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3-(naphthalene-1-methyl substituted) pyridine derivative and synthesis method and application thereof

A technology of derivatives and pyridine, applied in new compounds and their application fields, can solve problems such as no alternative drugs, low activity, and large toxic and side effects

Active Publication Date: 2018-08-24
SOUTHERN MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Benzbromarone is currently the most effective uricosuric drug, but it has severe side effects, especially can cause fulminant hepatitis, so it has not been approved by the FDA to be marketed in the United States, and it was once stopped in Europe because there is no more suitable drug. Alternative drugs, except in France, are currently in clinical use again
In December 2015, the first selective inhibitor targeting hURAT1, Lesinurad, was approved by the FDA, but its activity is much lower than that of benzbromarone (about 1 / 100)

Method used

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  • 3-(naphthalene-1-methyl substituted) pyridine derivative and synthesis method and application thereof
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  • 3-(naphthalene-1-methyl substituted) pyridine derivative and synthesis method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Synthesis of 2-[[3-[(4-cyanonaphthalen-1-yl)methyl]pyridin-4-yl]thio]acetic acid (Ia-1):

[0045] 1) Synthesis of 4-(4-chloronicotinoyl)-1-naphthalenecarbonitrile (compound 3a-1)

[0046]

[0047] Add magnesium chips (58mg, 2.4mmol) and catalytic amount of iodine particles in a three-necked flask equipped with a reflux condenser and a constant pressure dropping funnel, heat until the surface of the magnesium chips is purple, then add a small amount of tetrahydrofuran to cover the magnesium chips . 3-Bromo-4-chloropyridine (384mg, 2mmol) was dissolved in 5ml of tetrahydrofuran, and a small amount was added dropwise into a three-neck flask, and after being slightly heated to initiate the reaction, the remaining solution was slowly dropped into. After dropping, the reaction bottle was kept at 40° C. for 2 hours, and allowed to stand still to return to room temperature. 356mg (2mmol) of 1,4-dicyanonaphthalene and 20mL of tetrahydrofuran were cooled to 0°C, and the abov...

Embodiment 2

[0062] Synthesis of 2-[[3-[(4-fluoronaphthalen-1-yl)methyl]pyridin-4-yl]thio]acetic acid (Ia-2):

[0063]

[0064] The target compound Ia-2 was synthesized according to the synthesis method of the target compound Ia-1, and the yield was 88%.

[0065] 1 H NMR (400MHz, DMSO-d 6 )δ12.90(bs,1H),8.63(d,J=5.3Hz,1H),8.49(s,1H),8.29-8.21(m,2H),7.83-7.70(m,1H),7.63-7.57 (m,1H),7.45(d,J=7.0Hz,1H),7.40(d,J=5.3Hz,1H),7.30(d,J=7.5Hz,1H),5.70(s,2H),4.32 (s,2H).ESI-MS m / z: 326.4[M-H]-.

Embodiment 3

[0067] Synthesis of 2-[[3-[(4-chloronaphthalen-1-yl)methyl]pyridin-4-yl]thio]acetic acid (Ia-3):

[0068]

[0069] The target compound Ia-3 was synthesized according to the synthesis method of the target compound Ia-1, and the yield was 93%. 1 H NMR (400MHz,

[0070] 1 H NMR (400MHz, DMSO-d 6 )δ13.19(bs,1H),8.65(d,J=5.5Hz,1H),8.46(s,1H),8.40-8.24(m,2H),7.80-7.71(m,1H),7.65-7.56 (m,1H),7.50(d,J=7.3Hz,1H),7.43(d,J=5.4Hz,1H),7.38(d,J=8.3Hz,1H),5.62(s,2H),4.32 (s,2H).ESI-MS m / z:342.6[M-H]

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Abstract

The invention discloses a 3-(naphthalene-1-methyl substituted) pyridine derivative and a synthesis method and application thereof. The derivative comprises a compound having a structural formula as shown in the specification, or a pharmaceutically acceptable salt, hydrate, solvate, polymorphic substance, tautomer, stereoisomer or prodrug thereof, the derivative has high hURAT1(human urate transporter) inhibitory activity, has strong uric acid transport inhibitory activity of MDCK-hURAT1 cells, can be used for preparation of drugs for treatment and / or prevention and / or delay and / or adjuvant treatment and / or treatment of diseases associated with hURAT1 (human urate transporter) transport uric acid, especially hyperuricemia. By combining with other drugs for treatment of the hyperuricemia,the derivative is expected to achieve better therapeutic effects on the hyperuricemia.

Description

technical field [0001] The present invention relates to novel compounds and their applications, in particular to 3-(naphthalene-1-methyl-substituted) pyridine derivatives and their synthesis methods and applications. Background technique [0002] The reduction of uric acid excretion is the main cause of hyperuricemia. The incidence of gout caused by uric acid has increased significantly in recent years, and it tends to be younger, which makes people pay more and more attention to the treatment of gout. [0003] 2 / 3 of the urate in the human body is excreted through the kidneys, and most of the urate filtered by the kidneys is reabsorbed by the human body. Human urate transporter 1 (hURAT1, human urate transporter 1) is a urate transporter located at the brush border of renal tubular epithelial cells, and belongs to the SLC22 family of organic anion transporters (OATs). This transporter can promote the reabsorption of uric acid by renal tubules and determine how much uric a...

Claims

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Application Information

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IPC IPC(8): C07D213/61C07D213/70C07D213/68C07D213/74C07D213/55C07D213/73C07D213/30A61K31/44A61P19/06
CPCA61P19/06C07D213/30C07D213/55C07D213/61C07D213/68C07D213/70C07D213/73C07D213/74
Inventor 张嘉杰田元新庞建新
Owner SOUTHERN MEDICAL UNIVERSITY
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