Alpha 1a adrenergic receptor antagonists

Details Alpha 1a adrenergic receptor antagonists Alpha 1a adrenergic receptor antagonists

2000-05-02

2001-11-20

Raymond, Richard L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

Reexamination Certificate

active

06320049

ABSTRACT:

FIELD OF THE INVENTION
The present invention provides pharmaceutically acceptable salts, and process for manufacture, of an alpha 1a adrenergic receptor antagonist. More specifically, the invention provides crystalline pharmaceutically acceptable salts (e.g., the tartrate salt) of the alpha 1a adrenergic receptor, Compound A, having substantially improved physical properties as compared to the previously known amorphous salts.
The present invention also provides an improved process for making an alpha 1a adrenergic receptor antagonist useful for treating benign prostatic hyperplasia. More specifically, the invention provides an enzymatic resolution of a dihydropyrimidinone methyl ester which is an intermediate in the preparation of the alpha 1a adrenergic receptor antagonist, Compound A.
The present invention further provides a chemical process for making a class of dihydropyrimidinone compounds of which Compound A is a member. The process involves deprotonating a dihydropyrimidinone and then coupling the deprotonated derivative with a primary amine.
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.
Recently, a number of alpha 1a adrenergic receptor antagonist compounds have been disclosed as being useful in the treatment of BPH. These alpha 1a adrenergic receptor antagonists and their utility in treating BPH and inhibiting contraction of lower urinary tract tissue are described in PCT International Application Publication No. WO 96/14846, published May 23, 1996. More particularly, the compound (+)-5-Methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]}-carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine, disclosed in Example 30 of WO 96/14846, and referred to herein as “Compound A,” is a potent and selective antagonist of the alpha 1a adrenergic receptor antagonist and is useful in the treatment of BPH.
Compound A is prepared according to the procedure of Example 30 in WO 96/14846 or according to the processes disclosed in detail herein. The identification of Compound A as an alpha 1a adrenergic receptor antagonist was established according to the assays described in WO 96/14846.
Preparation of an acceptable salt of Compound A suitable for pharmaceutical development proved problematic. Numerous attempts to isolate a crystalline salt form of Compound A failed as only amorphous salts could be isolated. Additionally, the free base of Compound A was also isolated as an amorphous solid. The lack of a crystalline form of Compound A necessitated that Compound A had to be isolated from reaction mixtures by chromatography on silica gel. Separation from reaction impurities was tedious, large volumes of eluent were required, assay of dozens of fractions for concentration and purity was required and concentration of the desired fractions was time intensive. The product was isolated by chromatography on gram scale as an amorphous solid. Thus, development of a kilogram scale process requiring chromatographic separation would be expensive and time consuming, while scalability to a factory process was unknown but unlikely.
These problems were solved by identification of the crystalline pharmaceutically acceptable salts of Compound A of the present invention. More specifically, crystallization of pharmaceutically acceptable salts of Compound A directly from the crude or semi-purified reaction mixture obviates the need for chromatographic purification. This eliminates the tedious separation, large solvent requirements, and multiple assay requirements. Moreover, a crystallization process allows for more reproducible purity and yield upon scale up. Additionally, the crystalline tartrate salt of Compound A is isolated as a white, free-flowing solid allowing for easy isolation and manipulation. Still another advantage of the L-tartrate salt crystallization is that it enriches the chiral purity of Compound A.
Previous preparations of chiral Compound A were accomplished by following the teaching of PCT Int. Appl. WO 96/14846, wherein the racemic dihydropyrimidinone was converted to diastereomeric urea derivatives by treatment with 4-nitrophenyl chloroformate in the presence of base, followed by (R)-(+)-&agr;-methyl benzylamine. The diastereomers were separated by chromatography on silica gel, then the chiral urea was cleaved to afford the desired (+)-dihydropyrimidinone isomer. This teaching essentially followed the prior art set forth by Atwal, et.al. (J. Med. Chem. 1990, 33, 2629) wherein this diastereomeric resolution was first described for a similar dihydropyrimidinone analog. In another report, Kappe et.al. (Tetrahedron 1992, 5473) have described the hydrogenolysis of a benzyl ester to afford the racemic acid derivative. The acid enantiomers were resolved by crystallization as the diastereomeric ammonium salts using either (R)-(+)-&agr;-methyl benzylamine or (S)-(−)-&agr;-methyl benzylamine.
The previously known methods for resolution of the dihydropyrimidinone suffer from several problems. The approach described in the teaching of PCT Int. Appl. WO 96/14846 or by Atwal, et. al. (J. Med. Chem. 1990, 33, 2629) requires a multi-step sequence for the preparation of diastereomers. These must then be separated by either fractional crystallization or chromatography on silica gel. Finally, the pure diasteromeric urea derivatives must be cleaved to their respective enantiomers and purified from the chiral resolving agent. In the method described by Kappe et.al. (Tetrahedron 1992, 5473) the ester substituent must be a benzyl group in order for effective hydrogenolysis to afford the carboxylic acid, which has been reported to be unstable. Following resolution by fractional crystallization, the salts were cleaved with acid to afford the pure acid enantiomers. If ester derivatives were desired, it was then necessary to esterify the carboxylic acid in an additional step. Since none of the chemical steps described in these processes are quantitative, each manipulation leads to a loss of product. Separation by chromatography on silica gel requires large volumes of solvent, multiple assays to determine purity of the collected fractions, and time consuming concentration of the desired fractions. Conditions for the fractional crystallization of either the diastereomeric ureas or diastereomeric ammonium salts must be determined for each derivative. Commonly, the yield for the multi-step resolution process was low.
The prior art methods depend on the efficiency of a chromatographic separation or fractional crystallization for their success. Slight variations in the purification conditions may easily lead to degradation of purity of the product. The multistep derivatization and separation sequence involves several chemical manipulations. The cost of obtaining the reagents and solvents, along with the costs of disposal or recovery of waste streams, is inefficient.
These problems of the prior art methods were solved by identification of the bioresolution process of the present invention. More specifically, the bioresolution process offers several advantages over these existing methodologies. It is a one step process, run in an aqueous media, which proceeds in high yield. This results in less wasted time and manpower for its practice, and requires a minimum amount of reagents, and solvents to perform.
SUMMARY OF THE INVENTION
The present invention provides a crystal

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