CN112920170A - N- (indole-5-yl) aromatic heterocyclic amide compound and preparation method and application thereof - Google Patents

N- (indole-5-yl) aromatic heterocyclic amide compound and preparation method and application thereof Download PDF

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CN112920170A
CN112920170A CN202110129114.6A CN202110129114A CN112920170A CN 112920170 A CN112920170 A CN 112920170A CN 202110129114 A CN202110129114 A CN 202110129114A CN 112920170 A CN112920170 A CN 112920170A
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indol
cyano
indole
carboxamide
benzyl
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孟繁浩
涂顺
张廷剑
王朝冉
张旭
王秋银
路鹏飞
胡森森
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    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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Abstract

The invention belongs to the field of medicines, and relates to an N- (indole-5-yl) aromatic heterocyclic amide compound, and a preparation method and application thereof. The structural general formula of the N- (indole-5-yl) aromatic heterocyclic amide compound is as follows:

Description

N- (indole-5-yl) aromatic heterocyclic amide compound and preparation method and application thereof
Technical Field
The invention belongs to the field of medicines, and relates to an N- (indole-5-yl) heteroaromatic amide compound, a preparation method thereof and application thereof in treating gout.
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.
In previous studies, applicants discovered that a series of N- (3-substituted-1H-indol-5-yl) amides were published or reported by the applicants as XO inhibitors (CN 111072634A). The isonicotinamide structural fragment is twisted, and cannot be stably combined with amino acid residues of an active pocket, so that the activity of the isonicotinamide structural fragment is better than that of allopurinol, but is much lower than that of topiroxostat.
Disclosure of Invention
The invention aims to provide N- (indole-5-yl) aromatic heterocyclic amides, a preparation method and application thereof, and the prepared compounds show good effects in-vitro xanthine oxidase inhibitory activity tests.
In order to achieve the purpose, the invention adopts the following technical scheme.
An N- (indole-5-yl) aromatic heterocyclic amide compound, which is a compound shown as a general formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof,
Figure BDA0002924553410000021
wherein:
x and Y are N or CH; 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.
The N- (indole-5-yl) aromatic heterocyclic amide compound has a general formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof, and the structure of the compound is selected from any one of the following compounds:
n- (1-propyl-3-cyano-1H-indol-5-yl) pyrimidine-5-carboxamide (TA 1);
n- (1-benzyl-3-cyano-1H-indol-5-yl) pyrimidine-5-carboxamide (TA 2);
n- (1-cyclopentyl-3-cyano-1H-indol-5-yl) pyrimidine-5-carboxamide (TA 3);
n- (1-propyl-3-cyano-1H-indol-5-yl) pyrimidine-4-carboxamide (TB 1);
n- (1-benzyl-3-cyano-1H-indol-5-yl) pyrimidine-4-carboxamide (TB 2);
n- (1-cyclopentyl-3-cyano-1H-indol-5-yl) pyrimidine-4-carboxamide (TB 3);
n- (1-propyl-3-cyano-1H-indol-5-yl) pyrazine-2-carboxamide (TC 1);
n- (1-benzyl-3-cyano-1H-indol-5-yl) pyrazine-2-carboxamide (TC 2);
n- (1-cyclopentyl-3-cyano-1H-indol-5-yl) pyrazine-2-carboxamide (TC 3);
n- (1-propyl-3-cyano-1H-indol-5-yl) nicotinamide (TD 1);
n- (1-benzyl-3-cyano-1H-indol-5-yl) nicotinamide (TD 2);
n- (1-cyclopentyl-3-cyano-1H-indol-5-yl) nicotinamide (TD 3);
n- (1-propyl-3-cyano-1H-indol-5-yl) picolinamide (TE 1);
n- (1-benzyl-3-cyano-1H-indol-5-yl) picolinamide (TE 2);
n- (1-benzyl-3-cyano-1H-indol-5-yl) picolinamide (TE 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- (indole-5-yl) aromatic heterocyclic amide 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- (indole-5-yl) aromatic heterocyclic amide compound, the pharmaceutically acceptable salt, the hydrate or the solvate thereof and a pharmaceutically acceptable carrier.
The N- (indole-5-yl) aromatic heterocyclic amide 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 effects:
the N- (indole-5-yl) aromatic heterocyclic amide compound provided by the invention provides more potential hydrogen bond receptors by introducing aromatic heterocycles of two nitrogen atoms, so that the N- (indole-5-yl) aromatic heterocyclic amide compound is more stably combined with an XO pocket. Compared with the prior art (CN111072634A) disclosed by the applicant, the compound disclosed by the invention has stronger molecular structure innovation and greatly improved activity. The preparation method of the compound of the general formula I 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- (indole-5-yl) aromatic heterocyclic amide compound, which is a compound shown as a general formula I or a pharmaceutically acceptable salt, hydrate or solvate thereof,
Figure BDA0002924553410000041
wherein:
x and Y are N or CH; each R1Independently is alkyl of 2-8 carbons, cycloalkyl of 3-8 carbons, allyl, benzyl or substituted benzyl; the substituted benzyl group may be a halobenzyl, cyanobenzyl, alkoxybenzyl, alkylbenzyl or alkylaminobenzyl group.
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 36.8-92.3%.
(1) N- (1-propyl-3-cyano-1H-indol-5-yl) pyrimidine-5-carboxamide (TA 1).
White solid powder, yield 92.3%. M/z304.1[ M + H]-
(2) N- (1-benzyl-3-cyano-1H-indol-5-yl) pyrimidine-5-carboxamide (TA 2).
White solid powder, yield 91.2%. M/z 352.1[ M + H ]]-
(3) N- (1-cyclopentyl-3-cyano-1H-indol-5-yl) pyrimidine-5-carboxamide (TA 3).
White solid powder, yield 88.2%. M/z330.1[ M + H ]]-
(4) N- (1-propyl-3-cyano-1H-indol-5-yl) pyrimidine-4-carboxamide (TB 1).
Pale yellow solid powder, yield 36.8%. M/z304.1[ M + H]-
(5) N- (1-benzyl-3-cyano-1H-indol-5-yl) pyrimidine-4-carboxamide (TB 2).
Pale yellow solid powder, yield 44.2%. M/z 352.1[ M + H ]]-
(6) N- (1-cyclopentyl-3-cyano-1H-indol-5-yl) pyrimidine-4-carboxamide (TB 3).
Pale yellow solid powder, yield 39.5%. M/z330.1[ M + H ]]-
(7) N- (1-propyl-3-cyano-1H-indol-5-yl) pyrazine-2-carboxamide (TC 1).
White solid powder, yield 56.8%.1H NMR(500MHz,DMSO-d6)δ10.82(s,1H),9.32 (s,1H),8.93(s,1H),8.82(s,1H),8.36(s,1H),8.30(s,1H),7.78(d,J=8.9Hz,1H), 7.70(d,J=8.9Hz,1H),4.21(t,J=6.8Hz,2H),1.81(dd,J=14.2,7.1Hz,2H),0.83 (t,J=7.3Hz,3H).13C NMR(125MHz,DMSO-d6)δ161.43,147.45,145.02,143.83, 143.05,137.07,132.88,132.17,127.08,117.60,115.86,111.56,109.91,83.27,47.83, 22.64,10.74。
(8) N- (1-benzyl-3-cyano-1H-indol-5-yl) pyrazine-2-carboxamide (TC 2).
White solid powder, yield 55.9%.1H NMR(500MHz,DMSO-d6)δ10.82(s,1H),9.31 (s,1H),8.93(s,1H),8.82(d,J=1.2Hz,1H),8.47(s,1H),8.38(s,1H),7.74(d,J=8.9Hz,1H),7.65(d,J=9.0Hz,1H),7.36–7.32(m,2H),7.32–7.26(m,3H),5.51 (s,2H).13C NMR(125MHz,DMSO-d6)δ161.45,147.47,144.98,143.84,143.04, 137.45,136.51,133.06,132.02,128.58(2C),127.68,127.25,127.13(2C),117.82, 115.67,111.87,109.99,83.93,49.82.
(9) N- (1-cyclopentyl-3-cyano-1H-indol-5-yl) pyrazine-2-carboxamide (TC 3).
White solid powder, yield 61.2%.1H NMR(500MHz,DMSO-d6)δ10.82(s,1H),9.32 (s,1H),8.93(d,J=2.0Hz,1H),8.82(s,1H),8.39(s,1H),8.36(s,1H),7.79(d,J= 9.0Hz,1H),7.72(d,J=8.9Hz,1H),4.94(dd,J=13.9,6.9Hz,1H),2.19(d,J=7.8 Hz,2H),1.91–1.82(m,4H),1.71(s,2H).13C NMR(125MHz,DMSO-d6)δ161.43, 147.45,145.02,143.83,143.04,134.36,132.98,132.25,127.24,117.50,115.95, 111.83,109.84,83.63,57.31,31.85(2C),23.30(2C).
(10) N- (1-propyl-3-cyano-1H-indol-5-yl) nicotinamide (TD 1).
White solid powder, yield 61.2%.1H NMR(600MHz,DMSO-d6)δ10.52(s,1H),9.20 (s,1H),8.81(s,1H),8.35(s,1H),8.29(s,1H),8.23(s,1H),7.69(s,2H),7.61(s,1H), 4.21(s,2H),1.81(s,2H),0.84(s,3H).13C NMR(150MHz,DMSO-d6)δ164.36, 152.39,149.04,137.65,135.95,134.19,132.64,131.27,127.76,124.18,118.00, 116.57,112.20,110.31,83.76,48.46,23.28,11.38。
(11) N- (1-benzyl-3-cyano-1H-indol-5-yl) nicotinamide (TD 2).
White solid powder, yield 61.2%.1H NMR(600MHz,DMSO-d6)δ10.50(s,1H),9.14(s, 1H),8.76(d,J=3.9Hz,1H),8.46(s,1H),8.32(d,J=7.8Hz,1H),8.24(s,1H),7.64 (q,J=9.0Hz,2H),7.57(dd,J=7.5,4.9Hz,1H),7.37–7.32(m,2H),7.29(d,J= 6.3Hz,3H),5.51(s,2H).13C NMR(150MHz,DMSO-d6)δ164.41,152.55,149.13, 138.04,137.17,135.87,134.38,132.50,131.04,129.22(2C),128.31,127.93, 127.72(2C),123.98,118.21,116.38,112.53,110.37,84.44,50.43.
(12) N- (1-cyclopentyl-3-cyano-1H-indol-5-yl) nicotinamide (TD 3).
White solid powder, yield 61.2%.1H NMR(600MHz,DMSO-d6)δ10.51(s,1H),9.16 (s,1H),8.77(s,1H),8.36(d,J=22.4Hz,2H),8.23(s,1H),7.70(s,2H),7.58(s,1H), 4.94(s,1H),2.19(s,2H),1.86(s,4H),1.71(s,2H).13C NMR(150MHz,DMSO-d6) δ164.37,152.52,149.14,135.85,134.94,134.28,132.72,131.06,127.92,123.96, 117.91,116.65,112.46,110.24,84.12,57.93,32.47(2C),23.90(2C)。
(13) N- (1-propyl-3-cyano-1H-indol-5-yl) picolinamide (TE 1).
White solid powder, yield 61.2%.1H NMR(600MHz,DMSO-d6)δ10.73(s,1H),8.74 (dd,J=15.5,3.6Hz,1H),8.40(s,1H),8.29(s,1H),8.18(d,J=7.4Hz,1H),8.08(t, J=7.1Hz,1H),7.77(d,J=8.4Hz,1H),7.68(d,J=8.8Hz,2H),4.21(s,2H),1.80 (dd,J=13.4,6.6Hz,2H),0.83(t,J=6.8Hz,3H).13C NMR(151MHz,DMSO-d6)δ 162.88,150.48,148.88,138.59,137.63,133.75,132.62,127.75,127.31,122.78, 118.08,116.60,112.20,110.09,83.82,48.43,23.29,11.38。
(14) N- (1-benzyl-3-cyano-1H-indol-5-yl) picolinamide (TE 2).
White solid powder, yield 61.2%.1H NMR(600MHz,DMSO-d6)δ10.75(s,1H),8.76 (d,J=4.5Hz,1H),8.47(s,1H),8.44(d,J=1.4Hz,1H),8.19(d,J=7.8Hz,1H), 8.08(td,J=7.7,1.3Hz,1H),7.75(dt,J=7.7,3.8Hz,1H),7.68(dd,J=6.8,5.3Hz, 1H),7.65(d,J=8.9Hz,1H),7.37–7.33(m,2H),7.30(dd,J=14.8,7.2Hz,3H), 5.52(s,2H).13C NMR(151MHz,DMSO-d6)δ162.91,150.44,148.87,138.59, 138.00,137.17,133.93,132.47,129.21(2C),128.31,127.93,127.76(2C),127.32, 122.80,118.32,116.41,112.51,110.18,84.50,50.44。
(15) N- (1-cyclopentyl-3-cyano-1H-indol-5-yl) picolinamide (TE 3).
White solid powder, yield 61.2%.1H NMR(600MHz,DMSO-d6)δ10.73(s,1H),8.75 (t,J=6.9Hz,1H),8.40(d,J=1.2Hz,1H),8.38(s,1H),8.18(d,J=7.7Hz,1H), 8.08(td,J=7.7,1.3Hz,1H),7.78(dd,J=8.9,1.5Hz,1H),7.72–7.67(m,2H),4.94 (dd,J=14.1,7.0Hz,1H),2.19(d,J=7.7Hz,2H),1.89–1.82(m,4H),1.73–1.69 (m,2H).13C NMR(151MHz,DMSO-d6)δ162.89,150.49,148.89,138.60,134.93, 133.85,132.71,127.91,127.32,122.79,117.99,116.68,112.48,110.02,84.18,57.90, 32.48(2C),23.93(2C)。
Example 6 xanthine oxidase inhibitory activity of N- (indol-5-yl) aromatic heterocyclic amide compounds.
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 900 ml 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:
Figure BDA0002924553410000081
in the formula ASample (A)、AYin (kidney)、ASample space、AYin space: the absorption peaks for the sample, blank, XOD control and enzyme control are shown, respectively. The test results are shown in Table 1.
TABLE 1 XO inhibition of the samples at a concentration of 33. mu.M.
Figure BDA0002924553410000091
Example 7 Activity comparison study of N- (indol-5-yl) heteroaromatic amide compounds with N- (3-substituted-1H-indol-5-yl) amide compound A9.
The N- (3-substituted-1H-indol-5-yl) amide compound is disclosed or reported by the applicant as an XO inhibitor (patent number CN111072634A), wherein the compound with the best activity is A9, and the molecular structure of the compound is as follows:
Figure BDA0002924553410000092
the experimental steps are as follows: xanthine oxidase (reaction concentration of 1.4U/L) and the tested drug (final concentration of 1.04 μ M, 0.52 μ M, 0.26 μ M and 0.13 μ M, respectively) were sequentially added to the reaction system, and after incubation at 25 ℃ for 15min, xanthine substrate (reaction concentration of 86 μ 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. Table 2 shows that the XO inhibitory activities of the representative compounds TC1, TC2, and TC3 of the present invention are improved by more than 10 times as compared with compound a9, and there is a very significant technical advance. 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.
Figure BDA0002924553410000101

Claims (7)

1. An N- (indole-5-yl) aromatic heterocyclic amide compound, which is characterized in that the compound is a compound shown as a general formula I or a pharmaceutically acceptable compoundA salt, a hydrate or a solvate thereof,
Figure FDA0002924553400000011
wherein: x and Y are N or CH; 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.
2. The N- (indol-5-yl) heteroaromatic amide compound according to claim 1, wherein the compound of formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, has a structure selected from any one of:
n- (1-propyl-3-cyano-1H-indol-5-yl) pyrimidine-5-carboxamide;
n- (1-benzyl-3-cyano-1H-indol-5-yl) pyrimidine-5-carboxamide;
n- (1-cyclopentyl-3-cyano-1H-indol-5-yl) pyrimidine-5-carboxamide;
n- (1-propyl-3-cyano-1H-indol-5-yl) pyrimidine-4-carboxamide;
n- (1-benzyl-3-cyano-1H-indol-5-yl) pyrimidine-4-carboxamide;
n- (1-cyclopentyl-3-cyano-1H-indol-5-yl) pyrimidine-4-carboxamide;
n- (1-propyl-3-cyano-1H-indol-5-yl) pyrazine-2-carboxamide;
n- (1-benzyl-3-cyano-1H-indol-5-yl) pyrazine-2-carboxamide;
n- (1-cyclopentyl-3-cyano-1H-indol-5-yl) pyrazine-2-carboxamide;
n- (1-propyl-3-cyano-1H-indol-5-yl) nicotinamide;
n- (1-benzyl-3-cyano-1H-indol-5-yl) nicotinamide;
n- (1-cyclopentyl-3-cyano-1H-indol-5-yl) nicotinamide;
n- (1-propyl-3-cyano-1H-indol-5-yl) picolinamide;
n- (1-benzyl-3-cyano-1H-indol-5-yl) picolinamide;
n- (1-benzyl-3-cyano-1H-indol-5-yl) picolinamide.
3. The method for preparing an N- (indol-5-yl) heteroaromatic amide compound according to claim 1, which specifically comprises the steps of:
step 1, preparing an intermediate 5-nitro-1H-indole-3-formaldehyde by using 5-nitroindole as an initial raw material 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.
4. A pharmaceutical composition, which comprises the N- (indol-5-yl) aromatic heterocyclic amide compound, the pharmaceutically acceptable salt, the hydrate or the solvate thereof and a pharmaceutically acceptable carrier.
5. The use of an N- (indol-5-yl) heteroaromatic amide compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition according to claim 4 for the preparation of anti-hyperuricemia and anti-gout drugs.
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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* Cited by examiner, † Cited by third party
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US20120184582A1 (en) * 2009-10-07 2012-07-19 Jeong Uk Song Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same
US20140154805A1 (en) * 2012-12-03 2014-06-05 City Of Hope Enhancers of induced pluripotent stem cell reprogramming
CN111072647A (en) * 2019-12-11 2020-04-28 沈阳药科大学 3-substituted indole-5-oxo-4, 5-dihydro-1, 2, 4-oxadiazole compound and application thereof
CN111072634A (en) * 2020-01-03 2020-04-28 中国医科大学 1-substituted-3-substituted-5-substituted amide-1H-indole compound and preparation method and application thereof
WO2020252240A1 (en) * 2019-06-14 2020-12-17 Ifm Due, Inc. Compounds and compositions for treating conditions associated with sting activity

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120184582A1 (en) * 2009-10-07 2012-07-19 Jeong Uk Song Novel compounds effective as xanthine oxidase inhibitors, method for preparing the same, and pharmaceutical composition containing the same
US20140154805A1 (en) * 2012-12-03 2014-06-05 City Of Hope Enhancers of induced pluripotent stem cell reprogramming
WO2020252240A1 (en) * 2019-06-14 2020-12-17 Ifm Due, Inc. Compounds and compositions for treating conditions associated with sting activity
CN111072647A (en) * 2019-12-11 2020-04-28 沈阳药科大学 3-substituted indole-5-oxo-4, 5-dihydro-1, 2, 4-oxadiazole compound and application thereof
CN111072634A (en) * 2020-01-03 2020-04-28 中国医科大学 1-substituted-3-substituted-5-substituted amide-1H-indole compound and preparation method and application thereof

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