Condensed compounds, their production and use

Details Condensed compounds, their production and use Condensed compounds, their production and use

1995-11-14

1999-12-07

Dentz, Bernard

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514302, 546 16, 546114, 546115, 540593, 548453, C07D49104, A61K 31435

Patent

active

059984333

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to new condensed furan compounds which exhibit excellent 2,3-oxidosqualene cyclase inhibiting and high-density lipoprotein-cholesterol elevating activities and a method of their production.
The compounds are useful as lipid-modifying agent and are of value in the prevention and the treatment of hyperlipidemia, hypercholesterolemia and atherosclerosis.
The present invention also relates to compositions containing the compounds, a cholesterogenesis inhibitor and an antifugal agent.


BACKGROUND ART

Many epidemiological studies have shown that hypercholesterolemia, hypertension and smoking comprise the three major risk factors for arteriosclerotic diseases, such as myocardial infarction, angina pectoris and cerebral infarction. Appropriate control of blood cholesterol level is therefore critical to the prevention or treatment of arteriosclerotic diseases, such as ischemic heart diseases. Among the drugs that decrease the blood cholesterol level are drugs that capture bile acid and inhibit its absorption, such as cholestyramine and colestipol (disclosed in U.S. Pat. No. 4,027,009, for instance) and drugs that inhibit acyl coenzyme A cholesterol acyl transferase (ACAT) and suppresses intestinal absorption of cholesterol, such as melinamide (disclosed in British Patent No. 1123004), as well as drugs that suppress cholesterol biosynthesis, which have drawn attention. Cholesterol biosynthesis suppressors in pharmaceutical use include lovastatin (disclosed in U.S. Pat. No. 4,231,938), simvastatin (disclosed in U.S. Pat. Nos. 4,231,938 and 4,444,784) and pravastatin (disclosed in U.S. Pat. No. 4,346,227), all inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. When HMG-COA reductase is inhibited, however, not only cholesterogenesis, but also biosynthesis of other components essential to be alive, such as ubiquinone, dolichol and heme A, are inhibited, resulting in adverse effects of concern. Ubiquinone, dolichol, heme A etc. are known to be biosynthesized from farnesyl pyrophosphate in the cholesterol biosynthesis pathway; to prevent adverse effects due to their reduction, it is desirable that the enzymes after farnesyl pyrophosphate in the cholesterogenesis are inhibited. For example, 2,3-oxidosqualene cyclase (EC 5.4.99.7) is an enzyme that converts 2,3-oxidosqualene to lanosterol; 2,3-oxidosqualene cyclase inhibition results in a diminishment of cholesterol synthesis, owing to inhibited production of lanosterol, which is used for conversion to cholesterol, eventually leading to lower blood cholesterol levels. Also, the 2,3-oxidosqualene accumulation, as a result of 2,3-oxidosqualene cyclase inhibition, is metabolically converted to oxysterol via dioxide squalene, which is known as an HMG-COA reductase repressor [F. R. Taylor et al., Journal of Biological Chemistry, 1986, vol. 261 (32), pp. 15039-15044]. 2,3-Oxidosqualene cyclase inhibitors are therefore capable of inhibiting cholesterogenesis potently by the synergetic effect of HMG-COA reductase suppression at the transcription level, in addition to the inhibition of one enzyme after farnesyl pyrophosphate in the cholesterogenesis pathway. Already reported 2,3-oxidosqualene cyclase inhibitors include diphenyl derivatives (disclosed in European Patent No. 464465), aminoalkoxybenzene derivatives (disclosed in European Patent No. 410359), piperidine derivatives (described by D. S. Dodd et al. in the Journal of Organic Chemistry, 1992, vol. 57, pp. 2794-2803 and 7226-7234; Japanese Patent Unexamined Publication No. 234362/1992), decalin derivatives, azadecalin derivatives and indane derivatives [described in WO 80/08450; Journal of Biological Chemistry, 1981, vol. 254, pp. 11258-11263; N. Gerst et al., Biochemical Pharmacology, 1988, vol. 37, pp. 1955-1964; M. W. Wannamaker, Journal of Medicinal Chemistry, 1992, vol. 35, pp. 3581-3583; Japanese Patent Unexamined Publication Nos. 140112/1993 and 3144/1989], 2-aza-2,3-dihydrosqualene and 2,3-epiminosqualene [described by A. Duriatti et al. in Biochem

REFERENCES:
patent: 4210649 (1980-07-01), Blanchard et al.
patent: 4335128 (1982-06-01), Blanchard et al.
patent: 5334596 (1994-08-01), Hartman et al.
patent: 5532240 (1996-07-01), Nakao et al.

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