Nicotinic acid esters and pharmaceutical compositions containing

Details Nicotinic acid esters and pharmaceutical compositions containing Nicotinic acid esters and pharmaceutical compositions containing

1998-03-03

2000-01-18

Davis, Zinna Northington

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514277, 546315, 546339, C07D21330, C07D21380, A61K 3144

Patent

active

060158212

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The invention relates to new esters and to compositions for pharmaceutical uses, particularly for managing cardiovascular diseases, inflammatory diseases, dermatological disorders including baldness, diabetes, cancer, psychiatric disorders and other appropriate medical and nutritional disorders.


BACKGROUND



Blood Cholesterol

There is considerable background in relation to the specific matter of blood cholesterol levels. As discussed in EPA 0 087 864, essential fatty acids (EFAs), particularly gammalinolenic acid (GLA) and dihomogammalinolenic acid (DGLA), act to lower blood cholesterol levels, the mechanism being unknown; these acids of course are the starting materials for 1-series PG synthesis, the bodily conversions of EFAs generally being as set out in Table 1 below:


TABLE 1 ______________________________________ n-6 EFA's n-3 EFA's ______________________________________ 18:2n-6 18:3n-3 (Linoleic acid, LA) (.alpha.-Linolenic acid, ALA) .dwnarw. .delta.-6-desaturase .dwnarw. 18:3n-6 18:4n-3 (.gamma.-Linolenic acid, GLA) (Stearidonic acid, SA) .dwnarw. elongation .dwnarw. 20:3n-6 20:4n-3 (Dihomo-.gamma.-linolenic acid, DGLA) .dwnarw. .delta.-5-desaturase .dwnarw. 20:4n-6 20:5n-6 (Arachidonic acid, AA) (Eicosapentaenoic acid, EPA) .dwnarw. elongation .dwnarw. 22:4n-6 22:5n-3 (Adrenic acid) .dwnarw. .delta.-4-desaturase .dwnarw. 22:5n-6 22:6n-3 (Docosahexaenoic acid, DHA) ______________________________________
The acids, which in nature are of the all-cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. z,z-octadeca-9,12-dienoic acid or z,z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoic acid, but numerical designations based on the number of carbon atoms, the number of centres of unsaturation and the number of carbon atoms from the end of the chain to where the unsaturation begins, such as, correspondingly, 18:2n-6 or 22:6n-3 are convenient. Initials, e.g., EPA and shortened forms of the name e.g. eicosapentaenoic acid are used as trivial names in some of the cases.
As also discussed in EPA 0 087 864, there are a number of agents which lower cholesterol levels in the blood by binding to bile salts in the gastro-intestinal tract and directly enhancing cholesterol excretion in the faeces. Illingworth et al in the Lancet for Feb. 7, 1981 pp 296-7 report use of the bile salt binder colestipol, plus nicotinic acid (niacin) against an inherited high blood-cholesterol condition, with "dramatic" effect. No mechanism is discussed, the article suggesting simply that therapy, in addition to taking binders, may best be directed towards reducing lipoprotein synthesis, and saying that niacin has been reported to do that.
Niacin is one of the two forms of Vitamin B3, the other being niacinamide; by an unknown mechanism it acts systematically to lower cholesterol levels in blood without any substantial effect on cholesterol excretion.
The effect of niacin is believed to be due to an effect it has in stimulating prostaglandin (PG) synthesis, specifically PGE.sub.1 synthesis from dihomogammalinolenic acid and PGD.sub.2 synthesis from arachidonic acid, as part of a mechanism that leads to reduced cholesterol synthesis and hence reduced levels in the blood. It is for example known that PGE.sub.1 stimulates the formation of cyclic AMP (adenosine monophosphate) and that cyclic AMP inhibits cholesterol synthesis. Further, niacin, in addition to its blood cholesterol lowering effect, causes flushing and tingling, effects that the inventor has noted are also among those of stimulating prostaglandin synthesis, particularly PGE.sub.1 and PGD.sub.2 synthesis.
Niacinamide, in contrast, though generally equivalent in its bodily effects to niacin, does not show this stimulating effect on PG synthesis, nor does it cause flushing and tingling or show a blood cholesterol lowering effect. Linkage of these facts as instances of the unusual existence of differences

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