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Non-peptide bradykinin antagonists and pharmaceutical compositions therefrom

A technology of compounds and mixtures, applied in the field of non-peptide compounds, which can solve problems such as destruction

Inactive Publication Date: 2010-10-13
意大利卢索药品研究有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Of these, the major action is exerted by kallikreins, but once released by precursors, their action is only short-lived as they are quickly destroyed by a series of circulating enzymes and membranes commonly defined as kallikreins

Method used

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  • Non-peptide bradykinin antagonists and pharmaceutical compositions therefrom
  • Non-peptide bradykinin antagonists and pharmaceutical compositions therefrom
  • Non-peptide bradykinin antagonists and pharmaceutical compositions therefrom

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] (4-(S)-amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonate Acylamino]tetrahydropyran-4-carbonyl}piperazin-1-yl)-5-oxo-pentyl)trimethyl-ammonium chloride, dihydrochloride

[0047] (compound of general formula I, wherein R=CH 3 , W=-O-, X=NH 2 , n=3, Y=N(CH 3 ) 3 + Cl - ).

[0048] The compound is synthesized according to the synthetic route illustrated in Scheme 2

[0049]

[0050] Flowchart 2

[0051] General method: Analytical HPLC: Flow rate: 1 mL / min; Mobile phase: A - 0.1% trifluoroacetic acid in water, B - 0.1% trifluoroacetic acid in acetonitrile; Column: Zorbax Eclipse XDBC8, 5 microns, 150 x 4.6 mm.

[0052] Intermediate (2) 2,4-dichloro-3-bromomethyl-benzenesulfonyl chloride

[0053] Under magnetic stirring at room temperature, 4.8 mL of 2,6-dichlorotoluene was added dropwise to 10 mL of chlorosulfonic acid over 2 hours. After the addition was complete, the mixture was heated at 40 °C for 2 hours, resulting in a pu...

Embodiment 2

[0095] (4-(S)-amino-5-(4-(4-(2,4-dichloro-3-(2-methyl-quinolin-8-yloxymethyl)-benzenesulfonylamino) Tetrahydropyran-4-carbonyl)-piperazin-1-yl-)5-oxo-pentyl)-trimethylammonium chloride, hydrochloride

[0096] 1 H NMR (DMSO-d 6 )δ: 8.90 (1H, s), 8.47-8.34 (4H, m), 8.02 (1H, d), 7.81 (1H, d), 7.73-7.37 (4H, m), 5.62 (2H, s), 4.57 -4.45(1H,m), 4.01-3.56(5H,m), 3.43-3.18(7H,m), 3.06(9H,s), 2.78-2.61(4H,m), 2.89(1H,s), 1.97 -1.60 (9H, m). HPLC: retention time = 9.26 min. MS: [M] + 749.

Embodiment 3

[0098] [5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-quinolin-8-yloxymethyl)-benzenesulfonylamino]tetrahydropyran- 4-Carbonyl}piperazin-1-yl)-5-oxo-pentyl]-trimethylammonium trifluoroacetate.

[0099] 1 H-NMR (DMSO-d 6 ): δ (ppm) 1.53 (s, 2H, m); 1.69 (m, 4H); 1.90 (m, 2H); 2.45 (t, 2H); 2.78 (m, 6H); 3.04 (9H, s); 3.23-3.57 (7H, m); 5.68 (2H, s); 7.38-8.18 (5H, m); 8.04 (1H, d, J=8.42Hz); 8.82 (1H, s). HPLC: retention time = 5.65 minutes. MS: [M] + 748.

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Abstract

Non-peptide compounds having activity as selective antagonists of bradykinin (BK) B2 receptor. The compounds are chemically characterized by the presence of an amino acid alpha substituted with a cyclic group and by a tetraalkylammonium group.

Description

technical field [0001] The present invention relates to non-peptide compounds having a quaternary ammonium group having specific antagonistic activity on the bradykinin (BK) B2 receptor, pharmaceutical compositions comprising these compounds and the use of these compounds in the treatment of all diseases involving activation of the bradykinin B2 receptor use in disease. Background technique [0002] Bradykinin (BK) belongs to the kinins and forms together with lysyl bradykinin and T-kinin a subclass of kinins, which are present in mammals. Kinins play important roles in the central and peripheral nervous systems as mediators of pain and inflammation. Specifically, bradykinin is a non-peptide (H-Arg 1 -Pro 2 -Pro 3 -Gly 4 -Phe 5 -Ser 6 -Pro 7 -Phe 8 -Arg 9 -OH). [0003] There are two types of kinin receptors: B1 and B2. The main feature of the B1 receptor is that it is more inducible than the constitutive form. It is expressed in tissues under conditions of infl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/47A61P29/00C07D215/26
CPCC07D215/26A61P1/04A61P1/16A61P11/00A61P13/10A61P13/12A61P17/00A61P17/06A61P17/14A61P19/02A61P27/16A61P29/00A61P31/12A61P35/00A61P37/00A61P37/08A61P43/00A61P9/00A61P9/10A61K31/496C07D405/12
Inventor P·费利切蒂C·I·芬奇安A·焦利蒂C·A·马吉L·夸尔塔拉C·罗西
Owner 意大利卢索药品研究有限公司
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