WO1998013333A1 - 2-amino-1-(4-hydroxy-2-methylphenyl)propanol derivatives - Google Patents

Abstract

2-Amino-1-(4-hydroxy-2-methylphenyl)propanol derivatives represented by general formula (I) and pharmacologically acceptable salts thereof, wherein one of Y and Z represents -A-CO-R [wherein A represents -O-D-E (wherein D represents alkylene; and E represents a single bond or phenylene) or ethylene; and R represents hydroxy, alkyl, alkoxy, aralkoxy, amino, dialkylamino or alicyclic amino] while another represents hydrogen; and the carbon atoms marked with (R) and (S) respectively represent those of R- and S-configurations. These compounds have effects of selectively stimulating β2-adrenaline receptors with relieved burden on the heart, such as frequent pulse, and are useful as drugs, for example, preventives for threatened abortion or premature birth and bronchodilators.

Description

 Specification

2-amino-1 (4-hydroxy-2-methylphenyl) propanol derivative Technical field

 The present invention relates to novel 2-amino-1- (4-hydroxy-12-methylphenyl) propanol derivatives which are useful as pharmaceuticals, and pharmacologically acceptable salts thereof.

More specifically, the present invention relates to a compound represented by the general formula: which has a potent and selective 32 ₂ -adrenergic receptor stimulating action, and is useful as a β ι -adrenergic receptor stimulant.

[In the formula, one of Y and Z is a general formula — A— C 0 — R (A in the formula is a general formula-0-D-E-(D is a lower alkylene group, and E is R is a hydroxyl group, a lower alkyl group, a lower alkoxy group, an alkoxy group, an amino group, a di-lower alkylamino group or a group of 3 to 7 which is a single bond or a phenylene group) or an ethylene group. The other is a hydrogen atom, the carbon atom with (R) is a carbon atom in the R configuration, and (S) is attached. The carbon atom represents the carbon atom in the S configuration.] The present invention relates to a 2-amino-1- (4-hydroxy-2-methylphenyl) propanol derivative represented by the formula: and pharmaceutically acceptable salts thereof. Background technology

Sympathetic - adrenergic receptors, the presence of three subtypes of beta iota and 3 ₃ are known. These subtypes are specifically distributed in each organ, and it is strongly known that there is a species difference in their distribution. For example, in humans; Adrenergic receptors are known to be distributed mainly in the heart, adrenergic receptors in the bronchi, uterus, vascular smooth muscle and ureters, and adrenergic receptors in the adipocytes and intestinal tract. I have.

At present, β2-adrenergic receptor stimulants are used clinically as bronchodilators and threatening flow and premature birth-preventing agents.They have side effects such as tachycardia based on the stimulatory action of β-adrenergic receptor. Due to concerns, the development of a highly selective ^ -adrenergic receptor stimulant having a stimulating effect of) S ₂ -adrenergic receptor, which is more potent than that of stimulating adrenergic receptor, has been desired. Disclosure of the invention

The present inventors have excellent) 3 ₂ - Adorenarin receptor agonists intensive studies and as a result to find that certain 2-Amino represented by the general formula (I) - 1 i (4-hydro Kishi 2 - Mechirufuweniru) propanol derivative is potent and selective yS ₂ - has ad Renarin receptor stimulating effect,) 8 ₂ - obtained a finding that it is very useful as adrenergic receptor agonists, forms of the invention Led to.

 The present invention has the general formula

[In the formula, one of Y and Z is a group represented by the general formula A—C 0—R (where A is a group represented by the general formula -0-D-E- (where D is a lower alkylene group, and E is R is a hydroxyl group, a lower alkyl group, a lower alkoxy group, an alkoxy group, an amino group, a di-lower alkylamino group, or a 3- to 7-membered group. The other is a hydrogen atom, the carbon atom with (R) is a carbon atom in the R configuration, and (S) is The carbon atom represents the carbon atom in the S configuration.] 2-amino-11- (4-hydroxy-2-methylphenyl) propanol derivatives and their pharmacological properties Pertains to salts that are acceptable.

 The present invention relates to a medicament containing the 2-amino-1_ (4-hydroxy-2-methylphenyl) pro, ethanol derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

 The present invention relates to an imminent flow / premature birth inhibitor, a bronchodilator comprising the 2-amino-1- (4-hydroxy-2-methylphenyl) propanol derivative or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention relates to a pain relieving agent for urolithiasis or a lithotripsy accelerator.

 The present invention relates to a method for preventing urgency and premature birth by administering the 2-amino-1- (4-hydroxyl-2-methylphenyl) propanol derivative or a pharmacologically acceptable salt thereof, and airway obstruction. The present invention relates to a method for preventing or treating dysfunction, a disease caused by bronchial stenosis, and a method for relieving pain in urolithiasis or facilitating stone removal.

 The present invention relates to the manufacture of a preparation for the prevention of imminent flow and premature birth, the prevention or treatment of diseases caused by airway obstructive disorder and bronchial stenosis, and the manufacture of a preparation for relieving pain in urolithiasis or promoting stone removal. The present invention relates to the use of an amino-1- (4-hydroxy-2-methylphenyl) propanol derivative or a pharmacologically acceptable salt thereof. The present invention relates to the imminent flow of the 2-amino-11- (4-hydroxy-2-methylphenyl) propanol derivative or a pharmacologically acceptable salt thereof · Preterm labor, bronchodilator, pain relief for urolithiasis It is related to its use as an agent or lithotripsy.

In the compound represented by the above general formula (I) of the present invention, a lower alkyl group is a straight-chain or branched alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl and isopropyl. A lower alkylene group means a linear or branched alkylene group having 1 to 6 carbon atoms such as a methylene group, an ethylene group, a trimethylene group, and a propylene group; a lower alkoxy group includes a methoxy group and an ethoxy group; A linear or branched alkoxy group having 1 to 6 carbon atoms, such as a group, a propoxy group, an isopropoxy group, etc., and the alkoxy group is the lower alkoxy group having an aryl group such as a phenyl group or a naphthyl group. The same as but different from the di-lower alkylamino group Refers to an amino group substituted with two of the lower alkyl groups which may be substituted, and a 3- to 7-membered alicyclic amino group refers to an oxygen atom such as 1-pyrrolidinyl group, piperidino group, and morpholino group. Refers to an alicyclic amino group which may be contained.

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

 For example, among the compounds represented by the general formula (I),

[In the formula, one of Y ¹ and Ζ ¹ is a group represented by the general formula A—CO—R ¹ (wherein R ¹ is a hydroxyl group, a lower alkyl group, a lower alkoxy group or an alkoxy group, and A is The other is a hydrogen atom, and the carbon atoms to which (R) and (S) are attached have the same meaning as described above. formula

(Wherein Y ¹ and Z ¹ in the formula have the same meanings as described above). If necessary, a protecting group is introduced, and the alcoholic hydroxyl group is converted into p-toluenesulfonyl by a conventional method. formula

(Wherein R ² is a protecting group for a hydroxyl group, and the carbon atoms to which (R) and (S) are attached have the same meaning as described above). It can be manufactured by removal. Further, among the compounds represented by the general formula (I) of the present invention,

[Wherein Y ² and Ζ ² are either forces, one of which is a general formula— 式 —C 0 —R ³ (wherein R ³ is an amino group, a di-lower alkylamino group or a 3- to 7-membered alicyclic amino group) A is a group having the same meaning as described above), the other is a hydrogen atom, and the carbon atoms to which (R) and (S) are attached have the same meanings as described above. The compound represented by the general formula

[In the formula, one of Y ³ and Ζ ³ is a group represented by the general formula: 1 -CO—R ⁴ (wherein R ⁴ is a lower alkoxy group, and A has the same meaning as described above) And the other is a hydrogen atom, and the carbon atoms to which (R) and (S) are attached have the same meaning as described above.

R ³ one H (IV)

(Wherein R ³ has the same meaning as described above).

Among the compounds represented by the general formula (Π) used as starting materials in the production method,

[In the formula, one of Y ⁴ and Z ⁴ is a group represented by a general formula—0-D—E—CO—R ′ (D, E and R ¹ in the formula have the same meanings as described above) And the other is a hydrogen atom).

(One of Y ⁵ and Z ⁵ in the formula is a hydroxyl group, and the other is a hydrogen atom

) And a general formula

XDE -CO-R ¹ (VI)

(Wherein X is a halogen atom as described above, and D, E and R ′ have the same meanings as described above). It can be produced by reacting in the presence and removing the protecting group if necessary.

Among the compounds represented by the general formula (Π) used as starting materials in the production method,

[Upsilon ^beta and Zeta ⁸ are either general formula in the formula _{- (CH 2) -CO-R} 1 (R in the formula 'have the same meanings as defined above) is a group represented by the other A compound represented by the general formula:

(Wherein one of Y ⁷ and あ り⁷ is a halogen atom and the other is a hydrogen atom), and a compound represented by the general formula COR ¹ (vm)

(Wherein R ¹ has the same meaning as described above). After introducing a protecting group as necessary, the compound is reacted in the presence of a palladium reagent, triphenylphosphine and a base, and if necessary, It can be produced by removing a protecting group.

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

(Wherein R ² and X have the same meanings as described above), and then reacting with a base such as butyllithium.

(Wherein R ⁵ is a protecting group for an amino group, and the carbon atom to which (S) is attached has the same meaning as described above). , And then reducing the carbonyl group with a reducing agent such as sodium borohydride.

The compounds of the present invention and salts thereof obtained by the above-mentioned production method can be separated by a conventional separation means such as a fractional recrystallization method, a purification method using column chromatography, It can be easily isolated and purified by the above method.

 The 2-amino-11- (4-hydroxy-2-methylphenyl) propanol derivative of the present invention represented by the above general formula (I) can be converted into a pharmacologically acceptable salt thereof by a conventional method. Examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p- Acid addition salts with organic acids such as toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, and aspartic acid; Examples thereof include salts with inorganic bases such as sodium and potassium, and salts with organic amines such as morpholine, piperidine and lysine. These salts also have the same pharmacological activity as the free form.

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

 Preferred compounds among the compounds represented by the general formula (I) of the present invention include 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxy-12 —Methylphenyl) -1-methylethyl] amino] ethyl] phenoxy] isopropyl acetate, 2- [4-1 (2-([((1S, 2R)) — 2-hydroxy-2- (4-hydroxy-12-methylphenyl) 1-1 -Methylethyl] amino] ethyl] phenoxy] benzyl acetate, 2- [4-1- [2-[[(IS, 2R) —2-hydroxy-2- (4-hydroxy-12-methylphenyl) -1-methylethyl] amino Ethyl] funinoxy] acetic acid and their pharmacologically acceptable salts.

The compound represented by the above general formula (I) of the present invention can be obtained by in vitro using a rat extirpated pregnant uterus. In the Adorenarin receptor stimulating effect measurement test, approximately 2. O xl O_ ⁸ ~8. Indicates 0 X 1 0- ⁷ molar action to relax 50% automatic movements of uterine smooth muscle by (EC _5. Value) Was. For example, 2- [4-1- [2-[[(1S, 2R) -2-hydroxy-12- (4-hydroxy-2-methylphenyl) -1-methylethyl] amino] ethyl] phenoxy] isopropyl acetate is 3 . 0 X 1 0- ⁸ molarity EC _5. The value was shown. Thus, the compounds of the present invention are non- Always strong yS ₂ - are those having adrenergic activity, 3 ₂ - is very useful as Adore Nalin receptor stimulants.

The adrenergic receptor stimulating effect of the compound represented by the above general formula (I) of the present invention was measured by an in vitro test using a rat isolated atria as usual. As a result, for example, 2- [4-1- [2-[[(IS, 2R) -2-hydroxy-2- (4-hydroxy-12-methylphenyl) -11-methylethyl] amino] ethyl] phenoxy] isopropyl acetate, 1. showed 0 X 1 0- ⁴ acts to per minute 2 0 times增加heart rate automatically movement of atrial smooth muscle in molar concentration (EC _2. value). As described above, the compound of the present invention is a compound having extremely weak adrenergic receptor stimulating action.

As described above, the compound of the present invention has) δ ₂ -adrenoceptor stimulating action very strong and か っ ^, —adrenoceptor stimulating action is extremely weak. It is a selective S ₂ -adrenergic receptor stimulant that is extremely useful as a drug, reducing the burden on the heart.

The compound of the present invention is a selective β ₂ -adrenoceptor stimulant, an agent for preventing imminent flow / premature birth, a bronchodilator (prophylactic or therapeutic agent for diseases caused by airway obstructive disorder, bronchial stenosis disorder) and It is a very useful compound as a medicinal product such as a pain relieving agent for urolithiasis or a lithotripsy accelerator.

 When the 2-amino-1- (4-hydroxy-2-methylphenyl) propanol derivative represented by the general formula (I) of the present invention and a pharmacologically acceptable salt thereof are used for actual treatment, an appropriate drug is used. It is orally or parenterally administered as a formulation, for example, as tablets, powders, fine granules, granules, capsules, injections and the like. These pharmaceutical preparations can be prepared by commonly used pharmaceutical methods using commonly used pharmaceutical carriers, excipients and the like.

The dose is determined as appropriate depending on the gender, age, weight, degree of symptoms, etc. of the target patient.For oral administration, generally 1 to 100 mg per adult per day, for parenteral administration, generally For adults, it is administered in a dose of 0.01 to 10 Omg per day, in single or divided doses. _ BEST MODE FOR CARRYING OUT THE INVENTION

Example

 The content of the present invention will be described in more detail with reference to the following Reference Examples, Examples and Test Examples, but the present invention is not limited to the content. The melting points of the compounds in Reference Examples and Examples are all uncorrected. Reference example 1

 (1 R, 2 S) — 2-amino-11- (4-benzyloxy-2-methylphenyl) propan-1-ol

'= 44.3 g of 4-bromo-3-methylphenyl ether was dissolved in 500 ral of tetrahydrofuran, and 98.6 ml of 1.69 molar n-butyllithium hexane solution was added under stirring at 78 ° C and an argon atmosphere for 1 hour. After the reaction, 16. lg of (S) -2- (tert-butoxycarbonylamino) -N-methoxy-N-methylpropionamide was added, and the temperature was raised to -10 ° C over 2 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride with stirring under ice-cooling, extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel flash column chromatography (elution solvent: hexane / ethyl acetate = 10/1), and the oily (S) -4′-benzyloxy 2- (Tert-butoxycarbonylamino) 1 2'-methylpropiophenone 15.8 g was obtained. IR (neat): 3423, 1713, 1680cm- ¹

Ή-NMR (CDC1 ₃₎

 <5ppm: 1.30 (3H, d, J = 7.1Hz), 1.6 (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 = 8.5Hz)

Specific rotation: ia) _D ²⁵ = +12.5. (C = 0.96, MeOH)

Dissolve 13.3 g of (S) -4'-benzyloxy-2- (tert-butoxycarbonylamino) -2 "-methylpropiophenone in 130 ml of methylene chloride, and add 65 ml of trifluoroacetic acid under ice cooling and stirring. Add a methylene solution (65 ml) and leave at room temperature for 30 minutes Reacted. After concentrating the reaction solution under reduced pressure, the residue was dissolved in 260 ml of methanol, and 6.8 g of sodium borohydride was added under ice-cooling and stirring, followed by reaction at room temperature for 12 hours. After concentrating the reaction solution under reduced pressure, water was added to the residue, the insolubles were collected by filtration, and (1R, 2S)-2-amino-1- (4-benzyloxy-2-) having a melting point of 104 to 107 ° C. Methylphenyl) propane-1-ol 7.5 g was obtained.

IR (KBr): 3353, 3283cm— ¹

 'Η—Marauder R (DMSO-de)

 5ppm: 0.91 (3H, d, J = 6.4Hz), 1.29 (2H, br), 2.27 (3H, s), 2.80-2.90

 (1H, m), 4.45 (1H, d, J = 4.7Hz), 4.89 (1H, br s), 5.07 (2H, s), 6.78 (1H, d, J = 2.6Hz), 6.83 (1H, dd , J = 8.4, 2.6Hz), 7.25-7.50

(6H, m)

Specific rotation: [α] _D ²⁵ = -10.3 ° (c-1.00, eOH) Reference example 2

2- [4- (2-hydroxyxyl) phenoxy] isopropylate

 2.29 g of 4-hydroxyphenethyl alcohol was dissolved in 33 ml of acetone, 2.29 g of potassium carbonate and 2.69 ml of t-tert-butyl 2-bromoacetate were added, and the mixture was heated under reflux for 12 hours. After cooling, the insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in getyl ether, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was dissolved in 83 ml of a saturated isopropyl alcohol solution of hydrogen chloride and reacted at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain 3.90 g of oily isopropyl 2- (4- (2-hydroxyethyl) phenoxy] acetate.

Ή-NMR (CDC1 ₃₎

<5ρρπι: 1.28 (6Η, d, J = 5.9Hz), 2.82 (2H, t, J = 6.5Hz), 3.82 (2H, t,

 J = 6.5Hz), 4.57 (2H, s), 5.05-5.25 (1H, m), 6.86 (2H, d,

J = 8.6Hz), 7.15 (2H, d, J = 8.6Hz) Reference example 3 2-f4- (2-Hydroxyethyl) phenoxy] benzyl acetate

 4-Hydroxyphenethyl alcohol l.OOg was dissolved in acetone 20 ml, and carbonic acid l.OOg and 1.2-ml benzyl acetate 1.26 ml were added, followed by heating under reflux for 12 hours. After cooling, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in getyl ether, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2.27 g of oily 2- [4- (2-hydroxyethyl) phenoxy] benzyl acetate.

 Ή-NMR (CDCls)

δρρπι: 1.37 (1H, t, J = 6. OHz), 2.81 (2H, t, J = 6.5Hz), 3.75-3.90 (2H, m),

 4.65 (2H, s), 5.24 (2H, s), 6.85 (2H, d, J = 8.6Hz), 7.14 (2H, d,

J = 8.6Hz), 7.30-7.40 (5H, m) Reference example 4

 4- (4- (2-hydroxyethyl) phenoxymethyl) ethyl benzoate

 The reaction was carried out in the same manner as in Reference Example 3 using ethyl 4-chloromethylbenzoate instead of benzyl 2-bromoacetate, and the melting point was 93-94 ° C (unrecrystallized). [Ethyl) phenoxymethyl] ethyl benzoate was obtained.

 • H-NMR (CDCls)

 dppm: 1.34 (1H, t, J = 5.9Hz), 1.40 (3H, t, J = 7.1Hz), 2.81 (2H, t, J = 6.5

 Hz), 3.83 (2H, dt, J = 6.5, 5.9Hz), 4.38 (2H, q, M.1Hz), 5.11

(2H, s), 6.91 (2H, d, J = 8.7Hz), 7.15 (2H, d, J = 8.7Hz), 7.49 (2H, d, J-8.5Hz), 8.06 (2H, d, J = (8.5Hz) Reference example 5

 3- (3- (2-Hydroxyethyl) phenyl] methyl propionate

A mixture of 1.70 g of 3-bromophenethyl alcohol, 948 mg of methyl acrylate, 133 mg of triphenylphosphine, 57 mg of palladium acetate and 1.54 ml of triethylamine was reacted in a sealed tube at 120 ° C. for 13 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent remains under reduced pressure The product was purified by silica gel, medium pressure liquid chromatography (elution solvent: hexane z ethyl acetate = 2Z1), and oily 3- [3- (2-hydroxyethyl) phenyl] methyl acrylate 1.02 g was obtained.

Ή-NMR (CDC1 ₃₎

(ρριη: 1.40 (1H, t, J = 5.8Hz), 2.90 (2H, t, J-6.5Hz), 3.81 (3H, s), 3.89 (2H, dt, J = 6.5, 5.8Hz), 6.45 ( 1H, d, J = 16.0Hz), 7.20-7.45 (4H, m), 7.68 (1H, d, J = 16.0Hz)

3- [3- (2-Hydroxyethyl) phenyl] Suspend 996 mg of methyl acrylate and 50 mg of 10% palladium on carbon in 9.6 ml of ethanol.

Stir for 1 hour. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain 915 mg of oily methyl 3- [3- (2-hydroxyxethyl) phenyl] propionate.

 Ή-NMR (CDCls)

 (5 pm: 1.46 (1H, t, J = 6.0Hz), 2.63 (2H, t, J = 7.8Hz), 2.85 (2H, t,

 J = 6.5Hz), 2.94 (2H, t, J = 7.8Hz), 3.67 (3H, s), 3.85 (2H, dt,

J = 6.5, 6.0Hz), 7.00-7.15 (3H, m), 7.25 (1H, d, J = 2.9Hz) Reference example 6

 2— [4- (2-hydroxyethyl) phenoxy] 1-methylpropionate j

1.40 g of 4-hydroxyphenyl alcohol was dissolved in 30 ml of tetrahydrofuran, 405 mg of sodium hydride in 60% oil was added under ice cooling and stirring, and the mixture was reacted at room temperature for 1 hour. Chloromethyl methyl ether (0.77 ml) was added to the reaction mixture under ice-cooling and stirring, and the mixture was reacted at room temperature for 16 hours. To the reaction mixture was added 405m of 60% sodium hydride in oil under ice cooling and stirring, and the mixture was stirred at room temperature for 1 hour. Then, benzyl bromide (1.2ml) was added under ice cooling, and the mixture was reacted at room temperature with stirring for 16 hours. The reaction solution was poured into ice water, extracted with getyl ether, washed with saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was dissolved in methylene chloride (20 ml), and trifluoroacetic acid (20ral) was added with stirring under ice-cooling, followed by reaction for 1 hour. Concentrate the reaction mixture under reduced pressure and add 2N to the residue. An aqueous sodium hydroxide solution (20 ml), water (20 ral) and getyl ether were added, and the mixture was shaken vigorously to separate the aqueous layer. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel medium pressure liquid column chromatography (eluting solvent: hexane / getyl ether = 2/1) to obtain 4 _ (2- Benzoxchetyl) phenol 440 nig was obtained.

Ή-NMR (CDC1 ₃₎

ippm: 2.86 (2H, t, .2Hz), 3.65 (2H, t, J = 7.2Hz), 4.53 (2H, s), 4.79 (1H, s), 6.74 (2H, d, J = 8.6Hz), 7.08 (2H, d, J = 8.6Hz), 7.20-7.0 (5H, m)

Dissolve 420 mg of 4- (2-benzyloxyshethyl) phenol and 690 mg of 1,1,1-trichloro-2-methyl-2-propanol 1Z dihydrate in 5 ml of acetone and add water under ice-cooling and stirring. After 960 mg of potassium oxide was added in three portions at 10 minute intervals, the reaction was carried out at room temperature for 16 hours. After the reaction solution was reduced under reduced pressure, the residue was dissolved in ice water, and washed with ethyl ether. The aqueous layer was acidified with hydrochloric acid, extracted with ethyl acetate, washed with brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was dissolved in a solution of 0.4 ml of thionyl chloride in 10 ml of ethanol and heated under reflux for 6 hours. After concentrating the reaction mixture under reduced pressure, the residue was purified by silica gel medium pressure liquid column chromatography (elution solvent: hexane Z getyl ether = 5/1) to give oily 2- (4- (2- 485 mg of ethyl 2-methylpropionate were obtained.

 Ή-NMR (CDCls)

 δρρπι: 1.25 (3Η, ΐ, J = 7.1Ηζ), 1.57 (6H, s), 2.86 (2H, t, J = 7.2Hz), 3.65 (2H, t, J = 7.2Hz), 4.23 (2H, q , J = 7.lHz), 4.52 (2H, s), 6.77 (2H, d, J = 8.6Hz), 7.08 (2H, d, J = 8.6Hz), 7.20-7.40 (5H, m)

2- [4- (2-benzyloxyshethyl) phenoxy] 480 mg of ethyl 2-methylpropionate and 30 mg of 10% palladium on carbon are suspended in 3 ml of ethanol, and the The mixture was stirred under a warm, hydrogen atmosphere for 48 hours. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel medium pressure liquid column chromatography (elution solvent: hexanenodiethyl ether = 1/1) to give an oily 2- [4-1-1 ( 2-Hydroxyethyl) phenoxy] Ethyl 310-ethyl 2-methylpropionate was obtained.

 Ή-NMR (CDCls)

 5ppm: 1.26 (3H, t, J = 7.1Ηζ), 1.58 (6H, s), 2.80 (2H, t, J = 6.5Hz), 3.82 (2H, t, J = 6.5Hz), 4.24 (2H, q , J = 7.1Hz), 6.80 (2H, d, J-8.7Hz), 7.09 (2H, d, J = 8.7Hz) Reference example 7

 3-C4- (2-hydroxyethyl) phenoxy] ethyl propionate

 Dissolve 300 mg of 4-hydroxyphenethyl alcohol in 10.5 ml of N, N-dimethylformamide, and stir at room temperature with stirring at room temperature with 1- (2-bromoethyl) -14-methyl-2,6,7-trioxabicyclo [2 2.2.2] Octane 566 mg and cesium carbonate 1.06 g were added, and the mixture was reacted at 120 ° C for 5 hours. Furthermore, 257 mg of 1- (2-promoethyl) -1,4-methyl-1,2,6,7-trioxabicyclo [2.2.2] octane and 35 g of cesium carbonate were added, and reacted at 120 ° C. for 1.5 hours. After cooling, water was added to the reaction solution, 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 (eluting solvent: hexane / ethyl acetate = 1/1) to obtain an oily 2- (4- [2- 247 mg of (4-monomethyl-1,2,6,7-trioxabicyclo [2.2.2] octane-1-yl) ethoxy] phenyl] ethanol were obtained.

'H-NMR (CDC1 ₃₎

 (5 pm: 0.82 (3H, s), 2.15-2.25 (2H, m), 2.80 (2H, t, J = 6.5Hz), 3.75 — 3.90 (2H, m), 3.91 (6H, s), 4.05- 4.15 (2H, m), 6.87 (2H, d,

J = 8.7Hz), 7.12 (2H, d, J = 8.7Hz)

2-[4-[2-(4-Methyl-2,6,7-trioxabicyclo [2.2.2] octane-1-yl) ethoxy] phenyl] Ethanol 247 mg in methanol The mixture was dissolved in 4.2 ml, and 0.84 ml of a 2N aqueous sulfuric acid solution was added thereto under ice-cooling and stirring, and the mixture was reacted for 15 minutes. To the reaction mixture was added 1.68 ml of a 2N aqueous sodium hydroxide solution under ice-cooling and stirring, and the mixture was reacted at room temperature for 1 hour. The insoluble material was removed by filtration, the filtrate was acidified with dilute hydrochloric acid, 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 (elution solvent: ethyl acetate) to obtain amorphous 3- (4-1 (2-hydroxyethyl) phenoxy) propionic acid 74rag. Obtained.

Ή-NMR (DMSO-d _e )

 5ppm: 2.60-2.75 (4H, m), 3.50-3.60 (2H, m), 4.13 (2H, t, J = 6.0Hz),

 4.60 (1H, br), 6.83 (2H, d, J = 8.6Hz), 7.12 (2H, d, J = 8.6Hz),

12.37 (1H, br)

3- (4- (2-Hydroxyethyl) phenoxy] Dissolve 91 mg of propionic acid in 1.2 ml of N, N-dimethylformamide, and add 49 rag of carbonic acid rim and 271 of iodide thiol under stirring at room temperature. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give an oily 3- (4- (2-hydroxyethyl). ) Fenoxy] 54 mg of ethyl propionate were obtained.

• H-NMR (CDC1 ₃₎

 5ppm: 1.28 (3H, t, J = 7.1Hz), 1.40 (1H, br), 2.78 (2H, t, J = 6.5Hz),

 2.81 (2H, t, J = 6.5Hz), 3.82 (2H, t, J = 6.5Hz), 4.19 (2H, q, J = 7.1Hz), 4.24 (2H, t, J = 6.5Hz), 6.86 ( 2H, d, J: 8.7Hz), 7.14 (2H, d, J = 8.7Hz) Reference Example 8

 2-[4-[(2-ethyl-1,3-dioxane-2-yl) methoxy] feninole] ethanol

Dissolve 2.00 g of 4-hydroxyphenethyl alcohol in 30 ml of N, N-dimethylformamide, and stir at room temperature with 1.78 ml of 1-promobutane-2-one and carbonic acid solution. 2.40 g of dimethyl ether was added and reacted for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with a 10% aqueous sodium carbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel medium pressure liquid column chromatography (elution solvent: hexane / ethyl acetate = 11) to obtain an oily 4- (2-hydroxyethyl). Phenoxy] butane 2-one 1.94 g obtained o

 5ppm: 1.11 (3H, t, J = 7.3Hz), 1.39 (1H, t, J = 6.0Hz), 2.63 (2H, q,

 ] = Ί.3Hz), (2H, t, J = 6.6Hz), 3.83 (2H, dd, J = 6.6, 6.0Hz), 4.54 (2H, s), 6.84 (2H, d, J = 8.7Hz) , 7.16 (2H, d, J = 8.7Hz)

Dissolve 1.00 g of 1- [4- (2-hydroxyethyl) phenoxy] butan-2-one in 48 ml of toluene, add 83 mg of p-toluenesulfonic acid monohydrate and 6.9 ml of 1,3-propanediol, The mixture was heated under reflux for 3 hours while removing water. After cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel medium-pressure liquid column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to obtain oily 2- [4 -— ((2-ethyl-1 1.15 g of 1,3-dioxane-2-yl) methoxy] phenyl] ethanol were obtained.

 Ή-NMR (CDCls)

 (5ρρπι: 0.92 (3Η, t, J = 7.5Hz), 1.38 (1H, t, J = 6.5Hz), 1.65-1.90 (2H, m),

 2.00 (2H, q, J = 7.5Hz), 2.81 (2H, q, J = 6.5Hz), 3.82 (2H, dd, J = 6.6, 6.1Hz), 3.90-4.10 (6H, m), 6.92 (2H , D, J = 8.7Hz), 7.14 (2H, d, J = 8.7Hz) Reference Example 9

2- [4- [2- (p-Toluenesulfonyloxy) ethyl] phenoxy] isopropyl acetate 2- [4- (2-Hydroxyethyl) phenoxy] Dissolve 3.90 g of isopropyl acetate in 83 ml of methylene chloride, add 4.63 ml of triethylamine and 3.80 g of p-toluenesulfonyl chloride under ice-cooling, and allow to stand at room temperature. The reaction was performed for 2 hours. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel flash column chromatography (elution solvent: ethyl hexane acetate = 3/1) to give oily 2- [4_ [2- (p-toluenesulfonyloxy) ethyl] phenoxy] acetic acid 4.89 g of isopropyl were obtained.

 — NMR (CDCla)

 5ppm: 1.27 (6H, d, J = 5.9Hz), 2.43 (3H, s), 2.89 (2H, t, J = 7.2Hz), 4.16

 (2H, t, 1 = 1.2Hz), 4.55 (2H, s), 5.05-5.25 (1H, m), 6.79 (2H, d, J = 8.4Hz), 7.03 (2H, d, J = 8.4Hz) , 7.29 (2H, d, J = 8.2Hz), 7.68 (2H, d, J = 8.2Hz) Reference example 10

 2- [4- (2-hydroxyethyl) phenoxy] The reaction was carried out in the same manner as in Reference Example 9 using the corresponding compound in place of isopropyl acetate, and the following compound was obtained.

2- [4- [2-((p-toluenesulfonyloxy) ethyl] phenoxy] acetic acid oil

^L H—NMR (CDCla)

 δρρπι: 2.43 (3Η, s), 2.89 (2H, t, J = 7.1Hz), 4.15 (2H, t, J = 7.1Hz), 4.64

 (2H, s), 5.24 (2H, s), 6.77 (2H, d, J = 8.7Hz), 7.01 (2H, d, J = 8.7Hz), 7.29 (2H, d, J = 8.2Hz), 7.30 -7.40 (5H, m), 7.68 (2H, d, J = 8.2Hz)

2-C4- [2- (p-Toluenesulfonyloxy) ethyl] phenoxy] ethyl acetate Melting point: 31-33 ° C (unrecrystallized)

Ή-NMR (CDC1 ₃₎

 5ppm: 1.30 (3H, t, J = 7.1Hz), 2.43 (3H, s), 2.89 (2H, t, J = 7.0Hz), 4.16

 (2H, t, J = 7.0Hz), 4.27 (2H, q, J = 7.1Hz), 4.58 (2H, s), 6.79 (2H, d, J = 8.6Hz), 7.03 (2H, d, J = 8.6Hz), 7.29 (2H, d, J = 8.2Hz),

7.68 (2H, d, J = 8.2Hz)

2-methyl-2- [4- [2- (p-toluenesulfonyloxy) ethyl] phenoxy] ethyl propionate

Oily

 iH—NMR (CDCla)

 5ppm: 1.25 (3H, t J = 7.1Hz), 1.57 (6H, s), 2.44 (3H, s), 2.88 (2H, t,

 J = 7.1Hz), 4.16 (2H, t, J = 7.lHz), 4.23 (2H, q, J = 7.1Hz), 6.73 (2H, d, J = 8.6Hz), 6.97 (2H, d, J = 8, 6Hz), 7.30 (2H, d, J = 8.0Hz), 7.65-7.75 (2H, m)

3- [4- [2- (p-Toluenesulfonyloxy) ethyl) phenyl] ethyl propionate

Oily

 5ppm: 1.28 (3H, t, J = 7.1Hz), 2.43 (3H, s), 2.78 (2H, t, J = 6.4Hz), 2.88

 (2H, t, J = 7.1Hz), 4.10-4.30 (6H, m), 6.78 (2H, d, J = 8.7Hz), 7.01

(2H, d, 1 = 8.7Hz), 7.25-7.35 (2H, m), 7.69 (2H, d, J = 8.3Hz)-[4- (2- (p-toluenesulfonyloxy) ethyl] phenoxymethyl] Ethyl benzoate

Melting point: 101-: 105. C (not recrystallized)

'N-NMR (CDC1 ₃₎

5.10 (2H, s), 6.855ppm: 1.40 (3Η, ΐ, J = 7.1Hz), 2.43 (3H, s), 2.89 (2H, t, J = 7.1Hz), 4.17 (2H, t,

5.10 (2H, s), 6.85

(2H, d, J = 8.6Hz), 7.03 (2H, d, J = 8.6Hz), 7.28 (2H, d, J = 8.3Hz),

7.48 (2H, d, J = 8.2Hz), 7.70 (2H, d, J = 8.3Hz), 8.06 (2H, d, J = 8.2Hz) p-toluenesulfonic acid 2— [4-1 ((2-ethyl) — 1,3-Dioxane-2-yl) _ (Toxi) phenyl) ethyl

Oily

Ή-NMR (CDC1 ₃₎

 Sppm: 0.92 (3H, t, J-7.5Hz), 1.65-1.90 (2H, m), 2.00 (2H, q, J = 7.5Hz),

 2.43 (3H, s), 2.89 (2H, t, J = 7.1Hz), 3.85-4.05 (6H, m), 4.16 (2H, t, J = 7.1Hz), 6.84 (2H, d, J = 8.7Hz) ), 7.01 (2H, d, J = 8.7Hz), 7.28 (2H, d, J = 8.3Hz), 7.69 (2H, d, J = 8.3Hz) 3-[3-[2— (p-toluenesulfonyl) Oxy) ethyl] phenyl] methyl propionate

Amorphous

 'H-NMR (CDCh)

 <ppm: 2.43 (3H, s), 2.55-2.65 (2H, m), 2.85-3.00 (4H, m), 3.67 (3H, s), 4.21 (2H, t, J = 7.1Hz), 6.90-7.00 (2H, m), 7.05 (1H, d,

J = 7.6Hz), 7.18 (1H, t, J = 7.6Hz), 7.29 (2H, d, J = 8.0Hz), 7.69 (2H, d, J = 8.0Hz)

 2— [4 [2 _ [[(1 S, 2 R) — 2-hydroxy-2- (4-hydroxy-12-methylphenyl) -1-methylethyl] amino] ethyl] phenoxy] isopropyl acetate

(1 R, 2 S) 12-amino-11- (4-benzyloxy-2-methylphenyl) 300 mg of propane-1-1-ol and 50 mg of 10% palladium on carbon in ethanol The mixture was suspended in 10 ml and stirred at room temperature under a hydrogen atmosphere for 1 hour. After removing the catalyst by filtration and concentrating the filtrate under reduced pressure, the residue was dissolved in 3 nil of N, N-dimethylformamide, and the mixture was stirred at 90 ° C with 2- (4-1) (2- (p-toluenesulfonylate). Xy) ethyl] phenoxy] A solution of 200 mg of isopropyl acetate in 5 ml of N, N-dimethylformamide was added, and the mixture was reacted at 90 ° C for 2 hours. After cooling, water was added to the reaction solution, extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by medium-pressure liquid-pressure column chromatography (elution solvent: chloroform / methyl alcohol = 30/1) to obtain an amorphous 2 — [4 -— [2-[[(1S, 2R) -12-hydroxy-12- (4-hydroxy-12-methylphenyl) -11-methylethyl] amino] ethyl] phenoxy] 90 nig isopropyl acetate was obtained.

1 R (neat): 3406, 1750cm— ¹

JH-NMR (CDC1 ₃₎

 <5ppm: 0.95 (3H, d, J = 6.4Hz), 1.31 (6H, d, J = 6.3Hz), 2.22 (3H, s), 2.60

 -3.10 (5H, m), 4.58 (2H, s), 4.76 (1H, d, J = 4.3Hz), 5.18 (1H, quint, J = 6.3Hz), 5.40 (1H, br), 6.53 (1H, d, J = 2.7Hz), 6.57 (1H, dd, J = 8.5, 2.7Hz), 6.78 (2H, d, J = 8.7Hz), 7.03 (2H, d, J = 8.7Hz), 7.19 (1H, d, J = 8.5Hz)

Specific rotation: [α] _D ²⁵ = + 2.6. (C = 0.50, MeOH) Example 2

 2- [4- [2- (p-Toluenesulfonyloxy) ethyl] phenoxy] The reaction was carried out in the same manner as in Example 1 using the corresponding ester derivative in place of isopropyl acetate and the following compound was obtained. .

2- [4- [2-[[(1S-1,2R) -12-hydroxy-12- (4-hydroxy-12-methylphenyl) -1-methylethyl] amino] ethyl] phenoxy] benzyl acetate hydrochloride

Melting point: 134 -137 ° C (unrecrystallized) 1 R (KBr): 3395, 2849, 1746cm— ¹

 Ή-NMR (CDCh)

 5ppm: 0.93 (3H, d, J = 6.4Hz), 2.22 (3H, s), 2.65-3.05 (5H, m), 4.66

 (2H, s), 4.79 (1H, d, J = 4.9Hz), 5.26 (2H, s), 6.53 (IH, d, 1 = 2.7Hz), 6.57 (IH, dd, J = 8.4, 2.7Hz) , 6.77 (2H, d, J = 8.7 Hz),

7.03 (2H, d, J = 8.7 Hz), 7.21 (1H, d, J = 8.4 Hz), 7.30-7.5 (5H, m) Specific rotation: [α] _D ²⁵ = -9.8 ° (c = (0.49, MeOH)

2-1 [4-1 [2-[[(IS, 2R)-2-hydroxy-1- (4-hydroxy-2-methylphenyl)-1-methylethyl] amino] ethyl] phenoxy] ethylethyl acetate

Melting point: 207-209 ° C (unrecrystallized)

IR (KBr): 3395, 2840, 1757cm- ¹

 ^-MR (DMSO-de)

5ρρηι: 0.99 (3H, d, J = 6.6Hz), 1.21 (3H, t, J = 7.lHz), 2.21 (3H, s), 2.85

 -3.40 (5H, m), 4.16 (2H, q, J = 7.1Hz), 4.75 (2H, s), 5.21 (IH, br s), 5.84 (1H, d, J = 3.6Hz), 6.56 (IH , d, J-2.4Hz), 6.63 (IH, dd, J = 8.5, 2.4Hz), 6.90 (2H, d, J = 8.7Hz), 7.20 (2H, d, J = 8.7Hz), 7.27 (IH , d, J = 8.5Hz), 8.68 (IH, br), 8.85 (IH, br),

 9.26 (1H, s)

Specific rotation: [α] D ²⁵ =-10.9 ° (c = 1.00, MeOH)

3- (4-[2— [[(1 S, 2 R) — 2-hydroxy-1- 2- (4-hydroxy-1--2-methylphenyl) -1-methylethyl] amino] ethyl] phenyloxy) ethyl ethyl pionate

Viscous oil

IR (neat): 3402, 1734cm- ¹

 Ή-NMR (CDCls)

δρρπι: 1.02 (3H, d, J = 6.3Hz), 1.32 (3H, t, J = 7.1Hz), 2.20 (3H, s), 2.50 -2.90 (7H, m), 2.95-3.05 (1H, m), 3.50 (1H, br), 4.15-4.30 (4H, m), 4.67 (1H, d, J = 6.0Hz), 5.95 (1H, br) ), 6.45-6.55 (2H, m), 6.75 (2H, d, J = 8.6Hz), 6.99 (2H, d, J = 8.6Hz), 7.06 (1H, d,

 J = 8.4Hz)

Specific rotation: [α] D ²⁵ = — 12.2 ° (c = 0.54, AcOH)

3- [3- [2-[[[(IS, 2R)-(2-hydroxy-2-(-hydroxy-l-methylphenyl) -l-methylethyl] amino] ethyl] phenyl] methyl propionate

Viscous oil

1 R (neat): 3395, 1737cm— ¹

 ^ -NMR (CDCh)

 (5ppm: 0.85 (3H, d, J = 6.3Hz), 2.24 (3H, s), 2.55-3.05 (9H, m), 3.30

 (1H, br), 3.68 (3H, s), 4.88 (1H, d, J = 3.9Hz), 6.59 (1H, d,

 1 = 2.9Hz), 6.60-6.70 (1H, m), 6.95-7.10 (3H, m), 7.15-7.25 (1H, m), 7.34 (1H, d, J = 8.3Hz)

Specific rotation: [α] _D ²⁵ = +3.6. (c = 1.01, MeOH)

 2-C4-(2-C [(1 S, 2 R) — 2-Hydroxy-1- (4-hydroxy: 2-methylphenyl)-1 -methylethyl] amino] ethyl] phenoxy] 1-methylpropionic acid Ethyl hydrochloride

Melting point: 197-205 ° C (decomposition) (not recrystallized)

IR (KBr): 3404, 3341, 1732 cm " ¹

 Ή-NMR (DMSO-de)

 (5ppm: 0.99 (3H, d, J = 6.7Hz), 1.18 (3H, t, J = 7.1Hz), 1.50 (6H, s), 2.21

(3H, s), 2.90-3.30 (5H, in), 4.16 (2H, q, J = 7.1Hz), 5.25 (1H, br s), 5.82 (1H, d, J = 3.7Hz), 6.56 (1H , d, J = 2.5Hz), 6.63 (1H, dd, J = 8.4, 2.5Hz), 6.77 (2H, d, J = 8.6Hz), 7.18 (2H, d, J = 8.6Hz), 7.27 (1H , D, J = 8.4Hz), 8.76 (1H, br), 9.03 (1H, br), 9.26 (1H, s) Specific rotation: [] D ²⁵ = — 11.1 ° (c = 1.00, MeOH) Example 3

 2— [4—— Γ2-[C (1 S, 2 R) — 2—hydroxy 2— (4-hydroxy 1-2-methylphenyl) 1-methylethyl] amino] ethyl] phenoxy] acetamide

2- [4- [2- [[(1 S, 2 R) Single 2- arsenide Dorokishi 2- (4-arsenide Doroki Sea 2- methylphenyl) Single 1 Mechiruechiru] Amino] Echiru] phenoxy] acetic acid Echiru 8l _m g It was dissolved in 1.5 ml of tetrahydrofuran, and 0.5 ml of a 28% aqueous ammonia solution was added thereto with stirring at room temperature, followed by a reaction for 5.5 hours. After concentrating the reaction mixture under low pressure, the residue was purified by medium-pressure liquid column chromatography on aminopropylated silica gel (eluent: chloroform / methanol-30/1) to obtain amorphous 2- [4-[ 63 mg of 2-[[(1S, 2R) -2-hydroxy-1-2- (4-hydroxy-2-methylphenyl) -11-methylethyl] amino] ethyl] phenoxy] acetamide was obtained.

1 R (film): 3292, 1680cm— ¹

'H-NMR (DMS0-d ₉ )

 5ppm: 0.84 (3H, d, J = 6.3Hz), 1.30 (1H, br), 2.16 (3H, s), 2.30-2.80

 (5H, m), 4.37 (2H, s), 4.68 (1H, br s), 4.69 (1H, br s), 6.8 (1H, d, J = 2.1Hz), 6.54 (1H, dd, J = 8.4, 2.1Hz), 6.83 (2H, d,

J = 8.3Hz), 7.08 (2H, d, J = 8.3Hz), 7.17 (1H, d, J = 8.4Hz), 7.38 (1H, br s), 7.48 (1H, br s), 9.09 (1H, br s)

Specific rotation: (a) _D ²⁵ = —16.9. (c = 0.52, AcOH) Example 4

 After heating in a sealed tube using the corresponding amine in place of the 28% aqueous ammonia solution, the same treatment as in Example 3 was performed to obtain the following compound.

2— [4 ー [2— [[(1 S, 2R) — 2-hydroxy 2 -— (4-hydroxy 1-Methylphenyl) 1 1-Methylethyl] amino] ethyl] phenoxy] 2

N, N—dimethylacetamide

Amorphous

 I R (Br): 3431, 1652 cm

 <5ρρπι: 1.13 (3Η, d, J = 6.2Hz), 2.15-2.30 (4H, m), 2.50-2.80 (4H, in),

 2.95-3.05 (IH, m), 3.07 (3H, s), 3.13 (3H, s), 4,58 (IH, d, J = 7.1Hz), 4.65-4.75 (2H, m), 6.45-6.55 ( 2H, m), 6.71 (2H, d, J = 8.6Hz), 6.85-7.00 (3H, m), 7.45 (1H, br s)

Specific rotation: (a) D ²⁵ = +4.4. (c = 0.50, THF)

1 [2-[4-[2-[(IS, 2R) 1-2-hydroxy 1-2-(4-hydroxy 2-methylphenyl)-1-methylethyl] amino] ethyl] Phenyl] Acetyl) piperidine

Amorphous

IR (KBr): 3409, 1638 cm one ¹

 Ή-NMR (CDCls)

 (5ppm: 1.11 (3H, d, J = 6.2Hz), 1.50-1.75 (7H, ID), 2.19 (3H, s), 2.20-

2.30 (IH, m), 2.50-2.80 (4H, m), 2.95-3.05 (IH, m), 3.51 (2H, t, J = 5.3Hz), 3.64 (2H, t, J = 5.3Hz), 4.59 (IH, d, J = 6.7Hz), 4.65-

4.75 (2H, m), 6.45-6.55 (2H, m), 6.72 (2H, d, J-8.7Hz), 6.90 (2H, d, J = 8.7Hz), 6.99 (1H, d, J = 8.6Hz) ), 7.30 (IH, br) Specific rotation: ία) ο ²⁶ = +3.8 ° (c = 1.04, THF) 4-[2-[4-1 [2-[[(1S, 2R)-2- Hydroxy-2- (4-hydroxy-2-methylphenyl) -1-methylethyl] amino] cell] phenoxy] acetyl] morpholine

Amorphous

IR (KBr): 3423, 1651 cnT ¹ Ή-NMR (CDC1 ₃₎

 (5ppm: 1.03 (3H, d, J = 6.3Hz), 2.18 (3H, s), 2.55-2.85 (4H, m), 2.90-3.05 (1H, m), 3.50-3.75 (8H, m), 4.67 (2H, s), 4.70 (1H, d,

 5.9Hz), 6.45-6.60 (2H, m), 6.77 (2H, d, J = 8.7Hz), 6.97 (2H, d, J = 8.7Hz), 7.09 (1H, d, J = 8.3Hz)

Specific rotation: [N] _D ²⁵ = — 16.9 ° (c = 0.59, AcOH) Example 5

 4-[4-[[2-[[(1 S, 2 R) — 2-hydroxy-2- (2-methyl-4-oxydoxyphenyl) -1-methylethyl] amino] ethyl] phenyloxymethyl disodium benzoate

 (1 S, 2R) — 2-Amino 1- (4-benzyloxy-2-methylphenyl) propane-1-ol 542 rag and 50 mg of 10% palladium on carbon are suspended in 10 ml of ethanol, and suspended at room temperature under a hydrogen atmosphere. Stirred for hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 10 ml of N, N-dimethylformamide, and stirred at room temperature under 4- (4-1- [2- (p-toluenesulfonyloxy)). [Ethyl] phenoxymethyl] ethyl benzoate (271 mg) was added, and the mixture was reacted for 3.5 hours with stirring. After cooling, water was added to the reaction solution, 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 chromatography on aluminopropylated silica gel (elution solvent: chloroform / methanol = 30/1). 96 mg of the obtained amorphous material was dissolved in 1. Oral of methanol, 2N aqueous sodium hydroxide solution 207 // 1 was added thereto with stirring at room temperature, and the mixture was reacted for 3 hours and further reacted at 50 ° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure to give amorphous 4-[[4 [[2 [[((1S, 2R) -12-hydroxy-12- (2-methyl-4-oxodophenyl) -1-methylethyl] amino. [Ethyl] phenoxymethyl] benzoic acid sodium salt 99 mg was obtained.

 I R (KBr): 3420, 1595cm

_{'H-NMR (CD 3 0D} )

5 pm: 1.13 (3H, d, J = 6.3Hz), 2.20 (3H, s), 2.55-2.95 (5H, m), 4.62 (ΙΗ 'd, J = 6.8Hz), 5.08 (2H, s), 6.49 (IE d, 1 = 2.5Hz), 6.52 (1H, dd, J = 8.4, 2.5Hz), 6.87 (2H, d, J = 8.7Hz), 6.99 (2H, d, J = 8.7Hz), 7.05 (1H, d, J = 8.4Hz), 7.43 (2H, d, J = 8.5Hz), 7.95 (2H, d,

 (J = 8.5Hz)

Specific rotation: ί) _D ²⁵ = 3.6 ° C (c = 1.00, MeOH) Example 6

 2- (4-(2-C ((1S, 2R)) 2-Hydroxy-1- (2-methyl-4-oxoxide)-1-methylethyl] amino] ethyl] phenoxy] acetic acid

 2- [4- [2-[[((1S, 2R) —2-hydroxy-2- (4-hydroxy-1-methylphenyl) -1-methylethyl] amino] ethyl] phenoxy] The ester hydrolysis reaction and treatment described in Example 5 were carried out in the same manner to obtain amorphous 2- [4-1- [2-([(1S, 2R) -12-hydroxy-12- (2-methyl-4-) Oxidophenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid disodium salt was obtained.

IR (KBr): 3383, 1609cm- ¹

 Ή-NMR (DMSO-de)

 <5ppm: 0.96 (3H, d, J = 6.4Hz), 1.98 (3H, s), 2.55-2.95 (5H, m), 4.02

 (2H, s), 4.15-4.35 (2H, m), 5.80-6.00 (2H, m), 6.60-6.75

(3H, m), 6.80-6.95 (2H, m)

Specific rotation: [α] _D ²⁵ =-4.1 ° (c = 1.00, MeOH) Example 7

 1-1 [4-1] [2-([((1S, 2R) —2-hydroxy-21- (4-hydroxy-12-methylphenyl) -11-methylethyl] amino] ethyl] phenoxy] bun-12-one

(IS, 2R) — 2-Amino-1- (4-benzyloxy-2-methylphenyl) 500mg of propane-1-ol and 50mg of 10% palladium on carbon in ethanol The mixture was suspended in 9 ml and stirred at room temperature under a hydrogen atmosphere for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 2.5 ral of N, N-dimethylformamide, and p-toluenesulfonic acid 2- (4--(2 —Ethyl—1,3-dioxane-1-yl) methoxyphenyl] ethyl 347 rag of N, N-dimethylformamide (2 ml) was added dropwise, and the mixture was allowed to react for 7 hours. The extract was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. (Eluent: ethyl acetate / ethanol == 7/1) Purified (yield: 249 mg) Dissolve 228 mg of the obtained amorphous substance in 2.7 ml of 1,2-dimethylxetethane, and stir with 1N hydrochloric acid under ice-cooling and stirring. ml was added dropwise and reacted at room temperature for 14 hours. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate under ice-cooling and stirring, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Elution solvent: Purified by chromatography on form / methanol = 10/1) to obtain an oily 1- [4-[2-[[(1S, 2R) -2-hydroxy-1-2- (4-hydroxy-2- Methylphenyl) 1-methylethyl] amino] ethyl] phenoxy] butan-2-one 249 mg IR (neat): 3346, 1721 cm- ¹

 Ή-NMR (CDCla)

 (5 pm: 0.90 (3H, d, J = 6.5Hz), 1.13 (3H, t, .3Hz), 1.60 (2H, br),

 2.23 (3H, s), 2.63 (2H, q, J = 7.3Hz), 2.70-3.05 (5H, m), 3.50 (1H, br), 4.58 (2H, s), 4.83 (1H, d, J 4.5Hz), 6.56 (1H, d, J = 2.5Hz), 6.61 (1H, dd, J = 8.4, 2.5Hz), 6.77 (2H, d, J = 8.5Hz), 7.07 (2H, d, J = 8.5Hz), 7.20-7.30 (1H, m)

Specific rotation: [α] _D ²⁵ = —13.2. (c = 0.82, AcOH) Test Example 1

Effects of drugs on isolated pregnancy uterine automatic movement

The uterus of an SD pregnant rat (day 2 of pregnancy) was excised, and a specimen about 5 mm in width and about 15 mm in length was made in the longitudinal muscle direction, avoiding the placenta attachment, and was prepared according to the Magnus method. Test was carried out. The sample was suspended at 37 ° C in a L0 cke_Ringer solution aerated with a mixture of 95% oxygen and 5% carbon dioxide, and a 1 g load was applied. Uterine motility was derived isometrically via a pressure transducer and recorded on a rectogram. The 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 concentration of the drug that inhibited 50% was evaluated as an EC ₅₀ value. Test example 2

Effects of drugs on cardiac contractility in isolated atrium

The atrium of an SD male rat (body weight 350-400 g) was excised and the experiment was performed according to the Magnus method. Specimens were suspended in Krebs-Henseleit solution aerated with 95% oxygen and 5% carbon dioxide at 37 ° C and loaded with 1 g. The systolic force was derived isometrically via a pressure transducer and recorded on a rectogram. In the drug efficacy evaluation, the drug concentration at the time of increasing the heart rate ₂₀ times per minute by adding the drug was evaluated as an EC ₂₀ value. Test example 3

Acute toxicity test

 For three 6-week-old ICR male mice, 2- [4- [2-[[((1S, 2R) -12-hydroxy-2- (4-hydroxy-12-methylphenyl) -1-methylethyl] amino [Ethyl] phenoxy] Isopropyl acetate was dissolved in physiological saline at a dose of 5 Omg / kg body weight, administered once intravenously, and observed over time. As a result, no deaths were observed 24 hours after the administration.

Claims

The scope of the claims  1. General formula

[In the formula, one of Y and Z is a group represented by the general formula A—CO—R (where A is a general formula -0-DE- (D is a lower alkylene group, and E is a single bond or R is a hydroxyl group, a lower alkyl group, a lower alkoxy group, an alkoxy group, an amino group, a di-lower alkylamino group, or a 3- to 7-membered ring aliphatic group. The other is a hydrogen atom, the carbon atom with (R) force is a carbon atom in the R configuration, and the carbon atom with (S) is 2-amino-11- (4-hydroxy-2-methylphenyl) propanol derivative represented by the following formula: and a pharmacologically acceptable salt thereof. 2. General formula

[In the formula, one of Y and Z is a group represented by the general formula A-C0-R] [A is a general formula -0-DE- (where D is a lower alkylene group, and E is a single bond. Or a phenylene group) or an ethylene group, and R is a hydroxyl group, a lower alkyl group, a lower alkoxy group, an alkoxy group, an amino group, a di-lower alkylamino group or a 3- to 7-membered ring. Is an alicyclic amino group), the other is a hydrogen atom, the carbon atom with (R) represents a carbon atom in the R configuration, and (S) with Wherein the added carbon atom represents a carbon atom in the S configuration.] A medicament comprising a 2-amino-11- (4-hydroxy-2-methylphenyl) propanol derivative or a pharmacologically acceptable salt thereof. 3. General formula

[In the formula, one of Y and Z is a group represented by the general formula A—C 0—R (where A is a general formula -0-DE- (D is a lower alkylene group, and E is a single bond.) Or a phenylene group) or an ethylene group, and R is a hydroxyl group, a lower alkyl group, a lower alkoxy group, an alkoxy group, an amino group, a di-lower alkylamino group or a 3- to 7-membered ring. The other is a hydrogen atom, the carbon atom with (R) indicates a carbon atom in the R configuration, and the carbon atom with (S) Represents a carbon atom in the S configuration.] An imminent stream containing a 2-amino-1- (4-hydroxy-2-methylphenyl) propanol derivative or a pharmaceutically acceptable salt thereof as an active ingredient Inhibitors, bronchodilators, urolithiasis pain relievers or Stone accelerator. 4. General formula

[In the formula, one of Y and Ζ is a general formula—A—C 0—R [A in the formula is a general formula -0-DE-(D in the formula is a lower alkylene group, and E is a single bond. Or Hueni R is a hydroxyl group, a lower alkyl group, a lower alkoxy group, an alkoxy group, an amino group, a di-lower alkylamino group, or a 3- to 7-membered alicyclic ring The other is a hydrogen atom, the carbon atom with (R) represents a carbon atom in the R configuration, and the carbon atom with (S) represents S A carbon atom of the configuration]. 2-amino-11- (4-hydroxy-2-methylphenyl) propanol derivative or a pharmacologically acceptable salt thereof is administered. Prevention methods, methods for preventing or treating diseases caused by airway obstructive disorders, bronchial stenosis disorders, and methods for relieving pain in urolithiasis or promoting stone removal. 5. Prevention of premature birth, prevention or treatment of diseases caused by airway obstructive disorder, bronchial stenosis, production of preparations for relieving pain in urolithiasis or promoting stone removal

[In the formula, one of Y and Ζ is a group represented by the general formula A—C 0—R (where A is a general formula -0-D-E- (D is a lower alkylene group, and E is R is a hydroxyl group, a lower alkyl group, a lower alkoxy group, an alkoxy group, an amino group, a di-lower alkylamino group, or a 3- to 7-membered group. The other is a hydrogen atom, the carbon atom marked with (R) indicates a carbon atom in the R configuration, and the atom marked with (S) The carbon atom represents a carbon atom in the S configuration.] 2-amino-1- (4-hydroxy-2-methylphenyl) propanol derivative or a pharmacologically acceptable salt thereof. 6. General formula

[In the formula, one of Y and Z is a general formula -A-CO-R [A is a general formula -0-DE- (D is a lower alkylene group, and E is a single bond. Or a phenylene group) or an ethylene group, and R is a hydroxyl group, a lower alkyl group, a lower alkoxy group, an alkoxy group, an amino group, a di-lower alkylamino group or a 3- to 7-membered ring. The other is a hydrogen atom, the carbon atom with (R) indicates a carbon atom in the R configuration, and the carbon atom with (S) Represents a carbon atom in the S configuration.] 2-amino-1- (4-hydroxy-2-methylphenyl) propanol derivative and its pharmacologically acceptable salt imminent flow, premature birth inhibitor, bronchodilator Use as a pain relieving agent for urolithiasis or a lithotripsy accelerator.