Benzyl pyrrole compound as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicines, relates to a benzyl pyrrole compound as well as a preparation method and application thereof, and in particular relates to a benzyl pyrrole compound as well as a preparation method and application thereof in preparation of antibacterial and anti-inflammatory medicines. The invention provides a benzyl pyrrole compound as shown in a general formula I or pharmaceutically acceptable salts thereof, and R1, R2 and R3 are described in the claims and the description. The invention further provides application of the benzyl pyrrole compound shown in the general formula I or the pharmaceutically acceptable salt or the pharmaceutical composition thereof in preparation of antibacterial drugs or anti-inflammatory drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and relates to benzylpyrrole compounds, their preparation methods and applications, specifically to benzylpyrrole compounds, their preparation methods and applications in the preparation of antibacterial and anti-inflammatory drugs. Background Art

[0002] Benzylpyrrole compounds are mainly derived from the fruits of the medicinal plant Moringa oleifera. Moringa oleifera, also known as the drumstick tree, is a perennial tropical deciduous tree of the genus Moringa in the family Moringaceae, and its origin is India. Moringa oleifera has dietary and health care effects and is known as the "tree of life" and the "diamond in plants". Moringa oleifera has high economic value, and its nutritional components, secondary metabolites and pharmacological activities have attracted extensive attention from scientific researchers.

[0003] At present, the content of benzylpyrrole compounds in nature is very low (less than one in one hundred thousand in dry weight), the number of benzylpyrrole compounds currently discovered is small, and there are even fewer synthetic preparation methods for them. There is no general method to synthesize compounds with various different substitution conditions. Moreover, there are no relevant reports on the application of such compounds in the preparation of antibacterial and anti-inflammatory drugs. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to overcome the defects of the prior art and provide a series of new benzylpyrrole compounds, and the benzylpyrrole compounds have obvious antibacterial and anti-inflammatory activities.

[0005] The present invention is achieved as follows:

[0006] The present invention provides a benzylpyrrole compound represented by the general formula I or a pharmaceutically acceptable salt thereof:

[0007]

[0008] Wherein,

[0009] R 1 is H, OH, halogen, unsubstituted or C 1 -C 6 alkyl-substituted C 1- C 6 ester group, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 carboxyl group, C 1 -C 6 alkyl-substituted sulfonic acid group, phenyl-substituted sulfonic acid group, and the phenyl can be substituted by one or more C 1 -C 6 alkyl;

[0010] R 2 is H, C 1 -C 6 alkyl acyl, C 1 -C 6 alkyl, -(CO)R;

[0011] R is H, OH, C 1 -C 6 alkyl;

[0012] R 3 is H, formyl, C 1 -C 6 alkyl.

[0013] The present invention preferably relates to a benzylpyrrole compound represented by the general formula I or a pharmaceutically acceptable salt thereof:

[0014] Wherein,

[0015] R 1 is H, OH, halogen, unsubstituted or C 1 -C 4 alkyl-substituted C 1- C 4 ester group, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 carboxyl, C 1 -C 4 alkyl-substituted sulfonic acid group, phenyl-substituted sulfonic acid group, the phenyl being substituted by one or more C 1 -C 4 alkyl;

[0016] R 2 is H, C 1 -C 4 alkyl acyl, C 1 -C 4 alkyl, -(CO)R;

[0017] R is H, OH, C 1 -C 4 alkyl;

[0018] R 3 is H, formyl, C 1 -C 4 alkyl.

[0019] The present invention preferably relates to a benzylpyrrole compound represented by the general formula I or a pharmaceutically acceptable salt thereof:

[0020] R 1 is para-substituted on the benzene ring.

[0021] The present invention preferably relates to a benzylpyrrole compound represented by the general formula I or a pharmaceutically acceptable salt thereof:

[0022]

[0023]

[0024]

[0025] Furthermore, the present invention provides a method for preparing a benzylpyrrole compound represented by the general formula I,

[0026] Compounds 1-5 are obtained by reacting benzyl bromide of various tosylates with pyrrole, or obtained through further hydrolysis reaction; Compounds 6-14, 21-27 are obtained by reacting halogen benzyl bromide with pyrrole derivatives; Compounds 15-20, 28-34 are obtained by acylation on the parent structure of Compounds 6-14, 21-27.

[0027] The present invention provides a pharmaceutical composition comprising a benzylpyrrole compound represented by the general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0028] The present invention further provides the use of a benzylpyrrole compound represented by the general formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of antibacterial drugs.

[0029] The antibacterial drug is a drug against Trichophyton rubrum, Trichophyton mentagrophytes, Candida albicans, Cryptococcus neoformans or methicillin-resistant Staphylococcus aureus.

[0030] The present invention further provides the use of a benzylpyrrole compound represented by the general formula I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in the preparation of anti-inflammatory drugs, which exerts anti-inflammatory effects by inhibiting inflammatory factors such as interleukin-6, interleukin-1β, and α-tumor necrosis factor. Detailed implementation manners

[0031] The following specific examples are used to further illustrate the present invention, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.

[0032] Among them, the reagents and instruments used in this example are as follows:

[0033] Reagents: 4-Hydroxybenzyl bromide, p-Toluenesulfonyl chloride, 4-Fluorobenzyl bromide, 4-Chlorobenzyl bromide, 4-Bromobenzyl bromide, 4-Iodobenzyl bromide, 4-(Methoxycarbonyl)benzyl bromide, N,N-Dimethylformamide, Phosphorus oxychloride, 2-Methylpyrrole, 2-Acetylpyrrole, THF, Potassium carbonate, Methanol, Petroleum ether, Ethyl acetate, Dichloromethane, etc.

[0034] Instruments: ABI Maldi-TOF and Qstar Elite high-resolution mass spectrometry systems; Bruker Avance 600MHz nuclear magnetic resonance spectrometer (Bruker Corporation, Switzerland); Agilent GC-MS; EYLA (SB-1200) rotary evaporator (Shanghai Ailan Instruments Co., Ltd.); C-MAG HS 7 magnetic stirrer (Shanghai Ailan Instruments Co., Ltd.); YUHUA (ZF-20D AN) dark box type ultraviolet analyzer (Shanghai Guanghao Analytical Instruments Co., Ltd.); KQ5200E ultrasonic cleaner (Kunshan Ultrasonic Instruments Co., Ltd.), SB-1200 water bath (Shanghai Ailan Instruments Co., Ltd.), A-1000S water aspirator (Shanghai Ailan Instruments Co., Ltd.).

[0035] Example 1

[0036] 1. Synthesis of target compounds 1 and 2 (taking 2 as an example)

[0037]

[0038] Add 2-Methylpyrrole (0.5 g, 6 mmol) to a 25 mL single-necked flask, evacuate, refill with argon, and add DMF (5.0 mL). Then add NaH (60%, 0.5 g, 12.5 mmol), stir for 30 minutes under argon protection, withdraw with a 10 mL syringe, and add dropwise to a previously prepared solution of 4-Benzyl bromide-p-toluenesulfonate (2.0 mg, 6 mmol, dissolved in 5.0 mL DMF) at 0 °C. After dropping, stir at room temperature for 1 hour, then add 100.0 mL of ethyl acetate / water (1:1) for extraction. Concentrate the organic layer and purify by silica gel column chromatography to obtain the target compound 2 (1.84 g, 90.0%), and the eluent is (petroleum ether / ethyl acetate = 20:1). Compound 1 can be prepared by the same method, and the physicochemical data of the compound are as follows:

[0039] 4-((2-Methyl-1H-pyrrol-1-yl)methyl)phenyl 4-methylbenzenesulfonate (2): White solid, mp 148 - 150 °C. 1 H NMR (600 MHz, CDCl 3) δ 7.73 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 6.89 - 6.93 (m, 4H), 6.62 (s, 1H), 6.13 (d, J = 1.8 Hz, 1H), 5.96 (s, 1H), 5.01 (s, 2H), 2.48 (s, 3H), 2.13 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 148.6, 145.4, 137.4, 132.3, 129.7 (2C), 128.5, 128.4 (2C), 127.4 (2C), 122.6 (2C), 120.7, 107.3, 107.2, 49.6, 21.6, 11.8. HRMS (ESI) calcd. for [C 19 H 18 NO 4 S + Na] + 379.0854, found 379.0855.

[0040] 4 - ((2 - Acetyl - 1H - pyrrol - 1 - yl)methyl)phenyl 4 - methylbenzenesulfonate (1): White solid, mp 164 - 166 °C. 1 H NMR (600 MHz, CDCl 3 ) δ 7.71 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 6.99 - 7.03 (m, 3H), 6.94 - 6.88 (m, 3H), 6.24 - 6.20 (m, 1H), 5.55 (s, 2H), 2.47 (s, 3H), 2.42 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 188.2, 148.6, 145.3, 137.3, 132.1, 130.3, 129.9, 129.6 (2C), 128.3 (2C), 128.0 (2C), 122.2 (2C), 120.4, 108.6, 51.6, 27.1, 21.5. HRMS (ESI) calcd. for [C 19 H 19 NO 3 S + Na] + 364.0983, found 364.0985.

[0041] 2. Synthesis of target compounds 3, 15 - 20, 28 - 34 (taking 3 as an example)

[0042]

[0043] Take a 25-mL single-necked flask, add a magnetic stir bar, evacuate the air, and refill with argon. Inject 0.5 mL of phosphorus oxychloride (5.0 mmol) into the previous flask using a syringe, cool it to 0 °C in an ice-water bath, and then slowly add anhydrous DMF (0.5 mL, 6.5 mmol). After the addition, if there are white lumps, sonicate for 5 minutes under ultrasound. Dissolve compound 2 (1.7 g, 5.0 mmol) in 3.0 mL of anhydrous DMF, and then add it dropwise to the previous salt solution at room temperature. After the addition, stir at room temperature for 1 hour, quench the reaction with 50.0 mL of ice water, and finally extract with 50.0 mL of EtOAc. Concentrate the organic solvent layer and purify by silica gel column chromatography to obtain compound 3 (1.4 g, 75.0%). Compounds 15 - 20, 34 are respectively prepared from 11, 8 - 10, 12, 6, 13 as raw materials; compounds 28 - 33 are respectively prepared from 22 - 27 as raw materials. The physicochemical data of the compounds are as follows: 4-((2-Formyl-5-methyl-1H-pyrrol-1-yl)methyl)phenyl 4-methylbenzenesulfonate (3): White solid, mp 175 - 177 °C. 1 H NMR(600MHz,CDCl 3 )δ9.43(s,1H),7.70(d,J=8.4Hz,2H),7.31(d,J=10.2Hz,2H),6.94 - 6.92(m,1H),6.92(s,4H),6.11(d,J=4.2Hz,1H),5.60(s,2H),2.46(s,3H),2.18(s,3H). 13 C NMR(150MHz,CDCl 3 )δ178.6,148.7,145.4,140.8,136.6,132.3,131.5,129.8(2C),128.5(2C),127.6(2C),125.5,122.6(2C),110.6,47.7,21.7,12.2.HRMS(ESI)calcd.for[C 20 H 19 NO 4 S+Na] + 392.0932,found 392.0934.

[0044] 1-(4-Fluorobenzyl)-5-(1-hydroxyvinyl)-1H-pyrrole-2-carbaldehyde(15): Colorless oil. 1 H NMR(600MHz,CDCl 3 )δ9.58(s,1H),7.02 - 6.95(m,5H),6.48(d,J=4.1Hz,1H),5.73(s,2H),5.70(d,J=1.6Hz,1H),5.49(d,J=1.6Hz,1H). 13 C NMR(150MHz,CDCl 3 )δ179.9,162.8(C-F),161.2(C-F),139.4,133.6,132.8,129.2,128.0,127.9,124.2,120.3,115.5,115.4 112.9,48.7.HRMS(ESI)calcd.for[C 14 H 12 FNO 2 +Na] + 268.0750,found 268.0751.

[0045] 1-(4-Chlorobenzyl)-5-(1-hydroxyvinyl)-1H-pyrrole-2-carbaldehyde(16): Colorless oil. 1 H NMR(600MHz,CDCl 3 )δ9.60 - 9.55(m,1H),7.26(dd,J=6.6,1.9Hz,2H),7.00 - 6.97(m,1H),6.97 - 6.94(m,2H),6.52 - 6.45(m,1H),5.72(s,2H),5.70(d,J=1.7Hz,1H),5.49(d,J=1.7Hz,1H). 13 C NMR(150MHz,CDCl 3 )δ179.9,139.4,136.4,133.1,132.8,129.1,128.8(2C),127.6(2C),124.2,120.3,112.9,48.8.HRMS(ESI)calcd.for[C 14 H 12 ClNO 2 +Na] +284.0454, found 284.0454. 1-(4-Bromobenzyl)-5-(1-hydroxyvinyl)-1H-pyrrole-2-carbaldehyde (17): Colorless oil. 1 H NMR (600 MHz, CDCl 3 ) δ 9.57 (s, 1H), 7.41 (d, J=7.9 Hz, 2H), 6.98 (t, J=12.7 Hz, 1H), 6.89 (d, J=8.1 Hz, 2H), 6.49 (d, J=3.8 Hz, 1H), 5.70 (brs, 3H), 5.49 (s, 1H). 13 C NMR (150 MHz, CDCl 3 ) δ 179.9, 139.4, 137.5, 136.9, 132.8, 131.7 (2C), 130.3, 128.0 (2C), 124.2, 120.4, 112.9, 48.9. HRMS (ESI) calcd. for [C 14 H 12 BrNO 2 +Na][ + 327.9949, found 327.9951.

[0046] 5-(1-Hydroxyvinyl)-1-(4-iodobenzyl)-1H-pyrrole-2-carbaldehyde (18): Colorless oil. 1 H NMR (600 MHz, CDCl 3 ) δ 9.56 (s, 1H), 7.63 - 7.59 (m, 2H), 7.00 - 6.97 (m, 1H), 6.77 - 6.74 (m, 2H), 6.49 (d, J=4.1 Hz, 1H), 5.73 (d, J=1.7 Hz, 1H), 5.66 (s, 2H), 5.49 (d, J=1.7 Hz, 1H). 13 C NMR (150 MHz, CDCl 3 ) δ 179.9, 139.4, 137.7 (2C), 137.6, 132.8, 129.1, 128.2 (2C), 124.2, 120.4, 112.9, 92.8, 49.0. HRMS (ESI) calcd. for [C 14 H 12 INO 2 +Na][ +375.9810, found 375.9812.

[0047] 5-(1-Hydroxyvinyl)-1-(4-methylbenzyl)-1H-pyrrole-2-carbaldehyde (19): Colorless oil. 1 H NMR (600 MHz, CDCl 3 ) δ 9.58 (s, 1H), 7.10 (d, J=7.9 Hz, 2H), 6.98 (d, J=3.4 Hz, 1H), 6.91 (d, J=7.9 Hz, 2H), 6.49 (d, J=3.4 Hz, 1H), 5.71 (s, 2H), 5.69 (d, J=1.6 Hz, 1H), 5.49 (d, J=1.6 Hz, 1H), 2.32 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 179.9, 139.4, 136.9, 134.9, 133.0, 129.3 (2C), 129.3, 126.1 (2C), 123.8, 120.0, 112.8, 49.2, 21.1. HRMS (ESI) calcd. for [C 15 H 15 NO 2 +Na] + 264.1000, found 264.1003.

[0048] Methyl 4-((2-formyl-5-(1-hydroxyvinyl)-1H-pyrrol-1-yl)methyl)benzoate (20): Colorless oil. 1 H NMR (600 MHz, CDCl 3 ) δ 9.57 (s, 1H), 7.96 (d, J=8.1 Hz, 2H), 7.04 (d, J=8.1 Hz, 2H), 7.01 (dd, J=4.1, 1.7 Hz, 1H), 6.50 (dd, J=4.1, 1.6 Hz, 1H), 5.80 (s, 2H), 5.67 (t, J=1.7 Hz, 1H), 5.46 (t, J=1.6 Hz, 1H), 3.90 (s, 3H). 13 C NMR (150 MHz, CDCl 3)δ179.9, 166.8, 143.0, 139.5, 132.9, 129.9(2C), 129.2, 129.0, 126.0(2C), 124.2, 120.4, 112.9, 52.1, 49.3. HRMS(ESI) calcd. for [C 16 H 15 NO 4 +Na] + 308.0899, found 308.0896.

[0049] 1-(4-Chlorobenzyl)-5-methyl-1H-pyrrole-2-carbaldehyde(28): Colorless oil. 1 H NMR(600 MHz, CDCl 3 )δ9.46(s, 1H), 7.27(d, J=8.1 Hz, 2H), 6.93 - 6.95(m, 3H), 6.13(d, J=4.0 Hz, 1H), 5.61(s, 2H), 2.22(s, 3H). 13 C NMR(150 MHz, CDCl 3 )δ178.6, 140.7, 136.1, 133.1, 131.6, 128.9(2C), 127.7(2C), 125.4, 110.5, 47.7, 12.2. HRMS(ESI) calcd. for [C 13 H 12 ClNO + Na] + 256.0505, found 256.0508.

[0050] 1-(4-Bromobenzyl)-5-methyl-1H-pyrrole-2-carbaldehyde(29): Colorless oil. 1 H NMR(600 MHz, CDCl 3 )δ9.46(s, 1H), 7.43(d, J=8.4 Hz, 2H), 6.95(d, J=3.8 Hz, 1H), 6.87(d, J=8.4 Hz, 2H), 6.14 - 6.12(m, 1H), 5.60(s, 2H), 2.22(s, 3H). 13 C NMR(150 MHz, CDCl 3)δ178.6,140.7,136.7,131.8(2C),131.6,128.0(2C),125.4,121.2,110.6,47.8,12.2.HRMS(ESI)calcd.for[C 13 H 12 BrNO+Na] + 300.0000,found 300.0005.

[0051] 1-(4-Iodobenzyl)-5-methyl-1H-pyrrole-2-carbaldehyde(30):Colorless oil. 1 H NMR(600MHz,CDCl 3 )δ9.46(s,1H),7.62(d,J=8.3Hz,2H),6.94(d,J=4.0Hz,1H),6.74(d,J=8.3Hz,2H),6.12(d,J=3.9Hz,1H),5.59(s,2H),2.22(s,3H). 13 C NMR(150MHz,CDCl 3 )δ178.6,140.7,137.8(2C),137.4,131.6,128.2(2C),125.4,110.5,92.6,47.9,12.2.HRMS(ESI)calcd.for[C 13 H 12 INO+Na] + 347.9861,found 347.9860.

[0052] 5-Methyl-1-(4-methylbenzyl)-1H-pyrrole-2-carbaldehyde(31):Colorless oil. 1 H NMR(600MHz,CDCl 3 )δ9.47(s,1H),7.11(d,J=7.7Hz,2H),6.93(d,J=3.8Hz,1H),6.90(d,J=7.9Hz,2H),6.10(d,J=3.3Hz,1H),5.61(s,2H),2.32(s,3H),2.23(s,3H). 13 C NMR(150MHz,CDCl 3)δ178.6,140.8,136.9,134.6,131.7,129.3(2C),126.2(2C),125.1,110.3,48.1,21.1,12.3.HRMS(ESI)calcd.for[C 14 H 15 NO+Na] + 236.1051,found 236.1057.

[0053] 1-Benzyl-5-methyl-1H-pyrrole-2-carbaldehyde(32):Colorless oil. 1 H NMR(600MHz,CDCl 3 )δ9.48(s,1H),7.30(d,J=7.5Hz,3H),7.25(t,J=7.3Hz,1H),7.00(d,J=7.5Hz,2H),6.95(d,J=3.9Hz,1H),6.12(d,J=3.9Hz,1H),5.66(s,2H),2.23(s,3H). 13 C NMR(150MHz,CDCl 3 )δ178.6,140.9,137.6,131.7,128.7(2C),127.2,126.2(2C),125.2,110.4,48.3,12.2.HRMS(ESI)calcd.for[C 13 H 13 NO+Na] + 222.0895,found 222.0899.

[0054] Methyl 4-((2-formyl-5-methyl-1H-pyrrol-1-yl)methyl)benzoate(33):Colorless oil. 1 H NMR(600MHz,CDCl 3 )δ9.47(s,1H),7.98(d,J=8.3Hz,2H),7.04(d,J=8.5Hz,2H),6.97(d,J=3.6Hz,1H),6.15(d,J=3.6Hz,1H),5.71(s,2H),3.91(s,3H),2.21(s,3H). 13 C NMR(150MHz,CDCl 3)δ178.7,166.8,142.8,140.7,131.7,130.1(2C),129.2,126.1(2C),125.4,110.6,52.1,48.2,12.2.HRMS(ESI)calcd.for[C 15 H 15 NO 3 +Na] + 280.0950,found 280.0955.

[0055] 1-Benzyl-5-(1-hydroxyvinyl)-1H-pyrrole-2-carbaldehyde(34):Colorless oil. 1 H NMR(600MHz,CDCl 3 )δ9.59(s,1H),7.30(d,J=7.4Hz,2H),7.24(t,J=7.3Hz,1H),7.02(d,J=7.6Hz,2H),7.00(d,J=4.1Hz,1H),6.51(d,J=4.1Hz,1H),5.78(s,2H),5.68(d,J=1.6Hz,1H),5.48(d,J=1.7Hz,1H). 13 C NMR(150MHz,CDCl 3 )δ179.9,139.4,137.9,133.0,129.2,128.6(2C),127.3,126.1(2C),123.9,120.1,112.9,49.4.HRMS(ESI)calcd.for[C 14 H 13 NO 2 +Na] + 250.0844,found 250.0846.

[0056] 3. Synthesis of target compounds 4, 5, and 7 (taking 4 as an example)

[0057]

[0058] Dissolve compound 3 (1.5 g, 4.0 mmol) in CH 3 OH (20.0 mL), then add NaOH (0.4 g, dissolved in 20.0 mL of water) solution. After stirring at 50 °C for 2 hours, distill off CH 3 OH, and add 30.0 mL of H 2O. The pH value was adjusted to 7 with concentrated hydrochloric acid, and then extracted with ethyl acetate. The organic solvent layer was separated, concentrated, and the extract was separated and purified by silica gel column to obtain 4 (0.6 g, 70.0%). The eluent was petroleum ether / ethyl acetate (v / v = 9:1). Compound 5 can be prepared from compound 1; compound 7 can be prepared from compound 6. The physicochemical data of the compounds are as follows:

[0059] 1-(4-Hydroxybenzyl)-5-methyl-1H-pyrrole-2-carbaldehyde (4): White solid, mp: 190 - 192 °C. 1 HNMR(600MHz,CD 3 OD)δ9.35(d,J=13.8Hz,1H),7.02(d,J=4.2Hz,1H),6.86(d,J=8.4Hz,2H),6.71(d,J=8.4Hz,2H),6.14(d,J=4.2Hz,1H),5.56(s,2H),2.24(s,3H). 13 C NMR(150MHz,CD 3 OD)δ178.7,156.4,142.0,131.5,128.5,127.3(2C),125.9,114.9(2C),110.4(2C),10.8.HRMS(ESI)calcd.for[C 13 H 13 NO 2 +Na] + 238.0844,found238.0845.

[0060] 1-(1-(4-Hydroxybenzyl)-1H-pyrrol-2-yl)ethan-1-one (5): White solid, mp: 190 - 192 °C. 1 H NMR(600MHz,CD 3 OD)δ7.16 - 7.13(m,1H),7.11(d,J=1.2Hz,1H),6.98(d,J=8.4Hz,2H),6.70(d,J=8.4Hz,2H),6.22 - 6.18(m,1H),5.48(s,2H),2.41(s,3H). 13 C NMR(150MHz,CD 3 OD)δ190.4,157.7,132.5,131.0,130.7,129.6(2C),122.8,116.1(2C),109.6,52.8,27.1.HRMS(ESI)calcd.for[C13 H 13 NO 2 +Na] + 238.0844, found 238.0846.

[0061] 4 - ((2 - Acetyl - 1H - pyrrol - 1 - yl)methyl)benzoic acid (7): White solid, mp: 264 - 266 °C. 1 H NMR (600 MHz, CD 3 OD) δ 7.96 - 7.92 (m, 2H), 7.22 - 7.21 (m, 1H), 7.20 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.29 (dd, J = 3.6, 3.0 Hz, 1H), 5.67 (s, 2H), 2.40 (s, 3H). 13 C NMR (150 MHz, CD 3 OD) δ 190.4, 169.6, 145.6, 133.1, 131.3, 130.9 (2C), 130.8, 127.6 (2C), 122.8, 110.0, 53.2, 27.0. HRMS (ESI) calcd. for [C 14 H 13 NO 3 +Na] + 266.0793, found 266.0795.

[0062] Compound 5 can also be prepared from compound 14:

[0063]

[0064] Compound 14 (2.3 g, 10.0 mmol) was placed in a 100 - mL single - necked flask, 50 mL of dichloromethane was added, and the mixture was stirred. At 0 °C, BBr 3 (1 mol / L, 12.0 mL) was added dropwise. The mixture was stirred at 0 °C for 5 hours, then quenched with ice - water, extracted with dichloromethane, concentrated, and purified by column chromatography. The eluent was petroleum ether / ethyl acetate (v / v = 9:1). Compound 5 (1.72 g, 80%) was obtained. 4. Synthetic routes of target compounds 6, 8 - 14, 21 - 27 (taking 6 as an example)

[0065]

[0066] 2-Acetylpyrrole (1.0 g, 9.0 mmol) was dissolved in 5.0 mL of DMF. At room temperature, NaH (60%, 0.5 g, 12.5 mmol) was added. After stirring for 20 minutes, a solution of methyl 4-(bromomethyl)benzoate (2.0 g, 9.0 mmol, dissolved in 5.0 mL of DMF) was added dropwise. After the addition, the mixture was stirred at room temperature for 2 hours. 5.0 mL of methanol was added to quench the reaction, and then the mixture was extracted with ethyl acetate and water (100 mL, v / v = 1:1). The organic solvent layer was separated, concentrated, and the residue was purified by silica gel column chromatography to obtain 6 (1.9 g, 80.0%). The eluent was petroleum ether / ethyl acetate (v / v = 10:1). The physicochemical data of the compound are as follows:

[0067] Methyl 4-((2-acetyl-1H-pyrrol-1-yl)methyl)benzoate (6): White solid, mp: 264 - 266 °C. 1 H NMR (600 MHz, CDCl 3 ) δ 7.98 (d, J = 8.2 Hz, 2H), 7.13 (t, J = 11.1 Hz, 2H), 7.07 - 7.02 (m, 1H), 6.95 (s, 1H), 6.29 - 6.22 (m, 1H), 5.64 (s, 2H), 3.91 (s, 3H), 2.42 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 188.4, 166.8, 143.6, 130.6, 130.3, 129.9 (2C), 129.2, 126.7 (2C), 120.6, 108.8, 52.4, 52.1, 27.2. HRMS (ESI) calcd. for [C 15 H 15 NO 3 +Na] + 280.0950, found 280.0951.

[0068] 1-(1-(4-Chlorobenzyl)-1H-pyrrol-2-yl)ethan-1-one (8): White solid, mp: 170 - 172 °C. 1 H NMR (600 MHz, CDCl 3 ) δ 7.29 - 7.26 (m, 2H), 7.06 (d, J = 8.4 Hz, 2H), 7.03 (dd, J = 4.2, 1.8 Hz, 1H), 6.94 - 6.91 (m, 1H), 6.23 (dd, J = 4.2, 2.4 Hz, 1H), 5.55 (s, 2H), 2.43 (s, 3H).13 C NMR (150 MHz, CDCl 3 ) δ 188.4, 136.8, 133.2, 130.4, 130.2, 128.7 (2C), 128.4 (2C), 120.6, 108.7, 52.0, 27.3. HRMS (ESI) calcd. for [C 13 H 12 ClNO + Na] + 256.0505, found 256.0507.

[0069] 1-(1-(4-Bromobenzyl)-1H-pyrrol-2-yl)ethan-1-one (9): White solid, mp: 264 - 266 °C. 1 H NMR (600 MHz, CDCl 3 ) δ 7.43 (d, J = 8.4 Hz, 2H), 7.03 (dd, J = 4.2, 1.8 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 6.94 - 6.92 (m, 1H), 6.23 (dd, J = 4.2, 3.0 Hz, 1H), 5.54 (s, 2H), 2.43 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 188.4, 137.4, 131.7 (2C), 130.4, 130.2, 128.7 (2C), 121.3, 120.6, 108.8, 52.1, 27.3. HRMS (ESI) calcd. for [C 13 H 12 BrNO + Na] + 300.0000, found 300.0002.

[0070] 1-(1-(4-Iodobenzyl)-1H-pyrrol-2-yl)ethan-1-one (10): White solid, mp: 170 - 172 °C. 1 H NMR (600 MHz, CDCl 3 ) δ 7.63 (d, J = 8.4 Hz, 2H), 7.03 (dd, J = 4.2, 1.8 Hz, 1H), 6.92 (d, J = 1.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.23 (dd, J = 4.2, 4.2 Hz, 1H), 5.53 (s, 2H), 2.43 (s, 3H). 13 C NMR (150 MHz, CDCl 3)δ188.4,138.1,137.6(2C),130.4,130.2,129.0(2C),120.6,108.8,92.9,52.2,27.3.HRMS(ESI)calcd.for[C 13 H 12 INO+Na] + 347.9861,found347.9865.

[0071] 1-(1-(4-Fluorobenzyl)-1H-pyrrol-2-yl)ethan-1-one(11):Colorless oil. 1 HNMR(600 MHz,CDCl 3 )δ7.14 - 7.10(m,2H),7.03(dd,J=4.2,1.8 Hz,1H),7.01 - 6.97(m,2H),6.94 - 6.92(m,1H),6.22(dd,J=4.2,4.2 Hz,1H),5.56(s,2H),2.44(s,3H). 13 C NMR(150MHz,CDCl 3 )δ188.5,162.0,134.1,130.3,130.2,128.9,128.8,120.6,115.5,115.4,108.7,51.9,27.3.HRMS(ESI)calcd.for[C 13 H 12 FNO+Na] + 240.0801,found 240.0807.

[0072] 1-(1-(4-Methylbenzyl)-1H-pyrrol-2-yl)ethan-1-one(12):Colorless oil. 1 HNMR(600 MHz,CDCl 3 )δ7.13(d,J=7.8 Hz,2H),7.05(d,J=7.8 Hz,2H),7.02(dd,J=4.2,1.8 Hz,1H),6.91(d,J=1.8Hz,1H),6.20(dd,J=4.2,4.2 Hz,1H),5.56(s,2H),2.44(s,3H),2.33(s,3H). 13 C NMR(150 MHz,CDCl 3)δ188.4,137.1,135.2,130.3,129.3(2C),129.1,127.2(2C),120.4,108.4,52.4,27.4,21.1.HRMS(ESI)calcd.for[C 14 H 15 NO+Na] + 236.1051,found 236.1057.

[0073] 1-(1-Benzyl-1H-pyrrol-2-yl)ethan-1-one(13):Colorless oil. 1 H NMR(600MHz,CDCl 3 )δ7.33(t,J=7.5 Hz,2H),7.27(t,J=6.7 Hz,1H),7.15(d,J=7.4 Hz,2H),7.05(dd,J=4.0,1.6 Hz,1H),6.95-6.92(m,1H),6.23(dd,J=3.9,2.6 Hz,1H),5.62(s,2H),2.45(s,3H). 13 C NMR(150 MHz,CDCl 3 )δ188.4,138.3,130.5,130.4,128.6(2C),127.4,127.1(2C),120.4,108.6,52.6,27.4.HRMS(ESI)calcd.for[C 13 H 13 NO+Na] + 222.0895,found222.0895.

[0074] 1-(1-(4-Methoxybenzyl)-1H-pyrrol-2-yl)ethan-1-one(14):Colorlessoil. 1 H NMR(600 MHz,CDCl 3 )δ7.13(d,J=8.6 Hz,2H),7.02(dd,J=4.0,1.6 Hz,1H),6.92-6.90(m,1H),6.86(d,J=8.7 Hz,2H),6.19(dd,J=4.0,2.6 Hz,1H),5.53(s,2H),3.79(s,3H),2.44(s,3H). 13 C NMR(150MHz,CDCl 3)δ188.4,159.0,130.3,130.2,128.7(3C),120.5,114.0(2C),108.4,55.3,52.1,27.4.HRMS(ESI)calcd.for[C 14 H 15 NO 2 +Na] + 252.1000,found252.1002.

[0075] 1-(4-Fluorobenzyl)-2-methyl-1H-pyrrole(21):Colorless oil. 1 H NMR(600MHz,CDCl 3 )δ7.02(dt,J=13.9,8.4 Hz,4H),6.66(s,1H),6.16(s,1H),5.99(s,1H),5.03(s,2H),2.18(s,3H). 13 C NMR(150 MHz,CDCl 3 )δ163.0(C-F),161.4(C-F),134.3,128.7,128.1(2C),120.8,115.6(2C),107.5,107.4,49.8,12.1.HRMS(ESI)calcd.for[C 12 H 12 FN+Na] + 212.0851,found 212.0852.

[0076] 1-(4-Chlorobenzyl)-2-methyl-1H-pyrrole(22):Colorless oil. 1 H NMR(600MHz,CDCl 3 )δ7.40(d,J=8.4 Hz,2H),7.05(d,J=8.4 Hz,2H),6.77-6.73(m,1H),6.29-6.25(m,1H),6.10(dd,J=9.4,8.6 Hz,1H),5.09(s,2H),2.27(s,3H). 13 C NMR(150 MHz,CDCl 3 )δ137.2,133.2,129.0(2C),128.7,127.9(2C),120.9,107.6,107.6,49.9,12.1.HRMS(ESI)calcd.for[C 12 H12 ClN+Na] + 228.0556, found 228.0559.

[0077] 1-(4-Bromobenzyl)-2-methyl-1H-pyrrole(23): Colorless oil. 1 H NMR(600MHz, CDCl 3 )δ7.50(d, J=8.4Hz, 2H), 6.94(d, J=8.4Hz, 2H), 6.71 - 6.69(m, 1H), 6.22 - 6.20(m, 1H), 6.06 - 6.04(m, 1H), 5.05(s, 2H), 2.22(s, 3H). 13 C NMR(150MHz, CDCl 3 )δ137.6, 131.9(2C), 128.7, 128.2(2C), 121.3, 120.9, 107.6, 107.5, 49.9, 12.1. HRMS(ESI) calcd. for [C 12 H 12 BrN+Na] + 272.0051, found 272.0056.

[0078] 1-(4-Iodobenzyl)-2-methyl-1H-pyrrole(24): Colorless oil. 1 H NMR(600MHz, CDCl 3 )δ7.70(d, J=8.3Hz, 2H), 6.81(d, J=8.1Hz, 2H), 6.70 - 6.67(m, 1H), 6.20(t, J=3.1Hz, 1H), 6.04(s, 1H), 5.03(s, 2H), 2.21(s, 3H). 13 C NMR(150MHz, CDCl 3 )δ138.3, 137.9(2C), 128.7, 128.4(2C), 120.9, 107.6, 107.5, 92.8, 50.0, 12.1. HRMS(ESI) calcd. for [C 12 H 12 IN+Na] + 319.9912, found 319.9917.

[0079] 2-Methyl-1-(4-methylbenzyl)-1H-pyrrole(25):Colorless oil. 1 H NMR(600MHz,CDCl 3 )δ7.26(d,J=7.9Hz,2H),7.05(d,J=7.9Hz,2H),6.76(s,1H),6.25(d,J=2.3Hz,1H),6.09(d,J=2.5Hz,1H),5.11(s,2H),2.46(s,3H),2.29(s,3H). 13 C NMR(150MHz,CDCl 3 )δ137.1,135.5,129.5(2C),128.8,126.5(2C),120.9,107.2,107.1,50.3 21.2,12.1.HRMS(ESI)calcd.for[C 13 H 15 N+Na] + 208.1102,found 208.1104.

[0080] 1-Benzyl-2-methyl-1H-pyrrole(26):Colorless oil. 1 H NMR(600MHz,CDCl 3 )δ7.43(dd,J=8.0,7.0Hz,2H),7.39-7.34(m,1H),7.12(d,J=7.4Hz,2H),6.76(s,1H),6.25(s,1H),6.08(s,1H),5.14(s,2H),2.27(d,J=4.9Hz,3H). 13 C NMR(150MHz,CDCl 3 )δ138.6,128.9,128.8(2C),127.4,126.5(2C),121.0,107.3,107.2,50.5,12.1.HRMS(ESI)calcd.for[C 12 H 13 N+Na] + 194.0946,found 194.0948.

[0081] Methyl 4-((2-methyl-1H-pyrrol-1-yl)methyl)benzoate(27):Colorlessoil. 1 H NMR(600MHz,CDCl3 ) δ 8.05 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.72 - 6.64 (m, 1H), 6.22 - 6.15 (m, 1H), 6.04 (ddd, J = 3.3, 1.7, 0.8 Hz, 1H), 5.12 (s, 2H), 3.95 (s, 3H), 2.18 (s, 3H). 13 C NMR (150 MHz, CDCl 3 ) δ 166.8, 143.8, 130.1 (2C), 129.3, 128.7, 126.3 (2C), 120.9, 107.6, 107.6, 52.2, 50.2, 12.0. HRMS (ESI) calcd. for [C 14 H 15 NO 2 +Na] + 252.1000, found 252.1008.

[0082] Example 2: Antibacterial and anti - inflammatory activity results of 34 kinds of benzylpyrrole compounds

[0083] 1. Antibacterial activity test

[0084] Test strains:

[0085] Bacteria Methicillin resistant Staphylococcus aureus (MRSA, ATCC 43300). The bacterial strain was inoculated and frozen in Tryptic Soy broth or agar (TSB; Tryptic Soy Agar, TSA; BD Biosciences, San Jose, CA, USA) medium. Fungi Candida albicans (ATCC 10231), Cryptococcus neoformans (ATCC 66031), Trichophyton mentagrophytes (ATCC 9533), Trichophyton rubrum (ATCC 28188). C. albicans was inoculated in YM liquid medium (Yeast malt, YM; Yeast malt agar, YMA; BD Biosciences, San Jose, CA, USA). C. neoformans, T. mentagrophytes, T. rubrum were inoculated in Sabouraud dextrose broth medium (Sabourauddextrose broth, SDB; Sabouraud dextrose agar, SDA; BD Biosciences, San Jose, CA, USA). All strains were inoculated in the corresponding liquid medium and stored frozen at -80 °C in a refrigerator for future use. Before each experiment, the strains were re-inoculated on solid agar culture plates and passaged at least once to revive the strains.

[0086] Experimental instruments and consumables: Microbial constant temperature incubator (IRM, Germany), ultra-low temperature refrigerator (-80 °C, Panasonic, Japan), laminar flow hood (ESCO, ESCO Singapore), tabletop constant temperature shaker (HNY-1008, Tianjin Ono Instruments Co., Ltd.), Eppendorf tabletop centrifuge (Eppendorf, Germany), Epoch microplate spectrophotometer (biotech, USA), bacterial culture plates (Guangzhou Jet Biotechnology Co., Ltd.).

[0087] Reagents: Tryptic Soy broth or agar (Tryptic Soy broth, TSB; Tryptic Soy Agar, TSA; BD Biosciences, San Jose, CA, USA), YM liquid medium (Yeast malt, YM; Yeast malt agar, YMA; BD Biosciences, San Jose, CA, USA), Sabouraud dextrose broth (Sabouraud dextrose broth, SDB; Sabouraud dextrose agar, SDA; BD Biosciences, San Jose, CA, USA).

[0088] Experimental method: Use a sterile inoculation loop to pick several monoclonal Candida albicans or Cryptococcus neoformans colonies from the agar culture plate, inoculate them into a sterile broth medium, and culture overnight at 30 °C and 200 rpm for activation. Take the bacterial liquid in the logarithmic growth phase and dilute it to an OD600 value between 0.03 and 0.06. Take the diluted bacterial liquid and add 195 μL per well to a 96-well plate, then add 5 μL of the drug and culture for 24 hours (Cryptococcus neoformans is cultured for 48 hours), and read the value at the OD600 wavelength.

[0089]

[0090] Table 1. Test results of the antibacterial activity (inhibition rate) of the compounds (concentration: 250 μM)

[0091]

[0092]

[0093] Note: The activity test is the average of the results of three experiments.

[0094] Experimental results and discussion:

[0095] The compounds of the present invention all have antifungal or antibacterial activities to varying degrees. Among them, in the test results of the activities of the four fungi, compounds 1, 5, 6, 13-16, 27, 28, and 30 have better antifungal activities, and compounds 16 and 30 have the strongest activities, indicating that when the para-position of the benzene ring is a halogen atom in the derivatives of benzylpyrrole compounds, the antibacterial activity is stronger, and the activity of chlorine atoms is the best; the acetyl group at the 2-position of the pyrrole ring is beneficial to enhancing the activity.

[0096] In the antibacterial activity test of bacteria, compounds 15 - 20, 34 showed good antibacterial activity, and compounds 16 and 18 had the strongest activity. This indicates that among the derivatives of benzylpyrrole compounds, when the para - position of the benzene ring is an electron - donating group and it is conducive to the formation of hydrogen bonds, the antibacterial activity can be significantly improved; the aldehyde group at the 2 - position and the enol structure at the 5 - position of the pyrrole ring are beneficial to the enhancement of activity.

[0097] 2. Anti - inflammatory activity results

[0098] Experimental method: The double - antibody sandwich enzyme - linked immunosorbent assay (ELISA) was used. Taking interleukin 6 (IL - 6) as an example, into the micro - wells pre - coated with the capture antibody of mouse interleukin 6 (IL - 6), the sample, standard product, biotin - labeled detection antibody, and HRP enzyme conjugate were added in sequence. After incubation and washing in the middle, the substrate TMB was used for color development. TMB was converted into blue under the catalysis of peroxidase (HRP) and then into the final yellow under the action of acid. The depth of the color was positively correlated with the mouse interleukin 6 (IL - 6) in the sample. The absorbance (OD value) was measured at a wavelength of 450 nm with an enzyme - label, and the sample concentration was calculated. The inhibition rate of each compound on IL - 6 was calculated.

[0099] Using the same method, the inhibition rates of each compound on IL - 1β and TNF - α were measured and calculated. The results are shown in Table 2.

[0100] Cell inhibition rate (%)=(Average OD value of the drug - free cell control well - OD value of the well with the drug) / Average OD value of the drug - free cell control well×100%.

[0101] Table 2. Effects of compounds on cellular inflammatory factors (inhibition rate) (20 μM)

[0102]

[0103]

[0104] The activity test was obtained from the average of the results of three experiments.

[0105] Experimental results and discussion:

[0106] Compounds all had inhibitory effects on cellular inflammatory factors to varying degrees. In the data for the cytokine IL - 1β, compounds 17, 20 had the strongest activity. Combining with the activity of compounds 15 - 20, it shows that among the derivatives of benzylpyrrole compounds, when the para - position of the benzene ring is an electron - donating group and it is conducive to the formation of hydrogen bonds, the anti - inflammatory activity can be significantly improved; the aldehyde group at the 2 - position and the enol structure at the 5 - position of the pyrrole ring are beneficial to the enhancement of activity.

[0107] Among the data for cytokine IL-6, compounds 5, 17, and 20 showed the strongest activity. Considering the activities of compounds 4 - 12, 15 - 20, it indicates that in the derivatives of benzylpyrrole compounds, when the para-position of the benzene ring is an electron-donating group and it is conducive to the formation of hydrogen bonds, the anti-inflammatory activity can be significantly enhanced; the aldehyde group at the 2-position and the enol structure at the 5-position of the pyrrole ring are beneficial to the enhancement of activity.

[0108] Among the data for cytokine TNF-α, compounds 4 and 5 showed the strongest activity. It indicates that in the derivatives of benzylpyrrole compounds, when the para-position of the benzene ring is a hydroxyl group, and the 2-position of the pyrrole ring is an acetyl group or the 2-position is an aldehyde group and the 5-position is a methyl group, the anti-inflammatory activity can be significantly enhanced;

[0109] It should be noted that compounds 4 and 5 simultaneously showed significant inhibitory effects on all three cytokines.

Claims

1. Benzylpyrrole compounds represented by general formula I or pharmaceutically acceptable salts thereof: Wherein, R 1 is H, OH, halogen, unsubstituted or C 1 -C 6 alkyl-substituted C 1- C 6 ester group, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 carboxyl group, C 1 -C 6 alkyl-substituted sulfonic acid group, phenyl-substituted sulfonic acid group, and the phenyl may be substituted by one or more C 1 -C 6 alkyl; R 2 is H, C 1 -C 6 alkyl acyl, C 1 -C 6 alkyl, -(CO)R; R is H, OH, C 1 -C 6 alkyl; R 3 is H, a formyl group, C 1 -C 6 alkyl group.

2. Benzylpyrrole compounds represented by general formula I of claim 1 or pharmaceutically acceptable salts thereof: Wherein, R 1 is H, OH, halogen, unsubstituted or C 1 -C 4 alkyl-substituted C 1- C 4 ester group, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 carboxyl, C 1 -C 4 alkyl-substituted sulfonic group, phenyl-substituted sulfonic group, the phenyl being substituted by one or more C 1 -C 4 alkyl; R 2 is H, C 1 -C 4 alkyl acyl, C 1 -C 4 alkyl, -(CO)R; R is H, OH, C 1 -C 4 alkyl; R 3 is H, a formyl group, C 1 -C 4 alkyl group.

3. Benzylpyrrole compounds represented by general formula I of claim 1 or pharmaceutically acceptable salts thereof:

4. Preparation method of the compound according to claim 3, Characterized in that, Compound 1-5 is obtained by reacting benzyl bromide of p-toluenesulfonate with pyrrole, or obtained through further hydrolysis reaction; Compounds 6-14, 21-27 are obtained by reacting halogenobenzyl bromide with pyrrole derivatives; Compounds 15-20, 28-3 are obtained by acylation on the parent structure of compounds 6-14, 21-27.

5. Pharmaceutical composition, comprising the benzylpyrrole compound or its pharmaceutically acceptable salt according to any one of claims 1-3 and a pharmaceutically acceptable carrier or excipient.

6. Use of the benzylpyrrole compound or its pharmaceutically acceptable salt according to any one of claims 1-3 or the pharmaceutical composition according to claim 5 in the preparation of antibacterial drugs.

7. The use according to claim 6, Characterized in that, The antibacterial drug is an antibacterial drug or an antifungal drug.

8. The use according to claim 7, Characterized in that, The bacterium is methicillin-resistant Staphylococcus aureus, and the fungi are Trichophyton rubrum, Trichophyton mentagrophytes, Candida albicans or Cryptococcus neoformans.

9. Use of the benzylpyrrole compound or its pharmaceutically acceptable salt according to any one of claims 1-3 or the pharmaceutical composition according to claim 5 in the preparation of anti-inflammatory drugs.

10. The use according to claim 9, Characterized in that, It exerts an anti-inflammatory effect by inhibiting inflammatory factors such as interleukin-6, interleukin-1β, α-tumor necrosis factor, etc.

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