CN110078668B - Phenyl imidazole XOR inhibitor, preparation and application - Google Patents
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Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and discloses a phenylimidazole XOR inhibitor, and preparation and application thereof. The structure of the phenylimidazole XOR inhibitor is shown as a formula (I) or a formula (II), wherein R, R 1 ，R 2 Each independently represents a C1-C9 alkyl group; or R 1 、R 2 Forming a single carbon atom of 3 to 9 with the N atom to which it is attachedA cyclic nitrogen-containing heterocyclic group. The phenyl imidazole XOR inhibitor has a chemical structure different from that of the known XOR inhibitor, has an excellent inhibition effect on xanthine oxidase related to gout, has an excellent inhibition effect in an acute hyperuricemia mouse model, and provides a new way for preparing anti-hyperuricemia or gout drugs.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a phenylimidazole XOR inhibitor, and preparation and application thereof.
Background
Gout is a metabolic disease caused by the increase of blood uric acid level caused by purine metabolic disorder or reduction of uric acid excretion in vivo and further the deposition of mono-natriuretic urate crystals on joints, cartilage, kidneys and the like. With the development of society, people eat increasingly high-purine foods, so that the content of uric acid in blood exceeds a dissolving range, and monosodium urate crystals are formed, so that the incidence rate of gout is on the rise year by year. Research shows that hyperuricemia or gout is closely related to the occurrence of diseases such as hypertension, hyperlipidemia, atherosclerosis, diabetes (excessive uric acid can cause insulin resistance) and the like.
Hyperuricemia caused by increased uric acid production or decreased excretion is a major cause of gout. The production of uric acid is mainly divided into exogenous and endogenous ones. Wherein the ratio of exogenous to endogenous is 1. Exogenous uric acid is mainly from food, endogenous uric acid is mainly catabolism of nucleotide, and therefore, high purine diet and nucleotide metabolic abnormality can cause rise of blood uric acid, and hyperuricemia is caused. In the endogenous uric acid production pathway, the key enzyme is xanthine oxidoreductase, which oxidizes hypoxanthine to xanthine and then uric acid. On the other hand, uric acid is mainly excreted through the kidney, and is mainly regulated by filtration, secretion, and reabsorption of the glomerulus, mainly reabsorption of uric acid by the renal tubules. Since urate is a polar molecule, ion channels are required to pass through the epithelial cell membrane of renal tubule, wherein the currently found ion channel (urate transporter), the anion exchanger (hurate-anion exchanger, haurat 1) is a key ion channel, which can promote the reabsorption of uric acid by renal tubule and determine the discharge of uric acid from kidney. In fact, uric acid in a suitable amount has a vital role in blood plasma, which is antioxidant, inhibits the decomposition and synthesis of specific enzymes, and also chelates metal ions. Therefore, the control of blood uric acid level stabilization in vivo plays a crucial role.
The treatment of gout is divided into the treatment of acute gout and the treatment of chronic gout. Standard treatments for acute gout are to reduce and control the inflammatory response, for example with colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids (oral, intra-articular or intramuscular injection); biological products for inhibiting interleukin-1 beta (1L-1 beta) such as anakinra, linacept, canamab, etc. Chronic gout therapy is mainly achieved by uric acid-lowering therapy (ULT) to control sUA <6mg/dL, and common uric acid-lowering agents can be divided into three categories: xanthine oxidoreductase inhibitors (XORIs), such as allopurinol, febuxostat, topiroxostat; uricosuric agents, such as probenecid, benzbromarone, rasidone; uricase, such as polyethylene glycol recombinant uricase. Lowering the sUA levels to 6mg/dL is the goal of ULTs, which is below the saturation concentration of uric acid in humans (6.8 mg/dL,404 μmol/L), which allows for gradual dissolution of MSU precipitate (tophus); even lower levels of sUA, such as 5mg/dL, are recommended for severe gout. Xorins are generally used as first-line drugs of treatment, and uricosuric drugs can be used as second-line drugs of treatment when patients are intolerant or contraindicated to xorins; uricase is only used when patients develop severe gout, such as tophaceous gout.
In the past decades, the development of XORIs has been slow, and only allopurinol and febuxostat are clinically used for XORIs. However, in recent years, the incidence of hyperuricemia and gout is increasing, which arouses the attention of researchers to the research of anti-gout drugs; meanwhile, with the intensive research on XOR, people find that the activity of inhibiting XOR can treat hyperuricemia, has certain curative effect on ischemia and reperfusion injury, especially heart failure, and XORIs with high efficiency and low toxicity have great development potential and application value. In the case of gout, the design of new drugs with XOR as the target has been paid attention to extensively, and many highly active compounds have already entered clinical trials, but still face many problems such as large toxic and side effects, and need to be studied more deeply.
Disclosure of Invention
Aiming at the defects and shortcomings of the prior art, the invention mainly aims to provide a phenylimidazole XOR inhibitor.
The invention also aims to provide a preparation method of the phenylimidazole XOR inhibitor.
The invention further aims to provide application of the phenyl imidazole XOR inhibitor in preparation of anti-hyperuricemia or gout drugs.
The purpose of the invention is realized by the following technical scheme:
a phenyl imidazole XOR inhibitor has a structure shown in formula (I) or formula (II):
wherein R, R 1 ，R 2 Each independently represents a C1-C9 alkyl group; or R 1 、R 2 A monocyclic nitrogen-containing heterocyclic group having 3 to 9 carbon atoms is formed with the N atom to which it is bonded.
Unless otherwise indicated, the terms of the present invention have the following meanings:
"Hydrogen" means protium (1H), which is the predominant stable isotope of hydrogen.
"alkyl" means a saturated aliphatic hydrocarbon group, including straight chain, branched chain, and cyclic groups.
Preferably, the phenylimidazole XOR inhibitor is a compound according to any one of the following:
1- (3-cyano-4-ethoxy-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-isopropoxy-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-isobutoxy-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-sec-butoxy-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-neopentyloxy-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4- (pentyl-3-oxy) -phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4- (2-ethylbutoxy-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-cyclopentyloxy-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-cyclohexyloxy-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-isobutyl-methylamino-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-tetrahydropyrrole-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-piperidine-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4- (4-methylpiperidine) -phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-cycloheptimido-phenyl) -imidazole-4-carboxylic acid. The preparation method of the phenylimidazole XOR inhibitor with the structure shown in the formula (I) comprises the following steps:
(1) Heating 5-bromo-2-hydroxy-1-cyanobenzene, halogenated alkane and inorganic base in an organic solvent for reaction to obtain 5-bromo-2-alkoxy-1-cyanobenzene;
(2) Under the protection of argon, carrying out C-N coupling reaction on 5-bromo-2-alkoxy-1-cyanobenzene, imidazole-4-ethyl formate, cuI, inorganic base and (E) -N' N-dimethyl-1, 2-cyclohexyldiamine in an organic solvent to obtain 1- (3-cyano-4-alkoxy-phenyl) -imidazole-4-ethyl formate;
(3) Carrying out alkaline hydrolysis on 1- (3-cyano-4-alkoxy-phenyl) -pyrazole-4-ethyl formate, and acidifying to obtain 1- (3-cyano-4-alkoxy-phenyl) -imidazole-4-formic acid;
the reaction of the above preparation method is shown as the following formula:
the preparation method of the phenylimidazole XOR inhibitor with the structure shown in the formula (II) comprises the following steps:
(1) 5-bromo-2-fluorobenzonitrile and a compound HNR 1 R 2 Heating and reacting with inorganic base in an organic solvent to obtain 5-bromo-2-alkylamino-1-cyanobenzene;
(2) Under the protection of argon, carrying out C-N coupling reaction on 5-bromo-2-alkylamino-1-cyanobenzene, imidazole-4-ethyl formate, cuI, inorganic base and (E) -N' N-dimethyl-1, 2-cyclohexyldiamine in an organic solvent to obtain 1- (3-cyano-4-alkylamino-phenyl) -imidazole-4-ethyl formate;
(3) Carrying out alkaline hydrolysis and acidification on 1- (3-cyano-4-alkylamino-phenyl) -pyrazole-4-ethyl formate to obtain 1- (3-cyano-4-alkylamino-phenyl) -imidazole-4-formic acid;
the reaction of the above preparation method is shown as the following formula:
preferably, the organic solvent used in steps (1) and (2) is DMF (N, N-dimethylformamide).
Preferably, the inorganic base used in the steps (1) and (2) is K 2 CO 3 。
Preferably, in the step (3), the alkaline hydrolysis and acidification means adding aqueous NaOH solution into a mixed solution of tetrahydrofuran and ethanol (EtOH/THF) for hydrolysis, and adding aqueous HCl solution for acidification.
The phenyl imidazole XOR inhibitor is applied to preparation of drugs for resisting hyperuricemia or gout.
Preferably, the anti-hyperuricemia or gout drug comprises the phenylimidazole XOR inhibitor or pharmaceutically acceptable salts and esters thereof as an effective component and a pharmaceutically acceptable carrier.
Preferably, the pharmaceutically acceptable salts include salts of phenylimidazole-based XOR inhibitors with metal ions, organic bases, salts that retain the biological effectiveness and properties of the parent compound.
More preferably, the metal ion is an alkali metal ion, an alkaline earth metal ion or an aluminum ion, and the organic base is ethanolamine, diethanolamine, triethanolamine, tromethamine, piperidine or piperazine.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the phenylimidazole-based XOR inhibitors of the present invention have a different chemical structure than known XOR inhibitors; as demonstrated in the examples below, they exhibit excellent inhibitory effects on xanthine oxidase associated with gout and, in a mouse model of acute hyperuricemia, excellent inhibitory effects; therefore, they can be used for the prevention and treatment of xanthine oxidase-related diseases, for example, hyperuricemia, heart failure, cardiovascular diseases, hypertension, renal diseases, inflammation, arthropathy, and the like.
Drawings
FIG. 1 shows that acute hyperuricemia mice were administered the compound A of example 14 14 And a time-dependent change graph of the uric acid content in the blood plasma after a Model control group (Model) and a positive control group (Febuxostat, 5 mg/kg).
FIGS. 2 to 4 show the administration of Compound A of example 14 to mice with long-term hyperuricemia 14 (5 mg/kg) and results of measurement of creatinine (Crea), urea Nitrogen (Urea Nitrogen) and Uric acid (Uric acid) in plasma after control (Vehicle), model control (Model), and positive control (Febuxostat, 5 mg/kg).
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Example 1
1- (3-cyano-4-ethoxy-phenyl) -imidazole-4-carboxylic acid (A) 1 ) The synthesis of (2):
(1) 5-bromo-2-hydroxy-1-cyanoBenzene (1.0 g,5.0 mmol) was dissolved in DMF (10 mL) and K was added 2 CO 3 (2.1g, 15.0 mmol) was stirred at room temperature for 1.0h, iodoethane (2.3g, 15.0 mmol) was added, the reaction was allowed to proceed at 80 ℃ for 3h, and the reaction was completed by TLC. Cooling to room temperature, diluting with 100mL of water, extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure, and purifying with silica gel column (V) Ethyl acetate :V Petroleum ether = 1), 5-bromo-2-ethoxy-benzonitrile (a) 1 ) 1.05g, yield 92%.
(2) Under the protection of argon, imidazole-4-ethyl formate (0.28g, 2.0mmol), cuI (38mg, 0.2mmol) and K are weighed 2 CO 3 (0.58g, 4.2mmol), 5-bromo-2-ethoxy-benzonitrile (a) 1 0.54g,2.4 mmol), (E) -N' N-dimethyl-1, 2-cyclohexyldiamine (56mg, 0.4 mmol) and DMF (5 mL) were charged into a 25mL flask and reacted at 110 ℃ for 24h. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and purified with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 1 ) 0.37g, yield 65%.
(3) 1- (3-cyano-4-ethoxy-phenyl) -imidazole-4-carboxylic acid ethyl ester (b) 1 0.29g and 1mmol) are dissolved in a mixed solution of THF (4 mL) and ethanol (4 mL), 1M NaOH 4mL is added, the mixture is refluxed for 1h, cooled to room temperature, 1M HCl is added to adjust the pH value to 2-3, water is added for dilution, solid is precipitated, the filtration is carried out, a filter cake is washed to be neutral by water, and the obtained product is dried to obtain 1- (3-cyano-4-ethoxy-phenyl) -imidazole-4-formic acid (A) 1 ) 0.23g, yield 90%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.63(s,1H,-NCH),8.52(s,1H,-NCH),8.25(d,J＝2.7Hz,1H,ArH),8.06(dd,J＝9.2,2.8Hz,1H,ArH),δ7.42(d,J＝9.2Hz,1H,ArH),4.27(q,J＝6.9Hz,2H,-OCH 2 CH 3 ),1.40(t,J＝6.9Hz,3H,-OCH 2 CH 3 ).
13 C NMR(101MHz,DMSO-d 6 )δ167.10,163.92,156.65,137.35,134.79,129.32,125.79,124.79,123.67,123.40,115.17,65.04,14.98。
example 2
1- (3-cyano-4-isopropoxy-phenyl) -imidazole-4-carboxylic acid (a) 2 ) The synthesis of (2):
(1) 5-bromo-2-hydroxy-1-cyanobenzene (1.0 g,5.0 mmol) was dissolved in DMF (10 mL), and K was added 2 CO 3 (2.1g, 15.0mmol) was stirred at room temperature for 1.0h, bromoisopropane (1.8g, 15.0mmol) was added thereto, the reaction was carried out at 80 ℃ for 3h, and the reaction was completed by TLC. Cooling to room temperature, diluting with 100mL of water, extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, evaporating the solvent under reduced pressure, and purifying with silica gel column (V) Ethyl acetate :V Petroleum ether = 1), 5-bromo-2-isopropoxy-benzonitrile (a) 2 ) 1.15g, yield 95%.
(2) Under the protection of argon, imidazole-4-ethyl formate (0.28g, 2.0mmol), cuI (38mg, 0.2mmol) and K are weighed 2 CO 3 (0.58g, 4.2mmol) and 5-bromo-2-isopropoxy-benzonitrile (a) 2 0.58g,2.4 mmol), (E) -N' N-dimethyl-1, 2-cyclohexyldiamine (56mg, 0.4 mmol) and DMF (5 mL) were charged into a 25mL flask and reacted at 110 ℃ for 24h. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and purified with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 2 ) 0.36g, yield 60%.
(3) 1- (3-cyano-4-isopropoxy-phenyl) -imidazole-4-carboxylic acid ethyl ester (b) 2 0.3g and 1mmol) is dissolved in a mixed solution of THF (4 mL) and ethanol (4 mL), 1M NaOH 4mL is added, the mixture is refluxed for 1h, cooled to room temperature, 1M HCl is added to adjust the pH value to 2-3, water is added for dilution, solid is precipitated, the filtration is carried out, a filter cake is washed to be neutral by water, and the obtained product is dried to obtain 1- (3-cyano-4-isopropoxy-phenyl) -imidazole-4-formic acid (A) 2 ) 0.26g, yield 95%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.40(d,J＝1.4Hz,1H,-NCH),8.33(d,J＝1.4Hz,1H,-NCH),8.21(d,J＝2.8Hz,1H,ArH),8.01(dd,J＝9.2,2.9Hz,1H,ArH),7.44(d,J＝9.3Hz,1H,ArH),4.92-4.83(m,1H,-OCH(CH 3 ) 2 ),1.34(d,J＝6.0Hz,6H,-OCH(CH 3 ) 2 ).
13 C NMR(101MHz,DMSO-d 6 )δ163.88,158.91,137.27,134.95,129.81,128.12,126.66,124.66,116.10,115.92,102.70,72.55,22.04。
example 3
1- (3-cyano-4-isobutoxy-phenyl) -imidazole-4-carboxylic acid (A) 3 ) The synthesis of (2):
(1) 5-bromo-2-hydroxy-1-cyanobenzene (1.0 g,5.0 mmol) was dissolved in DMF (10 mL), and K was added 2 CO 3 (2.1g, 15.0 mmol) was stirred at room temperature for 1.0h, bromoisobutane (2.1g, 15.0 mmol) was added, the reaction was carried out at 80 ℃ for 3h, and the reaction was followed by TLC to completion. Cooling to room temperature, diluting with 100mL of water, extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, evaporating the solvent under reduced pressure, and purifying with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 3 ) 1.24g, yield 97%.
(2) Under the protection of argon, imidazole-4-ethyl formate (0.28g, 2.0 mmol), cuI (38mg, 0.2mmol) and K are weighed 2 CO 3 (0.58g, 4.2mmol), and 5-bromo-2-isobutoxy-benzonitrile (a) 3 0.58g, 2.4mmol), (E) -N' N-dimethyl-1, 2-cyclohexyldiamine (56mg, 0.4mmol) and DMF (5 mL) were charged into a 25mL flask and reacted at 110 ℃ for 24 hours. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and purified with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 3 ) 0.47g, yield 75%.
(3) 1- (3-cyano-4-isobutoxy-phenyl) -imidazole-4-carboxylic acid ethyl ester (b) 3 0.31g, 1mmol) was dissolved in a mixed solution of THF (4 mL) and ethanol (4 mL), 1M NaOH was added at 4mL, refluxed for 1h, cooled to room temperature, adjusted to pH 2-3 by addition of 1M HCl, diluted with water, and precipitated as a solidTaking out, filtering, washing the filter cake to neutrality with water, drying to obtain 1- (3-cyano-4-isobutoxy-phenyl) -imidazole-4-formic acid (A) 3 ) 0.27g, yield 95%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.40(s,1H,-NCH),8.33(s,1H,-NCH),8.22(d,J＝2.6Hz,1H,ArH),8.03(dd,J＝9.1,2.6Hz,1H,ArH),7.40(d,J＝9.2Hz,1H,ArH),3.97(dd,J＝13.3,6.5Hz,2H,-OCH 2 ),2.08(m,1H,-OCH(CH 3 ) 2 ),1.02(d,J＝6.7Hz,6H,-OCH(CH 3 ) 2 ).
13 C NMR(101MHz,DMSO-d 6 )δ163.87,159.91,137.25,134.95,129.93,128.14,126.44,124.65,115.87,114.82,101.85,75.67,28.06,19.20。
example 4
1- (3-cyano-4-sec-butoxy-phenyl) -imidazole-4-carboxylic acid (A) 4 ) The synthesis of (2):
(1) 5-bromo-2-hydroxy-1-cyanobenzene (1.0 g,5.0 mmol) was dissolved in DMF (10 mL), and K was added 2 CO 3 (2.1g, 15.0 mmol) was stirred at room temperature for 1.0h, and bromo-sec-butyl-alkane (2.1g, 15.0 mmol) was added and reacted at 80 ℃ for 3h, followed by completion of the reaction by TLC. Cooling to room temperature, diluting with 100mL of water, extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, evaporating the solvent under reduced pressure, and purifying with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 4 ) 1.24g, yield 97%.
(2) Under the protection of argon, imidazole-4-ethyl formate (0.28g, 2.0mmol), cuI (38mg, 0.2mmol) and K are weighed 2 CO 3 (0.58g, 4.2mmol), and 5-bromo-2-sec-butoxy-benzonitrile (a) 4 0.58g,2.4 mmol), (E) -N' N-dimethyl-1, 2-cyclohexyldiamine (56mg, 0.4 mmol) and DMF (5 mL) were charged into a 25mL flask and reacted at 110 ℃ for 24h. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and purified with silica gel column (V) Ethyl acetate :V Petroleum ether = 1)(3-cyano-4-sec-butoxy-phenyl) -imidazole-4-carboxylic acid ethyl ester (b) 4 ) 0.42g, yield 67%.
(4) 1- (3-cyano-4-sec-butoxy-phenyl) -imidazole-4-carboxylic acid ethyl ester (b) 4 0.31g and 1mmol) are dissolved in a mixed solution of THF (4 mL) and ethanol (4 mL), 1M NaOH 4mL is added, the mixture is refluxed for 1h, cooled to room temperature, 1M HCl is added to adjust the pH value to 2-3, water is added for dilution, solid is precipitated, the filtration is carried out, a filter cake is washed to be neutral by water, and the obtained product is dried to obtain 1- (3-cyano-4-sec-butoxy-phenyl) -imidazole-4-formic acid (A) 4 ) 0.24g, yield 86%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.40(s,1H,-NCH),8.33(s,1H,-NCH),8.20(d,J＝2.8Hz,1H,ArH),8.01(dd,J＝9.2,2.8Hz,1H,ArH),7.44(d,J＝9.3Hz,1H,ArH),4.72-4.64(m,1H,-OCH(CH 3 )CH 2 CH 3 ),1.77-1.61(m,2H,-OCH(CH 3 )CH 2 CH 3 ),1.31(d,J＝6.1Hz,3H,-OCH(CH 3 )CH 2 CH 3 ),0.96(t,J＝7.4Hz,3H,-OCH(CH 3 )CH 2 CH 3 ).
13 C NMR(101MHz,DMSO-d 6 )δ163.85,159.24,137.30,134.89,129.78,128.18,126.71,124.69,116.04,115.86,102.65,77.18,28.82,19.27,9.63。
example 5
1- (3-cyano-4-neopentyloxy-phenyl) -imidazole-4-carboxylic acid (A) 5 ) The synthesis of (2):
(1) 5-bromo-2-hydroxy-1-cyanobenzene (1.0 g,5.0 mmol) was dissolved in DMF (10 mL), and K was added 2 CO 3 (2.1g, 15.0 mmol) was stirred at room temperature for 1.0h, bromoneopentane (2.3 g,15.0 mmol) was added, the reaction was carried out at 80 ℃ for 3h, and the reaction was followed by TLC to completion. Cooling to room temperature, diluting with 100mL of water, extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, evaporating the solvent under reduced pressure, and purifying with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 5 ) 1.22g, yield 90%.
(2) Under the protection of argon, the miami is weighedAzole-4-carboxylic acid ethyl ester (0.14g, 1.0mmol), cuI (19mg, 0.1mmol), K 2 CO 3 (0.29g, 2.1mmol), 5-bromo-2-neopentyloxy-benzonitrile (a) 5 0.32g,1.2mmol, (E) -N' N-dimethyl-1, 2-cyclohexyldiamine (28mg, 0.2mmol) and DMF (5 mL) were charged into a 25mL flask and reacted at 110 ℃ for 24h. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and purified with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 5 ) 0.21g, yield 53.8%.
(3) 1- (3-cyano-4-neopentyloxy-phenyl) -imidazole-4-carboxylic acid ethyl ester (b) 5 0.16g and 0.5mmol) is dissolved in a mixed solution of THF (2 mL) and ethanol (2 mL), 1M NaOH 2mL is added, the mixture is refluxed for 1h, the mixture is cooled to room temperature, 1M HCl is added to adjust the pH value to be 2-3, water is added to dilute the mixture, solid is separated out, the mixture is filtered, a filter cake is washed to be neutral by water and dried to obtain 1- (3-cyano-4-neopentyloxy-phenyl) -imidazole-4-formic acid (A) 5 ) 0.13g, yield 90%.
The structural characterization data of the product are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ8.40(d,J＝1.3Hz,1H,-NCH),8.33(d,J＝1.3Hz,1H,-NCH),8.22(d,J＝2.8Hz,1H,ArH),8.03(dd,J＝9.1,2.8Hz,1H,ArH),7.39(d,J＝9.2Hz,1H,ArH),3.87(s,2H,-OCH 2 C(CH 3 ) 3 ),1.04(s,9H,-OCH 2 C(CH 3 ) 3 ).
13 C NMR(151MHz,DMSO-d 6 )δ163.85,160.21,137.24,134.98,129.94,128.14,126.37,124.64,115.77,114.81,101.89,79.16,32.24,26.89,26.57。
example 6
1- (3-cyano-4- (pentyl-3-oxy) -phenyl) -imidazole-4-carboxylic acid (A) 6 ) The synthesis of (2):
(1) 5-bromo-2-hydroxy-1-cyanobenzene (1.0 g,5.0 mmol) was dissolved in DMF (10 mL), and K was added 2 CO 3 (2.1g, 15.0 mmol) was stirred at room temperature for 1.0h, 3-bromopentane (2.3g, 15.0 mmol) was added thereto, the reaction was carried out at 80 ℃ for 3h, and the reaction was followed by TLC to completion. Is cooled toDiluting with 100mL of water at room temperature, extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure, and purifying with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 6 ) 1.15g, yield 85%.
(2) Under the protection of argon, imidazole-4-ethyl formate (0.14g, 1.0mmol), cuI (19mg, 0.1mmol) and K are weighed 2 CO 3 (0.29g, 2.1mmol), 5-bromo-2- (pentyl-3-oxy) -benzonitrile (a) 6 0.32g,1.2mmol, (E) -N' N-dimethyl-1, 2-cyclohexyldiamine (28mg, 0.2mmol) and DMF (5 mL) were charged into a 25mL flask and reacted at 110 ℃ for 24h. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and purified with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 6 ) 0.23g, yield 70%.
(3) Weighing 1- (3-cyano-4- (pentyl-3-oxy) -phenyl) -imidazole-4-carboxylic acid ethyl ester (b) 6 0.16g and 0.5mmol) is dissolved in a mixed solution of THF (2 mL) and ethanol (2 mL), 1M NaOH 2mL is added, the mixture is refluxed for 1h, the mixture is cooled to room temperature, 1M HCl is added to adjust the pH value to be 2-3, water is added to dilute the mixture, solid is precipitated and filtered, a filter cake is washed by water to be neutral, and the mixture is dried to obtain 1- (3-cyano-4- (amyl-3-oxyl) -phenyl) -imidazole-4-formic acid (A) 6 ) 0.14g, yield 95%.
The structural characterization data of the product are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ8.56(s,1H,-NCH),δ8.48(s,1H,-NCH),8.22(d,J＝2.9Hz,1H,ArH),8.01(dd,J＝9.2,2.9Hz,1H,ArH),7.46(d,J＝9.3Hz,1H,ArH),4.58–4.52(m,1H,-OCH(CH 2 CH 3 ) 2 ),1.74-1.62(m,4H,-OCH(CH 2 CH 3 ) 2 ),0.94(t,J＝7.4Hz,6H,-OCH(CH 2 CH 3 ) 2 ).
13 C NMR(151MHz,DMSO-d 6 )δ163.23,159.96,137.38,133.74,129.49,128.46,127.02,124.86,115.95,115.87,102.60,81.98,25.88,9.50。
example 7
1- (3-cyano-4- (2-ethylbutoxy-phenyl) -imidazole-4-carboxylic acid (A) 7 ) The synthesis of (2):
(1) 5-bromo-2-hydroxy-1-cyanobenzene (1.0 g,5.0 mmol) was weighed out and dissolved in DMF (10 mL), and K was added 2 CO 3 (2.1g, 15.0 mmol) was stirred at room temperature for 1.0h, 1-bromo-2-ethylbutane (2.5g, 15.0 mmol) was added, the reaction was carried out at 80 ℃ for 3h, and the reaction was completed by TLC. Cooling to room temperature, diluting with 100mL of water, extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure, and purifying with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 7 ) 1.35g, yield 95%.
(2) Under the protection of argon, imidazole-4-ethyl formate (0.14g, 1.0mmol), cuI (19mg, 0.1mmol) and K are weighed 2 CO 3 (0.29g, 2.1mmol), 5-bromo-2-ethylbutyloxy-benzonitrile (a) 7 0.34g,1.2mmol, (E) -N' N-dimethyl-1, 2-cyclohexyldiamine (28mg, 0.2mmol) and DMF (5 mL) were charged into a 25mL flask and reacted at 110 ℃ for 24h. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and purified with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 7 ) 0.22g, yield 64%.
(3) 1- (3-cyano-4-ethylbutoxy-phenyl) -imidazole-4-carboxylic acid ethyl ester (b) 7 0.17g and 0.5 mmol) are dissolved in a mixed solution of THF (2 mL) and ethanol (2 mL), 1M NaOH 2mL is added, the mixture is refluxed for 1h, the mixture is cooled to room temperature, 1M HCl is added to adjust the pH value to 2-3, water is added to dilute the mixture, solid is precipitated and filtered, a filter cake is washed to be neutral by water and dried to obtain 1- (3-cyano-4-ethylbutoxy-phenyl) -imidazole-4-formic acid (A) 7 ) 0.15g, yield 95%.
The structural characterization data of the product are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ8.40(d,J＝1.3Hz,1H,-NCH),8.33(d,J＝1.3Hz,1H,-NCH),8.21(d,J＝2.8Hz,1H,ArH),8.03(dd,J＝9.1,2.8Hz,1H,ArH),7.43(d,J＝9.2Hz,1H,ArH),4.10(d,J＝5.7Hz,2H,-OCH 2 CH(CH 2 CH 3 ) 2 ),1.68(dq,J＝12.3,6.1Hz,1H,-OCH 2 CH(CH 2 CH 3 ) 2 ),1.52-1.39(m,4H,-OCH 2 CH(CH 2 CH 3 ) 2 ),0.92(t,J＝7.5Hz,6H,-OCH 2 CH(CH 2 CH 3 ) 2 ).
13 C NMR(151MHz,DMSO-d 6 )δ163.87,160.05,137.24,135.04,129.95,128.16,126.46,124.63,115.83,114.80,101.89,71.92,23.26,11.39。
example 8
1- (3-cyano-4-cyclopentyloxy-phenyl) -imidazole-4-carboxylic acid (A) 8 ) The synthesis of (2):
(1) 5-bromo-2-hydroxy-1-cyanobenzene (1.0 g,5.0 mmol) was dissolved in DMF (10 mL), and K was added 2 CO 3 (2.1g, 15.0 mmol) was stirred at room temperature for 1.0h, bromocyclopentane (2.2g, 15.0 mmol) was added and the reaction was continued at 80 ℃ for 3h, followed by TLC to completion. Cooling to room temperature, diluting with 100mL of water, extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, evaporating the solvent under reduced pressure, and purifying with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 8 ) 1.06g, yield 80%.
(2) Under the protection of argon, imidazole-4-ethyl formate (0.14g, 1.0mmol), cuI (19mg, 0.1mmol) and K are weighed 2 CO 3 (0.29g, 2.1mmol), 5-bromo-2-cyclopentyloxy-benzonitrile (a) 8 0.32g,1.2mmol, (E) -N' N-dimethyl-1, 2-cyclohexyldiamine (28mg, 0.2mmol) and DMF (5 mL) were charged into a 25mL flask and reacted at 110 ℃ for 24h. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and purified with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 8 ) 0.20g, yield 60%.
(3) 1- (3-cyano-4-cyclopentyloxy-phenyl) -imidazole-4-carboxylic acid ethyl ester (b) 8 0.16g and 0.5mmol) is dissolved in a mixed solution of THF (2 mL) and ethanol (2 mL), 1M NaOH 2mL is added, reflux is carried out for 1h, the mixture is cooled to room temperature, 1M HCl is added to adjust the pH value to 2-3, water is added to dilute the mixture, solid is precipitated and filtered, a filter cake is washed to be neutral by water and dried to obtain 1- (3-cyano-4-cyclopentyloxy-phenyl) -imidazole-4-formic acid (A) 8 ) 0.14g, yield 95%.
The structural characterization data of the product are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ8.40(s,1H,-NCH),8.33(s,1H,-NCH),8.20(d,J＝2.7Hz,1H,ArH),8.01(dd,J＝9.1,2.7Hz,1H,ArH),7.40(d,J＝9.2Hz,1H,ArH),5.11-5.04(m,1H,-CH(CH 2 ) 4 ),1.97(dd,J＝12.7,7.2Hz,2H,-CH(CH 2 ) 4 ),1.84-1.58(m,6H,-CH(CH 2 ) 4 ).
13 C NMR(151MHz,DMSO-d 6 )δ163.88,158.94,137.28,134.93,129.79,128.04,126.63,124.67,116.00,115.89,102.56,81.65,32.66,32.60,23.97,23.93。
example 9
1- (3-cyano-4- (2-cyclohexyloxy-phenyl) -imidazole-4-carboxylic acid (A) 9 ) The synthesis of (2):
(1) 5-bromo-2-hydroxy-1-cyanobenzene (1.0 g,5.0 mmol) was dissolved in DMF (10 mL), and K was added 2 CO 3 (2.1g, 15.0mmol) was stirred at room temperature for 1.0h, bromocyclohexane (2.4g, 15.0mmol) was added thereto, the reaction was carried out at 80 ℃ for 3h, and the reaction was completed by TLC tracing. Cooling to room temperature, diluting with 100mL of water, extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, evaporating the solvent under reduced pressure, and purifying with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 9 ) 1.26g, yield 90%.
(2) Under the protection of argon, imidazole-4-ethyl formate (0.14g, 1.0mmol), cuI (19mg, 0.1mmol) and K are weighed 2 CO 3 (0.29g, 2.1mmol), 5-bromo-2-cyclohexyloxy-benzonitrile (a) 9 0.34g, 1.2mmol), (E) -N' N-dimethyl-1, 2-cyclohexyldiamine (28mg, 0.2mmol) andDMF (5 mL) was added to a 25mL flask and reacted at 110 ℃ for 24h. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and purified with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 9 ) 0.20g, yield 60%.
(3) 1- (3-cyano-4-cyclohexyloxy-phenyl) -imidazole-4-carboxylic acid ethyl ester (b) 9 0.17g and 0.5 mmol) are dissolved in a mixed solution of THF (2 mL) and ethanol (2 mL), 1M NaOH 2mL is added, the mixture is refluxed for 1h, the mixture is cooled to room temperature, 1M HCl is added to adjust the pH value to be 2-3, water is added to dilute the mixture, solid is separated out, the mixture is filtered, a filter cake is washed to be neutral by water and dried to obtain 1- (3-cyano-4-cyclohexyloxy-phenyl) -imidazole-4-formic acid (A) 9 ) 0.14g, yield 92%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ8.40(s,1H,-NCH),8.34(s,1H,-NCH),8.20(d,J＝2.7Hz,1H,ArH),8.00(dd,J＝9.1,2.7Hz,1H,ArH),7.46(d,J＝9.3Hz,1H,ArH),4.74-4.55(m,1H,-OCH(CH 2 ) 5 ),1.96-1.65(m,4H,-OCH(CH 2 ) 5 ),1.60-1.35(m,6H,-OCH(CH 2 ) 5 ).
13 C NMR(151MHz,DMSO-d 6 )δ163.86,158.74,137.31,134.88,129.82,128.09,126.63,124.70,116.19,116.07,102.79,76.62,31.14,25.38,23.02。
example 10
1- (3-cyano-4-isobutyl-methylamino-phenyl) -imidazole-4-carboxylic acid (a) 10 ) The synthesis of (2):
(1) 5-bromo-2-fluorobenzonitrile (1.0 g,5.0 mmol) was weighed out and dissolved in DMF (10 mL), and K was added 2 CO 3 (2.1g, 15.0 mmol) was stirred at room temperature for 1.0h, N-methylisobutylamine (1.3 g,15.0 mmol) was added thereto, the reaction was carried out at 80 ℃ for 3h, and the reaction was followed by TLC to completion. Cooling to room temperature, diluting with 100mL of water, extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, evaporating the solvent under reduced pressure, and purifying with silica gel column (V) Ethyl acetate :V Petroleum productsEther compounds = 1) 10 ) 1.27g, yield 95%.
(2) Under the protection of argon, imidazole-4-ethyl formate (0.14g, 1.0mmol), cuI (19mg, 0.1mmol) and K are weighed 2 CO 3 (0.29g, 2.1mmol), and 5-bromo-2-isobutyl-methylamino-benzonitrile (a) 10 0.32g,1.2mmol, (E) -N' N-dimethyl-1, 2-cyclohexyldiamine (28mg, 0.2mmol) and DMF (5 mL) were charged into a 25mL flask and reacted at 110 ℃ for 24h. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and purified with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 10 ) 0.21g, yield 65%.
(3) Taking 1- (3-cyano-4-isobutyl-methylamino-phenyl) -imidazole-4-ethyl formate (b) 10 0.16g and 0.5mmol) is dissolved in a mixed solution of THF (2 mL) and ethanol (2 mL), 1M NaOH 2mL is added, the mixture is refluxed for 1h, the mixture is cooled to room temperature, 1M HCl is added to adjust the pH value to be 2-3, water is added to dilute the mixture, solid is precipitated and filtered, a filter cake is washed by water to be neutral, and the mixture is dried to obtain 1- (3-cyano-4-methylamino-phenyl) -imidazole-4-carboxylic acid (A) 10 ) 0.13g, yield 90%.
The structural characterization data of the product are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ8.35(d,J＝1.3Hz,1H,-NCH),8.28(d,J＝1.3Hz,1H,-NCH),8.02(d,J＝2.8Hz,1H,ArH),7.83(dd,J＝9.2,2.8Hz,1H,ArH),7.17(d,J＝9.3Hz,1H,ArH),3.28(d,J＝7.5Hz,2H,-NCH 3 CH 2 CH(CH 3 ) 2 ),3.06(s,3H,-NCH 3 CH 2 CH(CH 3 ) 2 ),1.99(m,1H,-NCH 3 CH 2 CH(CH 3 ) 2 ),0.87(d,J＝6.6Hz,6H,-NCH 3 CH 2 CH(CH 3 ) 2 ).
13 C NMR(151MHz,DMSO-d 6 )δ163.90,153.28,137.13,134.80,127.77,127.47,127.26,124.51,119.33,119.22,99.64,61.50,41.91,27.01,20.21。
example 11
1- (3-cyano-4-tetrahydropyrrole-phenyl) -imidazole-4-carboxylic acid (A) 11 ) The synthesis of (2):
(1) 5-bromo-2-fluorobenzonitrile (1.0 g,5.0 mmol) was dissolved in DMF (10 mL), and K was added 2 CO 3 (2.1g, 15.0 mmol) was stirred at room temperature for 1.0h, then tetrahydropyrrole (1.1g, 15.0 mmol) was added, reaction was carried out at 80 ℃ for 3h, and the reaction was completed by TLC. Cooling to room temperature, diluting with 100mL of water, extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, evaporating the solvent under reduced pressure, and purifying with silica gel column (V) Ethyl acetate :V Petroleum ether = 1), 5-bromo-2-tetrahydropyrrole-benzonitrile (a) is obtained 11 ) 1.19g, yield 95%.
(2) Under the protection of argon, imidazole-4-ethyl formate (0.14g, 1.0mmol), cuI (19mg, 0.1mmol) and K are weighed 2 CO 3 (0.29g, 2.1mmol), 5-bromo-2-tetrahydropyrrole-benzonitrile (a) 11 0.3g,1.2 mmol), (E) -N' N-dimethyl-1, 2-cyclohexyldiamine (28mg, 0.2 mmol) and DMF (5 mL) were charged to a 25mL flask and reacted at 110 ℃ for 24h. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and purified with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 11 ) 0.19g, yield 62%.
(3) 1- (3-cyano-4-tetrahydropyrrole-phenyl) -imidazole-4-carboxylic acid ethyl ester (b) 11 0.16g and 0.5mmol) is dissolved in a mixed solution of THF (2 mL) and ethanol (2 mL), 1M NaOH 2mL is added, the mixture is refluxed for 1h, the mixture is cooled to room temperature, 1M HCl is added to adjust the pH value to be 2-3, water is added to dilute the mixture, solid is precipitated and filtered, a filter cake is washed by water to be neutral, and the mixture is dried to obtain 1- (3-cyano-4-tetrahydropyrrole-phenyl) -imidazole-4-formic acid (A) 11 ) 0.13g, yield 95%.
The structural characterization data of the product are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ8.31(d,J＝1.3Hz,1H,-NCH),8.25(d,J＝1.3Hz,1H,-NCH),7.92(d,J＝2.8Hz,1H,ArH),7.75(dd,J＝9.3,2.8Hz,1H,ArH),6.87(d,J＝9.3Hz,1H,ArH),3.56(t,J＝6.5Hz,4H,-N(CH 2 ) 2 (CH 2 ) 2 ),1.98-1.94(m,4H,-N(CH 2 ) 2 (CH 2 ) 2 ).
13 C NMR(151MHz,DMSO-d 6 )δ163.92,149.39,137.04,134.65,127.64,127.44,125.73,124.50,120.32,116.30,93.79,50.28,25.70。
example 12
1- (3-cyano-4-piperidine-phenyl) -imidazole-4-carboxylic acid (A) 12 ) The synthesis of (2):
(1) 5-bromo-2-fluorobenzonitrile (1.0 g,5.0 mmol) was weighed out and dissolved in DMF (10 mL), and K was added 2 CO 3 (2.1g, 15.0 mmol) was stirred at room temperature for 1.0h, piperidine (1.3g, 15.0 mmol) was added, reaction was carried out at 80 ℃ for 3h, and the reaction was followed by TLC to completion. Cooling to room temperature, diluting with 100mL of water, extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure, and purifying with silica gel column (V) Ethyl acetate :V Petroleum ether = 1), 5-bromo-2-piperidine-benzonitrile (a) 12 ) 1.29g, yield 97%.
(2) Under the protection of argon, imidazole-4-ethyl formate (0.14g, 1.0mmol), cuI (19mg, 0.1mmol) and K are weighed 2 CO 3 (0.29g, 2.1mmol), 5-bromo-2-piperidine-benzonitrile (a) 12 0.3g,1.2mmol, (E) -N' N-dimethyl-1, 2-cyclohexyldiamine (28mg, 0.2 mmol) and DMF (5 mL) were charged into a 25mL flask and reacted at 110 ℃ for 24h. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and purified with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 12 ) 0.22g, yield 68%.
(3) 1- (3-cyano-4-piperidine-phenyl) -imidazole-4-carboxylic acid ethyl ester (b) 12 0.16g and 0.5mmol) is dissolved in a mixed solution of THF (2 mL) and ethanol (2 mL), 1M NaOH 2mL is added, the mixture is refluxed for 1h, the mixture is cooled to room temperature, 1M HCl is added to adjust the pH value to be 2-3, water is added to dilute the mixture, solid is precipitated and filtered, a filter cake is washed to be neutral by water and dried to obtain 1- (3-cyano-4-piperidine-phenyl) -imidazole-4-carboxylic acid (A) 12 ) 0.14g, yield 96%.
The structural characterization data of the product are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ8.39(s,1H,-NCH),8.33(s,1H,-NCH),8.16(d,J＝2.7Hz,1H,ArH),7.93(dd,J＝8.9,2.7Hz,1H,ArH),7.26(d,J＝9.0Hz,1H,ArH),3.17-3.15(m,4H,-N(CH 2 ) 2 (CH 2 ) 2 CH 2 ),1.72-1.67(m,4H,-N(CH 2 ) 2 (CH 2 ) 2 CH 2 ),1.57(dt,J＝11.4,5.8Hz,2H,-N(CH 2 ) 2 (CH 2 ) 2 CH 2 ).
13 C NMR(151MHz,DMSO-d 6 )δ163.85,155.69,137.17,134.95,130.08,127.21,126.82,124.50,120.69,117.91,105.57,52.93,26.08,23.85。
example 13
1- (3-cyano-4- (4-methylpiperidine) -phenyl) -imidazole-4-carboxylic acid (A) 13 ) The synthesis of (2):
(1) 5-bromo-2-fluorobenzonitrile (1.0 g,5.0 mmol) was dissolved in DMF (10 mL), and K was added 2 CO 3 (2.1g, 15.0mmol) was stirred at room temperature for 1.0h, 4-methylpiperidine (1.5g, 15.0mmol) was added thereto, the reaction was carried out at 80 ℃ for 3h, and the reaction was completed by TLC. Cooling to room temperature, diluting with 100mL of water, extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, evaporating the solvent under reduced pressure, and purifying with silica gel column (V) Ethyl acetate :V Petroleum ether = 1), 5-bromo-2- (4-methylpiperidine) -benzonitrile (a) 13 ) 1.37g, yield 98%.
(2) Under the protection of argon, imidazole-4-ethyl formate (0.14g, 1.0mmol), cuI (19mg, 0.1mmol) and K are weighed 2 CO 3 (0.29g, 2.1mmol), 5-bromo-2- (4-methylpiperidine) -benzonitrile (a) 13 0.3g,1.2mmol, (E) -N' N-dimethyl-1, 2-cyclohexyldiamine (28mg, 0.2 mmol) and DMF (5 mL) were charged into a 25mL flask and reacted at 110 ℃ for 24h. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and then applied to silica gelColumn purification (V) Ethyl acetate :V Petroleum ether = 1) 13 ) 0.22g, yield 65%.
(3) 1- (3-cyano-4- (4-methylpiperidine) -phenyl) -imidazole-4-carboxylic acid ethyl ester (b) 13 0.16g and 0.5mmol) is dissolved in a mixed solution of THF (2 mL) and ethanol (2 mL), 1M NaOH 2mL is added, the mixture is refluxed for 1h, the mixture is cooled to room temperature, 1M HCl is added to adjust the pH value to be 2-3, water is added to dilute the mixture, solid is precipitated and filtered, a filter cake is washed to be neutral by water and dried to obtain 1- (3-cyano-4- (4-methylpiperidine) -phenyl) -imidazole-4-formic acid (A) 13 ) 0.14g, yield 93%.
The structural characterization data of the product are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ8.39(d,J＝1.2Hz,1H,-NCH),8.32(d,J＝1.2Hz,1H,-NCH),8.15(d,J＝2.3Hz,1H,ArH),7.93(dd,J＝9.0,2.7Hz,1H,ArH),7.26(d,J＝9.0Hz,1H,ArH),3.52(d,J＝12.2Hz,2H,-NCH 2 ),2.84(dd,J＝11.9,10.3Hz,2H,-NCH 2 ),1.76(d,J＝10.9Hz,2H,-CH 2 CH 2 CHCH 3 ),1.58-1.50(m,1H,-CH 2 CH 2 CHCH 3 ),1.32(m,2H,-CH 2 CH 2 CHCH 3 ),0.97(d,J＝6.5Hz,3H,-CH 2 CH 2 CHCH 3 ).
13 C NMR(151MHz,DMSO-d 6 )δ163.86,155.46,137.16,134.96,130.05,127.19,126.80,124.48,120.73,117.92,105.49,52.21,34.35,30.23,22.10。
example 14
1- (3-cyano-4-cycloheptimido-phenyl) -imidazole-4-carboxylic acid (A) 14 ) The synthesis of (2):
(1) 5-bromo-2-fluorobenzonitrile (1.0 g,5.0 mmol) was weighed out and dissolved in DMF (10 mL), and K was added 2 CO 3 (2.1g, 15.0mmol) was stirred at room temperature for 1.0h, cycloheptylimine (1.7g, 15.0mmol) was added, the reaction was allowed to proceed at 80 ℃ for 3h, and the reaction was completed by TLC. Cooling to room temperature, diluting with 100mL of water, extracting with ethyl acetate (100 mL. Times.3), mixing the organic phases, washing with saturated brine, drying over anhydrous magnesium sulfate, evaporating the solvent under reduced pressure, and purifying with silica gel column (V) Acetic acid BEsters :V Petroleum ether = 1) 14 ) 1.35g, yield 92%.
(2) Under the protection of argon, imidazole-4-ethyl formate (0.14g, 1.0mmol), cuI (19mg, 0.1mmol) and K are weighed 2 CO 3 (0.29g, 2.1mmol), and 5-bromo-2-cycloheptimidoyl-benzonitrile (a) 14 0.35g,1.2mmol, (E) -N' N-dimethyl-1, 2-cyclohexyldiamine (28mg, 0.2mmol) and DMF (5 mL) were charged into a 25mL flask and reacted at 110 ℃ for 24h. Cooled to room temperature, diluted with 15mL of water, extracted with ethyl acetate (15 mL. Times.3), washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and purified with silica gel column (V) Ethyl acetate :V Petroleum ether = 1) 14 ) 0.24g, yield 67%.
(3) Taking 1- (3-cyano-4-cycloheptimidoyl-phenyl) -imidazole-4-ethyl formate (a) 14 0.18g and 0.5mmol) is dissolved in a mixed solution of THF (2 mL) and ethanol (2 mL), 1M NaOH 2mL is added, the mixture is refluxed for 1h, the mixture is cooled to room temperature, 1M HCl is added to adjust the pH value to 2-3, water is added to dilute the mixture, solid is precipitated and filtered, a filter cake is washed to be neutral by water and dried to obtain 1- (3-cyano-4-cycloheptimido-phenyl) -imidazole-4-formic acid (A) 14 ) 0.15g, yield 94%.
The structural characterization data of the product are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ8.32(d,J＝1.1Hz,1H,-NCH),8.26(d,J＝1.2Hz,1H,-NCH),7.93(d,J＝2.9Hz,1H,ArH),7.75(dd,J＝9.4,2.9Hz,1H,ArH),7.07(d,J＝9.5Hz,1H,ArH),3.76-3.71(m,4H,-N(CH 2 ) 2 (CH 2 ) 2 (CH 2 ) 3 ),1.77-1.73(m,4H,-N(CH 2 ) 2 (CH 2 ) 2 (CH 2 ) 3 ),1.59-1.46(m,6H,-N(CH 2 ) 2 (CH 2 ) 2 (CH 2 ) 3 ).
13 C NMR(151MHz,DMSO-d 6 )δ164.00,149.60,137.08,134.75,128.38,127.63,125.90,124.46,120.16,117.23,94.44,52.54,27.33,26.81,24.82.
evaluation of the activity of the product obtained in the above example:
1. compound A 1 -A 14 Evaluation of in vitro inhibitory Activity against XOR
(1) Solution preparation
Buffer solution: 10 XPBS (pH 7.4) was diluted to 1 XPBS. Unless otherwise stated, all references to PBS in the reaction system refer to 1 XPBS.
Substrate: weighing 15.2mg xanthine, adding 45mL PBS for ultrasonic dissolution promotion, adding PBS for constant volume to 200mL, and obtaining 0.5mmol/L substrate solution.
Enzyme solution: in ice bath, 10.2. Mu.L of the xanthine oxidoreductase stock solution was diluted with 20mL of PBS to obtain 0.5. Mu.g/100. Mu.L of the enzyme solution.
Test compounds: the products A of examples 1 to 14 were each weighed accurately 1 -A 14 The mixture was stored in DMSO as a 1mmol/L solution at 20 ℃ in the dark. Before use, the mixture is diluted to a required concentration by PBS, and the DMSO content is controlled within 5 percent to ensure that the DMSO content has no influence on enzyme activity.
(2) Measurement of
And sequentially adding the prepared PBS solution, sample or blank solution (the blank solution is the PBS solution) and 100 mu L of enzyme solution into a 96-well plate, incubating for 3min at 37 ℃ in an enzyme-linked immunosorbent assay, adding a substrate into the incubated microplate, starting reaction, reading once every 1min at 295nm for 5min, and performing parallel determination for three times in each group of experiments. The initial velocity of the test compound at each concentration was converted into a percentage (%) of inhibition based on the initial velocity in the absence of the inhibitor, and IC was calculated 50 The results are shown in Table 1.
TABLE 1 Compound A 1-14 In vitro inhibitory Activity on XOR (n = 3)
As is clear from the results in Table 1, compound A obtained in the present invention 1 -A 14 The following unexpected structure-activity relationship is shown: 1. for homologues both of which are substituted by alkoxy on the 4-C of the phenyl ring, combiningThing A 1 -A 9 The structure-activity relationship is shown as follows: the inhibitory activity gradually increased with increasing number of substituted alkane C. E.g. compounds A having a C number of 6 7 Has the strongest inhibitory activity, IC 50 It was 29.8nM. In addition, compounds substituted with branched alkane chains have better inhibitory activity than compounds substituted with cycloalkanes, e.g. A, at the same number of C' s 6 VS.A 8 ，A 7 VS.A 9 . 2. Compound A 10-14 Can be regarded as compound A 1-9 The biological electron isostere replacement modification is that alkoxy substitution on 4-C of a benzene ring is changed into alkylamino substitution, and the modification operation is favorable for improving the inhibiting activity on XOR, such as a compound A 10 To compound A 3 Activity of (2) is increased by about 3 times (IC) 50 27.1, 94.5nM, respectively), compound A 11 To compound A 8 Activity of (2) is increased by about a factor of (IC) 50 34.1, 63.0nM, respectively). Furthermore, among the A series compounds, the eight-membered alkylamino ring-substituted compound A 14 Exhibits the strongest XOR inhibition activity, IC 50 Is 8.0nM, comparable to febuxostat (P)>0.05)。
2. Compound A 14 Evaluation of uric acid-lowering Activity in mouse model of acute hyperuricemia
(1) After 18-22g SPF grade ICR mice were adaptively fed for one week, they were randomly divided into Model control groups (Model group, potassium Oxonate 250 mg. Kg) -1 + hypoxanthine 400 mg/kg -1 ) Positive control group (Potassium Oxonate 250 mg. Kg) -1 + hypoxanthine 400 mg/kg -1 + febuxostat 5mg/kg -1 )，A 14 Group (Potassium Oxonate 250 mg. Kg) -1 + hypoxanthine 400 mg/kg -1 +A 14 Compound 5mg/kg -1 )，I 3 Group (compound I in CN201711323589.9 patent 3 (1- (3 '-cyano-4' -sec-butylsulfanyl-phenyl) -pyrazole-4-carboxylic acid), potassium Oxonate 250mg kg -1 + hypoxanthine 400 mg/kg -1 +I 3 Compound 5mg/kg -1 ) Each group had 8.
(2) The body weight of the mice was measured before the experiment, and 250 mg/kg of Potassium Oxonate was subcutaneously injected into the model control group and each administration group -1 + intraperitoneal injection of hypoxanthine 400 mg.kg -1 And measuring the level of the blood uric acid (marked as 1h of blood uric acid) after 1h, immediately and respectively gavage each drug group to be measured, feeding an equivalent solvent to the gavage of the model control group, and respectively measuring the uric acid values (marked as 2h, 3h, 4h, 5h, 6h, 7h and 8h of blood uric acid) after 1h, 2h, 3h, 4h, 5h, 6h, 7h and 7h of the administration. The results are plotted as graphic 6.0 and statistically analyzed as one-labeled Students t-test, and are shown in FIG. 1 ([ P ] compared to the model control group)<0.05, P compared to model control group<0.01)。
As can be seen from FIG. 1, within 8h after administration, compound A 14 Can remarkably reduce the blood uric acid level of the mice with acute hyperuricemia.
3. Compound A 14 Evaluation of uric acid-lowering Activity in Long-term hyperuricemia mouse model
(1) After 18-22g of SPF grade ICR mice are adaptively fed for one week, the mice are randomly divided into a normal control group (Vehicle group, normal saline) and a Model control group (Model group, potassium oxonate 250 mg/kg) -1 + hypoxanthine 150 mg/kg -1 ) Positive control group (Febuxostat group, potassium Oxazinate 250 mg. Kg) -1 + hypoxanthine 150 mg/kg -1 + febuxostat 5mg/kg -1 )，A 14 Group (Potassium Oxonate 250 mg. Kg) -1 + hypoxanthine 150 mg/kg -1 +A 14 Compound 5mg/kg -1 )，I 3 Group (compound I in CN201711323589.9 patent 3 Potassium Oxonate 250 mg/kg -1 + hypoxanthine 150 mg/kg -1 +I 3 Compound 5mg/kg -1 ) Each group had 8.
(2) Before the experiment, the body weight of the mice was measured, and 250 mg/kg of potassium oxonate was subcutaneously administered to each of the model control group and the administration group at 9 -1 + intraperitoneal injection of hypoxanthine 150 mg/kg -1 The normal control group is given with the same amount of normal saline, the blood uric acid level (marked as 1h blood uric acid) is respectively measured after 1h, the drug to be tested is immediately and respectively administered to each drug group by intragastric gavage, the normal control group and the model control group are administered with the same amount of menstruum, and the experiment is continuously repeated for 7 days. Administering the therapeutic agent on the seventh day for 1 hr, immediately taking blood from eyeball, and standing at 0-4 deg.C for 10min to obtain the final productThe plasma creatinine (Crea), urea Nitrogen (Urea Nitrogen) and Uric acid (Uric acid) values were determined by an automated biochemical analyzer (Beckman Coulter, AU5811, tokyo, japan) using centrifugation at 10000r/min for 5min, careful aspiration of the upper plasma. The results were plotted as graphic 6.0 and statistically analyzed as two-labeled Student's t-test, and the results are shown in FIGS. 2 to 4 # Comparison with Normal group P<0.05， ## Comparison with Normal group P<0.01,. Comparison with model group P<0.05. Comparison with model group P<0.01)。
As can be seen from FIGS. 2 to 4, the blood uric acid level in the model group was significantly higher than that in the normal group, and the modeling was successful (P)<0.001 The levels of blood creatinine and urea nitrogen in the model group are obviously higher than those in the normal group, which indicates that long-term hyperuricemia can cause certain damage (P) to the renal function of the mouse<0.05). Comparison with model groups, A 14 、I 3 Febuxostat has obvious effect of reducing uric acid (P) of hyperuricemia mice<0.05 In addition, compounds A) 14 Shows a certain urea nitrogen and creatinine reduction effect (P)<0.05 And I) and I 3 And febuxostat does not show obvious urea nitrogen and creatinine reduction effects, which indicates that the compound A 14 Besides reducing blood uric acid activity, the medicine can also improve renal function injury to a certain extent. Based on the compounds A 14 Results of evaluation of uric acid-lowering Activity, compound A 14 Not only remains to be further studied, but also is expected to be a novel multi-target inhibitor.
4. Compound A 1 -A 14 Evaluation of inhibitory Activity of URAT1 in vitro
Based on compounds A 14 The urea-lowering effect in mice of long-term hyperuricemia models is stronger than that of febuxostat, and another drug of hyperuricemia treatment drugs is used for researching and developing target protein (URAT 1, transport protein for promoting uric acid reabsorption and improving blood uric acid level) to explore the activity of the A-class compounds.
The inhibitory activity of the target compound on URAT1 of HEK293T cells was determined by using expression cells (HEK 293T) stably expressing the URAT1 gene, and compared with the activity of the marketed drug benzbrolone. The concentration of the target compound was 100. Mu. Mol/L, and the activity of HEK293T cells was measuredLabeled probe substrate [ 2 ] 14 C]Uric acid) to characterize the activity of the target compound to inhibit URAT1 in HEK293T cells, and calculate IC 50 The results are shown in Table 2.
TABLE 2 Compound A 1-14 Inhibitory Effect on URAT1 (n = 3)
As is clear from the results in Table 2, compound A obtained in the present invention 1-14 The majority of compounds have URAT1 inhibitory activity, compound A 2 、A 5 、A 7 、A 9 、A 14 Particularly significant, it is to the IC of URAT1 50 Between 0.1 and 3.5 mu M. Wherein in the A series of compounds, the compound A is substituted by an octa-alkyl amino ring 14 Shows the strongest URAT1 inhibitory effect, IC thereof 50 0.10. Mu.M, IC of benzbromarone 50 It was 0.16. Mu.M.
In a word, the phenylimidazole XOR inhibitor compound A disclosed by the invention has a certain inhibiting effect on two key drug targets in a uric acid metabolic pathway, provides a good mechanism guarantee for the compound to show good uric acid reducing activity, shows a renal function improving effect which is not possessed by febuxostat in a long-term hyperuricemia mouse model, shows that the compound has a good development prospect, and is expected to develop a novel uric acid reducing drug with an action mechanism.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (9)
1. A phenylimidazole XOR inhibitor is characterized in that the structure of the phenylimidazole XOR inhibitor is as shown in formula (I) or formula (II):
The compound represented by the formula (I) or the formula (II) is as follows:
1- (3-cyano-4-isobutoxy-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-sec-butoxy-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-neopentyloxy-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4- (pentyl-3-oxy) -phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4- (2-ethylbutoxy-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-cyclopentyloxy-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-cyclohexyloxy-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-isobutyl-methylamino-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-tetrahydropyrrole-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-piperidine-phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4- (4-methylpiperidine) -phenyl) -imidazole-4-carboxylic acid;
1- (3-cyano-4-cycloheptimido-phenyl) -imidazole-4-carboxylic acid.
2. The method of preparing a phenylimidazole-based XOR inhibitor according to claim 1, characterized by comprising the steps of:
(1) Heating 5-bromo-2-hydroxy-1-cyanobenzene, halogenated alkane and inorganic base in an organic solvent for reaction to obtain a compound A;
(2) Under the protection of argon, carrying out C-N coupling reaction on a compound A, imidazole-4-ethyl formate, cuI, inorganic base and (E) -N' N-dimethyl-1, 2-cyclohexyl diamine in an organic solvent to obtain a compound B;
(3) The compound B is subjected to alkaline hydrolysis and acidification to obtain a structure shown in a formula (I);
the reaction of the above preparation method is shown as the following formula:
3. the method of preparing a phenylimidazole-based XOR inhibitor according to claim 1, characterized by comprising the steps of:
(1) 5-bromo-2-fluorobenzonitrile and a compound HNR 1 R 2 Heating and reacting with inorganic base in an organic solvent to obtain a compound a;
(2) Under the protection of argon, carrying out C-N coupling reaction on a compound a, imidazole-4-ethyl formate, cuI, inorganic base and (E) -N' N-dimethyl-1, 2-cyclohexyl diamine in an organic solvent to obtain a compound b;
(3) The compound b is subjected to alkaline hydrolysis and acidification to obtain a structure of a formula (II);
the reaction of the above preparation method is shown as the following formula:
4. the method of preparing a phenylimidazole-based XOR inhibitor according to claim 2 or claim 3, wherein: the organic solvent in the steps (1) and (2) is DMF.
5. The method for preparing phenylimidazole-based XOR inhibitors according to claim 2 or claim 3, wherein: the inorganic base in the steps (1) and (2) is K 2 CO 3 。
6. The method for preparing phenylimidazole-based XOR inhibitors according to claim 2 or claim 3, wherein: and (3) performing alkaline hydrolysis and acidification, namely adding a NaOH aqueous solution into a mixed solution of tetrahydrofuran and ethanol for hydrolysis, and then adding a HCl aqueous solution for acidification.
7. The use of the phenylimidazole-based XOR inhibitor according to claim 1 in the preparation of an anti-hyperuricemia drug.
8. The use of the phenylimidazole-based XOR inhibitor according to claim 7 in the preparation of an anti-hyperuricemia drug, wherein: the anti-hyperuricemia drug comprises a phenylimidazole XOR inhibitor serving as an active ingredient or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
9. The use of the phenylimidazole-based XOR inhibitor according to claim 8 in the preparation of an anti-hyperuricemia drug, wherein: the pharmaceutically acceptable salt comprises a salt formed by the phenylimidazole XOR inhibitor, metal ions and organic base; the metal ion is an alkali metal ion, an alkaline earth metal ion or an aluminum ion, and the organic base is ethanolamine, diethanolamine, triethanolamine, tromethamine, piperidine or piperazine.
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