Novel application of (2E,6E)-2-(3,5-dimethoxy phenylidene)-6-(4-chlorphenyl methylene)cyclohexanone and derivative thereof

A 4-N, 2-clph technology, applied in medical preparations containing active ingredients, drug combinations, organic active ingredients, etc., can solve the acute attack of gout without treatment effect, serious side effects, kidney and cardiovascular safety hazards and other problems, to achieve the effect of reducing ankle swelling and serum uric acid level, good dual inhibitory activity, and high safety

Active Publication Date: 2016-08-10
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these drugs not only have serious side effects, but also have no therapeutic effect on the acute attack of gout
In December 2015, the FDA just approved Zurampic, a new drug for the treatment of gout. Although its combination with xanthine oxidase inhibitors can well control the content of serum uric acid, it also has renal and cardiovascular safety risks
In terms of anti-inflammatory drugs, clinically commonly used western medicines such as colchicine, non-steroidal anti-inflammatory drugs and glucocorticoids can be used to relieve acute gouty arthritis, but these drugs are used in large amounts and have many side effects. intolerable
Although the emerging interleukin-1 (IL-1) receptor blocker Rilonacept and anti-IL-1β monoclonal antibody Canakinumab can significantly relieve the joint symptoms of gout patients who are ineffective or intolerable to conventional anti-inflammatory analgesic treatment, but Its research and development costs are expensive, the way of administration is limited, and there are serious safety problems

Method used

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  • Novel application of (2E,6E)-2-(3,5-dimethoxy phenylidene)-6-(4-chlorphenyl methylene)cyclohexanone and derivative thereof
  • Novel application of (2E,6E)-2-(3,5-dimethoxy phenylidene)-6-(4-chlorphenyl methylene)cyclohexanone and derivative thereof
  • Novel application of (2E,6E)-2-(3,5-dimethoxy phenylidene)-6-(4-chlorphenyl methylene)cyclohexanone and derivative thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Embodiment 1, E-2-(3,5-dioxybenzyl)-cyclohexanone (I a ) and E-2-(3,5-dioxybenzyl)-cyclopentanone (I b )Synthesis:

[0027] Add cyclohexanone or cyclopentanone (0.11mol) and morpholine (10.4g, 0.12mol) to 20mL of benzene, install a water separator, reflux and azeotrope until anhydrous is formed, evaporate benzene and morpholine under reduced pressure phyllolines to give enamines. Add enamine (6.54g, 0.043mol) and 3,5-dimethoxybenzaldehyde (5.40g, 0.033mol) to 20mL of benzene, install a water trap, and reflux to azeotrope until no water is formed. A total of 8 hours, cooled to room temperature, slowly added 6mg / L hydrochloric acid under stirring, stirred at room temperature for 2 hours, separated the benzene layer, extracted the water layer with the benzene layer, combined the benzene layer, dried over anhydrous sodium sulfate, concentrated, petroleum ether and ethanol weight Crystallized yellow needle-like crystals (I a or I b ).

[0028] Will I a or I b(1.22mmo...

Embodiment 2

[0031] Example 2, (2E,6E)-2-(3,5-dimethoxyphenylmethylene)-6-(3-chlorophenylmethylene)cyclohexanone (I 2 )Synthesis

[0032] See Example 1 for the synthesis method.

[0033] Mp: 107.5~108.4℃. 1 H-NMR (400MHz, CDCl 3 ), δ(ppm): 7.72(s,1H,=CH),7.70(s,1H,=CH),7.43(s,1H,ArH),7.30~7.36(m,3H,ArH),6.61(d ,2H,J=2.1Hz,ArH),6.47(t,1H,J=2.1Hz,ArH),3.82(s,6H,-OCH 3 ),2.88~2.95(m,4H,-CH 2 ), 1.81 (quint, 2H, J=6.5Hz, -CH 2 ).

[0034] 13 C-NMR (400MHz, CDCl 3 ), Δ (PPM): 190.257,160.841,137.985,137.876,137.577,137.541,136.631,134,134.564,172,128.795, 101.1062,8.70.70.70.70.7062,8,8,70.70.70.70.70.7062,8,8,70.70.70.70.70.7062,8,8,70.70.70.70.70.7062,8.70.7062,8,70.70.7062,8,70.

[0035] HR-MS: Calcd. For C 22 h 21 ClO 3 [M+H] + :369.1252,Found:369.1257.

Embodiment 3

[0036] Example 3, (2E,6E)-2-(3,5-dimethoxyphenylmethylene)-6-(2-chlorophenylmethylene)cyclohexanone (I 3 )Synthesis

[0037] See Example 1 for the synthesis method.

[0038] Mp: 104.0~104.7℃. 1 H-NMR (400MHz, CDCl 3 ),δ(ppm):7.88(s,1H,=CH),7.74(s,1H,=CH),7.43~7.45(m,1H,ArH),7.32~7.34(m,1H,ArH),7.27 ~7.30(m,2H,ArH),6.61(d,2H,J=2.0Hz,ArH),6.47(t,1H,J=2.1Hz,ArH),3.82(s,6H,-OCH 3 ),2.94(t,2H,J=5.6Hz,-CH 2 ),2.76(t,2H,J=5.5Hz,-CH 2 ), 1.77 (quint, 2H, J=6.2Hz, -CH 2 ).

[0039] 13 C-NMR (400MHz, CDCl 3 ),δ(ppm):190.280,160.837,138.169,137.948,137.752,136.739,135.260,134.694,133.913,130.818,130.009,129.827,126.555,108.627,101.090,55.706,28.983,28.483,23.363.

[0040] HR-MS: Calcd. For C 22 h 21 ClO 3 [M+H] + :369.1252,Found:369.1251.

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Abstract

The invention belongs to the technical field of pharmacy, and in particular relates to novel application of (2E,6E)-2-(3,5-dimethoxy phenylidene)-6-(4-chlorphenyl methylene)cyclohexanone and a derivative thereof. With a moderate/high dose, the (2E,6E)-2-(3,5-dimethoxy phenylidene)-6-(4-chlorphenyl methylene)cyclohexanone and the derivative thereof provided by the invention can remarkably reduce the acute gouty arthritis mouse ankle joint swelling degree and the serum uric acid level, meanwhile have very good NLRP3 and TLR4 dual inhibition activity, have effects better than that of a positive control dexamethasone, can be used for preparing medicines for treating hyperuricemia or acute gouty arthritis, and is small in side effect and high in safety.

Description

technical field [0001] The invention belongs to the field of pharmaceutical technology, in particular to curcumin α, β-unsaturated cyclic ketone derivatives ((2E,6E)-2-(3,5-dimethoxyphenylmethylene)-6-(4 The new application of -chlorophenylmethylene) cyclohexanone and its derivatives), especially its application in the preparation of medicines for the treatment of hyperuricemia and acute gouty arthritis. Background technique [0002] Hyperuricemia is a common metabolic disease that seriously endangers human health caused by increased uric acid synthesis or decreased uric acid excretion. Recent studies have found that elevated blood uric acid is an independent risk factor for kidney disease, and may be a pathogenic factor for kidney disease. Gout is a crystal-associated arthropathy caused by the deposition of monosodium urate (MSU), which is directly related to hyperuricemia caused by purine metabolic disorders and / or decreased uric acid excretion, and is a metabolic disease...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C49/753C07C225/22C07C317/24A61K31/122A61K31/136A61P19/06A61P19/02
CPCC07C49/753C07C225/22C07C317/24
Inventor 李环球敖桂珍万茜雯顾陈成
Owner SUZHOU UNIV
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