Antitumor use of substituted indan-imidazole compounds

Abstract

The present application relates to the antitumor use of substituted indenyl imidazole compounds of formula (I), belonging to the antitumor pharmaceutical technical field. The compounds include the compounds shown below or pharmaceutically acceptable salts thereof, and formulations formed by the same. The compounds of the present application and their pharmaceutically acceptable salts and formulations thereof can be used to inhibit breast cancer and melanoma but are not limited to the above-mentioned tumors, thereby providing a new option for the treatment of related tumors.

Description

TECHNICAL FIELD

[0001] The present application relates to the use of substituted dihydroindenyl imidazole compounds, pharmaceutically acceptable salts, racemates, enantiomers, solvates, hydrates, crystal forms or co-crystals thereof in the manufacture of a product for treating tumors. BACKGROUND

[0002] Cancer is one of the diseases that endanger human life and health the most, and a large number of people die from cancer every year. The research and development of anticancer drugs has always been a hot spot in pharmaceutical research. Therefore, the development of highly efficient and low-toxicity, high-targeting antitumor drugs is a problem to be solved at present. SUMMARY

[0003] The present application relates to the use of compounds of formula I, pharmaceutically acceptable salts, racemates, enantiomers, solvates, hydrates, crystal forms or co-crystals thereof or compositions containing compounds of formula I, pharmaceutically acceptable salts, racemates, enantiomers, solvates, hydrates, crystal forms or co-crystals thereof in the manufacture of a product for treating tumors,

[0004]

[0005] R1, R2 are each independently selected from the group consisting of H, D, F, Cl, Br, I and C 1-6 alkyl.

[0006] In certain embodiments, R1, R2 in formula I are each independently selected from the group consisting of H, D, F, Cl, Br, I and C 1-4 alkyl.

[0007] In certain embodiments, R1, R2 in formula I are each independently selected from the group consisting of H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0008] In certain embodiments, R1, R2 in formula I are each independently selected from the group consisting of H, D, F, Cl, Br, I, methyl, ethyl, n-propyl and n-butyl.

[0009] In certain embodiments, R1, R2 in formula I are each independently selected from the group consisting of H, D, F, Cl, Br, I and methyl.

[0010] In certain embodiments, R1, R2 in formula I are each independently selected from the group consisting of H, F, Cl, Br, I and methyl.

[0011] In certain embodiments, R1 in formula I is selected from the group consisting of F, Cl, Br, I and methyl, and R2 is selected from the group consisting of H, F, Cl, Br and I.

[0012] In certain embodiments, the compound is selected from the group consisting of:

[0013]

[0014] In certain embodiments, the compound is selected from:

[0015] In certain embodiments, the compound is selected from:

[0016] In certain embodiments, the tumor is a breast cancer or a melanoma. In certain embodiments, the tumor is a melanoma.

[0017] In certain embodiments, the product is a medicament.

[0018] In certain embodiments, the composition further comprises one or more pharmaceutically acceptable carriers.

[0019] In certain embodiments, the composition further comprises an additional drug, which is a chemotherapeutic agent (such as cyclophosphamide, fluorouracil, platinum, paclitaxel, etc.) or an immunomodulatory agent (such as immune checkpoint inhibitors like ipilimumab and nivolumab, etc., tyrosine kinase inhibitors like imatinib and osimertinib, etc., proteasome inhibitors like bortezomib, etc., antibiotic agents like bleomycin, etc., alkylating agents like nitrogen mustard, etc., antimetabolites like methotrexate and cytarabine, etc., hormonal agents like tamoxifen, etc., immunologically active agents, interferon active agents, and mixed active agents, etc.).

[0020] In certain embodiments, the compound of the present application is selected from:

[0021]

[0022]

[0023] The compounds of the present application can exist in tautomeric forms, as racemates or as enantiomers, and the present application is meant to include all such forms.

[0024] The present application encompasses all possible crystalline forms or polymorphs of the compounds, which can be a single polymorph or a mixture of more than one polymorph in any ratio.

[0025] The compounds of the present application can exist in the form of solvates (such as hydrates), wherein the compounds of the present application contain a solvent, such as water, methanol or ethanol, as an integral part of the crystal lattice of the compound. The amount of the solvent can be present in stoichiometric or non-stoichiometric ratios.

[0026] In the present application, the term "pharmaceutically acceptable" or "medicinally acceptable" used interchangeably therewith, for example in the description of "pharmaceutically acceptable salts", means that the salt is not only acceptable physiologically to the subject, but also synthetically useful material, for example, the salt formed as an intermediate in the process of chiral resolution, although the intermediate salt cannot be directly administered to the subject, but the salt can play a role in obtaining the final product of the present application.

[0027] The compounds of the present application of formula I can also be in the form of salts, generally salts with organic or inorganic bases or acids. Preferred are pharmaceutically acceptable salts according to the present application. Pharmaceutically acceptable salts of the compounds of the present application can be salts of the present substances with inorganic acids, carboxylic acids or sulfonic acids, particularly preferred are for example salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, embonic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, tannic acid. Other acids, such as oxalic acid, although not pharmaceutically acceptable themselves, can be useful in the preparation of salts useful as intermediates in obtaining the compounds of the present application and their pharmaceutically acceptable salts.

[0028] In the present application, the term "pharmaceutically acceptable carrier" refers to a carrier that is compatible, in pharmacological and / or physiological terms, with the subject and the active ingredient, and is well known in the art (see, e.g., Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995). Pharmaceutically acceptable carriers include, but are not limited to, pH adjusting agents, surfactants, ionic strength enhancers, diluents, agents for maintaining osmotic pressure, agents for delaying absorption, preservatives, stabilizers. For example, pH adjusting agents include, but are not limited to, phosphate buffers. Surfactants include, but are not limited to, cationic, anionic or non-ionic surfactants, such as Tween-80. Ionic strength enhancers include, but are not limited to, sodium chloride. Preservatives include, but are not limited to, various antibacterial agents and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Agents for maintaining osmotic pressure include, but are not limited to, sugars, NaCl, and the like. Agents for delaying absorption include, but are not limited to, monostearate and gelatin. Diluents include, but are not limited to, water, aqueous buffers (such as buffered saline), alcohols and polyols (such as glycerol), and the like. Preservatives include, but are not limited to, various antibacterial agents and antifungal agents, such as thiomersal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, and the like. Stabilizers have the meaning commonly understood by those skilled in the art, and are capable of stabilizing the desired activity of the active ingredient in the pharmaceutical, including, but not limited to, sodium glutamate, gelatin, SPGA, sugars (such as sorbitol, mannitol, starch, sucrose, lactose, dextran, or glucose), amino acids (such as glutamic acid, glycine), proteins (such as dried lactose, albumin or casein) or their degradation products (such as lactalbumin hydrolysate), and the like.

[0029] In the present application, the term "treatment" aims to alleviate, reduce, ameliorate or eliminate the disease state or condition in question. A subject is successfully "treated" if one or more signs and symptoms are observed and / or detectable reduced or ameliorated in the subject who has received a therapeutic amount of the compound, its pharmaceutically acceptable salt, racemate, enantiomer, solvate, hydrate, crystal form or co-crystal according to the methods described herein. It should also be understood that the treatment of the disease state or condition in question includes not only the complete treatment, but also the incomplete treatment, which achieves some biologically or medically relevant result.

[0030] The compounds according to the present application can have systemic and / or local effects as active ingredients and can therefore be administered in suitable ways, such as orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, transdermally, conjunctivally, topically or in the form of an implant.

[0031] Suitable for oral administration are the well-known forms of presentation of the active ingredient, which allow a rapid and / or modified release of the active ingredient, such as tablets (uncoated or coated tablets, such as enteric-coated or film-coated tablets), capsules, sugar-coated tablets, granules, pellets, powders, emulsions, suspensions and aerosols.

[0032] Parenteral administration can be performed by injection (intravenous, intraarterial, intracardiac, intraspinal or intrathecal administration) or by infusion (intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration). Suitable for parenteral administration are forms of presentation of the preparation in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders for injection and infusion.

[0033] Suitable for other routes of administration are, for example, drugs for inhalation (in particular powder inhalation, spray), nasal drops / solutions, sprays; tablets or capsules for lingual, sublingual or buccal administration, suppositories, preparations for the ear and the eye, vaginal capsules, aqueous suspensions (lotions, shake-mixes), lipophilic suspensions, ointments, creams, emulsions, pastes, powders for dusting or implants, such as stents.

[0034] The compounds according to the application can be converted into the stated forms of presentation using known methods.

[0035] The compounds according to the application or the compositions containing them can be administered in unit dose form. The stated compositions can contain from 0.01 mg to 1000 mg of the compounds according to the application, pharmaceutically acceptable salts, racemates, enantiomers, solvates, hydrates, crystal forms or co-crystals thereof.

[0036] It must be appreciated that the optimal dose and interval of administration of the compounds according to the application are determined by the nature of the compound and by external conditions such as the form, route and site of administration and the particular mammal being treated, and that this optimal dose can be determined using routine techniques. It must also be appreciated that the optimal course of treatment, i.e. the daily dose of the compound over a given period of time, can be determined using methods known in the art.

[0037] Actual dosage levels of the active ingredients in the compositions or medicaments of this application can be varied up to the maximum tolerable by the host without causing adverse effects, depending on the nature and severity of the condition being treated and on the host's condition and prior medical history. However, it is presently contemplated that pharmaceutical compositions containing compounds of the present application will contain an effective amount of the active compound to treat, prevent, or delay the onset of the particular disease or disorder for which it is administered. Generally, an effective amount of the compound of the present application will be in the range of from 0.001 to 1000 mg / kg body weight per day, particularly 0.01 to 500 mg / kg body weight per day, more particularly 0.1 to 100 mg / kg body weight per day.

[0038] Advantages of the present application

[0039] The substituted indan-imidazole compound of formula I provided by the present application has a significant inhibitory effect on the growth of breast cancer cells 4T1 and melanoma cells B16F, has anticancer activity, and can be used for preparing an antitumor drug. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1 The anti-tumor effects of compounds S-7-45-2, S-7-18 and S-7-46 in mice are shown, wherein: A shows the inhibitory effect of the compounds on mouse breast cancer cell 4T1 transplanted tumors; B shows the body weight changes of 4T1 transplanted tumor mice during administration; C shows the inhibitory effect of the compounds on mouse breast cancer cell B16F transplanted tumors; D shows the body weight changes of B16F transplanted tumor mice during administration. DETAILED DESCRIPTION

[0041] The essential content of the present application will be further illustrated below in combination with specific embodiments of the present application. It should be understood that the following embodiments are only used to illustrate the present application, but do not limit the protection scope of the present application. In the following examples, the specific conditions are not specified, and are carried out according to the conventional conditions or the manufacturer's recommendations. The reagents and instruments used are not specified by the manufacturer, and are conventional products that can be obtained by purchase.

[0042] Although many of the materials and methods used in the following examples are well known in the art, the present application is described in as much detail as possible. It is clear to those skilled in the art that the materials and methods used in the following examples are well known in the art if not specifically mentioned.

[0043] [Example of bioactivity test]

[0044] The anti-tumor activity test of the compounds in mice was used to test the effect of the compounds of the present application on inhibiting tumors in mice, with dexmedetomidine and clonidine as controls. The experimental methods and results are as follows:

[0045] 1. Materials and reagents

[0046] Table 1 Experimental materials and reagents used in the anti-tumor test in mice

[0047]

[0048] 2. Operation method

[0049] Mouse breast cancer cells 4T1 and melanoma cells B16F were routinely cultured in high glucose DMEM containing 10% fetal bovine serum at 37°C, 5% CO2 incubator. After three generations in vitro, when the cells grew to more than 80% and the fusion rate reached the required amount, the cells were collected after digestion and washed with PBS. The cell concentration was adjusted to about 5 x 10 7 / mL and placed in a 4 mL centrifuge tube on ice for standby.

[0050] Female BALB / c mice aged 6-12 weeks were subcutaneously inoculated with mouse breast cancer cells 4T1 and melanoma cells B16F. The mice were caught and placed on their sides, and the forelimb axillary was disinfected with 75% alcohol. 100 μL of cell suspension was injected subcutaneously into the axillary with a 1 mL syringe, i.e. about 5 x 10 6 cells per mouse per 100 μL.

[0051] 3. Experimental animal grouping and administration

[0052] After the tumor grew to 90-150 mm 3 , the animals were randomly divided into groups, 6 animals per group, and fed according to different administration forms, respectively:

[0053] Model control group: intraperitoneal injection of the same volume of blank solvent (DMSO: 0.5% sodium carboxymethyl cellulose: distilled water = 1:1:8) every day;

[0054] Test group: intraperitoneal injection of 1 mg / kg (mouse weight) compound solution every day.

[0055] Positive control group: intraperitoneal injection of 5 mg / kg (mouse weight) clonidine (CLD) solution and 1 mg / kg (mouse weight) dexmedetomidine (DMED) solution every day.

[0056] The administration route was intraperitoneal injection, the administration frequency was once a day, and the administration was continuous for 13 days. The first day of administration was defined as the first day of the experiment, and the tumor volume change of the mice was measured and recorded twice a day. The tumor volume was measured using a vernier caliper to measure the long diameter (a) and short diameter (b) of the tumor, and the tumor volume was calculated, V (mm 3 ) = a x b 2 / 2. After the experiment, the mice were dissected and the tumor weight was measured. The data were entered and statistically analyzed by GraphPad Prism 6 software. The data were expressed as mean ± SEM (Standard Error of Mean).

[0057] 4. Experimental results

[0058] The results of evaluating the anti-tumor activity of compounds S-7-18, S-7-46 and S-7-45-2 in mice are shown in Table 2. Figure 1 As shown in Table 2, the dihydroindenyl imidazole compounds provided by the present application have significant inhibitory effects on the growth of breast cancer cells 4T1 and melanoma cells B16F, and the inhibitory effect on B16F is much better than that of the positive drug CLD. With the extension of the administration time, no significant tumor growth was observed in the groups of compounds S-7-18 and S-7-46, and the tumor inhibition rate of compound S-7-18 reached 95.3% at a dosage of 1 mg / kg, which was significantly better than that of the positive drug CLD (the tumor inhibition rate was only 20.0% at a dosage of 5 mg / kg). Thus, it is proved that the dihydroindenyl imidazole compounds of the present application have anticancer activity and can be used for preparing anti-tumor drugs.

[0059] Table 2. Inhibitory effects of compounds S-7-18, S-7-46 and S-7-45-2 on breast cancer cell 4T1 and melanoma cell B16F transplanted tumors, respectively

[0060]

[0061] Although the specific embodiments of the present application have been described in detail, those skilled in the art will understand that various modifications and substitutions can be made to those details based on all the teachings disclosed herein, and such changes are within the scope of the present application. The entire scope of the present application is given by the appended claims and any equivalents thereof.

Claims

1. The use of a compound or a pharmaceutically acceptable salt thereof, or a composition containing said compound or a pharmaceutically acceptable salt thereof, in the preparation of a product for treating tumors, wherein said compound is selected from: The tumor in question is a melanoma.

2. The use of a compound or a pharmaceutically acceptable salt thereof, or a composition containing said compound or a pharmaceutically acceptable salt thereof, in the preparation of a product for treating tumors, wherein said compound is selected from: The tumor in question is breast cancer.

3. The use as described in any one of claims 1-2, wherein the product is a pharmaceutical.

4. The use as described in any one of claims 1-2, wherein the composition further comprises one or more pharmaceutically acceptable carriers.

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