Stable derivatives of ubiquinole, processes for their production

Details Stable derivatives of ubiquinole, processes for their production Stable derivatives of ubiquinole, processes for their production

1999-08-03

2000-10-03

Carr, Deborah

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

514546, 514553, 514576, 514720, A01N 3702, A01N 3708

Patent

active

061274178

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to stable derivatives of ubiquinole, processes for their Production and the pharmaceutical use thereof.


BACKGROUND ART

Ubiquinone, (2,3-dimethoxy-5-methyl-6-decaprenylbenzoquinone) or coenzyme Q.sub.10 (CoQ.sub.10) is a quinone of lipidic nature, an essential redox component of the mitochondrial respiratory chain, where it acts as an electron shuttle, controlling the efficiency of oxidative phophorylation. Ubiquinone also exerts another important biological function, acting as an antioxidant for cell membranes, in harmony and in synergism with Vitamin E. Recent studies (Takahashi T., et al., (1993) Lipids 28, 803-809; Aberg F., et al., (1992) Arch-Biophys. 295, 230-234) have demonstrated that in certain human and animal test tissues (liver, heart, kidney, pancreas, etc.) the levels of ubiquinone (CoQ.sub.10), especially in its reduced form, known as ubiquinole (CoQ.sub.10 H.sub.2) are higher than those of Vitamin E.
The following reaction scheme shows the balance between the oxidised and reduced forms. ##STR1##
Ubiquinone, especially in its reduced form ubiquinole, appears to have a higher effectiveness than Vitamin E in inhibiting lipidic peroxidation of membranes; this function of ubiquinone is explicated in a different site (the central level of the lipidic bi-layer) from that in which Vitamin E acts (close to the surface of the bi-layer). Ubiquinole would appear to form in the tissues following the reduction of ubiquinone or the co-enzyme Q semiquinone (CoQ.sub.10 H) by the enzymatic systems present in the membranes and generally indicated as quinone-reductases (NAD (P) H-dependent electron carriers), which are theoretically inextinguishable in perfectly functional aerobic organisms.
Aberg et al. (cited work) have determined the ubiquinole content as a percentage ratio of ubiquinone, in human tissues, as indicated in the following table.


______________________________________ Content CoQ.sub.10 H.sub.2 Tissue .mu.g/g tissue (%) ______________________________________ heart 114.0 61 kidney 66.5 75 liver 54.9 95 muscle 39.7 65 pancreas 32.7 100 thyroid 24.7 70 spleen 24.6 85 brain 13.4 23 intestine 11.5 93 colon 10.7 87 testicle 10.5 85 lung 7.9 25 ______________________________________
This study demonstrates that the reduced form ubiquinole almost always prevails over the oxidised form, to the extent that, in the pancreas, it is practically the only form present.
The above has been demonstrated in the case of healthy aerobic organisms, that is to say when the ubiquinole prevails over the ubiquinone and when, as demonstrated in scientific literature (Ernster L., et al. (1993) The Clinical Invest. 71, 60-65; Frei B., et al., (1990) Medical Sciences 87, 4879-4883; Hauska G. et al., (1983) Biochim. Biophys. Acta 726, 97-133; Kroger A. et al., (1973) European J. Biochem 24, 358-368) the quinone-reductases are practically inextinguishable.
However, it has been found that in conditions of continuous (or high) intracellular oxidative stress, for example in diseases connected with ageing or in the case of acquired immuno-deficiency syndrome (AIDS), the enzymatic electron carrier systems lose their ability to perform their biological reducing function properly, or entirely, and this causes a drop in the ubiquinole levels in tissues. Furthermore, in the case of the diseases mentioned above, the reduced endogenous synthesis of ubiquinone is another factor that causes a drop in the levels of ubiquinole in tissues.
There was therefore a problem in the state of the art relating to how, in cases of intracellular oxidative stress, to restore the levels of ubiquinole in tissues to levels close to or equivalent to those found in a healthy organism. The proposed pharmacological solution consisted in the administration of ubiquinone of exogenous origin. However, this solution created a problem of low efficiency, as the quinone-reductases, that is to say the enzymes capable of reducing ubiquinone to ubiquinole, although theore

REFERENCES:
patent: 3068295 (1962-12-01), Folkers et al.

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