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Naphthyl sulfamide amino acid derivative, preparation method and medical application thereof

A technology of naphthyl sulfonamide and amino acid, which is applied in the field of medicinal chemistry, can solve the problems that cannot, and rarely can, improve the etiology of inflammation, and achieve the effect of reducing inflammatory damage and improving the microenvironment of inflammation

Active Publication Date: 2018-06-01
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The anti-inflammatory drugs currently used clinically produce anti-inflammatory effects by inhibiting the inflammatory response, and cannot or rarely improve the cause of inflammation

Method used

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  • Naphthyl sulfamide amino acid derivative, preparation method and medical application thereof
  • Naphthyl sulfamide amino acid derivative, preparation method and medical application thereof
  • Naphthyl sulfamide amino acid derivative, preparation method and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054]

[0055] (4-((4-methoxyphenyl)sulfonylamino)naphthalene-1-yl)-L-proline (I-a-1)

[0056] (1) 4-nitro-1-naphthol (1-1)

[0057] Dissolve 1-nitronaphthalene (8.5g, 49.1mmol) in 20.0mL DMSO (dimethyl sulfoxide), then dissolve potassium hydroxide (11.0g, 196.3mmol) in 10.0mL water, and add dropwise under ice-cooling In the reaction system, 10.0 mL of DMSO solution dissolved in tert-butanol peroxide (9.8 mL, 98.2 mmol) was added dropwise into the reaction system. After the dropwise addition, stir for about 10.0 min, remove the ice bath, and react at room temperature. React for 4h, add Na 2 S 2 o 3 (1.5g, 9.3mmol) was stirred for 1.0h, then 200.0mL of water was added, the pH was adjusted to 4 with dilute hydrochloric acid, extracted three times with 30mL of EA (ethyl acetate), the organic layers were combined, washed three times with saturated sodium chloride solution, Adjust the pH to 10 with 4M sodium hydroxide, wash the aqueous layer 3 times with EA, adjust the pH ...

Embodiment 2

[0067]

[0068] (4-((N-(carboxymethyl)-4-methoxyphenyl)sulfonylamino)naphthalene-1-yl)-L-proline (I-a-2)

[0069] The synthesis of 1-4 is the same as in Example 1

[0070] (1) (4-((4-methoxy-N-(2-methoxy-2-oxoethyl)phenyl)sulfonylamino)naphthalene-1-yl)-L-proline Methyl ester (2-1)

[0071]Compound (1-4) (200.0 mg, 454 μmol) was dissolved in 5.0 mL DMF, potassium carbonate (280.0 mg, 2.0 mmol) was added, and finally methyl bromoacetate (83.0 mg, 545 μmol) was added and stirred at room temperature. React for 4h, add water to the solution until the solid precipitates, extract three times with EA (30ml), combine the organic phases, and wash three times with saturated aqueous NACl solution (30ml), then wash the organic phase with anhydrous NaCl 2 SO 4 Drying, sand making, and column chromatography gave 190 mg of a light yellow oily substance with a yield of 82%. 1 H-NMR (300MHz, CDCl 3 )δ8.22 (d, J=8.8Hz, 1H), 8.08-7.94 (m, 1H), 7.69 (ddd, J=11.1, 8.8, 2.5Hz, 2H), 7.46 (s,...

Embodiment 3

[0075]

[0076] (4-((4-acetylaminophenyl)sulfonylamino)naphthalene-1-yl)-L-proline (I-a-3)

[0077] The synthesis of 1-3 is the same as in Example 1

[0078] (1) (4-((4-acetylaminophenyl)sulfonylamino)naphthalene-1-yl)-L-proline methyl ester (3-1)

[0079] The same synthesis method as compound (1-4), compound (1-3) (500mg, 1.67mmol) hydrogenolysis with 4-acetamidobenzenesulfonyl chloride (468mg, 2mmol), pyridine (404μL, 5.01mmol) as raw materials , 258 mg of white solid was obtained, the yield was 33%, m.p.109-112°C. 1 H-NMR (300MHz, C) δ8.17 (d, J = 7.8Hz, 1H), 7.84 (d, J = 7.8Hz, 1H), 7.62 (d, J = 8.5Hz, 2H), 7.56 (s, 1H), 7.48(d, J=8.6Hz, 2H), 7.39(s, 2H), 7.11(d, J=8.3Hz, 2H), 6.90(d, J=8.2Hz, 1H), 6.74(s, 1H), 4.47(s, 1H), 3.91(d, J=8.7Hz, 1H), 3.54(s, 3H), 3.15(s, 1H), 2.45(d, J=10.8Hz, 1H), 2.15( s,5H), 2.01(s,3H); EI-MS m / z: 468[M+H] + .

[0080] (2) (4-((4-acetylaminophenyl)sulfonylamino)naphthalene-1-yl)-L-proline (I-a-3)

[0081] With compound (I-a-1), wit...

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Abstract

The invention discloses a naphthyl sulfamide amino acid derivative, a preparation method and medical application thereof. A naphthyl sulfamide amino acid derivative R3 substituent group represents a substituent group with an amino acid structure; the amino acid structure refers that the substituent group at least contains one carboxyl and one secondary amine or tertiary amine, and the substituentgroup is connected onto a mother nucleus through the secondary amine or the tertiary amine. The naphthyl sulfamide amino acid derivative provided by the invention can interfere with Keap1-Nrf2 combination and activate Nrf2, so that inflammatory injury is reduced, an inflammation microenvironment is improved, and the naphthyl sulfamide amino acid derivative has potential anti-inflammatory activity.The technician in the field knows that an Nrf2 activating agent can be used for inhibiting inflammatory reaction of diseases, so that the compound provided by the invention can be used for preparingan anti-inflammatory drug for treating diseases associated with inflammation, including chronic obstructive pulmonary diseases, Alzheimer diseases, Parkinson, atherosclerosis, chronic renal diseases,diabetes, intestinal inflammation, rheumatoid arthritis and the like.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of compounds having anti-inflammatory activity and taking naphthyl sulfonamide amino acid as the basic skeleton, and also relates to a preparation method of these compounds and their medical application in the anti-inflammatory field. Background technique [0002] Anti-inflammatory drugs commonly used at present are mainly divided into steroidal anti-inflammatory drugs, mainly corticosteroids and non-steroidal anti-inflammatory drugs, mainly cyclooxygenase inhibitors. Although the chemical structures of non-steroidal anti-inflammatory drugs are different, most of them exert their antipyretic, analgesic and anti-inflammatory effects by inhibiting the synthesis of prostaglandins. These anti-inflammatory drugs currently used clinically produce anti-inflammatory drug effects by inhibiting the inflammatory response, and cannot or rarely improve the cause of inflam...

Claims

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Application Information

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IPC IPC(8): C07D207/16C07C311/29C07C311/46C07C311/21C07C303/40C07C323/58C07D257/04A61P11/00A61P25/28A61P25/16A61P9/10A61P13/12A61P3/10A61P1/00A61P19/02A61P29/00
CPCC07B2200/07C07C311/21C07C311/29C07C311/46C07C323/58C07D207/16C07D257/04
Inventor 尤启冬姜正羽谭世界陆朦辰吴沣周海山
Owner CHINA PHARM UNIV
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