Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Patent
1994-12-02
1997-01-21
Prior, Kimberly J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C07J 7500
Patent
active
055961096
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US93/02974, filed Mar. 24, 1993.
The present invention relates to a novel polymorphic form of N-t-butyl-androst-3,5-diene-17.beta.-carboxamide-3-carboxylic acid.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. I is an Infra-red Spectrum of N-t-butyl-androst-3,5-diene-17.beta.-carboxamide-3-carboxylic acid polymorph A.
FIG. II is an enhanced FT-IR spectra of the 3399-3501 cm.sup.-1 region of Polymorph A disclosing the characteristic N-H stretch of Polymorph A.
DETAILED DESCRIPTION OF THE INVENTION
N-t-butyl-androst-3,5-diene-17.beta.-carboxamide-3-carboxylic acid is a compound which is disclosed and claimed as being useful in the treatment of benign prostatic hypertrophy in U.S. Pat. No. 5,017,568, the entire disclosure of which is incorporated by reference. Said compound can be prepared by methods such as described in U.S. Pat. No. 5,017,568. The isolation and identification of the polymorphic forms of said compound is advantageous in identifying desirable physical characteristics of the different crystal forms of said compound.
It has now been found that a polymorphic form (hereinafter Polymorph A) of the compound N-t-butyl-androst-3,5-diene-17.beta.-carboxamide-3-carboxylic acid can be obtained in a high state of polymorphic purity by triturating, by crystallizing or by precipitating said compound from a solvent consisting of or primarily consisting of ethyl acetate or from a solvent consisting of or primarily consisting of t-butyl methyl ether. The substantially pure polymorphic A form of said compound can also obtain by trituration, by crystallization or by precipitation from N-butyl acetate and isopropyl acetate. Contemplated herein is the process of obtaining substantially pure polymorph A from a solvent consisting of or primarily consisting of an organic solvent or a combination of organic solvents which contain an acetate substituent. Also, contemplated herein is the process of obtaining substantially pure polymorph A by trituration, by crystallizing or by precipitating said compound from a solvent consisting of or primarily consisting of an organic solvent which contains an acetate group, preferably ethyl acetate, and t-butyl methyl ether. Typically, a slurry of crude N-t-butyl-androst-3,5-diene-17.beta.-carboxamide-3-carboxylic acid is stirred at above ambient temperature in a solvent consisting primarily of ethyl acetate. Preferably a 12-40% by weight slurry of N-t-butyl-androst-3,5-diene-17 .beta.-carboxamide-3-carboxylic acid in ethyl acetate is warmed above ambient temperature, preferably in the range of 65.degree.-70.degree. C., and stirred, preferably for about an hour, followed by filtration which is typically conducted below ambient temperature, preferably in the range of 0.degree.-5.degree. C. Most preferably said slurry is a 14-20% slurry.
Presently, N-t-butyl-androst-3,5-diene-17.beta.-carboxamide-3-carboxylic acid is known to assume only two polymorphic forms, A and B.
Polymorph A and Polymorph B were individually subjected to intense grinding in a mortar with a pestle for a period of approximately five minutes. Infra-red spectral absorbencies of the post-grinding Polymorph B compound indicated that approximately 5-10% of said polymorph had converted to the Polymorph A form. Infra-red spectral absorbencies of the post-grinding Polymorph A compound indicated retention of polymorphic identity and purity. The above findings indicate that the polymorphic A form of N-t-butyl-androst-3,5-diene-17.beta.-carboxamide-3-carboxylic acid is thermodynamically more stable than the polymorphic B form. The themodynamically more stable polymorphic form of a compound is advantageous for maintaining crystal integrity during manufacture, storing, shipping and handling of solid compositions of said compound. Since, as described above, the polymorphic B form of N-t-butyl-androst-3,5-diene-17.beta.-carboxamide-3-carboxylic acid does not retain its crystal integrity upon grinding and the polymorphic A form retains crystal integrity, Polymorph A is particularly advantageous in th
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Baine Neil H.
Holder Neville L.
Klein Donald N.
Webb Robert L.
Zuber Gary E.
Dustman Wayne J.
Kinzig Charles M.
Lentz Edward T.
Prior Kimberly J.
SmithKline Beecham Corporation
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