Patent Publication Number: US-4546102-A

Title: 1-(6,7-Dimethoxyquinazol-4-yl)semicarbazides

Description:
This invention relates to novel semicarbazides and salts thereof, to methods of preparing these compounds, to pharmaceutical compositions containing them as active ingredients, and to a method of using them as cardiotonics. 
     More particularly, the present invention relates to a novel class of semicarbazides represented by the formula ##STR2## wherein R 1  is hydrogen, alkyl of 1 to 4 carbon atoms or trifluoromethyl; 
     R 2 , R 3  and R 4  are each independently hydrogen, methyl or ethyl; 
     R 5  is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl-(alkyl of 1 to 8 carbon atoms), cycloalkyl of 3 to 7 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonyl-methyl, phenyl, substituted phenyl, naphthyl or substituted naphthyl; or 
     R 4  and R 5 , together with each other, are alkylene of 4 to 5 carbon atoms, optionally interrupted by --O-- or --NR 6  --, where R 6  is alkyl of 1 to 4 carbon atoms; 
     and non-toxic, pharmacologically acceptable acid addition salts thereof. 
     The alkyl moieties in the substituents defined above may be straight or branched. 
     The preferred alkyl embodiments of R 1  are methyl and ethyl. 
     In the case of R 5 , the C 1  -C 8  -alkyl moiety preferably has 3 to 5 carbon atoms, and the cycloalkyl group has 5 to 6 carbon atoms, while the alkoxy moiety in the alkoxycarbonylmethyl group is preferably methoxy or ethoxy. The substituents in the aromatic groups are, in particular, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine and CF 3 . Methyl, methoxy and chlorine should be particularly emphasized. Up to three identical or different substituents may be present. If R 4  and R 5  represent an alkylene chain optionally interrupted by --0-- or --NR 6  --, they may, for example, represent a group such as --(CH 2 ) 4  --, --(CH 2 ) 5  --, --CH 2  --CH 2  --O--CH 2  --CH 2  -- or --CH 2  --CH 2  --NCH 3  --CH 2  --CH 2  --. The group R 1  preferably represents H or CH 3 . The substituents R 2 , R 3  and R 4  preferably represent H. 
     The compounds embraced by formula I may be prepared by the following methods: 
     Method A 
     By reacting a 6,7-dimethoxy-quinazoline of the formula ##STR3## wherein X is chlorine or another substituent which can be exchanged for an amino group, and 
     R 1  has the meanings previously defined, with a semicarbazide of the formula 
     
         HNR.sub.2 --NR.sub.3 --CO--NR.sub.4 R.sub.5                (III) 
    
     wherein R 2 , R 3 , R 4  and R 5  have the meanings previously defined, in a solvent which is inert under the reaction conditions. 
     Suitable solvents include, for example, dimethylformamide, acetonitrile, tetrahydrofuran and alkanols. Depending on the reactivity of the reactants, the reaction is carried out at temperatures between room temperature and the boiling point of the reaction mixture, preferably between 40° and 120° C., in the presence of a basic substance such as sodium carbonate, potassium carbonate or a tertiary amine. 
     Method B 
     By reacting a quinazoline of the formula ##STR4## wherein R 1 , R 2  and R 3  have the meanings previously defined, with an isocyanate of the formula 
     
         OCN--R.sub.5                                               (V) 
    
     wherein R 5  has the meanings previously defined, in a solvent which is inert under the reaction conditions, to yield a compound of the formula I wherein R 4  is hydrogen. 
     The reaction is carried out in a solvent such as tetrahydrofuran, dioxane, ether, dimethylformamide, toluene, acetone or acetonitrile, preferably at room temperature or while gently heating. The compound of the formula IV may be present in suspension. 
     Method C 
     By reacting a compound of the formula IV with a carbarmoyl chloride of the formula 
     
         R&#39;.sub.4 R&#39;.sub.5 --COCl                                   (VI) 
    
     wherein R&#39; 4  and R&#39; 5  have the same meanings as R 4  and R 5 , respectively, with the exception of hydrogen, in a solvent which is inert under the reaction conditions. Compounds of the formula I are thus obtained wherein R 4  and R 5  have the meanings previously defined except hydrogen. 
     The solvents mentioned in method B, particularly dimethylformamide, are also suitable for use in this method. An acid-binding agent, such as potassium carbonate or sodium carbonate, a tertiary organic base or an excess of the amine, is conveniently used. 
     Method D 
     By reacting a compound of the formula IV with a carbamic acid ester of the formula 
     
         R.sub.4 R.sub.5 N--COOR                                    (VII) 
    
     wherein R 4  and R 5  have the meanings previously defined, and R represents an optionally substituted, saturated or unsaturated, aliphatic or araliphatic group, at elevated temperatures in a solvent which is inert under the reaction conditions. 
     The solvent may be, for example, acetone, dimethylformamide or an alkanol. The reaction temperature is generally between 40° and 80° C. If solvents with a suitable boiling point, such as methanol, are used, the reaction may be carried out at reflux temperature. 
     Method E 
     By reacting a compound of the formula ##STR5## wherein R 1 , R 2 , R 3  and R have the meanings previously defined, with a primary or secondary amine of the formula 
     
         HNR.sub.4 R.sub.5                                          (IX) 
    
     wherein R 4  and R 5  have the meanings previously defined, at elevated temperatures in a solvent which is inert under the reaction conditions. 
     In this process, the solvent and reaction temperatures mentioned in method D may be used. 
     If salts are obtained as the end products in methods A to E, these may, if desired, be converted into the free bases of the formula I or into salts of other acids. The compounds embraced by formula I are basic substances and therefore form addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric, tartaric, maleic or fumaric acid. The starting compounds are known, or else may be obtained by conventional methods. 
     The following examples illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below. 
    
    
     EXAMPLE 1 
     1-(6,7-Dimethoxyquinazol-4-yl)-semicarbazide 
     2.2 g of 6,7-dimethoxy-4-chloro-quinazoline were dissolved in 50 ml of absolute dimethylformamide, 2.2 g of semicarbazide hydrochloride and 5 g of anhydrous potash were added thereto while stirring. The mixture was stirred for 5 hours at 50° C., and the precipitate formed thereby was suction-filtered off, stirred with water, and then recrystallized from dimethylformamide. The crude product was obtained with a 30% yield; m.p. 247°-249° C. 
     EXAMPLE 2 
     1-n-Butyl-4-(6,7-dimethoxyquinazol-4-yl)-semicarbazide hydrochloride 
     3 g of 6,7-dimethoxy-4-chloro-quinazoline were stirred with 3.5 g of 4-n-butyl-semicarbazide in 100 ml of n-amyl alcohol for 2 hours at 100° C. Then, the precipitate which had formed was suction-filtered off, suspended while in hot ethanol and brought to pH 5 by the addition of 2N hydrochloric acid. The clear solution was filtered through charcoal, cooled, suction-filtered and dried in a circulating air drier. The hydrochloride of 4-n-butyl-4-(6,7-dimethoxyquinazol-4-yl)-semi-carbazide, which was obtained with a 70% yield, melted at 216°-217° C. The following compounds were obtained analogously. 
     1-n-Butyl-4-(6,7-dimethoxy-2-trifluoromethylquinazol-4-yl)-semicarbazide hydrochloride (Mp. 210°-212° C.). 
     1-n-Butyl-4-(6,7-dimethoxy-2-methylquinazol-4-yl)-semicarbazide hydrochloride (Mp. 295°-297° C.). 
     The following compounds were also obtained analogously, where 
     
         __________________________________________________________________________
 ##STR6##                                                                 
                            Yield [in %                                   
                            of theory]                                    
                                  Mp. [°C.]                        
__________________________________________________________________________
RNHNHCONHCH.sub.2COOCH.sub.3 × HCl                                  
                            48    214-5                                   
RNHNHCONHCH.sub.3 × HCl                                             
                            89    246-7                                   
 ##STR7##                   52    207-8                                   
 ##STR8##                   30    203-4                                   
RNHNHCONHC(CH.sub.3).sub.3  × HCl                                   
                            43    296-7                                   
RNHNHCONHC.sub.6 H.sub.5 × HCl                                      
                            57    199                                     
RNHNHCONH(4-ClC.sub.6 H.sub.4)                                            
                            59    198-199                                 
RNHNHCONH(3-CH.sub.3C.sub.6 H.sub.4)                                      
                            55    194- 95                                 
 ##STR9##                   35    210-211                                 
 ##STR10##                  35    248-51                                  
RNHNHCON(CH.sub.3).sub.2 × HCl                                      
                            40    246-48                                  
 ##STR11##                  36    287-88                                  
RNHNHCON(i-C.sub.3 H.sub.7).sub.2                                         
                            38    256-57                                  
RNHNHCONH(CH.sub.2).sub.5CH.sub.3 × HCl                             
                            73    213-214                                 
RNHNHCONH(CH.sub.2).sub.4CH.sub.3 × HCl                             
                            49    210-211                                 
RNHNHCONHCH(CH.sub.3)C.sub.6 H.sub.5 × HCl                          
                            53    212                                     
RNHNHCONHCH.sub.2C.sub.6 H.sub.5 × HCl                              
                            79    210-211                                 
RNHNHCONHCH(CH.sub.3)C.sub.3 H.sub.7 × HCl                          
                            56    204                                     
RNHNHCONHCH(C.sub.2 H.sub.5 ).sub.2 × HCl                           
                            76    218-219                                 
RNHNHCONHCH.sub.2C(CH.sub.3).sub.3 × HCl                            
                            84    208                                     
RNHNHCONHCH(CH.sub.3)CH(CH.sub.3).sub.2 × HCl                       
                            77    197-199                                 
RNHNHCONHC.sub.2 H.sub.5 × HCl                                      
                            80    226-227                                 
RNHNHCONHCH(CH.sub.3).sub.2 × HCl                                   
                            81    220-221                                 
RNHNHCONH(CH.sub.2).sub.7CH.sub.3 × HCl                             
                            83    208-209                                 
 ##STR12##                  75    207-209                                 
 ##STR13##                  82    200-201                                 
RNHNHCONHn-C.sub.4 H.sub.9 × HCl                                    
                            69    295-297                                 
__________________________________________________________________________
 
    
     EXAMPLE 3 
     1-n-Butyl-4-(6,7-dimethoxyqyinazolin-4-yl)-semicarbazide hydrochloride ##STR14## 
     5.12 g of 6,7-Dimethoxy-4-hydrazino-quinazoline were partially dissolved in 200 ml of absolute acetonitrile. Then 5 ml of n-butylisocyanate were added thereto all at once. While the temperature rose slightly, a solution was rapidly obtained. This solution was stirred for 4 hours, and was then allowed to stand overnight. The precipitate formed thereby was suction-filtered off, dissolved in hot ethanol, and mixed with the calculated quantity of ethanolic hydrochloric acid. The hydrochloride of 1-n-butyl-4-(6,7-dimethoxy-quinazolin-4-yl)-semicarbazide crystallized out. After cooling, it was suction-filtered off and dried in a circulating air drier. The end product, which was obtained with a 60% yield, had a melting point of 216°-217° C. 
     EXAMPLE 4 
     1-n-Butyl-4-(6,7-dimethoxy-2-methylquinazol-4-yl)-semicarbazide hydrochloride 
     2.2 of 6,7-dimethoxy-4-hydrazino-2-methyl-quinazoline were suspended in 100 ml of absolute acetonitrile. 2 g of butylisocyanate were added all at once, and the mixture was stirred for 3 hours at room temperature. The base was suction-filtered off, dissolved in ethanol, and then the calculated quantity of ethereal hydrochloric acid was added. 
     The hydrochloride precipitated thereby (2.3 g, 66% of theory) was suction-filtered off and dried in a drying chamber (Mp. 295°-297° C.). 
     The 6,7-dimethoxy-4-hydrazino-2-methyl-quinazoline (Mp. 227°-229° C.) needed as the starting compound was obtained by reacting 4-chloro-6,7-dimethoxy-2-methyl-quinazoline with excess hydrazine in dimethylformamide. 
     Using the same procedure, 1-n-butyl-4-(6,7-dimethoxy-2-trifluoromethylquinazol-4-yl)-semicarbazide hydrochloride (Mp. 210°-212° C.) was also prepared with a 73% yield. 
     The following compounds were synthesized in analogy to Examples 3 and 4, where R is 6,7-dimethoxyquinazolin-4-yl: 
     
         __________________________________________________________________________
                            Yield [in %                                   
                            of theory]                                    
                                  Mp. [°C.]                        
__________________________________________________________________________
RNHNHCONHCH.sub.2COOCH.sub.3 × HCl                                  
                            48    214-5                                   
RNHNHCONHCH.sub.3 × HCl                                             
                            89    246-7                                   
 ##STR15##                  52    207-8                                   
 ##STR16##                  30    203-4                                   
RNHNHCONHC(CH.sub.3).sub.3 × HCl                                    
                            43    296-7                                   
RNHNHCONHC.sub.6 H.sub.5 × HCl                                      
                            57    199                                     
RNHNHCONH(4-ClC.sub.6 H.sub.4)                                            
                            63    198-199                                 
RNHNHCONH(3-CH.sub.3C.sub.6 H.sub.4)                                      
                            70    194-95                                  
 ##STR17##                  62    210-211                                 
RNHNHCONH.sub.2 × HCl       247-249                                 
RNHNHCONH C.sub.2 H.sub.5 × HCl                                     
                            76    226-227                                 
RNHNHCONHCH(CH.sub.3).sub.2 × HCl                                   
                            87    220-221                                 
RNHNHCONHn-C.sub.5 H.sub.11 × HCl                                   
                            50    210-211                                 
RNHNHCONHCH(CH.sub.3)n-C.sub.3 H.sub.7 × HCl                        
                            53    204                                     
RNHNHCONHCH(C.sub.2 H.sub.5).sub.2 × HCl                            
                            84    218-219                                 
RNHNHCONHCH.sub.2C(CH.sub.3).sub.3 × HCl                            
                            80    208                                     
RNHNHCONHCH(CH.sub.3)CH(CH.sub.3).sub.2 × HCl                       
                            73    197-199                                 
RNHNHCONHn-C.sub.6 H.sub.13 × HCl                                   
                            70    213-214                                 
RNHNHCONHn-C.sub.8 H.sub.17 × HCl                                   
                            80    208-209                                 
RNHNHCONHCH.sub.2C.sub.6 H.sub.5 × HCl                              
                            85    210-211                                 
RNHNHCONHCH(CH.sub.3)C.sub.6 H.sub.5 × HCl                          
                            59    212                                     
 ##STR18##                  72    200-201                                 
 ##STR19##                  70    207-209                                 
RNHNHCON(CH.sub.3).sub.2 × HCl                                      
                                  246-248                                 
RNHNHCON(iC.sub.3 H.sub.7).sub.2 × HCl                              
                                  256-257                                 
 ##STR20##                        248-251                                 
 ##STR21##                        287-288                                 
__________________________________________________________________________
 
    
     EXAMPLE 5 
     6,7-Dimethoxy-4-(2-morpholinocarbonyl)-hydrazino-quinazoline hydrochloride 
     2.2 g of 6,7-Dimethoxy-4-hydrazino-quinazoline were dissolved in 20 ml of dimethylformamide. 2.76 g of anhydrous potash were added, and then 1.7 g of morpholinocarbamic acid chloride were added dropwise thereto, while stirring. The mixture was allowed to react for 2 hours at room temperature, was then poured into ice water, and the precipitate formed thereby was separated by suction filtration. The filter cake was then dissolved in ethanol and converted into the hydrochloride by the addition of ethereal hydrochloric acid. After suction-filtering and drying in a circulating air drier, the hydrochloride of 6,7-dimethoxy-2-(2-morpholinocarbonyl)-hydrazino-quinazoline was obtained with a 40% yield: m.p. 248°-251° C. The following compounds were synthesized in analogy to Example 5, where R is 6,7-dimethoxy-quinazolin-4-yl: 
     
         __________________________________________________________________________
                            Yield [in %                                   
                            of theory]                                    
                                  Mp. [°C.]                        
__________________________________________________________________________
 ##STR22##                  30    246-248                                 
 ##STR23##                  35    287-288                                 
RNHNHCON(i-C.sub.3 H.sub.7).sub.2                                         
                            38    256-257                                 
RNHNHCONH.sub.2 × HCl       247-249                                 
RNHNHCONHC.sub.2 H.sub.5 × HCl                                      
                            76    226-227                                 
RNHNHCONHCH(CH.sub.3).sub.2 × HCl                                   
                            87    220-221                                 
RNHNHCONHc-C.sub.4 H.sub.9 × HCl                                    
                                  216-217                                 
RNHNHCONHC(CH.sub.3).sub.3 × HCl                                    
                                  296-297                                 
RNHNHCONHn-C.sub.5 H.sub.11 × HCl                                   
                            50    210-211                                 
RNHNHCONHCH(CH.sub.3)n-C.sub.3 H.sub.7 × HCl                        
                            53    204                                     
RNHNHCONHCH(C.sub.2 H.sub.5).sub.2 × HCl                            
                            84    218-219                                 
RNHNHCONHCH.sub.2C(CH.sub.3).sub.3 × HCl                            
                            80    208                                     
RNHNHCONHCH(CH.sub.3)CH(CH.sub.3).sub.2 × HCl                       
                            73    197-199                                 
RNHNHCONHn-C.sub.6 H.sub.13 × HCl                                   
                            70    213-214                                 
RNHNHCONHn-C.sub.8 H.sub.17 × HCl                                   
                            80    208-209                                 
RNHNHCONHC.sub.6 H.sub.5 × HCl                                      
                                  199                                     
RNHNHCONHCH.sub.2C.sub.6 H.sub.5 × HCl                              
                            85    210-211                                 
RNHNHCONHCH(CH.sub.3)C.sub.6 H.sub.5 × HCl                          
                            59    212                                     
 ##STR24##                  72    200-201                                 
 ##STR25##                  70    207-209                                 
RNHNHCONH(3-CH.sub.3C.sub.6 H.sub.4) × HCl                          
                                  194-195                                 
RNHNHCONH(4-ClC.sub.6 H.sub.4) ×  HCl                               
                                  198-199                                 
 ##STR26##                        207-208                                 
 ##STR27##                        210-211                                 
 ##STR28##                        203-204                                 
__________________________________________________________________________
 
    
     EXAMPLE 6 
     1-Methyl-4-(6,7-dimethoxyquinazolin-4-yl)-semicarbazide hydrochloride ##STR29## 
     2.2 g of 6,7-dimethoxy-4-hydrazino-quinazoline were suspended in 100 ml of methanol. After the addition of 1.8 g of methyl N-methylcarbamate, the mixture was refluxed for 4 hours. The resulting clear solution was cooled, the precitate formed thereby was suction-filtered off, dissolved again in hot methanol, and the solution was mixed with the calculated quantity of ethereal hydrochloric acid. This mixture was cooled, and the precipitate was suction-filtered off and dried in a circulating air dryer. The hydrochloride of 1-methyl-4-(6,7-dimethoxyquinazolin-4-yl)-semicarbazdie was obtained with a 50% yield; m.p. 246°-247° C. 
     The following compounds were prepared in analogy to Example 6, where 
     
         __________________________________________________________________________
 ##STR30##                                                                
                            Yield [in %                                   
                            of theory]                                    
                                  Mp. [°C.]                        
__________________________________________________________________________
RNHNHCONHCH.sub.2 COOCH.sub.3 × HCl                                 
                            48    214-15                                  
 ##STR31##                  52    207-8                                   
 ##STR32##                  30    203-4                                   
RNHNHCONHC(CH.sub.3).sub.3 × HCl                                    
                            43    296-7                                   
RNHNHCONHC.sub.6 H.sub.5 × HCl                                      
                            57    199                                     
RNHNHCONH(4-ClC.sub.6 H.sub.4)                                            
                            52    198-199                                 
RNHNHCONH(3-CH.sub.3C.sub.6 H.sub.4)                                      
                            56    194-95                                  
 ##STR33##                  35    210-211                                 
 ##STR34##                  22    248-51                                  
RNHNHCON(CH.sub.3).sub.2 × HCl                                      
                            28    246-48                                  
 ##STR35##                  35    287-88                                  
RNHNHCON(i-C.sub.3 H.sub.7).sub.2                                         
                            36    256-57                                  
RNHNHCONH.sub.2 × HCl       247-249                                 
RNHNHCONHC.sub.2 H.sub.5 × HCl                                      
                                  226-227                                 
RNHNHCONHCH(CH.sub.3).sub.2 × HCl                                   
                                  220-221                                 
RNHNHCONHn-C.sub.4 H.sub.9 × HCl                                    
                                  216-217                                 
RNHNHCONHn-C.sub.5 H.sub.11 × HCl                                   
                                  210-211                                 
RNHNHCONHCH(CH.sub.3)C.sub.3 H.sub.7 × HCl                          
                                  204                                     
RNHNHCONHCH(C.sub.2 H.sub.5).sub.2 × HCl                            
                                  218-219                                 
R NHNHCONHCH.sub.2C(CH.sub.3).sub.3 × HCl                           
                                  208                                     
RNHNHCONHCH(CH.sub.3)CH(CH.sub.3).sub.2 × HCl                       
                                  197-199                                 
RNHNHCONHc-C.sub.6 H.sub.13 × HCl                                   
                                  213-214                                 
RNHNHCONHn-C.sub.8 H.sub.17 × HCl                                   
                                  208-209                                 
RNHNHCONHCH.sub.2COOCH.sub.3 × HCl                                  
                                  214-215                                 
RNHNHCONHCH.sub.2C.sub.6 H.sub.5 × HCl                              
                                  210-211                                 
RNHNHCONHCH(CH.sub.3)C.sub.6 H.sub.5 × HCl                          
                                  212                                     
 ##STR36##                        200-201                                 
 ##STR37##                        207-209                                 
__________________________________________________________________________
 
    
     In addition, the following compounds were prepared analogously: 
     1-n-Butyl-4-(6,7-dimethoxy-2-trifluoromethylquinazol-4-yl)-semicarbazide hydrochloride (Mp. 210°-212° C.). 
     1-n-Butyl-4-(6,7-dimethoxy-2-methylquinazol-4-yl)-semicarbazide hydrochloride (Mp. 295°-297° C.). 
     EXAMPLE 7 
     1-Methyl-4-(6,7-dimethoxyquinazolin-4-yl-semicarbazide hydrochloride 
     1.5 g of 6,7-dimethoxy-4-(2-carbethoxy)-hydrazino-quinazoline, which was obtained by reacting 6,7-dimethoxy-4-hydrazino-quinazoline with ethyl chlorocarbonate, were dissolved in 30 ml of dioxane. After the addition of 2 ml of a 40% methylamine solution, the mixture was heated at 60° C. for 3 hours. The precipitated crystals were suctionfiltered off, suspended in hot ethanol, then the calculated quantity of ethanolic hydrochloric acid was added. A solution was rapidly obtained, which was cooled, suctionfiltered, and the filter cake was dried. The hydrochloride of 1-methyl-4-(6,7-dimethoxyquinazolin-4-yl)-semicarbazide (Mp. 246°-7° C.) was obtained with a 20% yield. 
     The following compounds were prepared analogously: 
     1-n-Butyl-4-(6,7-dimethoxy-2-trifluoromethylquinazol-4-yl)-semicarbazide hydrochloride (Mp. 210°-212° C.). 
     1-n-Butyl-4-(6,7-dimethoxy-2-methylquinazol-4-yl)-semicarbazide hydrochloride (Mp. 295°-297° C.). 
     The following were also prepared in analogy to Example 7, where 
     
         __________________________________________________________________________
 ##STR38##                                                                
                            Yield [in %                                   
                            of theory]                                    
                                  Mp. [°C.]                        
__________________________________________________________________________
RNHNHCONHCH.sub.2COOCH.sub.3 × HCl                                  
                            48    214-5                                   
 ##STR39##                  52    207-8                                   
 ##STR40##                  30    203-4                                   
RNHNHCONHC(CH.sub.3).sub.3 × HCl                                    
                            43    206-7                                   
RNHNHCONHC.sub.6 H.sub.5 × HCl                                      
                            57    199                                     
RNHNHCONH(4-ClC.sub.6 H.sub.4)                                            
                            52    198-99                                  
RNHNHCONH(3-CH.sub.3C.sub.6 H.sub.4)                                      
                            46    194-95                                  
 ##STR41##                  42    210-11                                  
 ##STR42##                  35    248-51                                  
RNHNHCON(CH.sub.3).sub.2 × HCl                                      
                            30    246-48                                  
 ##STR43##                  28    287-88                                  
RNHNHCON(i-C.sub.3 H.sub.7).sub.2                                         
                            35    256-57                                  
RNHNHCONH.sub.2 × HCl       247-249                                 
RNHNHCONHC.sub.2 H.sub.5 × HCl                                      
                            76    226-227                                 
RNHNHCONHCH(CH.sub.3).sub.2 × HCl                                   
                            87    220-221                                 
RNHNHCONHn-C.sub.4 H.sub.9 × HCl                                    
                                  216-217                                 
RNHNHCONHn-C.sub.5 H.sub.11 × HCl                                   
                            50    210-211                                 
RNHNHCONHCH(CH.sub.3)n-C.sub.3 H.sub.7 × HCl                        
                            53    204                                     
RNHNHCONHCH(C.sub.2 H.sub.5).sub.2 × HCl                            
                            84    218-219                                 
RNH NHCONHCH.sub.2C(CH.sub.3).sub.3 × HCl                           
                            80    208                                     
RNHNHCONHCH(CH.sub.3)CH(CH.sub.3).sub.2 × HCl                       
                            73    197-199                                 
RNHNHCONHn-C.sub.6 H.sub.13 × HCl                                   
                            70    213-214                                 
RNHNHCONHn-C.sub.8 H.sub.17 × HCl                                   
                            80    208-209                                 
RNHNHCONHCH.sub.2C.sub.6 H.sub.5 × HCl                              
                            85    210-211                                 
RNHNHCONHCH(CH.sub.3)C.sub.6 H.sub.5 × HCl                          
                            59    212                                     
 ##STR44##                  72    200-201                                 
 ##STR45##                  70    207-209                                 
__________________________________________________________________________
 
    
     The compounds of the present invention, that is, those embraced by formula I above and non-toxic, pharmacologically acceptable acid addition salts thereof, have useful pharmacodynamic properties. More particularly, they exhibit longlasting phosphodiesterase-inhibiting and heart-stimulating activities in warm-blooded animals. They increase the contractile force of the heart muscle without significantly affecting the heart rate. 
     This selectivity, in particular, makes them useful for the therapeutic and prophylactic treatment of pathological heart conditions, particularly heart failure. Apart from their effect on heart muscle, the compounds according to the invention also have vasodilating and hypotensive properties, and in some cases they increase the circulation of blood through the kidneys and broncholysis. The therapeutic and prophylactic dose depends on the nature and gravity of the disorder and on the route of administration. 
     For pharmaceutical purposes the compounds of the present invention are administered to warm-blooded animals perorally or parenterally as active ingredients in customary pharmaceutical compositions, that is, compositions consisting essentially of an inert pharmaceutical carrier and an effective amount of the active ingredient, such as tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups and the like. An effective amount of the compounds according to the present invention for oral administration is from 20 to 1000 mg per day, administered in 2 to 4 separate doses, and the effective amount for parenteral administration is 1 to 300 mg. 
     The following examples illustrate a few pharmaceutical compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of using the invention. The parts are parts by weight. 
     EXAMPLE 8 
     Tablets 
     The tablet composition is compounded from the following ingredients: 
     
         ______________________________________                                    
1-(6,7-dimethoxyquinazol-4-yl)-                                           
                    100 parts                                             
semicarbazide                                                             
Colloidal silicic acid                                                    
                     10 parts                                             
Lactose             118 parts                                             
Potato starch        60 parts                                             
Polyvinylpyrrolidone                                                      
                     6 parts                                              
Sodium cellulose glycolate                                                
                     4 parts                                              
Magnesium stearate   2 parts                                              
TOTAL               300 parts                                             
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     Preparation: 
     The ingredients are processed in the usual way to form 300 mg-tablets each of which contains 100 mg of the active ingredient. 
     EXAMPLE 9 
     Capsules 
     The capsule filler composition is compounded from the following ingredients: 
     
         ______________________________________                                    
1-(6,7-dimethoxyquinazol-4-yl)-                                           
                    200 parts                                             
semicarbazide                                                             
Corn starch         200 parts                                             
TOTAL               400 parts                                             
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     Preparation: 
     The ingredients are intimately admixed with each other, and 400 mg-portions of the mixture are filled into gelatin capsules of suitable size. Each capsule contains 200 mg of the active ingredient. 
     Any one of the other compounds embraced by formula I or a non-toxic, pharmacologically acceptable acid addition salt thereof may be substituted for the particular active ingredient in Examples 8 and 9. Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements. 
     While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.