JPH07502039A - New tetrahydronaphthalene derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] New tetrahydronaphthalene derivatives The present invention relates to the following general formula (I): R1 represents a hydrogen atom; R' represents a hydrogen atom, cl-4alkoxycarbonylalkyl or benzyl group or R1 and R' are of the formula -(CHI)! − together with the groups represented by; R3 is hydroxy, c, -4 alkoxy or benzyloxy group, or the following general formula (A): (Here, R8 is cl-, an alkyl group); n is 0. 1. 2. A tetrahydronaphthalene derivative represented by 3 or 4, and pharmaceutically acceptable salts thereof, as well as methods for preparing said compounds.

Compounds of general formula (I) can exist in the (E) form.

In C+-<alkyl or C3-, alkoxy group, the alkyl group is linear or branched. Branched saturated hydrocarbon groups, i.e. methyl, ethyl, n- or isopropyl, Additionally, there may be n-, 5ec- or t-butyl groups.

The novel compounds of general formula (1), which are known to be biologically active, have significant Provides an anti-ulcer, i.e. cytoprotective effect.

The present invention further provides the general formula I (wherein R', R', R' and n are as defined above) ) and pharmaceutically acceptable salts thereof. It also relates to pharmaceutical compositions containing the same, as well as methods of preparing the same.

The therapeutic efficacy of compounds of general formula (I) was investigated in the following tests.

Cytoprotective effect in acidic alcohol-induced gastric ulcer model (A, Robe rt: Gasjroenterology, 77, 761-767, 19 79) This study involved subjects with a body weight of 120-150 g and fed for 24 hours. The study was carried out in female rats that had not been born. The test compound was Tween80 It was administered by gavage as a suspension prepared by.

After 30 minutes, acidic alcohol at a dose of 0.5 ml per 100 g of body weight It was added by gavage. After an hour, the animals were killed and their stomachs removed. and cut along the curve. Red-brown strips (bleeding lesions) measured and their average length forestomach calculated. Protective effect of test compound was determined compared to the control group. Effect of the compound described in Example 1: EDa o=0. Img/kg p, o.

Cytoprotective effect in acetic acid-induced chronic gastric ulcer model (Tagaki: , Japanese Journal of Pharmacology 19 ．． 418　426゜This study involved female rats deprived of food for 24 hours. It was held in The abdominal wall was incised under ether anesthesia, and 25μ of 2096 acetic acid solution was added. 1 was injected into the subserosal layer of the linear portion of the stomach near the pylorus. The abdominal wall is then closed and The animals were given food and water. Treatment started on the 5th day after surgery and l Administration was continued once daily for O days. Animals were killed 155 days after surgery and Their stomachs were removed. Evaluation measures the diameter of the gangrenous areas and their This was done by calculating the surface. The therapeutic effect of a test compound is determined according to the following formula: It was calculated as: Ulcer surface (control) - Ulcer surface (test compound) Ulcer surface (control) The therapeutic efficacy of the compound of Example 1 was 39% at a dose of 10 mg/kg p,o. .

Pharmacological studies have demonstrated that the compounds of this invention and their pharmaceutically acceptable salts have potential anti-inflammatory properties. It was confirmed that it was an ulcer agent.

The present invention also provides the general formula (I) (wherein R', R''l R' and n are as described above) Regarding the preparation method of the tetrahydronaphthalene derivative represented by The notation method is 4-oxo-4-(5,6,7,8 -tetrahydro-2-naphthyl)-2(E)-butenoic acid and the following: General formula [wherein R1 and R1 are as above, and R4 is 01-4 alco oxy or benzyloxy group, or formula A (where R6 represents a cl-4 alkyl group) 〉representing a group represented by 〉representing an amino acid derivative represented by hand Optionally, the general formula (I) (wherein R1 and R2 are as described above, and R 3 represents a t-butyloxy group) is subjected to acidolysis. and/or optionally, general formula (I) (wherein R1 and R1 are as described above) and R″ represents a hydroxyl group) and a piperazine derivative containing a group of formula A (where R'' is as above) or the compound of general formula (I) is an inorganic compound. or converted into a salt with an organic base.

The compounds of general formula (I [I) from the starting materials applied in the present invention are commercially available products. be.

4-oxo-4-(5,6,7,8-tetrahydro-2-naphthi of general formula (n)) -2(E)-butenoic acid, D, Papa, etc.: J, Am.

Chem, Soc, near 0.3356. According to 1948 Fr1edel- 112 by Krafts reaction, 3. 4-tetrahydronaphthalene and nothing It can be prepared from water maleic acid.

According to a preferred embodiment of the present invention, the intermediate form between general formula (II) and (I[[) First, the 4-year-old xo-4-(5,6,7°8-tetrahydro -2-naphthyl)-2(E)-butenoic acid is activated in situ and then deactivated. Reacting the activation compound with an amine compound of formula (I[) in an organic solvent. It is done by.

The carboxy group of the compound of formula (II) is preferably , an inert organic solvent, preferably a halogenated aliphatic hydrocarbon, conveniently In dichloromethane, substoichiometric amounts of carbodiimide-type reagents, i.e. Can be activated by dicyclohexylcarbodiimide. other preferred types Activation is by a mixed anhydride method, where chloroformate, preferably is applied to ethyl chloroformate. The reaction is preferably carried out at -20''C~ At a temperature range of 0°C, a stoichiometric amount of t-amine base, preferably triethylamine, in the presence of an inert organic solvent, i.e. a cyclic ether, preferably tetrahydro It takes place in Fran. General formula (I) (where R1 and R2 are as above) and R3 is a hydroxy group) is a piperazine-derived compound. When reacted with a conductor, the acid can be reacted with any of the above methods, i.e. with mixed anhydrides. activated by either the method or the carbodiimide method.

Optionally, the general formula (I) (wherein R1 and R1 are as described above, and R 3 is a hydroxy group) is a known compound represented by an organic or inorganic base. can be converted into alkali metal, alkaline earth metal or zinc salts by the method of

General formula (I) prepared by the method of the present invention, where R', R2 and R2 are as defined above The compound represented by , and can be purified by recrystallization.

The compounds of the present invention may be present in a non-toxic, inert solid or liquid carrier and/or Pharmaceutical preparations suitable for parenteral or oral administration by mixing with excipients can be converted into Water, gelatin, lactose, starch, pectin, stearin magnesium acids, stearic acid, talc, and vegetable oils such as peanut oil, Olive oil, etc. can be used as a carrier. The active ingredient is included in the pharmaceutical composition. solid forms, i.e. round or rectangular tablets, coated tablets, as is customary in , gelatin capsules, tablets or suppositories.

The composition may optionally contain customary auxiliary agents such as preservatives, stabilizers, wetting agents, emulsifiers, etc. can include. They are prepared in the usual way, i.e. in the case of solid preparations, by sieving. It can be prepared by dividing, mixing, granulating and compressing. The preparation is carried out using conventional pharmaceutical techniques. In other words, it is left to the sterilization method.

The following examples are illustrative and do not limit the scope of the invention.

Example 1 4-year-old xo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E )-butenoyl-L-proline ethyl ester 4-year-old xo-4-(5,6,7 , 4.6 g of 8-tetrahydro-2-naphthyl-2(E)-butenoic acid (0,02 mol) in 100 ml of anhydrous dichloromethane, then 5. mol of triethylamine. 6 ml (0.04 mol) are added. The solution was cooled to -15°C, then 2. Ethyl chloroformate dissolved in 10 ml of anhydrous dichloromethane. OImI (0,022 mol), then dissolved in 10 ml of anhydrous dichloromethane at -15°C. Add 4.0 g (0,022 mol) of radish monoproline ethyl ester hydrochloride. Ru. The reaction mixture was first mixed at -15°C for 30 minutes and then at room temperature for 2 hours, The mixture is then extracted with the following solutions in the following order: IN hydrochloric acid, water, 5% Sodium carbonate and saturated sodium chloride solution. Organic layer over sodium sulfate dry and evaporate. The evaporation residue is mixed with cyclohexane-petroleum ether. Crystallizes from (1:I).

Yield: 5.03g (7096) M, p,: 63-66°C [α) o2′: 78.8° (c=0.5, chloroform) Example 2 N-[4-year-old xo-4- (5,6,7,8-tetrahydro-2-naphthyl') -2(E)-butenoyl)-L-proline 4-oxo-4-(5,6,7,8 -tetrahydro-2-naphthyl) -2(E)-butenoyl-L-proline [- 7.66 g (0.02 mol) of butyl ester were dissolved in 2.4 N (7 mol) in dioxane. ) Stir in 200 m/ml of hydrochloric acid solution for 24 hours and then evaporate the mixture. the steam Dissolve the residue in 200 ml of dichloromethane and dissolve the solution in water and saturated chloride. Extract with sodium solution. Dry the organic layer over anhydrous magnesium sulfate and Evaporate the solvent to obtain an oil.

Collection 1. : 6.50g (9996) Example 3 N-[4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)- 2(E)-Butenoyl)-L-proline zinc salt tetrahydrate prepared according to the steps in Example 2 N-[4-oxo-4-(3,6゜7.8-tetrahydro-2-naphthyl )-2(E)Butenoyl)-L-proline 6.5g was added to 10ml of water and Torie Dissolved in a mixture of 2.78 m/(0.02 mol) of thylamine, then 10 ml of water In the middle, 1.36 g of zinc chloride is added. The precipitated compound was filtered and mixed with ice-water and ethyl alcohol. Wash with alcohol and diethyl ether. The product has a flame yellow color.

Yield: 4.9g (629g) M, p,: 122-124℃ Cα]o”: 82.4°C (c=I, methanol).

Flight”− N-[4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)- 2(E)-Butenoyl)-D-as/(ragic acid diethyl ester 4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E) - Dissolve 4.6 g (0.02 mol) of butenoic acid in 50 ml of anhydrous tetrahydrofuran. 5.6 ml (0.04 mol) of triethylamine are added and the solution Cool to -10°C. This solution was added to Slowly add a solution of 2.01 mt' (22 mmol) of methyl chloroformate do. Thereafter, anhydrous dichloromethane was added while maintaining the reaction mixture at a temperature of -10°C. Tan solution 20m (! Medium, D-asunocuclic acid diethyl ester 4.5g (0 ,02 mol) is added. The reaction mixture was heated to -10''C for 30 minutes, followed by room temperature. Stir for 1 hour at warm temperature, then pour it onto 200 ml of water. Dichloromethane Extract by ton.

The organic layer was extracted repeatedly with 5% sodium carbonate and saturated sodium chloride solutions. do. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. flame yellow Colored crystals are formed from the evaporation residue after the addition of petroleum ether.

Yield: 5.6g (70%) M, +1. :95~97℃ [α]. ″・−0.33° (c=0.5, chloroform).

” 1-(N-(4-oxo-4-(5,6,7,8-tetrahydro-2-naphthi )-2(E)-butenoyl)-L-broyl]-4-ethoxycarbonyl- piperazine 4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E) -butenoic acid 4.24g (18.4mmol) in anhydrous tetrahydrofuran 80- Dissolve and add triethylamine 2.57 rRI (18.4 mmol), then add ethyl chloroforme in water tetrahydrofuran 1.76 ml (1 8.4 mmol) is added. This mixture was added in 30 ml of anhydrous tetrahydrofuran. , 1-L-broyl-4-ditochloride prepared according to step b) of generating starting materials Add 4.7 g of cycarbonylpiperazine. The reaction mixture was heated to -15°C. , then stirred for 30 minutes at -1O<0>C and for 1 hour at room temperature. Then add the mixture to water. Pour onto 400 ml and extract with dichloromethane. First, remove the organic layer from 5 % sodium carbonate solution, then water and finally saturated sodium chloride solution. . The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. residual oil The product is recrystallized from a mixture of diethyl ether and isopropanol.

Yield: 4.87 (57%) M, Il: 110-112℃ [α]l) 2″: +9.4° (c=1, chloroform).

Example 6 N-[4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)- 2(E)-Butenoyl)-L-proline benzyl ester L-proline benzyl ester hydrochloride 14.5 g (0.06 mol) and carbonate 8.3 g (0.06 mol) of lithium, 100 ml of water and dichloromethane +00 Dissolve in the +++4' mixture. Dry the organic layer and evaporate the solvent. residue The oil is directly processed in the next step.

4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E) -13.8 g (0.06 mol) of butenoic acid in 150 ml of anhydrous tetrahydrofuran and cool the solution to -15°C. Next, triethylamine, 8.4 ml (0.06 mol) and subsequently in 20 ml of anhydrous tetrahydrofuran , 6.1 ml (66 mmol) of ethyl chloroformate are added. then before In 20 ml of anhydrous tetrahydrofuran, L-proline benzyl ether obtained in step Add the solution of Stell base. The reaction mixture was heated to -15°C for 30 minutes and then Stir for 1 hour at room temperature, then pour it onto 400 ml of water and dichloromethane. Extract by. The organic layer was first washed with 596 sodium carbonate solution and then with water. and finally with saturated sodium chloride solution. The organic layer was immersed in anhydrous sulfuric acid. Dry over Si and evaporate the solvent. The residue was crystallized with petroleum ether. , and recrystallized from a mixture of acetone-〇-hexane.

Yield: 12.0g (4896) M, p,: 95-96°C [α), ts: 411’ (c=I, chloroform).

Example 7 N-[4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)- 2(E)-Butenoyl]-β-alanine ethyl ester 4-oxo-4-(5, 2.3 g of 6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoic acid ( 0.01 mol) and β-alanine ethyl ester hydrochloride 1.53 g (0.01 mol) mol) in 50 ml of anhydrous dichloromethane and cooled to 0°C. Next 1. N-methyl-morpholine in 20 ml of anhydrous dichloromethane. Olg (0 ,01 mol) and finally 2.06 g of dicyclohexylcarbodiimide (0,01 mol) 01 mol) is added to the suspension. The reaction mixture was heated at 0 °C for 1 h and room temperature. Heat and stir for 1 hour.

Filter the precipitated dicycloquinurea and transfer the filtrate to the following solvents in order: Extract with: IN hydrochloric acid, water, saturated sodium carbonate solution and finally sodium chloride. um solution. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated.

The residue is crystallized by addition of diethyl ether.

Yield: 1.3g (4196) M, p,: 112~+14°C Example 8 N-[4-oxo-4-(3,6,7,8-tetrahydro-2-naphthyl)- 2(E)-Butenoyl]-6-aminohexanoic acid ethyl ester 4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E )-butenoic acid 2.3 g (0.01 mol) and ethyl 6-aminohexanoate 1.95 g (1.01 mol) of ester was suspended in 60 ml of anhydrous dichloromethane, It was then cooled to 0°C. This mixture was first added in 20ml of anhydrous dichloromethane. , N-methylmorpholine 1. A solution of Olg (0.01 mol), then to dicyclo 2.06 g (0.01 mol) of xylcarbodiimide are added. the reaction mixture Stir for 1 hour at 0°C and 1 hour at room temperature. Precipitated dicyclohexyl Filter the urea and extract the filtrate with the following solutions in the order listed = IN Hydrochloric acid, water, saturated sodium carbonate solution and finally saturated sodium chloride solution. organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. Convert the residue into diethyl Crystallize from a mixture of ether and n-hexane.

Yield: 1.48g (40%) M, p, near 4-76°C.

Example 9 N-[4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)- 2(E)-Butenoyl)-L-phenylalanine methyl ester L-phenylalanine methyl ester hydrochloride 4.3 g (0.02 mol) and 4 -oxo-4-(5,6,7,8-tetrahydro-2-naphthyl')-2(E )-butenoic acid (4.6 g (0.02 mol)) was suspended in 80 ml of anhydrous dichloromethane. Cloudy and cooled to 0°C. To this mixture, in 30 ml of anhydrous dichloromethane, A solution of 2.03 g (0.02 mol) of N-methylmorpholine, then to dicyclo- 4.12 g (0.02 mol) of xylcarbodiimide are added. the reaction mixture Stir for 1 hour at 0°C and 1 hour at room temperature. Precipitated dicyclohexyl The urea is filtered and the filtrate is extracted with the following solutions in the following order: 1N hydrochloric acid, water, saturated sodium carbonate solution and finally saturated sodium hydrochloride solution.

The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. evaporation residue crystallized from diethyl ether and ethyl acetate and diethyl ether Recrystallize from a mixture of

Yield: 3.7g (47%) M, I): 145~+47°C [α),”: −22,5° (C=1, methanol).

Example 10 1-(N-(4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl )-2(E)-Butanoyl)-L-broyl]-4-ethoxyluponylbivera gin Oily N-(4-year-old xo-4-(5, 6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl)-L-propylene 6.5 g of Lorin was dissolved in 150 ml of anhydrous dichloromethane, cooled to 0°C, Next, 3.16 g (0.02 mol) of 1-ethoxycarbonylpiperazine and the catalyst of 4-dimethylaminopyridine. Add anhydrous dichloromethane to this mixture. Dicyclohexylcarbodiimide 4.54g (22mmol) in 20mj' Add under constant stirring.

The reaction mixture is stirred at room temperature for 24 hours. Precipitated dicyclohexyl urea Filter and wash with dichloromethane. Add the organic layer to the next solution in this order. Extract with: IN hydrochloric acid, water, 10% sodium carbonate solution, water and finally, Saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. and evaporate the solvent. The resulting oil was diluted with diethyl ether and isopropyl ether. Recrystallize from the Patur mixture.

Yield: 5.1g (55%) M, l): 110-112℃ [α) o”: +9.2° (C21, chloroform).

Preparation of starting materials a) N-(4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl) -2(E)-butenoyl)-L-proline t-butyl ester L-proline t-butyl ester oxacy) 5.23 g (0.02 mol) , suspended in 50 ml of dichloromethane, and the mixture was heated until the solution became clear. by a solution of 2.76 g (0.02 mol) of potassium carbonate in 50 ml of water until Extract. The organic layer is separated, dried over anhydrous sodium sulfate and evaporated.

Yield: 3.7 g of Shi-proline t-butyl ester.

4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E )-butenoic acid (4.6 g (0.02 mol)) in anhydrous tetrahydrofuran 50- and add 2.8 d (0.02 mol) of triethylamine. So The reaction mixture was cooled to -15°C and then evaporated into A solution of 2.01+d (22 mmol) of methyl chloroformate is added and the Then, in 20% of anhydrous tetrahydrofuran, 3.7% of L-proline t-butyl ester g (22 mmol) of the above prepared solution are added. The reaction mixture is -1 Stir for 30 minutes at 5°C and 30 minutes at room temperature, then pour it onto 200+1' of water. Pour and extract with dichloromethane. The organic layer was washed with the following solutions in the following order: Extract: 5% sodium carbonate solution, saturated sodium chloride solution and finally water. Yes The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue is petroleum Crystallizes on addition of ether.

Yield + 3.89g (5196) M, p,: 95-98°C [α) o”: 81.2° (c=0.5.chloroform).

b) 1-(N-benzyloxycarbonyl-shi-broyl)-4-ethoxycal Bonyl-piperazine N-benzyloxycarbonyl-proline 12.45g (0.05 mol) as well as! -Ethoxycarbonyl-piperazine 7.91 g (0.05 mol) Dissolved in 150 ml of aqueous dichloromethane, cooled to +5°C, then anhydrous dichloromethane. In 50ml of tank, 11.35g of dicyclohexylcarbodiimide (55mmol ) solution. The mixture was stirred at room temperature for 24 hours and the precipitated dicyclo Filter the hexylurea and extract the filtrate with the following solutions in the following order: IN of hydrochloric acid, water, 10% sodium carbonate solution and finally water. The organic layer was soaked in anhydrous sulfuric acid magne. Dry over silicon and evaporate the solvent. The product crystallizes upon refrigeration Begin to. The white crystals are filtered and washed with cold diethyl ether.

Yield: 14. og (72%) M, p,: 90.5-92℃ [α]. ”Knee 11.4° (c=1, methanol).

c) l-L-broyl-4-ethoxyluponylbiverazine I prepared above -(N-benzyloxycarbonyl-shi-broyl)-4-ethoxycarbonyl Dissolve 7.4 g (19 mmol) of piperazine in anhydrous methanol + 5 (W) and The solution is then subjected to hydrogenation for 2 hours in the presence of a Pd--C catalyst. the solution , after removal of the catalyst, yield: 4.7 g (96.9%) Special Table Sen7-502039 (7) Continuation of front page (51) rnt, C1,' Identification symbol Internal office reference number CO7D 295/1 8 A 8217-4C (72) Inventor Ezer, Elemer Hungary, 1026 Budapest, Lepegne Utsa 6-8゜ (72) Inventor: Fischel, János Hungarian State, 1111 Buda Pesto, Partok Bela Woot 32° (72) Inventor: Hayos, Gyurzy, Hungary, 1026 Budapest , Garpol Aaron Uzza 59゜ I (72) Inventor Mattousz, Judith Hungary, 1025 Budapest , Oezguida Uzza 32° (72) Inventor Marbanjos, Edehungary, 1139 Budapé Stroke, Beketail 5゜ (72) Inventor Sergei, Katalin Hungary, 1082 Budapest, Illoej Ut 60-62. ’ (72) Inventor: Sporgne, László, Hungary, 1114 Budapest To, Saborčka M, Uzza 7゜

Claims (9)

[Claims] 1. The following general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1 represents a hydrogen atom; R2 represents a hydrogen atom, C1-4 alkoxycarbolalkyl or benzyl group or R1 and R2 together represent a group represented by the formula -(CH2)3-; R3 is hydroxy, C1-4 alkoxy or benzyloxy group, or the following general formula (A): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(A) (Here, R5 is a C1-4 alkyl group n is 0, 1, 2, 3 or 4]; and pharmaceutically acceptable salts thereof. 2. A compound of general formula (I) according to claim 1, i.e. 4-oxo-4- (5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl-L -Proline ethyl ester, N-[4-oxo-4-(5,6,7,8-tetra Hydro-2-naphthyl)-2(E)-butenoyl]-L-proline zinc salt tetrahydrate N-[4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl) -2(E)-butenoyl]-D-aspartic acid diethyl ester, 1-[N- (4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E )-butenoyl)-L-proyl]-4-ethoxycarbonylpiperazine, N- [4-oxo-4-(5,6,7,8-tetrahydro-2-naphthyl)-2(E )-butenoyl]-L-proline benzyl ester, N-[4-oxo-4-( 5,6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoyl]-β -alanine ethyl ester, N-[4-oxo-4-(5,6,7,8-tetra Ethyl hydro-2-naphthyl-2(E)-butenoyl]-6-aminohexanoate ester, N-[4-oxo-4-(5,6,7,8-tetrahydro-2-na phthyl)-2(E)-butenoyl]-L-phenylalanine methyl ester Compounds selected. 3. As an active ingredient, general formula (I) according to claim 1: [wherein, R1 represents a hydrogen atom; R2 represents a hydrogen atom, C1-4 alkoxycarbonylalkyl or benzyl group or R1 and R2 together represent a group represented by the formula -(CH2)3-; R3 is hydroxy, C1-4 alkoxy or benzyloxy group, or the general formula (A ): (Here, R5 is a C1-4 alkyl group); n is 0, 1, 2, 3 or 4], and a tetrahydronaphthalene derivative represented by a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and/or excipient. A pharmaceutical composition comprising. 4. Mammals (including humans) with various inflammations and ulcers of the trachea, stomach and duodenum for treatment and/or prophylactic purposes, comprising a therapeutically effective amount of General formula (I) described in box 1: [wherein, R1 represents a hydrogen atom; R2 represents a hydrogen atom, C1-4 alkoxycarbonylalkyl or benzyl group or R1 and R2 together represent a group represented by the formula -(CH2)3-; R3 is hydroxy, C1-4 alkoxy or benzyloxy group, or the general formula (A ): (Here, R5 is a C1-4 alkyl group); n is 0, 1, 2, 3 or 4], and a tetrahydronaphthalene derivative represented by Pharmaceutically acceptable salts thereof, in the form of pure substances or containing them as active ingredients A method comprising administering as a pharmaceutical composition. 5. The following general formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R1 represents a hydrogen atom; R2 represents a hydrogen atom, C1-4 alkoxycarbonylalkyl or benzyl group or R1 and R2 together represent a group represented by the formula -(CH2)3-; R3 is hydroxy, C1-4 alkoxy or benzyloxy group, or the following general formula (A): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(A) (Here, R5 is a C1-4 alkyl group n is 0, 1, 2, 3 or 4]; A method for preparing a tetrahydronaphthalene derivative and a pharmaceutically acceptable salt thereof. Therefore, the following general formula II: ▲There are mathematical formulas, chemical formulas, tables, etc.▼4-oxo-4-(5 , 6,7,8-tetrahydro-2-naphthyl)-2(E)-butenoic acid activation inducer Conductor and the following general formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, R1 and R2 are as shown above. and R4 is a C1-4 alkoxy or benzyloxy group, or a formula A ( where R5 represents a C1-4 alkyl group) react with an amino acid derivative; and Optionally, the general formula (I) (wherein R1 and R2 are as described above and R 2 represents a t-butyloxy group) is subjected to acidolysis. and/or optionally, general formula (I) (wherein R1 and R2 are as described above) and R3 represents a hydroxy group) and a piperazine derivative containing a group of formula A (where R5 is as above) or the compound of general formula (I) is reacted with an inorganic conductor. or a method comprising conversion into a salt with an organic base. 6. The carboxy group is preferably removed by a carbodiimide type reagent or a mixed 6. The method of claim 5, comprising in situ activation by an anhydride process. 7. Applying 1-ethoxycarbonylpiperazine as a piperazine derivative 6. The method of claim 5, comprising: 8. converting the carboxylic acid into an alkali metal, alkaline earth metal or zinc salt; 6. The method of claim 5, comprising: 9. A method for preparing a pharmaceutical composition comprising the general formula (I): R1 represents a hydrogen atom; R2 represents a hydrogen atom, C1-4 alkoxycarbonylalkyl or benzyl group or R1 and R2 together represent a group represented by the formula -(CH2)3-; R3 is hydroxy, C1-4 alkoxy or benzyloxy group, or the general formula (A ): (Here, R5 is a C1-4 alkyl group); n is 0, 1, 2, 3 or 4], and a tetrahydronaphthalene derivative represented by a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier and/or excipient. A method comprising mixing and converting the same into a pharmaceutical composition.