A naphthothiopyranone derivative represented by the formula: ##STR1## (wherein R.sup.1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) and an acid addition salt thereof have more excellent antagonist effect at serotonin 3 receptors than the prior art compounds and the effects based thereon, e.g. anti-vomiting effect, gastrointestinal movement regulating effect and anti-anxiety effect.

DESCRIPTION 
1. Technical Field 
The present invention relates to naphthothiopyranone derivatives, and more 
particularly relates to naphthothiopyranone derivatives having the 
antagonist effect of 5-HT (serotonin) at 5-HT.sub.3 (serotonin 3) 
receptors. 
Background Art 
Compounds described in EP-A-364274 have heretofore been known as having the 
structure and effect similar to those of the compounds of the present 
invention, but they do not have a satisfactory degree of the drug effect. 
An object of the present invention is to provide compounds having more 
excellent anti-vomiting effect, gastrointestinal movement regulating 
effect and anti-anxiety effect based on the antagonist effect at serotonin 
3 receptors than the prior art compounds. 
DISCLOSURE OF THE INVENTION 
The present invention is a naphthothiopyranone derivative represented by 
the formula: 
##STR2## 
(wherein R.sup.1 is a hydrogen atom or an alkyl group having 1 to 4 carbon 
atoms) or an acid addition salt thereof, and further a compound 
represented by the formula: 
##STR3## 
which is an intermediate of the compound of Formula (I). 
In the present invention, the alkyl group having 1 to 4 carbon atoms means 
a straight or branched chain alkyl group. The acid addition salt of the 
compound of Formula (I) means an addition salt of a pharmacologically 
acceptable acid, for example, hydrochloride, hydrobromide, hydroiodide, 
sulfate, acetate, citrate, maloate, maleate, tartarate and succinate. 
The compound of Formula (I) of the present invention can be prepared, for 
example, by the following processes. 
A compound of Formula (II) is first reacted with a halogenating agent of 
common use (e.g. hydrobromic acid, thionyl chloride, phosphorus 
pentachloride, thionyl bromide and phosphorus tribromide) in an organic 
solvent or without solvent to give a compound represented by the formula: 
##STR4## 
(wherein X is a halogen atom). The halogen atom herein means a chlorine 
atom, a bromine atom or an iodine atom. Examples of the organic solvent to 
be used are tetrahydrofuran, dioxane, ether, benzene, toluene, chloroform, 
dichloromethane, carbon tetrachloride, pyridine and a mixture of these 
solvents with hexamethylphosphorus triamide. A base such as triethylamine 
can also be added. 
The compound obtained above is reacted with a compound represented by the 
formula: 
##STR5## 
(wherein R.sup.1 is as defined above) or an acid addition salt thereof in 
an organic solvent in the presence or absence of a base to give a compound 
of Formula (I). Examples of the base to be used in the reaction are 
triethylamine, pyridine, potassium carbonate, sodium carbonate, lithium 
carbonate, cesium carbonate, sodium bicarbonate, sodiumshydride, sodium 
hydroxide, potassium hydroxide, sodium ethoxide and potassium t-butoxide 
("base" used hereinafter in the term of the disclosure of the invention is 
the same as defined herein). Examples of the organic solvent to be used 
are dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 
diethyl ether, dioxane, N,N-dimethylformamide, benzene, toluene and 
alcohols. In addition, iodides (e.g. potassium iodide) or phase-transfer 
catalysts (e.g. tetrabutylammonium bromide) can be used as a catalyst to 
accelerate the reaction. 
On the other hand, the compound of Formula (II) of the intermediate is a 
novel compound and can be prepared, for example, by the following 
processes. 
A known compound represented by the formula: 
##STR6## 
which can be prepared by the method described in Journal of Chemical 
Society, Parkin Trans. I, vol. 6, pp. 787-792 (1972), is reacted with 
formaldehyde in the presence of a base in an organic solvent at from room 
temperature to the boiling point of the solvent to give the compound of 
Formula (II). Examples of the organic solvent to be used in the reaction 
are tetrahydrofuran, dioxane, methanol, ethanol, isopropanol and 
N,N-dimethylformamide. 
On the other hand, the compound of Formula (III) is reacted with formamide 
in the presence of a base in an organic solvent at from a temperature 
under ice-cooling to room temperature, and then the resulting compound 
represented by the formula: 
##STR7## 
is reacted with a base to give the compound of Formula (II). Examples of 
the organic solvent to be used herein are tetrahydrofuran, dioxane, 
methanol, ethanol, isopropanol and N,N-dimethylformamide. 
The compound of Formula (I) of the present invention can be formulated into 
the dosage form such as tablets, granules, capsules, powders, pills, 
injections, solutions and suppositories and administered orally, directly 
(e.g. intramascularly and intravenously) or rectally. The above dosage 
form can be prepared by using conventional fillers (e.g. crystalline 
cellulose, starch and lactic acid), binders (e.g. hydroxypropyl cellulose 
and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate and 
talc) according to a conventional manner (e.g. the method regulated in the 
Pharmacopoea of Japan, 12th Edition). The dose of the compound of Formula 
(I) depends on the condition, age and body weight of the patient, but 
usually the daily dose to adult may be from 0.5 mg to 50 mg, 
administration being effected once or several times depending on the 
condition.

BEST MODE OF CARRYING OUT THE INVENTION 
The present invention is hereinafter illustrated in more detail by the 
following examples and experiment. 
EXAMPLE 1 
2-[(4-Methyl-1-imidazolyl)methyl]-1H-naphtho-[2,1-b]thiopyran-1-one 
(1) To a solution of 11.1 g of 
2-bromo-2,3-dihydro-1H-naphtho[2,1-b]thiopyran-1-one in 300 ml of methanol 
were added 29 ml of 35% formalin and 5.74 g of potassium carbonate, and 
stirring was continued at 60.degree. C. for 6 hours. After evaporation of 
the methanol under reduced pressure, the residue was dissolved in ethyl 
acetate, and the resulting solution was washed successively with 3N 
hydrochloric acid, water and a saturated aqueous sodium chloride solution, 
and dried over anhydrous sodium sulfate. 
After evaporation of the solvent under reduced pressure, purification by 
silica gel column chromatography (eluant; n-hexane:ethyl acetate=5:1) and 
recrystallization from ethyl acetate - n-hexane gave 3.70 g of 
2-hydroxymethyl-1H-naphtho[2,1-b]thiopyran-1-one. 
m.p. 158.degree.-159.degree. C. 
(2) To a solution of 1.49 g of the compound obtained in the item (1) in 20 
ml of tetrahydrofuran and 1.6 ml of hexamethylphosphorus triamide was 
added dropwise 0.52 ml of thionyl chloride with stirring under 
ice-cooling. Stirring was further continued at room temperature for 3 
hours, and the reaction solution, after addition of ice water, was 
extracted with ethyl acetate. The organic layer was washed successively 
with water, a saturated aqueous sodium bicarbonate solution, water and a 
saturated aqueous sodium chloride solution, and dried over anhydrous 
magnesium sulfate. 
After evaporation of the solvent, the residue was recrystallized from 
dichloromethane - n-hexane to give 1.23 g of 
2-chloromethyl-1H-naphtho[2,1-b]thiopyran-1-one. 
m.p. 151.degree.-153.degree. C. 
(3) To a solution of 0.30 g of the compound obtained in the item (2) and 
0.10 g of 4-methylimidazole in 10 ml of N,N-dimethylformamide was added 
gradually 51 mg of sodium hydride (60% oil) under a nitrogen stream and 
ice cooling with stirring, and further stirring was continued for 20 
minutes. The reaction solution, after addition of water, was extracted 
with ethyl acetate, and the organic layer was washed successively with 
water and a saturated aqueous sodium chloride solution and dried over 
anhydrous sodium sulfate. 
After evaporation of the solvent under reduced pressure, the residue was 
purified by silica gel column chromatography (eluant; 
dichloromethane:methanol:35% ammonia water=90:10:0.5) and recrystallized 
from dichloromethane - n-hexane to give 66 mg of the title compound. 
m.p. 180.degree.-181.degree. C. 
EXAMPLE 2 
2-Hydroxymethyl-1H-naphtho[2,1-b]thiopyran-1-one obtained in Example 1(1) 
was also prepared by another method as follows. (1) To a solution of 64.7 
g of 2-bromo-2,3-dihydro-1H-naphtho [2,1-b]thiopyran-l-one in 200 ml of 
tetrahydrofuran were added 258 ml of 35% formalin and 32.2 g of potassium 
carbonate, and stirring was continued under ice cooling for 1.5 hours. 
After evaporation of about 100 ml of the tetrahydrofuran under reduced 
pressure, water was added to the residue, and the resulting crystals were 
collected by filtration to give 64.3 g of 2-bromo-2- 
hydroxymethyl-2,3-dihydro-1H-naphtho[2,1-b]thiopyran- 1-one. 
m.p. 85.degree.-87.degree. C. 
(2) To a solution of 64.3 g of the compound obtained in the item (1) in 200 
ml of tetrahydrofuran was added 29.3 g of triethylamine, and stirring was 
continued for 1.5 hours. 
After evaporation of about 100 ml of the tetrahydrofuran under reduced 
pressure, water was added to the residue, and the resulting crystals were 
collected by filtration and recrystallized from dichloromethane - n-hexane 
to give 38.8 g of 2-hydroxymethyl-1H-naphtho[2,1-b]thiopyran-l-one. 
m.p. 156.degree.-158.degree. C. 
EXAMPLE 3 
2-[(2-Methyl-1-imidazolyl)methyl]-1H-naphtho- [2,1-b]thiopyran-1-one 
To a suspension of 0.17 g of sodium hydride in 10 ml of 
N,N-dimethylformamide was added 0.35 g of 2-methylimidazole under a 
nitrogen stream and ice cooling, and stirring was continued for 20 
minutes. A solution of 1.0 g of the compound obtained in Example 1(2) in 
20 ml of N,N-dimethylformamide was added under ice cooling, and stirring 
was continued for an hour. The reaction solution, after addition of water, 
was extracted with ethyl acetate, and the organic layer was washed 
successively with water and a saturated aqueous sodium chloride solution 
and dried over anhydrous sodium sulfate. 
After evaporation of the solvent under reduced pressure, the residue was 
purified by silica gel column chromatography (eluant; 
dichloromethane:methanol:ammonia water=90:10:0.5) and recrystallized from 
dichloromethane - n-hexane to give 0.62 g of the title compound. 
m.p. 212.degree.-213.degree. C. (decomposition). 
EXAMPLE 4 
2-[(2-Methyl-1-imidazolyl)methyl]-1H-naphtho-[2,1-b]thiopyran-1-one 
hydrochloride 
0.1 g of 2-[(2-methyl-1-imidazolyl)methyl]- 
1H-naphtho[2,1-b]thiopyran-1-one obtained in Example 3, after dissolving 
in methanol, was converted into the hydrochloride with conc. hydrochloric 
acid. After evaporation of the solvent under reduced pressure, the residue 
was recrystallized from methanol - diethyl ether to give 64 mg of the 
title compound. 
m.p. 230.degree. C. or above. 
.sup.1 H-NMR (DMSO-d.sub.6) .delta. ppm: 
10.00(1H, m), 8.55(1H, s), 8.28(1H, d, J=8.5Hz), 8.11(1H, m), 7.92(1H, d, 
J=8.5Hz), 7.68-7.83(2H, m), 7.66(1H, d, J=2Hz), 7.58(1H, d, J=2Hz), 
5.34(2H, s), 2.76(3H, s). 
Experiment [Anti-vomiting Effect Test] 
Emesis induced by cisplatin is known to be inhibited by antagonists at 
5-HT.sub.3 receptors. The anti-vomiting effect of the compound of the 
present invention was compared with that of the compound described in 
Example of Japanese Patent Kokai 2-209876 according to the method of 
Matsumoto et al [Japanese Journal of Pharmacology, vol. 48, pp. 303-306 
(1988)]. 
Test samples 
The compound obtained in Example 4 (hereinafter referred to as "Compound 
A") and the compound described in Example 1 of Japanese Patent Kokai 
2-209876 (hereinafter referred to as "Compound B") were each suspended in 
0.4% aqueous carboxymethylcellulose solution to give test samples. 
Test method 
Group each of six suncus of either sex weighing 40-60 g (male) and 30-50 g 
(female) were used. Each animal was placed with a chronic intravenous 
cannula 3 days before vomiting test. The samples prepared above were 
orally administered in the doses of 0.03-3 mg/kg to each group of the 
animals. After 45 minutes 30 mg/kg of cisplatin was administered 
intravenously, and number of emesises was determined for a period of 2 
hours. Number of emesises for a period of 2 hours of a control group 
treated with 0.4% carboxymethylcellulose suspension alone was determined 
as well. 
Test results 
Number of emesises obtained above was expressed as compared with 100% of 
the control, and IC.sub.50 value was calculated by number of emesises. 
Results are shown in Table 1. 
TABLE 1 
______________________________________ 
Dose % value to 
IC.sub.50 value 
Sample (mg/kg) control (.mu.g/kg) 
______________________________________ 
Compound A 0.03 77.8 90.4 
0.3 17.0 
3 4.4 
Compound B 0.03 142.9 412.5 
0.3 68.6 
3 0.0 
______________________________________ 
INDUSTRIAL UTILIZATION 
The compounds of the present invention have the antagonist effect of 
serotonin at serotonin 3 recetors, and therefore are effective for the 
improvement and treatment of gastrointestinal dysfunctions (e.g. 
dyspepsia, peptic ulcer, gastritis, reflux esophagitis and irritable colon 
syndromes), symptoms accompanied by these dysfunctions, migraine and pain 
of trigemiral neuralgia. Particularly they are also effective for the 
treatment of nausea and vomiting caused by cancer chemotherapy and 
radiotherapy, arrhythmia and anxiety.