Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2001-07-23
2002-04-23
Geist, Gary (Department: 1614)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S433000, C562S442000
Reexamination Certificate
active
06376707
ABSTRACT:
This application is a 371 of PCT/JP00/00168, which claims priority of JP 13639.
TECHNICAL FIELD
The present invention relates to a novel crystalline polymorph of an aminoethylphenoxyacetic acid derivative which is useful as a medicament.
More particularly, the present invention relates to a crystalline polymorph (crystalline form &agr;) of an amino-ethylphenoxyacetic acid derivative represented by the formula:
(chemical name: 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid) which has potent &bgr;
2
- and &bgr;
3
-adrenoceptor stimulating effects and is useful as an agent for relieving pain and promoting the removal of calculi in urolithiasis, and the like.
BACKGROUND ART
2-[4-[2-[[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid is a novel compound and is not disclosed in any literature. Therefore, its physical properties and pharmacological activities are not known at all.
The inventors of the present invention have investigated the properties of 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl ]-phenoxy]acetic acid. It was found that it is hard to obtain this compound of uniform quality since the compound has several crystalline polymorphs and the sort and ratio vary depending upon differences in method and condition for preparing.
In a compound having crystalline polymorphs, each crystalline polymorph generally differs in various properties. Even if compounds are chemical-structurally same each other, there are cases where their effects are quite different. Especially, it is known that such compounds show different solubility, solubility rate, stability and the like in medicaments. That is, in case that same compound is used, it is considered that it can not attain desired effects depending upon difference in crystalline polymorphs. On the other hand, it is also considered that unexpected effects result in an accidental case. Accordingly, it requires to provide a compound of uniform quality so as to show continually constant effects. Therefore, when a compound having crystalline polymorphs is used as a medicament, it is requested that an established crystalline compound is stably provided to attain uniform quality and constant effects which should be required as a medicament. In addition, a stable crystalline polymorph which can keep same quality in storage is desired.
2-[4-[2-[[(1S,2R)-2-Hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid has several crystalline polymorphs. Some crystalline polymorphs would be mixed depending upon methods for preparing. Furthermore, it is hard to keep quality of the prepared crystalline polymorph uniform because its form would vary depending upon an external environment in storage. Thus, it is eagerly desired to find a stable crystalline polymorph of the above compound in order to keep uniform quality and constant effects which are required as a medicament and to establish a method for preparing such crystalline polymorph continually and constantly.
DISCLOSURE OF THE INVENTION
The present invention relates to a crystalline polymorph (crystalline form &agr;) of 2-[4-[2-[[(1S,2R)-2 -hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]-phenoxy]acetic acid having strong diffraction peaks (diffraction angle: 2&thgr;±0.1°) at 10.8, 19.1, 19.3, 19.8, 20.6 and 27.0° in powder X-ray diffraction pattern.
That is, the inventors of the present invention conducted extensive investigation of crystalline polymorphs of 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-l-methylethyl]amino]ethyl]phenoxy]acetic acid which is useful as an agent for relieving pain and promoting the removal of calculi in urolithiasis, and the like. As a result, it was found that the crystalline polymorph of the present invention can be uniformly prepared according to the following method and that the crystalline polymorph of the present invention have an excellent low hygroscopicity and the like, and therefore is extremely useful as a medicament, thereby resulting in the accomplishment of the present invention.
For example, the crystalline polymorph of the present invention can be prepared by hydrolyzing ethyl 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyl-ethyl]amino]ethyl]phenoxy]acetate phosphate by sodium hydroxide, adding an aqueous phosphoric acid solution at 40° C. and over, collecting the resulting 2-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1 -methylethyl]-amino]ethyl]phenoxy]acetic acid by filtration, adding a mixed solvent of water and methanol (1:1 or more in volume) or methanol to the wet solid, and stirring the suspension at 40° C. to reflux temperature for 30 minutes to several hours. The temperature and the time of stirring can be appropriately decided depending on the volume to be treated, and the sort and volume of the solvent used.
As examples of crystalline polymorphs other than the crystalline polymorph of the present invention, there are the crystalline polymorph (crystalline form &ggr;) having strong diffraction peaks (diffraction angle: 2&thgr;±0.1°) at 18.1, 19.7, 20.3, 21.2 and 22.4° and the crystalline polymorph (crystalline form 67) having strong diffraction peaks (diffraction angle: 2&thgr;±0.1°) at 10.2, 13.2, 17.6, 19.8 and 20.6° in powder X-ray diffraction pattern. These crystalline polymorphs easily absorb moisture to convert into their hydrates while the crystalline polymorph (crystalline form &agr;) of the present invention does not absorb moisture even if it is allowed to stand for 10 days under relative fumidities of 51-93%. Thus, the crystalline polymorph of the present invention has an excellent low hygroscopicity and good storage. In addition, the crystalline polymorph of the present invention shows solubility of 2.7 mg/mL in water (37° C.) and has more excellent solubility than 1.8 mg/mL of the crystalline form &dgr;. Thus, the crystalline polymorph of the present invention is favorable to oral administration and has a favorable efficiency in preparing liquid preparations such as injections. Furthermore, the crystalline polymorph of the present invention shows an excellent drug absorption when it is orally administered.
The crystalline form &ggr; can be prepared by dissolving 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid in an aqueous sodium hydroxide solution, neutralizing the solution with hydrochloric acid under ice-cooling, collecting the resulting crystals by filtration, and drying at 40-60° C. for several hours under reduced pressure. The crystalline form &dgr; can be prepared by dissolving 2-[4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid in water and methanol (about 7:3 in volume), concentrating the solution under reduced pressure with care to avoid high temperature, collecting the resulting crystals by filtration, and drying at 40-60° C. for about 10-20 hours under reduced pressure.
REFERENCES:
patent: WO 99/05090 (1999-04-01), None
Kasai Kiyoshi
Sonehara Junichi
Tamai Tetsuro
Tanaka Nobuyuki
Toda Michio
Geist Gary
Kissei Pharmaceutical Co. Ltd.
Reyes Hector M
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