Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-05-31
1998-04-14
Spivack, Phyllis G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 31335
Patent
active
057391599
DESCRIPTION:
BRIEF SUMMARY
This case is a 371 of PCT/DE94/01395 filed Nov. 24, 1994.
The invention relates to a new use of known oxirane carboxylic acids for the preparation of drugs for the treatment of cardiac insufficiency.
STATE OF THE ART
In European Patent Application No. EP-A-0 046 590, phen(alk) oxy-substituted oxirane carboxylic acids with a hypoglycemic and hypoketonemic activity, and in European Patent EP-A-0 231 365 phen(alk)oxy-substituted oxirane carboxylic acids with a hypocholesterolemic and hypotriglyceridemic activity, are described, which are to be used for the treatment of diabetes mellitus as well as diseases which are due to an elevated cholesterol and/or triglyceride concentration in the blood, such as coronary sclerosis and arteriosclerosis, as well as all associated disease variants which can be embraced under the general term "coronary heart diseases." The heart output and contractile force is limited in such diseases due to insufficient coronary blood supply, especially in diabetic hearts; coronary infarctions are often the result when local vessel blockage interrupts the heart's supply of nutrients and oxygen.
A heart muscle disease in the sense of a primary coronary insufficiency due to reduced performance of the heart muscle when there is no disturbance of the blood supply, does not exist in these cases.
A number of publications in scientific periodicals describe another characteristic of the known oxirane carboxylic acids, namely their ability to decrease intracellular acylcarnitine concentrations by inhibiting fatty acid oxidation, and by varying the acylcarnitine content in the muscle cell membranes, to affect the electro-physiological processes during heart contraction in the sense of an "anti-arrhythmic" activity (summarized in J.Clin.Invest.83, 1989, 917-936).
Some more recent works also report favorable effects of the known oxirane carboxylic acids on ischemic, hypoxic and diabetic hearts (summarized in G. D. Lopaschuk et al. in Current Concepts in Carnitine Research, 1992, 231-243) as well as a modifying action on the expression of the various myosine isoenzymes in rat hearts subjected to high blood-pressure rat hearts (H. Rupp et al., FASEB J. 6, 1992, 2349-2353; see also N. S. Dhalla et al., Molecul. Cellul. Biochem. 116, 1992, 3-9).
DESCRIPTION OF THE INVENTION
It has now been found that the known oxirane carboxylic acids disclosed in EP-A-0 046590 in human beings with dilative cardiomyopathy (cardiac insufficiency) vary the function of the contractile proteins such that a substantial improvement in heart performance is achieved. In particular, the use of the known oxirane carboxylic acids improves the cardiac output curve in patients with coronary insufficiency subjected to physical stress (stress ECG).
The subject matter of the invention is therefore the use of oxirane carboxylic acids of Formula I ##STR2## wherein R1 represents a hydrogen atom, a halogen atom, a 1-4C alkyl group, a 1-4C alkoxy group, a nitro group or a trifluoromethyl group, pharmacologically acceptable salts of the carboxylic acids, for the preparation of medicaments for the prophylaxis and/or treatment of cardiac insufficiency.
The 1-4C alkyl groups can be straight-chain or branched alkyl moieties with 1 to 4 carbon atoms. Examples of straight-chain alkyl moieties are the methyl, ethyl, n-propyl and n-butyl moieties, of which the methyl and the ethyl moieties are preferred. Branched-chain alkyl moieties are, for example, the isopropyl, isobutyl, sec.-butyl and tert.-butyl moieties.
The alkyl moieties of 1-4C alkoxy groups can be either straight-chain or branched lower alkyl groups. The methoxy group is preferred as the 1-4C alkoxy group.
Halogen atoms are fluorine, chlorine and bromine atoms, of which fluorine, and especially chlorine, are preferred.
The substituents R1 and R2 of the phenyl ring are preferably in the meta or para position to the (alk)oxyalkylene oxirane carboxylic acid moiety.
The salts can be salts with inorganic and organic bases. As cations for the salt formation, the cations of the alkali metal
REFERENCES:
patent: 4946866 (1990-08-01), Wolf et al.
Lapaschuk et al., "Response of Isolated Working Hearts to Fatty . . . ", Circulation Research, vol. 65, No. 2, (Aug. 1989), pp. 378-387.
Lopaschuk et al., "Glucose and Palmitate Oxidation in Isolated Working Rat Hearts . . . ", Circulation Research, vol. 66, No. 2 (1990), pp. 546-553.
Rupp et al., "Metabolically-Modulated Growth and Phenotype of the Rat Heart", European Heart Journal, vol. 13, Supplement D, (1992), pp. 56-61.
Tahiliani et al., "Diabetes-Induced Abnormalities in the Myocardium", Life Sciences, vol. 38, No. 11 (1986) pp. 959-974.
Bressler et al., "A Role of Fatty Acid Oxidation in Cardiac Hypertrophy", Cardioscience, vol. 4, No. 3 (Sep. 1993), pp. 133-142.
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