JPH0696577B2 - Tiananaphthene derivative and method for producing the same - Google Patents

Description

TECHNICAL FIELD OF THE INVENTION The present invention provides a platelet aggregation inhibitory activity and thromboxane A ₂
(Hereinafter, abbreviated as TXA ₂ ) has a biosynthesis inhibitory effect, thrombosis,
The present invention relates to a novel thianaphthene derivative which is useful as a medicine for preventing and treating cardiovascular disorders such as stroke, myocardial infarction and angina, and a method for producing the same.

Structure of the Invention The thianaphthene derivative of the present invention has the general formula Is a compound represented by.

In the above formula, Y represents an imidazolyl group or a pyridyl group, and Z is methylene which may optionally have a lower alkyl group, a cycloalkyl group, a substituent or an unsubstituted aryl group or a heterocyclic group as a substituent. Group, ethylene group,
Represents a trimethylene group or a vinylene group, W represents a direct bond, a methylene group optionally having a lower alkyl group or a substituted or unsubstituted aryl group as a substituent, an ethylene group or a vinylene group, R ₁ and R ₂
Are the same or different and represent a hydrogen atom, a lower alkyl group or a substituted or unsubstituted aryl group, and n is 1 or 2
The dotted line indicates a single bond or a double bond.

However, when the 4,5-position is a double bond, the 6,7-position is a single bond, the substituent -Z-Y is bonded to the 5-position, and when the 6,7-position is a double bond, The 4,5-position is a single bond, and the substituent -Z-Y is 6
Join to the rank.

In the general formula (1), preferably Y represents a 1-imidazolyl group or a 3-pyridyl group, and Z is optionally, for example, methyl, ethyl, n-propyl, isopropyl, n.
-A straight-chain or branched alkyl group having 1 to 4 carbon atoms such as butyl, isobutyl, sec-butyl, tert-butyl, for example, 3 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
A cycloalkyl group having from 6 to 6, an aryl group which may have a substituent described later on an aromatic ring or a heterocyclic ring such as phenyl, 1-naphthyl, 2-naphthyl or a furyl, thienyl, imidazolyl, thiazolyl Nitrogen atoms, such as, oxazolyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl, isodryl,
A methylene group, an ethylene group, a trimethylene group or a vinylene group which may have a monocyclic or bicyclic heterocyclic group containing 1 to 3 oxygen atoms or sulfur atoms as a substituent, and its aromatic ring Further, as the substituent of the heterocycle, for example, a linear or branched alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, n-propyl and isopropyl, for example, methoxy, ethoxy, n-propoxy, A linear or branched alkoxy group having 1 to 3 carbon atoms such as isopropoxy, for example, acetoxy, propionyloxy, n-butyryloxy,
Lower aliphatic acyloxy groups such as isobutyryloxy or for example benzoyloxy, o-, m-, p-toluoyloxy, o-, m-, p-anisoyloxy, o-, m
An acyloxy group such as an aromatic acyloxy group such as-, p-chlorobenzoyloxy, a lower aliphatic acylamino group such as acetylamino, propionylamino, n-butyrylamino, isobutyrylamino or benzoylamino, o-, m-, p-toluoylamino,
Acylamino group such as aromatic acylamino group such as aromatic acylamino group such as o-, m-, p-anisoylamino, o-, m-, p-chlorobenzoylamino, trifluoromethyl group or fluorine, for example, Examples thereof include halogen atoms such as chlorine and bromine, and these substituents may be the same or in combination and may be substituted 1 to 3. W represents a methylene group, an ethylene group or a vinylene group which may have an alkyl group having 1 to 4 carbon atoms or an aryl group having the same meaning as Z described above as a direct bond or a substituent, and R ₁ and R ₂ is the same or different and is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an aryl group having the same meaning as the above-mentioned group in Z, n is 1 or 2, and the dotted line portion is a single bond or the above It represents a double bond under the conditions, and the substituent —Z—Y is bonded to the 5 or 6 position.

Specific examples of the thianaphthene derivative having the general formula (1) obtained according to the present invention include the compounds listed in Tables 1, 2, 3, and 4 below.

Of the above-exemplified compounds, preferred compounds are compound 1,
2,5,13,17,20,23,32,39,40,45,52,59,69,70,73,81,85,8
8,91,100,107,108,120,127,137,141,146,153,156,168,1
81,187,193,205,209,217,224,236,249,255,262, and the most preferred compound is compound 1,32,45,69,10.
0,113,137,168,181,205,236 and 249.

The novel compound (1) according to the present invention can be synthesized by the method shown below.

Manufacturing method (1) General formula (In the formula, R ₁ , R ₂ , W, n and the dotted line have the same meanings as described above, Y ₁ represents a ₁ -imidazolyl group, and Z ₁ has the same meaning as the corresponding substituent of Z. A thianaphthene derivative having optionally a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted aryl group or a methylene group which may have a heterocyclic group, an ethylene group or a trimethylene group is represented by the general formula (In the formula, Z ₁ , R ₁ , R ₂ , A ₁ , W and n have the same meanings as described above, and X is a halogen atom such as chlorine, bromine or iodine, methanesulfonyloxy or ethanesulfonyloxy). Represents a lower alkanesulfonyloxy group or an arylsulfonyloxy group such as benzenesulfonyloxy or p-toluenesulfonyloxy, wherein A is a hydrogen atom or methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert- And a compound having the formula Y ₁ H (3) (wherein Y ₁ has the same meaning as defined above) or lithium, sodium, It is obtained by reacting with a salt of an alkali metal such as potassium, and hydrolyzing the obtained compound if necessary.

In carrying out this method, as a solvent, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride: alcohols such as methanol, ethanol and t-butanol; such as benzene, toluene and xylene. Aromatic hydrocarbons; acetonitrile; dimethylformamide and the like are used. The reaction temperature is from 10 ° C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature and the like, but is usually 1 to 20 hours.

The hydrolysis step, which is carried out if necessary, is carried out according to a conventional method.

The hydrolysis reaction is carried out by bringing the ester compound obtained by the above reaction into contact with an acid or a base which is a hydrolysis reagent. As the acid or base used, an acid or base used in a usual hydrolysis reaction can be used without particular limitation, but mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, alkalis such as sodium hydroxide and potassium hydroxide, etc. A metal hydroxide can be mentioned as a suitable reagent. The reaction is usually performed in the presence of a solvent. Suitable solvents to be used are alcohols such as methanol and ethanol, and mixed tablets of these alcohols and water. The reaction temperature is not particularly limited, but is usually room temperature to about 110 ° C. The reaction time mainly depends on the reaction temperature, the hydrolysis reagent used, etc.
10 minutes to 6 hours.

After completion of the reaction, the reaction mixture is treated by a conventional method to obtain the compound having the general formula (1a). Further, if necessary, it can be purified by column chromatography, recrystallization or distillation.

The general formula (In the formula, R ₁ , R ₂ , W, Y ₁ , Z ₁ and n have the same meanings as described above.) Is a compound in which the dotted line portion on the structural formula thereof represents a double bond ( It can also be obtained by a reduction reaction of the ester of 1a) or (1a).

The reduction reaction is an organic solvent that does not participate in the reaction (for example, esters such as ethyl acetate, aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane). In the presence of a catalyst such as palladium chloride or platinum chloride, the reaction mixture is subjected to catalytic reduction in the presence of a catalyst, the reaction mixture is treated according to a conventional method, and when an ester is used, the above hydrolysis is further performed. The target compound (1b) can be obtained.

Production method (2) The thianaphthene derivative having the general formula (1a) has the general formula: (Wherein R ₁ , R ₂ , Z ₁ , W, n and A have the same meanings as described above) and a compound having the formula (In the formula, Y ₁ has the same meaning as described above.) N, N′-thionyldiimidazole represented by the above is reacted, and the obtained compound is hydrolyzed if necessary.

As a solvent, halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene can be used as a solvent for the reaction of the compounds (3) and (4). Kinds etc. are used. This reaction is carried out in the presence of a base such as 4-dimethylaminopyridine, but the reaction temperature is from 0 ° C to near the boiling point of the solvent used. The reaction time varies depending on the reaction temperature and the like, but is usually 1 minute to
72 hours. After completion of the reaction, the reaction mixture is poured into water, treated by a conventional method, and if necessary, purified by column chromatography, recrystallization or distillation.

The hydrolysis reaction, which is carried out if necessary, is carried out according to a conventional method. That is, it can be carried out in exactly the same manner as the reaction used in the production method (1).

Manufacturing method (3) General formula (Wherein R ₁ , R ₂ , Z, W and n have the same meanings as described above, and Y ₂ represents a pyridyl group.) (In the formula, R ₁ , R ₂ , W, n and A have the same meanings as described above, and R ₃ is a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aryl group which may have a substituent. Or a heterocyclic group, m is an integer of 0 to 2, and a compound of the general formula Y ₂ —Li (6) (wherein Y ₂ has the same meaning as described above). General formula obtained by reacting compounds (In the formula, R ₁ , R ₂ , R ₃ , Y ₂ , W, A, m and n have the same meanings as described above.) After reduction or dehydration of the compound, It can be obtained by disassembling.

The reaction of the compounds (5) and (6) uses ethers such as ether and tetrahydrofuran as a solvent. The reaction temperature is -73 ° C to 30 ° C, and the reaction time is 30 minutes to 5 hours. After the reaction is complete, an aqueous solution of ammonium chloride is added, and the mixture is treated by a conventional method and, if necessary, column chromatography,
Purify by recrystallization or distillation.

The reduction reaction of the compound (7) is carried out in an equimolar amount in an organic solvent that does not participate in the reaction (eg, esters such as ethyl acetate, aromatic hydrocarbons such as benzene and toluene, alcohols such as methanol and ethanol). The above mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid are added and subjected to catalytic reduction in the presence of a catalyst such as palladium chloride or platinum chloride. After the reaction is completed, the reaction mixture is treated according to a conventional method. By doing so, it is possible to obtain the target compound (1c) in which Z represents a methylene group, an ethylene group or a trimethylene group which may have the above-mentioned substituent.

The dehydration reaction of the compound (7) (in the formula, m represents 1),
Organic solvents that do not participate in the reaction (for example, aromatic hydrocarbons such as benzene, toluene, xylene, dioxane,
By adding a catalytic amount of para-toluenesulfonic acid or a mineral acid such as hydrochloric acid, hydrobromic acid, or sulfuric acid in ethers such as tetrahydrofuran), heating to azeotropic, and optionally hydrolyzing as described above. , Z is a vinylene group which may have the above-mentioned substituent, and thus the target compound (1c) can be obtained. After completion of the reaction, the reaction mixture can be treated by a conventional method and, if necessary, further purified by column chromatography or recrystallization.

Manufacturing method (4) General formula (In the formula, R ₁ , R ₂ , Y ₁ , W and n have the same meanings as described above, and Z ₂ is a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted aryl group or a heterocyclic group as a substituent. A thianaphthene derivative having a vinylene group (Wherein R ₁ , R ₂ , R ₃ , W, A and n have the same meanings as described above, and m ′ represents 1) (In the formula, Y ₁ has the same meaning as described above.), And the obtained compound is hydrolyzed as the case requires. The reaction between the compounds (5) and (4) can be obtained under the reaction conditions and the reaction treatment exactly the same as those in the production method (2).

Manufacturing method (5) General formula (In the formula, R ₁ , R ₂ , Y ₁ , W, and n have the same meanings as described above, and Z ₃ is each optionally a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted aryl group, or A thianaphthene derivative having an ethylene group, a trimethylene group or a vinylene group having a heterocyclic group is represented by the general formula (Wherein R ₁ , R ₂ , W, A, Y ₁ and n have the same meanings as described above, and p represents 1 or 2) or the compound of the general formula R ₄ Li (9) or R ₄ MgX ′ (10) (wherein R ₄ represents a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted aryl group or a heterocyclic group having the same meaning as the substituent of the corresponding R ₃ , X'represents a halogen atom such as chlorine, bromine, or iodine). (In the formula, R ₁ , R ₂ , R ₄ , Y ₁ , W, A ', p and n have the same meanings as described above.) After reduction or dehydration of the compound having It can be obtained by disassembling.

The reaction of the compound (8) with the organolithium compound (9) uses ethers such as ether and tetrahydrofuran as a solvent. Reaction temperature is -73 ℃ to 30 ℃, reaction time is 30
5 minutes to 5 hours. After completion of the reaction, an aqueous solution of ammonium chloride is added, and the mixture is treated by a conventional method, and if necessary, purified by column chromatography, recrystallization, or distillation.

In the reaction of the compound (8) with the Grignard reagent (10), ethers such as ether and tetrahydrofuran are used as a solvent, the reaction temperature is 0 ° C. to the boiling point of the solvent, and the reaction time is 30 minutes to 10 hours. After completion of the reaction, it can be obtained by the same treatment as the reactions of (8) and (9).
Further, the reduction of the compound (8) with a metal hydride compound such as sodium borohydride or sodium cyanoborohydride is carried out at a reaction temperature of 0 ° C. with an ether, an ether such as tetrahydrofuran, an alcohol such as methanol as a solvent. From the boiling point of the solvent used. The reaction time is 30 minutes to 5 hours. After completion of the reaction, the reaction is carried out by a conventional method and, if necessary, purified by column chromatography, recrystallization, or distillation.

An organic solvent that does not participate in the reduction reaction of compound (11) (eg ethers, ethers such as tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene)
Inside, add sodium hydride and stir for 30 minutes to 2 hours,
Then, carbon disulfide and methyl iodide are added and reacted.
The reaction time is 10 minutes to 1 hour, but the reaction temperature is 0.
It is carried out at a temperature of from ℃ to the boiling point of the solvent used. The general formula thus obtained (Wherein R ₁ , R ₂ , R ₄ , Y ₁ , A, p, W and n have the same meanings as described above) with tributyltin hydride (n-Bu ₃ SnH). It can be obtained by reducing or dehydrating, and then optionally hydrolyzing.

The radical reduction reaction of compound (12) with tributyltin hydride is performed by an organic solvent (eg ether,
Heating in ethers such as tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, or mixed solvents thereof in the presence of α, α'-azobisisobutyronitrile (AIBN) for 10 to 30 hours. By refluxing, Z is a methylene group which may have the above substituent,
The target compound (1
e) can be obtained.

The dehydration reaction of the compound (12) is carried out by using a catalytic amount of para-toluenesulfonic acid or hydrochloric acid in an organic solvent that does not participate in the reaction (eg, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as dioxane, tetrahydrofuran). , Hydrobromic acid, and a mineral acid such as sulfuric acid are added, the mixture is heated to azeotropy, and optionally hydrolyzed as described above, so that Z may have a vinylene group which may have the above-mentioned substituent. The target compound (1e) shown can be obtained. After completion of the reaction, the reaction mixture is treated in a conventional manner,
Further, if necessary, it can be purified by column chromatography or recrystallization.

The starting compound in the production method of the present invention can be produced, for example, according to the production method shown below.

Manufacturing method A In the above formula, A'represents the protective group for the carboxyl group in A described above, and X has the same meaning as described above.

This reaction route is a production method in which Z is a methylene group and W represents a direct bond. The compound (13) is reduced to obtain a compound (14), which is halogenated or sulfonylated to give a compound ( 15) get. This is subjected to Friedel-Crafts reaction, and the resulting compound (16) is oxidized and esterified to obtain compound (2a).

Manufacturing method B In the above formula, R ₅ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group contained in the Z portion described above, and A ′ and X have the same meanings as described above.

This reaction route is a production method in which Z is an ethylene group which may have a substituent and W is a direct bond. The compound (17) is a compound (18) whose carbon number is extended. Then, this is hydrolyzed and decarboxylated to obtain the compound (19). Then, the compound (20) is reduced and dehydrated to obtain a compound (21) which is further reduced, halogenated or sulfonylated to obtain a compound (22), which is subjected to Friedel-Crafts reaction to obtain The compound (23) is oxidized and esterified to obtain the compound (2b).

Manufacturing method C In the above formula, A ′, R ₄ and R ₅ have the same meanings as described above.

In this reaction route, the compound (20) obtained in the production method B is used as a chloride to obtain a compound (25) by a Grignard reaction. Then, it is subjected to Friedel-Crafts reaction to oxidize the obtained compound (26) and then esterify it to obtain the compound (5a).

Manufacturing method D In the above formula, A ′ and Y ₁ have the same meanings as described above.

In this reaction route, the compound (13 ') is chlorinated to form the compound (27).
Which was then reacted with Grignard reagent to give compound (28)
After obtaining the compound (29) by Friedel-Crafts reaction, the compound (30) is obtained by oxidation and esterification. This is brominated and then reacted with imidazole to obtain a ketone body (8a).

Although the substitution product at the 5-position has been described above, the substitution product at the 6-position can also be synthesized by the same method as the substitution product at the 5-position. That is, instead of the starting material (13) of production method A To get Instead of manufacturing B starting material (17) To get Instead of the starting material (20) of manufacturing method C To get Instead of the starting material (13 ') of production D To get

According to the above-mentioned production methods A, B, C, D and the 6-position substitution product,
In order to obtain the 5,6,7-tetrahydrothianaphthene compound, according to the following formula The ester compounds (36), (37), (38) and (39) are synthesized by catalytic reduction of the compounds (13), (32), (20) and (34), and the above-mentioned production methods A, B and C are prepared. And the obtained compounds (36), (37), instead of the compounds (13), (32), (20) and (34) described in the method for producing D- and 6-position substitution products.
The purpose is achieved by using (38) and (39).

Manufacturing method E In the above formula, A ′ and X have the same meaning as described above.

This reaction route is a production method when Z is a methylene group and W is a vinylene group. The compound (2c) is obtained by the Witteich reaction of the compound (16).

Manufacturing method F In the above formula, X has the same meaning as described above. This reaction route is when W is a methylene group. The compound (16) is subjected to Witteich reaction to obtain a compound (40), which is oxidized to obtain a compound (2d). Although the above-mentioned production methods E and F are the production method of the 5-position substitution product, the 6-position substitution product can also be synthesized in exactly the same manner. That is, instead of the starting material (16) Using To get

In accordance with the above production method and the production method of the E, F and 6-position substitution products, 4,
In order to obtain the 5,6,7-tetrahydrothianaphthene compound, the object is achieved by using the compound (36) obtained by the above-mentioned reduction reaction.

The thianaphthene derivative having the above-mentioned general formula (1) synthesized by the above production method can be obtained as a free base or free acid or a pharmacologically acceptable salt by the production method. The pharmacologically acceptable acid addition salts are salts of mineral acids such as hydrochloric acid, phosphoric acid, sulfuric acid and nitric acid, oxalic acid, tartaric acid, citric acid, malic acid, lactic acid, maleic acid, methanesulfonic acid and other organic compounds. Carboxylic acid salts include alkali metal salts such as sodium and calcium, or alkaline earth metal salts, aluminum salts, ammonium salts, triethylamine, dicyclohexylamine, benzylamine, morpholine and piperidine. Examples thereof include organic bases and salts of basic amino acids such as lysine and arginine.

Further, the thianaphthene derivative (1) of the present invention can be converted into an ester form which is easily hydrolyzed in vivo according to a conventional method. Examples of the ester group in this case include lower alkyl groups such as methyl, ethyl, propyl, isopropyl and butyl, acetoxymethyl, propionyloxymethyl, aliphatic acyloxyalkyl groups such as bivaloyloxymethyl, 1-methoxycarbonyloxyethyl,
Examples thereof include lower alkoxycarbonyloxyalkyl groups such as 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl, or (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group.

The thianaphthene derivative in the general formula (1) has an optical isomer because it has an asymmetric carbon atom. Therefore, when the thianaphthene derivative of the general formula (1) is obtained as a mixture of optical isomers, each isomer can be obtained by optical resolution according to a conventional method. In the compound having the general formula (1), the optical isomers and the mixture of optical isomers are all represented by a single formula, but the scope of the present invention is not limited thereby.

EFFECTS OF THE INVENTION The thianaphthene derivative having the above general formula (1) of the present invention has excellent platelet aggregation inhibitory action and thromboxane A ₂ biosynthesis inhibitory action, which are excellent in pharmacological tests.

That is, the compound of the present invention shows 100% inhibition at 10 ⁻⁵ g / ml of platelet aggregation-inhibitory action induced by collagen using, for example, rabbit PRP (platelet-rich plasma), and further 10 ⁻⁸ mol. While it inhibits TXZ ₂ biosynthesis by 50% at a concentration, its cyclooxygenase and prostacyclin synthetase inhibitory effects are very weak. Further, in the in vivo experimental system, the effect of preventing the embolism and lethality of rabbits and mice by intravenous injection of arachidonic acid by orally administering the compound of the present invention is extremely strong.

Therefore, the thianaphthene derivative having the above general formula (1) of the present invention can be used for diseases caused by TXA ₂ , such as inflammation, hypertension,
It is useful as a therapeutic drug for thrombosis, cerebral hemorrhage, asthma, etc., and is particularly useful for treating and / or preventing thromboembolism in mammals including humans. For example, the compounds of the present invention are useful in the treatment and prevention of myocardial infarction, cerebral vascular thrombosis and ischemic peripheral vascular disease; in the treatment and prevention of post-operative thrombosis; is there.

The dose of the compound of the present invention required for the therapeutic or prophylactic effect for the above-mentioned diseases varies depending on the administration form, age and type of symptoms to be treated, etc., but usually the daily oral dose for adults is 50 to 50. It is 1800 mg and can be administered in 2 to 3 divided doses per day.

While it is possible for the compounds of the present invention to be administered neat, it is usually preferable to present them as a pharmaceutical formulation. Examples of the preparation include oral dosage forms such as tablets, capsules, powders, granules and syrups, and parenteral dosage forms such as suppositories, subcutaneous or intravenous injections.

Next, the present invention will be described more specifically with reference to Examples and Reference Examples.

Example-1. 2-Methoxycarbonyl-5- (1-imidazolylmethyl) -4,5,6,7-tetrahydrothianaphthene Imidazole was added to a suspension of 0.12 g of sodium hydride (oil) in dimethylformamide (10 ml) under a nitrogen atmosphere.
A 0.35 g solution of dimethylformamide (10 ml) was added dropwise at room temperature. After 30 minutes, 0.78 g of 2-methoxycarbonyl-
A solution of 5-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene in dimethylformamide (20 ml) was added dropwise, and the mixture was further heated to 50 ° C and reacted for 2 hours. After completion of the reaction, the mixture was treated by a conventional method and purified by silica gel column chromatography (ethyl acetate: ethanol: triethylamine = 20: 1: 1) to obtain 0.49 g of the desired product as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ peak, TMS internal standard); 3.85 (straight line, 3H, −COO CH ₃ ), 3.95 (double line, coupling constant 6 Hz, −CH ₂ —N), 6.85 to 7.6 (4H , H-3 and −
Imidazole ring).

Example-2. 2- [5- (1-imidazolylmethyl) -4,5,6,7-tetrahydrothianaphthene] carboxylic acid / hydrochloride 2-Methoxycarbonyl-5-obtained from Example-1
0.47 g of (1-imidazolylmethyl) -4,5,6,7-tetrahydrothianaphthene was dissolved in 5 ml of glacial acetic acid and 5 ml of concentrated hydrochloric acid and heated under reflux for 6 hours. After completion of the reaction, the mixture was treated by a conventional method and reprecipitated from isopropyl alcohol and diethyl ether to obtain 0.47 g of the desired product as a colorless amorphous solid.

Infrared absorption spectrum (KBr method): 1680 cm ^-1 Elemental analysis value Calculated value as C ₁₃ H ₁₄ N ₂ O ₂ S.HCl: C, 52.26; H, 5.06; N, 9.38; S, 10.73; Cl, 11.87% Experimental value: C, 52.38; H, 5.13; N, 9.16; S, 10.55; Cl, 12.01% Example-3 2-methoxycarbonyl-5- (1-imidazolylmethyl) -6,7-dihydrothianaphthene In the same manner as in Example-1, 0.39 g of the desired product was obtained as an oily substance from 0.63 g of 2-methoxycarbonyl-5-methanesulfonyloxymethyl-6,7-dihydrothianaphthene.

Nuclear magnetic resonance spectrum (heavy chloroform, δ value, TMS internal standard); 3.88 (single line, 3H, −COO CH ₃ ), 4.63 (single line, 2H,
_{- CH 2 -N), 6.5~7.6 (} 5H, H-3, H-4 and imidazole ring).

Example-4 2- [5- (1-imidazolylmethyl) -6,7-dihydrothianaphthene] carboxylic acid hydrochloride In the same manner as in Example-2, from 0.31 g of 2-methoxycarbonyl-5- (1-imidazolylmethyl) -6,7-dihydrothianaphthene obtained in Example-3, the desired product was obtained.
0.27 g was obtained as a colorless amorphous solid.

Infrared absorption spectrum (KBr method): 1690 cm ^-1 Elemental analysis value Calculated value as C ₁₃ H ₁₂ N ₂ O ₂ S ・ HCl: C, 52.61; H, 4.42; N, 9.44; S, 10.80; Cl, 11.95% Experimental value: C, 52.77; H, 4.44; N, 9.20; S, 11.03; Cl, 12.01% Example-5 2-methoxycarbonyl-6- (1-imidazolylmethyl) -4,5,6,7-tetrahydro Tianaphten In the same manner as in Example-1, from 0.80 g of 2-methoxycarbonyl-6-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene, 0.87 g of the desired product was obtained as a colorless amorphous solid. .

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.83 (single line, 3H, −COO CH ₃ ), 3.96 (double line, coupling constant 6 Hz, −CH ₂ —N), 6.9 to 7.6 ( 4H, H-3 and imidazole ring).

Example-6 2- [6- (1-imidazolylmethyl) -4,5,6,7-tetrahydrothianaphthene] carboxylic acid hydrochloride In the same manner as in Example-2, 0.74 g of 2-methoxycarbonyl-6- (1-imidazolylmethyl) -4,5,6,7-tetrahydrothianaphthene obtained in Example-5 was used to obtain the desired product. 0.51 g was obtained as a colorless amorphous solid.

Infrared absorption spectrum (KBr method): 1685 cm ^-1 Elemental analysis value C ₁₃ H ₁₄ N ₂ O ₂ Calculated value as S ・ HCl: C, 52.26; H, 5.06; N, 9.38; S, 10.73; Cl, 11.87% Experimental value: C, 52.03; H, 4.99; N, 9.53; S, 10.71; Cl, 11.72% Example-7 2-methoxycarbonyl-6- (1-imidazolylmethyl) -4,5-dihydrothianaphthene In the same manner as in Example-1, 0.29 g of the desired product was obtained as a colorless amorphous solid from 0.35 g of 2-methoxycarbonyl-6-methanesulfonyloxymethyl-4,5-dihydrothianaphthene.

Nuclear magnetic resonance spectrum (heavy chloroform, δ value, TMS internal standard); 3.84 (singlet, 3H, − COOCH ₃ ), 4.68 (singlet, 2H,
_{- CH 2 -N), 6.5~7.6 (} 5H, H-3, H-7 and imidazole ring).

Example-8 2- [6- (1-Imidazolylmethyl) -4,5-dihydrothianaphthene] carboxylic acid hydrochloride In the same manner as in Example-2, from 0.29 g of 2-methoxycarbonyl-6- (1-imidazolylmethyl) -4,5-dihydrothianaphthene obtained in Example-7, the desired product was obtained.
0.23 g was obtained as a colorless amorphous solid.

Infrared absorption spectrum (KBr method): 1690 cm ^-1 Elemental analysis value Calculated value as C ₁₃ H ₁₂ N ₂ O ₂ S ・ HCl: C, 52.26; H, 4.42; N, 9.44; S, 10.80; Cl, 11.95% Experimental value: C, 52.40; H, 4.32; N, 9.60; S, 10.59; Cl, 11.88% Example-9 2-methoxycarbonyl-5- [2- (1-imidazolyl) ethyl] -4,5,6 , 7-Tetrahydrothianaphthene In the same manner as in Example-1, 2-methoxycarbonyl-5- [2- (1-imidazolyl) ethyl] -4,5,6,7
-From 1.50 g of tetrahydrothianaphthene, 1.28 g of the desired product was obtained as an oily substance.

Nuclear magnetic resonance spectrum (deuteriochloroform, δ value, TMS internal standard); 3.90 (singlet line, 3H, −COO CH ₃ ), 4.05 (triplet line, coupling constant 6.5Hz, −CH ₂ —N), 6.9 to 7.6 ( 4H, H-3 and imidazole ring).

Example-10 2- [5- [2- (1-imidazolyl) ethyl] -4,5,
6,7-Tetrahydrothianaphthene] carboxylic acid / hydrochloride 2-Methoxycarbonyl-5- [2- (1-imidazolyl) ethyl] -4,5,6,7-tetrahydrothianaphthene obtained in Example-9 was prepared in the same manner as in Example-2.
From 1.00 g, 0.27 g of the desired product was obtained as a colorless amorphous solid.

Infrared absorption spectrum (KBr method): 1690 cm ^-1 Elemental analysis value Calculated value as C ₁₄ H ₁₆ N ₂ O ₂ S.HCl: C, 53.76; H, 5.48; N, 8.96; S, 10.25; Cl, 11.33% Experimental value: C, 53.70; H, 5.51; N, 9.13; S, 10.39; Cl, 11.27% Reference Example-1 5-hydroxymethyl-4,5,6,7-tetrahydrothianaphthene 5-methoxycarbonyl-4, A solution prepared by dissolving 3.20 g of 5,6,7-tetrahydrothianaphthene in 35 ml of ether was added dropwise to a suspension of 0.62 g of lithium aluminum hydride in 30 ml of ether at 10 ° C or lower, and after 10 minutes, sodium sulfate 10 hydrate was added. The substance was added and stirred. The reaction solution is a super-auxiliary agent (Celite 545)
The solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 2.59 g of the desired product as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.53 (doublet, 2H, − CH ₂ —OH), 6.68 and 7.00
(Each double wire, coupling constant 6Hz, each 1H, H-2 and H-3).

Reference Example-2 5-Methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene 5-Hydroxymethyl-5,4,5, obtained in Reference Example-1
1.09 g of 6,7-tetrahydrothianaphthene was added to 30 ml of methylene chloride.
ml and triethylamine 2.71 ml, a solution of methanesulfonyl chloride (1.00 ml) in methylene chloride (10 ml) was added dropwise under ice-water cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was treated by a conventional method and purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 1.38 g of the desired product as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 2.98 (single line, 3H, −OSO ₂ CH ₃ ), 4.16 (double line,
Coupling constants _{5Hz, 2H, - CH 2 -O} ), 6.72 and 7.05 (each doublet, coupling constant 5 Hz, each IH, H-2 and H-3).

Reference Example-3 2-formyl-5-methanesulfonyloxymethyl-4,
5,6,7-Tetrahydrothianaphthene 1.18 g of 5-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene obtained from Reference Example-2 was dissolved in 35 ml of methylene chloride to give anhydrous aluminum chloride.
-30 ℃ under nitrogen stream in a suspension of 0.96g methylene chloride in 40ml.
It was dripped at. Further, the mixture was reacted with stirring at 0 ° C. for 2 hours. After completion of the reaction, the reaction mixture was treated by a conventional method and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 0.85 g of the desired product as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard): 3.06 (single line, 3H, −OSO ₂ CH ₃ ), 4.24 (double line,
Coupling _{constants, 5Hz, 2H, - CH 2} -O), 7.46 ( singlet, IH, H-
3), 9.85 (single line, 1H, -CHO).

Reference Example-4 2-Methoxycarbonyl-5-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene 2-Formyl-5-methanesulfonyloxymethyl-4,5, obtained in Reference Example-3 A solution of 0.80 g of 6,7-tetrahydrothianaphthene and 1.77 g of sulfamic acid in 48 ml of dioxane water (5: 1 v / v) was added with 0.40 g of chlorous acid in water.
The solution dissolved in ml was added dropwise at room temperature. After the reaction was completed, it was treated by a conventional method. The crude product obtained was treated with methanol (150 m).
It was dissolved in 1 and heated to reflux in the presence of concentrated sulfuric acid catalyst. After completion of the reaction, the mixture was treated by a conventional method and purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain 0.78 g of the desired product as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.03 (single line, 3H, −OSO ₂ CH ₃ ), 3.86 (single line, 3
_{H, -COO CH 3), 4.22} ( doublet, coupling constant 5Hz, 2H, - CH ₂ O
-), 7.48 (single line, 1H, H-3).

Reference Example-5 5-Hydroxymethyl-6,7-dihydrothianaphthene In the same manner as in Reference Example-1, 2.05 g of 5-methoxycarbonyl-6,7-dihydrothianaphthene was used to convert 1.65 g of the target product into an oily substance. Obtained.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 4.19 (doublet, coupling constant, 6Hz, 2H, − CH ₂ —OH), 6.
41 (triple line, coupling constant 1.5Hz, 1H, H-4), 6.81 and 7.0
3 (each double wire, coupling constant 5Hz, each 1H, H-2 and H-
3).

Reference Example-6 5-Methanesulfonyloxymethyl-6,7-dihydrothianaphthene 5-Hydroxymethyl-6,7-dihydrothianaphthene obtained in Reference Example-5 in the same manner as in Reference Example-2.
From 1.14 g, the desired product (1.07 g) was obtained as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.02 (single line, 3H, −OSO ₂ CH ₃ ), 4.31 (single line, 2
_{H, - CH 2 -O -)} , 6.45 ( triplet, coupling constant 1.5 Hz, IH, H-
4), 6.85 and 7.06 (each double wire, coupling constant 5Hz, each 1H, H
-2 and H-3).

Reference Example-7 2-formyl-5-methanesulfonyloxymethyl-6,
7-Dihydrothianaphthene In the same manner as in Reference Example-3, 0.99 g of 5-methanesulfonyloxymethyl-6,7-dihydrothianaphthene obtained in Reference Example-6 was used to give 0.82 g of the desired product as an oily substance. Obtained.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.07 (single line, 3H, −OSO ₂ CH ₃ ), 4.33 (single line, 2
H, − CH ₂ O−), 6.46 (triple line, coupling constant 1.5Hz, 1H, H−
4), 7.49 (single line, 1H, H-3), 9.89 (single line, 1H, -CH
O).

Reference Example-8 2-Methoxycarbonyl-5-methanesulfonyloxymethyl-6,7-dihydrothianaphthene 2-formyl-5-methanesulfonyl obtained in Reference Example-7 in the same manner as in Reference Example-4. Oxymethyl-
From 0.75 g of 6,7-dihydrothianaphthene, 0.69 g of the desired product was obtained as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.02 (single line, 3H, −OSO ₂ CH ₃ ), 3.88 (single line, 3
_{H, -COO CH 3), 4.30} ( _{singlet, 2H, - CH 2 -O -} ), 6.43
(Triple line, coupling constant 1.5Hz, 1H, H-4), 7.50 (single line, 1
H, H-3).

Reference Example-9 6-Hydroxymethyl-4,5,6,7-tetrahydrothianaphthene 6-Methoxycarbonyl-4,5,6,7-tetrahydrothianaphthene From 4.85 g, in the same manner as in Reference Example-1,
3.91 g of the desired product was obtained as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.57 (doublet, coupling constant, 6Hz, 2H, − CH ₂ — OH),
6.69 and 7.00 (each double line, coupling constant 5Hz, each 1H, H-2 and H-3).

Reference Example-10 6-Methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene 6-Hydroxymethyl-4,5,6 obtained by Reference Example-9 in the same manner as in Reference Example-2. From 3.50 g of 6,7-tetrahydrothianaphthene, 4.28 g of the desired product was obtained as an oily substance.

Nuclear magnetic resonance spectrum (heavy chloroform, δ value, TMS internal standard); 2.98 (single line, 3H, −OSO ₂ CH ₃ ), 4.17 (double line,
Coupling _{constants, 6Hz, 2H, - CH 2} -O -), 6.72 and 7.04 (each doublet, coupling constant 5 Hz, each IH, H-2 and H-3).

Reference Example-11 2-formyl-6-methanesulfonyloxymethyl-4,
5,6,7-Tetrahydrothianaphthene In the same manner as in Reference Example-3, from 4.11 g of 6-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene obtained in Reference Example-10, 2.92 g of the desired product was obtained as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.05 (single line, 3H, −OSO ₂ CH ₃ ), 4.24 (double line,
Coupling constants _{5Hz, - CH 2 -O -)} , 7.46 ( singlet, 1H, H-3),
9.85 (single line, 1H, -CHO).

Reference Example-12 2-methoxycarbonylmethyl-6-methanesulfonyloxymethyl-4,5,6,7-tetrahydrothianaphthene 2-formyl obtained in Reference Example-11 in the same manner as in Reference Example-4. -6-Methanesulfonyloxymethyl-
From 4,5,6,7-tetrahydrothianaphthene 2.32g, the target product
2.19 g were obtained as colorless needles (mp, 188-191 ° C).

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.05 (single line, 3H, −OSO ₂ CH ₃ ), 3.86 (single line, 3
_{H, -COO CH 3), 4.20} ( doublet, coupling _{constant, 5Hz, 2H, - CH 2} -
O-), 7.48 (single line, 1H, H-3).

Reference Example-13 6-Hydroxymethyl-4,5-dihydrothianaphthene In the same manner as in Reference Example-1, from 1.64 g of 6-methoxycarbonyl-4,5-dihydrothianaphthene, 1.19 g of the desired product was obtained.
Was obtained as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 4.22 (double line, coupling constant, 6Hz, 2H, − CH ₂ — O
-), 6.43 (triple line, coupling constant 1.5Hz, 1H, H-7), 6.71 and 7.02 (each double line, coupling constant 5Hz, 1H, H-2 and H each)
-3).

Reference Example-14 6-Methanesulfonyloxymethyl-4,5-dihydrothianaphthene 6-Hydroxymethyl-4,5-dihydrothianaphthene obtained in Reference Example-13 in the same manner as in Reference Example-2.
From 1.03 g, 0.82 g of the desired product was obtained as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.01 (single line, 3H, −OSO ₂ − CH ₃ ), 4.33 (single line,
2H, − CH ₂ O−), 6.48 (triple line, coupling constant 1.5Hz, 1H, H−
7), 6.81 and 7.06 (each double wire, coupling constant 5Hz, each 1H, H
-2 and H-3).

Reference Example-15 2-formyl-6-methanesulfonyloxymethyl-4,
5-Dihydrothianaphthene In the same manner as in Reference Example-3, from 0.73 g of 6-methanesulfonyloxymethyl-4,5-dihydrothianaphthene obtained in Reference Example-14, 0.49 g of the desired product as an oily substance was obtained. Obtained.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.05 (single line, 3H, −OSO ₂ CH ₃ ), 4.31 (single line, 2
H, − CH ₂ O−), 6.47 (triple line, coupling constant 1.5Hz, 1H, H−
7), 7.50 (single line, 1H, H-3), 9.88 (single line, 1H, -CH
O).

Reference Example-16 2-Methoxycarbonyl-6-methanesulfonyloxymethyl-4,5-dihydrothianaphthene 2-formyl-6-methanesulfonyl obtained in Reference Example-15 in the same manner as in Reference Example-4. Oxymethyl-
From 0.40 g of 4,5-dihydrothianaphthene, 0.39 g of the desired product was obtained as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.02 (single line, 3H, −OSO ₂ CH ₃ ), 3.87 (single line, 3
_{H, -COO CH 3), 4.29} ( _{singlet, 2H, - CH 2 O -} ), 6.42 ( triplet, binding constants 1.5Hz, 1H, H-7) , 7.49 ( singlet, IH, H-
3).

Reference Example-17 5- (2-hydroxyethyl) -4,5,6,7-tetrahydrothianaphthene From 5-methoxycarbonylmethyl-4,5,6,7-tetrahydrothianaphthene 4.50 g, Reference Example-1 By the same method, 3.75 g of the desired product was obtained as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.85 (quartet, coupling constant 6.5Hz, − CH ₂ OH), 6.68
And 7.00 (each double wire, coupling constant 6Hz, each 1H, H-2 and H-3).

Reference Example-18 5- (2-Methanesulfonyloxyethyl) -4,5,6,7
-Tetrahydrothianaphthene In the same manner as in Reference Example-2, from 3.68 g of 5- (2-hydroxyethyl) -4,5,6,7-tetrahydrothianaphthene obtained in Reference Example-17, the desired product 3.72 g was obtained as an oil.

Nuclear magnetic resonance spectrum (deuteriochloroform, δ value, TMS internal standard); 2.91 (singlet line, 3H, −OSO ₂ CH ₃ ), 4.25 (triplet line,
Coupling constants _{6Hz, 2H, - CH 2 O} -), 6.73 and 7.07 (each doublet, coupling constant 5 Hz, each IH, H-2 and H-3).

Reference Example-19 5- (2-Methanesulfonyloxyethyl) -2-formyl-4,5,6,7-tetrahydrothianaphthene 5 Obtained by Reference Example-18 in the same manner as in Reference Example-3. -(2-Methanesulfonyloxyethyl) -4,5,6,
From 7-tetrahydrothianaphthene 3.51g, the target product 2.29g
Was obtained as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.06 (singlet line, 3H, −OSO ₂ CH ₃ ), 4.19 (triplet line,
Coupling constant 6.5Hz, 2H, − CH ₂ O−), 7.44 (single line, 1H, H−
3), 9.88 (single line, 1H, -CHO).

Reference Example-20 2-Methoxycarbonyl-5- (2-methanesulfonyloxyethyl) -4,5,6,7-tetrahydrothianaphthene Obtained by Reference Example-19 in the same manner as in Reference Example-4. From 2.13 g of 5- (2-methanesulfonyloxyethyl) -2-formyl-4,5,6,7-tetrahydrothianaphthene, 1.93 g of the desired product was obtained as an oily substance.

Nuclear magnetic resonance spectrum (deuterated chloroform, δ value, TMS internal standard); 3.04 (single line, 3H, −OSO ₂ CH ₃ ), 3.88 (single line, 3
_{H, -COO CH 3), 4.19} ( triplet, binding constants 6.5Hz, 2H, - CH ₂ O
-), 7.50 (single line, 1H, H-3).

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Takeshi Oshima 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (56) Reference JP 57-181084 (JP, A) JP Sho 58-15972 (JP, A) US Patent 4611059 (US, A)

Claims (3)

[Claims] 1. A general formula [In the formula, Y represents an imidazolyl group, Z represents a methylene group or an ethylene group, W represents a direct bond, R ₁ and
R ₂ represents a hydrogen atom, and the dotted line part represents a single bond or a double bond. However, when the 4,5-position is a double bond, the 6,7-position is a single bond, the substituent —Z—Y is further bonded to the 5-position, and when the 6,7-position is a double bond, it is 4 The 5-position is a single bond, and the substituent
Z-Y binds to the 6-position. ] The thianaphthene derivative which has these, its pharmacologically acceptable salt, and its lower alkyl ester. 2. General formula [In the formula, X represents a halogen atom, a lower alkanesulfonyloxy group or an arylsulfonyloxy group, Z ₁ represents a methylene group or an ethylene group, W represents a direct bond, and R ₁ and R ₂ represent hydrogen atoms. , A represents a hydrogen atom or a protecting group for a carboxyl group, and the dotted line portion represents a single bond or a double bond. However, when the 4,5-position is a double bond, the 6,7-position is a single bond and the substituent -Z ₁ -X is bonded to the 5-position, and when the 6,7-position is a double bond, it is 4 The 5-position is a single bond, and the substituent -Z ₁ -X is bonded to the 6-position. A compound having, in the formula Y ₁ H [wherein, Y ₁ represents a 1-imidazolyl group. ] The compound of the general formula characterized by hydrolyzing the resulting compound, if necessary. [Wherein Y ₁ , Z ₁ , W, R ₁ and R ₂ have the same meanings as described above. ] The manufacturing method of the thianaphthene derivative which has these, its pharmacologically acceptable salt, and its lower alkyl ester. 3. General formula [Wherein Z ₁ represents a methylene group or an ethylene group, W represents a direct bond, R ₁ and R ₂ represent a hydrogen atom, A represents a hydrogen atom or a protecting group for a carboxyl group, and a dotted line portion represents a single atom. Indicates a bond or a double bond. However, when the 4,5-position is a double bond, the 6,7-position is a single bond, the substituent —Z ₁ —OH is bonded to the 5-position, and when the 6,7-position is a double bond, The 4,5-position is a single bond, and the substituent —Z ₁ —OH is bonded to the 6-position. A compound having, in the formula Y ₁ -SO-Y ₁ [formula, Y ₁ is a 1-imidazolyl group. ] The compound of the general formula characterized by hydrolyzing the resulting compound, if necessary. [Wherein Y ₁ , Z ₁ , W, R ₁ and R ₂ have the same meanings as described above. ] The thiananaphthene derivative which has these, its pharmacologically acceptable salt, and the manufacturing method of its lower alkyl ester.