Anti-tumor application of substituted indenyl imidazole compound

Abstract

The invention relates to anti-tumor application of a substituted indenyl imidazole compound shown as a formula (I), and belongs to the technical field of anti-tumor pharmacy. The compound comprises a compound shown in the specification or a pharmaceutically acceptable salt thereof, and a preparation formed by the compound or the pharmaceutically acceptable salt. The compound as well as the medicinal salt and the preparation thereof can be used for inhibiting breast cancer and melanoma but not limited to the breast cancer and the melanoma, so that a new choice is provided for treating related tumors. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the use of substituted indenyl imidazole compounds, pharmaceutically acceptable salts, racemates, enantiomers, solvates, hydrates, crystal forms or co-crystals thereof in preparing products for treating tumors. Background Art

[0002] Cancer is one of the most harmful diseases to human life and health, and a large number of people die from cancer every year. The research and development of anticancer drugs has always been a hot topic in pharmaceutical research. Therefore, the development of highly effective, low-toxic, and highly targeted anti-tumor drugs is an urgent problem to be solved. Summary of the invention

[0003] The present invention relates to the use of a compound represented by formula I, a pharmaceutically acceptable salt, racemate, enantiomer, solvate, hydrate, crystal form or co-crystal thereof, or a composition containing a compound represented by formula I, a pharmaceutically acceptable salt, racemate, enantiomer, solvate, hydrate, crystal form or co-crystal thereof in the preparation of a product for treating tumors.

[0004]

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

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

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

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

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

[0010] In certain embodiments, R1 and R2 in Formula I are each independently selected from H, F, Cl, Br, I and methyl.

[0011] In certain embodiments, in Formula I, R1 is selected from F, Cl, Br, I and methyl, and R2 is selected from H, F, Cl, Br and I.

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

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

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

[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 immunomodulator (such as immune checkpoint inhibitors such as ipilimumab and nivolumab, tyrosine kinase inhibitors such as imatinib and osimertinib, proteasome inhibitors such as bortezomib, antibiotics such as bleomycin, alkylating agents such as nitrogen mustard, antimetabolites such as methotrexate and cytarabine, hormone drugs such as tamoxifen, immunoactive agents, interferon-type active agents and mixed active agents, etc.).

[0020] In certain embodiments, the compounds described herein are selected from the following:

[0021]

[0022]

[0023] The compounds of the present invention may exist in tautomeric forms, racemic forms or enantiomer forms, and the present invention also encompasses such forms.

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

[0025] The compounds of the present invention may exist in the form of solvates (such as hydrates), wherein the compounds of the present application contain a solvent as a structural element of the crystal lattice of the compound, such as water, methanol or ethanol. The amount of the solvent may exist in a stoichiometric ratio or a non-stoichiometric ratio.

[0026] In the present invention, the term "pharmaceutically acceptable" or "pharmaceutically usable" which is used interchangeably therewith, for example, when describing a "pharmaceutically acceptable salt", means that the salt may not only refer to a synthetic substance that is physiologically acceptable to a subject, but also refer to a synthetic substance that has pharmaceutical use value, such as a salt formed as an intermediate when performing chiral separation. Although the salt of this intermediate cannot be directly administered to a subject, the salt may play a role in obtaining the final product of the present invention.

[0027] The compound shown in formula I of the present invention can also be in the form of its salt, generally a salt formed with an organic or inorganic base or acid. Pharmaceutically acceptable salts are preferred in the present invention. The pharmaceutically acceptable salt of the compound of the present invention can be a salt formed by the substance of the present invention and an inorganic acid, a carboxylic acid or a sulfonic acid, and particularly preferably, for example, a salt formed 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, pamoic 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 in themselves, can be used to prepare salts used as intermediates to obtain the compound of the present invention and its pharmaceutically acceptable salts.

[0028] In the present invention, the term "pharmaceutically acceptable carrier" refers to a carrier that is pharmacologically and / or physiologically compatible with a subject and an active ingredient, which is well known in the art (see, for example, 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 regulators, surfactants, ionic strength enhancers, diluents, agents that maintain osmotic pressure, agents that delay absorption, preservatives, and stabilizers. For example, pH regulators include, but are not limited to, phosphate buffers. Surfactants include, but are not limited to, cationic, anionic or nonionic 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 and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. Agents that maintain osmotic pressure include, but are not limited to, sugars, NaCl, and the like. Agents that delay 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), etc. Preservatives include, but are not limited to, various antibacterial and antifungal agents, such as thimerosal, 2-phenoxyethanol, parabens, chlorobutanol, phenol, sorbic acid, etc. Stabilizers have the meanings commonly understood by those skilled in the art, which can stabilize the desired activity of the active ingredient in the drug, 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 whey, albumin or casein) or their degradation products (such as lactalbumin hydrolysate), etc.

[0029] In the present invention, the term "treatment" aims to alleviate, mitigate, improve or eliminate the disease state or condition. If the subject receives a therapeutic amount of the compound, its pharmaceutically acceptable salt, racemate, enantiomer, solvate, hydrate, crystal form or co-crystal according to the method described herein, and one or more signs and symptoms of the subject show an observable and / or detectable reduction or improvement, the subject is successfully "treated". It should also be understood that the treatment of the disease state or condition includes not only complete treatment, but also failure to achieve complete treatment, but achieving some biological or medically relevant results.

[0030] The compounds of the present invention as active ingredients may have systemic and / or local effects and can therefore be administered by a suitable route, such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, topical administration or in the form of an implant.

[0031] Suitable for oral administration are known administration forms which deliver the active ingredient rapidly and / or in a modified manner, such as tablets (uncoated or coated, such as tablets with enteric coating or film coating), capsules, dragees, granules, pellets, powders, emulsions, suspensions and aerosols.

[0032] With parenteral administration it is possible to avoid the absorption step (intravenous, intraarterial, intracardiac, intraspinal or intralumbar administration) or to include absorption (intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration). Administration forms suitable for parenteral administration include preparations in the form of solutions, suspensions, emulsions, lyophilizates and sterile powders for injection and infusion.

[0033] Suitable other routes of administration include, for example, drugs for inhalation (particularly powder inhalation, spray), nasal drops / solutions, sprays; tablets or capsules for tongue, sublingual or buccal administration, suppositories, preparations for ears and eyes, vaginal capsules, aqueous suspensions (lotions, shaken mixtures), lipophilic suspensions, ointments, creams, emulsions, pastes, dusting powders or implants, such as stents.

[0034] The compounds according to the invention can be converted into the stated administration forms by known methods.

[0035] The compound of the present invention or a composition containing the same can be administered in a unit dosage form, wherein the composition can contain 0.01 mg to 1000 mg of the compound of the present invention, or a pharmaceutically acceptable salt, racemate, enantiomer, solvate, hydrate, crystal form or co-crystal thereof.

[0036] It must be recognized that the optimal dosage and interval of the compounds of the present invention are determined by the properties of the compounds and external conditions such as the form, route and site of administration and the specific mammals to be treated, and this optimal dosage can be determined by conventional techniques. It must also be recognized that the optimal course of treatment, i.e., the daily dosage of the compound within a specified time, can be determined by methods known in the art.

[0037] The actual dosage level of each active ingredient in the composition or drug of the present invention can be changed so that the amount of active compound obtained can effectively obtain the desired therapeutic response for a specific patient, composition and administration method. The dosage level must be selected based on the activity of the specific compound, the route of administration, the severity of the condition to be treated, and the condition and previous medical history of the patient to be treated. However, it is common practice in the art to start the dosage of the compound from the level required to obtain the desired therapeutic effect and gradually increase the dosage until the desired effect is obtained. In general, the dosage of the compound of the present invention for mammals, especially humans, can be between 0.001-1000 mg / kg body weight / day.

[0038] Beneficial effects of the present invention

[0039] The substituted indanyl imidazole compounds shown in formula I provided by the present invention have a significant inhibitory effect on the growth of breast cancer cells 4T1 and melanoma cells B16F, have anti-cancer activity, and can be used to prepare anti-tumor drugs. BRIEF DESCRIPTION OF THE 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 4T1 mouse breast cancer cell transplanted tumors; B shows the weight changes of 4T1 transplanted tumor mice during the administration period; C shows the inhibitory effect of the compounds on B16F mouse breast cancer cell transplanted tumors; D shows the weight changes of B16F transplanted tumor mice during the administration period. DETAILED DESCRIPTION

[0041] The substantive content of the present invention will be further described below in conjunction with specific embodiments of the present invention. It should be understood that the following examples are only used to illustrate the present invention, but are not intended to limit the scope of protection of the present invention. In the following examples, those without specifying specific conditions are carried out according to normal conditions or manufacturer recommendations. Reagents and instruments used are not specified by manufacturers and are all conventional products that can be obtained commercially.

[0042] Although many materials and operating methods used in the following examples are well known in the art, the present invention is still described in as much detail as possible. It is clear to those skilled in the art that the materials and operating methods used in the following examples are well known in the art unless otherwise specified.

[0043] [Biological Activity Test Example]

[0044] The compound was tested for its anti-transplanted tumor activity in mice, with dexmedetomidine and clonidine as controls, to test the inhibitory effect of the compound on mouse tumors. The experimental method and results are as follows:

[0045] 1. Materials and Reagents

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

[0047]

[0048] 2. Operation method

[0049] Mouse breast cancer cells 4T1 and melanoma cells B16F were routinely cultured in a 37°C, 5% CO2 incubator with high-glucose DMEM containing 10% fetal bovine serum. After three generations in vitro, when the cells grew to more than 80% and the fusion rate reached the required amount, the cells were digested and collected, washed with PBS and counted, and the cell concentration was adjusted to about 5×10 7 Place the 500 μg / mL in a 4 mL centrifuge tube and place on ice for later use.

[0050] Female BALB / c mice aged 6 to 12 weeks were selected and inoculated subcutaneously with mouse breast cancer cells 4T1 and melanoma cells B16F. The mice were grasped and placed on their side. The axilla of the forelimbs was disinfected with 75% alcohol. 100 μL of cell suspension was drawn with a 1 mL syringe and injected into the axilla subcutaneously, i.e., about 5×10 6 cells / mouse / 100μL.

[0051] 3. Experimental Animal Grouping and Drug Administration

[0052] When the tumor grows to 90-150 mm 3 Afterwards, the animals were randomly divided into groups, with 6 animals in each group, and fed according to different dosing forms, namely:

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

[0054] Test group: 1 mg / kg (mouse body weight) of compound solution was intraperitoneally injected every day.

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

[0056] The administration route was intraperitoneal injection, and the administration frequency was once a day for 13 consecutive days. The first day of administration was defined as the first day of the experiment. The changes in the tumor volume of the mice were measured and recorded every two days. Tumor volume was measured using a vernier caliper to measure the long diameter (a) and short diameter (b) of the tumor and calculate the tumor volume, tumor volume V (mm 3 )=a×b 2 / 2. After the experiment, the mice were dissected and the tumor weight was weighed. The data were entered and statistically analyzed using GraphPad Prism 6 software. The data were expressed as mean±SEM (Standard Error of Mean, standard error).

[0057] 4. Experimental Results

[0058] The results of the anti-tumor activity evaluation of compounds S-7-18, S-7-46 and S-7-45-2 in mice are as follows: Figure 1 As shown in Table 2, the dihydroindenyl imidazole compounds provided by the present invention have a significant inhibitory effect on the growth of breast cancer cells 4T1 and melanoma cells B16F, especially the inhibitory effect on B16F is much better than the positive drug CLD. With the extension of the administration time, no obvious tumor growth phenomenon occurred in the compound S-7-18 and S-7-46 groups. At a dosage of 1 mg / kg, the tumor inhibition rate of compound S-7-18 reached 95.3%, which was significantly better than the positive drug CLD (the tumor inhibition rate at 5 mg / kg was only 20.0%). This proves that the dihydroindenyl imidazole compounds of the present invention have anticancer activity and can be used to prepare antitumor 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

[0060]

[0061] 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 substitutions may be made to those details based on 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 of formula I, a pharmaceutically acceptable salt, racemate, enantiomer, solvate, hydrate, crystal form or co-crystal thereof, or a composition containing a compound of formula I, a pharmaceutically acceptable salt, racemate, enantiomer, solvate, hydrate, crystal form or co-crystal thereof in the preparation of a product for treating tumors, R1 and R2 are each independently selected from H, D, F, Cl, Br, I and C 1-6 alkyl.

2. The method of claim 1, wherein R1 and R2 are each independently selected from H, D, F, Cl, Br, I and C 1-4 alkyl.

3. The method of claim 1 or 2, wherein R1 and R2 are each independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

4. The method according to any one of claims 1 to 3, wherein R1 and R2 are each independently selected from H, D, F, Cl, Br, I, methyl, ethyl, n-propyl and n-butyl.

5. The method according to any one of claims 1 to 4, wherein R1 and R2 are each independently selected from H, D, F, Cl, Br, I and methyl.

6. The method according to any one of claims 1 to 5, wherein R1 and R2 are each independently selected from H, F, Cl, Br, I and methyl.

7. The use according to any one of claims 1 to 6, wherein R1 is selected from F, Cl, Br, I and methyl, and R2 is selected from H, F, Cl, Br and I; Preferably, the compound is selected from: Preferably, the compound is selected from:

8. The use according to any one of claims 1 to 7, wherein the tumor is breast cancer or melanoma.

9. The use according to any one of claims 1 to 8, wherein the product is a medicament.

10. The use according to any one of claims 1 to 8, wherein the composition further comprises one or more pharmaceutically acceptable carriers; Preferably, the composition further comprises an additional drug, which is a chemotherapeutic agent (such as cyclophosphamide, fluorouracil, platinum, paclitaxel, etc.) or an immunomodulator (such as immune checkpoint inhibitors such as ipilimumab and nivolumab, tyrosine kinase inhibitors such as imatinib and osimertinib, proteasome inhibitors such as bortezomib, antibiotics such as bleomycin, alkylating agents such as nitrogen mustard, antimetabolites such as methotrexate and cytarabine, hormone drugs such as tamoxifen, immunoactive agents, interferon-type active agents and mixed active agents, etc.).

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