Chalcone compound containing alpha, beta-unsaturated hydroxamic acid group as well as preparation method and application thereof

Abstract

The invention relates to a chalcone compound containing an alpha, beta-unsaturated hydroxamic acid group and a preparation method and application thereof.The structure of the chalcone compound containing the alpha, beta-unsaturated hydroxamic acid group is shown in the formula I. Preliminary experiments verify that the compound has the cell-level anti-tumor activity and can be used for preparing anti-tumor drugs. And a new thought and a new choice are provided for tumor treatment. # imgabs0 #

Description

Technical Field

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

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

[0003] Histone deacetylase (HDAC) is a class of enzymes that play an important role in chromosome structure modification and gene expression regulation. It has been proven 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. It is considered to be a first-line drug for tumor treatment. The development of HDACi has good application prospects, and the search for highly efficient and low-toxic small molecule HDACi has become a hot research topic in the field of anti-tumor at home and abroad.

[0004] HDACi are mainly divided into hydroxamic acid, benzamide, short-chain fatty acid and cyclotetrapeptide according to their chemical structure. Among them, hydroxamic acid HDACi is the most thoroughly studied and widely used type. The hydroxamic acid group can directly react with the Zn of HDAC. 2+ The structure of HDAC is bound to inhibit HDAC activity. Among the five HDACi that have been marketed, vorinostat contains a hydroxamic acid group, while belinostat and panobinostat contain α,β-unsaturated hydroxamic acid groups.

[0005] Based on the above background, the applicant studied hydroxamic acid histone deacetylase inhibitors in order to obtain a new type of HDACi with low cost, easy synthesis and high anti-tumor effect. Summary of the invention

[0006] The technical problem to be solved by the present invention is to provide a chalcone compound containing an α, β-unsaturated hydroxamic acid group and a preparation method and application thereof.

[0007] To solve the above problems, the technical solution adopted by the present invention 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 or branched alkyl, 5-6 membered heteroaryl, 3-8 membered cycloalkyl, benzene ring;

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

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

[0013] As a further improvement of the present invention, the structure of the chalcone compound containing an α,β-unsaturated hydroxamic acid group is as 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 or branched alkyl groups;

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

[0019] As a further improvement of the present invention, the C1-C6 straight or branched alkyl group is selected from -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)4 CH3, —CH2CH(CH3)CH2CH2CH3, —CH2CH2CH(CH3)CH2CH3, —CH2CH(CH3)CH2CH2CH3, —CH2CH2CH2CH(CH3)2;

[0020] The 3-6 membered cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

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

[0022] Said for

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

[0024]

[0025]

[0026] Technical Theme 2

[0027] A method for preparing a chalcone compound containing an α,β-unsaturated hydroxamic acid group as described in the first technical theme comprises the following steps:

[0028] S1:

[0029]

[0030] The substrate II is dissolved in anhydrous ethanol to prepare a liquid A, and the substrate I is dissolved in anhydrous ethanol to prepare a liquid B; KOH solution is slowly added to the liquid B at 0-5°C to mix, and then the mixed solution is added to the liquid A at 0-5°C. After the addition is completed, the mixture is stirred at room temperature for reaction. After the reaction is completed, hydrochloric acid is added at 0-5°C until the precipitation is completely precipitated, and the solid is extracted with ethyl acetate, and the solvent is allowed to stand and evaporate, and then dried to obtain the substrate III;

[0031] S2:

[0032]

[0033] The substrate III obtained in S1, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 4-dimethylaminopyridine are dissolved in tetrahydrofuran and stirred evenly, and then O-(tetrahydro-2H-pyran-2-yl)hydroxylamine and N,N-diisopropylethylamine are added, and the mixture is stirred and reacted at room temperature. After the reaction is completed, the mixture is allowed to stand for evaporation and drying to obtain a crude product of substrate IV;

[0034] S3:

[0035]

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

[0037] The definitions of R1, R2 and R3 in the steps are the same as those in the above general formula.

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

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

[0040] As a further improvement of the present invention, 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 Theme 3

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

[0045] As used herein, a "pharmaceutical composition" contains a therapeutically effective amount of the chalcone compound containing an α,β-unsaturated hydroxamic acid group of formula I and one or more pharmaceutically acceptable carriers, prepared in the form of tablets, capsules, granules, powders, suspensions, emulsions, powders, solutions, gels, syrups, pills, tinctures, wine preparations, decoctions, lozenges, mixtures, suppositories, injections, inhalants or sprays. The pharmaceutical composition preferably contains 0.1% to 99.5% by weight of the chalcone compound containing an α,β-unsaturated hydroxamic acid group of the present invention as an active ingredient, and more preferably contains 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, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. Those skilled in the art 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 preparations such as tablets, capsules, granules and pills can be prepared, containing 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, polyvinyl pyrrolidone and polyethylene glycol), disintegrants (e.g., cellulose derivatives such as sodium carboxymethyl cellulose, polyvinyl pyrrolidone), lubricants (e.g., talc, calcium stearate, magnesium stearate, spermaceti, boric acid, sodium benzoate, leucine), stabilizers (methyl parahydroxybenzoate, propyl parahydroxybenzoate, etc.), flavoring agents (e.g., commonly used sweeteners, acidulants and spices, etc.). When used for parenteral administration, an injection can be prepared, including sterile powder for injection and solvent for injection, and the carrier or excipient used includes sterile water, Ringer's solution and isotonic sodium chloride solution, and suitable additives such as antioxidants, buffers and antibacterial agents can also be added according to the properties of the drug. When used for rectal administration, the drug can be prepared into suppositories, etc. When used for pulmonary administration, the drug can be prepared into inhalants or sprays, etc. There are many resources available to those skilled in the art, which describe pharmaceutically acceptable excipients and can be used to select suitable pharmaceutically acceptable excipients, such as books such as "Remington's Pharmaceutical Encyclopedia", "Chinese Pharmaceutical Annals", and "Pharmaceutics".

[0047] The present invention can be administered by any suitable method known in the art, for example, orally, intravenously, intraperitoneally, intramuscularly, topically, transdermally, ocularly, nasally, by inhalation, subcutaneously, intramuscularly, buccally, sublingually, and rectal administration, and the compound as described above can be administered in any amount of 1 μg to 2000 mg / kg of the subject's body weight, for example, 1 μg to 1000 mg / kg body weight / day, 50 μg to 1000 mg / kg body weight / day, 100 μg to 1000 mg / kg body weight / day, 1 to 500 mg / kg body weight / day, 2 to 200 mg / kg body weight / day, and 5 to 100 mg / kg body weight / day. In some embodiments of the present invention, the compound as described above can be administered 4 times a day, 3 times a day, 2 times a day, 1 time a day, 1 time every two days, 1 time a week, or other intervals, and the dosage regimen as described above can be repeated weekly or monthly as appropriate. In the present invention, 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, gender, administration method, and course of treatment.

[0048] The compounds of the present invention can be used alone, or in combination with one or more other active ingredients for the treatment, prevention, inhibition or improvement of a disease or condition, wherein the combined use of the drugs is safer or more effective than the use of any one drug alone. Such other drugs can be administered simultaneously or sequentially with the compounds of the present invention in the manner and amount commonly used therefor. When the compounds of the present invention are used simultaneously with one or more other drugs, a pharmaceutical composition containing the other drugs and the compounds of the present invention in a unit dosage form is preferred, particularly in combination with a pharmaceutically acceptable carrier. However, combined therapy can also include treatment with the compounds of the present invention and one or more other drugs in different overlapping schedules. It can also be expected that when used in combination with one or more other active ingredients, the compounds of the present invention and other active ingredients can be used in lower doses than when each is used alone. Therefore, in addition to the compounds of the present invention, the pharmaceutical compositions of the present invention also include those compositions containing one or more other active ingredients.

[0049] Technical Theme 4

[0050] The invention relates to the use of chalcone compounds containing α, β-unsaturated hydroxamic acid groups in the preparation of drugs for inhibiting histone deacetylase.

[0051] Technical Theme 5

[0052] The application of chalcone compounds containing α,β-unsaturated hydroxamic acid groups in the preparation of anti-tumor drugs according to the first technical theme.

[0053] The beneficial effects of adopting the above technical solution are:

[0054] Experimental verification shows that the compounds disclosed in the present invention have anti-tumor activity at the cellular level, providing new ideas and options for the treatment of tumors.

[0055] The invention also discloses a method for preparing raw materials of the compound. The raw materials and reagents used in the preparation are simple and easy to obtain, the method is simple, the conditions are mild, the purification is easy, and the method is suitable for industrial production. DETAILED DESCRIPTION

[0056] In order to make the objectives, technical solutions and advantages of the present invention more clear, the present invention is clearly and completely described below in conjunction with specific embodiments.

[0057] Terms and Definitions

[0058] As used herein, the term "tumor" refers to a local mass formed by abnormal cell proliferation under the action of various pathogenic factors in the body, including benign tumors, malignant tumors and borderline tumors.

[0059] As used herein, the term "treatment" is intended to alleviate or eliminate the disease state or condition being targeted. If the subject receives a therapeutic amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, according to the methods described herein, and one or more signs and symptoms of the subject show an observable and / or detectable decrease 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 not achieving complete treatment, but achieving some biological or medically relevant results.

[0060] In this article, the minimum and maximum values ​​of the carbon atom content in the hydrocarbon group are indicated by prefixes, for example, the prefix Ca-Cb refers to a carbon atom containing "a" to "b". Exemplarily, "C1-Cn" refers to a straight or branched 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 a straight or branched hydrocarbon chain group that is fully saturated (without double or triple bonds). The alkyl group can have 1 to 8 carbon atoms (whenever it appears in this article, a numerical range such as "1 to 8" refers to each integer in a given range; for example, "1 to 8 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 8 carbon atoms, although the definition also covers the occurrence of the term "alkyl", but no numerical range is specified). The alkyl group can also be a medium-sized alkyl group with 1 to 8 carbon atoms, such as "C1-6". The alkyl group can also be a low alkyl group with 1 to 4 carbon atoms. The alkyl group of the compound can be designated as "C1-C4 alkyl", "C1-4 alkyl" or similar names. By way of example only, "C1-C4 alkyl" or "C1-4 alkyl" means 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 tert-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like.

[0062] The term "cycloalkyl" or "carbocyclyl" refers to, for example, 3 to 8, 3 to 6 carbon saturated or partially unsaturated hydrocarbon groups (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 and pyrazole.

[0064] The term "heterocycle" is recognized in the art and refers to, for example, a saturated or partially unsaturated monocyclic or bicyclic structure, or, for example, a 3- to 8-membered or 5- to 6-membered saturated ring structure, and its 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 were prepared by the following route:

[0066] The definitions of R1, R2, and R3 in the route are the same as those in the aforementioned general formula;

[0067] S1:

[0068]

[0069] Weigh 4mmol of substrate II (0.70468g) and dissolve it in 15mL of anhydrous ethanol to prepare solution A, weigh 4mmol of substrate I and dissolve it in 15mL of anhydrous ethanol to prepare solution B; slowly add 6.5mL of 55% KOH solution to solution B under ice bath and mix well, then add the mixed solution to solution A under ice bath, and stir in a round-bottom flask at room temperature for 24h. After the reaction is completed, add 1mol / L HCl solution under ice bath until the precipitation is complete, filter under reduced pressure, extract with ethyl acetate 3 times, stand and evaporate to dry, and 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) and place them in 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) and add them to the round-bottom flask, stir at room temperature for 24 h, and after the reaction is completed, let it stand to evaporate and dry to obtain a crude product of substrate IV.

[0073] S3:

[0074]

[0075] Place all the crude product of substrate IV in a round-bottom flask, add 15 mL of methanol to dissolve, add 20 mL of 1 mol / L HCl solution dropwise, stir at room temperature for 24 h. After the reaction is completed, filter under reduced pressure, wash with water 3 times and ethyl acetate 3 times. The insoluble matter obtained is the target compound.

[0076] Example 1 Compound 5a

[0077]

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

[0079] S2: Weigh substrate III (2mmol), EDCI (0.57510g, 3mmol), 4-dimethylaminopyridine (DMAP, 0.24434g, 2mmol) and place them in a round-bottom flask, add 20mL THF and stir for 30min, then weigh O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (0.23430g, 2mmol) and N,N-diisopropylethylamine (DIPEA, 0.77544g, 6mmol) and add them to the round-bottom flask, and stir at room temperature for 24h. After the reaction is completed, stand and evaporate to dryness to obtain a crude product of substrate IV.

[0080] S3: Put all the crude product of substrate IV into a round-bottom flask, add 15 mL of methanol to dissolve, add 20 mL of 1 mol / L HCl solution dropwise, and stir at room temperature for 24 h. After the reaction is completed, filter under reduced pressure, wash with water 3 times and ethyl acetate 3 times, and the insoluble matter obtained is the target compound 5a. 5a is a yellow-white solid with a purity of >95% and a yield of 45%; 1 H NMR (600MHz, DMSO-d6) δ7.80(d,J=8.1Hz,2H),7.62(d,J=8.1Hz,2H),7.48(d,J=15.8Hz,1H),7.40(d,J= 15.9Hz,1H),7.35–7.29(m,3H),7.23(t,J=7.5Hz,1H),6.55(d,J=15.8Hz,1H),2.31(s,3H),2.22(s,3H).

[0081] 13 C NMR(151MHz,DMSO)δ197.00,162.94,144.78,140.25,138.14,137.88,137.48,1 35.67,134.55,132.08,129.79,128.45,128.03,125.80,120.92,20.29,16.70.

[0082] Example 2 Compound 5b

[0083]

[0084] Referring to the method of Example 1, 1-(2,3-dimethylphenyl)ethanone was replaced with 1-(4-ethylphenyl)ethanone to obtain a yellow-white solid 5b with a purity of >95% and a yield of 49%; 1H NMR (600MHz, DMSO-d6) δ8.11(d,J=8.3Hz,2H),7.98(d,J=15.6Hz,1H),7.94(d,J=8.1Hz,2H),7.74(d,J=15.6Hz,1H),7.66(d,J= 8.1Hz,2H),7.50(d,J=15.9Hz,1H),7.43(d,J=8.1Hz,2H),6.57(d,J=15.8Hz,1H),2.72(q,J=7.6Hz,2H),1.23(t,J=7.6Hz,3H).

[0085] 13 C NMR (151MHz, DMSO) δ189.05,163.93,150.19,143.27,137.63,136.15,135.75,129.88,129.27,128.69,128.44,122.76,120.77,28.69,15.69.

[0086] Example 3 Compound 5c

[0087]

[0088] Referring to the method of Example 1, 1-(2,3-dimethylphenyl)ethanone was replaced with 1-(4-n-propylphenyl)ethanone to obtain a yellow solid 5c with a purity of >95% and a yield of 53%; 1 H NMR (600MHz, DMSO-d6) δ8.10(d,J=8.2Hz,2H),7.98(d,J=15.6Hz,1H),7.94(d,J=8.1Hz,2H),7.74(d,J=15.6Hz,1H),7.66(d,J=8.0Hz,2H ),7.50(d,J=15.8Hz,1H),7.40(d,J=8.0Hz,2H),6.57(d,J=15.8Hz,1H),2.67(t,J=7.6Hz,2H),1.68–1.60(m,2H),0.92(t,J=7.3Hz,3H).

[0089] Example 4 Compound 5d

[0090]

[0091] Referring to the method of Example 1, 1-(2,3-dimethylphenyl)ethanone was replaced with 1-(4-isopropylphenyl)ethanone to obtain a yellow solid 5d with a purity of >95% and a yield of 50%; 1H NMR (600MHz, DMSO-d6) δ8.11(d,J=8.2Hz,2H),7.97(d,J=15.6Hz,1H),7.94(d,J=8.1Hz,2H),7.74(d,J=15.6Hz,1H),7.66(d,J=8 .0Hz,2H),7.50(d,J=15.9Hz,1H),7.46(d,J=8.1Hz,2H),6.57(d,J=15.8Hz,1H),3.01(hept,J=6.9Hz,1H),1.26(d,J=6.9Hz,6H).

[0092] 13 C NMR (151MHz, DMSO) δ189.07,163.00,154.65,143.25,137.69,137.30,136. 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] Referring to the method of Example 1, 1-(2,3-dimethylphenyl)ethanone was replaced with 1-(4-n-butylphenyl)ethanone to obtain a yellow solid 5e with a purity of >98% and a yield of 55%; 1 H NMR (600MHz, DMSO-d6) δ8.10(d,J=8.2Hz,2H),7.98(d,J=15.6Hz,1H),7.94(d,J=8.2Hz,2H),7.74(d,J=15.6Hz,1H),7.66(d,J=8.2Hz,2H),7.51(d, J=15.8Hz,1H),7.40(d,J=8.1Hz,2H),6.56(d,J=15.8Hz,1H),2.69(t,J=7 .7Hz,2H),1.64–1.57(m,2H),1.33(h,J=7.4Hz,2H),0.92(t,J=7.4Hz,3H).

[0096] 13 C NMR(151MHz,DMSO)δ189.03,163.00,148.83,143.23,137.99,137.28,136.15, 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] Referring to the method of Example 1, 1-(2,3-dimethylphenyl)ethanone was replaced with 1-(4-n-pentylphenyl)ethanone to obtain a light orange solid 5f with a purity of >98% and a yield of 52%; 1 H NMR (600MHz, DMSO-d6) δ8.10(d,J=8.2Hz,2H),7.98(d,J=15.6Hz,1H),7.94(d,J=8.1Hz,2H),7.74(d,J=15.6Hz,1H),7.66(d,J=8.0Hz,2H),7.50(d, J=15.8Hz,1H),7.40(d,J=8.0Hz,2H),6.57(d,J=15.8Hz,1H),2.68(t,J=7 .7Hz,2H),1.62(p,J=7.5Hz,2H),1.35–1.26(m,4H),0.87(t,J=7.0Hz,3H).

[0100] 13 C NMR (151MHz, DMSO) δ189.03,163.01,148.85,143.24,137.99,137.30,136.15,135 .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] Referring to the method of Example 1, 1-(2,3-dimethylphenyl)ethanone was replaced with 1-(4-n-hexylphenyl)ethanone to obtain 5 g of a yellow solid with a purity of >95% and a yield of 51%; 1H NMR (600MHz, DMSO-d6) δ8.10(d,J=8.2Hz,2H),7.98(d,J=15.6Hz,1H),7.94(d,J=8.2Hz,2H),7.74(d,J=15.6Hz,1H),7.66(d,J=8.1Hz,2H),7.50(d, J=15.8Hz,1H),7.40(d,J=8.1Hz,2H),6.57(d,J=15.8Hz,1H),2.68(t,J=7 .7Hz,2H),1.61(p,J=7.5Hz,2H),1.33–1.28(m,6H),0.86(t,J=6.4Hz,3H).

[0104] 13 C NMR (151MHz, DMSO) δ189.02,161.53,148.85,143.24,137.90,137.31,136.14,135.74 ,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] Referring to the method of Example 1, 1-(2,3-dimethylphenyl)ethanone was replaced with 1-(benzo[d][1,3]dioxol-5-yl)ethanone to obtain a yellow solid 5p with a purity of >98% and a yield of 57%; 1 H NMR (600MHz, DMSO-d6) δ7.97(d,J=15.5Hz,1H),7.94(d,J=8.1Hz,2H),7.89(dd,J=8.2,1.8Hz,1H),7.71(d,J=15.5Hz,1H),7. 68(d,J=1.7Hz,1H),7.65(d,J=8.1Hz,2H),7.50(d,J=15.5Hz,1H),7.10(d,J=8.2Hz,1H),6.57(d,J=15.8Hz,1H),6.18(s,2H).

[0108] 13C NMR(151MHz,DMSO)δ187.33,163.02,152.10,148.51,143.05,137.99,137.22,13 6.20,132.68,129.88,128.40,125.65,122.91,120.73,108.65,108.40,102.58.

[0109] Example 9 Compound 5q

[0110]

[0111] Referring to the method of Example 1, 1-(2,3-dimethylphenyl)ethanone was replaced with 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethanone to obtain a yellow solid 5q with a purity of >95% and a yield of 54%; 1 H NMR (600MHz, DMSO-d6) δ7.97(d,J=15.6Hz,1H),7.94(d,J=8.2Hz,2H),7.75(dd,J=8.5,2.1Hz,1H),7.72(s,1H),7.70(d,J=15.4Hz,1H ),7.65(d,J=8.0Hz,2H),7.50(d,J=15.8Hz,1H),7.03(d,J=8.4Hz,1H),6.56(d,J=15.8Hz,1H),4.38–4.35(m,2H),4.34–4.31(m,2H).

[0112] 13 C NMR (151MHz, DMSO) δ187.56,163.02,148.53,143.86,142.96,138.01,137.21,136. 21,131.59,129.89,128.40,123.16,122.86,120.72,118.07,117.69,65.07,64.42.

[0113] Example 10 Compound 5r

[0114]

[0115] Referring to the method of Example 1, 1-(2,3-dimethylphenyl)ethanone was replaced with 1-(4-cyclohexylphenyl)ethanone to obtain a light orange solid 5r with a purity of >95% and a yield of 49%; 1H NMR (600MHz, DMSO-d6) δ8.10(d,J=8.3Hz,2H),7.97(d,J=15.6Hz,1H),7.93(d,J=8.1Hz,2H),7.73(d,J=15.6Hz,1H),7.66(d,J=8.1Hz,2H) ,7.50(d,J=15.7Hz,1H),7.43(d,J=8.3Hz,2H),6.57(d,J=15.8Hz,1H),2.67–2.59(m,1H),1.82(dt,J=10.4,2.7Hz,4H),1.52–1.21(m,6H).

[0116] 13 C NMR (151MHz, DMSO) δ189.03,163.01,153.74,143.21,137.98,137.29,136.15,135 .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] Referring to the method of Example 1, 1-(2,3-dimethylphenyl)ethanone was replaced with 1-([1,1'-biphenyl]-4-yl)ethanone to obtain a yellow solid 5s with a purity of >95% and a yield of 55%; 1 H NMR (600MHz, DMSO-d6) δ8.28(d,J=8.4Hz,2H),8.05(d,J=15.6Hz,1H),7.97(d,J=8.0Hz,2H),7.89(d,J=8.4Hz,2H),7.80(d,J=7.5Hz,2H), 7.79(d,J=15.6Hz,1H),7.67(d,J=8.1Hz,2H),7.53(d,J=7.7Hz,2H),7.53(d,J=15.4Hz,1H),7.46(t,J=7.4Hz,1H),6.58(d,J=15.8Hz,1H).

[0120] 13C NMR (151MHz, DMSO) δ188.99,163.00,145.06,143.59,139.38,137.98,137.39,136.8 2,136.12,129.97,129.81,129.58,128.91,128.45,127.52,127.47,123.05,120.83.

[0121] Example 12 Compound 5u

[0122]

[0123] Referring to the method of Example 1, 1-(2,3-dimethylphenyl)ethanone was replaced with 1-(4-(1H-pyrazol-1-yl)phenyl)ethanone to obtain a yellow solid 5u with a purity of >95% and a yield of 61%; 1 H NMR (600MHz, DMSO-d6) δ8.71(d,J=2.6Hz,1H),8.33(d,J=8.8Hz,2H),8.07(d,J=8.8Hz,2H),8.06(d,J=15.5Hz,1H),7.97(d,J=8.2Hz,2H),7.8 6(d,J=1.7Hz,1H),7.79(d,J=15.5Hz,1H),7.67(d,J=8.0Hz,2H),7.51(d,J=15.8Hz,1H),6.64(dd,J=2.6,1.7Hz,1H),6.58(d,J=15.8Hz,1H).

[0124] 13 C NMR(151MHz,DMSO)δ188.17,163.00,143.62,143.33,142.55,137.98,137.39,13 6.12,135.33,130.88,129.99,128.88,128.45,122.88,120.83,118.42,109.24.

[0125] Effect Example 1: MTT method to detect tumor cell proliferation inhibition experiment

[0126] Human pancreatic adenocarcinoma cells in situ (BXPC3), human prostate cancer cells (DU145), human colorectal adenocarcinoma cells (SW620), human hepatoma cells (Huh7), human thyroid cancer cells (TPC-1), human pancreatic cancer cells (Panc1), and human pancreatic cancer cells (SW1990) were inoculated into 96-well plates at 8,000 cells per well. After culturing in a 37°C, 5% CO2 incubator with DMEM high-glucose medium for 24 hours, the drug was administered by changing the medium, and the 20 mM mother solution of the compound prepared in the embodiment was diluted with DMEM high-glucose medium to a final concentration of 50, 25, 12.5, 6.25, 3.125, 1.5625, and 0.78125 μmol / L, respectively. The original culture medium was discarded, and 200 μL of drug-containing culture medium was added to each well. At the same time, a blank control group and a positive drug group (paclitaxel, panobinostat) were set up, and 5 replicates were set up for each group. After culturing for 24 h in a 37°C, 5% CO2 incubator, the cells were protected from light, the original culture medium was discarded, 100 μL of PBS solution containing 0.5 mg / mL MTT was added, and the cells were incubated for 3 h. The drug solution was discarded, 100 μL of DMSO solution was added, and the OD value at 570 nm was measured after sufficient shaking to dissolve the formazan crystals, and the corresponding half-maximal inhibitory concentration (IC 50 ), the results are shown in Table 1.

[0127] Table 1

[0128]

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

[0130] Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art may still modify the technical solutions described in the aforementioned embodiments, or make equivalent substitutions for some of the technical features therein; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A chalcone compound containing an α,β-unsaturated hydroxamic acid group, characterized in that: Its structure is shown in Formula I: (1) When R2 and R3 are H, R1 is independently selected from C2-C8 straight or branched alkyl, 5-6 membered heteroaryl, 3-8 membered cycloalkyl, benzene ring; (2) When R1 is H, R2 and R3 are independently selected from C1-C8 straight or branched alkyl groups; (3) When R3 is H, R1 and R2 are connected to each other and together with the carbon atoms on the benzene ring form a 3-8 membered heterocyclic ring containing 1-3 N, S, and O atoms.

2. The chalcone compound containing an α,β-unsaturated hydroxamic acid group according to claim 1, characterized in that: Its structure is shown in Formula I or Formula II: 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; (2) When R1 is H, R2 and R3 are independently selected from C1-C6 straight or branched alkyl groups; In formula II, ring A is selected from a 5-6 membered heterocyclic ring containing 1-2 O atoms.

3. A chalcone compound containing an α,β-unsaturated hydroxamic acid group according to claim 2, characterized in that: The C1-C6 straight or branched alkyl group is selected from —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)C H2CH3, —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; The 3-6 membered cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; The 5-6 membered heteroaryl group is selected from pyridine, furan, pyrrole, thiophene, thiazole, and pyrazole; Said for 4. The chalcone compound containing an α,β-unsaturated hydroxamic acid group according to claim 1, characterized in that: The compound is selected from the following structures:

5. A method for preparing a chalcone compound containing an α,β-unsaturated hydroxamic acid group according to any one of claims 1 to 4, characterized in that: The steps include: S1： The substrate II is dissolved in anhydrous ethanol to prepare a liquid A, and the substrate I is dissolved in anhydrous ethanol to prepare a liquid B; KOH solution is slowly added to the liquid B at 0-5°C to mix, and then the mixed solution is added to the liquid A at 0-5°C. After the addition is completed, the mixture is stirred at room temperature for reaction. After the reaction is completed, hydrochloric acid is added at 0-5°C until the precipitation is completely precipitated, and the solid is extracted with ethyl acetate, and the solvent is allowed to stand and evaporate, and then dried to obtain the substrate III; S2： The substrate III obtained in S1, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 4-dimethylaminopyridine are dissolved in tetrahydrofuran and stirred evenly, and then O-(tetrahydro-2H-pyran-2-yl)hydroxylamine and N,N-diisopropylethylamine are added, and the mixture is stirred and reacted at room temperature. After the reaction is completed, the mixture is allowed to stand for evaporation and drying to obtain a crude product of substrate IV; S3： Dissolve the crude product of substrate IV obtained from S2 in methanol, add excess HCl solution dropwise, and react by stirring at room temperature. After the reaction is completed, filter and wash with water and ethyl acetate respectively. The insoluble matter obtained is the target compound; In each step, R1, R2, and R3 have the same definitions as those in the above general formula.

6. The preparation method according to claim 5, characterized in that: The dosage relationship is as follows: the molar ratio of substrate I to substrate II in S1 is 1:0.8-1.2; The molar ratio of substrate III, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 4-dimethylaminopyridine, O-(tetrahydro-2H-pyran-2-yl)hydroxylamine, and N,N-diisopropylethylamine in S2 is 1:1-2:0.8-1.2:0.8-1.2:2-4.

7. The preparation method according to claim 5, characterized in that: The stirring reaction time in S1 is 20-30h; The stirring reaction time in S2 is 20-30h; The stirring reaction time in S3 is 20-30h.

8. A pharmaceutical composition comprising the chalcone compound containing an α,β-unsaturated hydroxamic acid group according to any one of claims 1 to 5 and, optionally, one or more pharmaceutically acceptable carriers or excipients.

9. Use of the chalcone compound containing an α,β-unsaturated hydroxamic acid group according to any one of claims 1 to 5 in the preparation of a drug for inhibiting histone deacetylase.

10. Use of a chalcone compound containing an α,β-unsaturated hydroxamic acid group according to any one of claims 1 to 5 in the preparation of anti-tumor drugs.

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