Compound with effect of treating and preventing hyperuricemia or gout and preparation method as well as application thereof

A technology for hyperuricemia and compounds, applied in the field of medicine, can solve problems such as lowering, insensitivity to probenecid, and inability to reach serum uric acid levels, etc.

Active Publication Date: 2015-08-05
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Probenecid can increase uric acid secretion in the renal tubules, but long-term use can dislodge urate stones in the body, and it has been reported that 25-50% of individuals treated with probenecid could not achieve a reduction in serum uric acid levels to <6 mg / L
Insensitivity to probenecid due to drug intolerance, concomitant salicylate intake, and renal impairment; in addition, uricosuric agents also cause side effects such as urinary stones, gastrointestinal obstruction, jaundice, and anemia

Method used

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  • Compound with effect of treating and preventing hyperuricemia or gout and preparation method as well as application thereof
  • Compound with effect of treating and preventing hyperuricemia or gout and preparation method as well as application thereof
  • Compound with effect of treating and preventing hyperuricemia or gout and preparation method as well as application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1: the preparation of the compound of No. 1 in table 1

[0050] (4-oxo-4,5-dihydro-1-hydrogen-pyrazolo[3,4-d]pyrimidin-1-yl)methyl-2-((5-bromo-4-(4-ring Preparation of methyl propylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)acetate (4, compound no. 1 in Table 1):

[0051]

[0052] a) Preparation of 1-(hydroxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (3):

[0053] Take a 250mL single-necked bottle and dry it, add the raw material allopurinol (5.0g, 36.7mmol) into it, and add 250mL of a 2M formaldehyde solution with a pH of 7 that has been prepared. Stir overnight at room temperature for 24 hours, a white solid can be seen to be precipitated, and filtered to obtain 1-(hydroxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one 3, 6.0 g, yield 98% , MS (ESI) m / z: 166.03 (M+H + ), used directly in the next reaction.

[0054] b) (4-oxo-4,5-dihydro-1-hydrogen-pyrazolo[3,4-d]pyrimidin-1-yl)methyl-2-((5-bromo-4-(4 Preparation of -cyclopropylnaphthalen-1-yl)-4H-...

Embodiment 2

[0056] Embodiment 2: the preparation of the compound of No. 2 in table 1

[0057] (4-oxo-4,5-dihydro-1-hydrogen-pyrazolo[3,4-d]pyrimidin-1-yl)methyl-2-((5-bromo-4-(4-ring Preparation of methyl propylnaphthalen-1-yl)-4H-1,2,4-triazol-3-yl)thio)-2-methylpropanoate (5, compound no. 2 in Table 1):

[0058]

[0059] a) 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylsulfanyl)-2-methylpropionic acid ethyl ester (2) Preparation:

[0060] Take a 25mL round-bottomed flask for drying, and the raw material 5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-l,2,4-triazole-3-thiol (0.200g, 0.578mmol ), ethyl 2-bromo-2-methylpropionate (0.112g, 0.578mmol) and diisopropylethylamine (0.224g, 1.734mmol) were dissolved in DMF (5mL), heated to 60°C and stirred for reaction one day. After the reaction was completed, the solvent was evaporated to dryness under reduced pressure, dissolved in ether, washed and extracted with 1M hydrochloric acid solution, the aqueous layer was extra...

Embodiment 3

[0065] Embodiment 3: the preparation of the compound of No. 3 in table 1

[0066] Compound No. 3 in Table 1 (4-oxo-4,5-dihydro-1-hydrogen-pyrazolo[3,4-d]pyrimidin-1-yl)methyl-2-((4-( 4-cyclopropylnaphthalene-1-yl)-4H-1,2,4-triazol-3-yl)thio)methyl acetate can be corresponding raw material 2-((4-(4-cyclopropylnaphthalene -1-yl)-4H-1,2,4-triazol-3-yl)thio)acetic acid was prepared by referring to the general method of the compound in Example 1. Yield 78%, MS (ESI) m / z: 474.13 (M+H + ).

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Abstract

The invention discloses a compound with an effect of treating and preventing hyperuricemia or gout and a preparation method as well as application thereof. The general structural formula of the compound is shown as a formula (I); the proportion of lesinuard and an allopurinol medicament can be effectively controlled by the series of the compounds, the dose and frequency are reduced, the effect of combination medication can be achieved by single-time medication, meanwhile the preparation process can be simplified, and the production cost is saved; since a linking group exists between the two compounds, the compound can only be hydrolyzed into two medicaments under the action of an enzyme for a certain time after the compound is orally taken and absorbed; thus, the half-life in vivo of the compound is increased by the process, namely the medicament achieve a slow release effect through a chemical coupling method.

Description

technical field [0001] The present invention relates to the technical field of medicine, and is a kind of twin drug or its solvate represented by formula (I) composed of urate reabsorption transporter 1 (URAT1) inhibitor and allopurinol spliced ​​through different linkers , pharmaceutical salts or polymorphs, which have the effects of treating and preventing hyperuricemia or gout. Background technique [0002] Uric acid is a product of xanthine oxidation, and elevated blood uric acid levels may be due to increased uric acid production and / or decreased renal excretion of uric acid. Causes of hyperuricemia may include: obesity / weight gain, excessive alcohol use, excessive intake of purine-rich foods in the diet, certain medications, etc. Hyperuricemia may be asymptomatic but may be accompanied by the following conditions: gout, gouty arthritis, urolithiasis, tophi, uric acid nephropathy, impaired renal function, which may lead to chronic and acute renal failure. The incidenc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P19/06
CPCC07D487/04
Inventor 吴国球范小波
Owner SOUTHEAST UNIV
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