Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-15
2002-08-27
Berch, Mark L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06441162
ABSTRACT:
TECHNICAL FIELD
This invention relates to a new, crystalline substance of Cefditoren pivoxyl and also relates to new processes for the production of the new, crystalline substance of Cefditoren pivoxyl. Cefditoren pivoxyl is an orally administrable pro-drug which belongs to an antibacterially active antibiotic of cephalosporin-type and is a compound usually named as 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester.
BACKGROUND ART OF INVENTION
Cefditoren is a cephem compound which is represented by the following formula (A):
and named as (+)-(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)-ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. This cephem compound of the generic name “Cefditoren” is also nominated as 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid(syn-isomer, cis-isomer) in Japanese patent No. 1698887(Japanese patent publication “Kokoku” No. Hei-3-64503 published on Oct. 7, 1991), U.S. Pat. No. 4,839,350 and European patent No. 0175610.
A pivaloyloxymethyl ester of Cefditoren, in which the 4-carboxyl group has been esterified with the pivaloyloxymethyl group for the purpose of enhancing the absorbability of the cephem compound via the digestive tubes upon the oral administration thereof, is such a pro-drug which is known by a generic name “Cefditoren pivoxyl” and is represented by the following formula (B):
and which has a chemical name “(−)-(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid 2,2-dimethylpropionyl-oxymethyl ester”. Cefditoren pivoxyl is known to be a pale yellow colored and powdery substance having a melting point of 127 to 129° C. (see the “Merck Index”, 12th-edition, page 317).
Cefditoren has a low toxicity to mammals but exhibits a very much broad antibacterial spectrum against positive-bacteria and gram-negative bacteria. Cefiditoren pivoxyl is, by itself, antibacterially inactive but is useful as a pro-drug which is adminstrable orally and can be converted into the antibacterially active Cefditoren in the digestive tubes of mammals, with cleaving the ester-forming pivaloyloxymethyl group therefrom. Cefditoren and Cefditoren pivoxyl are known to be a highly excellent therapeutic agent which has extensively been utitilixed for the therapeutic treatments and preventive treatments of bacterial infections caused by a variety of gram-positive bacteria and gram-negative bacteria.
Such products of Cefditoren pivoxyl which are produced and available commercially at present are usually and exclusively in the form of an amorphous and powdery substance. This amorphous substance of Cefditoren pivoxyl is usually prepared by such a method in which a reaction solution containing Cefditoren pivoxyl as synthetized is mixed with isopropyl ether to precipitate an amorphous powder of Cefditoren pivoxyl and this amorphous powder of Cefditoren pivoxyl is dissolved in methanol, and in which the resulting solution of Cefditoren pivoxyl in methanol is added with aqueous isopropanol to precipitate an amorphous powder of Cefditoren pivoxyl and this amorphous powder is then recovered (see, for example, Example 2 of U.S. Pat. No. 4,839,350 and European patent No. 0175610).
Thus, hitherto, any crystalline substance or form of Cefditoren pivoxyl has neither been known nor obtained, as far as we have been aware of. The known, amorphous substance of Cefditoren pivoxyl has widely been utilized as an excellent, antibiotic drug, as stated in the above, but it is not yet a completely satisfactory drug in that it is not stable to a sufficient extent when stored at an elevated temperature and under highly humid conditions. Besides, it has been found that the presently commercially available, amorphous substance of Cefditoren pivoxyl usually has a purity of 94% to 95.5% for the Cefditoren pivoxyl component when analysed by a liguid chromatography on a reverse phase silica gel column as detected with a ultra-violet ray absorption.
Accordingly, there exists an outstanding demand to provide such a new product of Cefditoren pivoxyl which would be much more pure and much more stable than the known, amorphous substance of Cefditoren pivoxyl. There is further presented an another demand to provide such a new process which is able to produce a highly pure product of Cefditoren pivoxyl in an efficient way on a commercial scale.
DISCLOSURE OF INVENTION
We, the present inventors, have conducted extensive investigations in order to solve the above-mentioned problems, and we have then presumed that, if Cefditoren pivoxyl can be obtained in a crystalline form, it will be a much more highly pure and stable product.
The present inventors have thus made further investigations in an attempt to produce a crystalline form of Cefditoren pivoxyl. As a result of these further investigations, we have now found that, when an amorphous substance of Cefditoren pivoxyl is once dissolved in an anhydrous, first organic solvent which can dissolve well the amorphous Cefditoren pivoxyl therein, and when the resulting solution of Cefditoren pivoxyl in said first organic solvent is concentrated to a reduced volume of the solution at a temperature of not higher than 15° C. by evaporation of the first organic solvent under a reduced pressure, followed by admixing the resultant concentrated solution with a volume of a anhydrous alkanol containing 1 to 5 carbon atoms, as a second organic solvent miscible with the first organic solvent, and then by repeating several times the concentration of the solution and the admixing of the concentrated solution with further amounts of the alkanol of 1 to 5 carbon atoms at a temperature of not higher than 15° C., in such an ingenious way as detailed hereinafter, thereby to prepare a concentrated solution containing 50 to 250 mg/ml of Cefditoren pivoxyl dissolved in substantially only one second organic solvent, the alkanol, and when the resultant concentrated solution containing 50 to 250 mg/ml of Cefditoren pivoxyl in the alkanol is subsequently mixed with a volume of water at a temperature of not higher than 10° C., then Cefditoren pivoxyl can start to deposit in a crystalline particle form from said concentrated solution and a complete crystallization of Cefditoren pivoxyl can be achieved by agitation of the aqueous mixture of the remaining solution with the deposited crystal particles, at a temperature of 10° C. or below, and a crystalline substance of Cefditoren pivoxyl can be separated and harvested from the remaining solution (the liquid phase) by filtration or centrifugation.
Thus, the present inventors, have now succeeded in obtaining such a crystalline substance of Cefditoren pivoxyl which has a high purity of 97% to 98% for the Cefditoren pivoxyl component and can exhibit a remarkably higher storage stability at an elevated temperature, as compared with the known, amorphous substance of Cefditoren povoxyl.
This crystalline substance of Cefditoren pivoxyl now obtained is in the orthorhombic form as measured by an X-ray powder diffractometer and an X-ray single-crystal diffractometer, and said crystalline substance of Cefditoren pivoxyl comprises single crystals having a density of 1.21 to 1.23 g/cm
3
. This crystalline substance of Cefditoren pivoxyl further has a melting point of 206.2° C. to 215.7° C. with decomposition, as evaluated from the peak of thermal absorption shown in such a heat flow curve which was determined by testing the crystalline substance in a differential scanning calorimeter. It is considered that this crystalline substance of Cefditoren pivoxyl having the orthorhombic form and having the above-mentioned physico-chemical characteristics should be a novel substance, since any product or substance of Cefdit
Iinuma Katsuharu
Murai Yasushi
Onodera Masahiro
Sukegawa Masamichi
Watanabe Tatsuo
Berch Mark L.
Larson & Taylor PLC
Meiji Seika Kaisha Ltd.
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