KR100786315B1 - Phenylethanolaminotetralincarboxamide derivatives - Google Patents

Abstract

The present invention has a selective β ₂ -adrenergic receptor stimulating action to reduce the burden on the heart, such as tachycardia, Formula 1

(Formula 1)

(Wherein A is a lower alkylene group, B is an amino group, a lower alkylamino group or a 3-7 membered alicyclic amino group which may contain an oxygen atom in the ring, and the carbon atom with * is a carbon atom of R or S configuration) Or phenylethanolaminotetralinecarboxylic acid amide derivatives thereof represented by a carbon atom to which they are mixed and a carbon atom with (S) represents a carbon atom of S configuration), and a pharmacologically acceptable salt thereof. It is useful as an anti-acid, bronchodilator, or pain relief agent for urolithiasis.

Description

Phenylethanolamino tetralin carboxylic acid amide derivative {PHENYLETHANOLAMINOTETRALINCARBOXAMIDE DERIVATIVES}

The present invention relates to novel phenylethanolaminotetralinecarboxylic acid amide derivatives useful as pharmaceuticals.

In more detail, the present invention has a selective β ₂ -adrenergic receptor stimulating action in which the burden on the heart, such as tachycardia, has been alleviated.

(Wherein A is a lower alkylene group, B is an amino group, a lower alkylamino group, or a 3-7 membered alicyclic amino group which may contain an oxygen atom in the ring, and the carbon atom with * is a carbon atom of R or S configuration) Or a phenylethanolaminotetralinecarboxylic acid amide derivative represented by the above, which represents a mixed carbon atom, and a carbon atom with (S) represents a carbon atom of the S configuration) and pharmacologically acceptable salts thereof.

Substituted phenylethanolaminotetraline derivatives having, for example, long-acting sympathetic stimulation and anti-urinary action

Wherein R ^a is a hydrogen atom or an ethyl group, Y is a hydrogen atom or a chlorine atom, a hydrochloride or oxalate thereof or a mono-isomer thereof

A compound represented by (wherein, a carbon atom with (R) represents a carbon atom of R configuration, and a carbon atom with (S) represents a carbon atom of S configuration) is disclosed (Japanese Patent Publication No. H6-6-676676, H6). -506955). These compounds, however, a remarkable β ₃ - adrenoceptor stimulation is about - β ₃ adrenergic receptor has a stimulating effect.

Disclosure of the Invention

The compound of the present invention, Formula 1

(Formula 1)

(Wherein A is a lower alkylene group, B is an amino group, a lower alkylamino group, or a 3-7 membered alicyclic amino group which may contain an oxygen atom in the ring, and the carbon atom with * is a carbon atom of R or S configuration) Or a phenylethanolaminotetralinecarboxylic acid amide derivative represented by the above, which represents a mixed carbon atom, and a carbon atom with (S) represents a carbon atom of the S configuration) and pharmacologically acceptable salts thereof.

The present invention relates to a medicament comprising the phenylethanolaminotetralinecarboxylic acid amide derivative or a pharmacologically acceptable salt thereof.

The present invention relates to the pain of urges, premature birth inhibitors, bronchodilatants, urolithiasis, containing the phenylethanolaminotetralinecarboxylic acid amide derivatives or pharmacologically acceptable salts thereof as an active ingredient.疼痛) It relates to a laxative or stone stone accelerator.

The present invention provides a method for preventing urges and preterm birth, airway obstructive disorder, and bronchiostenosis disorder by administering the phenylethanolaminotetralinecarboxylic acid amide derivative or pharmacologically acceptable salt thereof. The present invention relates to a method for preventing and treating urinary tract stones and for promoting pain relief.

The present invention provides a phenylethanolamino tetralincar for the preparation of a preparation for the prevention of urges, premature birth, airway obstructive disorder, bronchial stenosis disorders, pain relief of urolithiasis or promotion of stones. Amide acid derivatives or pharmacologically acceptable salts thereof.

Furthermore, the present invention relates to the use of the phenylethanolaminotetralinecarboxylic acid amide derivative or the pharmacologically acceptable salt thereof as a scab, antiacid, bronchodilator, urinary tract stones or pain relief agent.

Implement the invention  for Best  shape

The present inventors have diligently studied to find an excellent β ₂ -adrenergic receptor stimulant, and as a result, the phenylethanolaminotetralinecarboxylic acid amide derivative of the species represented by the formula (1) is a strong and selective β ₂ -adrenergic receptor. It has been found to have a stimulating action and is very useful as a β ₂ -adrenergic receptor stimulant, thus completing the present invention.

That is, the present invention is _one β-adrenergic receptor has a stimulating effect, the reduction of β ₂ of the burden to the heart, such as a tachycardia-adrenergic receptor stimulating effect β ₂ with high selectivity in comparison with the adrenergic receptor stimulating effect, the formula (1)

(Formula 1)

(Wherein A is a lower alkylene group, B is an amino group, a lower alkylamino group, or a 3-7 membered alicyclic amino group which may contain an oxygen atom in the ring, and the carbon atom with * is a carbon atom of R or S configuration) Or a phenylethanolaminotetralinecarboxylic acid amide derivative represented by the above, which represents a mixed carbon atom, and a carbon atom with (S) represents a carbon atom of the S configuration), and pharmacologically acceptable salts thereof.

Here, in the compound represented by the formula (1) of the present invention, as the lower alkylamino group, di-substituted with a linear or branched alkyl group having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group and isopropyl group For example, amino groups, such as a dimethylamino group, a diethylamino group, and an ethylmethylamino group, are mentioned. Moreover, as a lower alkylene group, it is a C1-C3 linear alkylene group of a methylene group, an ethylene group, and a trimethylene group, and as a 3-7 membered alicyclic amino group which may contain an oxygen atom, it is 1-. A pyrrolidinyl group, a piperidine group, a morpholino group, etc. are mentioned.

The compound represented by Chemical Formula 1 of the present invention may be prepared as follows.

For example, Formula 2

An amino compound represented by the following formula (wherein R is a lower alkyl group and the carbon atoms to which A and (S) are attached has the same meaning as described above).

After N-alkylation using an alkylating agent represented by formula R ⁰ is a protecting group of a hydroxyl group and X is a halogen atom, reduction is carried out according to a conventional method, and if desired, the protecting group of a hydroxyl group is removed,

Wherein R ¹ is a hydrogen atom or a protecting group of a hydroxyl group, and the carbon atoms with A, R and (S) have the same meaning as above.

B-H

It can be manufactured by amidating according to a conventional method using the amino compound represented by (wherein B has the same meaning as above), and removing the protecting group of the hydroxyl group if necessary.

In addition, the compound represented by the formula (1) of the present invention, formula (6)

The amino compound represented by the above formula (A, B and (S) carbon atoms have the same meaning as described above) is subjected to N-alkylation using an alkylating agent represented by the above formula (3), followed by reduction according to a conventional method. And it can manufacture by removing the protecting group of a hydroxyl group further.

Furthermore, the compound represented by the formula (1) of the present invention, formula (7)

A mandelic acid derivative represented by the formula (R ⁰ has the same meaning as described above),

The amino compound represented by the formula (S) having the same meaning as described above has the same meaning as described above.

After obtaining a compound represented by the formula (carbon atoms with R ° and (S) in the above meaning), it is reduced by using a reagent such as boranedimethylsulfide complex,

(The carbon atom with R ° and (S) in the formula has the same meaning as described above), and if desired, after protecting the alcoholic hydroxyl group and amino group using a reagent such as anhydrous trifluoroacetic acid , Formula 11

X-A-COB

It can be manufactured by performing O-alkylation of a phenolic hydroxyl group using the alkylating agent represented by Formula (A, B, and X have the same meaning as the above), and removing a protecting group again.

The amino compounds represented by the formulas (2) and (8) used as starting materials in the production method can be produced by methods described in the literature or by methods similar thereto (for example, Eur. J. Med. Chem., 29, pp. 259-267. 1994; Japanese Patent Laid-Open No. 3-14548).

The compound represented by the formula (3) used as the starting material in the production method is, for example, according to a known method described in the literature or a method similar thereto,

The ketone compound represented by (wherein R ² is a suitable protecting group of a hydroxyl group in the above reaction) can be prepared by halogenating using a halogenating agent and, if desired, exchanging with a protecting group of another hydroxyl group (Bull. Chem. Soc. Jpn., Vol. 65, pp. 295-297 (1992); Synthesis, 7, pp. 545-546 (1988); Synthesis, 12, pp. 1018-1020 (1982) et al.

The amine compound represented by the formula (6) used as a starting raw material in the production method is represented by the formula (13)

(Wherein R ³ is a protecting group of an amino group, and the carbon atom with (S) has the same meaning as described above), after O-alkylation of the phenolic compound represented by the above-described general formula (11) After removing the protecting group or protecting the amino group of the amine compound represented by Chemical Formula 2 using a suitable reagent, the amine compound represented by Chemical Formula 5 may be induced into a free carboxylic acid or a reactive sensory derivative thereof as desired. It can be prepared by using amidation reacted in the presence or absence of a condensation agent and removing the protecting group of the amino group.

In the compound represented by the formula (1) of the present invention, the monoisomer is, for example, fractionated recrystallization of the diastereomer-mixture obtained by the above-described method by a conventional method, or

An optically active mandelic acid derivative represented by formula (C) wherein (R) is a carbon atom of R configuration, and R ° has the same meaning as described above

Wherein the optically active mandelic acid derivative represented by (wherein the carbon atom with R ° and (S) has the same meaning) and the amine compound represented by the formula (8) are reacted in the presence of a condensing agent,

A homoisomer represented by formula (17) having the same meaning as described above, wherein the carbon atom with R ° and (R) and the carbon atom with (S)

After obtaining the monoisomer represented by (the carbon atom to which R ° and (S) are attached) has the same meaning as above, it is reduced by using a reagent such as boranedimethylsulfide complex and formula (18).

Or a compound represented by the following formula (19), wherein the carbon atom with R ° and (R) and the carbon atom with (S) have the same meaning

(The carbon atom with R ° and (S) in the formula has the same meaning as described above). A compound prepared by protecting a alcoholic hydroxyl group and an amino group using a reagent such as anhydrous trifluoroacetic acid Thereafter, the alkylating agent represented by the above formula (11) can be used to carry out 0-alkylation of the phenolic hydroxyl group, followed by removal of the protecting group.

In the compound represented by the formula (1) of the present invention, the monoisomer is separated into a diastereomer-mixture prepared as a manufacturing intermediate in the above production method into a monoisomer corresponding to column chromatography or fractional recrystallization. Then, it can be prepared by reacting in the same manner using the homoisomer.

The mandelic acid derivatives represented by the above formulas (7), (14) and (15), which are used as starting materials in the above production method, can be obtained, for example, by manufacturing according to a method described in the literature or a method similar thereto.

The bromine represented by the formula (R ° has the same meaning as described above) is reacted with diethyl oxalate, and the resulting phenylglyoxylic acid derivative is reduced with a reagent such as sodium borohydride, and then the ester compound is After decomposing to obtain a mandelic acid derivative represented by the formula (7), it can be prepared by optical separation by a conventional method using a splitting reagent such as optically active 1-phenylethylamine as desired.

The compound of the present invention obtained by the above production method can be easily isolated and purified by a fractional recrystallization method, conventional purification means using column chromatography, a solvent extraction method, and the like.

The phenylethanolaminotetralinecarboxylic acid amide derivative represented by the formula (1) of the present invention can be used as its pharmacologically acceptable salt by a conventional method. Such salts include acid addition salts of mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid and citric acid. Inorganic bases such as acid addition salts, sodium salts and potassium salts with organic acids such as succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid and aspartic acid Examples of salts are as follows. Their salts also have pharmacological activity in the same form as the free-body.

Moreover, the compound represented by the said General formula (1) of this invention also includes the solvate of hydrate and the solvent which is accept | permitted as pharmaceuticals, such as ethanol.

In the compound represented by the formula (1) of the present invention, two kinds of isomers of a compound having an R group and a compound having an S configuration are present in the present invention. It may be a mixture of these isomers.

Compounds represented by the formula (1) of the present invention in the in vitro β ₂ -adrenergic receptor stimulation measurement test using a conventionally extracted uterine uterus of rats, respectively, at 5.0 X 10 ^-9-5.0 X 10 ^-6 molar concentration, respectively, In the automatic movement of smooth muscle, it showed the effect of relaxing 50% of its contraction (EC ₅₀ value). For example, 2-[(2S) -2-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene- 7-yloxy] -N, N-dimethylacetamide showed an EC ₅₀ value at a 1.5 × 10 ⁻⁸ molar concentration. As described above, the compound of the present invention has an excellent strong β ₂ -adrenergic receptor stimulating action and is excellently useful as a β ₂ -adrenergic receptor stimulant.

The compound represented by the formula (1) of the present invention, in vitro β ₁ -adrenergic receptor stimulation measurement test using a conventional extraction of atrial rats, the automatic movement of atrial smooth muscle at a molar concentration of 1.0 X 10 ^-6 or more, respectively Showed an effect of increasing the heart rate 20 times per minute (EC ₂₀ value). For example, 2-[(2S) -2-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene- 7-yloxy] -N, N-dimethylacetamide showed an EC ₂₀ value at 1.6 × 10 ⁻⁶ molarity. As such, the compound of the present invention is a compound having a significantly weaker β ₁ -adrenergic receptor stimulation compared to the β ₂ -adrenergic receptor stimulating action.

Thus, the compounds of the invention significantly strong β ₂ - have a adrenergic receptor stimulating effect, at the same time β ₁ - shows the adrenergic receptor stimulating effect, β ₁ - - adrenoceptor stimulation remarkably selective high β ₂ as compared with the action of adrenaline It is a remarkably useful selective β ₂ -adrenergic receptor stimulant which suppresses adverse effects on the heart such as tachycardia in which receptor stimulation is exhibited and reduces the burden on the heart.

The present invention is a selective β ₂ -adrenergic receptor stimulant, urgency, premature birth, bronchodilators (airway obesity growth, prevention and treatment of diseases caused by bronchial stenosis disorder), pain relief or urinary stones of urolithiasis, etc. As a compound, it is remarkably useful.

Moreover, the compound represented by the said Formula (1) of this invention is a remarkably stable compound, and is excellent in storageability.

When the phenylethanolaminotetralinecarboxylic acid amide derivative represented by the formula (1) of the present invention or a pharmacologically acceptable salt thereof is used in the actual treatment, a suitable pharmaceutical composition, for example, a tablet, a powder, a granulating agent It may be administered orally or parenterally, in the form of granules, capsules, injections and the like. These pharmaceutical compositions can be prepared by using a pharmaceutical carrier, an excipient, and other additives which are usually used by a pharmaceutical method performed in general preparation.

The dosage is appropriately determined by the sex, age, weight, and the sum of symptoms of the subjects, but in the case of oral administration, 1-1000 mg per day for each adult, and for parenteral administration, 0.01-100 mg per day for each adult. It is in the range of and is administered once or divided into several.

The content of the present invention will be described in more detail with reference to the following reference examples, examples and test examples, but the present invention is not limited thereto. In addition, melting | fusing point of the compound of a reference example and an Example is completely uncorrected value.

Reference Example 1

2-[(2S) -2-[[(2RS) -2-hydroxy-2- (4-hydroxyphenyl) ethyl) amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy ] Ethyl acetate

860 mg of 2-bromo-4'-hydroxyacephenone was dissolved in 20 ml of methylene chloride, and 550 µl of 3,4-dihydro-2H-pyran and 100 mg of p-toluenesulfonic acid pyridinium were added with stirring at room temperature for 17 hours. I was. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel pressure liquid column chromatography- (elution solvent: hexane / ethyl acetate = 10/1), and 2-bromo-4 '-((2RS) -2-tetrahydro at melting point 102-104 占 폚. 1.01 g of pyranyloxy) acetphenone was obtained.

Dissolve 1.14 g of (S)-(2-amino-1,2,3,4-tetrahydronaphthalene-7-yloxy) ethyl acetate in 15 ml of N, N-dimethylformamide and 2-bromo under ice-cooled stirring 600 mg of -4 '-((2RS) -2-tetrahydropyranyloxy) acephenone was added and then reacted at room temperature for 1 hour. 380 mg of sodium borohydride and 10 ml of ethanol were added to the reaction mixture under ice-cooling stirring, and the mixture was allowed to react for 1 hour. The reaction solution was poured into ice water, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml of tetrahydrofuran, 2 ml of triethanolamine was added, and the mixture was heated to reflux for 17 hours. After cooling, water was added to the reaction solution, extraction was performed with ethyl acetate, and the mixture was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel-liquid liquid column chromatography (elution solvent: ethyl acetate) to give the oily 2-[(2S) -2-[[(2RS) -2-hydroxy- 780 mg of 2- [4- (2RS) -2-tetrahydropyranyloxy) phenyl] ethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy] ethyl acetate were obtained.

IR (neat): 3304, 1760 cm ^-1

2-[(2S) -2-[[(2RS) -2-hydroxy-2- [4- (2RS) -2-tetrahydropyranyloxy) phenyl] ethyl] amino] -1,2,3, 780 mg of 4-tetrahydronaphthalene-7-yloxy] ethyl acetate was dissolved in 20 ml of ethanol, and 34 ml of 1 normal hydrochloric acid was added thereto under ice-cooled stirring, followed by reaction for 1 hour. An aqueous sodium hydrogencarbonate solution was added to the reaction solution to neutralize it, followed by extraction with ethyl acetate, followed by washing with water, followed by drying over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel-liquid liquid column chromatography (eluent: ethyl acetate) to obtain an amorphous 2-[(2S) -2-[[(2RS) -2- 238 mg of hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1, 2,3,4-tetrahydronaphthalen-7-yloxy] ethyl acetate were obtained.

IR (Film): 3294, 1754 cm ^-1

Reference Example 2

4-[(2S) -2-[[(2RS) -2- (4-benzyloxyphenyl) -2-hydroxyethyl) amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy ] -N, N-dimethylbutyric acid amide

400 mg of (S) -2- (tert-butoxycarbonylamino) -7-hydroxytetraline was dissolved in 8 ml of N, N-dimethylformamide, 3.16 g of cesium carbonate and 4-bromobutyrate under room temperature stirring 650 µl was added and reacted for 1.5 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel-liquid liquid column chromatography (elution solvent: hexane / ethyl acetate = 1/1), and (S) -4- [2- ( 488 mg of tert-butoxycarbonylamino) -1,2,3,4-tetrahydronaphthalen-7-yloxy] butyric acid ethyl was obtained.

988 mg of ethyl (S) -4- [2- (tert-butoxycarbonylamino) -1,2,3,4-tetrahydronaphthalen-7-yloxy) butyrate was mixed with a mixed solution of 15 ml of ethanol and 15 ml of methanol. It dissolved, 3.0 ml of 2-normal sodium hydroxide aqueous solution was added under room temperature stirring, and it was made to react for 2 hours. The reaction solution was concentrated under reduced pressure, 10% aqueous citric acid solution was added to the residue, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and (S) -4- [2- (tert-butoxycarbonylamino) -1,2,3,4-tetrahydronaphthalen-7-yloxy] butyric acid had a melting point of 150-153 占 폚. 914 mg was obtained.

Dissolve 399 mg of (S) -4- [2- (tert-butoxycarbonylamino) -1,2,3,4-tetrahydronaphthalene-7-yloxy] butyric acid in 5 ml of tetrahydrofuran and stir with ice-cooling 204 mg of N, N'-carbonyldiimidazole was added thereto and reacted for 2 hours. Under ice-cooled stirring, a 2 ml solution of 1.40 g of dimethylamine tetrahydrofuran was added to the reaction mixture, and the mixture was allowed to react for 45 minutes, followed by 45 minutes at room temperature. The reaction solution was concentrated under reduced pressure, water was added to the residue, the mixture was extracted with diethyl ether, washed sequentially with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and (S) -4- [2- (tert-butoxycarbonylamino) -1,2,3,4-tetrahydronaphthalen-7-yloxy]-at a melting point of 97-101 ° C. 396 mg of N, N-dimethylbutyric acid amide was obtained.

(S) -4- [2- (tert-butoxycarbonylamino) -1,2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylbutyamide 396 mg 5 ml methylene chloride It was dissolved in the solution, and 5 ml of a methylene chloride solution of 5 ml of trifluoroacetic acid was added under ice-cooled stirring, stirred for 15 minutes, and then reacted at room temperature for 15 minutes. After the reaction solution was concentrated under reduced pressure, methylene chloride, water and sodium hydrogencarbonate were added to the residue, the mixture was stirred at room temperature for 30 minutes, the organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 263 mg of an oily (S) -4- (2-amino-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N, N-dimethylbutyric acid amide.

IR (pure substance): 3404, 1618 cm ^-1

196 mg of (S) -4- (2-amino-1,2,3,4-tetrahydronaphthalen-7-yloxy) -N, N-dimethylbutyric acidamide and 270 μl of triethylamine were added to N, N-dimethyl It was dissolved in 3 ml of formamide, and a solution of 1 ml of 4'-benzyloxy-2-bromoacephenone 195 mg of N, N-dimethylformamide was added thereto under ice-cooled stirring, and reacted for 15 minutes. Under ice-cooled stirring, 240 mg of sodium borohydride and 3 ml of ethanol were added to the reaction mixture, and the mixture was allowed to react for 2 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, and washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, 5 ml of a tetrahydrofuran solution of 200 mg of triethanolamine was added to the residue, and the mixture was heated to reflux for 16 hours. After cooling, water was added to the reaction solution, extraction was performed with ethyl acetate, and the mixture was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel-liquid liquid column chromatography (elution solvent: ethyl acetate / ethanol = 6/1) to obtain amorphous 4-[(2S) -2-[[(2RS) 85 mg of 2- (4-benzyloxyphenyl) -2-hydroxyethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylbutyamide was obtained.

IR (Film): 3348, 1639 cm ^-1

Reference Example  3

2-[(2S) -2-[[(2R) -2- (4-benzyloxyphenyl) -2-hydroxyethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy ] -N, N-dimethylacetamide

2.02 g of (R) -4-hydroxymandelic acid was dissolved in 24 ml of N, N-dimethylformamide, and 3.57 ml of benzyl bromide and 3.65 g of potassium carbonate were added and reacted for 12 hours under room temperature stirring. Ice-water was added to the reaction solution, and the precipitated crystals were filtered off. The obtained crystals were suspended in 24 ml of methanol, 12 ml of 1 normal sodium hydroxide solution was added thereto under ice-cooled stirring, and the mixture was allowed to react at room temperature for 2 hours. 12 ml of 1 normal hydrochloric acid was added to the reaction solution under ice-cooling stirring, and the precipitated crystals were collected by filtration to obtain 2.43 g of (R) -4-benzyloxymandelic acid having a melting point of 161-163 ° C.

2.43 g of (R) -4-benzyloxymandelic acid, 2.87 g of (S) -2-amino-7-hydroxytetraline hydrobromide and 2.88 ml of triethylamine were dissolved in 38 ml of methylene chloride and stirred at room temperature. 4.58 g of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate was added and reacted for 15 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed sequentially with water, 1 normal hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel-liquid liquid column chromatography (elution solvent: chloroform / ethyl acetate = 1/1), and then recrystallized by ethyl acetate-hexane, and the melting point was 137-139 ° C ( 2R) -2- (4-benzyloxyphenyl) -2-hydroxy-N-((2S) -7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl) acetamide 3.48 g Got.

(2R) -2- (4-benzyloxyphenyl) -2-hydroxy-N-((2S) -7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl) acetamide 605 Mg was dissolved in 7.5 ml of tetrahydrofuran, 2.25 ml of a 2 molar concentration borane dimethyl sulfide complex tetrahydrofuran solution was added under room temperature stirring, and the mixture was heated and refluxed for 3 hours. Then, 2.5 ml solution of 1.12 g of tetraethanolamine was added thereto. Then, the mixture was heated to reflux for 15 hours. After cooling, water was added to the reaction solution, extraction was performed with ethyl acetate, and the mixture was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from ethyl acetate and (1R) -1- (4-benzyloxyphenyl) -2-[((2S) -7-hydroxy- at a melting point of 132-134 ° C. 350 mg of 1,2,3,4-tetrahydronaphthalen-2-yl) amino] ethanol was obtained.

(1R) -1- (4-benzyloxyphenyl) -2-[((2S) -7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl) amino] ethanol 350 mg and N 0.78 mL of, N-diisopropylethylamine was added to 3.6 mL suspension of methylene chloride, 0.38 mL of trifluoroacetic anhydride was added to the mixture under stirring at -15 ° C, and allowed to react for 30 minutes. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 4.5 ml of N, N-dimethylformamide, 350 mg of powdered molecular sieve 4A, 0.11 ml of 2-bromo-N, N-dimethylacetamide and 880 mg of cesium carbonate were added and stirred for 2 hours at room temperature. After that, 0.11 ml of diethylamine was added again and allowed to react for 20 minutes at room temperature. 3.5 ml of water and 3.5 ml of methanol were added to the reaction solution, and the mixture was stirred at room temperature for 1.5 hours. Then, saturated brine was added, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by aminopropylated silica gel under reduced pressure column chromatography (eluent: chloroform / methanol = 50/1) to obtain amorphous 2-[(2S) -2-[[( 2R) -2- (4-benzyloxyphenyl) -2-hydroxyethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylacetamide Got it.

Reference Example  4

In the reaction shown in Reference Example 3, 1-bromoacetylpiperidine or 4-bromoacetylmorpholine instead of 2-bromo-N, N-dimethylacetamide was used for reaction and treatment as in Reference Example 3. The following compound was obtained.

1- [2-[(2S) -2-[[(2R) -2- (4-benzyloxyphenyl) -2-hydroxyethyl] amino] -1,2,3,4-tetrahydronaphthalene-7 -Yloxy] acetyl] piperidine

Amorphous

4- [2-[(2S) -2-[[(2R) -2- (4-benzyloxyphenyl) -2-hydroxyethyl] amino] -1,2,3,4-tetrahydronaphthalene-7 -Yloxy] acetyl] morpholine

Amorphous

IR (Film): 3365, 1653 cm ^-1

Reference Example  5

2-[(2S) -2-[[(2S) -2- (4-benzyloxyphenyl) -2-hydroxyethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy ] -N, N-dimethylacetamide

40.8 g of 4-benzyloxymandelic acid was dissolved in 405 ml of methanol and 405 ml of ethyl acetate, 200 ml of methanol of 20.4 ml of (S) -1-phenylethylamine and 200 ml of ethyl acetate were added and left to stand at room temperature to precipitate. 37.9 g of crystals were obtained. The obtained crystals were recrystallized with 926 ml of methanol to obtain 24.8 g of a salt of (S) -4-benzyloxymandelic acid and (S) -1-phenylethylamine at a melting point of 174-180 ° C.

1.0 g of a salt of (S) -4-benzyloxymandelic acid and (S) -1-phenylethylamine was suspended in a mixed solution of 20 ml of ethyl acetate and 20 ml of water, and 3.0 ml of 1 normal hydrochloric acid was added thereto under ice cooling for 30 minutes. Stirring. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 595 mg of (S) -4-benzyloxymandelic acid at a melting point of 158-162 ° C.

1.80 g of (S) -4-benzyloxymandelic acid and 1.87 g of (S) -2-amino-7-hydroxytetraline hydrobromide and benzotriazol-1-yloxytris (dimethylamino) phosphonium hexa 3.39 g of fluorophosphate was dissolved in 21 ml of N, N-dimethylformamide, 2.03 ml of triethylamine was added under ice-cooled stirring, and the mixture was allowed to react at room temperature for 1 hour. Water and diethyl ether were added to the reaction solution, and the precipitate was collected by filtration, and powdered (2S) -2- (4-benzyloxyphenyl) -2-hydroxy-N-((2S) -7-hydroxy- 2.64 g of 1,2,3,4-tetrahydronaphthalen-2-yl) acetamide were obtained.

(2S) -2- (4-benzyloxyphenyl) -2-hydroxy-N-((2S) -7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl) acetamide 2.50 The solution was dissolved in 31 ml of tetrahydrofuran, 1.76 ml of boranedimethylsulfide complex was added and refluxed for 4 hours, and then 4.6 ml of tetrahydrofuran solution of 4.62 g of triethanolamine was added and heated and refluxed for 11 hours. After cooling, water was added to the reaction solution, extraction was performed with ethyl acetate, and the mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel-liquid liquid column chromatography (elution solvent: ethyl acetate / ethanol = 7/1) to give (1S) -1- (4-benzyloxyphenyl) -2 amorphous. 1.63 g of-[((2S) -7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl) amino] ethanol was obtained.

1.30 g of (1S) -1- (4-benzyloxyphenyl) -2-[((2S) -7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl) amino] ethanol and N To a 16.7 mL suspension of 1.91 mL of methylene chloride of 2.91 mL of N-diisopropylethylamine, 1.41 mL of trifluoroacetic anhydride was added and stirred for 20 minutes. Water was added to the reaction solution, extraction was performed with methylene chloride, washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in 8.6 ml of N, N-dimethylformamide, 860 mg of powdered molecular sieve 4A, 571 mg of 2-bromo-N, N-dimethylacetamide, and 2.52 g of cesium carbonate were added and reacted at room temperature for 2.5 hours. . Water and methanol were added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 12 hours, after which the insolubles were filtered off and the filtrate was concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, crystallization was carried out by adding diethyl ether to the residue, and 2-[(2S) -2-[[(2S) -2- (4-benzyloxyphenyl) -2 at a melting point of 103-106 占 폚 was obtained. 437 mg of -hydroxyethyl] amino] -1,2,3 and 4-tetrahydronaphthalen-7-yloxy) -N, N-dimethylacetamide were obtained.

Reference Example  6

Among the reactions shown in Reference Example 5, reaction and treatment were performed as in Reference Example 5 using 1-bromoacetylpiperidine or 4-bromoacetylmorpholine instead of 2-bromo-N, N-dimethylacetamide, Was obtained.

1- [2-[(2S) -2-[[(2S) -2- (4-benzyloxyphenyl) -2-hydroxyethyl] amino] -1,2,3,4-tetrahydronaphthalene-7 -Yloxy) acetyl] piperidine

Paid

IR (pure material): 3304, 1638 cm ^-1

4- [2-[(2S) -2-[[(2S) -2- (4-benzyloxyphenyl) -2-hydroxyethyl] amino] -1,2,3,4-tetrahydronaphthalene-7 -Yloxy) acetyl] morpholine

Amorphous

Example  One

2-[(2S) -2-[[(2RS) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy ] -N, N-dimethylacetamide

2-[(2S) -2-[[(2RS) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy ] 250 mg of ethyl acetate was dissolved in 5 ml of tetrahydrofuran, 1 ml of dimethylamine was added under ice-cooling, and the mixture was allowed to react at 60 ° C in a sealed tube for 60 hours. The reaction solution was concentrated under reduced pressure, and then the residue was purified by aminopropylated silica gel medium pressure liquid column chromatography (eluent solvent: ethyl acetate / ethanol = 10/1) to obtain amorphous 2-[(2S) -2- [ [(2RS) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylacetamide 189 Mg was obtained.

Example  2

Of the reactions shown in Example 1, piperidine, morpholine, or pyrrolidine was used instead of dimethylamine to react and treat as in Example 1 to obtain the following compounds.

1- [2-[(2S) -2-[[(2RS) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-7 -Yloxy] acetyl] piperidine

Amorphous

4- [2-[(2S) -2-[[(2RS) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-7 -Yloxy] acetyl] morpholine

Amorphous

1- [2-[[(2S) -2-[[(2RS) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene- 7-yloxy] acetyl] pyrrolidine

Amorphous

Example  3

2-[(2S) -2-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy ] -N, N-dimethylacetamide

2-[(2S) -2-[[(2R) -2- (4-hydroxyphenyl) -2-hydroxyethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy 273 mg of] -N, N-dimethylacetamide and 60 mg of 10% palladium carbon were suspended in 5.5 ml of ethanol, and the mixture was stirred at room temperature under hydrogen atmosphere for 12 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure, and then the residue was recrystallized from methanol to obtain 2-[(2S) -2-[[(2R) -2-hydroxy-2- at a melting point of 169-172 ° C. 200 mg of (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylacetamide was obtained.

IR (KBr): 3255,1656 cm ^-1

Example  4

2-[(2S) -2-[[(2R) -2- (4-benzyloxyphenyl) -2-hydroxyethyl] amino] -1,2,3,4-tetra during the reaction shown in Example 3 Instead of hydronaphthalen-7-yloxy] -N, N-dimethylacetamide, the following compound was obtained by reacting and treating in the same manner as in Example 3 using the corresponding amide compound.

1- [2-[(2S) -2-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-7 -Yloxy] acetyl] piperidine

Amorphous

4- [2-[(2S) -2-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-7 -Yloxy] acetyl] morpholine

Melting Point: 98-101 ° C (Recrystallized Solvent: Chloroform-Diethyl Ether)

2-[(2S) -2-[[(2S) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy ] -N, N-dimethylacetamide

Melting Point: 181-183 ° C (Recrystallized Solvent: Ethanol-Ethyl Acetate)

1- [2-[(2S) -2-[[(2S) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-7 -Yloxy] acetyl] piperidine

Amorphous

4- [2-[(2S) -2-[[(2S) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-7 -Yloxy] acetyl] morpholine

Amorphous

4-[(2S) -2-[[(2RS) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy ] -N, N-dimethylbutyric acid amide

Amorphous

IR (Film): 3220, 1616 cm ^-1

Example  5

2-[(2S) -2-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy ] -N, N-dimethylacetamide hydrochloride

2-[(2S) -2-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy 210 mg of] -N, N-dimethylacetamide was suspended in 10.5 ml of ethanol, and 546 µl of 1 normal hydrochloric acid was added thereto and dissolved under heating. After cooling, the precipitated crystals were filtered off to obtain 2-[(2S) -2-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino]-at a melting point of 165-168 ° C. 100 mg of 1,2,3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylacetamide hydrochloride was obtained.

Example  6

2-[(2S) -2-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy ] -N, N-dimethylacetamide and L-tartrate or 1 normal sulfuric acid aqueous solution were used, and the following compound was obtained by the same method as Example 5.

2-[(2S) -2-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy ] -N, N-Dimethylacetamide0.5L-Tartrate

Melting Point: 178-181 ° C (Recrystallized Solvent: Ethanol)

2-[(2S) -2-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalen-7-yloxy ] -N, N-dimethylacetamide 0.5 sulfate

Melting Point: 202-205 ° C (Decomposition) (Recrystallized Solvent: Ethanol)

Example  7

1- [2-[(2S)-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-7-yljade The following compound was obtained in the same manner as in Example 5 using c] acetyl] piperidine and L-tartrate or D-tartrate.

1- [2-[(2S)-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-7-yljade Acetyl] piperidine0.5L-Tartrate

Melting Point: 208-210 ° C. (Recrystallized Solvent: Ethanol)

1- [2-[(2S)-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-7-yljade Acetyl] piperidine 0.5D-Tartrate

Melting Point: 206-208 ° C (Recrystallized Solvent: Ethanol)

Example  8

4- [2-[(2S)-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-7-yljade The following compounds were obtained in the same manner as in Example 5 using c] acetyl] piperidine and L-tartrate, D-tartrate or fumaric acid.

4- [2-[(2S)-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-7-yljade Acetyl morpholine 0.5L-Tartrate

Melting Point: 199-201 ° C (Recrystallized Solvent: Ethanol)

4- [2-[(2S)-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-7-yljade Morpholine 0.5D-Tartrate

Melting Point: 202-204 ° C (Recrystallized Solvent: Ethanol)

4- [2-[(2S)-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-7-yljade Acetyl] morpholine 0.5 fumarate

Melting Point: 193-197 ° C (Recrystallized Solvent: Ethanol)

Test Example  One

Extraction pregnant Automatic uterine movement  Action of the drug on

Uterus of SD-pregnant rats (21 days of pregnancy) was extracted, and a specimen of about 5 mm width and 15 mm length was prepared in the direction of the main rotator muscle, avoiding the placental attachment area, and tested according to the Magnus method. The specimens were suspended in a Locke-Ringer liquid ventilated with a mixed gas containing 95% oxygen and 5% carbon dioxide at 37 ° C, and a load of 1 g was applied. Automatic uterine movement was derived isometrically by means of a pressure transducer and recorded on a gramgram. In the efficacy evaluation, the sum of the height of uterine contraction for 5 minutes before the addition of the drug was compared with the sum of the height of uterine contraction for 5 minutes after the addition of the drug, and the drug concentration inhibiting 50% was evaluated by EC ₅₀ .

Test Example  2

Extraction atrium Deep contraction  Action of the drug on

Atrium of SD male rats (weight 350-400 g) was extracted and tested according to the Magnus method. The specimens were suspended in a Krebs-Henseleit liquid vented with a mixed gas containing 95% oxygen and 5% carbon dioxide at 37 ° C. and loaded with 1 g load. Deep contraction force was drawn isometrically via a pressure transducer, and recorded on the rackgram. The drug concentration at the time of addition of the drug, increases the heart rate per minute 20 times EC ₂₀ Value was evaluated.

Test Example  3

Acute Toxicity Test

Using four examples of 4 week old ICR male mice, 2-[(2S) -2-[[(2R) -2-hydroxy-2- (4-hydroxyphenyl) ethyl] amino] -1,2, 3,4-tetrahydronaphthalen-7-yloxy] -N, N-dimethylacetamide was dissolved in physiological saline at a dose of 50 mg / kg body weight and administered once intravenously. As a result, no death was observed 24 hours after administration.

Claims (8)

Formula 1 (Formula 1) (Wherein A is a linear alkylene group having 1 to 3 carbon atoms, B is an amino group or 3-7 which may contain an oxygen atom in an amino group or ring di-substituted with a linear or branched alkyl group having 1 to 6 carbon atoms). A cyclic ethanol amino group, a carbon atom with * indicates a carbon atom of R or S configuration or a carbon atom mixed with them, and a carbon atom with (S) represents a carbon atom of S configuration) Tralinecarboxylic acid amide derivatives and pharmacologically acceptable salts thereof. According to claim 1, Formula 21 (Wherein A is a linear alkylene group having 1 to 3 carbon atoms, B is an amino group or an amino group which is di-substituted with a linear or branched alkyl group having 1 to 6 carbon atoms or may contain an oxygen atom in the ring) 3-7 A cyclic ethanol amino group, wherein a carbon atom with (R) represents a carbon atom of R configuration, and a carbon atom with (S) represents a carbon atom of S configuration) Acidamide derivatives and pharmacologically acceptable salts thereof. According to claim 2, Formula 22 A phenylethanolaminotetralinecarboxylic acid amide derivative characterized by the formula (C) wherein (R) represents a carbon atom of R configuration, and a carbon atom of (S) represents a carbon atom of S configuration. Pharmacologically acceptable salts thereof. Formula 1 (Formula 1) (Wherein A is a linear alkylene group having 1 to 3 carbon atoms, B is an amino group or 3-7 which may contain an oxygen atom in an amino group or ring di-substituted with a linear or branched alkyl group having 1 to 6 carbon atoms). A cyclic ethanol amino group which is an alicyclic amino group, and a carbon atom with * represents a carbon atom of R or S configuration or a carbon atom mixed with them, and a carbon atom with (S) represents a carbon atom of S configuration) A scab, an anti-acid, bronchodilator, pain relief and urolithiasis, characterized in that it contains a traline carboxylic acid amide derivative or a pharmacologically acceptable salt thereof as an active ingredient. The method of claim 4, wherein Formula 21 Formula 21 (Wherein A is a linear alkylene group having 1 to 3 carbon atoms, B is an amino group or 3-7 which may contain an oxygen atom in an amino group or ring di-substituted with a linear or branched alkyl group having 1 to 6 carbon atoms). A phenylethanolaminotetralinecarboxylic acid amide derivative represented by an alicyclic amino group having a cyclic ring, and a carbon atom with (R) represents a carbon atom of R configuration, and a carbon atom with (S) represents a carbon atom of S configuration) or A rust-free, midwife, bronchodilator, pain relief and urolithiasis agent, comprising pharmacologically acceptable salt thereof as an active ingredient. The method of claim 5, wherein Formula 22 (Formula 22) A phenylethanolaminotetralinecarboxylic acid amide derivative represented by (wherein the carbon atom with (R) represents a carbon atom of R configuration, and the carbon atom with (S) represents a carbon atom of S configuration) An edible algae, premature birth preventive agent, bronchodilator, pain relief and urinary stones of urolithiasis, comprising an acceptable salt as an active ingredient. Formula 1 (Formula 1) (Wherein A is a linear alkylene group having 1 to 3 carbon atoms, B is an amino group or 3-7 which may contain an oxygen atom in an amino group or ring di-substituted with a linear or branched alkyl group having 1 to 6 carbon atoms). A cyclic ethanol amino group, a carbon atom with * indicates a carbon atom of R or S configuration or a carbon atom mixed with them, and a carbon atom with (S) represents a carbon atom of S configuration) Prevention of urges, premature birth, airway obstruction, prevention and treatment of diseases caused by bronchial stenosis, characterized in using traline carboxylic acid amide derivative or pharmacologically acceptable salt thereof, urolithiasis A method for the preparation of a preparation for pain relief and stone palpation. Formula 1 (Formula 1) (Wherein A is a linear alkylene group having 1 to 3 carbon atoms, B is an amino group or 3-7 which may contain an oxygen atom in an amino group or ring di-substituted with a linear or branched alkyl group having 1 to 6 carbon atoms). A cyclic ethanol amino group which is an alicyclic amino group, and a carbon atom with * represents a carbon atom of R or S configuration or a carbon atom mixed with them, and a carbon atom with (S) represents a carbon atom of S configuration) A method for producing a therapeutic agent for pain relief and palpation of urinary stones, characterized by using a traline carboxylic acid amide derivative or a pharmacologically acceptable salt thereof.