JP2001114736A - 2-aminopropanol derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new compound having excellent β3-adrenoceptor stimulation action and useful as a prophylactic or therapeutic agent for obesity, hyperglycemia and a disease originating from movement of intestine accentuation, pollakisuria and incontinence, depression, gallstone or a disease originating from biliary tract hyperkinesia. SOLUTION: The new compound is a 2-aminopropanol derivative represented by formula I [R1 is H or an alkyl; R2 is H or a halogen; A is a single bond, an alkylene or CH=CH-(CH2)n (n is an integer of 0 to 4); and the configuration of two carbon atoms marked with * has an erythro form] or its pharmacologically permissible salt. The compound is obtained by alkylating a compound of formula II with a compound of formula III (R1a is an alkyl; and X is a leaving group) and, if necessary, hydrolyzing the resultant compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel 2-aminopropanol derivative which is useful as a pharmaceutical.

More specifically, the present invention relates to a compound of the general formula (I) having a β ₃ -adrenoreceptor stimulating action:

[0003]

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[Wherein R ¹ is a hydrogen atom or a lower alkyl group, R ² is a hydrogen atom or a halogen atom, and A is a single bond, a lower alkylene group or a general formula -CH
_{= CH- (CH 2) n -} (n in the formula is an integer of 0 to 4)
Wherein the two carbon atoms marked with * are carbon atoms having a relative configuration of erythro,
Or a mixture of any one of the single absolute isomers in any kind of absolute configuration] or a pharmacologically acceptable salt thereof. .

[0005]

2. Description of the Related Art There are three subtypes of β-adrenergic receptors of the sympathetic nerve classified as β ₁ , β ₂ and β ₃ , which are distributed to specific organs and have specific functions. It is known.

For example, β ₁ -adrenergic receptor is mainly present in the heart, and stimulation via the receptor causes an increase in heart rate and cardiac contractility. β ₂ -adrenoceptors are present mainly in vascular, bronchial and uterine smooth muscle,
Stimulation via the receptor results in dilation of blood vessels and bronchi and suppression of uterine contractions, respectively. It is known that β ₃ -adrenergic receptor mainly exists in adipocytes, gallbladder and intestinal tract, and also in brain, liver, prostate, stomach and the like. It has been reported that enhanced degradation, suppression of intestinal motility, promotion of glucose uptake, antidepressant action, and the like are caused (Drugs of the Future,
18, No. 6, pp. 529-549 (1993)
Year), Molecular Brain Research
ch, Vol. 29, pp. 369-375 (1995
Year), European Journal of Pha
rmology, 289, 223-228 (1995), Pharmacology, 5
1, 288-297 (1995)).

[0007] Recently, β _3-
It has been reported that an adrenergic receptor is present, and that a human urinary bladder is relaxed by a β ₃ -adrenoceptor stimulant (Japanese Urological Association, Vol. 88, No. 2, p. 183 (1997), NEUROUROLOGY AN
D URODYNAMICS, Vol. 16, No. 5, 363-
365 pages (1997)).

[0008] Many β ₁ -adrenoceptor stimulants and β ₂ -adrenoceptor stimulants have been developed so far, and they are used in medicine as inotropic agents, bronchodilators, and agents for preventing imminent flow / premature birth. I have.

On the other hand, β ₃ -adrenergic receptor stimulants are used for diseases caused by obesity, hyperglycemia, intestinal hypermotility,
It has been found to be useful as a preventive or therapeutic agent for pollakiuria, urinary incontinence, depression, diseases caused by gallstones or hyperbiliary motility, and is currently being used for the development of excellent β ₃ -adrenoceptor stimulants. Research is being actively conducted toward
₃ -adrenergic receptor stimulants have not yet been launched (Drugs of The Future, 1
8, No. 6, pp. 529-549 (1993),
European Journal of Pharma
, vol. 219, pages 193-201 (1
992) etc.).

[0010]

An object of the present invention is to provide a novel β ₃ -adrenoreceptor stimulant which is useful as a pharmaceutical.

Preferably, by having a strong β ₃ -adrenergic receptor stimulating action as compared with β ₁ and / or β ₂ -adrenergic receptor stimulating action, β ₁ or / and
And β ₂ -adrenergic receptor stimulating action,
For example, it is an object of the present invention to provide a selective β ₃ -adrenoceptor stimulant in which side effects such as palpitations and finger tremor are reduced.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The present inventors have conducted intensive studies to solve the above-mentioned problems, and found that certain 2-aminopropanol derivatives and pharmacologically acceptable salts thereof are excellent in β ₃ -adrenaline. The present inventors have found that they have a receptor stimulating action, and have accomplished the present invention.

That is, the present invention relates to a compound represented by the general formula having an excellent β ₃ -adrenoreceptor stimulating action

[0014]

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(Wherein the two carbon atoms marked with R ¹ , R ² , A and * have the same meaning as described above)
The present invention relates to an aminopropanol derivative or a pharmacologically acceptable salt thereof.

In the compound of the present invention represented by the general formula (I), the lower alkyl group is a methyl group, an ethyl group,
Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, tert-
A linear or branched alkyl group having 1 to 6 carbon atoms such as a pentyl group and a hexyl group, and a lower alkylene group is a methylene group, an ethylene group, a trimethylene group, a tetramethylene group or the like having 1 to 6 carbon atoms. It refers to an alkylene group, and a halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The compound of the present invention represented by the general formula (I) 2-
The aminopropanol derivative can be produced by the following method. For example, the general formula

[0018]

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(The two carbon atoms marked with * in the formula have the same meanings as described above).

[0020]

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(Wherein R ^1a is a lower alkyl group;
Is a leaving group, and R ² and A have the same meaning as described above) in the presence or absence of a base such as N, N-diisopropylethylamine using an alkylating agent represented by the formula (1). It can be produced by alkylating in an inert solvent such as dimethylformamide and, if desired, hydrolyzing the ester group according to a conventional method.

The amine compound represented by the general formula (II) used as a starting material in the above-mentioned production method may be obtained as a commercial product, or may be obtained by optically resolving a commercially available mixture of enantiomers according to a conventional method, or by a method described in the literature. (For example, J. Med. Che)
m. , 20, 7, 978-981 (19
77)).

The compound represented by the general formula (III) used as a starting material in the above production method can be produced by a method described in a literature or a method similar thereto. For example, among the compounds represented by the general formula (III),

[0024]

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Wherein A ¹ is a lower alkylene group;
R ^1a has the same meaning as described above),

[0026]

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Wherein A ¹ and R ^1a have the same meanings as described above,

[0028]

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A Friedel-Crafts reaction is carried out using an acid bromide represented by the following formula.

[0030]

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(A ¹ and R ^1a in the formula have the same meanings as described above), and can be produced by reducing the carbonyl group of an acetyl group according to a conventional method.

Among the compounds represented by the above general formula (III),

[0033]

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Wherein A ² is a group represented by the general formula -CH = CH- (CH
₂ ) _n- (wherein n is an integer of 0 to 4), and R ^1a and X have the same meaning as described above.

[0035]

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Using the benzaldehyde derivative represented by the formula (for example, Journal of Am)
erican Chemical Society, 1
07, 217-226 (1985), Te
Trahedron Letters, Vol. 22, 41
The reaction can be carried out using the corresponding Wittig reagent in accordance with the following general formula:

[0037]

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(Wherein R ^1a and A ² have the same meanings as described above), and can be produced by converting a hydroxyl group into a leaving group according to a conventional method.

Among the compounds represented by the above general formula (III),

[0040]

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The compound represented by the formula (wherein R ^1a has the same meaning as described above) can be prepared by the method described in the literature (Tetrahed
ron Letters, 37, 42, 7507
~ Page 7510 (1996))

[0042]

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After the carboxylic acid derivative represented by the formula (1) is produced, the acetyl group is halogenated according to a conventional method, and then the carbonyl of the acetyl group is reduced according to a conventional method.

Among the compounds represented by the above general formula (III),

[0045]

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A ³ in the formula is a lower alkylene group having 2 or more carbon atoms or a general formula —CHＣＨCH— (CH ₂ ) _n — (wherein n is an integer of 0 to 4) And R ^1a and X have the same meanings as described above.
General formula

[0047]

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The alcoholic hydroxyl group of the alcohol compound represented by the formula is acetylated according to a conventional method,

[0049]

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After obtaining the compound represented by the formula, trifluoromethanesulfonic anhydride is reacted in an inert solvent such as dichloromethane in the presence of a base such as triethylamine and N, N-dimethylaniline to obtain a compound represented by the general formula

[0051]

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A compound represented by the general formula:

[0053]

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A Heck reaction is carried out using an ester compound represented by the formula (wherein R ^1a and n have the same meanings as described above), and

[0055]

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After producing a compound represented by the formula (wherein R ^1a and n have the same meanings as described above), the acetyl group is hydrolyzed according to a conventional method, and if desired, the vinyl group is reduced. It can be produced by converting to a leaving group according to a conventional method.

Among the compounds represented by the above general formula (III),

[0058]

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The compound represented by the formula (wherein R ^1a , A ¹ and X have the same meaning as described above) is represented by the general formula (VIII)
The vinyl group of the compound represented by
It can be produced by performing a reaction using a halogenating reagent such as rt-butyl hypochlorite and then converting a hydroxyl group to a leaving group according to a conventional method.

In the above-mentioned production method, the two types of positional isomers represented by the general formula (X) used as starting materials include a phenolic hydroxyl group of 4-hydroxyphenylethyl alcohol which is a methoxymethyl group and a tert-butyl group. After the protection with tert-butyl hypochlorite, a chlorine atom is introduced into the aromatic ring using tert-butyl hypochlorite, and then the resulting mixture is purified by column chromatography, and each is produced by removing a protecting group according to a conventional method. be able to.

Further, among the compounds represented by the general formula (X) used as starting materials in the above production method,

[0062]

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The compound represented by the formula is

[0064]

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Can be produced by reducing the compound represented by the formula (1) according to a conventional method.

The formulas (IV), (XIII), (V), (V)
The compounds represented by II) and (IX) can be obtained as a commercial product, or can be produced by a method described in the literature or a method similar thereto (for example, Journal o).
f Medicinal Chemistry, 38
Vol., Pp. 1608-1628 (1995), WO
94/27973 publication).

In the above-mentioned production method, the leaving group means a leaving group generally used in N-alkylation reactions of p-toluenesulfonyloxy group, methanesulfonyloxy group, chlorine atom, bromine atom, iodine atom and the like. Say.

In the compound of the present invention represented by the above general formula (I), in which A in the formula is a group having an unsaturated bond, there are two types of geometric isomers, cis isomer and trans isomer. In the present invention, any of the geometric isomers can be used.

The compound of the present invention represented by the general formula (I) 2-
The aminopropanol derivative can be converted into a pharmacologically acceptable salt according to 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-toluene Acid addition salts with organic acids such as sulfonic acid, propionic acid, citric acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, sodium salts, potassium Salts, salts with inorganic bases such as calcium salts, triethylamine, piperidine,
Salts with organic bases such as morpholine, pyridine and lysine can be mentioned.

The compounds of the present invention and their salts obtained by the above-mentioned production methods can be isolated and purified by a conventional separation means such as fractional recrystallization, purification using chromatography, solvent extraction and the like. .

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

The β ₃ -adrenoreceptor stimulating action of the compound of the present invention represented by the above general formula (I) was examined as follows.

That is, a ferret's bladder was excised to prepare a specimen, which was tested according to the Magnus method. The tension when the test compound was not added was 100%, and the tension after addition of ^10-5 M forskolin was maximally relaxed. The test compound concentration at which the test compound was cumulatively added and the tension was reduced by 50% was defined as an EC ₅₀ value as an index of β ₃ -adrenoceptor stimulating action, assuming that the tension at time was 0% (Journal of the Japan Urological Association, 89, 2
Issue, p. 272 (1998)).

For example, 3- [4- [2-[[(1S, 2
R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl]
The β ₃ -adrenoceptor stimulating action of propionic acid is
1.7 × 10 ⁻⁸ M (EC ₅₀ value).

As described above, the compound represented by the general formula (I) of the present invention is an excellent β ₃ -adrenoceptor stimulant having a strong β ₃ -adrenoceptor stimulating action.

The β ₁ and β ₂ -adrenergic receptor stimulating action of the compound of the present invention represented by the general formula (I) was examined as follows.

That is, the atrium of a rat was excised to prepare a specimen, and a test was conducted in accordance with the Magnus method. The increase in the heart rate after the addition of 10 ^-8 M isoproterenol was defined as 100%, and the test compound was accumulated. The test compound concentration at the time of adding and increasing the heart rate by 50% was used as an index of β ₁ -adrenergic receptor stimulating action as an EC ₅₀ value.

The uterus of a pregnant rat was excised to prepare a specimen, which was tested according to the Magnus method. The sum of the uterine contractions for 5 minutes before the addition of the test compound was defined as 100%, and the test compound was accumulated. When the sum of the uterine contraction height for 5 minutes after the addition was reduced to 50% before the addition, the test compound concentration was changed to E
The C ₅₀ value was used as an index of β ₂ -adrenergic receptor stimulating action.

For example, 3- [4- [2-[[(1S, 2
R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl]
Β ₁ and β ₂ -adrenoreceptor stimulating action of propionic acid was 4.9 × 10 ⁻⁵ M (EC ₅₀ value) and 3.9 × 10 ⁵ M, respectively.
^-7 M (EC ₅₀ value).

As described above, many of the compounds represented by the general formula (I) of the present invention have a greater effect on stimulating β ₁ and β ₂ -adrenergic receptors than on stimulating action on β ₃ -adrenergic receptors. It has reduced effects and is very suitable as a selective β ₃ -adrenoceptor stimulant. Specifically, in the compound represented by the general formula (I) of the present invention, a preferable compound is 3- [4- [2-
[[(1R ^* , 2S ^* )-2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] propionic acid, trans-3- [4-
[2-[[(1R ^* , 2S ^* )-2-hydroxy-2-
(4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] acrylic acid, 3- [4- [2-
[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] propionic acid, 3- [2-chloro-4-
[2-[[(1S, 2R) -2-hydroxy-2- (4
-Hydroxyphenyl) -1-methylethyl] amino]
Ethyl] phenyl] propionic acid, trans-3-
[2-Chloro-4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] acrylic acid and their pharmacological properties And particularly preferred compounds are 3- [4- [2-
[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] propionic acid, 3- [2-chloro-4-
[2-[[(1S, 2R) -2-hydroxy-2- (4
-Hydroxyphenyl) -1-methylethyl] amino]
Ethyl] phenyl] propionic acid, trans-3-
[2-Chloro-4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] acrylic acid and their pharmacological properties Can be mentioned.

The compound of the present invention represented by the general formula (I) 2-
Aminopropanol derivatives and pharmacologically acceptable salts thereof have an excellent β ₃ -adrenoceptor stimulating action, and are characterized by obesity, hyperglycemia, diseases caused by increased intestinal motility, pollakiuria, urine It is a very useful compound as a medicament such as an agent for preventing or treating diseases caused by incontinence, depression, gallstones or hyperbiliary hyperactivity.

Further, the compound represented by the above general formula (I) of the present invention is a compound having extremely high safety. For example, in an acute toxicity test using rats, 3- [4-
[2-[[(1S, 2R) -2-hydroxy-2- (4
-Hydroxyphenyl) -1-methylethyl] amino]
Ethyl] phenyl] propionic acid did not cause death even at a dose of 400 mg / kg.

The compound of the present invention represented by the general formula (I) 2-
When aminopropanol derivatives and their pharmacologically acceptable salts are used in the actual treatment, for example, powders,
It is orally or parenterally administered as granules, fine granules, tablets, capsules, injections, solutions, ointments, suppositories and the like. These pharmaceutical preparations can be prepared by commonly used pharmaceutical methods using commonly used carriers and excipients for preparations.

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

[0085]

EXAMPLES 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.

Reference Example 1 Ethyl 4- [4- (2-bromoethyl) phenyl] butyrate Bromoacetylbromide (1.1 ml) was added to a suspension of aluminum chloride (1.7 g) in methylene chloride (12 ml) under ice-cooling and stirring.
And ethyl 4-phenylbutyrate (2.3 g) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel medium pressure liquid column chromatography (elution solvent: hexane / diethyl ether = 3/1), and the obtained 4- [4- (2-
Ethyl bromoacetyl) phenyl] butyrate was dissolved in trifluoroacetic acid (20 ml), and triethylsilane (1.4 ml) was added with stirring at room temperature. After stirring at 50 ° C. for 30 minutes, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel medium pressure liquid column chromatography (elution solvent: hexane / methylene chloride = 1/1) to give 4- [4- Ethyl (2-bromoethyl) phenyl] butyrate (1.2 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.25 (3H, t, J =
7.1Hz), 1.94 (2H, quint, J = 7.5Hz), 2.31 (2H, t, J =
7.5Hz), 2.63 (2H, t, J = 7.5Hz), 3.13 (2H, t, J = 7.7H
z), 3.55 (2H, t, J = 7.7Hz), 4.12 (2H, q, J = 7.1Hz),
7.13 (4H, s)

Reference Example 2 Ethyl 5- [4- (2-bromoethyl) phenyl] valerate In the same manner as in Reference Example 1, 5-ethyl valerate was used in place of ethyl 4-phenylbutyrate. 4
-(2-Bromoethyl) phenyl] ethyl valerate was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.25 (3H, t, J =
7.1Hz), 1.60-1.75 (4H, m), 2.25-2.35 (2H, m), 2.
55−2.65 (2H, m), 3.13 (2H, t, J = 7.7Hz), 3.55 (2H,
t, J = 7.7Hz), 4.12 (2H, q, J = 7.1Hz), 7.12 (4H, s)

Reference Example 3 Methyl trans-3- [4- (2-hydroxyethyl) phenyl] acrylate trans-3- [4- [2- (tert-butyldimethylsilyloxy) ethyl] phenyl] acrylate ( To a solution of 1.0 g) in tetrahydrofuran (10 ml) was added a 1 molar solution of tetra-n-butylammonium fluoride-tetrahydrofuran (3.5 ml) under stirring at room temperature, followed by stirring for 1 hour. Water was added to the reaction mixture, extracted with diethyl ether, washed with water and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (eluent: diethyl ether), and methyl trans-3- [4- (2-hydroxyethyl) phenyl] acrylate (393 mg) was added. Obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.45 (1H, br),
2.89 (2H, t, J = 6.5Hz), 3.80 (3H, s), 3.88 (2H, t,
J = 6.5Hz), 6.41 (1H, d, J = 16.0Hz), 7.26 (2H, d, J =
8.1Hz), 7.48 (2H, d, J = 8.1Hz), 7.68 (1H, d, J = 16.0H
z)

Reference Example 4 Methyl trans-3- [4- [2- (p-toluenesulfonyloxy) ethyl] phenyl] acrylate Methyl trans-3- [4- (2-hydroxyethyl) phenyl] acrylate (393 mg) ) Methylene chloride (5m
l) To the solution, stir at room temperature, triethylamine (320μl)
And p-toluenesulfonyl chloride (400 mg) were added, and the mixture was stirred for 12 hours. Water was added to the reaction mixture, extracted with methylene chloride, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel flash column chromatography (elution solvent: hexane / methylene chloride /
Purified with ethyl acetate = 4/2/1), trans-3-
Methyl [4- [2- (p-toluenesulfonyloxy) ethyl] phenyl] acrylate (607 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 2.42 (3H, s),
2.97 (2H, t, J = 6.8Hz), 3.81 (3H, s), 4.22 (2H, t,
J = 6.8Hz), 6.41 (1H, d, J = 16.0Hz), 7.13 (2H, d, J =
8.1Hz), 7.26 (2H, d, J = 8.5Hz), 7.40 (2H, d, J = 8.1H
z), 7.60−7.70 (3H, m)

Reference Example 5 4- [2- (p-toluenesulfonyloxy) ethyl]
Ethyl benzoate 4- [2-hydroxyethyl) ethyl benzoate was used in place of methyl trans-3- [4- (2-hydroxyethyl) phenyl] acrylate, and 4- [ Ethyl 2- (p-toluenesulfonyloxy) ethyl] benzoate was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.40 (3H, t, J =
7.1Hz), 2.42 (3H, s), 3.00 (2H, t, J = 6.7Hz), 4.24
(2H, t, J = 6.7Hz), 4.38 (2H, q, J = 7.1Hz), 7.16 (2H,
d, J = 8.4Hz), 7.26 (2H, d, J = 8.4Hz), 7.66 (2H, t,
J = 8.4Hz), 7.91 (2H, t, J = 8.4Hz)

Reference Example 6 trans-3- [4- (2-acetoxyethyl) -2
-Chlorophenyl] methyl acrylate 2- (3-chloro-4-hydroxyphenyl) acetic acid (2.
To a solution of 0 g) in tetrahydrofuran (20 ml) was added a 1 molar borane-tetrahydrofuran complex tetrahydrofuran solution (21.4 ml) under ice-cooling and stirring. After stirring at room temperature for 1 hour, acetic acid (2.5 ml) was added to the reaction mixture, and the solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue (1.02 g) in methylene chloride (3
0ml) solution and triethylamine (3.3 m
l), 4-dimethylaminopyridine (578 mg) and acetyl chloride (1.0 ml) were added, and the mixture was stirred for 5 minutes. Diethyl ether (200 ml) was added to the reaction mixture, the insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution solvent: hexane / ethyl acetate = 7/1) to obtain 2- (3-chloro-4-hydroxyphenyl) ethyl acetate (223 mg).

¹ H-NMR (CDCl ₃ ) δ ppm: 2.04 (3H, s),
2.84 (2H, t, J = 7.0Hz), 4.23 (2H, t, J = 7.0Hz), 5.44
(1H, s), 6.95 (1H, d, J = 8.3Hz), 7.02 (1H, dd, J = 8.
3, 2.0Hz), 7.17 (1H, d, J = 2.0Hz)

A solution of 2- (3-chloro-4-hydroxyphenyl) ethyl acetate (676 mg) in methylene chloride (15 ml) was stirred under ice cooling with triethylamine (880 μl), N,
N-Dimethylaniline (154 mg) and trifluoromethanesulfonic anhydride (635 μl) were added, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, extracted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by flash column chromatography on aminopropylated silica gel (eluent: hexane / ethyl acetate = 1/1) to obtain 2- (3-chloro-acetic acid).
4-trifluoromethanesulfonyloxyphenyl)
Ethyl (990 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 2.04 (3H, s), 2.
95 (2H, t, J = 6.8Hz), 4.28 (2H, t, J = 6.8Hz), 7.19 (1
H, dd, J = 8.5, 2.1Hz), 7.29 (1H, d, J = 8.5Hz), 7.39
(1H, d, J = 2.1Hz)

2- (3-chloro-4-trifluoromethanesulfonyloxyphenyl) ethyl acetate (603 m
g), a mixture of methyl acrylate (235 μl), triphenylphosphine (55 mg), palladium acetate (23 mg) and tetramethylethylenediamine (394 μl) in a sealed tube,
The mixture was stirred at 110 ° C for 11 hours. Ethyl acetate was added to the reaction mixture, washed with water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by aminopropylated silica gel medium pressure liquid column chromatography (elution solvent: hexane / ethyl acetate = 6/1), and trans-3-
Methyl [4- (2-acetoxyethyl) -2-chlorophenyl] acrylate (185 mg) was obtained. ¹ H-NMR (CDC
l ₃ ) δ ppm: 2.04 (3H, s), 2.93 (2H, t, J = 6.8Hz),
3.82 (3H, s), 4.28 (2H, t, J = 6.8Hz), 6.42 (1H, d,
J = 16.0Hz), 7.13 (1H, dd, J = 8.0, 1.4Hz), 7.29 (1H,
d, J = 1.4Hz), 7.56 (1H, d, J = 8.1Hz), 8.06 (1H, d, J
= 16.0Hz)

Reference Example 7 Methyl 3- [2-chloro-4- [2- (p-toluenesulfonyloxy) ethyl] phenyl] propionate trans-3- [4- (2-acetoxyethyl) -2
To a solution of methyl [-chlorophenyl] acrylate (64 mg) in methanol (3 ml) was added a catalytic amount of concentrated sulfuric acid while stirring at room temperature, and the mixture was stirred under heating and reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extracted with ethyl acetate.
After washing with water, it was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue, a suspension of 10% palladium on carbon (50 mg) and methanol (250 μl) in chlorobenzene (2 ml) were stirred at room temperature under a hydrogen atmosphere for 2 hours. After removing the catalyst by filtration and concentrating the filtrate under reduced pressure, triethylamine (62 ml) was added to a solution of the residue in methylene chloride (1.1 ml) at room temperature with stirring.
μl) and p-toluenesulfonyl chloride (47 mg).
The mixture was stirred at room temperature for 16 hours. After the reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel flash column chromatography (elution solvent: hexane / ethyl acetate = 8/1), and 3- [2-chloro-4- [2- (p-toluene) Methyl sulfonyloxy) ethyl] phenyl] propionate (73 mg) was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 2.44 (3H, s),
2.62 (2H, t, J = 7.8Hz), 2.89 (2H, t, J = 6.8Hz), 3.02
(2H, t, J = 7.8Hz), 3.68 (3H, s), 4.19 (2H, t, J = 6.8
Hz), 6.95 (1H, dd, J = 7.8, 1.8Hz), 7.05 (1H, d, J =
1.8Hz), 7.13 (1H, d, J = 7.8Hz), 7.29 (2H, d, J = 8.5H
z), 7.68 (2H, d, J = 8.5Hz)

REFERENCE EXAMPLE 8 Ethyl trans-3- [2-chloro-4- [2- (p-toluenesulfonyloxy) ethyl] phenyl] acrylate Except for the reduction reaction using 10% palladium on carbon, Reference Example 7
In the same manner as in trans-3- [2-chloro-4-
Ethyl [2- (p-toluenesulfonyloxy) ethyl] phenyl] acrylate was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 2.43 (3H, s),
2.93 (2H, t, J = 6.5Hz), 3.83 (3H, s), 4.23 (2H, t,
J = 6.5Hz), 6.41 (1H, d, J = 16.0Hz), 7.00−7.10 (1H,
m), 7.11 (1H, d, J = 1.7Hz), 7.20−7.30 (2H, m), 7.4
9 (1H, d, J = 8.0Hz), 7.65 (2H, d, J = 8.4Hz), 8.04 (1
(H, d, J = 16.0Hz)

Example 1 5- [4- [2-[[(1R ^* , 2S ^* )-2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] valeric acid Ethyl hydrochloride (compound 1) and 5- [4- [2-[[(1R ^* , 2
S ^* )-2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl]
Valeric acid (compound 2) (1R ^* , 2S ^* )-2-amino-1- (4-hydroxyphenyl) propan-1-ol (640 mg) and 5- [4
-(2-bromoethyl) phenyl] ethyl valerate (600m
g) in N, N-dimethylformamide (2 ml)
Stirred at C for 3 hours. After cooling, the reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure,
The residue was purified by medium-pressure liquid column chromatography on aminopropylated silica gel (eluent: chloroform / ethanol = 20/1) to give 5- [4- [2-[[(1
R ^* , 2S ^* )-2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] ethylvalerate (610 mg) was obtained. 5- [4- [2
-[[(1R ^* , 2S ^* )-2-hydroxy-2- (4-
To a solution of hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] ethylvalerate (100 mg) in ethyl acetate (3 ml) was added a 4N hydrochloric acid-ethyl acetate solution (1 ml) at room temperature with stirring, and then the pressure was reduced. The solvent was distilled off underneath. After the residue was suspended in diethyl ether, the insolubles were collected by filtration, and 5- [4- [2-[[(1R ^* , 2S ^* )-2-hydroxy-2- (4-hydroxyphenyl)- 1-Methylethyl] amino] ethyl] phenyl] valeric acid ethyl hydrochloride (compound 1) (85 mg) was obtained.

¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.96 (3H, d,
J = 6.7Hz), 1.16 (3H, t, J = 7.1Hz), 1.45-1.65 (4H,
m), 2.25-2.35 (2H, m), 2.50-2.60 (2H, m), 2.90-3.0
5 (2H, m), 3.10-3.40 (3H, m), 4.04 (2H, d, J = 7.1H
z), 5.04 (1H, br s), 5.95 (1H, br s), 6.76 (2H, dd,
J = 8.5, 1.2Hz), 7.10-7.25 (6H, m), 8.65-8.90 (2H,
br), 9.39 (1H, s)

5- [4- [2-[[(1R ^* , 2S ^* )-
2-hydroxy-2- (4-hydroxyphenyl) -1
-Methylethyl] amino] ethyl] phenyl] ethylvalerate (100 mg) in 1N aqueous sodium hydroxide solution (1 ml)
And stirred at room temperature for 2 hours. After 1N hydrochloric acid (1 ml) was added to the reaction mixture, the precipitate was collected by filtration and treated with 5- [4
-[2-[[(1R ^* , 2S ^* )-2-hydroxy-2-
(4-Hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] valeric acid (Compound 2) (68 mg)
I got

¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.82 (3H, d,
J = 6.4Hz), 1.45-1.60 (4H, m), 2.20 (2H, t, J = 7.0Hz),
2.45-2.85 (7H, m), 4.43 (1H, d, J = 4.3Hz), 6.60-6.
70 (2H, m), 7.00-7.10 (6H, m)

Example 2 3- [4- [2-[[(1R ^* , 2S ^* )-2-hydroxy-1-methyl-2- (4-oxidephenyl) ethyl] amino] ethyl] phenyl] propionic acid Disodium salt (compound 3) (1R ^* , 2S ^* )-2-amino-1- (4-hydroxyphenyl) propan-1-ol (1.23 g) and 3- [4
A solution of methyl (2-bromoethyl) phenyl] propionate (1.00 g) in N, N-dimethylformamide (20 ml) was stirred at 95 ° C. for 3 hours. After cooling, water was added to the reaction mixture, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by medium-pressure liquid column chromatography on aminopropylated silica gel (eluent: chloroform / methanol = 20/1) to obtain 3- [4- [2-[[(1R ^* , 2S ^* )-2-
Methyl hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] propionate (904 mg) was obtained. 3- [4- [2-[[(1
R ^* , 2S ^* )-2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] methyl propionate (1.01 g) in methanol (14
ml) solution, 2N aqueous sodium hydroxide solution (2.8 ml) was added to the solution while stirring at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to give 3- [4- [2-[[(1R ^* , 2S ^* )-].
2-hydroxy-1-methyl-2- (4-oxidephenyl) ethyl] amino] ethyl] phenyl] propionic acid disodium salt (Compound 3) (1.10 g) was obtained.

¹ H-NMR (CD ₃ OD) δ ppm: 1.11 (3H, d, J =
6.3Hz), 2.35-2.45 (2H, m), 2.55-2.95 (7H, m), 4.29
(1H, d, J = 6.8Hz), 6.64 (2H, d, J = 8.5Hz), 6.95-7.0
5 (4H, m), 7.11 (2H, d, J = 8.1Hz)

Example 3 The corresponding alkylating agent was used and if necessary (1
R ^* , 2S ^* )-2-Amino-1- (4-hydroxyphenyl) propan-1-ol (1R, 2S)
The following compounds were obtained in the same manner as in Example 1 or Example 2 using -2-amino-1- (4-hydroxyphenyl) propan-1-ol. 4- [2-
[[(1R ^* , 2S ^* )-2-hydroxy-1-methyl-
2- (4-oxidephenyl) ethyl] amino] ethyl] benzoic acid disodium salt (compound 4)

¹ H-NMR (CD ₃ OD) δ ppm: 1.19 (3H, d, J =
7.0Hz), 2.65-2.95 (5H, m), 4.34 (1H, d, J = 6.5Hz),
6.64 (2H, d, J = 8.5Hz), 7.01 (2H, d, J = 8.5Hz), 7.13
(2H, d, J = 8.1Hz), 7.84 (2H, d, J = 8.1Hz)

Trans-3- [4- [2-[[(1R
^* , 2S ^* )-2-Hydroxy-1-methyl-2- (4-
Oxidophenyl) ethyl] amino] ethyl] phenyl] acrylic acid disodium salt (compound 5)

¹ H-NMR (CD ₃ OD) δ ppm: 1.02 (3H, d, J =
6.3Hz), 2.45-2.85 (5H, m), 4.21 (1H, d, J = 6.7Hz),
6.37 (1H, d, J = 16.0Hz), 6.45-6.60 (2H, m), 6.90 (2
H, d, J = 8.5Hz), 7.02 (2H, d, J = 8.1Hz), 7.26 (1H, d,
J = 16.0Hz), 7.31 (2H, d, J = 8.1Hz)

4- [4- [2-[[(1R ^* , 2S ^* )-
2-hydroxy-2- (4-hydroxyphenyl) -1
-Methylethyl] amino] ethyl] phenyl] butyric acid (compound 6)

¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.83 (3H, d,
J = 6.4Hz), 1.76 (2H, quint, J = 7.4Hz), 2.17 (2H, t,
J = 7.4Hz), 2.45-2.85 (7H, m), 4.42 (1H, d, J = 4.3H
z), 6.67 (2H, d, J = 8.5Hz), 7.00-7.10 (6H, m)

3- [4- [2-[[(1S, 2R) -2
-Hydroxy-2- (4-hydroxyphenyl) -1-
Methylethyl] amino] ethyl] phenyl] propionic acid (compound 7)

¹ H-NMR (D ₂ O + DMSO-d ₆ ; reference substance DOH =
4.80ppm) δ ppm: 1.66 (3H, d, J = 6.7Hz), 3.01 (2H,
t, J = 7.7Hz), 3.46 (2H, t, J = 7.7Hz), 3.54 (2H, t, J
= 7.6Hz), 3.70-3.95 (3H, m), 5.53 (1H, d, J = 3.0Hz),
7.46 (2H, d, J = 8.5Hz), 7.80-7.90 (6H, m) Specific rotation: [α] _D ²⁵ = −7.9 ° (c = 1.01, acetic acid)

3- [2-chloro-4- [2-[[(1
S, 2R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] propionic acid (compound 8)

¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.84 (3H, d,
J = 6.5Hz), 2.40-3.00 (9H, m), 4.56 (1H, d, J = 3.5Hz),
6.68 (2H, d, J = 8.6Hz), 7.00-7.15 (3H, m), 7.20-7.
30 (2H, m)

Trans-3- [2-chloro-4- [2
-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] acrylic acid (compound 9)

¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.85 (3H, d,
J = 6.4Hz), 2.70-3.05 (5H, m), 4.61 (1H, d, J = 3.7Hz),
6.51 (1H, d, J = 15.9Hz), 6.69 (2H, d, J = 8.5Hz), 7.
09 (2H, d, J = 8.5Hz), 7.20 (1H, d, J = 8.1Hz), 7.38
(1H, s), 7.72 (1H, d, J = 15.9Hz), 7.76 (1H, d, J = 8.
1 Hz)

Test Example 1 β_Three-Adrenergic receptor stimulating action assay test The bladder of a male ferret (weight 1100-1400g) was excised,
A bladder smooth muscle specimen about 10 mm in length and about 2 mm in width was prepared and Magnu
The experiment was performed according to the s method. Specimens are 95% oxygen and 5% at 37 ° C
Krebs-Hensele ventilated with a gas mixture containing
It was suspended in the it solution and a load of 1 g was applied. The bladder resting tension is
Isometrically derived via a tension transducer and
Recorded on the chigram. The drug is cumulative with Magnu approximately every 5 minutes.
s was added into the tube. Efficacy was evaluated by bladder smoothing before drug treatment.
100% muscle tension, Forskolin 10^-FiveMaximum relaxation after M treatment
The relaxation tension is 0%, and the drug concentration at the time of 50% relaxation is E
C ₅₀It was evaluated as a value. The results are shown in Table 1 below.
It is a cage.

[0124]

[Table 1]

Test Example 2 β ₁ -Adrenergic Receptor Stimulating Activity Assay Test The atrium of a male SD rat (body weight 250-400 g) was excised and
The experiment was performed according to the nus method. Specimens were Krebs-Hens aerated with a gas mixture containing 95% oxygen and 5% carbon dioxide at 37 ° C.
The suspension was suspended in the eleit solution and a load of 0.5 g was applied. The systolic force was derived isometrically via a tension transducer and recorded on a rectogram via an instantaneous heart rate monitor. Drugs were added cumulatively into Magnus tubes. The drug efficacy was evaluated by assuming that the increase in heart rate per minute when isoproterenol 10 ^-8 M was added was 100% and the drug concentration when increasing the heart rate per minute by 50% was EC.
_The evaluation was made as ₅₀ values. The results are as shown in Table 2 below.

[0126]

[Table 2]

Test Example 3 β ₂ -Adrenergic Receptor Stimulation Measurement Test The uterus of an SD pregnant rat (21st day of gestation) was excised, avoiding the placenta attachment, and about 5 mm wide and about 5 mm long in the longitudinal muscle direction. A 15 mm specimen was prepared, and an experiment was performed according to the Magnus method. 37 specimens
The mixture was suspended in a Locke-Ringer solution ventilated with a mixed gas containing 95% of oxygen and 5% of carbon dioxide at a temperature of 0 ° C, and a load of 0.5 g was applied. Uterine motility was derived isometrically via a tension transducer and recorded on the rectogram. About 5 drugs
Cumulatively added to the Magnus tube every minute. The efficacy evaluation was performed by comparing the sum of the uterine contraction height for 5 minutes before addition of the drug with 100% and comparing the sum of the uterine contraction height for 5 minutes after addition of the drug at each concentration with 50%.
The% inhibitory drug concentration was evaluated as the EC ₅₀ value. The results are as shown in Table 3 below.

[0128]

[Table 3]

Test Example 4 Acute toxicity test 4-week-old ICR male mice were treated with 3- [4- [2-[[(1
A single intravenous dose of 400 mg / kg of (S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenyl] propionic acid was administered. Thereafter, when observed over time for 24 hours, no deaths were observed.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61P 3/10 A61P 3/10 13/00 13/00 43/00 111 43/00 111 (72) Inventor Masuo Akabane Nagano 1686-7 Satoyamabe, Matsumoto City, Prefecture F term (reference) 4C206 AA01 AA02 AA03 FA14 MA01 MA04 NA14 ZA12 ZA66 ZA70 ZA75 ZA81 ZC35 4H006 AA01 AA03 AB20 BJ50 BM10 BM30 BS10 BU32

Claims (5)

[Claims] 1. A compound of the general formula Wherein R ¹ is a hydrogen atom or a lower alkyl group;
R ² is a hydrogen atom or a halogen atom, and A is a single bond, a lower alkylene group or a general formula -CH = CH- (C
H ₂ ) _n- (wherein n is an integer of 0 to 4), and two carbon atoms marked with * are carbon atoms having a relative configuration of erythro. Or a mixture of any one of the two absolute configurations, or a mixture of these in any ratio], or a pharmaceutically acceptable salt thereof. 2. A compound of the general formula Wherein R ¹ is a hydrogen atom or a lower alkyl group;
R ² is a hydrogen atom or a halogen atom, and A is a single bond, a lower alkylene group or a general formula -CH = CH- (C
H ₂ ) _n — (wherein n is an integer of 0 to 4), wherein the carbon atom with (R) represents a carbon atom in the (R) configuration, and (S) Represents a carbon atom in the (S) configuration], or the pharmacologically acceptable salt thereof. 3. A pharmaceutical composition comprising the 2-aminopropanol derivative according to claim 1 or a pharmacologically acceptable salt thereof. 4. A β ₃ -adrenoreceptor stimulant comprising the 2-aminopropanol derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. 5. A disease or a disease caused by obesity, hyperglycemia, or increased intestinal motility, comprising the 2-aminopropanol derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. An agent for preventing or treating urine, urinary incontinence, depression, gallstones, or diseases caused by hyperbiliary hyperactivity.