Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-11-02
2001-06-26
Berch, Mark L. (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06252063
ABSTRACT:
BACKGROUND OF THE INVENTION
The carbapenem antibiotic designated herein as Compound I:
is disclosed in U.S. Pat. No. 5,756,725 (WO 97/40048) and has been shown to be a highly effective, broad spectrum antibiotic. However, formulation of this compound into a form suitable for the market place has been hampered by the unavailability of a stable crystalline form.
Prior to this invention, purification of Compound I was performed by column chromatography and the thermally and hydrolytically unstable amorphous chloride or triflate salt forms and their formulations had to be stored at low temperatures. Now with the present invention there are provided non-hygroscopic, thermally stable, crystalline salts readilly obtainable by a crystallization process which serves to purify the product as well, thus, avoiding the use of chromatographic techniques.
SUMMARY OF THE INVENTION
This invention is concerned with highly stable crystalline salts of Compound I and processes for their preparation, which processes incidentally serve to purify Compound I, especially by removal of palladium, ruthenium and tin contaminants.
The invention is also concerned with pharmaceutical formulations comprising one of the salts of Compound I as active ingredient.
It is also concerned with a method of treating infections with the salts of this invention.
DETAILED DESCRIPTION OF THE INVENTION
The Compound I salts of this invention are as shown below:
wherein R
−
is selected from:
Each of these salt forming anions is well known in the art and known to be non-toxic and pharmaceutically acceptable.
A process for the preparation of the salts of this invention comprises treating a solution of Compound I with an alkali metal salt of formula M
+
R
−
, wherein M
+
is an alkali metal cation. A group of alkali metal cations includes sodium (Na
+
), potassium (K
+
) and cesium (Cs
+
). A sub-group includes Na
+
and K
+
, and exemplary of this sub-group is Na
+
.
The counter ion associated with Compound I forming the starting material for the process of this invention includes any counter ion, X
−
, that will provide a water soluble salt thereof. A group of such counter ions includes chloride, triflate, hemisulfate, mopsylate
(4-morpholinepropanesulfonate), bromide, acetate and mesylate. A sub-group includes chloride and triflate. Exemplary of this sub-group is triflate.
The temperature at which the reaction is conducted is not critical. However, because of the limited stability of the Compound I starting material, the reaction temperature should be maintained at about 5 to about 25° C., and room temperature (about 15 to about 25° C.) is convenient.
In one embodiment of the process of this invention, a solution of Compound I suitable for treatment with the alkali metal salt MR is obtained in the last step in the synthesis of Compound I which involves the hydrogenolysis of an activated ester of Compound I such as the p-nitrotoluyl , benzyl, allyloxy, or p-methoxybenzyl ester.
REFERENCES:
patent: 5756725 (1998-05-01), Wilkening et al.
Ceglia Scott S.
Miller Ross A.
Ayler Sylvia A.
Berch Mark L.
Daniel Mark R.
Merck & Co. , Inc.
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