Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-09-24
2000-12-12
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544182, C07D 2522, C07D40112, A61K 3153, A61P 306
Patent
active
061599743
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to an LDL receptor gene expression promoter, which are useful in the treatment of hyperlipidemia. More particularly, the present invention relates to a novel 1,2,4-triazine derivative having an activity for promoting expression of LDL receptor gene.
BACKGROUND OF THE INVENTION
It has been known that a low density lipoprotein (LDL) receptor in hepatic cells plays an important role in the regulation of cholesterol level in the blood. That is, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor inhibits the synthesis of cholesterol in hepatic cells, by which the expression of LDL receptor is indirectly promoted. As a result, the uptake of LDL by a LDL receptor from the blood is increased, and then the cholesterol level in the blood is reduced.
In addition, 1,2,4-triazine derivatives are disclosed, for example, in Liebigs Annalen der Chemie, p. 631, 1990; Chemical and Pharmaceutical Bulletin, p. 926, 1973; Yakugaku-Zasshi, vol. 112, p. 729, 1992; Journal of Organic Chemistry, vol. 52, p. 4287, 1987; Japanese Patent Publication No. 63-225366; Japanese Patent Publication No. 5-45816, etc., but these derivatives have not been known as an LDL receptor gene expression promoter or as an agent for treatment of hyperlipidemia.
DISCLOSURE OF INVENTION
HMG-COA reductase inhibitors have been highly valued in the clinical field as an agent for reducing the blood cholesterol level. However, HMG-COA reductase inhibitors cannot sufficiently reduce the blood cholesterol level to the desired lower level in patients with familial hypercholesterolemia or in patient with coronary artery diseases. Under these circumstances, it is desired to develop an antihyperlipidemic agent showing more effective reducing activity of LDL level in the blood in such patients.
While HMG-COA reductase inhibitors indirectly promote the synthesis of LDL receptors by inhibition of cholesterol synthesis, an LDL receptor gene expression promoter can be expected to show more potent reducing activity of LDL level in the blood by more directly promoting the synthesis of LDL receptors.
In the upstream of each gene of LDL receptor, there is a sequence named SRE (Sterol Regulatory Element), of which transcription is regulated by a free cholesterol in the cells (cf., Goldstein & Brown, Nature, vol. 343, p. 425, 1990). Recently, SREBPs (SRE binding proteins) were identified as substances binding to the SRE of LDL receptor gene (cf., Goldstein, Brown, et al., The Journal of Biological Chemistry, vol. 268, p. 14497, 1993), and it has been reported that the transcription of LDL receptor gene is activated by the SREBP's binding to the SRE of LDL receptor gene (cf., Goldstein, Brown, et al., Cell, vol. 75, p. 187, 1993 and Proceeding of the Natural Academy of Science, vol. 90, p. 11603, 1993). Based on these findings, it is possible to develop a medicament with a completely new mechanism showing an activity of reducing the cholesterol level in the blood by selectively activating the expression of LDL receptor.
The present invention provides an LDL receptor gene expression promoter, which either directly or indirectly regulates the synthesis of LDL receptor with respect to gene transcription, and is useful in the treatment of hyperlipidemia. The present invention also provides a novel compound, which is useful in the regulation of the synthesis of LDL receptor, in the reduction of LDL cholesterol level in the blood, and in the treatment or prevention of arteriosclerosis.
That is, the present invention relates to an LDL receptor gene expression promoter which comprises a 1,2,4-triazine derivative of the formula (I): ##STR2## wherein R.sup.1 is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted heterocyclic group,
R.sup.2 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted 5- to 6-membered aromatic heterocyclic group, a substituted or unsubstituted alkyl
REFERENCES:
patent: 5187161 (1993-02-01), Goto et al.
patent: 5571816 (1996-11-01), Kampe et al.
Shoetsu Konno et al., Yakugaku Zasshi, vol. 112, No. 10, pp. 729-741 (1992).
Konno et al., Heterocycles, 26, 3259-3264 (1987).
Konno et al., Chemical Abstract, 109:109970 (1988).
Konno, S. et al., vol. 26, (No. 12) pp. 3259-3264, (1987).
Neunhoeffer, H. et al., Liebigs Ann. Chem.; 1990 (No. 7), pp. 631-640.
Chemical Abstracts vol. 124 (No. 13), Mar. 25, 1996, pp. 1288-1289.
Morishita Koji
Muraoka Masami
Ohashi Naohito
Ueno Yoshihide
McKenzie Thomas
Shah Mukund J.
Sumitomo Pharmaceuticals Company Limited
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