Urethanes, thio and dithio analogues and their use as...

Details Urethanes, thio and dithio analogues and their use as... Urethanes, thio and dithio analogues and their use as...

1999-03-24

2002-02-12

Chang, Ceila (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

N-c doai

C514S481000, C514S484000, C560S019000, C560S115000

Reexamination Certificate

active

06346545

ABSTRACT:

The present invention relates to new urethanes, the thio and dithio analogues thereof, the salts thereof with physiologically acceptable organic and inorganic acids, processes for preparing these compounds and pharmaceutical compositions containing them.
The compounds according to the invention are inhibitors of cholesterol biosynthesis, particularly inhibitors of the enzyme 2,3-epoxysqualene-lanosterol-cyclase, a key enzyme in cholesterol biosynthesis. The compounds according to the invention are suitable for the treatment and prophylaxis of hyperlipidaemias, hypercholesterolaemias and atherosclerosis. Other possible applications are in the treatment of hyperproliferative skin and vascular diseases, tumours, gallstone problems and mycoses.
Compounds which affect cholesterol biosynthesis are important for the treatment of a number of diseases. These include in particular hypercholesterolaemias and hyperlipidaemias which are risk factors for the occurrence of atherosclerotic vascular changes and their sequelae such as coronary heart disease, cerebral ischaemia, Claudicatio intermittens and gangrene.
The significance of elevated serum-cholesterol levels as a main risk factor for the occurrence of atherosclerotic vascular changes is generally known. Extensive clinical studies have led to the finding that the risk of developing coronary heart diseases can be reduced by lowering serum cholesterol (Current Opinion in Lipidology 2(4), 234 [1991]; Exp. Opin. Ther. Patents 7(5), 441-455 [1997]). Since the majority of the cholesterol is synthesised in the body itself and only a small proportion is taken in with the food, inhibiting biosynthesis is a particularly attractive method of lowering raised cholesterol levels.
In addition, other possible applications for cholesterol biosynthesis inhibitors are the treatment of hyperproliferative skin and vascular diseases and tumours, the treatment and prophylaxis of gallstone problems and their use in treating mycoses. The latter case involves intervening in the ergosterol biosynthesis in fungal organisms which proceeds substantially analogously to cholesterol biosynthesis in mammalian cells.
The cholesterol or ergosterol biosynthesis takes place, starting from acetic acid, via a large number of reaction steps. This multi-stage process offers a number of possible interventions, of which the following are examples:
For inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-synthase, &bgr;-lactones and &bgr;-lactams with a potential antihypercholesterolaemic activity are mentioned (cf. J. Antibiotics 40, 1356 [1987], U.S. Pat. No. 4,751,237, EP-A-0 462 667, U.S. Pat. No. 4,983,597).
Examples of inhibitors of the enzyme HMG-CoA-reductase are 3,5-dihydroxycarboxylic acids of the mevinolin type and their &dgr;-lactones, of which lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin are used in the treatment of hypercholesterolaemias. Other possible applications for these compounds are fungal infections (U.S. Pat. No. 4,375,475, EP-A-0 113 881, U.S. Pat. No. 5,106,992), skin diseases (EP-A-0 369 263) and gallstone problems and tumour diseases (U.S. Pat. No. 5,106,992; Lancet 339, 1154-1156 [1992]).
The inhibition of the proliferation of smooth muscle cells by lovastatin is described in Cardiovasc. Drugs. Ther. 5, Suppl. 3, 354 [1991]. Tocotrienol, an unsaturated analogue of vitamin E, and its analogues make up another class of substances which act on HMG-CoA-reductase (Exp. Opin. Ther. Patents 7 (5), 446 [1997]).
Inhibitors of the enzyme squalene-synthetase are e.g. isoprenoid-(phosphinylmethyl)-phosphonates, the suitability of which for treating hypercholesterolaemias, gallstone problems and tumour diseases is described in EP-A-0 409 181 and in J. Med. Chemistry 34, 1912 [1991], and also &agr;-phosphonosulfinate compounds (EP-A-0 698 609), the compounds J-104,118 and J-104,123 (Tetrahedron 52, 13881-13894, [1996]) and cyclobutane derivatives (WO 96/33159). A survey of squalene-synthethase inhibitors can be found in Exp. Opin. Ther. Patents 7 (5), 446-448 [1997].
Known inhibitors of the enzyme squalene-epoxidase are allylamines such as naftifine and terbinafine, which have been used in therapy to fight fungal diseases, and also the allylamine NB-598 with an antihypercholesterolaemic activity (J. Biol. Chemistry 265, 18075-18078 [1990]) and fluorosqualene derivatives with a hypocholesterolaemic activity (U.S. Pat. No. 5,011,859). Moreover, piperidines and azadecalines with a potential hypocholesterolaemic and/or antifungal activity are described, the mechanism of activity of which has not been fully explained and which are squalene epoxidase and/or 2,3-epoxisqualene-lanosterol-cyclase inhibitors (EP-A-0 420 116, EP-A-0 468 434, U.S. Pat. No. 5,084,461 and EP-A-0 468 457). Other examples are described in Exp. Opin. Ther. Patents 7 (5), 448-449 [1997].
Examples of inhibitors of the enzyme 2,3-epoxisqualene-lanosterol-cyclase are diphenyl derivatives (EP-A-0 464 465), aminoalkoxybenzene derivatives (EP-A-0 410 359, J. Lipid. Res. 38, 373-390, [1997]) and piperidine derivatives (J. Org. Chem. 57, 2794-2903 [1992] which have an antifungal activity. Moreover this enzyme is inhibited in mammalian cells by decalines, azadecalines and indane derivatives (WO 89/08450; J. Biol. Chemistry 254, 11258-11263 [1981]; Biochem. Pharmacology 37, 1955-1964 [1988] and J 64 003 144), and also by 2-aza-2,3-dihydro-squalene and 2,3-epiminosqualene (Biochem. Pharmacology 34, 2765-2777 [1985]), by squalenoid-epoxide-vinylether (J. Chem. Soc. Perkin Trans. I, 461 [1988]) and 29-methylidene-2,3-oxidosqualene (J. Amer. Chem. Soc. 113, 9673-9674 [1991]). Other examples are pyridine and pyrimidine derivatives (WO 97/06802), heterobicyclic alkylamines (WO 96/11201), imidazole derivatives (EP-A-0 757 988) and isoquinoline derivatives (J. Med. Chemistry 39, 2302-2312, [1996]). Other compounds described are ureas (DE-A-4 438 021) oximes (DE-A-4 412 692), a number of amides (DE-A-4 407 134, DE-A-4 407 135, DE-A-4 407 136, DE-A-4 407 138, DE-A-4 407 139, DE-A-4 412 691, DE-A-4 437 999, DE-A-4 438 000, DE-A-4 438 020, DE-A-4 438 082, DE-A-4 438 029, DE-A-4 438 054, DE-A-4 438 055, DE-A-4 438 082, DE-A-4 438 083, EP-A-0 599 203, EP-A-0 596 326) and esters (WO 95/29148). Other examples are described in Exp. Opin. Ther. Patents 7(5), 448-449 [1997].
Finally, inhibitors of the enzyme lanosterol-14&agr;-demethylase also include steroid derivatives with a potential antihyperlipidaemic activity which simultaneously influence the enzyme HMG-CoA-reductase (U.S. Pat. No. 5,041,431; J.Biol. Chemistry 266, 20070-20078 [1991]; U.S. Pat. No. 5,034,548) . This enzyme is also inhibited by the antimycotics of the azole type which constitute N-substituted imidazoles and triazoles. This class includes, for example, the commercially available antimycotics ketoconazole and fluconazole.
The compounds of the following general formula I are new. It has been found that, surprisingly, they are highly effective inhibitors of the enzyme 2,3-epoxisqualene-lanosterol-cyclase (International Classification: EC 5.4.99.7).
The enzyme 2,3-epoxisqualene-lanosterol-cyclase catalyses a key step of cholesterol or ergosterol biosynthesis, namely the conversion of 2,3-epoxisqualene into lanosterol, the first compound with a steroid structure in the biosynthesis cascade. Inhibitors of this enzyme lead one to expect the advantage of higher selectivity, compared with inhibitors of earlier stages of biosynthesis, such as for example HMG-CoA-synthase and HMG-CoA-reductase, since inhibiting these early stages of biosynthesis leads to a reduction in biosynthetically formed mevalonic acid and consequently may have a negative effect on the biosynthesis of the mevalonic acid-dependent substances dolichol, ubiquinone and isopentenyl-t-RNA (cf. J. Biol. Chemistry 265, 18075-18078 [1990&r

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