Patent Abstract:
A benzopylpiperazine ester of the following formula: ##STR1## wherein A represents a single bond or an alkylene group, vinylene group, --O--alkylene group or methine group, R 1  represents a bicyclic carbon ring residue which may be substituted with a lower alkyl group, lower alkoxy group, oxo group or nitro group or a halogen atom, or may be partially saturated; a fluorene residue which may contain an oxo group; a fluorenylidene group; an anthracene residue; a phenanthrene residue which may be substituted with a lower alkyl group, or may be partially saturated; a benzofuran residue or thianaphthene residue which may be substituted with a lower alkyl group or lower alkoxy group; a benzopyran residue or benzoazine residue which may be substituted with an oxo group or phenyl group and partially saturated; a phthalimide residue; a benzodiazine residue; an isozazole residue which may be substituted with a lower alkyl group or phenyl group; or an alkylene dioxybenzene residue or xanthene residue; and R 2  represents an alkyl group, cycloalkyl group, cycloalkylalkyl group or aralkyl group, excepting the case where A is a single bond, R 1  is ##STR2## and R 2  is a methyl group, exhibits excellent chymotrypsin inhibitive activity.

Full Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates generally to novel benzoylpiperazine esters and to a process for producing such esters. 
     More particularly, the invention is concerned with a benzoylpiperazine ester represented by the following formula (I): ##STR3## wherein A represents a single bond or an alkylene group, vinylene group, --O--alkylene group or methine group; R 1  represents a bicyclic carbon ring residue which may be substituted with a lower alkyl group, lower alkoxy group, oxo group or nitro group or a halogen atom, or may be partially saturated; a fluorene residue which may contain an oxo group; a fluorenylidene group; an anthracene residue; a phenanthrene residue which may be substituted with a lower alkyl group, or may be partially saturated; a benzofuran residue or thianaphthene residue which may be substituted with a lower alkyl group or lower alkoxy group; a benzopyran residue or benzoazine residue which may be substituted with an oxo group or phenyl group and partially saturated; a phthalimide residue; a benzodiazine residue; an isooxazole residue which may be substituted with a lower alkyl group or phenyl group; or an alkylene dioxybenzene residue or xanthene residue; and R 2  represents an alkyl group, cycloalkyl group, cycloalkylalkyl group or aralkyl group, excepting the case where A is a single bond, R 1  is ##STR4## and R 2  is a methyl group. 
     DESCRIPTION OF THE PRIOR ART 
     The present inventors have previously discovered that various phenyl esters have excellent chymotrypsin inhibitive effects (see Japanese laid-open patent specification No. 158737/1981). 
     The inventors have further synthesized analogous compounds to study their pharmacological effects. In the studies leading to the present invention, it has been found that novel benzoylpiperazine derivatives represented by the formula (I) above and acid addition salts thereof exert more excellent chymotrypsin inhibitive effects. 
     SUMMARY OF THE INVENTION 
     Accordingly, it is one object of the invention to provide benzoylpiperazine esters of the formula (I) which possess substantially superior chymotrypsin inhibitive activity and can be widely used, for example, as medicines such as those for the therapy of pancreatopathy. 
     Another object of the invention is to provide a process for producing such esters. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The compounds of the formula (I) of the invention can be produced by esterification of carboxylic acids of the formula (II) and substituted phenols of the formula (III), for example, in accordance with the following reaction scheme. ##STR5## wherein the symbols each have the same meaning as above. 
     The esterifying reaction between the compounds of the formulae (II) and (III) is carried out using any conventional techniques. Suitable techniques useful in the invention include a method of reacting a reactive derivative of the compound (II), for example, an acid halide, an acid anhydride, a mixed acid anhydride, an active ester, an active azide or the like, with the compound (III), and a method of reacting the compounds (II) and (III) in the presence of a dehydrating agent such as dicyclohexyl carbodiimide. 
     Eligible bicyclic carbon ring residues for the symbol R 1  in the formula (I) include such residues as derived from an indene group, naphthyl group and benzosberyl group. Eligible benzoazine residues include such residues as derived from quinoline and isoquinoline. Eligible benzodiazine residues include such residues as derived from quinoline and quinoxaline. Eligible alkylene dioxybenzene residues include such residues as derived from methylene dioxybenzene and benzodioxane. 
     The compound (I) obtained in this way may be further converted by a conventional method to an inorganic acid salt, for example, of hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid; and an organic acid salt, for example, of acetic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, citric acid, methane sulfonic acid, benzene sulfonic acid or toluene sulfonic acid. 
     The chymotrypsin inhibitive activity of the compounds according to the invention will be readily understood by reference to the following test results. 
     MEASURING METHOD 
     A solution prepared by mixing 0.1 ml of a dimethylsulfoxide solution containing a compound to be tested, 0.1 ml of water and 0.1 ml of a buffer solution containing 10 ug/ml of chymotrypsin (0.1M tris-hydrochloric acid buffer solution, pH 8.0) was incubated for 10 minutes by the method of Muramatsu et al. [see The Journal of Biochemistry, 62, 408 (1967)]. 0.2 ml of a buffer solution containing 25 mM of an acetyl-L-tyrosine ethyl ester was mixed with the above-prepared solution and reacted at 30° C. for 30 minutes. The amount of the remaining substrate was determined by causing the same to develop color by the Hestrin Method and measuring the absorbance at 530 nm. For comparative purposes, use was made of tosylphenylalanine chloromethyl ketone which was known as a chymotrypsin inhibitor (Comparative Compound I). 
     RESULTS 
     The results are as shown in Table 1. 
     
                       TABLE 1______________________________________           Chymotrypsin inhibitive           activity [50% inhibitionTest compounds  concentration (M)]______________________________________Present       1     3 × 10.sup.-6compounds         2     1 × 10.sup.-7         3     9 × 10.sup.-7         4     5 × 10.sup.-6         9     1 × 10.sup.-6         15    8 × 10.sup.-7         17    8 × 10.sup.-7         18    6 × 10.sup.-7         20    5 × 10.sup.-6         21    9 × 10.sup.-6         22    3 × 10.sup.-6         24    5 × 10.sup.-7         30    9 × 10.sup.-6         32    7 × 10.sup.-6         40    1 × 10.sup.-6         65    8 × 10.sup.-7         66    9 × 10.sup.-7         67    8 × 10.sup.-7         68    9 × 10.sup.-7Comparative   I     5 × 10.sup.-4compound______________________________________ Note: The number for each test compound of the invention indicates the corresponding example as will appear hereinafter. 
    
     The above disclosure generally describes the present invention. A more complete understanding will be obtained by the following specific examples which are provided for purposes of illustration only and are not construed as limiting to the invention. 
     EXAMPLE 1 
     1-Isopropyl-4-[4-(5,6,7,8-tetraphydronaphthalene-1-acetyloxy)benzoyl]piperazine.hydrochloride 
     To a 20 ml ethyl acetate solution containing 1.9 g (10 mmol) of 5,6,7,8-tetrahydronaphthalene-1-acetic acid, 2.48 g (10 mmol) of 1-(4-hydroxybenzoyl)-4-isopropylpiperazine and 122 mg (1 mmol) of 4-dimethylaminopyridine was added 2.48 g (12 mmol) of dicyclohexyl carbodiimide, and the mixture was stirred at room temperature for 3 hours. Any insoluble matter was then removed by filtration, and the filtrate was extracted up to 20 ml of 1N hydrochloric acid. After being washed with ethyl acetate, the extract was neutralized with sodium hydrogen carbonate and then extracted with ethyl acetate. After being washed with saturated saline water, the extract was dried over sodium sulfate and then concentrated under reduced pressure. Purification of the concentrate on silica gel column chromatography (80 g of silica gel, eluting solution: chloroform-methanol 30:1) gave a colorless oily substance in a quantitative yield, and the oily substance was then dissolved in 20 ml of ethanol. The resulting solution was added under ice cooling, with an ethanol solution containing an equimolar amount of hydrogen chloride, and thereafter, further with ether, thereby obtaining colorless crystals. 
     
         ______________________________________Yield              2.96 g (64.7%)Melting point      214-216° C.Elementary analysis              as C.sub.26 H.sub.32 N.sub.2 O.sub.3.HCl        C            H      N______________________________________Calculated (%)        68.33        7.28   6.13Measured (%) 68.30        7.24   6.28______________________________________ 
    
     EXAMPLE 2 
     1-Isopropyl-4-[4-(9-fluorenylidene acetyloxy)benzoyl]piperazine 
     To a 20 ml chloroform solution containing 2.67 g (12 mmol) of 9-fluorenylidene acetic acid, 2.48 g (10 mmol) of 1-(4-hydroxybenzoyl)-4-isopropylpiperazine and 122 mg (1 mmol) of 4-dimethylaminopyridine was added 2.48 g (12 mmol) of dicyclohexyl carbodiimide, and the mixture was stirred at room temperature for 3 hours. Any insoluble matter which had formed was removed by filtration, and the filtrate was concentrated under reduced pressure. Thereafter, any insoluble matter was removed by filtration using 20 ml of ethyl acetate, and the filtrate was extracted up to 60 ml of 1N hydrochloric acid. After being washed with ethyl acetate, the extract was neutralized with sodium hydrogen carbonate and extracted up to 60 ml of chloroform. After being washed twice with water, the extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain yellow crystals. Recrystallization of the crystals from ethyl acetate-petroleum ether gave yellow prismatic crystals. 
     
         ______________________________________Yield                56.7%Melting point        169-170° C.Elementary analysis  as C.sub.29 H.sub.28 N.sub.2 O.sub.3        C            H      N______________________________________Calculated (%)        76.97        6.24   6.19Measured (%) 76.97        6.19   5.97______________________________________ 
    
     EXAMPLE 3 
     1-Isopropyl-4-[(4-(thianaphthene-2-acetyloxy)benzoyl]piperazine.methanesulfonate 
     To a 40 ml of chloroform solution containing 2.2 g of 1-isopropyl-4-(4-hydroxybenzoyl)piperazine and 2.0 g of thianaphthene-2-acetic acid was added 2.2 g of dicyclohexyl carbodiimide, and the mixture was stirred overnight at room temperature. Any insoluble matter was then removed by filtration, and the filtrate was extracted with 24 ml of 0.5N hydrochloric acid. After the extract was washed with ethyl acetate, the aqueous phase was neutralized with 2N sodium hydroxide and then extracted with ethyl acetate. The extract was washed with water and dried, followed by removal of the solvent by distillation, to give a crude oily product. The product was further converted in a conventional manner to methanesulfonate, thereby obtaining colorless prismatic crystals. 
     
         ______________________________________Yield            2.1 g (45.7%)Melting point    175-177° C.Elementary analysis            as C.sub.24 H.sub.26 N.sub.2 O.sub.3 S.CH.sub.3 SO.sub.3            H        C            H      N______________________________________Calculated (%)        57.89        5.85   5.40Measured (%) 57.63        5.93   5.12______________________________________ 
    
     EXAMPLES 4-64 
     The same procedures as in Examples 1-3 were repeated to obtain various compounds shown in Table 2. 
     
                                           TABLE 2__________________________________________________________________________ ##STR6##                                                   (Ia)In Formula (Ia)                       Acid Addi-                                       Yield       Melting PointExampleR.sub.1           A       R.sub.2                                 tion Salt                                       (%) Appearance                                                   (°C.)__________________________________________________________________________ ##STR7##         --                           ##STR8##                                 HCl   54.7                                           Needle-like pale yellow                                           crystals                                                   222˜226                                                   (decomp.)5 ##STR9##         CH.sub.2                           ##STR10##                                 HCl   41.5                                           Needle-like colorless                                           crystals                                                   243˜2446 ##STR11##        --                           ##STR12##                                 HCl   61.8                                           Platy colorless crystals                                                   236˜237                                                   (decomp.)7 ##STR13##        --                           ##STR14##                                 HCl   80.4                                           Colorless crystals                                                   252˜257                                                   (decomp.)8 ##STR15##        CH.sub.2                           ##STR16##                                 CH.sub.3 SO.sub.3 H                                       32.4                                           Colorless crystals                                                   211˜2129 ##STR17##        CH.sub.2                           ##STR18##                                 HCl   40.1                                           Needle-like pale yellow                                           crystals                                                   208˜21010 ##STR19##        CH.sub.2                           ##STR20##                                 --    18.2                                           Colorless crystals                                                   131˜13511 ##STR21##        OCH.sub.2                           ##STR22##                                 CH.sub.3 SO.sub.3 H                                       29.6                                           Colorless crystals                                                   175˜17712 ##STR23##        --                           ##STR24##                                 CH.sub.3 SO.sub.3 H                                       58.5                                           Platy colorless crystals                                                   165˜16713 ##STR25##        CH.sub.2                           ##STR26##                                 HCl   49.3                                           Needle-like colorless                                           crystals                                                   218˜21914 ##STR27##        CH.sub.2 CH.sub.2                           ##STR28##                                 HCl   64.6                                           Needle-like colorless                                           crystals                                                   206˜20815 ##STR29##        --                           ##STR30##                                 CH.sub.3 SO.sub.3 H                                       73.7                                           Colorless prismatic                                           crystals                                                   178˜18016 ##STR31##        --                           ##STR32##                                 (COOH).sub.2                                       8.9 Yellow prismatic crystals                                                   135˜13817 ##STR33##        --                           ##STR34##                                 CH.sub.3 SO.sub.3 H                                       42.7                                           Needle-like  colorless                                           crystals                                                   190˜19618 ##STR35##        --                           ##STR36##                                 CH.sub.3 SO.sub.3 H                                       61.9                                           Needle-like colorless                                           crystals                                                   218˜21919 ##STR37##        --                           ##STR38##                                 CH.sub.3 SO.sub.3 H                                       33.0                                           Platy colorless crystals                                                   167˜16920 ##STR39##        --                           ##STR40##                                 --    29.7                                           Colorless crystals                                                   85˜8721 ##STR41##        --                           ##STR42##                                 CH.sub.3 SO.sub.3 H                                       51.4                                           Needle-like colorless                                           crystals                                                   180˜185                                                   (decomp.)22 ##STR43##        CH.sub.2                           ##STR44##                                 HCl   53.6                                           Needle-like colorless                                           crystals                                                   224˜22623 ##STR45##        --                           ##STR46##                                 --    55.7                                           Colorless crystals                                                   117˜11924 ##STR47##        CH.sub.2                           ##STR48##                                 CH.sub.3 SO.sub.3 H                                       81.2                                           Colorless crystals                                                   197˜201.525 ##STR49##        OCH.sub.2                           ##STR50##                                 --    57.4                                           Needle-like colorless                                           crystals                                                   107˜10926 ##STR51##        CH.sub.2 CH.sub.2                           ##STR52##                                 HCl   41.0                                           Needle-like colorless                                           crystals                                                   188˜19127 ##STR53##        CHCH                           ##STR54##                                 --    78.8                                           Needle-like colorless                                           crystals                                                   123˜12428 ##STR55##        --                           ##STR56##                                 --    72.0                                           Needle-like colorless                                           crystals                                                   142˜14329 ##STR57##        CH.sub.2                           ##STR58##                                 --    60.1                                           Colorless crystals                                                   115˜11730 ##STR59##        OCH.sub.2                           ##STR60##                                 --    62.0                                           Needle-like colorless                                           crystals                                                   103˜10531 ##STR61##        CHCH                           ##STR62##                                 --    75.8                                           Needle-like colorless                                           crystals                                                   141˜14232 ##STR63##        CH.sub.2 CH.sub.2                           ##STR64##                                 HCl   47.4                                           Needle-like colorless                                           crystals                                                   233˜234.533 ##STR65##        --                           ##STR66##                                 CH.sub.3 SO.sub.3 H                                       67.2                                           Powderous colorless                                           crystals                                                   200˜21234 ##STR67##        --                           ##STR68##                                 HCl   62.2                                           Colorless crystals                                                   213˜21435 ##STR69##        --                           ##STR70##                                 --    46.4                                           Needle-like colorless                                           crystals                                                   95˜9636 ##STR71##        --                           ##STR72##                                 --    44.5                                           Prismatic pale yellow                                           crystals                                                   126˜12837 ##STR73##        --                           ##STR74##                                 --    40.1                                           Needle-like pale yellow                                           crystals                                                   148˜15038 ##STR75##        CHCH                           ##STR76##                                 --    54.4                                           Pale yellow crystals                                                   192˜19539 ##STR77##        --                           ##STR78##                                 HCl   36.5                                           Colorless crystals                                                   195.5˜20140 ##STR79##        CH.sub.2                           ##STR80##                                 HCl   58.0                                           Colorless crystals                                                   225˜22841 ##STR81##        --                           ##STR82##                                 --    63.3                                           Prismatic yellow crystals                                                   134˜13642 ##STR83##        --                           ##STR84##                                 --    66.7                                           Platy yellow crystals                                                   140˜14743 ##STR85##        --                           ##STR86##                                 --    14.4                                           Prismatic colorless                                           crystals                                                   181˜18344 ##STR87##        --                           ##STR88##                                 (COOH).sub.2                                       9.6 Needle-like colorless                                           crystals                                                   136˜139                                                   (decomp.)45 ##STR89##        --                           ##STR90##                                 --    45.8                                           Colorless crystals                                                   118˜12046 ##STR91##        CH.sub.2                           ##STR92##                                 --    27.0                                           Platy colorless crystals                                                   117˜11847 ##STR93##        CHCH                           ##STR94##                                 --    67.6                                           Colorless crystals                                                   159˜16048 ##STR95##        --                           ##STR96##                                 --    54.4                                           Pale yellow crystals                                                   92˜9449 ##STR97##        CH.sub.2                           ##STR98##                                 CH.sub.3 SO.sub.3 H                                       75.8                                           Pale yellow crystals                                                   205˜20750 ##STR99##        --                           ##STR100##                                 CH.sub.3 SO.sub.3 H                                       20.0                                           Needle-like colorless                                           crystals                                                   150˜15651 ##STR101##       --                           ##STR102##                                 --    8.1 Needle-like colorless                                           crystals                                                   110˜12052 ##STR103##       --                           ##STR104##                                 --    92.1                                           Needle-like colorless                                           crystals                                                   168˜17053 ##STR105##       --                           ##STR106##                                 --    58.5                                           Prismatic colorless                                           crystals                                                   120˜12254 ##STR107##       --                           ##STR108##                                 --    50.5                                           Prismatic pale yellow                                           crystals                                                   118˜12055 ##STR109##       --                           ##STR110##                                 --    51.7                                           Needle-like colorless                                           crystals                                                   135˜13756 ##STR111##       --                           ##STR112##                                 --    52.6                                           Needle-like colorless                                           crystals                                                   124˜12757 ##STR113##       --                           ##STR114##                                 --    29.5                                           Needle-like pale yellow                                           crystals                                                   138˜14058 ##STR115##       CH.sub.2                           ##STR116##                                 --    65.4                                           Colorless crystals                                                   113˜11559 ##STR117##       --                           ##STR118##                                 --    20.4                                           Pale yellow crystals                                                   103˜10460 ##STR119##       --                           ##STR120##                                 HCl   43.1                                           Needle-like yellow                                           crystals                                                   238 (decomp.)61 ##STR121##       --                           ##STR122##                                 HCl   29.6                                           Needle-like colorless                                           crystals                                                   253˜25562 ##STR123##       --                           ##STR124##                                 --    56.4                                           Prismatic colorless                                           crystals                                                   87˜8963 ##STR125##       CH.sub.2                           ##STR126##                                 --    67.4                                           Colorless crystals                                                   113˜114.564 ##STR127##       --                           ##STR128##                                 --    14.4                                           Prismatic colorless                                           crystals                                                   133˜134__________________________________________________________________________ 
    
     EXAMPLE 65 
     1-Methyl-4-[4-(7-methoxyl-1,2,3,4-tetrahydro-1-naphtoyloxy)benzoyl]piperazine.methanesulfonate 
     To a 100 ml solution of actonitrile containing 4.4 g of 1-methyl-4-(4-hydroxybenzoyl)piperazine and 4.94 g of 7-methoxy-1,2,3,4-tetrahydro-1-naphthylcarboxylic acid was added 4.94 g of dicyclohexyl carbodiimide, and the mixture was stirred overnight at room temperature. After removal of any insoluble matter by filtration, the filtrate was concentrated under reduced pressure, incorporated with 50 ml of 0.5N hydrochloric acid and washed with ethyl acetate. After being neutralized with a saturated solution of sodium bicarbonate, the aqueous phase was extracted with ethyl acetate. The extract was washed with water and dried, followed by removal of the solvent by distillation, to obtain a crude oily product. Purification of the product on silica gel column chromatography (eluting solution: chloroform-methanol 30:1) gave 7.57 g of an oily product. The oily product was further converted in a conventional manner to methanesulfonate, thereby obtaining 6.2 g of needle-like pale yellow crystals having a melting point of 150°-151° C. (yield: 61.6%). 
     EXAMPLES 66-73 
     The same procedure as in Example 65 was repeated to obtain several compounds shown in Table 3. 
     
                                           TABLE 3__________________________________________________________________________In Formula (Ia)                Acid Addi-                                Yield      Melting PointExampleR.sub.1       A R.sub.2   tion Salt                                (%) Appearance                                           (°C.)__________________________________________________________________________66 ##STR129##   --                 ##STR130##                          CH.sub.3 SO.sub.3 H                                86.2                                    Needle-like colorless crystals                                           205˜20767 ##STR131##   --                 ##STR132##                          CH.sub.3 SO.sub.3 H                                89.7                                    Needle-like colorless crystals                                           180˜18268 ##STR133##   --                CH.sub.2 CH.sub.3                          CH.sub.3 SO.sub.3 H                                69.2                                    Needle-like colorless crystals                                           140˜14369 ##STR134##   --                CH.sub.3  --    56.8                                    Colorless oils                                           --70 ##STR135##   --                 ##STR136##                          CH.sub.3 SO.sub.3 H                                77.4                                    Needle-like colorless crystals                                           188˜19071 ##STR137##   --                CH.sub.3  --    42.2                                    Oils   --72 ##STR138##   --                CH.sub.2 (CH.sub.2).sub.4 CH.sub.3                          CH.sub.3 SO.sub.3 H                                52.5                                    Pale yellow crystals                                           153˜15573 ##STR139##   --                 ##STR140##                          CH.sub.3 SO.sub.3 H                                55.4                                    Colorless crystals                                           227˜229__________________________________________________________________________ 
    
     EXAMPLE 74 
     1-Methyl-4-[3-(1,2,3,4-tetrahydro-1-naphthoyloxy)-benzoyl]piperazine.hydrochloride 
     The same procedure as in Example 65 was repeated using 1-methyl-4-(3-hydroxybenzoyl)piperazine and 1,2,3,4-tetrahydro-1-naphthylcarboxylic acid to obtain the title compound having a melting point of 218°-220° C. as needle-like pale yellow crystals 
     (yield: 62.7%). 
     EXAMPLES 75 AND 76 
     The same procedure as in Example 74 was repeated to obtain two compounds shown below. 
     
         ______________________________________Appearance    Colorless crystalsMelting point 175-178° C.Yield         39.5%Appearance    Needle-like pale yellow crystalsMelting point 193-197° C.Yield         42.6%______________________________________ 
    
     This invention now being fully described, it is apparent to those skilled in the art that many changes and modifications can be made thereto without departing the spirit or scope of the invention set forth herein.

Technology Classification (CPC): 2