WO1999009001A1

WO1999009001A1 - Phenylethanolaminotetralin derivatives and bronchodilators

Info

Publication number: WO1999009001A1
Application number: PCT/JP1998/003545
Authority: WO
Inventors: Tetsuro Tamai; Nobuyuki Tanaka; Hideyuki Muranaka; Ken Kikuchi; Naoyuki Tsutsumi; Masuo Akahane
Original assignee: Kissei Pharmaceutical Co., Ltd.
Priority date: 1997-08-19
Filing date: 1998-08-10
Publication date: 1999-02-25
Also published as: ZA987425B; AU8562098A; CO4960653A1

Abstract

Phenylethanolaminotetralin derivatives represented by general formula (I) and pharmacologically acceptable salts thereof, which have potent and selective bronchodilating effects and are highly useful as bronchodilators, wherein A represents lower alkylene; B represents amino, di(lower alkyl)amino or 3- to 7-membered alicyclic amino optionally containing oxygen; n is an integer of 1 or 2; and the carbon atoms provided with (R) mean each one with the R-configuration.

Description

Description Phenylethanolaminotetralin derivative and bronchodilator

[Technical field]

The present invention relates to phenylethanolaminotetralin derivatives useful as pharmaceuticals and pharmacologically acceptable salts thereof.

[Background technology]

As a substituted phenylethanolaminotetralin derivative, for example, a compound having an intestinal-selective sympathomimetic action and an anti- pollakiuria action,

(Where the carbon atom attached to the (R) force ^s in the formula represents a carbon atom in the R configuration), and a compound represented by the formula

(The (S) -powered carbon atom in the formula represents a carbon atom in the S configuration, and the carbon atom to which (R) is attached has the same meaning as described above.) (Japanese Patent Publication No. 6-506666, No. 6-5006955). But force ^s et al., These compounds are marked / 3 ₃ - having adrenergic activity /? _{3—A is a} drenerin receptor stimulant.

[Disclosure of the Invention]

The present inventors have conducted intensive studies to find compounds useful as bronchodilators. As a result, certain phenylethanolaminotetralin derivatives in which the 3- and 4-positions of the phenyl moiety have been substituted and the 7-position of the tetralin moiety has been substituted with a carbamoylalkoxy group have potent and selective bronchodilator effects. Have been found to be very useful as bronchodilators, leading to the present invention.

That is, the present invention provides a compound represented by the general formula

Wherein A is a lower alkylene group, B is an amino group, a di-lower alkylamino group or a 3- to 7-membered alicyclic amino group which may contain an oxygen atom, and n is 1 or 2 And (R) indicates the carbon atom in the R configuration.) And a pharmaceutically acceptable salt thereof. .

The present invention relates to a medicament comprising a phenylethanolaminotetralin derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof.

The present invention relates to a bronchodilator comprising, as an active ingredient, a phenylethanolaminotetralin derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof.

The present invention provides an airway obstruction disorder or a bronchial stenosis disorder caused by administering a phenylethanolaminotetralin derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof. It relates to a method for preventing or treating a disease caused by the disease.

The present invention relates to a phenyletano represented by the general formula (I) for the manufacture of a medicament for preventing or treating a disease caused by an airway obstructive disorder or a bronchial stenosis disorder.

—Ruaminotetralin derivatives or pharmacologically acceptable salts thereof. The present invention relates to the use of a phenylethanolaminotetralin derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as a bronchodilator.

The present invention provides an airway obstructive agent comprising using a phenylethanolaminotetralin derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient of a drug. The present invention relates to a method for producing a medicament for preventing or treating a disease caused by a disorder or a bronchial stenosis disorder.

Here, in the compound represented by the general formula (I) of the present invention, the di-lower alkylamino group means a linear or linear alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group and an isopropyl group. An amino group di-substituted by a branched, same or different alkyl group, such as a dimethylamino group, a getylamino group, an ethylmethylamino group, and the like.The lower alkylene group includes a methylene group, an ethylene group and Refers to a linear alkylene group having 1 to 3 carbon atoms in the trimethylene group. Examples of the 3- to 7-membered alicyclic amino group which may contain an oxygen atom include a 1-pyrrolidinyl group, a piperidino group, and a morpholino group. The compound represented by the general formula (I) of the present invention can be produced as follows.

For example, the compound represented by the general formula (I) of the present invention has the general formula

(Wherein R ¹ is a hydroxyl-protecting group, and n and (R) the carbon atom to which the force is applied have the same meaning as described above);

X (ΠΙ)

(Where the (R) force 'attached carbon atom has the same meaning as described above), and reacts in the presence of a condensing agent with an optically active amine compound represented by the general formula: Ri (IV)

(Where R ¹ n and the carbon atom with (R) force have the same meaning as described above), and then using a reagent such as borane dimethyl sulfide complex Reduce to the general formula

(V)

Wherein the R ¹ n and the (R) -enforced carbon atoms have the same meanings as described above, and, if desired, alcoholic reaction with a reagent such as trifluoroacetic anhydride. After protecting the hydroxyl group and the amino group, the obtained phenol compound is represented by the general formula

X-A-COB (V I)

(Wherein X is a halogen atom, and A and B have the same meanings as described above). Can be.

The optically active mandelic acid derivative represented by the general formula (II) used as a starting material in the production method can be obtained by producing according to a method described in a literature or a method similar thereto.

(Wherein R ¹ and n have the same meanings as described above), and the phenyllithium derivative is treated with alkyllithium, and the obtained phenyllithium derivative is reacted with getyl oxalate to obtain the obtained phenyllithium derivative. After reducing the benzylglyoxylic acid derivative using a reagent such as sodium borohydride, the ester compound is hydrolyzed, and formula

( ^VI11 )

(Wherein R ¹ and n in the formula have the same meanings as described above), and then obtained optically according to a conventional method using a resolving reagent such as optically active 1- (1-naphthyl) ethylamine. It can be manufactured by dividing.

The amine compound represented by the formula (III) used as a starting material in the production method can be produced by a method described in a literature or a method similar thereto (for example, Eur. J. Med. C. hem., No. 29, 259-2

67 (1994); Japanese Patent Publication No. 3-14548).

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

The phenylethanolaminotetralin derivative represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt by a conventional method. Examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, menthoxyacetic acid, methanesulfonic acid, benzenesulfonic acid, p-Toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, lingic acid, carbonic acid, glutamic acid, aspartic acid, etc. Salts with inorganic bases such as acid addition salts, sodium salts and potassium salts can be mentioned.

The compound represented by the general formula (I) of the present invention also includes a solvate with a pharmaceutically acceptable solvent such as hydrated ethanol.

The bronchodilator effect (? ₂ -adrenergic receptor stimulating effect) of the compound represented by the general formula (I) of the present invention can be measured by an in vitro test using an isolated trachea of a guinea pig described below, For example, Compound 1 described in Example 1 is 2. 5 X 10 ^_10 molarity indicates histamine 1. 0 X 10- ⁵ molar concentration of 50% relaxation effect on contraction of tracheal smooth muscle according to (EC ₅ 0 value), Example 2 compound described 2 the EC ₅₀ of value was 5. 0X 1 0- ⁹ molar. As described above, the compound of the present invention is an excellent compound having a very strong bronchodilator effect.

The effect of the compound represented by the above general formula (I) of the present invention on the heart (i.e., an adrenergic receptor stimulating effect) is measured by an in vitro test using an isolated atria of a guinea pig described below. can be, example 1 compound 1 described, 7. 8 X 10- ⁹ molar concentration effect of increasing per minute 20 times the heart rate _(Ε <: Δ2 ₍₎ value) indicates, example 2 described The EC _Δ20 value of Compound 2 was 6.6 × 10— ° molar. As described above, the compound of the present invention is a compound having a very weak cardiac action (adrenergic receptor stimulating action) as compared with the above bronchodilator action (/? _2— adrenergic receptor stimulating action).

That is, the compound of the present invention has a very strong bronchodilator effect, has a weak side effect on the heart such as tachycardia, reduces the burden on the heart, and is useful as a powerful and selective bronchodilator. . Therefore, the compounds of the present invention are very useful for prevention or treatment of diseases caused by airway obstructive disorders such as bronchial asthma or bronchial stenosis disorders.

Further, the compound represented by the general formula (I) of the present invention is a very stable compound and has excellent storage stability.

When the phenylethanolaminotetralin derivative represented by the above general formula (I) of the present invention and a pharmacologically acceptable salt thereof are used for actual treatment, an appropriate pharmaceutical composition, for example, a tablet or powder It is orally or parenterally administered as fine granules, granules, capsules, inhalants, injections and the like. These pharmaceutical compositions can be prepared by a pharmaceutical method performed in a general preparation, by using carriers, excipients and other additives commonly used for pharmaceuticals.

The dosage is determined appropriately according to the gender, age, weight, degree of symptoms, etc. of the target patient.In the case of oral administration, it is generally 1 to 1000 mg per adult per day. In the case of parenteral administration (injection, etc.), the dosage is generally in the range of 0.01 to 100 mg per adult per day, in single or divided doses. In the case of inhalation, the dose is generally in the range of 0.05 to 50 mg / adult. [Industrial applicability]

The compound of the present invention has a strong and selective bronchodilator effect, and is very suitable for preventing or treating diseases caused by airway obstructive disorders such as bronchial asthma or bronchial stenosis disorders.

[Best Mode for Carrying Out the Invention]

The content of the present invention will be described in more detail in the following Reference Examples, Examples and Test Examples. The present invention is not limited to the content. Reference example 1

(+)-(2 R)-2-(2.2-dimethylbenzo 1-2-d) 1-1-3-dioxane 1-6 -yl) 1-2-hydroxy-1 N-((2R) _ 7 -Hydroxy-1. 2.3.4-Tetrahydronaphthalene-2-yl) acetoamide

Dissolve 30.0 g of 6-promo 2,2-dimethylbenzo [1,2_d] 1-1,3-dioxane in 610 ml of tetrahydrofuran and add 1.56 molar n-butyllithium hexane solution under stirring at 80 ° C under an argon atmosphere. After adding 136 ml, the mixture was reacted for 15 minutes. The reaction mixture was added to a solution of 21.6 g of getyl oxalate in 200 ml of tetrahydrofuran under stirring at 80 ° C under an argon atmosphere and allowed to react for 1 hour.Then, 100 ml of ethanol and 1.40 g of sodium borohydride in 100 ml of ethanol were successively added. added. The mixture was stirred at −30 ° C. for 30 minutes, 8.26 ml of acetic acid was added, and after stirring for 5 minutes, a solution of 14.8 g of hydrogen bicarbonate in 50 ml of water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the residue, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel medium pressure liquid chromatography (elution solvent: hexane Z ethyl acetate = 5Z1). Then, 25.1 g of oily 2- (2,2-dimethylbenzo [1,2-d] -11,3-dioxan-16-yl) -12-hydroxyethyl acetate was obtained.

_{1 H-NMR (CDC 1 3} ) 5 p pm:

1.24 (3H, t, J = 7.1Hz), 1.54 (6H, s), 3.39 (1H, d, J = 5.6Hz), 4.10-4.35 (2H, m), 4.84 (2H, s), 5.06 (1H , D, J = 5.6Hz), 6.80 (1H, d, J = 8.4Hz), 7.03 (1H, d, J = 1.9Hz), 7.19 (1H, dd, J = 8.4, 1.9Hz)

Dissolve 78.3 g of 2- (2,2-dimethylbenzo [1,2-d] _l, 3-dioxane-1-6-yl) -12-hydroxyacetate in 145 ml of ethanol, and stir with ice-cooled 2N water After adding 176 ml of an aqueous sodium oxide solution, the mixture was reacted at room temperature for 1.5 hours. After adding 174 ml of 2N aqueous sulfuric acid to the reaction mixture under stirring with water cooling, water and saturated saline were added, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue and (R)-(+)-111- (1-naphthyl) ethylamine 50.3 were dissolved in ethanol (210 ml), and the mixture was left at room temperature to obtain 48.3 g of precipitated crystals. Was. The obtained crystals were recrystallized from 88 ml of ethanol and had a melting point of 164 to 165 ° C and (I)-(R) -2- (2,2-dimethylbenzo [1,2-d] -I, 1,3-dioxane 13.6-yl-2-hydroxyacetic acid and (R)-(+)-l- (1-naphthyl) ethylamine and 43.6 g of a 1: 1: 1 salt of ethanol were obtained.

_{1 H-NMR (CDC 1 3} ) $ p pm:

1.15-1.30 (9H, m), 1.38 (3H, s), 3.70 (2H, q, J = 7.0Hz), 4.15 (1H, s), 4.38 (1H, d, J = 15.2Hz), 4.49 (1H , D, J = 15.2Hz), 4.71 (1H, q, J = 6.7Hz), 6.46 (1H, d, J = 8.4Hz), 6.53 (1H, d, J = 1.8Hz), 6.61 (1H, dd , J = 8.4, 1.8Hz), 7.30-7.45 (2H, m), 7.50-7.65 (2H, m), 7.75 (1H, d, J = 8.4Hz), 7.84 (1H, d, J = 7.9Hz) , 7.91 (1H, d, J = 8.1Hz) Specific rotation: [H] _D ²⁵ = — 33.7 ° (c = 0.52, methanol)

(1) 1 (R)-2-(2,2-Dimethylbenzo [1,2_d] 1, 1-dioxane 1 -6-yl) 1 -Hydroxyacetic acid and (R)-(+)- 1-(1- Naphthyl) 43.6 of a 1: 1: 1 salt of ethylamine and ethanol was suspended in a two-layer mixture of 200 ml of water and 300 ml of ethyl acetate, and 47.9 ml of a 2N aqueous sulfuric acid solution was added under ice-cooling and stirring, followed by stirring for 30 minutes. The reaction mixture was filtered using Celite (registered trademark), and the organic layer of the filtrate was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was recrystallized from ethyl acetate-diisopropyl ether to give a (I)-(R) -2- (2,2-dimethylbenzene) having a melting point of 115 to 118 ° C (decomposition). , 2-d] 1, 1 -dioxane-1-6-yl) 1-2-hydroxyacetic acid 22.8 g was obtained. ¹ H-NMR (DMS 0- d ₆ ) 8 ppm:

1.45 (6H, s), 4.81 (2H, s), 4.92 (1H, s), 5.30-6.00 (1H, br), 6.75 (1H, d, J = 8.4Hz), 7.09 (1H, d, J = 1.8Hz), 7.18 (1H, dd, J = 8.4, 1.8Hz), 12.50 (1H, br)

Specific rotation: [α] _D ²⁵ = _l 13.3 ° (c = l. 54, acetonitrile)

(-)-(R) —2— (2,2-Dimethylbenzo [1,2-d] -11,3-dioxane-1-6-yl) 1,2-Hydroxyacetic acid 5.2 g, (R) — 5.4 g of 2-amino-7-hydroxytetralin hydrobromide and 10.2 g of benzotriazole-1-yloxytris (dimethylamino) phosphoniumhexafluorophosphate in N, N-dimethylformamide Then, 9.2 ml of triethylamine was added thereto while stirring at room temperature, and the mixture was reacted for 14 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel medium pressure liquid chromatography (eluent: hexane Z ethyl acetate = 1Z2) to obtain amorphous (+) — (2R)- 2- (2,2-Dimethylbenzo [1,2-d] -11,3-dioxane-1-yl) _2-Hydroxy-N-((2R) -17-Hydroxy-1,2,3 7.4 g of 1,4-tetrahydronaphthalene-1-yl) acetamide were obtained. _{1 H-NMR (CDC 1 3} ) S p pm:

1.50-1.60 (6H, m), 1.65-1.80 (1H, m), 2.00-2.10 (1H, m), 2.54 (1H, dd, J = 16.2, 8.1Hz), 2.70-2.90 (2H, m), 3.00 (1H, dd, J = 16.2, 5.0Hz), 3.30 (1H, d, J = 3.4Hz), 4.20-4.30 (1H, m), 4.82 (2H, s), 4.88 (1H, s), 4.95 (1H, d, J = 3.4Hz), 6.15 (1H, d, J = 8.3Hz), 6.48 (1H, d, J = 2.6Hz), 6.62 (1H, dd, J = 8.1, 2.6Hz), 6.81 (1H, d, J = 8.4Hz), 6.94 (1H, d, J = 8.1Hz), 7.00 (1H, brs), 7.16 (1H, dd, J = 8.4, 1.9Hz) Specific rotation: ["] _D ²⁵ = + 9.1 ° (c = 0.53, methanol)

Reference example 2

(+) One 2— f (2 R)-2-“ί (2 R) — 2— (2.2-dimethylbenzo)“ 1.2— (1Ί-1.3_dioxane-1-6-yl) one 2 -Hydroxyethyl] amino-1-1, 2, 3. 4-tetrahydronaphthalene 7-yloxy —Ν. Ν-dimethylacetamide

(+) — (2 R) — 2— (2,2-Dimethylbenzo [1,2-d] _1,3-Dioxane-6-yl) 1-2-Hydroxy-1 N— ((2R) -17 —Hydroxy 1,2,3,4-tetrahydronaphthalene-1-yl) Acetamide (7.4 g) is dissolved in tetrahydrofuran (100 ml), and a 10 molar borane dimethyl sulfide complex (4.2 ml) is added at room temperature. The mixture was stirred under reflux for 4 hours. After cooling, a solution of 11.5 g of triethanolamine in 20 ml of tetrahydrofuran was added at room temperature, and the mixture was further stirred under heating and reflux for 35 hours. After cooling, the solvent was distilled off under reduced pressure, water was added to the residue, extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was dissolved in 100 ml of tetrahydrofuran, and 7.7 ml of 5N aqueous sodium hydroxide solution and 4.2 g of 2-promo N, N-dimethylacetamide were added under ice-cooling and stirring, followed by a reaction for 2 hours. After stirring, 2.0 ml of getylamine was added to the mixture while stirring at room temperature, followed by stirring for 1 hour. Water was added to the reaction mixture, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, 20 ml of a mixture of ethyl acetate Z ethanol = 30Z1 was added to the residue, and the precipitate was collected by filtration, and amorphous (+) — 2— [(2 R) — 2— [[ (2R) — 2- (2,2-dimethylbenzo [1,2-d] -l, 3-dioxane-l-6-yl) 12-hydroxyl-ethyl] amino] -l, 2,3,4-tetrahydro Naphthalene-1 7-yloxy] 4.29 g of 1N, N-dimethylacetamide was obtained.

_{1 H-NMR (CDC 1 3} ) S p pm: 1.50-1.70 (7H, m), 2.00-2.15 (IH, m), 2.50-3.20 (13H, m), 4.60 (1H, dd, J = 9.2, 3.5Hz), 4.64 (2H, s), 4.85 ( 2H, s), 6.65 (IH, d, J = 2.6Hz), 6.74 (IH, dd, J = 8.3, 2.6Hz), 6.80 (IH, d, J = 8.4Hz), 6.95-7.05 (2H, m ), 7.14 (IH, dd, J = 8.4, 2.3Hz) Specific rotation: [<<] _D ²⁵ = + 28.7 ° (c = 0.30, methanol)

Reference example 3

(+) 1 4 1 Γ 2-ί (2 R) —2— “(2 R) —2— (2.2-Dimethylbenzo“ 1.2 — d ”1 1.3 _Dioxane 1—6 1) 2-Hydroxystyl (amino) — 1. 2.3.4 4-tetrahydronaphthalene-1 7-yloxy] acetyl] morpholine

Using 4- (2-bromoacetyl) morpholine in place of 2-bromo-N, N-dimethylacetamide, and in the same manner as in Reference Example 2, the amorphous (+)-4-[2-([2 R)-2-[[(2 R) — 2- (2,2-dimethylbenzo [1,2-d] -11,3-dioxane-1-yl) -12-hydroxyethyl] amino] — 1 , 2,3,4-Tetrahydronaphthalene-1 7-yloxy] acetyl] morpholine.

¹ H-NMR (DMS 0- d ₆ ) δ p pm:

1.45 (6H, s), 1.60-1.75 (IH, m), 1.85-2.00 (IH, m), 2.35-2.95 (7H, m), 3.40-3.65 (8H, m), 4.50-4.60 (IH, m ), 4.72 (2H, s), 4.75-4.85 (2H, m), 5.17 (IH, d, J = 4.1Hz), 6.61 (IH, d, J = 2.5Hz), 6.65 (IH, dd, J = 8.3, 2.5Hz), 6.72 (1H, d, J = 8.3Hz), 6.94 (IH, d, J = 8.3Hz), 7.04 (1H, s), 7.13 (IH, d, J = 8.3Hz)

Specific rotation: [<<] _D ²⁹ = + 27.5 ° (c = l.07, methanol)

Reference example 4

(-)-(2R)-2-"4-Benzyloxy-3- (2-benzyloxyethyl) phenyl 1 -2-hydroxy N- ((2R) -7 -Hydroxy 1. 2. 3. 4-tetrahydronaphthalene-2-yl) acetamide

Benzyl [2- (2_benzyloxyshethyl) phenyl] ether 159mg And 123 mg of sodium acetate were suspended in 2 ml of acetic acid, and after adding bromine 291 under stirring at room temperature, the mixture was reacted for 1 hour. To the reaction solution was added a solution of sodium sulfite heptahydrate (100 mg) in water (20 ml), extracted with ethyl acetate, washed successively with water, a saturated aqueous solution of sodium hydrogen carbonate and water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by medium pressure liquid chromatography on silica gel (elution solvent: hexane Z methylene chloride = 2/1), and the oily benzyl [2- (2- 173 mg of benzyloxethyl) 4-bromophenyl] ether were obtained.

1 H - NM R (CDC 1 3) § ppm:

2.97 (2H, t, J = 7.0Hz), 3.68 (2H, t, J = 7.0Hz), 4.50 (2H, s), 5.02 (2H, s), 6.75 (1H, d, J = 8.7Hz), 7.20-7.40 (12H, m) benzyl [2- (2-benzyloxyshethyl) -14-bromophenyl] ether 24.0 g is dissolved in tetrahydrofuran 200 ml, and 1.57 molar n-butyllithium hexane solution 47.0 ml Was added under an argon atmosphere at 195 ° C with stirring, and reacted for 15 minutes. The reaction solution was added to a solution of 10.8 g of getyl oxalate in 300 ml of tetrahydrofuran under stirring at 195 ° C under an argon atmosphere, and reacted for 1 hour. Then, 200 ml of ethanol and 755 mg of sodium borohydride were sequentially added. After stirring the reaction solution at -35 ° C for 45 minutes, 4.70 ml of acetic acid was added, and after stirring for 15 minutes, a solution of 6.9 g of sodium hydrogen carbonate in 300 ml of water was added, and the reaction solution was concentrated under reduced pressure. The residue was extracted with ethyl acetate, 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 medium pressure liquid chromatography (elution solvent: hexane z ethyl acetate = 3/1) to give oily 2- (4-benzyloxy-3-) (2-benzyloxyphenyl) phenyl] 19.9 g of ethyl 2-hydroxyacetate was obtained. 1 H - NM R (CDC 1 3) S ppm:

1.21 (3H, t, J = 7.1Hz), 3.02 (2H, t, J = 7.3Hz), 3.34 (1H, d, J = 5.9Hz), 3.70 (2H, t,

J = 7.3Hz), 4.10-4.30 (2H, m), 4.51 (2H, s), 5.05 (2H, s), 5.08 (1H, d, J = 5.9Hz), 6.87 (1H, d, J = 8.4 Hz), 7.20-7.40 (12H, m) 39.7 g of 2- [4-benzyloxy-1- (2-benzyloxyshethyl) phenyl] _2-hydroxyacetate was suspended in 40 ml of ethanol, and 57 ml of a 2N aqueous sodium hydroxide solution was added under ice-cooling and stirring. Thereafter, the reaction was carried out at room temperature for 1 hour. 57 ml of a 2 N aqueous sulfuric acid solution was added to the reaction solution under ice-cooling and stirring, followed by extraction with ethyl acetate, washing with water and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 35.1 g of oily 2- [4-benzyloxy-3- (2-benzyloxyshethyl) phenyl] -2-hydroxyponic acid.

_{1 H-NMR (CDC 1 3} ) § p pm:

3.01 (2H, t, J = 7.1Hz), 3.71 (2H, t, J = 7.1Hz), 4.50 (2H, s), 5.06 (2H, s), 5.16 (H, s), 6.89 (IH, d , J = 8.4Hz), 7.20-7.40 (12H, m)

2-[4-Benzyloxy-3- (2-benzyloxyshethyl) phenyl] — 16.31 g of 2-hydroxyacetic acid and 6.29 g of D-phenylalaninol are dissolved in 23 ml of ethanol by heating and dissolved at room temperature. Left for hours. The precipitated crystals are collected by filtration and recrystallized from ethanol, and (R) -2- (4-benzyloxy-3- (2-benziloxicetyl) phenyl) -12-hydroxyacetic acid D-phenylalaninol salt 6.36 g was obtained. (R) —2— [4-Benzyloxy-3- (2-benzyloxyxethyl) phenyl] -12-Hydroxyacetic acid 2.7 g of D-phenylalaninitol was suspended in a two-layer mixture of 10 ml of water and 15 ml of ethyl acetate. Then, 5.0 ml of a 1N aqueous sulfuric acid solution was added thereto under ice-cooling stirring, followed by stirring for 30 minutes. The reaction mixture was separated, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.21 g of (R) -2- [4-benzyloxy-3- (2-benzyloxyshethyl) phenyl] -12-hydroxyacetic acid.

_{1 H-NMR (CDC 1 3} ) δ p pm:

3.01 (2H, t, J = 7.1Hz), 3.71 (2H, t, J = 7.1Hz), 4.50 (2H, s), 5.06 (2H, s), 5.16 (IH, s), 6.89 (1H, d , J = 8.4Hz), 7.20-7.40 (12H, m).

(R) 1-2-[4-benzyloxy 1-3-(2 -benzyloxyshethyl) 2.21 g of 2-hydroxyacetic acid, 1.22 g of (R) -2-amino-7-hydroxytraline hydrobromide and benzotriazole-1-yloxytris (dimethylamino) phosphoniumhexafluoro 2.20 g of phosphate was dissolved in 10 ml of N, N-dimethylformamide, and 1.39 ml of triethylamine was added thereto while stirring at room temperature, followed by a reaction for 12 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated aqueous sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by medium pressure liquid chromatography on silica gel (elution solvent: methylene chloride Z ethyl acetate = 1Z1), and (1) 1 (2R) — 2 — [4_benzyloxy-3- (2-benzyloxyshethyl) phenyl] -1-hydroxy N _ ((2R) — 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2 —Ill) 2.01 g of acetoamide was obtained.

_{1 H-NMR (CDC 1 3} ) S p pm:

1.65-1.75 (IH, m), 1.90-2.05 (IH, m), 2.45-2.55 (IH, m), 2.70-2.80 (2H, m), 2.90-3.05 (3H, m), 3.49 (IH, d , J = 3.2Hz), 3.70 (2H, t, J = 7.1Hz), 4.15-4.30 (IH, m), 4.50 (2H, s), 4.93 (IH, d, J = 3.4Hz), 5.04 (2H , s), 5.63 (IH, br s), 6.29 (1H, d, J = 8.2Hz), 6.41 (IH, d, J = 2.7Hz), 6.59 (IH, dd, J = 8.2, 2.7Hz), 6.85 (IH, d, J = 8.2Hz), 6.90 (1H, d, J = 8.3Hz), 7.15-7.40 (11H, m)

Specific rotation: [a] _D ³¹ = + 10.7 ° (c = 0.73, black-hole form)

Reference example 5

(+) — 2 — Γ (2 R)-2-ί “(2 R)-2-ί 4-benzyloxy-1 31-(2-benzyloxyshenyl) phenyl] _ 2 -hydroxyethyl] amino — 1. 2. 3. 4—Tetrahydronaphthalene-1 7-yloxy, _Ν. Ν—Dimethyl acetylacetamide

(-) 1 (2 R) 1 2— [4-benzyloxy 3- (2-benzyloxyethyl) phenyl] 1-hydroxyl-((2R) — 7-hydroxy-1,2,3,4 Dissolve 1.95 g of acetoamide in 20 ml of tetrahydrofuran and add 10 molar borane dimethyl sulfide at room temperature. 1.23 ml of a metal complex was added, and the mixture was stirred under heating and reflux for 3 hours. After cooling, a solution of 3.06 g of triethanolamine in 3 ml of tetrahydrofuran was added, and the mixture was further heated and refluxed for 6 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel medium pressure liquid column chromatography (elution solvent: methylene chloride, methanol = 2/1), and (+)-(1R)-1-[4 —Benzyloxy 3— (2-benzyloxyshenyl) phenyl) 1-2 — ((2R) -7-hydroxy-1,2,3,4-tetrahydrodronaphthalene-1-ylamine) ethanol 1.10 g Obtained.

1 H-NMR (DMS 0- d ₆ ) δ p pm:

1.35-1.50 (1H, m), 1.60-1.70 (1H, m), 1.85-2.00 (1H, m), 2.30-2.95 (8H, m), 3.62 (2H, t, J = 7.2Hz), 4.45- 4.55 (3H, m), 5.09 (2H, s), 5.15 (1H, d, J = 4.2Hz), 6.42 (1H, d, J = 2.6Hz), 6.48 (1H, dd, J = 8.2, 2.6Hz) ), 6.82 (1H, d, J = 8.2Hz), 6.97 (1H, d, J = 8.5Hz), 7.15 (1H, dd, J = 8.5, 2.1Hz), 7.19 (1H, d, J = 2.1Hz) ), 7.20-7.45 (thigh, m), 8.97 (1H, s)

Specific rotation:] D ^{30 =} + 28.7 ° (c = 0.78, methanol)

(+)-(1 R) — 1- (4-benzyloxy-3- (2-benzyloxyethyl) phenyl) 1-2- ((2R) — 7-hydroxy 1,2,3,4-tetrahydro Dissolve 1.08 g of naphthalene-2-ethanol in ethanol in 12 ml of tetrahydrofuran, add 5N aqueous sodium hydroxide solution 936 1 and 505 mg of 2-promo N, N-dimethylacetamide to the mixture under stirring at room temperature for 2 hours. After the reaction, getylamine 3151 was added at room temperature and stirred for 30 minutes. Water was added to the reaction mixture, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by medium-pressure liquid column chromatography on aluminopropylated silica gel (elution solvent: methylene chloride Z methanol == 50/1), and (+)-2-[(2R) —2— [(2R) 1 2— [4 1-benzyloxy 13- (2_benzyloxyshethyl) phenyl] 1 2—Hydroxyshetti 1.Amino] -1,2,3,4-tetrahydronaphthalene-17-yloxy] -N, N-dimethylacetamide 1.18 g was obtained.

1 H-NMR (DMS 0- d ₆ ) dp pm:

1.40-1.55 (1H, m), 1.60-1.75 (1H, m), 1.85-2.00 (1H, m), 2.35-3.00 (14H, m), 3.62 (2H, t, J = 7.1Hz), 4.46 ( 2H, s), 4.50-4.60 (1H, m), 4.69 (2H, s), 5.09 (2H, s), 5.16 (1H, d, J = 4.2Hz), 6.58 (1H, d, J = 2.5Hz) ), 6.64 (1H, dd, J = 8.4, 2.5Hz), 6.93 (1H, d, J = 8.4Hz), 6.97 (1H, d, J = 8.3Hz), 7.15 (1H, dd, J = 8.3, 2.1Hz), 7.20 (1H, d,

J = 2.1Hz), 7.20-7.45 (10H, m)

Specific rotation: [shed] _{^{D 2 9 = + 2 4. 2}} . (c = 3.01, methanol)

Example 1

(+)-2-"(2 R)-2-ί" (2 R) — 2-hydroxy 2- (4-hydroxy 3-hydroxymethylphenyl) ethyl, amino 4-Tetrahydronaphthalene-1 7-yloxy] Ν. Ν-Dimethylacetamide (Compound 1)

(+)-2-{(2 R) — 2— [[(2 R) 1 2— (2,2-dimethylbenzo [1, 2, 2-d] 1 l, 3-dioxane 1-6-yl) 1,2-Hydroxitytyl] amino] 1,1,2,3,4-Tetrahydronaphthalene-17-yloxy] 4.8 g of 1N, N-dimethylacetoamide are dissolved in 50 ml of tetrahydrofuran, and 1N is stirred under ice-cooling and stirring. Hydrochloric acid (50 ml) was added and reacted for 2 hours. The reaction mixture was neutralized by adding 50 ml of a 1N aqueous sodium hydroxide solution under ice-cooling and stirring, concentrated to dryness under reduced pressure, methylene chloride was added to the residue, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by medium-pressure liquid-pressure column chromatography on aluminopropylated silica gel (elution solvent: methylene chloride / methanol = 15/1) to obtain amorphous (+) I 2 — [(2R) -2 — [[(2R) I 2—Hydroxy_2— (4-Hydroxy-3-Hydroxymethylphenyl) ethyl] amino] I 1,2,3, There was obtained 3.2 g of 4-tetrahydrodronaphthalene-1 7-yloxy] _N, N-dimethylacetamide. This amorphous is crystallized using ethanol, melting point 95-98 ° C Was obtained.

^{_{X H-NMR (CDC 1 3}} ) p pm:

1.45-1.65 (1H, m), 1.90-2.05 (IH, m), 2.35-2.50 (1H, m), 2.60-2.90 (6H, m), 2.96 (3H, s), 3.06 (3H, s), 4.51 (1H, dd, J = 8.8, 3.7Hz), 4.61 (2H, s), 4.67 (2H, s), 6.56 (IH, d, J = 2.5Hz), 6.67 (IH, dd, J = 8.4, 2.5Hz), 6.75 (IH, d, J = 8.3Hz), 6.90-7.00 (2H, m), 7.04 (IH, dd, J = 8.3, 1.8Hz)

Specific rotation: ["] _D ³¹ = + 30.7 ° (c = l.07, methanol) Example 2

(+) —4— Γ2-“(2 R) — 2—“ “(2 R) — 2-hydroxy-1-2- (4-hydroxy-3-phenylhydroxyphenyl) ethylamino I 1. 2. 3. 4-tetrahydrodronaphthalene-1 7-yloxyacetyl Ί morpholine

(+) —2— [(2 R) —2— [[(2 R) 1 2— (2,2-dimethylbenzo [1,2-d] 1 1,3 _dioxane 1-6-yl) 1-2-Hydroxitytyl] amino] 1,1,2,3,4-tetrahydrodonaphthalene-17-yloxy] Instead of N, N-dimethylacetamide, (+) — 4-—2 — [(2R ) — 2-[[(2R) -2- (2,2-dimethylbenzo [1,2-d] -11,3-dioxane-1-6-yl) 1-2-hydroxyxethyl] amino] 1,2 , 3,4-tetrahydronaphthalene-1 7-yloxy] acetyl] morpholine and amorphous (+) — 4— [2 _ [(2R) —2 — [(( 2 R) — 2-Hydroxy-1- (4-hydroxy-3-hydroxymethylphenyl) ethyl] amino] -1,2,3,4-tetrahydronaphthalene-17-yloxy To obtain a cetyl] morpholine.

1 H-NMR (DMSO-d ₆ ) 8 p pm:

1.40-1.55 (1H, m), 1.65 (1H, br), 1.85-2.00 (IH, m), 2.35-2.50 (IH, m), 2.55-2.95 (6H, m), 3.40-3.65 (8H, m ), 4.40-4.55 (3H, m), 4.72 (2H, s), 4.80-5.15 (2H, m), 6.62 (IH, d, J = 2.7Hz), 6.65 (IH, dd, J = 8.3, 2.7 Hz), 6.69 (IH, d, J = 8.2Hz), 6.94 (1H, d, J = 8.3Hz), 7.01 (IH, dd, J = 8.2, 2.1Hz), 7.27 (1H, d, J = 2.1Hz), 9.15 (1H, br) Specific rotation: [α] _D ²⁹ = + 28.3 ° (c = l. 59, methanol)

Example 3

(+)-2-"(2 R)-2" "(2 R)-2-Hydroxy 2-(4-Hydroxy-3-Hydroxymethylphenyl) ethyl] Amino] 1 1.2 3.4-tetrahydronaphthalene-1 7-yloxy] 1 N.N-dimethylacetamide 0.5 fumarate (Compound 3)

(+) — 2— [(2 R) —2— [[(2 R) 1-2-Hydroxy_2— (4-Hydroxy-3-Hydroxymethylphenyl) ethyl] Amino] 1-1, 2, 3 , 4-Tetrahydronaphthalene-17-yloxy] 154 mg of 1N, N-dimethylacetamide was dissolved in 10 ml of ethanol, and 22 mg of fumaric acid was added, followed by dissolving with heating. After cooling, the precipitated crystals were collected by filtration, and had a melting point of 174 to 177 ° C (decomposition) of (+) — 2— [(2R) -2-[[(2R) — 2_hydroxy 2— (4 -Hydroxy-3-hydroxymethylphenyl) ethyl] amino] _ 1,2,3,4-Tetrahydronaphthalene-1 7-yloxy] 1 N, N-dimethylacetamide 0.5 fumarate 153mg I got

1 H-NMR (DMSO-d ₆ ) δ p pm:

1.50-1.65 (IH, m), 2.00-2.15 (IH, m), 2.50-3.10 (13H, m), 4.47 (2H, s), 4.60-4.75 (3H, m), 4.95 (1H, br), 6.46 (IH, s), 6.60-6.70 (2H, m), 6.72 (1H, d, J = 8.3Hz), 6.95 (1H, d, J = 8.3Hz), 7.04 (IH, dd, J = 8.3, 2.1Hz), 7.30 (1H, d, J = 2.1Hz), 9.25 (IH, br) Specific rotation: [a] _D ³¹ = + 1 9.6 ° (c = 0.48, water)

Example 4

(+) — 2 — “(2R) —2—“ f (2R) -12-hydroxy-1-2- (4-hydroxy-3-hydroxymethylphenyl) ethyl] amino 1.2-1. 3.4-tetrahydronaphthalene-1 7-yloxy] _N.N-dimethylacetamide 0.5 sulfate (Compound 4) Using a 1N aqueous sulfuric acid solution in place of fumaric acid, in the same manner as in Example 3, (+) — 2 — [(2R) —2 -— [((2R) —2-—with a melting point of 155 to 158 ° C. Hydroxy-1- (4-hydroxy-3-hydroxymethylphenyl) ethyl] amino]-1,2,3,4-tetrahydronaphthalene-17-yloxy] 1 N, N-dimethylacetamide 0.5 Sulfate Salt was obtained.

¹ H-NMR (DMS 0- d ₆ ) δ ppm:

1.60-1.75 (1H, m), 2.15-2.30 (1H, m), 2.60-3.20 (12H, m), 3.25-3.40 (IH, m), 4.49 (2H, s), 4.71 (2H, s), 4.83 (IH, dd, J = 9.7, 2.8Hz), 5.00 (IH, br), 6.65 (IH, d, J = 2.6Hz), 6.68 (1H, dd, J = 8.4, 2.6Hz), 6.76 (IH , d, J = 8.2Hz), 6.97 (1H, d, J = 8.4Hz), 7.08 (IH, dd, J = 8.2, 2.1Hz), 7.34 (IH, d, J = 2.1Hz), 9.35 (1H , Br) Specific rotation: [<<] _D ^{3 1} = + 2 1.6 ° (c = 0.51, water)

Example 5

(+)-2-"(2 R)-2-" Γ (2 R) 1-2-hydroxy 1-2-4-hydroxy 1-3-(2-hydroxyshetyl) phenyl acetyl 1 amino 1-1 .

2.3.4-Tetrahydronaphthalene-17-yloxy] -1-N-N-dimethylacetamide (Compound 5)

(+)-2-[(2 R)-2-[[(2 R) —2

3-(2-benzyloxyshenyl) phenyl] 1-2-hydroxysethyl] amino] _ 1, 2, 3, 4-tetrahydrodronaphthalene-1 7-yloxy] _N, N

— 1.10 g of dimethylacetamide and 55 mg of 10% palladium carbon were suspended in 10 ml of acetic acid, and the mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by aluminopropylated silica gel medium pressure liquid chromatography (elution solvent: methylene chloride / methanol = 10/1). ) —2— [(2 R) -2-[[(2 R) — 2 _ hydroxy 2-[4 _ hydroxy 1 3-(2-hydroxyethyl) phenyl] ethyl] amino] twenty three,

4-Tetrahydronaphthalene-1 7-yloxy] 1 N, N-dimethylacetamide 702 mg was obtained. ¹ H-NMR (DMS 0- d ₆ ) δ p pm:

1.35-1.70 (2H, m), 1.85-2.00 (1H, m), 2.35-3.00 (14H, m), 3.50-3.60 (2H, m), 4.40-4.50 (IH, m), 4.69 (2H, s ), 5.05 (IH, d, J = 3.8Hz), 6.59 (IH, d, J = 2.7Hz), 6.63 (1H, dd, J = 8.3, 2.7Hz), 6.70 (IH, d, J = 8.1Hz) ), 6.93 (1H, d, J = 8.3Hz), 6.98 (IH, dd, J = 8.1, 2.1Hz), 7.03 (IH, brs), 9.10 (IH, br)

Specific rotation: [Hi] _D ³⁰ = +23.2. (c = 0.56, methanol)

Example 6

(+) 1 2— Γ (2 R) 1 2— “(2 R) —2-Hydroxy 2 _“ 4-Hydroxy 13- (2-Hydroxitytyl) phenyl] ethyl] Amino] 1 1.2 3.4.4-Tetrahydronaphthalene-1 7-yloxy-N-N-dimethylacetamide 0.5 fumarate (Compound 6)

(+)-2-[(2 R)-2-[[(2 R) 1-2-hydroxy 2-[4- 1-hydroxy 3-(2-hydroxyethyl) phenyl] ethyl] Amino] _ 1 2,2,3,4-Tetrahydronaphthalene-17-yloxy] 1 N, N-dimethylacetamide (2 g) was dissolved in ethanol (10 ml), fumaric acid (271 mg) was added, and the mixture was dissolved under heating. After cooling, the precipitated crystals were collected by filtration and had a melting point of 185 to 187 ° C (decomposition), (+)-2-[(2R)-2-[[(2R) 1-2-hydroxy 2-[4 1-hydroxy-1- (2-hydroxyethyl) phenyl] ethyl] amino] 1,1,2,3,4-tetrahydronaphthalene-17-yloxy] 1 N, N-dimethylacetamide 0.5 fumarate 1.3 g I got

1 H-NMR (DMS 0- d ₆ ) δ p pm:

1.50-1.65 (IH, m), 2.00-2.15 (1H, m), 2.55-3.15 (15H, m), 3.55 (IH, t, J = 7.4Hz), 4.55-4.65 (IH, m), 4.71 ( IH, s), 6.46 (IH, s), 6.62 (1H, d, J = 2.5Hz), 6.66 (IH, dd, J = 8.4, 2.5Hz), 6.74 (IH, d, J = 8.2Hz), 6.96 (1H, d, J = 8.4Hz), 7.01 (1H, dd, J = 8.2, 1.9Hz), 7.07 (1H, d, J = 1.9Hz)

Specific rotation: [a] _D ²³ = + 20.4 ° (c = 0.49, water) ΟΛν

ο ο

(+) -2-"(2 R)-2-" Γ (2 R) 1-2-hydroxy 2-["4--hydroxy 1 3-(2-hydroxyxethyl) phenyl] ethyl, amino-1. 2.3.4-tetrahydronaphthalene-1 7-yloxy] -1-N-N-dimethylacetamide hydrofluoride (Compound 9)

1 H-NMR (DMS 0- d ₆ ) δ p pm:

1.65-1.80 (IH, m), 2.25-2.35 (IH, m), 2.60-2.95 (8H, m), 2.98 (3H, s), 3.05-3.20 (2H, m), 3.25-3.55 (2H, m ), 3.57 (2H, t, J = 7.3Hz), 4.65-4.85 (4H, m), 6.00 (IH, br s), 6.68 (IH, d, J = 2.3Hz), 6.71 (IH, dd, J = 8.3, 2.3Hz), 6.79 (IH, d, J = 8.2Hz), 7.00 (IH, d, J = 8.3Hz), 7.07 (IH, dd, J = 8.2, 1.9Hz), 7.13 (1H, d , J = 1.9Hz), 8.65 (IH, br), 8.80 (IH, br), 9.37 (1H, s)

Specific rotation: [D] D ^{2 3} = + 2 4. (c = 0.52, methanol) Melting point: 194-195 ° C (decomposition) (recrystallization solvent: ethanol)

(+)-2-"(2 R)-2-" "(2 R) — 2-Hydroxy 2-f 4-Hydroxy _ 3 — (2-Hydroxyshenyl) phenyl] ethyl diamino] 1. 2.3.4-Tetrahydronaphthalene-1 7-yloxyΊ—N.N-Dimethylacetamide D—Tartrate (Compound 10)

1 H-NMR (DMS 0- d ₆ ) δ p pm:

1.60-1.75 (IH, m), 2.20-2.30 (IH, m), 2.60-2.90 (8H, m), 2.95-3.15 (6H, m), 3.30-3.40 (IH, m), 3.56 (2H, t , J = 7.3Hz), 3.95 (2H, s), 4.70-4.80 (3H, m), 6.66 (IH, d, J = 2.6Hz), 6.69 (IH, dd, J = 8.4, 2.6Hz), 6.77 (IH, d, J = 8.2Hz), 6.98 (IH, d, J = 8.4Hz), 7.06 (IH, dd, J = 8.2, 2.1Hz), 7.11 (1H, d, J = 2.1Hz)

Specific rotation: [<<] _D ^{2 3} = + 26.4 ° (c = 0.51, water)

Melting point: 120-122 ° C (recrystallization solvent: ethanol) Test Example 1

Effects of drugs on isolated guinea pig trachea

Male H artley guinea pigs (body weight 450-600 g) were exsanguinated and the trachea was killed. Removed. Four to five tracheal rings are joined with a thread to form a strip-chain, and a mixed gas containing 95% oxygen and 5% carbon dioxide is aerated at 37 ° C in a Magnus tube filled with K rebs—Hense 1 eit liquid. Was suspended under a load of about 1 g, and the displacement was recorded on a rectogram through a tension transducer. Relaxing effect of the test drug was studied by accumulating administered under histamine (1 0 one ⁵ M) contracts. Na us, and the maximum relaxation effect of Fuorusu choline (1 0- ⁵ M) and 1 100% slack slow reaction of the specimens were evaluated drug concentration to relax 50% as EC _{5 ()} value.

Test example 2

Effects of drugs on isolated guinea pig atrium

Atria of male H art 1 ey guinea pigs (body weight 450-600 g) were excised and subjected to experiments according to the Magnus method. Specimens were suspended in a 37 ° C K rebs-Hense 1 eit solution aerated with a mixed gas containing 95% oxygen and 5% carbon dioxide and loaded with 0.5 g. Automatic pulsations were recorded on the rectogram via a tension transducer. The drug concentration at which the test drug was added and the heart rate was increased 20 times per minute was evaluated as Ε〇Δ _{2 ()} value.

Test example 3 Sharp poison test

5-week-old ICR male mice for a predetermined amount of the test drug followed _c Following a single dose intravenously over time was observed for 24 hours to determine the presence or absence of deaths. Compound dose (mgZkg) Fatal case

1 20 0/5

2 30 0/5

5 40 0/5

Claims

The scope of the claims

-General formula

Wherein A is a lower alkylene group, B is an amino group, a di-lower alkylamino group or a 3- to 7-membered alicyclic amino group which may contain an oxygen atom, and n is 1 or 2 And the pharmaceutically acceptable salts thereof are represented by the following formula: (R) The carbon atom indicated by (R) represents a carbon atom in the R configuration.

2. —General formula

(A in the formula is a lower alkylene group, B is an amino group, a di-lower alkylamino group or a 3- to 7-membered alicyclic amino group which may contain an oxygen atom,

(R) The carbon atom applied is a carbon atom in the R configuration). The phenylethanolaminoaminotetralin derivatives and pharmacologically acceptable salts thereof according to claim 1, wherein

3 expression

(The carbon atom attached to the (R) force ^s in the formula represents a carbon atom in the R configuration.) The phenylethanolaminotetralin derivative according to claim 2, and a pharmaceutically acceptable salt thereof. .

4. A medicament comprising the phenylethanolaminotetralin derivative according to claim 1, 2 or 3, or a pharmacologically acceptable salt thereof.

5. A bronchodilator comprising the phenylethanolaminotetralin derivative according to claim 1, 2 or 3 or a pharmacologically acceptable salt thereof as an active ingredient.

6. A disease caused by airway obstruction disorder or bronchial stenosis disorder by administering the phenylethanolaminotetralin derivative or the pharmacologically acceptable salt thereof according to claim 1, 2 or 3. Prevention or treatment method.

7. The phenylethanolaminotetralin derivative or the pharmacology thereof according to claim 1, 2 or 3 for the manufacture of a medicament for preventing or treating a disease caused by airway obstructive disorder or bronchial stenosis disorder. Use of chemically acceptable salts.

8. Use of the phenylethanolaminotetralin derivative according to claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof as a bronchodilator.

9. Use of the phenylethanolaminotetralin derivative according to claim 1, 2 or 3 or a pharmacologically acceptable salt thereof as an active ingredient of a drug. A method for producing a medicament for preventing or treating a disease caused by an airway obstructive disorder or a bronchial stenosis disorder.