Novel benzoheterocyclic compound of the formula (1): ##STR1## and pharmaceutically acceptable salts thereof, which show excellent anti-vasopressin activity and oxytocin antagonistic activity, and are useful as a vasopressin antagonist or oxytocin antagonist.

TECHNICAL FIELD 
The invention relates to novel benzoheterocyclic compounds which are useful 
as medicines. 
BACKGROUND ART 
Various benzoheterocyclic compounds analogous to the compounds of the 
present invention have been known to have anti-vasopressin activities in 
European Patent Publication 0382185 (published on Aug. 16, 1990), WO 
91/05549 (published on May 2, 1991), and EP-A-0470514 (published on Feb. 
12,1992). These known compounds are similar to the compounds of the 
present invention in the benzoheterocyclic nucleus of the chemical 
structure but are different from the compounds of the present invention in 
the substituent at 1-position and in the anti-vasopressin activities to 
some extent. 
DISCLOSURE OF THE INVENTION 
An object of the present invention is to provide benzoheterocyclic 
compounds of the formula (1): 
##STR2## 
wherein R.sup.1 is hydrogen atom or a halogen atom, 
R.sup.2 is hydrogen atom, oxo group, a lower alkylidene group, hydroxy 
group, a lower alkoxy group, a lower alkenyloxy group, a 
hydroxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted 
lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower 
alkylsulfonyloxy-substituted lower alkoxy group, a phthalimide-substituted 
lower alkoxy group, a hydroxy-substituted lower alkyl group, a group of 
the formula: --O--D--(CO).sub.l NR.sup.4 R.sup.5 (wherein D is a lower 
alkylene group, l is 0 or 1, R.sup.4 and R.sup.5 are the same or different 
and are hydrogen atom, a lower alkyl group, a lower alkanoyl group, a 
cycloalkyl group, or an amino-substituted lower alkyl group which may 
optionally have a lower alkyl substituent, or R.sup.4 and R.sup.5 may 
combine together with the nitrogen atom to which they bond to form a 5- or 
6-membered saturated heterocyclic group which may be intervened or not 
with a nitrogen atom, an oxygen atom or a sulfur atom, wherein said 
heterocyclic group may optionally be substituted by a lower alkyl group or 
a lower alkanoyl group), a group of the formula: --E--(CO).sub.l NR.sup.6 
R.sup.7 (wherein l is the same as defined above, E is a lower alkylene 
group, R.sup.6 and R.sup.7 are the same or different and are hydrogen 
atom, a lower alkyl group, an amino-substituted lower alkyl group which 
may optionally have a lower alkyl substituent, or a lower alkanoyl group, 
or R.sup.6 and R.sup.7 may combine together with the nitrogen atom to 
which they bond to form a 5- or 6-membered saturated heterocyclic group 
which may be intervened or not with a nitrogen atom, an oxygen atom or a 
sulfur atom, wherein said heterocyclic group may optionally be substituted 
by a lower alkyl group, a lower alkanoyl group or a lower alkoxycarbonyl 
group), a lower alkanoyloxy-substituted lower alkyl group, a lower 
alkoxycarbonyl-substituted lower alkyl group, an amino which may 
optionally be substituted by a lower alkyl group or a cycloalkyl group, a 
carboxy-substituted lower alkyl group, a lower 
alkylsulfonyloxy-substituted lower alkyl group, a phthalimide-substituted 
lower alkyl group, an imidazolyl-substituted lower alkyl group, a 
1,2,4-triazolyl-substituted lower alkyl group, an amino-substituted lower 
alkanoyloxy group which may optionally have a lower alkyl substituent, or 
an imidazolyl-substituted lower alkoxy group, 
R.sup.3 is hydrogen atom, a lower alkoxy group or a hydroxy-substituted 
lower alkyl group, 
B.sub.1 and B.sub.2 are each methylene group or a group of the formula: 
--NR.sup.8 -- (wherein R.sup.8 is hydrogen atom or a lower alkyl group), 
A is a 5- or 6-membered unsaturated heterocyclic residue having 1 to 2 
heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur 
atom, and 
R is a group of the formula: --NHR.sup.A or a group of the formula: 
##STR3## 
wherein R.sup.A is a group of the formula: 
##STR4## 
wherein m is an integer of 1 to 3, R.sup.18 is hydrogen atom, a lower 
alkyl group, a lower alkoxy group, a halogen atom, nitro group, a lower 
alkoxycarbonyl group, carboxy group, a lower alkoxycarbonyl-substituted 
lower alkoxy group, a hydroxy-substituted lower alkoxy group, a 
carboxy-substituted lower alkoxy group, a lower 
alkylsulfonyloxy-substituted lower alkoxy group, a phthalimide-substituted 
lower alkoxy group, or a group of the formula: --O--E--(CO).sub.l 
NR.sup.19 R.sup.20 (wherein E and l are the same as defined above, 
R.sup.19 and R.sup.20 are the same or different and are hydrogen atom or a 
lower alkyl group, or R.sup.19 and R.sup.20 may combine together with the 
nitrogen atom-to which they bond to form a 5- or 6-membered saturated 
heterocyclic group which may be intervened or not with a nitrogen atom or 
an oxygen atom, wherein said heterocyclic group may optionally be 
substituted by a lower alkyl group, or an amino group which may optionally 
be substituted by a lower alkanoyl group)!, thienylcarbonyl group, a 
cycloalkylcarbonyl group or a phenyl-lower alkanoyl group which may 
optionally have a lower alkyl substituent on the phenyl ring, or a salt 
thereof. 
The compounds of the formula (1) of the present invention and salts thereof 
show excellent vasopressin antagonistic activities, for examples, 
vasodilating activity, hypotensive activity, activity for inhibiting 
saccharide release in liver, activity for inhibiting growth of mesangium 
cells, water diuretic activity, platelet agglutination inhibitory 
activity, inhibitory activity for vomiting, and hence, they are useful as 
vasodilators, hypotensive agents, water diuretics, platelet agglutination 
inhibitor, etc., and are used in the prophylaxis or treatment of 
hypertension, edema, ascites, heart failure, renal function disorder, 
vasopressin parasecretion syndrome (SIADH), hepatocirrhosis, hyponatremia, 
hypokalemia, diabetic, circulation disorder, motion sickness, and the 
like. In addition, the compounds of the present invention and salts 
thereof show oxytocin antagonistic activities, for example, inhibitory 
effect on uterine smooth muscle constriction, inhibitory effect on milk 
secretion, inhibitory effect on synthesis and secretion of prostaglandin, 
and vasodilation activity, and hence, are useful in the protection or 
treatment of oxytocin-associated diseases, especially premature delivery, 
dysmenorrhea, endometritis, or in stopping labor preparatory to Caesarian 
delivery. Besides, the compounds of the present invention and salts 
thereof are characteristic in less side effects, and in prolonged action 
for a long time in living body. 
Each group in the above formula (1) specifically includes the following 
groups. 
The "lower alkoxy group" includes a straight chain or branched chain alkoxy 
group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, 
isopropoxy, butoxy, t-butoxy, pentyloxy, hexyloxy, and the like. 
The "lower alkyl group" includes a straight chain or branched chain alkyl 
group having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, 
isopropyl, butyl, t-butyl, pentyl, hexyl, and the like. 
The "halogen atom" includes fluorine atom, chlorine atom, bromine atom, and 
iodine atom. 
The "lower alkylene group" includes a straight chain or branched chain 
alkylene group having 1 to 6 carbon atoms, for example, methylene, 
ethylene, trimethylene, 2-methyltrimethylene, 2,2-dimethyltrimethylene, 
1-methyltrimethylene, methylmethylene, ethylmethylene, tetramethylene, 
pentamethylene, hexamethylene, and the like. 
The "hydroxy-substituted lower alkoxy group" includes a straight chain or 
branched chain alkoxy group having 1 to 6 carbon atoms which is 
substituted by 1 to 3 hydroxy groups, for example, hydroxymethoxy, 
2-hydroxyethoxy, 1-hydroxyethoxy, 3-hydroxypropoxy, 2,3-dihydroxyethoxy, 
4-hydroxybutoxy, 3,4-dihydroxybutoxy, 1,1-dimethyl-2-hydroxyethoxy, 
5-hydroxypentyloxy, 6-hydroxyhexyloxy, 2-methyl-3-hydroxypropoxy, 
2,3,4-trihydroxybutoxy, and the like. 
The "lower alkanoyl group" includes a straight chain or branched chain 
alkanoyl group having 1 to 6 carbon atoms, for example, formyl, acetyl, 
propionyl, butyryl, isobutyryl, pentanoyl, t-butylcarbonyl, hexanoyl, and 
the like. 
The "carboxy-substituted lower alkyl group" includes a carboxyalkyl group 
wherein the alkyl moiety is a straight chain or branched chain alkyl group 
having 1 to 6 carbon atoms, for example, carboxymethyl, 2-carboxylethyl, 
1-carboxyethyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 
6-carboxyhexyl, 1,1-dimethyl-2-carboxyethyl, 2-methyl-3-carboxypropyl, and 
the like. 
The "5- or 6-membered saturated heterocyclic group which is formed by 
combining the groups R.sup.4 and R.sup.5, or the groups of R.sup.6 and 
R.sup.7 with the nitrogen atom to which they bond, which may be intervened 
or not with nitrogen atom, oxygen atom or sulfur atom" includes 
pyrrolidinyl, piperidinyl, piperazinyl, morpholino, thiomorpholino, and 
the like. 
The "above mentioned heterocyclic group which is substituted by a lower 
alkyl group or a lower alkanoyl group" includes the above mentioned 
heterocyclic groups which are substituted by 1 to 3 groups selected from a 
straight chain or branched chain alkyl group having 1 to 6 carbon atoms 
and a straight chain or branched chain alkanoyl group having 1 to 6 carbon 
atoms, for example, 4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 
3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 
4-butylpiperidinyl, 3-pentylmorpholino, 3-methylthiomorpholino, 
4-hexylpiperazinyl, 4-acetylpiperazinyl, 4-formyl-3-methylpiperazinyl, 
3-propionylpyrrolidinyl, 2-butyrylpyrrolidinyl, 4-pentanoylpiperidinyl, 
3-hexanoylmorpholino, 3,4,5-triacetylpiperidinyl, and the like. 
The "above mentioned heterocyclic groups substituted by a lower alkyl 
group, a lower alkanoyl group or a lower alkoxycarbonyl group" includes 
the above mentioned heterocyclic groups substituted by 1 to 3 groups 
selected from a straight chain or branched chain alkyl group having 1 to 6 
carbon atoms, a straight chain or branched chain alkanoyl group having 1 
to 6 carbon atoms and a straight chain or branched chain alkoxycarbonyl 
group having 1 to 6 carbon atoms in the alkoxy moiety, for example, 
4-methylpiperazinyl, 3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 
2-propylpyrrolidinyl, 3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 
3-pentylmorpholino, 3-methylthiomorpholino, 4-hexylpiperazinyl, 
4-acetylpiperazinyl, 4-formyl-3-methylpiperazinyl, 
3-propionylpyrrolidinyl, 2-butyrylpyrrolidinyl, 4-pentanoylpiperidinyl, 
3-hexanoylmorpholino, 3,4,5-triacetylpiperidinyl, 
4-t-butoxycarbonylpiperazinyl, 3-methoxycarbonylpyrrolidinyl, 
2-ethoxycarbonylpyrrolidinyl, 4-propoxycarbonylpiperidinyl, 
3-pentyloxycarbonylmorpholino, 3-hexyloxycarbonylpiperidinyl, 
3,5-dimethyl-4-t-butoxycarbonylpiperazinyl, 
3-acetyl-4-t-butoxycarbonylpiperazinyl, and the like. 
The "5- or 6-membered unsaturated heterocyclic residue having 1 to 2 
heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom" 
includes imidazolyl, pyrrolyl, imidazolinyl, pyridyl, primidyl, oxazolyl, 
pyrazolyl, pyrazolinyl, thiazolyl, thiazolinyl, thienyl, furyl, pyranyl, 
isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrrolinyl, and the 
like. 
The "cycloalkylcarbonyl group" includes a cycloalkylcarbonyl group having 3 
to 8 carbon atoms in the cycloalkyl moiety, for example, 
cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, 
cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, and the like. 
The "phenyl-lower alkanoyl wherein the phenyl moiety may optionally have a 
lower alkyl substituent" includes phenylalkanoyl groups wherein the phenyl 
ring may optionally have 1 to 3 substituents of a straight chain or 
branched chain alkyl group having 1 to 6 carbon atoms and the alkanoyl 
moiety is a straight chain or branched chain alkanoyl group having 2 to 6 
carbon atoms, for example, phenylacetyl, 3-phenylpropionyl, 
2-phenylpropionyl, 4-phenylbutyryl, 2,2-dimethyl-3-phenylpropionyl, 
5-phenylpentanoyl, 6-phenylhexanoyl, (2-methylphenyl)acetyl, 
(3-methylphenyl)acetyl, (4-methylphenyl)acetyl, 
2-(2-ethylphenyl)propionyl, 3-(3-isopropylphenyl)propionyl, 
4-(3-butylphenyl)butyryl, 2,2-dimethyl-3-(4-pentylphenyl)propionyl, 
5-(4-hexylphenyl)pentanoyl, 6-(3,4-dimethylphenyl)hexanoyl, 
(3,4,5-trimethylphenyl)acetyl, and the like. 
The "hydroxy-substituted lower alkyl group" includes a straight chain or 
branched chain alkyl group having 1 to 6 carbon atoms which has 1 to 3 
hydroxy substituents, for example, hydroxymethyl, 2-hydroxyethyl, 
1-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxyethyl, 4-hydroxybutyl, 
3,4-dihydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxypentyl, 
6-hydroxyhexyl, 2-methyl-3-hydroxypropyl, 2,3,4-trihydroxybutyl, and the 
like. 
The "lower alkylidene group" includes a straight chain or branched chain 
alkylidene group having 1 to 6 carbon atoms, for example, methylidene, 
ethylidene, propylidene, isopropylidene, butylidene, pentylidene, 
hexylidene, and the like. 
The "lower alkoxycarbonyl-substituted lower alkoxy group" includes a 
straight chain or branched chain alkoxy group having 1 to 6 carbon atoms 
which is substituted by a straight chain or branched chain alkoxycarbonyl 
group having 1 to 6 carbon atoms in the alkoxy moiety, for example, 
methoxycarbonylmethoxy, 3-methoxycarbonylpropoxy, ethoxycarbonylmethoxy, 
3-ethoxycarbonylpropoxy, 4-ethoxycarbonylbutoxy, 
5-isopropoxycarbonylpentyloxy, 6-propoxycarbonylhexyloxy, 
1,1-dimethyl-2-butoxycarbonylethoxy, 2-methyl-3-t-butoxycarbonylpropoxy, 
2-pentyloxycarbonylethoxy, hexyloxycarbonylmethoxy, and the like. 
The "carboxy-substituted lower alkoxy group" includes a carboxyalkoxy group 
wherein the alkoxy moiety is a straight chain or branched chain alkoxy 
group having 1 to 6 carbon atoms, for example, carboxymethoxy, 
2-carboxyethoxy, 1-carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy, 
5-carboxypentyloxy, 6-carboxyhexyloxy, 1,1-dimethyl-2-carboxyethoxy, 
2-methyl-3-carboxypropoxy, and the like. 
The "lower alkylsulfonyloxy-substituted lower alkoxy group" includes an 
alkylsulfonyloxyalkoxy group wherein the alkylsulfonyloxy moiety is a 
straight chain or branched chain alkylsulfonyloxy group having 1 to 6 
carbon atoms and the alkoxy moiety is a straight chain or branched chain 
alkoxy group having 1 to 6 carbon atoms, for example, 
methylsulfonyloxymethoxy, 3-methylsulfonyloxypropoxy, 
ethylsulfonyloxymethoxy, 3-ethylsulfonyloxypropoxy, 
2-methylsulfonyloxyethoxy, 4-ethylsulfonyloxybutoxy, 
5-isopropylsulfonyloxypentyloxy, 6-propylsulfonyloxyhexyloxy, 
1,1-dimethyl-2-butylsulfonyloxyethoxy, 
2-methyl-3-t-butylsulfonyloxypropoxy, 2-pentylsulfonyloxyethoxy, 
hexylsulfonyloxymethoxy, and the like. 
The "phthalimide-substituted lower alkoxy": group includes a 
phthalimide-substituted alkoxy group wherein the alkoxy moiety is a 
straight chain or branched chain alkoxy group having 1 to 6 carbon atoms, 
for example, phthalimidomethoxy, 2-phthalimidoethoxy, 1-phthalimidoethoxy, 
3-phthalimidopropoxy, 4-phthalimidobutoxy, 5-phthalimidopentyloxy, 
6-phthalimidohexyloxy, 1,1-dimethyl-2-phthalimidoethoxy, 
2-methyl-3-phthalimidopropoxy, and the like. 
The "lower alkoxycarbonyl-substituted lower alkyl group" includes an 
alkoxycarbonylalkyl group wherein the alkoxycarbonyl moiety is a straight 
chain or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms in 
the alkoxy moiety and the alkyl moiety is a straight chain or branched 
chain alkyl group having 1 to 6 carbon atoms, for example, 
methoxycarbonylmethyl, 3-methoxycarbonylpropyl, ethoxycarbonylmethyl, 
3-ethoxycarobnylpropyl, 4-ethoxycarbonylbutyl, 5-isopropoxycarbonylpentyl, 
6-propoxycarbonylhexyl, 1,1-dimethyl-2-butoxycarbonylethyl, 
2-methyl-3-t-butoxycarbonylpropyl, 2-pentyloxycarbonylethyl, 
hexyloxycarbonylmethyl, and the like. 
The "amino which may optionally have 1 to 2 substituents of a lower alkyl 
group or a cycloalkyl group" includes an amino which may optionally be 
substituted by a straight chain or branched chain alkyl group having 1 to 
6 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, for 
example, amino, methylamino, ethylamino, propylamino, isopropylamino, 
butylamino, t-butylamino, pentylamino, hexylamino, dimethylamino, 
diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, 
N-methyl-N-ethylamino, N-ethyl-N-propylamino, N-methyl-N-butylamino, 
N-methyl-N-hexylamino, cyclopropylamino, cyclobutylamino, 
cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, 
dicyclopropylamino, dicyclobutylamino, dicyclopentylamino, 
dicyclohexylamino, dicycloheptylamino, dicyclooctylamino, 
N-methyl-N-cyclopropylamino, N-ethyl-N-cyclopropylamino, 
N-methyl-N-cyclopentylamino, N-ethyl-N-cyclohexylamino, and the like. 
The "lower alkenyloxy group" includes a straight chain or branched chain 
alkenyloxy group having 2 to 6 carbon atoms, for example, vinyloxy, 
allyloxy, 2-butenyloxy, 3-butenyloxy, 1-methylallyloxy, 2-pentenyloxy, 
2-hexenyloxy, and the like. 
The "cycloalkyl group" includes cycloalkyl groups having 3 to 8 carbon 
atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 
cyclopentyl, cyclooctyl, and the like. 
The "amino-substituted lower alkyl group which may optionally have a lower 
alkyl substituent" includes a straight chain or branched chain alkyl group 
having 1 to 6 carbon atoms which is substituted by an amino group 
optionally having 1 to 2 substituents of a straight chain or branched 
chain alkyl group having 1 to 6 carbon atoms, for example, aminomethyl, 
2-aminoethyl, 1-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 
6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, 
methylaminomethyl, 1-ethylaminoethyl, 2-propylaminoethyl, 
3-isopropylaminopropyl, 4-butylaminobutyl, 5-pentylaminopentyl, 
6-hexylaminohexyl, dimethylaminoethyl, 2-diethylaminoethyl, 
2-dimethylaminoethyl, (N-ethyl-N-propylamino)methyl, 
2-(N-methyl-N-hexylamino)ethyl, and the like. 
The "lower alkoxycarbonyl group" includes a straight chain or branched 
chain alkoxycarbonyl group having 1 to 6 carbon atoms in the alkoxy 
moiety, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 
isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, 
hexyoxycarbonyl, and the like. 
The "lower alkanoyloxy-substituted lower alkyl group" includes a straight 
chain or branched chain alkyl group having 1 to 6 carbon atoms which is 
substituted by a straight chain or branched chain alkanoyloxy group having 
2 to 6 carbon atoms, for example, acetyloxymethyl, 2-acetyloxyethyl, 
3-propionyloxypropyl, 4-butyryloxybutyl, 5-isobutyryloxypentyl, 
1,1-dimethyl-2-pentanoyloxyethyl, 5-hexanoyloxypentyl, 6-acetyloxyhexyl, 
2-methyl-3-acetyloxypropyl, and the like. 
The "lower alkylsulfonyloxy-substituted lower alkyl group" includes a 
straight chain or branched chain alkyl group having 1 to 6 carbon atoms 
which is substituted by a straight chain or branched chain 
alkylsulfonyloxy group having 1 to 6 carbon atoms, for example, 
methylsulfonyloxymethyl, 3-methylsulfonyloxypropyl, 
ethylsulfonyloxymethyl, 3-ethylsulfonyloxypropyl, 
2-methylsulfonyloxyethyl, 4-ethylsulfonyloxybutyl, 
5-isopropylsulfonyloxypentyl, 6-propylsulfonyloxyhexyl, 
1,1-dimethyl-2-butylsulfonyloxyethyl, 2-methyl-3-t-butylsulfonyloxypropyl, 
2-pentylsulfonyloxyethyl, hexylsulfonyloxymethyl, and the like. 
The "phthalimide-substituted lower alkyl group" includes a straight chain 
or branched chain alkyl group having 1 to 6 carbon atoms which is 
substituted by a phthalimide group, for example, phthalimidomethyl, 
2-phthalimidoethyl, 1-phthalimidoethyl, 3-phthalimidopropyl, 
4-phthalimidobutyl, 5-phthalimidopentyl, 6-phthalimidohexyl, 
1,1-dimethyl-2-phthalimidoethyl, 2-methyl-3-phthalimidopropyl, and the 
like. 
The "imidazolyl-substituted lower alkyl group" includes a straight chain or 
branched chain alkyl group having 1 to 6 carbon atoms which is substituted 
by an imidazolyl group, for example, (1-imidazolyl)methyl, 
2-(1-imidazolyl)ethyl, 1-(2-imidazolyl)ethyl, 3-(4-imidazolyl)propyl, 
4-(5-imidazolyl)butyl, 5-(1-imidazolyl)pentyl, 6-(2-imidazolyl)hexyl, 
1,1-dimethyl-2-(1-imidazolyl)ethyl, 2-methyl-3-(1-imidazolyl)propyl, and 
the like. 
The "1,2,4-imidazolyl-substituted lower alkyl group" includes a straight 
chain or branched chain alkyl group having 1 to 6 carbon atoms which is 
substituted by a 1,2,4-triazolyl group, for example, 
(1,2,4-triazol-1-yl)methyl, 2-(1,2,4-triazol-1-yl)ethyl, 
1-(1,2,4-triazol-1-yl)ethyl, 3-(1,2,4-triazol-3-yl)propyl, 
4-(1,2,4-triazol-5-yl)butyl, 5-(1,2,4-triazol-1-yl)pentyl, 
6-(1,2,4-triazol-3-yl)hexyl, 1,1-dimethyl-2-(1,2,4-triazol-5-yl)ethyl, 
2-methyl-3-(1,2,4-triazol-1-yl)propyl, and the like. 
The "imidazolyl-substituted lower alkoxy group" includes a straight chain 
or branched chain alkoxyl group having 1 to 6 carbon atoms which is 
substituted by an imidazolyl group, for example, (1-imidazolyl)methoxy, 
2-(1-imidazolyl)ethoxy, 1-(2-imidazolyl)ethoxy, 3-(4-imidazolyl)propoxy, 
4-(5-imidazolyl)butoxy, 5-(1-imidazolyl)pentyloxy, 
6-(2-imidazolyl)hexyloxy, 1,1-dimethyl-2-(1-imidazolyl)ethoxy, 
2-methyl-3-(1-imidazolyl)propoxy, and the like. 
The "amino-substituted lower alkanoyloxy group which may optionally have a 
lower alkyl substituent" includes a straight chain or branched chain 
alkanoyloxy group having 2 to 6 carbon atoms which is substituted by an 
amino group optionally being substituted by 1 to 2 straight chain or 
branched chain alkyl groups having 1 to 6 carbon atoms, for example, 
2-aminoacetyloxy, 3-aminopropionyloxy, 2-aminopropionyloxy, 
4-aminobutyryloxy, 5-aminopentanoyloxy, 6-aminohexanoyloxy, 
2,2-dimethyl-3-aminopropionyloxy, 2-methyl-3-aminopropionyloxy, 
2-methylaminoacetyloxy, 2-ethylaminopropionyloxy, 
3-propylaminopropionyloxy, 3-isopropylaminopropionyloxy, 
4-butylaminobutyryloxy, 5-pentylaminopentanoyloxy, 
6-hexylaminohexanoyloxy, 2-dimethylaminoacetyloxy, 
2-diethylaminoacetyloxy, 2-(N-ethyl-N-propylamino)acetyloxy, 
3-(N-methyl-N-hexylamino)propionyloxyl, and the like. 
The "an amino group which may optionally have a lower alkanoyl substituent" 
includes an amino group which may optionally have a substituent of a 
straight chain or branched chain alkanoyl group having 1 to 6 carbon 
atoms, for example, amino, acetylamino, propionylamino, isopropionylamino, 
butyrylamino, pentanoylamino, hexanoylamino, formylamino, and the like. 
The "5- or 6-membered saturated heterocyclic group which is formed by 
combining the groups R.sup.19 and R.sup.20 with the nitrogen atom to which 
they bond, which may be intervened or not with nitrogen atom or oxygen 
atom" includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, 
morpholino, and the like. 
The "above mentioned heterocyclic groups which are substituted by an amino 
group optionally being substituted by a lower alkyl group or a lower, 
alkanoyl group" includes, for example, the above mentioned heterocyclic 
groups which are substituted by 1 to 3 amino groups optionally being 
substituted by a straight chain or branched chain alkyl group having 1 to 
6 carbon atoms, or a straight chain or branched chain alkanoyl group 
having 1 to 6 carbon atoms, for example, 4-methylpiperazinyl, 
3,4-dimethylpiperazinyl, 3-ethylpyrrolidinyl, 2-propylpyrrolidinyl, 
3,4,5-trimethylpiperidinyl, 4-butylpiperidinyl, 3-pentylmorpholino, 
3-methyl-4-acetylaminopiperidinyl, 4-hexylpiperazinyl, 
4-acetylaminopiperidinyl, 4-aminopiperidinyl, 2-propionylaminopiperazinyl, 
2-isopropionylaminopyrrolidinyl, 3-butyrylaminomorpholino, 
4-methyl-3-acetylaminopiperazinyl, 3-pentanoylaminopiperazinyl, 
4-hexanoylaminopiperidinyl, and the like. 
The benzoheterocyclic compounds of the present invention can be prepared by 
the following processes. 
##STR5## 
wherein R, R.sup.1, R.sup.2, R.sup.3, A, B.sub.1 and B.sub.2 are the same 
as defined above. 
The process of Reaction Scheme-1 is carried out by reacting a 
benzoheterocyclic compound (2) and a carboxylic acid compound (3) by the 
conventional amino bond producing reaction. The amido bond producing 
reaction can be carried out under the conditions for the conventional 
amino bond producing reaction, for example, 
(a) a mixed acid anhydride process, i.e. a process of reacting the 
carboxylic acid compound (3) with an alkyl halocarbonate ester to form a 
mixed acid anhydride and reacting the resultant with the amine compound 
(2), 
(b) an activated ester process, i.e. a process of converting the carboxylic 
acid compound (3) into an activated ester such as p-nitrophenyl ester, 
N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, etc., and 
reacting the resultant with the amine compound (2), 
(c) a carbodiimide process, i.e. a process of condensing the carboxylic 
acid compound (3) and the amine compound (2) in the presence of an 
activating agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, 
etc., 
(d) other processes, i.e. a process of converting the carboxylic acid 
compound (3) into a carboxylic anhydride by treating it with a dehydrating 
agent such as acetic anhydride, and reacting the resultant with the amine 
compound (2); a process of reacting an ester of the carboxylic acid 
compound (3) with a lower alcohol and the amine compound (2) at a high 
temperature under high pressure; a process of reacting an acid halide 
compound of the carboxylic acid compound (3), i.e. a carboxylic acid 
halide, with the amine compound (2), and the like. 
The mixed acid anhydride used in the above mixed acid anhydride process (a) 
is obtained by the know Schotten-Baumann reaction, and the reaction 
product is used without isolating from the reaction mixture for the 
reaction with the amine compound (2) to give the desired compound (1) of 
the present invention. The Schotten-Baumann reaction is usually carried 
out in the presence of a basic compound. The basic compound is any 
conventional compounds used for the Schotten-Baumann reaction and 
includes, for example, organic basic compounds such as triethylamine, 
trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 
1,5-diazabicyclo4.3.0!nonene-5 (DBN), 1,8-diazabicyclo5.4.0!undecene-7 
(DBU), 1,4-diazabicyclo2.2.2!-octane (DABCO), and inorganic basic 
compounds such as potassium carbonate, sodium carbonate, potassium 
hydrogen carbonate, sodium hydrogen carbonate, etc. The reaction is 
usually carried out at a temperature from about -20.degree. C. to about 
100.degree. C., preferably at 0.degree. C. to about 50.degree. C., for 
about 5 minutes to about 10 hours, preferably for 5 minutes to about 2 
hours. 
The reaction between the mixed acid anhydride thus obtained and the amine 
compound (2) is usually carried out at -20.degree. C. to about 150.degree. 
C., preferably at 10.degree. C. to about 50.degree. C., for 5 minutes to 
about 10 hours, preferably for 5 minutes to 5 hours. The mixed acid 
anhydride process is usually carried out in a solvent. The solvent may be 
any conventional solvents which are usually used in the mixed acid 
anhydride process and includes, for example, halogenated hydrocarbons 
(e.g. chloroform, dichloromethane, dichloroethane, etc.), aromatic 
hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. diethyl 
ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, etc.), esters 
(e.g. methyl acetate, ethyl acetate, etc.), aprotic polar solvents (e.g. 
N,N-dimethylformamide, dimethylsulfoxide, acetonitrile, 
hexamethylphosphoric triamide, etc.), or a mixture of these solvents. The 
alkyl halocarbonate ester used in the mixed acid anhydride process 
includes, for example, methyl chloroformate, methyl bromoformate, ethyl 
chloroformate, ethyl bromoformate, isobutyl chloroformate, and the like. 
In said process, the carboxylic acid compound (3), the alkyl halocarbonate 
ester and the amine compound (2) are usually used in each equimolar 
amount, but preferably, the alkyl halocarbonate ester and the carboxylic 
acid compound (3) are used each in an amount of about 1 to 1.5 mole to 1 
mole of the amine compound (2). 
Among the above other processes (d), in case of the process of reacting the 
carboxylic acid halide with the amine compound (2), the reaction is 
usually carried out in the presence of a basic compound in an appropriate 
solvent. The basic compound is any conventional compounds and includes, 
for example, in addition to the basic compounds used for Schotten-Baumann 
reaction, sodium hydroxide, potassium hydroxide, sodium hydride, potassium 
hydride, and the like. The solvent includes, for example, in addition to 
the solvents used in the mixed acid anhydride process, alcohols (e.g. 
methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, 
ethylcellosolve, methylcellosolve, etc.), pyridine, acetone, water, and 
the like. The amount of the amine compound (2) and the carboxylic acid 
halide is not critical, but the carboxylic acid halide is usually used at 
least in equimolar amount, preferably about 1 to 5 moles to 1 mole of the 
amine compound (2). The reaction is usually carried out at a temperature 
from about -20.degree. C. to about 180.degree. C., preferably at 0.degree. 
C. to about 150.degree. C., for about 5 minutes to about 30 hours. 
The amido bond producing reaction in Reaction Scheme-1 may also be carried 
out by reacting the carboxylic acid compound (3) and the amine compound 
(2) in the presence of a condensing agent such as phosphorus compounds 
(e.g. triphenylphosphine, diphenylphosphonyl chloride, 
phenyl-N-phenylphosphoramide chloridate, diethyl chlorophosphate, diethyl 
cyanophosphate, diphenylphosphoric azide, 
bis(2-oxo-3-oxazolidinyl)phosphinic chloride, etc. The reaction is usually 
carried out in the presence of the solvent and the basic compound as used 
in the above reaction of the carboxylic acid halide and the amide compound 
(2) at a temperature from -20.degree. C. to 150.degree. C., preferably 
from 0.degree. C. to about 100.degree. C., for about 5 minutes to about 30 
hours. The condensing agent and the carboxylic acid compound (3) are used 
at least in equimolar amount, preferably about 1 to 2 moles, to 1 mole of 
the amine compound (2). 
##STR6## 
wherein R.sup.A, R.sup.1, R.sup.2, R.sup.3, A, B.sub.1 and B.sub.2 are the 
same as defined above. 
The reaction of the compound (4) and the compound (5) is carried out in the 
same conditions as in the reaction of the compound (2) and the compound 
(3) in Reaction Scheme-1. 
##STR7## 
wherein R, R.sup.1, R.sup.3, R.sup.4, R.sup.5, D, I, B.sub.1, A and 
B.sub.2 are the same as defined above, R.sup.2a is oxo group, R.sup.2b is 
hydroxy group, R.sup.2c is a group of the formula: --O--D(CO).sub.l 
NR.sup.4 R.sup.5 (D, l, R.sup.4 and R.sup.5 are the same as defined 
above), R.sup.2d is a lower alkylidene group, R.sup.2m is a lower alkoxy 
group or a lower alkenyloxy group, R.sup.21 is a lower alkyl group or a 
lower alkenyl group, and X is a halogen atom. 
The reaction of converting the compound (1a) into the compound (1b) is 
carried out by subjecting the compound (1a) to reduction reaction. The 
reduction reaction is preferably carried out by using a hydrogenation 
agent. The hydrogenation agent includes, for example, lithium aluminum 
hydride, sodium borohydride, sodium trimethoxyborohydride, lithium 
borohydride,. diborane, and the like. The hydrogenation agent is used at 
least in an equimolar amount, preferably 1 mole to 15 moles, to 1 mole of 
the starting compound. The reduction reaction is usually carried out in an 
appropriate solvent such as water, lower alcohols (e.g. methanol, ethanol, 
isopropanol, t-butanol, etc.), ethers (e.g. tetrahydrofuran, diethyl 
ether, diisopropyl ether, ethylene glycol dimethyl ether, diglyme, etc.), 
or a mixture thereof, at a temperature from -60.degree. C. to 150.degree. 
C., preferably at -30.degree. C. to 100.degree. C., for about 10 minutes 
to about 15 hours. In case that lithium aluminum hydride or diborane is 
used as a reducing agent, it is preferable to use an anhydrous solvent 
such as tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme, and 
the like. 
The reaction between the compound (1b) and the compound (6) is usually 
carried out in an appropriate inert solvent in the presence or absence of 
a basic compound. The inert solvent includes, for example, aromatic 
hydrocarbons (e.g. benzene, toluene, xylene, etc.), ethers (e.g. 
tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, etc.), 
halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon 
tetrachloride, etc.), lower alcohols (e.g. methanol, ethanol, isopropanol, 
butanol, t-butanol, etc.), acetic acid, ethyl acetate, acetone, 
acetonitrile, pyridine, dimethyl sulfoxide, dimethylformamide, 
hexamethylphosphoric triamide, or a mixture thereof. The basic compound 
includes, for example, metal carbonates and metal hydrogen carbonates 
(e.g. sodium carbonate, potassium carbonate, sodium hydrogen carbonate, 
potassium hydrogen carbonate, etc.), metal hydroxides (sodium hydroxide, 
potassium hydroxide, etc.), sodium hydride, potassium, sodium, sodium 
amide, metal alcoholates (e.g. sodium methylate, sodium ethylate, etc.), 
organic basic compounds (e.g. pyridine, N-ethyldiisopropylamine, 
dimethylaminopyridine, triethylamine, 1,5-diazabicyclo4.3.0!nonene-5 
(DBN), 1,8-diazabicyclo5.4.0!-undecene-7 (DBU), 
1,4-diazabicyclo2.2.2!octane (DABCO), and the like. The amount of the 
compound (1b) and the compound (6) is not critical, but the compound (6) 
is used at least in an equimolar molar, preferably in an amount of 1 mole 
to 10 moles, to 1 mole of the compound (1b). The reaction is usually 
carried out at a temperature from 0.degree. C. to about 200.degree. C., 
preferably 0.degree. C. to about 170.degree. C., for about 30 minutes to 
about 30 hours. An alkali metal halide such as sodium iodide, potassium 
iodide, etc. may be added to this reaction system. 
The reaction of converting the compound (1a) into the compound (1d) is 
carried out in an appropriate solvent in the presence of a phosphonium 
salt and a basic compound. The phosphonium salt includes, for example, a 
phosphorus compound of the following formula. 
EQU (R.sup.9).sub.3 P.sup.+ --CH.sub.2 --R.sup.10 X.sup.- ( 7) 
wherein R.sup.9 is phenyl group, R.sup.10 is hydrogen atom or a lower alkyl 
group, and X is the same as defined above. The basic compound includes, 
for example, inorganic bases such as sodium, potassium, sodium hydride, 
sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, 
potassium carbonate, sodium hydrogen carbonate, etc., and organic bases 
such as metal alcoholates (e.g. sodium methylate, sodium ethylate, 
potassium t-butoxide, etc.), alkyl lithium, aryl lithium or lithium amide 
(e.g. methyl lithium, n-butyl lithium, phenyl lithium, lithium 
diisopropylamide, etc.), pyridine, piperidine, quinoline, triethylamine, 
N,N-dimethylaniline, and the like. The solvent may be any one which does 
not affect the reaction, and includes, for example, ethers (e.g. diethyl 
ether, dioxane, tetrahydrofuran, monoglyme, diglyme, etc.), aromatic 
hydrocarbons (e.g. benzene, toluene, xylene, etc.), aliphatic hydrocarbons 
(e.g. n-hexane, heptane, cyclohexane, etc.), aprotic polar solvents (e.g. 
pyridine, N,N-dimethylaniline, N,N-dimethylformamide, dimethyl sulfoxide, 
hexamethylphosphoric triamide, etc.), alcohols (e.g. methanol, ethanol, 
isopropanol, etc.), and the like. The reaction is usually carried out at a 
temperature from -80.degree. C. to 150.degree. C., preferably at a 
temperature from -80 to about 120.degree. C., for 0.5 to about 15 hours. 
The reaction between the compound (1a) and the compound (21) can be carried 
out under the same conditions as those of the reaction between the 
compound (1b) and the compound (6). 
##STR8## 
wherein R, R.sup.1, A, B.sup.1 and B.sup.2 are the same as defined above, 
and R.sup.2e is methylidene group. 
The reaction of converting the compound (1e) into the compound (1f) is 
carried out by reacting with an oxidizing agent in the presence of a 
co-oxidizing agent in an appropriate solvent. The solvent used in the 
reaction with an oxidizing agent includes, for example, ethers (e.g. 
pyridine, dioxane, tetrahydrofuran, diethyl ether, etc.), aromatic 
hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated 
hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon 
tetrachloride, etc.), esters (e.g. ethyl acetate, etc.), water, alcohols 
(e.g. methanol, ethanol, isopropanol, t-butanol, etc.), or a mixture of 
these solvents. The co-oxidizing agent includes, N-oxides of organic 
amines such as pyridine N-oxide, N-ethyldiisopropylamine N-oxide, 
N-methylmorpholine N-oxide, trimethylamine N-oxide, triethylamine N-oxide, 
and the like. The oxidizing agent includes, for example, osmium 
tetraoxide, and the like. The oxidizing agent is used at least in 
equimolar amount, preferably in an amount of 1 mole to 5 moles, to 1 mole 
of the starting compound. The reaction is carried out at a temperature 
from about -20.degree. C. to about 150.degree. C., preferably at a 
temperature from room temperature to about 100.degree. C., for 1 to about 
10 hours. 
##STR9## 
wherein R, R.sup.1, R.sup.3, R.sup.6, R.sup.7, E, B.sub.1, A and B.sub.2 
are the same as defined above, R.sup.2f is a lower 
alkoxycarbonyl-substituted lower alkyl group, and R.sup.2g is a 
carboxy-substituted lower alkyl group. 
The hydrolysis of the compound (1g) is carried out in the presence of an 
acid or a basic compound in an appropriate solvent or without a solvent. 
The solvent includes, for example, water, alcohols (e.g. methanol, 
ethanol, isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, 
etc.), ethers (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl 
ether, etc.), fatty acids (e.g. acetic acid, formic acid, etc.), or a 
mixture of these solvents. The acid includes, for example, mineral acids 
(e.g. hydrochloric acid, sulfuric acid, hydrobromic acid, etc.) and 
organic acids (e.g. formic acid, acetic acid, aromatic sulfonic acid, 
etc.). The basic compound includes, for example, metal carbonates (e.g. 
sodium carbonate, potassium carbonate, etc.), metal hydroxides (e.g. 
sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.), and the 
like. The reaction is usually carried out at a temperature from room 
temperature to about 200.degree. C., preferably at a temperature from room 
temperature to about 150.degree. C., for 10 minutes to about 25 hours. 
The esterification of the compound (1h) is carried out by reacting the 
starting compound with an alcohol (e.g. methanol, ethanol, isopropanol, 
etc.) in the presence of a mineral acid (e.g. hydrochloric acid, sulfuric 
acid, etc.), or a halogenating agent (e.g. thionyl chloride, phosphorus 
oxychloride, phosphorus pentachloride, phosphorus trichloride) at a 
temperature from 0.degree. C. to 150.degree. C., preferably at a 
temperature from 50.degree. C. to 100.degree. C., for about 1 to about 10 
hours. 
The reaction between the compound (1h) and the compound (8) is carried out 
under the same conditions as those of the reaction between the compound 
(2) and the compound (3) in Reaction Scheme-1. 
##STR10## 
wherein R, R.sup.1, R.sup.3, A, B.sub.1, B.sub.2, R.sup.4, R.sup.5 and D 
are the same as defined above, R.sup.2h is a lower 
alkoxycarbonyl-substituted lower alkoxy group, R.sup.2i is a 
carboxy-substituted lower alkoxy group. 
The hydrolysis of the compound (1j) is carried out under the same 
conditions as those of the hydrolysis of the compound (1g) in Reaction 
Scheme-5. 
The esterification of the compound (1k) is carried out under the same 
conditions as those of the esterification of the compound (1h) in Reaction 
Scheme-5. 
The reaction between the compound (1k) and the compound (9) is carried out 
under the same conditions as those of the reaction between the compound 
(2) and the compound (3) in Reaction Scheme-1. 
##STR11## 
wherein R, R.sup.1, R.sup.3, R.sup.2h, R.sup.4, R.sup.5, A, B.sub.1, 
B.sub.2, D and X are the same as defined above, R.sup.2j is a 
hydroxy-substituted lower alkoxy group, R.sup.11 is a lower alkyl group, 
R.sup.2k is a lower alkylsulfonyloxy-substituted lower alkoxy group, 
R.sup.2l is a phthalimide-substituted lower alkoxy group, M is an alkali 
metal such as potassium, sodium, etc., R.sup.2t is a group of the formula: 
--O--D--NR.sup.4 R.sup.5 (wherein D, R.sup.4 and R.sup.5 are the same as 
defined above), and R.sup.2u is an imidazolyl-substituted lower alkoxy 
group. 
The reaction of converting the compound (1m) into the compound (1n) ia 
carried out under the same conditions as those of the reaction of 
converting the compound (1a) into the compound (1b) in Reaction Scheme-3. 
The reaction between the compound (1n) and the compound (10) is carried out 
under the same conditions as those of the reaction between the compound 
(1b) and the compound (6) in Reaction Scheme-3. 
The reaction between the compound (1o) and the compound (11) is carried out 
under the same conditions as those of the reaction between the compound 
(1b) and the compound (6) in Reaction Scheme-3. 
The reaction of converting the compound (1p) into the compound (1q) is 
carried out by reacting the compound (1p) with hydrazine, or by hydrolysis 
of the compound (1p), in an appropriate solvent. The solvent used in the 
reaction with hydrazine includes, for example, the solvents used for the 
reaction between the compound (2) and the compound (3) in Reaction 
Scheme-1 as well as water. The reaction is usually carried out at a 
temperature from 0.degree. C. to about 120.degree. C., preferably from 
0.degree. C. to about 100.degree. C., for 0.5 to about 5 hours. Hydrazine 
is used at least in equimolar amount, preferably in an amount of 1 mole to 
5 moles, to 1 mole of the compound (1p). 
The above hydrolysis is carried out in the presence of an acid or a basic 
compound in an appropriate solvent or without a solvent. The solvent 
includes, for example, water, alcohols (e.g. methanol, ethanol, 
isopropanol, etc.), ketones (e.g. acetone, methyl ethyl ketone, etc.), 
ethers (e.g. dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, 
etc.), fatty acids (e.g. acetic acid, formic acid, etc.), or a mixture of 
these solvents. The acid includes, for example, mineral acids (e.g. 
hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), and organic 
acids (e.g. formic acid, acetic acid, aromatic sulfonic acid, etc.). The 
basic compound includes, for example, metal carbonates (e.g. sodium 
carbonate, potassium carbonate, etc.), metal hydroxides (e.g. sodium 
hydroxide, potassium hydroxide, calcium hydroxide, etc.), and the like. 
The reaction is usually carried out at a temperature from room temperature 
to about 200.degree. C., preferably at a temperature from room temperature 
to about 150.degree. C., for 10 minutes to about 25 hours. 
The reaction between the compound (1o) and the compound (27), and the 
reaction between the compound (1o) and the compound (23) can be carried 
out under the same conditions as those of the reaction between the 
compound (1b) and the compound (6) in Reaction Scheme-3. 
##STR12## 
wherein R, R.sup.1, R.sup.3, A, B.sub.1, B.sub.2 and X are the same as 
defined above, R.sup.4a is a lower alkyl group, a cycloalkyl group or an 
amino-substituted lower alkyl group which may optionally have a lower 
alkyl substituent, R.sup.13 and R.sup.14 are each hydrogen atom or a lower 
alkyl group, R.sup.4b is a lower alkanoyl group, and R.sup.5a is hydrogen 
atom, a lower alkyl group, a lower alkanoyl group, a cycloalkyl group or 
an amino-substituted lower alkyl group which may optionally have a lower 
alkyl substituent. 
The reaction between the compound (1r) and the compound (12) is carried out 
under the same conditions as those of the reaction between the compound 
(1b) and the compound (6) in Reaction Scheme-3. 
The reaction between the compound (1r) and the compound (13) is carried out 
in the presence of a reducing agent in an appropriate solvent or without a 
solvent. The solvent includes, for example, water, alcohols (e.g. 
methanol, ethanol, isopropanol, etc.), acetonitrile, formic acid, acetic 
acid, ethers (e.g. dioxane, diethyl ether, diglyme, tetrahydrofuran, 
etc.), aromatic hydrocarbons (e.g. benzene, toluene, xylene, etc.), or a 
mixture thereof. The reducing agent includes, for example, formic acid, 
alkali metal salts of fatty acids (e.g. sodium formate, etc.), 
hydrogenation agents (e.g. sodium borohydride, sodium cyanoborohydride, 
lithium aluminum hydride, etc.), catalytic reducing agents (e.g. 
palladium-black, palladium-carbon, platinum oxide, platinum black, Ranney 
nickel, etc.), and the like. 
When formic acid is used as a reducing agent, the reaction is usually 
carried out at a temperature from room temperature to about 200.degree. 
C., preferably at about 50.degree. C. to about 150.degree. C., for about 
one to about 10 hours. Formic acid is used in an excess amount to the 
compound (1r). 
When a hydrogenation agent is used, the reaction is usually carried out at 
a temperature from about -30.degree. C. to about 100.degree. C., 
preferably about 0.degree. C. to about 70.degree. C., for about 30 minutes 
to about 12 hours. The hydrogenation agent is used in an amount of 1 mole 
to 20 moles, preferably in an amount of 1 mole to 6 moles, to 1 mole of 
the compound (1r). Especially, when lithium aluminum hydride is used as a 
reducing agent, the solvent is preferably ethers (e.g. diethyl ether, 
dioxane, tetrahydrofuran, diglyme, etc.) or aromatic hydrocarbons (e.g. 
benzene, toluene, xylene, etc.). 
Moreover, when a reducing agent is used, the reaction is usually carried 
out under atmospheric pressure to 20 atms of hydrogen, preferably, under 
atmospheric pressure to 10 atms of hydrogen, or in the presence of a 
hydrogen donor such as formic acid, ammonium formate, cyclohexene, 
hydrazine hydrate, etc., at -30.degree. C. to 100.degree. C., preferably 
at 0.degree. C. to 60.degree. C., for about one to 12 hours. The reducing 
agent is usually used in an amount of 0.1 to 40% by weight, preferably 1 
to 20% by weight to the amount of the compound (1r). The compound (13) is 
usually used at least in equimolar amount, preferably in equimolar to 
excess amount, to the compound (1r). 
The reaction between the compound (1r) and the compound (14) is carried out 
under the same conditions as those of the reaction between the compound 
(2) and the compound (3) in Reaction Scheme-1. 
##STR13## 
wherein R, R.sup.1, R.sup.3, A, B.sub.1, B.sub.2, R.sup.13, R.sup.14, E, 
R.sup.4b, l and X are the same as defined above, R.sup.6a is a lower alkyl 
group or an amino-substituted lower alkyl group which may optionally have 
a lower alkyl substituent, and R.sup.7a is hydrogen atom, a lower alkyl 
group, an amino-substituted lower alkyl group which may optionally have a 
lower alkyl substituent, or a lower alkanoyl group. 
The reaction between the compound (1u) and the compound (25) is carried out 
under the same conditions as those of the reaction between the compound 
(1b) and the compound (6) in Reaction Scheme-3. 
The reaction between the compound (1u) and the compound (13) is carried out 
under the same conditions as those of the reaction between the compound 
(1r) and the compound (13)in Reaction Scheme-8. The reaction between the 
compound (1u) and the compound (14) is carried out under the same 
conditions as those of the reaction between the compound (2) and the 
compound (3)in Reaction Scheme-1. 
##STR14## 
wherein R, R.sup.1, R.sup.2, R.sup.3, B.sub.1, B.sub.2, A, R.sup.8 and X 
are the same as defined above. 
The reaction between the compound (1wa) or the compound (1wb) and the 
compound (15) is carried out under the same conditions as those of the 
reaction between the compound (1b) and the compound (6) in Reaction 
Scheme-3. 
##STR15## 
wherein R, R.sup.1, R.sup.2a, R.sup.3, A, B.sub.1 and B.sub.2 are the same 
as defined above, and R.sup.15 and R.sup.16 are the same or different and 
are hydrogen atom, a lower alkyl group or a cycloalkyl group. 
The reaction of converting the compound (1a) into the compound (1y) is 
carried out in the presence or absence of a dehydrating agent in an 
appropriate solvent or without a solvent. The solvent includes, for 
example, alcohols (e.g. methanol, ethanol, isopropanol, etc.), aromatic 
hydrocarbons (e.g. benzene, toluene, xylene, etc.), halogenated 
hydrocarbons (e.g. dichloromethane, dichloroethane, chloroform, carbon 
tetrachloride, etc.), aprotic polar solvents (e.g. dimethylformamide, 
dimethylacetamide, N-methylpyrrolidone, etc.), or a mixture of these 
solvents. The dehydrating agent includes, for example, drying agents which 
are conventionally used for drying solvents (e.g. molecular sieve, etc.), 
mineral acids (e.g. hydrochloric acid, sulfuric acid, boron trifluoride, 
etc.), organic acids (e.g. p-toluenesulfonic acid, etc.), or a mixture 
thereof. The reaction is usually carried out at a temperature from room 
temperature to 250.degree. C., preferably at a temperature from about 
50.degree. C. to about 200.degree. C., for one to about 48 hours. The 
amount of the compound (16) is not critical, but it is used at least in 
equimolar amount, preferably 1 mole to excess amount, to 1 mole of the 
compound (1a). The dehydrating agent is used in an excess amount when a 
drying agent is used, and when an acid is used as a dehydrating agent, it 
is used in a catalytic amount. 
The subsequent reduction is carried out by various reduction reactions, for 
example, by catalytic hydrogenation in the presence of a catalyst in an 
appropriate solvent. The solvent includes, for example, water, acetic 
acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), hydrocarbons 
(e.g. hexane, cyclohexane, etc.), ethers (e.g. diethylene glycol dimethyl 
ether, dioxane, tetrahydrofuran, diethyl ether, etc.), esters (e.g. ethyl 
acetate, methyl acetate, etc.), aprotic polar solvents (e.g. 
dimethylformamide, etc.), or a mixture of these solvents. The catalyst is, 
for example, palladium, palladium-black, palladium-carbon, platinum, 
platinum oxide, copper chromite, Ranney nickel, and the like. The catalyst 
is usually used in an amount of 0.02 to 1 mole to 1 mole of the starting 
compound. The reaction is usually carried out at a temperature from 
-20.degree. C. to about 100.degree. C., preferably at a temperature from 
0.degree. C. to about 70.degree. C., under a pressure of 1 atm to 10 atms 
of hydrogen, for 0.5 to 20 hours. 
The above mentioned conditions for reduction can be employed in the present 
reduction, but the reduction using a hydrogenation agent is more 
preferable. The hydrogenation agent includes, for example, lithium 
aluminum hydride, sodium borohydride, diboran, etc., and is used at least 
in equimolar amount, preferably in an amount of 1 mole to 10 moles, to 1 
mole of the compound (1a). The reduction is carried out in an appropriate 
solvent such as water, lower alcohols (e.g. methanol, ethanol, 
isopropanol, etc.), ethers (e.g. tetrahydrofuran, diethyl ether, diglyme, 
etc.), dimethylformamide, or a mixture of these solvents, at a temperature 
of about -60.degree. C. to about 50.degree. C., preferably at a 
temperature from -30.degree. C. to room temperature, for about 10 minutes 
to about 15 hours. When lithium aluminum hydride or diboran is used as a 
reducing agent, anhydrous solvent such as diethyl ether, tetrahydrofuran, 
diglyme, etc., is preferably used. 
When at least one of R.sup.15 and R.sup.16 in the compound (1y) is hydrogen 
atom, the compound is converted into the compound (1y) wherein at least 
one of R.sup.15 and R.sup.16 is a lower alkyl group by reacting it with 
the compound (12) or the compound (13) under the same conditions as those 
of the reaction between the compound (1r) and the compound (12) or the 
compound (13)in Reaction Scheme-8. 
The starting compound (3) or (4) can be prepared by the following 
processes. 
##STR16## 
wherein R.sup.17 is a lower alkyl group, and R.sup.A and A are the same as 
defined above. 
The reaction between the compound (17) and the compound (18) is carried out 
under the same conditions as those of the reaction between the compound 
(2) and the compound (3) in Reaction Scheme-1. 
The hydrolysis of the compound (19) is carried out under the same 
conditions as those of the hydrolysis of the compound (1g) in Reaction 
Scheme-5. 
##STR17## 
wherein R.sup.1, R.sup.2, R.sup.3, A, B.sub.1 and B.sub.2 are the same as 
defined above. 
The reaction between the compound (2) and the compound (19) is carried out 
under the same conditions as those of the reaction between the compound 
(2) and the compound (3) in Reaction Scheme-1. 
The reduction of the compound (20) is carried out, for example, (i) by 
using a reducing catalyst in an appropriate solvent, or (ii) by using a 
mixture of a metal or a metal salt and an acid, or a mixture of a metal or 
a metal salt and an alkali metal hydroxide, sulfide, ammonium salt, etc., 
as a reducing agent in an inert solvent. 
When the method (i) is employed, the solvent includes, for example, water, 
acetic acid, alcohols (e.g. methanol, ethanol, isopropanol, etc.), 
hydrocarbons (e.g. hexane, cyclohexane, etc.), ethers (e.g. dioxane, 
tetrahydrofuran, diethyl ether, diethylene glycol dimethyl ether, etc.), 
esters (e.g.ethyl acetate, methyl acetate, etc.), aprotic polar solvents 
(e.g. N,N-dimethylformamide, etc.), or a mixture of these solvents. The 
reducing catalyst includes, for example, palladium, palladium-black, 
palladium-carbon, platinum, platinum oxide, copper chromite, Ranney 
nickel, and the like. The catalyst is usually used in an amount of 0.02 to 
1 mole to 1 mole of the starting compound. The reaction is usually carried 
out at a temperature from about -20.degree. C. to about 150.degree. C., 
preferably at a temperature from 0.degree. C. to 100.degree. C., under a 
pressure of 1 atm to 10 atms of hydrogen, for 0.5 to about 10 hours. An 
acid (e.g. hydrochloric acid) may be added to the reaction system. 
When the method (ii) is employed, there is used as a reducing agent a 
mixture of iron, zinc, tin or stannous chloride and a mineral acid (e.g. 
hydrochloric acid, sulfuric acid, etc.), or a mixture of iron, iron 
sulfide, zinc or tin and an alkali metal hydroxide (e.g. sodium hydroxide, 
etc.), sulfide (e.g. ammonium sulfide, etc.), aqueous ammonia, ammonium 
salt (e.g. ammonium chloride, etc.). The inert solvent includes, for 
example, water, methanol, ethanol, dioxane, acetic acid, and the like. The 
conditions for reduction can be selected according to the kinds of the 
reducing agent to be used. For example, when a mixture of iron and 
hydrochloric acid is used as a reducing agent, the reaction is preferably 
carried out at a temperature from 0.degree. C. to about 100.degree. C., 
for 0.5 to about 10 hours. The reducing agent may be used at least in 
equimolar amount, usually in an amount of 1 mole to 20 moles to 1 mole of 
the starting compound. 
##STR18## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.18, B.sub.1 and B.sub.2 are the 
same as defined above, p is 0, 1 or 2, R.sup.18a is a lower alkoxycarbonyl 
group, and R.sup.18b is carboxy group. 
The hydrolysis of the compound (1B) is carried out under the same 
conditions as those of the hydrolysis of the compound (1g) in Reaction 
Scheme-5. The esterification of the compound (1C) is carried out under the 
same conditions as those of the esterification of the compound (1h) in 
Reaction Scheme-5. 
##STR19## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.18, R.sup.19, R.sup.20, p, 
B.sub.1 and B.sub.2 are the same as defined above, R.sup.18c is a lower 
alkoxycarbonyl-substituted lower alkoxy group, R.sup.18d is a 
carboxy-substituted lower alkoxy group, R.sup.18e is a hydroxy-substituted 
lower alkoxy group, and R.sup.18f is a group of the formula: 
--O--E--CO--NR.sup.19 R.sup.20 (E, R.sup.19 and R.sup.20 are the same as 
defined above). 
The hydrolysis of the compound (1D) is carried out under the same 
conditions as those of the hydrolysis of the compound (1g) in Reaction 
Scheme-5. The esterification of the compound (1E) is carried out under the 
same conditions as those of the esterification of the compound (1h) in 
Reaction Scheme-5. 
The reaction of the compound (1E) with the compound (22) is carried out 
under the same conditions as those of the reaction between the compound 
(2) and the compound (3) in Reaction Scheme-1. 
The reaction of converting the compound (1D) into the compound (1F) is 
carried out under the same conditions as those of the reaction of 
converting the compound (1a) into the compound (1b) in Reaction Scheme-3. 
##STR20## 
wherein R.sup.1, R.sup.2, R.sup.18, p, R.sup.18e, R.sup.11, X, E, 
R.sup.12, R.sup.19, R.sup.20 and M are the same as defined above. 
The reaction of the compound (1F) with the compound (10) is carried out 
under the same conditions as those of the reaction between the compound 
(1n) and the compound (10) in Reaction Scheme-7. 
The reaction of the compound (1H) with the compound (22) is carried out 
under the same conditions as those of the reaction between the compound 
(1n) and the compound (10)in Reaction Scheme-7. 
The reaction of the compound (1H) with the compound (11) is carried out 
under the same conditions as those of the reaction of the compound (1o) 
with the compound (11) in Reaction Scheme-7. 
The reaction of converting the compound (1J) into the compound (1K) is 
carried out under the same conditions as those of the reaction of 
converting the compound (1p) into the compound (1q)in Reaction Scheme-7. 
In this reaction, there may optionally be obtained a compound of the 
formula: 
##STR21## 
but which can easily be removed from the desired compounds. 
##STR22## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.18, X, p, E, R.sup.4a, R.sup.13 
and R.sup.14 are the same as defined above, and R.sup.19a is hydrogen atom 
or a lower alkyl group. 
The reaction of the compound (1L) with the compound (12) is carried out 
under the same conditions as those of the reaction between the compound 
(1r) and the compound (12) in Reaction Scheme-8. The reaction of the 
compound (1L) with the compound (13) is carried out under the same 
conditions as those of the reaction between the compound (1r) and the 
compound (13) in Reaction Scheme-8. 
##STR23## 
wherein R, R.sup.1, R.sup.2f, B.sub.1, B.sub.2, R.sup.3, R.sup.11, X, 
R.sup.12, M, R.sup.6 and R.sup.7 are the same as defined above, R.sup.2m 
is a hydroxy-substituted lower alkyl group, R.sup.2n is a lower 
alkylsuflonyloxy-substituted lower alkyl group, R.sup.2o is a group of the 
formula: --E--NR.sup.6 R.sup.7 (E, R.sup.6 and R.sup.7 are the same as 
defined above), R.sup.2p is a phthalimide-substituted lower alkyl group, 
R.sup.2q is an imidazolyl-substituted lower alkyl group, R.sup.2r is a 
1,2,4-triazolyl-substituted lower alkyl group, and R.sup.2s is a lower 
alkanoyloxy-substituted lower alkyl group. 
The reaction of converting the compound (1N) into the compound (1O) is 
carried out under the same conditions as those of the reaction of 
converting the compound (1m) into the compound (1n)in Reaction Scheme-7. 
The reaction between the compound (1P) and the compound (8), the reaction 
of the compound (1P) with the compound (23) and the reaction of the 
compound (1P) with the compound (24) are carried out under the same 
conditions as those of the reaction of the compound (1n) with the compound 
(10) in Reaction Scheme-7. 
The reaction of the compound (1P) with the compound (11) is carried out 
under the same conditions as those of the reaction of the compound (1o) 
with the compound (11) in Reaction Scheme7. 
The reaction of converting the compound (1R) into the compound (1S) is 
carried out under the same conditions as those of the reaction of 
converting the compound (1p) into the compound (1s) in Reaction Scheme-7. 
The reaction of converting the compound (1O) into the compound (1V) is 
carried out by lower-alkanoylating the compound (1O) by using a compound 
of the formulae: (R.sup.22).sub.2 O (26) or R.sup.22 X (27) wherein 
R.sup.22 is a lower alkanoyl group, and X are the same as defined above!. 
This lower-alkanoylating reaction is carried out in the presence or 
absence of a basic compound. The basic compound includes, for example, 
alkali metals (e.g. sodium, potassium, etc.), hydroxides, carbonates, 
hydrogen carbonates of these alkali metals, or organic bases such as 
N,N-dimethylaminopyridine, pyridine, piperidine, and the like. The 
reaction can proceed either without a solvent, or in a solvent. The 
solvent includes, for example, ketones (e.g. acetone, methyl ethyle 
ketone, etc.), ethers (e.g. diethyl ether, dioxane, etc.), aromatic 
hydrocarbons (e.g. benzene, toluene, xylene, etc.), water, pyridine, and 
the like. The compounds (7) and (8) are used at least in equimolar amount 
to the starting compound, but they are preferably used in an amount of 1 
mole to excess amount to 1 mole of the starting compound. The above 
reaction is carried out at a temperature from 0.degree. to 200.degree. C., 
preferably at about 0.degree. C. to about 150.degree. C., for 5 minutes to 
about 5 days. 
Among the desired compounds (1) of the present invention, the compound (1) 
wherein the groups of R.sup.6 and R.sup.7 form a piperazine ring being 
substituted by a lower alkoxycarbonyl group at 4-position, can be 
hydrolyzed under the same conditions as those of the hydrolysis of the 
compound (1g) in Reaction Scheme-5, and converted into the compound (1) 
wherein the substituent at 4-position of said piperazine ring is hydrogen 
atom. 
Among the compounds (1), the compound (1) wherein both R.sup.2 and R.sup.3 
are a lower alkoxy group, and they bond at the same position, can be 
hydrolyzed under the same conditions as those of the hydrolysis of the 
compound (1g) in Reaction Scheme-5, and converted into the compound (1) 
wherein R.sup.2 is oxo group. 
Among the desired compounds (1) of the present invention, the compounds 
having an acidic group can easily be converted into salts by treating with 
a pharmaceutically acceptable basic compound. The basic compound includes, 
for example, metal hydroxides (e.g. sodium hydroxide, potassium hydroxide, 
lithium hydroxide, calcium hydroxide, etc.), alkali metal carbonates or 
hydrogen carbonates (e.g. sodium carbonate, sodium hydrogen carbonate, 
etc.) and alkali metal alcoholates (e.g. sodium methylate, potassium 
ethylate, etc.). Besides, among the desired compounds (1) of the present 
invention, the compounds having a basic group can easily be converted into 
acid addition salts thereof by treating with a pharmaceutically acceptable 
acid. The acid includes, for example, inorganic acids (e.g. sulfuric acid, 
nitric acid, hydrochloric acid, hydrobromic acid, etc.), and organic acids 
(e.g. acetic acid, p-tolunesulfonic acid, ethanesulfonic acid, oxalic 
acid, maleic acid, fumaric acid, citric acid, succinic acid, benzoic acid, 
etc.). These salts show as well excellent vasopressin antagonistic 
activity as the desired compounds (1). 
In addition, the compounds (1) of the present invention include 
stereoisomers and optical isomers, and these isomers are also useful as 
vasopressin antagonist. 
The compounds of the present invention thus obtained can easily be isolated 
and purified by conventional isolation methods. The isolation methods are, 
for example, distillation method, recrystallization method, column 
chromatography, ion exchange chromatography, gel chromatography, affinity 
chromatography, preparative thin layer chromatography, extraction with a 
solvent, and the like. 
The desired compounds (1) of the present invention and salts thereof are 
useful as a vasopressin antagonist, and are used in the form of a 
conventional pharmaceutical preparation. The preparation is prepared by 
using conventional diluents or carriers such as fillers, thickening 
agents, binders, wetting agent, disintegrators, surfactants, lubricants, 
and the like. The pharmaceutical preparations can be selected from various 
forms in accordance with the desired utilities, and the representative 
forms are tablets, pills, powders, solutions, suspensions, emulsions, 
granules, capsules, suppositories, injections (solutions, suspensions, 
etc.), and the like. In order to form in tablets, there are used carriers 
such as vehicles (e.g. lactose, white sugar, sodium chloride, glucose, 
urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic 
acid, etc.), binders (e.g. water, ethanol, propanol, simple syrup, glucose 
solution, starch solution, gelatin solution, carboxymethyl cellulose, 
shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, 
etc.), disintegrators (e.g. dry starch, sodium alginate, agar powder, 
laminaran powder, sodium hydrogen carbonate, calcium carbonate, 
polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic 
monoglyceride, starches, lactose, etc.), disintegration inhibitors (e.g. 
white sugar, stearin, cacao butter, hydrogenated oils, etc.), absorption 
promoters (e.g. quaternary ammonium base, sodium laurylsulfate, etc.), 
wetting agents (e.g. glycerin, starches, etc.), adsorbents (e.g. starches, 
lactose, kaolin, bentonite, colloidal silicates, etc.), lubricants (e.g. 
purified talc, stearates, boric acid powder, polyethylene glycol, etc.), 
and the like. Moreover, the tablets may also be in the form of a 
conventional coated tablet, such as sugar-coated tablets, gelatin-coated 
tablets, enteric coated tablets, film coating tablets, or double or 
multiple layer tablets. In the preparation of pills, the carriers include 
vehicles (e.g. glucose, lactose, starches, cacao butter, hydrogenated 
vegetable oils, kaolin, talc, etc.), binders (e.g. gum arabic powder, 
tragacanth powder, gelatin, ethanol, etc.), disintegrators (e.g. 
laminaran, agar, etc.), and the like. In the preparation of suppositories, 
the carriers include, for example, polyethylene glycol, cacao butter, 
higher alcohols, higher alcohol esters, gelatin, semi-synthetic 
glycerides, and the like. Capsules can be prepared by charging a mixture 
of the compound of the present invention and the above carriers into hard 
gelatin capsules or soft capsules in usual manner. In the preparation of 
injections, the solutions, emulsions and suspensions are sterilized and 
are preferably made isotonic with the blood. In the preparation of these 
solutions, emulsions and suspensions, there are used conventional 
diluents, such as water, ethyl alcohol, macrogol, propylene glycol, 
ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, 
polyoxyethylene sorbitan fatty acid esters, and the like. In this case, 
the pharmaceutical preparations may also be incorporated with sodium 
chloride, glucose, or glycerin in an amount sufficient to make them 
isotonic, and may also be incorporated with conventional solubilizers, 
buffers, anesthetizing agents. Besides, the pharmaceutical preparations 
may optionally be incorporated with coloring agent, preservatives, 
perfumes, flavors, sweeting agents, and other medicaments, if required. 
The amount of the desired compound of the present invention to be 
incorporated into the vasopressin antagonist is not specified but may be 
selected from a broad range, but usually, it is preferably in the range of 
1 to 70 % by weight, more preferably 5 to 50% by weight. 
The vasopressin antagonist containing as an active ingredient the compounds 
(1) of the present invention and a salt thereof may be administered in any 
method, and suitable method for administration may be determined in 
accordance with various forms of preparations, ages, sexes and other 
conditions of the patients, the degree of severity of diseases, and the 
like. For example, tablets, pills, solutions, suspensions, emulsions, 
granules and capsules are administered orally. The injections are 
intravenously administered alone or together with a conventional auxiliary 
liquid (e.g. glucose, amino acid solutions), and further are optionally 
administered alone in intramuscular, intracutaneous, subcutaneous, or 
intraperitoneal route, if required. Suppositories are administered in 
intrarectal route. 
The dosage of the vasopressin antagonist of the present invention may be 
selected in accordance with the usage, ages, sexes and other conditions of 
the patients, the degree of severity of the diseases, and the like, but it 
is usually in the range of about 0.6 to 50 mg of the active compound of 
the present invention per 1 kg of body weight of the patient per day. The 
active compound is preferably contained in an amount of about 10 to about 
1000 mg per the dosage unit.