Acrylamide compounds containing azole structures, preparation methods and applications thereof

Abstract

The present invention belongs to the field of medical technology, and relates to acrylamide compounds containing azole structures, preparation methods and medical uses thereof. The acrylamide compounds containing azole structures of the general formula (1) have a strong and broad-spectrum antifungal activity and have potential applications as antifungal drugs. The definition of R in the general formula (1) of the present invention is shown in the specification.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and relates to acrylamide compounds containing azole structures, a preparation method thereof, and medical uses thereof. Background Art

[0002] Azoles are the first-line drugs for the treatment of invasive fungal infections. They are the most numerous and most widely used in clinical practice. Azoles are cytochrome P450-14α-demethylase (CYP51) inhibitors that prevent the biosynthesis of ergosterol in fungi, leading to changes in cell membrane permeability and thus inhibiting fungal growth. Representative drugs include fluconazole and miconazole. Their main disadvantages are narrow antibacterial spectrum, unsatisfactory pharmacokinetic curves, obvious drug resistance and toxic side effects, which limit their clinical application.

[0003] Classical CYP51 inhibitors can be divided into three parts: (1) the azole ring part, which is the most important structural fragment for exerting activity. The azole part is perpendicular to the porphyrin plane and coordinates with Fe2+ through the N-3 or N-4 atom of the azole ring, preventing CYP51 from binding to the substrate molecule and exerting inhibitory activity; (2) the aromatic ring; (3) the large non-polar part of the molecule, which extends into a narrow protein cavity (substrate entrance channel). Therefore, the hydrophobic fragment is structurally modified to fully occupy the protein cavity, in order to obtain a CYP51 inhibitor with high efficiency, broad spectrum, anti-resistance and low toxicity for the treatment of invasive fungal infections. Summary of the invention

[0004] The purpose of the present invention is to design and synthesize acrylamide compounds containing azole structures, and a preparation method and medical use thereof.

[0005] To achieve the above purpose, the present invention adopts the following technical solution:

[0006] An acrylamide compound containing an azole structure, the compound is shown in the general formula (1)

[0007]

[0008] In the general formula:

[0009] X and Y may be the same or different and may be selected from N or CH;

[0010] R1 and R2 may be the same or different and may be selected from H, halogen, cyano, nitro, hydroxyl, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy which are unsubstituted or substituted by at least one of the following groups, which may be the same or different and may be selected from halogen, hydroxyl, cyano, nitro and amino; amino which is unsubstituted or substituted by the following groups, such as the following groups selected from C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-6 cyanoalkyl , C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C2-6 alkenylcarbonyl or C2-6 alkynylcarbonyl; unsubstituted or substituted sulfamide or amide, wherein the following group replacing the amino group in the sulfamide or amide is selected from C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-6 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, C2-6 alkenylcarbonyl or C2-6 alkynylcarbonyl;

[0011] R3 is selected from H, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, which are unsubstituted or substituted by at least one of the following groups, which groups may be the same or different and are selected from halogen, hydroxyl, cyano, nitro and amino; amino which is unsubstituted or substituted by the following groups, such as the following groups selected from C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-6 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkylsulfonyl, C1-6 alkylcarbonyl, phenyl, biphenyl, naphthyl, benzyl, pyridine ring, pyrazole ring, pyrrole ring, pyrimidine ring, quinoline ring, imidazole ring, morpholine ring, piperazine ring, pyridazine ring, pyrazine ring, piperidine ring, thiophene ring, pyran ring, indole ring, furan ring, which are unsubstituted or substituted with at least one of the following groups, the following groups may be the same or different and are selected from hydroxyl, hydroxymethyl, thiol, amino, sulfamide, carboxyl, ester, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-7 cycloalkyl, benzyloxycarbonyl, C1-6 haloalkyl;

[0012] Or, optical isomers or diastereomers of the compound represented by general formula (1).

[0013] Preferably, in the general formula:

[0014] X and Y may be the same or different and may be selected from N or CH;

[0015] R1, R2 may be the same or different and may be selected from H, halogen, cyano, nitro, hydroxyl, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy which are unsubstituted or substituted with at least one of the following groups, the following groups may be the same or different and may be selected from halogen, hydroxyl, cyano, nitro and amino; amino, sulfamide, amide;

[0016] R3 is selected from H, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, which are unsubstituted or substituted by at least one of the following groups, which groups may be the same or different and are selected from halogen, hydroxyl, cyano, nitro, amino; amino which is unsubstituted or substituted by the following groups, such as the following groups selected from C1-6 alkyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxyalkyl, C1-6 cyanoalkyl, C2-6 alkenyl, C2-6 alkynyl; phenyl, biphenyl, benzyl, pyridine ring, pyrazole ring, pyrrole ring, pyrimidine ring, quinoline ring, imidazole ring, morpholine ring, piperazine ring, pyridazine ring, pyrazine ring, piperidine ring, thiophene ring, pyran ring, indole ring, furan ring substituted or substituted by at least one of the following groups, the following groups may be the same or different and are selected from hydroxyl, hydroxymethyl, thiol, amino, sulfamide, carboxyl, ester, cyano, nitro, halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylamino, C3-7 cycloalkyl, C1-6 haloalkyl;

[0017] Or, optical isomers or diastereomers of the compound represented by general formula (1).

[0018] Further preferably, in the general formula:

[0019] X and Y may be the same or different and may be selected from N or CH;

[0020] R1, R2 may be the same or different and may be selected from H, halogen, cyano, nitro, hydroxyl, C1-4 alkyl or C1-4 alkoxy which is unsubstituted or substituted by at least one of the following groups, the following groups may be the same or different and may be selected from halogen, hydroxyl, cyano, nitro, amino;

[0021] R3 is selected from H, C1-6 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl which are unsubstituted or substituted by at least one of the following groups, which groups may be the same or different and are selected from hydroxyl, amino; amino which is unsubstituted or substituted by the following groups, such as the following groups are selected from C1-6 alkyl, C1-6 aminoalkyl, C2-6 alkenyl, C2-6 alkynyl; phenyl, pyridine ring, pyrazole ring, pyrrole ring, pyrimidine ring, imidazole ring, furan ring which are unsubstituted or substituted by at least one of the following groups, which groups may be the same or different and are selected from hydroxyl, methylol, thiol, amino, nitro, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, C3-7 cycloalkyl, C1-6 haloalkyl;

[0022] Or, optical isomers or diastereomers of the compound represented by general formula (1).

[0023] Still more preferably, in the general formula:

[0024] X and Y may be the same or different and may be selected from N or CH;

[0025] R1, R2 may be the same or different and may be selected from H, halogen, cyano, nitro, hydroxyl, C1-4 alkyl, C1-4 alkoxy;

[0026] R3 is selected from H, C1-4 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl which are unsubstituted or substituted by at least one of the following groups, which may be the same or different and are selected from hydroxyl, amino; amino which is unsubstituted or substituted by the following groups, such as the following groups are selected from C1-4 alkyl, C1-6 aminoalkyl, C2-6 alkenyl, C2-6 alkynyl; phenyl, imidazole ring, furan ring which are unsubstituted or substituted by at least one of the following groups, which may be the same or different and are selected from hydroxyl, amino, nitro, halogen, C1-4 alkyl, C1-4 alkoxy, C1-6 haloalkyl;

[0027] Or, optical isomers or diastereomers of the compound represented by general formula (1).

[0028] Still further preferably, in the general formula:

[0029] X and Y may be the same or different and may be selected from N or CH;

[0030] R1, R2 may be the same or different and are selected from H, halogen, C1-4 alkyl, C1-4 alkoxy;

[0031] R3 is selected from H, C1-4 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, which are unsubstituted or substituted with at least one of the following groups, which may be the same or different and are selected from hydroxyl, amino; phenyl which is unsubstituted or substituted with at least one of the following groups, which are selected from hydroxyl, amino, nitro, halogen, C1-4 haloalkyl, C1-4 alkyl, C1-4 alkoxy;

[0032] Or, optical isomers or diastereomers of the compound represented by general formula (1).

[0033] More preferably, in the general formula:

[0034] X and Y may be the same or different and may be selected from CH;

[0035] R1, R2 may be the same or different and are selected from halogen;

[0036] R3 is selected from H, C1-4 alkyl, C3-8 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, phenyl which is unsubstituted or substituted with 1-2 of the following groups, the following groups are selected from halogen, trifluoromethyl, C1-4 alkyl, C1-4 alkoxy;

[0037] Or, optical isomers or diastereomers of the compound represented by general formula (1).

[0038] Most preferably, the compound represented by the general formula (1) is the following C01-C18 compound and its optical isomers and diastereomers;

[0039]

[0040] A method for preparing the compound, the reaction formula is as follows: first, 1-(2,4-chlorophenyl)-2-(1H-imidazole)ethanol and methyl 4-bromomethylcinnamate react to obtain intermediate 1, then hydrolyze with potassium hydroxide to obtain intermediate 2, then chlorinate with oxalyl chloride to obtain intermediate 3, and then react with substituted amine to obtain a compound of general formula (1);

[0041]

[0042] A pharmaceutical composition comprises the compound and its optically active form, diastereoisomer and a pharmaceutically acceptable carrier.

[0043] The invention discloses an application of a compound and a composition, and an application of the compound and its optically active form, diastereoisomer or the composition in preparing a drug for inhibiting CYP51.

[0044] The application of the compound and its optically active form, diastereoisomer or the composition in the preparation of antifungal drugs.

[0045] The advantages of the present invention are:

[0046] The compounds of the present invention are designed according to the active cavity of CYP51 to obtain the compounds described in the general formula (1). The compounds have a nitrogen azole functional group coordinated with the heme iron porphyrin, an aromatic ring region, and a long chain fragment that can extend into the narrow protein cavity, thereby achieving the inhibitory activity of CYP51 and improving the antifungal activity. The antibacterial spectrum is broadened, and the compounds have potential applications as antifungal drugs. DETAILED DESCRIPTION

[0047] The following examples will provide a better understanding of the compounds of the present invention and their preparation. These examples are intended to illustrate but not to limit the scope of the present invention.

[0048] Example 1: 2-Acrylic acid, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, methyl ester (Intermediate 1)

[0049] In a 50 mL eggplant-shaped bottle, 1-(2,4-difluorophenyl)-2-(1H-imidazole)ethanol (0.50 g, 2 mmol), 4-bromomethylcinnamic acid methyl ester (0.51 g, 2 mmol, 1 eq), sodium hydride (0.12 g, 5 mmol, 2.5 eq), and tetrahydrofuran 5 mL were added. The mixture was heated at 70 °C for 3 h under stirring. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phases were combined, washed with water (3 × 10 mL) and saturated brine (10 mL) in turn, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain 1 as a yellow solid, with a yield of 0.73 g and a yield of 85.60%. 1 H NMR (400MHz, DMSO-d6) δ7.67–7.62(m,4H),7.50(s,1H),7.47(dd,J=8.4,2.1H z,1H),7.39(d,J=8.4Hz,1H),7.22(d,J=8.1Hz,2H),7.05(s,1H),6.87(s,1H) ,6.62(d,J=16.1Hz,1H),5.02(dd,J=6.9,3.9Hz,1H),4.44(d,J=12.6Hz,1H), 4.34(d,J=12.5Hz,1H),4.31–4.21(m,2H),3.72(s,3H).HRMS(ESI):Calcd.for C 22 H 20 Cl2N2O3[M+Na] + :453.0743,Found 453.0766[M+Na] + .

[0050] Example 2: 2-Acrylic acid, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-(2)

[0051] In a 50mL eggplant-shaped bottle, add intermediate 1 (0.5g, 1mmol), 1N potassium hydroxide solution, and 5mL methanol. Stir and react at room temperature for 1h. Distill off part of the solvent under reduced pressure, add 4N dilute hydrochloric acid to adjust the pH to 6, filter to obtain a solid, and recrystallize from ethanol to obtain intermediate 2, which is a white solid with an amount of 0.43g and a yield of 87.90%.

[0052] Example 3: 2-Acrylic acid, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, acid chloride (Intermediate 3)

[0053] In a 50 mL eggplant-shaped bottle, add intermediate 2 (0.5 g, 1 mmol) and 5 mL of anhydrous dichloromethane. Add oxalyl chloride dropwise under ice bath and stirring, and stir at 0°C for 1 h. After all solvents are evaporated under reduced pressure, no further purification is required to obtain intermediate 3.

[0054] Example 4: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-(C01)

[0055] In a 50mL eggplant-shaped bottle, add intermediate 3 (0.5g, 1mmol), 0.1mL ammonia water, and 5mL anhydrous dichloromethane. Stir and react at room temperature for 1h. Add 10mL of water to the reaction solution, extract with dichloromethane (3×10mL), combine the organic phases, wash with water (3×10mL) and saturated brine (10mL) in turn, dry with anhydrous sodium sulfate, filter the desiccant, and concentrate under reduced pressure to obtain a crude product, which is purified by column chromatography (dichloromethane: methanol = 20:1) to obtain C01 as a yellow solid, with an amount of 0.43g, and a yield of %. 1 HNMR(400MHz, DMSO-d6)δ7.67(d,J=2.1Hz,1H),7.56–7.44(m,5H),7.42–7.36(m,2H),7.19(d,J=8.0Hz,2H),7.16–6.94(m,2H),6. 87(s,1H),6.59(d,J=15.9Hz,1H),5.01(dd,J=6.9,3.9Hz,1H),4.44(d,J=12.4Hz,1H),4.34–4.24(m,3H).HRMS(ESI):Calcd.forC 21 H 19 Cl2N3O2[M+H]+ :416.0927,Found 416.0871[M+H] + .

[0056] Example 5: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-methyl(C02)

[0057] The preparation method of the compound of Example 5 is the same as that of Example 4, using intermediate 3 and methylamine as raw materials, and referring to the synthesis method of C02, C02 is obtained as a yellow solid. 1 H NMR(400MHz, DMSO-d6)δ8.06(q,J=4.6Hz,1H),7.66(d,J=2.1Hz,1H),7.52–7.45(m,4H),7.42–7.37(m,2H),7.19(d,J=8.0Hz,2H),7.05(s,1H),6.88 (s,1H),6.59(d,J=15.8Hz,1H),5.01(dd,J=6.9,3.9Hz,1H),4.43(d,J=12.4Hz,1H),4.34–4.22(m,3H),2.71(d,J=4.6Hz,3H).HRMS(ESI):Calcd.for C 22 H 21 Cl2N3O2[M+H] + :430.1084,Found 430.1030[M+H] + .

[0058] Example 6: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-ethyl (C03)

[0059] The preparation method of the compound of Example 6 is the same as that of Example 4, using intermediate 3 and ethylamine as raw materials, and referring to the synthesis method of C03, C03 is obtained as a yellow solid. 1H NMR(400MHz, DMSO-d6)δ8.10(t,J=5.6Hz,1H),7.67(d,J=2.1Hz,1H),7.53(s,1H),7.50–7. 46(m,3H),7.42–7.36(m,2H),7.19(d,J=8.0Hz,2H),7.06(s,1H),6.88(s,1H),6.58(d,J=1 5.8Hz,1H),5.01(dd,J=6.9,3.9Hz,1H),4.43(d,J=12.4Hz,1H),4.29(ddd,J=16.7,13.4,7 .2Hz,3H),3.19(tdd,J=7.2,5.6,1.6Hz,2H),1.07(t,J=7.2Hz,3H).HRMS(ESI):Calcd.for C 23 H 23 Cl2N3O2[M+H] + :444.1240,Found444.1174[M+H] + .

[0060] Example 7: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-propyl (C04)

[0061] The preparation method of the compound of Example 7 is the same as that of Example 4, using intermediate 3 and propylamine as raw materials, and referring to the synthesis method of C04, C04 is obtained as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.09(t,J=5.7Hz,1H),7.66(d,J=2.1Hz,1H),7.52(s,1H),7.48(d d,J=8.3,1.8Hz,3H),7.42–7.36(m,2H),7.19(d,J=8.0Hz,2H),7.06(s,1H),6.88(s,1H),6 .61(d,J=15.8Hz,1H),5.01(dd,J=6.9,3.9Hz,1H),4.43(d,J=12.5Hz,1H),4.34–4.23(m,3 H),3.16–3.10(m,2H),1.47(q,J=7.2Hz,2H),0.88(t,J=7.4Hz,3H).HRMS(ESI):Calcd.for C 24 H 25 Cl2N3O2[M+H] + :458.1397,Found458.1350[M+H] + .

[0062] Example 8: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-cyclopropyl (C05)

[0063] The preparation method of the compound of Example 8 is the same as that of Example 4, using intermediate 3 and cyclopropylamine as raw materials, and referring to the synthesis method of C05, C05 is obtained as a yellow solid. 1 H NMR(400MHz, DMSO-d6)δ8.19(d,J=4.5Hz,1H),7.66(d,J=2.1Hz,1H),7.51–7.37(m ,6H),7.19(d,J=8.0Hz,2H),7.05(s,1H),6.87(s,1H),6.52(d,J=15.8Hz,1H),5.00 (dd,J=6.9,3.9Hz,1H),4.43(d,J=12.4Hz,1H),4.34–4.23(m,3H),2.76(tt,J=8.4 ,3.6Hz,1H),0.67(td,J=7.0,4.8Hz,2H),0.49–0.43(m,2H).HRMS(ESI):Calcd.for C 24 H 23 Cl2N3O2[M+Na] + :478.1060,Found 478.1030[M+Na] + .

[0064] Example 9: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-isopropyl (C06)

[0065] The preparation method of the compound of Example 9 is the same as that of Example 4, using intermediate 3 and isopropylamine as raw materials, and referring to the synthesis method of C04, C06 is obtained as a yellow solid. 1H NMR(400MHz, DMSO-d6)δ7.98(d,J=7.7Hz,1H),7.66(d,J=2.1Hz,1H),7.52–7.44( m,4H),7.42–7.35(m,2H),7.19(d,J=8.0Hz,2H),7.05(s,1H),6.87(s,1H),6.59(d ,J=15.8Hz,1H),5.01(dd,J=7.0,3.9Hz,1H),4.43(d,J=12.4Hz,1H),4.34–4.22( m,3H),3.95(dq,J=13.4,6.7Hz,1H),1.11(d,J=6.6Hz,6H).HRMS(ESI):Calcd.for C24 H 25 Cl2N3O2[M+H] + :458.1397,Found 458.1340[M+H] + .

[0066] Example 10: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-butyl (C07)

[0067] The preparation method of the compound of Example 10 is the same as that of Example 4, using intermediate 3 and butylamine as raw materials, and referring to the synthesis method of C07, C07 is obtained as a yellow solid. 1 H NMR(400MHz, DMSO-d6)δ8.07(t,J=5.7Hz,1H),7.65(d,J=2.1Hz,1H),7.52–7.45(m,4H),7.42– 7.36(m,2H),7.19(d,J=8.0Hz,2H),7.05(s,1H),6.88(s,1H),6.61(d,J=15.8Hz,1H),5.01(dd, J=6.9,3.9Hz,1H),4.43(d,J=12.4Hz,1H),4.33–4.23(m,3H),3.17(td,J=6.9,5.6Hz,2H),1.4 7–1.40(m,2H),1.31(ddd,J=9.9,7.6,6.1Hz,2H),0.88(t,J=7.3Hz,3H).HRMS(ESI):Calcd.for C 25 H 27 Cl2N3O2[M+H] + :472.1553,Found 472.1445[M+H] + .

[0068] Example 11: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-phenyl (C08)

[0069] The preparation method of the compound of Example 11 is the same as that of Example 4, using intermediate 3 and aniline as raw materials, and referring to the synthesis method of C08, C08 is obtained as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ10.20 (s, 1H), 7.75–7.68 (m, 2H), 7.66 (d, J = 2.1Hz, 1H), 7.6 1–7.52(m,4H),7.48(dd,J=8.4,2.1Hz,1H),7.42(d,J=8.4Hz,1H),7.33(dd,J=8.5, 7.3Hz,2H),7.23(d,J=8.1Hz,2H),7.10–7.03(m,2H),6.92–6.79(m,2H),5.02(dd,J =7.0,3.9Hz,1H),4.46(d,J=12.5Hz,1H),4.36–4.22(m,3H).HRMS(ESI):Calcd.for C 27 H 23 Cl2N3O2[M+H] + :492.1240,Found 492.1173[M+H] + .

[0070] Example 12: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-4-fluorophenyl (C09)

[0071] The preparation method of the compound of Example 12 is the same as that of Example 4, using intermediate 3 and 4-fluoroaniline as raw materials, and referring to the synthesis method of C09, C09 is obtained as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.25 (s, 1H), δ7.74–7.70 (m, 2H), 7.66 (d, J = 2.1Hz, 1H ),7.59–7.52(m,4H),7.48(dd,J=8.4,2.1Hz,1H),7.41(d,J=8.4Hz,1H),7.24– 7.15(m,4H),7.07(s,1H),6.89(s,1H),6.79(d,J=15.8Hz,1H),5.02(dd,J=7.0 ,3.9Hz,1H),4.46(d,J=12.5Hz,1H),4.35–4.24(m,3H).HRMS(ESI):Calcd.forC 27 H 22 Cl2FN3O2[M+H] + :510.1146,Found 510.1080[M+H] + .

[0072] Example 13: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-4-chlorophenyl (C10)

[0073] The preparation method of the compound of Example 13 is the same as that of Example 4, using intermediate 3 and 4-chloroaniline as raw materials, and referring to the synthesis method of C10, C10 is obtained as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.99(s,1H),9.01(s,1H),7.83(d,J=8.9Hz,2H),7.70(d,J=2.1Hz,1H),7.63–7.51(m,6H),7.42(d,J=8.4Hz,1H),7.3 6(d,J=8.7Hz,2H),7.24(d,J=8.0Hz,2H),7.08(dd,J=15.8,3.8Hz,1H),5.14(dd,J=7.3,3.8Hz,1H),4.56–4.35(m,4H).HRMS(ESI):Calcd.for C 27 H 22 Cl3N3O2[M+Na] + :548.0670,Found 548.0601[M+Na] + .

[0074] Example 14: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-4-bromophenyl (C11)

[0075] The preparation method of the compound of Example 14 is the same as that of Example 4, using intermediate 3 and 4-bromoaniline as raw materials, and referring to the synthesis method of C11, C11 is obtained as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),7.69–7.65(m,4H),7.61–7.46(m,7H),7.42(d,J=8.4Hz,1H),7.22(d,J=8.0Hz,2H),7.13(s,1H ),6.92(s,1H),6.79(d,J=15.8Hz,1H),5.02(dd,J=6.7,4.2Hz,1H),4.45(d,J=12.6Hz,1H),4.35–4.30(m,3H).HRMS(ESI):Calcd.for C 27 H 22 BrCl2N3O2[M+H] + :570.0345,Found570.0315[M+H]+ .

[0076] Example 15: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-4-trifluoromethylphenyl (C12)

[0077] The preparation method of the compound of Example 15 is the same as that of Example 4, using intermediate 3 and 4-trifluoromethylaniline as raw materials, and referring to the synthesis method of C12, C12 is obtained as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H), δ7.91(d,J=8.4Hz,2H),7.72–7.53(m,7H),7.49(dd,J=8.4,2.1Hz,1H),7.42(d,J=8.4Hz,1H),7.24(d, J=8.0Hz,2H),7.07(s,1H),6.90–6.80(m,2H),5.02(dd,J=6.9,3.9Hz,1H),4.47(d,J=12.6Hz,1H),4.36–4.25(m,3H).HRMS(ESI):Calcd.for C 28 H 22 Cl2F3N3O2[M+H] + :560.1114,Found 560.1101[M+H] + .

[0078] Example 16: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-4-methylphenyl (C13)

[0079] The preparation method of the compound of Example 16 is the same as that of Example 4, using intermediate 3 and 4-methylaniline as raw materials, and referring to the synthesis method of C13, C13 is obtained as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ10.10 (s, 1H), δ7.67 (d, J = 2.1Hz, 1H), 7.56 (dt, J = 15.7, 5.7Hz ,6H),7.48(dd,J=8.4,2.1Hz,1H),7.42(d,J=8.4Hz,1H),7.22(d,J=7.9Hz,2H),7.13(d ,J=8.2Hz,2H),7.07(s,1H),6.89(s,1H),6.81(d,J=15.7Hz,1H),5.02(dd,J=6.9,3.9 Hz,1H),4.46(d,J=12.5Hz,1H),4.35–4.26(m,3H),2.26(s,3H).HRMS(ESI):Calcd.for C 28 H 25 Cl2N3O2[M+H] + :506.1397,Found 506.1371[M+H] + .

[0080] Example 17: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-4-methoxyphenyl (C14)

[0081] The preparation method of the compound of Example 17 is the same as that of Example 4, using intermediate 3 and 4-methoxyaniline as raw materials, and referring to the synthesis method of C14, C14 is obtained as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.06(s,1H), δ7.68–7.60(m,3H),7.57–7.47(m,5H),7.42(d,J=8.4Hz,1H),7.22(d,J=7.9Hz,2H),7.07(s,1H),6.95–6 .87(m,3H),6.79(d,J=15.7Hz,1H),5.02(dd,J=6.9,3.9Hz,1H),4.46(d,J=12.5Hz,1H),4.37–4.25(m,3H),3.73(s,3H).HRMS(ESI):Calcd.for C 28 H 25 Cl2N3O3[M+Na] + :544.1165,Found 544.1104[M+Na] + .

[0082] Example 18: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-3-chlorophenyl (C15)

[0083] The preparation method of the compound of Example 18 is the same as that of Example 4, using intermediate 3 and 3-chloroaniline as raw materials, and referring to the synthesis method of C15, C15 is obtained as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),7.94(s,1H),7.67(d,J=2.1Hz,1H),7.61–7 .52(m,5H),7.48(dd,J=8.4,2.1Hz,1H),7.43–7.34(m,2H),7.23(d,J=8.0Hz,2H), 7.14–7.11(m,1H),7.07(s,1H),6.89(s,1H),6.79(d,J=15.7Hz,1H),5.02(dd,J=7 .0,3.9Hz,1H),4.46(d,J=12.6Hz,1H),4.36–4.28(m,3H).HRMS(ESI):Calcd.forC 27 H 22 Cl3N3O2[M+H] + :526.0850,Found 526.0819[M+H] + .

[0084] Example 19: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-3-bromophenyl (C16)

[0085] The preparation method of the compound of Example 19 is the same as that of Example 4, using intermediate 3 and 3-bromoaniline as raw materials, and referring to the synthesis method of C16, C16 is obtained as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),8.08(s,1H),7.67(d,J=2.1Hz,1H),7. 60–7.53(m,5H),7.48(dd,J=8.4,2.1Hz,1H),7.41(d,J=8.4Hz,1H),7.31–7.2 2(m,4H),7.07(s,1H),6.89(s,1H),6.78(d,J=15.8Hz,1H),5.02(dd,J=7.0,3 .9Hz,1H),4.46(d,J=12.6Hz,1H),4.36–4.26(m,3H).HRMS(ESI):Calcd.forC 27 H22 BrCl2N3O2[M+H] + :570.0345,Found 570.0245[M+H] + .

[0086] Example 20: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-2-methylphenyl (C17)

[0087] The preparation method of the compound of Example 20 is the same as that of Example 4, using intermediate 3 and 2-methylaniline as raw materials, and referring to the synthesis method of C17, C17 is obtained as a yellow solid. 1 H NMR(400MHz, DMSO-d6)δ10.11(s,1H),δ7.66(d,J=2.1Hz,1H),7.58–7.47(m,7H),7.42(d,J=8.4Hz,1H),7.24–7.19(m,3H),7.07(s,1H),6.88(d, J=6.7Hz,2H),6.82(d,J=15.7Hz,1H),5.02(dd,J=6.9,3.9Hz,1H),4.46(d,J=12.5Hz,1H),4.37–4.25(m,3H),2.29(s,3H).HRMS(ESI):Calcd.for C 28 H 25 Cl2N3O2[M+H] + :506.1397,Found 506.1329[M+H] + .

[0088] Example 21: 2-Acrylamide, 3-[4-[1-(1H-imidazole)-2-(2,4-dichlorophenyl)-2-methoxyethyl]phenyl]-, N-2,4-dichlorophenyl (C18)

[0089] The preparation method of the compound of Example 21 is the same as that of Example 4, using intermediate 3 and 2,4-dichloroaniline as raw materials, and referring to the synthesis method of C18, C18 is obtained as a yellow solid. 1H NMR(400MHz, DMSO-d6)δ9.73(s,1H),8.00(dd,J=8.8,6.7Hz,1H),7.68–7.53(m,6H),7.49–7.41(m,3H),7.23(d,J=8.0Hz,2H), 7.14–7.06(m,2H),6.89(s,1H),5.02(dd,J=7.0,3.9Hz,1H),4.46(d,J=12.6Hz,1H),4.36–4.26(m,3H).HRMS(ESI):Calcd.for C 27 H 21 Cl4N3O2[M+H] + :562.0431,Found 562.0398[M+H] + .

[0090] Pharmacological studies of the present invention

[0091] The in vitro antifungal activities of compounds C01-C18 were determined by the two-fold concentration dilution method.

[0092] The experiment was conducted according to the 2003 edition of the spore-forming filamentous fungi susceptibility test protocol published by the National Committee for Clinical Laboratory Standards (NCCLS) of the United States.

[0093] Positive control drugs: Fluconazole and Miconazole.

[0094] Test strains: Seven test fungi were obtained through public channels and then preserved by the Microbiology Teaching and Research Department of Shenyang Pharmaceutical University, namely Candida albicans (CPCC400616 and ATCCSC5314), Cryptococcus neoformans (CGMCC2.3161), Candida zeylanoides CGMCC2.3739, Candida krusei (AS 2.1045), Candida glabrata (ATCC 22019) and Candida glabrata.

[0095] Preparation of target compound and control drug stock solutions: Weigh 4 mg of target compound and positive control drug respectively, dissolve in 5 mL of DMSO, add 5 mL of Tween 80 and 4.0 mL of distilled water to prepare stock solutions, and store at 4°C for future use.

[0096] Determination of in vitro minimum inhibitory concentration: Add RPM1640 culture medium to the 96-well plate, add 180 μL to the first well, add 100 μL to the growth control well and the experimental well, and add 200 μL to the blank control well. Then add 20 μL of the drug sample stock solution to the first well, mix well, and then aspirate 100 μL, and transfer it to the second well. After mixing well in the second well, aspirate 100 μL again, transfer it to the third well, and so on to all the experimental wells. No drug sample stock solution is added to the growth control well and the blank control well. Then add 100 μL of the prepared and diluted to 1×10 3 ~10 3 cuf / mL bacterial suspension. The 96-well plate was cultured in a 35°C incubator. The MIC values ​​of Candida albicans, Candida tropicalis, Candida krusei, Candida glabrata and Candida glabrata were read after 24 hours of culture, and the MIC values ​​of Cryptococcus neoformans were read after 72 hours of culture. All experiments were performed at least three times independently, and the experimental error did not exceed 10%.

[0097]

[0098] Note: MIC: minimum inhibitory concentration, Fluconazole: fluconazole, Miconazole: miconazole, C.alb: Candida albicans, C.alb(5314): Candida albicans SC5314, C.par: Candida glabrata, C.gla: Candida glabrata, C.kru: Candida krusei, C.tro: Candida tropicalis, C.neo: Cryptococcus neoformans.

[0099] It can be seen from the above that C01-C18 of the present invention has better in vitro antifungal activity, and the antifungal activity of some compounds is much better than that of positive drugs, and the antibacterial spectrum is also wider. The acrylamide compounds containing azole structures designed and synthesized by the present invention have strong antifungal activity and significantly improve their antibacterial effect compared with positive drugs.

Claims

1. An acrylamide compound containing an azole structure, characterized in that: The compound is shown in the general formula (1) In the general formula: X and Y are identically selected from CH; R1, R2 can be the same or different and are selected from H, halogen; R3 is selected from H, C1-6 alkyl, C3-8 cycloalkyl; phenyl which is unsubstituted or substituted by at least one of the following groups, which may be the same or different and are selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl.

2. The compound according to claim 1, characterized in that: In the general formula: X and Y are identically selected from CH; R1, R2 can be the same or different and are selected from H, halogen; R3 is selected from H, C1-6 alkyl, C3-8 cycloalkyl; phenyl which is unsubstituted or substituted by at least one of the following groups, which may be the same or different and are selected from halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl.

3. The compound according to claim 2, characterized in that: In the general formula: X and Y are identically selected from CH; R1, R2 can be the same or different and are selected from H, halogen; R3 is selected from H, C1-6 alkyl, C3-8 cycloalkyl; phenyl which is unsubstituted or substituted by at least one of the following groups, which may be the same or different and are selected from halogen, C1-4 alkyl, C1-4 alkoxy, C1-6 haloalkyl.

4. The compound according to claim 3, characterized in that: In the general formula: X and Y are identically selected from CH; R1, R2 can be the same or different and are selected from H, halogen; R3 is selected from H, C1-4 alkyl, C3-8 cycloalkyl; phenyl which is unsubstituted or substituted by at least one of the following groups, which may be the same or different and are selected from halogen, C1-4 alkyl, C1-4 alkoxy, C1-6 haloalkyl.

5. The compound according to claim 4, characterized in that: In the general formula: X and Y are identically selected from CH; R1, R2 can be the same or different and are selected from H, halogen; R3 is selected from H, C1-4 alkyl, C3-8 cycloalkyl; phenyl which is unsubstituted or substituted by at least one of the following groups, wherein the following groups are selected from halogen, C1-4 haloalkyl, C1-4 alkyl, C1-4 alkoxy.

6. The compound according to claim 4, characterized in that: In the general formula: X and Y are identically selected from CH; R1, R2 are the same or different and are selected from halogen; R3 is selected from H, C1-4 alkyl, C3-8 cycloalkyl; phenyl which is unsubstituted or substituted by 1-2 of the following groups, wherein the following groups are selected from halogen, trifluoromethyl, C1-4 alkyl, C1-4 alkoxy.

7. A method for preparing the compound according to claim 1, characterized in that: The reaction formula is as follows: first, 1-(2,4-chlorophenyl)-2-(1H-imidazole)ethanol and methyl 4-bromomethylcinnamate react to obtain intermediate 1, which is then hydrolyzed with potassium hydroxide to obtain intermediate 2, which is then chlorinated with oxalyl chloride to obtain intermediate 3, which is then reacted with a substituted amine to obtain a compound of general formula (1); 8. A pharmaceutical composition, characterized in that: The composition comprises the compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

9. Use of a compound and a composition, characterized in that: Use of the compound according to any one of claims 1 to 6 or the composition according to claim 8 in the preparation of a drug for inhibiting CYP51.

10. The use according to claim 9, characterized in that: Use of the compound according to any one of claims 1 to 6 or the composition according to claim 8 in the preparation of an antifungal drug.

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