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Nicotinic acid derivative and application thereof

A derivative, the technology of nicotinic acid, applied in the field of prevention or treatment of stroke diseases, can solve problems such as difficult to achieve the expected effect, and achieve good preventive and/or therapeutic effect

Active Publication Date: 2015-07-22
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, drugs with a single molecular target are difficult to achieve the expected effect in the treatment of stroke damage caused by multiple mechanisms

Method used

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  • Nicotinic acid derivative and application thereof
  • Nicotinic acid derivative and application thereof
  • Nicotinic acid derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] [Example 1] Synthesis of Nicotinic Acid 2-[4-(3H-1,2-dithiol-3-thiol-5-yl)phenoxy]ethyl ester (YC3-1)

[0055]

[0056] ADT-OH (1.000g, 8.13mmol), 2-bromoethyl nicotinate (0.757mL, 8.13mmol) and K2CO3 (2.240g, 16.26mmol) were cast in 60mL of acetone, and stirred at reflux for 18h. After the reaction was completed, filter, evaporate the solvent to dryness, and perform column chromatography [petroleum ether (60-90):ethyl acetate=10:1 (v / v)] to obtain a red solid with a yield of 75.9%.

[0057] 1 H NMR (400MHz, CDCl 3 ), δ (ppm): 9.25 (d, J = 1.5Hz, 1H, ArH), 8.80 (dd, J = 4.8, 1.7Hz, 1H, ArH), 8.32 (d, J = 8.0Hz, 1H, ArH) ,7.63(d,J=8.8Hz,2H,ArH),7.41(dd,J=8.0,5.0Hz,1H,ArH),7.39(s,1H,CH,ArH),7.03(d,J=8.9Hz ,2H,ArH),4.77–4.73(m,2H,CH 2 ),4.42–4.38(m,2H,CH 2 ).

[0058] 13 C NMR (400MHz, CDCl 3 ), δ (ppm): 215.32, 172.81, 165.27, 161.79, 153.87, 151.16, 137.31, 134.98, 128.80, 125.75, 124.90, 123.48, 115.69, 66.25, 63.40.

[0059] MS: Calcd. For C 17 h 13 NO 3...

Embodiment 2

[0060] [Example 2] Synthesis of Nicotinic Acid 3-[4-(3H-1,2-dithiol-3-thiol-5-yl)phenoxy]propyl ester (YC3-2)

[0061]

[0062] Referring to the method of Example 1, it was prepared from 3-bromopropyl nicotinate and ADT-OH, and the product was a red solid with a yield of 70.4%.

[0063] 1 H NMR (300MHz, CDCl 3 ), δ (ppm): 9.23 (s, 1H), 8.79 (d, J = 3.1Hz, 1H, ArH), 8.30 (d, J = 7.9Hz, 1H, ArH), 7.61 (d, J = 8.6Hz ,2H,ArH),7.42(dd,J=4.3,3.7Hz,1H,ArH),7.39(s,1H,ArH),6.98(d,J=8.6Hz,2H,ArH),4.59(t,J =6.1Hz,2H,CH 2 ), 4.21(t, J=5.8Hz, 2H, CH 2 ),2.36–2.30(m,2H,CH 2 ).

[0064] 13 C NMR (400MHz, CDCl 3 ), δ (ppm): 215.02, 172.94, 165.17, 161.98, 153.56, 150.83, 137.07, 134.63, 128.61, 125.93, 124.31, 123.37, 115.38, 64.76, 62.06, 28.51.

[0065] MS: Calcd. For C 18 h 15 NO 3 S 3 [M+H] + 389.0214,Found: 389.0293.

Embodiment 3

[0066] [Example 3] Synthesis of nicotinic acid 4-[4-(3H-1,2-dithiol-3-thiol-5-yl)phenoxy]butyl ester (YC3-3)

[0067]

[0068] Referring to the method of Example 1, it was prepared from 4-bromobutyl nicotinate and ADT-OH, and the product was a red solid with a yield of 70.4%.

[0069] 1 H NMR (300MHz, CDCl 3 ),δ(ppm):9.22(s,1H,ArH),8.78(s,1H,ArH),8.30(d,J=5.9Hz,1H,ArH),7.60(d,J=8.6Hz,2H, ArH), 7.38(m, 2H, ArH, CH), 6.97(d, J=7.9Hz, 2H, ArH), 4.46(s, 2H, CH 2 ),4.11(s,2H,CH 2 ),2.01(s,4H,CH 2 ).

[0070] 13 C NMR (400MHz, CDCl 3 ), δ (ppm): 215.11, 173.09, 165.30, 162.29, 153.52, 150.90, 137.11, 134.66, 128.67, 126.17, 124.22, 123.41, 115.48, 67.75, 65.01, 25.84, 25.53.

[0071] MS: Calcd. For C 19 h 17 NO 3 S 3 [M+H] + 404.0, Found: 403.9.

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Abstract

The invention relates to a novel nicotinic acid derivative and an application thereof and further relates to the application of the nicotinic acid derivative in preparation of medicine and pharmaceutic preparation for disease prevention or treatment, especially for prevention or treatment of stroke diseases. Experiments prove that the nicotinic acid derivative has a direct protection function on neurons on a cell model and substantially reduces the hindbrain infarct volume of a mouse with ischemic stroke in an animal model. Therefore, the application of the nicotinic acid derivative with the novel chemical structural formula in preparation of the medicine for prevention or treatment of the stroke diseases is provided. The nicotinic acid derivative contains a nicotinic acid pharmacophore as well as pharmacophores aiming at other pathogenic mechanisms, and the nicotinic acid derivative has better stroke disease prevention or / and treatment effect than the prototype drug nicotinic acid.

Description

technical field [0001] The invention belongs to the field of medicines, and specifically relates to novel niacin derivatives and applications, and also relates to applications in the preparation of medicines and pharmaceutical preparations for preventing or treating diseases, especially for preventing or treating stroke diseases. Background technique [0002] Stroke, also known as cerebrovascular accident, refers to the stenosis, occlusion or rupture of blood vessels in the brain caused by various predisposing factors in patients with cerebrovascular diseases, resulting in acute cerebral blood circulation disturbance. Stroke is mainly divided into two types, of which more than 70% is ischemic stroke, which refers to ischemic brain injury caused by various thrombi in different brain regions causing cerebral vascular blockage, the most common being middle cerebral artery blockage. The other 30% are cerebral hemorrhage and subarachnoid hemorrhage caused by rupture of cerebral b...

Claims

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Application Information

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IPC IPC(8): C07D409/12A61K31/455A61P25/00A61P9/00A61P9/10
CPCC07D409/12
Inventor 程坚熬桂珍贾佳
Owner SUZHOU UNIV
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