JP2000212139A - Crystal polymorphism of aminoethylphenoxyacetic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a crystal polymorphism of 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4- hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid having strong β2-adrenergic receptor stimulation action and β3-adrenergic receptor stimulation action and useful e.g. as a pain remission agent and a lithagogue for lithangiuria. SOLUTION: This crystal polymorphism gives a powder X-ray diffraction pattern having strong diffraction peaks at the diffraction angles (2θ±0.1) of 10.1, 10.4, 15.5, 17.0, 20.0 and 20.2 deg.. It can be produced by dissolving the compound in a mixture of water and methanol (at a volume ratio of 7:3 to 9:1), concentrating under reduced pressure, drying the precipitated crystal under reduced pressure at room temperature to 60 deg.C for several hours or longer and stirring in suspended state in methanol at room temperature to the refluxing temperature for several tens minutes to several hours.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel aminoethylphenoxyacetic acid derivative polymorph which is useful as a pharmaceutical.

More specifically, the present invention has a potent β ₂ -adrenoceptor stimulating action and β ₃ -adrenoceptor stimulating action, and is useful as an agent for relieving pain in urolithiasis and calculi. Na, expression

[0003]

Embedded image

An aminoethylphenoxyacetic acid derivative represented by the following formula (chemical name: 2- [4- [2-[[(1S, 2R)-
2-hydroxy-2- (4-hydroxyphenyl) -1
-Methylethyl] amino] ethyl] phenoxy] acetic acid)
(Β-type crystal).

[0005]

2. Description of the Related Art 2- [4- [2-[[(1S, 2R)-
2-hydroxy-2- (4-hydroxyphenyl) -1
-Methylethyl] amino] ethyl] phenoxy] acetic acid is a novel compound not described in any literature, and its physical properties and pharmacological activity are not known at all.

[0006]

DISCLOSURE OF THE INVENTION The present inventors have found that 2-
[4- [2-[[(1S, 2R) -2-hydroxy-2
Studies on-(4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid revealed that there are several types of polymorphs in the compound, and the crystals obtained are different depending on the production method and production conditions. We found that the types of polymorphs and their abundance ratios fluctuated, and that products of constant quality could not be obtained.

[0007] Usually, compounds having crystal polymorphs have different properties depending on the crystal polymorphs, so that even the same compound may exhibit completely different effects. In particular, it is known that there is a difference in solubility, dissolution rate, stability, etc. in pharmaceuticals, and even when the same compound is used, the intended effect cannot be obtained due to a difference in crystal polymorphism. Or produce a different effect than expected,
This can lead to unexpected situations. Therefore, there is a need to provide a compound of the same quality that can always expect a certain effect. Therefore, when a compound having a crystalline polymorph is used as a drug, it is necessary to stably provide a compound having a certain crystallinity in order to ensure uniform quality and certain effects required as a drug. In addition, a stable polymorph that can maintain the same quality in storage is desired.

2- [4- [2-[[(1S, 2R) -2
-Hydroxy-2- (4-hydroxyphenyl) -1-
Methylethyl] amino] ethyl] phenoxy] acetic acid is a compound having several types of polymorphs, and a plurality of polymorphs may be mixed depending on the production method. In addition, some polymorphs vary depending on the external environment during storage, and may not have a certain quality. Therefore, in order to ensure a certain effect and quality, which are indispensable requirements for pharmaceuticals, we have found a stable crystalline polymorph of the compound and established a manufacturing method to always obtain the crystalline polymorph constantly. I was eager to do it.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The inventors of the present invention have proposed 2- [4- [2-
As a result of intensive studies on the crystal polymorph of [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid, the crystal polymorph of the present invention was found to be The present inventors have found that the polymorph of the present invention can be produced with a certain quality according to the following method, and that the polymorph of the present invention is excellent in moisture resistance and the like, and is extremely useful as a pharmaceutical.

The present invention relates to a powder X-ray diffraction pattern with a diffraction angle (2θ ± 0.1 degrees) of 10.1, 10.4, 1
Novel 2- [4- [2-[[(1S, 2) showing strong diffraction peaks at 5.5, 17.0, 20.0 and 20.2 degrees.
R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid polymorph (β-form crystal).

The crystalline polymorph of the present invention is 2- [4- [2-
[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid is mixed with a mixed solvent of water and methanol (7: 3 to 9: After dissolving in 1), the mixture was concentrated under reduced pressure while avoiding high temperature, and the precipitated crystals were collected by filtration, dried under reduced pressure at room temperature to 60 ° C for several hours or more, and suspended in methanol at room temperature to reflux temperature for several tens of minutes. It can be manufactured by stirring for minutes to several hours. The stirring temperature and the stirring time can be adjusted appropriately depending on the amount to be treated, the amount of the solvent used, and the like.
The drying time of the compound to be suspended in methanol can be adjusted appropriately depending on the amount, state and drying temperature of the compound.

As the polymorph other than the polymorph of the present invention, for example, the diffraction angle (2θ ± 0.
1)), 18.1, 19.7, 20.3, 2
Crystal polymorphs (γ-type crystals) exhibiting strong diffraction peaks at 1.2 and 22.4 degrees, likewise 10.2, 13.2, 17.
Crystal polymorphs (δ-form crystals) exhibiting strong diffraction peaks at 6, 19.8 and 20.6 degrees are present, but these polymorphs absorb moisture and change to their hydrates. The crystalline polymorph of the invention has excellent moisture resistance and is desirable for storage. Also,
The crystalline polymorph of the present invention has a solubility in water (37 ° C.) of 3.
0 mg / mL, and the solubility of Form δ crystal was 1.8 mg / mL.
Since it shows superior solubility compared to mL, it has excellent drug absorbability when used in oral administration preparations. When the crystalline polymorph of the present invention is used in a liquid preparation such as an injection, the formulation efficiency is high.

The γ-type crystal is 2- [4- [2-
[[(1S, 2R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid is dissolved in a sodium hydroxide solution, and then hydrochloric acid under ice cooling. It can be produced by neutralizing and collecting the precipitated crystals by filtration and drying under reduced pressure at 40 to 60 ° C. for several hours. Further, the δ-type crystal is 2- [4- [2
-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid is dissolved in water and methanol (about 7: 3 by volume). It can be produced by concentrating under reduced pressure while avoiding a high temperature, collecting precipitated crystals by filtration, and drying under reduced pressure at 40 to 60 ° C. for about 10 to 20 hours.

The contents of the present invention will be described in detail with reference to the following Reference Examples, Examples, Comparative Examples and Test Examples. The melting points of various polymorphs are determined by Rigaku Co., Ltd., differential thermogravimetry (TG / DTA) Thermo plus TG81.
The temperature was measured at a heating rate of 10 ° C./min using No. 20 and indicated by the extrapolated melting onset temperature. In addition, powder X-ray diffraction data of various crystal polymorphs was obtained from Rigaku's X-ray diffractometer RINT1400.
Using CuKα radiation (1.541 °).

Reference Example 1 Ethyl 2- [4- (2-hydroxyethyl) phenoxy] acetate To a solution of 4- (2-hydroxyethyl) phenol (5 g) in acetone (45 mL) at room temperature was added anhydrous potassium carbonate (6.5 mL).
g) was added and stirred for 30 minutes. Ethyl bromoacetate (4.4 mL) was added dropwise to the mixture at an internal temperature of 40 to 45 ° C, and the mixture was further stirred at 40 ° C for 8 hours. The insolubles were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate) to give 2- [4
-(2-Hydroxyethyl) phenoxy] ethyl acetate (5.8 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.28 (3H, t, J = 7.1 Hz), 2.32 (1H, br), 2.76 (2H, t, J =
5.8Hz), 3.84 (2H, m), 4.24 (2H, q, J = 7.1Hz), 4.57 (2H
H, s), 6.88 (2H, d, J = 7.8Hz), 7.12 (2H, d, J = 7.8Hz)

Reference Example 2 Ethyl 2- [4- (2-methanesulfonyloxyethyl) phenoxy] acetate A solution of ethyl 2- [4- (2-hydroxyethyl) phenoxy] acetate (7.3 g) in ethyl acetate (22 mL) was used. Under a nitrogen stream, triethylamine (5.9 mL) was added at room temperature and stirred. Methanesulfonyl chloride (2.8 mL) was added dropwise to the mixture at an internal temperature of 0 to 15 ° C, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, the aqueous layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, ethyl acetate (8.6 mL) and 2-propanol (23 mL) were added to the residue, dissolved by heating, cooled to room temperature, and the precipitated crystals were collected by filtration Ethyl-[4- (2-methanesulfonyloxyethyl) phenoxy] acetate (7.2 g) was obtained.

¹ H-NMR (CDCl ₃ ) δ ppm: 1.29 (3H, t, J = 7.1 Hz), 2.84 (3H, s), 2.99 (2H, t, J =
6.9Hz), 4.26 (2H, q, J = 7.1Hz), 4.37 (2H, t, J = 6.9H
z), 4.60 (2H, s), 6.87 (2H, d, J = 8.7Hz), 7.15 (2H, d,
J = 8.7Hz)

Reference Example 3 Ethyl phosphorus 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetate Acid salt (1R, 2S) -2-amino-1- (4-hydroxyphenyl) propan-1-ol (8.8 g), 2- [4-
A mixture of (2-methanesulfonyloxyethyl) phenoxy] ethyl acetate (15.9 g), diisopropylamine (11 mL) and N, N-dimethylacetamide (61 mL) was stirred at 75 ° C. for 3.5 hours under a nitrogen stream. The reaction mixture was cooled to room temperature, a mixed solution of ethyl acetate / toluene (9/1) and water were added, the aqueous layer was separated, and the aqueous layer was mixed with a mixed solution of ethyl acetate / toluene (9/1). Extracted. The organic layers were combined, washed with water and 18% brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. After adding ethyl acetate (14 mL) and ethanol (92 mL) to the residue, a 16% phosphoric acid-ethanol solution (32 g) was added dropwise at room temperature with stirring.
The precipitated crystals were collected by filtration, and 2- [4- [2-[[(1
(S, 2R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid ethyl phosphate (12.4 g) was obtained.

¹ H-NMR (DMSO-d ₆ ) δ pp
m: 0.89 (3H, d, J = 6.6Hz), 1.23 (3H, t, J = 7.1Hz), 2.80-
3.15 (5H, m), 4.16 (2H, q, J = 7.1Hz), 4.73 (2H, s), 4.
92 (1H, br s), 6.71 (2H, d, J = 8.6Hz), 6.85 (2H, d, J =
8.6Hz), 7.13 (2H, d, J = 8.6Hz), 7.16 (2H, d, J = 8.6H
z), 7.92 (4H, br)

Reference Example 4 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (α form Crystal) 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid ethyl phosphate (62.0 g) with a 2 mol / L aqueous sodium hydroxide solution (3
93 mL), and the mixture was heated to 40 ° C. with stirring to dissolve. 4 mol / L phosphoric acid aqueous solution at an internal temperature of 40 to 46 ° C (115 mL)
After stirring at room temperature overnight, the precipitated crystals were collected by filtration,
Washing with water gave white crystals. The obtained crystals were suspended in a mixed solution (200 mL) of water / methanol (1/8), heated under reflux in a suspended state for 30 minutes, cooled to room temperature, and the crystals were collected by filtration. At 3 ° C. for 3 hours.
[2-[[(1S, 2R) -2-hydroxy-2- (4
-Hydroxyphenyl) -1-methylethyl] amino]
[Ethyl] phenoxy] acetic acid (α-form crystal) (50.0 g) was obtained.

Melting point: 235.1 ° C. (decomposition) ¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.91 (3H, d, J = 6.6 Hz), 2.55-2.75 (2H, m), 2.90-3.05
(2H, m), 3.15-3.25 (1H, m), 4.25-4.40 (2H, m), 5.00-
5.10 (1H, m), 6.65-6.80 (4H, m), 6.91 (2H, d, J = 8.6H
z), 7.13 (2H, d, J = 8.6 Hz), 9.40 (1H, br) Specific rotation: [α] _D ²⁵ = -10.0 ° (c = 1.0
0.1 mol / L hydrochloric acid)

Example 1 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (β form Crystal) 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (α-form crystal)
(2.0 g) was dissolved by heating in a mixture of methanol (30 mL) and water (70 mL) and cooled to room temperature. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure and left at room temperature for 30 minutes.
After the precipitated crystals were collected by filtration, they were dried under reduced pressure at 40 ° C. for 18 hours. Methanol (25 mL) was added to the obtained crystals, and the mixture was stirred at room temperature for about 20 minutes. The crystals were collected by filtration, dried at 40 ° C. for 2 hours under reduced pressure, and then subjected to 2- [4- [2-[[(1S, 2R) -2-
Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (β-form crystal) (1.6 g) was obtained.

Melting point: 237.2 ° C. (decomposition)

2- [4- [2-[[(1S, 2R) -2
-Hydroxy-2- (4-hydroxyphenyl) -1-
The powder X-ray diffraction pattern of the polymorph (β-form crystal) of methylethyl] phenoxy] acetic acid is as shown in FIG. 1 below.

[0026]

FIG.

Example 2 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (β form Crystal) 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (α-form crystal)
(1.0 g) was dissolved by heating in a mixture of methanol (8 mL) and water (72 mL) and cooled to room temperature. After removing the insolubles by filtration, the filtrate was concentrated under reduced pressure. After the precipitated crystals were collected by filtration, they were dried under reduced pressure at 40 ° C. for 2 hours. Methanol (12 mL) was added to the obtained crystals, and the mixture was stirred at room temperature for about 20 minutes. The crystals were collected by filtration, dried at 40 ° C. for 3 hours under reduced pressure, and then subjected to 2- [4-
[2-[[(1S, 2R) -2-hydroxy-2- (4
-Hydroxyphenyl) -1-methylethyl] amino]
Ethyl] phenoxy] acetic acid (β-form crystal) (0.72 g) was obtained. In addition, various physical property values were the same as in Example 1.

Comparative Example 1 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (γ-form Crystal) 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (α-form crystal)
(1.4 g) in 1 mol / L sodium hydroxide aqueous solution (20 m
L) and water (125 mL) and dissolved in ice-cooled and stirred, 1 mol / L hydrochloric acid (20 mL) was added. After stirring under ice-cooling for 30 minutes, the precipitated crystals were collected by filtration, washed with water, and washed at 50 ° C for 3 minutes.
After drying under reduced pressure for 2 hours, 2- [4- [2-[[(1S, 2
R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (γ-form crystal) (0.78 g) was obtained.

Melting point: 189.8 ° C. (decomposition)

2- [4- [2-[[(1S, 2R) -2
-Hydroxy-2- (4-hydroxyphenyl) -1-
The powder X-ray diffraction pattern of the crystalline polymorph (γ-form crystal) of methylethyl] amino] ethyl] phenoxy] acetic acid is shown in FIG.
As shown in FIG.

[0031]

FIG. 2

Comparative Example 2 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (δ-form Crystal) 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (α-form crystal)
(2.0 g) was dissolved by heating in a mixture of methanol (30 mL) and water (70 mL) and cooled to room temperature. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure and left at room temperature for 30 minutes. After the precipitated crystals were collected by filtration, dried under reduced pressure at 40 ° C for 18 hours,
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid (δ-form crystal)
(1.8 g) was obtained.

Melting point: 236.3 ° C. (decomposition)

2- [4- [2-[[(1S, 2R) -2
-Hydroxy-2- (4-hydroxyphenyl) -1-
The powder X-ray diffraction pattern of the polymorph (δ-form crystal) of methylethyl] amino] ethyl] phenoxy] acetic acid is shown in FIG.
As shown in FIG.

[0035]

FIG. 3

Test Example 1 β ₂ -Adrenergic Receptor Stimulating Action Uterus of an SD pregnant rat (21st day of gestation) was excised, avoiding the placenta attachment, and about 5 mm wide and about 1 mm long in the longitudinal muscle direction.
A 5 mm specimen was prepared, and an experiment was performed according to the Magnus method. Specimens were suspended in Locke-Ringer solution aerated with a mixed gas containing 95% oxygen and 5% carbon dioxide at 37 ° C. and loaded with 1 g. Uterine motility was derived isometrically via a tension transducer and recorded by lectchograph. 2- [4- [2-[[(1S,
2R) -2-Hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid was cumulatively added to the Magnus tube every 5 minutes. The drug evaluation of the present compound was performed by comparing the sum of the uterine contraction height for 5 minutes before the addition of the present compound with 100% and the sum of the uterine contraction height for 5 minutes after addition of the present compound at various concentrations. 3.1
× 10 ⁻⁸ (M) indicates the drug concentration (EC ₅₀ value) that inhibits the sum of uterine contractions by 50%.

Test Example 2 β ₃ -Adrenergic receptor stimulating action The ureter of male ferret (weight 1100-1400 g) was excised and the connective tissue was removed.
Was prepared, and an experiment was performed according to the Magnus method. Specimens were Krebs-Henseleit which was aerated with a mixed gas containing 95% oxygen and 5% carbon dioxide at 37 ° C.
It was suspended in the liquid and a load of 0.5 g was applied. Ureteral automatic movement isometrically derived via a tension transducer,
Recorded by rectigraph. 2- [4- [2-
[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid accumulates every three minutes in Magnus.
Added in tube. The drug evaluation of the present compound was made by comparing the sum of the ureteral contraction heights for 3 minutes before the addition of the present compound with 100% and comparing the sum of the ureteral contraction heights for 3 minutes after the addition of the present compound at various concentrations. The sum of ureteral contraction height is 50% at 4 × 10 ^-8 (M)
The inhibitory drug concentration (EC ₅₀ value) is shown.

[Brief description of the drawings]

FIG. 1 is a cross-sectional view of a 2- [4- [2-[[(1S, 2R)
-2-hydroxy-2- (4-hydroxyphenyl)-
Powder X-ray diffraction data of a polymorph (β-form crystal) of 1-methylethyl] amino] ethyl] phenoxy] acetic acid (using a monochromator). The vertical axis represents the intensity of the X-ray (kc
ps), and the horizontal axis indicates the diffraction angle (2θ).

FIG. 2 shows a crystalline polymorph of 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid ( X-ray powder diffraction data of a γ-type crystal (using a monochromator). The vertical axis indicates the intensity of X-rays (kcps), and the horizontal axis indicates the diffraction angle (2θ).

FIG. 3 shows a crystalline polymorph of 2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl] phenoxy] acetic acid ( X-ray powder diffraction data of a δ-type crystal) (using a monochromator). The vertical axis indicates the intensity of X-rays (kcps), and the horizontal axis indicates the diffraction angle (2θ).

Continued on the front page (72) Inventor Junichi Sonehara 62-16-1 Omi, Sakai-machi, Sakai-gun, Fukui Prefecture Dolly Mate House II 201 (72) Inventor ▲ Tsuru ▼ Eiji 1-2-34 Nomitsuki Woodworking, Matsumoto City, Nagano Prefecture Daini Seotoyu Dormitory F-term (reference) 4C206 AA03 FA44 KA16 KA17 MA01 MA04 ZA25 ZA81 ZC41 4H006 AA01 AB20 BJ50 BN10 BN30 BP30 BS10 BU40

Claims (1)

[Claims] 1. A diffraction angle (2θ ± 2) in a powder X-ray diffraction pattern.
0.1 degrees), 10.1, 10.4, 15.5,
2- [4- [2-[[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methyl] showing strong diffraction peaks at 17.0, 20.0 and 20.2 degrees. Crystalline polymorph of [ethyl] amino] ethyl] phenoxy] acetic acid.