Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Patent
1981-10-01
1983-02-08
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
42424856, 544162, A61K 31535, C07D29514
Patent
active
043729541
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel salts of phenoxyisobutyric acids. The pharmacological properties of the phenoxyisobutyric acids are known and notably those of p-chlorophenoxyisobutyric acid (clofibric acid) or those of its homolog, 4-(4-chloro-benzoyl)-phenoxyisobutyric acid. These acids and their derivatives) are valued for their action on the inhibition of cholesterol synthesis with a notable reduction in the cholesterol pool in the organism, on the inhibition of abnormally high blood levels of uric acid and of fibrinogen, and for their anti-atheromatous and platelet-antiaggregating actions.
However, at recognized doses, and in particular in patients whose albuminemia level is low, there is a possibility of the appearance of muscular cramps with an increase in the SGOT and the CPK. There have also been noted immuno-allergic incidents of the type of eruptions, skin rashs, leucopenia, as well as cases of biliary calculus, notably for 4-(4'-chloro-benzoyl) -phenoxyisobutyric acid. This is true for all the clofibrates and homologs at present known like aluminum clofibrate, hydroxy-aluminum clofibrate, magnesium clofibrate, ethylester of clofibric acid, isopropyl ester of 4-(4'-chloro-benzoyl)-phenoxyisobutyric acid etc. . . Other derivatives, like, for example, metformine clofibrate, have a very pronounced hypoglycemic effect, which particularly limits the usefulness of this salt.
It is therefore an object of the present invention to provide novel derivatives of phenoxyisobutyric acids which are more active, through this reason only requiring smaller doses and consequently, not resulting in undesirable side-effects.
GENERAL DESCRIPTION OF THE INVENTION
According to the invention there are provided novel salts of phenoxyisobutyric acids constituted by moroxydine phenoxyisobutyrates of the general formula I below: ##STR3## in which R represents a chlorine atom or a ##STR4## group, R' being a chlorine atom.
Moroxydine or (.alpha.-morpholine .alpha.-imino methylene)-guanidine is a known antiviral agent, which, associated, according to the invention, with clofibric or 4-(4'-chloro-benzoyl)-phenoxyisobutyric acid, potentiates surprizingly the hypolipemic properties of the latter and confers on the novel salts obtained, remarkable properties in the prevention and treatment of atheromatous and coronary manifestations and in the treatment of surface and deep veinous thromboses.
According to the invention, the moroxydine salt is prepared by reacting stoichiometric amounts of clofibric acid or of 4-(4'-chloro-benzoyl)-phenoxyisobutyric acid and moroxydine and isolating the salt obtained by crystallization.
Since moroxydine-base is difficult to handle and is not commercially available, it is preferable to start from a moroxydine salt, such as for example, moroxydine hydrochloride.
According to an advantageous embodiment of the process according to the present invention, to a clofibrate or to a 4-(4-chloro-benzoyl)-phenoxyisobutyrate is added an equimolecular amount of a moroxydine salt, in a suitable solvent medium.
According to another advantageous embodiment of the process according to the present invention, to a solution of phenoxyisobutyric acid is added an equimolecular amount of moroxydine-base obtained by passage over ion exchange resins.
Applicants have observed, to their great surprise, that moroxydine clofibrate forms a dihydrate little soluble in water below about 30.degree. C. This product can hence easily be prepared by mixing equimolecular amounts of a hot aqueous solution of a moroxydine salt having the following composition: ##STR5## and a hot aqueous solution of a clofibric acid salt having the following composition: ##STR6## A.sup.- and B.sup.+ respectively denoting an anion and a cation and being selected so that the A.sup.- B.sup.+ salt that they form is very easily soluble in water below 30.degree. C., while the crystalline moroxydine clofibrate dihydrate is separated from the reaction mixture.
According to an advantageous embodiment of the process according to the
REFERENCES:
patent: 4089957 (1977-12-01), Jonsson
Jonsson Nils A.
Moreau Pierre D.
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