| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | September 26, 1989 |
| PATENT TITLE |
Substituted benzamide derivatives, for enhancing gastrointestinal motility |
| PATENT ABSTRACT |
Compounds of the formula: ##STR1## wherein R is hydrogen, alkoxycarbonyl, benzyloxycarbonyl, heteroarylalkyl, phenylalkenyl, or --T--(Y).sub.p --R.sub.6 (wherein T is single bond or alkylene, Y is oxygen, sulfur or carbonyl, R.sub.6 is phenyl, substituted phenyl, naphthyl, or diphenylmethyl, and p is 0 or 1, provided that when T is single bond, p is 0); R.sub.1 is halogen, hydroxy, alkoxy, cycloalkyloxy, alkenyloxy, alkynyloxy, alkoxy interrupted by oxygen or carbonyl, alkylthio, amino, monosubstituted amino, or a substituted alkoxy; R.sub.2 is hydrogen; R.sub.3 is hydrogen, halogen, amino, alkylamino, dialkylamino, alkanoylamino, or nitro; R.sub.4 is hydrogen, halogen, nitro, sulfamoyl, alkylsulfamoyl, or dialkylsulfamoyl; or any two adjacent groups of the R.sub.1, R.sub.2, R.sub.3 and R.sub.4 may combine to form alkylenedioxy, and the remaining two groups are each hydrogen; R.sub.5 is hydrogen or alkyl; X is alkylene; m and n are each 1 or 2; provided that at least one of the groups R.sub.2, R.sub.3 and R.sub.4 is other than hydrogen, and acid addition salts, quaternary ammonium salts and N-oxide derivatives thereof, processes for preparation thereof, and pharmaceutical composition containing the same. Said compounds, salts and N-oxide derivatives thereof show excellent gastrointestinal motility enhancing activity. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | April 24, 1987 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT REFERENCES CITED |
CA:23071W Tahara et al, Morpholine derivatives, 8/8/78, 4 pp. CA:108:94575q Tatsuya et al, Prep. of N-(2-morpho linyl alkyl) bezamides and analogs, 11/4/87, 95 pp. |
| PATENT CLAIMS |
What is claimed is: 1. A compound of the formula: ##STR128## wherein R is --T--R.sub.6 wherein T is a C.sub.1 -C.sub.6 alkylene, and R.sub.6 is phenyl or a phenyl substituted by one to five groups, each independently selected from the group consisting of a halogen, a C.sub.1 -C.sub.4 alkyl, trifluoromethyl, a C.sub.1 -C.sub.4 alkoxy, nitro, cyano and amino, R.sub.1 is a halogen, hydroxy, a C.sub.1 -C.sub.12 alkoxy, a C.sub.3 -C.sub.6 cycloalkyloxy, a C.sub.3 -C.sub.8 alkenyloxy, a C.sub.3 -C.sub.8 alkynyloxy, a C.sub.2 -C.sub.6 alkoxy interrupted by one or two oxygens or carbonyls, a C.sub.1 -C.sub.4 alkylthio, amino, a monosubstituted amino in which the substituent is a C.sub.1 -C.sub.8 alkyl, a phenyl(C.sub.1 -C.sub.3) alkyl or a C.sub.3 -C.sub.6 cycloalkyl, a C.sub.2 -C.sub.6 alkoxy in which the carbon atom at any position other than the 1-position is substituted by one hydroxy or amino, or a substituted C.sub.1 -C.sub.6 alkoxy in which the substituent is a halogen, cyano, a C.sub.2 -C.sub.5 alkoxycarbonyl, phthalimido, a C.sub.3 -C.sub.6 cycloalkyl, a phenyl optionally substituted by one halogen, a phenoxy optionally substituted by one halogen, or a benzoyl optionally substituted by one halogen, R.sub.2 is hydrogen, R.sub.3 is hydrogen, a halogen, amino, a C.sub.1 -C.sub.4 alkylamino, a di(C.sub.1 -C.sub.4 alkyl)amino, a C.sub.2 -C.sub.5 alkanoylamino, or nitro, R.sub.4 is hydrogen, a halogen, nitro, sulfamoyl, a C.sub.1 -C.sub.4 alkylsulfamoyl, or a di(C.sub.1 -C.sub.4 alkyl)sulfamoyl, or any two adjacent groups of the R.sub.1, R.sub.2, R.sub.3, and R.sub.4 combine to form a C.sub.1 -C.sub.3 alkylenedioxy, and the remaining two groups are each hydrogen, R.sub.5 is hydrogen or a C.sub.1 -C.sub.4 alkyl, X is a C.sub.1 -C.sub.3 alkylene, m is 1 or 2, and n is 1, provided that at least one of the groups R.sub.2, R.sub.3 and R.sub.4 is not hydrogen, or a pharmaceuticlly acceptable acid addition salt, quaternary ammonium salt, or N-oxide derivative thereof. 2. The compound according to claim 1, wherein R is ##STR129## pentafluorobenzyl, 2-nitro-4-chlorobenzyl, or 1-phenyl-ethyl; R.sub.1 is hydroxy, a C.sub.1 -C.sub.10 alkoxy, a C.sub.5 -C.sub.6 cycloalkyloxy, a C.sub.3 -C.sub.5 alkenyloxy, a C.sub.3 -C.sub.5 alkynyloxy, a C.sub.2 -C.sub.4 alkoxy interrupted by one carbonyl, a C.sub.2 -C.sub.5 alkoxy in which the carbon atom at any position other than the 1-position is substituted by one hydroxy, or a substituted C.sub.1 -C.sub.5 alkoxy in which the substituent is a halogen, cyano, a C.sub.2 -C.sub.4 alkoxycarbonyl, a C.sub.3 -C.sub.5 cycloalkyl, a phenyl optionally substituted by one halogen, a phenoxy optionally substituted by one halogen, or a benzoyl optionally substituted by one halogen, R.sub.2 is hydrogen; R.sub.3 is amino, a di(C.sub.1 -C.sub.2 alkyl)amino or a C.sub.2 -C.sub.5 alkanoylamino; R.sub.4 is chlorine; R.sub.5 is hydrogen or methyl; R.sub.7 is hydrogen, fluorine, chlorine, trifluoromethyl, cyano or nitro, X is methylene or ethylene; m is 1; and n is 1, q is an integer ranging from 1-4 or a pharmaceutically acceptable acid addition salt, quaternary ammonium salt, or N-oxide derivative thereof. 3. The compound according to claim 1 which has the formula: ##STR130## wherein R.sub.a is benzyl, fluorobenzyl, chlorobenzyl, trifluoromethylbenzyl, or cyanobenzyl, R.sub.1a is a C.sub.1 -C.sub.7 alkoxy, cyclopentyloxy, 3-butenyloxy, 3-methyl-2-butenyloxy, 2-oxopropoxy, 2-hydroxypropoxy, or 2-chloroethoxy, R.sub.3 ' is amino, dimethylamino or a C.sub.2 -C.sub.3 alkanoylamino, R.sub.5 is hydrogen or methyl, and n is 1, or a pharmaceutically acceptable acid addition salt, quaternary ammonium salt, or N-oxide derivative thereof. 4. The compound according to claim 3, wherein R.sub.3 ' is amino, or a pharmaceutically accepable acid addition salt, quaternary ammonium salt, or N-oxide derivative thereof. 5. The compound according to claim 4, wherein R.sub.a is 4-cyanobenzyl, R.sub.1a is methoxy and R.sub.5 ' is hydrogen, or a pharmaceutically acceptable acid addition salt thereof. 6. A compound of the formula: ##STR131## wherein R.sub.b is benzyl, fluorobenzyl, or chlorobenzyl, and R.sub.1b is methoxy, ethoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, 3-methyl-2-butenyloxy, or 2-hydroxypropoxy, or a pharmaceutically acceptable acid addition salt or N-oxide derivative thereof. 7. The compound according to claim 6, which is 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-2-butoxy-5-chlorobenzamide, or a pharmaceutically acceptable acid addition salt thereof. 8. The compound according to claim 6, which is 4-amino-2-butoxy-5-chloro-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benz amide, or a pharmaceutically acceptable acid addition salt thereof. 9. The compound according to claim 6, which is 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-(3-methyl-2-butenylo xy)benzamide, or a pharmaceutically acceptable acid addition salt thereof. 10. The compound according to claim 6, which is 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-isopentyloxybenzamid e, or a pharmaceutically acceptable acid addition salt thereof. 11. The compound according to claim 6, which is 4-amino-5-chloro-N-[[4-(2-chlorobenzyl)-2-morpholinyl]methyl]-2-ethoxybenz amide, or a pharmaceutically accetpable acid addition salt thereof. 12. The compound according to claim 6, which is 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-ethoxybenzamide, or a pharmaceutically acceptable acid addition salt thereof. 13. The compound according to claim 6, which is 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxybenzamide, or a pharmaceutically acceptable acid addition salt thereof. 14. 4-Amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-mor pholinyl]methyl]benzamide or a pharmaceutically acceptable acid addition salt thereof. 15. A pharmaceutical composition comprising an effective amount of a compound as set forth in claim 1, or a pharmaceutically acceptable acid addition salt, quaternary ammonium salt, or N-oxide derivative thereof in admixture with a pharmaceutically acceptable carrier or diluent. 16. A pharmaceutical composition comprising an effective amount of a compound as set forth in claim 2, or a pharmaceutically acceptable acid addition salt, quaternary ammonium salt, or N-oxide derivative thereof in admixture with a pharmaceutically acceptable carrier or diluent. 17. A pharmaceutical composition comprising an effective amount of a compound as set forth in claim 3, or a pharmaceutically acceptable acid addition salt, quaternary ammonium salt, or N-oxide derivative thereof in admixture with a pharmaceutically acceptable carrier or diluent. 18. A pharmaceutical composition comprising an effective amount of a compound as set forth in claim 4, or a pharmaceutically acceptable acid addition salt, quaternary ammonium salt, or N-oxide derivative thereof in admixture with a pharmaceutically acceptable carrier or diluent. 19. A pharmaceutical composition comprising an effective amount of a compound as set forth in claim 5, or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable carrier or diluent. 20. A pharmaceutical composition comprising an effective amount of a compound as set forth in claim 6, or a pharmaceutically acceptable acid addition salt or N-oxide derivative thereof in admixture with a pharmaceutically acceptable carrier or diluent. 21. A pharmaceutical composition comprising an effective amount of a compound as set forth in claim 7, or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable carrier or diluent. 22. A pharmaceutical composition comprising an effective amount of a compound as set forth in claim 8, or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable carrier or diluent. 23. A pharmaceutical composition comprising an effective amount of a compound as set forth in claim 9, or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable carrier or diluent. 24. A pharmaceutical composition comprising an effective amount of a compound as set forth in claim 10, or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable carrier or diluent. 25. A pharmaceutical composition comprising an effective amount of a compound as set forth in claim 11, or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable carrier or diluent. 26. A pharmaceutical composition comprising an effective amount of a compound as set forth in claim 12, or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable carrier or diluent. 27. A pharmaceutical composition comprising an effective amount of a compound as set forth in claim 13, or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable carrier or diluent. 28. A pharmaceutical composition comprising an effective amount of a compound as set forth in claim 14, or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable carrier or diluent. |
| PATENT DESCRIPTION |
This invention relates to novel substituted benzamide derivatives having a gastrointestinal motility enhancing activity, processes for the preparation thereof, and a method of using the same, and pharmaceutical compositions containing said compound as an active ingredient. PRIOR ART It is disclosed in Japanese Patent Publication (unexamined) No. 90274/1978 [Chem. Abstr., 90, 23071W (1970)] that certain N-[(4-lower alkyl-2(or 3)-morpholinyl)methyl]benzamide derivatives have antireserpine activity, analgesic activity, etc. and are useful, for example, as antidepressants or analgesics. On the other hand, various benzamide derivatives have been synthesized and pharmacological properties thereof have been investigated since the mid-1960's, when 4-amino-5-chloro-N-[(2-diethylamino)ethyl]-2-methoxybenzamide [generic name: metoclopramide, cf. Merck Index, 10th Ed., 6019 (1983)] has been developed as an antiemetic agent or gastrointestinal motility enhancing agent. However, there is not yet found any substituted benzamide derivative having superior activity to that of metoclopramide as a gastrointestinal motility enhancing agent. SUMMARY DESCRIPTION OF THE INVENTION The present inventors have extensively studied in order to obtain novel substituted benzamide derivatives having excellent gastrointestinal motility enhancing activity and have found that certain substituted benzamide derivatives wherein the nitrogen atom in the amide moiety is bound with the carbon atom at 2-position of morpholine or hexahydro-1,4-oxazepine group via an alkylene group show the desired activity and further that some of these substituted benzamide derivatives show more potent gastrointestinal motility enhancing activity but show less adverse effects on the central nervous system than those of metoclopramide. An object of the invention is to provide novel substituted benzamide derivatives having excellent gastrointestinal motility enhancing activity. Another object of the invention is to provide processes for the preparation of the compounds. A further object of the invention is to provide a pharmaceutical composition containing as an active ingredient the compounds as set forth above which is useful as a gastrointestinal motility enhancing agent. These and other objects and advantages of the invention will be apparent to skilled persons in this field from the following description. DETAILED DESCRIPTION OF THE INVENTION The substituted benzamide derivatives of this invention are compounds of the formula: ##STR2## wherein R is hydrogen, a C.sub.2 -C.sub.5 alkoxycarbonyl, benzyloxycarbonyl, a heteroaryl(C.sub.1 -C.sub.3)alkyl in which the heteroaryl is furyl, thienyl, pyridyl, or 1,2-benzisoxazolyl, a phenyl(C.sub.3 -C.sub.5)alkenyl, or --T--(Y).sub.p --R.sub.6 (wherein T is a single bond or a C.sub.1 -C.sub.6 alkylene, Y is oxygen, sulfur or carbonyl, R.sub.6 is phenyl, a phenyl substituted by one to five members each independently selected from the group consisting of a halogen, a C.sub.1 -C.sub.4 alkyl, trifluoromethyl, a C.sub.1 -C.sub.4 alkoxy, nitro, cyano and amino, naphthyl, or diphenylmethyl, and p is 0 or 1, provided that when T is a single bond, p is 0), R.sub.1 is a halogen, hydroxy, a C.sub.1 -C.sub.12 alkoxy, a C.sub.3 -C.sub.6 cycloalkyloxy, a C.sub.3 -C.sub.8 alkenyloxy, a C.sub.3 -C.sub.8 alkynyloxy, a C.sub.2 -C.sub.6 alkoxy interrupted by one or two oxygens or carbonyls, a C.sub.1 -C.sub.4 alkylthio, amino, a monosubstituted amino in which the substituted is a C.sub.1 -C.sub.8 alkyl, a phenyl(C.sub.1 -C.sub.3)alkyl or a C.sub.3 -C.sub.6 cycloalkyl, a C.sub.2 -C.sub.6 alkoxy in which the carbon atom at any position other than the 1-position is substituted by one hydroxy or amino, or a substituted C.sub.1 -C.sub.6 alkoxy in which the substituent is a halogen, cyano, a C.sub.2 -C.sub.5 alkoxycarbonyl, phthalimido, a C.sub.3 -C.sub.6 cycloalkyl, a phenyl optionally substituted by one halogen, a phenoxy optionally substituted by one halogen, or a benzoyl optionally substituted by one halogen, R.sub.2 is hydrogen, R.sub.3 is hydrogen, a halogen, amino, a C.sub.1 -C.sub.4 alkylamino, a di(C.sub.1 -C.sub.4 alkyl)amino, a C.sub.2 -C.sub.5 alkanoylamino, or nitro, R.sub.4 is hydrogen, a halogen, nitro, sulfamoyl, a C.sub.1 -C.sub.4 alkylsulfamoyl, or a di(C.sub.1 -C.sub.4 alkyl)sulfamoyl, or any two adjacent groups of the R.sub.1, R.sub.2, R.sub.3 and R.sub.4 combine to form a C.sub.1 -C.sub.3 alkylenedioxy, and the remaining two groups are each hydrogen, R.sub.5 is hydrogen or a C.sub.1 -C.sub.4 alkyl, X is a C.sub.1 -C.sub.3 alkylene, and m and n are each 1 or 2, provided that at least one of the groups R.sub.2, R.sub.3 and R.sub.4 is not hydrogen, and pharmaceutically acceptable acid addition salts, quaternary ammonium salts and N-oxide derivatives thereof. The pharmaceutically acceptable acid addition salts of the compounds (I) include, for example, inorganic acid addition salts (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.) and organic acid addition salts (e.g. oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate, methanesulfonate, etc.). The pharmaceutically acceptable quaternary ammonium salts of the compounds (I) mean pharmaceutically acceptable ammonium salts of the compounds of the formula (I) wherein R is other than hydrogen, alkoxycarbonyl or benzyloxycarbonyl and include, for example, quaternary ammonium salts with lower alkyl halogenides (e.g. methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, etc.), lower alkyl lower alkylsulfonates (e.g. methyl methanesulfonate, ethyl methanesulfonate, etc.), lower alkyl arylsulfonates (e.g. methyl ptoluenesulfonate, etc.), or the like. The N-oxide derivatives of the compounds (I) mean N-oxide derivatives on the morpholine or hexahydro-1,4-oxazepine moiety of the compounds of the formula (I) wherein R is other than hydrogen, alkoxycarbonyl, benzyloxycarbonyl, thienylalkyl, pyridylalkyl, and --T'--S--R.sub.6 (R.sub.6 is as defined above and T' is an alkylene), and R.sub.1 is other than alkylthio. The compounds (I), acid addition salts, quaternary ammonium salts and N-oxide derivatives thereof may optionally be present in the form of a hydrate or solvate, and the hydrate and solvate are also included in this invention. The compounds of the formula (I) contain one or more asymmetric carbon atoms, and hence, they may be present in the form of various stereoisomers. This invention includes also these stereoisomers and a mixture thereof and racemic compounds. The terms for the atom or groups used in the present specification have the following meanings. The alkyl group, alkyl moiety, alkylene group, or alkylene moiety includes straight or branched chain groups. The "alkoxycarbonyl" includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and the like. The "alkylene" includes, for example, methylene, ethylene, methylmethylene, trimethylene, propylene, dimethylmethylene, tetramethylene, pentamethylene, hexamethylene, and the like. The "halogen" includes fluorine, chlorine, bromine, and iodine, preferably fluorine, chlorine, and bromine. The "alkyl" includes, for example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, and the like. The "alkoxy" includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, and the like. The "cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. The "alkenyloxy" means a group which has one double bond at the position other than the carbon atom adjacent to the oxygen atom, and includes, for example, allyloxy, 2-butenyloxy, 3-butenyloxy, 3-methyl-2-butenyloxy, 3- or 4-pentenyloxy, 4- or 5-hexenyloxy, 6-heptenyloxy, and the like. The "alkynyloxy" means a group which has one triple bond at the position other than the carbon atom adjacent to the oxygen atom, and includes, for example, 2-propynyloxy, 3-butynyloxy, 5-hexynyloxy, and the like. The "alkoxy interrupted by one or two oxygens or carbonyls" includes, for example, 2-methoxyethoxy, (2-methoxyethoxy)methoxy, 2,2-dimethoxyethoxy, 2-oxopropoxy, 3-oxobutoxy, and the like. The "alkanoylamino" includes, for example, acetylamino, propionylamino, butyrylamino, isobutyrylamino, and the like. Among the compounds of this invention, preferred ones are compounds of the formula (I) wherein R is pyridylmethyl, ##STR3## (wherein Y and p are as defined above, R.sub.7 is hydrogen, fluorine, chlorine, trifluoromethyl, cyano, or nitro, and q is an integer of 1 to 4), pentafluorobenzyl, 2-nitro-4-chlorobenzyl, 1-phenylethyl, or naphthylmethyl; R.sub.1 is hydroxy, a C.sub.1 -C.sub.10 alkoxy, a C.sub.5 -C.sub.6 cycloalkyloxy, a C.sub.3 -C.sub.5 alkenyloxy, a C.sub.3 -C.sub.5 alkynyloxy, a C.sub.2 -C.sub.4 alkoxy interrupted by one carbonyl, a C.sub.2 -C.sub.5 alkoxy in which the carbon atom at any position other than the 1-position is substituted by one hydroxy, or a substituted C.sub.1 -C.sub.5 alkoxy in which the substituent is a halogen, cyano, a C.sub.2 -C.sub.4 alkoxycarbonyl, a C.sub.3 -C.sub.5 cycloalkyl, a phenyl optionally substituted by one halogen, a phenoxy optionally substituted by one halogen, or a benzoyl optionally substituted by one halogen; R.sub.2 is hydrogen; R.sub.3 is amino, a di(C.sub.1 -C.sub.2 alkyl)amino or a C.sub.2 -C.sub.5 alkanoylamino; R.sub.4 is chlorine; R.sub.5 is hydrogen or methyl; X is methylene or ethylene; m is 1; and n is 1 or 2, and pharmaceutically acceptable acid addition salts, quaternary ammonium salts and N-oxide derivatives thereof. More preferred compounds are compounds of the formula: TABLE 1 ______________________________________ GLUCOAMYLASE ACTIVITY SECRETED BY THE TRANSFORMED YEAST STRAINS GLUCOAMYLASE ACTIVITY.sup.a TRANSFORMANT COMPLETE MEDIA ______________________________________ YEp(DEX)3 33.4 YEp(DEX)4 61.9 YEp(DEX)5 25.3 YEp(DEX)6 47.7 YEp(DEX)7 17.8 YEp(DEX)9 33.3 S. cerevisiae LL20 4.9 S. diastaticus (J3120-13C) 1449.7 ______________________________________ .sup.a Glucoamylase activity is expressed as the amount of glucose (.mu.g/ml) hydrolyzed from 2% dextrin at 25.degree. C. in 1 h, in a cell free system. wherein R.sub.a is pyridylmethyl, benzyl, fluorobenzyl, chlorobenzyl, trifluoromethylbenzyl, cyanobenzyl, or 3-(4-chlorophenoxy)propyl, R.sub.1a is a C.sub.1 -C.sub.7 alkoxy, cyclopentyloxy, 3-butenyloxy, 3-methyl-2-butenyloxy, 2-oxopropoxy, 2-hydroxypropoxy, or 2-chloroethoxy, R.sub.3 ' is amino, dimethylamino or a C.sub.2 -C.sub.3 alkanoylamino, R.sub.5 ' is hydrogen or methyl, and n is 1 or 2, and pharmaceutically acceptable acid addition salts, quaternary ammonium salts and N-oxide derivatives thereof. Particularly preferred compounds are compounds of the formula: ##STR4## wherein R.sub.b is pyridylmethyl, benzyl, fluorobenzyl, chlorobenzyl, or 3-(4-chlorophenoxy)propyl, and R.sub.1b is methoxy, ethoxy, butoxy, isobutoxy, pentyloxy, isopentyloxy, 3-methyl-2-butenyloxy, or 2-hydroxypropoxy, and pharmaceutically acceptable acid addition salts and N-oxide derivatives thereof. Specific examples of the particularly preferred compounds are the following compounds and pharmaceutically acceptable acid addition salts thereof: 4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benza mide, 4-amino-5-chloro-2-ethoxy-N-[[4-(3-pyridyl)methyl-2-morpholinyl]methyl]benz amide, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-(3-methyl-2-butenylox y)benzamide, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-2-butoxy-5-chlorobenzamide, 4-amino-2-butoxy-5-chloro-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benza mide, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-isopentyloxybenzamide 4-amino-5-chloro-N-[[4-(2-chlorobenzyl)-2-morpholinyl]methyl]-2-ethoxybenza mide, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-ethoxybenzamide, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxybenzamide, 4-amino-5-chloro-N-[[4-(4-cyanobenzyl)-2-morpholinyl]methyl]-2-methoxybenza mide, and 4-amino-5-chloro-N-[[4-[3-(4-chlorophenoxy)propyl]-2-morpholinyl]methyl]-2- methoxybenzamide. The compounds of this invention can be prepared by various processes, for example, by the following processes. Process (a): The compounds of the formula (I) can be prepared by reacting a compound of the formula: ##STR5## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as defined above, or a reactive derivative thereof with a compound of the formula: ##STR6## wherein R.sub.5, X, m and n are as defined above, and R' is the same as R except hydrogen, and when a compound of the formula (I) wherein R is a C.sub.2 -C.sub.5 alkoxycarbonyl, benzyloxycarbonyl or benzyl is obtained, optionally removing the said group from the group. The reactive derivative of the compound (II) includes, for example, activated esters, acid anhydrides, acid halides (particularly acid chloride) and lower alkyl esters. Suitable examples of the activated esters are p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, N-hydroxy-5-norbornene-2,3-dicarboximide ester, N-hydroxypiperidine ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ester, 2-hydroxy-4,5-dichlorophenyl ester, 2-hydroxypyridine ester, 2-pyridylthiol ester, and the like. The acid anhydrides include symmetric acid anhydrides and mixed acid anhydrides. Suitable examples of the mixed acid anhydrides are mixed acid anhydrides with alkyl chloroformates (e.g. ethyl chloroformate, isobutyl chloroformate, etc.), mixed acid anhydrides with aralkyl chloroformates (e.g. benzyl chloroformate, etc.), mixed acid anhydrides with aryl chloroformates (e.g. phenyl chloroformate, etc.), mixed acid anhydrides with alkanoic acids (e.g. isovaleric acid, pivalic acid, etc.), and the like. When the compounds (II) are used, the reaction can be carried out in the presence of a condensation agent, such as dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N'-carbonyldiimidazole, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, and the like. When dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is used as the condensation agent, such reagents as N-hydroxysuccinimde, 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydro-12,3-benzotriazine, or N-hydroxy-5-norbornene-2,3-dicarboximide may be added to the reaction system. The reaction of the compound (II) or a reactive derivative thereof and the compound (III) is carried out in a suitable solvent or without using any solvent. Suitable solvent is selected in accordance with the kinds of the starting compounds, and includes, for example, aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, etc.), ethyl acetate, acetonitrile, dimethylformamide, dimethyl sulfoxide, ethylene glycol, water, and the like. These solvents may be used alone or in combinaion of two or more thereof. When the acid is liberated during the course of the reaction, the reaction may optionally be carried out in the presence of a base. Suitable examples of the base are alkali metal bicarbonates (e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), and organic bases (e.g. triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, etc.). The compound (III) may be used in an excess amount to serve as the base. The reaction temperature may vary in accordance with the kinds of the starting compounds, but is usually in the range of from about -30.degree. C. to about 200.degree. C., preferably from about -10.degree. C. to about 150.degree. C., and the reaction period of time is usually in the range of from 1 hour to 48 hours. When the compound (II) has such a functional group which interferes with the reaction as an aliphatic amino, it is preferable to block previously the group with an appropriate protecting group such as a lower alkanoyl (e.g. acetyl). The protecting group can be removed after the reaction. When a compound of the formula (I) wherein R is a C.sub.2 -C.sub.5 alkoxycarbonyl, benzyloxycarbonyl, or benzyl is obtained by the above process (a), the group is removed to give a compound of the formula (I) wherein R is hydrogen. The removal of these groups can be carried out by a conventional method. For instance, in case of R being an alkoxycarbonyl, the product is subjected to hydrolysis under an alkaline condition, and in case of R being benzyloxycarbonyl or benzyl, the product is subjected to hydrogenolysis. The hydrolysis under an alkaline condition is carried out by using a base in an appropriate solvent. The solvent includes, for example, alcohols (e.g. methanol, ethanol, isopropyl alcohol, etc.), dioxane, water, or a mixture thereof. The base includes, for example, alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, etc.). The hydrolysis is usually carried out at a temperature of from about 50.degree. C. to about 100.degree. C. for 0.5 to 24 hours. The hydrogenolysis can be carried out in an appropriate solvent in the presence of a catalyst. The solvent includes, for example, alcohols (e.g. methanol, ethanol, isopropyl alcohol, etc.), ethyl acetate, acetic acid, dioxane, water, or a mixture thereof. The catalyst includes, for example, palladium on carbon, and the like. The hydrogenolysis is usually carried out at a temperature of from 20.degree. C. to about 80.degree. C. for 1 to 24 hours. When a compound of the formula (I) wherein R.sub.3 is a C.sub.2 -C.sub.5 alkanoylamino is obtained in the above process (a), the product may further be subjected to hydrolysis under an acidic or alkaline condition to give a compound of the formula (I) wherein R.sub.3 is amino. The alkanoyl group can easily be removed. For instance, when a lower alkyl ester of compound (II) wherein R.sub.3 is an alkanoylamino is reacted with a compound (III) at 120.degree.-150.degree. C., there can be obtained a compound of the formula (I) wherein R is amino. Many of the starting compounds (II) are known, and can easily be prepared by the methods as disclosed in literatures, for example, French Pat. No. 1,307,995, U.S. Pat. Nos. 3,177,252, 3,342,826 and 3,892,802, G.B. Pat. No. 1,153,796, European Pat. Nos. 76,530 and 102,195, and J. Chem. Soc., 1963, 4666. Novel compounds (II) can also be prepared by these known methods or by the methods as disclosed in Reference Examples 80, 81 and 83 to 87 hereinafter. The starting compounds (III) are novel and can be prepared, for example, by the methods as disclosed in Reference Examples 1, 3 to 6, 56, 58, 60 to 76, and 79 hereinafter. Process (b): The compounds of the formula: ##STR7## wherein R.sub.b is as defined above, and R.sub.1c is methoxy, ethoxy, butoxy, isobutoxy, pentyloxy, or isopentyloxy, can be prepared by chlorinating a compound of the formula: ##STR8## wherein R.sub.b and R.sub.1c are as defined above, and R.sub.3 " is a C.sub.2 -C.sub.5 alkanoylamino, followed by removing the alkanoyl group from the product. The first chlorination step can be carried out by a known method, for example, by reacting the compound (IV) with a chlorinating agent in an appropriate solvent. The chlorinating agent includes, for example, N-chlorosuccinimide, iodobenzene dichloride, t-butyl hypochlorite, and the like. The solvent may vary depending on the kinds of the chlorinating agent and the like, and includes, for example, halogenated hydrocarbons (e.g. dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (e.g. tetrahydrofuran, etc.), acetonitrile, dimethylformamide, pyridine, and the like. The reaction temperature may vary depending on the kinds of the chlorinating agent, and the like, but is usually in the range of from about -20.degree. C. to about 100.degree. C., and the reaction period of time is usually in the range of from 1 hour to 24 hours. The removal of the alkanoyl group from the chlorinated product is effected by hydrolysis or by treatment with an organic amine. The hydrolysis is carried out in an appropriate solvent under an acidic or alkaline condition. The solvent includes, for example, alcohols (e.g. methanol, ethanol, isopropyl alcohol, etc.), dioxane, water, or a mixture thereof. The acid includes mineral acids (e.g. hydrochloric acid, etc.), and the base includes alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), and the like. The treatment of the chlorinated product with an organic amine is carried out in the absence or presence of a solvent. The solvent includes, for example, aromatic hydrocarbons (e.g. benzene, toluene, etc.), ethers (e.g. tetrahydrofuran, dioxane, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, etc.), alcohols (e.g. methanol, ethanol, isopropyl alcohol, etc.), ethyl acetate, acetonitrile, and the like. The organic amine includes, for example, lower alkylamines (e.g. methylamine, ethylamine, etc.), di(lower alkyl)amines (e.g. dimethylamine, diethylamine, etc.), and the like. The removal of the alkanoyl group is usually carried out at a temperature of from about 20.degree. C. to about 100.degree. C. for 0.5 to 8 hours. The starting compound (IV) can be prepared, for example, by reacting an appropriate 4-alkanoylamino-2-alkoxybenzoic acid or a reactive derivative thereof with an appropriate 2-aminomethyl-4-substituted morpholine in the same manner as in the above process (a). Process (c): The compound (Ic) can also be prepared by reducing a compound of the formula: ##STR9## wherein R.sub.b and R.sub.1c are as defined above. The above reduction can be carried out by a conventional process, for example, by treating the compound (V) with a reducing agent in an appropriate solvent. The reducing agent includes a combination of a metal (e.g. tin, zinc, iron, etc.) or a metal salt (e.g. stannous chloride, etc.) and an acid (e.g. hydrochloric acid, acetic acid, etc.), and the like. Stannous chloride may be used alone as the reducing agent. Alternatively, the reduction can also be carried out by hydrogenating the compound (V) in the presence of a catalyst in a solvent. Suitable examples of the catalyst are palladium on carbon, and the like. A suitable solvent is selected in accordance with the kinds of the reducing agent or means, and includes, for example, alcohols (e.g. methanol, ethanol, isopropyl alcohol, etc.), ethyl acetate, acetic acid, dioxane, water, or a mixture thereof. The reaction temperature may vary depending on the kinds of the reducing agent or means, but is usually in the range of from about 10.degree. C. to about 100.degree. C., and for catalytic hydrogenation, preferably from about 10.degree. C. to about 50.degree. C. The reaction period of time is usually in the range of from 1 hour to 24 hours. The starting compound (V) can be prepared, for example, by reacting an appropriate 2-alkoxy-5-chloro-4-nitrobenzoic acid or a reactive derivative thereof with an appropriate 2-aminomethyl-4-substituted morpholine in the same manner as in the above process (a). The 2-alkoxy-5-chloro-4-nitrobenzoic acid can be prepared, for example, by the process disclosed in G.B. Patent No. 1,153,796. Process (d): The compound (Ic) can also be prepared by reacting a compound of the formula: ##STR10## wherein R.sub.b is as defined above, with a compound of the formula: Z--R.sub.8 (VII) wherein R.sub.8 is methyl, ethyl, butyl, isobutyl, pentyl, or isopentyl, and Z is a residue of a reactive ester of an alcohol. In the formula (VII) the residue of reactive ester of an alcohol as defined for Z includes, for example, a halogen atom (e.g. chlorine, bromine or iodine), a lower alkylsulfonyloxy (e.g. methanesulfonyloxy, ethanesulfonyloxy, etc.), an arylsulfonyloxy (e.g. benzenesulfonyloxy, p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy, etc.), a lower alkoxysulfonyloxy (e.g. methoxysulfonyloxy, ethoxysulfonyloxy, etc.), and the like. The above reaction is usually carried out in an appropriate solvent in the presence of a base. Suitable examples of the base are alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), quaternary ammonium hydroxides (e.g. tetrabutylammonium hydroxide, benzyltriethylammonium hydroxide, etc.), alkali metal alkoxides (e.g. sodium methoxide, sodium ethoxide, etc.), alkali metal hydrides (e.g. sodium hydride, potassium hydride, etc.), and the like. A suitable solvent may be selected in accordance with the kinds of the starting compound, base, and the like, and includes, for example, dichloromethane, acetone, acetonitrile, methanol, ethanol, isopropyl, alcohol, diglyme, dimethylformamide, dimethylacetamide, and the like. When the compound of the formula (VII) wherein Z is chlorine or bromine is used, the reaction can proceed more smoothly by adding an alkali metal iodide (e.g. sodium iodide, potassium iodide, etc.) to the reaction system. Alternatively, the above reaction can also be carried out in the presence of a strong base (e.g. sodium hydroxide, potassium hydroxide, etc.) and a phase transfer catalyst in a phase transfer solvent system such as dichloromethane-water. Suitable examples of the phase transfer catalyst are tetrabutylammonium bromide, cetyltrimethylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium bisulfate, and the like. The reaction temperature may vary depending on the kinds of the starting compound, and the like, but is usually in the range of from about 5.degree. C. to 150.degree. C., and the reaction period of time is usually in the range of 5 to 48 hours. The starting compound (VI) can be prepared, for example, by reacting 2-acetoxy-4-acetylamino-5-chlorobenzoic acid or a reactive derivative thereof with an appropriate 2-aminomethyl-4-substituted morpholine in the same manner as in the above process (a), followed by hydrolysis of the resulting product. The compound (VI) can also be prepared by demethylating the corresponding 2-methoxy compound with sodium ethanethiolate in dimethylformamide or with boron tribromide in dichloromethane. The compounds (I) prepared by the above processes can be isolated and purified by conventional techniques, such as chromatography, recrystallization of reprecipitation. The compounds (I) may be obtained in the form of a free base, acid addition salts, hydrate or solvate depending on the kinds of the starting compounds, the reaction and treating conditions, and the like. The acid addition salt can be converted into a free base by treating it with a base such as an alkali metal hydroxide or an alkali metal carbonate in the usual manner. On the other hand, the free base may be converted into an acid addition salt by treating it with various acids in the usual manner. For example, when a compound of the formula (I) is reacted with an appropriate acid in a solvent and the reaction product is purified by recrystallization or reprecipitation, there is obtained an acid addition salt of the compound (I). The solvent includes, for example, chloroform, acetone, methanol, ethanol, isopropyl alcohol, water, or a mixture thereof. The reaction temperature is usually in the range of from about 0.degree. C. to about 80.degree. C., and the reaction period of time is usually in the range of from 30 minutes to 48 hours. The compounds of the formula (I) in which R is other than hydrogen, alkoxycarbonyl or benzyloxycarbonyl may be converted into their quaternary ammonium salts in the usual manner. The quaternization is carried out by reacting the compound (I) with an appropriate quaternizing agent in the absence or presence of a solvent. The solvent includes, for example, aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), ketones (e.g. acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), acetonitrile, or a mixture thereof. The reaction temperature may vary depending on the kinds of the compound (I) and the quaternizing agent, but is usually in the range of about 10.degree. C. to 130.degree. C., and the reaction period of time is usually in the range of 1 to 72 hours. The compounds of the formula (I) in which R is other than hydrogen, alkoxycarbonyl, benzyloxycarbonyl, thienylalkyl, pyridylalkyl, or --T'--S--R.sub.6 wherein R.sub.6 and T' are as defined above may be converted into their N-oxide derivatives in the usual manner. The N-oxidation is carried out by reacting the compound (I) with an appropriate oxidizing agent in a solvent. The oxidizing agent includes, for example, hydrogen peroxide and organic peracids (e.g. peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, perphthalic acid, etc.). A suitable solvent is selected in accordance with the kinds of the oxidizing agent, and includes, for example, water, acetic acid, alcohols (e.g. methanol, ethanol, etc.), ketones (e.g. acetone, etc.), ethers (e.g. diethyl ether, dioxane, etc.), halogenated hydrocarbons (e.g. dichloromethane, chloroform, etc.), and the like. The reaction temperature may vary depending on the kinds of the oxidizing agent, but is usually in the range of 0.degree. C. to 100.degree. C., and the reaction period of time is usually in the range of 1 to 72 hours. The pharmacological activities of the compounds of the present invention are illustrated by the results of the following experiments, which were carried out on the representative compounds of the present invention. The reference compounds used in the experiments are as follows: A: Metoclopramide hydrochloride monohydrate, and B: N-[(4-Ethyl-2-morpholinyl)methyl]-2-methoxybenzamide fumarate which is disclosed in the aforementioned Japanese Patent Publication (unexamined) No. 90274/1978. TEST 1 Gastric emptying enhancing activity The test was carried out according to the method of Scarpignato et al. [cf. Arch. int. Pharmacodyn., 246, 286-294 (1980)]. Male Wistar rats, weighing 130-150 g, were fasted for 18 hours before experimentation, and 1.5 ml of a test meal (phenol red 0.05% in a 1.5% aqueous methylcellulose solution) was given by gastric tube. Fifteen minutes after administration of the meal the stomach was removed and the amount of phenol red remaining in the stomach was measured. The test compounds, dissolved or suspended in a 0.5% tragacanth solution, were orally administered 60 minutes before administration of the test meal. The rate of gastric emptying was calculated according to the amount of phenol red remaining in the stomach, and the activity of the test compounds was expressed in terms of increase in the emptying rate from the control. The number of animals used was 5 for the control and each dose of metoclopramide hydrochloride monohydrate and 4 for each dose of the other test compounds. The results are shown in Table 1. TABLE 1 ______________________________________ Gastric emptying enhancing activity Test Test com- Dose Increase com- Dose Increase pound (p.o.) (%) pound (p.o.) (%) ______________________________________ 1(1)* 0.2 mg/kg 39.5 81 2.0 mg/kg 52.9 1 2.0 mg/kg 49.8 86 2.0 mg/kg 55.0 6 2.0 mg/kg 49.2 88 0.2 mg/kg 32.8 7 2.0 mg/kg 74.0 88 0.5 mg/kg 42.9 8 2.0 mg/kg 44.9 88 2.0 mg/kg 53.7 14 2.0 mg/kg 47.5 89 2.0 mg/kg 49.9 16 2.0 mg/kg 47.3 90 2.0 mg/kg 55.4 18(2) 2.0 mg/kg 39.3 91 2.0 mg/kg 51.2 25 2.0 mg/kg 39.1 92 2.0 mg/kg 41.0 28 2.0 mg/kg 42.8 93 0.5 mg/kg 46.9 33 2.0 mg/kg 42.3 93 2.0 mg/kg 44.2 37 2.0 mg/kg 42.2 94 2.0 mg/kg 52.0 52 2.0 mg/kg 52.5 95 0.2 mg/kg 34.7 63(1) 0.5 mg/kg 33.9 95 2.0 mg/kg 61.6 63(1) 2.0 mg/kg 54.4 97 2.0 mg/kg 43.8 64 2.0 mg/kg 59.9 101 2.0 mg/kg 46.4 65 2.0 mg/kg 54.1 102 2.0 mg/kg 46.8 66(1) 2.0 mg/kg 41.3 104 2.0 mg/kg 43.8 67 2.0 mg/kg 57.5 105 2.0 mg/kg 52.0 68(1) 2.0 mg/kg 62.7 111 2.0 mg/kg 48.7 70 2.0 mg/kg 57.8 115 2.0 mg/kg 45.6 73 0.5 mg/kg 44.2 116 0.5 mg/kg 41.4 73 2.0 mg/kg 46.2 116 2.0 mg/kg 52.4 74 2.0 mg/kg 46.7 119 2.0 mg/kg 48.4 76 2.0 mg/kg 47.1 120 2.0 mg/kg 40.6 77 2.0 mg/kg 43.8 130 2.0 mg/kg 51.8 79 2.0 mg/kg 51.0 132 2.0 mg/kg 50.6 80(1) 2.0 mg/kg 65.6 244 2.0 mg/kg 51.8 ______________________________________ (Reference compound) ______________________________________ A 2.0 mg/kg 20.7 B 2.0 mg/kg 3.8 A 5.0 mg/kg 25.7 B 5.0 mg/kg -1.9 A 10.0 mg/kg 30.7 B 10.0 mg/kg 2.1 ______________________________________ (*)It means the compound of Example 1(1) (hereinafter, the same). As shown in Table 1, the compounds of this invention exhibited potent gastric emptying enhancing activity at a dose of 2.0 mg/kg or less. The effect was stronger than that of metoclopramide hydrochloride monohydrate. On the other hand, Compound B did not show any effect even at a dose of 10.0 mg/kg. TEST 2 Acute toxicity Male ddY mice, weighing 18-25 g, were used in groups of 10 animals each. The test compounds, dissolved or suspended in a 0.5% tragacanth solution, were orally administered at a prescribed dose to the animals. The mortality was observed for 7 days after the administration. The results are shown in Table 2. TEST 3 Effect on the central nervous system (CNS effect) Male ddY mice, weighing 18-25 g, were used in groups of 3 animals each. According to the method of Irwin [cf. Psychopharmacologia, 13, 222-227 (1968)], comprehensive observation of behavioral and physiologic states were carried out for 2 hours after the oral treatment with 100 mg/kg of the test compound, dissolved or suspended in a 0.5% tragacanth solution. Liability of the test compounds to the central nervous system effect was expressed with the following marks, according to the total sum of potencies for the individually analyzed effects, such as catalepsy, ptosis, hypolocomotin, etc. TABLE 2 ______________________________________ CNS effect and acute toxicity Acute toxicity Test CNS effect Dose No. of the dead/ compound (100 mg/kg, p.o.) (p.o.) No. of the total ______________________________________ 1(1)* - 1000 mg/kg 0/10 6 - 1000 mg/kg 2/10 8 - 1000 mg/kg 0/10 18(2) - 1000 mg/kg 6/10 63(1) - 1000 mg/kg 0/10 66(1) - 1000 mg/kg 0/10 67 - 1000 mg/kg 5/10 68(1) - 1000 mg/kg 0/10 70 - 1000 mg/kg 0/10 74 - 1000 mg/kg 0/10 80(1) - 1000 mg/kg 4/10 81 - 1000 mg/kg 0/10 88 - 1000 mg/kg 2/10 89 + 1000 mg/kg 0/10 90 - 1000 mg/kg 0/10 91 - 1000 mg/kg 4/10 93 - 1000 mg/kg 0/10 94 - 1000 mg/kg 3/10 95 - 1000 mg/kg 0/10 97 - 1000 mg/kg 0/10 101 - 1000 mg/kg 2/10 104 - 1000 mg/kg 3/10 105 - 1000 mg/kg 0/10 116 - 1000 mg/kg 1/10 119 - 1000 mg/kg 5/10 ______________________________________ (Reference compound) ______________________________________ A +++ 200 mg/kg 5/10 ______________________________________ (*)It means the compound of Example 1(1) (hereinafter, the same). -: No effect +: Slight effect ++: Moderate effect +++: Remarked effect As shown in Table 2, both CNS effect and acute toxicity of the compounds of this invention were weaker than those of metoclopramide hydrochloride monohydrate. These data suggest that the present compounds have a good separation between the dose for gastric emptying and that for adverse CNS effects. As is clear from the above experimental results, the compounds of the formula (I) and pharmaceutically acceptable acid addition salts, quaternary ammonium salts, or N-oxide derivatives thereof have excellent gastrointestinal motility enhancing activity with less toxicity, and hence, are useful as a gastrointestinal motility enhancing agent. They can be used in the prophylaxis and treatment of disorders associated with gastrointestinal motor impairment in mammals including human being, such as dyspepsia, esophageal reflux, gastric stasis, anorexia, nausea, vomiting, and abdominal discomfort which are seen in acute and chronic gastritis, gastric and duodenal ulcers, gastric neurosis, gastroptosis, and the like. They can also be used in the prophylaxis and treatment of esophageal and biliary duct disorders and constipation. Further, they can be used in the prophylaxis and treatment of nausea and vomiting associated with emetogenic cancer chemotherapeutic agents such as cisplatin. The compounds of the formula (I) and pharmaceutically acceptable acid addition salts, quaternary ammonium salts, or N-oxide derivatives thereof can be administered by oral, parenteral or intrarectal route. The clinical dose of the compounds (I) and pharmaceutically acceptable salts or N-oxide derivatives thereof may vary according to the kinds of the compounds, administration routes, severity of disease, age of patients, or the like, but is usually in the range of 0.001 to 20 mg per kg of body weight per day, preferably 0.004 to 5 mg per kg of body weight per day, in human. The dose may be divided and administered in two or several times per day. The compounds of the formula (I) and pharmaceutically acceptable salts or N-oxide derivatives thereof are usually administered to patients in the form of a pharmaceutical composition which contains a non-toxic and effective amount of the compounds. The pharmaceutical composition is usually prepared by admixing the active compounds (I), their salts or N-oxide derivatives with conventional pharmaceutical carrier materials which are unreactive with the active compounds (I), their salts or N-oxide derivatives. Suitable examples of the carrier materials are lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminosilicate tetrahydrate, synthetic aluminum silicate, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropylstarch, calcium carboxymethylcellulose, ion exchange resin, methylcellulose, gelatin, acacia, pullulan, hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, veegum, carboxyvinyl polymer,titanium dioxide, sorbitan fatty acid ester, sodium lauryl sulfate, cacao butter, glycerin, glycerides of saturated fatty acids, anhydrous lanolin, glycerogelatin, polysorbate, macrogol, vegetable oils, wax, propylene glycol, water, or the like. The pharmaceutical composition may be in the dosage form of tablets, capsules, granules, fine granules, powders, syrups, suspension, suppositories, injections, or the like. These preparations may be prepared by conventional methods. Liquid preparations may be prepared by dissolving or suspending the active compounds in water or other suitable vehicles, when used. Tablets, granules and fine granules may be coated in a conventional manner. The pharmaceutical composition may contain as the active ingredient the compound of the formula (I), its pharmaceutically acceptable salt or N-oxide derivative in the ratio of 0.5% by weight or more, preferably 1 to 70% by weight, based upon the whole weight of the composition. The composition may further contain one or more other therapeutically active compounds. This invention is illustrated by the following Examples and Reference Examples, but should not be construed to be limited thereto. The identification of the compounds is carried out by elementary analysis, mass spectrum, IR spectrum, NMR spectrum, and the like. In Examples and Reference Examples, the following abbreviations are somtimes used. Me: methyl Et: ethyl Pr: propyl Ph: phenyl Ac: acetyl A: ethanol AC: acetone AE: ethyl acetate CH: chloroform DO: dioxane DM: dichloromethane E: diethyl ether H: hexane IP: isopropyl alcohol M: methanol PE: diisopropyl ether T: toluene. |
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