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Chemical compounds containing a superoxide scavenger and an organic nitrate or nitrite moiety

Inactive Publication Date: 2005-07-28
TEIJIN LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009] According to the present invention there is provided a compound comprising a scavenger of superoxide and an organic nitrate or nitrite moiety. Such

Problems solved by technology

However, the cellular mode of action of organic nitrates, in particular, the details of nitrate to NO bio-transformation, still remain unclear.
However, it has since been discovered that glutathione-s-transferase catalyzes the reduction of organic nitrate to nitrite, and does not catalyze the reduction of nitrite to NO.
The major problem with nitrate therapy is the rapid development of tolerance and cross-tolerance during repeated dosing with these agents (Parker & Parker, 1998).
Clearly, the need to interrupt drug administration regularly reduces the effectiveness of this form of therapy.

Method used

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  • Chemical compounds containing a superoxide scavenger and an organic nitrate or nitrite moiety
  • Chemical compounds containing a superoxide scavenger and an organic nitrate or nitrite moiety

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of Antioxidant Nitrate Ester

Step 1

[0034] A solution of 2 g (8 mmol) of optically pure (R)-(+)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid (1) and 0.1 g of p-toluenesulphonic acid monohydrate in 40 ml methanol were stirred and re-fluxed for 4 hours. After cooling, the solution was diluted with water, extracted three times into ether that was subsequently washed with brine and aqueous sodium bicarbonate solution. The ether solution was washed, dried with MgSO4 and evaporated to give (R)-(+)-methyl 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylate (2).

Step 2:

[0035] To a stirred solution of 1.5 g (5.68 mmol) of (2) in 22 ml ether, was added a solution of 4.5 g (16.6 mmol) of ferric chloridehexahydrate in 17 ml of water and 17 ml of methanol. The addition was carried out drop-wise over 30 minutes. After 1 hour the ether layer was separated, and the aqueous phase was further extracted with ether. The combined ether laye...

example 2

Exemplification of Protective Effect of Antioxidant

[0038] Buffered solutions containing an organic nitrate as follows [all containing vitamin C between 1 and S equivalents]: (i) propyl nitrate, (ii) propyl nitrate plus one equivalent of compound (3) and (iii) compound (S) in the range of 1 to 10 μmol were prepared. These solutions were incubated in sealed glass vessels with appropriate concentrations of XO and NADH under both hypoxic and normoxic conditions. After 24 hours levels of NO were measured by aspirating the glass vessels and monitoring NO concentration directly. The results demonstrated the ability of superoxide scavengers to minimize superoxide interaction with NO upon activation of organic nitrates.

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Abstract

Compounds for use in the treatment of heart disease include a superoxide scavenger and an organic nitrate or nitrite moiety. The compounds can be represented by the formula (A)n(B)m, in which A is a superoxide scavenger, B is an organic nitrate or organic nitrite moiety, and n and m are values between 1 and 8. These compounds do not suffer from the problem of patient tolerance that is associated with the use of conventional agents such as organic nitrates.

Description

FIELD OF THE INVENTION [0001] The present invention relates to compounds suitable for use in the treatment of heart disease. These compounds do not suffer from the problem of patient tolerance that is associated with the use of conventional agents such as organic nitrates. BACKGROUND OF THE INVENTION [0002] Organic nitrates and nitrites have been widely prescribed for the prophylactic treatment of angina for over 100 years. More recently, these drugs have been extended to manage coronary artery disease, acute myocardial infarction and congestive heart failure (Parker & Parker, (1998) N. Engl. J. Med. 338; 520-531). Examples of such drugs include glyceryl trinitrate (GTN), 1,2-glyceryl dinitrate, 1,3-glyceryl dinitrate, isosorbide dinitrate, isosorbide-2-mononitrate and isosorbide-5-mononitrate. [0003] The primary action of organic nitrates is vasodilation, which is attributable primarily to nitrate-induced relaxation of vascular smooth muscle in veins, arteries, and arterioles. Orga...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61P9/00
CPCA61K47/48015A61K47/52A61P9/00
Inventor ZHANG, ZHINAUGHTON, DECLAN P.SUMI, YOSHIHIKOIMAIZUMI, ATSUSHI
Owner TEIJIN LTD
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