CN112535686B - Novel use of kinase inhibitors - Google Patents

Novel use of kinase inhibitors Download PDF

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CN112535686B
CN112535686B CN201910893109.5A CN201910893109A CN112535686B CN 112535686 B CN112535686 B CN 112535686B CN 201910893109 A CN201910893109 A CN 201910893109A CN 112535686 B CN112535686 B CN 112535686B
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antineoplastic agents
sialadenoma
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membered
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CN112535686A (en
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李彤
郭霞
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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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 a novel application of a CDK4/6 kinase inhibitor. In particular to a new application of a compound shown as a formula (I'), pharmaceutically acceptable salt thereof or crystal form thereof in preparing a medicament for treating sialadenoma.

Description

Novel 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 sialadenoma.
2. Background of the invention
Salivary gland tumor is also called salivary gland tumor, is a common tumor with high incidence in head, neck and face tumors, occurs in the parotid gland mostly, but is reported to occur in submandibular gland, sublingual gland and small salivary gland. The tumor can be developed from juvenile to elderly, but is most frequently seen in 40-60 years old. Clinically, most of the salivary gland tumors belong to benign tumors, but about 20 percent of the salivary gland tumors are malignant tumors. Most salivary gland malignant tumors are malignant tumors derived from salivary gland epithelial tissues, grow infiltratively, and have the characteristics of multiple tissue types and complex cell components.
Surgical resection is the first choice for treatment of sialadenoma. The sialadenoma is not very sensitive to radiotherapy, the effect of radical cure is difficult to achieve by simple radiotherapy, the requirement on the radiation dose is very strict, and a plurality of adverse reactions are easily caused by overhigh radiation dose. The synchronous radiotherapy and chemotherapy can improve the sensitivity of radiotherapy and effectively control the distant metastasis of a focus, but no very effective chemotherapeutic drug is found at present. For sialadenoma which can not be completely resected or has metastasized during operation, the chemotherapeutic drugs mainly comprise cisplatin, epirubicin and the like, but the chemotherapeutic drugs can bring huge side effects to patients, so that various pharmaceutical companies are dedicated to developing high-efficiency low-toxicity small-molecule targeted drugs. Currently, there is no specific small molecule therapeutic for the treatment of sialadenoma, and there is an unmet medical need in this field of treatment.
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 BDA0002209395670000011
PCT/CN2018/124418 discloses a crystal form of the following compound (hereinafter referred to as compound 1) which is high in purity, good in stability, and good in flowability and compressibility.
Figure BDA0002209395670000021
However, none of the patents disclose the therapeutic effect of the compounds on sialadenoma.
In the further research on the above patent compounds, the inventors unexpectedly found that the compound of formula (I ') has a good therapeutic effect on sialadenoma, 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 sialadenoma.
3. Summary of the invention
The invention relates to a novel application of a compound shown as a formula (I'), a pharmaceutically acceptable salt thereof or a crystal form thereof in preparing a medicament for treating salivary gland tumors.
The technical scheme of the invention is as follows:
use of a compound of formula (I'), a pharmaceutically acceptable salt thereof or a crystalline form thereof for the manufacture of a medicament for the treatment of sialadenoma,
Figure BDA0002209395670000022
wherein the content of the first and second substances,
A1and A2Each independently selected from nitrogen;
R1is selected from C1-6An alkyl group;
R2is selected from C1-6An alkyl group;
R3and R5Each independently selected from halogen or hydrogen, and R3And R5At least one is halogen;
R4selected 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;
Q2selected from amino, hydroxy, halogen, trifluoromethyl, cyano, C1-6Alkoxy, 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 BDA0002209395670000031
wherein the content of the first and second substances,
A1and A2Each independently selected from nitrogen;
R1is selected from C1-4An alkyl group;
R2is selected from C1-4An alkyl group;
R3and R5Each independently selected from halogen;
R4selected 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 bridged heterocyclic groupA nitrogen-containing spiro heterocyclic group,
Q2selected 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,
A1and A2Each independently selected from nitrogen;
R1is selected from isopropyl;
R2is selected from methyl;
R3and R5Each is fluorine;
R4selected 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,
R4selected 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,
R4selected from optionally Q2Substituted by
Figure BDA0002209395670000032
Wherein Q2Is selected from C1-4Alkyl or an 8-membered nitrogen-containing bridged heterocyclic group.
In certain embodiments, wherein the compound of formula (Γ) is selected from:
Figure BDA0002209395670000041
Figure BDA0002209395670000051
Figure BDA0002209395670000061
in certain embodiments, the compound is used in an amount of 200-500mg per day, preferably 300-400mg per day, and more preferably 320mg per day.
In certain embodiments, the compound is selected from the group consisting of the compound shown below (compound 1) or a pharmaceutically acceptable salt or crystalline form thereof:
Figure BDA0002209395670000062
in certain embodiments of the invention, the crystalline form is an episomal crystalline form of the compound.
In certain embodiments of the invention, the crystalline form is a maleate crystalline form of the compound.
In certain embodiments of the invention, the crystalline form is a dimaleate crystalline form of the compound.
In certain embodiments, the salivary gland tumor is selected from large salivary gland tumor and small salivary gland tumor.
In certain embodiments, the sialadenoma is selected from the group consisting of parotid gland, submandibular gland, sublingual gland, adenoid cystic carcinoma, and small salivary gland.
In certain embodiments, the sialadenoma is selected from the group consisting of benign sialadenoma and malignant sialadenoma.
In certain embodiments, the sialadenoma is a malignant sialadenoma.
In certain embodiments, the sialadenoma is a malignant sialadenoma in which metastasis occurs.
In certain embodiments, the sialadenoma is a sialadenoma that has developed pulmonary metastasis.
In certain embodiments, the sialadenoma is a sialadenoma in which lymph node metastasis occurs.
In certain embodiments, the salivary gland tumor is a salivary gland cancer.
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 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 analog antineoplastic agents, antibiotic antineoplastic agents, kinase inhibitor antineoplastic agents, targeted therapeutic agents, and the like.
The use of a pharmaceutical composition comprising a compound of formula (I'), a pharmaceutically acceptable salt or crystal form thereof, and a pharmaceutically acceptable carrier, optionally together with one or more other therapeutic agents selected from antimetabolite antineoplastic agents, growth factor inhibitor antineoplastic agents, antibody antineoplastic agents, mitosis inhibitor antineoplastic agents, hormone antineoplastic agents, alkylating agent antineoplastic agents, platinum antineoplastic agents, topoisomerase inhibitor antineoplastic agents, immunosuppressive antineoplastic agents, purine analogue antineoplastic agents, antibiotic antineoplastic agents, kinase inhibitor antineoplastic agents, targeted therapeutic agents, and the like.
In certain embodiments, the crystalline form is selected from free crystalline forms of the compound of formula (I').
4. Detailed description of the invention
The "halogen atom" as referred to herein includes, for example, a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
"C" according to the invention1-6Alkyl groups "may be straight or branched and include, for example," C1-4Alkyl group and 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-methylethylCyclopentyl, 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" according to the present invention means a saturated or partially saturated and non-aromatic cyclic group having at least one hetero atom (e.g., 1,2, 3,4 or 5 hetero 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. Examples thereof include "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) through 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 through 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 thereof include, but are not limited to:
Figure BDA0002209395670000091
Figure BDA0002209395670000092
Figure BDA0002209395670000093
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 BDA0002209395670000094
Figure BDA0002209395670000095
Figure BDA0002209395670000096
and the like.
The stereoisomers of the compounds of formula (I') according to the invention include all possible optical isomers and diastereoisomeric mixtures and pure or partially pure compounds. Optical isomers are meant when the compounds of the present invention contain one or more asymmetric centers and thus may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
The compounds of formula (I') according to the invention contain olefinic double bonds, and unless otherwise specified, the stereoisomers according to the invention include cis-and trans-isomers thereof.
The compounds of formula (I') according to the invention may exist in tautomeric forms, the individual tautomers as well as mixtures thereof being included within the scope of the invention.
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. When used for oral administration, the preparation 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.
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.
The present invention also provides a method of treating a patient having sialadenoma 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 can 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 (I') for the treatment of a patient suffering from sialadenoma.
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 drugs or reagents used are conventional products which are commercially available, not indicated by the manufacturer.
EXAMPLES preparation of test samples
The compound of formula (I') used in the following experimental examples was prepared according to the procedure of example 1 disclosed in patent application PCT/CN2014/095615 (i.e. compound 1). Compound 1 is then added to conventional excipients used to make tablets, and tablets of compound 1 are prepared by conventional methods known in the art.
Experimental examples the therapeutic Effect of Compounds of formula (I') on sialadenoma
Criteria for subjects to be enrolled:
1. male or female subjects 18-70 years of age (including 18 and 70 years of age);
2. a locally advanced or metastatic malignant sialadenoma subject that has been histologically or cytologically confirmed and has failed (disease progression or intolerance) or lacks standard treatment;
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), the count of the platelets is more than or equal to 100 multiplied by 109/L, and the 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 standard value Upper Limit (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 treatment process comprises the following steps:
one male patient of 52 years old, the high-grade ductal carcinoma of the left submaxillary gland is diagnosed in 2018, month 01 and day 10, and the left submaxillary gland cancer postoperative tumor bed and left cervical drainage area lymph node auxiliary radiotherapy, GTVtb, are performed in the general anesthesia downlink. After the operation of the left submaxillary adenocarcinoma, the tumor bed and suspicious positive lymph nodes are 95% PTVDt60Gy/30f, and the CTV left cervical draining lymph nodes are 95% PTVDt50Gy/25 f. Patients on 12.02/2018 routinely examined chest CT for "left pulmonary nodules, suggesting periodic review". Left submaxillary gland high grade ductal carcinoma (AJCC 6 th edition pT2N1M0, stage III).
Pre-enrollment baseline examinations were completed in 2019 for 2 months, according to protocol requirements.
CT of chest and abdomen examination basin: 1. the left pulmonary nodule; 2. the mediastinal small lymph nodes, partially calcified; 3. the inferior fascial cable foci of the two lungs; 4. low density shadow in liver, calcification focus in liver; 5. hyperplasia of prostate gland; 6. the bone changes are frequent.
Skull-enhanced MRI: 1. the left cerebellum is slightly thicker; 2. a big pillow and a big pool; 3. a submucosal cyst of the right maxillary sinus.
Bone scan ECT: 1. a left ilium concentrating stove; 2. the image of the left lower limb bone changes.
ECOG score is 1, and the life time is estimated to be more than or equal to 12 weeks according to the judgment of researchers; the results of vital signs, physical examination, electrocardiogram and laboratory safety examination all accord with the grouping standard of the research.
The administration scheme is as follows:
tablets of compound 1: the dose was 320mg once daily, orally administered, and fasted two hours before and after administration. One dosing cycle every 28 days.
Evaluation of curative effect of solid tumor:
evaluation criteria
Figure BDA0002209395670000121
Evaluation of Experimental results
Figure BDA0002209395670000131
Adverse events:
adverse events were grade 1-2, including diarrhea (grade 1), hypertriglyceridemia (grade 2), decreased white blood cell count (grade 2), clinically controllable. No Serious Adverse Events (SAE) occurred and cases of discontinuation of dosing, down-regulation of dose and early group withdrawal due to adverse events.
This time, first line treatment of sialadenoma, the patient's condition has now stabilized for 6 months, with a trend toward a stable tumor with a decrease in volume. By the end of the fifth dosing cycle, the sum of tumor major diameters had decreased by 12.5% from baseline. Therefore, the compound has better curative effect on treating the sialadenoma.

Claims (5)

1. The use of a compound shown below, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of sialadenoma,
Figure 737953DEST_PATH_IMAGE001
，
the sialadenoma is selected from submaxillary adenoma.
2. The use according to claim 1, wherein the sialadenoma is selected from the group consisting of benign sialadenoma and malignant sialadenoma.
3. The use according to claim 1, wherein the salivary gland tumor is a malignant salivary gland tumor with pulmonary metastasis.
4. Use of a pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt 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 a salivary tumor selected from submaxillary adenoma.
5. The use according to claim 4, 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.
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