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Spin trap nitronyl hindered phenols

a technology of nitronyl and spin trap, which is applied in the field ofnitronyl substituted phenols, can solve the problem that molecules have not been availabl

Inactive Publication Date: 2000-02-29
OKLAHOMA MEDICAL RES FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to the use of particular antioxidants in therapeutic treatment. These compositions have the following general formula: ##STR2## wherein R1 is a hydrogen, an aryl, or an alkyl and R2 is an alkyl or an aryl group. R1 can be any alkyl group, straight chain or branched, with or without double or triple bonds, with or without polar functions (e.g., esters, alcohols, halides, carboxylic acid, aldehydes, carboxamides, aralkyl, amino or nucleic acids). R2 can contain single, double or triple bonds and may also include polar constituents (e.g., esters, alcohols, halides, carboxylic acids, aldehydes, carboxamides, aralkyl, amino or nucleic acids). R2 can also be an aryl including substituted aryls, heterocyclic, polycyclic or acyclic. R3 and R4 can be hydrogen or any alkyl group, either straight chain or branched, preferably 1 to 4 carbons. R3 and R4 are preferably alkyls from 1 to 4 carbons in length. R3 and R4 are usually the same group. Based on animal studies the dosage of these compounds is in the range of 25 to 250 mg/kg. In the preferred embodiment, the range is between 25 and 125 mg/kg depending upon the dosage required to capture the free radical. One or more of the above compounds useful in th...

Problems solved by technology

Heretofore, such molecules have not been available.

Method used

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  • Spin trap nitronyl hindered phenols
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  • Spin trap nitronyl hindered phenols

Examples

Experimental program
Comparison scheme
Effect test

example 1

Lipid peroxidation (LPO) initiated by tert-butoxy radicals

Male Sprague-Dawley rats (175-200 g) that had been maintained on commercial rat chow were starved for 24 hours, sacrificed and the livers removed. Microsomes were prepared by homogenizing the minced livers in 0.15 M potassium phosphate buffer pH 7.4 5 ml / g) and then centrifuging at 12,000.times.g for 15 minutes. The supernatant fraction was then centrifuged at 105,000.times.g for 90 minutes. The microsomal pellets were washed twice by resuspending in buffer and centrifuging at 105,000.times.g for 60 minutes. The microsomal pellets were kept frozen at -80.degree. C. until ready for use. Rat liver microsome pellets were made up into microsomal suspension (MS) by adding one milliliter of 50 mM potassium phosphate buffer (pH 7.4) per gram of liver. The protein concentration of microsomal suspensions were determined by the method of O. H. Lowry et al., J. Biol. Chem. 193:265-75 (1951).

Reaction samples were 1 ml (milliliter) in vol...

example 2

LPO initiated by NADPH catalyzed cytochrome-P450 metabolism of CCl.sub.4

An amount equal to 0.09 mmole spin trap was weighed into a test-tube to give a final concentration of 30 mM. To this container was added 14 .mu.l .sup.13 CCL.sub.4 (to produce a final concentration of 50 mM). After shaking to dissolve the spin trap, 2.35 ml of 50 mM potassium phosphate buffer at pH 7.4 (KH.sub.2 PO.sup.4 and K.sub.2 HPO.sub.4) was added plus 0.3 ml microsomal suspension. The solution was vortexed and preincubated for 10 minutes at room temperature (25.degree. C.). At this point, 0.3 ml NADPH generating system (0.5 Kornberg units of glucose-6-phosphate dehydrogenase, 5 .mu.M glucose-6-phosphate and 0.3 mM NADPH) was added to start the reaction. After incubation for 15 min at room temperature, 1.0 ml toluene was added and the system vortexed. Following centrifugation for 30 minutes at 3000 rpm (Sorvell GLC-4 with swinging bucket rotor H1000) approximately 500 .mu.l supernatant solution is removed ...

example 3

Rat Brain Miocrosomes

Similar tests were performed with rat brain microsomes using the TBA test for MDA production as the result of LPO. Results on the same compounds were as follows:

______________________________________ Inhibitor Concentration for 50% Inhibition (IC.sub.50) ______________________________________ BHT (not available) PBN 1000 .mu.M DBBNP 0.7 .mu.M DBONP 0.3 .mu.M DMONP 70 .mu.M DMBNP 600 .mu.M ON 76 .mu.M ______________________________________

Although BHT was not available for this test it is not believed that it would be particularly effective with this particular system.

The data obtained demonstrates that DBBNP and DBONP are very good inhibitors in these systems.

______________________________________ IC.sub.50 RLM (I) RLM (II) RBM (III) ______________________________________ DBBNP 4.3 .mu.M 53 .mu.M 0.7 .mu.M (700 nM) DBONP 5.8 .mu.M 35 .mu.M 0.3 .mu.M (300 mM) ______________________________________

The above data in Examples 1, 2 and 3 are graphically represented, ...

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Abstract

The invention is the use of nitronyl substituted hindered phenols as antioxidants in therapeutic applications. In the preferred embodiment the compositions have the general formula: Wherein R1 is hydrogen, an alkyl or an aryl and R2 is an alkyl or an aryl; R3 is an alkyl; and R4 is an alkyl. Further, the invention relates to novel compositions useful as antioxidants. The novel compounds include: 2,6-di-tert-butyl-4-(N-tert-octyl)nitronyl phenol (DBONP); 2,6-dimethyl-4-(N-tert-octyl)nitronyl phenol (DMONP); N-tert-octyl-C-phenyl nitrone (OPN).

Description

TECHNICAL FIELD OF THE INVENTIONThe present invention relates to novel nitronyl substituted phenols. The present invention also relates to methods using nitronyl substituted hindered phenols as antioxidants in biological systems and therapeutic applications.BACKGROUND OF THE INVENTIONThe use of antioxidants has been proposed for therapeutic treatment and for other uses such as protecting polymers such as natural rubber and synthetic rubber from oxidation. Hindered phenols occur naturally, for example tocopherols (vitamin E), and have found use as antioxidants previously. Recently, free radicals have been postulated to have significant impact in tissue injury. Evidence suggests that the free radical mechanism has a significant impact on vascular injury and damage affecting nerve cells.The use of phenylbutyl nitrone compositions for the treatment of oxidative tissue damage and gastric ulceration has been disclosed in U.S. Pat. Nos. 5,025,032 and 5,036,097 entitled "Phenylbutyl Nitrone...

Claims

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Application Information

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IPC IPC(8): A61K31/135C07C291/00C07C291/02
CPCA61K31/135C07C291/02
Inventor JANZEN, EDWARD G.WILCOX, ALLAN L.
Owner OKLAHOMA MEDICAL RES FOUND
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