered.
  • RTV relative tumor volume
  • T/C relative tumor proliferation rate
  • T/C relative tumor proliferation rate
  • IR tumor inhibition percentage
  • Embodiment 4 clinical trials
  • Compound of formula I strength 2.5mg, 5mg and 10mg, tablet.
  • the expected survival period is more than 3 months
  • a) Blood routine examination (no blood transfusion and no hematopoietic stimulating factor drugs corrected within 7 days before screening): a) hemoglobin (HGB) ⁇ 80g/L; neutrophil count (NEUT) ⁇ 1.5 ⁇ 10 9 /L; Platelet count (PLT) ⁇ 90 ⁇ 10 9 /L;
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • TBIL total bilirubin
  • CRE creatinine
  • Coagulation function activated partial thrombin time (APTT), international normalized ratio (INR), prothrombin time (PT) ⁇ 1.5 ⁇ ULN;
  • the compound tablet of formula I, qd is administered under fasting conditions (not taking food within one hour after administration), and the time of each administration should be roughly similar.
  • Indicators include ORR, DCR, PFS, DOR, SD, PR, CR, etc.
  • the objective response rate (ORR) was 57% (4/7), 4 patients had partial response (PR), 2 patients had stable disease (SD), and the disease control rate (DCR) was 85.7% (6/7 ).
  • the treatment regimens of the present disclosure were found to have clinical benefit.
  • This product is a molecule proposed by Suzhou Taolue Biotechnology for the treatment of advanced malignant solid tumors with NTRK gene fusion.
  • This product is a molecule proposed by Simcere Pharmaceutical Group Co., Ltd. for the treatment of solid tumors.
  • each medication cycle is 28-32 days, for example, C6 represents 6 cycles of medication, each cycle is 28-32 days.
  • d represents the best curative effect that has been monitored so far.

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Abstract

L'invention concerne l'utilisation d'un composé macrocyclique contenant des acides aminés dans le traitement de tumeurs à médiation par kinase TRK. Spécifiquement, la présente invention concerne l'utilisation de (13E,14E,22R,24S)-12-amino-24,35-difluoro-4-oxa-7-aza-1(5,3)-pyrazolo[1,5-a]pyrimidine-3(3,2)-pyridine-2(1,2)-pyrrolidine cyclooctaphane-8-one ou d'un sel pharmaceutiquement acceptable correspondant dans le traitement de tumeurs à médiation par kinase TRK.
PCT/CN2022/114215 2021-08-23 2022-08-23 Utilisation d'un composé macrocyclique contenant un acide aminé dans le traitement de tumeurs à médiation par kinase trk WO2023025141A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011146336A1 (fr) * 2010-05-20 2011-11-24 Array Biopharma Inc. Composés macrocycliques en tant qu'inhibiteurs de kinase trk
WO2017004342A1 (fr) * 2015-07-02 2017-01-05 Tp Therapeutics, Inc. Macrocycles de diaryle chiraux à utiliser en tant que modulateurs de protéines kinases
WO2019037761A1 (fr) * 2017-08-23 2019-02-28 正大天晴药业集团股份有限公司 Macrocycle contenant de l'aminopyrazole et de la pyrimidine, composition pharmaceutique et utilisation de celui-ci
US20210401814A1 (en) * 2018-11-09 2021-12-30 Shandong Xuanzhu Pharma Co., Ltd. Macrocyclic tyrosine kinase inhibitor and uses thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011146336A1 (fr) * 2010-05-20 2011-11-24 Array Biopharma Inc. Composés macrocycliques en tant qu'inhibiteurs de kinase trk
RU2012155278A (ru) * 2010-05-20 2014-06-27 Эррэй Биофарма Инк. Макроциклические соединения в качестве ингибиторов киназы trk
WO2017004342A1 (fr) * 2015-07-02 2017-01-05 Tp Therapeutics, Inc. Macrocycles de diaryle chiraux à utiliser en tant que modulateurs de protéines kinases
WO2019037761A1 (fr) * 2017-08-23 2019-02-28 正大天晴药业集团股份有限公司 Macrocycle contenant de l'aminopyrazole et de la pyrimidine, composition pharmaceutique et utilisation de celui-ci
US20200291042A1 (en) * 2017-08-23 2020-09-17 Chia Tai Tianqing Pharmaceutical Group Co., Ltd. Macrocycle containing aminopyrazole and pyrimidine and pharmaceutical composition and use thereof
US20210401814A1 (en) * 2018-11-09 2021-12-30 Shandong Xuanzhu Pharma Co., Ltd. Macrocyclic tyrosine kinase inhibitor and uses thereof

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