Chalcone compounds containing an alpha, beta-unsaturated hydroxamic acid group, and methods of making and using the same

Abstract

The present application relates to a kind of chalcone compound containing α, β-unsaturated hydroxamic acid group and its preparation method and application, the structure of the chalcone compound containing α, β-unsaturated hydroxamic acid group is as shown in formula I, it is verified by preliminary experiment, the compound provided in the application has cell level antitumor activity, provides new idea and selection for the treatment of tumor.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a chalcone compound containing an α,β-unsaturated hydroxamic acid group and a preparation method and application thereof. BACKGROUND

[0002] Histone acetylation modification is a post-translational modification of proteins, which can regulate epigenetic modification and plays a key role in various biological processes. More and more studies have shown that there is a close relationship between histone acetylation modification and tumorigenesis. Abnormal acetylation modification state can affect the expression of tumor-related genes, thereby promoting the proliferation of tumor cells, inhibiting apoptosis and enhancing the invasion and metastasis ability.

[0003] Histone deacetylase (HDAC) is a class of enzymes that play an important role in chromatin structure modification and gene expression regulation, and has been proved to be an effective target for the treatment of diseases such as cancer and inflammation. HDAC can be divided into class I (HDAC1, 2, 3 and 8), class IIa (HDAC4, 5, 7 and 9), class IIb (HDAC6 and 10), class III (Sirtuin1-7) and class IV (HDAC11). Histone deacetylase inhibitors (HDACi) target HDAC and have attracted more and more attention in the field of clinical cancer treatment. HDACi plays a role in inducing tumor cell apoptosis and differentiation, mediating tumor cell cycle arrest, inhibiting tumor angiogenesis, metastasis and invasion, and enhancing immune response, and is considered as a first-line drug for tumor treatment. The development of HDACi has good application prospect, and finding high-efficiency and low-toxicity small-molecule HDACi has become a research hotspot in the field of anti-tumor at home and abroad.

[0004] HDACi can be mainly divided into hydroxamic acid, benzamide, short-chain fatty acid and cyclic tetrapeptide according to chemical structure. Among them, hydroxamic acid HDACi is the most thoroughly studied and the most widely used one, and the hydroxamic acid group can directly bind to the Zn 2+ structure of HDAC, thereby inhibiting the activity of HDAC. Among the five HDACis that have been marketed, vorinostat contains a hydroxamic acid group, and belinostat and panobinostat contain an α,β-unsaturated hydroxamic acid group.

[0005] In view of the above background, the applicant has researched hydroxamic acid histone deacetylase inhibitors in order to obtain a new HDACi with low cost, easy synthesis and high anti-tumor efficiency. SUMMARY

[0006] The present application aims to provide a chalcone compound containing an α,β-unsaturated hydroxamic acid group, a preparation method and application thereof.

[0007] To solve the above problems, the technical scheme adopted by the present application is:

[0008] A chalcone compound containing an α,β-unsaturated hydroxamic acid group, the structure of which is shown in formula I:

[0009]

[0010] (1) when R2 and R3 are H, R1 is independently selected from C2-C8 straight-chain or branched alkyl, 5-6 membered heteroaryl, 3-8 membered cycloalkyl, and benzene ring;

[0011] (2) when R1 is H, R2 and R3 are independently selected from C1-C8 straight-chain or branched alkyl;

[0012] (3) when R3 is H, R1 and R2 are connected to each other and form a 3-8 membered heterocyclic ring containing 1-3 N, S, and O together with the carbon atoms on the benzene ring.

[0013] As a further improvement of the present application, the chalcone compound containing an α,β-unsaturated hydroxamic acid group has a structure shown in formula I or formula II:

[0014]

[0015]

[0016] In formula I, (1) when R2 and R3 are H, R1 is independently selected from C2-C6 straight-chain or branched alkyl, 5-6 membered heteroaryl, 3-6 membered cycloalkyl, and benzene ring;

[0017] (2) when R1 is H, R2 and R3 are independently selected from C1-C6 straight-chain or branched alkyl;

[0018] In formula II, ring A is selected from a 5-6 membered heterocyclic ring containing 1-2 O.

[0019] As a further improvement of the present application, the C1-C6 linear or branched alkyl group is selected from the group consisting of —CH3, —CH2CH3, —CH(CH3)2, —(CH2)2CH3, —(CH2)3CH3, —CH2CH(CH3)2, —C(CH3)3, —CH(CH3)CH2CH3, —(CH2)4CH3, —CH(CH3)(CH2)2CH3, —CH(CH2CH3)2, —CH2C(CH3)3, —CH2CH(CH3)CH2CH3, —C(CH3)2CH2CH3, —CH(CH3)CH(CH3)2, —(CH2)2CH(CH3)2, —CH2CH(CH2CH3)2, —CH2(CH2)4CH3, —CH2CH(CH3)CH2CH2CH3, —CH2CH2CH(CH3)CH2CH3, —CH2CH(CH3)CH2CH2CH3, —CH2CH2CH2CH(CH3)2;

[0020] The 3-6 membered cyclic alkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0021] The 5-6 membered heteroaryl group is selected from the group consisting of pyridine, furan, pyrrole, thiophene, thiazole, pyrazole;

[0022] The 5-6 membered heteroaryl group is selected from the group consisting of pyridine, furan, pyrrole, thiophene, thiazole, pyrazole; As a further improvement of the present application, the compound is selected from the following structures:

[0023] As a further improvement of the present application, the compound is selected from the following structures:

[0024]

[0025]

[0026] Technical subject two

[0027] A method for preparing the chalcone compound containing α, β-unsaturated hydroxamic acid group as described in technical subject one, comprising the following steps:

[0028] S1:

[0029]

[0030] Substrate II is dissolved in anhydrous ethanol to prepare A liquid, and substrate I is dissolved in anhydrous ethanol to prepare B liquid; slowly add KOH solution to B liquid at 0-5℃ and mix well, then slowly add the mixed solution to A liquid at 0-5℃, after the addition is completed, stir the reaction at room temperature, after the reaction is completed, add hydrochloric acid at 0-5℃ until the precipitation is completely precipitated, and then extract the obtained solid with ethyl acetate, volatilize the solvent, and dry to obtain substrate III;

[0031] S2:

[0032]

[0033] The substrate III obtained in S1, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride, 4-dimethylaminopyridine are dissolved in tetrahydrofuran and stirred uniformly, then O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, N,N-diisopropylethylamine are added, and the reaction is stirred at room temperature. After the reaction is completed, the product is dried by volatilization after standing, to obtain the crude product of substrate IV;

[0034] S3:

[0035]

[0036] The crude product of substrate IV obtained in S2 is dissolved in methanol, and an excess of HCl solution is added dropwise, and the reaction is stirred at room temperature. After the reaction is completed, the product is washed with water and ethyl acetate, and the insoluble product is the target compound.

[0037] In the step, R1, R2, and R3 are defined as the same as the definitions of the general formula.

[0038] As a further improvement of the present application, the molar ratio of substrate 1 to substrate 2 in S1 is 1:0.8-1.2;

[0039] In S2, the molar ratio of substrate III, 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, 4-dimethylaminopyridine, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, and N,N-diisopropylethylamine is 1:1-2:0.8-1.2:0.8-1.2:2-4.

[0040] As a further improvement of the present application, the stirring reaction time in S1 is 20-30h;

[0041] The stirring reaction time in S2 is 20-30h;

[0042] The stirring reaction time in S3 is 20-30h.

[0043] Technical subject three

[0044] A pharmaceutical composition comprising the chalcone compound containing an α,β-unsaturated hydroxamic acid group according to technical subject one, and optionally, one or more pharmaceutically acceptable carriers or excipients.

[0045] As used herein, "pharmaceutical composition" contains a therapeutically effective amount of the chalcone compound having an α,β-unsaturated hydroxamic acid group of the formula I, together with one or more pharmaceutically acceptable carriers, prepared into a form such as tablets, capsules, granules, powders, suspensions, emulsions, powders, solutions, gels, syrups, pills, tinctures, elixirs, decoctions, lozenges, mixtures, suppositories, injections, inhalants or sprays, etc. The pharmaceutical composition preferably contains the chalcone compound having an α,β-unsaturated hydroxamic acid group of the present application as an active ingredient in an amount of 0.1 to 99.5% by weight, more preferably in an amount of 0.5 to 99.5% by weight of the active ingredient.

[0046] As used herein, "pharmaceutically acceptable carriers or excipients" include diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, taste-masking agents, coloring agents, anti-caking agents, humectants, chelating agents, plasticizers, viscosity enhancers, antioxidants, preservatives, stabilizers, surfactants, and buffers, and one of skill will understand that certain pharmaceutically acceptable excipients can be used in more than one function and in alternative functions, depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. For example: when used for oral administration, oral formulations such as tablets, capsules, granules, and pills, etc. can be made to contain fillers (e.g. sugar derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, dextrin, and carboxymethyl starch; cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium; gum arabic; dextran; silicate derivatives such as magnesium aluminum metasilicate; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.), binders (e.g. gelatin, polyvinylpyrrolidone, and polyethylene glycol), disintegrants (e.g. cellulose derivatives such as sodium carboxymethyl cellulose, polyvinylpyrrolidone), lubricants (e.g. talc, calcium stearate, magnesium stearate, sperm oil, boric acid, sodium benzoate, leucine), stabilizers (methyl paraben, propyl paraben, etc.), flavoring agents (e.g. commonly used sweeteners, souring agents, and spices, etc.). When used for parenteral administration, injectable formulations, including sterile powders for injection and solvents for injection, can be made using carriers or excipients including sterile water, Ringer's solution, and isotonic sodium chloride solution, and appropriate additional agents such as antioxidants, buffers, and bacteriostatic agents can be added depending on the nature of the drug. When used for rectal administration, the drug can be made into suppositories, etc. When used for pulmonary administration, the drug can be made into inhalants or sprays, etc. There are many resources available to those of skill in the art that describe pharmaceutically acceptable excipients and which can be used to select appropriate pharmaceutically acceptable excipients, such as the books Remington's Pharmaceutical Sciences, China Pharmaceutical Yearbook, Pharmaceutical Sciences, etc.

[0047] The present application can be administered by any suitable method known in the art, for example, orally, intravenously, intraperitoneally, intramuscularly, topically, transdermally, ophthalmically, nasally, by inhalation, subcutaneously, intramuscularly, buccally, sublingually, rectally, etc., in any amount from 1 μg to 2000 mg per kg of body weight of the subject, for example, in an amount from 1 μg to 1000 mg per kg of body weight per day, 50 μg to 1000 mg per kg of body weight per day, 100 μg to 1000 mg per kg of body weight per day, 1 to 500 mg per kg of body weight per day, 2 to 200 mg per kg of body weight per day, 5 to 100 mg per kg of body weight per day. In some embodiments of the present application, the compound can be administered 4 times per day, 3 times per day, 2 times per day, 1 time per day, 1 time per two days, 1 time per week, or other intervals, optionally repeating the dosing regimen as described above as appropriate, e.g., weekly or monthly. In the present application, the dosage of the compound can be adjusted according to the severity of the disease, age, body weight, sex, administration method, course of treatment, and other factors of the patient or subject.

[0048] The compounds of the present application can be used alone or in combination with one or more other active ingredients in the treatment, prevention, inhibition or amelioration of diseases or conditions of interest. Such other drugs can be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present application. When a compound of the present application is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present application is preferred. Accordingly, the pharmaceutical compositions of the present application also include those that also contain one or more other active ingredients, in addition to a compound of the present application.

[0049] Technical Subject Four

[0050] Use of the chalcone compound containing an α,β-unsaturated hydroxamic acid group according to Technical Subject One in the preparation of a drug for inhibiting histone deacetylase.

[0051] Technical Subject Five

[0052] Use of the chalcone compound containing an α,β-unsaturated hydroxamic acid group according to Technical Subject One in the preparation of an antitumor drug.

[0053] The beneficial effects produced by the above technical solution are that:

[0054] The compound disclosed in the application has been verified to have anti-tumor activity at a cell level, and provides a new idea and selection for tumor treatment.

[0055] The application also discloses a raw material preparation method of the compound. DETAILED DESCRIPTION

[0056] In order to make the purpose, technical scheme and advantages of the application clearer, the application will be clearly and completely described below in combination with specific examples.

[0057] Terms and definitions

[0058] As used herein, the term "tumor" refers to a local swelling of tissue caused by abnormal cell proliferation in response to various pathogenic factors, including benign tumors, malignant tumors and borderline tumors.

[0059] As used herein, the term "treatment" aims to alleviate or eliminate the disease state or condition targeted. A subject is successfully "treated" if the subject exhibits an observable and / or detectable reduction or improvement in one or more indicators and symptoms, according to the methods described herein, after receiving a therapeutic amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. It should also be understood that the treatment of the disease state or condition described not only includes complete treatment, but also includes incomplete treatment that achieves some biologically or medically relevant result.

[0060] In this document, the minimum and maximum values of the number of carbon atoms in a hydrocarbon group are indicated by a prefix, for example, the prefix Ca-Cb means containing "a" to "b" carbon atoms. Exemplarily, "C1-Cn" means a straight chain or branched chain saturated / unsaturated carbon chain containing 1, 2, 3, 4, 5, … or n carbon atoms; it is further understood that "C1-Cn" should be interpreted as any sub-range included therein, for example, C1-C8, C1-C6, C1-C5, C1-C3, etc.

[0061] As used herein, "alkyl" refers to straight chain or branched chain hydrocarbon groups that are fully saturated (i.e., no double or triple bonds), having 1 to 8 carbon atoms (as each range of values recited herein is meant to include each integer within the given range, e.g., "1 to 8" means 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; e.g., "1 to 8 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so forth, up to and including 8 carbon atoms, although the definition also contemplates that the numerical range can be less than 8, even though this is not expressed in the text). The alkyl group can also be a medium size alkyl group having 1 to 8 carbon atoms, e.g., "Ci-6". The alkyl group can also be a lower alkyl group having 1 to 4 carbon atoms. The alkyl group of a compound can be designated as "Ci-C4alkyl", "Ci-4alkyl", or similar designations. By way of example only, "Ci-C4alkyl" or "Ci-4alkyl" denotes that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are absolutely not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.

[0062] The term "cycloalkyl" or "carbocyclic" refers to saturated or partially unsaturated hydrocarbon groups of, for example, 3 to 8, 3 to 6 carbons (referred to herein as 3-8 membered cycloalkyl or 3-6 membered cycloalkyl, respectively). Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0063] The 5-6 membered heteroaromatic ring is selected from pyridine, furan, pyrrole, thiophene, thiazole, pyrazole.

[0064] The term "heterocycle" is art-recognized and refers to, for example, saturated or partially unsaturated monocyclic or bicyclic structures, or, for example, 3 to 8 membered or 5 to 6 membered saturated ring structures, and whose ring structure includes one to three heteroatoms, such as nitrogen, oxygen, and sulfur. Examples of heterocycles include, but are not limited to, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, oxetane, azetidine, tetrahydrofuran or dihydrofuran, 1,3-dioxolane or 1,4-dioxane.

[0065] The compounds of this example section were prepared by the following routes:

[0066] In the routes, R1, R2, R3are defined as the same as the definitions of the preceding general formula;

[0067] S1:

[0068]

[0069] Weigh 4 mmol of substrate II (0.70468 g) to prepare A liquid by dissolving in 15 mL of anhydrous ethanol, and weigh 4 mmol of substrate I to prepare B liquid by dissolving in 15 mL of anhydrous ethanol; slowly add 6.5 mL of 55% KOH solution to B liquid under ice bath, mix well, then add the mixed solution to A liquid under ice bath, and stir at room temperature in a round-bottom flask for 24 h. After the reaction is completed, add 1 mol / L HCl solution under ice bath until the precipitate is completely precipitated, reduce pressure and filter, extract with ethyl acetate for 3 times, and dry by standing and volatilization to obtain substrate III.

[0070] S2:

[0071]

[0072] Weigh substrate III (2 mmol), EDCI (0.57510 g, 3 mmol), and 4-dimethylaminopyridine (DMAP, 0.24434 g, 2 mmol) into a round-bottom flask, add 20 mL of THF and stir for 30 min, then weigh O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.23430 g, 2 mmol) and N,N-diisopropylethylamine (DIPEA, 0.77544 g, 6 mmol) into the round-bottom flask, and stir at room temperature for 24 h. After the reaction is completed, dry by standing and volatilization to obtain the crude product of substrate IV.

[0073] S3:

[0074]

[0075] Put all the crude product of substrate IV into a round-bottom flask, dissolve in 15 mL of methanol, and drop 20 mL of 1 mol / L HCl solution. Stir at room temperature for 24 h. After the reaction is completed, reduce pressure and filter, wash with water for 3 times, and wash with ethyl acetate for 3 times. The insoluble substance obtained is the target compound.

[0076] Example 1 Compound 5a

[0077]

[0078] S1: Weigh 4 mmol of 3-(4-formylphenyl) acrylic acid (0.70468 g) to prepare A liquid by dissolving in 15 mL of anhydrous ethanol, and weigh 4 mmol of 1-(2,3-dimethylphenyl) ethanone to prepare B liquid by dissolving in 15 mL of anhydrous ethanol; slowly add 6.5 mL of 55% KOH solution to B liquid under ice bath, mix well, then add the mixed solution to A liquid under ice bath, and stir at room temperature in a round-bottom flask for 24 h. After the reaction is completed, add 1 mol / L HCl solution under ice bath until the precipitate is completely precipitated, reduce pressure and filter, extract with ethyl acetate for 3 times, and dry by standing and volatilization to obtain substrate III.

[0079] S2: Substrate III (2 mmol), EDCI (0.57510 g, 3 mmol), 4-dimethylaminopyridine (DMAP, 0.24434 g, 2 mmol) were weighed into a round-bottom flask, 20 mL THF was added and stirred for 30 min, then O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.23430 g, 2 mmol), N,N-diisopropylethylamine (DIPEA, 0.77544 g, 6 mmol) were added into the round-bottom flask, and stirred at room temperature for 24 h. After the reaction was completed, the volatile was removed by standing, and the crude product of substrate IV was obtained.

[0080] S3: The crude product of substrate IV was placed in a round-bottom flask, 15 mL of methanol was added to dissolve it, 20 mL of 1 mol / L HCl solution was added dropwise, and stirred at room temperature for 24 h. After the reaction was completed, the volatile was removed by standing, and the crude product of substrate IV was obtained. 1 H NMR (600 MHz, DMSO-d6) δ 7.80 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 15.8 Hz, 1H), 7.40 (d, J = 15.9 Hz, 1H), 7.35 - 7.29 (m, 3H), 7.23 (t, J = 7.5 Hz, 1H), 6.55 (d, J = 15.8 Hz, 1H), 2.31 (s, 3H), 2.22 (s, 3H).

[0081] 13 C NMR (151 MHz, DMSO) δ 197.00, 162.94, 144.78, 140.25, 138.14, 137.88, 137.48, 135.67, 134.55, 132.08, 129.79, 128.45, 128.03, 125.80, 120.92, 20.29, 16.70.

[0082] Example 2 Compound 5b

[0083]

[0084] According to the method of Reference Example 1, 1-(4-ethylphenyl)ethanone was used instead of 1-(2,3-dimethylphenyl)ethanone to obtain yellow-white solid 5b with a purity of >95% and a yield of 49%; 1H NMR (600 MHz, DMSO-d6) δ 8.11 (d, J = 8.3 Hz, 2H), 7.98 (d, J = 15.6 Hz, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 15.6 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 15.9 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 6.57 (d, J = 15.8 Hz, 1H), 2.72 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H).

[0085] 13 C NMR (151 MHz, DMSO) δ 189.05, 163.93, 150.19, 143.27, 137.63, 136.15, 135.75, 129.88, 129.27, 128.69, 128.44, 122.76, 120.77, 28.69, 15.69.

[0086] Example 3 Compound 5c

[0087]

[0088] Following the procedure of Reference Example 1, replacing 1-(2,3-dimethylphenyl)ethanone with 1-(4-n-propylphenyl)ethanone, afforded 5c as a yellow solid, >95% purity, 53% yield; 1 H NMR (600 MHz, DMSO-d6) δ 8.11 (d, J = 8.3 Hz, 2H), 7.98 (d, J = 15.6 Hz, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 15.6 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 15.9 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 6.57 (d, J = 15.8 Hz, 1H), 2.72 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H).

[0089] Example 4 Compound 5d

[0090]

[0091] Following the procedure of Reference Example 1, replacing 1-(2,3-dimethylphenyl)ethanone with 1-(4-n-propylphenyl)ethanone, afforded 5c as a yellow solid, >95% purity, 53% yield; 1H NMR (600 MHz, DMSO-d6) δ 8.11 (d, J = 8.2 Hz, 2H), 7.97 (d, J = 15.6 Hz, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 15.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 15.9 Hz, 1H), 7.46 (d, J = 8.1 Hz, 2H), 6.57 (d, J = 15.8 Hz, 1H), 3.01 (hept, J = 6.9 Hz, 1H), 1.26 (d, J = 6.9 Hz, 6H).

[0092] 13 C NMR (151 MHz, DMSO) δ 189.07, 163.00, 154.65, 143.25, 137.69, 137.30, 136.15, 135.94, 129.87, 129.31, 128.44, 127.24, 123.15, 120.79, 34.02, 24.00.

[0093] Example 5 Compound 5e

[0094]

[0095] Following the procedure of Reference Example 1, replacing 1-(2,3-dimethylphenyl)ethanone with 1-(4-n-butylphenyl)ethanone, afforded 5e as a yellow solid, purity >98%, yield 55%; 1 H NMR (600 MHz, DMSO-d6) δ 8.10 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 15.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 15.6 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 15.8 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 6.56 (d, J = 15.8 Hz, 1H), 2.69 (t, J = 7.7 Hz, 2H), 1.64 - 1.57 (m, 2H), 1.33 (h, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H).

[0096] 13 C NMR (151 MHz, DMSO) δ 189.03, 163.00, 148.83, 143.23, 137.99, 137.28, 136.15, 135.74, 129.88, 129.20, 128.43, 123.10, 120.76, 35.29, 33.23, 22.23, 14.22.

[0097] Example 6 Compound 5f

[0098]

[0099] Reference Example 1, replacing 1-(2,3-dimethylphenyl)ethanone with 1-(4- n-pentylphenyl)ethanone to give 5f as a light orange solid, >98% purity, 52% yield; 1 H NMR (600 MHz, DMSO-d6) δ 8.10 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 15.6 Hz, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.74 (d, J = 15.6 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 15.8 Hz, 1H), 7.40 (d, J = 8.0 Hz, 2H), 6.57 (d, J = 15.8 Hz, 1H), 2.68 (t, J = 7.7 Hz, 2H), 1.62 (p, J = 7.5 Hz, 2H), 1.35 - 1.26 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H).

[0100] 13 C NMR (151 MHz, DMSO) δ 189.03, 163.01, 148.85, 143.24, 137.99, 137.30, 136.15, 135.75, 129.88, 129.20, 128.43, 123.10, 120.77, 35.56, 31.33, 30.75, 22.39, 14.38.

[0101] Example 7 Compound 5g

[0102]

[0103] Reference Example 1, replacing 1-(2,3-dimethylphenyl)ethanone with 1-(4- n-pentylphenyl)ethanone to give 5f as a light orange solid, >98% purity, 52% yield; 1H NMR (600 MHz, DMSO-d6) δ 8.10 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 15.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 15.6 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 15.8 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 6.57 (d, J = 15.8 Hz, 1H), 2.68 (t, J = 7.7 Hz, 2H), 1.61 (p, J = 7.5 Hz, 2H), 1.33 - 1.28 (m, 6H), 0.86 (t, J = 6.4 Hz, 3H).

[0104] 13 C NMR (151 MHz, DMSO) δ 189.02, 161.53, 148.85, 143.24, 137.90, 137.31, 136.14, 135.74, 129.88, 129.20, 128.77, 123.09, 120.80, 35.61, 31.53, 31.04, 28.78, 22.51, 14.42.

[0105] Example 8 Compound 5p

[0106]

[0107] Reference Example 1 was followed, replacing 1-(2,3-dimethylphenyl)ethanone with 1-(benzo[d][1,3]dioxol-5-yl)ethanone, to give 5p as a yellow solid, >98% purity, in 57% yield; 1 H NMR (600 MHz, DMSO-d6) δ 8.10 (d, J = 8.2 Hz, 2H), 7.98 (d, J = 15.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 15.6 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 15.8 Hz, 1H), 7.40 (d, J = 8.1 Hz, 2H), 6.57 (d, J = 15.8 Hz, 1H), 2.68 (t, J = 7.7 Hz, 2H), 1.61 (p, J = 7.5 Hz, 2H), 1.33 - 1.28 (m, 6H), 0.86 (t, J = 6.4 Hz, 3H).

[0108] 13C NMR (151 MHz, DMSO) δ 187.33, 163.02, 152.10, 148.51, 143.05, 137.99, 137.22, 136.20, 132.68, 129.88, 128.40, 125.65, 122.91, 120.73, 108.65, 108.40, 102.58.

[0109] Example 9 Compound 5q

[0110]

[0111] Following the procedure of Reference Example 1, replacing 1-(2,3-dimethylphenyl)ethanone with 1-(4-cyclohexylphenyl)ethanone, afforded 5r as a light orange solid, purity >95%, yield 49%; 1 H NMR (600 MHz, DMSO-d6) δ 7.97 (d, J = 15.6 Hz, 1H), 7.94 (d, J = 8.2 Hz, 2H), 7.75 (dd, J = 8.5, 2.1 Hz, 1H), 7.72 (s, 1H), 7.70 (d, J = 15.4 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 15.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 15.8 Hz, 1H), 4.38 - 4.35 (m, 2H), 4.34 - 4.31 (m, 2H).

[0112] 13 C NMR (151 MHz, DMSO) δ 187.33, 163.02, 152.10, 148.51, 143.05, 137.99, 137.22, 136.20, 132.68, 129.88, 128.40, 125.65, 122.91, 120.73, 108.65, 108.40, 102.58.

[0113] Example 10 Compound 5r

[0114]

[0115] Following the procedure of Reference Example 1, replacing 1-(2,3-dimethylphenyl)ethanone with 1-(4-cyclohexylphenyl)ethanone, afforded 5r as a light orange solid, purity >95%, yield 49%; 1H NMR (600 MHz, DMSO-d6) δ 8.10 (d, J = 8.3 Hz, 2H), 7.97 (d, J = 15.6 Hz, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 15.6 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 15.7 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 6.57 (d, J = 15.8 Hz, 1H), 2.67 - 2.59 (m, 1H), 1.82 (dt, J = 10.4, 2.7 Hz, 4H), 1.52 - 1.21 (m, 6H).

[0116] 13 C NMR (151 MHz, DMSO) δ 189.03, 163.01, 153.74, 143.21, 137.98, 137.29, 136.15, 135.92, 129.87, 129.28, 128.43, 127.60, 123.12, 120.77, 44.31, 34.03, 26.69, 25.97.

[0117] Example 11 Compound 5s

[0118]

[0119] Reference Example 1, replacing 1-(2,3-dimethylphenyl)ethanone with 1-([1,1'- biphenyl]-4-yl)ethanone, to give 5s as a yellow solid, purity >95%, yield 55%; 1 H NMR (600 MHz, DMSO-d6) δ 8.10 (d, J = 8.3 Hz, 2H), 7.97 (d, J = 15.6 Hz, 1H), 7.93 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 15.6 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 15.7 Hz, 1H), 7.43 (d, J = 8.3 Hz, 2H), 6.57 (d, J = 15.8 Hz, 1H), 2.67 - 2.59 (m, 1H), 1.82 (dt, J = 10.4, 2.7 Hz, 4H), 1.52 - 1.21 (m, 6H).

[0120] 13C NMR (151 MHz, DMSO) δ 188.99, 163.00, 145.06, 143.59, 139.38, 137.98, 137.39, 136.82, 136.12, 129.97, 129.81, 129.58, 128.91, 128.45, 127.52, 127.47, 123.05, 120.83.

[0121] Example 12 Compound 5u

[0122]

[0123] Reference Example 1 was followed, replacing 1-(2,3-dimethylphenyl)ethanone with 1-(4-(1H-pyrazol-1-yl)phenyl)ethanone to give 5u as a yellow solid, purity >95%, yield 61%; 1 H NMR (600 MHz, DMSO-d6) δ 8.71 (d, J = 2.6 Hz, 1H), 8.33 (d, J = 8.8 Hz, 2H), 8.07 (d, J = 8.8 Hz, 2H), 8.06 (d, J = 15.5 Hz, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.86 (d, J = 1.7 Hz, 1H), 7.79 (d, J = 15.5 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 15.8 Hz, 1H), 6.64 (dd, J = 2.6, 1.7 Hz, 1H), 6.58 (d, J = 15.8 Hz, 1H).

[0124] 13 C NMR (151 MHz, DMSO) δ 188.99, 163.00, 145.06, 143.59, 139.38, 137.98, 137.39, 136.82, 136.12, 129.97, 129.81, 129.58, 128.91, 128.45, 127.52, 127.47, 123.05, 120.83.

[0125] Example 1 Effect Example 1 Proliferation inhibition test of tumor cells by MTT method

[0126] Human pancreatic adenocarcinoma cells (BXPC3), human prostate cancer cells (DU145), human colorectal adenocarcinoma cells (SW620), human hepatocarcinoma cells (Huh7), human thyroid carcinoma cells (TPC-1), human pancreatic carcinoma cells (Panc1), human pancreatic carcinoma cells (SW1990) were respectively inoculated into 96-well plates at a cell amount of 8000 per well. After being cultured in a 37°C, 5% CO2 incubator for 24 h with DMEM high-sugar medium, the 20 mM compound mother liquor prepared in the examples was diluted with DMEM high-sugar medium to a final concentration of 50, 25, 12.5, 6.25, 3.125, 1.5625, 0.78125 μmol / L, respectively, the original culture medium was discarded, 200 μL of the drug-containing culture medium was added to each well, and a blank control group and a positive drug group (paclitaxel, pariprazine) were set up, and 5 replicate wells were set up for each group. After being continuously cultured in a 37°C, 5% CO2 incubator for 24 h, the light was avoided, the original culture medium was discarded, 100 μL of PBS containing 0.5 mg / mL MTT was added, and incubated for 3 h, the drug solution was discarded, 100 μL of DMSO solution was added, and the formazan crystal was dissolved by oscillation, and the OD value at 570 nm was measured, and the corresponding half-inhibitory concentration (IC 50 ) was calculated, and the results are shown in Table 1.

[0127] Table 1

[0128]

[0129] The results show that the compounds prepared in the present application have relatively strong proliferation inhibition effect on the above-mentioned 7 tumor cell lines, especially the inhibition effect on BXPC3 and SW620 cells is better, and the proliferation inhibition effect of some compounds is better than or equivalent to that of the positive drug pariprazine which also has an α, β-unsaturated hydroxamic acid structure. Among them, the inhibition effect of compound 5p on SW620 is the strongest (IC 50 = 0.98 ± 0.08 μmol / L).

[0130] Although the present application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions recorded in the foregoing embodiments, or make equivalent replacements to some of the technical features; and these modifications or replacements do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present application.

Claims

1. A chalcone compound containing an α,β-unsaturated hydroxamic acid group, characterized by, said compound is selected from the group consisting of the following structures:

2. A pharmaceutical composition comprising the α,β-unsaturated hydroxamic acid group-containing chalcone compound of claim 1 and optionally, one or more pharmaceutically acceptable carriers or excipients.

3. Use of the α,β-unsaturated hydroxamic acid group-containing chalcone compound of claim 1 in the manufacture of a medicament for inhibiting histone deacetylase.

4. Use of the α,β-unsaturated hydroxamic acid group-containing chalcone compound of claim 1 in the manufacture of a medicament for treating cancer.

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