CN114805192B - Tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid and preparation method and application thereof - Google Patents
Tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid and a preparation method and application thereof, belonging to the field of XOR/URAT1 dual inhibitors. The structure of the tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid is shown as a formula (A): wherein X is O or NH, R 1 Is hydrogen, alkyl, alkoxy, halogen or cyano, R 2 Is hydrogen, alkyl, alkoxy, halogen or cyano. The tricyclic XOR/URAT1 dual inhibitors containing 2-hydroxybenzoic acid of the present invention have a different chemical structure than the known XOR/URAT1 dual inhibitors; the inhibitor has excellent inhibition effect on two key action targets, namely XOR and URAT1, related to gout, and can be applied to preparation of anti-hyperuricemia or gout drugs.
Description
Technical Field
The invention belongs to the field of dual inhibitors of XOR/URAT1, and particularly relates to a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid, and a preparation method and application thereof.
Background
Epidemiological studies from different countries have shown that the prevalence and incidence of gout is increasing, bringing great economic burden to people. Hyperuricemia is an important risk factor for gout, and is associated with renal insufficiency, cardiovascular disease, hypertension, hyperlipidemia, cancer, diabetes, etc., and is caused by increased uric acid production, impaired uric acid excretion of renal function, or a combination of both. In hyperuricemia patients, 90% are due to inefficiency in renal excretion. In humans, 90% of uric acid is heavily reabsorbed into the blood by the proximal tubules of the kidneys, a process that is primarily dependent on human urate transporter 1 (hURAT 1, SLC22A 12), whose function is to regulate blood uric acid levels. Uric acid excretion can be promoted by inhibiting the transporter activity. On the other hand, about 10% of cases are caused by endogenous uric acid overproduction. In the endogenous uric acid production pathway, the key enzyme is Xanthine Oxidoreductase (XOR), which can oxidize hypoxanthine to xanthine and thus uric acid. XOR is one of important targets for early research on pathological mechanisms and pharmaceutical actions of hyperuricemia and gout.
Over the last 40 years, the development of uric acid lowering drugs has been mainly carried out around XOR and URAT 1. Three new drugs are most represented on the market: febuxostat (us market in 2009, XOR inhibitor), topiroxostat (japan market in 2013, XOR inhibitor), and lesinurad (ura 1 inhibitor, us market in 2015). However, febuxostat, which is the highest of interest, has not solved the problem of poor efficacy of XOR inhibitors for some patients (about 20-30% of hyperuricemia patients do not respond to febuxostat), and has been required to increase black frame warning by the FDA in 2019, possibly increasing the risk of cardiovascular events; on the other hand, although the effect of reducing uric acid is remarkable when the lesinurad is singly used, the safety window is narrow, kidney injury is easy to cause, and the compound (lesinurad+allopurinol) which is developed and marketed in the same time with the lesinurad is excellent in clinical performance, and the compound has good response rate and curative effect on allopurinol intolerance and patients with poor curative effect. Therefore, the uric acid lowering drug with the functions of inhibiting uric acid generation and promoting uric acid excretion can become a hotspot in the research field, and has more remarkable clinical effects and application prospects. XOR/URAT1 dual inhibitor PF-06743649 developed by the company of the Buddhist company IC for two targets 50 1.6nM and 0.237. Mu.M, respectively. In phase I clinic, patients orally take 4The uric acid level decreased by 69% after two weeks at 0 mg/day, further confirming that the combined inhibition of XOR with URAT1 is an effective strategy for rapid lowering of uric acid in vivo. The dual inhibitor KUX-1151 of XOR/URAT1 developed by Japanese orange pharmaceutical company has entered phase II clinic. The XOR/URAT1 dual inhibitor RLBN-1001 and its series analogues developed by Relburn-Metabolic company are in phase I clinical and preclinical research stages respectively. RLBN1001 is a prototype of a cancer drug that was found to cause hypouricemia during use in patients, and 50 cases of hypouricemia caused after administration of RLBN1001 and its analogues were clinically studied, and the drug was found to cause increased uric acid excretion by inhibiting URAT 1/XOR.
Currently, the general research of dual inhibitors of XOR/URAT1 is still in the early stage of development, requiring a great deal of early fumbling and accumulation. In particular, the in vitro activity of PF-06743649 is obviously improved compared with that of febuxostat and benzbromarone, and the two single-target inhibitors have stronger clinical effects than that of the currently available clinical combined administration, and the uric acid reaches the standard for a short time, but the uric acid can be the cause of kidney injury found in the phase I clinic. In conclusion, the development of dual XOR/URAT1 inhibitors of the new structural type has important practical significance for alleviating clinical medication needs.
Disclosure of Invention
In view of the above drawbacks and deficiencies of the prior art, a primary object of the present invention is to provide a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid.
Another object of the present invention is to provide a method for preparing the above tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid.
It is still another object of the present invention to provide the use of the above tricyclic XOR/URAT1 dual inhibitors containing 2-hydroxybenzoic acid in the preparation of a medicament for the prevention and treatment of XOR/URAT1 related diseases.
The aim of the invention is achieved by the following technical scheme.
A tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid has a structure shown in formula (A):
wherein X is O or NH, R 1 Is alkyl, alkoxy, halogen or cyano, R 2 Is alkyl, alkoxy, halogen or cyano.
Preferably, X is O or NH, R 1 Alkyl of C1-C7 and OCH 3 F, cl, br or CN, R 2 Alkyl of C1-C7 and OCH 3 F, cl, br or CN.
Preferably, the inhibitor is a compound of any one of the following:
4- (5-Phenoxypyridin-3-yl) 2-hydroxybenzoic acid
4- (5- (4-chlorophenoxy) pyridin-3-yl) -2-hydroxybenzoic acid
4- (5- (p-tolyloxy) pyridin-3-yl) 2-hydroxybenzoic acid
4- (5- (4- (tert-butyl) phenoxy) pyridin-3-yl) -2-hydroxybenzoic acid
4- (5- (3-chlorophenoxy) pyridin-3-yl) -2-hydroxybenzoic acid
4- (5- (Methanophenoxy) pyridin-3-yl) 2-hydroxybenzoic acid
4- (5- (Phenylamino) pyridin-3-yl) 2-hydroxybenzoic acid
4- (5- ((4-chlorophenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid
4- (5- ((4-methoxyphenyl) amino) pyridin-3-yl) 2-hydroxybenzoic acid
4- (5- (p-toluylamino) pyridin-3-yl) 2-hydroxybenzoic acid
4- (5- ((4- (tert-butyl) phenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid
4- (5- ((3-chlorophenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid
4- (5- ((3, 4-dichlorophenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid
4- (5- ((3-fluoro-4-methylphenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid.
The preparation method of the tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid, which comprises the following steps:
(1) Dissolving 3-hydroxy-5-bromopyridine and the compound I in an organic solvent, adding an organic base and copper acetate, and stirring at normal temperature to obtain a compound II, or dissolving 3-amino-5-bromopyridine and the compound I in the organic solvent, adding the organic base and copper acetate, and stirring at normal temperature to obtain a compound III;
(2) Dissolving compound II and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) benzoate in a mixed solvent of 1, 4-dioxabicyclo and water, adding a palladium catalyst, inorganic alkali and argon protection, and carrying out reflux reaction to obtain a 4- (5-substituted-pyridine-3-phenoxy) -2-hydroxybenzoic acid compound, or dissolving compound III and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) benzoate in a mixed solvent of 1, 4-dioxabicyclo and water, adding a palladium catalyst, inorganic alkali and argon protection, and carrying out reflux reaction to obtain the 4- (5-substituted-pyridine-3-phenylamino) -2-hydroxybenzoic acid compound.
Preferably, the organic solvent in the step (1) is methylene chloride, and the organic base is pyridine; the inorganic base in the step (2) refers to potassium carbonate; the palladium catalyst used in the step (2) is (1, 1-bis (diphenylphosphine) ferrocene) palladium dichloride.
Preferably, the molar equivalent ratio of 3-hydroxy-5-bromopyridine, compound I, organic base and copper acetate in step (1) is 1:2:2-3:0.5-1, wherein the molar equivalent ratio of the 3-amino-5-bromopyridine to the compound I to the organic base to the copper acetate is 1:2:2-3:0.5-1.
Preferably, the molar equivalent ratio of the compound II, the methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) benzoate, the inorganic base and the palladium catalyst in the step (2) is 1:1.5:3:0.03, wherein the molar equivalent ratio of the compound III to the methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxybenzaldehyde-2-yl) benzoate to the inorganic base to the palladium catalyst is 1:1.5:3:0.03.
the use of a tricyclic XOR/URAT1 dual inhibitor comprising 2-hydroxybenzoic acid as defined in any one of the preceding claims for the preparation of a medicament for the prophylaxis and treatment of diseases associated with XOR/URAT 1.
Preferably, the medicament is an anti-hyperuricemia or gout medicament.
Preferably, the anti-hyperuricemia or gout medicine comprises a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier as active ingredients.
Compared with the prior art, the invention has the following advantages:
the tricyclic XOR/URAT1 dual inhibitors containing 2-hydroxybenzoic acid of the present invention have novel chemical structures different from the known XOR/URAT1 dual inhibitors; the inhibitor of the invention has excellent inhibition effect on two key action targets, namely XOR and URAT1 related to gout. Thus, they can be used for the prevention and treatment of diseases associated with XOR/URAT1, such as hyperuricemia, heart failure, cardiovascular disease, hypertension, renal disease, inflammation, arthropathy, etc.
Drawings
FIG. 1 is a synthetic scheme of a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid according to the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the present invention are not limited thereto.
The synthetic route of the tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid is shown in figure 1.
Example 1
Synthesis of 4- (5-phenoxypyridin-3-yl) 2-hydroxybenzoic acid (A1)
3-hydroxy-5-bromopyridine (1.4 g,8.2 mmol) and phenylboronic acid (2.0 g,16.4 mmol) were dissolved in dichloromethane, pyridine (2.0 mL,24.6 mmol), copper acetate (0.4 g,2.2 mmol) was added, stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate: petroleum ether (volume ratio 1:5) column chromatography to obtain white solid 3-bromo-5-phenoxypyridine 0.5g, yield 22%.
3-bromo-5-phenoxypyridine (0.5 g,1.6 mmol) and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) benzoate (0.5 g,1.9 mmol) were dissolved in a mixture of 1, 4-dioxane and water (3:1 by volume), potassium carbonate (0.7 g,4.8 mmol), (1, 1-bis (diphenylphosphorus) ferrocene) palladium dichloride (0.04 g,0.05 mmol) was added, argon was replaced, and the mixture was refluxed and stirred. Diatomite is filtered, diluted hydrochloric acid is acidified, ethanol is recrystallized, and white solid 4- (5-phenoxypyridine-3-yl) 2-hydroxybenzoic acid A1.2 g is obtained, and the yield is 33%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ7.11-7.17(d,J＝8.0Hz,2H),7.18-7.25(t,J＝7.4Hz,1H),7.26-7.34(m,2H),7.41-7.49(t,J＝7.8Hz,2H),7.75-7.80(t,J＝2.2Hz,1H),7.84-7.91(d,J＝8.2Hz,1H),8.36-8.44(d,J＝2.7Hz,1H),8.73-8.78(s,1H).
13 C NMR(151MHz,DMSO-d 6 )δ172.09,161.91,156.49,153.90,143.55,143.26,141.01,136.01,131.51,130.76,124.67,124.44,119.19,118.41,115.84,113.31.
example 2
Synthesis of 4- (5- (4-chlorophenoxy) pyridin-3-yl) -2-hydroxybenzoic acid (A2)
3-hydroxy-5-bromopyridine (0.5 g,2.9 mmol) and 4-chloro-phenylboronic acid (0.9 g,5.7 mmol) were dissolved in dichloromethane, pyridine (0.5 mL,5.8 mmol), copper acetate (0.2 g,0.7 mmol) was added, stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate: petroleum ether (volume ratio 1:5) column chromatography to obtain white solid 3-bromo-5- (4-chlorophenoxy) pyridine 0.3g, yield 34%.
3-bromo-5- (4-chlorophenoxypyridine) (0.3 g,1 mmol) and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) benzoate (0.3 g,1.2 mmol) were dissolved in a mixture of 1, 4-dioxane and water (volume ratio: 3:1), potassium carbonate (0.4 g,2.9 mmol), (1, 1-bis (diphenylphosphorus) ferrocene) palladium dichloride (0.02 g,0.03 mmol) was added, argon was replaced, and the mixture was refluxed and stirred for 6h. Diatomite is filtered, diluted hydrochloric acid is acidified, ethanol is recrystallized, and 20.1g of white solid 4- (5-phenoxypyridine-3-yl) 2-hydroxybenzoic acid A is obtained, and the yield is 25%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ7.15-7.21(m,2H),7.28-7.33(dd,J＝1.9,8.2Hz,1H),7.33-7.37(d,J＝1.8Hz,1H),7.45-7.52(m,2H),7.82-7.86(t,J＝2.3Hz,1H),7.86-7.91(d,J＝8.2Hz,1H),8.41-8.47(d,J＝2.6Hz,1H),8.74-8.82(d,J＝1.9Hz,1H).
13 C NMR(151MHz,DMSO-d 6 )δ172.06,161.90,155.55,153.54,143.69,143.45,141.26,136.06,131.51,130.58,128.40,124.78,120.88,118.48,115.90,113.34.
example 3
Synthesis of 4- (5- (p-tolyloxy) pyridin-3-yl) 2-hydroxybenzoic acid (A3)
3-hydroxy-5-bromopyridine (1 g,5.5 mmol) and 4-methylphenylboronic acid (1.5 g,11.1 mmol) were dissolved in dichloromethane, pyridine (1.4 mL,16.5 mmol), copper acetate (0.3 g,1.4 mmol) was added, stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate: petroleum ether (volume ratio 1:5) column chromatography to obtain white solid 3-bromo-5-p-tolylpyridine 0.3g with 22% yield.
3-bromo-5-p-tolylpyridine (0.3 g,1.2 mmol) and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) benzoate (0.4 g,1.5 mmol) were dissolved in a mixture of 1, 4-dioxane and water (3:1 by volume), potassium carbonate (0.5 g,3.6 mmol) and (1, 1-bis (diphenylphosphorus) ferrocene) palladium dichloride (0.03 g,0.04 mmol) were added, argon was replaced, and the mixture was refluxed and stirred for 6h. Diatomite is filtered, diluted hydrochloric acid is acidified, ethanol is recrystallized, and 30.1g of white solid 4- (5-phenoxypyridine-3-yl) 2-hydroxybenzoic acid A is obtained, and the yield is 22%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ2.28-2.35(s,3H),7.02-7.08(d,J＝7.9Hz,2H),7.21-7.32(m,4H),7.67-7.71(s,1H),7.84-7.90(d,J＝8.2Hz,1H),8.33-8.38(d,J＝2.7Hz,1H),8.68-8.73(s,1H).
13 C NMR(151MHz,DMSO-d 6 )δ172.04,161.89,154.41,153.96,143.58,142.84,140.54,135.94,133.98,131.53,131.13,123.75,119.43,118.39,115.80,113.36,20.77.
example 4
Synthesis of 4- (5- (4- (tert-butyl) phenoxy) pyridin-3-yl) -2-hydroxybenzoic acid (A4)
3-hydroxy-5-bromopyridine (0.9 g,5 mmol) and 4-tert-butylphenylboronic acid (1.8 g,10 mmol) were dissolved in dichloromethane, pyridine (1.2 mL,15 mmol), copper acetate (0.2 g,1.3 mmol) was added, stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate: petroleum ether (volume ratio 1:5) column chromatography, obtaining white solid 5- (4- (tert-butyl) phenoxypyridine 0.4g, yield 27%.
5- (4- (tert-butyl) phenoxypyridine (0.4 g,1.4 mmol) and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) benzoate (0.5 g,1.6 mmol) were dissolved in a mixture of 1, 4-dioxane and water (3:1 by volume), potassium carbonate (0.6 g,4.1 mmol), (1, 1-bis (diphenylphosphorus) ferrocene) palladium dichloride (0.03 g,0.04 mmol) was added, argon was replaced, and stirred under reflux for 6h, celite was filtered, acidified with dilute hydrochloric acid, and recrystallized from ethanol to give 4- (5-phenoxypyridin-3-yl) 2-hydroxybenzoic acid A40.1g as a white solid in 19% yield.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ1.20-1.38(s,9H),7.04-7.11(m,2H),7.27-7.32(dd,J＝1.8,8.2Hz,1H),7.34-7.37(d,J＝1.8Hz,1H),7.41-7.48(m,2H),7.84-7.91(m,2H),8.37-8.41(d,J＝2.6Hz,1H),8.74-8.79(d,J＝1.8Hz,1H).
13 C NMR(151MHz,DMSO-d 6 )δ171.97,161.83,154.29,154.02,147.13,143.29,142.41,140.02,136.33,131.55,127.45,125.14,118.73,118.52,115.94,113.41,34.59,31.68.
example 5
Synthesis of 4- (5- (3-chlorophenoxy) pyridin-3-yl) -2-hydroxybenzoic acid (A5)
3-hydroxy-5-bromopyridine (1.7 g,9.6 mmol) and 3-chloro-phenylboronic acid (3.0 g,19.2 mmol) were dissolved in dichloromethane, pyridine (2.3 mL,28.8 mmol), copper acetate (0.4 g,2.2 mmol) was added, stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate: petroleum ether (volume ratio 1:5) column chromatography to obtain white solid 3-bromo-5- (3-chlorophenoxy) pyridine 0.4g, yield 16%.
3-bromo-5- (3-chlorophenoxy) pyridine (0.4 g,1.3 mmol) and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) benzoate (0.4 g,1.5 mmol) were dissolved in a mixture of 1, 4-dioxane and water (volume ratio: 3:1), potassium carbonate (0.5 g,3.8 mmol), (1, 1-bis (diphenylphosphorus) ferrocene) palladium dichloride (0.03 g,0.04 mmol) was added, argon was replaced, and stirred under reflux for 6h. Diatomite is filtered, diluted hydrochloric acid is acidified, ethanol is recrystallized, and white solid 4- (5-phenoxypyridine-3-yl) 2-hydroxybenzoic acid A5.1 g is obtained, and the yield is 17%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ7.14-7.19(m,1H),7.27-7.33(m,2H),7.34-7.40(dd,J＝1.8,8.3Hz,1H),7.42-7.44(d,J＝1.8Hz,1H),7.44-7.51(t,J＝8.0Hz,1H),7.86-7.93(d,J＝8.2Hz,1H),8.18-8.24(d,J＝2.2Hz,1H),8.57-8.62(d,J＝2.5Hz,1H),8.92-8.97(d,J＝1.8Hz,1H).
13 C NMR(151MHz,DMSO-d 6 )δ171.94,161.82,157.33,154.00,142.28,141.43,138.72,137.29,134.70,132.20,131.57,128.14,124.95,119.35,118.60,117.84,116.19,113.75.
example 6
Synthesis of 4- (5- (m-tolyloxy) pyridin-3-yl) 2-hydroxybenzoic acid (A6)
3-hydroxy-5-bromopyridine (1.54 g,8.8 mmol) and 3-methylphenylboronic acid (2.4 g,17.7 mmol) were dissolved in dichloromethane, pyridine (2.1 mL,26.4 mmol) was added, copper acetate (0.4 g,2.2 mmol) was stirred overnight at room temperature, dichloromethane extraction, anhydrous sodium sulfate drying, ethyl acetate: petroleum ether (volume ratio 1:5) column chromatography to obtain white solid 3-bromo-5-m-tolylpyridine 0.4g with 17% yield.
3-bromo-5-m-tolylpyridine (0.4 g,1.5 mmol) and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) benzoate (0.5 g,1.8 mmol) were dissolved in a mixture of 1, 4-dioxane and water (3:1 by volume), potassium carbonate (0.6 g,4.5 mmol), (1, 1-bis (diphenylphosphorus) ferrocene) palladium dichloride (0.03 g,0.04 mmol) was added, argon was replaced, and the mixture was refluxed and stirred for 6h. Diatomite is filtered, diluted hydrochloric acid is acidified, ethanol is recrystallized, and 60.1g of white solid 4- (5-phenoxypyridine-3-yl) 2-hydroxybenzoic acid A is obtained, and the yield is 20%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ2.29-2.33(s,3H),6.88-6.99(m,2H),6.99-7.05(d,J＝7.7Hz,1H),7.24-7.36(m,3H),7.73-7.79(t,J＝2.3Hz,1H),7.82-7.91(d,J＝8.2Hz,1H),8.33-8.40(d,J＝2.6Hz,1H),8.71-8.76(d,J＝1.9Hz,1H).
13 C NMR(151MHz,DMSO-d 6 )δ172.07,161.88,156.45,154.00,143.57,143.08,140.89,140.60,136.00,131.53,130.44,125.42,124.48,119.72,118.45,116.21,115.83,113.25,21.37.
example 7
Synthesis of 4- (5- (phenylamino) pyridin-3-yl) 2-hydroxybenzoic acid (A7)
3-amino-5-bromopyridine (0.8 g,4.6 mmol) and phenylboronic acid (1.1 g,9.2 mmol) were dissolved in dichloromethane, pyridine (2.0 mL,19.2 mmol), copper acetate (0.4 g,2.2 mmol) was added, stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate: petroleum ether (volume ratio 1:5) column chromatography to obtain white solid 3-bromo-5-aminopyridine 0.4g with 38% yield.
3-bromo-5-aminopyridine (0.4 g,1.8 mmol) and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) benzoate (0.6 g,2.1 mmol) were dissolved in a mixture of 1, 4-dioxane and water (3:1 by volume), potassium carbonate (0.7 g,5.3 mmol), (1, 1-bis (diphenylphosphorus) ferrocene) palladium dichloride (0.04 g,0.05 mmol) was added, argon was replaced, and the mixture was refluxed and stirred. Diatomite is filtered, diluted hydrochloric acid is acidified, ethanol is recrystallized, and yellow solid 4- (5-aminopyridine-3-yl) 2-hydroxybenzoic acid A7.1 g is obtained, and the yield is 18%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.43(dd,J＝11.2,2.2Hz,2H),7.94-7.86(m,2H),7.38-7.32(m,2H),7.31(d,J＝1.7Hz,1H),7.26(td,J＝8.5,1.6Hz,3H),7.00(td,J＝7.3,1.2Hz,1H).
13 C NMR(151MHz,DMSO-d 6 )δ171.56,162.23,145.10,143.72,140.65,140.64,140.13,134.08,132.44,129.45,122.20,120.63,119.01,117.54,115.25,114.24.
example 8
Synthesis of 4- (5- ((4-chlorophenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid (A8)
3-amino-5-bromopyridine (1.0 g,5.8 mmol) and 4-chloro-phenylboronic acid (1.8 g,11.6 mmol) were dissolved in dichloromethane, pyridine (0.9 mL,11.6 mmol), copper acetate (0.3 g,1.4 mmol) was added, stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate: petroleum ether (volume ratio 1:5) column chromatography to obtain white solid 3-bromo-5- (4-chlorophenyl) aminopyridine 0.4g with 24% yield.
3-bromo-5-aminopyridine (0.4 g,1.4 mmol) and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) benzoate (0.5 g,1.7 mmol) were dissolved in a mixture of 1, 4-dioxane and water (3:1 by volume), potassium carbonate (0.6 g,4.1 mmol), (1, 1-bis (diphenylphosphorus) ferrocene) palladium dichloride (0.03 g,0.04 mmol) was added, argon was replaced, and the mixture was refluxed and stirred for 6h. Diatomite is filtered, acidified by dilute hydrochloric acid and recrystallized by ethanol to obtain yellow solid 4- (5- ((4-chlorophenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid A8.1 g with 18% yield.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d6)δ9.57(s,1H),8.59(d,J＝1.7Hz,1H),8.45(d,J＝2.5Hz,1H),8.16(t,J＝2.1Hz,1H),7.93(d,J＝8.2Hz,1H),7.45-7.38(m,3H),7.36-7.30(m,3H).
13 C NMR(151MHz,DMSO-d 6 )δ171.89,161.82,143.11,142.03,139.80,137.85,132.20,131.72,130.38,129.97,126.78,125.94,121.22,118.52,116.17,114.07.
example 9
Synthesis of 4- (5- ((4-methoxyphenyl) amino) pyridin-3-yl) 2-hydroxybenzoic acid (A9)
3-amino-5-bromopyridine (0.2 g,1.1 mmol) and 4-methoxyphenylboronic acid (0.3 g,2.2 mmol) were dissolved in dichloromethane, pyridine (0.2 mL,2.2 mmol), copper acetate (0.1 g,0.6 mmol) was added, stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate: petroleum ether (volume ratio 1:5) column chromatography to obtain white solid 3-bromo-5- (4-methoxyphenyl) aminopyridine 0.1g with 37% yield.
3-bromo-5- (4-methoxyphenyl) aminopyridine (0.1 g,0.4 mmol) and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) benzoate (0.12 g,0.5 mmol) were dissolved in a mixture of 1, 4-dioxane and water (volume ratio: 3:1), potassium carbonate (0.2 g,1.3 mmol), (1, 1-bis (diphenylphosphorus) ferrocene) palladium dichloride (0.01 g,0.02 mmol) was added, argon was replaced, and the mixture was stirred under reflux for 6h. Diatomite is filtered, acidified by dilute hydrochloric acid and recrystallized by ethanol to obtain yellow solid 4- (5- ((4-methoxyphenyl) amino) pyridin-3-yl) 2-hydroxybenzoic acid A9.1 g with the yield of 28%.
The structural characterization data of the product are as follows:
1 H NMR(600MHz,DMSO-d 6 )δ9.31(s,1H),8.49(d,J＝1.7Hz,1H),8.24(d,J＝2.5Hz,1H),8.01(t,J＝2.0Hz,1H),7.93(d,J＝8.2Hz,1H),7.35(d,J＝1.8Hz,1H),7.31-7.24(m,3H),7.03-6.97(m,2H),3.77(s,3H).
13 C NMR(151MHz,DMSO-d 6 )δ171.86,161.78,156.53,145.34,141.86,138.14,132.66,131.76,129.35,127.03,124.63,123.54,118.43,116.11,115.43,114.14,55.75.
example 10
Synthesis of 4- (5- (p-toluylamino) pyridin-3-yl) 2-hydroxybenzoic acid (A10)
3-amino-5-bromopyridine (1.0 g,5.8 mmol) and 4-methylphenylboronic acid (1.6 g,11.6 mmol) were dissolved in dichloromethane, pyridine (0.9 mL,11.6 mmol) was added, copper acetate (0.5 g,2.9 mmol) was stirred overnight at room temperature, dichloromethane extraction, anhydrous sodium sulfate drying, ethyl acetate: petroleum ether (volume ratio 1:5) column chromatography to obtain white solid 3-bromo-5-p-toluidine 0.3g with yield of 22%.
3-bromo-5-p-tolylaminopyridine (0.3 g,1.3 mmol) and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) benzoate (0.4 g,1.6 mmol) were dissolved in a mixture of 1, 4-dioxane and water (3:1 by volume), potassium carbonate (0.5 g,3.9 mmol) and (1, 1-bis (diphenylphosphorus) ferrocene) palladium dichloride (0.03 g,0.04 mmol) were added, argon was replaced, and the mixture was refluxed and stirred for 6h. Diatomite is filtered, diluted hydrochloric acid is acidified, ethanol is recrystallized, and yellow solid 4- (5-phenoxypyridine-3-yl) 2-hydroxybenzoic acid A10.1 g is obtained, and the yield is 18%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.54(d,J＝1.7Hz,1H),8.34(d,J＝2.5Hz,1H),8.11(dd,J＝2.5,1.7Hz,1H),7.93(d,J＝8.2Hz,1H),7.37(d,J＝1.8Hz,1H),7.30(dd,J＝8.2,1.9Hz,1H),7.22(s,4H),2.30(s,3H).
13 C NMR(151MHz,DMSO-d 6 )δ171.86,161.80,144.41,141.87,138.10,137.55,133.26,131.77,130.64,130.28,128.21,125.35,120.82,118.45,116.13,114.18,20.93.
example 11
Synthesis of 4- (5- ((4- (tert-butyl) phenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid (A11)
3-amino-5-bromopyridine (0.8 g,4.6 mmol) and 4-tert-butylphenylboronic acid (1.2 g,6.9 mmol) were dissolved in dichloromethane, pyridine (0.8 mL,9.2 mmol), copper acetate (0.4 g,2.2 mmol) were added, stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate: petroleum ether (volume ratio 1:5) column chromatography to obtain white solid 3-bromo-5- ((4- (tert-butyl) phenyl) amino) pyridine 0.5g, yield 37%.
3-bromo-5- ((4- (tert-butyl) phenyl) amino) pyridine (0.5 g,1.4 mmol) and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) benzoate (0.5 g,1.7 mmol) were dissolved in a mixture of 1, 4-dioxane and water (volume ratio: 3:1), potassium carbonate (0.6 g,4.3 mmol), (1, 1-bis (diphenylphosphorus) ferrocene) palladium dichloride (0.03 g,0.04 mmol) was added, argon was replaced, and the mixture was refluxed and stirred for 6h. Diatomite is filtered, diluted hydrochloric acid is acidified, ethanol is recrystallized, and yellow solid 4- (5-phenoxypyridine-3-yl) 2-hydroxybenzoic acid A11.2 g is obtained, and the yield is 45%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.54-8.49(m,1H),8.38(d,J＝2.5Hz,1H),8.09(d,J＝3.2Hz,1H),7.93(d,J＝8.2Hz,1H),7.42(d,J＝2.0Hz,1H),7.40-7.34(m,2H),7.31(dd,J＝8.2,1.8Hz,1H),7.27-7.20(m,2H).
13 C NMR(151MHz,DMSO-d 6 )δ171.88,161.79,146.14,144.07,142.02,137.85,131.72,130.44,126.78,125.23,119.94,118.47,116.11,114.08,34.55,31.67.
example 12
Synthesis of 4- (5- ((3-chlorophenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid (A12)
3-amino-5-bromopyridine (1.0 g,5.8 mmol) and 3-chloro-phenylboronic acid (2.0 g,11.6 mmol) were dissolved in dichloromethane, pyridine (1.0 mL,11.6 mmol), copper acetate (0.32 g,1.7 mmol) was added, stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate: petroleum ether (volume ratio 1:5) column chromatography to obtain white solid 3-bromo-5- ((3-chlorophenyl) amino) pyridine 0.4g, yield 22%.
3-bromo-5- ((3-chlorophenyl) amino) pyridine (0.4 g,1.3 mmol) and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) benzoate (0.4 g,1.5 mmol) were dissolved in a mixture of 1, 4-dioxane and water (volume ratio: 3:1), potassium carbonate (0.5 g,3.9 mmol), (1, 1-bis (diphenylphosphorus) ferrocene) palladium dichloride (0.03 g,0.04 mmol) was added, argon was replaced, and the mixture was stirred under reflux for 6h. Diatomite is filtered, diluted hydrochloric acid is acidified, ethanol is recrystallized, and yellow solid 4- (5- ((3-chlorophenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid A12.1 g is obtained, and the yield is 20%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d6)δ9.61(s,1H),8.63(d,J＝1.7Hz,1H),8.51(d,J＝2.4Hz,1H),8.20(t,J＝2.1Hz,1H),7.94(d,J＝8.2Hz,1H),7.43-7.36(m,2H),7.35-7.30(m,2H),7.28(td,J＝8.1,2.2,1.0Hz,1H),7.09(td,J＝7.9,2.0,0.9Hz,1H).
13 C NMR(151MHz,DMSO-d 6 )δ171.89,161.81,142.96,142.50,141.71,138.06,134.40,131.74,131.72,129.78,127.23,122.88,118.89,118.52,117.63,116.24,114.13.
example 13
Synthesis of 4- (5- ((3, 4-dichlorophenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid (A13)
3-amino-5-bromopyridine (1.0 g,5.8 mmol) and 3, 4-dichloro-phenylboronic acid (2.2 g,11.6 mmol) were dissolved in dichloromethane, pyridine (0.9 mL,11.6 mmol), copper acetate (0.3 g,1.7 mmol) was added, stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate: petroleum ether (volume ratio 1:5) column chromatography to obtain white solid 3-bromo-5- (3, 4-dichlorophenyl) amino) pyridine 0.4g, yield 23%.
3-bromo-5 (3, 4-dichlorophenyl) amino) pyridine (0.4 g,1.4 mmol) and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) benzoate (0.5 g,1.7 mmol) were dissolved in a mixture of 1, 4-dioxane and water (volume ratio 3: 1) Potassium carbonate (0.5 g,4.1 mmol) and (1, 1-bis (diphenylphosphorus) ferrocene) palladium dichloride (0.03 g,0.04 mmol) were added, argon was replaced, and the mixture was stirred under reflux for 6 hours. Diatomite is filtered, diluted hydrochloric acid is acidified, ethanol is recrystallized, and yellow solid 4- (5-phenoxypyridine-3-yl) 2-hydroxybenzoic acid A13.1 g is obtained, and the yield is 24%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.65(d,J＝1.8Hz,1H),8.53(d,J＝2.5Hz,1H),8.23(t,J＝2.1Hz,1H),7.93(d,J＝8.2Hz,1H),7.58(d,J＝8.7Hz,1H),7.51(d,J＝2.6Hz,1H),7.41(d,J＝1.8Hz,1H),7.34(dd,J＝8.3,1.8Hz,1H),7.30(dd,J＝8.8,2.7Hz,1H).
13 C NMR(151MHz,DMSO-d 6 )δ171.89,161.81,142.74,141.57,141.28,138.10,132.25,132.01,131.78,131.71,130.02,127.55,124.31,120.61,119.27,118.53,116.27,114.14.
example 14
Synthesis of 4- (5- ((3-fluoro-4-methylphenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid (A14)
3-amino-5-bromopyridine (1.0 g,5.8 mmol) and 3-fluoro-4-methylphenylboronic acid (1.8 g,11.6 mmol) were dissolved in dichloromethane, pyridine (0.9 mL,11.6 mmol), copper acetate (0.5 g,2.9 mmol) was added, stirred overnight at room temperature, extracted with dichloromethane, dried over anhydrous sodium sulfate, ethyl acetate: petroleum ether (volume ratio 1:5) column chromatography to obtain white solid 3-bromo-5- ((3-fluoro-4-methylphenyl) amino) pyridine 0.4g, yield 22%.
3-bromo-5- ((3-fluoro-4-methylphenyl) amino) pyridine (0.4 g,1.7 mmol) and methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) benzoate (0.4 g,1.5 mmol) were dissolved in a mixture of 1, 4-dioxane and water (volume ratio: 3:1), potassium carbonate (0.5 g,3.8 mmol), (1, 1-bis (diphenylphosphorus) ferrocene) palladium dichloride (0.03 g,0.04 mmol) was added, argon was replaced, and the mixture was refluxed and stirred for 6h. Diatomite is filtered, diluted hydrochloric acid is acidified, ethanol is recrystallized, and yellow solid 4- (5-phenoxypyridine-3-yl) 2-hydroxybenzoic acid A14.1 g is obtained, and the yield is 20%.
The structural characterization data of the product are as follows:
1 H NMR(400MHz,DMSO-d6)δ9.35(s,1H),8.51(s,1H),8.47-8.39(m,1H),8.00(d,J＝2.2Hz,1H),7.91(d,J＝8.2Hz,1H),7.33(d,J＝1.8Hz,1H),7.28(dd,J＝8.2,1.8Hz,1H),7.24(t,J＝8.5Hz,1H),7.08-6.99(m,2H),2.19(d,J＝1.8Hz,3H).
13 C NMR(151MHz,DMSO-d 6 ) Delta 171.89,162.28-160.68 (fluorine split), 161.82,160.68,142.83,142.57,140.62,137.31,132.72,132.68,131.67,124.81,118.45,118.28,116.03,115.25,113.91,106.31,106.15,14.11.
Evaluation of the Activity of the product obtained in the above examples:
1. evaluation of in vitro inhibitory Activity of Compounds A1-14 on XOR:
diluted 10×pbs (ph=7.4) was 1×pbs, and the PBS in the following reaction system was 1×pbs. Xanthine (15.2 mg) was weighed and dissolved by ultrasonic wave with the addition of 250mL of PBS and 1mL of NaOH solution (1 mmol/L) to obtain a substrate solution of 0.4 mmol/L. 20 mu L of the XOR mother liquor is added with 20mL of PBS for dilution and is placed under ice bath for preservation, thus obtaining 0.5 mu g/100 mu L of enzyme liquor. Setting blank group, control group, test group, wherein the blank group is only added with inhibitor and xanthine solution, the control group is only added with xanthine solution and enzyme solution, and the test group is added with compounds A1-14In 96-well plate, PBS buffer, 100. Mu.L enzyme solution, 50. Mu.L inhibitor at each concentration were incubated at 37℃for 3min, and then taken out and immediately added with 30. Mu.L substrate for starting. The total volume of the reaction system was 200. Mu.L, and readings were taken every 30s at 295nm for 5min, and each set of experiments was performed in parallel 4 times. Converting absorbance values obtained at different times of each concentration of the compound into initial velocity of the compound to be tested, comparing with control group, and calculating to obtain IC of each compound 50 Values. See table 1.
TABLE 1 in vitro inhibitory Activity of Compounds A1-14 on XOR
2. Evaluation of in vitro inhibitory Activity of Compounds A1-14 on URAT1
And (3) performing activity measurement on the compound to be tested by adopting a self-built fluorescence detection method for measuring URAT1 activity. The 6-carboxyfluorescein is used as a substrate for URAT1 transportation, and the inhibition effect of the compound to be tested on URAT1 in vitro is determined according to the change of fluorescence values before and after the compound to be tested is added into a reaction system. HEK293T/hURAT1 stable transfer cell constructed by self and prepared with density of 2X 10 5 cell suspension of cells/mL was added to 96 Kong Yingguang plates at 200. Mu.L/well, and a blank, control, and experimental groups were set with 5 duplicate wells each, wherein HEK293T/hURAT1 cells were added to the control and experimental groups, and no cells were added to the blank. After 48h incubation, 100. Mu.L of HBSS (Cl-free) was added to the blank - ) Solution, control group added 100. Mu.L 6-carboxyfluorescein solution (final concentration 239.48. Mu. Mol/L), experimental group added 100. Mu.L 6-carboxyfluorescein containing (239.48. Mu. Mol/L) each concentration gradient of test compound solution. After 1h, the working solution was aspirated, and 100. Mu.L of NaOH solution (0.5 mol/L) was added to each well for 30min. In an enzyme labeling instrument, an excitation wavelength of 490nm, an emission wavelength of 525nm are set, and reading is carried out after oscillation. The results are shown in Table 2.
TABLE 2 in vitro inhibitory Activity of Compounds A1-14 against URAT1
As is clear from the results of tables 1 and 2, the compounds A1 to 14 obtained in the present invention have the following unexpected but clear structure-activity relationship. 1. The substitution of X with-NH-has better connection effect than that of the X with-O-, and the inhibition activity of the X with respect to XOR or URAT1 is obviously improved compared with that of the compounds A1-6; 2. r is R 2 Fixed as hydrogen, R 1 When substituted with different alkyl groups, the compounds have reduced inhibitory activity on XOR and URAT1, such as A1 and A4, A7 and a11, as the number of substituted alkyl carbons increases; 3. when the compound A12 and X are-NH-, R 1 Is H, R 2 When Cl is used for substitution, the in vitro activity of the compound has the best inhibitory activity on two targets, which respectively exceed that of febuxostat and benzbromarone. In a word, the tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid has a strong inhibition effect on two key drug targets in uric acid metabolic pathways, and has a potential and definite uric acid reducing treatment effect.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (9)
1. The tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid is characterized in that the structure is shown in a formula (A):
wherein X is O or NH, R 1 Is hydrogen, C1-C7 alkyl, OCH 3 F, cl, br or CN, R 2 Is hydrogen, C1-C7 alkyl, OCH 3 F, cl, br or CN.
2. A tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid according to claim 1, wherein the inhibitor is a compound of any one of:
4- (5-Phenoxypyridin-3-yl) 2-hydroxybenzoic acid
4- (5- (4-chlorophenoxy) pyridin-3-yl) -2-hydroxybenzoic acid
4- (5- (p-tolyloxy) pyridin-3-yl) 2-hydroxybenzoic acid
4- (5- (4- (tert-butyl) phenoxy) pyridin-3-yl) -2-hydroxybenzoic acid
4- (5- (3-chlorophenoxy) pyridin-3-yl) -2-hydroxybenzoic acid
4- (5- (Methanophenoxy) pyridin-3-yl) 2-hydroxybenzoic acid
4- (5- (Phenylamino) pyridin-3-yl) 2-hydroxybenzoic acid
4- (5- ((4-chlorophenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid
4- (5- ((4-methoxyphenyl) amino) pyridin-3-yl) 2-hydroxybenzoic acid
4- (5- (p-toluylamino) pyridin-3-yl) 2-hydroxybenzoic acid
4- (5- ((4- (tert-butyl) phenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid
4- (5- ((3-chlorophenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid
4- (5- ((3, 4-dichlorophenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid
4- (5- ((3-fluoro-4-methylphenyl) amino) pyridin-3-yl) -2-hydroxybenzoic acid.
3. A process for the preparation of a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid as claimed in any one of claims 1 to 2, comprising the steps of:
(1) Dissolving 3-hydroxy-5-bromopyridine and the compound I in an organic solvent, adding an organic base and copper acetate, and stirring at normal temperature to obtain a compound II, or dissolving 3-amino-5-bromopyridine and the compound I in the organic solvent, adding the organic base and copper acetate, and stirring at normal temperature to obtain a compound III;
(2) Dissolving the compound II and 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) methyl benzoate in a mixed solvent of 1, 4-dioxanone and water, adding a palladium catalyst, inorganic alkali and argon protection, and carrying out reflux reaction to obtain an A-1 compound, or dissolving the compound III and 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) methyl benzoate in a mixed solvent of 1, 4-dioxanone and water, adding the palladium catalyst, inorganic alkali and argon protection, and carrying out reflux reaction to obtain the A-2 compound.
4. A process according to claim 3, wherein the organic solvent in step (1) is methylene chloride and the organic base is pyridine; the inorganic base in the step (2) refers to potassium carbonate; the palladium catalyst used in the step (2) is (1, 1-bis (diphenylphosphine) ferrocene) palladium dichloride.
5. The method according to claim 3, wherein the molar equivalent ratio of 3-hydroxy-5-bromopyridine, compound I, organic base, copper acetate in step (1) is 1:2:2-3:0.5-1, wherein the molar equivalent ratio of the 3-amino-5-bromopyridine to the compound I to the organic base to the copper acetate is 1:2:2-3:0.5-1.
6. The process according to claim 3, wherein the molar equivalent ratio of the compound II, 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxabenzaldehyde-2-yl) benzoate, the inorganic base and the palladium catalyst in the step (2) is 1:1.5:3:0.03, wherein the molar equivalent ratio of the compound III to the methyl 2-hydroxy-4- (4, 5-tetramethyl-1, 3, 2-dioxybenzaldehyde-2-yl) benzoate to the inorganic base to the palladium catalyst is 1:1.5:3:0.03.
7. use of a tricyclic XOR/URAT1 dual inhibitor comprising 2-hydroxybenzoic acid as claimed in any one of claims 1 to 2 in the manufacture of a medicament for the prophylaxis and treatment of XOR/URAT 1-related disorders.
8. The use according to claim 7, wherein the medicament is an antihyperlipidemic or gout medicament.
9. The use according to claim 8, wherein the anti-hyperuricemia or gout drug comprises as an active ingredient a tricyclic XOR/URAT1 dual inhibitor containing 2-hydroxybenzoic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101010300A (en) * | 2004-08-27 | 2007-08-01 | 安斯泰来制药株式会社 | 2-phenylpyridine derivative |
| US20070275950A1 (en) * | 2004-08-27 | 2007-11-29 | Astellas Pharma Inc. | 2-Phenylpyridine Derivative |
| WO2010044411A1 (en) * | 2008-10-15 | 2010-04-22 | キッセイ薬品工業株式会社 | Phenylisonicotinic acid derivative and use thereof for medical purposes |
| CN111148735A (en) * | 2017-10-04 | 2020-05-12 | 日本烟草产业株式会社 | Nitrogen-containing heteroaryl compounds and pharmaceutical uses thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101010300A (en) * | 2004-08-27 | 2007-08-01 | 安斯泰来制药株式会社 | 2-phenylpyridine derivative |
| US20070275950A1 (en) * | 2004-08-27 | 2007-11-29 | Astellas Pharma Inc. | 2-Phenylpyridine Derivative |
| WO2010044411A1 (en) * | 2008-10-15 | 2010-04-22 | キッセイ薬品工業株式会社 | Phenylisonicotinic acid derivative and use thereof for medical purposes |
| CN111148735A (en) * | 2017-10-04 | 2020-05-12 | 日本烟草产业株式会社 | Nitrogen-containing heteroaryl compounds and pharmaceutical uses thereof |
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