CN112920169B - N-indolyl imidazole carboxamide compound and preparation method and application thereof - Google Patents
N-indolyl imidazole carboxamide compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of medicine, and relates toAnd an N-indolyl imidazole carboxamide compound, a preparation method and application thereof. The structural general formula of the compound is as follows:
Description
Technical Field
The invention belongs to the field of medicines, and relates to an N-indolyl imidazole carboxamide compound as well as a preparation method and application thereof.
Background
Gout (Gout) is a heterogeneous group of metabolic diseases that develop as a result of long-term Hyperuricemia (Hyperuricemia) resulting in the deposition of urate in joints and soft tissues. The clinical characteristics are as follows: hyperuricemia, acute and chronic arthritis, joint deformity, chronic interstitial nephritis, renal nodes and the like, and serious patients can also have life threatening complications of renal failure and cardiovascular and cerebrovascular diseases. Furthermore, hyperuricemia is also associated with a cooperative win-win chronic disease. Gout has been statistically the second largest metabolic disease after diabetes. In recent years, with the improvement of living standard of people and the change of dietary structure, the gout incidence rate of China is on the trend of increasing year by year, and huge pressure and heavy economic burden are brought to the society.
The pathogenesis of gout is as follows: when uric acid production is increased or excretion is reduced in vivo, uric acid level in vivo is increased, and when the uric acid level exceeds the limit of dissolution, uric acid is deposited on joints and soft tissues to cause an inflammatory reaction. Uric acid is the end product of human purine metabolism. Xanthine oxidase is a key enzyme in purine metabolism. In the final stage of purine metabolism, xanthine and hypoxanthine are catalyzed to be oxidized to generate uric acid, so that the inhibition of the activity of xanthine oxidase can effectively reduce the generation of uric acid, and the xanthine oxidase inhibitor plays a very important role in the treatment of hyperuricemia and gout.
The currently marketed xanthine oxidase inhibitors include Allopurinol (Allopurinol), Febuxostat (Febuxostat) and Topiroxostat (Topiroxostat), the types are very limited, and the xanthine oxidase inhibitors have certain toxic and side effects, so that the preparation of the xanthine oxidase inhibitors with high efficiency and low toxicity has good market prospects.
The patent CN202010005245.9(N- (3-substituted-1H-indol-5-yl) amide) applied by the applicant in the earlier studies has the most remarkable technical characteristic of having an isonicotinamide structure in the molecule, and the isonicotinamide is the most key structure of the compound with the XO inhibitory activity. Applicants have demonstrated that the activity is reduced or eliminated substantially by replacing isonicotinamide with nicotinamide, pyridine-2-carboxamide, benzamide, and that the indole fragment as a support group can be substituted with another aromatic ring (Eur J Med chem2019,183: 111717.). However, the applicant has also found that: due to their large size and the limited position of the nitrogen atom on the pyridine ring, isonicotinamides generally have low XO inhibitory activity. The best active compound A9 only reached an IC50 value of 0.9. mu.M.
Disclosure of Invention
The invention aims to provide an N-indolyl imidazole carboxamide compound and a preparation method and application thereof, wherein the compound provided by the invention has an imidazole carboxamide structure, and an aromatic ring (imidazole ring) with smaller volume is obtained by constructing the imidazole carboxamide structure, so that the compound is better matched with an XO active pocket; the double nitrogen atom structure is obtained, so that the double nitrogen atom structure can simultaneously form important interactions such as charge matching, multiple hydrogen bonds and the like with Glu1261 and Glu802 residues, the affinity is enhanced, and the activity is greatly improved. The compound shows good effect in the in vitro xanthine oxidase inhibition activity test.
In order to achieve the purpose, the invention adopts the following technical scheme.
An N-indolyl imidazole carboxamide compound, which is a compound shown as a general formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein: each R1Independently is alkyl of 2-8 carbons, cycloalkyl of 3-8 carbons, allyl, benzyl or substituted benzyl; substituted benzyl is halobenzyl, cyanobenzyl, alkoxybenzyl, alkylbenzyl or alkylaminobenzyl; each R2Independently H or C1-C6 alkyl, C3-C8 cycloalkyl, allyl, benzyl or substituted benzyl; the substitution sites for imidazole may be independently 2, 4 and 5.
The N-indolyl imidazole carboxamide compound has a general formula I, or pharmaceutically acceptable salt, hydrate or solvate thereof, and the structure of the N-indolyl imidazole carboxamide compound is selected from any one of the following compounds:
n- (1-propyl-3-cyano-1H-indol-5-yl) -1H-imidazole-4-carboxamide (ZA 1);
n- (1-benzyl-3-cyano-1H-indol-5-yl) -1H-imidazole-4-carboxamide (ZA 2);
n- (1-cyclopentyl-3-cyano-1H-indol-5-yl) -1H-imidazole-4-carboxamide (ZA 3);
n- (1-propyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-5-carboxamide (ZB 1);
n- (1-benzyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-5-carboxamide (ZB 2);
n- (1-cyclopentyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-5-carboxamide (ZB 3);
n- (1-propyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-4-carboxamide (ZC 1);
n- (1-benzyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-4-carboxamide (ZC 2);
n- (1-cyclopentyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-4-carboxamide (ZC 3);
n- (1-propyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-2-carboxamide (ZD 1);
n- (1-benzyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-2-carboxamide (ZD 2);
n- (1-cyclopentyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-2-carboxamide (ZD 3).
However, the compound is not limited to the above compounds, and the compound structural formula satisfies the general formula, which is defined in the present invention.
The preparation method of the N-indolyl imidazole carboxamide compound specifically comprises the following steps.
Step 1, taking 5-nitroindole as a starting material, and preparing an intermediate 5-nitro-1H-indole-3-formaldehyde through hydroformylation.
And 2, reacting the 5-nitro-1H-indole-3-formaldehyde with hydroxylamine, dehydrating and alkylating to obtain an important intermediate 5-nitro-1-alkyl-1H-indole-3-nitrile.
And 3, reducing the 5-nitro-1-alkyl-1H-indole-3-nitrile, and reacting with various types of acyl chloride to obtain a final product.
A pharmaceutical composition comprises the N-indolyl imidazole carboxamide compound, pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier.
The N-indolyl imidazole carboxamide compound or pharmaceutically acceptable salt, hydrate or solvate thereof or the pharmaceutical composition is applied to preparation of anti-hyperuricemia and anti-gout drugs.
Further, the dosage form of the drug is a pharmaceutically therapeutically acceptable dosage form.
Further, the dose of the drug is a pharmaceutically therapeutically acceptable dose.
Compared with the prior art, the invention has the following beneficial effects.
The compound provided by the invention has an imidazole carboxamide structure, and an aromatic ring (imidazole ring) with smaller volume is obtained by constructing the imidazole carboxamide structure, so that the compound is better matched with an XO active pocket; the double nitrogen atom structure is obtained, so that the double nitrogen atom structure can simultaneously form important interactions such as charge matching, multiple hydrogen bonds and the like with Glu1261 and Glu802 residues, the affinity is enhanced, and the activity is greatly improved. Compared with the molecule in the prior art CN202010005245.9, the molecule XO inhibitory activity of the compound provided by the invention is 10-100 times higher, and the compound has obvious technical progress. The preparation method of the compound provided by the invention is simple and feasible, has high yield and is easy for large-scale production.
Detailed Description
The following examples further illustrate the embodiments of the present invention in detail. The following examples are provided to illustrate the present invention, but these examples are only for illustrating the present invention and the present invention is not limited to these.
An N-indolyl imidazole carboxamide compound, which is a compound shown as a general formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof;
wherein: each R1Independently is alkyl of 2-8 carbons, cycloalkyl of 3-8 carbons, allyl, benzyl or substituted benzyl; substituted benzyl is halobenzyl, cyanobenzyl, alkoxybenzyl, alkylbenzyl or alkylaminobenzyl; each R2Independently H, alkyl of 1-6 carbons, cycloalkyl of 3-8 carbons, allyl, benzyl or substituted benzyl; the substitution sites for imidazole may be independently 2, 4 and 5.
The compound shown in the general formula I, wherein pharmaceutically acceptable salts comprise sodium salt, potassium salt, calcium salt, ethylenediamine salt and the like; pharmaceutically acceptable hydrates include monohydrate, dihydrate, pentahydrate, and the like; pharmaceutically acceptable solvates include ethanolates, diethanolates, and the like.
The compound shown in the general formula I can also be prepared into a composition preparation together with pharmaceutically acceptable auxiliary materials such as starch, microcrystalline cellulose, magnesium stearate, glycerol and the like.
The preparation of this compound is further illustrated by the following examples.
Example 15 preparation of nitro-1H-indole-3-carbaldehyde.
5-Nitroindole (5.00g,30.84mmol) was added to a 500mL reaction flask, phosphorus oxychloride (14.18g,92.51mmol) was added slowly with stirring at 0 deg.C, and after 1h of reaction at the maintenance temperature, the reaction was completed overnight at room temperature. After the reaction is finished, adding ice water, adjusting the pH value to 8-9, refluxing at 105 ℃ for 1h, cooling, pouring a large amount of ice water, performing suction filtration, washing a filter cake with a large amount of water to obtain a filter cake, and drying in an oven to obtain 11.7g of a yellow-brown solid, wherein the yield is as follows: 94.2 percent.
EXAMPLE 25 preparation of nitro-1H-indole-3-carbonitrile
Adding 5-nitro-1H-indole-3-formaldehyde (2.0g,10.52mmol), hydroxylamine hydrochloride (3.65g,52.59mmol), sodium formate (5.72g,57.92mmol) and formic acid (40mL) into a 150mL reaction bottle, carrying out reflux reaction at 110 ℃ for 2H, completely reacting, cooling, pouring into a large amount of ice water, stirring to separate out a precipitate, carrying out suction filtration, washing a filter cake with a large amount of water to obtain a filter cake, and drying in an oven to obtain a light yellow solid 1.72g, wherein the yield is 87.8%.
Example 35 preparation of nitro-1-alkyl-1H-indole-3-carbonitrile.
5-Nitro-1H-indole-3-carbonitrile (1.0g, 5.34mmol) was added to a 150mL reaction flask, sodium hydride (60%, 1.7g, 8.01mmol) was slowly added to the flask at-10 deg.C in DMF (30mL) for reaction for 2H, and then various bromo-or chloro-alkanes (8.01mmol) and potassium iodide (0.1g, 0.53mmol) were added to the flask for reaction at 60 deg.C for 15H. After the reaction is completed, filtrate is obtained by suction filtration, and the filtrate is dried in vacuum to obtain light yellow solid with the yield of 36.8-88.7%.
Example 45 preparation of amino-1-alkyl-1H-indole-3-carbonitrile.
Adding 5-nitro-1-alkyl-1H-indole-3-nitrile (1.0g), palladium carbon (0.1g) and ethanol (50mL) into a 150mL reaction bottle, stirring at room temperature under the pressure of hydrogen for 4 hours, performing suction filtration to obtain a filtrate, and concentrating under reduced pressure to dryness to obtain a crude product of 0.64g, wherein the yield is as follows: 76.7 to 78.4 percent.
Example 5 preparation of N- (1-alkyl-3-cyano-1H-indol-5-yl) heteroaromatic amide.
Adding various carboxylic acid aromatic heterocycles (10.00mmol) into a 100mL reaction bottle, adding thionyl chloride (3.57g, 30.00mmol) and two drops of DMF (dimethyl formamide) by taking chloroform (50mL) as a solvent, reacting for 5 hours at 50 ℃ under stirring, and after the reaction is finished, drying in vacuum to remove the solvent to obtain acyl chloride for later use.
5-amino-1-alkyl-1H-indole-3-carbonitrile (4.07mmol), triethylamine (1.24g, 12.22mmol) and tetrahydrofuran (80mL) were added to a 150mL reaction flask, and the prepared acid chloride (6.11mmol) was slowly added thereto with stirring at-10 deg.C, and after maintaining the reaction temperature for 30min, the reaction was allowed to proceed overnight at room temperature. After the reaction is finished, carrying out suction filtration, washing a filter cake with a large amount of tetrahydrofuran to obtain a filtrate, carrying out reduced pressure concentration to remove most of the solvent, adding a large amount of aqueous solution (pH is 11-12), precipitating, carrying out suction filtration, washing the filter cake with a large amount of water to obtain a filter cake, passing through a rapid silica gel column, and recrystallizing an ethanol-water system to obtain a refined product, wherein the yield is 58.8-88.7%.
(1) N- (1-propyl-3-cyano-1H-indol-5-yl) -1H-imidazole-4-carboxamide (ZA 1).
White solid powder, yield 72.5%.1H NMR(500MHz,DMSO-d6)δ12.72(s,1H),9.93(s,1H),8.27(d,J＝13.6Hz,2H),7.83(d,J＝13.8Hz,2H),7.66(d,J＝12.0Hz,2H),4.19(s,2H),1.80(s,2H),0.83(s,3H).13C NMR(125MHz,DMSO-d6)δ160.35,136.75,135.81,135.04,133.72,131.65,127.16,120.97,117.23,116.02,111.41,108.97,83.04,47.78,22.63,10.74。
(2) N- (1-benzyl-3-cyano-1H-indol-5-yl) -1H-imidazole-4-carboxamide (ZA 2).
White solid powder, yield 63.5%.1H NMR(500MHz,DMSO-d6)δ12.65(s,1H),9.91(s,1H),8.43(s,1H),8.33(s,1H),7.83(s,1H),7.80(s,1H),7.64(d,J＝8.7Hz,1H),7.58(d,J＝8.8Hz,1H),7.33(d,J＝7.1Hz,2H),7.29(d,J＝7.4Hz,3H),5.49(s,2H).13C NMR(125MHz,DMSO-d6)δ160.71,137.11,136.56,136.07,135.55,133.92,131.47,128.56(2C),127.65,127.33,127.11(2C),119.92,117.44,115.85,111.71,108.98,83.71,49.79.
(3) N- (1-cyclopentyl-3-cyano-1H-indol-5-yl) -1H-imidazole-4-carboxamide (ZA 3).
White solid powder, yield 58.8%.1H NMR(500MHz,DMSO-d6)δ13.75–11.54(m,1H),9.93(s,1H),8.35(s,1H),8.29(s,1H),7.83(s,1H),7.81(s,1H),7.67(s,2H),4.92(d,J＝6.5Hz,1H),2.18(d,J＝7.1Hz,2H),1.85(s,4H),1.70(s,2H).13C NMR(125MHz,DMSO-d6)δ160.39,135.86,135.34,134.03,133.84,131.71,129.47,127.32,117.11,116.12,111.69,108.85,83.38,57.25,31.83(2C),23.29(2C)。
(4) N- (1-propyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-5-carboxamide (ZB 1).
White solid powder, yield 88.7%.1H NMR(500MHz,DMSO-d6)δ10.10(s,1H),8.27(s,1H),8.16(s,1H),7.84(s,2H),7.67(d,J＝8.7Hz,1H),7.60(d,J＝8.6Hz,1H),4.20(t,J＝6.7Hz,2H),3.89(s,3H),1.80(dd,J＝13.9,6.8Hz,2H),0.83(t,J＝7.1Hz,3H).13C NMR(125MHz,DMSO-d6)δ158.34,142.29,136.83,133.55,132.71,131.78,127.19,125.79,117.23,115.96,111.46,109.36,83.06,47.82,33.47,22.64,10.74。
(5) N- (1-benzyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-5-carboxamide (ZB 2).
White solid powder, yield 85.6%.1H NMR(500MHz,DMSO-d6)δ10.10(s,1H),8.44(s,1H),8.17(s,1H),7.84(s,1H),7.83(s,1H),7.62(d,J＝8.8Hz,1H),7.57(d,J＝8.9Hz,1H),7.36–7.32(m,2H),7.28(d,J＝7.0Hz,3H),5.50(s,2H),3.88(s,3H).13C NMR(125MHz,DMSO-d6)δ158.34,142.31,137.22,136.53,133.73,132.71,131.66,131.32,128.56(2C),128.49,127.65,127.36,127.07(2C),125.77,117.44,115.76,111.78,109.43,83.75,49.79,33.47。
(6) N- (1-cyclopentyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-5-carboxamide (ZB 3).
White solid powder, yield 86.2%.1H NMR(500MHz,DMSO-d6)δ10.09(s,1H),8.36(s,1H),8.15(s,1H),7.83(s,2H),7.69(d,J＝8.9Hz,1H),7.60(d,J＝9.0Hz,1H),4.97–4.89(m,1H),4.02(q,J＝7.1Hz,1H),3.88(s,3H),2.19(d,J＝7.6Hz,2H),1.87(d,J＝14.5Hz,4H),1.71(s,2H).13C NMR(125MHz,DMSO-d6)δ158.35,142.30,134.14,133.65,132.72,131.88,127.35,125.78,117.14,116.04,111.74,109.28,83.41,57.30,33.47,31.84(2C),23.27(2C)。
(7) N- (1-propyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-4-carboxamide (ZC 1).
White solid powder, yield 88.2%.1H NMR(500MHz,DMSO-d6)δ9.88(s,1H),8.31(s,1H),8.25(s,1H),7.81(s,1H),7.77(s,1H),7.68(d,J＝8.9Hz,1H),7.62(d,J＝8.9Hz,1H),4.19(t,J＝6.8Hz,2H),3.74(s,3H),1.79(dd,J＝14.1,7.0Hz,2H),0.82(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)δ160.45,138.02,136.73,136.30,133.72,131.62,127.14,124.00,117.21,116.04,111.39,108.89,83.04,47.77,33.24,22.63,10.73。
(8) N- (1-benzyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-4-carboxamide (ZC 2).
White solid powder, yield 87.9%.1H NMR(500MHz,DMSO-d6)δ9.88(s,1H),8.42(s,1H),8.33(s,1H),7.81(s,1H),7.76(s,1H),7.63(d,J＝8.2Hz,1H),7.57(d,J＝8.4Hz,1H),7.32(d,J＝6.3Hz,2H),7.28(d,J＝6.3Hz,3H),5.49(s,2H),3.73(s,3H).13C NMR(125MHz,DMSO-d6)δ160.46,138.02,137.10,136.56,136.25,133.89,131.46,128.55(2C),127.64,127.32,127.11(2C),124.03,117.42,115.84,111.70,108.96,83.72,49.78,33.24。
(9) N- (1-cyclopentyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-4-carboxamide (ZC 3).
White solid powder, yield 84.3%.1H NMR(500MHz,DMSO-d6)δ9.88(s,1H),8.33(s,1H),8.31(s,1H),7.81(s,1H),7.77(s,1H),7.68(d,J＝8.9Hz,1H),7.64(d,J＝8.9Hz,1H),4.90(dd,J＝13.4,6.6Hz,1H),3.74(s,3H),2.17(d,J＝7.6Hz,2H),1.85(d,J＝15.7Hz,4H),1.69(s,2H).13C NMR(125MHz,DMSO-d6)δ160.45,138.02,136.31,134.00,133.82,131.70,127.32,123.99,117.10,116.12,111.66,108.82,83.40,57.26,33.25,31.82(2C),23.29(2C)。
(10) N- (1-propyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-2-carboxamide (ZD 1).
White solid powder, yield 88.4%.1H NMR(500MHz,DMSO-d6)δ10.41(s,1H),8.31(s,1H),8.27(s,1H),7.66(dd,J＝16.5,8.7Hz,2H),7.44(s,1H),7.09(s,1H),4.20(t,J＝6.4Hz,2H),4.02(s,3H),1.80(dd,J＝13.9,6.9Hz,2H),0.83(t,J＝7.2Hz,3H).13C NMR(125MHz,DMSO-d6)δ157.21,138.55,136.86,133.19,131.86,127.10,127.01,126.65,117.41,115.95,111.46,109.31,83.16,47.80,35.10,22.63,10.73。
(11) N- (1-benzyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-2-carboxamide (ZD 2).
White solid powder, yield 81.7%.1H NMR(500MHz,DMSO-d6)δ10.39(s,1H),8.43(s,1H),8.32(s,1H),7.64(d,J＝8.9Hz,1H),7.59(d,J＝8.8Hz,1H),7.43(s,1H),7.36–7.31(m,2H),7.29(d,J＝7.2Hz,3H),7.08(s,1H),5.49(s,2H),4.01(s,3H).13C NMR(125MHz,DMSO-d6)δ157.21,138.50,137.24,136.53,133.38,131.69,128.56(2C),127.66,127.27,127.12(2C),127.01,126.68,117.62,115.77,111.78,109.36,83.82,49.80,35.11。
(12) N- (1-cyclopentyl-3-cyano-1H-indol-5-yl) -1-methyl-1H-imidazole-2-carboxamide (ZD 3).
White solid powder, yield 74.3%.1H NMR(500MHz,DMSO-d6)δ10.42(s,1H),8.36(s,1H),8.31(s,1H),7.71–7.64(m,2H),7.44(s,1H),7.09(s,1H),4.92(dd,J＝13.7,6.8Hz,1H),4.02(s,3H),2.18(d,J＝7.5Hz,2H),1.89–1.81(m,4H),1.70(s,2H).13C NMR(125MHz,DMSO-d6)δ157.21,138.56,134.13,133.29,131.94,127.28,127.01,126.66,117.30,116.03,111.73,109.24,83.52,57.29,35.10,31.83(2C),23.29(2C)。
Example 6 xanthine oxidase inhibitory activity of N-indolylimidazole carboxamides.
1. The material was tested.
Reagent: xanthine oxidase (Sigma), xanthine, potassium dihydrogen phosphate, and sodium hydroxide. The instrument comprises the following steps: an electronic analytical balance (AR1140 model), an electric heating constant temperature water bath (DK-98-1 model) and a UV2100 type ultraviolet-visible spectrophotometer.
2. Experimental methods.
Reaction diluent: 50mM potassium phosphate buffer, pH 7.4.
Sample preparation: a10. mu. mmol sample was weighed out accurately, dissolved in 100. mu.L DMSO and added with 900ml PBS to obtain a 10mM stock solution.
Preparation of xanthine substrate: 9.127mg of xanthine was weighed out accurately, dissolved in a small amount of NaOH solution and diluted with PBS solution to 100mL of constant volume (ready for use each day).
The experimental steps are as follows: adding xanthine oxidase (reaction concentration of 1.4U/L) and test drug (positive drug is topiroxostat) into the reaction system in sequence, incubating at 25 deg.C for 15min, adding xanthine substrate (reaction concentration of 86 μ M), reacting for 60min, and measuring absorbance value at 294 nm. Each sample was run in parallel 3 times, the reaction rates were recorded separately, and the inhibition rates of the samples were calculated by taking the average.
The blank control group was prepared by adding the same volume of PBS as the sample without xanthine oxidase and recording the change in absorbance as a blank control.
The inhibition of XOD by the sample was calculated according to the following formula:
in the formula ASample (A)、AYin (kidney)、ASample space、AYin spaceThe absorption peaks of the sample, blank, XOD control and enzyme control are indicated, respectively. The test results are shown in Table 1.
TABLE 1 XO inhibition of the samples at 1. mu.M concentration.
Example 7 Activity comparison study with N- (3-substituted-1H-indol-5-yl) amide compounds.
The N- (3-substituted-1H-indol-5-yl) amide compound is an XO inhibitor disclosed by the applicant (patent number CN 202010005245.9), wherein the compound with the best activity is A9, and the molecular structure of the compound is as follows:
the experimental steps are as follows: xanthine oxidase (reaction concentration of 1.4U/L) and the tested drug (final concentration of 1.04. mu.M, 0.52. mu.M, 0.26. mu.M, 0.13. mu.M, 0.06. mu.M, respectively) were sequentially added to the reaction system, and after incubation at 25 ℃ for 15min, xanthine substrate (reaction concentration of 86. mu.M) was added, and after reaction for 60min, absorbance value at 294nm was measured. Each sample was run in parallel 3 times, the reaction rates were recorded separately, and the inhibition rates of the samples were calculated by taking the average. The results of the activity comparison study are shown in Table 2.
From table 2, it can be found that the XO inhibitory activities of the representative compounds of the present invention, ZA1, ZA2, ZA3, ZB3 and ZD1, were all significantly superior to a 9. The compound has remarkable advantages in molecular structure and pharmacological activity.
Table 2 XO inhibitory activity of different compounds at concentrations of 1.04 μ M, 0.52 μ M, 0.26 μ M, 0.13 μ M, 0.06 μ M.
Claims (7)
1. A kind ofNAn indolylimidazole carboxamide compound, which is characterized in that the compound is a compound shown as a general formula I or a pharmaceutically acceptable salt thereof,
wherein: each R1Independently alkyl with 2-8 carbon atoms, cycloalkyl with 3-8 carbon atoms, benzyl and substituted benzyl; the substituted benzyl is halogenated benzyl and cyanobenzyl; each R2Independently is H or alkyl of 1-6 carbons; substitution site for imidazoleIndependently 2, 4 and 5.
2. The method of claim 1N-indolylimidazole carboxamides, characterized in that the compounds of general formula I or their pharmaceutically acceptable salts have a structure selected from any one of the following:
N- (1-propyl-3-cyano-1)H-indol-5-yl) -1H-imidazole-4-carboxamide;
N- (1-benzyl-3-cyano-1)H-indol-5-yl) -1H-imidazole-4-carboxamide;
N- (1-cyclopentyl-3-cyano-1)H-indol-5-yl) -1H-imidazole-4-carboxamide;
N- (1-propyl-3-cyano-1)H-indol-5-yl) -1-methyl-1H-imidazole-5-carboxamide;
N- (1-benzyl-3-cyano-1)H-indol-5-yl) -1-methyl-1H-imidazole-5-carboxamide;
N- (1-cyclopentyl-3-cyano-1)H-indol-5-yl) -1-methyl-1H-imidazole-5-carboxamide;
N- (1-propyl-3-cyano-1)H-indol-5-yl) -1-methyl-1H-imidazole-4-carboxamide;
N- (1-benzyl-3-cyano-1)H-indol-5-yl) -1-methyl-1H-imidazole-4-carboxamide;
N- (1-cyclopentyl-3-cyano-1)H-indol-5-yl) -1-methyl-1H-imidazole-4-carboxamide;
N- (1-propyl-3-cyano-1)H-indol-5-yl) -1-methyl-1H-imidazole-2-carboxamide;
N- (1-benzyl-3-cyano-1)H-indol-5-yl) -1-methyl-1H-imidazole-2-carboxamide;
N- (1-cyclopentyl-3-cyano-1)H-indol-5-yl) -1-methyl-1H-imidazole-2-carboxamide.
3. The method of claim 1NThe preparation method of the-indolyl imidazole carboxamide compound is characterized by comprising the following steps:
step 1, preparing an intermediate 5-nitro-1 by using 5-nitroindole as an initial raw material through hydroformylationH-indole-3-carbaldehyde;
step 2, 5-Nitro-1HReacting indole-3-formaldehyde with hydroxylamine, dehydrating, alkylating to obtain important intermediate 5-nitro-1-alkyl-1H-indole-3-carbonitrile;
step 3, 5-Nitro-1-alkyl-1HThe indole-3-nitrile is reduced and then reacts with various types of acyl chloride to obtain the final product.
4. A pharmaceutical composition is characterized by comprisingN-indolylimidazole carboxamides, pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers.
5. The method of claim 1N-use of an indolylimidazole carboxamide compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 4 for the preparation of an anti-hyperuricemic and anti-gout drug.
6. The use of claim 5, wherein the medicament is in a pharmaceutically-therapeutically acceptable dosage form.
7. The use of claim 5, wherein the dose of the medicament is a pharmacotherapeutically acceptable dose.
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