Abstract:
Benzoyl indolecarboxylates of the formula: ##STR1## where R 1  is hydrogen, halogen, lower alkyl or lower alkoxy; R 2  is hydrogen, lower alkyl, acetyl or benzoyl; R 3  is hydrogen or lower alkyl; and A is a direct bond, or lower alkylene or vinylene substituted at the 2-, 3- or 5-position of the indole nucleus, are effective agents as chymotrypsin inhibitors.

Description:
BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     This invention relates to novel benzoyl indolecarboxylates. 
     More specifically, the invention relates to benzoyl indolecarboxylates represented by the following formula (I) and their acid addition salts: ##STR2## wherein 
     R 1  is a hydrogen or halogen atom, or a lower alkoxy or lower alkoxy group; 
     R 2  is a hydrogen atom, or a lower alkyl, acetyl or benzoyl group; 
     R 3  is a hydrogen atom or a lower alkyl group; and 
     A is a direct bond, or a lower alkylene or vinylene group substituted at the 2-, 3- or 5-position of the indole nucleus. 
     2. Description of the Prior Art 
     The present inventors have previously found various benzoyl indolecarboxylates which can exert excellent chymotrypsin inhibitory characteristics, as disclosed in Japanese Patent Publication (Kokai) No. 38243/58 (1983). 
     Through continuous research efforts directed to the syntheses of a homologous series of compounds and to the determinations of their physiological activities, it has now been discovered that compounds of the formula (I) above and their acid addition salts have more specific inhibitory effects on chymotrypsin. 
     SUMMARY OF THE INVENTION 
     Compounds of the formula (I) and their acid addition salts are effectively useful as therapeutic agents in cases where a chymotrypsin inhibitory action is required. For example, these compounds may be used to treat or relieve pancreatic diseases. 
     Accordingly, this invention provides novel benzoyl indolecarboxylates of the formula (I) and their pharmaceutically acceptable acid addition salts. 
     DETAILED DESCRIPTION 
     Compounds of the formula (I) according to this invention can be produced, for example, by esterifying 4-substituted phenols of the following formula (II) and indolecarboxylic acids of the following formula (III). This reaction may be formulated as follows: ##STR3## wherein the symbols R 1 , R 2 , R 3  and A are the same as defined hereinabove. 
     The esterification reaction under contemplation may be effected using conventional methods. One eligible method useful in the invention involves the reaction of reactive derivatives of the compounds of the formula (III), such as acid halogenides, acid anhydrides, mixed acid anhydrides, active esters, azides and the like, with the compounds of the formula (II). Another satisfactory method resides in allowing the compounds of the formula (II) to react with the compounds of the formula (III) in the presence of a dehydrating agent. Dicyclohexylcarbodiimide is a preferred example of such dehydrating agent. 
     The compounds of the formula (I) thus prepared, when found desirable, may be converted in known manner to their inorganic acid salts, such as hydrochlorides, sulfates, phosphates, hydrobromides and the like, or their organic acid salts, such as acetates, propionates, maleates, fumarates, tartrates, oxalates, citrates, methanesulfonates, benzenesulfonates, toluenesulfonates and the like. 
     Some selected compounds of this invention were tested with respect to their chymotrypsin inhibitory effects. 
     The tests were conducted in accordance with the procedure of Muramatsu et al [The Journal of Biochemistry, 62, 408 (1967)]. A mixture was prepared which was made up of 0.1 ml of a dimethylsulfoxide solution of each test compound, 0.1 ml of water and 0.1 ml of a buffer solution containing 10 μg/ml of chymotrypsin (0.1M Tris-HCl buffer, pH 8.0). The mixture was incubated for 10 minutes, followed by addition of 0.2 ml of a buffer solution containing 25 mM of an ethyl ester of acetyl-L-tyrosine. The resulting mixture was reacted at 37° C. for 30 minutes. The remaining substrate was caused to develop a color by the Hestrin method, whereupon its absorbance was measured at 530 nm. For comparative purposes, use was made of tosylphenylalanine chloromethyl ketone (TPCK) which is known as a good inhibitor for chymotrypsin. 
     The results are shown in Table 1. 
     
                       TABLE 1______________________________________         Inhibitory ActivityTest Compound 50% Inhibitory Concentration (M)______________________________________2             3 × 10.sup.-73             4 × 10.sup.-74             5 × 10.sup.-75             6 × 10.sup.-77             8 × 10.sup.-810            7 × 10.sup.-714            6 × 10.sup.-6Comparative   5 × 10.sup.-4compound (TPCK)______________________________________ Note: The numbers of the test compounds are indicated as those of the corresponding examples given hereunder. 
    
    
    
     The following examples are provided to further illustrate this invention, but it should be noted that the invention is not limited thereto. 
     EXAMPLE 1 
     1-Isopropyl-4-[4-(1-acetyl-5-methoxy-2-methylindole-3-acetyloxy)benzoyl]piperazine 
     To 30 ml of an ethyl acetate solution containing 2.61 g of 1-acetyl-5-methoxy-2-methylindole-3-acetic acid, 2.48 g of 1-(4-hydroxybenzoyl)-4-isopropylpiperazine and 0.12 g of 4-dimethylaminopyridine was added 2.27 g of dicychlohexylcarbodiimide. The reaction mixture was stirred at room temperature for 2 hours. Insoluble matter which had precipitated was removed by filtration, and the filtrate was extracted with 15 ml of 1N-hydrochloric acid. The extract was washed with ethyl acetate, neutralized with sodium hydrogencarbonate and then extracted with 30 ml of ethyl acetate. After being washed with water and dried, the ethyl acetate layer was concentrated under reduced pressure. The resulting crude crystals were recrystallized from ethyl acetate-petroleum ether to obtain 2.85 g (yield: 58.2%) of the title compound as colorless needle-like crystals having a melting point of 146° to 147° C. 
     EXAMPLE 2 TO 18 
     The procedure of Example 1 was repeated to obtain 17 compounds, their structural details and physical properties being tabulated in Table 2. 
     
                                           TABLE 2__________________________________________________________________________Ex-am-                                                       Meltingple   Present Compound                     Yield             PointNo.   R.sub.1  R.sub.2    R.sub.3                 A      Salt       (%) Appearance    (°C.)__________________________________________________________________________2  CH.sub.3 O  CH.sub.3   2-CH.sub.3                 3-CH.sub.2                        hydrochloric acid                                   63.6                                       colorless crystals                                                     223 226                                                     (decomp)3  CH.sub.3 O  H          2-CH.sub.3                 3-CH.sub.2                        &#34;          73.3                                       pink crystals 174 1754  CH.sub.3  H          2-CH.sub.3                 3-CH.sub.2                        oxalic acid                                   41.6                                       yellow needle                                                     123 125s                                                     (decomp)5  n-C.sub.4 H.sub.9  H          2-CH.sub.3                 3-CH.sub.2                        hydrochloric acid                                   40.1                                       &#34;             217 2196  --  H          H   5-     &#34;          56.4                                       colorless prism                                                     154 156s7  CH.sub.3 O  H          H   3-CH.sub.2                        oxalic acid                                   67.9                                       colorless crystals                                                     178 1828  CH.sub.3 O   ##STR4##  2-CH.sub.3                 3-CH.sub.2                        hydrochloric acid                                   71.8                                       &#34;             220 2259  Br  H          H   3-CH.sub.2                        &#34;          68.5                                       &#34;             139 14010 H   H          2-CH.sub.3                 3-CH.sub.2                        hydrochloric acid                                   62.3                                       light brown                                                     222 223s                                                     (decomp)11 H   H          H   2-     --         79.2                                       colorless prism                                                     179 180s12 H   H          H   3-     --          6.4                                       colorless crystals                                                     224 22713 H   H          H   3-(CH.sub.2).sub.3                        --         75.6                                       &#34;             101 10414 H   H          H   3-CH.sub.2                        --         47.7                                       light brown prism                                                     145 147s15 H   H          H   3-(CH.sub.2).sub.2                        --         60.6                                       colorless prism                                                     129 130s16 CH.sub.3 O  H          H   2-     --         70.2                                       colorless needle                                                     184 186s17 H   H          H   3-CHCH --         11.4                                       yellow prism                                                     229 230s18 CH.sub.3 O   ##STR5##  2-CH.sub.3                 3-CH.sub.2                        methanesulfonic acid                                   76.0                                       light yellow needle                                                     214__________________________________________________________________________                                                     215s