Abstract:
This disclosure describes compositions of matter containing substituted 3-(4-imidazolymethlene)carbazic and dithiocarbazic acid esters and the method of treating hypertension therewith.

Description:
SUMMARY OF THE INVENTION 
     This invention is concerned with a method of treating hypertension in mammals by the administration of a compound selected from those of the formula: ##STR1## wherein R 1  is selected from the group consisting of straight oR branched chain alkyl(C 1  -C 6 ), methoxymethyl and benzyl; R 2  is selected from the group consisting of hydrogen and methyl; and R 3  is selected from the group consisting of ##STR2## 
     BACKGROUND OF THE INVENTION 
     The 3-(4-imidazolylmethylene)carbazic and dithiocarbazic acid esters of the above formula are disclosed and claimed either generically or specifically in U.S. Pat. No. 4,124,766, together with methods for their preparation and disclosure as intermediates for the preparation of compounds which inhibit the enzyme cyclic-AMP phosphodiesterase. 
     DESCRIPTION OF THE INVENTION 
     The compounds of the present invention are active hypotensive agents as established in the following test described by P. S. Chan and D. W. Poorvin, Clinical and Experimental Hypertension, l(6), 817-830 (1979). 
     Male, 16 week old, spontaneously hypertensive rats of the Okamoto strain, having an average mean arterial blood pressure (MABP) of 160±1.5 mm of mercury, are used in this test. Normally, one to three rats are used per test compound. A rat is dosed by gavage with a test compound, suspended in 2% preboiled starch, at a concentration of 50 mg/ml, at the indicated dose, with 0.9% sodium chloride loading at a dose of 25 ml/kg of body weight. A second identical dose of the test compound, without sodium chloride loading, is given 24 hours later. At 28 hours after the initial dose, the mean arterial blood pressure is measured. The procedure is repeated in a second and third rat when necessary. 
     The results of this test on representative compounds of this invention appear in Table I. 
     
                       TABLE I______________________________________Hypotensive Activity              Dose     MABP     No. ofCompound           (mg/kg)  (mmHg)   Rats______________________________________3-[2,5-Dimethyl-4-imidazolyl)-              100      133      1methylene]carbazic acid, ethylester3-[(2-Benzyl-4-imidazolyl)-              100      130      1methylene]carbazic acid, ethylester3-[(2,5-Dimethyl-4-imidazolyl)-               50      123      2methylene]dithiocarbazic acid,methyl ester3-(5-Methyl-2-propyl-4-imidazol-              100      125      2ylmethylene)carbazic acid,ethyl ester3-[[2-(Methoxymethyl)-4-imidazol-               50      140      1yl]methylene]dithiocarbazic acid,methyl ester3-[(2-tert.-Butyl-5-methyl-4-              100      120      2imidazolyl)methylene]carbazicacid, ethyl ester______________________________________ 
    
     The compounds of this invention have thus been found to be highly useful for treating hypertension in mammals when administered in amounts ranging from about 5 mg to about 100 mg/kg of body weight per day. Such dosage units are employed that a total of from about 0.35 g to about 3.5 g of active compound for a subject of about 70 kg of body weight are administered in a 24 hour period. The dosage regimen may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. 
     A decided practical advantage is that these compounds may be administered by the oral route, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. 
     For oral therapeutic administration, the active compounds may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups and the like. Such compositions and preparations should contain at least 0.1% of active compound and normally this varies between 2% and 60% of the weight of the unit, such that a suitable dosage is obtained. 
     The tablets, capsules and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as alginic acid; a lubricating agent such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring. 
     When the dosage unit is a capsule it may contain, in addition to materials of the above-type, a liquid carrier such as a fatty oil. 
     Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. 
     All materials used must be pharmaceutically pure and substantially non-toxic in the amounts employed. 
    
    
     EXAMPLE 1 
     Preparation of 50 mg Tablets 
     
         ______________________________________                        Per 10,000Per Tablet    Ingredient          Tablets______________________________________0.050 g  3-[(tert.-Butyl-5-methyl-4-                        500     g    imidazolyl)methylene]carbazic    acid, ethyl ester0.080 g  Lactose             800     g0.010 g  Corn starch (for mix)                        100     g0.008 g  Corn starch (for paste)                        80      g0.148 g                      1480    g0.002 g  Magnesium stearate  20      g0.150 g                      1500    g______________________________________ 
    
     The 3-[(2-tert.-butyl-5-methyl-4-imidazolyl)-methylene]carbazic acid, ethyl ester, lactose and corn starch for mix are blended together. The corn starch (for paste) is suspended in 600 ml of water and heated with stirring to form a paste. This paste is then used to granulate the mixed powders. The wet granules are screened, dried at 120° F. and then rescreened. The mixture is lubricated with magnesium stearate and compressed into tablets. 
     EXAMPLE 2 
     Preparation of Oral Suspension 
     
         ______________________________________Ingredient                Amount______________________________________3-[(2,5-Dimethyl-4-imidazolyl)-                     500     mgmethylene]dithiocarbazic acid, methyl esterSorbitol solution (70% N.F.)                     40      mlSodium benzoate           150     mgSaccharin                 10      mgRed dye                   10      mgCherry flavor             50      mgWater qs                  100     ml______________________________________ 
    
     The sorbitol solution is added to 40 ml of water and the 3-[(2,5-dimethyl-4-imidazolyl)methylene]dithiocarbazic acid, methyl ester is suspended therein. The saccharin, sodium benzoate, flavor and dye are added and dissolved. The volume is adjusted to 100 ml with water. Each ml of suspension contains 5 mg of active compound.