Spiro compounds, their production and use

New spiro compounds of the formula: ##STR1## wherein n is an integer of 1 to 4, and X is halogen, lower alkyl, nitro, amino which may be substituted, hydroxyl which may be substituted, acyl, carboxyl, lower alkoxycarbonyl, carbamoyl which may be substituted, sulfamoyl which may be substituted, lower alkylthio or lower alkylsulfonyl, or two of X at the 5- and 6-positions together form --CH.dbd.CH--CH.dbd.CH--, exhibit inhibitory activity to thrombocyte aggregation and are useful for the prophylaxis or treatment of cardiovascular disturbance such as thrombosis.

The present invention relates to novel spiro compounds which are useful as 
drugs or intermediates for the drugs, to a method for producing the same, 
and to prophylactic and therapeutic agents for cardiovascular disturbance. 
More particularly, the compounds of the present invention are novel spiro 
compounds of the formula: 
##STR2## 
wherein 
n is an integer of 1 to 4, and 
X is halogen, lower alkyl, nitro, amino which may be substituted, hydroxyl 
which may be substituted, acyl, carboxyl, lower alkoxycarbonyl, carbamoyl 
which may be substituted, sulfamoyl which may be substituted, lower 
alkylthio or lower alkylsulfonyl, 
or two of X at the 5- and 6-positions together form 
--CH.dbd.CH--CH.dbd.CH--, 
and pharmaceutically acceptable salts thereof. 
With reference to the above formula (I), examples of the halogen atom 
represented by X include chlorine, bromine, fluorine and iodine, and as 
examples of the lower alkyl group there may be mentioned C.sub.1-6 alkyl 
(e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, 
tert-butyl, n-pentyl, isopentyl, n-hexyl, 2-methylpentyl and 
2-ethylbutyl). 
As examples of the amino group which may be substituted, there may be 
mentioned amino, hydroxyamino, mono- or di-alkylamino, acylamino, 
sulfonylamino and cyclic amino groups; such mono- or di-alkylamino group 
may include amino groups mono- or di-substituted by C.sub.1-4 alkyl, such 
as methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, 
dimethylamino, diethylamino, di-n-propylamino, methylethylamino and the 
like; the acylamino group is typified by C.sub.2-4 alkanoylamino (e.g. 
acetylamino, propionylamino, n-butyrylamino and isobutyrylamino); the 
sulfonylamino group may be exemplified by C.sub.1-4 alkylsulfonylamino 
(e.g. methylsulfonylamino and ethylsulfonylamino); and the cyclic amino 
group may be for example 5- or 6-membered cyclic amino groups which may 
contain N or O, such as pyrrolidinyl, piperidino, piperazinyl and 
morpholino, wherein the piperazinyl may be further substituted on the N 
atom at the 4-position by C.sub.1-4 alkyl (e.g. methyl and ethyl), 
phenyl-C.sub.1-4 alkyl (e.g. benzyl), C.sub.2-4 alkalnoyl (e.g. acetyl and 
propionyl), etc. 
Examples of the hydroxyl group which may be substituted include hydroxyl, 
alkoxy, aryloxy, aralkyloxy and acyloxy groups; such alkoxy group may 
preferably be alkoxy groups of 1 to 6 carbon atoms (e.g. methoxy, ethoxy, 
n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy 
groups); the aryloxy group may be exemplified by phenoxy and the like; the 
aralkyloxy group may be exemplified by phenyl-C.sub.1-4 alkyloxy (e.g. 
benzyloxy and phenethyloxy); and the acyloxy group which is preferred 
includes C.sub.2-6 alkanoyloxy (e.g. acetyloxy, propionyloxy, n-butyloxy 
and isobutyloxy groups), benzoyloxy and the like. The above alkoxy group 
may be substituted by carboxyl, C.sub.2-6 alkoxycarbonyl (e.g. 
methoxycarbonyl and ethoxycarbonyl) or carbamoyl, said carbamoyl being 
unsubstituted or substituted by C.sub.1-4 alkyl (e.g. methyl and ethyl) 
and/or C.sub.5-6 cycloalkyl (e.g. cyclopentyl and cyclohexyl). 
As examples of the acyl group there may be mentioned C.sub.2-6 alkanoyl 
(e.g. acetyl, propionyl, n-butyryl and iso-butyryl), benzoyl and the like. 
Examples of the lower alkoxycarbonyl group include C.sub.2-6 
alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 
iso-propoxycarbonyl and butoxycarbonyl). Examples of the carbamoyl group 
which may be substituted include carbamoyl and C.sub.1-4 alkyl-substituted 
carbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl and 
isopropylcarbamoyl). As examples of the sulfamoyl group which may be 
substituted there may be mentioned sulfamoyl, C.sub.1-4 alkyl-substituted 
sulfamoyl (e.g. methylsulfamoyl, ethylsulfamoyl, n-propylsulfamoyl and 
isopropylsulfamoyl), piperidinosulfonyl, morpholinosulfonyl and the like. 
The lower alkyl moiety in the lower alkylthio and lower alkylsulfonyl 
groups includes for example C.sub.1-4 alkyl groups (e.g. methyl, ethyl, 
n-propyl and isopropyl groups). 
In the above formula (I), n designates an integer of 1 to 4. This is to 
say, the substituent, X, may exist in number of not less than 1 but not 
more than 4 at any substitutable positions of the benzene ring. In the 
case of the presence of two or more substituent groups of X, they may be 
the same or different. 
In the present invention, a preferred embodiment provides spiro compounds 
of the formula (I) wherein 
n is an integer of 1 to 4, and 
X is halogen, C.sub.1-6 alkyl, nitro, amino, hydroxyamino, mono- or 
di-C.sub.1-4 alkylamino, C.sub.2-4 alkanoylamino, C.sub.1-4 
alkylsulfonylamino, pyrrolidinyl, piperidino, piperazinyl, morpholino, 
hydroxyl, C.sub.1-6 alkoxy, phenoxy, phenyl-C.sub.1-4 alkyloxy, C.sub.2-6 
alkanoyloxy, benzoyloxy, C.sub.2-6 alkanoyl, benzoyl, carboxyl, C.sub.2-6 
alkoxycarbonyl, carbamoyl, C.sub.1-4 alkylcarbamoyl, sulfamoyl, C.sub.1-4 
alkylsulfamoyl, piperidinosulfonyl, morpholinosulfonyl, C.sub.1-4 
alkylthio or C.sub.1-4 alkylsulfonyl, 
said piperazinyl being unsubstituted or substituted on the N atom at the 
4-position by C.sub.1-4 alkyl, phenyl-C.sub.1-4 alkyl or C.sub.2-6 
alkanoyl, and said C.sub.1-6 alkoxy being unsubstituted or substituted by 
carboxyl, C.sub.2-6 alkoxycarbonyl or carbamoyl which is unsubstituted or 
substituted by C.sub.1-4 alkyl and/or C.sub.5-6 cycloalkyl, or 
two of X at the 5- and 6-positions together form --CH.dbd.CH--CH.dbd.CH--. 
Among the substituent groups mentioned above for X, the halogen, C.sub.1-6 
alkyl group, nitro group, amino group, C.sub.2-4 alkanoylamino group, and 
C.sub.1-6 alkoxy group are conveniently employed, and n is desirably 1 or 
2. 
The spiro compound (I) of the present invention, for example, can be 
produced by subjecting to decarboxylation reaction a compound of the 
formula: 
##STR3## 
wherein n and X are as defined hereinbefore. 
The reaction is normally conducted in the presence of a catalyst promoting 
decarboxylation, and examples of such catalyst which are conveniently 
employed include metal halides (e.g. sodium chloride, sodium bromide, 
sodium iodide, potassium bromide, potassium chloride and potassium 
iodide), quarternary ammonium salts (e.g. tetramethyl ammonium bromide) 
and the like. The reaction temperature is normally in the range of about 
100.degree. C. to 200.degree. C. and, in particular, preferably in the 
range of about 140.degree. C. to 160.degree. C., although the reaction may 
be conducted at higher or lower temperatures for the purpose of 
controlling the rate of reaction. By replacing the reaction vessel with an 
inert gas (e.g. nitrogen and argon), side reactions are in some instances 
prevented, leading to an increase in yield. The reaction is normally 
conducted in an appropriate solvent, and such solvent includes any type of 
solvents, unless they inhibit the reaction. Normally, the solvents having 
higher boiling points than the reaction temperature (e.g. 
dimethylsulfoxide, N,N-dimethylformamide and hexamethylphosphortriamide) 
are conveniently employed. 
Further, the substituent of the compound (I) obtained in the above reaction 
can also be converted into different ones by means of the reaction 
conventional per se. For example, the compound (I) wherein the substituent 
of X is amino or hydroxyamino can also be produced by subjecting the 
previously introduced nitro to reduction reaction. The compound (I) 
wherein the substituent of X is mono- or di-alkylamino is obtained through 
reductive alkylation of the compound (I) wherein the substituent group is 
amino, namely by the procedures of reducing or catalytically reducing it 
with the use of metal hydrides such as sodium cyanoborohydride in the 
presence of a carbonyl compound (e.g. formalin, acetaldehyde and acetone) 
or by the procedure of reacting it with alkyl halide to thereby conduct 
mono- or di-alkylation. Furthermore, the compound (I) having mono- or 
di-alkylamino can be obtained by catalytically reducing nitro-substituted 
compound with the use of a catalyst such as platinum oxide and Raney 
nickel in the presence of the above-mentioned carbonyl compound. 
The objective compound (I) produced in this manner can be isolated and 
purified from reaction mixtures by conventional separation and 
purification procedures (e.g. distillation, recrystallization and column 
chromatography). Furthermore, the compound (I) may be isolated as a 
suitable salt corresponding to the type of the substituent group of X. In 
cases in which the substituent group is amino, mono- or di-alkyl and other 
groups, for example, the compounds can be isolated as acid addition salts 
(e.g. mineral acid salts such as hydrochloride and hydrobromide, and 
organic acid salts such as citrate, tartrate, maleate, fumarate and 
oxalate), while they can be isolated as alkali metal salts (e.g. sodium 
salt and potassium salt) in the case of the substituent group being 
carboxyl and other groups. 
The spiro compounds (I) of the present invention exhibits the superior 
thrombocyte aggregation inhibitory activity, and are of value as the 
prophylactic and therapeutic agent for cardiovascular disturbance in 
mammals (e.g. man, rat, mouse, guinea pig, dog and pig), such as 
thrombosis, cerebral apoplexy (e.g. cerebral hemmorrhage, cerebral 
thrombosis and cerebral embolism), myocardial infarction, angina pectoris, 
thrombophlebitis and glomerulonephritis. 
The compounds of the present invention are lowered in toxicity, and, in 
cases in which they are used as such drugs, the compounds (I) may be 
safely administered orally or parenterally, as such or as pharmaceutical 
compositions. The dosage depends on the subject, condition and the route 
of administration. The compound (I), when it is to be administered orally 
for example for the prophylaxis and therapy for thrombosis in an adult 
human, may be conveniently administered in general in a single dose of 
about 0.1 to 20 mg/kg body weight, about once to 3 times daily. In more 
particularly, it is preferred to administer it in a single dose of about 
0.5 to 4 mg/kg body weight for the prophylaxis of thrombosis, and in a 
single dose of about 4 to 10 mg/kg body weight for the therapy for 
thrombosis, respectively once to 3 times daily. 
The pharmaceutical composition to be used in the above-mentioned 
administration comprises an effective amount of the compound (I) as an 
active ingredient and a pharmaceutically acceptable carrier or excipient. 
Such composition may be presented in a form suitable for oral or 
parenteral administration. 
Thus, the compositions for oral administration are for example the solid or 
liquid dosage forms, specific examples of which are tablets (including 
sugar coated tablets and film coating tablets), pills, granules, powders, 
capsules (inclusive of soft capsules), syrups, emulsions and suspensions. 
Such compositions are produced by the procedures conventional per se and 
may comprise carriers or excipients conventionally employed in the field 
of pharmaceutical preparations. Examples of the carriers or excipients for 
tablets include lactose, starch, sucrose, magnesium stearate, etc. 
The compositions for parenteral administration may for example include 
injections, suppositories, etc. The injections include the dosage forms 
intended for use by intravenous and intramuscular infusions. Such 
injections are produced by the procedures conventional per se, or by 
dissolving, suspending or emulsifying the compound (I) in a sterile 
aqueous or oily solution normally employed for injections. The aqueous 
solution for injections may for example include physiological saline, 
isotonic solution, etc., and may be employed in combination with a 
suitable solubilizer such as alcohols (e.g. ethanol), polyalcohols (e.g. 
propyrene glycol, polyethylene glycol, etc.), non-ionic surface active 
agents [e.g. polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of 
hydrogenated castor oil)], etc. As examples of the oily solution there may 
be mentioned sesame oil and soybean oil, and they may be used in 
combination with a suitable solubilizer such as benzyl benzoate, benzyl 
alcohol, etc. The prepared injection may be normally filled into suitable 
ampoules. The suppositories for rectal administration are prepared by 
incorporating the compound (I) with a conventional excipient for 
suppositories. 
The above-mentioned, pharmaceutical compositions for oral or parenteral 
administration are advantageously formulated as dosage units, each unit 
being adapted to supply a fixed dose of the active ingredient. Examples of 
such dosage unit forms are tablets, pills, capsules, injections 
(ampoules), suppositories, etc., and each dosage unit form normally 
contains 10 to 500 mg of the compound (I). Among them, an injection 
ampoule preferably contains 10 to 100 mg, and each of other dosage forms 
preferably contains 25 to 250 mg of the compound (I). 
Each composition mentioned hereinbefore may contain other active ingredient 
or ingredients so far as they do not cause any unfavorable interaction 
when formulated in combination with the compound (I). 
The starting compound (II) which is useful in the method according to the 
present invention can be produced, for example, by the process described 
below or a process analogous thereto. 
##STR4## 
[wherein n and X are as defined hereinbefore].

Given below are Reference Examples, Examples, Test Examples and Preparation 
Examples to illustrate the present invention more specifically; these, 
however, are not intended to limit the scope of the present invention. 
REFERENCE EXAMPLE 1 
In 250 ml of water were dissolved 18.9 g of 5-chlorothiosalicyclic acid and 
26.5 g of sodium carbonate, and 25 g of 
.alpha.-bromo-.gamma.-butyrolactone was added dropwise to the solution 
under ice-cooling, followed by stirring at room temperature for 21 hours. 
100 ml of 3 N-HCl was added to the reaction solution at room temperature 
to acidify the solution, and the solution was subjected to extraction with 
ethyl acetate. The extract was washed with aqueous saturated solution of 
sodium chloride and dried, and then, the solvent was distilled off. The 
residue was dissolved in 300 ml of toluene and heated under reflux for 2 
hours while distilling off the produced water. After cooling the solution, 
insolubles were filtered off, and the filtrate was evaporated to dryness 
under reduced pressure, resulting in crude 
.alpha.-[(2-carboxy-4-chlorophenyl)thio]-.gamma.-butyrolactone. The crude 
product was dissolved in 200 ml of acetic anhydride and 40 ml of 
triethylamine, and heated under a stream of nitrogen at 130.degree. C. for 
10 minutes. The reaction solution was evaporated to dryness under reduced 
pressure and chromatographed on a column by use of 50 g of activated 
carbon, 50 g of silica gel and chloroform. Recrystallization from ethanol 
of the resulting crude crystals yielded 7.17 g of 
5-chloro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-di 
one as pale yellow needles. Melting point: 143.degree.-143.5.degree. C. 
Elementary analysis, for C.sub.11 H.sub.7 ClO.sub.3 S--Calcd. C, 51.87; H, 
2.77. Found C, 51.87; H, 2.56. 
REFERENCE EXAMPLE 2 
In 200 ml of water were dissolved 14.2 g of 4-chlorothiosalicylic acid and 
20 g of sodium carbonate, and 19.1 g of 
.alpha.-bromo-.gamma.-butyrolactone was added dropwise to the solution 
under ice-cooling. After stirring the solution at room temperature for 6 
hours, 35 ml of concentrated hydrochloric acid was added to the reaction 
solution at room temperature to acidify. After stirring at room 
temperature for 3 hours, the precipitate was collected, washed with water 
and dried, resulting in crude 
.alpha.-[(2-carboxy-5-chlorophenyl)thio]-.gamma.-butyrolactone. The crude 
product was dissolved in 150 ml of acetic anhydride and 30 ml of 
triethylamine, and heated under a stream of nitrogen at 130.degree. C. for 
10 minutes. The reaction solution was evaporated to dryness under reduced 
pressure, and the resulting residue was chromatographed on a column of 
activated carbon and silica gel. Recrystallization from ethanol of the 
resultant crude crystals yielded 1.60 g of 
6-chloro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'( 
2'H)-furan]-3,2'-dione as colorless needles. Melting point: 
157.degree.-158.degree. C. 
Elementary analysis, for C.sub.11 H.sub.7 ClO.sub.3 S--Calcd. C, 51.87; H, 
2.77. Found C, 51.85; H, 2.68. 
REFERENCE EXAMPLE 3 
In 135 ml of water were dissolved 8.5 g of 5-methylthiosalicylic acid and 
13.3 g of sodium carbonate, and 12.5 g of 
.alpha.-bromo-.gamma.-butyrolactone was added dropwise to the solution 
under ice-cooling with stirring. After stirring the solution at room 
temperature for 151/2 hours, 20 ml of concentrated hydrochloric acid was 
added to the solution to acidify. After stirring the solution at room 
temperature for 24 hours, the precipitate was collected by filtration, 
washed with water and dried, resulting in crude 
.alpha.-[(2-carboxy-4-methylphenyl)thio]-.gamma.-butyrolactone. 5 g of the 
crude product was dissolved in 50 ml of acetic anhydride and 10 ml of 
triethylamine, and the solution was heated under a stream of nitrogen at 
130.degree. C. for 10 minutes. The reaction solution was evaporated to 
dryness under reduced pressure, and the residue was dissolved in ethyl 
acetate, washed with saturated aqueous solution of sodium chloride, and 
dried, followed by distilling off the solvent. The residue was 
chromatographed on a column of activated carbon and silica gel. 
Recrystallization 120.degree.-124.degree. C. 
Elementary analysis, for C.sub.12 H.sub.10 O.sub.3 S--Calcd. C, 61.52; H, 
4.30. Found C, 61.45; H, 4.36. 
REFERENCE EXAMPLE 4 
In 500 ml of water were dissolved 12.6 g of 4,5-dimethoxythiosalicylic acid 
and 15.6 g of sodium carbonate, and 14.6 g of 
.alpha.-bromo-.gamma.-butyrolactone was added dropwise to the solution 
under ice-cooling with stirring. After stirring the solution at 0.degree. 
C. for 30 minutes and at room temperature for 3 hours, 30 ml of 
concentrated hydrochloric acid was added to the solution to acidify. After 
stirring the solution at room temperature for 63 hours, the precipitate 
was recovered by filtration, washed with water and dried, resulting in 
11.75 g of crude 
.alpha.-[(2-carboxy-4,5-dimethoxyphenyl)thio]-.gamma.-butyrolactone. The 
crude product was dissolved in 200 ml of acetic anhydride and 40 ml of 
triethylamine, and heated under a stream of nitrogen at 130.degree. C. for 
30 minutes. The reaction solution was evaporated to dryness under reduced 
pressure, and the residue was chromatographed on a column of activated 
carbon and silica gel. Recrystallization from ethanol of the resultant 
crude crystals yielded 6.5 g of 
5,6-dimethoxy-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2H')-furan]-3, 
2'-dione as pale yellow needles. Melting point: 236.degree.-237.degree. C. 
Elementary analysis, for C.sub.13 H.sub.12 O.sub.5 S--Calcd. C, 55.70; H, 
4.32. Found C, 55.90; H, 4.27. 
REFERENCE EXAMPLE 5 
In 200 ml of water was dissolved 4.45 g of dipotassium salt of 
5-nitrothiosalicylic acid, and 3.55 g of 
.alpha.-bromo-.gamma.-butyrolactone was added dropwise to the solution 
under ice-cooling with stirring. After stirring the solution at room 
temperature for 3.5 hours, 10 ml of concentrated hydrochloric acid was 
added to the solution to acidify, and the solution was subjected to 
extraction with ethyl acetate. The extract was washed with water, dried 
and evaporated to dryness under reduced pressure, resulting in 
.alpha.-[(2-carboxy-4-nitrophenyl)thio]-.gamma.-butyrolactone. The crude 
product was dissolved in 50 ml of acetic anhydride and 10 ml of 
triethylamine, and heated under a stream of nitrogen at 130.degree. C. for 
30 minutes. The reaction solution was evaporated to dryness under reduced 
pressure, and the residue was chromatographed on a column of activated 
carbon and silica gel. Recrystallization from ethanol of the resultant 
crude crystals yielded pale yellow needles of 
5-nitro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2' 
-dione. Melting point: 190.5.degree.-193.5.degree. C. 
Elementary analysis, for C.sub.11 H.sub.7 NO.sub.5 S--Calcd. C, 49.81; H, 
2.66; N, 5.28. Found C, 49.82; H, 2.83; N, 5.02. 
REFERENCE EXAMPLE 6 
In 200 ml of water was dissolved 4.4 g of dipotassium salt of 
4-nitrothiosalicylic acid, and 3.55 g of 
.alpha.-bromo-.gamma.-butyrolactone was added dropwise to the solution 
under ice-cooling with stirring. After stirring the solution at room 
temperature for 14 hours, 7 ml of concentrated hydrochloric acid was added 
to the reaction solution at room temperature so as to acidify. The 
precipitate was recovered by filtration, washed with water and dried, 
resulting in crude 
.alpha.-[(2-carboxy-5-nitrophenyl)thio]-.gamma.-butyrolactone. 
Recrystallization from ethanol gave pale yellow needles. Melting point: 
209.5.degree.-211.5.degree. C. 
Elementary analysis, for C.sub.11 H.sub.9 NO.sub.6 S--Calcd. C, 46.64; H, 
3.20; N, 4.95. Found C, 46.55; H, 3.02; N, 5.05. 
REFERENCE EXAMPLE 7 
In 50 ml of acetic anhydride and 10 ml of triethylamine was dissolved 2.5 g 
of .alpha.-[(2-carboxy-5-nitrophenyl)thio]-.gamma.-butyrolactone as 
obtained in Reference Example 6, and the solution was heated under a 
stream of nitrogen at 130.degree. C. for 30 minutes. The reaction solution 
was evaporated to dryness under reduced pressure, and the residue was 
chromatographed on a column of activated carbon and silica gel. 
Recrystallization from ethanol of the resultant crude crystals yielded 
pale yellow needles of 
6-nitro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2H')-furan]-3,2'-dio 
ne. Melting point: 184.degree.-187.degree. C. 
Elementary analysis, for C.sub.11 H.sub.7 NO.sub.5 S--Calcd. C, 49.81; H, 
2.66; N, 5.28. Found C, 49.82; H, 2.58; N, 5.28. 
REFERENCE EXAMPLE 8 
In 35 ml of ethyl acetate and 3.5 ml of acetic acid was dissolved 356.3 mg 
of 
6-nitro-4',5'-dihydrospiro[benzo[b]thiophen-2(3H),3'(2'H)-furan]-3,2'-dion 
e as obtained in Reference Example 7, and was subjected to catalytic 
reduction under atmospheric pressure at room temperature in the presence 
of 113.3 mg of 5% palladium carbon. After absorption of hydrogen stopped, 
the catalyst was filtered off, and the filtrate was evaporated to dryness 
under reduced pressure. Recrystallization of the residue from 
water-acetone (7:3) yielded yellow needles of 
6-hydroxyamino-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3 
,2'-dione. Melting point: 184.degree.-186.degree. C. 
Elementary analysis, for C.sub.11 H.sub.9 NO.sub.4 S--Calcd. C, 52.58; H, 
3.61; N, 5.58. Found C, 52.64; H, 3.55; N, 5.68. 
REFERENCE EXAMPLE 9 
To a solution of 2,2'-dithio-6-methylbenzoic acid (3.05 g) in ethanol (60 
ml) was added a solution of KOH(1.9 g) in ethanol (60 ml) at 70.degree. C. 
with stirring. After being stirred at 100.degree. C. for 1 hour, the 
mixture was evaporated in vacuo. 
To a solution of the resulting residue in water (100 ml) was added 
.alpha.-bromo-.gamma.-butyrolactone (3.55 g) at 0.degree. C. with 
stirring. After being stirred at 0.degree. C. for 2.5 hours and at room 
temperature for additional 14 hours, the mixture was filtered. The 
filtrate was acidified with conc. HCl (9 ml) and extracted with ethyl 
acetate. The extract was washed with water, dried over Na.sub.2 SO.sub.4 
and evaporated in vocuo to give crude 
.alpha.-[(2-carboxy-3-methylphenyl)thio]-.gamma.-butyrolactone. 
A mixture of this crude compound in acetic anhydride (70 ml) and 
triethylamine (15 ml) was heated at 130.degree. C. for 30 minutes under a 
stream of N.sub.2 gas with stirring. The mixture was evaporated in vacuo. 
The resulting residue was submitted to column chromatography on silica gel 
(100 g) and charcoal (20 g) eluting with CHCl.sub.3 to give 
4-methyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-di 
one as colorless needles [from C.sub.2 H.sub.5 OH--H.sub.2 O (3:2)], mp 
105.5.degree.-106.5.degree. C. Anal. Calcd. for C.sub.12 H.sub.10 O.sub.3 
S: C, 61.52; H, 4.30. Found: C, 61.57; H, 4.17. 
REFERENCE EXAMPLE 10 
6-Methyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dio 
ne was prepared by a similar procedure to that of Reference Example 9 
except for the use of 2,2'-dithio-4-methylbenzoic acid. Pale yellow 
needles [from C.sub.2 H.sub.5 OH--H.sub.2 O (6:5)], mp 
122.degree.-123.5.degree. C. Anal. Calcd. for C.sub.12 H.sub.10 O.sub.3 S: 
C, 61.52; H, 4.30. Found: C, 61.57; H, 4.15. 
REFERENCE EXAMPLE 11 
7-Methyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dio 
ne was prepared by a similar procedure to that of Reference Example 9 
except for the use of 2,2'-dithio-3-methylbenzoic acid. Pale yellow 
needles [from C.sub.2 H.sub.5 OH--H.sub.2 O (1:1)], mp 
98.5.degree.-99.5.degree. C. Anal. Calcd. for C.sub.12 H.sub.10 O.sub.3 S: 
C, 61.52; H, 4.30. Found: C, 61.61; H, 4.01. 
REFERENCE EXAMPLE 12 
Methyl 5-acetylsalicylate (10.0 g) was hydrogenated in the presence of 5% 
Pd-C (1.0 g) in ethyl acetate (200 ml) containing 70% HClO.sub.4 (2 ml) at 
room temperature under usual pressure of H.sub.2 gas with stirring. The 
catalyst was filtered off and the filtrate was evaporated in vacuo to give 
crude methyl 5-ethylsalicylate as pale brown oil. 
To a solution of this crude methyl 5-ethylsalicylate (0.928 g) and 1.7 g of 
1,4-diazabicyclo[2,2,2]octane (DABCO) in 10 ml of dimethylformamide (DMF) 
was added a solution of dimethylthiocarbamoyl chloride (2.5 g) in DMF (5 
ml) at room temperature with stirring. After being stirred at room 
temperature for 3 days, the mixture was poured into saturated NaCl aqueous 
solution and extracted with ethyl acetate. The extract was washed with 
H.sub.2 O, dried over Na.sub.2 SO.sub.4 and evaporated in vacuo. The 
resulting residue was submitted to column chromatography on silica gel (50 
g) eluting with CCl.sub.4 -ethyl acetate (5:1) to give 
O-(2-carboxy-4-ethylphenyl)dimethylthiocarbamate as colorless oil. Anal. 
Calcd. for C.sub.13 H.sub.17 NO.sub.3 S: C, 58.40; H, 6.41; N, 5.24. 
Found: C, 58.43; H, 6.24; N, 5.41. 
O-(2-Carbomethoxy-4-ethylphenyl)dimethylthiocarbamate (1.1 g) was heated at 
200.degree. C. for 16 hours. After being cooled to room temperature, the 
mixture was submitted to column chromatography on silica gel (50 g) 
eluting with CCl.sub.4 -ethyl acetate (2:1) to give 
S-(2-carbomethoxy-4-ethylphenyl)-dimethylthiocarbamate (627 mg) as 
colorless oil. Anal. Calcd. for C.sub.13 H.sub.17 NO.sub.3 S: C, 58.40; H, 
6.41; N, 5.24. Found: C, 58.44; H, 6.39; N, 5.32. To a solution of the 
above compound (2.14 g) in ethanol (60 ml) was added a solution of KOH(4.4 
g) in ethanol (100 ml) at room temperature with stirring. After being 
heated at 100.degree. C. for 1 hour, the mixture was evaporated in vacuo. 
To a solution of the resulting residue in H.sub.2 O (100 ml) was added 
.alpha.-bromo-.gamma.-butyrolactone (10 g) at 0.degree. C. with stirring. 
After stirring at room temperature for 11 hours, 
.alpha.-bromo-.gamma.-butyrolactone (2 g) was added again at room 
temperature with stirring. After being stirred at room temperature for 3 
hours, the mixture was filtered. The filtrate was added to conc. HCl (35 
ml) at room temperature with stirring. The resulting precipitate was 
collected, washed with H.sub.2 O, dried and recrystallized from benzene to 
give .alpha.-[(2-carboxy-4-ethylphenyl)thio]-.gamma.-butyrolactone as 
colorless needles, mp 167.degree.-169.5.degree. C. Anal. Calcd. for 
C.sub.13 H.sub.14 O.sub.4 S: C, 58.63; H, 5.30. Found: C, 58.38; H, 5.20. 
A mixture of .alpha.-[(2-carboxy-4-ethylphenyl)thio]-.gamma.-butyrolactone 
(1.0 g) in acetic anhydride (30 ml) and triethylamine (6 ml) was heated at 
130.degree. C. for 30 minutes under a stream of N.sub.2 gas with stirring. 
The mixture was evaporated in vacuo. The resulting residue was submitted 
to column chromatography on silica gel (20 g) and charcoal (5 g) eluting 
with CHCl.sub.3 to give 
5-ethyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dio 
ne as colorless oil. Anal. Calcd. for C.sub.13 H.sub.12 O.sub.3 S: C, 
62.88; H, 4.87. Found: C, 62.83; H, 4.83. 
REFERENCE EXAMPLE 13 
5-Acetyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dio 
ne was prepared by a similar procedure to that of Reference Example 12. 
Colorless needles, mp 139.degree.-140.5.degree. C. Anal. Calcd. for 
C.sub.13 H.sub.10 O.sub.4 S: C, 59.53; H, 3.84. Found: C, 59.15; H, 4.14. 
REFERENCE EXAMPLE 14 
4-[5-[4',5'-Dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dioxo] 
oxy]butyric acid was prepared by a similar procedure to that of Reference 
Example 12. Pale yellow needles, mp 124.degree.-126.degree. C. Anal. 
Calcd. for C.sub.15 H.sub.14 O.sub.6 S: C, 55.89; H, 4.38. Found: C, 
55.98; H, 4.39. 
REFERENCE EXAMPLE 15 
5-Nitro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dion 
e (1.0 g) was hydrogenated in the presence of 5% Pd-C (0.35 g) in acetic 
acid (100 ml) at room temperature under usual pressure of H.sub.2 gas with 
stirring. The catalyst was filtered off and the filtrate was evaporated in 
vacuo. The resulting residue was recrystallized from benzene to give 
5-amino-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dio 
ne as yellow needles, mp 187.degree.-190.degree. C. Anal. Calcd. for 
C.sub.11 H.sub.9 NO.sub.3 S: C, 56.15; H, 3.86; N, 5.96. Found: C, 56.61; 
H, 3.73; N, 5.96. 
REFERENCE EXAMPLE 16 
To ClSO.sub.3 H (15 ml) was added 
4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione (5.0 
g) at 0.degree. C. with stirring. After being stirred at room temperature 
for 1.5 hours, the mixture was poured into ice and extracted with ethyl 
acetate. The extract was washed with H.sub.2 O, dried over Na.sub.2 
SO.sub.4 and evaporated in vacuo. To a solution of the resulting residue 
in 100 ml of tetrahydrofuran (THF) was added 25% NH.sub.4 OH (3.2 ml) at 
0.degree. C. with stirring. After being stirred at 0.degree. C. for 30 
minutes, the mixture was dried over Na.sub.2 SO.sub.4 and evaporated in 
vacuo. The resulting residue was recrystallized from ethanol to give 
5-sulfamoyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2' 
-dione as colorless needles, mp 199.degree.-201.degree. C. Anal. Calcd. for 
C.sub.11 H.sub.9 NO.sub.5 S.sub.2 : C, 44.14; H, 3.03; N, 4.68. Found: C, 
44.09; H, 3.22; N, 4.49. 
REFERENCE EXAMPLE 17 
5-Piperidinosulfonyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-fur 
an]-3,2'-dione was prepared by a similar procedure to that of Reference 
Example 16 except for the use of piperidine. Colorless needles [from 
C.sub.2 H.sub.5 OH--H.sub.2 O (1:1)], mp 159.degree.-161.degree. C. Anal. 
Calcd. for C.sub.16 H.sub.17 NO.sub.5 S.sub.2 : C, 52.30; H, 4.66; N, 
3.81. Found: C, 52.14; H, 4.56; N, 3.77. 
REFERENCE EXAMPLE 18 
5-Morpholinosulfonyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-fur 
an]-3,2'-dione was prepared by a similar procedure to that of Reference 
Example 16 except for the use of morpholine. Colorless needles [from 
H.sub.2 O-acetone (3:1)], mp 220.degree.-222.5.degree. C. Anal. Calcd. for 
C.sub.15 H.sub.15 NO.sub.6 S.sub.2 : C, 48.77; H, 4.09; N, 3.79. Found: C, 
48.81; H, 4.04; N, 4.08. 
EXAMPLE 1 
In 13 ml of dimethylsulfoxide were dissolved 2.55 g of 
5-chloro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-di 
one as obtained in Reference Example 1 and 586.1 mg of sodium chloride, and 
heated under a stream of nitrogen at 150.degree. C. for 30 minutes. After 
cooling, the reaction solution was poured into 200 ml of saturated aqueous 
solution of sodium chloride and subjected to extraction with ethyl 
acetate. The extract was washed with saturated aqueous solution of sodium 
chloride, dried and evaporated to dryness under reduced pressure. The 
residue was chromatographed on a column of silica gel (100 g) with the use 
of carbon tetrachloride. Recrystallization of the resultant crystals from 
n-hexane-benzene (5:1) yielded 1.15 g of colorless needles of 
5-chlorospiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one. Melting 
point: 106.degree.-107.degree. C. 
Elementary analysis, for C.sub.10 H.sub.7 ClOS-- Calcd. C, 57.01; H, 3.35. 
Found: C, 56.91; H, 3.09. 
EXAMPLE 2 
In 20 ml of dimethylsulfoxide were dissolved 1.8999 g of 
6-chloro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-di 
one as obtained in Reference Example 2 and 491 mg of sodium chloride, and 
heated under a stream of nitrogen at 150.degree. C. for 11/4 hours. After 
cooling, the solution was poured into 300 ml of saturated aqueous solution 
of sodium chloride and subjected to extraction with ethyl acetate. The 
extract was washed with saturated aqueous solution of sodium chloride, 
dried and evaporated to dryness under reduced pressure. The residue was 
chromatographed on a column of silica gel (100 g) with the use of carbon 
tetrachloride. Recrystallization of the resultant crude crystals from 
methanol-water (22:5) yielded 1.08 g of colorless needles of 
6-chlorospiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one. Melting 
point: 84.degree. C. 
Elementary analysis, for C.sub.10 H.sub.7 ClOS-- Calcd. C, 57.01; H, 3.35. 
Found C, 56.91; H, 3.20. 
EXAMPLE 3 
In 10 ml of dimethylsulfoxide were dissolved 1.0 g of 
5-methyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-di 
one as obtained in Reference Example 3 and 282.6 mg of sodium chloride, and 
the solution was heated under a stream of nitrogen at 150.degree. C. for 
1.5 hours. After cooling, the reaction solution was poured into 200 ml of 
saturated aqueous solution of sodium chloride and subjected to extraction 
with ethyl acetate. The extract was washed with saturated aqueous solution 
of sodium chloride, dried and evaporated to dryness under reduced 
pressure. The residue was chromatographed on a column with the use of 10 g 
of activated carbon, 30 g of silica gel and carbon tetrachloride-methylene 
chloride (1:1). Recrystallization of the resultant crude crystals from 
ethanol-water (2:1) yielded 604.5 mg of colorless needles of 
5-methylspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one. Melting 
point: 68.degree.-69.5.degree. C. 
Elementary analysis, for C.sub.11 H.sub.10 OS-- Calcd. C, 69.44; H, 5.30. 
Found: C, 69.67; H, 5.31. 
EXAMPLE 4 
In 30 ml of dimethylsulfoxide were dissolved 2.8 g of 
5,6-dimethoxy-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3, 
2'-dione as obtained in Reference Example 4 and 656.6 mg of sodium 
chloride, and the solution was heated under a stream of nitrogen at 
150.degree. C. for 2.5 hours. After cooling, the reaction solution was 
poured into 400 ml of saturated aqueous solution of sodium chloride, and 
the resulting precipitate was recovered by filtration, washed with water 
and dried. The product obtained was chromatographed on a column with the 
use of 3 g of activated carbon, 15 g of silica gel and chloroform. 
Recrystallization of the resultant crude crystals from ethanol-water (2:1) 
yielded 2.1 g of colorless needles of 
5,6-dimethoxyspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one. Melting 
point: 167.5.degree.-169.5.degree. C. 
Elementary analysis, for C.sub.12 H.sub.12 O.sub.3 S-- Calcd. C, 60.99; H, 
5.12. Found: C, 61.10; H, 5.04. 
EXAMPLE 5 
In 10 ml of dimethylsulfoxide were dissolved 503.3 mg of 
5-nitro-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dio 
ne as obtained in Reference Example 5 and 130.1 mg of sodium chloride, and 
the solution was heated under a stream of nitrogen at 150.degree. C. for 
30 minutes. After cooling, the reaction solution was poured into 300 ml of 
saturated aqueous solution of sodium chloride and subjected to extraction 
with ethyl acetate. The extract was washed with saturated aqueous solution 
of sodium chloride, dried and evaporated to dryness under reduced 
pressure. The residue was chromatographed on a column of activated carbon 
and silica gel. Recrystallization of the resultant crude crystals yielded 
pale yellow needles of 
5-nitrospiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one. Melting point: 
126.5.degree.-127.5.degree. C. 
Mass spectrum (m/e): 221 (M.sup.+) 
Elementary analysis, for C.sub.10 H.sub.7 NO.sub.3 S-- Calcd. C, 54.29; H, 
3.19; N, 6.33. Found: C, 54.48; H, 3.39; N, 6.31. 
EXAMPLE 6 
In 4 ml of dimethylsulfoxide (DMSO) were dissolved 179.9 mg of 
6-hydroxyamino-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3 
,2'-dione and 101.4 mg of sodium chloride, and the solution was heated 
under a stream of nitrogen at 150.degree. C. for 2.5 hours. After cooling, 
the reaction solution was poured into 200 ml of saturated aqueous solution 
of sodium chloride and subjected to extraction with ethyl acetate. The 
extract was washed with saturated aqueous solution of sodium chloride, 
dried and evaporated to dryness under reduced pressure. The residue was 
chromatographed on a column of activated carbon and silica gel. 
Recrystallization of the resultant crude crystals from ethanol yielded 
pale yellow needles of 
6-aminospiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one. Melting point: 
196.degree.-200.degree. C. 
Mass spectrum (m/e): 191 (M.sup.+) 
EXAMPLE 7 
In 2 ml of acetic acid and 2 ml of acetic anhydride was dissolved 9.5 mg of 
6-aminospiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one as obtained in 
Example 6, and the solution was stirred at room temperature for 10 
minutes. The reaction solution was evaporated to dryness under reduced 
pressure, and the residue was chromatographed on a column of silica gel. 
Recrystallization of the resultant crude crystals from ethanol-water (1:2) 
yielded colorless needles of 
6-acetylaminospiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one. Melting 
point: 195.degree.-196.5.degree. C. 
Mass spectrum (m/e): 233 (M.sup.+) 
Elementary analysis, for C.sub.12 H.sub.11 NO.sub.2 S.H.sub.2 O-- Calcd. C, 
57.35; H, 5.21; N, 5.58. Found: C, 57.34; H, 5.16; N, 5.63. 
EXAMPLE 8 
A mixture of 
4-methyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-di 
one (505 mg) obtained in Reference Example 9 and NaCl (261 mg) in DMSO (15 
ml) was heated at 150.degree. C. for 2.5 hours under a stream of N.sub.2 
gas. After being cooled to room temperature, the mixture was poured into 
saturated NaCl aqueous solution. The resulting precipitate was collected, 
washed with H.sub.2 O and dried. This precipitate was submitted to column 
chromatography on silica gel (45 g) and charcoal (1.5 g) eluting with 
CCl.sub.4 -ethyl acetate (20:1) to give 
4-methylspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one as colorless 
needles [from C.sub.2 H.sub.5 OH--H.sub.2 O (3:1)], mp 
128.degree.-128.5.degree. C. Anal. Calcd. for C.sub.11 H.sub.10 OS: C, 
69.44; H, 5.30. Found: C, 69.69; H, 5.18. 
EXAMPLE 9 
6-Methylspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one was prepared by 
a similar procedure to that of Example 8 except for the use of 
6-methyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-di 
one obtained in Reference Example 10. Pale brown oil. Anal. Calcd. for 
C.sub.11 H.sub.10 OS: C, 69.44; H, 5.30. Found: C, 69.37; H, 5.20. 
EXAMPLE 10 
7-Methylspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one was prepared by 
a similar procedure to that of Example 8 except for the use of 
7-methyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-di 
one obtained in Reference Example 11. Pale yellow needles [from C.sub.2 
H.sub.5 OH--H.sub.2 O (1:1)], mp 74.degree.-75.degree. C. Anal. Calcd. for 
C.sub.11 H.sub.10 OS: C, 69.44; H, 5.30. Found: C, 69.32; H, 5.07. 
EXAMPLE 11 
5-Ethylspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one was prepared by 
a similar procedure to that of Example 8 except for the use of 
5-ethyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dio 
ne obtained in Reference Example 12. Colorless oil. Anal. Calcd. for 
C.sub.12 H.sub.12 OS: C, 70.55; H, 5.92. Found: C, 70.68; H, 5.82. 
EXAMPLE 12 
5-Acetylspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one was prepared by 
a similar procedure to that of Example 8 except for the use of 
5-acetyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-di 
one obtained in Reference Example 13. Colorless prisms, mp 
127.5.degree.-129.degree. C. Anal. Calcd. for C.sub.12 H.sub.10 O.sub.2 S: 
C, 66.03; H, 4.62. Found: C, 66.01; H, 4.42. 
EXAMPLE 13 
4-[5-[Spiro(benzo[b]thiophene-2(3H),1'-cyclopropan)-3-oxo]oxy]butyric acid 
was prepared by a similar procedure to that of Example 8 except for the 
use of 
4-[5-[4',5'-dihydrospiro(benzo[b]thiophene-2(3H),3'(2'H)-furan)-3,2'-dioxo 
]oxy]butyric acid obtained in Reference Example 14. Pale yellow needles, mp 
131.degree.-132.degree. C. Anal. Calcd. for C.sub.14 H.sub.14 O.sub.4 S: 
C, 60.41; H, 5.07. Found: C, 60.63; H, 5.05. 
EXAMPLE 14 
To a solution of 
4-[5-[spiro(benzo[b]thiophene-2(3H),1'-cyclopropan)-3-oxo]oxy]butyric acid 
(259 mg) obtained in Example 13 in dry THF (40 ml) and triethylamine (6 
ml) was added methyl chloroformate (4 ml) at -20.degree. C. to 31 
15.degree. C. with stirring. After stirring the solution at -20.degree. C. 
to -15.degree. C. for 15 minutes, N-methylcyclohexylamine was added to the 
mixture at the same temperature with stirring. After being stirred at 
5.degree. C. for 11 hours, the mixture was filtered. The filtrate was 
evaporated in vacuo. The resulting residue was submitted to column 
chromatography on silica gel eluting with CCl.sub.4 -ethyl acetate (5:1 
and 2:1) to give 
N-cyclohexyl-N-methyl-4-[5-[spiro(benzo[b]thiophene-2(3H),1'-cyclopropan)- 
3-oxo]oxy]butyramide as colorless needles, mp 102.degree.-104.degree. C. 
Anal. Calcd. for C.sub.21 H.sub.27 NO.sub.3 S: C, 67.52; H, 7.29; N, 3.75. 
Found: C, 66.81; H, 7.41; N, 3.80. 
EXAMPLE 15 
A mixture of 
5-amino-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dio 
ne (40.4 mg) obtained in Reference Example 15 and NaCl (20.6 mg) in DMSO 
(2.0 ml) was heated at 150.degree. C. for 3 hours under a stream of 
N.sub.2 gas with stirring. After being cooled to room temperature, the 
mixture was poured into satulated NaCl aqueous solution and extracted with 
ethyl acetate. The extract was washed with H.sub.2 O, dried over Na.sub.2 
SO.sub.4 and evaporated in vacuo. The resulting residue was recrystallized 
from ethanol to give 
5-aminospiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one as pale yellow 
needles, mp 147.5.degree.-149.5.degree. C. Anal. Calcd. for C.sub.10 
H.sub.9 NOS: C, 62.80; H, 4.74; N, 7.33. Found: C, 62.45; H, 4.75; N, 
7.06. 
EXAMPLE 16 
To a solution of 5-aminospiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one 
(200 mg) obtained in Example 15 in acetic acid (8 ml) was added acetic 
anhydride (8 ml) at room temperature with stirring. After being stirred 
for 30 minutes, the mixture was evaporated in vacuo. The resulting residue 
was recrystallized from C.sub.2 H.sub.5 OH-H.sub.2 O (2:1) to give 
5-acetylaminospiro[benzo[b]thiophene-2(3H),1'-cyclopropan-3-one as pale 
yellow needles, mp 205.degree.-208.5.degree. C. Anal. Calcd. for C.sub.12 
H.sub.11 NO.sub.2 S: C, 61.78; H, 4.75; N, 6.01. Found: C, 61.42, H, 4.81; 
N, 5.73. 
EXAMPLE 17 
5-Sulfamoylspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one was prepared 
by a similar procedure to that of Example 8 except for the use of 
5-sulfamoyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2' 
-dione obtained in Reference Example 16. Pale yellow needles (from C.sub.2 
H.sub.5 OH), mp 256.degree.-258.degree. C. (decomp.) Anal. Calcd. for 
C.sub.10 H.sub.9 NO.sub.3 S.sub.2 : C, 47.04; H, 3.55; N, 5.49. Found: C, 
47.18; H, 3.57; N, 5.44. 
EXAMPLE 18 
5-Piperidinosulfonylspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one was 
prepared by a similar procedure to that of Example 8 except for the use of 
5-piperidinosulfonyl 
4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione 
obtained in Reference Example 17. Colorless prisms (from C.sub.2 H.sub.5 
OH), mp 155.5.degree.-157.degree. C. Anal. Calcd. for C.sub.15 H.sub.17 
NO.sub.3 S: C, 55.70; H, 5.30; N, 4.33. Found: C, 55.74; H, 5.34; N, 4.50. 
EXAMPLE 19 
5-Morpholinosulfonylspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one was 
prepared by a similar procedure to that of Example 8 except for the use of 
5-morpholinosulfonyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-fu 
ran]3,2'-dione obtained in Reference Example 18. Colorless needles (from 
acetone --H.sub.2 O), mp 162.5.degree.-165.degree. C. Anal. Calcd. for 
C.sub.14 H.sub.15 NO.sub.4 S: C, 51.67; H, 4.65; N, 4.31. Found: C, 51.45; 
H, 4.55; N, 4.41. 
TEST EXAMPLE 
The platelet aggregation inhibitory activity of the compound of the present 
invention. 
[Testing procedure] 
With the use of an injection syringe containing a 3.15% citric acid 
solution (in the proportion of 1 against 9 of blood) as an anticoagulant, 
a blood sample was taken directly from the heart of a male rabbit, and 
then centrifuged at room temperature and 1,000 r.p.m. for 10 minutes to 
obtain a platelet rich plasma (PRP). 
Using 5-methylspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one as a test 
drug, the test drug solution was prepared as follows: The test drug was 
dissolved in dimethylsulfoxide to a concentration of 20 mM, and the 
solution was diluted to a test drug concentration of 6.times.10.sup.-5 M 
or 1.2.times.10.sup.-4 M by adding Tris-HCl buffer (50 mM: pH 7.5). To 250 
.mu.l of the above PRP was added 25 .mu.l of the test drug solution, and 
the aggregation of platelets, upon addition of arachidonic acid of 0.42 mM 
as the final concentration or of 25 .mu.l of 217 .mu.g/ml collagen, was 
measured with an aggregation meter (manufactured by Rika Denki K.K., 
Japan). The activity of the test drug was estimated by determining the 
inhibition rate for the maximum light transmittance of the control PRP 
which is altered by arachidonic acid or collagen. 
[Test results] 
Inhibition rate of the tested compound to the platelet aggregation by 
arachidonic acid: 
______________________________________ 
5 .times. 10.sup.-6 M 
15% 
______________________________________ 
Inhibition rate of the tested compound to the platelet aggregation by 
collagen: 
______________________________________ 
5 .times. 10.sup.-6 M 
23% 
1 .times. 10.sup.-5 M 
48% 
______________________________________ 
PREATION EXAMPLE 
Tablet 
Composition: 
______________________________________ 
(1) 5-Methylspiro[benzo[b]thiophene- 
2(3H),1'-cyclopropan]-3-one 
25 g 
(2) Lactose 70 g 
(3) Corn starch 20 g 
(4) Hydroxypropylcellulose 4 g 
(5) Magnesium stearate 1 g 
1000 tablets: 120 g 
______________________________________ 
Preparation: 
The mixture of (1), (2) and (3) was moistened with a 10% aqueous solution 
of (4), granulated through a 1.5 mm screen and dried at 40.degree. C. in 
vacuo. The resultant granulates were passed once more through the screen, 
mixed with (5) and pressed to produce 1000 tablets, each tablet containing 
25 mg of (1) and having 7 mm in diameter.