5-Methylthio-pyrimidine vasodilators
The invention is illustrated by the following Examples, in which the parts are parts by weight, unless the contrary is indicated. Preceding the Examples are Preparations 1 to 12 which are concerned with the preparation of the compounds of formula (II). 
     PREPARATION 1 
     60 parts by volume of benzene, 10 parts of 2,4,6-trichloro-5-methylthio-pyrimidine and 4.85 parts of triethylamine are placed in an apparatus. After heating under reflux for three hours, the reaction product is filtered, concentrated, and and recrystallised from alcohol. 7.9 parts of 2-N,N-diethylamino-4,6-dichloro-5-methylthio-pyrimidine of melting point 48°C. are obtained. 
     PREPARATIONS 2 TO 7 
     On operating as in Preparation 1, but using tripropylamine, N,N-(diethyl)-N-(ethoxycarbonylmethyl)amine, N-methyl-piperidine, N-methylmorpholine, N,N-dimethyl-N-benzylamine, and N-methyl-N,N-dibenzylamine instead of the triethylamine, the following compounds are respectively obtained: 
     
         Preparations                  M.p.                                        
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2      2-dipropylamine-5-methylthio-4,6-dichloro-                         
       pyrimidine             71°C.                                
3      2-N-ethyl-N-(ethoxycarbonylmethyl)amino-                           
       5-methylthio-4,6-dichloropyrimidine                                
                              106°C.                               
4      2-piperidino-5-methylthio-4,6-dichloro-                            
       pyrimidine             71°C.                                
5      2-morpholino-5-methylthio-4,6-dichloro-                            
       pyrimidine             116°C.                               
6      2-N,N-dimethylamino-5-methylthio-4,6-                              
       dichloro-pyrimidine    74°C.                                
7      2-N-methyl-N-benzylamino-5-methylthio-                             
       4,6-dichloro-pyrimidine                                            
                              73°C.                                
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     PREPARATION 8 
     23 parts of 2,4,6-trichloro-5-methylthio-pyrimidine, 15 parts of N,N-dimethylaniline and 0.05 parts of potassium iodide are mixed and heated until a very dark colour is obtained. The product crystallises on cooling, 25 parts of water and 50 parts by volume of 3N hydrochloric acid are added, and the product is filtered off, dried and recrystallised from ethyl alcohol. 27 parts of 2-N-methylphenylamino-4,6-dichloro-5-methylthio-pyrimidine of melting point 99°C. are obtained. 
     The following Table gives examples of compounds obtained in a similar way from particular N,N-dimethylanilines. 
     
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Preparations                  M.p.                                        
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 9     2-N-methyl-N(4-chloro-phenyl)amino-4,6-                            
       dichloro-5-methylthio-pyrimidine                                   
                              130°C.                               
10     2-N-methyl-N(4-methyl-phenyl)amino-                                
       4,6-dichloro-5-methylthio-pyrimidine                               
                              111°C.                               
11     2-N-methyl-N(3-trifluoromethyl-phenyl)-                            
       amino-4,6-dichloro-5-methylthio-pyrimidine                         
                              117°C.                               
12     2-N-methyl-N(3,4-dimethoxy-phenyl)                                 
       amino-4,6-dichloro-5-methylthio-                                   
       pyrimidine             151°C.                               
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     EXAMPLE 1 
     23.8 parts of 2-dimethylamino-4,6-dichloro-5-methylthio-pyrimidine are placed in 300 parts by volume of benzene and a solution of 12.2 parts of N,N-diethylethylenediamine and 16 parts of triethylamine is added. The mixture is heated under reflux for three hours. After filtering off the triethylamine hydrochloride, the mixture is concentrated, extracted with ether/water, and the organic phase is concentrated and recrystallised from ethyl alcohol. 2-dimethylamino-4-(2&#39;-diethylamine)ethylamino-5-methylthio-6-chloropyrimidine having a melting point of 56°C. is obtained. 
     The following products have been obtained in the same way either in the form of the base or in the form of the mono- or di-hydrobromide. 
     
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Examples                           M.p.                                   
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2    2-N-methyl-N-phenylamino-4-(2&#39;-diethylamino)-                        
     ethylamino-5-methylthio-6-chloro-pyrimidine                          
                               2HBr                                       
                                   162°C.                          
3    2-diethylamino-4-(2&#39;-diethylamino)-ethyl-                            
     amino-5-methylthio-6-chloro-pyrimidine                               
                               2HBr                                       
                                   110°C.                          
4    2-N-methyl-N-benzylamino-4-(2&#39;-diethylamino)-                        
     ethylamino-5-methylthio-6-chloro-pyrimidine                          
                               HBr 136°C.                          
5    2-dipropylamino-4-(2&#39;-diethylamino)-ethylamino-                      
     5-methylthio-6-chloro-pyrimidine                                     
                               2HBr                                       
                                   160°C.                          
6    2-N-methyl-2-N-(4-chloro-phenyl)amino-4-                             
     (2&#39;-diethylamino)-ethylamino-5-methylthio-                           
     6-chloro-pyrimidine       HBr 197°C.                          
7    2-N-methyl-N-phenyl-amino-4-(2&#39;-dimethyl-                            
     amino)-ethylamino-5-methylthio-6-chloro-                             
     pyrimidine                HBr 182°C.                          
8    2-dimethylamino-4-(2&#39;-dimethylamino)-                                
     ethylamino-5-methylthio-6-chloro-                                    
     pyrimidine                     69°C.                          
9    2-morpholino-4-(2&#39;-dimethylamino)-ethyl-                             
     amino-5-methylthio-6-chloro-pyrimidine                               
                                    80°C.                          
10   2-N-methyl-N-(ethoxycarbonylmethyl)-amino-                           
     4-(2&#39;-dimethylamino)-ethylamino-5-methylthio-                        
     6-chloro-pyrimidine            64°C.                          
11   2-N-methyl-N-benzylamino-4-(2&#39;-di-isopropyl-                         
     amino)-ethylamino-5-methylthio-6-chloro-                             
     pyrimidine                     70°C.                          
12   2-N-methyl-N-phenylamino-4-(2&#39;-di-isopropyl-                         
     amino)-ethylamino-5-methylthio-6-chloro-                             
     pyrimidine                HBr 163°C.                          
13   2-piperidino-4-(2&#39;-diisopropylamino)-                                
     ethylamino-5-methylthio-6-chloro-pyrimidine                          
                               HBr 202°C.                          
14   2-N-methyl-N(4-methyl-phenyl)amino-4-(2&#39;-                            
     diisopropylamino)-ethylamino-5-methylthio-6-                         
     chloro-pyrimidine              99°C.                          
15   2-N-methyl-N-(ethoxycarbonylmethyl)-amino-4-                         
     (2&#39;-diisopropylamino)-ethylamino-5-methyl-                           
     thio-6-chloro-pyrimidine  HBr 172°C.                          
16   2-diethylamino-4-(2&#39;-diisopropylamino)-                              
     ethylamino-5-methylthio-6-chloro-pyrimidine                          
                               HBr 188°C.                          
17   2-N-methyl-N(3-trifluoromethyl-phenyl)-                              
     amino-4-(2&#39;  -diisopropylamino)-ethylamino-                          
     5-methylthio-6-chloro-pyrimidine                                     
                               HBr 190°C.                          
18   2-N-methyl-N(4-chloro-phenyl)amino-4-(2&#39;-                            
     diisopropyl-amino)-ethylamino-5-methylthio-6-                        
     chloro-pyrimidine         HBr 192°C.                          
19   2-N-methyl-N(4-methyl-phenyl)amino-4-(2&#39;-                            
     diethylamino)-ethylamino-5-methyl-thio-6-                            
     chloro-pyrimidine         HBr 150°C.                          
20   2-N-methyl-N(3,4-dimethoxy-phenyl)amino-4-                           
     (2&#39;-diethylamino)-ethylamino-5-methylthio-6-                         
     chloro-pyrimidine         HBr 205°C.                          
21   2-N-methyl-N(3,4-dimethoxy-phenyl)amino-4-                           
     (2&#39;-diisopropylamino)-ethylamino-5-methylthio-6-                     
     chloro-pyrimidine              80°C.                          
22   2-N-methyl-N-(4-chloro-phenyl)amino-4-(2&#39;-2,6-                       
     dimethyl-morpholino)-ethylamino-5-methylthio-                        
     6-chloro-pyrimidine           104°C.                          
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     EXAMPLE 23 
     25 parts of 3-pyridine-methanol and 6 parts of caustic potash are mixed and heated. After formation of the potassium salt, 19.5 parts of 2-N-dimethylamino-4-(2&#39;-dimethyl-amino)-ethylamino-5-methylthio-6-chloro-pyrimidine are introduced. The mixture is heated at about 130°-140°C. for 3 hours, then taken up in water and in ether, and the organic phase is concentrated. The oily product formed is dissolved in alcohol, and 20 parts by volume of concentrated hydrobromic acid are added. The product precipitates and is recrystallised from alcohol. The hydrobromide of 2-N-dimethyl-amino-4-(2&#39;-dimethylamino)-ethylamino-5-methyl-thio-6-(3-pyridyl)-methoxy-pyrimidine of melting point 180°C. is obtained with a yield of 58%. 
     EXAMPLE 24 
     40.7 parts of 2N-methyl-N-phenyl-amino-4-(2&#39;-diisopropylamino)-ethylamino-5-methylthio-6-chloro-pyrimidine in 200 parts by volume of methanol and 7 parts of caustic potash are placed in an autoclave, and the mixture is heated at between 120°C. and 130°C. for 3 hours. 
     The product is concentrated in vacuo, washed with ether/water, and the organic phase is concentrated. The residual oil is dissolved in acetone. 24 parts by volume of hydrobromic acid are added and the product is precipitated with ether. On purification, the dihydrobromide of 2-N-methyl-N,phenylamino-4-(2&#39;-diisopropylamino)-ethylamino-5-methyl-thio-6-methoxy-pyrimidine of melting point 176°C. is obtained with a yield of 50 %. 
     The following products have been prepared according to the processes of the preceding Examples: 
     
         Examples                                 M.p.                             
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25   2-N-methyl-N(4-chloro-phenyl)amino-4-(2&#39;-diethylamino)-              
     ethylamino-5-methylthio-6-methoxy-pyrimidine                         
                                   HBr   175°C.                    
26   2-N-methyl-N-phenyl-amino-4-(2&#39;-dimethyl                             
     amino)-ethylamino-5-methylthio-6-methoxy-                            
     pyrimidine                    HBr   167°C.                    
                                   0.5 H.sub.2 O                          
27   2-N-methyl-N-benzyl-amino-4-(2&#39;-diiso-                               
     propyl-amino)-ethylamino-5-methyl-                                   
     thio-6-methoxy-pyrimidine           64°C.                     
28   2-N-methyl-N-(3,4-dimethoxy-phenyl)-amino-                           
     4-(2&#39;-diisopropyl-amino)-ethyl-amino-5-                              
     methylthio-6-methoxy-pyrimidine                                      
                                   HBr   198°C.                    
29   2-piperidino-4-(2&#39;-diisopropyl-amino)-                               
     ethylamino-5-methylthio-6-methoxy-                                   
     pyrimidine                    HBr   184°C.                    
30   2-N-methyl-N-phenyl-amino-4-(2&#39;-di-                                  
     isopropyl-amino)-ethylamino-5-methyl-                                
     thio-6-(dimethylaminoethyl)-methoxy-                                 
     pyrimidine                    2HBr  198°C.                    
31   2-N-methyl-2-N-benzylamino-4-(2&#39;-di-                                 
     isopropyl-amino)-ethylamino-5-methylthio-                            
     6-butoxy-pyrimidine           HBr   112°C.                    
32   2-N-methyl-N-phenylamino-4-(2&#39;-diiso-                                
     propyl-amino)-ethylamino-5-methyl-thio-6-                            
     butoxy-pyrimidine             HBr   169°C.                    
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     TOXICOLOGICAL PROPERTIES 
     The acute toxicities of the compounds according to the invention have been determined CD 1 mice (Charles RIVER) by intravenous and oral methods. The LD50 calculated by the quantal cumulative method of J. J. Reed and H. Muench (Amer. J. Hyg. 1938, 27, 493) are collected in the following Table: 
     
                          Acute toxicity to                                        
                 mice LD 50 (mg/kg)                                       
                 intravenous     orally                                   
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Product of Example                                                        
           1 (base)                                                       
                 53              200                                      
&#34;          2 (2HBr)                                                       
                 43              225                                      
&#34;          3 (2HBr)                                                       
                 64              225                                      
&#34;          4 (base)                                                       
                 45              525                                      
&#34;          5 (2HBr)                                                       
                 --              800                                      
&#34;          6 (HBr)                                                        
                 --              610                                      
&#34;          7 (HBr)                                                        
                 80              200                                      
&#34;          8 (base)                                                       
                 57              525                                      
&#34;          9 (base)                                                       
                 --              400                                      
&#34;          10(base)                                                       
                 79              900                                      
&#34;          11(base)                                                       
                 60              675                                      
&#34;          12(HBr)               600                                      
&#34;          13(HBr)                                                        
                 --         over 900                                      
&#34;          14(base)                                                       
                 92              900                                      
&#34;          15(HBr)                                                        
                 63         over 900                                      
&#34;          16(HBr)                                                        
                 --              600                                      
&#34;          17(HBr)                                                        
                 --         atoxic                                        
                                 900                                      
&#34;          18(HBr)                                                        
                 --         over 900                                      
&#34;          19(HBr)                                                        
                 --         about                                         
                                 675                                      
&#34;          20(HBr)                                                        
                 --              400                                      
&#34;          21(base)                                                       
                 --         about                                         
                                 600                                      
&#34;          22(base)                                                       
                 --         atoxic                                        
                                 900                                      
&#34;          23(2HBr)                                                       
                 22              175                                      
&#34;          24(2HBr)                                                       
                 22              600                                      
&#34;          25(HBr)                                                        
                 --         about                                         
                                 600                                      
&#34;          26(HBr)                                                        
                 70              225                                      
&#34;          27(base)                                                       
                  18.5           600                                      
&#34;          28(HBr)                                                        
                 --         about                                         
                                 200                                      
&#34;          29(HBr)                                                        
                 --         &#34;    200                                      
&#34;          30(2HBr)                                                       
                  9.5            200                                      
&#34;          31(HBr)                                                        
                 --         about                                         
                                 675                                      
&#34;          32(HBr)                                                        
                 --         about                                         
                                 525                                      
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     On the whole, the products according to the invention are not very toxic to mice since, taken orally, many are atoxic at 900 mg/kg and others have an LD 50 between 175 and more than 900 mg/kg. 
     PHARMACOLOGICAL PROPERTIES 
     1. Analgesic and antiserotonin activity: 
     The analgesic activities have been investigated with respect to abdominal spasms caused in mice by the intraperitoneal injection of 2-phenyl-1,4-benzoquinone according to E. Siegmund, E. Cadmus and G. Lu, Proc. Soc. exp. Biol. Med., 1957, 95, 729-731. The central antiserotonin properties have been determined by the &#34;Head-twitch&#34; technique in mice according to S. J. Corne, R. W. Pickering and B. T. Warner, Brit. J. Pharmacol., 1963, 20, 106-120. In this test, the antiserotonin products inhibit the sudden shaking of the head induced in mice by 5-hydroxy-tryptophan, the biological precursor of serotonin. 
     
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Mice                                                                      
Product                 Antiserotonin activity                            
 of    Analgesic activity P.B.Q.                                          
                        Head-twitch AD 50 (mg/                            
Example                                                                   
       AD 50 (mg/kg) oral                                                 
                        kg) oral                                          
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2        over 100        95                                               
3        over 100        35                                               
5        over 300       100                                               
6        --              65                                               
7        60             --                                                
12       100            --                                                
13       --             185                                               
16       70              90                                               
17       --             400                                               
18       over 300       205                                               
26       65             --                                                
27       95             --                                                
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     When given orally to mice, the compounds of Examples 7, 16 and 27 exert a marked analgesic activity, while those of Examples 2, 3, 6 and 16 are central antiserotonine. 
     2. Spasmolytic activities 
     The spasmolytic activities are known by means of the technique of R. Magnus (Arch. Ges. Physiol., 1904, 102, 123) on the isolated duodenum of rabbits. The spasmolytic neurotropes inhibit the contractions of the organ caused by acetylcholine, while the musculotropes prevent the spasms induced by barium chloride. The EC 50 expressed in mg/litre are collected in the following Table where EC denotes &#34;Effective concentration&#34;. 
     
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Spasmolytic activities EC 50 (mg/l)                                       
isolated duodenum of rabbit                                               
Products                                                                  
of      Neurotrope versus                                                 
                        Musculotrope versus                               
Examples                                                                  
        acetylcholine   BaCl.sub.2                                        
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1       5.50            1.40                                              
2       1.50            0.80                                              
3       1.30            0.30                                              
4       0.30            0.06                                              
5       1.00            0.90                                              
7       1.20            0.16                                              
8       4.90            2.80                                              
9       3.00            1.90                                              
10      0.50            0.50                                              
11      3.50            0.02                                              
14      0.08            0.04                                              
15      --              0.05                                              
16      --              0.30                                              
17      --              0.50                                              
23      8.60            1.00                                              
24      0.12            0.13                                              
27      --              0.08                                              
30      --              1.00                                              
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     The products according to the invention show interesting neurotropic and musculotropic spasmolytic properties. From the point of view of neurotropic activity, it is necessary to call attention to the products of Examples 4, 10, 14 and 24 while from the point of view of musculotropic effects, the products of Examples 4, 11, 14, 15 and 27 exert quite remarkable activities with EC 50 less than 0.1 mg/liter. 
     3. Coronaro-dilatatory activities 
     The technique of Langendorff, modified by F. E. Anderson, (J. Pharmacol. exp. Therap., 1948, 91, 135) using isolated rabbit heart permits the coronaro-dilatatory activity of the products to be studied. In this text, the cardiac perfusion liquid contains 0.5 UI/1 of posthypophysis. The results are expressed in the percentage variation of the coronary flow after affusion of the product to be tested, compared with the initial flow. 
     
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        Coronaro-dilatatory effect                                        
Products                                                                  
of                    Increase of the coronary                            
Examples  Dose in mg  flow in %                                           
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          0.01        + 56                                                
          0.03        + 58                                                
 2        0.10        + 64                                                
          0.30        + 91                                                
          0.003       + 8                                                 
          0.010       + 28                                                
 4        0.030       + 41                                                
          0.100       + 135                                               
          0.003       + 38                                                
          0.010       + 40                                                
 7        0.030       + 37                                                
          0.100       + 77                                                
11        0.001       + 168                                               
          0.003       + 172                                               
14        0.003       + 104                                               
          0.010       + 140                                               
          0.030       + 168                                               
15        0.003       + 16                                                
          0.010       + 24                                                
          0.030       + 44                                                
          0.100       + 28                                                
16        0.003       + 16                                                
          0.010       + 52                                                
24        0.003       + 26                                                
          0.01        + 32                                                
          0.03        + 58                                                
          0.10        + 67                                                
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     In this test, the products of Examples 2, 4, 7, 15, 16 and 24 and especially those of Examples 11 and 14 exert interesting coronaro-dilatatory activities. 
     4. Hypoglycemiant properties 
     The hypoglycemiant properties have been studied on the male CD rats (Charles RIVER) weighing 200 to 250 g, in which the glycemia is controlled before treatment and then after 4 days of daily oral treatment. The seric glucose is determined by the method of W. S. Hoffmann (J. Biol. Chem., 1937, 120, 51). Groups of 10 rats are used and the hypoglycemiant activity is expressed by the percentage variation of the average glycemia of the treated animals with respect to that of the controls. If it is necessary, the statistical significance of the difference is determined by the test of the coefficient &#34;t&#34; of Student. The results are collected in the following Table. 
     
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        Hypoglycemiant activity in the rat                                
Product of                                                                
          Dose mg/kg taken                                                
                       Variation of the glycemia                          
Example   orally       in % with respect to the                           
                       controls                                           
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5         300          - 23.sup.+.sup.+.sup.+                             
6         300          - 36.sup.+.sup.+.sup.+                             
7         100          - 10.sup.+                                         
11        300          - 17.sup.+.sup.+.sup.+                             
12        100          - 24.sup.+.sup.+.sup.+                             
          300          - 38.sup.+.sup.+.sup.+                             
13        300          - 17.sup.+.sup.+.sup.+                             
14        100           - 8.sup.+.sup.+                                   
17        400          - 22.sup.+.sup.+.sup.+                             
18        300          - 31.sup.+.sup.+.sup.+                             
24        300          - 34.sup.+.sup.+.sup.+                             
30        100          - 26.sup.+.sup.+.sup.+                             
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 significance of the variations:                                          
 .sup.+difference significant for p = 0.05                                
 .sup.+.sup.+difference significant for p = 0.01                          
 .sup.+.sup.+.sup.+difference significant for P = 0.001                   
 
    
     Among these various products, those of Examples 5, 6, 12, 13, 17, 18, 24 and 30 have strong hypoglycemiant properties. 
     THERAPEUTIC APPLICATION 
     The products according to the invention may be used in human therapeutics as analgesics, anti-serotonins, spasmolytic musculotropes and neurotropes, vasodilators and especially coronary dilators, hypoglycemiants and anti-diabetics. 
     They may be administered for example in the form of compressed tablets, lozenges, gelatine-coated pills, cachets, suppositories, injectable ampoules or drops in unitary doses which comprise, according to the form and the compound used, between 10 mg and 500 mg, and according to a daily dose between 50 mg and 2500 mg.