CN113811302A - Use of kinase inhibitors - Google Patents

Use of kinase inhibitors Download PDF

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CN113811302A
CN113811302A CN202080033803.0A CN202080033803A CN113811302A CN 113811302 A CN113811302 A CN 113811302A CN 202080033803 A CN202080033803 A CN 202080033803A CN 113811302 A CN113811302 A CN 113811302A
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membered
heterocyclic group
nitrogen
compound
antineoplastic agents
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CN113811302B (en
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郭霞
李彤
王静
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Xuanzhu Biopharmaceutical Co Ltd
Shandong Xuanzhu Pharma Co Ltd
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Xuanzhu Pharma Co Ltd
Xuanzhu Biopharmaceutical Co Ltd
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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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Abstract

The invention relates to application of a CDK4/6 kinase inhibitor. In particular to application of a compound shown as a formula (I'), pharmaceutically acceptable salt or crystal form thereof in preparing a medicament for treating thymoma.
Figure DDA0003339339600000011

Description

Use of kinase inhibitors 1. Field of the invention
The invention belongs to the field of medicines, and particularly relates to a CDK4/6 kinase inhibitor and a new application of a pharmaceutically acceptable salt or a crystal form thereof in preparation of a medicine for treating thymoma.
2. Background of the invention
Thymoma is a rare tumor, but the most common primary tumor of the anterior superior mediastinum accounts for about 20% -40% of all mediastinal tumors of adults, originates from thymic epithelium, is mostly located in the anterior mediastinum, is attached to the pericardium, is closely related to the great vessels in the mediastinum, and rarely occurs outside the mediastinum. Thymoma grows slowly and is considered painless, but is clinically potentially invasive and infiltrates surrounding tissues and organs. Thymoma patients typically manifest symptomatically as chest pain, dyspnea, superior vena cava syndrome, pericardial tamponade, and the like. Thymoma is closely related to autoimmune disorders, and is often accompanied by paraneoplastic syndromes such as Myasthenia Gravis (MG), granulocytopenia, erythrodysplasia, hypogammaglobulinemia, collagen vascular disease, and the like. Foreign literature shows that the annual incidence of thymoma in the population is 0.15/10 ten thousand, with a male-female ratio of 1: 1, the peak age of onset is 40-50 years old. The incidence rate of myasthenia gravis accompanied by thymoma is about 10-46%, and is mostly 30-40 years old. Childhood thymomas are rare but more malignant.
The pathogenesis of thymoma is currently unknown. The prior history of radiation therapy and EB virus infection in patients was thought by scholars to be likely related to thymoma. Surgical resection is the primary method of treatment for early stage thymoma and radiation therapy and chemotherapy may be used as an adjuvant and palliative approach in patients with inoperable or locally advanced thymus cancers. Thymoma is relatively sensitive to chemotherapy, and a combined chemotherapy scheme containing cisplatin, such as combined chemotherapy of cisplatin and doxorubicin or combined chemotherapy of doxorubicin, cisplatin, vincristine and cyclophosphamide, is mostly adopted at present, but chemotherapy brings huge side effects to patients. Therefore, various pharmaceutical companies are working on developing high-efficiency and low-toxicity small-molecule drugs. Currently, there is no specific small molecule therapeutic for the treatment of thymoma and there is an unmet medical need in the treatment field.
PCT/CN2014/095615 discloses a series of CDK4/6 kinase inhibitors. The research shows that the compound has excellent CDK4/6 kinase inhibitory activity, shows good blood brain barrier permeability, provides possibility for CDK inhibitors as tumor treatment and has good safety.
Figure PCTCN2020088874-APPB-000001
However, this patent does not disclose the therapeutic effect of the compounds on thymoma.
In the process of researching the above patent compounds, the inventors unexpectedly found that the compound of formula (I ') has good therapeutic effect on thymoma, and can significantly reduce the volume of tumor, which indicates that the compound of formula (I') is expected to be a specific drug for treating thymoma.
3. Summary of the invention
The invention relates to a novel application of a compound shown as a formula (I'), pharmaceutically acceptable salt thereof or crystal form thereof in preparing a medicament for treating thymoma.
The technical scheme of the invention is as follows:
the invention provides an application of a compound shown in a formula (I'), pharmaceutically acceptable salts thereof or crystal forms thereof in preparing a medicament for treating thymoma,
Figure PCTCN2020088874-APPB-000002
wherein the content of the first and second substances,
A 1and A2Each independently is nitrogen;
R 1is selected from C1-6An alkyl group;
R 2is selected from C1-6An alkyl group;
R 3and R5Each independently selected from halogen or hydrogen, and R3And R5At least one is halogen;
R 4selected from optionally Q2Substituted 5-6 membered nitrogen-containing heterocyclic group, 6-10 membered nitrogen-containing fused heterocyclic group, 7-9 membered nitrogen-containing bridged heterocyclic group or 7-11 membered nitrogen-containing spiro heterocyclic group;
Q 2selected from amino, hydroxy, halogen, trifluoromethyl, cyano, C1-6Alkoxy radicals, di C1-6Alkylamino, or C optionally substituted by substituents1-6Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl or 7-9 membered bridged heterocyclyl, said substituents being selected from amino, hydroxy, halogen, trifluoromethyl, cyano, C1-6Alkyl radical, C1-6Alkoxy, 3-6 membered cycloalkyl;
n is selected from 0 and 1.
In certain embodiments, wherein the compound has the structure of formula (I'),
Figure PCTCN2020088874-APPB-000003
wherein the content of the first and second substances,
A 1and A2Are respectively and independentlyIs nitrogen;
R 1is selected from C1-4An alkyl group;
R 2is selected from C1-4An alkyl group;
R 3and R5Each independently selected from halogen;
R 4selected from optionally Q2Substituted 5-6 membered nitrogen-containing heterocyclic group, 6-10 membered nitrogen-containing fused heterocyclic group, 7-9 membered nitrogen-containing bridged heterocyclic group or 7-11 membered nitrogen-containing spiro heterocyclic group,
Q 2selected from amino, hydroxy, trifluoromethyl, cyano, C1-4Alkyl radical, C1-4Alkoxy, 5-6 membered heterocyclyl or 7-9 membered bridged heterocyclyl.
In some embodiments of the present invention, the substrate is,
A 1and A2Each independently is nitrogen;
R 1is isopropyl;
R 2is methyl;
R 3and R5Each is fluorine;
R 4selected from optionally Q2Substituted 5-6 membered nitrogen containing heterocyclyl wherein Q2Selected from amino, hydroxy, trifluoromethyl, cyano, C1-4Alkyl radical, C1-4Alkoxy, 6-membered heterocyclyl or 8-membered bridged heterocyclyl.
In some embodiments of the present invention, the substrate is,
R 4selected from optionally Q2A substituted 5-6 membered nitrogen-containing heterocyclic group containing 1 to 2 nitrogen atoms, said 5-6 membered nitrogen-containing heterocyclic group being linked to a methylene group in the general formula (I') through a nitrogen atom, wherein Q2Selected from amino, hydroxy, trifluoromethyl, cyano, C1-4Alkyl radical, C1-4Alkoxy or an 8-membered nitrogen-containing bridged heterocyclic group.
In some embodiments of the present invention, the substrate is,
R 4selected from optionally Q2SubstitutionIs/are as follows
Figure PCTCN2020088874-APPB-000004
Wherein Q2Is selected from C1-4Alkyl or an 8-membered nitrogen-containing bridged heterocyclic group.
In certain embodiments, wherein said compound of formula (Γ) is selected from:
Figure PCTCN2020088874-APPB-000005
Figure PCTCN2020088874-APPB-000006
Figure PCTCN2020088874-APPB-000007
Figure PCTCN2020088874-APPB-000008
in certain embodiments, the compound is selected from the group consisting of compound (compound 1) shown below, or a pharmaceutically acceptable salt or crystalline form thereof:
Figure PCTCN2020088874-APPB-000009
in certain embodiments of the invention, the crystalline form is an episomal crystalline form of compound 1.
In certain embodiments of the present invention, the crystalline form is free form a of compound 1, which form a has characteristic peaks at 6.6 ± 0.2 °, 10.0 ± 0.2 °, 13.2 ± 0.2 °, 17.4 ± 0.2 °, 20.1 ± 0.2 °, 20.6 ± 0.2 ° in an X-ray powder diffraction pattern, expressed in terms of 2 θ angle, using Cu-ka radiation.
In certain embodiments of the invention, the crystalline form is free form a of compound 1, which form a has characteristic peaks at 6.6 ± 0.2 °, 8.7 ± 0.2 °, 10.0 ± 0.2 °, 10.9 ± 0.2 °, 13.2 ± 0.2 °, 15.7 ± 0.2 °, 16.4 ± 0.2 °, 17.4 ± 0.2 °, 20.1 ± 0.2 °, 20.6 ± 0.2 °, 30.4 ± 0.2 ° in an X-ray powder diffraction pattern expressed in terms of 2 θ using Cu-ka radiation.
In certain embodiments of the invention, the crystalline form is free form a of compound 1, which form a has characteristic peaks at 6.6 ± 0.2 °, 8.7 ± 0.2 °, 10.0 ± 0.2 °, 10.9 ± 0.2 °, 13.2 ± 0.2 °, 15.7 ± 0.2 °, 16.4 ± 0.2 °, 16.7 ± 0.2 °, 17.4 ± 0.2 °, 19.3 ± 0.2 °, 20.1 ± 0.2 °, 20.6 ± 0.2 °, 22.2 ± 0.2 °, 23.3 ± 0.2 °, 24.0 ± 0.2 °, 25.9 ± 0.2 °, 28.1 ± 0.2 °, 30.4 ± 0.2 ° in an X-ray powder diffraction pattern, expressed in terms of 2 θ, using Cu-ka radiation.
In certain embodiments of the invention, the crystalline form is free form a of compound 1, having an X-ray powder diffraction pattern obtained using Cu-ka radiation substantially as shown in figure 4.
In certain embodiments of the invention, the crystalline form is a crystalline form of a salt of compound 1.
In certain embodiments of the invention, the crystalline form is a maleate crystalline form of compound 1.
In certain embodiments of the invention, the crystalline form is a dimaleate crystalline form of compound 1.
In certain embodiments, the thymoma is an advanced and/or metastatic thymoma.
In certain embodiments, the thymoma is a locally advanced, advanced and/or metastatic thymoma.
In certain embodiments, the thymoma is one that has failed other anti-tumor therapy.
In certain embodiments, the additional anti-tumor therapy is selected from one or more of surgery, radiation therapy, chemotherapy, immunotherapy, and targeted therapy with a targeted drug other than a compound of formula (I'), pharmaceutically acceptable salts thereof, and crystalline forms thereof.
In certain embodiments, the patient with thymoma carries a GTF2I oncogene point mutation.
In certain embodiments, the thymoma is selected from the group consisting of benign thymoma and thymus carcinoma.
In certain embodiments, the thymoma is a thymoma.
In certain embodiments, the thymus cancer is selected from the following subtypes: squamous carcinoma of thymus, basal cell carcinoma of thymus, mucoepidermoid carcinoma, sarcomatoid carcinoma, adenocarcinoma, NUT cancer.
In certain embodiments, the thymoma is selected from the following subtypes: type a, type AB, type B1, type B2, and type B3.
In certain embodiments, the compound of formula (Γ), a pharmaceutically acceptable salt thereof, or a crystalline form thereof is administered alone or in combination with one or more other therapeutic agents.
In certain embodiments, the additional therapeutic agent is selected from the group consisting of antimetabolite antineoplastic agents, growth factor inhibitor antineoplastic agents, antibody antineoplastic agents, mitosis inhibitor antineoplastic agents, hormonal antineoplastic agents, alkylating agent antineoplastic agents, metal platinum antineoplastic agents, topoisomerase inhibitor antineoplastic agents, immunosuppressive antineoplastic agents, purine analog antineoplastic agents, antibiotic antineoplastic agents, kinase inhibitor antineoplastic agents, targeted therapeutic agents.
The invention also provides the use of a pharmaceutical composition comprising a compound of formula (I'), a pharmaceutically acceptable salt thereof, or a crystalline form thereof, and a pharmaceutically acceptable carrier, optionally, further comprising one or more additional therapeutic agents.
In certain embodiments, the additional therapeutic agent is selected from the group consisting of antimetabolite antineoplastic agents, growth factor inhibitor antineoplastic agents, antibody antineoplastic agents, mitosis inhibitor antineoplastic agents, hormonal antineoplastic agents, alkylating agent antineoplastic agents, metal platinum antineoplastic agents, topoisomerase inhibitor antineoplastic agents, immunosuppressive antineoplastic agents, purine analog antineoplastic agents, antibiotic antineoplastic agents, kinase inhibitor antineoplastic agents, targeted therapeutic agents.
In certain embodiments, the crystalline form is selected from free crystalline forms of the compound of formula (I').
4. Detailed description of the invention
"halogen" as referred to herein includes, for example, fluorine, chlorine, bromine and iodine.
"C" according to the invention1-6Alkyl groups "may be straight or branched and include, for example," C1-4Alkyl group "," C1-3Alkyl "and the like, specific examples of which include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-dimethylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like.
"C" according to the invention1-6Alkoxy, di-C1-6Alkylamino "means with C1-6alkyl-O-, (C)1-6Alkyl radical)2A group formed by the formula-N-, in which "C" is1-6Alkyl "is as defined above.
"C" according to the invention1-4Alkoxy, di-C1-4Alkylamino "means with C1-4alkyl-O-, (C)1-4Alkyl radical)2A group formed by the formula-N-, in which "C" is1-4Alkyl "is as defined above.
The "3-6 membered cycloalkyl group" as referred to herein means a cyclic alkyl group derived from an alkane moiety of 3 to 6 carbon atoms by removing one hydrogen atom, and includes, for example, "3-5 membered cycloalkyl group", "4-6 membered cycloalkyl group", "5-6 membered cycloalkyl group" and the like. Examples include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane and the like.
The "3-6-membered heterocyclic group" as used herein means a saturated or partially saturated cyclic group having at least one hetero atom (e.g., 1,2, 3,4 or 5 atoms) which is a nitrogen atom, an oxygen atom and/or a sulfur atom, and having 3 to 6 ring atoms, and optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxidized, and includes, for example, "5-6-membered heterocyclic group", "5-6-membered nitrogen-containing heterocyclic group", "6-membered nitrogen-containing heterocyclic group" and the like. Specific examples include, but are not limited to: 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuryl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, hexahydropyrimidinyl, hexahydropyridazinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, 2H-1, 2-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl and the like, preferably a "5-6-membered nitrogen-containing heterocyclic group".
The "linkage to a methylene group in the general formula (I") via a nitrogen atom "as used herein means that a nitrogen-containing group (for example, a nitrogen-containing heterocyclic group such as" 5-6-membered nitrogen-containing heterocyclic group "or" 6-membered nitrogen-containing heterocyclic group ", a nitrogen-containing fused heterocyclic group such as" 6-10-membered nitrogen-containing fused heterocyclic group ", a nitrogen-containing bridged heterocyclic group such as" 7-9-membered nitrogen-containing bridged heterocyclic group "or" 8-membered nitrogen-containing bridged heterocyclic group ", and a nitrogen-containing spiro heterocyclic group such as" 7-11-membered nitrogen-containing spiro heterocyclic group ") is linked to a methylene group via a nitrogen atom.
According to the rules of IUPAC compound nomenclature, a fused ring as referred to herein refers to a fused ring structure formed by two or more ring structures that share two adjacent atoms with each other (i.e., share a bond). The bridged ring of the invention refers to a bridged ring structure formed by connecting two or more cyclic structures sharing two non-adjacent carbon atoms. The spiro ring of the present invention is a spiro ring structure formed by connecting two or more cyclic structures sharing a carbon atom.
The "6-to 10-membered fused heterocyclic group" as used herein means a fused ring structure of 6 to 10 ring atoms having at least one hetero atom formed by two or more ring structures sharing two adjacent atoms (i.e., sharing one bond) and connecting each other, and includes, for example, "6-to 10-membered nitrogen-containing fused heterocyclic group" and the like. Specific examples include, but are not limited to: 3-azabicyclo [3.1.0] hexane, 3, 6-diazabicyclo [3.2.0] heptane, 3, 8-diazabicyclo [4.2.0] octane, 3, 7-diazabicyclo [4.2.0] octane, octahydropyrrolo [3,4-c ] pyrrole, octahydropyrrolo [3,4-b ] [1,4] oxazine, octahydro-1H-pyrrolo [3,4-c ] pyridine, octahydro-1H-pyrrolo [3,4-b ] pyridine, octahydro-1H-pyrido [3,4-b ] [1,4] oxazine, decahydro-2, 6-naphthalene, tetrahydroimidazo [4,5-c ] pyridyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, 3, 6-dihydroquinoxalinyl, Benzo [ d ] [1,3] dioxolyl, 1, 3-dihydroisobenzofuranyl, 2H-chromenyl, 2H-chromen-2-onyl, 4H-chromenyl, 4H-chromen-4-onyl, chromanyl, 4H-1, 3-benzoxazinyl, 4, 6-dihydro-1H-furo [3,4-d ] imidazolyl, 3a,4,6,6 a-tetrahydro-1H-furo [3,4-d ] imidazolyl, 4, 6-dihydro-1H-thieno [3,4-d ] imidazolyl, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazolyl, 4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazolyl, and the like.
The term "7-to 9-membered bridged heterocyclic group" as used herein means a bridged ring structure of 7 to 9 ring atoms having at least one heteroatom selected from N, S, O, CO, SO and/or SO, wherein any two rings share two non-adjacent atoms2And the like. These include, for example, "6-9 membered bridged heterocyclic group", "7-9 membered nitrogen-containing bridged heterocyclic group", "7-8 membered bridged heterocyclic group", "8 membered nitrogen-containing bridged heterocyclic group", etc. Examples include, but are not limited to:
Figure PCTCN2020088874-APPB-000010
Figure PCTCN2020088874-APPB-000011
Figure PCTCN2020088874-APPB-000012
and the like.
The "7-to 11-membered spiroheterocyclic group" of the present invention refers to a 7-to 11-membered spirocyclic structure having at least two rings sharing one atom and containing at least one heteroatom selected from N, S, O, CO, SO and/or SO2And the like. These include, for example, "6-11 membered spiroheterocyclic group", "7-11 membered nitrogen-containing spiroheterocyclic group", "7-10 membered spiroheterocyclic group", "7-9 membered spiroheterocyclic group", "7-8 membered spiroheterocyclic group" and the like. Examples include, but are not limited to:
Figure PCTCN2020088874-APPB-000013
Figure PCTCN2020088874-APPB-000014
Figure PCTCN2020088874-APPB-000015
and the like.
In the "pharmaceutically acceptable salt of the compound of formula (I ') according to the present invention", the molecular ratio of the compound of formula (I') to the corresponding alkali metal, other metal, organic base, inorganic acid, organic acid may be any value.
The pharmaceutical composition is any pharmaceutically acceptable dosage form, and is applied to a patient in need of the pharmaceutical composition in a mode of oral administration, parenteral administration, rectal administration or pulmonary administration. For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection solution, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, it can be made into suppository, etc. For pulmonary administration, it can be made into inhalant or spray.
The pharmaceutically acceptable carrier includes, but is not limited to: fillers, diluents, binders, wetting agents, disintegrants, lubricants, surfactants, preservatives, colorants, flavors, fragrances, effervescent agents, emulsifiers, flocculants, deflocculants, bacteriostats, and solubilizers.
The tumor, cancer or carcinoma of the present invention also includes metastases in the primary organ, tissue and/or any other location, regardless of the location of the tumor metastasis.
Failure of other anti-tumor treatments described herein refers to progression or intolerance of the disease using other anti-tumor treatments.
The thymoma of the present invention includes type a, type AB, type B1, type B2 and type B3 according to the World Health Organization (WHO) classification (fourth edition 2015).
The thymus cancer of the present invention is classified into the following subtypes according to WHO classification (fourth edition 2015): squamous cell carcinoma of thymus, basal cell carcinoma of thymus, mucoepidermoid carcinoma, sarcomatoid carcinoma, adenocarcinoma, NUT cancer, and the like. The thymus gland cancer comprises malignant thymus gland tumor.
The chemotherapy is the abbreviation of chemical drug therapy, and achieves the purpose of treatment mainly by using chemical treatment drugs to kill cancer cells, and the used chemical drugs are mainly drugs with cytotoxicity.
The "radiotherapy" in the invention refers to a tumor treatment method, i.e. tumor radiotherapy, which mainly uses radioactive rays to perform local tumor treatment, wherein the "radioactive rays" include alpha, beta and gamma rays generated by radioactive isotopes, and x rays, electron beams, proton beams and other particle beams generated by various x-ray treatment machines or accelerators.
The targeted therapy refers to a method for performing positioning accurate therapy by identifying specific proteins of tumor cells by using targeted drugs.
The term "immunotherapy" as used herein refers to a therapeutic method for controlling or eliminating tumor cells by activating the immune system in vivo.
In the present invention, the subject or patient may be any animal, preferably a mammal, such as bovine, equine, ovine, porcine, canine, feline, rodent, primate. Among these, particularly preferred subjects are humans.
"QD" as used herein means administered once daily.
The present invention also provides a method of treating thymoma comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I'), a pharmaceutically acceptable salt thereof, or a crystalline form thereof, which may be administered by any conventional and acceptable means known in the art, the therapeutically effective amount being adjusted according to the race, sex, age, body weight, medical condition, type of disease, severity of disease, route of administration and associated health condition of the patient, and other factors known to those skilled in the art.
As used herein, "therapeutically effective amount" refers to an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. It is well within the ability of those skilled in the art to determine such effective amounts. For example, an amount effective for therapeutic use will depend on the severity of the disease to be treated, the general state of the patient's own immune system, the general condition of the patient, e.g., age, weight and sex, the mode of administration of the drug, and other treatments administered concurrently, and the like.
The invention also provides a combination of a compound of formula (I') and one or more other therapeutic agents which may be administered simultaneously or sequentially with a compound of formula (1) for the treatment of a subject suffering from thymoma.
5. Attached drawing of the specification
Figure 1 CT radiographic image before compound 1 treatment.
Fig. 2 CT radiographs after eight cycles (about eight months) of compound 1 administration.
FIG. 3 percent change in target lesion tumor size after administration of Compound 1, with the abscissa representing time (days of study), where C3D1 represents day 1 of cycle 3, C5D1 represents day 1 of cycle 5, and so on, for about 28 days per cycle, corresponding specifically to the dosing regimen in the experimental example; the ordinate is the percent change in tumor volume.
Figure 4 is an X-ray powder diffraction pattern (XRPD pattern) of compound 1 form a with diffraction intensity (intensity) on the ordinate and diffraction angle (2 θ) on the abscissa.
Detailed Description
The present invention will be described in detail with reference to specific examples and experimental examples. It should be understood that the following examples and experimental examples are only for illustrating the present disclosure, but not for limiting the scope of the present disclosure. The following examples, which do not indicate specific conditions, were conducted according to conventional conditions or as recommended by the manufacturer. The medicines or reagents used are not indicated by manufacturers, and are all conventional products which can be obtained commercially.
The compounds of formula (I') used in the following examples or experimental examples were prepared according to the preparation method of example 1 described in patent application PCT/CN2014/095615 (i.e. compound 1).
The crystal form A of the compound 1 is the crystal form A of the compound shown as the formula (I) in the specification of the patent application PCT/CN2018/124418, and the content related to the preparation method is cited in the specification. For the crystalline form a of compound 1 mentioned in the present application, the parameter characterization, property test, etc. are referred to patent application PCT/CN2018/124418 and incorporated herein.
Preparation examples:
preparation method of crystal form A of compound 1
The preparation method comprises the following steps: and adding 75mL of acetone into 5.0g of the compound 1, dissolving under magnetic stirring to immediately separate out a white solid, stirring for 5 hours, carrying out suction filtration to obtain white powder, carrying out vacuum drying at 35 ℃ for 16 hours, and testing the obtained solid by XRPD to obtain the crystal form A.
The second preparation method comprises the following steps: adding 15mL of isopropanol into 500mg of compound 1, stirring at 80 ℃ in an oil bath, dissolving and clearing (within 4.0 h), naturally cooling to room temperature (32 ℃), precipitating white solid, continuously stirring at room temperature for 12h, cooling to 15 ℃, stirring for 4.0h, performing suction filtration, vacuum drying the obtained solid at 45 ℃ for 16h, XRPD, and,1And H-NMR analysis shows that the obtained solid is the crystal form A.
The preparation method comprises the following steps: taking 5.0g of compound 1 into a 100mL three-necked bottle, adding 75mL of sec-butyl alcohol, controlling the temperature of an oil bath at 95 ℃, and mechanically stirring for 0.5h to dissolve and become clear. Then cooling to oil bath 70 ℃, adding crystal seeds (namely crystal form A obtained by the first preparation method and the second preparation method) about 25mg, beginning to slowly separate out white solid, continuously cooling to oil bath 60 ℃, keeping the temperature for 0.5h, cooling to 55 ℃, keeping the temperature for 0.5h, continuously cooling to about 20 ℃, stirring for 1.5h, carrying out suction filtration, carrying out methyl tert-butyl ether leaching (2 x 10mL), carrying out vacuum drying on the obtained solid for 24h at 65 ℃,1H-NMR detection shows no solvent residue, and XRPD analysis shows that the crystal form A is formed.
The preparation method comprises the following steps:
1) preparing seed crystals: taking 40g of the compound 1 and 300g of n-amyl alcohol, heating to 75 ℃, wherein the rotating speed of a stirring paddle is 300R/min, starting to dissolve the raw material after about 0.5h, completely dissolving the raw material and keeping 75 ℃ stable for 0.5h after the raw material becomes clear. The stirring rate was reduced to R150R/min and the clear solution was rapidly cooled to 55 ℃ over about 0.5 h. And after the temperature reaches 55 ℃, increasing the stirring speed until R is 300R/min, continuously cooling at the speed of 9 ℃/h until the temperature reaches 5 ℃, slowly turbidity and separating out solids from the system, keeping the temperature for 2 hours after the temperature reaches 5 ℃, and performing suction filtration to obtain the solids, namely the seed crystals.
2) The preparation method of the crystal form A comprises the following steps: dispersing 50g of compound 1 in 300g of n-amyl alcohol, heating to 85 ℃, completely dissolving and becoming clear, quickly cooling to 58 ℃ (85-58 ℃/h), adding 0.1g of seed crystal obtained in the step 1), keeping the temperature for 60min, slowly cooling the system until the system becomes white solid at the constant temperature, keeping the temperature overnight at the constant temperature of 6 ℃/h until the system becomes white solid, then carrying out suction filtration, putting the obtained solid into a vacuum drying device, drying at 100 ℃ for 6h, drying the obtained solid for 24h at 65 ℃ in vacuum,1H-NMR detection showsShows no solvent residue and is analyzed by XRPD to be the crystal form A.
The product obtained by the first to fourth preparation methods is detected, the purity of the crystal form A is more than 99.7%, the single maximum impurity is less than 0.08%, and almost no solvent residue exists.
XRPD testing
The apparatus used was: bruker D2X ray powder diffractometer.
X-ray parameters: cu, Ka; entrance slit: 0.6 mm; divergent slit: 1 mm; scanning mode: continuously; scanning range: 3.0-45.0 ℃; sampling step length: 0.02 degree; scanning time of each step: 19.8 s; detector angle: 2.0 degrees.
Form a of compound I is shown in figure 4 by X-ray powder diffraction pattern, having peaks at the following diffraction 2 Θ angles: 6.6 +/-0.2 degrees, 8.7 +/-0.2 degrees, 10.0 +/-0.2 degrees, 10.9 +/-0.2 degrees, 13.2 +/-0.2 degrees, 15.7 +/-0.2 degrees, 16.4 +/-0.2 degrees, 16.7 +/-0.2 degrees, 17.4 +/-0.2 degrees, 19.3 +/-0.2 degrees, 20.1 +/-0.2 degrees, 20.6 +/-0.2 degrees, 22.2 +/-0.2 degrees, 23.3 +/-0.2 degrees, 24.0 +/-0.2 degrees, 25.9 +/-0.2 degrees, 28.1 +/-0.2 degrees and 30.4 +/-0.2 degrees.
Experimental examples the therapeutic Effect of Compounds of formula (I') on thymoma
And (3) testing the sample:
tablets of compound 1 form a. Adding proper auxiliary materials into the compound 1 crystal form A to prepare tablets with certain specifications.
Test grouping criteria:
1. male or female subjects 18-70 years of age (including 18 and 70 years of age);
2. a locally advanced or metastatic malignant thymoma subject that has been histologically or cytologically diagnosed and failed (disease progression or intolerance) or lacks standard therapy;
3. the subject must have at least one measurable lesion that meets RECIST v1.1 definition;
the ECOG score is 0-1;
5. all acute toxicity responses of previous anti-cancer treatments or surgeries were alleviated to baseline or grade 1 (NCI-CTCAE version v4.03, with the exception of hair loss or other toxicities that researchers believe there is no safety risk to the subject);
6. all the previous anti-tumor treatments (including chemotherapy, radiotherapy, immunotherapy and the like, but not castration treatment) are stopped for at least 4 weeks before the first administration (wherein the treatment stop of nitrosoureas or mitomycin is more than or equal to 6 weeks, and the oral breast cancer endocrine treatment drugs, small molecule targeted treatment drugs and anti-tumor traditional Chinese medicines (decoction or Chinese patent medicines) are stopped for at least 2 weeks);
7. the subjects' organs functioned well when enrolled and the laboratory examination data met the following criteria:
blood routine: the absolute count of the neutrophils is more than or equal to 2.0 multiplied by 109/L (or more than the lower limit of the normal value of a laboratory in a research center), and the platelet count is more than or equal to 100 multiplied by 109The hemoglobin is more than or equal to 100 g/L;
liver function: serum total bilirubin is less than or equal to 1.5 times of the upper limit of standard value (ULN), AST and ALT are less than or equal to 1.5 times of ULN;
renal function: CrCl is more than or equal to 60ml/min/1.73m2(calculated according to the Cockcroft-Gault formula);
8. the life of the expected subject is more than or equal to 12 weeks according to the judgment of a researcher;
9. male or female fertile subjects must agree to use effective methods of contraception, such as double barrier methods of contraception, condoms, oral or injectable contraceptives, intrauterine devices, and the like, during the study period and within 30 days of the last study medication;
10. prior to study initiation, subjects had to provide written informed consent.
The medical history:
a36-year-old male patient is diagnosed with cough, expectoration, abdominal distension, diarrhea and dry mouth in the last 7 th month of 2015, and PET-CT examination shows that: the left pleura is thickened frequently and has high metabolic activity, and the two lungs are provided with multiple spot shadows and micro-nodules. Puncture biopsy of pleural tumor: b1 (lymphocyte-rich) thymoma. In 7 months and 31 days, thoracoscopy assisted lower left thoracotomy exploration, thymoma resection of left lung upper lobe wedge-shaped resection, partial pericardial resection, pleura spallation and thoracic closed drainage are performed in thoracic surgery. Postoperative pathology: thymoma, type B2, invades the parietal pericardium, lung tissue, and the pleura of the visceral, parietal, and septal regions.
Postoperative assistance: paclitaxel + lobaplatin postoperative adjuvant chemotherapy was performed for 4 cycles on days 9, 16, 12, 10 in 2015. And in 2018, the paclitaxel + cisplatin + recombinant human endostatin regimen is carried out for 2 cycles on 13 days in 4 months and 17 days in 5 months.
The treatment process comprises the following steps:
admission diagnosis at 26 days 6 and 2018: thymoma, left lung and pleural metastases; otitis media; double pneumonia. The main complaints are: double tinnitus, occasionally cough, cough with phlegm, yellow and sticky phlegm, and more phlegm. Piperacillin sodium and tazobactam sodium anti-infection treatment is carried out on 28 days in 6 months, combined fluconazole antifungal treatment is carried out on 3 days in 7 months, moxifloxacin and voriconazole anti-infection treatment is carried out on 11 days in 7 months, and inflammation improvement is rechecked on 16 days in 7 months.
Baseline examination before completion of enrollment in 2018, 7 months and 19 days. CT is enhanced to examine the chest and abdomen basin: thymoma, post-pleural denudation changes; left anterior superior mediastinal soft tissue density shadow; infectious lesions of both lungs; the ECOG score is less than or equal to 1, and the life time is estimated to be more than or equal to 12 weeks according to the judgment of researchers; the vital signs, physical examination, electrocardiogram, echocardiogram and laboratory safety examination result all accord with the standard.
Evaluation criteria of target lesions
Figure PCTCN2020088874-APPB-000016
The administration scheme is as follows:
1)80mg QD was administered for 3 consecutive cycles (i.e., cycles 1-3);
2)160mg QD was administered for 4 consecutive cycles (i.e., cycles 4-7);
3)240mg QD was administered for 3 consecutive cycles (i.e., cycles 8-10);
4)320mg QD was administered for 3 consecutive cycles (i.e., cycles 11-13).
Adverse events:
adverse events include vomiting (grade 1), and the symptoms disappear after taking the medicine after the meal instead of taking the medicine on an empty stomach, and the clinical control is realized. No Serious Adverse Events (SAE) occurred and cases of discontinuation of dosing, down-regulation of dose and early group withdrawal due to adverse events.
The curative effect is as follows:
this time for second line treatment of malignant thymomas, the course of treatment underwent 3 dose upscaling, with a dose of 320mg QD currently used. The patient has now stabilized for a period of 12 months and, as shown in figure 3, at the end of cycle 12 dosing, tumor meridian and has shrunk by 38.6% from baseline, the target lesion meets the criteria of Partial Remission (PR).

Claims (15)

  1. The use of a compound of formula (I'), a pharmaceutically acceptable salt thereof or a crystalline form thereof in the manufacture of a medicament for the treatment of thymoma,
    Figure PCTCN2020088874-APPB-100001
    wherein the content of the first and second substances,
    A 1and A2Each independently is nitrogen;
    R 1is selected from C1-6An alkyl group;
    R 2is selected from C1-6An alkyl group;
    R 3and R5Each independently selected from halogen or hydrogen, and R3And R5At least one is halogen;
    R 4selected from optionally Q2Substituted 5-6 membered nitrogen-containing heterocyclic group, 6-10 membered nitrogen-containing fused heterocyclic group, 7-9 membered nitrogen-containing bridged heterocyclic group or 7-11 membered nitrogen-containing spiro heterocyclic group;
    Q 2selected from amino, hydroxy, halogen, trifluoromethyl, cyano, C1-6Alkoxy radicals, di C1-6Alkylamino, or C optionally substituted by substituents1-6Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl or 7-9 membered bridged heterocyclyl, said substituents being selected from amino, hydroxy, halogen, trifluoromethyl, cyano, C1-6Alkyl radical, C 1-6Alkoxy, 3-6 membered cycloalkyl;
    n is selected from 0 and 1.
  2. The use according to claim 1, wherein the compound has the structure of formula (I'),
    Figure PCTCN2020088874-APPB-100002
    wherein the content of the first and second substances,
    A 1and A2Each independently is nitrogen;
    R 1is selected from C1-4An alkyl group;
    R 2is selected from C1-4An alkyl group;
    R 3and R5Each independently selected from halogen;
    R 4selected from optionally Q2Substituted 5-6 membered nitrogen-containing heterocyclic group, 6-10 membered nitrogen-containing fused heterocyclic group, 7-9 membered nitrogen-containing bridged heterocyclic group or 7-11 membered nitrogen-containing spiro heterocyclic group,
    Q 2selected from amino, hydroxy, trifluoromethyl, cyano, C1-4Alkyl radical, C1-4Alkoxy, 5-6 membered heterocyclyl or 7-9 membered bridged heterocyclyl.
  3. Use according to claim 2, wherein
    A 1And A2Each independently is nitrogen;
    R 1is isopropyl;
    R 2is methyl;
    R 3and R5Each is fluorine;
    R 4selected from optionally Q2Substituted 5-6 membered nitrogen containing heterocyclyl wherein Q2Selected from amino,Hydroxy, trifluoromethyl, cyano, C1-4Alkyl radical, C1-4Alkoxy, 6-membered heterocyclyl or 8-membered bridged heterocyclyl.
  4. Use according to claim 3, wherein
    R 4Selected from optionally Q2A substituted 5-6 membered nitrogen-containing heterocyclic group containing 1 to 2 nitrogen atoms, said 5-6 membered nitrogen-containing heterocyclic group being linked to a methylene group in the general formula (I') through a nitrogen atom, wherein Q2Selected from amino, hydroxy, trifluoromethyl, cyano, C1-4Alkyl radical, C1-4Alkoxy or an 8-membered nitrogen-containing bridged heterocyclic group.
  5. The use as claimed in claim 4, wherein
    R 4Selected from optionally Q2Substituted by
    Figure PCTCN2020088874-APPB-100003
    Wherein Q2Is selected from C1-4Alkyl or an 8-membered nitrogen-containing bridged heterocyclic group.
  6. Use according to claim 1, said compound being selected from the following compounds:
    Figure PCTCN2020088874-APPB-100004
    Figure PCTCN2020088874-APPB-100005
    Figure PCTCN2020088874-APPB-100006
    Figure PCTCN2020088874-APPB-100007
  7. the use according to any one of claims 1 to 6, wherein the compound is selected from the following compounds:
    Figure PCTCN2020088874-APPB-100008
  8. the use according to any one of claims 1 to 7, wherein the thymoma is advanced and/or metastatic thymoma.
  9. The use of any one of claims 1 to 7, wherein the thymoma is one that has failed other anti-tumor therapy.
  10. The use of any one of claims 1 to 7, wherein the thymoma is thymus carcinoma.
  11. The use according to any one of claims 1 to 10, wherein the compound of formula (Γ), a pharmaceutically acceptable salt thereof, or a crystalline form thereof is administered alone or in combination with one or more other therapeutic agents.
  12. Use of a pharmaceutical composition comprising a compound of formula (I'), a pharmaceutically acceptable salt thereof, or a crystalline form thereof, in combination with a pharmaceutically acceptable carrier, optionally together with one or more other therapeutic agents, in the manufacture of a medicament for the treatment of thymoma.
  13. The use according to claim 11 or 12, wherein the other therapeutic agent is selected from antimetabolite antineoplastic agents, growth factor inhibitor antineoplastic agents, antibody antineoplastic agents, mitosis inhibitor antineoplastic agents, hormone antineoplastic agents, alkylating antineoplastic agents, metal platinum antineoplastic agents, topoisomerase inhibitor antineoplastic agents, immunosuppressive antineoplastic agents, purine analogue antineoplastic agents, antibiotic antineoplastic agents, kinase inhibitor antineoplastic agents, targeted therapeutic agents.
  14. Use according to any one of claims 1 to 13, wherein the crystalline form is selected from free crystalline forms of the compound of formula (Γ).
  15. The use according to any one of claims 1 to 14, wherein the crystalline form is selected from form a of a compound having characteristic peaks at 6.6 ± 0.2 °, 10.0 ± 0.2 °, 13.2 ± 0.2 °, 17.4 ± 0.2 °, 20.1 ± 0.2 °, 20.6 ± 0.2 ° in an X-ray powder diffraction pattern, expressed in terms of 2 Θ angles, using Cu-ka radiation;
    preferably, the form A has characteristic peaks at 6.6 +/-0.2 °, 8.7 +/-0.2 °, 10.0 +/-0.2 °, 10.9 +/-0.2 °, 13.2 +/-0.2 °, 15.7 +/-0.2 °, 16.4 +/-0.2 °, 17.4 +/-0.2 °, 20.1 +/-0.2 °, 20.6 +/-0.2 ° and 30.4 +/-0.2 ° in an X-ray powder diffraction pattern expressed by using Cu-Kalpha radiation and 2 theta angles;
    preferably, the crystal form A has characteristic peaks at 6.6 +/-0.2 °, 8.7 +/-0.2 °, 10.0 +/-0.2 °, 10.9 +/-0.2 °, 13.2 +/-0.2 °, 15.7 +/-0.2 °, 16.4 +/-0.2 °, 16.7 +/-0.2 °, 17.4 +/-0.2 °, 19.3 +/-0.2 °, 20.1 +/-0.2 °, 20.6 +/-0.2 °, 22.2 +/-0.2 °, 23.3 +/-0.2 °, 24.0 +/-0.2 °, 25.9 +/-0.2 °, 28.1 +/-0.2 ° and 30.4 +/-0.2 ° in an X-ray powder diffraction pattern expressed by using Cu-Kalpha radiation and 2 theta angles;
    preferably, said form a has an X-ray powder diffraction pattern obtained using Cu-ka radiation substantially as shown in figure 4;
    Figure PCTCN2020088874-APPB-100009
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