Patent Publication Number: US-4318858-A

Title: Thioethylamide derivatives

Description:
The present invention relates to compounds of the formula: ##STR2## [wherein R is dimethylamino or 1-pyrrolidinyl; 
     R 1  and R 2  each is hydrogen or C 1  -C 3  alkyl; 
     R 3  is hydrogen, C 1  -C 3  alkyl (optionally substituted by one member selected from the group consisting of cyano, C 1  -C 3  alkoxy, phenyl, and 5- or 6-membered heterocyclic group), C 3  -C 6  cycloalkyl, C 2  -C 5  alkenyl (optionally substituted by one member selected from the group consisting of C 1  -C 3  alkoxy, phenyl, and phenoxy), C 6  -C 10  aryl (optionally substituted by one or two members selected from the group consisting of hydroxy, halogen, nitro, sulfamoyl, C 1  -C 3  alkyl, C 1  -C 3  alkoxy, C 1  -C 3  alkanoyl, C 2  -C 4  alkoxycarbonyl, C 2  -C 4  dialkylamino, and C 1  -C 3  alkanesulfonyl), or 5- or 6-membered heterocyclic group (optionally substituted by one member selected from the group consisting of oxo, halogen, C 1  -C 3  alkyl, and C 1  -C 3  alkoxy); 
     and X is oxygen or sulfur] 
     and their pharmaceutically acceptable acid addition salts. 
     More particularly, the present invention relates to compounds of the formula: ##STR3## [wherein R, R 3  and X each has the same significance as defined above]. 
     Concrete illustration of the terms used in the above definition is shown below: 
     alkyl includes methyl, ethyl, propyl, and isopropyl; 
     cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; 
     alkenyl includes vinyl, allyl, butenyl, butadienyl, pentadienyl, etc; 
     alkoxy includes methoxy, ethoxy, propoxy and isopropoxy; 
     alkoxycarbonyl includes methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; 
     alkanoyl includes formyl, acetyl and propionyl; 
     dialkylamino includes dimethylamino, diethylamino, methylethylamino and methylpropylamino; 
     alkanesulfonyl includes methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl; 
     halogen includes fluorine, chlorine, bromine, iodine, etc.; aryl includes phenyl, naphthyl, etc.; 5- or 6-membered hetrocyclic ring includes furyl, thienyl, pyridyl, morpholinyl, pyrrolidinyl, etc. 
     The pharmaceutically acceptable acid addition salts includes those of inorganic acids (e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphonic acid) and organic acids (e.g. acetic acid, citric acid, oxalic acid, lactic acid, succinic acid, tartaric acid, mandelic acid, methanesulfonic acid). 
     As this type of histamine H 2  blocker, cimetidine is dissolved in G. J. Durant, C. R. Ganellin, et al., J. Med. Chem., Vol. 20, 901 (1977; U.S. Pat. Nos. 3,876,647; 3,897,444 and 3,975,530. 
     An object of the present invention is to provide the novel thioethyl-amide derivatives (I) showing excellent histamine H 2  blocking activity. 
     The objective compounds (I) of the present invention are prepared according to the following scheme: ##STR4## (wherein R, R 1 , R 2 , R 3  and X have each the same significance as defined above). 
     Thus the compounds (I) are prepared by reacting the starting amines (II) with an acylating agent containing a moiety of R 3  CO--. This acylation may be performed appropriately in a conventional manner such as by the acid anhydride prorcess, acid chloride process, acid/DCC process or acid/triphenylphosphine process. 
     Illustrative embodiments of the acylation adopted in the present invention are shown as follows: 
     (a) Acid anhydride process: 
     Amine (II) is reacted with the corresponding acid anhydride, or mixed anhydride e.g. (R 3  CO) 2  O, R 3  COOCOC 2  H 5 . The reaction is conducted in an appropriate solvent, e.g. pyridine, at room temperature or under heating up to reflux temperature. 
     (b) Acid chloride process: 
     Amine (II) is reacted with the corresponding acid chloride R 3  COCl in the presence of an acid removing agent such as pyridine, triethylamine, HMPA, which also works as a solvent. The reaction is conducted at room temperature or under cooling or heating. 
     (c) Acid/DCC process: 
     Amine (II) is reacted with the corresponding free acid R 3  COOH in the presence of DCC (dicyclohexylcarbodiimide) in an appropriate solvent such as dichloroethane, chloroform, ether, dimethylformamide or dimethylsulfoxide at room temperature or under heating. 
     (d) Acid/triphenylphosphine/disulfide process: 
     Amine (II) is reacted with the corresponding free acid R 3  COOH in the presence of triphenylphosphine and a disulfide (e.g. 2,2&#39;-bis(N-methylformamidophenyl)disylfide, 2,2&#39;-dipyridyl disulfide). The reaction may be performed in a solvent like acetonitrile. 
     The starting amines (II) may be prepared according to the following scheme: ##STR5## (wherein R, R 1  and R 2  each has the same significance as defined above). Thus the compounds (II) can be prepared by reacting the compounds (III) with paraformaldehyde (CH 2  O) n  in the presence of butyl lithium n-BuLi and reacting the resulting alcohols (IV) with 2-mercaptoethylamine in the presence of conc. hydrochloric acid as a condensing agent. 
     The compounds (I) of the present invention and their pharmaceutically acceptable acid addition salts bind the active site of the histamine H 2  receptor in competition with histamine to show a histamine H 2  blocking activity. In Table 1 the pA 2  column shows the degree of inhibiting the palpitation number of guinea pig&#39;s enucleated atrium by the compounds (I) (the oxalates). ##STR6## 
     
                                           TABLE 1                                 
__________________________________________________________________________
Test                                                                      
No.                                                                       
   R     R.sup.1                                                          
            R.sup.2                                                       
                   R.sup.3        X n pA.sub.2                            
__________________________________________________________________________
1  (CH.sub.3).sub.2 N                                                     
         H  H                                                             
                                  O 1 6.19                                
2  &#34;     &#34;  &#34;                                                             
                    ##STR7##      &#34; 2.5                                   
                                      6.08                                
3  &#34;     &#34;  &#34;                                                             
                    ##STR8##      &#34; 1 6.17                                
4  &#34;     &#34;  &#34;                                                             
                    ##STR9##      &#34; 0 6.33                                
5  &#34;     &#34;  &#34;      CHCHCHCHCH.sub.3                                       
                                  &#34; 1 5.72                                
6  &#34;     &#34;  &#34;      H              &#34; 1.5                                   
                                      5.73                                
7  &#34;     &#34;  &#34;                                                             
                    ##STR10##     &#34; 1 6.82                                
    ##STR11##                                                             
         H  H                                                             
                    ##STR12##     S 1 6.26                                
9  &#34;     &#34;  &#34;                                                             
                    ##STR13##     &#34; 1 6.04                                
10 &#34;     CH.sub.3                                                         
            H                                                             
                    ##STR14##     &#34; 0 5.66                                
11 &#34;     H  CH(CH.sub.3).sub.2                                            
                    ##STR15##     &#34; 1.5                                   
                                      6.30                                
12 &#34;     CH.sub.3                                                         
            H                                                             
                    ##STR16##     O 1 6.07                                
13 Cimetidine                         6.63                                
__________________________________________________________________________
 Note:                                                                    
 The pA.sub.2 value is defined as a negative logarithm of the concentratio
 of the compound (I) required to shift the doseresponse of histamine to th
 high concentration side by 2fold. [Ariens, E.J., Molecular Pharmacology, 
 (1964), Academic Press, New York and London].                            
 
    
     Further N-[2-[[(5-dimethylaminomethyl-2-furyl)-methyl]thio]ethyl]-4-sulfamoylbenzamide oxalate showed ED 50  2.54 mg/kg in the gastric acid secretion inhibiting activity tested in Donryu male rats, in which the antagonism to histamine was confirmed by measuring the pH value in the stomach; acute toxicity LD 50  150 mg/kg i.v. and above 1,000 mg/kg p.o. in mice. Other compounds also showed similar activities. 
     Accordingly the compounds (I) of the present invention showing powerful histamine H 2  inhibition are useful as remedies for diseases to be alleviated by inhibiting the histamine H 2  activity, for example, gastric ulcers. 
     The compounds (I) of the present invention or their pharmaceutically acceptable acid addition salts may be orally or parenterally administered. In using as an injection, the compounds (I) may be administered in the form of aqueous solution by conventional techniques such as intravenous, intramuscular or subcutaneous administration. The compounds (I) may be sealed in ampoules in the form of a solution but may preferably be preserved as crystals, fine crystals or lyophilisates in ampoules or vials and dissolved in water immediately before use. 
     Furthermore, the compounds (I) or their pharmaceutically acceptable acid addition salts may be formulated into external or internal preparations in combination with pharmaceutically acceptable additives such as diluents (e.g., starch, sucrose, lactose, calcium carbonate, kaolin), fillers (e.g. lactose, starch, calcium phosphate, kaolin, bentonite, or talc), lubricants (e.g. stearic acid, sodium benzoate), and the like. Such formulations include solutions, suspensions, powders, granules, capsules, tablets, injections, emulsions and suppositories, and these preparations may be prepared in a conventional manner for pharmaceutical practice. An appropriate daily dosage of the compounds (I) is ordinarily in 2-40 mg/kg body weight at 2 to 3 divided doses for treating patients suffering from peptic ulcer. However, such a dosage may be increased or decreased appropriately depending upon the symptoms, histories, ages, and sexes of the patients. 
    
    
     Presently preferred and practical embodiments of the present invention are illustratively shown in the following examples. 
     EXAMPLE 1 
     Preparation of N-[2-[[(5-dimethylaminomethyl-2-furyl)methyl]thio]ethyl]-2-thiophenecarbonamide: ##STR17## 
     To a solution of Compound 1 (0.428 g) in HMPA (2 ml) is added 2-thenoyl chloride (0.322 g) under ice-cooling and the resultant mixture is stirred at room temperature for 2 hours and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium hydrogencarbonate and shaken with ether. The organic layer is washed with water, dried and concentrated. The residue is purified by chromatography on a column of silica gel/methanol to give Compound 2 as an oil. 
     NMR, δCDCl 3  : 2.27 (6H), 3.45 (2H), 3.80 (2H), 6.77 (1H, br.), 6.18 (2H) 
     The product is treated with an oxalic acid/ethanol solution and then with ether to give the oxalate of Compound 2 (0.51 g). mp 117°-118° C. (dec.) (recrystallized from ethanol). Anal. Calcd. for C 15  H 20  N 2  O 2  S 2 .(COOH) 2  : C, 49.26; H, 5.35; N, 6.76; S, 15.47. Found: C, 49.27; H, 5.41; N, 6.71; S, 15.44. 
     EXAMPLES 2-12 
     The reaction is performed as in Example 1 using Compound 1, whereby the following products (Ia) are obtained: 
     
         ______________________________________                                    
 ##STR18##                                                                
Example                                                                   
No.    R.sup.3        n     mp(°C.)                                
                                     Yield (%)                            
______________________________________                                    
        ##STR19##     2.5   152-154 d.                                    
                                     57.0                                 
3                                                                         
        ##STR20##     0      77-79   82.0                                 
4      CH.sub.2CH     0     oil      --                                   
5                                                                         
        ##STR21##     1     104-114 d.                                    
                                     70.8                                 
6                                                                         
        ##STR22##     1     134-135 d.                                    
                                     67.0                                 
7                                                                         
        ##STR23##     1     112-114 d.                                    
                                     40.3                                 
8                                                                         
        ##STR24##     1     103-106 d.                                    
                                     73.7                                 
9                                                                         
        ##STR25##     1     122-125 d.                                    
                                     24.6                                 
10                                                                        
        ##STR26##     1      75-78 d.                                     
                                     24.5                                 
11     CH.sub.3       0     oil      --                                   
12                                                                        
        ##STR27##     1     131-133  67.4                                 
______________________________________                                    
 Note: d. means decomposition.                                            
 
    
     EXAMPLE 13 ##STR28## 
     To a solution of Compound 1 (0.428 g) and sorbic acid (0.225 g) in chloroform (10 ml) is added DCC (0.413 g) and the resultant mixture is stirred at room temperature for 1.5 hours. The reaction mixture is allowed to stand overnight and the precipitate is filtered off. The filtrate is concentrated, and the residue is chromatographed on a column of silica gel/methanol to give Compound 3 as an oil. 
     NMR δCDCl 3  : 1.83 (d., J=5, 3H), 2.25 (6H), 3.43 (2H), 3.73 (2H), 6.15 (2H) 
     The product is treated with oxalic acid/ethanol solution and then with ether to give the oxalate of Compound 3 (0.4 g). Yield is 50%. mp. 95°-97° C.(d.) (recrystallized from ethanol). 
     Anal. Calcd. for C 16  H 24  N 2  SO 2 .(COOH) 2 .1/2H 2  O: C, 53.65; H, 6.63; N, 6.95; S, 7.96. Found: C, 53.56; H, 6.71; N, 6.81; S, 7.61. 
     EXAMPLES 14-15 
     The reaction is performed as in Example 13 using Compound 1, whereby the following products are obtained. 
     
         ______________________________________                                    
 ##STR29##                                                                
Example                                                                   
No.     R.sup.3     n      mp (°C.)                                
                                    Yield (%)                             
______________________________________                                    
14      H           1.5    110-113 d.                                     
                                    80.6                                  
15      CNCH.sub.2  1      140-142 d.                                     
                                    62.8                                  
______________________________________                                    
 
    
     EXAMPLE 16 ##STR30## 
     A suspension of 2,2&#39;-bis(N-methylformamidophenyl) disulfide (0.997 g), triphenylphosphine (0.715 g) and 4-sulfamoylbenzoic acid (0.604 g) in acetonitrile (15 ml) is stirred for 70 minutes. Compound 1 (0.643 g) is added to the suspension, which is stirred at room temperature for 2 hours. The reaction mixture is allowed to stand overnight and the precipitate is filtered off. The filtrate is concentrated and the residue is chromatographed on a column of silica gel/methanol to give Compound 4 as an oil. 
     NMR, δCDCl 3  : 2.13 (6H), 3.32 (2H), 3.68 (2H), 4.08 (br., 2H), 6.08 (2H), 7.40 (br., 1H), 7.70 (4H) 
     The product is treated with oxalic acid/ethanol and then with ether to give the oxalate of Compound 4 (0.93 g). 
     Yield is 63.7%. mp. 126°-128° C. (d.). 
     Anal. Calcd. for C 17  H 23  N 3  O 4  S 2 .(COOH) 2  : C, 46.81; H, 5.17; N, 8.62; S, 13.15. Found: C, 46.74; H, 5.09; N, 8.48; S, 13.19. 
     The reaction is performed similarly using 2,2&#39;-dipyridyl disulfide in lieu of 2,2&#39;-bis(N-methylformamidophenyl) disulfide. Yield is 57.2%. 
     EXAMPLES 17-18 
     The reaction is performed as in Example 16 using Compound 1, whereby the following products are obtained: 
     
         ______________________________________                                    
 ##STR31##                                                                
Example                                                                   
No.    R.sup.3    Appearance NMR δ.sup.CDCl.sbsp.3                  
______________________________________                                    
17                                                                        
        ##STR32## oil        2.23 (6H), 3.40 (2H), 3.70 (2H), 6.10 (2H)   
18                                                                        
        ##STR33## oil        2.25 (6H), 3.42 (2H), 3.75 (2H), 6.12        
______________________________________                                    
                             (2H)                                         
 
    
     EXAMPLE 19 ##STR34## 
     To a solution of 5-bromothiophene-2-carboxylic acid (0.977 g) in HMPA (5 ml) and acetonitrile (0.5 ml) cooled at -10° C. is added thionyl chloride (0.28 ml) and the resultant mixture is stirred at the same temperature for 20 minutes. Compound 1 (0.643 g) is added to the mixture, which is stirred at room temperature for 3 hours and allowed to stand overnight. The reaction mixture is neutralized with aqueous sodium hydrogencarbonate and shaken with ethyl acetate. The organic layer is washed with water, dried and concentrated. The residue is chromatographed on a column of silica gel/methanol, and the eluate is concentrated to give an oil. The oil is treated with oxalic acid/ethanol and then with ether to give the oxalate of Compound 5 (0.81 g). 
     Yield is 55%. mp. 133°-135° C. (d.). 
     Anal. Calcd. for C 15  H 19  N 2  O 2  S 2  Br.(COOH) 2  : C, 41.38; H, 4.29; N, 5.68; S, 13.00; Br, 16.19. Found: C, 41.30; H, 4.20; N, 5.70; S, 12,78; Br, 16.55. 
     EXAMPLES 20-22 
     The reaction is performed as in Example 19 using Compound 1, whereby the following products are obtained. 
     
         ______________________________________                                    
 ##STR35##                                                                
Example                                                                   
No.    R.sup.3        n     mp (°C.)                               
                                    Yield (%)                             
______________________________________                                    
20                                                                        
        ##STR36##     1     113-115d.                                     
                                    57.1                                  
21                                                                        
        ##STR37##     2     136-138d.                                     
                                    65.5                                  
22                                                                        
        ##STR38##     1     157-159d.                                     
                                    65.2                                  
______________________________________                                    
 Note: Preparations of Compound 1: U.S. Pat. No. 4,165,377 is referred to.
 
    
     EXAMPLES 23-34 
     Compounds (Ib) are prepared from Compound 6 below according to the respective processes: 
     
         __________________________________________________________________________
 ##STR39##                                                                
Example                        Yield                                      
No.  R.sup.3         n    mp (°C.)                                 
                               (%) Process                                
__________________________________________________________________________
23   H               1    145-146                                         
                               93  c                                      
24   CH.sub.3        1    oil  91  a                                      
25                                                                        
      ##STR40##      1    130-131.5                                       
                               85  b                                      
26                                                                        
      ##STR41##      1    oil  91  &#34;                                      
27                                                                        
      ##STR42##      1    156-157                                         
                               92  &#34;                                      
28                                                                        
      ##STR43##      1 . 1/2H.sub.2 O                                     
                          135-137d                                        
                               99  &#34;                                      
29                                                                        
      ##STR44##      1    138-139                                         
                               42  &#34;                                      
30                                                                        
      ##STR45##      1    146-147                                         
                               58  &#34;                                      
31                                                                        
      ##STR46##      1    133-135                                         
                               94  d                                      
32                                                                        
      ##STR47##      1    oil  64  &#34;                                      
33   CH.sub.3CHCHCHCH                                                     
                     1    &#34;    99  &#34;                                      
34                                                                        
      ##STR48##      1    &#34;    80  &#34;                                      
__________________________________________________________________________
 Note: Compound 6 is prepared according to the following route:           
 ##STR49##                                                                
 ##STR50##                                                                
 ##STR51##                                                                
 LAH = lithium aluminum hydride                                           
 THF = tetrahydrofuran                                                    
 
    
     EXAMPLES 35-45 
     The products (Ic) are prepared from the following Compound 12 according to the respective processes. 
     
         ______________________________________                                    
 ##STR52##                                                                
Ex-                                                                       
am-                                                                       
ple                                 Yield Pro-                            
No.  R.sup.3           n     np (°C.)                              
                                    (%)   cess                            
______________________________________                                    
35   H                 1     101-102                                      
                                    57    c                               
36   CH.sub.3          1     oil    70    a                               
37                                                                        
      ##STR53##        1     &#34;      40    b                               
38                                                                        
      ##STR54##        1     &#34;      56    &#34;                               
39                                                                        
      ##STR55##        1     164-165                                      
                                    48    &#34;                               
40                                                                        
      ##STR56##        1     112-114                                      
                                    38    &#34;                               
41                                                                        
      ##STR57##        1     oil    29    &#34;                               
42                                                                        
      ##STR58##        1     &#34;      34    &#34;                               
43                                                                        
      ##STR59##        1     165-166d.                                    
                                    63    d                               
44                                                                        
      ##STR60##        1     oil    65    &#34;                               
45   CH.sub.3 CHCHCHCH 1     &#34;      80    &#34;                               
______________________________________                                    
Compound 12 is prepared according to the following route:                 
 ##STR61##                                                                
 ##STR62##                                                                
 ##STR63##                                                                
 ##STR64##                                                                
 ##STR65##                                                                
 ##STR66##                                                                
 ##STR67##                                                                
 ##STR68##                                                                
 ##STR69##                                                                
 
    
     EXAMPLES 46-49 
     The products (Id) are prepared from the following Compound 21 according to the respective methods: 
     
         ______________________________________                                    
 ##STR70##                                                                
Ex.                                 Yield Pro-                            
No.  R.sup.3          n     mp(°C.)                                
                                    (%)   cess                            
______________________________________                                    
46                                                                        
      ##STR71##       1.5   149-152 d.                                    
                                    80    b                               
47   H                1     159-161 d.                                    
                                    68.8  c                               
48                                                                        
      ##STR72##       1     172-174 d.                                    
                                    78.7  b                               
49                                                                        
      ##STR73##       1     195-197 d.                                    
                                    56.5  d                               
______________________________________                                    
 Note:-                                                                   
 Compound 21 is prepared according to the following route:                
 ##STR74##                                                                
 -                                                                        
 ##STR75##                                                                
 [J. Am. Chem. Soc.,77,4066(&#39;55)]-                                        
 ##STR76##                                                                
 ##STR77##                                                                
 
    
     EXAMPLES 50-53 
     The products (Ie) is prepared from the following Compound 26 according to the respective processes. 
     
         ______________________________________                                    
 ##STR78##                                                                
Ex.                               Yield                                   
No.  R.sup.3        n     mp(°C.)                                  
                                  (%)   Process                           
______________________________________                                    
50   H              1.5   150-153 d.                                      
                                  86.5  c                                 
51                                                                        
      ##STR79##     0     111-113 29.4  d                                 
52                                                                        
      ##STR80##     1.5   155-157 d.                                      
                                  84.2  b                                 
53                                                                        
      ##STR81##     1     182-189 d.                                      
                                  62.1  b                                 
______________________________________                                    
 Note:-                                                                   
 Compound 26 is prepared according to the following route:                
 ##STR82##                                                                
 ##STR83##                                                                
 ##STR84##                                                                
 ##STR85##                                                                
 
    
     EXAMPLE 54 
     Preparation of N-[2-[[(5-dimethylaminomethyl-2-furyl)methyl]thio]ethyl]-4-hydroxyphenylacetamide: ##STR86## 
     A suspension of Compound 1 (0.536 g), p-hydroxyphenylacetic acid (0.456 g) and DCC (0.619 g) in chloroform (15 ml) is stirred at room temperature for 48 hours. The reaction mixture is washed with water and the organic layer is dried and concentrated. The residue is purified by chromatography on a column of silica gel/methanol to give Compound 30 as an oil. The product is treated with oxalic acid/ethanol and then ether for crystallization to give the oxalate of Compound 30 (0.49 g). Yield is 41.2%. mp. 101°-103° C. (d.) (recrystallized from ethanol). 
     Anal. Calcd. for C 18  H 24  N 2  O 3  S.(COOH) 2 .1/2H 2  O: C, 53.68; H, 6.08; N, 6.26; S, 7.16. Found: C, 53.99; H, 5.96; N, 6.03; S, 6.81. 
     Free base: NMR, δCDCl 3  : 2.30 (6H), 3.45 (2H), 3.48 (2H), 6.10 (2H). 
     EXAMPLE 55 
     Compound 31 is prepared by reacting Compound 1 with monoethyl maleate and thionyl chloride in HMPA and acetonitrile. ##STR87## 
     NMR, δCDCl 3  : 1.30 (t., J=7, 3H), 2.27 (6H) 3.40 (2H) 3.70 (2H), 4.29 (q., J=7 Hz, 2H), 6.12 (2H), 6.83 (br., 2H). 
     The oxalate of Compound 31: 
     Anal. Calcd. for C 16  H 24  N 2  O 4  S.(COOH) 2  : C, 50.22; H, 6.09; N, 6.51; S, 7.43. Found: C, 50.04; H, 6.13; N, 6.40; S, 7.33. 
     EXAMPLE 56 
     Preparation of N-[2-[[[4-methyl-5-(1-pyrrolidinylmethyl)-2-furyl]methyl]thio]ethyl]-4-methoxycarbonylbenzamide: ##STR88## 
     To a solution of Compound 32 (Brit. pat. 2,006,771) (400 mg) in pyridine (4 ml) is added methyl 4-(chloroformyl)-benzoate (357 mg) at -5° C. and the resultant mixture is allowed to stand at room temperature overnight. The reaction mixture is concentrated in vacuo and the residue is distributed between 5% aqueous sodium hydrogencarbonate and chloroform. The organic layer is washed with water, dried and concentrated. The residue is chromatographed on a column of silica gel/methanol to give Compound 33 (317 mg). Yield is 48%. 
     NMR, δCDCl 3  : 1.95 (3H), 3.62 (2H), 3.70 (2H), 3.90 (3H), 6.02 (1H). 
     The mono-oxalate, mp. 164°-165° C. 
     Anal. Calcd. for C 24  H 30  N 2  O 8  S: C, 56.90; H, 5.97; N, 5.53; S, 6.33. Found: C, 56.62; H, 6.07; N, 5.56; S, 6.39. 
     EXAMPLES 57-61 
     The following products (If) are prepared from Compound 34 according to the acid chloride/pyridine method. ##STR89## 
     b.p. 0.8 148°-150° C. (Belg. pat. 867,105) 
     
         ______________________________________                                    
Ex.                                                                       
No.   R.sup.3        n      mp (°C.)                               
                                     Yield (%)                            
______________________________________                                    
57                                                                        
       ##STR90##     1      178-179 d.                                    
                                     80                                   
58                                                                        
       ##STR91##     2.5    150-152  82                                   
59    H              1      114-116  80                                   
60                                                                        
       ##STR92##     1      102-105 d.                                    
                                     98                                   
61                                                                        
       ##STR93##     1      142-144  62                                   
______________________________________                                    
 
    
     EXAMPLES 62-67 
     Compounds (Ig) below are prepared from Compound 35. 
     
         ______________________________________                                    
 ##STR94##                                                                
Ex.                               Yield                                   
No.   R.sup.3       n     mp (°C.)                                 
                                  (%)   Process                           
______________________________________                                    
62    H             1.5   135-138 d.                                      
                                  63.8  c                                 
63                                                                        
       ##STR95##    2.5   150-152 d.                                      
                                  95.4  b                                 
64                                                                        
       ##STR96##    1     88-91 d.                                        
                                  27.2  b                                 
65                                                                        
       ##STR97##    1     145-148 d.                                      
                                  64.5  b                                 
66                                                                        
       ##STR98##    1     150-155 d.                                      
                                  49    d                                 
67                                                                        
       ##STR99##    1     154-156 d.                                      
                                  52    d                                 
______________________________________                                    
 
    
     EXAMPLES 68-70 
     The following products (Ih) are obtained from Compound 34 using the system of 2,2&#39;-dipyridyl disulfide/triphenylphosphine/methylene chloride. 
     
         ______________________________________                                    
 ##STR100##                                                               
Ex.                                    Yield                              
No.     R.sup.3       n     mp (°C.)                               
                                       (%)                                
______________________________________                                    
68                                                                        
         ##STR101##   1     100-102    43                                 
69                                                                        
         ##STR102##   1     100-102    55                                 
70                                                                        
         ##STR103##   1     129-130    67                                 
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