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Amide for inhibition of IL-8-induced chemiotaxis of neutrophil leucocytes

A kind of aryl propionamide and compound technology, which is applied in the field of amides for inhibiting neutrophil chemotaxis induced by interleukin 8, and can solve problems such as disease deterioration

Inactive Publication Date: 2004-03-03
DOMPE FARM SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] On the other hand, inhibition of the synthesis of prostaglandins (PGs), especially the (S) enantiomers of 2-arylpropionic acids and some of their derivatives, has a negative effect on IL-8-stimulated neutrophil-associated inflammatory processes. Dynamics appear to have negative effects, such as causing disease to worsen

Method used

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  • Amide for inhibition of IL-8-induced chemiotaxis of neutrophil leucocytes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0184] (R, S')-2-[(4'-isobutyl)phenyl]-N-(2-carboxyethylpropionamide

[0185] To a solution of R(-) ibuprofen (5 g; 24.24 mmol) in DMF was added 3 g of 1-hydroxybenzothiazole (HOBT) (22.2 mmol) with stirring and cooled to about 0°C. After 15 minutes, a DMF solution (5 mL) of a mixture of L-alanine methyl ester hydrochloride (3.2 g; 22.2 mmol) and triethylamine (3 mL) was added; finally, a total of 5 g of DCC was continuously added in portions . The mixture was stirred at 0°C for 2 hours, then at room temperature overnight. After dicyclohexylurea precipitate was filtered off, the filtrate was diluted with ethyl acetate (50 mL). The organic phase was washed successively with 10% citric acid solution (2×20 mL), saturated sodium bicarbonate solution (2×20 mL) and saturated sodium chloride solution (20 mL). Dry over sodium sulfate, and evaporate the solvent under low pressure to obtain a residue (3.86 g), which is suspended in hexane (60 mL), stirred overnight, and a white cryst...

Embodiment 2

[0191] By the step of embodiment 1, L-alanine is changed into D-alanine methyl ester and glycine methyl ester, can make following compound:

[0192] (R,R')-2-[(4'-isobutyl)phenyl]-N-(2"-carboxyethyl)propionamide, which is a light butter, [α] D =+5 (c=0.5%; Methanol)

[0193] 1 H-NMR (CDCl 3 ): δ7.20-7.07(m, 4H); 5.97(bs, CONH); 4.45(m, 1H); 3.60(m, 1H), 2.45(d, 2H, J=7Hz); 2.45(d, 2H , J=7 Hz); 1.85 (m, 1H); 1.53 (d, 3H); 1.35 (d, 3H); 0.91 (d, 6H, J=7 Hz).

[0194] R(-)-2-[(4'-isobutyl)phenyl]-N-carboxymethylpropionamide, melting point is 87-90°C;

[0195] 1 H-NMR (CDCl3 ): δ7.23-7.07(m, 4H); 5.93(bs, CONH); 4.13-3.93(m, 2H); 3.63(q, 1H, J1=8Hz, J2=15Hz), 2.45(d, 2H, J = 7 Hz); 1.87 (m, 1H); 1.53 (d, 3H, J = 7 Hz); 0.93 (d, 6H, J = 7 Hz).

Embodiment 3

[0197] (R)-N-[2′-(4”-isobutylphenyl)propionyl]-2-aminoacrylic acid

[0198] According to the steps of Example 1, (R, R')-2-[(4'-isobutyl)phenyl]-N-2"-(3"- Mercapto-carboxyethyl) propionamide. Under an inert atmosphere, a solution of 3 g of this compound in anhydrous dichloromethane was cooled to -10°C, and a 1M solution of boron tribromide in dichloromethane (6 mL) was added dropwise with stirring. The reaction mixture was stirred at -10°C for 1 hour and at room temperature for 6 hours. The resulting mixture was diluted with water (20 mL), the phases were separated and the aqueous phase was further extracted with dichloromethane. The combined organic phases were washed with saturated sodium bicarbonate solution (3 x 20 mL). The basic aqueous phase was acidified to pH = 2 with 2N hydrochloric acid and extracted with dichloromethane (3 x 10 mL). The organic extracts were mixed, after drying over sodium sulfate and evaporating the solvent, a butter oil (R) N-[2'-(4"-isobutylp...

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Abstract

N-(2-aryl-propionyl)-amides of formula (I) are described. The process for their preparation and pharmaceutical preparations thereof are also described. The amides of the invention are useful in the prevention and treatment of tissue damage due to the exacerbate recruitment of polymorphonuclear neutrophils (leukocytes PMN) at the inflammatory sites. In particular, the invention relates to the R enantiomers of N-(2-aryl-propionyl)amides of formula (I) for use in the inhibition of the chemotaxis of neutrophils induced by IL-8. The compounds of the invention are used in the treatment of psoriasis, ulcerative cholitis, glomerular nephritis, acute respiratory insufficiency, idiopathic fibrosis, and rheumatoid arthritis.

Description

technical field [0001] The invention relates to N-(2-aryl-propionyl)-amides, processes for their preparation and pharmaceutical preparations for the prevention and treatment of tissue damage caused by the acute recruitment of polymorphonuclear leukocytes (leukocytes PMN) at inflamed sites damage. In particular, the present invention relates to the R enantiomer of N-(2-aryl-propionyl)-amides useful for inhibiting neutrophil chemotaxis induced by interleukin 8 (IL-8). Background technique [0002] Chemokines constitute a family of low molecular weight cytokines directly involved in inflammatory responses, translocation of immune cells and directed transplantation of cellular components. The technical term "chemokine" is an abbreviation of the words "chemotaxis" and "cytokine", which emphasizes the general biological function of these cellular mediators. [0003] Chemokines are divided into two subspecies, which are distinguished by the sequence of the amino acids CC and CXC,...

Claims

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Application Information

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IPC IPC(8): A61K31/12A61K31/16A61K31/165A61K31/197A61K31/221A61K31/223A61K31/4035A61K31/4402A61K31/4406A61K31/4409A61K31/495A61K31/4965A61K31/505A61K38/00A61P1/04A61P9/10A61P11/00A61P13/12A61P17/06A61P19/02A61P21/02A61P29/00C07C51/353C07C57/42C07C59/52C07C69/157C07C233/11C07C233/22C07C233/51C07C233/52C07C235/34C07C235/78C07C237/20C07C259/06C07C271/64C07D209/46C07D213/75C07D233/61C07D239/42C07D241/28C07D409/12C07K5/06
CPCC07C235/34C07C233/52C07C271/64C07B2200/07C07D239/42C07C235/78C07D213/75C07C233/51C07C2101/14C07C233/22A61K38/00C07K5/06026C07C233/11C07C237/20C07C2601/14A61P1/04A61P1/06A61P11/00A61P13/12A61P17/06A61P19/02A61P21/02A61P29/00A61P43/00A61P9/10
Inventor M·阿莱格蒂R·贝尔蒂尼B·辛齐V·萨巴蒂尼G·卡塞利M·C·切斯塔C·甘多利F·科洛塔
Owner DOMPE FARM SPA
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