JPH10152460A - 2-amino-1- (4-hydroxy-2-methylphenyl) propanol derivative - Google Patents

Abstract

(57) Abstract: A novel 2-amino-1- (4-hydroxy-2-methylphenyl) propanol derivative having a potent and selective β ₂ -adrenoreceptor stimulating action. SOLUTION: The general formula useful as a drug such as an agent for preventing imminent flow / premature birth, a bronchodilator, etc. [One of Y ¹ and Z ¹ is a group represented by the general formula —O—A—R (A is an alkylene group, an alkenylene group, R is a hydroxyl group, an alkoxy group,
An aralkyloxy group, a phenyl group or a heterocyclic group which may have a hydroxyl group as a substituent), the other being a hydrogen atom, and a carbon atom to which (R) or (S) is attached. The atoms represent carbon atoms in the R and S configurations, respectively.
A 2-amino-1- (4-hydroxy-2-methylphenyl) propanol derivative represented by the formula: and pharmacologically acceptable salts thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel 2-amino-1- (4-hydroxy-2-) useful as a pharmaceutical.
The present invention relates to a (methylphenyl) propanol derivative and a pharmacologically acceptable salt thereof.

More specifically, the present invention has a potent and selective β ₂ -adrenoceptor stimulating action, thereby reducing the burden on the heart such as tachycardia.
A general formula useful as a drug, such as an agent for preventing premature birth, a bronchodilator, a pain relieving agent for urolithiasis, and a lithotripsy accelerator

[0003]

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[In the formula, one of Y ¹ and Z ¹ is a general formula —O—A—R (A is a lower alkylene group or a lower alkenylene group, and R is a hydroxyl group, a lower alkoxy group, An alkyloxy group, a phenyl group which may have a hydroxyl group as a substituent, or a 5- to 7-membered heterocyclic group containing one or two nitrogen or oxygen atoms in the ring)
Wherein the other is a hydrogen atom, the carbon atom with (R) represents a carbon atom in R configuration, and the carbon atom with (S) represents a carbon atom in S configuration. A 2-amino-1- (4-hydroxy-2-methylphenyl) propanol derivative represented by the formula: and their pharmacologically acceptable salts.

[0005]

SUMMARY OF THE INVENTION The object of the present invention is to provide β ₁
-Β _2- Stronger than adrenergic receptor stimulatory action-has a stimulating action on the heart such as tachycardia due to having a stimulating action of adrenergic receptor, thereby reducing the risk to the heart such as tachycardia; It is an object of the present invention to provide a novel compound which is useful as a pharmaceutical such as a pain relieving agent and a stone excretion promoting agent.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present inventors have conducted intensive studies to find excellent β ₂ -adrenoceptor stimulants,
Certain 2-amino-1-types represented by the general formula (I)
(4-Hydroxy-2-methylphenyl) propanol derivative has a potent and selective β ₂ -adrenoceptor stimulating action, and has been found to be very useful as a β ₂ -adrenoceptor stimulant. The present invention has been accomplished.

The present invention relates to a compound represented by the general formula (1) having a selective β ₂ -adrenoceptor stimulating action:

[0008]

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[In the formula, one of Y ¹ and Z ¹ is a general formula —O—A—R wherein A is a lower alkylene group or a lower alkenylene group, and R is a hydroxyl group, a lower alkoxy group, An alkyloxy group, a phenyl group which may have a hydroxyl group as a substituent, or a 5- to 7-membered heterocyclic group containing one or two nitrogen or oxygen atoms in the ring)
Wherein the other is a hydrogen atom, the carbon atom with (R) represents a carbon atom in R configuration, and the carbon atom with (S) represents a carbon atom in S configuration. A 2-amino-1- (4-hydroxy-2-methylphenyl) propanol derivative represented by the formula: and their pharmacologically acceptable salts.

In the compound of the present invention represented by the general formula (I), the lower alkylene group is a carbon atom such as a methylene group, an ethylene group, a trimethylene group, a propylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group and the like. Number 1
Refers to a linear or branched alkylene group of from 6 to 6,
A lower alkenylene group is a vinylene group, a propenylene group,
A linear or branched alkenylene group having 2 to 6 carbon atoms, such as a butenylene group, a pentenylene group, and a hexenylene group, is referred to as a lower alkoxy group. ~ 6
A aralkyloxy group refers to the lower alkoxy group having an aryl group such as a phenyl group or a naphthyl group, and one or two nitrogen atoms or oxygen atoms in the ring. The 5- to 7-membered heterocyclic group includes an aliphatic or aromatic heterocyclic group such as a tetrahydrofuranyl group, a tetrahydropyranyl group, a 1,3-dioxolanyl group, and a pyridyl group.

The compound represented by the general formula (I) of the present invention can be produced as follows.

For example, the general formula

[0013]

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(In the formula, R ¹ is a hydroxyl group which may have a protecting group, and a carbon atom to which (R) is attached and (S)
Has the same meaning as described above) and an amine compound represented by the general formula

[0015]

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[In the formula, one of Y ² and Z ² is a group represented by the general formula —O—A—R ⁰ (where R ⁰ represents a lower alkoxy group, an aralkyloxy group, a hydroxyl group protected as a substituent) A phenyl group or a 5- to 7-membered heterocyclic group containing one or two nitrogen atoms or oxygen atoms in the ring, and A has the same meaning as described above. And the other is a hydrogen atom], and if necessary, removing the protecting group of the hydroxyl group according to a conventional method, followed by hydrolysis if desired.

The amine compound represented by the general formula (II) used as a starting material in the production method is as follows:
General formula

[0018]

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(Wherein R ² is a protecting group for a hydroxyl group;
Is a halogen atom), and reacting the compound with a base such as butyllithium.

[0020]

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(Wherein R ³ is a protecting group for an amino group,
The compound represented by (S) has the same meaning as described above), and the carbonyl group is reduced using a reducing agent such as sodium borohydride. After removing the protecting group, the compound can be produced by removing the protecting group for the hydroxyl group, if desired.

The compound represented by the general formula (III) used as a starting material in the production method is represented by the general formula:

[0023]

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Wherein one of Y ³ and Z ³ in the formula is a hydroxyl group and the other is a hydrogen atom;

XAR ⁰ (VII)

(A in the formula, R ⁰ and X have the same meanings as described above), and the reaction is carried out in the presence of a base such as potassium carbonate. It can be manufactured by introducing.

The compounds represented by the general formulas (IV), (V), (VI) and (VII) used in the above production method can be obtained by purchasing a commercially available reagent or by using a conventional synthesis means. It can be easily obtained by manufacturing.

The compound of the present invention represented by the general formula (I) 2-
Amino-1- (4-hydroxy-2-methylphenyl)
The propanol derivative can be converted into a pharmacologically acceptable salt by a conventional method. Such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid. Acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid,
Examples thereof include acid addition salts with organic acids such as butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, and aspartic acid, and salts with inorganic bases such as sodium salts and potassium salts.

The compounds of the present invention and salts thereof 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, a solvent extraction method and the like. be able to.

The compounds of the present invention also include solvates with pharmaceutically acceptable solvents such as water and ethanol.

In the compound represented by the general formula (I) of the present invention, the compound having an unsaturated bond includes two types of geometric isomers, E-form and Z-form. Geometric isomers may be used.

Among the compounds represented by the above general formula (I) of the present invention, compounds having an asymmetric carbon include two types of compounds having an R configuration and an S configuration on the asymmetric carbon. Although optical isomers exist, any isomer may be used in the present invention, and a mixture of these isomers may be used.

The compound represented by the above general formula (I) of the present invention can be prepared by the method of using a normal isolated rat uterus in a rat.
In a test for measuring β ₂ -adrenergic receptor stimulating action in vitro, approximately 1.0 × 10 ⁻⁸ 8.0 × 10
Automatic movement of uterine smooth muscle ^-7 molar showed an effect of 50% inhibition _{(EC 50} value). For example, (1R, 2
EC for S) -2-[[2- [4- (2-benzyloxyethoxy) phenyl] ethyl] amino] -1- (4-hydroxy-2-methylphenyl) propan-1-ol
_{The 50} value was 1.13 × 10 ⁻⁸ molar.

As described above, the compound of the present invention is a compound having a very strong β ₂ -adrenoceptor stimulating action.

The compound represented by the above general formula (I) of the present invention can be prepared by using i.
In adrenoceptor stimulating effects measurement test, β ₂ - - β ₁ of n vitro had no particular effect on the heart rate at doses showing an EC ₅₀ value in adrenergic activity measurement test. For example, (1R, 2S) -2-[[2
-[4- (2-Benzyloxyethoxy) phenyl] ethyl] amino] -1- (4-hydroxy-2-methylphenyl) propan-1-ol provides a heart rate at 1.0 × 10 ⁻⁷ molar concentration. The rate of increase was about twice per minute, and the rate of increase was 1% or less.

Tachycardia due adrenoceptor stimulating effects - [0036] Thus, the compounds of the present invention is beta ₂ - adrenergic receptor stimulating effect is very strong, and beta ₁ - for adrenoceptor stimulating action is extremely weak, beta ₁ burden on the heart, etc. is reduced, highly useful beta ₂ as pharmaceuticals - adrenoceptor stimulant.

The compound of the present invention has a selective β ₂ -adrenergic receptor stimulating action, and is used as an agent for preventing imminent flow / premature birth, a bronchodilator, an agent for relieving pain in urolithiasis or promoting calculi. It is a compound useful as a pharmaceutical.

The compound of the present invention represented by the general formula (I) 2-
Amino-1- (4-hydroxy-2-methylphenyl)
When propanol derivatives and their pharmacologically acceptable salts are used in actual treatments, appropriate pharmaceutical preparations such as tablets, powders, fine granules, granules, capsules, injections, etc. Administered parenterally or parenterally. These pharmaceutical preparations can be prepared by commonly used pharmaceutical methods using commonly used carriers, excipients and the like.

The dose is appropriately determined depending on the age, sex, weight, degree of symptoms and the like of the subject patient.
In the case of oral administration, generally 1 to 1000 m per adult per day
g, in the case of parenteral administration, generally 0.01-
It is administered once or several times within a range of 100 mg.

The contents of the present invention will be described in more detail with reference to the following Reference Examples, Examples and Test Examples, but the present invention is not limited to the contents. The melting points of the compounds in Reference Examples and Examples are all uncorrected.

[0041]

【Example】

Reference Example 1 (1R, 2S) -2-amino-1- (4-benzyloxy-2-methylphenyl) propan-1-ol 44.3 g of benzyl-4-bromo-3-methylphenyl = ether was added to 500 ml of tetrahydrofuran. Melted,
1.69 molar n under -78 ° C and argon atmosphere stirring
And 98.6 ml of a butyllithium hexane solution.
After reacting for an hour, (S) -2- (tert-butoxycarbonylamino) -N-methoxy-N-methylpropionamide (16.1 g) was added, and the temperature was raised to -10 ° C over 2 hours. The reaction solution was poured into a saturated aqueous ammonium chloride solution under ice-cooling and stirring, 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 flash column chromatography on silica gel (eluent: hexane / ethyl acetate = 1).
0/1) to give an oily (S) -4′-benzyloxy-2- (tert-butoxycarbonylamino)-
15.8 g of 2'-methylpropiophenone was obtained.

IR (neat): 3423, 1713,
^{1680cm -1 1 H-NMR (CDCl} 3) δppm: 1.30 (3
H, d, J = 7.1 Hz), 1.46 (9H, s),
2.50 (3H, s), 5.05-5.25 (3H,
m), 5.50-5.60 (1H, m), 6.80-
6.90 (2H, m), 7.30-7.45 (5H,
m), 7.73 (1H, d, J = 8.5 Hz)

(S) -4'-benzyloxy-2- (t
13.3 g of tert-butoxycarbonylamino) -2′-methylpropiophenone was dissolved in 130 ml of methylene chloride, a solution of 65 ml of trifluoroacetic acid in 65 ml of methylene chloride was added under ice-cooling and stirring, and the mixture was reacted at room temperature for 30 minutes. After the reaction solution was concentrated under reduced pressure, the residue was
The solution was dissolved in 60 ml, and 6.8 g of sodium borohydride was added thereto under ice-cooling and stirring, and reacted at room temperature for 12 hours. After concentrating the reaction solution under reduced pressure, water was added to the residue, and the precipitated crystals were collected by filtration. 7.5 g of phenyl) propan-1-ol were obtained.

IR (KBr): 3353, 3283 cm
^{-1 1 H-NMR (DMSO-} d 6) δppm: 0.91
(3H, d, J = 6.4 Hz), 1.29 (2H, b
r), 2.27 (3H, s), 2.80-2.90 (1
H, m), 4.45 (1H, d, J = 4.7 Hz),
4.89 (1H, brs), 5.07 (2H, s),
6.78 (1H, d, J = 2.6 Hz), 6.83 (1
H, dd, J = 8.4, 2.6 Hz), 7.25-7.
50 (6H, m)

Reference Example 2 2- [4- (2-benzyloxyethoxy) phenyl]
Ethanol 2-benzyloxyethanol (4.0 ml) was dissolved in methylene chloride (145 ml), and carbon tetrabromide was dissolved at room temperature with stirring.
After adding 0 g, 8.84 g of triphenylphosphine was added over 5 minutes, and the mixture was reacted for 1 hour. 450 ml of hexane was added to the reaction solution, and the insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, 200 ml of hexane was added to the residue, and the insolubles were removed again. After the filtrate was concentrated under reduced pressure, the residue was purified by medium-pressure liquid column chromatography on aminopropylated silica gel (eluent: hexane) to give oily benzyl =
4.84 g of 2-bromoethyl ether were obtained.

¹ H-NMR (CDCl ₃ ) δ ppm:
3.49 (2H, d, J = 6.2 Hz), 3.79 (2
H, d, J = 6.2 Hz), 4.59 (2H, s),
7.25-7.40 (5H, m)

4-hydroxyphenethyl alcohol
83 g was dissolved in 50 ml of acetone, and potassium carbonate was added.
A solution of 11 g and benzyl 2-bromoethyl = ether (4.84 g) in acetone (50 ml) was added, and the mixture was heated under reflux for 23 hours. After concentrating the reaction mixture under reduced pressure, the residue was N, N
-Dissolve in 100 ml of dimethylformamide, 120 ° C
The reaction was performed for 2 hours with stirring. After cooling, the insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by aminopropylated silica gel medium pressure liquid column chromatography (elution solvent: hexane / ethyl acetate = 1/1) to give an oil. 2-
4.48 g of [4- (2-benzyloxyethoxy) phenyl] ethanol was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm:
1.33 (1H, t, J = 6.0 Hz), 2.81 (2
H, t, J = 6.6 Hz), 3.75-3.90 (4
H, m), 4.10-4.20 (2H, m), 4.63
(2H, s), 6.88 (2H, d, J = 8.7H)
z), 7.13 (2H, d, J = 8.7 Hz), 7.2
0-7.40 (5H, m)

Reference Example 3 The following compound was obtained in the same manner as in Reference Example 2, using the corresponding halogen derivative instead of benzyl 2-bromoethyl ether.

2- [3- (5-benzyloxypentyloxy) phenyl] ethanol

Oily ¹ H-NMR (CDCl ₃ ) δ ppm: 1.38 (1
H, t, J = 6.5 Hz), 1.50-1.90 (6
H, m), 2.84 (2H, t, J = 6.5 Hz),
3.50 (2H, t, J = 6.5 Hz), 3.85 (2
H, q, J = 6.5 Hz), 3.95 (2H, t, J =
6.5 Hz), 4.50 (2H, s), 6.70-6.
85 (3H, m), 7.15-7.40 (6H, m)

2- [3- (4-benzyloxybutoxy) phenyl] ethanol

Oily ¹ H-NMR (CDCl ₃ ) δ ppm: 1.39 (1
H, br), 1.75-1.95 (4H, m), 2.8.
4 (2H, t, J = 6.5 Hz), 3.55 (2H,
t, J = 6.2 Hz), 3.85 (2H, t, J = 6.
5Hz), 3.97 (2H, t, J = 6.2Hz),
4.52 (2H, s), 6.70-6.85 (3H,
m), 7.15-7.40 (6H, m)

2- [4- (2-methoxyethoxy) phenyl] ethanol

Oily ¹ H-NMR (CDCl ₃ ) δ ppm: 1.43 (1
H, t, J = 6.0 Hz), 2.75-2.85 (2
H, m), 3.45 (3H, s), 3.75 (2H,
t, J = 4.7 Hz), 3.80-3.90 (2H,
m), 4.11 (2H, t, J = 4.7 Hz), 6.8
9 (2H, d, J = 8.7 Hz), 7.14 (2H,
d, J = 8.7 Hz)

2- [4- (2-ethoxyethoxy) phenyl] ethanol

Oily ¹ H-NMR (CDCl ₃ ) δ ppm: 1.25 (3
H, t, J = 7.0 Hz), 1.50 (1H, br)
s), 2.75-2.85 (2H, m), 3.61 (2
H, q, J = 7.0 Hz), 3.75-3.90 (4
H, m), 4.11 (2H, t, J = 4.9 Hz),
6.88 (2H, d, J = 8.7 Hz), 7.13 (2
H, d, J = 8.7 Hz)

(E) -2- (4-cinnamyloxyphenyl) ethanol

Melting point: 94 to 101 ° C. (unrecrystallized) ¹ H-NMR (CDCl ₃ ) δ ppm: 1.36 (1
H, t, J = 6.0 Hz), 2.82 (2H, t, J =
6.5 Hz), 3.83 (2H, dt, J = 6.5,
6.0 Hz), 4.69 (2H, dd, J = 5.8,
1.5 Hz), 6.42 (1H, dt, J = 16.0,
5.8 Hz), 6.73 (1H, d, J = 16.0H)
z), 6.92 (2H, d, J = 8.6 Hz), 7.1
6 (2H, d, J = 8.6 Hz), 7.20-7.45
(5H, m)

2- [4-[(1,3-dioxolan-2
-Yl) methoxy] phenyl] ethanol

Oily ¹ H-NMR (CDCl ₃ ) δ ppm: 1.39 (1
H, brs), 2.81 (2H, t, J = 6.5H)
z), 3.75-4.10 (8H, m), 5.28 (1
H, t, J = 4.1 Hz), 6.89 (2H, d, J =
8.6 Hz), 7.14 (2H, d, J = 8.6 Hz)

Reference Example 4 2- [4- [2- (4-benzyloxyphenyl) ethoxy] phenyl] ethanol 1.38 g of 4-hydroxyphenethyl alcohol was dissolved in 50 ml of acetone, and 2.07 g of potassium carbonate and benzyl chloride were dissolved in 50 ml of acetone. 73 ml was added, and the mixture was stirred for 16 hours while heating under reflux. After cooling, the insolubles were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel medium pressure liquid column chromatography (eluent: hexane / ethyl acetate = 1/1) to give a melting point of 87-88. 1.42 g of 4-benzyloxyphenethyl alcohol at <RTIgt;

¹ H-NMR (CDCl ₃ ) δ ppm:
1.34 (1H, t, J = 5.9 Hz), 2.81 (2
H, t, J = 6.5 Hz), 3.82 (2H, dt, J
= 6.5, 5.9 Hz), 5.05 (2H, s), 6.
93 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.6 Hz)
d, J = 8.6 Hz), 7.30-7.50 (5H,
m)

1.41 g of 4-benzyloxyphenethyl alcohol was dissolved in 60 ml of methylene chloride, 3.06 g of carbon tetrabromide was added with stirring at room temperature, and 1.94 g of triphenylphosphine was added over 5 minutes, followed by 1 hour. Reacted. After concentrating the reaction solution under reduced pressure, the residue was purified by silica gel medium pressure liquid column chromatography (elution solvent: hexane / ethyl acetate = 1/1), and benzyl = 4- (2-bromoethyl) having a melting point of 65-67 ° C. ) 1.71 g of phenyl ether were obtained.

¹ H-NMR (CDCl ₃ ) δ ppm:
3.10 (2H, t, J = 7.6 Hz), 3.53 (2
H, t, J = 7.6 Hz), 5.05 (2H, s),
6.93 (2H, d, J = 8.7 Hz), 7.13 (2
H, d, J = 8.7 Hz), 7.30-7.50 (5
H, m)

874 mg of benzyl 4- (2-bromoethyl) phenyl = ether was dissolved in 15 ml of acetone, and 415 mg of potassium carbonate and 276 mg of 4-hydroxyphenethyl alcohol were added under stirring at room temperature.
Heated to reflux for an hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 15 ml of N, N-dimethylformamide.
The mixture was reacted for 12 hours while stirring at 0 ° C. After cooling, the reaction mixture was concentrated under reduced pressure, and the residue was subjected to aminopropylated silica gel medium pressure liquid column chromatography (elution solvent: hexane / hexane).
Purified with ethyl acetate = 1/1) to obtain amorphous 2-
310 mg of [4- [2- (4-benzyloxyphenyl) ethoxy] phenyl] ethanol were obtained.

¹ H-NMR (CDCl ₃ ) δ ppm:
1.32 (1H, t, J = 6.0 Hz), 2.80 (2
H, t, J = 6.5 Hz), 3.03 (2H, t, J =
7.1 Hz), 3.82 (2H, dt, J = 6.5,
6.0 Hz), 4.12 (2H, t, J = 7.1H)
z), 5.05 (2H, s), 6.85 (2H, d, J
= 8.6 Hz), 6.93 (2H, d, J = 8.7H)
z), 7.12 (2H, d, J = 8.6 Hz), 7.1
9 (2H, d, J = 8.7 Hz), 7.30-7.50
(5H, m)

Reference Example 5 2- [4- (2-benzyloxyethoxy) phenyl] ethyl p-toluenesulfonate 3.86 g of 2- [4- [2- (4-benzyloxyphenyl) ethoxy] phenyl] ethanol was added. 5. Dissolve in 70 ml of methylene chloride, and triethylamine under ice-cooling and stirring.
0 ml and p-toluenesulfonyl chloride 3.00
g was added and reacted at room temperature for 15 hours. The reaction solution was washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel medium pressure liquid column chromatography (eluent: hexane / ethyl acetate = 3/1), melting point 44-46 ° C
5.04 g of 2- [4- (2-benzyloxyethoxy) phenyl] ethyl p-toluenesulfonate was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm:
2.42 (3H, s), 2.89 (2H, t, J = 7.
1 Hz), 3.80-3.90 (2H, m), 4.05
-4.25 (4H, m), 4.63 (2H, s), 6.
80 (2H, d, J = 8.7 Hz), 7.01 (2H, d, J = 8.7 Hz)
d, J = 8.7 Hz), 7.25-7.40 (7H,
m), 7.69 (2H, d, J = 8.3 Hz)

Reference Example 6 The following compound was obtained in the same manner as in Reference Example 5, except that 2- [4- [2- (4-benzyloxyphenyl) ethoxy] phenyl] ethanol was replaced with the corresponding compound. .

P-Toluenesulfonic acid 2- [3- (5-
Benzyloxypentyloxy) phenyl] ethyl

Oily ¹ H-NMR (CDCl ₃ ) δ ppm: 1.50-1.
85 (6H, m), 2.42 (3H, s), 2.91
(2H, t, J = 7.1 Hz), 3.50 (2H, t,
J = 6.5 Hz), 3.90 (2H, t, J = 6.5H)
z), 4.20 (2H, t, J = 7.1 Hz), 4.5
1 (2H, s), 6.60-6.80 (3H, m),
7.14 (1H, t, J = 7.9 Hz), 7.25−
7.40 (7H, m), 7.69 (2H, d, J = 8.
5Hz)

P-Toluenesulfonic acid 2- [3- (4-
Benzyloxybutoxy) phenyl] ethyl

Oily ¹ H-NMR (CDCl ₃ ) δ ppm: 1.70-1.
95 (4H, m), 2.42 (3H, s), 2.91
(2H, t, J = 7.1 Hz), 3.55 (2H, t,
J = 6.2 Hz), 3.92 (2H, t, J = 6.2H)
z), 4.19 (2H, t, J = 7.1 Hz), 4.5
2 (2H, s), 6.62 (1H, brs), 6.6
8 (1H, d, J = 7.7 Hz), 6.73 (1H, d
d, J = 8.1, 1.9 Hz), 7.14 (1H, d
d, J = 8.1, 7.7 Hz), 7.20-7.40
(7H, m), 7.69 (2H, d, J = 8.3 Hz)

P-Toluenesulfonic acid 2- [4- (2-
Methoxyethoxy) phenyl] ethyl

Oily ¹ H-NMR (CDCl ₃ ) δ ppm: 2.43 (3
H, s), 2.89 (2H, t, J = 7.1 Hz),
3.45 (3H, s), 3.70-3.80 (2H,
m), 4.05-4.15 (2H, m), 4.16 (2
H, t, J = 7.1 Hz), 6.81 (2H, d, J =
8.6 Hz), 7.01 (2H, d, J = 8.6H)
z), 7.28 (2H, d, J = 8.2 Hz), 7.6
9 (2H, d, J = 8.2 Hz)

P-Toluenesulfonic acid 2- [4- (2-
Ethoxyethoxy) phenyl] ethyl

Oily ¹ H-NMR (CDCl ₃ ) δ ppm: 1.24 (3
H, t, J = 7.0 Hz), 2.43 (3H, s),
2.88 (2H, t, J = 7.1 Hz), 3.60 (2
H, q, J = 7.0 Hz), 3.70-3.85 (2
H, m), 4.09 (2H, t, J = 4.9 Hz),
4.16 (2H, t, J = 7.1 Hz), 6.80 (2
H, d, J = 8.8 Hz), 7.01 (2H, d, J =
8.8 Hz), 7.28 (2H, d, J = 8.1H)
z), 7.69 (2H, d, J = 8.1 Hz)

P-Toluenesulfonic acid 2- [4-
[(1,3-dioxolan-2-yl) methoxy] phenyl] ethyl

Amorphous ¹ H-NMR (CDCl ₃ ) δ ppm: 2.43 (3
H, s), 2.89 (2H, t, J = 7.1 Hz),
3.90-4.20 (8H, m), 5.28 (1H,
t, J = 4.0 Hz), 6.82 (2H, d, J = 8.
7 Hz), 7.01 (2H, d, J = 8.7 Hz),
7.25-7.30 (2H, m), 7.69 (2H,
d, J = 8.3 Hz)

P-Toluenesulfonic acid 2- [4- [2-
(4-benzyloxyphenyl) ethoxy] phenyl]
ethyl

Oil ¹ H-NMR (CDCl ₃ ) δ ppm: 2.41 (3
H, s), 2.88 (2H, t, J = 7.1 Hz),
3.02 (2H, t, J = 7.1 Hz), 4.10 (2
H, t, J = 7.1 Hz), 4.16 (2H, t, J =
7.1 Hz), 5.05 (2H, s), 6.77 (2
H, d, J = 8.7 Hz), 6.93 (2H, d, J =
8.7 Hz), 7.00 (2H, d, J = 8.7H)
z), 7.19 (2H, d, J = 8.7 Hz), 7.2
5-7.45 (7H, m), 7.69 (2H, d, J =
8.4Hz)

(E) -p-Toluenesulfonic acid 2- (4
-Cinnamyloxyphenyl) ethyl

Melting point: 121 to 124 ° C. (unrecrystallized) ¹ H-NMR (CDCl ₃ ) δ ppm: 2.43 (3
H, s), 2.90 (2H, t, J = 7.1 Hz),
4.17 (2H, t, J = 7.1 Hz), 4.67 (2
H, dd, J = 5.8, 1.5 Hz), 6.41 (1
H, dt, J = 16.0, 5.8 Hz), 6.73 (1
H, d, J = 16.0 Hz), 6.84 (2H, d, J)
= 8.7 Hz), 7.03 (2H, d, J = 8.7H)
z), 7.20-7.45 (7H, m), 7.70 (2
(H, d, J = 8.3 Hz)

Example 1 (1R, 2S) -2-[[2- [4- (2-benzyloxyethoxy) phenyl] ethyl] amino] -1- (4
-Hydroxydroxy-2-methylphenyl) propan-1-ol (1R, 2S) -2-amino-1- (4-benzyloxy-2-methylphenyl) propan-1-ol 1.4
8 g and 150 mg of 10% palladium carbon were suspended in 28 ml of ethanol, and the mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 25 ml of N, N-dimethylformamide.
Under stirring at room temperature, p-toluenesulfonic acid 2- [4- (2-
Benzyloxyethoxy) phenyl] ethyl 1.11 g
Was added to a solution of N, N-dimethylformamide in 15 ml,
The reaction was performed at 90 ° C. for 3 hours. After cooling, add water to the reaction solution,
The mixture was 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 column chromatography (eluent: chloroform / methanol = 30/1) to obtain an oily (1).
R, 2S) -2-[[2- [4- (2-benzyloxyethoxy) phenyl] ethyl] amino] -1- (4-hydroxydroxy-2-methylphenyl) propane-1
-352 mg of all were obtained.

IR (neat): 3401, 3338c
^{m -1 1 H-NMR (CDCl} 3) δppm: 0.99 (3
H, d, J = 6.3 Hz), 2.18 (3H, s),
2.60-2.85 (4H, m), 2.90-3.05
(1H, m), 3.80-3.90 (2H, m), 4.
10-4.20 (2H, m), 4.65-4.75 (3
H, m), 6.46 (1H, d, J = 2.6 Hz),
6.51 (1H, dd, J = 8.4, 2.6 Hz),
6.76 (2H, d, J = 8.6 Hz), 6.99 (2
H, d, J = 8.6 Hz), 7.10 (1H, d, J =
8.4 Hz), 7.25-7.45 (5H, m)

Example 2 The following compound was obtained in the same manner as in Example 1 except that the corresponding compound was used instead of 2- [4- (2-benzyloxyethoxy) phenyl] ethyl p-toluenesulfonate. .

(1R, 2S) -1- (4-hydroxy-
2-methylphenyl) -2-[[2- [4- (2-methoxyethoxy) phenyl] ethyl] amino] propane-
1-all

[0089] Amorphous ^{IR (film): 3289cm -1 1} H-NMR (CDCl 3) δppm: 1.03 (3
H, d, J = 6.3 Hz), 2.19 (3H, s),
2.60-2.85 (4H, m), 2.95-3.10
(1H, m), 3.51 (3H, s), 3.80-3.
90 (2H, m), 4.10-4.20 (2H, m),
4.66 (1H, d, J = 6.2 Hz), 6.45 (1
H, d, J = 2.6 Hz), 6.50 (1H, dd, J)
= 8.4, 2.6 Hz), 6.74 (2H, d, J =
8.6 Hz), 6.97 (2H, d, J = 8.6H)
z), 7.07 (1H, d, J = 8.4 Hz)

(1R, 2S) -2-[[2- [4- (2
-Ethoxyethoxy) phenyl] ethyl] amino] -1
-(4-hydroxy-2-methylphenyl) propane-
1-all

[0091] Amorphous ^{IR (film): 3284cm -1 1} H-NMR (CDCl 3) δppm: 1.07 (3
H, d, J = 6.2 Hz), 1.30 (3H, t, J =
7.0 Hz), 2.18 (3H, s), 2.55-2.
85 (4H, m), 2.95-3.05 (1H, m),
3.69 (2H, q, J = 7.0 Hz), 3.80 −
3.95 (2H, m), 4.05-4.20 (2H,
m), 4.61 (1H, d, J = 6.6 Hz), 6.4
4 (1H, d, J = 2.5 Hz), 6.48 (1H, d
d, J = 8.4, 2.5 Hz), 6.72 (2H, d,
J = 8.6), 6.94 (2H, d, J = 8.6H)
z), 7.02 (1H, d, J = 8.4 Hz)

(1R, 2S) -2-[[2- [4-
[(1,3-dioxolan-2-yl) methoxy] phenyl] ethyl] amino] -1- (4-hydroxy-2-
Methylphenyl) propan-1-ol

[0093] Amorphous ^{IR (film): 3402cm -1 1} H-NMR (DMSO-d 6) δppm: 0.84
(3H, d, J = 6.3 Hz), 1.33 (1H, b
r), 2.16 (3H, s), 2.45-2.80 (5
H, m), 3.80-4.05 (6H, m), 4.64
(1H, br s), 4.74 (1H, br s),
5.17 (1H, t, J = 3.9 Hz), 6.48 (1
H, s), 6.54 (1H, dd, J = 8.3, 2.0
Hz), 6.82 (2H, d, J = 8.4 Hz), 7.
05 (2H, d, J = 8.4 Hz), 7.16 (1H,
d, J = 8.3 Hz), 9.06 (1H, brs)

(1R, 2S)-(E) -2-[[2-
(4-cinnamyloxyphenyl) ethyl] amino]-
1- (4-hydroxy-2-methylphenyl) propan-1-ol

[0095] mp: 182~193 ℃ ^{(non-recrystallization) IR (KBr): 3395,3322cm -1} 1 H-NMR (DMSO-d 6) δppm: 0.99
(3H, d, J = 6.6 Hz), 2.20 (3H,
s), 2.90-3.05 (2H, m), 3.10-
3.35 (3H, m), 4.71 (2H, d, J = 5.
8Hz), 5.21 (1H, brs), 5.85 (1
H, d, J = 3.6 Hz), 6.50 (1H, dt, J)
= 16.0, 5.8 Hz), 6.55 (1H, d, J =
2.5 Hz), 6.63 (1H, dd, J = 8.4,
2.5Hz), 6.76 (1H, d, J = 16.0H)
z), 6.97 (2H, d, J = 8.6 Hz), 7.1
5-7.30 (4H, m), 7.35 (2H, t, J =
7.4 Hz), 7.45-7.50 (2H, m), 8.
70 (1H, br), 8.88 (1H, br), 9.2
6 (1H, s)

Example 3 4- [3- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxy-2-methylphenyl) -1-]
Methylethyl] amino] ethyl] phenoxy] butane-
1-ol hydrochloride (1R, 2S) -2-amino-1- (4-benzyloxy-2-methylphenyl) propan-1-ol 518
mg and 434 mg of 2- [3- (4-benzyloxybutoxy) phenyl] ethyl p-toluenesulfonate were dissolved in 2.87 ml of N, N-dimethylformamide.
The reaction was performed for 3 hours under stirring at 75 ° C. After the reaction solution was concentrated under reduced pressure, the residue was purified by aminopropylated silica gel flash column chromatography (elution solvent: hexane / ethyl acetate = 1/1). The obtained amorphous 5
Acetic acid 1
The suspension was stirred at room temperature under a hydrogen atmosphere for 12 hours. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to aminopropylated silica gel flash column chromatography (elution solvent: chloroform / methanol = 15).
/ 1). The obtained amorphous was dissolved in ethyl acetate (5.0 ml), and a saturated hydrogen chloride diethyl ether solution was added under stirring at room temperature until a white precipitate was not generated, and the precipitate was collected by filtration. −
[3- [2-[[(1S, 2R) -2-hydroxy-2
-(4-hydroxy-2-methylphenyl) -1-methylethyl] amino] ethyl] phenoxy] butane-1-
170 mg of all hydrochloride were obtained.

IR (KBr): 3388, 2458 cm
^{-1 1 H-NMR (DMSO-} d 6) δppm: 0.99
(3H, d, J = 6.6 Hz), 1.50-1.80
(4H, m), 2.20 (3H, s), 2.90-3.
50 (7H, m), 3.96 (2H, t, J = 6.5H
z), 4.46 (1H, t, J = 5.1 Hz), 5.1
7 (1H, br s), 5.85 (1H, br s),
6.50-6.70 (2H, m), 6.80-6.90
(3H, m), 7.20-7.30 (2H, m), 8.
65 (2H, br), 9.29 (1H, s)

Example 4 The following compound was obtained in the same manner as in Example 3 except that the corresponding compound was used instead of 2- [3- (4-benzyloxybutoxy) phenyl] ethyl p-toluenesulfonate. .

5- [3- [2-[[(1S, 2R) -2
-Hydroxy-2- (4-hydroxy-2-methylphenyl) -1-methylethyl] amino] ethyl] phenoxy] pentan-1-ol

Amorphous IR (film): 3388 cm^{-1 1} H-NMR (CDCl₃) Δ ppm: 0.80-1.
00 (4H, m), 1.50-1.90 (6H, m),
2.23 (3H, s), 2.70-3.10 (5H,
m), 3.35 (1H, brs), 3.71 (2H,
t, J = 6.2 Hz), 3.96 (2H, t, J = 6.
3 Hz), 4.87 (1H, d, J = 3.8 Hz),
6.55-6.85 (5H, m), 7.15-7.25
(1H, m), 7.01 (2H, d, J = 8.4 Hz)

(1R, 2S) -1- (4-hydroxy-
2-methylphenyl-2-[[2- [4- [2- (4-
Hydroxyphenyl) ethyloxy] phenyl] ethyl] amino] propan-1-ol hydrochloride

[0102] Amorphous ^{IR (KBr): 3401cm -1 1} H-NMR (DMSO-d 6) δppm: 0.99
(3H, d, J = 6.7 Hz), 2.20 (3H,
s), 2.80-3.00 (4H, m), 3.10-
3.40 (3H, m), 4.08 (2H, t, J = 7.
0 Hz), 5.10-5.25 (1H, m), 5.80
−5.90 (1H, m), 6.55 (1H, d, J =
2.4 Hz), 6.63 (1H, dd, J = 8.4,
2.4 Hz), 6.69 (2H, d, J = 8.5H)
z), 6.89 (2H, d, J = 8.6 Hz), 7.0
9 (2H, d, J = 8.5 Hz), 7.18 (2H,
d, J = 8.6 Hz), 7.27 (1H, d, J = 8,
4 Hz), 8.50-8.85 (2H, m), 9.19
(1H, d, J = 1.8 Hz), 9.26 (1H, s)

Test Example 1 Effect of Drug on Extirpated Pregnant Uterus Automatic Movement The uterus of an SD pregnant rat (21st day of gestation) was excised and about 5 mm wide and about 15 mm long in the longitudinal muscle direction, avoiding the placenta attachment.
A sample of mm was prepared and an experiment was performed according to the Magnus method. The sample was suspended in Locke-Ringer solution aerated with a mixture of 95% oxygen and 5% carbon dioxide at 37 ° C., and 1 g of the suspension was added. Uterine motility was derived isometrically via a pressure transducer and recorded on a rectogram. The drug efficacy was evaluated by comparing the sum of the uterine contraction height for 5 minutes before the addition of the drug and the sum of the uterine contraction height for 5 minutes after the addition of the drug, and the drug concentration that inhibited 50% was evaluated as an EC ₅₀ value.

Test Example 2 Effect of Drug on Cardiac Contractility of Isolated Atria The atrium of a male SD rat (body weight 350-400 g) was isolated and subjected to an experiment according to the Magnus method. Specimen 3
1 g suspended in a Krebs-Henseleit solution aerated with a mixed gas of 95% oxygen and 5% carbon dioxide at 7 ° C.
Was added. The systolic force was derived isometrically via a pressure transducer and recorded on a rectogram.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 319/06 C07D 319/06 521/00 521/00 // C07M 7:00 (72) Inventor Nobuyuki Tanaka Sasaga, Matsumoto City, Nagano Prefecture 6083-1 (72) Inventor Hiroaki Kobayashi 7-1-9, Juboku, Matsumoto-shi, Nagano Prefecture (72) Inventor Ken Kikuchi 1-2-34 Nomizo Woodworking, Matsumoto-shi, Nagano Kissei Daini Seotoyu Dormitory (72) Inventor Village Hideyuki Naka 4509 Kashiwara, Hodaka-cho, Minamiazumi-gun, Nagano Pref.

Claims (1)

[Claims] 1. A compound of the general formula Wherein either ^one of Y ¹ and Z ¹ is a group represented by the general formula -O-
A—R (A in the formula is a lower alkylene group or a lower alkenylene group, R is a hydroxyl group, a lower alkoxy group, an aralkyloxy group, a phenyl group which may have a hydroxyl group as a substituent or a nitrogen atom in the ring; And a 5- to 7-membered heterocyclic group containing 1 or 2 oxygen atoms), the other is a hydrogen atom, and the carbon atom to which (R) is attached has the R configuration. A carbon atom, and the carbon atom to which (S) is attached indicates a carbon atom in the S configuration]] and the pharmacology of the 2-amino-1- (4-hydroxy-2-methylphenyl) propanol derivative Acceptable salts.