CN112920170B - N- (indol-5-yl) aromatic heterocyclic amide compound and preparation method and application thereof - Google Patents
N- (indol-5-yl) aromatic heterocyclic amide compound and preparation method and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic 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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- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- C—CHEMISTRY; METALLURGY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom 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- (indol-5-yl) aromatic heterocyclic amide compound is as follows:
Description
Technical Field
The invention belongs to the field of medicines, and relates to an N- (indole-5-yl) aromatic heterocyclic amide compound, a preparation method thereof and application thereof in treating gout.
Background
Gout (Gout) is a heterogeneous group of metabolic diseases formed by deposition of urate on joints and soft tissues due to long-term Hyperuricemia (Hyperuricemia). The clinical characteristics are as follows: hyperuricemia, acute and chronic arthritis, joint deformity, chronic interstitial nephritis, renal nodule and the like, and serious cases also can be complicated with renal failure and cardiovascular and cerebrovascular diseases to endanger life. Furthermore, hyperuricemia is also associated with co-win chronic diseases. Gout has been counted as the second most metabolic disease next to diabetes. In recent years, with the improvement of the living standard of people and the change of the diet structure, the incidence rate of gout in China tends to rise year by year, and huge pressure and heavy economic burden are brought to society.
The pathogenesis of gout is as follows: elevated uric acid levels in the body can result when uric acid production is increased or excretion is decreased in the body, and uric acid can deposit in joints and soft tissues when its solubility limit is exceeded, causing an inflammatory response. Uric acid is the final product of purine metabolism in humans. Xanthine oxidase is a key enzyme in purine metabolism. In the final stage of purine metabolism, xanthine and hypoxanthine are catalyzed to oxidize to generate uric acid, so that inhibiting the activity of xanthine oxidase can effectively reduce the generation of uric acid, and xanthine oxidase inhibitors play a very important role in the treatment of hyperuricemia and gout.
The xanthine oxidase inhibitors which are currently marketed are Allopurinol (Allopurinol), febuxostat (topirox) and topirox (topirox), and have very limited types and certain toxic and side effects, so that the development of the xanthine oxidase inhibitor with high efficiency and low toxicity has good market prospect.
In previous studies, applicants have found that a range of N- (3-substituted-1H-indol-5-yl) amides are disclosed or reported by applicants as XO inhibitors (CN 111072634 a). Because the isonicotinamide structural fragment is twisted in direction and cannot be stably combined with the amino acid residue of the active pocket, the activity is far lower than topiroxostat although being superior to allopurinol.
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 inhibition activity tests.
In order to achieve the above purpose, the present invention adopts the following technical scheme.
An N- (indol-5-yl) aromatic heterocyclic amide compound, which is a compound shown in a general formula I or pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein:
x and Y are N or CH; each R is 1 Independently alkyl of 2 to 8 carbons, cyclic alkyl of 3 to 8 carbons, allyl, benzyl or substituted benzyl; the substituted benzyl is halobenzyl, cyanobenzyl, alkoxybenzyl, alkylbenzyl or alkylaminobenzyl.
The N- (indol-5-yl) aromatic heterocyclic amide compound has a structure selected from any one of the following compounds with a general formula I or pharmaceutically acceptable salts, hydrates or solvates thereof:
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) pyridine amide (TE 1);
n- (1-benzyl-3-cyano-1H-indol-5-yl) pyridine amide (TE 2);
n- (1-benzyl-3-cyano-1H-indol-5-yl) pyridine amide (TE 3).
But not limited to the above compounds, as long as the structural formula of the compounds satisfies the general formula, are all within the scope of the present invention.
The preparation method of the N- (indol-5-yl) aromatic heterocyclic amide compound specifically comprises the following steps.
Step 1, using 5-nitroindole as a starting material, and carrying out hydroformylation to obtain an intermediate 5-nitro-1H-indole-3-formaldehyde.
Step 2, reacting 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 then reacting with various types of acyl chloride to obtain a final product.
A pharmaceutical composition comprises the N- (indol-5-yl) aromatic heterocyclic amide compound, a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier.
The N- (indol-5-yl) aromatic heterocyclic amide compound or pharmaceutically acceptable salt, hydrate or solvate thereof or the application of the pharmaceutical composition in preparing anti-hyperuricemia and anti-gout drugs.
Further, the dosage form of the medicament is a pharmaceutically acceptable dosage form.
Further, the dosage of the drug is a pharmaceutically acceptable dosage.
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 acceptors by introducing aromatic heterocyclic rings with two nitrogen atoms, so that the N- (indole-5-yl) aromatic heterocyclic amide compound can be combined with an XO pocket more stably. Compared with the prior art (CN 111072634A) disclosed by the applicant, the compound disclosed by the invention has stronger molecular structure innovation and greatly improves the activity. The preparation method of the compound shown in the general formula I is simple and feasible, has high yield and is easy for mass production.
Detailed Description
The following describes the present invention in further detail with reference to examples. The following examples are given for the purpose of illustration of the invention, but are not intended to be limiting.
An N- (indol-5-yl) aromatic heterocyclic amide compound, which is a compound shown in a general formula I or pharmaceutically acceptable salt, hydrate or solvate thereof,
wherein:
x and Y are N or CH; each R is 1 Independently alkyl of 2 to 8 carbons, cyclic alkyl of 3 to 8 carbons, allyl, benzyl or substituted benzyl; the substituted benzyl group may be a halobenzyl group, cyanobenzyl group, alkoxybenzyl group, alkylbenzyl group or alkylamino benzyl group.
The compound shown in the general formula I, and pharmaceutically acceptable salts thereof 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 ethanolate, diethanolate, and the like.
The compound shown in the general formula I can also be prepared into a composition preparation 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 (5.00 g,30.84 mmol) was added to a 500mL reaction flask, phosphorus oxychloride (14.18 g,92.51 mmol) was slowly added with stirring at 0deg.C, and after maintaining the temperature for 1h, the reaction was completed at room temperature overnight. After the reaction is finished, adding ice water, regulating the pH to 8-9, refluxing for 1h at 105 ℃, pouring a large amount of ice water after cooling, 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 11.7g of yellowish-brown solid with the yield: 94.2%.
Example 25 preparation of nitro-1H-indole-3-carbonitrile.
5-nitro-1H-indole-3-carbaldehyde (2.0 g,10.52 mmol), hydroxylamine hydrochloride (3.65 g,52.59 mmol), sodium formate (5.72 g,57.92 mmol) and formic acid (40 mL) were added into a 150mL reaction flask, the reaction was carried out at 110℃for 2H under reflux, the reaction was completed, the solution was cooled and poured into a large amount of ice water, the precipitate was precipitated by stirring, the solution was filtered off with suction, the filter cake was washed with a large amount of water, and the filter cake was dried in an oven to obtain 1.72g of pale yellow solid, and the yield was 87.8%.
Example 35 preparation of nitro-1-alkyl-1H-indole-3-carbonitrile.
In a 150mL reaction flask was added 5-nitro-1H-indole-3-carbonitrile (1.0 g,5.34 mmol) and sodium hydride (60%, 1.7g,8.01 mmol) was slowly added at-10℃in DMF (30 mL) to react for 2H, followed by various brominated or chlorinated alkanes (8.01 mmol) and potassium iodide (0.1 g,0.53 mmol) at 60℃for 15H. And after the reaction is completed, carrying out suction filtration to obtain filtrate, and carrying out vacuum drying on the filtrate to obtain light yellow solid, wherein the yield is 36.8% -88.7%.
Example 4 5 preparation of amino-1-alkyl-1H-indole-3-carbonitrile.
5-nitro-1-alkyl-1H-indole-3-carbonitrile (1.0 g), palladium on carbon (0.1 g) and ethanol (50 mL) were added to a 150mL reaction flask, stirred at room temperature under hydrogen pressure for 4H, and then suction filtered to give a filtrate, which was concentrated to dryness under reduced pressure to give a crude product of 0.64g, yield: 76.7-78.4%.
Example 5 preparation of N- (1-alkyl-3-cyano-1H-indol-5-yl) aromatic heterocyclic amide.
Into a 100mL reaction flask, various carboxylic aromatic heterocycles (10.00 mmol) were added, chloroform (50 mL) was used as a solvent, thionyl chloride (3.57 g,30.00 mmol) and two drops of DMF were added, and the mixture was stirred at 50℃for 5 hours, and after the reaction was completed, the solvent was removed by vacuum drying to prepare an acid chloride for use.
5-amino-1-alkyl-1H-indole-3-carbonitrile (4.07 mmol), triethylamine (1.24 g,12.22 mmol) and tetrahydrofuran (80 mL) were added to a 150mL reaction flask, and the prepared acid chloride (6.11 mmol) was slowly added with stirring at 10℃and reacted overnight at room temperature after maintaining the reaction temperature for 30 min. After the reaction is finished, carrying out suction filtration, washing a filter cake with a large amount of tetrahydrofuran to obtain a filtrate, concentrating under reduced pressure to remove most of the solvent, adding a large amount of aqueous solution (pH=11-12), precipitating and carrying out suction filtration, washing the filter cake with a large amount of water to obtain a filter cake, carrying out 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%. 1 H NMR(500MHz,DMSO-d 6 )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). 13 C NMR(125MHz,DMSO-d 6 )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%. 1 H NMR(500MHz,DMSO-d 6 )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). 13 C NMR(125MHz,DMSO-d 6 )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%. 1 H NMR(500MHz,DMSO-d 6 )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). 13 C NMR(125MHz,DMSO-d 6 )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%. 1 H NMR(600MHz,DMSO-d 6 )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). 13 C NMR(150MHz,DMSO-d 6 )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%. 1 H NMR(600MHz,DMSO-d 6 )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). 13 C NMR(150MHz,DMSO-d 6 )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%. 1 H NMR(600MHz,DMSO-d 6 )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). 13 C NMR(150MHz,DMSO-d 6 ) 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) pyridine amide (TE 1).
White solid powder, yield 61.2%. 1 H NMR(600MHz,DMSO-d 6 )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). 13 C NMR(151MHz,DMSO-d 6 )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) pyridine amide (TE 2).
White solid powder, yield 61.2％。 1 H NMR(600MHz,DMSO-d 6 )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). 13 C NMR(151MHz,DMSO-d 6 )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) pyridine amide (TE 3).
White solid powder, yield 61.2%. 1 H NMR(600MHz,DMSO-d 6 )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). 13 C NMR(151MHz,DMSO-d 6 )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 study of xanthine oxidase inhibitory Activity of N- (indol-5-yl) aromatic heterocyclic amides.
1. Test material.
Reagent: xanthine oxidase (from bovine, sigma), xanthine, potassium dihydrogen phosphate, sodium hydroxide.
Instrument: electronic analytical balance (AR 1140 type), electric constant temperature water bath (DK-98-1 type), UV2100 type ultraviolet visible spectrophotometer.
2. Experimental methods.
Reaction diluent: 50mM potassium phosphate buffer, pH 7.4.
Sample preparation: accurately weighing 10 mu mmol of sample, adding 100 mu L of DMSO for dissolution, and then adding 900 of ml of PBS to obtain 10mM mother solution.
Preparation of xanthine substrate: 9.127mg of xanthine is accurately weighed, a small amount of NaOH solution is added for dissolution, and PBS solution is added for dilution to 100mL of constant volume (prepared at present every day).
The experimental steps are as follows: xanthine oxidase (reaction concentration 1.4U/L) and a tested drug (positive drug adopts topiroxostat) are sequentially added into a reaction system, incubated at 25 ℃ for 15min, then xanthine substrate (reaction concentration 86 mu M) is added, and after 60min of reaction, the absorbance value at 294nm is measured. Each sample was run 3 times in parallel, the reaction rates were recorded separately, and the inhibition rates of the samples were calculated by taking the average.
The blank group was not added with xanthine oxidase, PBS of the same volume as the sample was added, and the change in absorbance was recorded as a blank.
The inhibition of XOD by the sample was calculated according to the following formula:
in which A Sample 、A Yin type vagina 、A Sample space 、A Yin hollow : the absorbance peaks of the sample, blank, XOD control and enzyme control are shown, respectively. The test results are shown in Table 1.
Table 1. Inhibition of XO by the sample at a concentration of 33 μm.
Example 7 comparison of the Activity of N- (indol-5-yl) aromatic heterocyclic amide compound with N- (3-substituted-1H-indol-5-yl) amide compound A9.
The N- (3-substituted-1H-indol-5-yl) amide compound is an XO inhibitor (patent No. CN 111072634A) disclosed or reported by the applicant, wherein the compound with the best activity is A9, and the molecular structure is as follows:
the experimental steps are as follows: xanthine oxidase (reaction concentration: 1.4U/L) and test drugs (final concentrations: 1.04. Mu.M, 0.52. Mu.M, 0.26. Mu.M, 0.13. Mu.M) were sequentially added to the reaction system, incubated at 25℃for 15min, and then xanthine substrate (reaction concentration: 86. Mu.M) was added thereto, followed by measurement of absorbance at 294nm after 60min of reaction. Each sample was run 3 times in parallel, 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. As can be seen from Table 2, the XO inhibition activity of the compounds TC1, TC2 and TC3 of the invention is improved by more than 10 times compared with that of the compound A9, and the invention has very remarkable technical progress. The compounds of the invention have significant advantages in both molecular structure and pharmacological activity.
Table 2 XO inhibitory activity of the different compounds at concentrations of 1.04 μm,0.52 μm,0.26 μm,0.13 μm.
Claims (6)
1. The method comprises the following steps ofN- (indol-5-yl) aromatic heterocyclic amide compound, characterized in that the compound or a pharmaceutically acceptable salt thereof has a structure selected from any one of the following:
N- (1-propyl-3-cyano-1)H-indol-5-yl) pyrazine-2-carboxamide;
N- (1-benzyl-3-cyano-1)H-indol-5-yl) pyrazine-2-carboxamide;
N- (1-cyclopentyl-3-cyano-1)H-indol-5-yl) pyrazine-2-carboxamide.
2. The method as claimed in claim 1NThe preparation method of the- (indol-5-yl) aromatic heterocyclic amide compound is characterized by comprising the following steps of:
step 1, using 5-nitroindole as a starting material, and carrying out hydroformylation to obtain an intermediate 5-nitro-1H-indole-3-carbaldehyde;
step 2, 5-nitro-1HReacting-indole-3-formaldehyde with hydroxylamine, dehydrating, and alkylating to obtain an important intermediate 5-nitro-1-alkyl-1H-indole-3-carbonitrile;
step 3, 5-nitro-1-alkyl-1HThe indole-3-nitrile reacts with various types of acyl chloride after being reduced, and the final product is obtained.
3. A pharmaceutical composition comprising the composition of claim 1N- (indol-5-yl) aromatic heterocyclic amide compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.
4. The method as claimed in claim 1NUse of an- (indol-5-yl) heteroaromatic amide compound or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 3 in the preparation of an anti-hyperuricemia and anti-gout medicament.
5. The use of claim 4, wherein the pharmaceutical dosage form is a pharmaceutically acceptable dosage form.
6. The use of claim 4, wherein the dose of the medicament is a pharmaceutically acceptable dose.
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| 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 |
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| 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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