Abstract:
The moroxydine phenoxyisobutyrates of the present invention are characterized in that they correspond to the following general formula I: ##STR1## in which R represents a chlorine atom or a ##STR2## group, R&#39; being a chlorine atom. Medicaments containing these compounds are useful for the inhibition of platelet aggregation and lowering fibrinogen.

Description:
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&#39;-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&#39;-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&#39; being a chlorine atom. 
     Moroxydine or (α-morpholine α-imino methylene)-guanidine is a known antiviral agent, which, associated, according to the invention, with clofibric or 4-(4&#39;-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&#39;-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° 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 -  and B +  respectively denoting an anion and a cation and being selected so that the A -  B +  salt that they form is very easily soluble in water below 30° C., while the crystalline moroxydine clofibrate dihydrate is separated from the reaction mixture. 
     According to an advantageous embodiment of the process according to the present invention, the moroxydine clofibrate dihydrate is dried in order to obtain an anhydrous salt. 
     According to another advantageous embodiment of the process according to the present invention, the A -  anion is selected from the group which comprises Cl - , Br - , NO 3   - , and SO 4   -- , and the B +  cation from the group which comprises Na + , K + , NH 4   +  and organic amines. 
     According to another aspect of the present invention there are also provided medicaments constituted by or containing moroxydine phenoxyisobutyrates according to the present invention. 
     In certain particular cases, it is desirable to break the stoichiometric equilibrium between the constituents of these medicaments, in order to provide a medicament of which the proportion of its two constituents is no longer 1:1 but, on the contrary, a medicament in which one of the constituents is in excess with respect to the other. Thus, for example, when it is desired to increase the hypolipidemic action of the medicament, it is necessary to increase the phenoxyisobutyric acid proportion. 
     The present invention consequently also provides medicaments containing phenoxyisobutyric acid (PBA) and moroxydine (MOR) in molecular proportions which vary from 0.10/1 to 1/0.10. 
     In an advantageous embodiment according to the invention, the excess phenoxyisobutyric acid is in the form of a pharmaceutically compatible inorganic and/or organic salt. 
     In another advantageous embodiment according to the invention, the excess moroxydine is salted by hydrochloride and/or sulfate and/or phosphate and/or carbonate and/or hydrobromide and/or nitrate ions. 
     Besides the foregoing features, the invention comprises other features, which will emerge from the description which follows. 
    
    
     DESCRIPTION OF PREFERRED EMBODIMENTS 
     EXAMPLES OF THE PREPARATION 
     Equilibrated salts 
     Peparation of moroxydine clofibrate 
     (1) 430 g of clofibric acid is dissolved in 800 ml of water containing 80 g of sodium hydroxide, brought to 70° C. This solution is then added to a hot aqueous solution (about 70° C.) of 414 g of moroxydine hydrochloride in 800 ml of water. The mixture obtained was stirred for some time, then cooled to about 5° C. for 2 to 4 hours. The moroxydine clofibrate (in the form of crystalline dihydrate) is separated by filtration, washed 4 times with 300 ml of ice water each time, dried for 12 hours at room temperature, then at 80° C. to constant weight. The anhydrous product obtained weighed 644 g (84% yield) and melts at around 216° C. 
     
         ______________________________________Analysis  C         H       Cl      N     O______________________________________theory 49.8%     6.27%   9.19%   18.1% 16.8%found  49.4%     6.17%   9.43%   18.2% 16.6%______________________________________ 
    
     its content of NaCl was less than 0.1%. 
     (b 2) Potassium clofibrate was solubilized in ethanol; 
     to this solution, in equimolecular proportions, was added an ethanol solution of moroxydine hydrochloride; 
     the KCl precipitate formed was removed by filtration; 
     the ethanol was evaporated; 
     the moroxydine clofibrate was crystallized in isopropyl alcohol. 
     Preparation of products whose constituents are not in stoichiometric proportions 
     (1) Example of the preparation of the product containing one proportion 
     Desired Formula: PBA/MOR=1:4 
     
         ______________________________________             MG/Day   MG/per tablet______________________________________Clofibric ion     1200     150Moroxydine ion    4000     500             5200     650Posology8 tablets per dayComposition                GramsMoroxydine clofibrate 1:1(prepared according toExample 1)                 270Moroxydine hydrochloride   462Wheat starch               100Magnesium stearate          6______________________________________ 
    
     Preparation: 
     A granulation was prepared by mixing moroxydine clofibrate, moroxydine hydrochloride and wheat starch and by granulating their mixture by incorporating in a paste of 25 g of starch and 100 ml water. The granulate so-obtained was dried and the magnesium stearate was mixed with the dry granulate and the resulting mixture was compressed into 1000 tablets. 
     (2) Second Eample 
     Desired formula: PBA/MOR=10:1 
     
         ______________________________________              MG/day    MG/per tablet______________________________________Clofibric ion      2600      650Moroxydine ion      200       50              2800      700Posology: 4 tablets per day.Composition:                 GramsMoroxydine clofibrate 1:1(prepared according to Example 1)                        113Clofibric acid               589Wheat starch                 100Magnesium Stearate            6______________________________________ 
    
     Preparation 
     This preparation was carried out identically with that of Example 1 for 1000 tablets. 
     REPORT OF PHARMACOLOGICAL TESTS 
     Each result recorded in the following Tables corresponds to an average obtained in 15 animals. The experiments were carried out on male rats of the AF Han. EOPS WISTAR breed weighing about 250 g. 
     Each time the results obtained in rats treated with a product according to the invention, namely moroxydine clofibrate, were compared with those obtained by the action of clofibrate alone and of moroxydine alone. 
     The administration of the product was carried out orally and the amount administered was equal to 35 mg per day. 
     
                                           TABLE I__________________________________________________________________________RATS ON HYPERLIPIDEMIC DIET&#34;Blood analysis&#34;            Average values                   Chol.                       Cholesterol                              ratio            Free Chol.                   ester                       of the HDL                              HDL/    Fibrinogen                                             glycemia                                                  SGPT ureaProducts         mg/100ml                   mg/l                       g/l    LDL + VLDL                                      g/l    g/l  IU   g/l__________________________________________________________________________Controls         10.3   36.7                       0.36   3.1     1.91   1.22 28   0.37Product according to theinvention ##STR7##        8.4    25.8                       0.30   2.4     1.47   1.24 30   0.38 ##STR8##        9.2    34.1                       0.35   3       1.85   1.22 45   0.52 ##STR9##        6.0    22.0                       0.29   2.2     1.70   1.40 32   0.50 ##STR10##       7.9    31.-                       0.37   3.3     1.95   1.20 27   0.35Clofibrate alone 6.4    22.2                       0.29   2.2     1.59   1.43 32.5 0.44Moroxydine alone 7.9    32.1                       0.38   3.3     1.99   1.20 27.1 0.36__________________________________________________________________________ 
    
     
                                           TABLE II__________________________________________________________________________RATS ON HYPERLIPIDEMIC DIET            Average values                  Chol.                      Cholesterol            Free Chol.                  ester                      of the HDL                            HDL/    SGPT                                        fibrinogen                                              ureaProducts         mg/100ml                  mg/l                      g/l   LDL + VLDL                                    IU  g/l   g/l__________________________________________________________________________Controls         19.65 28.24                      0.23  2.1     126.4                                        2.16  0.28Product according to theinvention ##STR11##       11.32 21.79                      0.25  1.62    188.1                                        1.96  0.29 ##STR12##       17.2  26.7                      0.27  0.65    420.-                                        2.19  0.50 ##STR13##       10.57 21.71                      0.39  0.77    302.-                                        2.10  0.30 ##STR14##       17.6  29.5                      0.25  0.90    340.-                                        1.92  0.26Clofibrate alone 10.57 21.7                      0.38  0.773   302.1                                        2.2   0.26Moroxydine alone 17.5  29.3                      0.25  0.867   349.9                                        1.80  0.30__________________________________________________________________________ 
    
     
                                           TABLE III__________________________________________________________________________RABBITS SEQUENTIAL DIET            Average values            End of 2nd month                      End of 5th month            Trigly-                Cholesterol Total     Cholesterol                                            Gly-Products         cer.                of the HDL                      Fibrinogen                            Choles.                                Triglycer.                                      of the HDL                                            cemia                                                Urea__________________________________________________________________________Controls         1.07                0.32  3.84  0.73                                1.36  0.22  1.28                                                0.32Product according to theinvention ##STR15##       0.82                0.36  2.06  0.66                                0.86  0.17  1.18                                                0.33 ##STR16##       1.12                0.32  3.54  0.72                                1.34  0.17  1.28                                                0.42 ##STR17##       0.90                0.30  2.78  0.65                                1.24  0.17  1.40                                                0.40 ##STR18##       1.25                0.35  2.90  0.60                                1.35  0.16  1.35                                                0.33__________________________________________________________________________ 
    
     
                                           TABLE IV__________________________________________________________________________Rats in normal dietComparison of platelet aggregation (ADP method)                   Intensity at the end of    Velocity in % at                   3 minutes             7 micro-                   One minute                             2 minutes 15   7    15 microosmoles             osmoles of                   15 micro-                        7 micro-                             15 micro-                                  7 micro-                                       micro-                                            micro-    of ADP   ADP   osmoles                        osmoles                             osmoles                                  osmoles                                       osmoles                                            osmoles__________________________________________________________________________Controls 50.86    43.70 61.1 58.2 70.45                                  63.02                                       66.09                                            52.8Product accordingto the invention    33.82    27.09 44.8 35.46                             55.15                                  41.22                                       52.58                                            31.10Clofibrate    40.42    35.58 51.14                        43.05                             59.07                                  47.54                                       55.33                                            33.47Moroxydine    44.22    36.20 52.54                        42.96                             58.02                                  46.67                                       50.09                                            34.08__________________________________________________________________________ 
    
     The products according to the invention have very interesting properties which appear to singularize them with respect to the effects of clofibrate and moroxydine alone. 
     The more distinct effects are the inhibition of platelet aggregation and the lowering of fibrinogen; these effects are to be found also both in the normolipidic rat and the hyperlipidic rat and in the rabbit (Although the best results are still those obtained with the stoichiometric product 1/1, in certain pathological cases it may be advantageous to have an unbalanced product). 
     TOXICITY 
     The intravenous LD50 (average 25 mice) is 380 mg/kg. The product is hence devoid of toxicity. 
     It is to be concluded from the foregoing description that whatever the type of application or administration, the derivatives of phenoxyisobutyric acids which are the subject of the present invention have with respect to previously known derivatives, numeorus advantages and notably those represented by a higher activity, the absence of side effects and the complete absence of toxicity and hypoglycemic effect. 
     As emerges from the foregoing, the invention is in no way limited to those of its types of application, embodiments, and uses which have just been described more explicitly; it encompasses, on the contrary, all modifications which may come to the spirit of the technician skilled in the art, without departing from the framework or the scope, of the present invention.