Use of compounds for treating tumors

Abstract

The invention belongs to the technical field of medicines, and relates to application of a compound for treating tumors. Particularly, the invention relates to application of the compound, pharmaceutically acceptable salts, stereoisomers, solvates, crystal forms, isotope markers or prodrugs thereof in preparation of drugs, the drugs are used for preventing or treating tumors, and the invention also relates to a pharmaceutical composition containing the compound. Compounds having a structure represented by formula (I): # imgabs0 #

Description

Field of the Invention

[0001] The present invention belongs to the field of medical technology, and in particular, the present invention relates to the use of a compound for treating a tumor and a pharmaceutical composition comprising the compound. Background Art

[0002] In recent years, the incidence and mortality of malignant tumors (cancer) have continued to rise, seriously endangering human health.

[0003] Although many anti-tumor drugs are already on the market, there is still a need to develop anti-tumor drugs with higher activity and better safety. Summary of the invention

[0004] The inventors of the present application creatively discovered a new compound with anti-tumor activity, thereby providing the following invention:

[0005] In one aspect, the present application provides the use of a compound, a pharmaceutically acceptable salt, a stereoisomer, a solvate, a crystal form, an isotope label or a prodrug thereof in the preparation of a drug, wherein the drug is used to prevent or treat a tumor, and the compound has a structure shown in formula (I):

[0006]

[0007] The chemical name of the above compound is 2-(7,8-dihydroxy-4-methyl-2-oxo-2H-chromen-3-yl)-N-(5-methyl-1,3-thiazol-2-yl)-acetamide, CAS number 919741-06-3, MCULE ID 1949933163. The above compound can be obtained commercially.

[0008] In certain preferred embodiments, the compound, its pharmaceutically acceptable salt, stereoisomer, solvate, crystal form, isotope label or prodrug can be used as an active ingredient to form a pharmaceutical composition with a pharmaceutically acceptable carrier or excipient for the prevention or treatment of tumors.

[0009] In one aspect, the present application also relates to a pharmaceutical composition, which comprises a compound having a structure represented by formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate, crystal form, isotope label or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0010] The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form, such as an oral dosage form or a non-oral dosage form; for example, tablets, capsules, powders, pills, granules, solutions, suspensions, syrups, injections (including injection solutions, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays.

[0011] The pharmaceutical composition can be administered to patients or subjects in need in any suitable manner of administration, such as oral, parenteral, rectal, pulmonary or topical administration. When used for oral administration, the pharmaceutical composition can be prepared into oral preparations, such as oral solid preparations, such as tablets, capsules, pills, granules, etc.; or, oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When prepared into oral preparations, the pharmaceutical composition may also contain suitable fillers, binders, disintegrants, lubricants, etc. When used for parenteral administration, the pharmaceutical composition may be prepared into injections, including injections, sterile powders for injection and concentrated solutions for injection. When prepared into injections, the pharmaceutical composition may be produced by conventional methods in the existing pharmaceutical field. When preparing injections, additives may not be added to the pharmaceutical composition, or suitable additives may be added according to the properties of the drug. When used for rectal administration, the pharmaceutical composition may be prepared into suppositories, etc. When used for pulmonary administration, the pharmaceutical composition may be prepared into inhalants or sprays, etc.

[0012] In certain preferred embodiments, the compound is present in a pharmaceutical composition in a therapeutically or prophylactically effective amount. In certain preferred embodiments, the compound is present in a pharmaceutical composition in the form of a unit dose. In certain preferred embodiments, the dosage of the compound can be adjusted according to factors such as the severity of the patient's or subject's condition, age, weight, sex, mode of administration, and course of treatment.

[0013] In the present invention, the tumor preferably refers to a malignant tumor, including but not limited to lung cancer, liver cancer, gastric cancer, head and neck cancer, bone marrow cancer, intestinal cancer, prostate cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, bone cancer, laryngeal cancer, brain cancer, leukemia, melanoma, breast cancer, etc. In particular, the tumor can be selected from non-small cell lung cancer, liver cancer, chronic myeloid leukemia, acute promyelocytic leukemia, cecal cancer, rectal cancer, colon cancer, melanoma and breast cancer.

[0014] The compounds of the present invention may be used in combination with one or more additional anti-tumor agents. Therefore, in some embodiments, the pharmaceutical compositions of the present invention further comprise one or more additional anti-tumor agents.

[0015] In some embodiments, the additional anti-tumor agent is selected from one or more of the following: methotrexate, capecitabine, gemcitabine, doxifluridine, pemetrexed disodium, pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib, Herceptin, bevacizumab, rituximab, trastuzumab, paclitaxel, vinorelbine, docetaxel, doxorubicin, hydroxycamptothecin, mitomycin, epirubicin, pirarubicin, bleomycin, letrozole, tamoxifen, Fen, fulvestrant, triptorelin, flutamide, leuprolide, anastrozole, ifosfamide, busulfan, cyclophosphamide, carmustine, nimustine, semustine, nitrogen mustard, melphalan, leuprolide, carboplatin, cisplatin, oxaliplatin, tropoplatin, topotecan, camptothecin, topotecan, everolimus, sirolimus, tecan, 6-mercaptopurine, 6-thioguanine, azathioprine, streptomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, plicamycin and aminoglutethimide.

[0016] In one aspect, the present application also relates to a method for treating tumors, comprising administering to a subject in need thereof an effective amount of a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate, crystalline form, isotope-labeled substance or prodrug thereof, or a pharmaceutical composition of the present invention.

[0017] Definition of terms

[0018] As used herein, the term "pharmaceutically acceptable salt" refers to (i) salts formed by acidic functional groups present in the compounds provided by the present invention and appropriate inorganic or organic cations (bases), and includes, but is not limited to, alkali metal salts, such as sodium salts, potassium salts, lithium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; other metal salts, such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic base salts, such as ammonium salts; organic base salts, such as tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucosamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenethylamine salts, piperazine salts, tetramethylamine salts, tris(hydroxymethyl)aminomethane salts. And, (ii) salts formed by the basic functional groups present in the compounds provided by the present invention and appropriate inorganic or organic anions (acids), and including but not limited to, hydrohalides, such as hydrofluorides, hydrochlorides, hydrobromides, hydroiodides, etc.; inorganic acid salts, such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkane sulfonates, such as methanesulfonates, trifluoromethanesulfonates, ethanesulfonates, etc.; aryl sulfonates, such as benzenesulfonates, p-toluenesulfonates, etc.; organic acid salts, such as acetates, malates, fumarates, succinates, citrates, tartrates, oxalates, maleates, etc.; amino acid salts, such as glycine, trimethylglycine, arginine, ornithine, glutamate, aspartate, etc.

[0019] As used herein, the term "solvate" refers to a substance formed by the association of a compound of the present invention with a solvent molecule. The solvent may be water or an organic solvent (e.g., methanol, ethanol, propanol, acetonitrile, etc.), for example, the compound of the present invention may form an ethanolate with ethanol. The solvate formed by the compound of the present invention and water may also be referred to as a hydrate.

[0020] As used herein, the term "crystal form" refers to the crystal structure of a substance. When a substance crystallizes, various factors may affect the intramolecular or intermolecular bonding mode, causing molecules or atoms to be arranged differently in the lattice space, forming different crystal structures. The compounds of the present invention may exist in one crystal structure or in multiple crystal structures, i.e., have "polymorphism". The compounds of the present invention may exist in different crystal forms.

[0021] As used herein, the term "stereoisomer" includes conformational isomers and configurational isomers, wherein the configurational isomers mainly include cis-trans isomers and optical isomers. The compounds of the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomer forms, and any combination or any mixture thereof. For example, a single enantiomer, a single diastereomer or a mixture of the above. When a compound contains an olefin double bond, unless otherwise specified, it includes cis-isomers and trans-isomers, and any combination thereof.

[0022] As used herein, the term "prodrug" refers to a compound that can be converted into the present invention by reactions such as oxidation, reduction, hydrolysis, etc. in the subject. The prodrug itself may or may not have the biological activity of the compound of formula (I). Further information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACSSymposium Series (T Higuchi and W Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association).

[0023] As used herein, the term "pharmaceutically acceptable carrier or excipient" refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with a subject and an active ingredient, which is well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), and includes, but is not limited to, disintegrants, binders, surfactants, glidants, lubricants, pH adjusters, ionic strength enhancers, agents that maintain osmotic pressure, agents that delay absorption, diluents, antioxidants, colorants, flavoring agents, preservatives, taste masking agents, etc. For example, non-limiting examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Non-limiting examples of binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Non-limiting examples of diluents include lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, glucose, sucrose, sorbitol, microcrystalline cellulose, starch and calcium hydrogen phosphate dihydrate. Non-limiting examples of surfactants include sodium lauryl sulfate and polysorbate 80. Non-limiting examples of glidants include silicon dioxide and talc. Non-limiting examples of lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and a mixture of magnesium stearate and sodium lauryl sulfate. Non-limiting examples of pH regulators include but are not limited to phosphate buffers. Ionic strength enhancers include but are not limited to sodium chloride. Reagents that maintain osmotic pressure include but are not limited to sugar, NaCl and the like. Reagents that delay absorption include but are not limited to monostearate and gelatin. Preservatives include, but are not limited to, various antibacterial and antifungal agents such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, and the like.

[0024] As used herein, the term "prevention" refers to a method implemented in order to prevent or delay the occurrence of a disease or illness or symptom in a subject. As used herein, the term "treatment" refers to a method implemented in order to obtain a beneficial or desired clinical result. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, alleviating symptoms, reducing the scope of the disease, stabilizing (i.e., no longer worsening) the state of the disease, delaying or slowing the development of the disease, improving or alleviating the state of the disease, and alleviating symptoms (whether partially or completely), whether detectable or undetectable. In addition, "treatment" can also refer to, compared with the expected survival period (if not receiving treatment), extending the survival period.

[0025] The "effective amount" of the present invention refers to an amount sufficient to obtain or at least partially obtain the desired effect. For example, an "effective amount for preventing a disease" refers to an amount sufficient to prevent, prevent or delay the occurrence of a disease; an "effective amount for treating a disease" refers to an amount sufficient to cure or at least partially prevent the disease and its complications in patients who already have the disease. Determining such an effective amount is entirely within the capabilities of those skilled in the art. For example, an effective amount for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the patient's general condition such as age, weight and gender, the mode of administration of the drug, and other treatments administered simultaneously, etc.

[0026] As used herein, the term "subject" refers to a mammal, such as bovine, equine, porcine, canine, feline, rodent, primate; for example, a human.

[0027] Advantageous Effects of the Invention

[0028] The compound of formula (I) of the present invention, its pharmaceutically acceptable salt, stereoisomer, solvate, crystal form, isotope label or prodrug shows excellent anti-tumor effect and has excellent therapeutic effect on tumors.

[0029] Embodiments of the present invention will be described in detail below in conjunction with examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention, rather than to limit the scope of the present invention. According to the following detailed description of preferred embodiments, various objects and advantages of the present invention will become apparent to those skilled in the art.

[0030] Example 1 Evaluation of the antitumor efficacy of the compound in vivo

[0031] Cell culture medium: Gibco DMEM high glucose medium was purchased from ThermoFisher; 10% fetal bovine serum (FBS) was purchased from ThermoFisher; 10% penicillin-streptomycin mixed solution (Pen / Strep) was purchased from ThermoFisher; culture medium 1640 was purchased from ThermoFisher.

[0032] 7-10 week old NOD.CB17-Prkdcscid / J mice (SPF grade, purchased from The Jackson Laboratory) weighing 18g-22g were housed in separate cages (5 mice / cage) with an ambient temperature of 22±2°C and a humidity of 60±5% to maintain ventilation.

[0033] After one week of adaptive feeding with clean water and standard feed, mice were injected with MDA-MB231 (human breast cancer cells), MC38 (mouse colon cancer cells), B16 (mouse melanoma cells), or A549 (human non-small cell lung cancer cells). Twelve mice were selected for each tumor model. The cells were expressed as 1×10 6 / 0.2ml matrigel density injection. Among them, MDA-MB231 was injected into the mouse mammary gland and the fourth mammary gland fat pad, and the other cell lines were modeled by dorsal tumor implantation.

[0034] The size of the subcutaneous tumor was observed 7 days after injection, and the tumor size and mouse weight were measured every 2 days. After 30-45 days of feeding, when the tumor grew to a diameter of 0.8 cm, the drug (compound of formula (I)) was intravenously injected into the mouse, and the dosage was shown in Table 1. The compound was obtained from WuXi AppTec labnetwork, dissolved in DMSO, and the concentration was 5 mg / mL, and the drug was administered once every two days.

[0035] DMSO was used as a control, and the volume, frequency, and method of use were consistent with those of the drug-treated group.

[0036] Table 1 Drug dosage and injection method

[0037]

[0038] Tables 2 to 5 show the tumor volume of each mouse after 31 days of administration and the average tumor volume of each group.

[0039] Tumor volume = tumor width × tumor width × tumor length / 2.

[0040] Table 2 Tumor volume of MDA-MB231 transplanted tumor model after 31 days of administration

[0041]

[0042] Table 3 Tumor volume of B16 transplanted tumor model after 31 days of administration

[0043]

[0044] Table 4 Tumor volume of MC38 transplanted tumor model after 31 days of administration

[0045]

[0046] Table 5 Tumor volume of A549 transplanted tumor model after 31 days of administration

[0047]

[0048] The tumor inhibition rate was calculated based on the average tumor volume of each drug administration group. The results are shown in Table 6. Tumor inhibition rate = 100% - (tumor volume of drug administration group / tumor volume of control group × 100%) Table 6 Tumor inhibition rate

[0049] Transplanted tumor Tumor inhibition rate MDA-MB231 14.51％ B16 10.94％ MC38 15.70％ A549 9.84％

[0050] It can be seen from the above results that the compound of formula (I) exhibits excellent anti-tumor effect and has an excellent therapeutic effect on tumors.

[0051] Although the specific embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that various modifications and changes may be made to the details according to all the teachings disclosed, and these changes are within the scope of protection of the present invention. The full scope of the present invention is given by the attached claims and any equivalents thereof.

Claims

1. Use of a compound, a pharmaceutically acceptable salt, stereoisomer, solvate, crystal form, isotope-labeled substance or prodrug thereof in the preparation of a drug for preventing or treating tumors, wherein the compound has a structure represented by formula (I):

2. The use of claim 1, wherein The compound is used as an effective ingredient and combined with a pharmaceutically acceptable carrier or excipient to form a pharmaceutical composition for preventing or treating tumors.

3. The use according to claim 1 or 2, wherein the tumor is a malignant tumor.

4. The use according to any one of claims 1 to 3, wherein the tumor is selected from the group consisting of lung cancer, liver cancer, gastric cancer, head and neck cancer, bone marrow cancer, intestinal cancer, prostate cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, bone cancer, laryngeal cancer, brain cancer, leukemia, melanoma, and breast cancer.

5. The use according to any one of claims 1 to 3, wherein the tumor is selected from the group consisting of non-small cell lung cancer, liver cancer, chronic myeloid leukemia, acute promyelocytic leukemia, cecal cancer, rectal cancer, colon cancer, melanoma and breast cancer.

6. The use according to any one of claims 1 to 5, wherein the compound, its pharmaceutically acceptable salt, stereoisomer, solvate, crystal form, isotope label or prodrug is used in combination with one or more additional anti-tumor agents.

7. A pharmaceutical composition comprising a compound having a structure represented by formula (I), a pharmaceutically acceptable salt, stereoisomer, solvate, crystal form, isotope-labeled substance or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients.

8. The pharmaceutical composition of claim 7, further comprising one or more additional anti-tumor agents.

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