EP0643722A4 - POLYMORPHE B DE L'ACIDE N-T-BUTYLE-ANDROST-3,5-DIENE-17-g(b)-CARBOXAMIDE-3-CARBOXYLIQUE. - Google Patents

POLYMORPHE B DE L'ACIDE N-T-BUTYLE-ANDROST-3,5-DIENE-17-g(b)-CARBOXAMIDE-3-CARBOXYLIQUE.

Info

Publication number
EP0643722A4
EP0643722A4 EP93908611A EP93908611A EP0643722A4 EP 0643722 A4 EP0643722 A4 EP 0643722A4 EP 93908611 A EP93908611 A EP 93908611A EP 93908611 A EP93908611 A EP 93908611A EP 0643722 A4 EP0643722 A4 EP 0643722A4
Authority
EP
European Patent Office
Prior art keywords
polymorph
androst
diene
butyl
carboxamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP93908611A
Other languages
German (de)
English (en)
Other versions
EP0643722A1 (fr
Inventor
Neil Howard Baine
Karl Erhard
Michael David Goodyear
Franklin F Owings
Robert Lee Webb
Gary Edward Zuber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP0643722A1 publication Critical patent/EP0643722A1/fr
Publication of EP0643722A4 publication Critical patent/EP0643722A4/fr
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0066—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by a carbon atom forming part of an amide group

Definitions

  • ACID POLYMORPH B The present invention relates to a novel polymorphic form of N-t-butyl-androst-3,5-diene-17 ⁇ - carboxamide-3-carboxylic acid.
  • Figure I is an Infa-red spectrum of N-t-butyl- androst-3,5-diene-17 ⁇ -carboxylic acid polymorph B.
  • Figure II is an enhanced FT-IR spectrum of the 3399-3501 cm -1 region of polymorph B disclosing the characteristic N-H stretch of polymorph B.
  • N-t-butyl-androst-3,5-diene-17 ⁇ -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. Patent No. 5,017,568, the entire disclosure of which is hereby incorporated by reference.
  • Said compound can be prepared by methods such as described in U.S. Patent 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.
  • polymorph B a polymorphic form of the compound N-t-butyl- androst-3,5-diene-17 ⁇ -carboxamide-3-carboxylic acid can be obtained in a high state of polymorphic purity by crystallization or by precipitation of said compound from or by the trituration of said compound in a solvent consisting of or primarily consisting of acetonitrile, 2-butanone, methanol or tetrahydrofuran.
  • contemplated herein is the process of obtaining substantially pure polymorph B by crystallization or by precipitation of said compound from or by the trituration of said compound in a solvent consisting of a combination of solvents selected form acetonitrile, 2- butanone, methanol and tetrahydrofuran.
  • a solvent consisting of a combination of solvents selected form acetonitrile, 2- butanone, methanol and tetrahydrofuran.
  • a solvent consisting of a combination of solvents selected form acetonitrile, 2- butanone, methanol and tetrahydrofuran.
  • a solvent consisting of a combination of solvents selected form acetonitrile, 2- butanone, methanol and tetrahydrofuran.
  • crude N-t-butyl-androst-3,5-diene-17 ⁇ -carboxamide-3- carboxylic acid is dissolved in and substantially pure polymorph B is crystalized from a solution of boiling acet
  • a 12-40% by weight slurry of N- t-butyl-androst-3,5-diene-17 ⁇ -carboxamide-3-carboxylic acid in acetonitrile is stirred at above ambient temperature.
  • a 14-20% by weight slurry of N- t-butyl-androst-3,5-diene-17 ⁇ -carboxamide-3-carboxylic acid in boiling acetonitrile is stirred, preferably for about an hour.
  • crude N-t-butyl-androst-3,5- diene-17 ⁇ -carboxamide-3-carboxylic acid is dissolved in and substantially pure polymorph B is precipitated from 2-butanone by concentration and with the addition of petroleum ether.
  • N-t-butyl-androst-3,5-diene-17 ⁇ - carboxamide-3-carboxylic acid is known to assume only two polymorphic forms, A and B.
  • Table 1 displays the results of equilibrium solubility studies carried out on the two polymorphic forms of N-t-butyl-androst-3,5-diene-17 ⁇ -carboxamide-3- carboxylic acid. The studies were carried out at ambient temperature and the concentration of N-t-butyl- androst-3,5-diene-17 ⁇ -carboxamide-3-carboxylic acid in each solution was measured by ultra violet spectroscopy,
  • the polymorph B form is more soluble and has a faster rate of dissolution in water than the polymorph A form.
  • Such enhanced solubility properties are advantageous in the preparation of pharmaceutical formulations of N-t-butyl- androst-3,5-diene-17 ⁇ -carboxamide-3-carboxylic acid, such as creams or ointments, and indicates increased Ln vivo bioavailability of said compound.
  • N-t-butyl-androst-3, 5-diene-17 ⁇ - carboxamide-3-carboxylic acid is meant a compound of the structure
  • N-t-butyl-androst-3, 5-diene-17 ⁇ -carboxamide-3- carboxylic acid polymorph B (prepared by crystallization from acetonitrile) was analyzed by an X-ray powder diffraction (X-ray diffractometry (XRD) obtained from Micron Incorporated of Wilmington, Delaware) .
  • XRD X-ray diffractometry
  • the characteristic d-spacings, intensities, and 2-theta values for the diffraction pattern of Polymorph B are listed in Table 2 below.
  • Acid Polymorph B 33 g of crude N-t-butyl-androst-3,5-diene-17 ⁇ - carboxamide-3-carboxylic acid was added to 150 ml of acetonitrile. The resulting slurry was heated to reflux and stirred for about two hours. The product was isolated by filtration and afforded 27.2 g of substantially pure N-t-butyl-androst-3,5-diene-17 ⁇ - carboxamide-3-carboxylic acid as its B polymorph. The infa-red spectrum of the product is shown in figures one and two.
  • An FT-IR spectra of polymorph B is shown in figure 1 below.
  • the resolution enhanced FT-IR spectra of the 3399-3501 cm _ l region disclosing said characteristic N-H stretch of polymorph B is shown in Figure 2 below.
  • N-t-butv]-androst-3,5-diene-17 ⁇ -carboxamid -3-r.arboxylic. acid Polymorph B Substantially pure N-t-butyl-androst-3,5-diene-17 ⁇ - carboxamide-3-carboxylic acid Polymorph B was obtained by precipitating approximately 10 g of crude N-t-butyl- androst-3,5-diene-17 ⁇ -carboxamide-3-carboxylic acid, from 100 mL of 2-butanone by concentrating the solution under vacuum to about 20 mL and then treating the solution with 163 mL of petroleum ether. The product was collected by filtration, and was dried under vacuum at about 50°C to afford 6.4 g of substantially pure N-t- butyl-androst-3,5-diene-17 ⁇ -carboxamide-3-carboxylic acid Polymorph B.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
EP93908611A 1992-03-24 1993-03-24 POLYMORPHE B DE L'ACIDE N-T-BUTYLE-ANDROST-3,5-DIENE-17-g(b)-CARBOXAMIDE-3-CARBOXYLIQUE. Ceased EP0643722A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9206414 1992-03-24
GB929206414A GB9206414D0 (en) 1992-03-24 1992-03-24 N-t-butyl-androst-3,5-diene-17b-carboxamide-3-carboxylic acid polymorph b
PCT/US1993/002862 WO1993019080A1 (fr) 1992-03-24 1993-03-24 POLYMORPHE B DE L'ACIDE N-T-BUTYLE-ANDROST-3,5-DIENE-17β-CARBOXAMIDE-3-CARBOXYLIQUE

Publications (2)

Publication Number Publication Date
EP0643722A1 EP0643722A1 (fr) 1995-03-22
EP0643722A4 true EP0643722A4 (fr) 1995-05-17

Family

ID=10712750

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93908611A Ceased EP0643722A4 (fr) 1992-03-24 1993-03-24 POLYMORPHE B DE L'ACIDE N-T-BUTYLE-ANDROST-3,5-DIENE-17-g(b)-CARBOXAMIDE-3-CARBOXYLIQUE.

Country Status (5)

Country Link
EP (1) EP0643722A4 (fr)
JP (1) JPH07505369A (fr)
AU (1) AU3937393A (fr)
GB (1) GB9206414D0 (fr)
WO (1) WO1993019080A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0289327A2 (fr) * 1987-04-29 1988-11-02 Smithkline Beecham Corporation Inhibiteurs de stéroides-5-alpha-réductase

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5162543A (en) * 1990-02-16 1992-11-10 E. R. Squibb & Sons, Inc. Selective processes for fosinopril polymorphs

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0289327A2 (fr) * 1987-04-29 1988-11-02 Smithkline Beecham Corporation Inhibiteurs de stéroides-5-alpha-réductase

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO9319080A1 *

Also Published As

Publication number Publication date
JPH07505369A (ja) 1995-06-15
WO1993019080A1 (fr) 1993-09-30
GB9206414D0 (en) 1992-05-06
EP0643722A1 (fr) 1995-03-22
AU3937393A (en) 1993-10-21

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