CN113811302B - Use of kinase inhibitors - Google Patents

Use of kinase inhibitors Download PDF

Info

Publication number
CN113811302B
CN113811302B CN202080033803.0A CN202080033803A CN113811302B CN 113811302 B CN113811302 B CN 113811302B CN 202080033803 A CN202080033803 A CN 202080033803A CN 113811302 B CN113811302 B CN 113811302B
Authority
CN
China
Prior art keywords
antineoplastic agents
thymoma
compound
agents
use according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202080033803.0A
Other languages
Chinese (zh)
Other versions
CN113811302A (en
Inventor
郭霞
李彤
王静
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xuanzhu Biopharmaceutical Co Ltd
Shandong Xuanzhu Pharma Co Ltd
Original Assignee
Xuanzhu Pharma Co Ltd
Xuanzhu Biopharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xuanzhu Pharma Co Ltd, Xuanzhu Biopharmaceutical Co Ltd filed Critical Xuanzhu Pharma Co Ltd
Publication of CN113811302A publication Critical patent/CN113811302A/en
Application granted granted Critical
Publication of CN113811302B publication Critical patent/CN113811302B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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 present invention relates to the use of a CDK4/6 kinase inhibitor. In particular to the application of a compound shown in a formula (I'), pharmaceutically acceptable salt or crystal form thereof in preparing medicaments for treating thymoma.

Description

Use of kinase inhibitors
1. Technical field
The invention belongs to the field of medicines, and in particular relates to a CDK4/6 kinase inhibitor and a novel application of a pharmaceutically acceptable salt or a crystal form thereof in preparation of a medicine for treating thymoma.
2. Background art
Thymoma is a rare tumor, but is the most common primary tumor of the anterior superior mediastinum, accounting for about 20% -40% of all mediastinal tumors in adults, and originates from the thymus epithelium, mostly in the anterior mediastinum, attached to the pericardium, in close relationship with the large vessels in the mediastinum, and a minority occurs outside the mediastinum. Thymoma grows slowly and is considered painless, but is potentially invasive in clinic and tends to infiltrate surrounding tissues and organs. Thymoma patients typically present symptomatically with chest pain, dyspnea, superior vena cava syndrome, pericardial tamponade, and the like. Thymoma is closely related to autoimmune disorders, and is often associated with myasthenia gravis (mysasthenia gravis, MG), various granulocytopenias, erythrodysplasia, hypogammaglobulinemia, collagenous vascular disease, and other paraneoplastic syndromes (paraneoplastic syndromes). Foreign literature shows that the annual incidence rate of thymoma in the crowd is 0.15/10 ten thousand, the ratio of men and women is 1:1, and the incidence peak age is 40-50 years. The incidence of thymoma complicated with myasthenia gravis is about 10% to 46%, and is usually between 30 and 40 years old. Children have rare thymoma but are more malignant.
The pathogenesis of thymoma is currently unknown. The scholars believe that the prior history of radiation therapy and epstein barr virus infection in patients may be associated with thymoma. Surgical excision is the primary method of early-stage thymoma treatment, and radiation therapy and chemotherapy can be used as an adjunct and palliative method for patients who are unable to operate or have locally advanced thymic carcinoma. Thymoma is relatively sensitive to chemotherapy, and currently, a combination chemotherapy scheme containing cisplatin, such as combination chemotherapy of cisplatin and doxorubicin or combination chemotherapy of doxorubicin, cisplatin, vincristine and cyclophosphamide, is mostly adopted, but the chemotherapy brings huge side effects to patients. Therefore, various pharmaceutical companies are working on developing high-efficiency low-toxicity small molecule drugs. At present, there is no specific small molecule therapeutic for treating thymoma, and there is an unmet need in the therapeutic field.
PCT/CN2014/095615 discloses a series of CDK4/6 kinase inhibitors. Studies show that the compound has excellent CDK4/6 kinase inhibition activity, shows good blood brain barrier trafficability, provides possibility for CDK inhibitors to treat tumors, and has good safety.
However, this patent does not disclose the therapeutic effect of the compounds on thymoma.
In the course of studying the above-mentioned patent compounds, the inventors have unexpectedly found that the compound of formula (I ') has a good therapeutic effect on thymoma and can significantly reduce the tumor volume, which suggests that the compound of formula (I') is expected to be a specific drug for treating thymoma.
3. Summary of the invention
The present invention relates to novel uses 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.
The technical scheme of the invention is as follows:
the invention provides an application of a compound shown in a formula (I'), pharmaceutically acceptable salt or crystal form thereof in preparing a medicament for treating thymoma,
wherein,
A 1 and A 2 Each independently is nitrogen;
R 1 selected from C 1-6 An alkyl group;
R 2 selected from C 1-6 An alkyl group;
R 3 and R is 5 Independently selected from halogen or hydrogen, and R 3 And R is 5 At least one is halogen;
R 4 selected from optionally by Q 2 Substituted 5-6 membered nitrogen-containing heterocyclyl, 6-10 membered nitrogen-containing thick heterocyclyl, 7-9 membered nitrogen-containing bridged heterocyclyl or 7-11 membered nitrogen-containing spiro heterocyclyl;
Q 2 selected from amino, hydroxy, halogen, trifluoromethyl, cyano, C 1-6 Alkoxy, di C 1-6 Alkylamino, or optionally substituted C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl or 7-9 membered bridged heterocyclyl, said substituents being selected from amino, hydroxy, halogen, trifluoromethyl, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3-6 membered cycloalkyl;
n is selected from 0 and 1.
In certain embodiments, wherein the compound has the structure of formula (I'),
wherein,
A 1 and A 2 Each independently is nitrogen;
R 1 selected from C 1-4 An alkyl group;
R 2 selected from C 1-4 An alkyl group;
R 3 and R is 5 Each independently selected from halogen;
R 4 selected from optionally by Q 2 Substituted 5-6 membered nitrogen-containing heterocyclic group, 6-10 membered nitrogen-containing condensed heterocyclic group, 7-9 membered nitrogen-containing bridged heterocyclic group or 7-11 membered nitrogen-containing spiro heterocyclic group,
Q 2 selected from amino, hydroxy, trifluoromethyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, 5-6 membered heterocyclyl or 7-9 membered bridged heterocyclyl.
In some embodiments of the present invention, in some embodiments,
A 1 and A 2 Each independently is nitrogen;
R 1 is isopropyl;
R 2 is methyl;
R 3 and R is 5 Each is fluorine;
R 4 selected from optionally by Q 2 Substituted 5-6 membered nitrogen containing heterocyclyl wherein Q 2 Selected from amino, hydroxy, trifluoromethyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, 6 membered heterocyclyl or 8 membered bridged heterocyclyl.
In some embodiments of the present invention, in some embodiments,
R 4 selected from optionally by Q 2 Substituted 5-6 membered nitrogen-containing heterocyclic group containing 1-2 nitrogen atoms, said 5-6 membered nitrogen-containing heterocyclic group being linked to methylene group of the general formula (I') through a nitrogen atom, wherein Q 2 Selected from amino, hydroxy, trifluoromethyl, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or 8 membered nitrogen containing bridged heterocyclyl.
In some embodiments of the present invention, in some embodiments,
R 4 selected from optionally by Q 2 SubstitutedWherein Q is 2 Selected from C 1-4 Alkyl or 8 membered nitrogen containing bridged heterocyclyl.
In certain embodiments, wherein the compound of formula (I') is selected from:
。
in certain embodiments, the compound is selected from the group consisting of the following compounds (compound 1) or a pharmaceutically acceptable salt thereof, or a crystalline form thereof:
in certain embodiments of the invention, the crystalline form is the free-form crystalline form of compound 1.
In certain embodiments of the invention, the crystalline form is free form a of compound 1, which 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 terms of 2θ angle using cu—kα radiation.
In certain embodiments of the invention, the crystalline form is free form a of compound 1, which 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 terms of 2θ angle using Cu-ka radiation.
In certain embodiments of the invention, the crystalline form is free bulk form a of compound 1, which 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° as expressed by 2θ angle using cu—kα radiation.
In certain embodiments of the invention, the crystalline form is the free-form a of compound 1, which form a has an X-ray powder diffraction pattern obtained using Cu-ka radiation substantially as shown in fig. 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 the maleate salt 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 a thymoma that has failed other anti-tumor treatments.
In certain embodiments, the additional anti-tumor therapy is selected from one or more of surgical therapy, radiation therapy, chemotherapy, immunotherapy, and targeted therapy with targeted drugs other than the compound of formula (I'), pharmaceutically acceptable salts thereof, and crystalline forms thereof.
In certain embodiments, the thymoma patient carries a GTF2I oncogene point mutation.
In certain embodiments, the thymoma is selected from the group consisting of benign thymoma and thymus cancer.
In certain embodiments, the thymoma is thymus cancer.
In certain embodiments, the thymus cancer is selected from the following subtypes: squamous cell carcinoma of thymus, basal cell carcinoma of thymus, epidermoid carcinoma of mucous, sarcoidosis, adenocarcinoma, NUT carcinoma.
In certain embodiments, the thymoma is selected from the following subtypes: type a, AB, B1, B2 and B3.
In certain embodiments, the compound of formula (I'), 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, metallic platinum antineoplastic agents, topoisomerase inhibitor antineoplastic agents, immunosuppressive antineoplastic agents, purine analog antineoplastic agents, antibiotic antineoplastic agents, kinase inhibitor antineoplastic agents, and 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 together 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, metallic platinum antineoplastic agents, topoisomerase inhibitor antineoplastic agents, immunosuppressive antineoplastic agents, purine analog antineoplastic agents, antibiotic antineoplastic agents, kinase inhibitor antineoplastic agents, and targeted therapeutic agents.
In certain embodiments, the crystalline form is selected from the free bulk crystalline forms of the compound of formula (I').
4. Detailed description of the invention
"halogen" as used herein includes, for example, fluorine, chlorine, bromine and iodine.
"C" as described in the present invention 1-6 The alkyl group "may be linear or branched and includes, for example," C 1-4 Alkyl "," C 1-3 Alkyl ", etc., 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" as described in the present invention 1-6 Alkoxy, di C 1-6 Alkylamino "means C 1-6 alkyl-O-, (C) 1-6 Alkyl group 2 -an N-formed group, wherein "C 1-6 The definition of alkyl "is as described above.
The invention is thatThe said "C 1-4 Alkoxy, di C 1-4 Alkylamino "means C 1-4 alkyl-O-, (C) 1-4 Alkyl group 2 -an N-formed group, wherein "C 1-4 The definition of alkyl "is as described above.
The term "3-6-membered cycloalkyl" as used herein means a cyclic alkyl group derived from an alkane moiety having 3 to 6 carbon atoms by removing one hydrogen atom, and includes, for example, "3-5-membered cycloalkyl", "4-6-membered cycloalkyl", "5-6-membered cycloalkyl", etc. Examples include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like.
"3-6 membered heterocyclic group" as used herein means a saturated or partially saturated and non-aromatic cyclic group containing at least one hetero atom (e.g., containing 1,2, 3,4 or 5) and having 3 to 6 ring atoms, and the hetero atom is a nitrogen atom, an oxygen atom and/or a sulfur atom, and optionally, a ring atom (e.g., a carbon atom, a nitrogen atom or a sulfur atom) in the cyclic structure may be oxo-substituted, including, 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-dioxanyl, 1, 4-dioxanediyl, tetrahydrofuranyl, 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-thiopyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl and the like, preferably being a "5-membered nitrogen-containing heterocyclic group".
As used herein, "attached to a methylene group of formula (I") through a nitrogen atom "means that a nitrogen-containing group (e.g., a nitrogen-containing heterocyclic group such as a" 5-6 membered nitrogen-containing heterocyclic group "or a" 6 membered nitrogen-containing heterocyclic group ", a nitrogen-containing fused heterocyclic group such as a" 6-10 membered nitrogen-containing fused heterocyclic group ", a nitrogen-containing bridged heterocyclic group such as a" 7-9 membered nitrogen-containing bridged heterocyclic group "or an" 8 membered nitrogen-containing bridged heterocyclic group ", a nitrogen-containing spiro heterocyclic group such as a" 7-11 membered nitrogen-containing spiro heterocyclic group ") is attached to a methylene group through a nitrogen atom.
According to the rules of IUPAC compound naming, the fused ring as described herein refers to a fused ring structure formed by two or more cyclic structures connected to each other by two adjacent atoms (i.e., sharing a bond). The bridged ring of the present invention refers to a bridged ring structure formed by two or more cyclic structures that share two non-adjacent carbon atoms with each other. The spiro ring refers to a spiro ring structure formed by connecting two or more cyclic structures which share one carbon atom.
The "6-10 membered fused heterocyclic group" as used herein refers to a fused ring structure of 6-10 ring atoms containing at least one hetero atom, which is formed by connecting two or more cyclic structures together in common with two adjacent atoms (i.e., in common with one bond), and includes, for example, "6-10 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 ] pyridinyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo [ d ] [1,3] dioxolyl, 1, 3-dihydroisobenzofuran, 2H-oxazinyl, 3H-2H-imidazo [3,4-b ] pyridinyl, 3H-1H-pyrido [3,4-b ] [1, 4-oxazinyl, 3, 4-3H-imidazo [3,4-b ] pyridinyl, 3, 4-imidazo [3, 4-H-2, 6-naphthyridinyl, 3-2, 6-dihydro-2, 6-naphthyridinyl, 7-tetrahydro-1H-benzo [ d ] imidazolyl, and the like.
The invention relates to a 7-9 membered bridged heterocyclic group, which refers to any two rings sharingBridged ring structures of 7-9 ring atoms containing at least one heteroatom selected from N, S, O, CO, SO and/or SO formed by two non-adjacent atoms 2 Etc. 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", and the like. Examples include, but are not limited to: etc.
The term "7-11 membered spiroheterocyclyl" as used herein refers to a spiro ring structure having 7-11 ring atoms containing at least one heteroatom selected from N, S, O, CO, SO and/or SO and having at least two rings sharing one atom 2 Etc. These include, for example, "6-11 membered spiroheterocyclyl", "7-11 membered nitrogen-containing spiroheterocyclyl", "7-10 membered spiroheterocyclyl", "7-9 membered spiroheterocyclyl", "7-8 membered spiroheterocyclyl", and the like. Examples include, but are not limited to: etc.
In the "pharmaceutically acceptable salts of the compounds of formula (I '), the molecular ratio of the compounds of formula (I') to the corresponding alkali metal, other metal, organic base, inorganic acid, organic acid may be any value.
The "pharmaceutical composition" of the invention is any pharmaceutically acceptable dosage form, and is administered to a patient in need thereof by oral, parenteral, rectal or pulmonary administration, and the like. For oral administration, conventional solid preparations such as tablets, capsules, pills, granules, etc. can be prepared; can also be made into oral liquid preparation such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. may be added. For parenteral administration, it can be formulated into injections, including injectable solutions, injectable sterile powders, and injectable concentrated solutions. When the injection is prepared, the conventional method in the existing pharmaceutical field can be adopted for production, and when the injection is prepared, no additive can be added, and the proper additive can be added according to the property of the medicine. For rectal administration, it can be made into suppository. For pulmonary administration, the composition can be formulated into inhalant or spray.
The pharmaceutically acceptable carriers include, but are not limited to: fillers, diluents, binders, wetting agents, disintegrants, lubricants, surfactants, preservatives, colorants, flavoring agents, fragrances, effervescent agents, emulsifiers, flocculants, deflocculants, bacteriostats, solubilizing agents.
The tumors, cancers or carcinomas described herein also include 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 as described herein refers to the occurrence of disease progression or intolerance with other anti-tumor treatments.
The "thymoma" according to the present invention includes type a, AB, B1, B2, B3 according to the World Health Organization (WHO) classification (fourth edition 2015).
The "thymus cancer" according to 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, epidermoid carcinoma of mucous, sarcoidosis, adenocarcinoma, NUT carcinoma, etc. The thymus cancer comprises malignant thymus tumor.
The invention relates to a chemical drug for killing cancer cells by using chemical drug, which is a cytotoxic drug.
The invention relates to a method for treating tumor, namely tumor radiotherapy, which mainly utilizes radioactive rays to treat tumor locally, wherein the radioactive rays comprise alpha rays, beta rays, gamma rays generated by radioactive isotopes, x rays, electron rays, proton beams, other particle beams generated by various x-ray therapeutic machines or accelerators, and the like.
The invention relates to a targeting therapy method, which is a method for carrying out positioning accurate therapy by recognizing specific proteins of tumor cells by a targeting drug.
The term "immunotherapy" as used herein refers to a therapeutic method that involves the control or elimination of tumor cells by activating the immune system in the body.
In the present invention, the subject or patient may be any animal, preferably a mammal, such as a bovine, equine, ovine, porcine, canine, feline, rodent, primate. Of these, particularly preferred subjects are humans.
The term "QD" as used herein refers to a single daily administration.
The present invention also provides a method of treating a 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, weight, medical condition, type of disease, severity of disease, route of administration and related health condition of the patient, and other factors known to those skilled in the art.
As used herein, a "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. Determination of such effective amounts is well within the ability of those skilled in the art. For example, the 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 such as age, weight and sex, the mode of administration of the drug, and other treatments administered simultaneously, 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 patient suffering from a thymoma.
5. Drawing of the specification
Figure 1 CT radiological image of compound 1 prior to treatment.
Figure 2 is a CT radiographic image of a subject taken with compound for 1 eight cycles (about eight months).
FIG. 3 shows the percent change in tumor size of the target lesion after administration of Compound 1, the abscissa shows time (days of experimental study), wherein C3D1 shows the first day of cycle 3, C5D1 shows the first day of cycle 5, and so on, each administration cycle is about 28 days, specifically corresponding to the administration regimen of the experimental example; the ordinate is the percent change in tumor volume.
FIG. 4X-ray powder diffraction pattern (XRPD pattern) for form A of compound 1, with the ordinate representing diffraction intensity and the abscissa representing diffraction angle (2. Theta.).
Detailed Description
The present invention will be described in further detail with reference to specific examples and experimental examples. It should be understood that the following examples and experimental examples are only for illustration of the present disclosure, but are not intended to limit the scope of the present disclosure. The specific conditions are not noted in the examples below, and are carried out according to conventional conditions or manufacturer's recommendations. The drugs or reagents used were conventional products commercially available without the manufacturer's attention.
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).
Form a of compound 1 is the form a of the compound of formula (I) in the specification of the patent application PCT/CN2018/124418, and the relevant content of the preparation method is cited in the specification. For the relevant matters of parameter characterization, property test and the like of the crystal form A of the compound 1 mentioned in the application, see patent application PCT/CN2018/124418, and the like, the relevant matters are cited herein.
Preparation examples:
preparation method of crystal form A of compound 1
The preparation method comprises the following steps: taking 5.0g of compound 1, adding 75mL of acetone, dissolving under magnetic stirring to immediately precipitate a white solid, stirring for 5 hours, carrying out suction filtration to obtain white powder, and carrying out vacuum drying at 35 ℃ for 16 hours, wherein the obtained solid is subjected to XRPD test to obtain a crystal form A.
The preparation method comprises the following steps: 500mg of Compound 1 was taken, 15mL of isopropanol was added, stirred in an oil bath at 80℃and dissolved and allowed to become clear (within 4.0 h), naturally cooled to room temperature (32 ℃) and white solid precipitated, stirred continuously at room temperature for 12h, cooled to 15℃and stirred for 4.0h, suction filtered, and the resulting solid was dried at 45℃under vacuum for 16h, via XRPD, 1 H-NMR analysis gave solid as form A.
And the preparation method comprises the following steps: 5.0g of Compound 1 was taken in a 100mL three-necked flask, 75mL of sec-butanol was added, the temperature of the oil bath was controlled at 95℃and the mixture was mechanically stirred for 0.5h, dissolved and turned clear. Then cooling to 70 ℃ in oil bath, adding about 25mg of seed crystal (i.e. the crystal form A obtained by the first and second preparation methods), starting to slowly separate out white solid, continuing cooling to 60 ℃ in oil bath, keeping the temperature for 0.5h, cooling to 55 ℃ and keeping the temperature for 0.5h, continuing cooling to 20 ℃ and stirring for 1.5h, filtering, leaching with methyl tert-butyl ether (2X 10 mL), vacuum drying the obtained solid at 65 ℃ for 24h, 1 H-NMR detection showed no solvent residue, which was analyzed by XRPD as form A.
The preparation method is as follows:
1) Seed crystal preparation: 40g of Compound 1 and 300g of n-pentanol are taken, heated to 75℃and after about 0.5h the starting material starts to dissolve, after complete dissolution and after becoming clear, is kept stable for 0.5h at 75 ℃. The stirring rate was reduced to r=150r/min and the clear solution was rapidly cooled to 55 ℃ in about 0.5h. After the temperature reaches 55 ℃, the stirring speed is increased to R=300R/min, the temperature is continuously reduced at the speed of 9 ℃/h until the temperature reaches 5 ℃, the system slowly clouds to separate out solid, the temperature is kept constant for 2 hours after the temperature reaches 5 ℃, and the obtained solid is the seed crystal.
2) The preparation method of the crystal form A comprises the following steps: 50g of Compound 1 was dispersed in 300g of n-pentanol, heated to 85℃and completely dissolved and turned clear, rapidly cooled to 58℃C (85-5)8 ℃/h), adding 0.1g of the seed crystal obtained in the step 1), keeping the temperature for 60min, slowly clouding the system until the system turns into white solid, slowly cooling at the speed of 6 ℃/h until the temperature reaches 5 ℃, continuously keeping the temperature constant overnight, then carrying out suction filtration, putting the obtained solid into a vacuum drying device, drying at 100 ℃ for 6h, drying the obtained solid at 65 ℃ for 24h in vacuum, 1 H-NMR detection showed no solvent residue, which was analyzed by XRPD as form A.
And detecting products obtained by the preparation methods one to four, wherein 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 remains.
XRPD test
The instrument used is as follows: bruker D2X-ray powder diffractometer.
X-ray parameters: cu, kα; entrance slit: 0.6mm; divergence slit: 1mm; scanning mode: continuous; scanning range: 3.0 to 45.0 degrees; sampling step length: 0.02 degree; scanning time per step: 19.8s; angle of detector: 2.0 degrees.
Form a of compound I is shown in fig. 4 in an X-ray powder diffraction pattern having peaks at the following diffraction 2θ angles: 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 °.
Experimental example curative effect of Compounds of formula (I') on thymoma
Test article:
tablets of compound 1 form a. Adding proper auxiliary materials into the compound 1 crystal form A to prepare tablets with certain specification.
Test group entry criteria:
1. male or female subjects aged 18-70 years (including 18 and 70 years);
2. a subject with locally advanced or metastatic malignant thymoma diagnosed histologically or cytologically, and failed (disease progression or intolerance) or lacking standard treatment by standard treatment;
3. the subject must have at least one measurable lesion that meets the RECIST v1.1 definition;
ecog score 0-1;
5. all acute toxic responses to prior anti-cancer treatments or surgery were alleviated to baseline or No. 1 (NCI-CTCAE v4.03 edition, alopecia or other toxicities considered by researchers to be safe to the subject);
6. all prior antitumor treatments (including chemotherapy, radiotherapy, immunotherapy, and the like, excluding castration) have been stopped for at least 4 weeks (wherein nitrosoureas or mitomycin stop treatment should be more than or equal to 6 weeks, oral breast cancer endocrine treatment drugs, small molecule targeted treatment drugs, and antitumor traditional Chinese medicines (decoction or Chinese patent medicines) are stopped for at least 2 weeks) before the first administration;
7. the subject's organ was functioning well at the time of group entry and laboratory test data met the following criteria:
blood convention: the absolute count of neutrophil is more than or equal to 2.0X10 9 /L (or greater than the lower limit of laboratory values at the research center), platelet count is greater than or equal to 100X 10 9 Per liter, the hemoglobin is more than or equal to 100 g/liter;
liver function: serum total bilirubin is less than or equal to 1.5 times the Upper Limit (ULN) of standard value, AST and ALT are less than or equal to 1.5 times ULN;
renal function: crCl is more than or equal to 60ml/min/1.73m 2 (calculated according to the Cockcroft-Gault formula);
8. the life of the expected subjects is more than or equal to 12 weeks according to the judgment of researchers;
9. male or female subjects with fertility must agree to use effective contraceptive methods, such as dual barrier contraceptive methods, condoms, oral or injectable contraceptive agents, intrauterine devices, etc., during the study period and within 30 days of the last study medication;
10. prior to the start of the study, subjects must provide written informed consent.
Medical history:
a36-year-old male patient, a patient in late 7 th 2015 who had a diagnosis of cough, expectoration, abdominal distension, diarrhea and dry mouth, and a PET-CT examination showed that: thickening of the left pleura and increased metabolic activity, double lung multiple patch speckle shadows and micro nodules. Pleural tumor aspiration biopsy: type B1 (lymphocyte-enriched) thymoma. 7 months and 31 days under the assistance of thoraco-surgery thoracoscopy, left side thoracotomy is performed, left lung upper lobe wedge-shaped excision is cut by thoracomatous tumor, partial pericardial excision and pleural peeling are performed, and the thoraco-closed drainage is performed. Postoperative pathology: thymoma, type B2, invasion of pericardial wall layer, lung tissue, and visceral layer, parietal layer, diaphragmatic pleura.
Postoperative assistance: paclitaxel on 16-12 months 10 days after 2015, adjuvant chemotherapy for 4 cycles. Paclitaxel + cisplatin + recombinant human vascular endothelial inhibin regimen at 13, 4,5, 17 days in 2018 for 2 cycles.
The treatment process comprises the following steps:
diagnosis of admission at 2018, 6, 26: thymoma, left lung and pleural metastasis; otitis media; double pneumonia. Complaints: tinnitus is accompanied by cough, expectoration, sticky yellow phlegm, and excessive phlegm. The anti-infective therapy of piperacillin sodium tazobactam sodium is carried out on 28 days of 6 months, the anti-fungal therapy of fluconazole is combined on 3 days of 7 months, the anti-infective therapy of moxifloxacin and voriconazole is carried out on 11 days of 7 months, and the inflammation is improved after 16 days of 7 months.
Baseline examination before group entry was completed at 7.19.2018. Chest, abdomen and basin examination enhanced CT shows: changes after thymoma and pleural denudation; left anterior superior mediastinum soft tissue density shadow; infectious lesions of both lungs; ECOG score is less than or equal to 1, and estimated lifetime is more than or equal to 12 weeks through judgment of researchers; vital signs, physical examinations, electrocardiography, echocardiography, and laboratory safety examination results all meet the criteria.
Evaluation criteria for target lesions
Dosing regimen:
1) 80mg QD is 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 is administered for 3 consecutive cycles (i.e., cycles 8-10);
4) 320mg QDs were administered for 3 consecutive cycles (i.e., cycles 11-13).
Adverse events:
adverse events included vomiting (grade 1), the symptoms disappeared after the administration of the medicine changed from empty stomach to post-prandial administration, and the clinical control was possible. Serious Adverse Events (SAE) did not occur, and administration was discontinued, the dose was down-regulated, and the group was advanced due to adverse events.
Curative effect:
the present treatment is for malignant thymoma with two lines, the treatment course is subjected to up-regulation of 3 doses, and the current dose is 320mg QD. The patient has now stabilized for a period of 12 months and at the end of cycle 12 dosing, tumor meridian and has been reduced by 38.6% from baseline, as shown in figure 3, the target lesion has reached a criterion of Partial Remission (PR).

Claims (11)

1. Use of compound 1, a pharmaceutically acceptable salt thereof, or a crystalline form thereof, in the manufacture of a medicament for the treatment of thymoma, wherein compound 1 has the structure:
2. the use according to claim 1, wherein the thymoma is an advanced and/or metastatic thymoma.
3. The use according to claim 1, wherein the thymoma is a thymoma which has failed other anti-tumour therapy.
4. The use according to claim 1, wherein the thymoma is thymus cancer.
5. Use of a pharmaceutical composition comprising compound 1, a pharmaceutically acceptable salt thereof or a crystalline form thereof according to claim 1 and a pharmaceutically acceptable carrier, optionally together with one or more other therapeutic agents, in the manufacture of a medicament for the treatment of thymoma.
6. The use of claim 5, wherein the additional therapeutic agent is selected from the group consisting of antimetabolite antineoplastic agents, growth factor inhibitor antineoplastic agents, antibody antineoplastic agents, mitotic inhibitor antineoplastic agents, hormonal antineoplastic agents, alkylating agent antineoplastic agents, metallic platinum antineoplastic agents, topoisomerase inhibitor antineoplastic agents, immunosuppressive antineoplastic agents, purine analog antineoplastic agents, antibiotic antineoplastic agents, kinase inhibitor antineoplastic agents, targeted therapeutic agents.
7. The use according to any one of claims 1 to 6, wherein the crystalline form is selected from the free-form crystalline forms of compound 1.
8. The use according to any one of claims 1-6, wherein the 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 terms of 2Θ angle using Cu-ka radiation;
9. the use of claim 8, wherein 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 terms of 2Θ angle using Cu-ka radiation;
10. the use of claim 9, wherein 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°, 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°, using Cu-ka radiation, expressed in terms of 2Θ angle;
11. use according to claim 10, wherein the form a has an X-ray powder diffraction pattern obtained using Cu-ka radiation substantially as shown in figure 4;
CN202080033803.0A 2019-05-08 2020-05-07 Use of kinase inhibitors Active CN113811302B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
CN201910378887 2019-05-08
CN2019103788870 2019-05-08
CN201910906244 2019-09-24
CN2019109062449 2019-09-24
PCT/CN2020/088874 WO2020224609A1 (en) 2019-05-08 2020-05-07 Use of kinase inhibitor

Publications (2)

Publication Number Publication Date
CN113811302A CN113811302A (en) 2021-12-17
CN113811302B true CN113811302B (en) 2023-12-29

Family

ID=73050661

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202080033803.0A Active CN113811302B (en) 2019-05-08 2020-05-07 Use of kinase inhibitors

Country Status (2)

Country Link
CN (1) CN113811302B (en)
WO (1) WO2020224609A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20240075032A1 (en) * 2020-12-31 2024-03-07 Xuanzhu Biopharmaceutical Co., Ltd. A Pharmaceutical Composition for Treating Cancer
CN114748479B (en) * 2021-01-08 2023-10-20 轩竹生物科技股份有限公司 Pharmaceutical composition for preventing and/or treating cancer

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010106028A1 (en) * 2009-03-20 2010-09-23 Nerviano Medical Sciences S.R.L. Use of a kinase inhibitor for the treatment of thymoma
WO2015101293A1 (en) * 2013-12-31 2015-07-09 山东轩竹医药科技有限公司 Kinase inhibitor and use thereof
WO2016040858A1 (en) * 2014-09-12 2016-03-17 G1 Therapeutics, Inc. Combinations and dosing regimes to treat rb-positive tumors
WO2019144759A1 (en) * 2018-01-29 2019-08-01 海南轩竹医药科技有限公司 Crystal form targeting cdk4/6 kinase inhibitor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010106028A1 (en) * 2009-03-20 2010-09-23 Nerviano Medical Sciences S.R.L. Use of a kinase inhibitor for the treatment of thymoma
WO2015101293A1 (en) * 2013-12-31 2015-07-09 山东轩竹医药科技有限公司 Kinase inhibitor and use thereof
WO2016040858A1 (en) * 2014-09-12 2016-03-17 G1 Therapeutics, Inc. Combinations and dosing regimes to treat rb-positive tumors
WO2019144759A1 (en) * 2018-01-29 2019-08-01 海南轩竹医药科技有限公司 Crystal form targeting cdk4/6 kinase inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Loss of p16INK4AExpression and Homozygous CDKN2A Deletion Are Associated with Worse Outcome and Younger Age in Thymic Carcinomas;Scott W. Aesif等;《Journal of Thoracic Oncology》;第12卷(第4期);860-871 *

Also Published As

Publication number Publication date
CN113811302A (en) 2021-12-17
WO2020224609A1 (en) 2020-11-12

Similar Documents

Publication Publication Date Title
JP5005532B2 (en) Treatment of T-cell lymphoma with 10-propargyl-10-deazaaminopterin
RU2764116C2 (en) Combination containing palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidine-3-yl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid and application thereof for treating cancer
EP3672591B1 (en) Synergistic antitumor effect of bcl-2 inhibitor combined with rituximab and/or bendamustine or bcl-2 inhibitor combined with chop
US11666574B2 (en) Combination therapy involving diaryl macrocyclic compounds
EP2793892A1 (en) Combination therapies for treating hematologic malignancies using pyridopyrimidinone inhibitors of pi3k/mtor with bendamustine and/or rituximab
CN113811302B (en) Use of kinase inhibitors
CN107296811B (en) Quinoline derivative for treating gastric cancer
US20190307723A1 (en) Compositions and methods for intravenous administration of 2-bromo-1-(3,3-dinitroazetidin-1-yl)ethanone
KR101401220B1 (en) Potentiator of radiation therapy
EP3279201B1 (en) Cdk inhibitor, eutectic crystal of mek inhibitor, and preparation method therefor
WO2010081266A1 (en) A new use of tetrahydropalmatine
WO2023107706A1 (en) Stat3 degraders and uses thereof
WO2019146130A1 (en) Antitumor agent for biliary cancer and treatment method of biliary cancer
US20230038138A1 (en) Combination therapy for treating cancer
WO2022051491A1 (en) Pharmaceutical compositions of tetracyclic quinolone analogs and their salts
CN112535686B (en) Novel use of kinase inhibitors
KR20140032586A (en) A pharmaceutical composition for radiation therapy of egfr-tki-resistant lung cancer caused by pten function deficiency
CN111757736B (en) Quinoline derivatives for treating nasopharyngeal carcinoma
CN111821303A (en) Application of vortioxetine and salts thereof in preparation of antitumor drugs
JP2015515476A (en) Method for treating cancer using PI3K inhibitor and MEK inhibitor
CN111432817A (en) Method of inhibiting tumor metastasis
US20230029336A1 (en) Combination Therapy for Treating a Hematological Malignancy
CN111939165B (en) Application of non-natural ginsenoside 3 beta-O-Glc-DM in preparation of medicine for preventing or treating glioblastoma
JP2018502873A (en) Cancer combination therapy
CN117956999A (en) Use of heteroaryloxy naphthalenes

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
CB02 Change of applicant information

Address after: No. 2518, Tianchen Road, Ji'nan high tech Zone, Shandong, Shandong

Applicant after: XUANZHU PHARMA Co.,Ltd.

Applicant after: Xuanzhu Biotechnology Co.,Ltd.

Address before: No. 2518, Tianchen Road, Ji'nan high tech Zone, Shandong, Shandong

Applicant before: XUANZHU PHARMA Co.,Ltd.

Applicant before: Xuanzhu Biotechnology Co.,Ltd.

CB02 Change of applicant information
GR01 Patent grant
GR01 Patent grant