Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-13
2001-12-11
Chang, Celia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S209000
Reexamination Certificate
active
06329393
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to crystalline pharmaceutically acceptable salts of an oxazolidinone derivative which is useful as an alpha 1a adrenergic receptor antagonist. More specifically, the invention provides a crystalline pharmaceutically acceptable, benzensulfonic acid salt of Compound A (defined below), pharmaceutical compositions employing the crystalline salt, and processes for making and using the crystalline salt.
BACKGROUND OF THE INVENTION
Benign prostatic hyperplasia, also known as benign prostatic hypertrophy or BPH, is an illness typically affecting men over fifty years of age, increasing in severity with increasing age. The symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra. Concommitantly, the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra.
Recent advances in molecular biology have identified the alpha 1a adrenoceptor subtype as the predominant alpha 1 receptor that mediates the contraction of prostate and lower urinary tract smooth muscle. Several classes of compounds have been disclosed to be selective alpha 1a adrenergic receptor antagonists useful for treating BPH. For example, WO 96/14846, WO 97/17969 and WO 97/42956 each disclose certain dihydropyrimidine derivatives (e.g., certain 1,2,3,6-tetrahydro-2-oxo-pyrimidine derivatives) which are selective antagonists for the human alpha 1a receptor and useful for treatment of BPH, impotency, cardiac arrhythmia, and other diseases where antagonism of the alpha 1a receptor may be useful.
Compound A is a potent and selective antagonist of the alpha 1a adrenergic receptor antagonist and is useful in the treatment of BPH. More particularly, the compound is (4S,5S)-4-(3,4-difluorophenyl)-N-[3-[4-(4-fluorophenyl)-1-piperidinyl]propyl]-5-methyl-2-oxo-3-oxazolidine carboxamide and has the formula:
Because free base Compound A can be sensitive to bases and, with the nitrogen atom not being protonated, can also be susceptible to oxidation, a pharmaceutically acceptable salt of Compound A is desirable. Preparation of an acceptable salt of Compound A suitable for pharmaceutical development has been problematic. Numerous attempts to isolate a crystalline salt formn of Compound A failed as only amorphous salts could be isolated. A crystalline salt which was isolated had too low a melting point to be practical for processing into pharmaceutical compositions.
These problems were solved by identification of the crystalline pharmaceutically acceptable benzenesulfonic acid salt of Compound A of the present invention.
SUMMARY OF THE INVENTION
The present invention provides a crystalline pharmaceutically acceptable salt, which is the benzenesulfonic acid salt of Compound A of Formula (I):
or a solvate thereof.
In one embodiment of the invention is the crystalline benzensulfonic acid salt of Compound A of Formula (II)
or a solvate thereof.
In another embodiment of the invention is a crystalline salt of Compound A characterized by a differential scanning calorimetry (DSC) curve at a heating rate of 10° C./min in an open cup under flowing nitrogen, exhibiting an endotherm with an extrapolated onset temperature of about 166° C., a peak temperature of about 168° C. and an associated heat of about 83 J/gm.
In still another embodiment of the invention is a crystalline salt of Compound A characterized by an x-ray powder diffraction pattern having d-spacings of 19.1, 13.3, 7.16, 6.87, 5.47, 5.05, 4.85, 4.70, 4.42, 4.10, 3.85, 3.62, 3.56, 3.38 and 3.14 Å.
The present invention includes a pharmaceutical composition comprising a crystalline benzenesulfonic acid salt of Compound A, or solvate thereof, and a pharmaceutically acceptable carrier. In one embodiment, the pharmaceutical composition further comprises a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor. The testosterone 5-alpha reductase inhibitor can be a type 1, a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising the crystalline salt as described above combined with both a type 1 testosterone 5-alpha reductase inhibitor and a type 2 testosterone 5-alpha reductase inhibitor) or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor. In an aspect of this embodiment, the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor. In another aspect, the testosterone 5-alpha reductase inhibitor is finasteride.
The invention also includes a pharmaceutical composition made by combining a crystalline benzenesulfonic acid salt of Compound A, or solvate thereof, and a pharmaceutically acceptable carrier, and optionally a testosterone 5-alpha reductase inhibitor as set forth in the preceding paragraph.
The present invention also includes a process for making a pharmaceutical composition comprising combining a crystalline benzenesulfonic acid salt of Compound A, or solvate thereof, and a pharmaceutically acceptable carrier.
The present invention further includes methods of treating benign prostatic hyperplasia, of inhibiting contraction of prostate tissue and of relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a crystalline benzenesulfonic acid salt of Compound A, or a solvate thereof, or pharmaceutical compositions described above. In one embodiment, the methods of treating BPH, of inhibiting contraction of prostate tissue and of relaxing lower urinary tract tissue in a subject in need thereof wherein the crystalline salt of Compound A, or solvate thereof, is administered in combination with a testosterone 5-alpha reductase inhibitor; e.g., finasteride.
The present invention also includes a process for making a crystalline pharmaceutically acceptable benzensulfonic acid salt of Compound A of formula:
or a solvate thereof, which comprises:
(a) dissolving Compound A and benzensulfonic acid in a solvent to form a solution; and
(b) treating the solution of step (a) to form the crystalline salt.
In an embodiment of the process, at least about one mole equivalent of benzenesulfonic acid is dissolved in the solution per mole equivalent of Compound A.
In another embodiment of the process, dissolution step (a) comprises mixing Compound A in the solvent with the benzenesulfonic acid and then heating the mixture to form the solution. In an aspect of this embodiment, treatment step (b) comprises cooling the heated solution to form the crystalline salt.
In still another embodiment of the process, the solvent employed in dissolution step (a) is selected from methanol, ethanol, 2-propanol, ethyl acetate, isopropyl acetate, butanol, hexanes, toluene, ethyl ether, or a mixture thereof. A preferred solvent is ethanol.
In still another embodiment of the process, Compound A is dissolved in a solvent to form a (first) solution and benzenesulfonic acid is added thereto to form a final solution, which is treated to form the crystalline salt. In one aspect of this embodiment, the acid is added as a solution of the acid in a second solvent (which can be the same or different from the first solvent used to dissolve the free base of Compound A). The solvents set forth in the preceding paragraph are each independently suitable for use as the (first) solvent used to dissolve Compound A and the (second) solvent used to dissolve benzenesulfonic acid.
Exemplary of the invention is a process for forming a crystalline salt of formula:
and solvates thereof, which comprises:
(a) heating a mixture of Compound A and benzensulfonic acid in ethanol to form a solution, wherein the mixture contains at least about one mole equivalent of benzensulfonic acid per mole equivalent of Compound A; and
(b)
Amato Joseph S.
Li Zhen
McCauley James A.
Brown Baerbel R.
Chang Celia
Merck & Co. , Inc.
Walton Kenneth R.
Winokur Melvin
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