Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-02-11
1995-08-22
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514444, 549 59, 549 60, 549 78, 549 80, C07D33316, C07D33318, A61K 3138
Patent
active
054440840
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP93/co723 filed May 20, 1993.
TECHNICAL FIELD
This invention relates to novel substituted heterocyclic derivatives, and more detailedly relates to substituted heterocyclic derivatives useful in the medicinal field, particularly in the field of treatment and prophylaxis of hypercholesterolemia, hyperlipidemia and further arteriosclerosis, and their use.
BACKGROUND ART
In recent years, it is pointed out that the occurrence frequency of arteriosclerosis and various diseases of coronary and encephalic arteries caused thereby is increasing due to increase of the rate of persons of advanced ages, changes of diet, etc. Various factors are considered for occurrence of this arteriosclerosis, and particularly, the increase of cholesterol in the blood is one of the most principal dangerous factors, and agents lowering cholesterol in the blood are effective for prophylaxis and treatment of arteriosclerosis [Agents Used to Treat Hyperlipidemia, Drug Evaluations 6th. edition, 903-926, (1986)]. Further, among these agents lowering cholesterol in the blood, agents inhibiting biosynthesis of cholesterol in the living body are highly rated because of their clear action mechanism and strong medicinal virtues [Proc. Natl. Acad. Sci., 77, 3957 (1980)]. However, since most of cholesterol biosynthesis-inhibiting agents so far known are inhibitors acting at the early stage or the late stage of the biosynthetic pathway, they have problems, for example, that they inhibit formation of other various physiologically important biological products simultaneously when they inhibit cholesterol biosynthesis, and further that accumulation of the precursors formed by the inhibition becomes a cause of other diseases.
The present inventors previously reported that a series of substituted alkylamine derivatives selectively inhibits squalene epoxidase located at the middle stage of the cholesterol biosynthesis system of mammals, and as a result are useful as an agent lowering cholesterol in the blood which has a mode of action different from that of known cholesterol biosynthesis-inhibiting agents (see Japanese Laid-Open Patent Publication No. 193746/1991, EP 0318860A2, WO 90/5132 and EP 0448078A2). Although several reports were made lately, besides the reports of the present inventors, on agents inhibiting squalene epoxidases of mammals, any of the disclosed compounds has only a low activity, and particularly, it is almost impossible to expect their effects on human beings, dogs, etc. [J. Chem. Research (s), 18-19 (1988); J. Am. Chem. Soc., 111, 1508-1510 (1989); ibid., 114, 360-361 (1992); J. Med. Chem., 32, 2152-2158 (1989); Japanese Laid-Open Patent Publication No. 3144/1989].
DISCLOSURE OF INVENTION
A main object of this invention is to provide an anti-hypercholesterolemia agent, an anti-hyperlipidemia agent and an agent for treatment and prophylaxis of arteriosclerosis each having higher safety and an excellent anti-cholesterol action, compared with known drugs.
As stated above, the present inventors previously reported that a series of substituted alkylamine derivatives selectively inhibits squalene epoxidases of mammals and at the same time has a strong anti-cholesterol action (see Japanese Laid-Open Patent Publication No. 93746/1991, EP 0318860A2, WO 90/5132 and EP 0448078A2).
As a result of further intense researches, the present inventors have, unexpectedly, found this time that substituted heterocyclic derivatives represented by the following general formula [I], which have no nitrogen atom so far considered to be essential for manifestation of activities, have further excellent characteristics, compared with the previously reported group of compounds.
Namely, accordingly to this invention, there is provided a substituted heterocyclic derivative represented by the general formula ##STR2## wherein R denotes a 5- or 6-membered heterocyclic group containing one or two hetero atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms; Q.sup.1 denotes a group repres
REFERENCES:
Moore, et al., Am. Chem. Soc., (1992), 114:360-361, "Terminal Difluoro Olefin Analogues of Squalene Are Time-Dependent Inhibitors of . . . ".
Sen, et al., J. Med. Chem. (1989), 32:2152-2158, "Squalene Analogues Containing Isopropylidene Mimics as Potential Inhibitors of . . . ".
Mancuso, et al., J. Org. Chem. (1978), 43:2480-2482, "Oxidation of Long-Chain and Related Alcohols to Carbonyls by Dimethyl Sulfoxides . . . ".
Yamamoto, et al., J. Biol. Chem., (1970), 245:1670-1674, "Studies on Squalene Epoxidase of Rat Liver".
Ono, et al., J. Biol. Chem., (1975), 250:1571-1579, "Solubilization and Partial Characterization of Rat Liver Squalene Epoxidase".
"Agents Used to Treat Hyperlipidemia", Drug Evaluations, 6th Ed., 903-926 (1986).
Alberts, et al., Proc. Nat'l. Acad. Sci. USA (1980), 77:3957-3961.
Ceruti, et al. J. Chem. Res. (1988), 18-19, "Synthesis of Squalenoid Acetylenes and Allenes, as Inhibitors of Squalene Epoxidase".
Sen, et al., J. Am. Chem. Soc., (1989), 111:1508-1510, "Trisnorsqualene Alcohol, a Potent Inhibitor of Vertebrate Squalene Epoxidase".
Hayashi Masahiro
Kamei Toshio
Mitsuya Morihiro
Nomoto Takashi
Nonoshita Katsumasa
Banyu Pharmaceutical Co. Ltd.
Cebulak Mary C.
Raymond Richard L.
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