Esters of p-carbonylphenoxy-isobutyric acids
This application is a cip application of my previous U.S. Pat. application Ser. No. 326 188 of Jan. 24, 1973 now U.S. Pat. No. 3,907,792 which was itself a cip application of my U.S. Pat. application Ser. No. 8071 of Feb. 2, 1970 now U.S. Pat. 3,914,286. 
    
    
     This invention is concerned with esters of p-carbonylphenoxy-isobutyric acids. 
     This application is concerned with esters of the general formulae ##STR2## WHEREIN R is a phenyl group substituted by one or two halogen atoms; 
     R&#39; is H, CH 3 , C 6  H 5 , OCH 3 , or, SO 2  CH 3  ; 
     R&#34; is CH 3  or C 2  H 5   
     Y is C 1  - C 4  alkoxy, phenoxy, phenoxy substituted by one or two halogen atoms, or OCH 2  O--CO--C(CH 3 ) 3  ; 
     Z is C 1  -C 4  alkyl, phenyl, or, R 1   
     Nr 1  r 2  is N(CH 3 ) 2  N(C 2  H 5 ) 2 , morpholino, piperidino, pyrrolidino, or, azepino. 
     This application is also concerned with acid addition salts obtained from formula Ia compounds with inorganic and organic acids. 
     All the compounds of formula I and Ia have useful therapeutic properties. All of them are lipids and cholesterol reducing agents, moreover they act as normolipidemiant and hypocho lesterolemiant agents. The acids (Y = OH): from which esters I and Ia derived, induce gastric ulcers when administered by oral route, while their ester derivatives I and Ia do not develop gastric ulcers. 
     Some acids of the isobutyric type have been previously disclosed or suggested. AINSWORTH et al, J. Med. Chem., (1967), 10, 158-161 described two acids, namely the p-hexanoyl- and p-octanoylphenoxyisobutyric acids. NAKANISHI (US patent No. 3 494957) suggested the p-acetylphenoxy-isobutyric acid. CRAGOE (US Pat. No. 3 704 314) suggested two acids, namely the p-butyrylphenoxy isobutyric acid and 2,3-dichloro -4-(2-methylenebutyryl-phenoxy-isobutyric acid, and an ester, namely the ethyl p-formylphenoxy-isobutyrate. On one hand these known acids present the disadvantage of inducing gastric ulcers, and on the other hand ethyl p-formylphenoxy-isobutyrate is less active than Clofibrate taken as a reference product. By halogen atoms I mean fluorine, chlorine, bromine and iodine atoms, the preferred halogen atom being chlorine. Thus, in the definition of R are included within the scope of this invention the 4-chlorophenyl, 3-chlorophenyl, 3,4-dichlorophenyl and 2,6-dichlorophenyl groups. The preferred R group is 4-chlorophenyl. The preferred R&#39; and R&#34; are respectively R&#39; = H and R&#34; = CH 3 . 
     The esters of formula I are more active than their homologue compounds in which R is alkyl or cycloalkyl such as cyclohexyl. Moreover when the esters are p-carbonylphenoxy-isobutyric acid aminoethyl esters (i.e. compounds of the formula Ia), it is noticed that the presence of the OCH 2  CH 2  NR 1  R 2  group enhances the hypocholesterolemiant and hypolipidemiant activities of the p-alkylcarbonyl compounds. 
     The preferred compound, that is to say the most useful therapeutically, is the isopropyl p-(4-chlorobenzoyl)-phenoxy-isobutyrate of formula I, which is coded as No. 178. Then comes the fumarate of β-azepino-ethyl p-(4-chlorobenzoyl)-phenoxy-isobutyrate of formula Ia, which is coded as No. 229. 
     The isobutyric acids (Y=OH) can be synthesized according to a method known per se. The methods I recommend are summed up by the following reaction schemes A and B, scheme B being the preferred one since it gives higher yields than A. ##STR3## 
     The esters I and Ia are obtained from the acids by a known process. For instance the esters may be prepared by esterification from the corresponding acids or by transesterification from another ester. For obtaining esters Ia the transesterification method is preferred. 
     Preparation I 
     p-(4-Chlorobenzoyl)-phenoxy-isobutyric acid (Code No. 153) 1 mole of 4-hydroxy-4&#39;-chlorobenzophenone is dissolved in anhydrous acetone and then 5 moles of powdered sodium hydroxide is added. The corresponding sodium phenate precipitates. Refluxing is effected, and then, 1.5 mole of CHCl 3  diluted with anhydrous acetone is added and the resulting mixture is refluxed for 10 hours. After cooling, water is added, the acetone is evaporated, the aqueous phase is washed with ether and acidified and the organic phase is redissolved in ether and extracted into a solution of bicarbonate. The bicarbonate solution is then acidified to obtain the desired acid, having a melting point of 185° C, with a yield of 75%. 
     Preparation II 
     Isopropyl (p-4-chlorobenzoyl)-phenoxy-isobutyrate ##STR4## 1 mole of the acid obtained in preparation I is converted into its acid chloride using thionyl chloride (2.5 moles). 1 mole of the acid chloride is then condensed with 1.05 mole of isopropyl alcohol in the presence of 0.98 mole of pyridine in an inert solvent such as benzene. 
     Since traces of SO 2  (which has a bad smell) may be obtained from the thionyl chloride; it is preferable to avoid this disadvantage by carrying out the esterification directly. 
     In table I, I have given examples of p-carbonylphenoxy-isobutyric acids which are used as intermediate compounds for the preparation of the esters according to this invention. They have been obtained according to reaction scheme A or B. 
     Tables II and III are respectively concerned with esters of formula I and esters of formula Ia. I have given in table IV reference or comparison products. Moreover, p-alkylcarbonyl-phenoxy-isobutyric acid esters of table IV may be used for preparing the corresponding esters Ia by transesterification. 
     
                       TABLE I                                                     
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 ##STR5##                                                                 
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                                       Melting or                         
Ex-   Code                             Boiling                            
ample No.     R           R&#39;      R&#34;   point                              
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Ex 1   82    CH.sub.3 CH.sub.2                                            
                          H       CH.sub.3                                
                                       F=96° C                     
Ex 2(a)      C.sub.6 H.sub.5                                              
                          H       CH.sub.3                                
Ex 3(b)      CH.sub.3 (CH.sub.2).sub.4                                    
                          H       CH.sub.3                                
Ex 4(b)      CH.sub.3 CH.sub.2).sub.6                                     
                          H       CH.sub.3                                
Ex 5(c)      CH.sub.3     H       CH.sub.3                                
Ex 6(a)                                                                   
(d)          CH.sub.3 (CH.sub.2).sub.2                                    
                          H       CH.sub.3                                
                                       F=88° C                     
Ex 7  153    4-ClC.sub.6 H.sub.4                                          
                          H       CH.sub.3                                
                                       F=185° C                    
Ex 8  198    CH.sub.3 (CH.sub.2).sub.3                                    
                          H       CH.sub.3                                
                                       F=62° C                     
Ex 9  243    CH.sub.3     3-CH.sub.3                                      
                                  CH.sub.3                                
                                       F=98° C                     
Ex 10 --     CH.sub.3     2-C.sub.6 H.sub.5                               
                                  CH.sub.3                                
                                       F=106° C                    
Ex 11 305    4-ClC.sub. 6 H.sub.4                                         
                          H       C.sub.2 H.sub.5                         
                                       F=140° C                    
Ex 12 406    3-ClC.sub.6 H.sub.4                                          
                          H       CH.sub.3                                
                                       F=121° C                    
Ex 13 404    3,4-Cl.sub.2C.sub.6 H.sub.3                                  
                          H       CH.sub.3                                
                                       F=155° C                    
Ex 14 401    2,6-Cl.sub.2C.sub.6 H.sub.3                                  
                          H       CH.sub.3                                
                                       F=196° C                    
Ex 15 391    cyclohexyl   H       CH.sub.3                                
                                       F=146° C                    
Ex 16 --     CH.sub.3     3-SO.sub.2 CH.sub.3                             
                                  CH.sub.3                                
                                       --                                 
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 Notes-                                                                   
 (a) disclosed in my previous U.S. Pat. Application Ser. No. 8071         
 (b) disclosed by AINSWORTH                                               
 (c) suggested by NAKANISHI                                               
 (d) suggested by CRAGOE                                                  
 
    
     
                                           TABLE II                                
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 ##STR6##                                                                 
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                                Melting or                                
     Code                       Boiling                                   
Example                                                                   
     No.                                                                  
         R      R&#39;   Y          point                                     
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Ex 17                                                                     
     162                                                                  
        4-ClC.sub.6 H.sub.4                                               
                H    OCH.sub.5  F=89° C                            
Ex 18                                                                     
     163                                                                  
        4-ClC.sub.6 H.sub.4                                               
                H    OC.sub.2 H.sub.5                                     
                                F=79° C                            
Ex 19                                                                     
     178                                                                  
        4-ClC.sub.6 H.sub.4                                               
                H    OCH(CH.sub.3).sub.2                                  
                                F=78° C                            
Ex 20                                                                     
     217                                                                  
        4-ClC.sub.6 H.sub.4                                               
                H    p-OC.sub.6 H.sub.4 Cl                                
                                F=135° C                           
Ex 21                                                                     
     403                                                                  
        3-ClC.sub.6 H.sub.4                                               
                H    OCH(CH.sub.3).sub.2                                  
                                F=79° C                            
Ex 22                                                                     
     405                                                                  
        3,4-Cl.sub.2C.sub.6 H.sub.3                                       
                H    OCH(CH.sub.3).sub.2                                  
                                F=69° C                            
Ex 23                                                                     
     402                                                                  
        2,6-Cl.sub.2C.sub.6 H.sub.3                                       
                H    OCH(CH.sub.3).sub.2                                  
                                F=115° C                           
Ex 24                                                                     
     253                                                                  
        4-ClC.sub.6 H.sub.4                                               
                3-CH.sub.3                                                
                     OCH(CH.sub.3).sub.2                                  
                                --                                        
Ex 25                                                                     
     297                                                                  
        4-ClC.sub.6 H.sub.4                                               
                H    OCH.sub.2 OCOC(CH.sub.3).sub.3                       
                                F=80° C                            
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                       table iii                                                   
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 ##STR7##                                                                 
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                                       melting or                         
    Code                               Boiling                            
Ex  No.    Z          R&#39;  OCH.sub.2 CH.sub.2 NR.sub.1 R.sub.2             
                                       point                              
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Ex 26                                                                     
    208    C.sub.6 H.sub.5                                                
                      H                                                   
                           ##STR8##    F = 100° C                  
Ex 27                                                                     
    209    C.sub.6 H.sub.5                                                
                      H                                                   
                           ##STR9##    F = 118° C                  
Ex 28                                                                     
    210    CH.sub.3   H                                                   
                           ##STR10##   F = 134° C                  
Ex 29                                                                     
    211    C.sub.6 H.sub.5                                                
                      H                                                   
                           ##STR11##   F = 115°  C                 
Ex  212    C.sub.6 H.sub.5                                                
                      H   OCH.sub.2 CH.sub.2 NEt.sub.2                    
                                       F =  62° C                  
30                        maleate                                         
Ex 31                                                                     
    229    4-ClC.sub.6 H.sub.4                                            
                      H                                                   
                           ##STR12##   F = 120° C                  
Ex  230    4-ClC.sub.6 H.sub.4                                            
                      H   OCH.sub.2 CH.sub.2 NEt.sub.2                    
                                       F = 104° C                  
32                        HCl                                             
Ex 33                                                                     
    231    4-ClC.sub.6 H.sub.4                                            
                      H                                                   
                           ##STR13##   F = 116° C                  
Ex  232    CH.sub.3 (CH.sub.2).sub.3                                      
                      H   OCH.sub.2 CH.sub.2 NEt.sub.2                    
                                       F =  72° C                  
34                        HCl                                             
Ex 35                                                                     
    233    CH.sub.3 (CH.sub.2).sub.3                                      
                      H                                                   
                           ##STR14##   F = 118° C                  
Ex 36                                                                     
    239    4-ClC.sub.6 H.sub.5                                            
                      H                                                   
                           ##STR15##   F = 145° C                  
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                                           table iv                                
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reference, comparison and/or other intermediate compounds                 
 ##STR16##                                                                
                               Melting or                                 
     Code                      Boiling                                    
Example                                                                   
     No.                                                                  
        R      R&#39;    Y         point                                      
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Ex 37 (c)                                                                 
     180                                                                  
        C.sub.6 H.sub.5                                                   
               H     OCH.sub.3 F = 58° C                           
Ex 38 (a)                                                                 
     186                                                                  
        C.sub.6 H.sub.5                                                   
               H     OC.sub.2 H.sub.5                                     
                               F = 87° C                           
Ex 39 (a)                                                                 
     190                                                                  
        C.sub.6 H.sub.5                                                   
               H     OCH(CH.sub.3).sub.2                                  
                               F = 84° C                           
Ex 40                                                                     
     -- CH.sub.3                                                          
               H     OC.sub.2 H.sub.5                                     
                               E.sub.0.03 = 120° C                 
Ex 41                                                                     
     -- CH.sub.3 CH.sub.2 CH.sub.2                                        
               H     OC.sub.2 H.sub.5                                     
                               E.sub.0.005 = 144° C                
Ex 42                                                                     
     140                                                                  
        CH.sub.3                                                          
               H     OCH.sub.3 F = 62° C                           
Ex 43                                                                     
     188                                                                  
        CH.sub.3 (CH.sub.2).sub.3                                         
               H     OCH.sub.3 E.sub. 0.05 = 147 - 9° C            
Ex 44                                                                     
     187                                                                  
        CH.sub.3 (CH.sub.2).sub.3                                         
               H     OC.sub.2 H.sub.5                                     
                               E.sub.0.05 = 157 - 8° C             
Ex 45                                                                     
     189                                                                  
        CH.sub.3 (CH.sub.2).sub.3                                         
               H     OCH(CH.sub.3).sub.2                                  
                               E.sub.0.05 = 156 - 7° C             
Ex 46                                                                     
     -- H      H     OC.sub.2 H.sub.5                                     
                               --                                         
Ex 47                                                                     
     390                                                                  
        cyclohexyl                                                        
               H     OCH(CH.sub.3).sub.2                                  
                               F = 148° C                          
Ex 48                                                                     
     238                                                                  
        4-ClC.sub.6 H.sub.5                                               
               H                                                          
                      ##STR17##                                           
                               F = 144° C                          
                     HCl                                                  
Ex 49                                                                     
     240                                                                  
        CH.sub.3                                                          
               3-CH.sub.3                                                 
                     OCH.sub.3 E.sub.0.05 = 132° C                 
Ex 50                                                                     
     241                                                                  
        CH.sub.3                                                          
               3-CH.sub.3                                                 
                     OC.sub.2 H.sub.5                                     
                               E.sub.0.05 = 136° C                 
Ex 51                                                                     
     242                                                                  
        CH.sub.3                                                          
               3-CH.sub.3                                                 
                     OCH(CH.sub.3).sub.2                                  
                               E.sub.0.05 = 139° C                 
Ex 52                                                                     
     -- CH.sub.3                                                          
               3-SCH.sub.3                                                
                     OCH(CH.sub.3).sub.2                                  
                               E.sub.1 = 198° C                    
Ex 53                                                                     
     -- CH.sub.3                                                          
               3-SO.sub.2 CH.sub.3                                        
                     OCH(CH.sub.3).sub.2                                  
                               F =  86° C                          
Ex 54                                                                     
     -- CH.sub.3                                                          
               2-C.sub.6 H.sub.5                                          
                     OCH(CH.sub.3).sub.2                                  
                               F = 95° C                           
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 Notes (a) and (c) see table I                                            
 
    
     The hypolipemiant and hypocholesterolemiant properties were exhibited in the rat. Each batch of rats (15 animals) is put on a fast at time t = 0. A blood sample is taken at time t + 15 hours, and then each product being tested is immediately administered orally. A new blood sample is taken at time t + 39 hours. The variation (diminution) in the total amount of blood cholesterol and total amount of blood lipids is measured between t + 15 hours and t + 39 hours, and this variation is expressed in % in Table V in which the results obtained with the products according to this invention and reference products are shown. 
     The invention also relates to therapeutic compositions containing, in combination with a physiologically acceptable excipient, at least one compound of formula I or Ia or one of their non-toxic acid-addition salts. 
     
                       TABLE V                                                     
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                      variation   variation                               
Example   dosage      cholesterol lipids                                  
(Code No.)                                                                
          mg/kg       %           %                                       
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Ex 19 (178)                                                               
          50          - 30         - 32                                   
Ex 21 (403)                                                               
          100         - 21         - 18                                   
Ex 22 (405)                                                               
          100         - 10         -  4                                   
Ex 23 (402)                                                               
          100         -  9         -  5                                   
Ex 27 (209)                                                               
          75          - 19         - 34                                   
Ex 31 (229)                                                               
          50          - 35         - 34                                   
Ex 36 (239)                                                               
          50          - 18         - 22                                   
Ex 24 (253)                                                               
          70          - 15         - 25                                   
Ex 28 (210)                                                               
          400         - 35         - 16                                   
Ex 35 (233)                                                               
          300         - 16         - 15                                   
Ex 38 (186)                                                               
          100         - 21         - 32                                   
Ex 39 (190)                                                               
          50          - 30         - 32                                   
Ex 40     300         - 28         - 34                                   
Ex 41     400         - 22         - 31                                   
Ex 47 (390)                                                               
          100         N.S.         -  3                                   
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