WO1993018007A1 - Novel carbostyril derivative - Google Patents

Abstract

A carbostyril derivative represented by general formula (I), which selectively acts upon β2-adrenaline receptor, and a pharmacologically acceptable salt thereof, wherein -OY represents hydroxy, lower alkoxy or protected hydroxy; Z represents hydrogen, hydroxy, alkoxy or -OCH2-A; A represents lower alkoxycarbonyl, N-(un)substituted carbamoyl, or linear alkylene substituted by lower alkoxycarbonyl or hydroxy; the broken line between the 3- and the 4-positions indicates that the bond therebetween is either single or double.

Description

 Description New Carbostyril Derivatives Technical Field

The present invention is 3 ₂ - has a § Dorenari emissions receptor stimulating effect, and relates to weak novel carbostyril derivative action on the heart. Background art

 Propoterol having a carbostyril skeleton has been reported as a compound with a high ^ 2-adrenergic receptor stimulating activity and selectivity (Gianlob Ob Medicinal Chemistry, 19, 9 No., 1138-111, pp. 197).

However, beta ₂ - since with the side effect of Many increased heart rate Ryo Dorenari down acceptor compound having stimulating effects (tachycardia), a strong 3 ₂ - has a § drain Nalin receptor stimulating action, and cardiac There is a continuing demand for the emergence of compounds that have a weaker effect on CO2.

Therefore, an object of the present invention is to provide a compound having excellent selectivity for β ₂ -drainine receptor (particularly, having a weak effect on the heart). Disclosure of the invention

According to the present invention, / 3 ₂ - A general formula U below with § Dorenari emissions receptor stimulating effect)

 ]

(Wherein OY is a lower alkoxy group optionally protected by a hydroxyl group or a phenyl group or a protected hydroxyl group, and Ζ is a hydrogen atom, or a hydroxyl group as a substituent, or an alkoxy group having 1 to 5 carbon atoms. group or represents an OCH ₂ one a group, a 4 or 1 to carbon atoms having a lower alkoxycarbonyl group as a substituent, N-substituted or unsubstituted force Rubamoiru group or a lower alkoxycarbonyl Nirumotoma other represents a hydroxyl group, Wherein the dashed lines at positions 3 and 4 represent saturated or double bonds at positions 3 and 4. Carbostyril derivatives represented by the formula: and pharmacologically acceptable salts thereof. Is provided.

 Since the compound (I) of the present invention has two asymmetric carbons, there are four kinds of optical isomers. The present invention includes all of these four optical isomers and mixtures thereof in its scope.

In this specification, the meanings of Γ (RR) isomer J and “(RS) isomer” are described before the coordination of the asymmetric carbon at the 5-position substituent of CH 2 (OH) of carbostyril. The coordination of the asymmetric carbon at the 2-position of the tetrahydronaphthyl group is shown below. For example, in the Γ (RS) isomer, the configuration of the asymmetric carbon at one CH (OH) position is the (R) configuration, and the configuration of the asymmetric carbon at the 2-position of the tetrahydronaphthyl group is (S ) Indicates coordination. Furthermore, the compound (I) having a double bond at the 3- and 4-positions can take two types of tautomers which can be interconverted as shown in the following formula. It includes any of these tautomers.

OH Ή

CH-CH. One N

H OY

OH H

本発明化合物 （ I ) の塩としては、 薬理学的に許容される塩であれば 特に限定されるものでなく、 例えば塩酸、 硝酸、 硫酸、 臭化水素酸、 ョ ゥ化水素酸、 リ ン酸等の無機酸との塩、 酢酸、 酒石酸、 フマル酸、 マレ イン酸、 リ ンゴ酸、 安息香酸、 メタンスルホン酸、 エタンスルホン酸、 カンファースルホン酸、 ベンゼンスルホン酸、 トルエンスルホン酸等の 有機酸との塩、 ナトリウム、 カリウムまたはカルシウム等のアルカリ金 属またはアルカリ土類金属との塩等が挙げられる。 また、 本発明化合物 ( I ) 及びその薬理学的に許容されるその塩の水和物も本発明に包含さ れる。

The salt of the compound (I) of the present invention is not particularly limited as long as it is a pharmacologically acceptable salt. For example, hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydrofluoric acid, phosphorus Salts with inorganic acids such as acids, organic acids such as acetic acid, tartaric acid, fumaric acid, maleic acid, lingoic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, benzenesulfonic acid and toluenesulfonic acid And salts with an alkali metal or alkaline earth metal such as sodium, potassium or calcium. The present invention also includes hydrates of the compound (I) of the present invention and a pharmacologically acceptable salt thereof. It is.

 The compound (I) of the present invention can be produced according to the following steps 1 to 9.

 [Step 1]

 The adduct (IV) is produced by subjecting the epoxy compound (II) and the amino compound (III) to a reaction without a solvent or using an appropriate solvent. Examples of the reaction solvent include alcohols such as methanol, ethanol, and isopropanol, chloroform, dimethyl sulfoxide, and the like, but are not particularly limited. The reaction temperature is from 110 to 120, preferably from 20 to 90. Good to do in C. Eight

^H O -:

^H O-:

 [H] [III]

Process 1

(In the formula, OY is a lower group which may be substituted with a hydroxyl group or a phenyl group. Alkoxy is a group or a protected hydroxyl group, Z is represents a hydroxyl group, containing 1-5 alkoxy group having a carbon or an O CH ₂ one A group, as a hydrogen atom or, or a substituent, A is lower alkoxy as substituent It represents a carbonyl group, an N-substituted or unsubstituted rubamoyl group or a lower alkoxycarbonyl group, or a linear alkylene chain having 1 to 4 carbon atoms and having a hydroxyl group. )

 In this reaction, as the protecting group Y, various protecting groups usually used for protecting a hydroxyl group can be used, and a benzyl group is particularly preferable.

 [V]

[Step 2]

Removal of the protecting group at the 8-position hydroxyl group of the adduct (IV) can be carried out by a conventional method. When Y is a benzyl group, catalytic reduction or CTH (catalytic transfer nodrogenesis) is performed in the presence of a catalyst. (V) is produced by de-benzylation by the transfer hydrogenation method.

 For catalytic reduction, palladium-carbon (Pd-C), palladium black, etc. are used as catalysts. As the reaction solvent, for example, alcohols such as methanol, ethanol, and isopropanol, tetrahydrofuran, water, and a mixed solvent thereof are used, but are not particularly limited. The reaction is preferably carried out under normal pressure at 0 to 100 ° C, especially at 20 to 40. By continuing the catalytic reduction for a longer period of time after the generation of the debenzylated product, it is possible to obtain a compound in which the double bond at the 3- and 4-positions has been reduced simultaneously with the debenzylation of the adduct.

 When debenzylation is performed by the CTH method, an excess of ammonium formate, preferably 50 to 300 times, is used in the presence of a catalyst such as palladium-carbon (Pd-C) using alcohols such as methanol and ethanol as a reaction solvent. The reaction is carried out at normal temperature and normal pressure by adding molar ammonium formate.

 (Wherein OY represents a protected hydroxyl group, preferably a benzyl group,

Z represents a hydrogen atom, or a hydroxyl group, an alkoxy group having 1 to 5 carbon atoms, or one OCH ₂ —A group as a substituent. A has the same meaning as described above. The dashed lines at positions 3 and 4 indicate that positions 3 and 4 are saturated or double bonds. )

 [Step 3]

Treating the adduct (VI) (where the dotted lines at positions 3 and 4 indicate that the positions 3 and 4 are saturated or double bonds) with an appropriate demethylating agent such as boron tribromide Thus, (VII) can be produced. Examples of the reaction solvent include, but are not particularly limited to, methylene chloride, chloroform and the like. The reaction is preferably carried out at 170 to 30 ° C, especially at 130 to 20 ° C.

 Oh 83

C 84

[Step 4]

 The alkylation of the adduct (VII) (where the dotted lines at positions 3 and 4 indicate that the positions 3 and 4 are saturated or double bonds) is carried out at room temperature in an alcohol solution such as methanol as a reaction solvent. (VIII) can be produced by methylation using diazomethane in the above.

[Step 5] (XI) (where the dotted lines at positions 3 and 4 are saturated or double bonds at positions 3 and 4, R ₂ is a hydrogen atom or a lower alkyl group, and n represents an integer of 1 to 5) Is prepared by reacting the ester group in the side chain of (IX) with an excess of amide (X). As the reaction solvent, alcohol such as methanol or ethanol is used, and the reaction is preferably carried out at 50 to 150 ° C, particularly 70 to 100 ° C, in a sealed tube.

【XI】 一般式 （ I ) の化合物は 4種の異なる光学異性体の混合物である。 そ れぞれの光学異性体は下記に示す方法 （工程 6〜9) で製造することが できる。 Two

[XI] The compound of the general formula (I) is a mixture of four different optical isomers. Each optical isomer can be produced by the method shown below (Steps 6 to 9).

 [Step 6]

Epoxy (II) and optically active amine (XII) (Y is benzyl group) Wherein z has the same meaning as described above) under the same conditions as in Step 1 to produce the adduct (XIII). When the (XIII) is an optically active (2R) -amino form (XII), a diastereomer mixture of the (RR) form and the (SR) form is obtained, and the optically active (2S) -amino form (XIII) is obtained. When XII) is used, a diastereomer mixture of (RS) form and (SS) form can be produced. Eight

OH

I H CH-CH, I N

[XIII] Hereinafter, a method for separating a mixture of two diastereomers of the (RR) form and the (SR) form will be described.

 [Step 7]

(XI II), which is a mixture of two diastereomers of the (RR) form and the (SR) form, is converted to an optically active acylating agent (XIV) to form a diacyl form (XV) (Y is a benzyl group, and Z is Having the same meaning) It can be separated by gel column chromatography. Examples of the optically active acylating agent (XIV) include L-proline derivatives and camphorsulfonic acid chloride. Among the L-proline derivatives, (S)-(-1) -N- (trifluoroacetyl) prolyl chloride Is particularly preferred. As the reaction solvent, methylene chloride, chloroform, or the like is used, but is not particularly limited. The reaction is preferably carried out at a temperature of from 170 to 30 ° C, especially from 0 to 10 ° C. The optically active acylating agent (XIV) is required to be twice as much as (XIII).

OH

I H CH-CH, I N,

H OY

 [XIII] D 87

R ₃ -COCI [XIV]

[Step 8]

The diisyl form (XV), which was separated and purified by silica gel column chromatography in step 7, was subjected to alkali hydrolysis to give pure optical isomers (XVI) [(RR) form and (SR) form] (Υ Benzil And Z has the same meaning as described above). An alcohol such as methanol or ethanol is used as a reaction solvent, but is not particularly limited. The reaction is preferably carried out at 130 to 50 ° C, especially at 10 to 30 ° C.

 [XVI]

[Step 9]

 The debenzylation of the pure optical isomer (XVI) [(1¾1¾) -isomer and (51-isomer) can be performed by the CTH method used in step 2. From the (RR) -isomer to the (RR) -isomer (XV II ) And (SR) form to (SR) form (XV II).

By using the optically active (2S) -amino form in the same manner, optically active (RS) form and (SS) form (XVII) can be produced.

 [XVI]

[XVII] The compound of the present invention has an excellent and selective _2- adrenergic receptor stimulating action. The pharmacological actions of representative compounds of the present invention are shown below.

 [Experimental example 1]

A guinea pig tracheal muscle was excised by a conventional method to prepare a specimen. Preparation This mixed gas _{(95% 0 2, 5%} C0 2) under aeration, Sakae kept at 37 ^e C nutrient solution (Tyrode's solution, 0. 03MM Asukorubin acid, 0. 03mM EDTA, IOM Fuwentorami down) the filled And suspended in an organbath with a load of 1 g. The test compound was cumulatively added to the feeding tank at 10 minute intervals, and the change in tracheal muscle relaxation due to the addition of the test compound was recorded on a recorder. The tracheal muscle dilation was expressed as the molar concentration (EC ₅ ) of the test compound at which 50% relaxation relative to the maximum relaxation by isoproterenol occurred.

[Experimental example 2] By a conventional method, were excised right atrium of the guinea pig, a mixed gas _{(95% 0 2, 5%} C0 2) under aeration, Krebs solution kept at at 37, 0. 03mM Asuko Rubin acid, 0. 0 3 mM EDTA, The patient was suspended in a nutrient tank (organbath) filled with 10 M pentamine, loaded with 0.5 g, and the systolic force and the number of beats were recorded on a recorder. The test drug was cumulatively added to the nutrient tank at _2.5 minute intervals, and the EC ₂₅ (25% enhancement value) was determined from the pulse rate before and after administration.

The results are shown in Table 1. For comparison, the values of propotent hydrochloride (indicated by PRO in the table) reported as a β ₂ -drainergic receptor-selective stimulant (bronchodilator) are also shown.

Effects of representative compounds on isolated guinea pig tracheal muscle and right atrial specimens

 Monoremot tracheal muscle (^ 2) Guinea pig right atrium (/ 3!) Relative ratio

ED ₅ . (NM) EC ₂₅ (nM) Compound 1 0.1 1 1 20 2.3 Compound 2 0.32 9 00 5.9 Compound 3 0.2 1 720 7.2 Compound 4 0.00.088> 3 00 00> 720 0 Compound 5 0.03 2> 300 0 0> 200 0 Compound 6 1.1> 300 00> 0 58 Compound 7 1.9> 3 00 00> 33 Compound 8 0.0048 670 29 Compound 9 0.72 22000 6 5 Compound 1 0 0.16>30000> 40 0 Compound 1 1 0.61> 3 00 0 0> 100 Compound 1 21.5> 30 00> 42 Compound 1 33.8> 300 0 0> 17 Compound 1 4 0.0 0.0 0070 3 1 0 93 0 Compound 1 5 0.034 1 0 8.7

P RO ^£ 0. 1 9 90 1. 0

#: Terol hydrochloride

* Ratio is a value obtained by dividing the value of the right atrium (EC ₂₅ ) by the value of the tracheal muscle (EC _S ), relative to the value of pro-power terol.

 note)

 Compound 1: (Compound of Example 7)

8—Hydroxy 5— [1—Hydroxy 2— (7—Hydroxy I 1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] carbostyryl hydrochloride

Compound 2: (Compound of Example 42)

 8—Hydroxy 5— [1-Hydroxy-1 —— (6-Methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl hydrochloride

Compound 3: (Compound of Example 4)

 8—Hydroxy 5— [1—Hydroxy 2— (7—Methoxy 1,

2,3,4-tetrahydro 2-naphthyl) aminoethyl] carbostyryl hydrochloride

Compound 4: (Compound of Example 12)

 8-Hydroxy 5— [1-Hydroxy 2— (7-ethoxycarbonyl methoxy 1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] carbostyryl hydrochloride

Compound 5: (Compound of Example 19)

 8—Hydroxy 5— [1—Hydroxy 2— (7-Ethoxycarbonylylbutoxy 1,2,3,4-Tetrahydroxy 2-naphthyl) aminoethyl] carbostyril

Compound 6: (Compound of Example 8)

 8—Methoxy 5— [1—Hydroxy 2— (7—Methoxy 1,

2,3,4-tetrahydro 2-naphthyl) aminoethyl] carbostyryl hydrochloride

Compound 7: (Compound of Example 6)

8—Hydroxy 5— [1—Hydroxy 1 2— (7—Pentyloxy 1,2,3,4-TetrahiDraw 2—Naphthyl) Aminoethyl] Carbostyril * Hydrochloride Compound 8: (Compound of Example 26)

 8—Hydroxy-1-5-((1R S) -Hydroxy (2R) — (7-Methoxy 1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] carbostyryl hydrochloride

Compound 9: (Compound of Example 28)

 8—Hydroxy 5— [C 1 R S) —Hydroquinone (2S) — (7-Methoxy 1,2,3,4-Tetrahi draw 2-Naphthyl) aminoethyl] Carbostyril.Salt

Compound 10: (Compound of Example 32)

 8—Hydroxy 5 — [(1R) -Hydroxy (2R) — (7—Methoxy-1,2,3,4-tetrahydro 2-naphthyl) aminomethyl] Carbostyril * hydrochloride

Compound 11: (Compound of Example 36)

 8—Hydroxy 5 — [(1R) -Hydroxy (2S) — (7-Methoxy-1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] Carbostyril hydrochloride

Compound 12: (Compound of Example 31)

 8-Hydroxy 5-((1S) -Hydroxy (2R) — (7-Methoxy 1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] carbostyryl hydrochloride

 Compound 13: (Compound of Example 35)

 8—Hydroxy 5 — [(1S) -Hydroxy (2S) — (7-Methoxy-1,2,3,4-tetrahydro 2-naphthyl) aminomethyl] Carbostyril hydrochloride

 Compound 14: (Compound of Example 38)

8—Hydroxy 5— [CIRS) —Hydroxy (2R) — (7 1-ethoxyquin carbonyl methoxide 1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl * hydrochloride

 Compound 15: (Compound of Example 40)

8—Hydroxy-1-5-((1RS) -Hydroxy (2S) — (7-Ethoxycarbonylmethoxy-1,2,3,4-Tetrahydro-1--2-naphthyl) aminoethyl] carbostyryl hydrochloride Salt The compound of the present invention has a strong 32 ₂ -adrenoceptor stimulating action and has an extremely weak effect on the heart. Therefore, it has a bronchodilator, an antihypertensive, an impending premature birth preventive, and a therapeutic agent for bowel disease. Can be used as

 Hereinafter, production examples of typical compounds of the present invention are shown.

 [Example 1]

 8 A mixture of monobenzyloxy-5-oxylanylcarbostyril (0.8 g) and 2-amino-7-methoxytetralin (1.6 g) in isopropyl alcohol (30 ml) was heated to reflux for 8 hours, and then the solvent was removed. Is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform: methanol: concentrated aqueous ammonia = 100: 4: 0.1) to give 8-benzyloxy 5 -— [1-hydroxy 2-— as a pale yellow oil. (7-Methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyril is obtained in 0.75 g (yield: 59%).

_{1 H - NMR (CDC 1 3} ) δ ppm:

1.53-1.70 (1H, m). 2.00-2.14 (1H, m), 2.52-3.16 (7H, m), 3.76 (3H, s) ), 5.09 (1 H, dd), 5.17 (2 H, s), 6.58—6.59 (1H, m), 6.67 (1H, d), 6.7 0 (1H, dd), 7.01 (2H, t), 7.27 (1H, d), 7.39-7.44 (5H, m), 8.11, 8 1 2 (total 1 H, d each) o It was produced according to the production method of Example 1 using 8-benzyloxy-5-oxylanylcarbostyril and an appropriately selected 1,2,3,4-tetrahydronaphthalene derivative (tetralin derivative), and Obtain the compound.

 [Example 2]

 From 8-benzyloxy-5-oxylanylcarbostyril (0.39 g) and 2-amino-7-ethoxytetralin (0.76 g), 8-benzyloxy-5- [1-hydroxy-2- ( 0.36 g (yield: 56%) of 7-ethoxy 1,2,3,4-tetrohydro draw 2-naphthyl) aminoethyl] carbostyril was obtained.

_{1 H-NMR (CDC 1 3} ) δ ppm:

 1.38 (3 H, t, J = 6.7 Hz), 1.8-157 (1 H, m), 1.95-2.10 (1 H, m), 2.9-2 63 (1H, m), 2.68-3.10 (6H, m), 3.96, 3.97 (2H in total, q, J = 6.7Hz respectively), 5 08-5.20 ■ (1 H, m), 5.15 (2H, s), 6.57 (1 H, s), 666 (1 H, d, J = 9.8 Hz), 6.66 (1 H, dd, J = 104 HZ, 2.4 Hz), 6.97 (1 H, d, J = 9.2 Hz), 7.00 (1 H, d, J = 9.2Hz), 7.26 (1H, d, J = 10.4Hz), 7.33-7.50 (5H, m), 8.14 (1H, d, J = 9.8Hz).

 [Example 3]

From 8-benzyloxy-5-oxylanylcarbostyril (0.77 g) and 2-amino-7-pentyloxytetralin (1.8 g), 8-benzyloxy-5- [1-hydroxy-1- ( 7-pentyloxy 1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] carbostyryl was obtained in an amount of 0.61 g (yield: 4'4%). 1 H one _{NMR (CDC 1 3) δ ppm} :

 0.92 (3 H, t, J = 7.3 Hz), 1.29-1.50 (4 H, m), 1.54-1.84 (3 H, m), 1. 9 9—2.1 2 (1 H, m), 2.5 1-2.69 (3 H, m), 2.69-2.90 (3 H, m), 3.91 (2H , t, J = 6.3 Hz), 5.03-5.15 (1H, m), 5.18 (2H, s), 6.60 (1H, s), 6.68 (1 H, d, J = 9.8Hz), 6.69 (1H, d, J = 10.7Hz), 6.99 (1H, d, J = 12.2Hz), 7.03 (1H, d, J = 12.2Hz), 7.27 (1H, d, J = 8.3Hz), 7.35-7.50 (5H, m) , 8. 1 2 (1 H, d, J = 10.2 Hz).

 [Example 4]

 Of 8-benzyloxy 5- (1-hydroxy-2- (7-methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl (0.26 g) obtained in Example 1 Add 10% Pd-C (5 Omg) to the ethanol (26 ml) solution and hydrogenate at room temperature and 1 atm. When the raw materials disappear, the reaction is stopped and the catalyst is filtered off. The filtrate was distilled off under reduced pressure, and the residue was crystallized by adding ethyl acetate. As white crystals, 8-hydroxy-5- [1-hydroxy-12- (7-methoxy-1,2,3,4) was obtained. -Tetrahydro-2-naphthyl) aminoethyl] carbostyryl was obtained in an amount of 10 Omg (yield: 48%).

1 H-NMR (CD ₃ OD) δ ppm

 1.74-2.00 (1Η.m), 2.23-2.44 (1Η, m), 2.74-3.68 (7Η, m), 3.74 (3Η, s) , 5.42 (1 H, dt), 6.69-6.76 (3 H, m), 7.03 (2 H, dd), 7.33 (1 H, d), 8 3 9 (1 H, d).

[Example 5] 8-benzyloxy-5- [1-hydroxy-2- (7-ethoxy-1,2,3,4-tetrahydro-1-naphthyl) aminoethyl] carbostyryl (0.36 g) methanol (20 ml) Add ammonium formate (1.0 g) to the solution and stir at room temperature for 10 minutes. 10% Pd-C (0.10 g) is added to the reaction solution, and the mixture is stirred at room temperature for a while. After confirming the disappearance of the raw materials, the catalyst is filtered off, water is added to the residue, and the mixture is purified by ODS short column chromatography (0DS: octadecylsilyl, reverse-phase silica gel column chromatography). In other words, the target substance is adsorbed to ODS by flowing only with ion-exchanged water as an eluent. Next, the column was washed with a sufficient amount of ion-exchanged water, and the desired product was eluted with methanol to give 8-hydroxy-5- [1-hydroxy2- (7-ethoxy-1,2,3,3) as an oil. 4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl was obtained in an amount of 0.10 g (yield: 34%).

_{1 H-NMR (CD 3 0} D) δ ppm:

 1.349, 1.353 (3 H in total, each t, J = 7.3 Hz),

1.63-1.84 (1 H, m), 2.11-2.28 (1 H, m),

2.68-2.93 (3 H, m), 3.00-3.33 (4 H, m),

3.95, 3.96 (2H, q, J = 7.3Hz), 5.33 (1H, brs), 6.54-6.76 (2H, m), 6.65 (IH, d, J = 9.8 Hz), 7.00 (1 H, d, J = 7.9 Hz), 7.27 (1 H, d, J = 7.9 Hz), 8 . 36 (1 H, d, J = 9.8 Hz) o

Dissolve the free base (100 mg) in isopropanol (3 ml), add a solution of isopropanol containing hydrogen chloride to make it weakly acidic, and evaporate the solution under reduced pressure. Ethyl succinate was added to the residue, and 8-hydroxy-5— [1-hydroxy-2— (7-ethoxy-1,2,3,4-tetrahydro-2-) Naphthyl) aminoethyl] carbostyryl 'hydrochloride is obtained as white crystalline powder in 90 mg (yield: 83%).

 [Example 6]

 According to the method of Example 5, 8-benzyloxy 5- [1-hydroxy-2- (7-pentyloquinone 1.2,3,4-tetrahydrodraw 2-naphthyl) aminoethyl] carbostyryl (Example Debenzylation of (compound 3) (20 g) was performed to give 8-hydroxy 5— [1-hydroxy 2- (7-pentyloxy 1,2,3,4-tetrahydro 2-naphthyl) [Aminoethyl] carbostyryl was obtained in an amount of 114 g (yield: 84%).

 1 H-NMR (C DsOD) δ p p m:

 0.93 (3 H, t, J = 7.3 H z), 123-1.49 (5 H, m), 1.62-1.86 (3 H, m), 2.10- 2.35 (1 H, m), 2.66-2.93 (3 H, m), 3.00-3.37 (4 H, m), 3.88, 3.89 2H, J = 6.1 Hz respectively), 5.33 (1H, brs), 6.54-6.74 (2H, m), 6.66 (1H, d, J = 9 8Hz), 6.96 (1H, d, J = 8.5Hz), 7.00 (1H, d, J = 7.9Hz), 7.27 (1H, d, J = 7. 9 Hz), 8.37 (1 H, d, J = 9.8 Hz).

 The free base (14 Omg) was converted into the hydrochloride according to the method of Example 5 to give 8-hydroxy-5- [1-hydroxy-2- (7-pentyloxy-1,2,3,4-tetrahydro-2-). Naphthyl) aminoethyl] carbostyryl hydrochloride was obtained in 12 Omg (yield: 78%).

 [Example 7]

Under a stream of argon, 8-benzyloxy 5— [1-hydroxy 2— (7-methoxy 1,2,3,4-tetrahydro 2-naphthyl) Noethyl] carbostyryl (27 Omg) (compound of Example 1) in methylene chloride (24 ml) was added dropwise at a temperature of 30 ° C. or lower with 4 ml of a solution of boron tribromide in methylene chloride (1 M solution). I do. After completion of the dropwise addition, the temperature is gradually returned to room temperature, and the mixture is stirred as it is. After 1 hour, pour the reaction solution into water, and make it weakly basic with aqueous ammonia. The precipitated crystals are collected by filtration, washed with water, and dried to give a pale yellow-brown powder of 8-hydroxy-5- [1-hydroxy-2- (7-hydroxy 1,2,3,4-tetrahydro-2-naphthyl) [Aminoethyl] carbostyryl is obtained in an amount of 76 mg (yield: 40%).

1 H-NMR (DMS 0- d ₆ ) δ ppm:

 1.40-1.65 (1 H, m), 1.88-2.10 (1 H, m),

5.09-5.20 (1H.m), 6.46-6.56 (3H, m),

6.85 (1H, d), 6.96 (1 H, d d), 7.13 (1H, d d), 8.20 (1 H, d d), 8.98 (1 H, b rs).

 In addition, hydrochloride was prepared in accordance with the method of Example 5, and 8-hydroxy-5- [1-hydroxy-2- (7-hydroxy-1,2,3,4-tetrahydro-12-naphthyl) aminoethyl] carboethyl was used. 6 Omg (yield: 85%) of styryl hydrochloride is obtained as a light tan powder.

 [Example 8]

 According to the method of Example 7, the benzyl form (the compound of Example 1) (0.18 g) was converted from 8-hydroxy 5 -— [1-hydroxy 2 -— (7-hydroxy 1,2,3,4). [Tetrahedro-2-naphthyl) aminoethyl] carbostyryl is obtained, and this compound is dissolved again in methanol (1 Oml). Under stirring at room temperature, an excess amount of a diazomethane ether solution is added, and the mixture is left for a while. After distilling off the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: mouth-form: methanol: concentrated ammonia water = 100: 4: 0.

1) and 8—Methoxy 5— [1—Hydroxy 1 2— (7—Methoxy) C 1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] force Obtain 59 mg (yield: 39%) of rubostyril as a yellow glassy powder.

1 H one _{NMR (CDC 1 3) δ ppm} :

 1.52-1.70 (1H, m), 1.98-2.13 (1H, m), 2.52-3.10 (7H, m), 3.75, 3.76 (3 H, s for each), 3.94 (3 H, s), 5.13 (1 H, dd, J = 3.4 Hz, 9.3 Hz), 6.57 ( 2 H, t, J = 2, 4 Hz), 6.62 (1 H, d, J = 9.8 Hz), 6.68 (1 H, dd, J = 2.4 Hz, 8.3 Hz), 6.93 (1H, d, J = 8.3Hz), 6.99 (1H, d, J = 8.3Hz), 7.28 (1H, d, J 8. 10. 0, 8. 11 (1 H in total, d, J = 9.8 Hz, respectively). In addition, hydrochloride was prepared according to the method of Example 5 to give 8-methoxy-5- [1-hydroxy-2- (7-methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl. 53 mg (yield: 82%) of hydrochloride is obtained as a pale yellow powder.

1 H - NMR (CD ₃ shed D) 5 p pm:

1.80-1.98 (1 H, m), 2.30-2.44 (1 H, m), 2.80-3.05 (3 H, m), 3.20-3.43 (3 H, m), 3.52-3.68 (1 H, m), 3.74 (3 H, s), 4.04 (3 H, s), 5.54 (1 H, t, J = 6.4 Hz), 6.68 (1 H, m), 6.72 (1 H, dd, J = 2.4 Hz, 8.3 Hz), 6.83 (1 H, d, J = 9.8 Hz), 7.03 (1 H, d, J = 8.3 Hz), 7.26 (1H, d, J = 8.3 Hz), 7.53 (1 H , d, J = &. 3Hz), 8.57 (1 H, d, J = 9.8 Hz) ₀

[Example 9] A mixture of 8-benzyloxy-5-oxylanylcarbostyril (0.4 g) and 2-aminotetralin (1.2 g) in isopropyl alcohol (15 ml) is heated under reflux for 5 hours, and then the solvent is distilled off under reduced pressure. . The residue was subjected to silica gel column chromatography (eluent: chloroform: methanol: concentrated ammonia water = 100: 4: 0.1) to give 8-benzyloxy-5- [1-hydroxy-2- ( 1,1,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl was obtained as a colorless oil (0.31 g, yield: 52%).

_{1 H-NMR (CDC 1 3} ) δ p pm:

 1.52-1.72 (1 H, m), 2.00-2.14 (1 H, m), 2.50-3.13 (7 H, m), 5.10 (1 H, m) dd, J = 3.4 Hz, 9.3 Hz), 5.15 (2 H, s), 6.63 (1 H, d, J = 9.8 Hz), 6.98-7 1 3 (5 H, m), 7.26 (1 H, d, J = 8.3 Hz), 7.35-7.45 (5 H, m), 8.10, 8.1 1 (total 1H, d each).

 [Example 10]

8-Benzyloxy 5- (1-hydroxy-2- (1,2,3,4-tetrahydro-2-naphthyl) aminoethyl) Carbostyril (0.30 g) in a solution of methanol (20 ml) in ammonium formate (0.5 g) ) And stir at room temperature for 10 minutes. Add 10% Pd—C (0.10 g) to the reaction mixture and stir at room temperature for 2 hours. Further, ammonium formate (1.0 g) is added, and the mixture is stirred at room temperature for 2 hours. After confirming the disappearance of the raw materials, the catalyst is filtered off, water is added to the residue, and the mixture is purified by ODS short column chromatography. That is, starting as an eluent, flowing only with ion-exchanged water, the target substance is adsorbed to ODS. Next, the column was washed with a sufficient amount of ion-exchanged water, and the desired product was eluted with MeOH to give 8-hydroxy-5- [1-hydrogen as an oil. Mouth Xy 2 — (1,2,3,4-tetrahydro-1-naphthyl) aminomethyl] carbostyryl is obtained in an amount of 106 mg (yield: 46%).

1 H-NMR (CD ₃ OD) 6 ppm:

 1.77-2.00 (1H, m), 2.28-2.45 (1H, m), 2.80-3.07 (3H, m), 3. 15-3.40 (3H, m), 3.50-3.66 (1H, m), 5.44 (1H, dt), 6.69 (1H, d , J = 9.8 Hz), 7.05 (1 H, d, J = 8.3 Hz), 7.3 2 (1 H, d, J = 8.3 Hz), 8. 39 (1H, d, J = 9.8Hz), 8.51 (1H, s).

 In addition, hydrochloride was prepared according to the method of Example 5, and 8-hydroxy-5- [1-hydroxy-2— (1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyril hydrochloride was used. Get.

 [Example 11]

 8 A mixture of 1-benzyloxy-5-oxylanylcarbostilinole (0.6 g) and 2-amino-7-ethoxyquin methoxytetralin (2.5 g) in isopropyl alcohol (30 ml) is heated for 8 hours. After refluxing, the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: chloroform: methanol: concentrated aqueous ammonia = 1100: 4: 0.1) to give 8-benzyloxy-5- [1-hydroxy-2- (7-ethoxy). There is obtained 0.35 g (yield: 38%) of carbonyl methoxy 1,2,3,4-tetrahydro-2- (naphthyl) aminoethyl] carbostyril as a colorless oil.

_{1 H - NMR (CDC 1 3} ) δ ppm:

1.30 (3 H, t, J = 6.8 Hz), 1.50-1.70 (1 H, m), 2.000-2.14 (1 H, m) , 2.51-3.18 (7H, m), 4.26 (2H, q, J = 6.8Hz), 4.57 (2H, s), 5.08 (1 H, dd, J = 3.4 Hz, 8.8 Hz), 5.18 (2H, s), 6.60-6.63 (1 H, m), 6.68 (1 H, d, J = 10.3 Hz), 6.70 (1 H, dd, J = 2.9 Hz, 8.3 Hz), 7.02 (2H, t, J = 8.8 Hz) ), 7.27 (1H, d, J = 8.3Hz), 7.39-7.44 (5H, m), 8.11, 8.12 (1H, d, respectively) J = 10.3 Hz).

 [Example 12]

 8—Benzyloxy 5— [1-Hydroxy 2— (7-ethoxyproponyl methoxy-1,2,3,4-tetrahydroxy-1-naphthyl) amino] ethyl] Carbostyril (0.29 g) of methanol (1 0 ml) Add ammonium formate (0.5 g) to the solution, stir at room temperature for 10 minutes, add 10% Pd-C (0.15 g) to the reaction solution, and further add room temperature for 2 hours. Stir. After filtering off the catalyst, add water to the residue and discard the supernatant. The residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 10: 1), and then crystallized using ethyl acetate to give 8-hydroxy-5-hydroxy as pale yellow crystals. 1-Hydroxy-2- (7-ethoxycarbonyl methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminonoethyl] carbostyryl was obtained in an amount of 130 mg (yield: 54%).

1 H-NMR (CD ₃ OD) δ ppm:

1.27 (3 H, t, J = 6.8 Hz), 175-1.98 (1 H, m), 2.23-2.40 (1 H, m), 2.77-3. 60 (7 H, m), 4.23 (2 H, q, J = 6.8 Hz) 4.64 (2 H, s), 5.40 (1 H, dt. J = 6.4 H z), 6 68-6.76 (3 H, m). 7.03 (2 H, d, J = 8.3 H z) 7.3 1, 7. 32 (1 H in total, d , J = 8.3 Hz), 8.39 (1H, d, J = 10.3 Hz), 8.50 (1H, s). In addition, hydrochloride was prepared according to the method of Example 5, and 8-hydroxy-5- [1—hydroxy-2- (7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydroxy-2-naphthyl) aminoethyl ] Carbostyril hydrochloride is obtained.

 [Example 13]

 8-benzyloxy 5— [1-hydroxy-2- (7-ethoxyquinone 1,2,3,4-tetrahidr 2-naphthyl) aminoethyl] carbostyril (compound of Example 11) (6 Omg) in ethanol (2 ml), add 10% Pd-C (1 Omg), stir at room temperature under normal pressure for 1 晚, and perform hydrogenation. After confirming that the raw materials and the compound of Example 4 have disappeared on TLC, the catalyst is filtered off. The filtrate was evaporated under reduced pressure to give 8-hydroxy-5- [1-hydroxy21- (7-ethoxyquin carbonyl 1,1,2,3,4-tetrahydro-2-naphthyl) as a white crystalline powder. ) Aminoethyl] 1,3,4-dihydrocarbostyril was obtained in an amount of 2 Omg (yield: 40%).

_{1 H- NMR (CD 3 0 D} ) 6 ppm:

 1.27 (3 H, t, J = 7.3 Hz), 1.75-2.000 (1 H, m), 2.26-2.43 (1 H, m), 2.59 (2H, t), 2.74-3.40 (8H, m), 3.43-3.68 (1H, m), "4.23 (2 H, q, J = 7.3 Hz), 4.64 (2H, s), 5.12-5.25 (1H, m), 6.70 (1H, brs), 6 74 (1H, dd), 6.79 (1H, d), 7.03 (1H, d), 7.13, 7.14 (1H, d each).

Dissolve the free base (16 mg) in isopropanol (3 ml), add a solution of hydrogen chloride in isopropanol to make it slightly acidic, and distill off the solution under reduced pressure. Ethyl acetate was added to the residue, and 8-hydroxy-5- [1-hydrogen 2- (7-ethoxycarbonylmethoxy 1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] 1,3,4-dihydrocarbostyryl hydrochloride as white crystalline powder 16 mg ( (Yield: 93%) «

 [Example 14]

 8-Hydroxy 5— [1-Hydroxy 2— (7-ethokinylcarbonylmethoxy-1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] carbostyril (Compound of Example 12) (3 Omg Add 2 ml of concentrated aqueous ammonia to a solution of 5 ml of methanol in 5) and seal the tube. Stir at an external temperature of 65-70 for 3 hours. The mixture was treated in the same manner as in Example 5 (ODS column chromatography), and then treated with 8-hydroxy-5- [1-hydroxy2- (7-force rubamoyl methoxy-1,2,3,4-tetrahydro 2-1). Naphthyl) aminoethyl] carbostyryl (17 mg, yield: 65%).

_{1 H-NMR (CD 3 0} D) δ ppm:

 1.50-1.74 (1H, m), 2.00-2.13 (1H, m), 2.50-3.08 (7H, m), 4.41, 4.42 (2 H, s each), 5.17-5.27 (1 H, m), 6.62-6.78 (4 H, m), 6.94-7.03 (2 H , m), 7.2 1, 7.22 (total 1 H, d each), 8.37, 8.38 (total 1 H, d each).

 In addition, hydrochloride was prepared according to the method of Example 5, and 8-hydroxy-5- [1-hydroxy-2- (7-potassium rubamoyl methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl ] Carbostyril. The hydrochloride is obtained as a light tan powder.

[Example 15] 8-Hydroxy-1--5- [1-Hydroxy-2—7-Ethkincarbonyl methoxy-1,2,3,4-Tetrahidr 2-Naphthyl) aminoethyl] Carbostyrinole hydrochloride (50 mg) To the ethanol (5 ml) solution, add 2 ml of 70 o / o ethylamine aqueous solution, seal the tube, and stir at an external temperature of 70 ° C for 6.5 hours. After treating by the same procedure as in Example 14 (ODS column chromatography), the product was repurified by preparative TLC, and 8-hydroxy-5- [1-hydroxy-2- (7-N- 1,2,3,4-Tetrahydro-2-naphthyl) aminoethyl] power To obtain 18 mg of rubostyril (yield: 39%).

 1 H-NMR (C DaOD) δ p m:

 1.14 (3 H, t, J = 7.0 Hz), 1.62-1.82 (1 H, m), 2.15-2.26 (1 H, m), 2. 63-2.95 (3H, m), 3.00-3.40 (6H, m), 4.41, 4.42 (2H in total, s each), 5.24-5 40 (1H, m), 6.6 2 — 6.80 (3H, m), 7.00 (2H, d, J = 8.3Hz), 7.26 (1H, d, J = 8.3 Hz), 8.39 (1 H, d, J = 9.8 Hz). In addition, hydrochloride was prepared according to the method of Example 5 to give 8-hydroxy-5- [1-hydroxy-2- (7-N-ethylcarbamoylmethoxy-1,2,3,4-tetrahydro-2-naphthyl). Amaminoethyl] carbostyryl hydrochloride is obtained as a light tan powder.

 Using 8-benzyloxy-5-oxylanylcarbostyril and an appropriately selected 1,2,3,4-tetrahydronaphthalene derivative (tetralin derivative) according to the production method of the above Examples 11 and 12, The indicated compound was prepared.

 [Example 16]

8-benzyloxy 5-hydroxylanilcarbostyril (0.46 g) And 2-amino-7-ethoxycarbonylpropoxytetralin (1.31 g) from 8-benzyloxy-5- [1-hydroxy-2- (7-ethoxycarbonylpropoxy-1,2,3,4-tetrahi Draw 2-naphthyl) aminocetyl] carbostyryl was obtained in an amount of 0.39 g (yield: 44%).

_{1 H-NMR (CDC 1 3} ) δ ppm:

1.26 (3 H, t, J = 7.3 Hz), 1.50-1.70 (1 H, m), 2.09 (2H, t, J = 6.7 Hz), 2. 04-2. 1 1 (1 H, m), 2.50 (2H, t, J = 7.3 Hz), 2.6 1 -3.02 (9 H, m), 3.96 (2H, m t, J = 6.1 Hz), 4.14 (2 H, q, J = 7.3 Hz), 5.08 (1 H, dd, J = 3.1 Hz, 9.2 Hz), 5.18 (2 H, s), 6.59 (1 H, s), 6.68 (1 H, d, J = 8.5 Hz), 6.69 (1 H, d, J = 9.8 Hz), 6.99 (1 H, d, J = 8.6 Hz), 7.04 (1 H, d, J = 8.6 Hz), 7.27 (1 H , d, J = 7.9 Hz), 7.39-7.44 (5 H, m), 8.12 (1 H, d, J = 9.8 Hz) ₀

 [Example 17]

 8-benzyloxy 5- (1-hydroxy-1--2- (7-ethoxycarbonylpropoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl (compound of Example 16) (0. From 39 g), 93 mg of 8-hydroxy-5- [1-hydroxy-2- (7-ethoxycarbonylcarbonylpropoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyril was obtained (yield: 93 mg). : 28%)

1 H-NMR (CD ₃ OD) δ ppm:

1.24 (3 H, t, J = 7.3 Hz), 1.70-1.90 (1 H, m), 2.04 (2H, t.J = 6.7 Hz), 2.10 -2. 30 (1 H, m), 2.49 (2H, t, J = 7.3 Hz), 2.70 -3. 40 (7H, m), 3.96 (2H, t, J = 6.1Hz), 4.13 (2H, q, J = 7.3Hz), 4.85 (2H, brs ), 5.30-5.40 (1H, m), 6.63-6.72 (3H, m), 6.99 (1H, d, J = 8.5H z), 7.02 (1H, d, J = 7.3Hz), 7.29 (1H, dd, J = 7.9Hz, 1.8Hz), 8.3 8 (1H, d, J = 9.8Hz), 8.55 (1H, s).

 In addition, hydrochloride was prepared according to the method of Example 5 to give 8-hydroxy-5- [1-hydroxy-2- (7-ethoxycarbonylpropoxy-1,2,3,4-tetrahydroxy-2-naphthyl) aminoethyl] Obtain carbostyryl 'hydrochloride.

_{1 H - NMR (CD 3 0} D) δ ppm:

1.24 (3 H, t, J = 7.3 Hz), 1.80-2.00 (1 H, m), 2.04 (2 H, t, J = 6.1 H z), 2.30-2.40 (1 H, m), 2.49 (2 H, t, J = 6.1 Hz), 2.80-3.6 2 (7 H, m), 3.96 (2H, t, J = 6.lHz), 4.13 (2H, q, J = 7.3Hz), 4.86 (2H, brs ), 5.46 (1H, t), 6.68 (1H, brs), 6.73 (1H, dd, J = 7.9Hz, 2.4OHz), 6 80 (1 H, d, J = 9.8 Hz), 7.03 (1 H, d, J = 8.6 Hz), 7.09 (1 H, d, J = 7.9 Hz), 7.39 (1 H, d, J = 7.9 Hz), 8.52 (1 H, d, J = 9.8 Hz) ₀ [Example 18]

8-Benzyloxy-5-oxylanylcarbostilinole (0.45 g) and 2-amino-7-ethoxycarbonylbutoxytetralin (1.34 g) give 8-benzyloxy-5— [1-hydroxy2 — (7-ethoxycarbonylbutoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl is obtained in an amount of 0.422 g (yield: 47%). _{1 H-NMR (CDC 1 3} ) δ ppm:

1.25 (3 H, t, J = 6.8 Hz), 1.55-1.70 (1 H, m), 1.80 (4 H, brs), 2.0 0 — 2.10 (1 H, m), 2.37 (2 H, brs), 2.55-3.20 (7 H, m), 3.93 (2 H, brs), 4. 1 3 (2 H, q , J = 6. 8 H z), 5. 0 9 (1 H t dd, 9. 3 H z), 5. 1 8 (2H, s), 6. 5 9 (1 H, s), 6.68 (2 H, d, J = 10.3 Hz), 6.99 (1 H, d, J = 8.3 Hz), 7.04 (1H, d, J = 8.3Hz), 7.27 (1H, d, J = 7.8Hz), 7.30-7.50 (5H, m), 8.1 2 (1 H, d, J = 9.8 H z) ₀

 [Example 19]

 8—Benzyloxy 5— [1-Hydroxy 2— (7-ethoxycarbonylcarbonylbutoxy 1,2,3,4-tetrahydro 2-naphthyl) aminotine] Carbostyril (Compound of Example 18) (0.4 From 2 g), 15-mg of 8-hydroxy-5- [1-hydroxy-2- (7-ethoxycarbonylbutoxy-1,2-, 3-, 4-tetrahydro-2-naphthyl) aminonoethyl] carbostyryl was obtained. Rate: 43%).

_{1 H -NMR (CD 3 0 D} ) δ ppm:

1.23 (3H, t, J = 7.3Hz), 1.75 (5H, brs), 2.16-2.30 (1H, m), 2.36 (2 H, brs), 2.70-2.90 (3 H, m), 3.00 — 3.33 (7 H, m), 3, 89 (2 H, brd), 4.10 (2 H, q, J = 7.3 H z), 4.88 (2 H, brs), 5.45 (1 H, t), 6.60 (1 H, d , J = 3.1 Hz), 6.64 (2 H, d, J = 9.2 Hz), 6.93 (1 H, d, J = 8.5 Hz), 7. 0 0 (lH, d, J = 7.9 Hz), 7.27 (1H, d, J = 7.9 Hz), 8.42 (1H, d, J = 9. 8 Hz).

 In addition, hydrochloride was prepared according to the method of Example 5, and 8-hydroxy-5- [1-hydroxy-2- (7-ethoxyquincarbonylbutoxy-1,2,3,4-tetrahydro-2-naphthyl) amino was prepared. Noethyl] carbostyryl hydrochloride is obtained.

_{1 H - NMR (CD 3 0} D) δ ppm:

 1.24 (3 H, t, J = 7.3 Hz), 1.70-2.000 (5 H, m), 2.36-2.40 (3 H, m) , 2.90-3.60 (7 H, m), 3.92 (2 H, t), .1 1 (2 H, q, J = 7.3 Hz), 4.87 (2H, brs), 5.49 (1H, t), 6.68 (1H, brs), 6.73 (1H, dd, 3 = 7.9Hz), 6. 8 5 (1 H, d, J = 9.8 H z), 7.02 (1 H, d, J = 8.6 H z), 7.1 1 (1 H, d, J = 8. 6Hz), 7.42 (1H, d, J = 7.9Hz), 8.59 (1H, d, J = 10.4Hz).

 [Example 20]

 8-Benzyloxy-5-oxylanylcarbostyril (0.46 g) and 2-amino-7-ethoxycarbonylpentyloxytetralin (1.45 g) give 8-benzyloxy-5— [1-hydroxy2 — (7-Ethoxycarbonylpentyloxy-1,2,3,4-tetrahydro-1--2-naphthyl) aminoethyl] carbostyryl is obtained in an amount of 0.52 g (yield: 55%).

_{1 H - NMR (CDC l a} ) δ ppm:

1.25 (3 H, t, J = 7.3 Hz), 1.49-1.81 (9 H, m), 2.000-2.10 (1 H, m) , 2.33 (2 H, t, J = 6.7 H z), 2.50 — 3.20 (7 H, m), 3.92 (2 H, t. J = 6. 7 H z), 4.13 (2H, q, J = 7.3 H z), 5.08 (1 H, dd, J = 3.l Hz, 9.1 Hz), 5.18 (2 H, s), 6.59 (1 H, s), 6.68 (1 H, d, J = 7.3 Hz), 6.69 (1 H, d, J = 9.8 Hz), 6.99 (1 H, d, J = 8.6 Hz), 7.04 ( 1H, d, J = 8.6Hz), 7.27 (1H, d, J = 7.9Hz), 7.40-7.44 (5H, m), 8.12 (1H, d , J = 9.2 Hz).

 [Example 21]

 8—Benzyloxy 5— [1-Hydroxy 2— (7—Ethoxycarbonylpentyloxy 1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] carbostyryl (Compound of Example 20) (0 From 5 2 g), 8—hydroxy 5— [1-hydroxy 2— (7—ethoxycarbonylpentyloxy 1,2,3,4-tetrahydro 2-naphthyl) aminoamino] carbostyril mg (yield: 59%).

1 H-NMR (CD ₃ OD) δ ppm:

1.2 3 (3 H, t, J = 7.3 H z), 1.8-1.78 (7 H, m), 2.0 0-2.20 (1 H, m), 2.3.4 (2 H, t _f = 7.3 H z), 2.60-3.20 (7 H, m), 3.92 (2 H.t, J = 7.3 H .. z) 8 6 (2 H, brs), 5. 3 0 (1 H r t), 6. 5 9 - 6. 67 (2H, m), 6. 67 (1 H, d, J = 9 8H z), 6.96 (1 H, d, J = 8.5 Hz), 6.99 (1 H, d, J = 8.5 Hz), 7.25 (1 H , d, J = 8.5 Hz), 8.39 (1 H, d, J = 9.8 Hz).

 In addition, hydrochloride was prepared according to the method of Example 5, and 8-hydroxy-5- [1-hydroxy-2- (7-ethoxyquincarbonylpentyloxy 1.2,3,4-tetrahydro-2-naphthyl) was used. Aminoethyl] carbostyryl * hydrochloride is obtained.

1 H-NMR (CD ₃ OD) δ ppm: 1.24 (3 H, t, J = 7.3 Hz), 1.8-1.78 (7 H, m), 2.33 (3 H, t), 2.80-3.4 0 (6 H, m), 3.60 (1 H, m), 3.92 (2 H, t, J = 6.7 Hz), 4.1 1 (2 H, q, J = 7 3H z), 4.87 (2 H, brs), 5.5 1 (1 H, t), 6.67 (1 H, brs), 6.72 (1 H, dd, J = 8. 6 Hz, 2.4 Hz), 6.84 (1 H, d, J = 9.8 Hz), 7.01 (1 H, d, J = 8.5 Hz), 7.1 1 (1 H, d, J = 8.0 Hz), 7.42 (1 H, d, J = 8.6 Hz), 8.60 (1 H, d, J = 9.8 H z).

 [Example 22]

 From 8-benzyloxy-5-oxylanylcarbostyril (0.23 g) and 2-amino-7- (5-hydroxypentyloxy) tetralin (0.59 g), 8-benzyloxy-5- [1- 0.25 g (yield: 58%) of droxy 2- (7- (5-hydroxypentyloxy) -1,2,3,4-tetrahydro-12-naphthyl) aminoethyl] carbostyril obtain.

 1 H-NMR (C DC) δ p p m:

 1.20-1.90 (1 0 H, m) .2.0 1-2.10 (1 H, m), 2.53-3.20 (7 H, m), 3.68 (2 H , t, J = 6.4Hz), 3.93 (2H, t, J = 6.4Hz), 5.08 (1H, dd, J = 3.1Hz, 6.1Hz) ), 5.18 (2 H, s), 6.60 (1 H, s), 6.69 (2 H, d, J = 10.4 Hz), 6.99 (1 H, d J = 8.6 Hz), 7.04 (1 H, d, J = 8.6 Hz), 7.27 (1 H, d, J = 6.1 Hz), 7. 33-7.50 (5H, m), 8.12 (1H, d. J = 9.8Hz).

[Example 23] 8—Benzyloxy 5 — [1 —Hydroxy 2 — (7- (5-Hydroxypentyloxy) 1-1,2,3,4-Tetrahydroxy 2-naphthyl) aminoethyl] carbostyril (Example 2) (Compound 2) (0.25 g) from 8—hydroxy-1 5 — [1 —hydroxy-1 2 — (7- (5-hydroxypentyloxy) 1 1, 2,3,4— There are obtained 148 mg (yield: 72%) of tetrahydro 2-naphthyl) aminoethyl] carbostyril.

_{1 H - NMR (CD 3 0} D) δ ppm:

 1.35-1.50 (6 H, m), 1.50-1.82 (1 H, m), 2.00-2.18 (1 H, m), 2. 5 0-3.05 (7 H, m), 3.57 (2 H, dd, J = 6. Hz), 3.92 (2 H, dd, J = 6.4 Hz) , 4.86 (3 H, s), 5.20 (1 H, t), 6.58-6.66 (3 H, m), 6.89 (1 H, d, J = 8.5 Hz),

6.93 (1H, d, J = 8.5Hz), 7.18 (1H, d, 3 = 7.9Hz), 8.39 (1H, d, J = 9.8 Hz).

 In addition, hydrochloride was prepared in accordance with the method of Example 5, and 8-hydroxy-5- [1-hydroxy-2- (7- (5-hydroxypentyloxy) -11,2,3,4-tetrahydro-2-naphthyl) was used. ) Aminoethyl] carbostyryl. Hydrochloride is obtained.

1 H-NMR (CD ₃ OD) 6 ppm:

 1.40-2.000 (7 H, m), 2.30-2.40 (1 H, m),

2.80-3.40 (6 H, m), 3.50-3.70 (3 H, m),

3.93 (2 H, t, J = 6.1 Hz), 4.86 (3 H, brs), 5.51 (1 H, t), 6.68 (1 H, brs ), 6.72 (1H, d, J = 8.6Hz), 6.86 (1H, d, J = 9.8Hz), 7.02 (1H, d, J = 8.6 Hz), 7.12 (1 H, d, J = 8.6 Hz),

7.4.3 (1H, d.J = 8.6Hz) .8.62 (1H, d, J = 9. 8 Hz).

 [Example 24]

 8—Hydroxy— 5— [1—Hydroxy—2— (7—Ethoxycarboxylpentyloxy 1,2,3,4-Tetrahi Draw 2-Naphthyl) Aminoethyl] carbostyryl hydrochloride (implemented Example 21 Compound (1) To a solution of (78 mg) in ethanol-ion-exchanged water (1: 1) was added 10% Pd-C, and the mixture was stirred at 3 atm at room temperature and hydrogenated. After confirming that the raw material and the compound of Example 20 have disappeared on TLC, the catalyst is filtered off. After evaporating the filtrate under reduced pressure, a solution of hydrochloric acid and ethanol was added to the residue to form a hydrochloride salt of 8-hydroxy-5- [1-hydroxy-2- (7-ethoxycarbonylpentyloxy 1,2,3,4— There are obtained 42 mg (yield: 54%) of tetrahydro 2- (naphthyl) aminoethyl] -1,3,4-dihydrocarbostyril.

_{1 H - NMR (CD 3 0} D) δ ppm:

1.23 (3 H, t, J = 7.3 H z), 1.20-2.00 (7 H, m), 2.33 (3 H, t), 2.50-3.30 ( 1 0 H, m), 3.50-3.70 (1 H, m), 3.92 (2 H, t) 4.1 1 1 (2 H, q, J = 7.3 Hz), 4.86 (2H, brs), 5.20 (1H, brs), 6.70 (2H, d), 6.80 (1H, d), 7.00 (1H, d) , 7.13 (1 H, d) ₀ .

 [Example 25]

8 1-Benzyloxy-5-oxylanylcarbostyrinole (0.5 g) and (R) -2-amino-7-methoxytolamine (0.72 g) mixed with isopropyl alcohol (20 ml) Heat the solution to reflux for 8 hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: chloroform: methanol: concentrated aqueous ammonia = 100: 4: 0.1). 8-benzyloxy-5-[(1RS) -hydroxyl (2R)-(7-methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbo as a pale yellow oil 0.41 g (yield: 51%) of styryl was obtained.

 [Example 26]

 8-benzyloxy 5-((1RS) -hydroxyl (2R) — (7-methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl (obtained in Example 25) The debenzylation of 0.14 g) was performed by the CTH method (see Example 5) to give 8-hydroxy-5-[(1RS) -hydroxy (2R)-(7-methoxy1,2 , 3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl (69 mg, yield: 61%).

 The hydrochloride was prepared according to the method of Example 5 to give 8-hydroxy-5-[(1RS) -hydroxy (2R) — (7-methoxy-1,2,3,4-tetrahydro-2-naphthyl) Aminoethyl] carbostyryl (a mixture of two optical isomers) is obtained.

 [Example 27]

A solution of 8-benzyloxylcarboxystyryl (0,8 g) and (S) —2-amino-7-methoxytetralin (1.2 g) in isopropyl alcohol (35 ml) Heat to reflux for 1 hour. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: chloroform: methanol: concentrated aqueous ammonia = 100: 0.1) to give 8-benzyloquinone-5 as a pale yellow oil. — [(1 RS) — Hydroxy (2 S) — (7-Methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] 0.53 g of carbostyryl (yield: 1%) ) Get. [Example 28]

 Example 2 The debenzylation of the compound of 7 was carried out by the CTH method, and 8-hydroxy-5-[(1RS) -hydroxy (2S)-(7-methoxy-1,2,3,4 —Tetrahydro 2-naphthyl) aminoethyl] carbostyryl hydrochloride (mixture of two optical isomers).

 [Example 29]

 8-benzyloxy-5-[(1RS) -hydroxyl (2R) — (7-methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl obtained in Example 25 To a solution of 0.35 g) in methylene chloride (10 ml) was added triethylamine (0.25 ml), and the mixture was stirred under ice-cooling and stirred. (S) — (I) 1N— (trifluoroacetyl) Add 0.1 M solution of methylene chloride (15 ml) of the prolyl capped light. After the addition, return to room temperature and stir for 1 hour. Water is added to the reaction solution, extracted with ethyl acetate, and the organic layer is washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: quenched form: methanol = 100: 1) to separate the formed diastereomer. The fraction eluted first is referred to as diastereomer (α), and the fraction eluted later is referred to as diastereomer (^). Each diastereomer (α) is a colorless oil, 192 mg, and diastereomer, β is a colorless oil. mg.

 [Example 30]

After dissolving the diastereomer (α) (192 mg) obtained in Example 29 in ethanol (1 Om 1), a 1N NaOH aqueous solution (3 ml) is added, and the mixture is stirred at room temperature overnight. After confirming the disappearance of the raw materials by TLC, 1N hydrochloric acid aqueous solution (3.5 ml) is added. Further, the reaction solution is made weakly basic by adding aqueous ammonia, and extracted with ethyl acetate. After washing the organic layer with water, anhydrous magnesium sulfate And dry it. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: chloroform: methanol: concentrated aqueous ammonia = 100: 4: 0.1) to give 8-benzyloxy-5-[( 1S) -Hydroxy (2R) — (7-Methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyril is obtained as a colorless oil (99 mg).

[a] D = + 73. 3 ° (c = 0. 9 9, CHC 1 3)

 Similarly, from the diastereomer (β) (248 mg) obtained in Example 29, 8-1-benzyloxy 5-([1R) -hydroxy (2R) — (7-methoxy-1,2,3,4-tetrahydro) 2-naphthyl) aminoethyl] carbostyryl is obtained as a colorless oil (106 mg).

[a] _D = +0.6. (C = l. 06, CHC 13)

 [Example 31]

8—Benzyloxy 5 — [(1S) -Hydroxy (2R) — (7-Methoxy 1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] Carbostyril (99 mg) in methanol (5 ml) ) Ammonium formate (0.6 g) was added to the solution, and the mixture was stirred at room temperature for 10 minutes. Then, ammonium formate (0.6 g) and 10% Pd—C (30 mg) were added, and the mixture was stirred at room temperature for 2 hours. Again, add ammonium formate (0.6 g) and 10% Pd-Ic (3 Omg) and stir. After confirming the disappearance of the raw materials on TLC, the catalyst is filtered off, water is added to the residue, and the mixture is purified by ODS short column chromatography. That is, first, only the ion-exchanged water is flown as an eluent, and the target substance is adsorbed to ODS. Next, the column was washed with a sufficient amount of ion-exchanged water, and the desired product was eluted with methanol to give 8-hydroxy-5-[(1S) -hydroxy (2R)-(7-medium) as an oil. Toxi 1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] carbostyril 59 mg (yield: 74%) is obtained as a yellow powder.

 8-Hydroxy 5-([1S) -Hydroxy (2R)-(7-Methoxy-1,2,3,4-tetrahydroxy 2-naphthyl) Aminoethyl] carbostyryl 'hydrochloride is obtained.

 • [a] D = +8 4.0 ° (c = 0.44, Me OH)

 [Example 3 2]

 Example 3 According to the method of 1, 8-benzyloxy 5-([1R) -hydroxyl (2R)-(7-methoxy-1,2,3,4-tetrahydro-2-naphthyl) Amaminoethyl] carbostyryl (106 mg) from 8-hydroxy-5-[(1R) -hydroquinine-1 (2R) — (7-methoxy1,2,3,4-tetrahydro-2-naphthyl) [Aminoethyl] carbostyryl is obtained as a pale yellow powder (52 mg, yield: 62%). 8-Hydroxy-5-[(1R) -Hydroxy (2R) — (7-Methoxy-1,2,3,4-tetrahydroxy-2-naphthyl) [Aminoethyl] carbostyryl. Hydrochloride is obtained.

 [a] D = +25.9. (C = 0.39, Me OH)

 [Example 33]

8-Benzyloxy obtained in Example 27 5-[(1RS) -Hydroxy- (2S)-(7-Methoxy-1,2,3.4-tetrahydro-1--2-naphthyl) aminoethyl] Triethylamine (0.35 ml) was added to a solution of carbostyryl (0.49 g) in methylene chloride (10 ml), and the mixture was stirred under ice-cooling and stirred. (Methyl chloride) solution (0.1 ml) in 0.1 M methylene chloride solution. After the addition, return to room temperature and stir for 20 minutes. Add water to the reaction mixture and extract with ethyl acetate. The organic layer is separated, washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue is subjected to silica gel column chromatography (eluent: chloroform: methanol = 100: 1) to separate the diastereomers formed. The fraction eluted first is referred to as diastereomer (α), and the fraction eluted later is referred to as diastereomer (/ 3). Each diastereomer (α) is taken as a colorless oil, 34 O mg, and diastereomer (^) is taken as colorless oil. To obtain 3 32 mg.

 [Example 3 4]

 After dissolving the diastereomer (na) (34 Omg) obtained in Example 33 in ethanol (10 ml), an aqueous solution of 1 N NaOH (3.5 ml) was added, and the mixture was stirred at room temperature for one hour. . After confirming the disappearance of the raw materials by TLC, add 1N hydrochloric acid aqueous solution (3.6 ml). Further, the reaction solution is made weakly basic by adding aqueous ammonia, and extracted with ethyl acetate. After washing the organic layer with water, it is dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: chloroform: methanol: 'concentrated aqueous ammonia = 100: 4: 0.1), and 8-benzyloxy 5- [( 1S) -Hydroxy (2S) — (7-Methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl is obtained as a colorless oil, 184 mg.

[N] _D =-0.4 ° (c = 1.3.6, CHC 13)

 Similarly, from the diastereomer (β) (33 O mg) obtained in Example 33, (1) 18-benzyloxy 5 — [(1R) -hydroxy (2S)-(7— methoxy 1, 2,3,4-Tetrahydro-2-naphthyl) aminocetyl] carbostyryl is obtained as a colorless oil, 177 mg.

[] D =-7 2.1. (C = l. 4 5, . CHC 1 3)

[Example 35] 8—Benzyloxy 5 — [(1S) -Hydroxy (2S) — (7-Methoxy-1,2,3,4-tetrahydro 2-Naphthyl) aminoethyl] carbostyryl (155 mg) Ammonium formate (0.6 g) was added to a methanol (5 ml) solution, and the mixture was stirred at room temperature for 10 minutes. Subsequently, 10% Pd-C (7 Omg) was added, and the mixture was stirred at room temperature for 2 hours. Again, add ammonium formate (1. Og) and 10% Pd-C (3 Omg) and stir. After confirming the disappearance of the raw materials on TLC, the catalyst is filtered off, ion-exchanged water is added to the residue, and the mixture is purified by 0 DS short column chromatography. Immediately, the solution is started as a syneresis, and is flushed with only ion-exchanged water to adsorb the target substance to ODS. Next, the column was washed with a sufficient amount of ion-exchanged water, and the desired product was eluted with MeOH to give 8-hydroxy-5-[(1S) -hydroxy (2S) — (7- Obtain 84 mg (yield: 67%) of methoxy 1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyril as a pale yellow powder.

 8-Hydroxy-5-[(1S) -hydroxy (2S) — (7-methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl ] Obtain Carbostyril 'hydrochloride.

 [a] D = -25.3. (C = 0.62, M e O H)

 [Example 36]

According to the method of Example 35, 8-benzyloxy 5 — [(1R) -hydroxy (2S) — (7-methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] Carbostyril (16 Omg) to 8-hydroxy-1-5-((1R) -hydroxy (2S) — (7-methoxy-1,2,3,4-tetrahydro-2-naphthyl) [Aminoethyl] galbostyril is obtained as a pale yellow powder (73 mg, yield 57%). 8-Hydroxylic acid as a white crystalline powder 5 — [(1R) —Hydroxy (2S) — (7—Methoxy 1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] carbostyryl 'hydrochloride.

 [a] D = -8 8.6. (C = 0.53, e 0 H)

 [Example 37]

 A mixed solution of 8-benzyloxy-5-oxylanylcarbostyril (0.48 g) and (R) —2-amino-7-ethoxycarbonylmethoxytetralin (1.0 g) in isopropyl alcohol (25 ml) was added to 1 Heat to reflux for 2 hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel chromatography (eluent: chloroform: methanol: concentrated aqueous ammonia = 100: 4: 0.1) to give a pale yellow oil as a pale yellow oil. —Benzyloxy 5— [(1 RS) —Hydroxy (2 R) — (7-Ethoxycarbonylmethoxy 1, 2,2,3,4-Tetrohydr-2--2-naphthyl) aminoethyl] carbostyril as colorless oil 0.32 g (yield: 36%).

 [Example 38]

 8-benzyloxy-5-[(1RS) -hydroxy- (2R)-(7-ethoxycarbonylmethoxy 1,2.3,4-tetrahydro-2-naphthyl) aminoethyl] carbenstyril (100 mg) The reaction was carried out by the CTH method, and 8-hydroxy-5-[(1RS) -hydroxy-1 (2R) — (7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-2-naphthyl) Aminoethyl] carbostyryl was obtained as a pale yellow oil (4 Omg, yield: 48%).

The hydrochloride was converted into a light yellow-brown crystalline powder according to the usual method. 8-Hydroxie 5-([1RS) -Hydroxy (2R)-(7-Ethoxycarbonyl methoxy-1,2,3,4- Tetrahydro 2-naphthyl) aminoethyl] carbostyryl. Hydrochloride (mixture of two optical isomers). [Example 39]

 Example 3 According to the method of 7, from 8-benzyloxy 5-hydroxyxylanicarbarstyryl (0.5 g) and (S) -2-amino 7-ethoxycarbonyl methoxytetralin (1.0 g). 8—Benzyloxy 5 — [(1RS) —Hydroxy (2S) — (7-Ethoxycarbonylmethoxie 1,2,3,4-tetrahydro 2-naphthyl) aminoethyl] Carbostyril as colorless oil 0.53 g (yield: 57%).

 [Example 40]

 8-1-Benzyloxy 5 -— ((1RS) -Hydroxy (2S) — (7-Ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] Carbostyril (500 mg) The debenzylation was carried out by the CTH method, and 8-hydroxy-5-[(1RS) -hydroxy-1 (2S) -1- (7-ethoxycarbonylmethoxy-1,2,3,4-tetrahi draw 2-naphthyl) aminoethyl] carbostyryl was obtained as pale yellow-brown crystalline powder (165 mg, yield: 40%). It is converted into the hydrochloride according to the conventional method, and as a pale yellow-brown crystalline powder, 8-hydroxy-5-[(1RS) -hydroxy (2S)-(7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydrodraw) 2-naphthyl) aminoethyl] carbostyryl 'hydrochloride (mixture of two optical isomers).

 [Example 4 1]

8 After heating a mixture of monobenzyloxy-5-oxylanylcarbostyril (0.29 g) and 2-amino-6-methoxytetralin (0.46 g) in isopropyl alcohol (10 ml), The solvent is distilled off under reduced pressure. The residue was subjected to silica gel gel chromatography (eluent: chloroform: methanol: concentrated aqueous ammonia = 100: 4: 0.1) to give 8-benzyloxy-5- [1-hi as a pale yellow oil. Droxy 2— (6 -Methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyril was obtained in an amount of 0.34 g (yield: 71%).

_{1 H-NMR (CDC 1 3} ) δ ppm:

 1. 5 1-1.70 (1 H, m), 2.00— 2.10 (1 H, m), 2.50-3.10 (7H, m), 3.76 (3 H, m) s), 5.10 (1 H, d'd), 5.16 (2H, s), 6.61 (1 H, s), 6.64 (1 H, d, J = 9.8 Hz ), 6.69 (1H, brs), 6.95 (1H, dd, J = 8.5Hz), 7.01 (1H, d, J = 8.5Hz), 7.26 (1H, d, J = 8.5Hz), 7.39-7.43 (5H, m), 8.11, 8.12 (1H, d each).

 [Example 42]

 Example 4 8-Benzyloxy-5- [1-hydroxy-2- (6-methoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyril obtained in 1 (0.15 g) Debenzylation was carried out according to the method of Example 10 (CTH method) using 8-hydroxy-5- [1'-hydroxyl 2- (6-methoxy-1,2,3,4-tetrahydro-2-). Naphthyl) aminoethyl] Carbostyril was obtained in an amount of 108 mg (yield: 95%).

1 H-NMR (CD ₃ OD) δ ppm:

1.60-1.80 (1H, m), 2.10-2.30 (1H, m), 2.60-3.28 (7H, m), 3.74 (3H, s) , 4.89 (2H, brs), 5.25-5.37 (1 H, m), 6.63 -6.70 (3H, m) _r 6.95-7.02 (2 H, m) , 7.27 (1H, d, J = 9.2Hz), 8.38 (1H, d. J = 9.2Hz).

 [Example 43]

8—Benzyloxy 5— [i—Hydroxy 2— (6—Methoxy 1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] Carbostyryl (compound of Example 41) (138 mg) in methylene chloride (15 ml) was cooled to 140, and then boron tribromide was added. Drop 1.8 ml of methylene chloride (1 M solution). After dropping, gradually return to room temperature and stir for 2 hours. Methanol (10 m 1) is added to the reaction solution, and the mixture is stirred for 1 hour, and the solvent is distilled off under reduced pressure. The residue was fractionated using p-TLC (preparative thin-layer chromatography: developing solution, chromatographic form: methanol = 10: 3), and 8-hydroxy-5- [1-hydroxy-1-2- (6- Hydroxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl. 61 mg (yield: 46%) of hydrobromic acid is obtained.

1 H-NMR (CD ₃ OD) δ ppm:

 1.80-2.00 (1H, m), 2.30-2.50 (1H, m), 2.80-3.70 (7H, m), 4.91 (2H, s), 5.18 (1 H, brd), 6.52 (1 H, d, 3 = 2.4 Hz), 6.57 (1 H, dd, J = 2.4 Hz, 8.3 Hz) ), 6.73 (1 H, d, J = 8.3 Hz), 6.92 (1 H, d, J = 7.3 Hz), 7.08 (1 H, d, J = 7.8 Hz), 7.27 (1 H, d, J = 8.3 Hz), 8.49 (1 H, d, J = 7.8 Hz).

Claims

The scope of the claims  —General formula (I)

 1 (In the formula, OY is a lower alkoxy group which may be substituted with a hydroxyl group, a fuunyl group or a protected hydroxyl group, and Ζ is a hydrogen atom, or a hydroxyl group, an alkoxy group, or 10 CH ₂ as a substituent. — Represents a Α group, where A is a lower alkoxycarbonyl group, a substituted or unsubstituted N-substituted or unsubstituted alkoxy group or a straight-chain alkylene chain having 1 to 4 carbon atoms and a hydroxyl group. The dashed lines at positions 3 and 4 indicate that the positions 3 and 4 are saturated or a double bond.) Carbostyril derivatives represented by the formula: and pharmacologically acceptable salts thereof.  2. — OY is a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms or a benzyl group, and Z is a hydrogen atom or a hydroxyl group as a substituent, or an alkoxy group having 1 to 5 carbon atoms. The compound according to the above. 3. OY represents a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms or a benzyl group, Z represents 10 CH ₂ —A group, and A represents an alkoxycarbonyl group having 1 to 4 carbon atoms as a substituent. The compound according to claim 1, which has a linear, alkylene chain having 1 to 4 carbon atoms having a group, an N-substituted or unsubstituted alkoxy group having 1 to 4 carbon atoms, or a hydroxyl group. Compound.  4. The compound according to any one of claims 1 to 3, wherein the asymmetric carbon substituted at the 5-position of the carbostyril group has an absolute configuration (R).  5. 8—Hydroxy 5-((1R) -Hydroxy (2R) — (7-Methoxy-1,2,3,4-tetrahydro 2-naphthyl) aminonoethyl] Carbostyril, 8—Hydroxy Droxy 5— [1-Hydroxy-l 2 -— (7-Ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-l-l-naphthyl) aminoethyl] carbostyril, 8—Hydroxy 5 -— ((1R)- Hydroxy-2- (7-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyryl, 8-hydroxy-5— [1-hydroxy2— (7-hydroxy -1,2,3,4-tetrahydrido-2-naphthyl) aminoethyl] carbostyryl, 8-hydroxy-5- [1-hydroxy-2- (7-ethoxycarbonylmethoxy-1,2,3,4) —Tetrahi Draw 2—Naphthyl) Minoethyl] 1,3,4-dihydroxycarbostyril, 8-hydroxy-5- [1-hydroxy2— (7-ethoxycarbonylbutoxy-1,2,3,4-tetrahydro-2-naphthyl) aminoethyl ] Carbostyril, 8-hydroxy-5- [1—Hydroxy-2- (6-methoxy1,2,3,4-tetrahydro-2-naphthyl) aminoethyl] carbostyril, 8-methoxy-5- [ 2. The carbostyril derivative according to claim 1, which is 1-hydroquinine-1- (7-methoxy-1,2,3.4-tetrahydro-2-naphthyl) aminoethyl] carbostyril and a pharmacologically acceptable derivative thereof. salt.