Abstract:
The invention relates to pharmaceutical compositions possessing valuable antianginal activity. These compositions show higher activity and more favorable therapeutic indices than the reference compound Prenylamine. Preparation of different kinds of pharmaceutical compositions, such as tablets, dragees, capsules and injectable solutions, containing compounds of general formula (I) ##STR1## or their acid addition salts as active ingredients, is disclosed, wherein in formula (I) 
     R is phenyl or 4-chlorophenyl; 
     R 1  and R 2  each represent hydrogen, methyl or isopropyl; 
     R 3  and R 4  are hydrogen, or together form a chemical bond; 
     n is an integer from 4 to 6; 
     A means trimethylene, if n is 4 or 6; or ethylene, if n is 5.

Description:
FIELD OF THE INVENTION 
     The Invention relates to pharmaceutical compositions containing basic oxime ethers having antianginal activity, their use in the therapy and a process for their preparation. 
     BACKGROUND OF THE INVENTION 
     It is known from Hungarian patent specification No. 169,298 that the basic oxime ethers of formula (IX) ##STR2## possess antidepressant, antiparkinsonic and local anaesthetic activities; in formula (IX) 
     R&#39; stands for phenyl, optionally substituted by Hal, or one or more hydroxy, nitro or C 1-4  alkoxy groups(s), 
     R 3&#39;  and R 4&#39;  each represents hydrogen, or together they form a chemical bond; 
     A&#39; is a straight or branched chain alkylene group having 2 to 4 carbon atoms; 
     R 1&#39;  and R 2&#39;  each is hydrogen or C 1-4  alkyl, or together they form an alkylene group consisting of 4 to 7 carbon atoms being optionally interrupted by a heteroatom, namely an oxygen or nitrogen atom, the latter being optionally substituted by a benzyl or a C 1-3  alkyl group; 
     n&#39; is an integer from 3 to 7. 
     DESCRIPTION OF THE INVENTION 
     It has now been found that compounds of the general formula (I) ##STR3## which fall within the above mentioned formula (IX) but have not been specifically disclosed therein, have valuable therapeutical, namely antianginal properties, and thus are suitable for use in pharmaceutical compositions. 
     The invention therefore provides pharmaceutical compositions with antianginal activity containing as active agent a compound of the general formula (I). In respect of the preparation of the compounds of general formula (I) only the present disclosure refers to the mentioned Hungarian patent specification No. 169,298 which describes the following process variants (a) to (d): 
     (a) reacting a ketone or thione of formula (II) ##STR4##  with a hydroxylamine derivative of formula (III) ##STR5##  or an acid addition salt thereof; (b) reacting a chloro compound of formula (IV) ##STR6##  with a hydroxylamine derivative of formula (III) or an acid addition salt thereof; 
     (c) reacting an oxime of the formula (V) ##STR7##  with a haloalkyl amine derivative of the formula (VI) ##STR8##  in an inert solvent medium, in the presence of a basic condensing agent; (d) reacting an oxime of formula (V) with a dihalo alkane of formula (VII) 
     
         Hal--CH.sub.2 --A&#34;--Hal&#39;                                   (VII) 
    
      and aminating the haloalkyl ether thus obtained with an amine of the formula (VIII). ##STR9## 
     The compounds of the formula (I) obtained by one of the above routes may--if desired--be converted into their acid addition salts by using a pharmaceutically acceptable acid. The compounds of the formula (I) and their acid addition salts can be formulated to pharmaceutical compositions by methods known per se. 
     In the above formulae 
     if n=4, then 
     (A 1 ) 
     R 3  and R 4  together form a chemical bond, 
     R is phenyl, 
     A means trimethylene, 
     R 1  and R 2  represent a methyl group each, and the molecule has an (E,Z) configuration; or 
     (A 2 ) 
     R 3  and R 4  together form a chemical bond, 
     R means 4-chlorophenyl, 
     A is ethylene, 
     R 1  is isopropyl, 
     R 2  is hydrogen, and the molecule has an (E,E) configuration; or 
     (A 3 ) 
     R 3  and R 4  together form a chemical bond, 
     R is 4-chlorophenyl, 
     A is trimethylene, 
     R 1  and R 2  represent an isopropyl group each, and the molecule has an (E,E) configuration; or 
     (A 4 ) 
     R 3  and R 4  together form a chemical bond, 
     R means phenyl, 
     A 1  is trimethylene, 
     R 1  and R 2  represent an isopropyl group each, and the molecule has an (E,E) configuration; or 
     (A 5 ) 
     R 3  and R 4  together form a chemical bond, 
     R is phenyl, 
     A means ethylene, 
     R 1  stands for isopropyl, 
     R 2  is hydrogen, and the molecule has an (E,E) configuration; or 
     (A 6 ) 
     R 3  and R 4  together form a chemical bond, 
     R means phenyl, 
     A is ethylene, 
     R 1  and R 2  stand for an isopropyl group each, and the molecule has an (E,E) configuration; or 
     if n=5, then 
     (B 1 ) 
     R 3  and R 4  together form a chemical bond, 
     R is phenyl, 
     A is ethylene, 
     R 1  and R 2  represent a methyl group each, and the molecule has a (Z,E) configuration; or 
     (B 2 ) 
     R 3  and R 4  stand for hydrogen each, 
     R means phenyl, 
     A is ethylene, 
     R 1  and R 2  stand for a methyl group each, and the molecules has an (E,E) configuration; or 
     (B 3 ) 
     R 3  and R 4  together form a chemical bond, 
     R is phenyl, 
     A stands for ethylene, 
     R 1  and R 2  represent a methyl group each, and the molecule has an (E,E) configuration; or 
     (B 4 ) 
     R 3  and R 4  together form a chemical bond, 
     R means phenyl, 
     A is ethylene, 
     R 1  and R 2  represent an isopropyl group each, and the molecule has a (Z,E) configuration; or 
     if n=6, then 
     (C) 
     R 3  and R 4  together form a chemical bond, 
     R is phenyl, 
     A stands for trimethylene, 
     R 1  and R 2  represent a methyl group each, and the molecules has an (E,E) configuration. 
     Further, in the above formulae (I) to (VIII) 
     Y stands for an oxygen or a sulfur atom; 
     Hal means halogen; 
     A&#39; represents an alkylene containing one less methylene than A does; 
     Hal&#39; represents a halogen that may be identical with or different from the halogen represented by Hal. 
     The following compounds of the formula (I) or pharmaceutically acceptable acid addition salts thereof can be prepared by the method described in said Hungarian patent specification and can preferably be used as active ingredients in pharmaceutical compositions according to the present invention: 
     2-(E)-phenylmethylene]-1-[(Z)-(3-dimethylaminopropyloxyimino)]-cyclohexane (compound A); 
     2-[(Z)-phenylmethylene]-1-[(E)-(2-dimethylaminoethoxyimino)]-cycloheptane (compound B); 
     2-[(E)-(4-chlorophenyl)-methylene]-1-[(E)-(2-isopropylamino-ethoxyimino)]-cyclohexane (compound C); 
     2-benzyl-1-[(E)-(2-dimethylamino-ethoxyimino)]-cycloheptane (compound D); 
     2-[(E)-phenylmethylene]-1-[(E)-(2-dimethylaminoethoxyimino)]-cycloheptane (compound E); 
     2-[(E)-(4-chlorophenyl)-methylene]-1-[(E)-(3-diisopropylamino)-propyloxyimino]-cyclohexane (compound F); 
     2-[(E)-phenylmethylene]-1-[(E)-(3-diisopropylaminopropyloxyimino)]-cyclohexane (compound G); 
     2-[(Z)-phenylmethylene]-1-[(E)-2-diisopropylaminoethoxyimino)]-cycloheptane (compound H); 
     2-[(E)-phenylmethylene]-1-[(E)-(3-dimethylaminopropyloxyimino)]-cyclooctane (compound I); 
     2-[(E)-phenylmethylene]-1-[(E)-(2-isopropylaminoethoxyimino)]-cyclohexane (compound K); 
     2-[(E)-phenylmethylene]-1-[(Z)-(2-diisopropylaminoethoxyimino)]-cyclohexane (compound L). 
     Pharmaceutically acceptable acid addition salts of compounds of formula (I) may be those formed with inorganic and organic acids, e.g. hydrogen chloride, hydrogen bromide, sulfuric, phosphoric, acetic, propionic, methanesulfonic, p-toluolsulfonic, tartaric, succinic, maleinic, fumaric, citric, malic or lactic acid, generally used in the pharmaceutical practice. 
     Antianginal effects of compounds of the formula (I) were tested by using the method of Nieschulz E., Popendiker, K. and Hofmann I. (Arzneimittelforschung, 5, 680; 1955). 
     The test compounds were intravenously administered to rats. The results obtained were summarized in Table I: 
     
                       TABLE I______________________________________Testedcompound       Dose, mg/kg                     Activity %______________________________________compound A     2          81.5compound B     2          43.6compound C     4          80.3compound D       0.5      47.5compound E     2          59.5compound F       0.5      72.0compound G       0.5      57.0compound H     2          41.3compound I     2          84.0compound K     2          32.5compound L     4          87.0          1          38.0Prenylamine    1          23.0          2          32.0          4          42.0______________________________________ 
    
     The data tabulated above show that compounds of general formula (I) exhibit an equal or even multiple enhanced activity, compared to Prenylamine (N-3,3-di-phenylpropyl-1-methylphenyl-ethylamine) in respect of the said test. 
     The most active derivatives of the compounds of general formula (I) have much higher therapeutic indices than Prenylamine used as reference. The respective figures are shown in Table II below. 
     
                       TABLE II______________________________________Tested   LD.sub.50    ED.sub.50 Therapeuticcompound mg/kg iv.    mg/kg iv. index______________________________________compound G    12.5         0.38      32.90compound F    42.0         0.35      120.00compound D    40.0         0.52      76.90Prenylamine    11.5         6.50       1.77______________________________________ 
    
     For oral administration, tablets, dragees, intestinosolvent pills or dragees, or capsules may be prepared. They contain 10 to 100 mg. of active ingredient per unit dose. 
     Preferably, tablets containing 25 mg., dragees of 50 mg. or capsules of 25 mg. of active ingredient, respectively, further injectable solutions with a concentration of 25 mg. of active ingredient per milliliter can be prepared. 
     Pharmaceutical preparations for oral administration (tablets, dragees or capsules) may contain carriers and auxiliary substances, for example sodium citrate, calcium carbonate, calcium phosphate, starches, such as potato, maize, or carboxymethylated starch, silicic acid, or binders, such as polyvinyl pyrrolidone, gelatine, etc. Tablet formulations can further be complemented with lubricants, for example with magnesium stearate, talc, or sodium dodecylsulfate. When preparing aqueous suspensions and/or elixirs, the active ingredient may be mixed with several kinds of flavoring substances, dyestuffs, emulsifiers, wetting agents and/or diluents, such as water, ethanol, propylene glycol, glycerol, etc. 
     Tablets may be manufactured by dry or wet granulation procedure. When preparing dragees, the dragee kernels can be provided with an appropriate coating in a manner known per se. In case of capsules, the suitably prepared preblended mixture of components may be filled into hard or soft gelatine capsules. 
     Suppositories for rectal administration may contain 25 to 100 mg. of active ingredient. In these formulations the active compounds of general formula (I), having antianginal acitivity, may be complemented with sedatives. When so, the rectal suppository may contain not more than 50 mg. of active compound of general formula (I). Preparation of said suppository formulations can be carried out in such a way that after evenly dispersing the active ingredient in the molten vehicle of the formulation (e.g. in cocoabutter) the dispersion is chilled, filled into forms, and the ready wares are wrapped into tinfoil. 
     Injections for parenteral use may be administered intravenously, intramuscularly, intraperitoneally or subcutaneously. The injectable solutions contain 5 to 50 milligrams of active ingredient per milliliter, preferably 25 mg./ml. It is advantageous to make use of ampoules of 2 ml. capacity in the practice; hence, the active ingredient content of the ampoules will generally range from 10 to 100 mg./ampoule. The injectable solutions for parenteral use may contain diluents, for example sesame oil, peanut oil, aqueous propylene glycol, or pharmaceutically acceptable organic solvents or, preferably, water. The aqueous solutions may, if desired, be buffered in a known manner, or the osmolality of the liquid diluents may be adjusted to isotonic by adding appropriate amounts of sodium chloride or glucose. The prepared solutions can, if desired, be sterilized by methods usually applied in the practice. 
     The pharmaceutical compositions having antianginal activity, prepared according to the present invention, can generally be administered in daily doses from 0.25 mg. to 40 mg. per kg. of body weight. The preferred dose ranges from 1 to 20 mg. per kg. of body weight. The daily regime of delivery comprises one to three administrations a day. The proper choice of the dose to be administered -- depending upon the activity of the active substance used, the mode of administering of the drug, the physical status of the patient, and other factors--should always rely upon the doctor&#39;s prescription. 
    
    
     SPECIFIC EXAMPLES 
     The invention is elucidated in detail by the aid of the following non-limiting formulational Examples. 
     EXAMPLE 1 
     The composition of tablets is as follows: 
     
         ______________________________________active ingredient      25.0 mg.[compound offormula (I)]maize starch           97.0 mg.polyvinyl pyrrolidone  175.0 mg.magnesium stearate     3.0 mg.                  300.0 mg.______________________________________ 
    
     The active ingredient and the maize starch are humidified by an aqueous polyvinyl pyrrolidone solution of approx. 15% w/v., followed by granulation, and drying of the wet granules at about 40°-45° C. The dried granulate is thoroughly mixed with magnesium stearate, and the mixture so obtained is further processed by a tablet machine, equipped with an appropriate pressing tool, to give tablets of 300 mg. weight containing 25 mg. of active ingredient. One manufacturing lot includes 1000 tablets. 
     EXAMPLE 2 
     Dragees of the following composition are prepared: 
     
         ______________________________________active ingredient      50.0 mg.[compound offormula (I)]lactose                94.0 mg.polyvinyl pyrrolidone  4.0 mg.magnesium stearate     2.0 mg.                  300 mg.______________________________________ 
    
     Granulates are prepared according to Example 1, and from them dragee kernels of 150 mg. weight are pressed. The dragee kernels are coated with a layer containing sugar and talc in a manner known per se, followed by colouring with an approved food colorant and polishing with bee wax. 
     EXAMPLE 3 
     25 mg. of active ingredient of formula (I) are dissolved in 1000 ml. of distilled water. The solution is filled into 500 ampoules. In this way ampoules containing 2 ml. of a solution containing 25 mg./ml. of active agent each are obtained. 
     EXAMPLE 4 
     Gelatine capsules of the following composition are prepared: 
     
         ______________________________________active ingredient     25.0 mg.[compound offormula (I)]maize starch          122.0 mg.colloidal silica      3.0 mg.                 150.0 mg.______________________________________ 
    
     The ingredients are homogenized, and the homogenate is filled into hard gelatine capsules. 1000 pieces of capsules of 150 mg. (filling) weight each, containing 25.0 mg. of active ingredient per capsule, make a lot.