CN112194631B - Schiff base bridged sulfaimidazole compound and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the technical field of chemical synthesis, and discloses a Schiff base bridged sulfaimidazole compound, and a preparation method and application thereof. A schiff base-bridged sulphamidazol compound of general formula I or a pharmaceutically acceptable salt thereof:

wherein R is ¹ ，R ² Each independently represents hydrogen, alkyl or an alkyl derivative, alkenyl or an alkenyl derivative, alkynyl or an alkynyl derivative, aryl, cyano, acyl, ester group or carboxyl; r ³ Represents hydrogen or acetyl. The compound or the pharmaceutically acceptable salt thereof has good inhibitory activity effect on gram-positive bacteria and gram-negative bacteria, particularly has good antibacterial effect on methicillin-resistant staphylococcus aureus, and is not easy to generate drug resistance; the compound or the pharmaceutically acceptable salt thereof has the advantages of simple raw materials, low price, easy obtainment and short synthetic route, and has important significance in the application of resisting infection.

Description

Schiff base bridged sulfaimidazole compound and preparation method and application thereof

Technical Field

The invention belongs to the technical field of chemical synthesis, and particularly relates to a Schiff base bridged sulfaimidazole compound, and a preparation method and application thereof.

Background

The acceleration of resistance to pathogens is a major challenge facing global public health today due to abuse of antibacterial drugs (e.g., antibiotics). Over the past few decades, antibiotic abuse has led to a dramatic increase in the variety of drug-resistant pathogenic bacteria. Therefore, the design and synthesis of novel antibacterial agents with drug-resistant strains become extremely urgent, and the development of antibacterial agents with high efficiency, low toxicity and low susceptibility to pathogenic bacteria resistance has become a subject of intense research.

The high morbidity and mortality caused by pathogenic infections has posed a serious threat to human health and survival. Sulfonamides, as a first class of artificially synthesized antibacterial agents, have attracted a high degree of attention in the fields of biology and medicine for further development thereof. To date, a large number of sulfonamides and sulfonamides having various pharmacological activities have been widely used in clinical applications, such as amprenavir and tipranavir for antiviral, methamphetamine for antiparasitic, acetazolamide and methazolamide for carbonic anhydrase inhibitors, glibenclamide and chlorpropamide tablets for lowering blood glucose, and the like. In particular, in the antibacterial aspect, many sulfadiazine antibacterial drugs, such as sulfamylone, sulfadimethoxine, sulfapyridine, sulfathiazole, sulfamethoxazole, sulfamethazine, etc., have played an important role in the treatment of infectious diseases. However, pathogen resistance and drug side effects from abuse of antibacterial drugs limit their clinical use. Therefore, research on novel sulfonamides having low toxicity and high activity and being less likely to cause drug resistance against pathogenic bacteria has been the focus of research.

The imidazole ring is an important five-membered aromatic heterocycle, contains abundant electrons, is easy to interact with an active target in a biological cell through a plurality of non-covalent bonds such as coordination bonds, hydrogen bonds, pi-pi accumulation and the like, and improves the physicochemical and pharmacokinetic properties of drug molecules, thereby improving the bioavailability and the drug selectivity. The structure endows the imidazole compounds with a plurality of special properties, has wide application prospect in a plurality of fields such as chemistry, pharmacy, biology, material science and the like, and shows great development value. In recent years, imidazole compounds have been studied abnormally actively and are clinically useful for the treatment of bacterial infections, such as antibacterial metronidazole and ornidazole.

Therefore, it is necessary to provide an antibacterial compound or a drug which has low toxicity and high activity and is less likely to cause drug resistance against germs.

Disclosure of Invention

The present invention is directed to solving at least one of the problems of the prior art described above. To this end, it is an object of the present invention to provide schiff-base-bridged sulfaimidazole compounds or pharmaceutically acceptable salts thereof. The second purpose of the invention is to provide a preparation method of Schiff base bridged sulfaimidazole compound or pharmaceutically acceptable salt thereof. The invention also aims to provide a medicine containing the Schiff base bridged sulfaimidazole compound or the pharmaceutically acceptable salt thereof. The fourth purpose of the invention is to provide the application of the Schiff base bridged sulfaimidazole compound or the pharmaceutically acceptable salt thereof in preparing antibacterial drugs.

In order to achieve the purpose, the invention provides the following technical scheme:

according to one of its objects, the present invention provides a schiff-base-bridged sulphamidazole compound represented by general formula I:

wherein R is ¹ ，R ² Each independently represents hydrogen, alkyl or an alkyl derivative, alkenyl or an alkenyl derivative, alkynyl or an alkynyl derivative, aryl, cyano, acyl, ester group or carboxyl; r ³ Represents hydrogen or acetyl.

Preferably, the carbon number of the alkyl group is 1 to 12; more preferably, the carbon number of the alkyl group is 1 to 9; more preferably, the number of carbons of the alkyl group is 1, 3, 5, 7, 9.

Preferably, the alkyl derivative comprises methoxy, ethoxy, propoxy or hydroxyethyl.

Preferably, the carbon number of the alkenyl group is 3 to 11; more preferably, the carbon number of the alkyl group is 3 to 9; more preferably, the number of carbons of the alkyl group is 3, 4, or 5.

Preferably, the carbon number of the alkynyl is 3 to 11; more preferably, the carbon number of the alkyl group is 3 to 9; more preferably, the number of carbon atoms of the alkyl group is 3, 4, or 5.

Preferably, the aryl group comprises benzyl or halobenzyl; further preferably, the halobenzyl group is a benzyl group containing F or Cl.

Preferably, the pharmaceutically acceptable salt of the schiff base-bridged sulfimidazole compound shown in the general formula I is hydrochloride, nitrate, acetate or sulfate.

Further preferred, the schiff-base-bridged sulphamidazol compound has the structural formula of any one of:

wherein n-Bu represents n-butyl;

the compounds represented by the numbers I-1 to I-17 and II-1 to II-17 are Schiff base bridged sulphamidezole compounds represented by the general formula I, the compounds represented by the I-1 can be converted into the compounds represented by the II-1 through hydrolysis reaction, and the compounds represented by the numbers I-2 to I-17 and II-2 to II-17 can also be converted through hydrolysis reaction.

According to a second object of the present invention, there is provided a process for preparing the above schiff-base-bridged sulfamimidazole compound or a pharmaceutically acceptable salt thereof, comprising the steps of:

and adding the intermediate III, the intermediate IV and an acid catalyst into a solvent for reaction to obtain the Schiff base bridged sulphamidezole compound shown in the general formula I.

Preferably, the process for the preparation of said intermediate III is described in the references "B.Wang, Z.C.Yan, L.Y.Liu et al.TBN-mediated regio-and stereoselective sulfonation&oximation(oximosulfonylation)of alkynes with sulfonyl hydrazines in EtOH/H ₂ O.Green chem.2019,21,205-212. "the preparation method disclosed.

Preferably, the preparation method of the intermediate III comprises the following steps: acetanilide is used as an initial raw material to perform sulfonation reaction with chlorosulfonic acid to obtain p-acetamino benzene sulfonyl chloride, and the product is prepared through amination reaction; further preferably, the temperature of the sulfonation reaction is 0-60 ℃; the solvent used in the amination reaction is tetrahydrofuran.

Preferably, the intermediate IV is prepared by the method disclosed in "H.H.Gong, K.Baathula, J.S.Lv et al.Synthesis and biological evaluation of Schiff base-linked imide nanoparticles and novel potential anti-MRSA agents. Med.Chem.Commun.2016,7,924-931".

Preferably, containing different substituents (R) ² ) The preparation method of the intermediate IV comprises the following steps: the compound is prepared by taking 2-butyl-4-chloro-1-H-imidazole-5-aldehyde as a starting material and carrying out substitution reaction with a substance containing halogenated alkyl, alkenyl, alkynyl or halobenzyl in an acetonitrile solution at the temperature of 45-50 ℃; further preferably, the molar ratio of the compound 2-butyl-4-chloro-1-H-imidazole-5-aldehyde to the substance containing a haloalkyl, alkenyl, alkynyl or halobenzyl group is 1 (0.5-2); more preferably, the molar ratio is 1: 1.

Preferably, the solvent is an alcohol; further preferably, the solvent is ethanol.

Preferably, the acid catalyst is an organic acid; further preferably, the organic acid is acetic acid, formic acid or propionic acid; more preferably, the organic acid is acetic acid.

Preferably, the molar ratio of the intermediate III to the intermediate IV is 1 (0.5-2); further preferably, the molar ratio of intermediate III to intermediate IV is 1: 1.

Preferably, the amount of the acid catalyst used is small, and for example, the mass of the acid catalyst may be 0.05% or more of the mass of the intermediate III.

Preferably, the reaction temperature is 70-90 ℃, and the reaction time is 5-12 hours; further preferably, the reaction temperature is 80-85 ℃ and the reaction time is 6-10 hours.

Preferably, the conversion process between the compounds of numbers I-1 to I-17 and II-1 to II-17 is:

and (3) carrying out hydrolysis reaction on the Schiff base bridged sulphamidezole compounds shown in the numbers I-1 to I-17 to prepare the Schiff base bridged sulphamidezole compounds shown in the numbers II-1 to II-17.

Preferably, the temperature of the hydrolysis reaction is 75-85 ℃; further preferably, the temperature of the hydrolysis reaction is 80 ℃.

Further preferably, the hydrolysis reaction is carried out under the conditions of hydrochloric acid as a catalyst and ethanol reflux.

Preferably, the preparation method of the pharmaceutically acceptable salt of the Schiff base bridged sulfaimidazole compound shown in the general formula I comprises the following steps:

dissolving the Schiff base bridged sulfaimidazole compound shown in the general formula I in an organic solvent, and adding a pharmaceutically acceptable acid for reaction to obtain the pharmaceutically acceptable salt of the Schiff base bridged sulfaimidazole compound shown in the general formula I.

Preferably, the organic solvent is at least one of chloroform, acetone, acetonitrile, diethyl ether or tetrahydrofuran.

Preferably, the pharmaceutically acceptable acid is hydrochloric acid, nitric acid, acetic acid or sulfuric acid.

According to a third object of the invention, the invention provides a medicament, which comprises a Schiff base bridged sulfaimidazole compound shown in the general formula I or a pharmaceutically acceptable salt thereof, and an auxiliary material.

Preferably, the auxiliary materials are pharmaceutically acceptable auxiliary materials; further preferably, the auxiliary material is selected from at least one of a filler, a lubricant, a disintegrant, a binder or a glidant.

Preferably, the filler comprises lactose, sucrose, starch, microcrystalline cellulose or powdered cellulose.

Preferably, the lubricant comprises stearic acid, magnesium stearate, calcium stearate or zinc stearate.

Preferably, the disintegrant comprises sodium starch glycolate, sodium carboxymethyl starch, or low-substituted hydroxypropyl cellulose.

Preferably, the binder comprises hydroxypropylmethylcellulose or polyethylene glycol.

Preferably, the glidant comprises talcum powder, anhydrous colloidal silicon dioxide or micropowder silica gel.

Preferably, the dosage form of the medicament is any dosage form; preferably, the medicament is in the form of one of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments, aerosols, powders, dropping pills, solutions, suspensions, emulsions, gels, films, transdermal patches, controlled release preparations or nano preparations.

According to the fourth object of the present invention, the present invention provides the use of the above schiff base-bridged sulfimidazole compound or a pharmaceutically acceptable salt thereof for the preparation of antibacterial agents.

Preferably, the bacteria are gram bacteria, including gram positive and/or gram negative bacteria.

Preferably, the gram-positive bacteria include methicillin-resistant staphylococcus aureus, enterococcus faecalis, staphylococcus aureus ATCC25923, or staphylococcus aureus ATCC 29213.

Preferably, the gram-negative bacteria include klebsiella pneumoniae, escherichia coli, pseudomonas aeruginosa ATCC27853, escherichia coli ATCC25922, or acinetobacter baumannii.

Compared with the prior art, the invention has the following beneficial effects:

(1) the invention utilizes the drug design split principle, imidazole compounds containing different substituents are bridged on a sulfonamide structure through Schiff bases, a series of Schiff base bridged sulfaimidazole compounds with novel structures are designed and synthesized, and the compounds are found to have good inhibitory activity effects on gram-positive bacteria and gram-negative bacteria through in vitro antimicrobial activity detection, so that the compounds or pharmaceutically acceptable salts thereof can be used for preparing antibacterial drugs, thereby providing more efficient and safe candidate drugs for clinical antimicrobial treatment, and being beneficial to solving clinical treatment problems of increasingly serious drug resistance, stubborn germs, newly appeared harmful microorganisms and the like.

(2) The compound I-8 has a good antibacterial effect on methicillin-resistant staphylococcus aureus, and the compound I-8 is used for carrying out a methicillin-resistant staphylococcus aureus test to find that the methicillin-resistant staphylococcus aureus is not easy to generate drug resistance, and the antibacterial effect is superior to that of drugs norfloxacin and sulfathiazole on methicillin-resistant staphylococcus aureus.

(3) The compound or the pharmaceutically acceptable salt thereof has the advantages of simple raw material preparation, low price, easy obtainment and short synthetic route, and has important significance in the application of resisting infection.

Drawings

FIG. 1 is a graph comparing the resistance of compound I-8 to the reference drugs norfloxacin and sulfathiazole to methicillin-resistant Staphylococcus aureus (MRSA).

Detailed Description

In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples are given for illustration. It should be noted that the following examples are not intended to limit the scope of the claimed invention.

The starting materials, reagents or apparatuses used in the following examples are conventionally commercially available or can be obtained by conventionally known methods, unless otherwise specified.

Example 1: preparation of intermediate III

Preparation of intermediate III references B.Wang, Z.C.Yan, L.Y.Liu et al.TBN-mediated regio-and stereoselective sulfonation&oximation(oximosulfonylation)of alkynes with sulfonyl hydrazines in EtOH/H ₂ O.Green chem.2019,21,205-212. "the preparation method disclosed.

Example 2: preparation of intermediate IV

Preparation of intermediate IV is described in the references "H.H.Gong, K.Baathula, J.S.Lv et al Synthesis and biological evaluation of Schiff base-linked imidazole naphthalimides as novel reactive anti-MRSA agents, Med.chem.Commun.2016,7, 924-931".

Example 3: preparation of Compound I-1

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1-hydro-imidazole-5-aldehyde (0.93g, 5.00mmol) (i.e., R) ² Intermediate IV) as hydrogen, 5 drops of acetic acid and 25mL of ethanol as solvent are added into a 50mL round-bottom flask and reacted at 80 ℃ and stirred for 6 h. After completion of the reaction by thin layer chromatography, the reaction mixture was cooled to room temperature, ethanol was evaporated under reduced pressure and then subjected to silica gel column chromatography and dried to obtain compound I-1(1.43g) in 71.8% yield.

The compound I-1 is a white solid, and the melting point is 134-136 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:12.58(s,1H,Im-NH),11.22(s,1H,SO ₂ NH),10.34(s,1H,NHCOCH ₃ ),7.85-7.81(m,2H,Ph-2,6-H),7.78-7.74(m,2H,Ph-3,5-H),7.73(s,1H,NCH),2.59(t,J＝7.6Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.07(s,3H,COCH ₃ ),1.62-1.53(m,2H,CH ₂ CH ₂ CH ₃ ),1.27(m,J＝14.9,7.4Hz,2H,CH ₂ CH ₃ ),0.87(t,J＝7.4Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.5,151.3,143.8,135.8,132.9,131.1,128.9,120.5,118.9,30.2,27.8,24.6,22.1,14.0ppm。

example 4: preparation of Compound II-1

Compound I-1(0.39g,1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl and reflux at 80 ℃ for 8 h. And (3) tracking by using the thin-layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-1(0.21g), wherein the yield is 60.1%.

The compound II-1 is brown solid with a melting point of 105-107 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.00(s,1H,SO ₂ NH),7.74(s,1H,NCH),7.53(d,J＝8.8Hz,2H,Ph-2,6-H),6.62(d,J＝8.8Hz,2H,Ph-3,5-H),2.61(t,J＝7.6Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),1.58(m,J＝15.0,7.6Hz,2H,CH ₂ CH ₂ CH ₃ ),1.27(m,J＝14.8,7.4Hz,2H,CH ₂ CH ₃ ),0.87(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:153.0,151.0,134.9,130.2,129.7,124.6,120.9,113.4,30.2,27.6,22.1,14.0ppm。

example 5: preparation of Compound I-2

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1-methyl-1-hydro-imidazole-5-carboxaldehyde (1.00g,5.00mmol) (i.e., R) ² Intermediate IV) which is methyl, 5 drops of acetic acid and 25mL of ethanol are used as solvents and added into a 50mL round-bottom flask for reaction at 80 ℃, the mixture is stirred for 6 hours, thin layer chromatography is used for tracking till the reaction is finished, the mixture is cooled to room temperature, the ethanol is evaporated under reduced pressure and then is separated and dried by silica gel column chromatography, and the compound I-2(1.49g) is obtained, and the yield is 72.5%.

The compound I-2 is a white solid with a melting point of 184-186 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.25(s,1H,SO ₂ NH),10.35(s,1H,NHCOCH ₃ ),7.80(s,1H,NCH),7.78(s,4H,Ph-2,3,5,6-H),3.62(s,3H,Im-N-CH ₃ ),2.62–2.57(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.08(s,3H,COCH ₃ ),1.56(m,J＝15.2,7.7Hz,2H,CH ₂ CH ₂ CH ₃ ),1.36–1.27(m,2H,CH ₂ CH ₃ ),0.88(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.5,151.6,143.9,136.7,132.6,131.8,129.0,120.6,119.0,33.2,29.0,26.1,24.6,22.2,14.1ppm。

example 6: preparation of Compound II-2

Compound I-2(0.41g,1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl and refluxing at 80 ℃ for 8h, followed by TLC until the reaction was complete, heating was stopped, and cooling to room temperature was carried out. And (3) removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-2(0.22g), wherein the yield is 60.6%.

The compound II-2 is a white solid with a melting point of 115-117 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:10.91(s,1H,SO ₂ NH),7.77(s,1H,NCH),7.46(d,J＝8.7Hz,2H,Ph-2,6-H),6.62–6.58(m,2H,Ph-3,5-H),6.05(s,2H,NH ₂ ),3.64(s,3H,Im-N-CH ₃ ),2.64–2.59(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),1.58(m,J＝15.3,7.5Hz,2H,CH ₂ CH ₂ CH ₃ ),1.33(m,J＝14.9,7.4Hz,2H,CH ₂ CH ₃ ),0.89(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:153.6,151.4,135.8,131.4,129.8,123.8,120.8,113.0,33.2,29.0,26.1,22.2,14.1ppm。

example 7: preparation of Compound I-3

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1-propyl-1-hydro-imidazole-5-aldehyde (1.14g,5.00mmol) (i.e., R) ² Intermediate IV) is propyl, 5 drops of acetic acid and 25mL of ethanol are used as solvents and added into a 50mL round-bottom flask for reaction at 80 ℃, the mixture is stirred for 6 hours, and thin layer chromatography is carried out until the reaction is finishedAfter cooling to room temperature, ethanol was evaporated under reduced pressure and then subjected to silica gel column chromatography and dried, compound I-3(1.54g) was obtained in 70.2% yield.

The compound I-3 is a white solid, and the melting point is 174-176 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.34(s,1H,SO ₂ NH),10.36(s,1H,NHCOCH ₃ ),7.81(s,1H,NCH),7.80–7.74(m,4H,Ph-2,3,5,6-H),4.02–3.96(m,2H,Im-N-CH ₂ ),2.63–2.58(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.08(s,3H,COCH ₃ ),1.59(m,J＝15.2,7.6Hz,2H,Im-N-CH ₂ CH ₂ ),1.41(m,J＝15.1,7.5Hz,2H,CH ₂ CH ₂ CH ₃ ),1.32(m,J＝14.9,7.4Hz,2H,CH ₂ CH ₃ ),0.88(t,J＝7.3Hz,3H,Im-N-CH ₂ CH ₂ CH ₃ ),0.75(t,J＝7.4Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.6,151.3,143.9,136.3,132.8,132.5,128.9,120.0,119.0,46.7,29.5,25.9,24.6,23.4,22.2,14.1,10.9ppm。

example 8: preparation of Compound II-3

Adding the compound I-3(0.44g,1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-3(0.22g), wherein the yield is 54.5%.

The compound II-3 is a white solid, and the melting point is 135-137 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:10.99(s,1H,SO ₂ NH),7.78(s,1H,NCH),7.46–7.43(m,2H,Ph-2,6-H),6.61(d,J＝8.8Hz,2H,Ph-3,5-H),6.06(s,2H,NH ₂ ),4.04–3.99(m,2H,Im-N-CH ₂ ),2.64–2.59(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),1.63–1.58(m,2H,Im-N-CH ₂ CH ₂ ),1.46(m,J＝15.1,7.5Hz,2H,CH ₂ CH ₂ CH ₃ ),1.33(m,J＝14.9,7.4Hz,2H,CH ₂ CH ₃ ),0.89(t,J＝7.3Hz,3H,Im-N-CH ₂ CH ₂ CH ₃ ),0.79(t,J＝7.4Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:153.6,151.1,135.5,132.1,129.6,124.0,120.1,113.0,46.7,29.5,25.9,23.5,22.2,14.2,11.0ppm。

example 9: preparation of Compound I-4

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1-pentyl-1-hydro-imidazole-5-aldehyde (1.28g,5.00mmol) (i.e. R) ² Pentyl intermediate IV), 5 drops of acetic acid and 25mL of ethanol as solvents were added to a 50mL round-bottomed flask at 80 ℃, reacted, stirred for 6h, followed by thin layer chromatography until the reaction was complete, cooled to room temperature, evaporated under reduced pressure and then chromatographed on a silica gel column, oven dried to give compound I-4(1.67g) in 71.4% yield.

The compound I-4 is a white solid, and the melting point is 196-198 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.36(s,1H,SO ₂ NH),10.36(s,1H,NHCOCH ₃ ),7.81(s,1H,NCH),7.79(d,J＝9.0Hz,2H,Ph-2,6-H),7.75(d,J＝9.0Hz,2H,Ph-3,5-H),4.04(t,J＝7.4Hz,2H,Im-N-CH ₂ ),2.59(t,J＝7.6Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.08(s,3H,COCH ₃ ),1.64–1.55(m,2H,Im-N-CH ₂ CH ₂ ),1.35(m,J＝22.4,7.5Hz,4H,(CH ₂ ) ₂ CH ₃ ),1.19–1.11(m,2H,Im-N-CH ₂ CH ₂ CH ₂ ),1.10–1.01(m,2H,Im-N-CH ₂ CH ₂ CH ₂ CH ₂ ),0.88(t,J＝7.3Hz,3H,Im-N-(CH ₂ ) ₄ CH ₃ ),0.80(t,J＝7.2Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.5,151.3,143.9,136.3,132.8,132.5,128.8,119.9,119.0,45.3,29.9,29.4,28.3,25.9,24.6,22.3,22.2,14.3,14.1ppm。

example 10: preparation of Compound II-4

Compound I-4(0.47g,1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl and refluxing at 80 ℃ for 8h, followed by TLC until the reaction was complete, heating was stopped, and cooling to room temperature was carried out. And (3) removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-4(0.26g), wherein the yield is 60.2%.

The compound II-4 is gray solid with a melting point of 146-148 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.01(s,1H,SO ₂ NH),7.78(s,1H,NCH),7.44(d,J＝8.7Hz,2H,Ph-2,6-H),6.60(d,J＝8.7Hz,2H,Ph-3,5-H),4.09–4.03(m,2H,Im-N-CH ₂ ),2.60(t,J＝7.6Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),1.61(m,J＝15.2,7.5Hz,2H,Im-N-CH ₂ CH ₂ ),1.48–1.40(m,2H,CH ₂ CH ₂ CH ₃ ),1.33(m,J＝14.9,7.4Hz,2H,CH ₂ CH ₃ ),1.22(m,J＝13.6,6.8Hz,2H,Im-N-CH ₂ CH ₂ CH ₂ ),1.17–1.09(m,2H,Im-N-CH ₂ CH ₂ CH ₂ CH ₂ ),0.89(t,J＝7.4Hz,3H,Im-N-(CH ₂ ) ₄ CH ₃ ),0.85(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:153.6,151.0,135.4,132.0,129.6,124.0,120.1,113.0,45.3,30.0,29.5,28.4,25.9,22.3,14.3,14.1ppm。

example 11: preparation of Compound I-5

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1-heptyl-1-hydro-imidazole-5-aldehyde (1.42g,5.00mmol) (i.e., R) ² Intermediate IV) of heptyl group, 5 drops of acetic acid and 25mL of ethanol are added into a 50mL round-bottom flask as a solvent, the mixture is stirred for 6 hours, thin layer chromatography is carried out until the reaction is finished, the mixture is cooled to room temperature, the ethanol is evaporated under reduced pressure and then is separated by silica gel column chromatography and dried, and the compound I-5(1.7g) is obtained, and the yield is 70.9%.

The compound I-5 is a white solid, and the melting point is 174-176 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.36(s,1H,SO ₂ NH),10.36(s,1H,NHCOCH ₃ ),7.81(s,1H,NCH),7.81–7.77(m,2H,Ph-2,6-H),7.77–7.73(m,2H,Ph-3,5-H),4.04(t,J＝7.4Hz,2H,Im-N-CH ₂ ),2.62–2.57(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.07(s,3H,COCH ₃ ),1.64–1.55(m,2H,Im-N-CH ₂ CH ₂ ),1.38–1.29(m,4H,(CH ₂ ) ₂ CH ₃ ),1.24(m,J＝13.8,7.0Hz,2H,Im-N-CH ₂ CH ₂ CH ₂ ),1.17–1.10(m,4H,Im-N-CH ₂ CH ₂ CH ₂ (CH ₂ ) ₂ ),1.09–1.02(m,2H,Im-N-CH ₂ (CH ₂ ) ₄ CH ₂ ),0.88(t,J＝6.6Hz,3H,Im-N-(CH ₂ ) ₆ CH ₃ ),0.85(t,J＝6.5Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.5,151.3,143.9,136.3,132.8,132.5,128.8,119.9,118.9,45.4,31.7,30.2,29.5,28.9,26.1,25.9,24.6,22.5,22.2,14.4,14.1ppm。

example 12: preparation of Compound II-5

Compound I-5(0.49g,1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl and refluxing at 80 ℃ for 8h, followed by TLC until the reaction was complete, heating was stopped, and cooling to room temperature was carried out. And (3) removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-5(0.27g), wherein the yield is 60.6%.

The compound II-5 is a yellow solid, and the melting point is 71-73 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.00(s,1H,SO ₂ NH),7.78(s,1H,NCH),7.44(d,J＝8.8Hz,2H,Ph-2,6-H),6.62–6.58(m,2H,Ph-3,5-H),4.08–4.02(m,2H,Im-N-CH ₂ ),2.63–2.58(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),1.61(m,J＝15.2,7.5Hz,2H,Im-N-CH ₂ CH ₂ ),1.49–1.40(m,2H,CH ₂ CH ₂ CH ₃ ),1.36–1.25(m,4H,CH ₂ CH ₃ ,Im-N-CH ₂ CH ₂ CH ₂ ),1.20(m,J＝13.0,10.4Hz,6H,Im-N-CH ₂ CH ₂ CH ₂ (CH ₂ ) ₃ ),0.90(d,J＝7.4Hz,3H,Im-N-(CH ₂ ) ₆ CH ₃ ),0.86(d,J＝7.2Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:153.6,151.0,135.4,132.0,129.6,124.0,120.1,113.0,45.4,31.7,30.2,29.5,28.8,26.2,25.9,22.5,22.2,14.4,14.1ppm。

example 13: preparation of Compound I-6

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1-nonyl-1-hydro-imidazole-5-carboxaldehyde (1.57g,5.00mmol) (i.e., R) ² Nonyl intermediate IV), 5 drops of acetic acid and 25mL of ethanol are added as solvents to a 50mL round-bottom flask at 80 ℃, reacted and stirred for 6h, followed by thin layer chromatography until the reaction is finished, cooled to room temperature, and subjected to reduced pressure evaporation of ethanol, separation by silica gel column chromatography and drying to obtain compound I-6(1.80g) with a yield of 68.8%.

The compound I-6 is a white solid, and the melting point is 149-151 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.36(s,1H,SO ₂ NH),10.35(s,1H,NHCOCH ₃ ),7.81(s,1H,NCH),7.79(d,J＝9.0Hz,2H,Ph-2,6-H),7.74(d,J＝9.0Hz,2H,Ph-3,5-H),4.04(t,J＝7.4Hz,2H,Im-N-CH ₂ ),2.59(t,J＝7.6Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.07(s,3H,COCH ₃ ),1.64–1.55(m,2H,Im-N-CH ₂ CH ₂ ),1.38–1.29(m,4H,(CH ₂ ) ₂ CH ₃ ),1.23(d,J＝12.0Hz,6H,Im-N-CH ₂ CH ₂ (CH ₂ ) ₃ ),1.14(d,J＝3.3Hz,4H,Im-N-CH ₂ (CH ₂ ) ₄ (CH ₂ ) ₂ ),1.06(m,J＝8.3,5.6Hz,2H,Im-N-CH ₂ (CH ₂ ) ₆ CH ₂ ),0.88(t,J＝5.6Hz,3H,Im-N-(CH ₂ ) ₈ CH ₃ ),0.85(t,J＝5.2Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.4,151.3,143.9,136.3,132.8,132.5,128.8,119.9,118.9,45.4,31.7,30.2,29.4,29.2,26.1,25.9,24.6,22.6,22.2,14.4,14.1ppm。

example 14: preparation of Compound II-6

Adding the compound I-6(0.52g,1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-6(0.26g) with the yield of 53.2%.

The compound II-6 is orange liquid; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.01(s,1H,SO ₂ NH),7.78(s,1H,NCH),7.44(d,J＝8.8Hz,2H,Ph-2,6-H),6.60(d,J＝8.8Hz,2H,Ph-3,5-H),4.07–4.02(m,2H,Im-N-CH ₂ ),2.63–2.58(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),1.59(m,J＝15.2,7.7Hz,2H,Im-N-CH ₂ CH ₂ ),1.49–1.41(m,2H,CH ₂ CH ₂ CH ₃ ),1.33(m,J＝15.0,7.5Hz,2H,CH ₂ CH ₃ ),1.24(s,12H,Im-N-CH ₂ CH ₂ (CH ₂ ) ₆ ),0.89(t,J＝5.7Hz,3H,Im-N-(CH ₂ ) ₈ CH ₃ ),0.85(m,J＝6.5,3.9Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:153.5,151.0,135.4,132.0,129.6,124.1,120.2,113.1,45.4,31.7,30.2,29.4,29.1,26.2,25.9,22.6,22.2,14.4,14.1ppm。

example 15: preparation of Compound I-7

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1-allyl-1-hydro-imidazole-5-aldehyde (1.13g,5.00mmol) (i.e., R) ² Intermediate IV) which is allyl, 5 drops of acetic acid and 25mL of ethanol are used as solvents and added into a 50mL round-bottom flask at 80 ℃, reacted and stirred for 6h, the reaction is tracked by thin layer chromatography until the reaction is finished, the mixture is cooled to room temperature, and after ethanol is evaporated under reduced pressure, the mixture is separated by silica gel column chromatography and dried to obtain compound I-7(1.43g) with the yield of 65.3%.

The compound I-7 is yellow solid with the melting point of 173-175 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.30(s,1H,SO ₂ NH),10.35(s,1H,NHCOCH ₃ ),7.78(s,1H,NCH),7.74(t,J＝7.4Hz,4H,Ph-2,3,5,6-H),5.74(m,J＝10.1,4.8Hz,1H,CHCH ₂ ),5.00(m,J＝10.4,1.1Hz,1H,CHCH ₂ ),4.80(d,J＝4.7Hz,2H,Im-N-CH ₂ ),4.71(m,J＝17.2,1.1Hz,1H,CHCH ₂ ),2.57(t,J＝7.6Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.08(s,3H,COCH ₃ ),1.63–1.55(m,2H,CH ₂ CH ₂ CH ₃ ),1.31(m,J＝14.9,7.4Hz,2H,CH ₂ CH ₃ ),0.87(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.5,151.6,143.9,136.1,133.6,132.6,132.3,129.0,120.1,119.1,116.5,47.3,29.2,25.8,24.6,22.2,14.1ppm。

example 16: preparation of Compound II-7

Adding the compound I-7(0.44g,1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-7(0.22g) with the yield of 55.7%.

The compound II-7 is yellow solid, and the melting point is 134-136 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:10.96(s,1H,SO ₂ NH),7.76(s,1H,NCH),7.43(d,J＝8.7Hz,2H,Ph-2,6-H),6.60(d,J＝8.8Hz,2H,Ph-3,5-H),6.05(s,2H,NH ₂ ),5.78(m,J＝15.4,10.2,5.0Hz,1H,CHCH ₂ ),5.05(m,J＝10.4,1.1Hz,1H,CHCH ₂ ),4.79(m,J＝20.7,3.2Hz,3H,CHCH ₂ ,Im-N-CH ₂ ),2.60–2.55(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),1.60(m,J＝15.2,7.5Hz,2H,CH ₂ CH ₂ CH ₃ ),1.32(m,J＝14.6,7.4Hz,2H,CH ₂ CH ₃ ),0.87(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:153.6,151.4,135.3,133.7,131.8,129.8,123.8,120.2,116.7,113.0,47.3,29.3,25.9,22.2,14.1ppm。

example 17: preparation of Compound I-8

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1-enylbutyl-1-hydro-imidazole-5-carboxaldehyde (1.20g,5.00mmol) (i.e. R) ² Intermediate IV) of allyl butyl, 5 drops of acetic acid and 25mL of ethanol are used as solvents and added into a 50mL round-bottom flask at 80 ℃, reacted and stirred for 6 hours, and thin layer chromatography is carried out until the reaction is completedAfter completion, the reaction mixture was cooled to room temperature, ethanol was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography and dried to obtain compound I-8(1.63g) in a yield of 72.4%.

The compound I-8 is a white solid, and the melting point is 170-172 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.35(s,1H,SO ₂ NH),10.35(s,1H,NHCOCH ₃ ),7.81(s,1H,NCH),7.79–7.74(m,4H,Ph-2,3,5,6-H),5.67(m,J＝17.2,10.4,6.9Hz,1H,CHCH ₂ ),5.00–4.92(m,2H,CHCH ₂ ),4.10(t,J＝7.2Hz,2H,Im-N-CH ₂ ),2.62–2.56(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.21(m,J＝14.2,7.2Hz,2H,Im-N-CH ₂ CH ₂ ),2.07(s,3H,COCH ₃ ),1.60(m,J＝15.2,7.5Hz,2H,CH ₂ CH ₂ CH ₃ ),1.38–1.27(m,2H,CH ₂ CH ₃ ),0.88(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.5,151.5,143.9,136.4,134.6,132.7,132.6,128.9,119.9,119.0,118.1,44.6,34.2,29.4,26.0,24.6,22.2,14.1ppm。

example 18: preparation of Compound II-8

Adding the compound I-8(0.45g and 1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin-layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-8(0.25g) with the yield of 60.3%.

The compound II-8 is yellow solid with the melting point of 90-92 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.00(s,1H,SO ₂ NH),7.78(s,1H,NCH),7.47–7.43(m,2H,Ph-2,6-H),6.61–6.57(m,2H,Ph-3,5-H),6.06(s,2H,NH ₂ ),5.77–5.65(m,1H,CHCH ₂ ),5.02–4.96(m,2H,CHCH ₂ ),4.15–4.10(m,2H,Im-N-CH ₂ ),2.63–2.58(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.24(m,J＝14.3,7.2Hz,2H,Im-N-CH ₂ CH ₂ ),1.64–1.57(m,2H,CH ₂ CH ₂ CH ₃ ),1.33(m,J＝14.9,7.5Hz,2H,CH ₂ CH ₃ ),0.89(t,J＝7.4Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:153.6,151.2,135.5,134.7,132.1,129.7,123.9,120.1,118.1,113.0,44.6,34.3,29.4,26.0,22.2,14.2ppm。

example 19: preparation of Compound I-9

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1-enepentyl-1-hydro-imidazole-5-aldehyde (1.27g,5.00mmol) (i.e. R) ² Intermediate IV) in the form of an alkenyl group, 5 drops of acetic acid and 25mL of ethanol as solvents were added to a 50mL round-bottomed flask at 80 ℃ to react, stirred for 6 hours, followed by thin layer chromatography until the reaction was completed, cooled to room temperature, evaporated under reduced pressure and subjected to silica gel column chromatography to separate and dry the product, thereby obtaining compound I-9(1.61g) with a yield of 69.2%.

The compound I-9 is a white solid with a melting point of 191-193 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.36(s,1H,SO ₂ NH),10.35(s,1H,NHCOCH ₃ ),7.81(s,1H,NCH),7.80–7.77(m,2H,Ph-2,6-H),7.77–7.74(m,2H,Ph-3,5-H),5.75(m,J＝16.8,10.2,6.4Hz,1H,CHCH ₂ ),5.02–4.94(m,2H,CHCH ₂ ),4.06–4.01(m,2H,Im-N-CH ₂ ),2.62–2.57(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.08(s,3H,COCH ₃ ),1.93(m,J＝14.6,7.0Hz,2H,Im-N-CH ₂ CH ₂ CH ₂ ),1.60(m,J＝15.1,7.4Hz,2H,CH ₂ CH ₂ CH ₂ ),1.50(m,J＝15.0,7.5Hz,2H,CH ₂ CH ₂ CH ₃ ),1.32(m,J＝14.9,7.4Hz,2H,CH ₂ CH ₃ ),0.87(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.5,151.3,143.9,138.0,136.3,132.7,132.6,128.8,120.0,119.0,115.6,45.0,30.3,29.4,29.1,25.9,24.6,22.2,14.1ppm。

example 20: preparation of Compound II-9

Compound I-9(0.47g,1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl and refluxing at 80 ℃ for 8h, followed by TLC until the reaction was complete, heating was stopped, and cooling to room temperature was carried out. And (3) removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, precipitating a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-9(0.23g), wherein the yield is 53.7%.

The compound II-9 is yellow solid with a melting point of 101-103 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:7.80(s,1H,NCH),7.45(d,J＝8.7Hz,2H,Ph-2,6-H),6.60(d,J＝8.7Hz,2H,Ph-3,5-H),6.07(s,2H,NH ₂ ),5.80(m,J＝16.8,10.3,6.5Hz,1H,CHCH ₂ ),5.06–4.97(m,2H,CHCH ₂ ),4.09–4.02(m,2H,Im-N-CH ₂ ),2.60(t,J＝7.6Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),1.98(m,J＝14.3,7.0Hz,2H,Im-N-CH ₂ CH ₂ CH ₂ ),1.59(m,J＝14.8,7.3Hz,4H,Im-N-CH ₂ CH ₂ CH ₂ ,CH ₂ CH ₂ CH ₃ ),1.34(m,J＝14.8,7.4Hz,2H,CH ₂ CH ₃ ),0.88(t,J＝7.4Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:153.6,151.0,138.1,135.3,132.0,129.6,124.0,120.2,115.7,113.0,45.0,30.4,29.5,29.2,25.9,22.2,14.1ppm。

example 21: preparation of Compound I-10

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1-propargyl-1-hydro-imidazole-5-aldehyde (1.12g,5.00mmol) (i.e., R) ² Intermediate IV) which is propargyl, 5 drops of acetic acid and 25mL of ethanol are added as solvents into a 50mL round-bottom flask at 80 ℃, reacted and stirred for 6h, the reaction is followed by thin layer chromatography until the reaction is finished, the mixture is cooled to room temperature, and after ethanol is evaporated under reduced pressure, the mixture is separated by silica gel column chromatography and dried to obtain compound I-10(1.59g) with the yield of 72.9%.

The compound I-10 is a yellow solid with a melting point of 117-119 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.37(s,1H,SO ₂ NH),10.33(s,1H,NHCOCH ₃ ),7.82–7.79(m,3H,NCH,Ph-2,6-H),7.78–7.75(m,2H,Ph-3,5-H),5.12(d,J＝2.3Hz,2H,CH ₂ CCH),3.32(t,J＝2.4Hz,1H,CH ₂ CCH),2.68(t,J＝7.6Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.08(s,3H,COCH ₃ ),1.65(m,J＝15.2,7.5Hz,2H,CH ₂ CH ₂ CH ₃ ),1.39–1.29(m,2H,CH ₂ CH ₃ ),0.89(t,J＝7.4Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.5,151.6,143.9,136.1,132.6,132.2,128.9,119.9,119.2,78.5,76.0,35.0,29.0,26.0,24.6,22.2,14.1ppm。

example 22: preparation of Compound II-10

Compound I-10(0.44g,1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl followed by reflux at 80 ℃ for 8h, TLC followed to completion of the reaction, heating was stopped, and cooling to room temperature was allowed to occur. And (3) removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-10(0.22g), wherein the yield is 56.3%.

The compound II-10 is gray solid, and the melting point is 88-90 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:7.66(s,1H,NCH),7.44(d,J＝8.7Hz,2H,Ph-2,6-H),6.56(d,J＝8.7Hz,2H,Ph-3,5-H),5.78(s,2H,NH ₂ ),5.21(d,J＝2.2Hz,2H,CH ₂ CCH),3.32(t,J＝2.4Hz,1H,CH ₂ CCH),2.69–2.65(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),1.67–1.61(m,2H,CH ₂ CH ₂ CH ₃ ),1.35(d,J＝7.4Hz,2H,CH ₂ CH ₃ ),0.90(s,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:149.3,147.5,136.5,129.4,127.1,125.6,113.1,112.7,78.9,75.8,29.5,29.0,26.0,22.2,14.1ppm。

example 23: preparation of Compound I-11

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1-alkynylbutyl-1-hydro-imidazole-5-carboxaldehyde (1.19g,5.00mmol) (i.e., R) ² Intermediate IV) of acetylenic butyl, 5 drops of acetic acid and 25mL of ethanol were added as solvents to a 50mL round-bottomed flask at 80 ℃ for reaction, stirred for 6h, followed by thin layer chromatography until the reaction was completed, cooled to room temperature, evaporated under reduced pressure and then chromatographed on silica gel column, and dried to obtain compound I-11(1.42g) with a yield of 63.2%.

The compound I-11 is a white solid, and the melting point is 196-198 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.36(s,1H,SO ₂ NH),10.37(s,1H,NHCOCH ₃ ),7.80(d,J＝2.0Hz,5H,NCH,Ph-2,3,5,6-H),4.15(t,J＝6.8Hz,2H,Im-N-CH ₂ ),2.92(t,J＝2.6Hz,1H,CCH),2.72–2.67(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.42(m,J＝6.7,2.5Hz,2H,Im-N-CH ₂ CH ₂ ),2.08(s,3H,COCH ₃ ),1.62(m,J＝15.3,7.5Hz,2H,CH ₂ CH ₂ CH ₃ ),1.39–1.29(m,2H,CH ₂ CH ₃ ),0.89(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.6,152.1,144.0,136.2,132.8,132.5,129.1,119.9,119.0,80.9,73.9,43.8,29.2,26.2,24.6,22.2,19.4,14.2ppm。

example 24: preparation of Compound II-11

Adding the compound I-11(0.45g and 1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin-layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-11(0.20g) with the yield of 50.2%.

The compound II-11 is a yellow solid with a melting point of 154-156 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.03(s,1H,SO ₂ NH),7.77(s,1H,NCH),7.51–7.47(m,2H,Ph-2,6-H),6.64–6.60(m,2H,Ph-3,5-H),6.08(s,2H,NH ₂ ),4.17(t,J＝6.8Hz,2H,Im-N-CH ₂ ),2.91(t,J＝2.6Hz,1H,CCH),2.72–2.68(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.44(m,J＝6.7,2.5Hz,2H,Im-N-CH ₂ CH ₂ ),1.65–1.60(m,2H,CH ₂ CH ₂ CH ₃ ),1.35(m,J＝14.9,7.4Hz,2H,CH ₂ CH ₃ ),0.90(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:153.7,151.9,135.3,132.3,129.9,123.7,120.1,113.1,81.0,73.9,43.8,29.2,26.2,22.2,19.4,14.2ppm。

example 25: preparation of Compound I-12

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1-alkynylpentyl-1-hydro-imidazole-5-aldehyde (1.26g,5.00mmol) (i.e., R) ² Intermediate IV) of propargyl, 5 drops of acetic acid and 25mL of ethanol are used as solvents and added into a 50mL round-bottom flask at 80 ℃, reacted and stirred for 6h, and a thin layer is formedAfter the completion of the reaction by tracing with a chromatograph, it was cooled to room temperature, and subjected to separation by silica gel column chromatography after evaporation of ethanol under reduced pressure, followed by drying to obtain Compound I-12(1.08g) in 46.5% yield.

The compound I-12 is a white solid with a melting point of 188-190 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.37(s,1H,SO ₂ NH),10.35(s,1H,NHCOCH ₃ ),7.81(s,1H,NCH),7.79–7.75(m,4H,Ph-2,3,5,6-H),4.10–4.03(m,2H,Im-N-CH ₂ ),2.85(t,J＝2.6Hz,1H,CCH),2.66–2.60(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.11(m,J＝7.2,2.6Hz,2H,Im-N-CH ₂ CH ₂ CH ₂ ),2.08(s,3H,COCH ₃ ),1.66–1.56(m,4H,Im-N-CH ₂ CH ₂ CH ₂ ,CH ₂ CH ₂ CH ₃ ),1.33(m,J＝14.9,7.5Hz,2H,CH ₂ CH ₃ ),0.89(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.5,151.4,143.9,136.2,132.7,132.6,128.9,120.1,119.1,83.7,72.1,44.6,29.5,29.0,25.9,24.6,22.2,15.4,14.1ppm。

example 26: preparation of Compound II-12

Adding the compound I-12(0.46g,1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin-layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-12(0.21g) with the yield of 49.1%.

The compound II-12 is yellow liquid; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.08(s,1H,SO ₂ NH),7.80(s,1H,NCH),7.48–7.45(m,2H,Ph-2,6-H),6.66–6.63(m,2H,Ph-3,5-H),4.10–4.06(m,2H,Im-N-CH ₂ ),2.86(t,J＝2.6Hz,1H,CCH),2.66–2.62(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.14(m,J＝7.1,2.5Hz,2H,Im-N-CH ₂ CH ₂ CH ₂ ),1.67–1.59(m,4H,Im-N-CH ₂ CH ₂ CH ₂ ,CH ₂ CH ₂ CH ₃ ),1.34(m,J＝14.9,7.4Hz,2H,CH ₂ CH ₃ ),0.90(t,J＝4.6Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:153.2,151.1,135.4,132.0,129.6,124.2,120.2,113.4,83.7,72.2,44.5,29.5,29.0,25.9,22.2,15.4,14.1ppm。

example 27: preparation of Compound I-13

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1- (2-fluorobenzyl) -1-hydro-imidazole-5-aldehyde (1.47g,5.00mmol) (i.e. R) ² Intermediate IV) of 2-fluorobenzyl, 5 drops of acetic acid and 25mL of ethanol are added as solvents to a 50mL round-bottom flask at 80 ℃ for reaction, the mixture is stirred for 6 hours, thin layer chromatography is carried out until the reaction is finished, the mixture is cooled to room temperature, the ethanol is evaporated under reduced pressure and then is separated by silica gel column chromatography and dried, and the compound I-13(1.92g) is obtained, and the yield is 76.2%.

The compound I-13 is a white solid with a melting point of 200-202 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.35(s,1H,SO ₂ NH),10.28(s,1H,NHCOCH ₃ ),7.84(s,1H,NCH),7.60(d,J＝8.9Hz,2H,Ph-2,6-H),7.51(d,J＝8.9Hz,2H,Ph-3,5-H),7.06(t,J＝8.8Hz,2H,Im-N-CH ₂ -Ph-3,4-H),6.91(m,J＝8.6,5.5Hz,2H,Im-N-CH ₂ -Ph-5,6-H),5.47(s,2H,Im-N-CH ₂ ),2.52(d,J＝7.9Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.09(s,3H,COCH ₃ ),1.48–1.40(m,2H,CH ₂ CH ₂ CH ₃ ),1.22(m,J＝14.7,7.3Hz,2H,CH ₂ CH ₃ ),0.77(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.4,163.0,160.6,152.0,143.8,136.3,133.2,132.7,132.4,128.6,128.5,120.3,118.9,115.9,115.7,47.4,29.1,26.1,24.6,22.0,14.0ppm。

example 28: preparation of Compound II-13

Adding the compound I-13(0.46g,1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-13(0.28g) with the yield of 61.2%.

The compound II-13 is a white solid with a melting point of 137-139 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:7.68(s,1H,NCH),7.20(d,J＝8.7Hz,2H,Ph-2,6-H),7.12–7.07(m,2H,Im-N-CH ₂ -Ph-3,4-H),7.03–6.98(m,2H,Im-N-CH ₂ -Ph-5,6-H),6.43(d,J＝8.6Hz,2H,Ph-3,5-H),5.76(s,2H,NH ₂ ),5.53(s,2H,Im-N-CH ₂ ),2.52(d,J＝8.0Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),1.46(m,J＝15.2,7.5Hz,2H,CH ₂ CH ₂ CH ₃ ),1.23(m,J＝14.9,7.4Hz,2H,CH ₂ CH ₃ ),0.81–0.77(m,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:163.0,160.6,152.4,150.4,133.7,129.1,129.0,127.1,121.7,116.0,115.8,115.6,112.8,112.7,47.1,29.3,26.1,22.1,14.0ppm。

example 29: preparation of Compound I-14

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1- (4-fluorobenzyl) -1-hydro-imidazole-5-aldehyde (1.47g,5.00mmol) (i.e. R) ² Intermediate IV) for 4-fluorobenzyl, 5 drops of acetic acid and 25mL of ethanol as solvent were added to 50mLReacting at 80 ℃ in a round-bottomed flask, stirring for 6h, tracking by thin layer chromatography until the reaction is finished, cooling to room temperature, evaporating ethanol under reduced pressure, separating by silica gel column chromatography, and drying to obtain compound I-14(1.90g) with a yield of 75.1%.

The compound I-14 is a white solid with a melting point of 190-192 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.30(s,1H,SO ₂ NH),10.26(s,1H,NHCOCH ₃ ),7.83(s,1H,NCH),7.60–7.56(m,2H,Ph-2,6-H),7.45–7.41(m,2H,Ph-3,5-H),7.33(m,J＝7.4,1.5Hz,1H,Im-N-CH ₂ -Ph-6-H),7.26–7.19(m,1H,Im-N-CH ₂ -Ph-2-H),7.04(m,J＝7.6,1.0Hz,1H,Im-N-CH ₂ -Ph-5-H),6.47(m,J＝7.6,6.6Hz,1H,Im-N-CH ₂ -Ph-3-H),5.56(s,2H,Im-N-CH ₂ ),2.52(m,J＝3.8,1.9Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.09(s,3H,COCH ₃ ),1.46(m,J＝15.3,7.5Hz,2H,CH ₂ CH ₂ CH ₃ ),1.26–1.16(m,2H,CH ₂ CH ₃ ),0.77(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.4,161.0,158.5,152.1,143.7,136.1,132.5,129.8,128.4,127.4,125.2,123.9,120.6,118.9,115.9,42.9,29.0,25.9,24.6,22.0,14.0ppm。

example 30: preparation of Compound II-14

Compound I-14(0.46g,1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl and refluxing at 80 ℃ for 8h, followed by TLC until the reaction was complete, heating was stopped, and cooling to room temperature was carried out. And (3) removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, separating out a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-14(0.28g), wherein the yield is 60.7%.

The compound II-14 is a white solid with a melting point of 122-124 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:7.66(s,1H,NCH),7.34(m,J＝7.4,1.6Hz,1H,Im-N-CH ₂ -Ph-6-H),7.24(m,J＝9.3,6.7,1.0Hz,1H,Im-N-CH ₂ -Ph-2-H),7.14–7.10(m,2H,Ph-2,6-H),7.06(m,J＝7.6,1.1Hz,1H,Im-N-CH ₂ -Ph-5-H),6.58(t,J＝7.1Hz,1H,Im-N-CH ₂ -Ph-3-H),6.38–6.34(m,2H,Ph-3,5-H),5.67(s,2H,NH ₂ ),5.63(d,J＝6.2Hz,2H,Im-N-CH ₂ ),2.49–2.44(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),1.45(m,J＝15.2,7.5Hz,2H,CH ₂ CH ₂ CH ₃ ),1.21(m,J＝14.9,7.4Hz,2H,CH ₂ CH ₃ ),0.77(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:161.0,158.6,152.3,150.6,129.7,128.9,127.8,127.1,125.1,124.5,122.0,115.6,112.8,112.7,42.4,29.1,25.9,22.1,14.0ppm。

example 31: preparation of Compound I-15

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1- (2-chlorobenzyl) -1-hydro-imidazole-5-aldehyde (1.55g,5.00mmol) (i.e., R) ² Intermediate IV) of 2-chlorobenzyl, 5 drops of acetic acid and 25mL of ethanol are added as solvent into a 50mL round-bottom flask at 80 ℃, reacted and stirred for 6h, the reaction is followed by thin layer chromatography, cooled to room temperature, the ethanol is evaporated under reduced pressure and then separated by silica gel column chromatography and dried to obtain compound I-15(1.85g) with 70.9% yield.

The compound I-15 is a white solid with a melting point of 210-212 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.27(s,1H,SO ₂ NH),10.24(s,1H,NHCOCH ₃ ),7.83(s,1H,NCH),7.55(s,1H,Im-N-CH ₂ -Ph-3-H),7.54–7.51(m,2H,Ph-2,6-H),7.37–7.33(m,2H,Ph-3,5-H),7.30(m,J＝7.8,1.3Hz,1H,Im-N-CH ₂ -Ph-4-H),7.18(m,J＝7.6,1.0Hz,1H,Im-N-CH ₂ -Ph-5-H),6.23(d,J＝6.8Hz,1H,Im-N-CH ₂ -Ph-6-H),5.56(s,2H,Im-N-CH ₂ ),2.46(t,J＝7.6Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.09(s,3H,COCH ₃ ),1.50–1.42(m,2H,CH ₂ CH ₂ CH ₃ ),1.25–1.16(m,2H,CH ₂ CH ₃ ),0.75(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.4,152.1,143.6,136.0,134.3,132.6,132.4,131.4,129.9,129.3,128.3,128.0,126.2,120.7,118.8,46.5,28.9,25.8,24.6,22.0,14.0ppm。

example 32: preparation of Compound II-15

Compound I-15(0.52g,1.00mmol) and 12mL of ethanol were added to a 25mL round bottom flask, followed by dropwise addition of 0.5mL concentrated HCl and refluxing at 80 ℃ for 8h, followed by TLC until the reaction was complete, heating was stopped, and cooling to room temperature was carried out. And (3) removing ethanol by rotary evaporation, dropping the system into a saturated sodium bicarbonate solution, precipitating a solid, performing suction filtration, and performing vacuum drying on the collected product to obtain a compound II-15(0.29g) with the yield of 61.1%.

The compound II-15 is yellow solid with the melting point of 176-178 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.06(s,1H,SO ₂ NH),7.84(s,1H,NCH),7.56(m,J＝8.0,1.1Hz,1H,Im-N-CH ₂ -Ph-3-H),7.38–7.33(m,1H,Im-N-CH ₂ -Ph-4-H),7.22(m,J＝7.6,1.1Hz,1H,Im-N-CH ₂ -Ph-5-H),7.14–7.10(m,2H,Ph-2,6-H),6.46(d,J＝8.7Hz,2H,Ph-3,5-H),6.28(d,J＝6.7Hz,1H,Im-N-CH ₂ -Ph-6-H),5.59(s,2H,Im-N-CH ₂ ),2.46(t,J＝7.6Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),1.47(m,J＝15.2,7.5Hz,2H,CH ₂ CH ₂ CH ₃ ),1.21(m,J＝14.9,7.4Hz,2H,CH ₂ CH ₃ ),0.75(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:151.8,135.3,134.4,132.1,131.5,130.2,129.9,129.4,129.2,128.1,126.4,124.8,120.9,113.8,46.5,28.9,25.8,22.0,14.0ppm。

example 33: preparation of Compound I-16

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1- (4-chlorobenzyl) -1-hydro-imidazole-5-aldehyde (1.55g,5.00mmol) (i.e., R) ² Intermediate IV) of 4-chlorobenzyl, 5 drops of acetic acid and 25mL of ethanol as solvents were added to a 50mL round-bottomed flask at 80 ℃ for reaction, stirred for 6 hours, followed by thin layer chromatography until the reaction was completed, cooled to room temperature, evaporated under reduced pressure and then chromatographed on a silica gel column, and dried to obtain compound I-16(1.94g) with a yield of 74.4%.

The compound I-16 is a white solid with a melting point of 208-210 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.35(s,1H,SO ₂ NH),10.28(s,1H,NHCOCH ₃ ),7.83(s,1H,NCH),7.64–7.60(m,2H,Ph-2,6-H),7.53–7.49(m,2H,Ph-3,5-H),7.30–7.26(m,2H,Im-N-CH ₂ -Ph-3,5-H),6.87(d,J＝8.5Hz,2H,Im-N-CH ₂ -Ph-2,6-H),5.47(s,2H,Im-N-CH ₂ ),2.53–2.51(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.09(s,3H,COCH ₃ ),1.45(m,J＝15.3,7.5Hz,2H,CH ₂ CH ₂ CH ₃ ),1.26–1.17(m,2H,CH ₂ CH ₃ ),0.77(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.4,152.0,143.8,136.2,136.0,132.7,132.4,129.0,128.6,128.3,120.4,118.9,47.5,29.1,26.0,24.7,22.0,14.0ppm。

example 34: preparation of Compound II-16

Adding the compound I-16(0.52g,1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-16(0.30g) with the yield of 62.5%. .

The compound II-16 is a white solid with a melting point of 133-135 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:7.59(s,1H,NCH),7.33–7.30(m,2H,Ph-2,6-H),7.18–7.15(m,2H,Im-N-CH ₂ -Ph-3,5-H),6.96(d,J＝8.5Hz,2H,Im-N-CH ₂ -Ph-2,6-H),6.40(d,J＝8.7Hz,2H,Ph-3,5-H),5.61(s,2H,NH ₂ ),5.54(s,2H,Im-N-CH ₂ ),2.48(d,J＝7.6Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),1.48–1.44(m,2H,CH ₂ CH ₂ CH ₃ ),1.23(d,J＝7.4Hz,2H,CH ₂ CH ₃ ),0.80–0.78(m,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:151.5,149.3,136.9,132.2,129.1,128.8,128.7,127.1,126.1,122.7,112.7,47.1,29.3,26.1,22.1,14.1ppm。

example 35: preparation of Compound I-17

Intermediate III (1.15g,5.00mmol), 2-butyl-4-chloro-1- (2, 4-dichlorobenzyl) -1-hydro-imidazole-5-aldehyde (1.72g,5.00mmol) (i.e., R) ² Intermediate IV) of 2, 4-dichlorobenzyl, 5 drops of acetic acid and 25mL of ethanol as solvents were added to a 50mL round-bottomed flask at 80 ℃ for reaction, stirred for 6 hours, followed by thin layer chromatography until the reaction was completed, cooled to room temperature, evaporated under reduced pressure and subjected to silica gel column chromatography for separation and drying to obtain compound I-17(2.05g) with a yield of 73.8%.

The compound I-17 is a white solid with a melting point of 228-; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:11.34(s,1H,SO ₂ NH),10.27(s,1H,NHCOCH ₃ ),7.82(s,1H,NCH),7.63–7.60(m,2H,Ph-2,6-H),7.59(s,1H,Im-N-CH ₂ -Ph-3-H),7.43–7.39(m,2H,Ph-3,5-H),7.21(m,J＝8.4,2.1Hz,1H,Im-N-CH ₂ -Ph-5-H),6.19(d,J＝8.4Hz,1H,Im-N-CH ₂ -Ph-6-H),5.48(s,2H,Im-N-CH ₂ ),2.46(t,J＝7.6Hz,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),2.09(s,3H,COCH ₃ ),1.50–1.42(m,2H,CH ₂ CH ₂ CH ₃ ),1.26–1.16(m,2H,CH ₂ CH ₃ ),0.76(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:169.4,152.1,143.7,135.8,133.5,133.0,132.7,132.3,129.4,128.4,128.1,127.6,120.6,118.8,46.2,29.0,25.8,24.7,22.0,14.0ppm。

example 36: preparation of Compound II-17

Adding the compound I-17(0.56g and 1.00mmol) and 12mL of ethanol into a 25mL round-bottom flask, then dropwise adding 0.5mL of concentrated hydrochloric acid, refluxing at 80 ℃ for 8h, tracking by thin layer chromatography until the reaction is finished, stopping heating, cooling to room temperature, removing ethanol by rotary evaporation, dropwise adding the system into a saturated sodium bicarbonate solution, precipitating a solid, carrying out suction filtration, and carrying out vacuum drying on the collected product to obtain the compound II-17(0.32g) with the yield of 61.5%.

The compound II-17 is a white solid with a melting point of 148-150 ℃; the characterization results of the hydrogen spectrum and the carbon spectrum of the nuclear magnetic resonance are as follows: ¹ H NMR(600MHz,DMSO-d ₆ )δ:7.68(d,J＝2.1Hz,1H,Im-N-CH ₂ -Ph-3-H),7.61(s,1H,NCH),7.28–7.26(m,1H,Im-N-CH ₂ -Ph-5-H),7.05(d,J＝8.6Hz,2H,Ph-2,6-H),6.46–6.43(m,1H,Im-N-CH ₂ -Ph-6-H),6.36–6.33(m,2H,Ph-3,5-H),5.60(s,2H,NH ₂ ),5.57(d,J＝5.4Hz,2H,Im-N-CH ₂ ),2.42–2.37(m,2H,CH ₂ CH ₂ CH ₂ CH ₃ ),1.46–1.41(m,2H,CH ₂ CH ₂ CH ₃ ),1.23–1.19(m,2H,CH ₂ CH ₃ ),0.76(t,J＝7.3Hz,3H,CH ₂ CH ₃ )ppm； ¹³ C NMR(150MHz,DMSO-d ₆ )δ:149.3,136.7,134.3,134.1,133.5,133.3,132.9,132.4,129.2,128.6,128.1,127.1,112.7,45.7,29.1,25.8,22.0,14.0ppm。

example 37: preparation of tablets containing Compound I-2

Prescription: the tablet is prepared from compound I-210 g, lactose 187g, corn starch 50g, magnesium stearate 3.0g, and ethanol solution with volume percentage concentration of 70% in a proper amount, and is prepared into 1000 tablets.

The preparation method comprises the following steps: drying corn starch at 105 deg.C for 5 hr; mixing compound I-2 with lactose and corn starch, making soft mass with 70% ethanol solution, sieving to obtain wet granule, adding magnesium stearate, and tabletting; each tablet weighs 250mg, and the content of active ingredients is 10 mg.

Example 38: preparation of capsules containing Compound I-8

Prescription: compound I-825 g, modified starch (120 meshes) 12.5g, microcrystalline cellulose (100 meshes) 7.5g, low-substituted hydroxypropyl cellulose (100 meshes) 2.5g, talcum powder (100 meshes) 2g, sweetening agent 1.25g, orange essence 0.25g, proper amount of pigment and water, and the capsule is prepared into 1000 capsules.

The preparation method comprises the following steps: micronizing compound I-8 into superfine powder, mixing with modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, pulvis Talci, sweetener, orange essence and pigment, making into soft material with water, granulating with 12-14 mesh sieve, drying at 40-50 deg.C, sieving, grading, and making into capsule; each capsule has a weight of 50mg and an active ingredient content of 25 mg.

Example 39: preparation of granules containing Compound II-2

Prescription: compound II-226 g, dextrin 120g and cane sugar 280 g.

The preparation method comprises the following steps: mixing compound II-2, dextrin and sucrose, granulating by wet method, drying at 60 deg.C, and packaging to obtain granule.

Example 40: preparation of injection containing Compound II-15

Prescription: compound II-1510 g, propylene glycol 500mL, and water for injection 500mL, together were prepared as a 1000mL injection.

The preparation method comprises the following steps: weighing the compound II-15, adding propylene glycol and injection water, stirring for dissolving, adding 1g of activated carbon, fully stirring, standing for 15 minutes, filtering with a 5-micron titanium rod for decarbonization, sequentially fine-filtering with microporous filter membranes with the pore diameters of 0.45 micron and 0.22 micron, finally encapsulating in a 10mL ampoule bottle, and sterilizing with 100 ℃ circulating steam for 45 minutes to obtain the injection.

Example 41: preparation of powder injection containing compound I-8

The preparation method comprises the following steps: and subpackaging the sterile powder of the compound I-8 under the aseptic condition to obtain the compound I-8.

Example 42: preparation of eye drops containing Compound I-16

Prescription: the volume of the compound I-163.78 g, sodium chloride 0.9g, phenethyl alcohol 3g, appropriate amount of boric acid buffer solution and distilled water is added to 1000 mL.

The preparation method comprises the following steps: weighing the compound I-16 and sodium chloride, adding into 500mL of distilled water, dissolving completely, adjusting pH to 6.5 with boric acid buffer solution, adding distilled water to 1000mL, stirring well, filtering with microporous membrane, filling, sealing, and sterilizing with 100 deg.C flowing steam for 1 hr to obtain eye drop.

Example 43: preparation of Liniment containing Compound II-12

Prescription: adding compound II-124 g, potassium soap 7.5g, camphor 5g and distilled water to 100 mL.

The preparation method comprises the following steps: dissolving camphor with 95 percent ethanol solution by volume percentage for later use; heating potassium soap to liquefy, weighing compound II-12, adding potassium soap solution and Camphora ethanol solution under stirring, gradually adding distilled water, emulsifying completely, and adding distilled water to full amount to obtain liniment.

Example 44: preparation of suppository containing compound II-6

Prescription: adding compound II-64 g, gelatin 14g, glycerol 70g and distilled water to 100 mL.

The preparation method comprises the following steps: weighing gelatin and glycerol, adding distilled water to 100mL, heating in water bath at 60 deg.C to melt into paste, adding compound II-6, stirring, pouring into vaginal suppository mold when it is nearly solidified, cooling and solidifying to obtain suppository.

Example 45: preparation of an ointment containing Compound I-12

Prescription: 120.5-2 g of compound I, 6-8g of hexadecanol, 8-10g of white vaseline, 8-19g of liquid paraffin, 2-5g of monoglyceride, 2-5g of polyoxyethylene (40) stearate, 5-10g of glycerol, 0.1g of ethylparaben and distilled water added to 100 g.

The preparation method comprises the following steps: heating cetyl alcohol, white vaseline, liquid paraffin, monoglyceride and polyoxyethylene (40) stearate to completely melt, mixing, and keeping the temperature at 80 deg.C to obtain oil phase; adding ethylparaben into glycerol and distilled water, heating to 85 deg.C for dissolving, adding oil phase under stirring, emulsifying, adding compound I-12, stirring, and cooling to obtain ointment.

Example 46: preparation of compound powder injection containing compound I-12 and metronidazole

Prescription: compound I-1250 g, metronidazole 50g, sodium benzoate 1g, make 100 bottles altogether.

The preparation method comprises the following steps: taking the compound I-12, metronidazole and sodium benzoate according to the prescription amount, uniformly mixing under a sterile state, and subpackaging 100 bottles to obtain the compound powder injection.

Example 47: preparation of Aerosol containing Compound II-15

Prescription: compound II-152.5 g, Span20 (sorbitan monolaurate) 3g, talcum powder (100 mesh) 4g, trichlorofluoromethane added to appropriate amount.

The preparation method comprises the following steps: respectively drying the compound II-15, the Span20 and the talcum powder in a vacuum drying oven for several hours, cooling in a drier to room temperature, crushing into micro powder by using an airflow crusher, uniformly mixing according to the prescription amount, filling into a closed container, and adding trichloromonofluoromethane to a specified amount to obtain the aerosol.

Product effectiveness testing

1. In vitro antimicrobial Activity of Schiff base bridged Sulfamidazole Compounds prepared in examples 3-36

The Schiff base bridged Sulfamidazole compounds prepared in examples 3-36 were tested for the Minimal Inhibitory Concentration (MIC) against gram-positive bacteria (methicillin-resistant Staphylococcus aureus (MRSA), enterococcus faecalis, Staphylococcus aureus ATCC25923, Staphylococcus aureus ATCC29213) and gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922, Acinetobacter baumannii) by a 96-well microdilution method in accordance with the Clinical Laboratory Standards (CLSI) set by the American national Committee, dissolving the compound to be tested in a small amount of dimethyl sulfoxide, diluting the solution with water to a concentration of 1.28mg/mL, diluting the solution to 128. mu.g/mL, culturing at 35 ℃ for 24-72 hours, shaking the culture plate on an oscillator sufficiently, MIC was measured at 490nm, and for the control group, intermediate III, Norfloxacin (Norfloxacin) and Sulfathiazole (Sulfathiazole) were obtained, and the results are shown in tables 1-2.

Table 1: in vitro gram-positive activity data (MIC, μ g/mL) for Schiff base-bridged Sulfamidazole Compounds prepared in examples 3-36

As can be seen from Table 1, the compounds prepared in examples 3-36 of the present invention showed certain inhibitory effect on the tested bacteria, and in particular, the methyl-and Egylcutyl-substituted Schiff base-bridged Sulfamidezole compounds I-2 and I-8 showed higher antibacterial activity on MRSA, and the MIC values were all 1 μ g/mL. The antibacterial activity of part of compounds can be compared with that of the sulfathiazole and norfloxacin serving as reference medicaments, and is even stronger. In addition, compound I-8 was tested against the reference drugs norfloxacin and sulfathiazole for methicillin-resistant staphylococcus aureus (MRSA) with the results shown in fig. 1. As shown in FIG. 1 (the abscissa "passage of MRSA strains" in FIG. 1 indicates the passage number of MRSA, and Compund I-8 indicates Compound I-8), compared with the reference drugs norfloxacin and sulfathiazole, Compound I-8 has substantially unchanged inhibitory activity against MRSA, which is a drug-resistant bacterium, and is less likely to cause drug resistance even when cultured for MRSA.

Table 2: in vitro gram-negative activity data (MIC, μ g/mL) for Schiff base-bridged Sulfamidazole Compounds prepared in examples 3-36

As can be seen from Table 2, the compounds prepared in examples 3-36 of the present invention showed certain inhibitory effect on the tested bacteria, and in particular, the methyl-substituted Schiff base-bridged sulfaimidazole compound I-2 showed higher antibacterial activity on Acinetobacter baumannii, and the MIC values were all 16 μ g/mL. The antibacterial activity of part of compounds can be compared with that of the sulfathiazole and norfloxacin serving as reference medicaments, and is even stronger.

2. Pharmaceutical application of Schiff base bridged sulfaimidazole compound

According to the antimicrobial activity detection result, the Schiff base bridged sulfaimidazole compound has better antibacterial activity, and can be prepared into antibacterial drugs for clinical use. The medicines can be single preparations, for example, prepared by a Schiff base bridged sulfaimidazole compound with a structure and pharmaceutically acceptable auxiliary materials; or a compound preparation, for example, prepared by the sulfaimidazole compound bridged by Schiff base with one structure, the existing antibacterial active ingredients (such as sulfamethoxazole, sulfathiazole and the like) and pharmaceutically acceptable auxiliary materials, or prepared by the sulfaimidazole compound bridged by Schiff base with different structures and pharmaceutically acceptable auxiliary materials. The preparation types include, but are not limited to, tablets, capsules, powders, granules, dripping pills, injections, powder injections, solutions, suspensions, emulsions, suppositories, ointments, gels, films, aerosols, transdermal patches and other dosage forms, and various sustained-release and controlled-release preparations and nano preparations.

Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims (13)

1. A schiff base-bridged sulphamidazol compound of general formula I or a pharmaceutically acceptable salt thereof:

wherein R is ¹ ，R ² Each independently represents hydrogen, alkyl or an alkyl derivative, alkenyl, alkynyl, benzyl or halobenzyl, cyano or carboxyl; r ³ Represents hydrogen or acetyl;

the alkyl derivative is methoxy, ethoxy, propoxy or hydroxyethyl;

the carbon number of the alkyl is 1-12; the carbon number of the alkenyl is 3-11; the carbon number of the alkynyl is 3-11.

2. The Schiff base bridged sulfaimidazole compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt of the Schiff base bridged sulfaimidazole compound represented by the general formula I is hydrochloride, nitrate, acetate or sulfate.

3. A schiff-base-bridged sulphamidazol compound or a pharmaceutically acceptable salt thereof, characterized in that it is selected from one of the following compounds:

4. a process for the preparation of a schiff-base-bridged sulphaimidazoles compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-2, comprising the steps of:

and adding the intermediate III, the intermediate IV and an acid catalyst into a solvent for reaction to obtain the Schiff base bridged sulfaimidazole compound shown in the general formula I.

5. The method according to claim 4, wherein the acid catalyst is an organic acid.

6. The preparation method according to claim 4, wherein the molar ratio of the intermediate III to the intermediate IV is 1 (0.5-2).

7. The method according to claim 4, wherein the reaction temperature is 70 to 90 ℃ and the reaction time is 5 to 12 hours.

8. The method according to claim 4, wherein the Schiff base-bridged sulphamidazole compound of formula I, which is a pharmaceutically acceptable salt thereof, is prepared by the following steps:

dissolving the Schiff base bridged sulfaimidazole compound shown in the general formula I in an organic solvent, and adding a pharmaceutically acceptable acid for reaction to obtain the pharmaceutically acceptable salt of the Schiff base bridged sulfaimidazole compound shown in the general formula I.

9. A medicament comprising the schiff-base-bridged sulfimidazole compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, and an adjuvant.

10. The medicament of claim 9, wherein the excipient is selected from at least one of a filler, a lubricant, a disintegrant, a binder, or a glidant.

11. The medicament of claim 9, wherein the medicament is in the form of any one of tablets, capsules, granules, injections, powder injections, eye drops, liniments, suppositories, ointments, aerosols, powders, dropping pills, emulsions, gels, films, transdermal patches, controlled release preparations or nano preparations.

12. Use of a schiff-base-bridged sulphamidazole compound as claimed in any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the manufacture of an antibacterial medicament.

13. Use according to claim 12, wherein the bacteria are gram bacteria.

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