Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-10-28
1999-07-06
Stockton, Laura L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548161, 548169, A61K 31425, C07D27774, C07D27782, C07D27768
Patent
active
059198079
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new benzothiazoles and benzoxazoles, 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, and more particularly inhibitors of the enzyme 2,3-epoxysqualene-lanosterol-cyclase, a key enzyme of cholesterol biosynthesis. The compounds according to the invention are suitable for the treatment and prevention of hyperlipidaemia, hypercholesterolaemia and atherosclerosis. Other possible uses include the treatment of hyperproliferative skin and vascular diseases, tumours, gallstones and mycoses.
Compounds which intervene in cholesterol biosynthesis are important for the treatment of a number of syndromes. Particular mention should be made of hypercholesterolaemias and hyperlipidaemias which are risk factors for the formation of atherosclerotic vascular changes and diseases resulting therefrom such as coronary heart disease, cerebral ischaemia, Claudicatio intermittens and gangrene.
The significance of excessively high serum-cholesterol levels as the chief risk factor for the occurrence of atherosclerotic vascular changes is generally recognised.
Extensive clinical trials have shown that by reducing the serum cholesterol the risk of suffering from coronary heart diseases can be reduced (Current cholesterol is synthesised in the body itself and only a small part is taken with the food, inhibiting biosynthesis is a particularly attractive way of lowering the raised cholesterol level.
In addition, other possible uses for cholesterol biosynthesis inhibitors are the treatment of hyperproliferative skin and vascular disorders and tumour diseases, the treatment and prevention of gallstone problems and use in mycoses. The latter is concerned with intervention in ergosterol biosynthesis in fungal organisms which largely progresses analogously to cholesterol biosynthesis in mammalian cells.
Cholesterol or ergosterol biosynthesis proceeds, starting from acetic acid, through a fairly large number of reaction steps. This multi-step process offers a number of ways of intervening, of which the following are given by way of example:
For inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA)-synthase, .beta.-lactones and .beta.-lactams with a potential antihypercholesterolaemic activity are mentioned (see J. Antibiotics 40, 4,983,597).
Inhibitors of the enzyme HMG-CoA-reductase are 3,5-dihydroxycarboxylic acids of the Mevinolin type and the .delta.-lactones thereof; Lovastatin, Simvastatin and Pravastatin are examples of these which are used in the treatment of hypercholesterolaemias. Other 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, means of Lovastatin is described in Cardiovasc. Drugs. Ther. 5, Suppl. 3,
Inhibitors of the enzyme squalene-synthetase include, for example, isoprenoid-(phosphinylmethyl)phosphonates, the suitability of which for the treatment of hypercholesterolaemia, gallstone problems and tumour diseases is described in EP-A-0 409 181 and J. Med. Chemistry 34, 1912
Known inhibitors of the enzyme squalene-epoxidase are the allylamines such as Naftifin and Terbinafin, which have been used in therapy as agents for treating fungal diseases, as well as allylamine NB-598 with an antihypercholesterolaemic activity (J. Biol. Chemistry 265, 18075-18078, activity (U.S. Pat. No. 5,011,859). Piperidines and azadecalines with a potential hypocholesterolaemic and/or antifungal activity are also described, although the mechanism of activity is not clearly established, these compounds being 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).
Examples of inhibitors of the enzyme 2,3-epoxisqualene-lanoste
REFERENCES:
patent: 2578757 (1949-03-01), Steiger et al.
The Merck Index, 1989, Merck & Company, Rahway, N.J. (see Diamthazole Dihydrochloride(compound No. 2967, on p. 2974).
Chemical Abstracts Registry Handbook-Number Section, 1991 Supplement, Registry Nos. 132979-00-1-thru 134653-09-1, see compound with RN=133688-59-2.
Chemical Abstracts, vol. 114, No. 21, 1991, Abstract No. 207259j, Nishi, T., et al: "Preparation of Benzothiazoles and benzimidazoles as Blood Platelet Aggregation Inhibitors".
Chemical Abstracts, vol. 54, No. 11. Jun. 10, 1980; Abstract No. 11052d, Crookes Laboratories Ltd. (by F. Stephens), Brit. 825 016, "Therapeutic Derivatives of Arylbenzothiazoles", see 6-diethylaminoethoxy-2-(p-chlorophenyl) benzothiazole.
Chemical Abstracts Registry Handbook-Number Section, 1972, "Registry Nos. 33913-69-8 thru 38053-994-0" see RN=36612-16-5.
Budzinski Ralph-Michael
Eisele Bernhard
Hallermayer Gerhard
Hurnaus Rudolph
Maier Roland
Devlin Mary-Ellen
Dr. Karl Thomae GmbH
Raymond Robert P.
Stempel Alan R.
Stockton Laura L.
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