A compound represented by formula (I): ##STR1## wherein R.sub.1 represents a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group, a trifluoromethyl group, a lower alkylthio group, an acyl group, a carboxyl group, a mercapto group or an amino group; R.sub.2 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, an alkoxy group, an acyl group, an aryl group or a heterocyclic group; R.sub.3 represents a lower alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group; R.sub.4 represents a hydrogen atom, a lower alkyl group, an aryl group, a heterocyclic group, --OR.sub.5, --SR.sub.5 or --NR.sub.6 R.sub.7 (wherein R.sub.5, R.sub.6, and R.sub.7 each represent a lower alkyl group, etc.); X and Y each represent --CH.sub.2 --, --NH-- or --O--; and n represents an integer of from 0 to 4, and an intermediate for synthesis thereof are disclosed. The compound of the present invention exhibits selective antagonism against gastrin receptors without causing side effects attributed to CCK-A receptor antagonism and is useful for the treatment and prevention of peptic ulcers, gastritis, reflux esophagitis, and Zollinger-Ellison syndrome, and for the treatment of neoplasm originating in the gastrointestinal system.

FIELD OF THE INVENTION 
This invention relates to an indolin-2-one derivative which exhibits 
selective antagonism against gastrin receptors without causing side 
effects attributed to CCK-A receptor antagonism and is useful for the 
treatment and prevention of diseases of digestive organs, such as peptic 
ulcers, gastritis, reflux esophagitis, and Zollinger-Ellison syndrome, and 
for the treatment of tumours originating in the gastrointestinal system. 
The compounds also exhibit selective antagonism against CCK-B receptors 
and are useful for the treatment of CCK-related disorders in the appetite 
control system, enhancement and prolongation of analgesia through opiate 
or non-opiate, induction of anesthesia or analgesia, and the treatment and 
prevention of symptoms of psychotic disorders including anxiety and panic 
disorder. 
BACKGROUND OF THE INVENTION 
Gastrin is a typical gastrointestinal hormone, like CCK, secretin, etc. It 
is known that gastrin accelerates secretion of gastric acid and pepsin and 
also accelerates growth of gastric mucous cells and especially histamine 
secretory cells. While gastric acid secretion is stimulated by histamine, 
acetylcholine, and gastrin, gastrin is the most powerful of these internal 
substances. Currently known drugs for controlling gastric acid secretion 
include muscarinic receptor antagonists such as Pirenzepine, histamine 
H.sub.2 receptor antagonists such as Cimetidine, and H.sup.+ -K.sup.+ 
ATPase inhibitors such as Omeprazole. However, it has been reported that 
these drugs induce hypergastrinemia during maintained administration due 
to the potent inhibitory activity on gastric acid secretion, and the high 
gastrin level induces an increase of histamine content in the gastric 
mucosa. The reports also reveal that discontinuation of administration of 
these drugs is followed by an increase of acid secretion, called rebound, 
and a high rate of relapses. 
The study of gastrin has recently been progressed, and participation of 
gastrin in various diseases has been elucidated. As a result, it has been 
suggested that a selective antagonist to gastrin receptors would be useful 
for the treatment and prevention of diseases induced by disorders of 
physiological functions related to gastrin, i.e., diseases of digestive 
organs, particularly peptic ulcers, gastritis, reflux esophagitis, and 
Zollinger-Ellison syndrome; prevention of a relapse following treatment 
with an H.sub.2 receptor antagonist or an H.sup.+ -K.sup.+ ATPase 
inhibitor; or the treatment and prevention of tumours originating in the 
gastrointestinal system. 
Recently, several gastrin receptor antagonists have been reported. For 
example, amino acid (glutamic acid) derivatives such as Proglumide and 
benzodiazepin derivatives such as L-365,260 (Japanese Patent Application 
Laid-Open No. 238069/88) are known. Proglumide exhibits very weak binding 
activity to gastrin receptors. L-365,260, while having high binding 
activity to gastrin receptors, do not exert powerful inhibitory activity 
on gastric acid secretion when administered in vivo. 
On the other hand, CCK is widely distributed through the gastrointestinal 
system and the central nervous system. It is known that CCK exhibits its 
activities at the peripheries chiefly via CCK-A receptors accelerating 
pancreatic secretion, gastrointestinal motility and contractions of the 
gall bladder, inhibition of gastric emptying, and acceleration of growth 
of some kinds of tumor cells. It is also known that CCK participates in 
appetite control, analgesia through opiate, and symptoms of psychotic 
disorders including anxiety and panic disorder in the central nervous 
system via CCK-B receptors. Accordingly, drugs having a selective 
antagonistic action to CCK-B receptors are expected to be useful for the 
treatment of CCK-related disorders in the appetite control system, 
enhancement and prolongation of analgesia through opiate or non-opiate, 
induction of anesthesia or analgesia, and the treatment and prevention of 
symptoms of psychotic disorders including anxiety and panic disorders. 
While amino acid (glutamic acid) derivatives such as Proglumide are 
reported as a CCK-B receptor antagonist, their binding activity to CCK-B 
receptors is very weak. 
An object of the present invention is to provide a compound which 
selectively antagonizes to gastrin receptors without causing side effects 
attributed to the CCK-A receptor antagonism and inhibits gastric acid 
secretion in vivo and is useful for the treatment and prevention of 
diseases of digestive organs, such as peptic ulcers, gastritis, reflux 
esophagitis, and Zollinger-Ellison syndrome, and for the treatment of 
tumour originating in the gastrointestinal system and which also 
selectively antagonizes to CCK-B receptors without causing side effects 
attributed to the CCK-A receptor antagonism and is useful for the 
treatment of CCK-related disorders in the appetite control system, 
enhancement and prolongation of analgesia through opiate or non-opiate, 
induction of anesthesia or analgesia, and the treatment and prevention of 
symptoms of psychotic disorders including anxiety and panic disorder, and 
an intermediate useful for the synthesis of the compound. 
DISCLOSURE OF THE INVENTION 
We have conducted extensive investigations for the purpose of developing a 
selective gastrin receptor antagonist and a selective CCK-B receptor 
antagonist. As a result, we have found that the above purpose can be 
achieved by a compound represented by formula (I): 
##STR2## 
wherein R.sub.1 represents a halogen atom, a lower alkyl group, a lower 
alkoxy group, a hydroxyl group, a nitro group, a trifluoromethyl group, a 
lower alkylthio group, an acyl group, a carboxyl group, a mercapto group, 
or a substituted or unsubstituted amino group; R.sub.2 represents a 
hydrogen atom, a substituted or unsubstituted lower alkyl group, a 
substituted or unsubstituted lower alkenyl group, a substituted or 
unsubstituted lower alkynyl group, a substituted or unsubstituted lower 
alkoxy group, a substituted or unsubstituted acyl group, a substituted or 
unsubstituted aryl group, or a substituted or unsubstituted heterocyclic 
group; R.sub.3 represents a substituted or unsubstituted lower alkyl 
group, a substituted or unsubstituted cycloalkyl group, a substituted or 
unsubstituted aryl group, or a substituted or unsubstituted heterocyclic 
group; R.sub.4 represents a hydrogen atom, a substituted or unsubstituted 
lower alkyl group, a substituted or unsubstituted aryl group, a 
substituted or unsubstituted heterocyclic group, --OR.sub.5, --SR.sub.5, 
or --NR.sub.6 R.sub.7, wherein R.sub.5, R.sub.6, and R.sub.7, which may be 
the same or different, each represent a hydrogen atom, a substituted or 
unsubstituted lower alkyl group, a substituted or unsubstituted cycloalkyl 
group, a substituted or unsubstituted aryl group, a substituted or 
unsubstituted heterocyclic group, a lower alkoxy group, or a substituted 
or unsubstituted amino group; or R.sub.6 and R.sub.7 are taken together to 
form --(CH.sub.2).sub.m -- or --(CH.sub.2).sub.l NR.sub.8 (CH.sub.2).sub.k 
-- (wherein k, l, and m each represent an integer of from 1 to 8; and 
R.sub.8 represents a hydrogen atom or a lower alkyl group); X and Y, which 
may be the same or different, each represent --CH.sub.2 --, --NH-- or 
--O--; and n represents an integer of from 0 to 4, or a salt thereof, thus 
having reached the present invention. We have also found that a compound 
represented by formula (II): 
##STR3## 
wherein R.sub.1, R.sub.3, and n are as defined above; and R.sub.9 
represents a group represented by formula (III): 
##STR4## 
wherein R.sub.10 and R.sub.11 each represent a substituted or 
unsubstituted lower alkyl group, 
or a group represented by formula (IV): 
##STR5## 
wherein Z represents a substituted or unsubstituted lower alkylene group, 
and a compound represented by formula (V): 
##STR6## 
wherein R.sub.1, R.sub.9, and n are as defined above, are useful 
intermediates for the synthesis of compound represented by formula (I). 
GENERAL DEFINITIONS OF TERMS USED 
In the present invention, the term "lower alkyl group" denotes a 
straight-chain or branched alkyl group having 1 to 6 carbon atoms, 
including a methyl group, an ethyl group, a n-propyl group, an isopropyl 
group, a n-butyl group, a sec-butyl group, a t-butyl group, a pentyl 
group, and a hexyl group. 
The term "lower alkenyl group" denotes a straight-chain or branched alkenyl 
group having from 2 to 6 carbon atoms, including a vinyl group, an allyl 
group, a butenyl group, a pentenyl group, and a hexenyl group. 
The term "lower alkynyl group" means a straight-chain or branched alkynyl 
group having 2 to 6 carbon atoms, including an ethynyl group, a propynyl 
group, and a butynyl group. 
The term "lower alkoxy group" denotes a straight-chain or branched alkyloxy 
group having 1 to 6 carbon atoms, including a methyloxy group, an ethyloxy 
group, a n-propyloxy group, an isopropyloxy group, a n-butyloxy group, a 
sec-butyloxy group, a t-butyloxy group, a pentyloxy group, and a hexyloxy 
group. 
The term "acyl group" indicates a carbonyl group attaching a hydrogen atom, 
a substituted or unsubstituted alkyl group, a substituted or unsubstituted 
aryl group, a substituted or unsubstituted alkoxy group, a substituted or 
unsubstituted amino group, etc., including an alkylcarbonyl group, such as 
an acetyl group, a propionyl group, a pivaloyl group, and a 
cyclohexanecarbonyl group; and an arylcarbonyl group, such as a benzoyl 
group, a naphthoyl group and a toluoyl group. 
The term "aryl group" means an aromatic hydrocarbon with one hydrogen atom 
removed therefrom, such as a phenyl group, a tolyl group, a xylyl group, a 
biphenyl group, a naphthyl group, an anthryl group, or a phenanthryl 
group. 
The term "alkylene group" denotes a straight-chain or branched alkylene 
group having 1 to 6 carbon atoms, including a methylene group, an ethylene 
group, a propylene group, a butylene group, a pentylene group, and a 
hexylene group. 
The term "cycloalkyl group" denotes a cyclic saturated hydrocarbon group 
having 3 to 8 carbon atoms, such as a cyclopropyl group, a cyclobutyl 
group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group. The 
substituted cycloalkyl group includes a menthyl group and an adamantyl 
group. 
The term "aralkyl group" denotes a lower alkyl group substituted with an 
aryl group, such as a benzyl group, a diphenylmethyl group, a trityl 
group, a phenethyl group or a naphthylmethyl group, with a benzyl group or 
phenethyl group being preferred. 
The term "heterocyclic group" means an aromatic heterocyclic group having 
at least one hetero atom, such as a pyridyl group, a furyl group, a 
thienyl group, an imidazolyl group, a pyrazinyl group or a pyrimidyl 
group. 
The substituent includes a halogen atom, a lower alkyl group, a cycloalkyl 
group, an aryl group, a hydroxyl group, an alkoxy group, an aryloxy group, 
an alkylthio group, a heterocyclic group, a formyl group (which may be 
protected with an acetal, etc.), an alkylcarbonyl group, an arylcarbonyl 
group, a carboxyl group, an alkoxycarbonyl group, a substituted or 
unsubstituted amino group, an imino group, a thioacetal group, a nitro 
group, a nitrile group, and a trifluoromethyl group. 
R.sub.1 is preferably a lower alkyl group or nil (n=0), still preferably 
nil (n=0). 
R.sub.2 is preferably an alkoxy-substituted lower alkyl group, still 
preferably a lower alkyl group having two alkoxy groups or an --O--Z--O-- 
group (wherein Z represents a substituted or unsubstituted lower alkylene 
group) on one carbon atom thereof. A 2,2-diethoxyethyl group is 
particularly preferred. 
R.sub.3 is preferably a substituted or unsubstituted aryl group, still 
preferably a phenyl group substituted with a lower alkyl group or a lower 
alkoxy group. A phenyl group substituted with a methyl group or a methoxy 
group is particularly preferred. 
R.sub.4 is preferably --NR.sub.6 R.sub.7 in which one of R.sub.6 and 
R.sub.7 is a hydrogen atom with the other being a substituted or 
unsubstituted aryl group or a substituted or unsubstituted heterocyclic 
group, still preferably --NR.sub.6 R.sub.7 in which one of R.sub.6 and 
R.sub.7 is a hydrogen atom with the other being a phenyl group substituted 
with a lower alkyl group, a lower alkoxy group or a substituted or 
unsubstituted amino group, particularly a phenyl group substituted with a 
methyl group or an N,N-dimethylamino group. 
X is preferably --NH--. 
Y is preferably --CH.sub.2 --. 
Of optically active compounds of formula (I) or salts thereof preferred are 
(+)-compounds. 
The compounds of the present invention are novel compounds which have not 
been reported in any literature and can be synthesized, for example, as 
follows. 
##STR7## 
wherein R.sub.1, R.sub.3, and n are as defined above; R.sub.12 represents 
a lower alkyl group; R'.sub.2 represents a substituted or unsubstituted 
lower alkyl group, a substituted or unsubstituted lower alkenyl group, a 
substituted or unsubstituted lower alkynyl group, a substituted or 
unsubstituted aryl group, or a substituted or unsubstituted heterocyclic 
group; and X represents a halogen atom or a trifluoromethanesulfonyloxy 
group. 
##STR8## 
wherein R.sub.1, R'.sub.2, R.sub.3, X, and n are as defined above; and 
R.sub.13 represents a lower alkyl group. 
##STR9## 
wherein R.sub.1, R'.sub.2, R.sub.3, R.sub.13, and n are as defined above; 
R' represents a lower alkyl group; and R.sub.14 represents a substituted 
or unsubstituted lower alkyl group, a substituted or unsubstituted 
cycloalkyl group, a substituted or unsubstituted aryl group, or a 
substituted or unsubstituted heterocyclic group. 
##STR10## 
wherein R.sub.1, R'.sub.2, R.sub.3, R.sub.13, and n are as defined above; 
and R.sub.15 and R.sub.16, which may be the same or different, each 
represent a hydrogen atom, a substituted or unsubstituted lower alkyl 
group, a substituted or unsubstituted cycloalkyl group, a substituted or 
unsubstituted aryl group, a substituted or unsubstituted heterocyclic 
group, a lower alkoxy group, or a substituted or unsubstituted amino 
group; or R.sub.15 and R.sub.16 are taken together to form 
--(CH.sub.2).sub.m -- or --(CH.sub.2).sub.l NR.sub.8 (CH.sub.2).sub.k --, 
wherein k, l, and m each represent an integer of from 1 to 8; and R.sub.8 
represents a hydrogen atom or a lower alkyl group. 
##STR11## 
wherein R.sub.1, R'.sub.2, R.sub.3, R.sub.13, R.sub.15, R.sub.16, and n 
are as defined above; and R.sub.a preferably represents a substituted or 
unsubstituted lower alkyl group, still preferably a substituted or 
unsubstituted methyl group, most preferably a methyl group or a benzyl 
group. 
##STR12## 
wherein R.sub.1, R.sub.3, R.sub.15, R.sub.16, and n are as defined above; 
R.sub.26 represents a lower alkyl group; R.sub.17 represents a lower alkyl 
group or a lower hydroxyalkyl group; R.sub.18 and R.sub.19 each represent 
a lower alkyl group, or they are taken together to form an alkylene group; 
R.sub.20 represents a lower alkyl group or a lower mercaptoalkyl group; 
R.sub.22 and R.sub.23 each represent a lower alkyl group, or they are 
taken together to form an alkylene group; and R.sub.24 and R.sub.25 each 
represent a lower alkyl group, or they are taken together to form an 
alkylene group. 
##STR13## 
wherein R.sub.1, R'.sub.2, R.sub.3, R.sub.15, R.sub.16, and n are as 
defined above; R" represents a lower alkyl group, a primary amino group, a 
secondary amino group or an alkoxy group; and R.sub.21.sup.* represents an 
optically active group. 
##STR14## 
wherein R.sub.1, R'.sub.2, and n are as defined above. 
Diurea derivative (5) can be prepared by substitution reaction between the 
acetal moiety of acetal intermediate (4) and an urea derivative as shown 
in Reaction Route 1. Intermediate (4) can be prepared by two reactions, 
i.e., alkylation and acetal formation, whichever may precede, as shown in 
Reaction Route 1. 
The isatin derivative which can be used as a starting material in this 
process is a known compound and is commercially available or can easily be 
synthesized in a conventional manner. Various urea derivatives are also 
commercially available or can easily be synthesized in a conventional 
manner (J. Heterocyclic Chem., Vol. 19, p. 1453 (1982)). 
The preparation of diurea derivative (5) can preferably be carried out as 
follows. Isatin derivative (1) is dissolved or suspended in an inert 
solvent, such as dry N,N-dimethylformamide, dry dimethyl sulfoxide or dry 
tetrahydrofuran, and a requisite amount of a base, such as a metal hydride 
or a metal alkoxide, preferably sodium hydride or potassium t-butoxide, is 
added thereto at a temperature in the range from ice-cooling to room 
temperature. After stirring the mixture for a while at a temperature in 
the range from ice-cooling to room temperature, an equimolar amount or a 
slight excess, with respect to isatin derivative (1), of a halide is added 
thereto, followed by stirring for 1 to 15 hours at room temperature or 
under heating. After completion of the reaction, the solvent is removed by 
evaporation under reduced pressure. Water is added to the residue, and the 
mixture is extracted with an appropriate solvent, such as chloroform or 
ethyl acetate, dried, and concentrated under reduced pressure. The 
resulting crude product is purified by a proper method to obtain 
N-substituted isatin (3). 
Then, N-substituted isatin (3) and an adequate amount of an appropriate 
trialkyl orthoformate are dissolved or suspended in an appropriate 
alcohol, and an adequate amount of an acid catalyst, for example, 
p-toluenesulfonic acid monohydrate, camphorsulfonic acid or sulfuric acid, 
is added thereto, followed by heating for 4 to 48 hours with stirring. The 
reaction mixture is concentrated under reduced pressure, and to the 
residue is added a base, for example, saturated aqueous sodium 
hydrogencarbonate, followed by extraction with an appropriate solvent, 
such as chloroform or ethyl acetate. The extract is dried and concentrated 
under reduced pressure. The resulting crude product is purified by an 
appropriate method to obtain acetal intermediate (4). 
Alternatively, acetal intermediate (4) can be obtained by conducting the 
above-mentioned two reactions in reverse order, i.e., via intermediate (2) 
shown in Reaction Route 1. This process is preferred in case where the 
reaction for synthesizing N-substituted isatin (3) requires heating. 
An excess, with reference to acetal intermediate (4), preferably 2 to 3 
mol, per mol of acetal intermediate (4), of a Lewis acid, such as 
anhydrous aluminum chloride, boron trifluoride ethyl etherate, titanium 
tetrachloride, tin tetrachloride, magnesium bromide ethyl etherate, or 
zinc bromide, preferably anhydrous aluminum chloride, is dissolved in an 
inert solvent, such as dry tetrahydrofuran, dichloromethane, toluene, or 
dry dioxane, preferably dry tetrahydrofuran. To the solution are added 
successively a solution of acetal intermediate (4) in dry tetrahydrofuran, 
etc. and an urea derivative in excess, preferably in an amount of 2 mol 
per mol of acetal intermediate (4) at a temperature in the range from 
ice-cooling to room temperature, followed by heating for 1 to 8 hours with 
stirring. After completion of the reaction, an appropriate organic 
solvent, such as ethyl acetate, is added to the reaction mixture, and the 
mixture is washed with water, dried, and concentrated under reduced 
pressure. The residue is purified by a proper method to obtain diurea 
derivative (5). 
Diamide derivative (10) can be prepared by dialkylation of the 3-position 
of commercially available 2-oxindole (6), followed by alkylation of the 
1-position, followed by conversion of ester to amide as illustrated in 
Reaction Route 2. 
The preparation of diamide derivative (10) can preferably be carried out as 
follows. 2-Oxindole (6) is dissolved in an inert solvent, such as dry 
dimethyl sulfoxide, dry N,N-dimethylformamide or dry tetrahydrofuran, 
preferably dry dimethyl sulfoxide, and a solution of an equimolar amount 
of a base, such as a metal hydride or a metal alkoxide, preferably sodium 
hydride or potassium t-butoxide, in dry dimethyl sulfoxide is added 
thereto at a temperature in the range from ice-cooling to room 
temperature, followed by stirring at a temperature in the range from 
ice-cooling to room temperature for several minutes. An equimolar amount 
of an appropriate bromoacetic ester with reference to (6) is then added 
thereto, followed by stirring at room temperature for several tens of 
minutes. To the reaction mixture are further added an equimolar amount of 
the same base as used above and an equimolar amount of the same 
bromoacetic ester as used above at the same temperature, followed by 
stirring at room temperature for several tens of minutes. After completion 
of the reaction, water is added to the residue, and the mixture is 
extracted with an appropriate solvent, such as diethyl ether. The extract 
is dried and concentrated under reduced pressure. Since the resulting 
crude product contains a 1-substituted derivative, it is purified by a 
proper method, such as silica gel column chromatography, to give both 
3,3-bis(alkoxycarbonylmethyl)indolin-2-one (7) and 
1,3,3-tris(alkoxycarbonylmethyl)indolin-2-one. 
3,3-Bis(alkoxycarbonylmethyl)indolin-2-one (7) is dissolved or suspended in 
an inert solvent, such as dry N,N-dimethylformamide, dry dimethyl 
sulfoxide or dry tetrahydrofuran, and a requisite amount of a base, such 
as a metal hydride or a metal alkoxide, preferably sodium hydride or 
potassium t-butoxide, is added thereto at a temperature in the range from 
ice-cooling to room temperature, followed by stirring for several minutes 
at a temperature in the range from ice-cooling to room temperature. An 
equimolar amount or a slight excess, with respect to (7), of an 
appropriate halide is added thereto, followed by stirring for 1 to 15 
hours at room temperature or under heating. After completion of the 
reaction, the solvent is removed by evaporation under reduced pressure. 
Water is added to the residue, and the mixture is extracted with an 
appropriate solvent, such as chloroform or ethyl acetate, dried, and 
concentrated under reduced pressure. The resulting crude product may be 
either purified by a proper method to obtain 1-substituted 
3,3-bis(alkoxycarbonylmethyl)indolin-2-one (8) or be used in the 
subsequent reaction without further purification. 
1-Substituted 3,3-bis(alkoxycarbonylmethyl)indolin-2-one (8) is dissolved 
in a solvent uniformly miscible with water, such as ethanol or methanol, 
and an aqueous solution of a moderately excess base, such as potassium 
hydroxide, sodium hydroxide or potassium carbonate, is added thereto at 
room temperature, followed by stirring for 1 to 24 hours at room 
temperature or under heating. After completion of the reaction, the 
reaction mixture is concentrated under reduced pressure. The concentrate 
is dissolved in water and washed with an appropriate organic solvent, such 
as chloroform. The aqueous layer is acidified with an acid, e.g., 2N 
hydrochloric acid and then extracted with an appropriate organic solvent, 
such as ethyl acetate, to obtain 1-substituted 
3,3-bis(hydroxycarbonylmethyl)indolin-2-one (9). The crude product as 
obtained may be used in the subsequent reaction either without 
purification or after being purified by an appropriate method. 
1-Substituted 3,3-bis(hydroxycarbonyl-methyl)indolin-2-one (9) is converted 
to an amide compound in a conventional manner to obtain diamide compound 
(10). For example, 1-substituted 
3,3-bis(hydroxycarbonylmethyl)indolin-2-one (9) is dissolved in an inert 
solvent, such as dry N,N-dimethylformamide or dichloromethane, and 2 to 4 
moles, per mol of (9), of dicyclohexylcarbodiimide or 
1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride is added 
thereto as a condensing agent. Subsequently, 0 to 4 mol of 
1-hydroxybenzotriazole or 4-dimethylaminopyridine as an activating agent 
and 2 to 4 mol of an amine, each per mol of (9) are preferably added 
thereto at room temperature. The mixture is stirred at room temperature 
for 6 to 24 hours. To the reaction mixture, either as obtained or after 
concentration under reduced pressure, is added dilute hydrochloric acid. 
The product is extracted with an appropriate organic solvent, and the 
organic layer is washed with an appropriate base, such as saturated 
aqueous sodium hydrogencarbonate, dried, and concentrated. The concentrate 
is purified by an appropriate method to obtain diamide compound (10). 
As shown in Reaction Route 3, monocarbamate (13) can be prepared by Aldol 
reaction of N-substituted isatin derivative (3) as a starting material, 
conversion of the reaction product to an amide compound, and reaction of 
the resulting tertiary alcohol (12) with an isocyanate using a catalyst. 
The preparation of monocarbamate derivative (13) can preferably be carried 
out as follows. A lithium enolate of an acetic ester is prepared by mixing 
a lithium salt of a secondary amine, such as lithium diisopropylamide or 
lithium hexamethyldisilazide, with an acetic ester at an equimolar ratio 
in a solvent which gives no adverse influence to the reaction, such as dry 
tetrahydrofuran, dry diethyl ether or dry dioxane, preferably dry 
tetrahydrofuran, by stirring under a nitrogen atmosphere at a low 
temperature for several minutes. To the resulting reaction solution is 
added 0.5 mol of N-substituted isatin (3) per mol of the lithium enolate 
at a low temperature, followed by stirring at a low temperature for 
several tens of minutes, and the reaction mixture is poured into water to 
quench the reaction. The reaction product is extracted with an appropriate 
organic solvent, and the extract is dried and concentrated to obtain ester 
intermediate (11). This crude product (11) may be used in the subsequent 
reaction either without purification or after purification by a proper 
method. 
An amine is dissolved in a solvent giving no adverse influence to the 
reaction, such as dry tetrahydrofuran, dry diethyl ether or dry dioxane, 
preferably dry tetrahydrofuran, and an equimolar amount of an alkyl 
lithium, preferably n-butyl lithium, is added to the solution under a 
nitrogen atmosphere at a low temperature, followed by stirring at a low 
temperature for several minutes. To the resulting solution is added 0.5 
mol of ester intermediate (11) per mol of the amine, and the mixture is 
stirred at a low temperature for several tens of minutes. The reaction 
mixture is poured into water to quench the reaction, and the product is 
extracted with an appropriate organic solvent. The extract is dried and 
concentrated, and the concentrate is purified by a proper method to obtain 
amide intermediate (12). 
Amide intermediate (12) and excess isocyanate compound are dissolved in an 
inert solvent, such as dry tetrahydrofuran, dichloromethane, acetonitrile 
or toluene, preferably dry tetrahydrofuran, and a small proportion, with 
reference to (12), of an acid or a base, such as a titanium tetraalkoxide, 
a boron trifluoride ethyl etherate, dibutyltin diacetate or 
diisopropylethylamine, preferably dibutyltin diacetate, is added to the 
solution, followed by stirring for 10 to 24 hours at room temperature or 
under heating. The reaction mixture is washed with water, extracted with 
an appropriate solvent, dried, and concentrated. The concentrate is 
purified by a proper method to obtain monocarbamate compound (13). 
Monourea compound (19) can be prepared through either of the processes 
illustrated in Reaction Routes 4 and 5. 
Some ureido intermediates (15) shown in Reaction Route 4 are known 
compounds and can be synthesized by starting with isatin derivative (1) in 
accordance with the process described in patents (Japanese Patent 
Publication Nos. 6710/92 and 6711/92). An acetic ester is bonded to the 
thus prepared ureido intermediate (15), and the resulting ester is 
hydrolyzed to give carboxylic acid (17). The 1-position of (17) is 
selectively alkylated to give compound (18), which is then converted to 
monourea compound (19) by amidation. The alkylation and the subsequent 
amidation of carboxylic acid (17) may be carried out in one step. 
Ureido intermediate (23) in Reaction Route 5 can be synthesized by starting 
with N-substituted isatin (3) in accordance with the process described in 
patents (Japanese Patent Publication Nos. 6710/92 and 6711/92). 
Alternatively, it may be prepared by converting isatin derivative (1) to 
alkyloxime or aralkyloxime (20), for example, methyloxime or benzyloxime, 
alkylating the 1-position, hydrogenation of oxime, and then leading the 
product to urea. N-Substituted isatin (3) can also be synthesized by 
alkylating the 1-position of starting indole (32) to obtain 1-substituted 
indole (33), followed by oxidizing the indole ring with, for example, 
sodium hypochlorite to give (34), which is then hydrolyzed as shown in 
Reaction Route 8. Where a bulky group, such as a secondary alkyl group, a 
2,2-dialkoxyethyl group or a 2,2-dialkylethyl group, is to be introduced 
to the 1-position, the reaction route by way of alkyloxime or aralkyloxime 
(20) or the route including oxidation of 1-substituted indole (33) are 
preferred. An acetic ester is bonded to the thus prepared ureido 
intermediate (23), and the resulting ester is hydrolyzed to give 
carboxylic acid (18), which is then converted to monourea compound (19) by 
amidation. Alternatively, an acetamide derivative can directly be added to 
(23) to prepare (19). Most of bromoacetamide derivatives (25) which can be 
used in this reaction are known compounds and can easily be synthesized by 
mixing bromoacetyl bromide and an amine in the presence of a base. 
The preparation of monourea compound (19) through Reaction Route 4 can 
preferably be carried out as follows. Isatin derivative (1) is dissolved 
in an inert solvent, such as ethanol or methanol, and an equimolar or 
excessive molar amount, with reference to (1), of a hydroxylamine 
hydrochloride or a hydroxylamine sulfate, and the same quantity of a base, 
such as a sodium acetate aqueous solution, are added thereto, followed by 
stirring for 1 to 10 hours at room temperature or under ice-cooling. The 
reaction mixture is concentrated, and the concentrate is purified by a 
proper method to give oxime derivative (14). Oxime derivative (14) is 
stirred in an inert solvent, such as ethanol, methanol or acetic acid, in 
the presence of an appropriate catalyst, such as palladium-on-carbon, 
rhodium-on-carbon, platinum oxide, or Raney nickel, under a hydrogen 
atmosphere of 1 to 6 atm at room temperature. After removal of the 
catalyst by filtration, the filtrate is concentrated to give an amine 
intermediate. Since this compound is susceptible to air oxidation, it is 
preferably subjected to the subsequent reaction without further 
purification. The unpurified product is dissolved in an inert solvent, 
such as dichloromethane, chloroform, N,N-dimethylformamide, or 
acetonitrile, and an equimolar or slightly excessive amount, with 
reference to the amine, of an isocyanate is added thereto at a temperature 
in the range from ice-cooling to room temperature, followed by stirring at 
a temperature in the range from ice-cooling to room temperature for 1 to 
10 hours. The reaction product is purified by a proper method to give 
ureido intermediate (15). 
Ureido intermediate (15) is dissolved in an inert solvent, such as dry 
N,N-dimethylformamide, dry dimethyl sulfoxide or dry tetrahydrofuran, 
preferably dry dimethyl sulfoxide, and a solution of an equimolar amount, 
with reference to ureido intermediate (15), of a base, such as a metal 
hydride or a metal alkoxide, preferably sodium hydride or potassium 
t-butoxide, in dry dimethyl sulfoxide is added thereto at a temperature in 
the range from ice-cooling to room temperature, followed by stirring at a 
temperature in the range from ice-cooling to room temperature for 10 to 30 
minutes. Then, a bromoacetic ester is added thereto in an equimolar amount 
with reference to ureido intermediate (15), and the mixture is stirred at 
room temperature for several tens of minutes. After completion of the 
reaction, water is added to the reaction mixture, and the mixture is 
extracted with an appropriate solvent, such as diethyl ether. The extract 
is dried and concentrated under reduced pressure, and the residue is 
purified by a proper method to obtain ester compound (16). 
Ester compound (16) is stirred in a solvent uniformly miscible with water, 
such as ethanol or methanol, together with an aqueous solution of a 
moderate excess of a base, such as potassium hydroxide, sodium hydroxide 
or potassium carbonate, at room temperature for 1 to 24 hours. After 
completion of the reaction, the reaction mixture is concentrated under 
reduced pressure. The concentrate is dissolved in water and washed with an 
appropriate organic solvent, such as chloroform. The aqueous layer is 
acidified with 2N hydrochloric acid and then extracted with an appropriate 
organic solvent, such as ethyl acetate, to obtain carboxylic acid (17). 
The resulting crude product may be used in the subsequent reaction either 
as it is or after being purified by a proper method. 
Carboxylic acid (17) is dissolved in a solvent giving no adverse influence 
to the reaction, such as dry dimethyl sulfoxide or dry tetrahydrofuran, 
preferably dry dimethyl sulfoxide, and a solution of 2 mol, per mol of 
carboxylic acid (17), of a base, such as a metal hydride or a metal 
alkoxide, preferably sodium hydride or potassium t-butoxide, in dry 
dimethyl sulfoxide is added thereto at room temperature, followed by 
stirring at room temperature for 10 to 30 minutes. A halide is added 
thereto in an equimolar amount with carboxylic acid (17), followed by 
stirring at room temperature for several tens of minutes. After completion 
of the reaction, water is added to the reaction mixture, and the mixture 
is extracted with an appropriate solvent, such as diethyl ether. The 
extract is dried and concentrated under reduced pressure to obtain 1-alkyl 
compound (18). The resulting crude product may be used in the subsequent 
reaction either as it is or after being purified by a proper method. 
1-Alkyl compound (18) is dissolved in an inert solvent, such as dry 
N,N-dimethylformamide or dichloromethane, and 1 to 4 mol, per mol of 
1-alkyl compound (18), of a condensing agent, such as 
dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide 
hydrochloride, is added to the solution. To the solution are further added 
successively 0 to 4 mol of 1-hydroxybenzotriazole or 
4-dimethylaminopyridine as an activating agent and 1 to 4 mol of an amine, 
each per mol of 1-alkyl compound (18) at room temperature. The mixture is 
stirred at room temperature for 1 to 24 hours. 
Alternatively, 1-alkyl compound (18) is dissolved in an inert solvent, such 
as chloroform or dichloromethane, and an equimolar amount or a slight 
excess, with reference to 1-alkyl compound (18), of a base, such as 
4-dimethylaminopyridine, triethylamine, pyridine or a mixture thereof, and 
an equimolar amount of a halogenating agent, preferably thionyl chloride, 
are added thereto at 0.degree. C. to room temperature. After stirring the 
mixture for 30 minutes to 2 hours, an equimolar amount or a slight excess, 
with reference to 1-alkyl compound (18), of a base, such as 
4-dimethylaminopyridine, triethylamine, pyridine or a mixture thereof, and 
an equimolar amount or a slight excess of an amine are added thereto, 
followed by stirring at room temperature or under ice-cooling for 30 
minutes to 4 hours. 
Dilute hydrochloric acid is added to the reaction mixture either as 
obtained or after being concentrated under reduced pressure, and the 
mixture is extracted with an appropriate organic solvent. The organic 
layer is washed with an appropriate base, such as saturated aqueous sodium 
hydrogencarbonate, dried, and concentrated. The residue is purified by an 
appropriate method to give monourea compound (19). 
Monourea compound (19) can also be prepared from carboxylic acid (17) 
without isolating (18). Carboxylic acid (17) is dissolved in a solvent 
giving no adverse influence to the reaction, such as dry 
N,N-dimethylformamide, dry dimethyl sulfoxide or dry tetrahydrofuran, 
preferably dry dimethyl sulfoxide. A solution of 2 mol, per mol of 
carboxylic acid (17), of a base, such as a metal hydride or a metal 
alkoxide, preferably sodium hydride or potassium t-butoxide, in dry 
dimethyl sulfoxide is added to the solution at room temperature, followed 
by stirring at room temperature for 10 to 30 minutes. To the mixture is 
further added a halide in an equimolar amount with carboxylic acid (17), 
followed by stirring at room temperature for several tens of minutes. 
After completion of the reaction, 1 to 3 mol, per mol of carboxylic acid 
(17), of a condensing agent, such as dicyclohexylcarbodiimide or 
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is added to 
the reaction mixture. Subsequently, 0 to 3 mol, per mol of 1-alkyl 
compound (18), of 1-hydroxybenzotriazole or 4-dimethylaminopyridine is 
preferably added thereto as an activating agent, and then 1 to 3 mol, per 
mol of 1-alkyl compound (18), of an amine is further added thereto, 
followed by stirring at room temperature for 6 to 24 hours. Water is added 
to the reaction mixture, and the mixture is extracted with an appropriate 
solvent, such as diethyl ether. The extract is dried, concentrated under 
reduced pressure, and purified by an appropriate method to give monourea 
compound (19). 
The preparation of monourea compound (19) through Reaction Route 5 can 
preferably be carried out as follows. First of all, ureido intermediate 
(23) with its 1-position alkylated is prepared by starting with 
N-substituted isatin (3), which is synthesized by the process shown in 
Reaction Route 8 or by alkylation of isatin derivative (1), in the same 
manner as in the preparation of ureido intermediate (15) shown in Reaction 
Route 4. Alternatively, ureido intermediate (23) may be prepared as 
follows. Isatin derivative (1) is dissolved or suspended in an inert 
solvent, such as ethanol or methanol, and to the solution or suspension 
are added an equimolar or excess molar amount, with reference to (1), of 
an O-alkylhydroxylamine or an O-aralkylhydroxylamine, such as O-methyl or 
benzylhydroxylamine hydrochloride, and an aqueous solution of excess base, 
such as sodium acetate, and the mixture is stirred at room temperature for 
1 to 10 hours. The reaction mixture is concentrated and purified by a 
proper method to obtain alkyloxime (e.g., methyloxime) or aralkyloxime 
(e.g., benzyloxime) derivative (20). Then, an equimolar amount or a slight 
excess, with reference to (20), of a base, such as sodium hydride or 
potassium t-butoxide, is dissolved or suspended in an inert solvent, such 
as dry N,N-dimethylformamide, dry dimethyl sulfoxide or dry 
tetrahydrofuran. Alkyloxime derivative or aralkyloxime derivative (20) is 
added to the solution or suspension at room temperature or under 
ice-cooling. After stirring at the same temperature for 30 minutes to 1 
hour, an equimolar amount or a slight excess, with reference to (20), of a 
halide is added thereto, followed by further stirring at room temperature 
or under heating for 1 to 15 hours. After completion of the reaction, the 
solvent was evaporated under reduced pressure, water is added to the 
residue, and the mixture is extracted with an appropriate solvent. The 
extract is dried and concentrated under reduced pressure. The resulting 
crude product is purified by a proper method to obtain N-substituted 
compound (21), which is hydrogenated and reacted with isocyanate in the 
same manner as for the preparation of ureido intermediate (15) shown in 
Reaction Route 4 to thereby obtain ureido intermediate (23) with the 
1-position alkylated. 
The thus obtained ureido intermediate (23) is subjected to acetic ester 
addition reaction and ester hydrolysis reaction as shown in Reaction Route 
5 in the same manner as in the preparation of carboxylic acid (17) shown 
in Reaction Route 4 to give intermediate (18) common to both reaction 
routes, which is converted to monourea compound (19) in the same manner as 
in Reaction Route 4. 
Alternatively, monourea compound (18) can be prepared from ureido 
intermediate (23) in one step as described below. Ureido intermediate (23) 
is dissolved in an inert solvent, such as dry N,N-dimethylformamide, dry 
dimethyl sulfoxide or dry tetrahydrofuran, preferably dry dimethyl 
sulfoxide. To the solution is added a solution of an equimolar amount, 
with reference to ureido intermediate (23), of a base, such as a metal 
hydride or a metal alkoxide, preferably sodium hydride or potassium 
t-butoxide, in dried dimethyl sulfoxide at a temperature in the range from 
ice-cooling to room temperature, followed by stirring at a temperature in 
the range from ice-cooling to room temperature for 10 to 30 minutes. To 
the solution is further added an equimolar amount or a slight excess, with 
reference to ureido intermediate (23), of a bromoacetamide derivative 
(25), followed by stirring at room temperature for several tens of 
minutes. After completion of the reaction, water is added to the reaction 
mixture, and the mixture is extracted with an appropriate solvent, such as 
diethyl ether. The extract is dried and concentrated under reduced 
pressure. The residue is purified by a proper method to give monourea 
compound (19). 
The preparation of N-substituted isatin (3) according to Reaction Route 8 
can preferably be carried out as follows. Indole (32) is dissolved in a 
solvent giving no adverse influence to the reaction, such as dry 
N,N-dimethylformamide or dry tetrahydrofuran, preferably dry dimethyl 
sulfoxide, and a solution of an equimolar amount or an excess, with 
reference to indole (32), of a base, such as sodium hydride or potassium 
t-butoxide, in dry dimethyl sulfoxide, is added thereto at room 
temperature, followed by stirring at room temperature for 10 minutes to 1 
hour. An equimolar amount or an excess molar amount, with reference to 
indole (32), of a halide is then added thereto, followed by stirring at 
room temperature or under heating for several tens of minutes to 10 hours. 
After completion of the reaction, water is added to the reaction mixture, 
followed by extraction with an appropriate solvent, such as diethyl ether. 
The extract is dried and concentrated under reduced pressure to give 
1-substituted indole (33). The resulting crude product may be used in the 
next reation or may be purified by a proper method. Then, 1-substituted 
indole (33) and, as a proton source, excess potassium dihydrogenphosphate 
or sodium dihydrogenphosphate are suspended in an appropriate solvent, 
such as ethyl acetate, and an aqueous solution of excess sodium 
hypochlorite is added thereto at room temperature or under ice-cooling, 
followed by stirring at that temperature for 5 to 30 minutes. After 
completion of the reaction, the reaction mixture is washed successively 
with water and a base, dried, and concentrated to give dichloro compound 
(34). The resulting crude product may be used in the subsequent reaction 
or may be purified by a proper method. Dichloro compound (34) is dissolved 
in an appropriate solvent, such as dimethyl sulfoxide, and excess base 
suitable for hydrolysis, for example, an aqueous solution of sodium 
hydroxide, is added thereto dropwise, followed by stirring for 10 minutes 
to 1 hour. To the mixture is slowly added an acid, e.g., concentrated 
hydrochloric acid, in excess over the base previously added, followed by 
stirring at room temperature for several hours. To the reaction mixture is 
added ethyl acetate, and the mixture is washed successively with water and 
a base. The organic layer is dried and concentrated to give N-substituted 
isatin (3). The resulting crude product can be used as an intermediate in 
Reaction Route 5 either without purification or after being purified by a 
proper method. 
Of monourea compounds (19), those containing an acetal group or an amino 
group in the substituent at the 1-position can be prepared by the 
processes shown in Reaction Routes 4 and 5. In addition, monourea compound 
(19) containing acetal at the 1-substituent, i.e., monourea compound (28) 
can be prepared by acetal exchange from another acetal compound or by 
hydrolyzing the another acetal compound to once give aldehyde compound 
(27) which is then converted to acetal compound (28). Monourea compound 
(19) containing an amino group at the 1-substituent, i.e., monourea 
compound (29) can be prepared by reductive amination reaction of aldehyde 
compound (27). 
The preparation of monourea compound (28) containing acetal at the 
1-substituent can preferably be carried out as follows. Acetal compound 
(26) prepared by the process shown in Reaction Route 4 or 5 is dissolved 
in an alcohol for acetal exchange and stirred for 6 hours to 2 days while 
heating in the presence of an appropriate acid, such as p-toluenesulfonic 
acid, sulfuric acid or camphorsulfonic acid, as a catalyst. The reaction 
mixture is concentrated, and an appropriate base, for example, an aqueous 
solution of sodium hydrogencarbonate, is added thereto, followed by 
extraction with an appropriate organic solvent. The extract is dried and 
concentrated under reduced pressure. The residue is purified by a proper 
method to obtain (28). Alternatively, (26) is dissolved or suspended in an 
inert solvent, such as acetone, an alcohol, water or a mixture thereof, 
and an adequate amount of an appropriate acid, such as p-toluenesulfonic 
acid, sulfuric acid or camphorsulfonic acid, is added thereto, followed by 
stirring at room temperature or under heating for 1 to 18 hours. The 
reaction mixture is concentrated, an appropriate base, e.g., a sodium 
hydrogencarbonate aqueous solution, is added thereto, the mixture is 
extracted with an appropriate organic solvent, and the extract is dried 
and concentrated under reduced pressure to give aldehyde compound (27). 
This crude product may be used in the subsequent reaction without 
purification or after being purified by a proper method. Aldehyde compound 
(27) and an appropriate alcohol or diol in excess over aldehyde compound 
(27) are dissolved or suspended in an inert solvent, preferably toluene or 
benzene, and stirred in the presence of an appropriate acid catalyst, such 
as p-toluenesulfonic acid, sulfuric acid or camphorsulfonic acid, for 6 to 
48 hours under heating while azeotropically removing produced water 
together with the solvent. The reaction mixture is washed with an 
appropriate base, such as an aqueous solution of sodium hydrogencarbonate, 
dried, and concentrated. The concentrate is purified by a proper method to 
give acetal compound (28). 
The preparation of monourea compound (28) containing an amino group at the 
1-substituent can preferably be carried out as follows. Aldehyde compound 
(27) and an equivalent or excess of an amine or an aqueous solution 
thereof are dissolved in an inert solvent, such as methanol. After 
neutralizing the solution with an appropriate acid, such as acetic acid, 
trifluoroacetic acid or hydrochloric acid, an equivalent or excess, with 
reference to (27), of a hydrogenating agent, such as sodium 
cyanoborohydride, is added to the solution, followed by stirring at room 
temperature for 4 to 48 hours. The reaction mixture is concentrated, water 
is added thereto, the mixture is extracted with an appropriate organic 
solvent. The extract is dried and concentrated, and the residue is 
purified by a proper method to give amino compound (29). 
The preparation of monourea compound (30) containing thioacetal in the 
1-substituent can preferably be carried out as follows. Acetal compound 
(26) prepared by the process shown in Reaction Route 4 or 5 is dissolved 
in an inert solvent, such as dry tetrahydrofuran, acetonitrile or 
dichloromethane, preferably dichloromethane. A mercaptan in an amount of 2 
mol per mol of (26) or in excess over (26) and 2 equivalents, with 
reference to acetal (26), of an appropriate Lewis acid, such as boron 
trifluoride ethyl etherate, are added to the solution at room temperature 
or a low temperature, followed by stirring at room temperature for 10 
minutes to 2 hours. The reaction mixture is concentrated, an appropriate 
base, such as 1N sodium hydroxide, is added thereto, and the mixture is 
extracted with an appropriate organic solvent. The extract is dried and 
concentrated under reduced pressure, and the residue is purified by a 
proper method to give (30). 
Each enantiomer of monourea compound (19) can be prepared by 
stereospecifically bonding an optically active acetic ester to racemic 
ureido intermediate (23) to give (31), which is recrystallized to give a 
single diastereomer, hydrolyzing the diastereomer, and converting the 
resulting carboxylic acid to an amide as shown in Reaction Route 7. The 
single diastereomer of (31) can also be obtained by once preparing a 
diastereomer mixture of (31) by nonselective addition of an optically 
active acetic ester to racemic ureido intermediate (23) or by 
esterification of racemic carboxylic acid intermediate (18) and then 
resolving the mixture by recrystallization from an appropriate solvent. 
The preparation of each enantiomer of monourea compound (19) by Reaction 
Route 7 can preferably be carried out as follows. Ureido intermediate (23) 
is dissolved in a solvent giving no adverse influence to the reaction, 
preferably dry tetrahydrofuran or dry dioxane, under a nitrogen 
atmosphere, and an equivalent, with reference to (23), of a lithium agent, 
such as an alkyl lithium, lithium amide or a lithium alkoxide, is added 
thereto at a low temperature, followed by stirring at a low temperature 
for 1 to 30 minutes. Additionally, an equivalent, with reference to (23), 
of an optically active bromoacetic ester, preferably L- or D-menthyl 
bromoacetate is added thereto at a low temperature, followed by stirring 
at -10.degree. C. to room temperature for 4 to 24 hours. Water is added to 
the reaction mixture, and the mixture is extracted with an appropriate 
organic solvent. The extract is dried and concentrated, and the residue is 
recrystallized 1 to 5 times from an appropriate solvent, such as ethyl 
ether, isopropyl ether, hexane, an alcohol, water or a mixture thereof, to 
give a single diastereomer of (31). The optical purity of (31) can be 
analyzed by high performance liquid chromatography, high resolution 
nuclear magnetic resonance spectrum, and the like. Subsequently, the 
single diastereomer of (31) is hydrolyzed in the same manner as in the 
preparation of carboxylic acid (17) in Reaction Route 4 to obtain 
optically active intermediate (18) common to both reaction routes, which 
is then led to optically active monourea compound (19) in the same manner 
as in Reaction Route 4.