Patent Publication Number: US-5254590-A

Title: Acylaminophenol compounds

Description:
The subject of the present invention is new acylaminophenol compounds. 
     Numerous ethylaminophenyl compounds have been described in the literature. Some of them exhibit acyl CoA-cholesterol-acyl transferase--or ACAT--inhibiting properties. 
     This is the case, more particularly, for the compounds described in the patents EP 242 610, U.S. Pat. No. 4 716 175, EP 344 425, EP 384 320 or U.S. Pat. No. 4 623 662. 
     The compounds of the present invention are distinct from those described in the prior art not only by virtue of the fact that they are acylaminophenols comprising at least three other substituents on this ring but also by the intensity and the originality of their pharmacological and therapeutic properties. 
     In fact, these compounds have demonstrated, on the one hand, their acyl CoA-cholesterol-acyl transferase (ACAT)--inhibiting activity and, on the other hand, their ability to protect low density human lipoproteins (LDL) which ensure the transportation of cholesterol, with respect to the oxidative modifications induced by copper. 
     The ACAT activity which is responsible for the intracellular esterification of free cholesterol is present at the level of intestinal cells (enterocytes) and plays an important role in the intestinal absorption of cholesterol. 
     It is also found at the level of the smooth vascular muscle cells and of macrophages and is involved in the accumulation of cholesterol esters at the level of these cells which contribute to the formation of atherosclerotic vascular lesions. 
     The ACAT activity inhibiting power of the compounds of the invention gives them the potential on the one hand to reduce the plasma levels of cholesterol by reducing its intestinal absorption and, on the other hand, to limit the progression of atherosclerotic vascular lesions by inhibiting the accumulation of cholesterol esters in the vascular wall. 
     The oxidative modifications of the LDLs appear moreover to constitute an important mechanism for the formation and the extension of atherosclerotic vascular lesions. Accordingly, the inhibitory properties of the oxidative modification of LDLs constitute a second therapeutic activity which is quite advantageous. 
     This dual activity of the compounds of the invention, which has never been shown for the compounds described in the prior art, makes it possible to envisage their use as medication in the treatment of the various types of dyslipidemias and atheroscleroses with their different peripheral, coronary and cerebral vascular localizations. 
     More specifically, the present invention relates to the compounds of formula (I): ##STR2## in which: R represents a linear or branched (C 8  -C 21 ) alkyl group, a linear or branched 1- [(C 8  -C 21 )alkyl](C 3  -C 6 )cycloalk-1-yl group, or a linear or branched (C 8  -C 21 ) alkenyl group comprising one to three double bonds, 
     and either 
     R 3  represents a hydroxyl group, R 1  and R 2 , which are different, represent a hydrogen atom or a linear or branched (C 1  -C 6 ) alkyl group, R 4  and R 5 , which are identical or different, represent a linear or branched (C 1  -C 6 ) alkyl group or a linear or branched (C 1  -C 6 ) alkoxy group, or 
     R 1  and R 4  represent simultaneously a hydroxyl group, R 2 , R 3  and R 5 , which are identical or different, represent a linear or branched (C 1  -C 6 ) alkyl group or a linear or branched (C 1  -C 6 ) alkoxy group, 
     their enantiomers, diastereoisomers and epimers, their cis/trans isomers as well as their addition salts to a pharmaceutically acceptable base. 
     Of the pharmaceutically acceptable bases, there may be mentioned, with no limitation being implied, sodium hydroxide or potassium hydroxide and the like. 
     The present invention also relates to the process for preparing compounds of formula (I), wherein the raw material used is a compound of formula (II) ##STR3## in which the substituents A, B or C, which are identical or different, represent a linear or branched (C 1  -C 6 ) alkyl group or a linear or branched (C 1  -C 6 ) alkoxy group 
     which is reacted: 
     1 either in the presence of an alkali metal persulfate in the presence of a base, 
     to give the diphenol of formula (II/a): ##STR4## in which the substituents B and C have the same meaning as before, 
     which is treated with nitric acid in an acetic medium, to give a p-benzoquinone of formula (III): ##STR5## in which the substituents A, B and C have the same meaning as before, 
     which is then treated 
     either 
     in the case where the compounds of formula (I) which it is desired to obtain possess an R 3  ═OH group, in which case A, B and C may be replaced by R 5 , R 4  and R 2  respectively, 
     in the presence of hydroxylamine in a hydrochloric medium to give the compound of formula (IV): ##STR6## in which: 
     R 2 , R 4  and R 5  have the same meaning as in formula (I), 
     or 
     in the case where the compounds of formula (I) which it is desired to obtain possess R 1  ═R 4  ═OH groups, in which case A, B and C may be replaced by R 2 , R 3  and R 5  respectively, 
     in the presence of hydrochloric acid in an aqueous medium and then of nitric acid to give the compound of formula (V): ##STR7## in which: 
     R 2 , R 3  and R 5  have the same meaning as in formula (I) 
     which is then reacted in the presence of sodium azide, to give the compound of formula (VI): ##STR8## in which R 2 , R 3  and R 5  have the same meaning as in formula (I), 
     2 or in the presence of sodium nitrate and using lanthanum trinitrate hexahydrate as catalyst in a hydrochloric medium, 
     to give a mixture of the compounds (VII) and (VIII) which are separated by a conventional separation technique, 
     in the case where the compounds of formula (I) which it is desired to obtain possess: 
     a R 1  ═R 4  ═OH groups, in which case A, B and C may be replaced by R 2 , R 3  and R 5  respectively or 
     b an R 3  ═OH group, in which case A, B and C may be replaced by R 4 , R 5  and R 1  respectively ##STR9## in which 
     R 2 , R 3 , R 4  and R 5  have the same meaning as in the formula (I), 
     which derivative of formula (VII) is reacted with an aqueous solution of an alkali metal persulfate in the presence of a base and which is then treated with concentrated sulfuric acid, to give the compound of formula (IX): ##STR10## in which 
     R 2 , R 3  and R 5  have the same meaning as in the formula (I), 
     which derivatives of formulae (IV), (VI), (VIII) and (IX) are subjected to a catalytic hydrogenation, 
     to give the compounds of formulae (X), (XI) and (XII), which are stored under an inert atmosphere: ##STR11## in which: 
     R 1 , R 2 , R 3 , R 4  and R 5  have the same meaning as in the formula (I), 
     which derivatives of formulae (X), (XI) and (XII) are reacted under an inert atmosphere: 
     either with a compound of formula (XIII): 
     
         R--CO--O--CO--O--CH.sub.2 --CH.sub.3                       (XIII) 
    
     in which R has the same meaning as in the formula (I), 
     or with a compound of formula (XIV) in the presence of an organic base: 
     
         R--CO--Cl                                                  (XlV) 
    
     in which R has the same meaning as in the formula (I), to give respectively the compounds of formula (I/a), (I/b) and (I/c) which constitute the set of compounds of formula (I): ##STR12## which compounds of formula (I/a), (I/b) and (I/c) are purified by a conventional purification technique, from which are separated, where appropriate, the optical or cis/trans isomers by conventional separation techniques and which can be converted to their addition salts to a pharmaceutically acceptable base. 
     The subject of the present invention is also the pharmaceutical compositions containing as active ingredient a compound of general formula (I) or one of its addition salts to a pharmaceutically acceptable base, alone or in combination with one or more inert, nontoxic excipients or vehicles. 
     Of the pharmaceutical compositions according to the invention, there can be mentioned those which are suitable for oral, rectal, parenteral or nasal administration, simple or sugared tablets, sublingual tablets, sachets, packets, hard gelatin capsules, sublingual preparations, troches, suppositories and the like. 
     The dosage varies according to the age and the weight of the patient, the nature and the severity of the infection as well as the route of administration. Generally, the unit dosage varies between 50 and 750 mg for a treatment in 1 to 3 takings per 24 hours. 
     The following examples illustrate the invention but do not imply any limitation. 
     PREPARATION A 
     The following preparation gives intermediates which are useful in the process for synthesizing the compounds of the invention. 
     2,3,5-Trimethyl-6-nitrophenol and 2,3,5-trimethyl-4-nitrophenol 
     A solution containing 300 mmols of 2,3,5-trimethylphenol in 900 ml of ethyl ether is added dropwise to a vigorously stirred solution containing 300 mmols of sodium nitrate and 3 mmols of lanthanum trinitrate hexahydrate in 300 ml of water and 180 ml of 37% hydrochloric acid while maintaining the temperature at around 6° C. After this addition, the reaction mixture is stirred at 20° C. for 4 hours and then the aqueous phase is removed after settling. 
     The organic phase is washed with water, dried and evaporated. The residue is chromatographed on a silica column (elution solvent: hexane/ethyl acetate: 85/15) and leaves the two expected products. 
     2,3,5-Trimethyl-6-nitrophenol 
     Yield: 38 %. 
     Melting point: 77°-78° C. 
     
         ______________________________________                                    
Elemental microanalysis:                                                  
            C %         H %    N %                                        
______________________________________                                    
calculated  59.66       6.12   7.73                                       
found       60.07       6.34   7.77                                       
______________________________________                                    
 
    
     2,3,5-Trimethyl-4-nitrophenol 
     Yield: 18 %. 
     Melting point: 80°-81° C. 
     
         ______________________________________                                    
Elemental microanalysis:                                                  
            C %         H %    N %                                        
______________________________________                                    
calculated  59.66       6.12   7.73                                       
found       59.58       6.17   8.06                                       
______________________________________                                    
 
    
    
    
     EXAMPLE 1 
     4-(9-Octadecenamido)-2,3,5-trimethylphenol, cis isomer 
     STAGE A: 2,3,5-Trimethyl-4-aminophenol 
     The expected product is obtained by catalytic hydrogenation of 8 mmols of 2,3,5-trimethyl-4-nitrophenol obtained in Preparation A in solution in 20 ml of anhydrous tetrahydrofuran, at low pressure, in the presence of 50 mg of platinum oxide at 20° C. 
     STAGE B: 4-(9-Octadecenamido)-2,3,5-trimethylphenol, cis isomer 
     A suspension of carbethoxy oleate (prepared by reacting at -10° C., in 15 minutes, under a nitrogen atmosphere, 8 mmols of oleic acid with 8 mmols of ethyl chloroformate in the presence of 8 mmols of triethylamine in 20 ml of anhydrous tetrahydrofuran) is added to the preceding solution at 5° C. under a nitrogen atmosphere. 
     The reaction mixture is stirred for one hour at 20° C. The solvent is then evaporated and the residue is taken up with 50 ml of ethyl acetate. The organic phase is washed with water, dried and evaporated. The expected product is obtained by recrystallization in isopropyl ether. 
     Yield 72%. 
     Stage B of this example constitutes Method A of our synthesis process. 
     EXAMPLE 2 
     2,3,6-Trimethyl-4-nonanamidophenol 
     STAGE A: 2,3,5-Trimethylhydroquinone 
     A solution containing 100 mmols of potassium persulfate in one liter of water is added dropwise with stirring, at 20° C., to a solution containing 100 mmols of 2,3,5-trimethylphenol in 100 ml of a 10% solution of sodium hydroxide. After stirring for 20 hours, the reaction mixture is neutralized with concentrated sulfuric acid and the solid formed is filtered. The remaining aqueous solution is acidified by slowly adding 220 ml of concentrated sulfuric acid, and heated for 30 minutes at 80° C. The oil formed is decanted and extracted with ethyl ether. The expected product is obtained after drying the ether phase, evaporating and recrystallizing in ethyl acetate. 
     Yield: 93%. 
     Melting point: 172°-174° C. 
     STAGE B: 2,3,5-Trimethyl-p-benzoquinone 
     80 mmols of the product obtained in the preceding stage in solution in 75 ml of acetic acid are treated at 16° C. by dropwise addition of a solution containing 3.8 ml of nitric acid in 15 ml of acetic acid. After stirring for one hour at 20° C., the reaction mixture is poured onto 350 ml of ice cold water. The expected product is obtained in the form of a precipitate which is filtered, washed with ice cold water and dried. 
     Yield: 95%. 
     Melting point: 29°-30° C. 
     
         ______________________________________                                    
Elemental microanalysis:                                                  
                  C %    H %                                              
______________________________________                                    
calculated        71.98  6.71                                             
found             71.76  6.65                                             
______________________________________                                    
 
    
     STAGE C:2,3,6-Trimethyl-4-hydroxyimino-p-benzoquinone 
     33 mmols of the product obtained in the preceding stage and 33 mmols of hydroxylamine hydrochloride are refluxed in 340 ml of 2N hydrochloric acid for 6 hours. The expected product is obtained by filtering the precipitate after cooling, washing with water and then with cyclohexane. 
     Yield: 85%. 
     Melting point: 185°-186° C. 
     
         ______________________________________                                    
Elemental microanalysis:                                                  
            C %         H %    N %                                        
______________________________________                                    
calculated  65.44       6.71   8.48                                       
found       65.56       6.78   8.66                                       
______________________________________                                    
 
    
     STAGE D: 2,3,6-Trimethyl-4-aminophenol 
     STAGE E: 2,3,6-Trimethyl-4-nonanamidophenol 
     Stages D and E are identical to Stages A and B of Example 1. 
     EXAMPLE 3 
     2,3-Dimethoxy-6-methyl-4-nonanamidophenol 
     STAGE A: 2,3-Dimethoxy-5-methyl-p-benzoquinone 
     The expected product is obtained using the same procedure as that described in Stages A and B of Example 2. 
     STAGE C: 2,3-Dimethoxy-6-methyl-4-hydroxyimino- p-benzoquinone 
     A mixture containing 88 mmols of the product obtained in the preceding stage, 158 mmols of hydroxylamine hydrochloride and 11 mmols of sodium acetate in 160 ml of methanol is refluxed for 3 hours. After evaporating the methanol, the expected product is obtained at 0° C. by filtering the precipitate formed. 
     Yield: 68%. 
     Melting Point: 141°-142° C. 
     
         ______________________________________                                    
Elemental microanalysis:                                                  
            C %         H %    N %                                        
______________________________________                                    
calculated  54.82       5.62   7.10                                       
found       54.45       5.57   7.21                                       
______________________________________                                    
 
    
     STAGE D: 2,3-dimethoxy-6-methyl-4-aminophenol 
     STAGE E: 2,6-dimethoxy-6-methyl-4-nonanamidophenol 
     Stages D and E are identical to Stages A and B of Example 1. 
     EXAMPLE 4 
     2,3,6-Trimethyl-4-(2-methylundecanamido)phenol 
     STAGES A, B and C: 2,3,6-Trimethyl-4-aminophenol 
     Stages A, B and C are identical to Stages A, B and C described in Example 3. 
     STAGE D: 2,3,6-Trimethyl-4-(2-methylundecanamido)phenol 
     8 mmols of triethylamine and 8 mmols of 2- methylundecanoic acid chloride are successively added to the preceding solution. After stirring overnight at 20° C., the solvent is evaporated and the oily residue is dissolved in 75 ml of ethyl ether. The ether phase is washed with water, dried and concentrated under vacuum. The expected product is obtained by recrystallization of the residue in isopropyl ether. 
     Yield: 64% 
     Stage D of this example constitutes Method B of our synthesis process. 
     Examples 5 to 35 as well as 57 and 58 were prepared according to one of the methods A or B described in Examples 1 or 4 and using the 4-aminophenol derivatives prepared according to any one of the processes described in Examples 1 or 2. The methods, A or B, used are specified in Table I, as well as the yields, melting points and results of elemental microanalysis. 
     EXAMPLE 5 
     2,3,6-Trimethyl-4-decanamidophenol 
     EXAMPLE 6 
     2,3,6-Trimethyl-4-undecanamidophenol 
     EXAMPLE 7 
     2,3,6-Trimethyl-4-dodecanamidophenol 
     EXAMPLE 8 
     2,3,6-Trimethyl-4-tridecanamidophenol 
     EXAMPLE 9 
     2,3,6-Trimethyl-4-tetradecanamidophenol 
     EXAMPLE 10 
     2,3,6-Trimethyl-4-hexadecanamidophenol 
     EXAMPLE 11 
     2,3,6-Trimethyl-4-octadecanamidophenol 
     EXAMPLE 12 
     2,3,6-Trimethyl-4-(2-methyldecanamido)phenol 
     EXAMPLE 13 
     2,3,6-Trimethyl-4-(2,2-dimethyldecanamido)phenol 
     EXAMPLE 14 
     2,3,6-Trimethyl-4-(2,2-dimethylundecanamido)phenol 
     EXAMPLE 15 
     2,3,6-Trimethyl-4-(2,2-dimethyldodecanamido)phenol 
     EXAMPLE 16 
     2,3,6-Trimethyl-4-(2,2-dimethyltridecanamido)phenol 
     EXAMPLE 17 
     2,3,6-Trimethyl-4-(2,2-dimethyloctadecanamido)phenol 
     EXAMPLE 18 
     2,3,6-Trimethyl-4-(9-octadecenamido)phenol, cis isomer 
     EXAMPLE 19 
     2,3,6-Trimethyl-4-(9-octadecenamido)phenol, trans isomer 
     EXAMPLE 20 
     2,3,6-Trimethyl-4-(2-methyl-9-octadecenamido)phenol cis isomer 
     EXAMPLE 21 
     2,3,6-Trimethyl-4-(9,12-octadecadienamido)phenol cis, cis isomer 
     EXAMPLE 22 
     2,3,6-Trimethyl-4-(9,12,15-octadecatrienamido)phenol 
     EXAMPLE 23 
     2,3,6-Trimethyl-4-(6,9,12-octadecatrienamido)phenol 
     EXAMPLE 24 
     2,3,5-Trimethyl-4-undecanamidophenol 
     EXAMPLE 25 
     2,3,5-Trimethyl-4-tetradecanamidophenol 
     EXAMPLE 26 
     2,3,5-Trimethyl-4-octadecanamidophenol 
     EXAMPLE 27 
     2,3,5-Trimethyl-4-(9,12-octadecadienamido)phenol, cis, cis isomer 
     EXAMPLE 28 
     2,3-Dimethoxy-6-methyl-4-decanamidophenol 
     EXAMPLE 29 
     2,3-Dimethoxy-6-methyl-4-undecanamidophenol 
     EXAMPLE 30 
     2,3-Dimethoxy-6-methyl-4-dodecanamidophenol 
     EXAMPLE 31 
     2,3-Dimethoxy-6-methyl-4-tridecanamidophenol 
     EXAMPLE 32 
     2,3-Dimethoxy-6-methyl-4-tetradecanamidophenol 
     EXAMPLE 33 
     2,3-Dimethoxy-6-methyl-4-hexadecanamidophenol 
     EXAMPLE 34 
     2,3-Dimethoxy-6-methyl-4-octadecanamidophenol 
     EXAMPLE 35 
     2,3-Dimethoxy-6-methyl-4-(9-octadecenamido)phenol, cis isomer 
     EXAMPLE 36 
     3,5,6-Trimethyl-2-nonanamidohydroquinone 
     STAGE A: 3,5,6-Trimethyl-2-nitrohydroquinone 
     A solution containing 97 mmols of potassium persulfate in 1100 ml of water is added dropwise with stirring, at 20° C., to a suspension containing 97 mmols of 2,3,5-trimethyl-6-nitrophenol (obtained in Preparation A) in 195 ml of a 10% solution of sodium hydroxide. After stirring for 20 hours, the reaction mixture is neutralized with concentrated sulfuric acid. The solid formed is filtered. The remaining aqueous solution is acidified by adding 200 ml of concentrated sulfuric acid, and heated for 30 minutes at 70° C. The oil formed is decanted and extracted with ethyl ether. The expected product is obtained after drying the ether phase, and evaporating and recrystallizing in an ethyl acetate/hexane mixture. 
     Yield 85% 
     Melting point: 105°-106° C. 
     
         ______________________________________                                    
Elemental microanalysis:                                                  
            C %         H %    N %                                        
______________________________________                                    
calculated  54.82       5.62   7.10                                       
found       54.68       5.62   7.30                                       
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     STAGE B: 2-Amino-3,5,6-trimethylhydroquinone 
     Catalytic hydrogenation of the product obtained in Stage A is carried out according to the same procedure as that described in Stage A of Example 1. 
     STAGE C: 3,5,6-Trimethyl-2-nonanamidohydroquinone 
     The procedure used is Method A described in Stage B of Example 1. The following examples were synthesized following the same procedure as that described in the first two stages of Example 36 and using in Stage C one of the methods A or B as specified in Table 11. Table II contains the yields, melting points and results of elemental microanalysis of the products obtained. 
     EXAMPLE 37 
     3,5,6-Trimethyl-2-decanamidohydroquinone 
     EXAMPLE 38 
     3,5,6-Trimethyl-2-undecanamidohydroquinone 
     EXAMPLE 39 
     3,5,6-Trimethyl-2-dodecanamidohydroquinone 
     EXAMPLE 40 
     3,5,6-Trimethyl-2-tridecanamidohydroquinone 
     EXAMPLE 41 
     3,5,6-Trimethyl-2-tetradecanamidohydroquinone 
     EXAMPLE 42 
     3,5,6-Trimethyl-2-hexadecanamidohydroquinone 
     EXAMPLE 43 
     3,5,6-Trimethyl-2-octadecanamidohydroquinone 
     EXAMPLE 44 
     3,5,6-Trimethyl-2-(2,2-dimethyloctadecanamido)hydroquinone 
     EXAMPLE 45 
     3,5,6-Trimethyl-2-(9-octadecenamido)hydroquinone, cis isomer 
     EXAMPLE 46 
     3,5,6-Trimethyl-2-(9-octadecenamido)hydroquinone, trans isomer 
     EXAMPLE 47 
     3,5,6-Trimethyl-2-(9,12-octadecadienamido)hydroquinone 
     EXAMPLE 48 
     3,5,6-Trimethyl-2-(9,12,15-octadecatrienamido)hydroquinone 
     EXAMPLE 49 
     5,6-Dimethoxy-3-methyl-2-dodecanamidohydroquinone 
     STAGE A: 2,3-Dimethoxy-6-methyl-p-benzoquinone 
     This stage is identical to Stage A of Example 2. 
     STAGE B: 2,3-Dimethoxy-5-chloro-6-methyl-p- benzoquinone 
     A suspension containing 270 mmols of the product obtained in Stage A in 300 ml of 37% hydrochloric acid and 100 ml of water is stirred for three hours at room temperature. This suspension is then poured onto one liter of ice cold water and extracted with ethyl ether. The ether phases are washed with a sodium chloride-saturated aqueous solution until they are neutral, and evaporated. The residue is taken up with one liter of ether cooled to 0° C. and treated with 35 ml of nitric acid for three hours. After stirring for one hour at 10° C., the mixture is poured onto one liter of ice cold water and extracted with ethyl ether. The aqueous phase is washed with 100 ml of a sodium chloride-saturated solution, dried and concentrated. The expected product is obtained after recrystallization of the residue in cyclohexane. 
     Yield 70%. 
     Melting point: 66°-68° C. 
     
         ______________________________________                                    
Elemental microanalysis:                                                  
            C %         H %    N %                                        
______________________________________                                    
calculated  49.90       4.19   16.37                                      
found       49.74       4.13   16.24                                      
______________________________________                                    
 
    
     STAGE C: 2,3-Dimethoxy-5-azido-6-methyl-p-benzoquinone 
     A solution containing 37 mmols of sodium azide in 30 ml of water is added to a solution containing 18.5 mmols of the product obtained in the preceding stage in 80 ml of 95% ethanol. After stirring for one hour at room temperature, the reaction mixture is poured onto 300 ml of ice cold water and extracted with ether. The ether phases are dried and concentrated. The expected product is obtained by recrystallization of the residue in cyclohexane. 
     Yield 87%. 
     Melting point: 48°-50° C. 
     
         ______________________________________                                    
Elemental microanalysis:                                                  
            C %         H %    N %                                        
______________________________________                                    
calculated  48.42       4.04   18.83                                      
found       48.31       4.10   18.64                                      
______________________________________                                    
 
    
     STAGE D: 5,6-Dimethoxy-3-methyl-2-dodecanamidohydroquinone 
     The expected product is obtained by carrying out the procedure as in Stage B of Example 1 but replacing the oleic acid with lauric acid. 
     Yield: 84%. 
     The following examples were synthesized following the same procedure as that described in the first three stages of Example 48 and using in Stage D one of the methods A or B as specified in Table II. TabIe II also contains the yields, melting points and results of elemental microanalysis of the products obtained. 
     EXAMPLE 50 
     5,6-Dimethoxy-3-methyl-2-decanamidohydroquinone 
     EXAMPLE 51 
     5,6-Dimethoxy-3-methyl-2-undecanamidohydroquinone 
     EXAMPLE 52 
     5,6-Dimethoxy-3-methyl-2-tridecanamidohydroquinone 
     EXAMPLE 53 
     5,6-Dimethoxy-3-methyl-2-tetradecanamidohydroquinone 
     EXAMPLE 54 
     5,6-Dimethoxy-3-methyl-2-hexadecanamidohydroquinone 
     EXAMPLE 55 
     5,6-Dimethoxy-3-methyl-2-octadecanamidohydroquinone 
     EXAMPLE 56 
     5,6-Dimethoxy-3-methyl-2-(9-octadecenamido)hydroquinone, cis isomer 
     EXAMPLE 57 
     2,3,6-Trimethyl-4-[(1-decyl-cyclopent-1-yl)carboxamido]phenol 
     EXAMPLE 58 
     2,3,6-Trimethyl-4-(2-methyl-9,12-octadecadienamido)phenol, cis, cis isomer 
     
         TABLE I
  ##STR13##
   Melting point Elemental microanalysis Example No R.sub.1 R.sub.2
 R.sub.4 R.sub.5 R Method Yield (%) (°C.)  C % H % N %
  1 CH.sub.3 H CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.7CHCH(CH.sub.2).su
 b.7 A 72 107-108 calculated 78.02 10.91 3.37      (cis)    found 77.99
 10.71 3.40  2 H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.7 A 69
 143-145 calculated 74.18 10.03 4.81          found 73.84 10.03 4.74  3 H
 CH.sub.3 CH.sub.3 O CH.sub.3 O CH.sub.3(CH.sub.2).sub.7 A 63 61-62
 calculated 66.84   9.04 4.33          found 66.61  8.97 4.20  4 H
 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.8CHCH.sub.3 B 64
 149-151 calculated 75.63 10.58 4.20          found 75.10 10.51 4.24  5 H
 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.8 A 77 136-138
 calculated 74.71 10.23 4.59          found 74.44 10.13 4.79  6 H
 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.9 A 82 142-144
 calculated 75.19 10.41 4.38          found 75.28 10.31 4.32  7 H
 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.10 A 80 137-140
 calculated 75.63 10.58 4.20          found 75.51 10.95 4.23  8 H
 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.11 A 80 140-141
 calculated 76.03 10.73 4.03          found 76.12 10.64 4.05  9 H
 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.12 A 77 142-144
 calculated 76.40 10.87 3.87          found 76.05 10.97 4.13 10 H
 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.14 A 79 135-138
 calculated 77.07 11.12 3.59          found 76.85 10.97 3.51 11 H
 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.16 A 80 138-140
 calculated 77.64 11.34 3.35          found 77.31 11.40 3.33 12 H
 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.7CHCH.sub.3 B 68
 148-150 calculated 75.19 10.41 4.38          found 74.97 10.40 4.71 13 H
 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.7C(CH.sub.3).sub.2 B
 58 68-71 calculated 75.63 10.58 4.20          found 75.63 10.49 4.30 14
 H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 (CH.sub.2).sub.8C(CH.sub.3).sub.2
 B 63 87-89 calculated 76.03 10.73 4.03          found 75.67 10.34 4.50
 15 H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.9C(CH.sub.3).sub.2
  B 60 75-76 calculated 76.40 10.87 3.87          found 76.30 10.77 4.11
 16 H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.10C(CH.sub.3).sub.
 2 B 58 80-82 calculated 76.75 11.00 3.73          found 76.55 11.40 4.00
 17 H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.15C(CH.sub.3).sub.
 2 B 64 79-81 calculated 78.15 11.53 3.14          found 78.41 11.52 3.02
 18 H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.7CHCH(CH.sub.2).su
 b.7 A 57 125-127 calculated 78.02 10.91 3.37      (cis)    found 77.97
 10.99 3.64 19 H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub. 3(CH.sub.2).sub.7CHCH(
 CH.sub.2).sub.7 A 59 127-129 calculated 78.02 10.91 3.37      (trans)
 found 78.15 10.94 3.31 20 H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2)
 .sub.7CHCH(CH.sub.2).sub.6CH(CH.sub.3) B 55 125-127 calculated 78.27
 11.03 3.26      (cis)    found 78.04 10.95 3.20 21 H CH.sub.3 CH.sub.3
 CH.sub.3 CH.sub.3(CH.sub.2).sub.3(CH.sub.2CHCH).sub.2(CH.sub.2).sub.7 A
 68 130-132 calculated 78.40 10.48 3.39      (cis, cis)    found 78.11
 10.45 3.67 22 H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2CHCH).sub.3(C
 H.sub.2).sub.7 A 66 117-118 calculated 78.78 10.04 3.40          found
 78.91 10.23 3.55 23 H CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.3(
 CH.sub.2CHCH).sub.3(CH.sub.2).sub.4 A 71 106-109 calculated 78.78 10.04
 3.40          found 77.93  9.88 3.91 24 CH.sub.3 H CH.sub.3 CH.sub.3
 CH.sub.3(CH.sub.2).sub.9 A 67 118-120 calculated 75.19 10.49 4.38
   found 75.10 10.42 4.56 25 CH.sub.3 H CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.
 2).sub.12 A 74 122-124 calculated 76.40 10.87 3.87          found 76.39
 10.97 3.77 26 CH.sub.3 H CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.16 A
 72 123-125 calculated 77.64 11.34 3.35          found 77.68 11.52 3.40
 27 CH.sub.3 H CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.3(CH.sub.2CHCH).su
 b.2(CH.sub.2).sub.7 A 59 102-104 calculated 78.40 10.48 3.39      (cis,
 cis)    found 77.81 10.42 3.29 28 H CH.sub.3 CH.sub.3 O CH.sub.3 O
 CH.sub.3(CH.sub.2).sub.8 A 64 72-73 calculated 67.63  9.26 4.15
 found 67.27  9.24 4.11 29 H CH.sub.3 CH.sub.3 O CH.sub.3
  O CH.sub.3(CH.sub.2).sub.9 A 68 73-75 calculated 68.34  9.46 3.98
    found 68.30  9.37 4.13 30 H CH.sub.3 CH.sub.3 O CH.sub.3
  O CH.sub.3(CH.sub.2).sub.10 A 68 82-83 calculated 69.01  9.65 3.83
     found 68.65  9.65 3.91 31 H CH.sub.3 CH.sub.3 O CH.sub.3
  O CH.sub.3(CH.sub.2).sub.11 A 65 76-78 calculated 69.62  9.83 3.69
     found 69.41  9.83 3.87 32 H CH.sub.3 CH.sub.3 O CH.sub.3
  O CH.sub.3(CH.sub.2).sub.12 A 62 87-90 calculated 70.19  9.99 3.56
     found 69.45  9.84 3.77 33 H CH.sub.3 CH.sub.3 O CH.sub.3
  O CH.sub.3(CH.sub.2).sub.14 A 69 93-95 calculated 71.22 10.28 3.32
     found 70.87 10.06 3.35 34 H CH.sub.3 CH.sub.3 O CH.sub.3
  O CH.sub.3(CH.sub.2).sub.16 A 75 97-98 calculated 72.12 10.54 3.11
     found 71.78 10.53 3.14 35 H CH.sub.3 CH.sub.3 O CH.sub.3
  O CH.sub.3(CH.sub.2).sub.7CHCH(CH.sub.2).sub.7 A 78 54-56 calculated
 72.44 10.13 3.13      (cis)    found 72.28  9.95 3.21  57 H CH.sub.3
 CH.sub.3 CH.sub.3
  ##STR14##
  B 53  99-101 calculatedfound 77.4777.33 10.6611.05 3.613.79  58 H
 CH.sub.3 CH.sub.3 CH.sub.3
  ##STR15##
  A 68 120-122 calculatedfound 78.6478.48 10.6110.76 3.283.47
 
    
     
         TABLE II
  ##STR16##
   Melting point Elemental microanalysis Example No R.sub.2 R.sub.3
 R.sub.5 R Method Yield (%) (°C.)  C % H % N %
   36 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.7 A 77 174-178
 calculated 70.32  9.51 4.56         found 70.71  9.56 4.62  37 CH.sub.3
 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.8 A 72 165-167 calculated 70.99
  9.72 4.36         found 70.70  9.65 4.30 38 CH.sub.3 CH.sub.3 CH.sub.3
 CH.sub.3(CH.sub.2).sub.9 A 80 157-159 calculated 71.60  9.91 4.17
  found 71.66
  9.95 4.34 39 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.10 A 82
 159-162 calculated 72.17 10.09 4.01         found 71.81  9.99 4.07 40
 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.11 A 78 155-157
 calculated 72.69 10.26 3.85         found 73.21 10.23 3.74 41 CH.sub.3
 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).sub.12 A 84 162-163 calculated
 73.17 10.41 3.71         found 73.25 10.76 3.77 42 CH.sub.3 CH.sub.3
 CH.sub.3 CH.sub.3(CH.sub.2).sub.14 A 82 158-160 calculated 74.03 10.69
 3.45         found 73.84 10.66 3.41 43 CH.sub.3 CH.sub.3 CH.sub.3
 CH.sub.3(CH.sub.2).sub.16 A 80 153-155 calculated 74.78 10.92 3.23
   found 74.85 11.08 3.21 44 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2)
 .sub.15C(CH.sub.3).sub.2 B 66 108-110 calculated 75.44 11.13 3.03
  found 75.27 11.19 2.97 45 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2).
 sub.7CHCH(CH.sub.2).sub.7 A 76 155-158 calculated 75.13 10.51 3.24
 (cis)    found 75.19 10.49 3.01 46 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH
 .sub.2).sub.7CHCH(CH.sub.2).sub.7 A 81 178-180 calculated 75.13 10.51
 3.24     (trans)    found 75.55 10.58 3.18 47 CH.sub.3 CH.sub.3 CH.sub.3
 CH.sub.3(CH.sub.2).sub.3(CH.sub.2CHCH).sub.2(CH.sub.2).sub.7 A 71
 162-164 calculated 75.48 10.09 3.26     (cis, cis)    found 75.56  9.94
 3.00 48 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3(CH.sub.2CHCH).sub.3(CH.sub.2)
 .sub.7 A 68 132-134 calculated 75.84  9.66 3.28         found 76.17
 9.73 3.28 49 CH.sub.3 O CH.sub.3 O CH.sub.3 CH.sub.3(CH.sub.2).sub.10 A
 84 86-89 calculated 66.11  9.25 3.67         found 65.91  9.21 3.50 50
 CH.sub.3 O CH.sub.3 O CH.sub.3 CH.sub.3(CH.sub.2).sub.8 A 80 90-92
 calculated 64.56  8.84 3.96         found 64.58  8.87 3.98 51 CH.sub.3 O
 CH.sub.3 O CH.sub.3 CH.sub.3(CH.sub.2).sub.9 A 76 95-96 calculated 65.37
  9.05 3.81         found 65.24  8.99 3.77 52 CH.sub.3 O CH.sub.3 O
 CH.sub.3 CH.sub.3(CH.sub.2).sub.11 A 82  99-102 calculated 66.81  9.43
 3.54         found 66.81  8.99 3.38 53 CH.sub.3 O CH.sub.3 O CH.sub.3
 CH.sub.3(CH.sub.2).sub.12 A 84 101-103 calculated 67.45  9.60 3.42
   found 67.29  9.63 3.64 54 CH.sub.3 O CH.sub.3
  O CH.sub.3 CH.sub.3(CH.sub.2).sub.14 A 81 107-109 calculated 68.62
 9.90 3.20         found 68.81  9.90 3.31 55 CH.sub.3 O CH.sub.3 O
 CH.sub.3 CH.sub.3(CH.sub.2).sub.16 A 79 108-110 calculated 69.64 10.17
 3.01         found 69.79 10.30 2.95 56 CH.sub.3 O CH.sub.3 O CH.sub.3
 CH.sub.3(CH.sub.2).sub.7CHCH(CH.sub.2).sub.7 A 68 85-87 calculated 69.94
  9.78 3.02     (cis)    found 70.33
  9.90 3.23
 
    
     PHARMACOLOGICAL STUDY OF THE DERIVATIVES OF THE INVENTION 
     The inhibitory action of the compounds of the present invention was demonstrated on the one hand at the level of acyl CoA-cholesterol-acyl transferase (ACAT) of a macrophage line and, on the other hand, with respect to the oxidative modification of LDLs induced in vitro by copper sulfate. 
     EXAMPLE 58 
     Determination of ACAT 
     The action of the compounds of the present invention at the level of ACAT was demonstrated by means of an experimental test in vitro using a macrophage line J 774 according to the technique described by MAZIERE et al. (Atherosclerosis, 81, 151-160, 1990). This test consists in evaluating the efficacy of a product to inhibit the esterification of free intracellular cholesterol by oleic acid by determining the amount of radiolabeled cholesterol oleate formed after incubating radioactive oleyl enzyme A in the presence of a macrophage J 774 homogenate. The test products or the placebo are incubated in the presence of the macrophages for 24 hours at the concentration of 10 -5  M. The efficacy of these compounds is evaluated by calculating the ACAT activity of the macrophages incubated in the presence of a product relative to that of macrophages incubated in the presence of the placebo and is therefore expressed as a percentage inhibition. Under these conditions, the compounds of the invention exhibited a ACAT--inhibiting activity of the macrophages which could reach an inhibition greater than 90%. 
     This is the case in particular for the compounds of the following examples: 
     
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Example 4:                                                                
         91% inhibition                                                   
                      Example 21:                                         
                                 90% inhibition                           
Example 14:                                                               
        92% inhibition                                                    
                      Example 23:                                         
                                94% inhibition                            
Example 15:                                                               
        93% inhibition                                                    
                      Example 57:                                         
                                98% inhibition                            
Example 16:                                                               
        96% inhibition                                                    
                      Example 58:                                         
                                97% inhibition                            
Example 20:                                                               
        95% inhibition                                                    
______________________________________                                    
 
    
     This activity is all the more useful as it is much more potent than that determined for two reference products: 2,4,6-trimethoxy-(9-(Z)octadecenamido)benzene (Ref. 1) and 2,4,6-trimethoxy-(2,2-dimethyldodecanamido)benzene (Ref. 2) which, under the same conditions, exhibits only 75% inhibition. 
     The IC 50  of the compound described in Example 20 is equal to 2×5×10 -7  M whereas those for the reference compounds are equal to 3×10 -6  M for Ref. 1 and 6×10 -6  M for Ref. 2. 
     EXAMPLE 59 
     Modification of the LDLs by copper sulfate 
     The human LDLs are incubated for 24 hours in the presence of copper sulfate (5×10 -6  M) with or without the test compounds (concentrations between 10 -7  M and 10 -4  M). After incubation, the peroxidation of the LDLs is evaluated by electrophoresis on agar gel and by the formation of one of the products of lipid peroxidation: malondialdehyde (MDA) according to the technique described by PARTHASARATHY et al. (J. Clin. Invest. 77, 641-644, 1986). The activity of the compounds tested is evaluated by calculating the concentrations reducing by 50% (IC 50 ) the production of MDA relative to the control. The compounds of the invention exhibit-. an antioxidant activity towards human LDLs which is comparable with that of probucol taken as reference. The IC 50  values are between 3×10 -6  and 5×10 -6  for the compounds of the invention whereas the ACAT--inhibiting reference products (Ref. 1 and Ref. 2) completely lack this activity. 
     EXAMPLE 60 
     Effect of the compounds of the invention in hypercholesterolemic hamsters 
     Syrian golden hamsters were subjected to a 0.2% hypercholesterolemic diet for 3 weeks. They were then treated orally either by the vehicle for the compounds tested (control group), or by a reference product, or by an original product at the dose of 10 mg/kg/day for 2 weeks. At the end of the treatment, the total cholesterol was measured in the plasma. 
     Results 
     The hamsters subjected to the cholesterol enriched diet exhibited in a stable manner an increase of 100% in their level of plasma cholesterol relative to the hamsters subjected to a normal diet. The compound of Example 20 administered orally at the daily dose of 10 mg/kg exerts an excellent hypocholesterolemiant activity which normalizes the level of cholesterol in the hypercholesterolemic animals at the end of the 15 days of treatment. This activity is considerably higher than that of the reference products tested (Ref. 1 and Ref. 2) under the same conditions. 
     EXAMPLE 61 
     Pharmaceutical composition 
     Tablet: preparation formula for 1000 tablets containing a dose of 50 mg of active ingredient. 
     
         ______________________________________                                    
2,3,6-Trimethyl-4-(2-methyl-9-octadecenamido)                             
                          50      g                                       
phenol (cis isomer)                                                       
Hydropropyl cellulose     2       g                                       
Wheat starch              10      g                                       
Lactose                   100     g                                       
Magnesium stearate        3       g                                       
Talc                      3       g                                       
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