Crystal polymorph 2-[4-[2-[[(1s,2r)-2-hydroxy-2-(4 - hydroxyphenyl)-1 - methylethyl]amino]ethyl]phenoxy]acetic acid

 

The present invention relates to crystalline polymorpha 2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino] ethyl] phenoxy] acetic acid, having strong diffraction peaks (angle of diffraction 20,1) when 10,8, 19,1, 19,3, 19,8, 20,6 and 27,0in the diffraction pattern, obtained by powder x-ray diffraction analysis, which has a strong stimulating effect in relation to2and3-adrenergic receptors and is useful as a drug for the relief of pain and promoting the removal of stones urolithiasis. 3 Il.

The present invention relates to a new crystalline polymorpha derived aminomethylpropanol acid which is useful as a medicine.

More specifically, the present invention relates to crystalline polymorpha (crystal form) derived aminomethylpropanol acid represented by the formula

(chemical name: 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyp the R2and3action and is useful as a tool for alleviating pain and promoting the removal of stones urolithiasis, etc.

Background of invention.

2-[4-[2-[[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methyl-ethyl]amino]ethyl]phenoxy]acetic acid is a novel compound not disclosed in the literature. Therefore, its physical properties and pharmacological activity completely unknown.

In the present invention was investigated properties 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid. It was found that this compound is difficult to obtain uniform quality, since it has several crystalline polymorphs, type and value of which varies depending on the method and conditions for the receipt.

In connection with crystalline polymorphs, as a rule, each crystal polymorph very different in the various properties. Even if the compounds by their chemical structure are the same, there are cases when their effect is very different. Especially it is known that such compounds in drugs show different solubility, dissolution rate, stabilin the constituent effect due to differences in the crystal structure of polymorph. On the other hand, it is also considered that in emergency cases, there may be unexpected effects. Therefore, it is necessary to provide the connection of uniform quality, so that it constantly showed steady action. Therefore, when used as a compound having a crystalline polymorphs, as a drug, you want a stable getting installed crystalline compounds to achieve uniform quality and consistency of actions are required of drugs. In addition, the desired crystalline polymorph, which can maintain the same quality during storage.

2-[4-[2-[[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methyl-ethyl]amino]ethyl]phenoxy]acetic acid has several crystalline polymorphs. Some crystalline polymorphs can be mixed depending on the methods for their preparation. In addition, it is difficult to maintain the quality of the obtained crystalline polymorph homogeneous because its shape will change depending on the external environment during storage. Thus, it is desirable to find a stable crystalline polymorph the above connection in order to maintain uniform quality otherwise obtaining such crystalline polymorph.

Description of the invention

The present invention relates to crystalline polymorpha (crystal form) 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]-acetic acid, having strong diffraction peaks (angle of diffraction: 20,1) when 10,8, 19,1, 19,3, 19,8, 20,6 and 27,0in the diffraction pattern, obtained by powder x-ray diffraction analysis.

Thus, in the present invention were carried out a comprehensive study of the crystalline polymorphs 2-[4-[2[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid, which are useful as a means for the relief of pain and as contributing to the removal of stones urolithiasis, etc. In the result it was found, that crystal polymorph of the present invention it is possible to obtain a homogeneous using the following method and that of the crystal polymorph of the present invention has excellent low hygroscopicity, etc., and therefore it is extremely useful as a drug, thus, was completed nastojashi 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy] acetate phosphate with sodium hydroxide, the addition of an aqueous solution of phosphoric acid at 40C and above, the fee received 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-metaliteracy]amino]ethyl]phenoxy] acetic acid by filtration, added to the wet solid product of a mixed solvent consisting of water and methanol (1:1 or more by volume) or methanol, and stirring the resulting suspension at 40C to the boiling temperature for from 30 minutes to several hours. Temperature and mixing time can be selected depending on the volume that is to be processed, and the type and amount of solvent used.

As examples of the crystalline polymorphs, non-crystalline polymorph of the present invention, there are crystalline polymorph (crystal form), having strong diffraction peaks (angle of diffraction: 20,1) when 18,1, 19,7, 20,3, 21,2 and 22.4and crystal polymorph (crystal form), having strong diffraction peaks (angle of diffraction: 20,1) according to the present invention does not absorb moisture, even if it is left for 10 days at a relative humidity 51-93%. So, crystalline polymorph of the present invention has excellent low hygroscopicity and well kept. In addition, the crystal polymorph of the present invention has a solubility in water of 2.7 mg/ml (37C) and has a better solubility than 1.8 mg/ml crystalline forms. Thus, the crystal polymorph of the present invention is preferred for oral administration and has a preferred effectiveness of obtaining liquid preparations such as injections. In addition, the crystal polymorph of the present invention shows excellent absorption of drugs after oral administration.

Crystalline formcan be obtained by dissolving 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid in an aqueous solution of hydroxide NAT is wsysa crystals by filtration and drying at a temperature of 40-60C for several hours under reduced pressure. Crystalline formcan be obtained by dissolving 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid in water and methanol (about 7:3 by volume), the concentration of the solution under reduced pressure, while avoiding high temperature, collecting the resulting crystals by filtration and drying at a temperature of 40-60C for about 10-20 hours under reduced pressure.

Brief description of drawings

Fig.1 is a powder x-ray diffraction pattern analysis of crystal polymorph (crystal form) 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid according to the present invention, obtained using a monochromator. The y-axis represents the diffraction intensity (kHz/sec), and the axis of abscisses shows the diffraction angle (2).

Fig.2 is a powder x-ray diffraction pattern analysis of crystal polymorph (crystal form) 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic the axis of abscisses shows the diffraction angle (2).

Fig.3 is a powder x-ray diffraction pattern analysis of crystal polymorph (crystal form) 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid according to the present invention, obtained using a monochromator. The y-axis represents the diffraction intensity (kHz/sec), and the axis of abscisses shows the diffraction angle (2).

The best way of carrying out the invention

Further, the present invention is illustrated in more detail with the aid of reference examples, examples, comparative examples and examples of tests. The melting temperature of different crystalline polymorphs were measured by thermogravimetric method and using the analyzer temperature differential (TG/DTA), thermo plus TG8120 (Rigaku) at a heating rate of 10C/min and were expressed as extrapolated initial temperature. The powder x-ray diffraction pattern analysis of different crystalline polymorphs were obtained using beam SiC(1,541) using the analyzer x-ray diffraction, RINT1400 (Rigaku).

Reference example 1

Ethyl 2-[4-(2-hydroxy what I (6.5 g) at room temperature, and the mixture was stirred for 30 minutes. To the reaction mixture was added dropwise ethylbromoacetate (4,4 ml) at 40-45C for 8 hours. After filtering off nerastvorim materials, the filtrate was concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: hexane/ethyl acetate) to obtain ethyl 2-[4-(2-hydroxyethyl)phenoxy]acetate (5.8 g).

1H-NMR (CDCl3)memorial plaques:

of 1.28 (3H, t, J=7,1 Hz), 2,32 (1H, usher.), was 2.76 (2H, t, J=5.8 Hz), a-3.84 (2H, m), are 4.24 (2H, q, J=7,1 Hz), of 4.57 (2H, s), to 6.88 (2H, d, J=7.8 Hz), 7,12 (2H, d, J=7,8 Hz).

Reference example 2

Ethyl 2-[4-methanesulfonylaminoethyl)phenoxy]acetate

To a solution of ethyl 2-[4-(2-hydroxyethyl)phenoxy]acetate (7,3 g) in ethyl acetate (22 ml) was added triethylamine (5,9 ml) at room temperature in a nitrogen atmosphere, and the mixture was stirred. Was added dropwise methanesulfonanilide (2.8 ml) at an internal temperature of the mixture 0-15C, and the mixture was stirred at room temperature for 30 minutes. After adding to the reaction mixture water the aqueous layer was separated and was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and saturated saline solution, and the Yali acid ethyl ester (8.6 ml) and 2-propanol (23 ml), and the mixture was heated to dissolve. After cooling to room temperature, the resulting crystals were collected by filtration to obtain ethyl 2-[4-(2-methanesulfonylaminoethyl)phenoxy]acetate (7.2 g).

1H-NMR (CDCl3)memorial plaques:

of 1.29 (3H, t, J=7,1 Hz), 2,84 (3H, s) to 2.99 (2H, t, J=6.9 Hz), 4.26 deaths (2H, sq J=7,1 Hz), 4,37 (2H, t, J=6, 9 Hz), 4,60 (2H, s), 6.87 in (2H, d, J=8.7 Hz), to 7.15 (2H, d, J=8.7 Hz).

Reference example 3

Ethyl 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetate phosphate

A mixture of (1R,2S)-2-amino-1-(4-hydroxyphenyl) propan-1-ol (8.8 g), ethyl 2-[4-(2-methanesulfonylaminoethyl)phenoxy]acetate (15.9 g), Diisopropylamine (11 ml) and N,N-dimethylacetamide (61 ml) was stirred at 75C for 3.5 hours under nitrogen atmosphere. After cooling to room temperature, to the reaction mixture was added a solvent mixture of ethyl acetate and toluene (9/1) and water. The aqueous layer was separated and was extracted with a mixture solvent of ethyl acetate and toluene (9/1). The combined organic layers were washed with water and 18% aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, to the residue was added ethyl acetate (14 ml) and ethanol (92 ml), and to the mixture at room temperature in Raleigh by filtration to obtain ethyl 2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl] phenoxy]acetate phosphate (12.4 g).

1H-NMR (CDCl3)memorial plaques:

to 0.89 (3H, d, J=6.6 Hz), of 1.23 (3H, t, J=7,1 Hz), 2,80 is 3.15 (5H, m) to 4.16 (2H, sq J=7,1 Hz), to 4.73 (2H, s) to 4.16 (2H, q, J=7,1 Hz) to 4.92 (1H, user. C) of 6.71 (2H, d, J=8.6 Hz), 6,85 (2H, d, J=8.6 Hz), 7,13 (2H, d, J=8.6 Hz), 7,16 (2H, d, J=8.6 Hz), 7,92 (4H, user.)

Example 1

2-[4-(2-[[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid

To 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetate phosphate (62,0 g) was added 2 mol/l aqueous solution of sodium hydroxide (393 ml), and the mixture was heated to 40the internal temperature of the mixture under stirring for dissolution. To the solution at an internal temperature 40-46With added dropwise 4 mol/l aqueous solution of phosphoric acid (115 ml). After stirring overnight at room temperature, the resulting crystals were collected by filtration and washed with water to obtain white crystals. The obtained crystals suspended in the solvent mixture (200 ml) of water and methanol (1/8), boiled under reflux for 30 minutes. After cooling to room temperature, the crystals were collected by filtration and dried at 40-50C for 3 hours under reduced pressure to obtain 2-img src="https://img.russianpatents.com/chr/945.gif">) (50.0 g). The diffraction pattern obtained by powder x-ray diffraction analysis of crystalline polymorph (crystal form), shown in the attached Fig.1.

Melting point: 235,1C (decomposition).

1H-NMR (DMSO-d6)memorial plaques:

of 0.91 (3H, d, J=6.6 Hz), 2,55 is 2.75 (2H, m), 2,90 was 3.05 (2H, m), 3.15 and is 3.25 (1H, m), 4,25-and 4.40 (2H, m), 5,00-5,10 (1H, m), 6,65-to 6.80 (4H, m) 6,91 (2H, d, J=8.6 Hz), 7,13 (2H, d, J=8.6 Hz), 9,40 (1H, usher.).

Specific rotation: []25D=-10,0(C=1,00, 1 mol/l chloride-hydrogen acid).

Comparative example 1

2-[4-[2-[[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid (crystalline form)

2-[4-[2-[[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methyl-ethyl]amino]ethyl]phenoxy]acetic acid (crystalline form) (1.4 g) was dissolved in a solvent mixture of 1 mol/l aqueous sodium hydroxide solution (20 ml) and water (125 ml), and to the solution under stirring and cooling with ice was added 1 mol/l chloride-hydrogen acid (20 ml). After stirring for 30 minutes under ice cooling the resulting crystals were collected by filtration, industrial is[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid (crystalline form) (0,78 g). The diffraction pattern of the powder x-ray diffraction analysis of crystalline polymorph (crystal form) is represented in the attached Fig.2.

Melting point: 189,8C (decomposition)/

Comparative example 2

2-[4-[2-[[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid (crystalline form)

2-[4-[2-[[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methyl-ethyl]amino]ethyl]phenoxy]acetic acid (crystalline form) (2.0 g) was dissolved in a mixture solvent of methanol (30 ml) and water (70 ml) under heating. After cooling to room temperature, any insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. After keeping at room temperature for 30 minutes the resulting crystals were collected by filtration and dried at 40C for 18 hours under reduced pressure to obtain 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy] acetic acid (crystalline form) (1.8 g). The diffraction pattern of the powder x-ray diffraction analysis of crystalline polymer: 236,3C (decomposition).

The test example 1

Stimulating effect on2-adrenergic receptors

The uterus of pregnant SD rats (21 days of pregnancy) were separated and prepared longitudinal samples of approximately 15 mm and approximately 5 mm wide, not containing basal lamina. The experiment was performed according to the method of Magnus. The samples in tension of 1 g was placed in the solution, Locke-Ringer supported at 37 With and processed in a gas mixture of 95% oxygen and 5% carbon dioxide. Spontaneous contractions of myometrium were measured isometrically using transmitter power offset and recorded on ractogram. 2-[4-[2-[[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid cumulatively added to the bath Magnus every 5 minutes. The effectiveness of the drugs was assessed by comparing the total of the uterus within 5 minutes after adding the drug, with a total reduction for 5 minutes before adding the drug, which was expressed as 100%. The drug concentration at 50% inhibition (i.e., the value of EU50this connection is 3.110-8M

The test example 2

Times body 1100-1400 g) was separated and prepared longitudinal samples of about 20 mm long, not containing connective tissue. The experiment was performed according to the method of Magnus. The samples in tension of 0.5 g was placed in a solution of Krebs-Henseleit supported at 37 With and processed by a gas mixture of 95% oxygen and 5% carbon dioxide. Spontaneous contractions of the ureter was measured isometrically using transmitter power offset and recorded on ractogram. 2-[4-[2-[[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino] ethyl]phenoxy]acetic acid cumulatively added to the bath Magnus every 3 minutes. The effectiveness of the drugs was assessed by comparing the overall reduction of the ureter within 3 minutes after adding the drug, with a total reduction for 3 minutes before adding the drug, which was expressed as 100%. The drug concentration at 50% inhibition (i.e., the value EC50this connection is 1.410-8M

Claims

Crystal polymorph 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid, having strong diffraction peaks (angle of diffraction (20,1)

 

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