Novel benzo-furan(or -thiophene) derivative of the formula: ##STR1## wherein R.sup.1 is hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl-lower alkyl group or a substituted or unsubstituted phenyl group, R.sup.2 is hydrogen atom, a lower alkyl group, an acyl group or phenyl group, R.sup.3 is hydrogen atom, a halogen atom, nitro group, a lower alkoxy group, amino group or an acylamino group, R.sup.4 is a group of the formula: ##STR2## A is a lower alkylene group optionally substituted with hydroxy group, B is single bond or a lower alkylene group, one of R.sup.5 and R.sup.6 is hydrogen atom or a lower alkyl group and the other is a lower alkyl group or a phenyl-lower alkyl group, or R.sup.5 and R.sup.6 combine together with adjacent nitrogen atom to form a heteromonocyclic group, R.sup.7 is a lower alkyl group, X is oxygen atom or sulfur atom, Y is oxygen atom, imino group, a lower alkylimino group or a phenyl-lower alkylimino group and a salt thereof are disclosed. Said compound (I) and a salt thereof have a potent inhibitory activity against reflective contraction of urinary bladder.

This invention relates to a benzo-furan(or -thiophene) derivative and 
processes for preparing the same. More particularly, it relates to a 
benzo-furan(or -thiophene) derivative of the formula: 
##STR3## 
wherein R.sup.1 is hydrogen atom, a lower alkyl group, a cycloalkyl group, 
a phenyl-lower alkyl group or a substituted or unsubstituted phenyl group, 
R.sup.2 is hydrogen atom, a lower alkyl group, an acyl group or phenyl 
group, R.sup.3 is hydrogen atom, a halogen atom, nitro group, a lower 
alkoxy group, amino group or an acylamino group, R.sup.4 is a group of the 
formula: 
##STR4## 
A is a lower alkylene group optionally substituted with hydroxy group, B 
is single bond or a lower alkylene group, one of R.sup.5 and R.sup.6 is 
hydrogen atom or a lower alkyl group and the other is a lower alkyl group 
or a phenyl-lower alkyl group, or R.sup.5 and R.sup.6 combine together 
with adjacent nitrogen atom to from a heteromonocyclic group, R.sup.7 is a 
lower alkyl group, X is oxygen atom or sulfur atom, Y is oxygen atom, 
imino group, a lower alkylimino group or a phenyl-lower alkylimino group, 
or a salt thereof. 
Pollakiuria (i.e., frequent micturition) is a symptom of diminition in 
effective bladder capacity and causes a person much trouble in his daily 
life. Since micturition is caused by reflective contraction of urinary 
bladder, a drug which inhibits the reflective contraction is useful for 
treatment of pollakiuria. A typical example of such a drug is flavoxate 
[chemical name: 2-piperidinoethyl 
3-methyl-4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylate (The Journal of 
Clinical Pharmacology, Vol. 10, 65-68 (1970))]. 
The compound (I) of the present invention and a salt thereof have potent 
inhibitory activity against the reflective contraction of the urinary 
bladder. For example, when 2-pyrrolidinoethyl 
2-phenylbenzofuran-7-carboxylate was administered intravenously to 
anesthetized rats, the inhibitory activity of this compound against the 
reflective contraction of the urinary bladder was more than 1.5 times as 
strong as that of flavoxate. 
Examples of the compound of the present invention include those of the 
formula (I) in which R.sup.1 is hydrogen atom, a lower alkyl group (e.g., 
methyl, ethyl, propyl, butyl or pentyl), a cycloalkyl group (e.g., 
cyclopropyl, cyclopentyl or cyclohexyl), a phenyl-lower alkyl group (e.g., 
benzyl) or phenyl group, or R.sup.1 is a phenyl group having a substituent 
selected from a halogen atom (e.g., chlorine, bromine or iodine), nitro 
group, a lower alkoxy group (e.g., methoxy, ethoxy, propoxy or butoxy), 
amino group, a di(lower alkyl)amino group (e.g., dimethylamino or 
diethylamino) and an acylamino group (e.g., a lower alkanoylamino group 
such as acetylamino or propionylamino, benzoylamino or 
benzylcarbonylamino); R.sup.2 is hydrogen atom, a lower alkyl group (e.g., 
methyl, ethyl, propyl, butyl or pentyl), an acyl group (e.g., a lower 
alkanoyl group such as acetyl or benzoyl) or phenyl group; R.sup.3 is 
hydrogen atom, a halogen atom (chlorine, bromine or iodine), nitro group, 
a lower alkoxy group (e.g., methoxy, ethoxy, propoxy, butoxy or 
pentyloxy), amino group or an acylamino group (e.g., a lower alkanoylamino 
group such as acetylamino or propionylamino, benzoylamino or 
benzylcarbonylamino); R.sup.4 is a group of the formula: 
##STR5## 
A is a lower alkylene group optionally substituted with hydroxy group 
(e.g., methylene, ethylene, trimethylene, tetramethylene, pentamethylene, 
1-methylethylene, 1,1-dimethylethylene or 2-hydroxytrimethylene), B is 
single bond or a lower alkylene group (e.g., methylene, ethylene, 
trimethylene, tetramethylene or pentamethylene), one of R.sup.5 and 
R.sup.6 is hydrogen atom or a lower alkyl group (e.g., methyl, ethyl, 
propyl, butyl or pentyl) and the other is a lower alkyl group (e.g., 
methyl, ethyl, propyl, butyl or pentyl) or a phenyl-lower alkyl group 
(e.g., benzyl), or R.sup.5 and R.sup.6 combine together with adjacent 
nitrogen atom to form a heteromonocyclic group (e.g., pyrrolidino, 
piperidino or morpholino); R.sup.7 is a lower alkyl group (e.g., methyl, 
ethyl, propyl, butyl or pentyl); X is oxygen atom or sulfur atom; Y is 
oxygen atom, imino group, a lower alkylimino group (e.g., methylimino, 
ethylimino, propylimino, butylimino or pentylimino) or a phenyl-lower 
alkylimino group (e.g., benzylimino or phenethylimino). 
Among the compound (I) of the present invention, a preferred subgenus is 
those of the formula: 
##STR6## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, X and Y are the same as 
defined above. 
More preferred subgenus is those of the formula (i) in which R.sup.1 is 
hydrogen atom, a C.sub.1-4 alkyl group, a C.sub.3-7 cycloalkyl group, a 
phenyl-C.sub.1-4 alkyl group, phenyl group, a halogenophenyl group, 
nitrophenyl group, a C.sub.1-4 alkoxyphenyl group, aminophenyl group, a 
di(C.sub.1-4 alkyl)amino-phenyl group or a C.sub.2-5 alkanoylaminophenyl 
group; R.sup.2 is hydrogen atom, a C.sub.1-4 alkyl group, a C.sub.2-5 
alkanoyl group, benzoyl group or phenyl group; R.sup.3 is hydrogen atom, 
chlorine atom, nitro group, a C.sub.1-4 alkoxy group, amino group or a 
C.sub.2-5 alkanoylamino group; R.sup.4 is a group of the formula: 
##STR7## 
A is a C.sub.1-6 alkylene group optionally substituted with hydroxy group; 
B is single bond or a C.sub.1-6 alkylene group; one of R.sup.5 and R.sup.6 
is hydrogen atom or a C.sub.1-4 alkyl group and the other is a C.sub.1-4 
alkyl group or benzyl group, or R.sup.5 and R.sup.6 combine together with 
adjacent nitrogen atom to form pyrrolidino, piperidino or morpholino 
group; R.sup.7 is a C.sub.1-4 alkyl group; X is oxygen atom or sulfur 
atom; Y is oxygen atom, imino group, a C.sub.1-4 alkylimino group or a 
phenyl-C.sub.1-4 alkylimino group. 
Another preferred subgenus is those of the formula (i) in which R.sup.1 is 
hydrogen atom, a C.sub.1-4 alkyl group or nitrophenyl group, R.sup.2 is 
hydrogen atom or a C.sub.2-4 alkanoylamino group, R.sup.4 is a group of 
the formula: 
##STR8## 
A is a C.sub.1-4 alkylene group, B is a C.sub.1-4 alkylene group, R.sup.5 
and R.sup.6 combine together with adjacent nitrogen atom to form 
pyrrolidino, piperidino or morpholino group, and R.sup.7 is a C.sub.1-4 
alkyl group. 
Further preferred subgenus is those of the formula (i) in which R.sup.1 is 
hydrogen atom, methyl, phenyl or nitrophenyl group, R.sup.2 is hydrogen 
atom or phenyl group, R.sup.3 is hydrogen atom or acetylamino group, and 
R.sup.4 is 2-pyrrolidinoethyl, 2-piperidinoethyl or 2-morpholinoethyl 
group. 
The compound (I) in which R.sup.4 is a group of the formula: 
##STR9## 
and A is a lower alkylene group containing hydroxy group or a 
branched-lower alkylene group (e.g., methylethylene) can exist in the form 
of two optical isomers. The present invention also includes these optical 
isomers or a mixture thereof within its scope. 
According to the present invention, the compound (I) in which Y is oxygen 
atom or imino group, i.e., the compound of the formula: 
##STR10## 
wherein Y.sup.1 is oxygen atom or imino group, and R.sup.1, R.sup.2, 
R.sup.3, R.sup.4 and X are the same as defined above, or a salt thereof 
can be prepared by the step or steps of: 
[A-(1)] condensing the following two compounds of the formula: 
##STR11## 
wheren one of Z.sup.1 and Z.sup.2 is a group of the formula: --Y.sup.1 --H 
and the other is a reactive residue, or Z.sup.1 is hydroxy group and 
Z.sup.2 is a group of the formula: --Y.sup.1 --H, and R.sup.1, R.sup.2, 
R.sup.3, R.sup.4, X and Y.sup.1 are the same as defined above; and 
[A-(2)] if required, further converting the thus-obtained product into a 
salt thereof. 
Alternatively, the compound (I) in which Y is oxygen atom, i.e., the 
compound of the formula: 
##STR12## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and X are the same as defined 
above, or a salt can be prepared by the step or steps of: 
[B-(1)] subjecting a compound of the formula: 
##STR13## 
wherein R.sup.8 is a lower alkyl group, and R.sup.1, R.sup.2, R.sup.3 and 
X are the same as defined above and a compound of the formula: 
EQU R.sup.4 --OH (III-A) 
wherein R.sup.4 is the same as defined above to transesterification 
reaction; and 
[B-(2)] if required, further converting the thus-obtained product into a 
salt thereof. 
Further, the compound (I) in which Y is a lower alkylimino group or a 
phenyl-lower alkylimino group, i.e., the compound of the formula: 
##STR14## 
wherein R.sup.9 is a lower alkyl group or a phenyl-lower alkyl group, 
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and X are the same as defined above, or 
a salt thereof can be prepared by the step or steps of: 
[C-(1)] reacting a compound of the formula: 
##STR15## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and X are the same as defined 
above, with a compound of the formula: 
EQU R.sup.9 --W (V) 
wherein R.sup.9 is the same as defined above and W is a reactive residue; 
and 
[C-(2)] if required, further converting the product into a salt thereof. 
[D] When R.sup.1 is a phenyl group substituted with nitro group and/or 
R.sup.3 is nitro group, said nitro group(s) may be if required, reduced to 
amino group(s) and said amino groups(s) may be, if required, further 
acylated to acylamino group(s), before the step A-(2), B-(2) or C-(2). 
In the above-mentioned reactions, the starting compounds (II), (III), (IV) 
and (I-D), if required, can be used in the form of a salt thereof. 
Examples of the salt of said compounds include hydrochloride, 
hydrobromide, sulfate, oxalate, fumarate, methansulfonate and the like. 
Further, when one of Z.sup.1 and Z.sup.2 is a reactive residue, examples 
of the reactive residue include a halogen atom such as chlorine, bromine 
or iodine. Moreover, examples of the reactive residue W include a halogen 
atom such as chlorine or bromine, methanesulfonyloxy and 
p-toluenesulfonyloxy. 
[Step A-(1)] 
The condensation reaction of the compound (II) (Z.sup.1 =reactive residue) 
with the compound (III) (Z.sup.2 =--Y.sup.1 --H) and the condensation 
reaction of the compound (II) (Z.sup.1 =--Y.sup.1 --H) with the compound 
(III) (Z.sup.1 =reactive residue) can be carried out in the presence or 
absence of an acid acceptor in a solvent. Suitable examples of the solvent 
which is used in the former condensation reaction are dichloromethane, 
dichloroethane, chloroform, carbon tetrachloride, ether, tetrahydrofuran, 
pyridine, benzene, toluene and the like. On the other hand, suitable 
examples of the solvent which is used in the latter condensation reaction 
are lower alkanoyl (e.g., methanol, ethanol and the like), acetone, 
tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide and the 
like. Examples of the acid acceptor include, for example, inorganic bases 
such as alkali metal hydroxides (e.g., sodium hydroxide, potassium 
hydroxide), alkali metal carbonates (e.g., sodium carbonate, potassium 
carbonate), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium 
bicarbonate), alkaline earth metal hydroxides (e.g., calcium hydroxide, 
barium hydroxide) or silver hydroxide; and organic bases such as 
triethylamine or pyridine. It is preferred to carry out the reaction at a 
temperature of 0.degree. to 100.degree. C., especially 0.degree. to 
30.degree. C. 
Concomitantly, the starting compound (II) in which Z.sup.1 is a reactive 
residue can be prepared by reacting the compound (II) in which Z.sup.1 is 
hydroxy group, with a halogenating agent (e.g., a thionyl halide such as 
thionyl chloride or thionyl bromide, an oxalyl halide such as oxalyl 
chloride or oxalyl bromide). 
Further, the condensation reaction of the compound (II) (Z.sup.1 =hydroxy 
group) with the compound (III) (Z.sup.2 =--Y.sup.1 --H) can be carried out 
in the presence of a condensing agent in a solvent. Chloroform, 
dichloromethane, tetrahydrofuran, dimethylsulfoxide, acetonitrile and the 
like are suitable as the solvent. Suitable examples of the condensing 
agent include N,N-dicyclohexylcarbodiimide, a combination of 
N,N-dicyclohexylcarbodiimide and N-hydroxysuccinimide or 
N-hydroxybenzotriazole, carbonyldiimidazole, ethyl chlorocarbonate, 
isobutyl chlorocarbonate and the like. It is prefered to carry out the 
reaction at a temperature of -20.degree. to 50.degree. C., especially 
0.degree. to 30.degree. C. 
[Step B-(1)] 
The transesterification reaction between the compound (IV) and the compound 
(III-A) can be carried out in the presence of a catalyst in a solvent. 
Examples of the catalyst include orthotitanic acid esters such as 
tetraethyl orthotitanate, tetrapropyl orthotitanate, tetraisopropyl 
orthotitanate or tetrabenzyl orthotitanate and alkali metals such as 
sodium. Dimethyfomamide, dimethylsulfoxide, benzene, xylene and the like 
are preferably used as the solvent. It is preferred to carry out the 
reaction at a temperature of 20.degree. to 150.degree. C., especially 
80.degree. to 150.degree. C. 
[Step C-(1) ] 
The reaction of the compound (I-D) with the compound (V) can be carried out 
in the presence of an acid acceptor in a solvent. Dimethylformamide, 
tetrahydrofuran, dimethylsulfoxide, dioxane and the like are preferablly 
used as the solvent. Examples of the acid acceptor include alkali metal 
hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal 
hydrides such as sodium hydride, alkali metal carbonates such as sodium 
carbonate or potassium carbonate, alkali metal alkoxides such as sodium 
methoxide or sodium ethoxide and the like. It is preferred to carry out 
the reaction at a temperature of -10.degree. to 100.degree. C., especially 
at -10.degree. to 20.degree. C. in case the alkali metal hydride is used, 
or at 50.degree. to 100.degree. C. in case the alkali metal hydroxide or 
alkali metal carbonate is used. 
[Step D] 
The optional reduction of the nitro group(s) can be conducted in a 
traditional manner. For example, said reduction can be carried out by 
treating the nitro-compound obtained in Step A-(1), Step B-(1) or Step 
C-(1) either with a reducing agent (e.g., stannous chloride, tin-acetic 
acid, tin-mineral acid, iron-acetic acid, iron-mineral acid and the like) 
or with ammonium formate or hydrogen gas in the presence of a catalyst 
(e.g., palladium-carbon, platinum, Raney nickel and the like). It is 
preferred to carry out the reaction in a solvent (e.g., methanol, ethanol, 
tetrahydrofuran, ethyl acetate and the kike) at a temperature of 
20.degree. to 100.degree. C., especially at 50.degree. to 100.degree. C. 
in case the reducing agent is used, at 50.degree. to 80.degree. C. in case 
ammonium formate is used, or at room temperature in case hydrogen gas is 
used. 
The optional acylation of the amino-compound obtained in the 
afore-mentioned reduction can be carried out by treating said compound 
with an acylating agent in the presence or absence of an acid acceptor in 
a solvent. Examples of the acylating agent include reactive derivatives 
(e.g., anhydride or halide such as chloride) of lower alkanoic acids 
(e.g., acetic acid) or phenyl-lower alkanoic acids (e.g., phenylacetic 
acid). Ethyl acetate, benzene, toluene or a mixture of water and said 
organic solvent is preferably used as the solvent. Examples of the acid 
acceptor include alkali metal carbonates such as sodium carbonate or 
potassium carbonate, alkali metal bicarbonates such as sodium bicarbonate 
or potassium bicarbonate, alkali metal hydrides such as sodium hydride, 
alkali metal alkoxides such as sodium methoxide or sodium ethoxide, 
tri-lower alkylamine such as triethylamine and pyridine. It is preferred 
to carry out the reaction at a temperature of 0.degree. to 100.degree. C., 
especially 0.degree. to 50.degree. C. 
[Steps A-(2), B-(2) and C-(2)] 
The compound (I) obtained in the above-mentioned reactions can be readily 
converted into a salt thereof in a traditional manner, for example, by 
treatment with an acid. 
As mentioned hereinbefore, the benzo-furan(or -thiophene) derivative (I) of 
the present invention and a salt thereof have a potent inhibitory activity 
against the reflective contraction of urinary bladder and are useful for 
treatment and/or prophylaxis of urinary system diseases associated with 
contracting function disorder of urinary bladder or ureter, for example, 
pollakiuria (frequent micturition), dyuria (painful urination), nocturia 
(voiding during the night), enuresis (bed-wetting at night), irritable 
bladder, and the like. 
The compound (I) of the present invention can be used for pharmaceutical 
use either in the free form or in the form of a pharmaceutically 
acceptable salt thereof. Examples of the salt of the compound (I) include 
inorganic acid addition salts such as hydrochloride, hydrobromide or 
sulfate, and organic acid addition salts such as oxalate, sulfamate, 
acetate, fumarate, maleate, citrate or methanesulfonate. 
The compound (I) or a salt thereof can be administered either orally or 
parenterally. For oral administration, the compound (I) and a salt thereof 
may be used in the solid form such as tablets, powders, capsules or 
granules, which may contain conventional carriers, binders, diluents, 
disintegrators, wetting agents and the like. They may also be used in 
liquid form such as aqueous or oily suspensions, solutions, syrups or 
elixirs. On the other hand, for parenteral administration, the compound 
(I) and a salt thereof may be used, for example, in the form of 
injections. 
The dose of the compound (I) or a salt thereof may vary over a wide range 
depending on the administration route, the age, body weight or conditions 
of patients and the kind and severity of diseases to be treated. In 
general, however, preferred daily dose of the compound (I) or a salt 
thereof is in the range of 0.2 to 30 mg/kg/day, especially 3 to 30 
mg/kg/day in case of oral administration, or 0.2 to 2 mg/kg/day in case of 
parenteral administration. 
Concomitantly, the starting compound (II) in which Z.sup.1 is hydroxy group 
or a group of the formula: --Y.sup.1 --H and the compound (IV) may be 
prepared by either one of the methods shown in the following reaction 
schemes (a) to (f). Besides, the starting compound (IV) may also be 
prepared by esterifying the compound (II) in which Z.sup.1 is hydroxy 
group. Further, the starting compound (II) in which Z.sup.1 is hydroxy 
group may also be prepared by hydrolyzing the compound (IV) obtained in 
the methods shown in the following reaction schemes. Furthermore, the 
starting compounds (II) and (IV) in which R.sup.1 is an acylaminophenyl 
group or a di(lower alkyl)aminophenyl group may also be prepared by 
reducing the corresponding nitropheny-compounds, followed by acylation or 
alkylation. Moroever, the compound (II) and (IV) in which R.sup.3 is 
hydrogen atom, may be prepared by reducing the compound (II) in which 
R.sup.3 is a halogen atom, and the compound (II) and (IV) in which R.sup.3 
is an acylamino group may be prepared by reducing the compounds (II) and 
(IV) in which R.sup.3 is nitro group, followed by acylation. 
##STR16## 
In the above-mentioned reactions (a) to (f), R.sup.10 is hydrogen atom or a 
lower alkyl group, and R.sup.1, R.sup.2, R.sup.3, R.sup.8 and X are the 
same as defined above. 
On the other hand, the starting compound (II) in which Z.sup.1 is amino 
group (i.e., the compound (II) in which Z.sup.1 is a group of the formula: 
--Y.sup.1 --H and Y.sup.1 is imino group) may be prepared by amidating the 
compound (IV) in a traditional manner. 
Throughout the specification and claims, the terms "lower alkyl", "lower 
alkoxy", "lower alkanoyl" and "lower alkylene" should be interpreted as 
referring to straight or branched alkyl of one to 6 carbon atoms, straight 
or branched alkoxy of one to 6 carbon atoms, straight or branched alkanoyl 
of 2 to 7 carbon atoms and straight or branched alkylene of one to 6 
carbon atoms, respectively. 
Experiment 
(Method) 
Female rats (body weight: 200-300 g; age: 10-14 weeks old) were 
anesthetized with urethane (1.0-1.2 g/kg, s.c.). A catheter was inserted 
into the urinary bladder via the urethra meatus of each of the rats and 
the external urethral orifice was ligated. One end of the catheter was 
connected to a syringe filled with saline and a pressure transducer 
through a T-tube. Saline was injected into the urinary bladder via the 
catheter, and the change in intravesical pressure was measured. A 
physiological saline solution was injected into the urinary bladder. After 
it was confirmed that rhythmical contractions occured, a test compound 
(dose: 2-4 mg/kg) dissolved in a physiological saline solution was 
administered to the rat through a catheter inserted into the femoral vein. 
The rhythmical contraction loss time (i.e., a period of time from 
disappearance of contractions to recovery thereof) was measured and the 
inhibitory activity of the test compound against rhythmical contractions 
of urinary bladder was estimated by comparing said rhythmical contraction 
loss time with that in the case of administration of flavoxate 
hydrochloride (dose: the same as the test compound). 
(Result) 
The following compounds shown in Table 1 exhibited more than 1.5 times 
stronger inhibitory activity against contractions of the urinary bladder 
than flavoxate hydrochloride. 
TABLE 1 
__________________________________________________________________________ 
##STR17## 
Comp. No. 
X R.sup.1 R.sup.2 
R.sup.3 R.sup.4 salt 
__________________________________________________________________________ 
1 O H H 
##STR18## hydrochloride 
2 O H H 
##STR19## hydrochloride 
3 O H H 
##STR20## hydrochloride 
4 O H H 
##STR21## hydrochloride 
5 O H H H 
##STR22## hydrochloride 
6 O CH.sub.3 H H 
##STR23## hydrochloride 
7 O 
##STR24## 
H H 
##STR25## methanesulfonate 
8 O 
##STR26## 
H NHCOCH.sub.3 
##STR27## hydrochloride 
9 S H 
##STR28## 
H 
##STR29## hydrochloride 
__________________________________________________________________________

EXAMPLE 1 
(1) A mixture of 102 g of 5-chloro-2-hydroxybenzoic acid, 166 g of 
hexamethylenetetramine and 600 ml of trifluoroacetic acid is heated at 
100.degree. C. overnight. 2.95 liters of water and 1.48 liters of 10% 
hydrochloric acid are added to the mixture and said mixture is heated at 
the same temperature for 15 minutes. After cooling, the resultant crystals 
are collected by filtration to give 96.9 g of 
5-chloro-3-formyl-2-hydroxybenzoic acid. 
M.p. 218.degree. C. 
(2) 193 g of 5-chloro-3-formyl-2-hydroxybenzoic acid are dissoved in 2 
liters of methanol and the solution is saturated with hydrogen chloride. 
100 ml of thionyl chloride are added to the solution and the mixture is 
refluxed for 8 hours. After cooling, the resultant crystals are collected 
by filtration and dried to give 190 g of methyl 
5-chloro-3-formyl-2-hydroxybenzoate. 
m.p. 132.degree.-134.degree. C. 
(3) A mixture of 3.0 g of methyl 5-chloro-3-formyl-2-hydroxybenzoate, 3.44 
g of methyl .alpha.-bromophenylacetate, 8.28 g of potassium carbonate and 
50 ml of dimethylformamide is heated at 70.degree.-80.degree. C. for 15 
minutes and further heated at 100.degree. C. for 10 minutes. After 
cooling, water is added to the mixture, and the aqueous mixture is 
acidified with 10% hydrochloric acid and then extracted with ethyl 
acetate. The extract is washed with an aqueous saturated sodium chloride 
solution, dried and evaporated to remove solvent. The residue is dissolved 
in 50 ml of ethanol, and 4.5 g of potassium hydroxide are added to the 
solution. The mixture is refluxed for 1 hour and then evaporated to remove 
solvent. Water is added to the residue, and the aqueous mixture is 
acidified with 10% hydrochloric acid and extracted with ethyl acetate. The 
extract is dried and evaporated to remove solvent. 150 ml of xylene and 30 
mg of p-toluenesulfonic acid are added to the residue and the mixture is 
refluxed for 1 hour. The reaction mixture is evaporated to remove solvent 
and the residue is dissolved in ethyl acetate. The solution is washed, 
dried and evaporated to remove solvent. The residue is crystallized from 
isopropyl ether to give 2.32 g of 5-chloro-2-phenylbenzofuran-7-carboxylic 
acid. 
M.p. 255.degree.-258.degree. C. 
(4) 1.46 g of 5-chloro-2-phenylbenzofuran-7-carboxylic acid are dissolved 
in a mixture of 15 ml of ethyleneglycol monomethylethers and 15 ml of 
methanol. 500 mg of 10% palladium-carbon and 1.6 g of ammonium formate are 
added to the solution and the solution is heated at 40.degree. C. for 1.5 
hours. The reaction mixture is filtered and the filtrate is concentrated 
under reduced pressure. The residue is dissolved in ethyl acetate. The 
solution is washed successively with 10% hydrochloric acid and water, 
dried and evaporated to remove solvent to give 
2-phenylbenzofuran-7-carboxylic acid. 
M.p. 212.degree.-214.degree. C. 
(5) 1.10 g of 2-phenylbenzofuran-7-carboxylic acid are dissolved in a 
mixture of 25 ml of tetrahydrofuran and 25 ml of benzene, and 1.27 g of 
oxalyl chloride and 2 drops of dimethylformamide are added to the 
solution. The mixture is stirred at room temperature for 1 hour. The 
reaction mixture is evaporated to remove solvent and the residue is 
dissolved in 20 ml of methylene chloride. The solution is added dropwise 
to a mixture of 0.98 g of 2-(dimethylamino)ethanol and 0.91 g of 
triethylamine in 20 ml of methylene chloride under ice-cooling. The 
mixture is stirred at the same temperature for 30 minutes. The reaction 
mixture is washed with water, dried and evaporated to remove solvent. The 
residue is recrystallized from n-hexane to give 1.29 g of 
2-(dimethylamino)ethyl 2-phenylbenzofuran-7-carboxylate. 
M.p. 56.5.degree.-58.degree. C. 
Hydrochloride: colorless needles. 
M.p. 183.degree.-185.degree. C. (recrystallized from methanol-ether). 
EXAMPLE 2 
A mixture of 1.5 g of 2-phenylbenzofuran-7-carboxylic acid, 4.5 ml of 
thionyl chloride, 0.2 ml of pyridine and 20 ml of chloroform is stirred at 
room temperature for 2 hours and evaporated under reduced pressure to 
remove solvent. The residue is dissolved in 20 ml of methylene chloride 
and the solution is added dropwise to a solution of 0.8 g of 
2-pyrrolidinoethanol and 1.27 g of triethylamine in 20 ml of methylene 
chloride under ice-cooling. The mixture is stirred at the same temperature 
for 1 hour. The reaction mixture is washed with water, dried and 
evaporated to remove solvent. The residue is treated with hydrochloric 
acid-ether and recrystallized from isopropanolisopropyl ether to give 1.96 
g of 2-pyrrolidinoethyl 2-phenylbenzofuran-7-carboxylic hydrochloride as 
colorless needles. 
M.p. 165.degree.-167.degree. C. 
EXAMPLE 3-18 
The corresponding starting compounds are treated in the same manner as 
described in Example 1-(5) or Example 2 to give the following compounds 
shown in Table 2. 
TABLE 2 
__________________________________________________________________________ 
##STR30## (I-a) 
Exp. 
Compound (I-a) 
Nos. 
R.sup.1 R.sup.3 
R.sup.4 properties 
__________________________________________________________________________ 
3 
##STR31## H 
##STR32## hydrochloride yield: 73.8% M.p. 
178-182.degree. C. (recrystallized from 
isopropanol) 
4 
##STR33## H 
##STR34## oxalate yield: 70.9% M.p. 149-150.degree. 
C. (recrystallized from isopropanol) 
5 
##STR35## H 
##STR36## hydrochloride yield: 75.1% M.p. 
185-187.degree. C. (recrystallized from 
isopropanol-isopropyl ether) 
6 
##STR37## H 
##STR38## hydrochloride yield: 85.2% M.p. 
188-189.degree. C. (recrystallized from 
isopropanol) 
7 
##STR39## H 
##STR40## hydrochloride yield: 81.5% M.p. 
178-180.degree. C. (recrystallized from 
ethanol-ether) 
8 
##STR41## H 
##STR42## hydrochloride yield: 80.8% M.p. 
194-195.degree. C. (recrystallized from 
isopropanol) 
9 
##STR43## H 
##STR44## hydrochloride yield: 82.0% M.p. 
183-185.degree. C. (recrystallized from 
isopropanol) 
10 
##STR45## H 
##STR46## sulfate yield: 75.0% M.p. 146-149.degree. 
C. (recrystallized from ethanol-ether) 
11 
##STR47## H 
##STR48## oxalate yield: 57.0% M.p. 
155.5-156.5.degree. C. (recrystallized 
from tetrahydrofuran) 
12 
##STR49## H 
##STR50## hydrochloride yield: 78.5% M.p. 
218-219.degree. C. (recrystallized from 
isopropanol) 
13 
##STR51## H 
##STR52## hydrochloride yield: 63.6% M.p. 
243-245.degree. C. (recrystallized from 
isopropanol) 
14 
##STR53## H 
##STR54## hydrochloride yield: 50.9% M.p. 
&gt; 167.degree. C. (decomp.) (recrystallized 
from isopropanol-acetonitrile) 
15 
##STR55## H 
##STR56## methanesulfonate yield: 74.7% M.p. 
186-187.degree. C. (recrystallized from 
ethanol-ether) 
16 
##STR57## H 
##STR58## hydrochloride yield: 68.4% M.p. 
215-216.degree. C. (recrystallized from 
isopropanol) 
17 
##STR59## H 
##STR60## hydrochloride yield: 72.0% M.p. 
199-205.degree. C. (recrystallized from 
isopropanol) 
18 
##STR61## Cl 
##STR62## hydrochloride yield: 89.5% M.p. 
227-229.degree. C. (recrystallized from 
methanol-ether) 
__________________________________________________________________________ 
EXAMPLE 19 
(1) 2.5 g of 2-phenylbenzofuran-7-carboxylic acid is dissolved in a mixture 
of 80 ml of methanol and 16 ml of tetrahydrofuran and 0.5 g of platinum 
oxide is added to the solution. The mixture is subjected to catalytic 
hydrogenation under atmospheric pressure. The reaction mixture is filtered 
and the filtrate is evaporated to remove solvent. The residue is purified 
by silica gel column chromatography (solvent; chloroform:methanol=20:1) to 
give 1.54 g of 2-cyclohexylbenzofuran-7-carboxylic acid as colorless oil. 
Mass(m/e): 244 (M.sup.+). 
(2) 1.22 g of 2-cyclohexylbenzofuran-7-carboxylic acid is treated in the 
same manner as described in Example 1-(5) to give 1.12 g of 
2-piperidinoethyl 2-cyclohexylbenzofuran-7-carboxylate oxalate. yield: 
50.2%. 
M.p. &gt;165.degree. C. (recrystallized from isopropanol-ether). 
EXAMPLE 20 
(1) 15 g of 2-hydroxy-5-methoxybenzoic acid is treated in the same manner 
as described in Example 1-(1) to (3) to give 10.8 g of 
5-methoxy-2-phenylbenzofuran-7-carboxylic acid. yield: 45%. 
M.p. 185.degree.-187.degree. C. 
(2) 1.34 g of 5-methoxy-2-phenylbenzofuran-7-carboxylic acid and 0.77 g of 
2-piperidinoethanol are treated in the same manner as described in Example 
1-(5) to give 2.08 g of 2-piperidinoethyl 
5-methoxy-2-phenylbenzofuran-7-carboxylate hydrochloride. 
yield: 77.5%. 
M.p. 200.degree.-202.degree. C. (recrystallized from isopropanol). 
EXAMPLE 21-24 
(1)-(i) A mixture of 420 mg of methyl benzofuran-7-carboxylate, 5 ml of an 
aqueous 10% sodium hydroxide solution and 5 ml of methanol is stirred at 
room temperature for 1 hour. The reaction mixture is evaporated to remove 
solvent. The residue is dissolved in water and the solution is acidified 
with 10% hydrochloric acid. The resultant crystals are collected by 
filtration and dried to give 321 mg of benzofuran-7-carboxylic acid as 
colorless crystals. 
M.p. 159.degree.-161.degree. C. 
The corresponding methyl ester compounds are treated in the same manner as 
described above to give the following compounds. 
(ii) 2-methylbenzofuran-7-carboxylic acid 
M.p. 144.degree.-147.degree. C. (recrystallized from aqueous ethanol). 
(iii) 2-benzylbenzofuran-7-carboxylic acid white powder 
IR .nu..sub.max.sup.Nujol (cm.sup.-1): 1680. 
(iv) 5-nitro-2-phenylbenzofuran-7-carboxylic acid 
M.p. 297.degree.-298.5.degree. C. (decomp.) (recrystallized from 
tetrahydrofuran-n-hexane). 
(2) The compounds obtained in (1)-(i), (ii), (iii) or (iv) and 
2-piperidinoethanol are treated in the same manner as described in Example 
2 to give the following compounds shown in Table 3. 
TABLE 3 
__________________________________________________________________________ 
##STR63## 
Ex. 
Compound (I-a) 
Nos. 
R.sup.1 R.sup.3 
R.sup.4 Properties 
__________________________________________________________________________ 
21 H H 
##STR64## 
hydrochloride yield: 71.5% M.p. 210-212.degree. 
C. (recrystallized from isopropanol) 
22 CH.sub.3 H 
##STR65## 
hydrochloride yield: 71.2% M.p. 200-202.degree. 
C. (recrystallized from isopropanol-isopropyl 
ether) 
23 
##STR66## 
H 
##STR67## 
hydrochloride yield: 68.8% (recrystallized from 
isopropanol-isopropyl ether) 
24 
##STR68## 
NO.sub.2 
##STR69## 
methanesulfonate yield: 91.1% M.p. 
201.5-202.5.degree. C. (recrystallized from 
tetrahydrofuran-ether) 
__________________________________________________________________________ 
EXAMPLE 25 
(1) A diazomethane-ether solution (prepared from 5.0 g of 
nitrosomethylurea) is added to a solution of 6.0 g of 
2-(4-nitrophenyl)benzofuran-7-carboxylic acid in 60 ml of tetrahydrofuran 
and the mixture is stirred at room temperature for 1 hour. The reaction 
mixture is evaporated to remove solvent and the residue is dissolved in 
ethyl acetate. The solution is washed with water, dried and evaporated to 
remove solvent. The residue is washed with ethyl acetate and dried to give 
3.82 g of methyl 2-(4-nitrophenyl)benzofuran-7-carboxylate as pale brown 
powder. 
IR .nu..sub.max.sup.Nujol (cm.sup.31 1): 1720. 
(2) A mixture of 3.1 g of methyl 2-(4-nitrophenyl)benzofuran-7-carboxylate, 
11.7 g of stannous chloride dihydrate and 100 ml of ethyl acetate is 
heated at 70.degree. C. for 1 hour. After cooling, the reaction mixture is 
alkalized with an aqueous sodium bicarbonate solution and extracted with 
ethyl acetate. The extract is washed with water, dried and evaporated to 
remove solvent to give 2.6 g of methyl 
2-(4-aminophenyl)benzofuran-7-carboxylate as yellow crystals. 
M.p. 158.degree.-161.degree. C. 
(3) A mixture of 2.6 g of methyl 2-(4-aminophenyl)benzofuran-7-carboxylate, 
1.52 ml of methyl iodide, 6.72 g of potassium carbonate and 25 ml of 
dimethylformamide is stirred at room temperature for 1 hour. 2.2 ml of 
methyl iodide are added to the mixture and the mixture is stirred for 2 
hours. The reaction mixture is poured into water and the aqueous mixture 
is extracted with ethyl acetate. The extract is washed with water, dried 
and evaporated to remove solvent. The residue is purified by silica gel 
column chromatography (solvent; n-hexane:ethyl acetate=1:4) to give 2.0 g 
of methyl 2-(4-dimethylaminophenyl)benzofuran-7-carboxylate as orange 
needles. 
M.p. 145.degree.-148.degree. C. 
(4) 920 mg of methyl 2-(4-dimethylaminophenyl)benzofuran-7-carboxylate are 
dissolved in a mixture of 20 ml of methanol and 20 ml of tetrahydrofuran. 
10 ml of an aqueous 1N sodium hydroxide solution are added to the solution 
and the mixture is heated at 50.degree. C. for 40 minutes. After cooling, 
the reaction mixture is neutralized with 10% hydrocloric acid and 
extracted with ethyl acetate. The extract is dried and evaporated to 
remove solvent to give 870 mg of 
2-(4-dimethylaminophenyl)benzofuran-7-carboxylic acid as yellow powder. 
IR .nu..sub.max.sup.Nujoul (cm.sup.-1): 1690. 
(5) 0.61 g of 2-(4-dimethylaminophenyl)benzofuran-7-carboxylic acid and 
0.56 g of 2-piperidinoethanol are treated in the same manner as described 
in Example 1-(5) to give 0.82 g of 2-piperidinoethyl 
2-(4-dimethylaminophenyl)benzofuran-7-carboxylate oxalate as yellow 
powder. Yield: 78.8% 
IR .nu..sub.max.sup.Nujol (cm.sup.-1): 1710. 
EXAMPLE 26 
(1) A solution of 5.0 g of propiophenone oxime in 35 ml of 
dimethylformamide is added dropwise to a solution of 1.55 g of 62.5% 
sodium hydride in 80 ml of dimethylformamide under ice-colling, and the 
mixture is stirred at the same temperature for 20 minutes. A solution of 
4.24 g of 2-chlorobenzonitrile in 20 ml of dimethylformamide is added 
dropwise to the mixture and the mixture is stirred at room temperature for 
3 hours. The reaction mixture is poured into ice-water and the aqueous 
mixture is extracted with ethyl acetate. The extract is washed with a 
saturated sodium chloride solution, dried and evaporated to remove 
solvent. The residue is purified by silica gel column chromatography 
(solvent; n-hexane:ethyl acetate=6:1) to give 2.19 g of propiophenone 
O-(2-cyanophenyl)oxime as oil. 
IR .nu..sub.max.sup.Nujol (cm.sup.-1): 2225. 
(2) A mixture of 227 mg of propiophenone O-(2-cyanophenyl)oxime and 5 ml of 
21% hydrochloric acid-ethanol is refluxed for 1 hour and the reaction 
mixture is evaporated to remove solvent. The residue is dissolved in ethyl 
acetate, and the solution is washed with water, dried and evaporated to 
remove solvent. The residue is purified by silica gel column 
chromatography (solvent; n-hexane:ethyl acetate=6:1) and recrystallized 
from isopropanol to give 63 mg of 3-methyl-2-phenylbenzofuran-7-nitrile as 
colorless needles. 
M.p. 86.degree.-87.degree. C. 
(3) A mixture of 364 mg of 3-methyl-2-phenylbenzofuran-7-nitrile, 3 g of an 
aqueous 30% sodium hydroxide solution and 8 ml of ethylene glycol is 
refluxed for 2 hours. After cooling, the reaction mixture is poured into 
water, acidified with 10% hydrochloric acid and then extracted with ethyl 
acetate. The extract is washed with a saturated sodium chloride solution, 
dried and evaporated to remove solvent. The residue is recrystallized from 
tetrahydrofuran-n-hexane to give 257 mg of 
3-methyl-2-phenylbenzofuran-7-carboxylic acid as colorless prisms. 
M.p. 219.5.degree.-222.5.degree. C. 
(4) 0.37 g of 3-methyl-2-phenylbenzofuran-7-carboxylic acid and 0.23 g of 
2-piperidinoethanol are treated in the same manner as described in Example 
2 to give 0.43 g of 2-piperidinoethyl 
3-methyl-2-phenylbenzofuran-7-carboxylate hydrochloride as colorless 
needles. yield: 73.6%. 
M.p. 190.degree.-191.5.degree. C. (recrystallized from isopropanol). 
EXAMPLE 27 
A mixture of 1.16 g of 2-phenylbenzofuran-7-carboxylic acid, 1.0 g of 
2-(diisopropylamino)ethyl chloride hydrochloride, 0.66 g of potassium 
hydroxide and 20 ml of isopropanol is refluxed for 1 hour. After cooling, 
ethyl acetate and water are added to the reaction mixture. The organic 
layer is collected, washed with a saturated sodium chloride solution and 
evaporated to remove solvent. The residue is purified by silica gel column 
chromatography (solvent; chloroform:methanol=20:1) to give 1.51 g 
2-(diisopropylamino)ethyl 2-phenylbenzofuran-7-carboxylate as colorless 
oil. 
Hydrochloride: colorless needles 
M.p. 199.5.degree.-201.5.degree. C. (recrystallized from methanol-ether). 
EXAMPLE 28 
1.43 g of 2-phenylbenzofuran-7-carboxylic acid are dissolved in 10 ml of 
tetrahydrofuran, and 1.08 g of carbonyldiimidazole are added to the 
solution. The mixture is stirred at room temperature for 2 hours and a 
solution of 0.76 g of 2-(t-butylamino)ethanol in 4 ml of tetrahydrofuran 
is added thereto. The mixture is stirred at room temperature for 15 hours 
and evaporated to remove solvent. Water is added to the residue and the 
aqueous mixture is extracted with ethyl acetate. The extract is washed 
with water, dried, and evaporated to remove solvent to give 1.72 g of 
2-(t-butylamino)ethyl 2-phenylbenzofuran-7-carboxylate as pale yellow oil. 
Methanesulfonate: colorless needles 
M.p. 249.degree.-250.degree. C. (recrystallized from methanol-ether). 
EXAMPLE 29-31 
The corresponding starting compounds are treated in the same manner as 
described in Example 28 to give the following compounds shown in Table 4. 
TABLE 4 
______________________________________ 
##STR70## 
##STR71## 
Ex. Compound (I-b) 
Nos. R.sup.1 A Properties 
______________________________________ 
29 
##STR72## 
##STR73## oxalate yield: 70.0% M.p. 148.5- 
149.5.degree. C. (re- crystallized from 
sopropanol) 
30 
##STR74## 
##STR75## hydrochloride yield: 67.0% M.p. 192- 
197.degree. C. (re- crystallized from 
isopropanol) 
31 
##STR76## (CH.sub.2).sub.2 
hydrochloride yield: 73.0% M.p. 201- 
202.degree. C. (re- crystallized from 
isopropanol- ether) 
______________________________________ 
EXAMPLE 32-33 
(1)-(i) A suspension of 6.72 g of 60% sodium hydride in 40 ml of 
tetrahydrofuran is added dropwise to a solution of 24.17 g of 
2-bromophenol in 210 ml of tetrahydrofuran at 4.degree. C. and the mixture 
is stirred at the same temperature for 15 minutes. A solution of 30.66 g 
of phenacyl bromide in 60 ml of tetrahydrofuran is added dropwise to the 
mixture. The mixture is stirred at the same temperature for 30 minutes and 
further refluxed for 2.5 hours. The reaction mixture is evaporated to 
remove solvent, and water is added to the residue. The aqueous mixture is 
extracted with ethyl acetate and the extract is washed, dried and 
evaporated to remove solvent. The residue is purified by silica gel column 
chromatography and recrystallized from a mixture of ethyl acetate and 
n-hexane to give 21.49 g of (2-bromophenyl)(benzoylmethyl)ether as 
colorless needles. 
M.p. 111.5.degree.-113.degree. C. 
(2)-(i) 21.49 g of (2-bromophenyl)(benzoylmethyl)ether are added to 180 ml 
of polyphosphoric acid and the mixture is stirred at 123.degree. C. for 
2.5 hours. After cooling, the reaction mixture is poured into ice-water 
and extracted with ethyl acetate. The extract is washed successively with 
water and an aqueous sodium bicarbonate solution, dried and evaporated to 
remove solvent. The residue is purified by silica gel column 
chromatography and recrystallized from aqueous ethanol to give 10.04 g of 
7-bromo-3-phenylbenzofuran as colorless needles. 
M.p. 69.5.degree.-71.5.degree. C. 
(3)-(i) 2.4 ml of methyl iodide are added dropwise to a solution of 3.9 g 
of magnesium in 16 ml of tetrahydrofuran and the mixture is stirred at 
room temperature for 20 minutes. A solution of 11.0 g of 
7-bromo-3-phenylbenzofuran in tetrahydrofuran is added dropwise to the 
mixture and the mixture is refluxed for 4 hours. After cooling, the 
reaction mixture is poured to dry ice, acidified with 10% hydrochloric 
acid and extracted with ethyl acetate. The extract is washed with water, 
dried and evaporated to remove solvent. The residue is recrystallized from 
ethyl acetate to give 6.31 g of 3-phenylbenzofuran-7-carboxylic acid as 
pale yellow prisms. 
M.p. 220.degree.-222.degree. C. 
2-Bromothiophenol instead of 2-bromophenol is treated in the same manner as 
described in Step (1)-(i)-(3)-(i) to give the following compound. 
(ii) 3-phenylbenzothiophene-7-caboxylic acid: pale yellow needles 
M.p. 277.degree.-282.degree. C. (decomp.) (recrystallized from ethanol). 
(4) The compound obtained in Step (3)-(i) or (ii) and 2-piperidinoethanol 
are treated in the same manner as described in Example 28 to give the 
following compounds. 
(32) 2-piperidinoethyl 3-phenylbenzofuran-7-carboxylate; yield: 60% 
colorless needles 
M.p. 201.degree.-202.degree. C. (recrystallized from isopropanol). 
(33) 2-piperidinoethyl 3-phenylbenzothiophene-7-carboxylate; yield: 72% 
colorless needles 
M.p.&gt;205.degree. C. (decomp.) (recrystallized from isopropanol). 
EXAMPLE 34 
(1) 7.0 g of 2-phenylbenzofuran-7-carboxylic acid are dissolved in 70 ml of 
methanol, and 6.4 ml of thionyl chloride are added dropwise thereto at 
0.degree. C. The mixture is refluxed for 1 hour and evaporated to remove 
solvent. The residue is dissolved in ethyl acetate, and the solution is 
washed with water, dried and evaporated to remove solvent. The residue is 
recrystallized from n-hexane to give 7.04 g of methyl 
2-phenylbenzofuran-7-carboxylate as colorless needles. 
M.p. 45.degree.-47.degree. C. 
(2) A mixture of 0.76 g of methyl 2-phenylbenzofuran-7-carboxylate, 0.46 g 
of 2-piperidinoethanol, 0.05 g of tetraisopropyl orthotitanate and 5 ml of 
xylene is refluxed for 4 hours. Toluene and an aqueous 10% sodium 
hydroxide solution are added to the reaction mixture and the mixture is 
filtered. The filtrate is washed with water, dried and evaporated to 
remove solvent. The residue is purified by silica gel column 
chromatography (solvent; chloroform:methanol=10:1) to give 1.01 g of 
2-piperidinoethyl 2-phenylbenzofuran-7-carboxylate as pale yellow oil. 
IR.nu..sub.max.sup.Nujol (cm.sup.-1): 1710. 
EXAMPLE 35-37 
The corresponding starting compounds are treated in the same manner as 
described in Example 34-(2) to give the following compounds shown in Table 
5. 
TABLE 5 
______________________________________ 
##STR77## 
##STR78## 
Exp. Compound (I-c) 
Nos. R.sup.1 
R.sup.2 A Properties 
______________________________________ 
35 CH.sub.3 
CH.sub.3 (CH.sub.2).sub.2 
hydrochloride 
yield: 82.8% 
M.p. &gt;217.degree. C. 
(decomp.) (re- 
crystallized from 
isopropanol) 
36 CH.sub.3 
COCH.sub.3 (CH.sub.2).sub.2 
hydrochloride 
yield: 60.5% 
M.p. &gt;243.degree. C. 
(decomp.) (re- 
crystallized from 
isopropanol- 
acetonitrile) 
37 CH.sub.3 
##STR79## (CH.sub.2).sub.2 
hydrochloride yield: 95.2% M.p. 154.5- 
56.degree. C. (re- crystallized from 
isopropanol) 
______________________________________ 
EXAMPLE 38 
A mixture of 1.5 g of 2-piperidinoethyl 
5-nitro-2-phenylbenzofuran-7-carboxylate, 4.29 g of stannous chloride 
dihydrate and 100 ml of ethyl acetate is heated at 70.degree.-80.degree. 
C. for 2 hours. The reaction mixture is neutralized with an aqueous 
saturated sodium bicarbonate solution and extracted with ethyl acetate. 
The extract is washed, dried and evaporated to remove solvent. The residue 
is recrystallized from isopropanol to give 995 mg of 2-piperidinoethyl 
5-amino-2-phenylbenzofuran-7-carboxylate as yellow needles. 
M.p. 126.5.degree.-128.degree. C. 
Dioxalate: pale yellow needles 
M.p.&gt;105.degree. C. (decomp.) (recrystallized from tetrahydrofuran). 
EXAMPLE 39 
1.18 g of 2-piperidinoethyl 2-(4-nitrophenyl)benzofuran-7-carboxylate is 
treated in the same manner as described in Example 38 to give 0.76 g of 
2-piperidinoethyl 2-(4-aminophenyl)benzofuran-7-carboxylate as colorless 
needles. yield: 70%. 
IR.nu..sub.max.sup.Nujol (cm.sup.-1): 3480, 3380, 1710. 
hydrochloride: pale yellow powder 
M.p.&gt;170.degree. C. (decomp.) (recrystallized from methanol-ether). 
EXAMPLE 40 
A solution of 147 mg of acetyl chloride in 2 ml of toluene is added 
dropwise to a mixture of 522 mg of 2-piperidinoethyl 
5-amino-2-phenylbenzofuran-7-carboxylate, 210 mg of sodium bicarbonate and 
10 ml of ethyl acetate under ice-cooling. The mixture is stirred at the 
same temperature for 30 minutes and the reaction mixture is extracted with 
ethyl acetate. The extract is washed with water, dried and evaporated to 
remove solvent. The residue is recrystallized from ethyl acetate to give 
467 mg of 2-piperidinoethyl 5-acetamido-2-phenylbenzofuran-7-carboxylate 
as pale yellow needles. 
M.p. 172.5.degree.-174.degree. C. 
hydrochloride: colorless needles 
M.p. 255.degree.-257.degree. C. (decomp.) (recrystallized from 
isopropanol). 
EXAMPLE 41 
0.65 g of 2-piperidinoethyl 2-(4-aminophenyl)benzofuran-7-carboxyate is 
treated in the same manner as described in the same manner as described in 
Example 40 to give 0.53 g of 2-piperidinoethyl 
2-(4-acetamidophenyl)benzofuran-7-carboxylate as yellow needles. yield: 
73.6%. 
M.p. 155.degree.-157.degree. C. 
EXAMPLE 42 
3.0 g of 2-phenylbenzofuran-7-carboxylic acid are dissolved in 40 ml of 
chloroform, and 9 ml of thionyl chloride and 0.4 ml of pyridine are added 
thereto. The mixture is stirred at room temperature for 2 hours. The 
reaction mixture is evaporated to remove solvent and the residue is 
dissolved in 40 ml of methylene chloride. The solution is added dropwise 
to a solution of 1.78 g of N-(2-aminoethyl)piperidine and 2.55 g of 
triethylamine in 30 ml of methylene chloride under ice-cooling and the 
mixture is stirred at the same temperature for 1 hour. The reaction 
mixture is washed with water, dried and evaporated to remove solvent. The 
residue is crystallized from ether to give 4.12 g of 
2-phenylbenzofuran-7-N-(2-piperidinoethyl)carboxamide as colorless 
needles. 
M.p. 75.degree.-77.degree. C. (recrystallized from ethanol-ether). 
Oxalate: colorless needles 
M.p. 187 .degree.-188.degree. C. (recrystallized from ethanol-ether). 
EXAMPLE 43 
490 mg of 2-phenylbenzofuran-7-carboxylic acid are dissolved in 10 ml of 
chloroform, and 0.5 ml of oxalyl chlorode and 0.1 ml of pyridine are added 
thereto. The mixture is stirred at room temperature for 3 hours. The 
reaction mixture is evaporated under reduced pressure to remove solvent 
and the residue is dissolved in 5 ml of methylene chloride. The solution 
is added dropwise to a solution of 340 mg of N,N-diethylethylenediamine 
and 290 mg of triethylamine in 10 ml of methylene chloride under 
ice-cooling. The mixture is stirred at the same temperature for 1 hour. 
The reaction mixture is washed with water, dried and evaporated to remove 
solvent. The residue is crystallized from ether to give 660 mg of 
2-phenylbenzofuran-7-N-[2-(diethylamino)ethyl]carboxamide as yellow oil. 
IR.nu..sub.max.sup.liquid (Cm.sup.-1): 3410, 1660. 
Oxalate: colorless needles 
M.p. 165.degree.-167.degree. C. (recrystallized from ethanol-ether). 
EXAMPLE 44 
1.68 g of 2-phenylbenzofuran-7-N-[2-(diethylamino)ethyl]carboxamide are 
dissolved in 5 ml of dimethylformamide and the solution is added dropwise 
to a suspension of 0.24 g of 62.5% sodium hydride in 10 ml of 
dimethylformamide under ice-cooling. The mixture is stirred at room 
temperature for 30 minutes and 0.83 g of methyl iodide is added to the 
mixture. The mixture is stirred for 3 hours. The reaction mixture is 
poured into ice-water and the aqueous mixture is extracted with ethyl 
acetate. The extract is washed with water, dried and evaporated to remove 
solvent. The residue is treated with hydrochloric acid-ether and 
recrystallized from ethanol-ether to give 1.44 g of 
2-phenylbenzofuran-7-N-[2-(diethylamino)ethyl]-N-methylcarboxamide 
hydrochloride as pale yellow needles. 
M.p. 191.degree.-193.degree. C. 
EXAMPLE 45 
1.3 g of 2-phenylbenzofuran-7-N-[2-(diethylamino)ethyl]carboxamide and 0.63 
g of benzyl chloride are treated in the same manner as described in 
Example 44 to give 1.44 g of 
2-phenylbenzofuran-7-N-benzyl-N-[2-(diethylamino)ethyl]carboxamide 
hydrochloride. 
M.p. 209.degree.-211.degree. C. (recrystallized from ethanol). 
Preparation 1 
(1) A mixture of 73.2 g of 5-chloro-3-formyl-2-hydroxybenzoic acid, 350 ml 
of ethylene glycol and 129 ml of trimethylchlorosilane is stirred at room 
temperature for 2 hours. The reaction mixture is poured into a mixture of 
an aqueous saturated sodium bicarbonate solution and trimethylamine, and 
the mixture is extracted with ethyl acetate. The extract is washed with 
water, dried and evaporated to remove solvent to give 86 g of methyl 
5-chloro-3-(1,3-dioxolan-2-yl)-2-hydroxybenzoate as yellow powder. 
(2) 86 g of methyl 5-chloro-3-(1,3-dioxolan-2-yl)-2-hydroxybenzoate are 
dissolved in a mixture of 700 ml of methanol and 50 ml of tetrahydrofuran, 
and 70 ml of triethylamine and 7 g of 10% palladium-carbon are added to 
the solution. The mixture is subjected to catalytic hydrogenation under 
atmospheric pressure. The reaction mixture is filtered and the filtrate is 
evaporated to remove solvent. 10% hydrochloric acid is added to the 
residue and the mixture is concentrated. Water is added to the residue and 
the aqueous mixture is extracted with ethyl acetate. The extract is dried 
and evaporated to remove solvent. The resultant crystals are collected, 
washed with cold ethanol and dried to give 51.1 g of methyl 
3-formyl-2-hydroxybenzoate as colorless needles. 
M.p. 82.degree.-84.degree. C. 
(3) A mixture of 2.0 g of methyl 3-formyl-2-hydroxybenzoate, 3.51 g of 
methyl .alpha.-bromo-p-chlorophenylacetate, 5.55 g of potassium carbonate 
and 60 ml of dimethylformamide is heated at 70.degree.-80.degree. C. for 
15 minutes and further heated at 100.degree. C. for 10 minutes. The 
reaction mixture is filtered and washed with ethyl acetate. The washings 
and the filtrate are combined and water is added to the mixture. The 
mixture is acidified with 10% hydrochloric acid. The organic layer is 
collected and the aqueous layer is extracted with ethyl acetate. The 
organic layer and the extract are combined, washed with water, dried and 
evaporated to remove solvent. The residue is dissolved in 30 ml of ethanol 
and 3.25 g of potassium hydroxide are added to the solution. The mixture 
is refluxed for 1 hour. The reaction mixture is evaporated to remove 
solvent, and water is added to the residue. The aqueous mixture is 
acidified with 10% hydrochloric acid and extracted with ethyl acetate. The 
extract is washed with water, dried and evaporated to remove solvent. 100 
ml of xylene and 150 mg of p-toluenesulfonic acid are added to the residue 
and the mixture is refluxed for 1 hour. After cooling, ethyl acetate is 
added to the reaction mixture. The mixture is washed with water, dried and 
evaporated to remove solvent. The residue is recrystallized from ethyl 
acetate to give 1.84 g of 2-(4-chlorophenyl)benzofuran-7-carboxylic acid 
as colorless needles. 
M.p. 228.degree.-230.degree. C. 
The corresponding starting compounds are treated in the same manner as 
described above to give the following compounds. 
(i) 2-(4-methylphenyl)benzofuran-7-carboxylic acid 
M.p. 227.degree.-229.degree. C. (recrystallized from ethyl 
acetate-n-hexane) 
(ii) 2-(4-methoxyphenyl)benzofuran-7-carboxylic acid 
M.p. 249.degree.-250.5.degree. C. (recrystallized from 
tetrahydrofuran-isopropyl ether). 
Preparation 2 
(1) A mixture of 5.0 g of methyl 3-formyl-2-hydroxybenzoate, 11.7 g of 
4-nitrobenzyl bromide, 11.7 g of potassium carbonate and 70 ml of 
dimethylformamide is stirred at room temperature for 1 hour. The reaction 
mixture is poured into water and the aqueous mixture is extracted with 
ethyl acetate. The extract is dried and evaporated to remove solvent to 
give 8.70 g of methyl 3-formyl-2-(4-nitrobenzyloxy)benzoate as colorless 
powder. 
(2) 16.1 g of methyl 3-formyl-2-(4-nitrobenzyloxy)benzoate are dissolved in 
100 ml of dimethylformamide and a solution of 5.4 g of sodium methoxide in 
20 ml of methanol is added dropwise to the solution at 120.degree. C. The 
mixture is stirred at the same temperature for 10 minutes. The reaction 
mixture is acidified with 10% hydrochloric acid and then extracted with 
ethyl acetate. The extract is washed with water, dried and evaporated to 
remove solvent. The resultant crystals are collected, washed and dried to 
give 8.65 g of 2-(4-nitrophenyl)benzofuran-7-carboxylic acid as pale 
orange powder. 
IR.nu..sub.max.sup.Nujol (cm.sup.-1): 1710. 
Preparation 3 
(1) A mixture of 1.90 g of methyl 3-formyl-2-hydroxybenzoate, 3.0 g of 
nitroethane, 0.15 ml of piperidine and 30 ml of toluene is refluxed 
overnight while removing water. The reaction mixture is poured into 
ice-water and the aqueous mixture is extracted with ethyl acetate. The 
extract is washed successively with 10% hydrochloric acid and an aqueous 
saturated sodium chloride solution, dried and evaporated to remove 
solvent. The residue is recrystallized from methanol to give 2.05 g of 
methyl 2-hydroxy-3-(2-nitro-1-propenyl)benzoate. 
M.p. 119.degree.-121.degree. C. 
(2) A mixture of 2.02 g of methyl 2-hydroxy-3-(2-nitro-1-propenyl)benzoate, 
4.75 g of iron powder and 40 ml of acetic acid is heated at 70.degree. C. 
for 25 minutes. Toluene is added to the reaction mixture, and the mixture 
is filtered and washed with chloroform. The washings and the filtrate are 
combined and the mixture is evaporated under reduced pressure to remove 
solvent. 50 ml of toluene, 2.43 g of p-toluenesulfonic acid monohydrate 
and 1 ml of water are added to the residue. The mixture is refluxed for 50 
minutes and further refluxed 20 minutes while removing water 
azeotropically. Ethyl acetate is added to the reaction mixture. The 
mixture is washed successively with water and an aqueous saturated sodium 
bicarbonate solution, dried and evaporated to remove solvent. The residue 
is purified by silica gel column chromatography to give 1.24 g of methyl 
2-methylbenzofuran-7-carboxylate as colorless oil. 
Mass(m/e): 190 (M.sup.+). 
The corresponding starting compound is treated in the same manner as 
described above to give the following compound. 
(i) methyl 2-benzylbenzofuran-7-carboxylate 
IR.nu..sub.max.sup.liquid (cm.sup.-1): 1720. 
Preparation 4 
(1) A mixture of 3.0 g of methyl 3-formyl-2-hydroxybenzoate, 3.31 g of 
t-butyl chloroacetate, 12.0 g of potassium carbonate and 40 ml of 
dimethylformamide is heated at 70.degree. C. for 2.5 hours. After cooling, 
the reaction mixture is poured into water and the aqueous mixture is 
extracted with ethyl acetate. The extract is washed with an aqueous 
saturated sodium chloride solution, dried and evaporated to remove 
solvent. The residue is dissolved in trifluoroacetic acid and the solution 
is stirred at room temperature for 30 minutes. The reaction mixture is 
concentrated under reduced pressure and the residue is treated with ether 
to give 2.09 g of (2-methoxycarbonyl-6-formylphenoxy)acetic acid as pale 
yellow powder. 
(2) A mixture of 2.09 g of (2-methoxycarbonyl-6-formylphenoxy)acetic acid, 
1.48 g of sodium acetate and 7 ml of acetic anhydride is refluxed for 1.5 
hours. After cooling, water is added to the reaction mixture, and the 
aqueous mixture is alkalized with potassium carbonate and extracted with 
ethyl acetate. The extract is washed with water, dried and evaporated to 
remove solvent. The residue is purified by silica gel column 
chromatography to give 0.39 g of methyl benzofuran-7-carboxylate as 
colorless oil. 
IR.nu..sub.max.sup.liquid (cm.sup.-1): 1720. 
Preparation 5 
(1) A solution of 17.25 g of acetophenone oxime in 100 ml of 
dimethylformamide is added dropwise to a suspension of 5.92 g of 62.5% 
sodium hydride in 400 ml of dimethylformamide under ice-cooling. The 
mixture is stirred at the same temperature for 1.5 hours. A solution of 
25.04 g of methyl 2-chloro-5-nitrobenzoate in 150 ml of dimethylformamide 
is added to the mixture, the mixture is stirred for 1 hour. The reaction 
mixture is poured into ice-water and the aqueous mixture is extracted with 
ethyl acetate. The extract is washed with an aqueous saturated sodium 
chloride solution, dried and evaporated to remove solvent. The residue is 
recrystallized from isopropanol to give 26.7 g of acetophenone 
O-(2-methoxycarbonyl-4-nitrophenyl)oxime as yellow needles. 
M.p. 108.5.degree.-109.5.degree. C. 
(2) A mixture of 26.7 g of acetophenone 
O-(2-methoxycarbonyl-4-nitrophenyl)oxime and 250 ml of formic acid is 
refluxed for 6 hours and the reaction mixture is evaporated under reduced 
pressure to remove solvent. The residue is recrystallized from ethyl 
acetate to give 9.22 g of methyl 5-nitro-2-phenylbenzofuran-7-carboxylate 
as yellow needles. 
M.p. 186.degree.-188.5.degree. C. 
Preparation 6 
(1) 5.3 g of methyl 3-acetylsalicylate are dissolved in 50 ml of 
dimethylformamide and the solution is added dropwise to a suspension of 
1.26 g of 62.5% sodium hydride in 15 ml of dimethylformamide, and the 
mixture is stirred for 20 minutes. 5.40 g of methyl 2-bromo-propionate are 
added dropwise to the mixture and the mixture is heated at 
60.degree.-80.degree. C. for 7 hours. The reaction mixture is poured into 
ice-water and the aqueous mixture is extracted with ethyl acetate. The 
extract is washed with water, dried and evaporated to remove solvent. The 
residue is purified by silica gel column chromatography (solvent; 
n-hexane:ethyl acetate=3:1) to give 5.10 g of methyl 
2-(2-methoxycarbonyl-6-acetylphenoxy)propionate as colorless oil. 
(2) A mixture of 4.42 g of methyl 
2-(2-methoxycarbonyl-6-acetylphenoxy)propionate, 20 ml of 6N hydrochloric 
acid and 20 ml of dioxane is refluxed for 10 minutes, and water is added 
to the reaction mixture. The aqueous mixture is extracted with ethyl 
acetate. The extract is washed with water, dried and evaporated to remove 
solvent. The residue is dissolved in 30 ml of tetrahydrofuran, and 5.55 ml 
of oxalyl chloride and a drop of dimethylformamide are added to the 
solution. The mixture is stirred for 1 hour. The reaction mixture is 
evaporated to remove solvent and the residue is dissolved in 100 ml of 
benzene. The solution is added dropwise to a refluxed solution of 6.66 ml 
of triethylamine in benzene and the mixture is refluxed for 5 hours. The 
reaction mixture is washed successively with 2% hydrochloric acid and 
water, dried and evaporated to remove solvent. The residue is purified by 
silica gel column chromatography (solvent; n-hexane:ethyl acetate=5:1) to 
give 1.48 g of methyl 2,3-dimethylbenzofuran-7-carboxylate. 
M.p. 54.5.degree.-55.5.degree. C. 
PREATION 7 
A mixture of 1.0 g of methyl 2-methylbenzofuran-7-carboxylate, 1.24 g of 
acetyl chloride, 2.15 g of aluminum chloride and 20 ml of dichloroethane 
is heated at 50.degree.-60.degree. C. for 1 hour. The reaction mixture is 
poured into ice-water and the aqueous mixture is extracted with 
chloroform. The extract is washed with water, dried and evaporated to 
remove solvent. The residue is recrystallized from ethyl acetate-n-hexane 
to give 1.08 g of methyl 3-acetyl-2-methylbenzofuran-7-carboxylate as 
colorless needles. 
M.p. 115.degree.-117.degree. C. 
(i) The corresponding starting compounds are treated in the same manner as 
described above to give methyl 3-benzoyl-2-methylbenzofuran-7-carboxylate 
as colorless needles. 
M.p. 70.degree.-72.degree. C. (recrystallized from isopropyl ether).