Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-07-12
1998-06-09
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514434, 514455, 514468, 514641, 514681, 514682, A01N 4320
Patent
active
057634793
DESCRIPTION:
BRIEF SUMMARY
This application is a 35 USC 371 filing of PCT/GB92/00196, published as WO/92/01353 on Aug. 20, 1992.
FIELD OF THE INVENTION
This invention relates to naphthoquinone derivatives, many of which are known, for which a new therapeutic utility has been found.
BACKGROUND OF THE INVENTION
Many 1,4-naphthoquinones are known. One example is menadione, or vitamin K.sub.3.
Menadione (2-methyl-1,4-naphthoquinone) is a redox, hydrogen-acceptor compound that has the property of a prothrombogenic vitamin. The potential value of redox drugs, including menadione, is described by Chayen (1982), Agents and Actions 12(4): 530-535.
Rheumatoid arthritis involves a considerable increase in the activity of the oxidative section of the pentose-phosphate pathway of the synovial lining cells that grow out to form one of the histological manifestations of the disease in the affected joint. This pathway is the main source of ribose sugars that are essential for many metabolic processes, including proliferation; of greater significance is the fact that it is also a major source of the reduced coenzyme (NADPH) that is essential for many aspects of cellular activity, as reviewed by Chayen and Bitensky (1982), "Metabolism of the Rheumatoid and Non-Rheumatoid Synovial Lining", in Articular Synovium, ed. Franchimont, pub, Karger, Basle. This NADPH is provided by the activities of the first and the third component of the pathway, namely glucose 6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (6PGD). The second component of the pathway is 6-phosphogluconolactonase (6PGL).
Pitsillides et al (1990), Cell Biochem. Funct. 8, 221-226, show that menadione significantly ameliorates the immune arthritis that can be induced experimentally in the rabbit (which closely resembles human rheumatoid arthritis both structurally and metabolically). By contrast with control animals, rabbits fed with menadione (by gavage) exhibited marked diminution in the chronic inflammation assessed both histologically and by the activity of which is characteristically increased in the sync lining cells in both the human and the rabbit condition
Chayen et al (1973), Practical Biochemistry, Wiley, disclose that, in many cytochemical reactions, on sections of various tissues, menadione is as effective as phenazine methosulphate in transferring redu equivalents from the reduced coenzyme to the indicated neotetrazolium chloride. However, it apparently does act in this way in synovial lining cells in section human and rabbit synovium. Its mechanism of action therefore cannot be readily understood.
SUMMARY OF THE INVENTION
Naphthoquinone derivatives have been found to therapeutic utility or activity superior to menadione. present invention is in part based on the realisation that in synovial linings, menadione might be converted to epoxide, but would not be rapidly metabolised further Consequently, the unusual effect of menadione would be to the epoxide.
The present invention is also based on the realisation that menadione has a reactive site at C-3 which may make an unsuitable for oral administration, e.g. owing interaction with glutathione (reduced form). In accordance with the present invention, compounds; which have desired activity, i.e. of the same order as, or preferably better than, menadione, with respect to chronic arthritis inflammation, are better adapted to oral administration having either a 2,3-double bond, in which case there a and 3-substituents, or a 2,3-single bond.
DESCRIPTION OF THE INVENTION
One type of compound for use in the present invention is a 1,4-naphthalenedione (or imine analogue) which has a reactive site, by being substituted at the 2 and positions, e.g. of formula I. Specific examples compounds of this type are 2,3-dimethyl-1,4-naphthalenedione and 2,3-dimethoxy-1,4-naphthalenedione.
An alternative type of compound for use in the present invention is a 1,2,3,4-tetrahydro-1,4-dioxonaphthalene (or imine analogue). Depending on their substitution, such compounds can exist in a tautomeric form that is more readily ap
REFERENCES:
patent: 2367302 (1945-01-01), Moore et al.
patent: 4628062 (1986-12-01), Opitz et al.
Pitsillides, A.A., et al. "The effect of menadione epoxide on the experimental immune arthritis in the rabbit", Int. J. Exp. Path., 72, pp. 301-309, 1991.
Fontagne, J. et al., "Inflammatory and anti-inflammatory properties of some oxidizing substances", Arch. Int. Pharmacodyn. Ther., 206(2), pp. 242-252, 1973.
Rabotnikov, Yu. M., "Characteristics and analysis of the antiphlogistic effect of vikasol", Sb. Nauch. Tr., 63, pp. 126-42, 1966.
Agents and Actions, vol. 12, No. 4, 1982, Birkhauser Verlag, Basel, CH; J. Chayen: "Editorial Concerning the possibiliity of redox drugs", pp. 530-535.
The Journal of Rheumatology, vol. 11, No. 5, Oct. 1984; F. Huck et al: "Reducing Property of Some Slow Acting Antirheumatic Drugs", pp. 605-609.
Pitsillides et al., "Amelioration by Menadione of the Experimental Chronic Immune Arthritis in the Rabbit", Cell Biochemisty and Function, vol. 8, (1990).
Chayen et al., "The Use of Menadione as an Intermediate Hydrogen-Carrier for Measuring Cytoplasmic Dehydrogenatng Enzyme Activities", Histochemie, vol. 35, (1973), pp. 75-80.
Chayen et al., "Practical Histochemistry", John Wiley & Sons, New York, pp. 192-193 (1973).
Moore, M., "The Antihemorrhagic Activity of Sulfonated Derivatives of 2-Methylnaphthalene", Aug. 1941, pp. 2049-2051.
Chayen et al., "Metablism of Rheumatoid and Non-Rheumatoid Synovial Lining Cells", Articular Synovium. Int. Symp., Bruges 1981, pp. 59-74.
Paladin, Doklady Akad. Nank -USSR, vol. 41, pp. 258-261 (1943).
Bitensky Lucille
Chayen Joseph
Frost George T. B.
Ivy C. Warren
KS Biomedix Ltd.
Smith Lyman H.
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