WO1993019080A1 - N-T-BUTYL-ANDROST-3,5-DIENE-17β-CARBOXAMIDE-3-CARBOXYLIC ACID POLYMORPH B - Google Patents

N-T-BUTYL-ANDROST-3,5-DIENE-17β-CARBOXAMIDE-3-CARBOXYLIC ACID POLYMORPH B Download PDF

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Publication number
WO1993019080A1
WO1993019080A1 PCT/US1993/002862 US9302862W WO9319080A1 WO 1993019080 A1 WO1993019080 A1 WO 1993019080A1 US 9302862 W US9302862 W US 9302862W WO 9319080 A1 WO9319080 A1 WO 9319080A1
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Prior art keywords
polymorph
androst
diene
butyl
carboxamide
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PCT/US1993/002862
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French (fr)
Inventor
Neil Howard Baine
Karl Erhard
Michael David Goodyear
Franklin F. Owings
Robert Lee Webb
Gary Edward Zuber
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Smithkline Beecham Corporation
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Publication date
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Priority to JP5516851A priority Critical patent/JPH07505369A/en
Priority to EP93908611A priority patent/EP0643722A4/en
Publication of WO1993019080A1 publication Critical patent/WO1993019080A1/en

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    • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

Polymorph 'B' is a novel polymorphic form of N-t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid. Novel processes for preparing polymorph 'B' are also disclosed.

Description

N-T-BUTYL-ANDROST-3.5-DIENE-17β-CARBOXAMIDE-3-CARBOXYLTC
ACID POLYMORPH B The present invention relates to a novel polymorphic form of N-t-butyl-androst-3,5-diene-17β- carboxamide-3-carboxylic acid.
Brief Description of the Drawings
Figure I is an Infa-red spectrum of N-t-butyl- androst-3,5-diene-17β-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.
Detailed Description of the Invention N-t-butyl-androst-3,5-diene-17β-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.
It has now been found that a polymorphic form (hereinafter polymorph B) of the compound N-t-butyl- androst-3,5-diene-17β-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. Also, 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. Preferably, crude N-t-butyl-androst-3,5-diene-17β-carboxamide-3- carboxylic acid is dissolved in and substantially pure polymorph B is crystalized from a solution of boiling acetonitrile, said solution optionally containing a co- solvent, preferably methylene chloride, to aid dissolution. Preferably a 12-40% by weight slurry of N- t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid in acetonitrile is stirred at above ambient temperature. Preferably a 14-20% by weight slurry of N- t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid in boiling acetonitrile is stirred, preferably for about an hour. Preferably, crude N-t-butyl-androst-3,5- diene-17β-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.
Presently, N-t-butyl-androst-3,5-diene-17β- 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-17β-carboxamide-3- carboxylic acid. The studies were carried out at ambient temperature and the concentration of N-t-butyl- androst-3,5-diene-17β-carboxamide-3-carboxylic acid in each solution was measured by ultra violet spectroscopy,
Table 1
Figure imgf000005_0001
* 0.1 N Na2HP04, pH 7.5
** ND = Not detected, limit of detection was 0.001 mg/ml
As indicated in Table 1 above, 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-17β-carboxamide-3-carboxylic acid, such as creams or ointments, and indicates increased Ln vivo bioavailability of said compound. - A -
By the term "crude" as used herein is meant that the isolated N-t-butyl-androst-3, 5-diene-17β- carboxamide-3-carboxylic acid starting material exist as an amorphous solid, in an undesired polymorphic form or as a plurality of polymorphic forms .
By the term "N-t-butyl-androst-3, 5-diene-17β- carboxamide-3-carboxylic acid" as used herein is meant a compound of the structure
Figure imgf000006_0001
N-t-butyl-androst-3, 5-diene-17β-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) . The characteristic d-spacings, intensities, and 2-theta values for the diffraction pattern of Polymorph B are listed in Table 2 below.
Table 2
X-ray diffraction pattern listing of N-t-butyl- androst-3,5-diene-17β-carboxamide-3-carboxylic acid polymorph B.
Figure imgf000006_0002
- 5 -
Figure imgf000007_0001
The following examples illustrate the preparation of N-t-butyl-androst-3,5-diene-17β-carboxamide-3- carboxylic acid polymorph B. The examples are not intended to limit the scope of the invention as defined hereinabove or as claimed below. - 6 - Example 1
N-t-butyl-androst-3,5-dienβ-17β-carboxamJd -3-carboxylir. acid Polymorph B 33 g of crude N-t-butyl-androst-3,5-diene-17β- 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-17β- carboxamide-3-carboxylic acid as its B polymorph. The infa-red spectrum of the product is shown in figures one and two.
Infra-red spectral absorbancies of N-t-butyl- androst-3,5-diene-17β-carboxamide-3-carboxylic acid polymorph B (prepared by crystallization from acetonitrile) were obtained (spectrm obtained from Nujol (mineral oil) on sodium chloride plates) (Apparatus; Nicolet 6000 FT-IR using a mercury Cadmiun Telluride Detector, analysis time 7.6 minutes (800 scans), Enhancement Program Nicolet IRDCON) .
Characteristic Polymorph B form bands occur at 3455, 3446 cm"1 (N-H stretch); and 1670 cm-1 (acid and amide C=0 stretch) . 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.
Example 2
N-t-butyl-androst-3,5-diene-17β-carboxamide-3-carobyxlic
Acid Polymorph B Crude N-t-butyl-androst-3,5-diene-17β-carboxamide- 3-carboxylic acid (10 grams) was dissolved in methylene chloride (250 L) . The reaction solution was distilled at atmospheric pressure to about 85 mL and about 50 mL of acetonitrile was added. The mixture was again distilled until the head temperature reached 78°C, and the resulting suspension was then heated at reflux for about 1 hour. The slurry was chilled in an ice bath for about 1 hour. The product was isolated by filtration, washed thoroughly with cold acetonitrile, and dried under vacuum at 50-60°C to afford 9.7 grams of N-t- butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid as polymorph B.
Example 3
N-t-butv]-androst-3,5-diene-17β-carboxamid -3-r.arboxylic. acid Polymorph B Substantially pure N-t-butyl-androst-3,5-diene-17β- carboxamide-3-carboxylic acid Polymorph B was obtained by precipitating approximately 10 g of crude N-t-butyl- androst-3,5-diene-17β-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-17β-carboxamide-3-carboxylic acid Polymorph B.

Claims

What is claimed is:
1. A compound of the structure
Figure imgf000010_0001
substantially in polymorph B form.
2. A compound according to Claim 1 having the infa-red spectrum as shown in Figure 1 and the x-ray diffraction pattern listing shown in Table 2.
3. A compound according to claim 1 having the infa-red spectrum as shown in Figure 2 and the x-ray diffraction pattern listing shown in Table 2.
4. A process for preparing a compound of the structure
Figure imgf000010_0002
substantially in the polymorph B form, which process comprises triturating or crystallizing or precipitating crude N-t-butyl-androst-3, 5-diene-17β-carboxamide-3- carboxylic acid from a solution consisting of or primarily consisting of acetonitrile, 2-butanone, methanol or tetrahydrofuran with subsequent isolation of said polymorph. 5. A process according to claim 4 which comprises triturating crude N-t-butyl-androst-3,
5-diene-17β- carboxamide-3-carboxylic acid in a solution of boiling acetonitrile with subsequent isolation of said polymorph.
6. A process according to claim 4 which comprises precipitating crude N-t-butyl-androst-3, 5-diene-17β- carboxamide-3-carboxylic acid from 2-butanone by concentration and with the addition of petroleum ether with subsequent isolation of 'said polymorph.
7. A process for preparation of a compound of the structure
Figure imgf000011_0001
substantially in the polymorph B form, which comprises triturating or crystallizing or precipitating crude N-t- butyl-androst-3, 5-diene-17β-carboxamide-3-carboxylic acid from a solvent consisting of a combination of solvents selected from acetonitrile, 2-butanone, methanol and tetrahydrofuran with subsequent isolation of said polymorph.
PCT/US1993/002862 1992-03-24 1993-03-24 N-T-BUTYL-ANDROST-3,5-DIENE-17β-CARBOXAMIDE-3-CARBOXYLIC ACID POLYMORPH B WO1993019080A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP5516851A JPH07505369A (en) 1992-03-24 1993-03-24 N-t-butyl-androst-3,5-diene-17β-carboxyamido-3-carboxylic acid polymorph B
EP93908611A EP0643722A4 (en) 1992-03-24 1993-03-24 N-T-BUTYL-ANDROST-3,5-DIENE-17-g(b)-CARBOXAMIDE-3-CARBOXYLIC ACID POLYMORPH B.

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GB9206414.6 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

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Citations (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

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4910226A (en) * 1987-04-29 1990-03-20 Smithkline Beckman Corporation Steroid 5-alpha-reductase inhibitors

Patent Citations (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

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
Biochemistry, 1990, LEVY et al., "Inhibition of Rat-Liver Steroid 5x-Reductase by 3-Androstene -3-carboxylic Acids: Mechanism of Enzyme - Inhibitor Interaction", pp. 2815-2823, see p. 2817. *
Bioorganic Chemistry, 1989, METCALF et al., "Potent Inhibitor of Human Steroid 5x-Reductase by 3-Androstene -3-Carboxylic Acids", pp. 372-376, see p. 374. *
Bioorganic Chemistry, 1991, LEVY et al., "3-Phosphinic Acid and 3-Phosphonic Acid Steroids as Inhibitors of Steroid 5x-Reductase: Species Comparison and Mechanistic Studies", pp. 245-260, see p. 246, 254. *
Endocrinology, 1992, LAMB et al., "Prostatic Involution in Rats Induced by a Novel 5x - Reductase Inhibitor, SK&F 105657: Role for Testosteroe in the Androgenic Response", pp. 685-694, see 686. *
Journal of Medicinal Chemistry, 1990, HOLT et al., "Inhibition of Steroid 5x-Reductase by Unsaturated 3-Carboxysteroids", pp. 943-950, see p. 945. *
Journal of Steroid Biochemistry, 1989, LEVY et al., "Interaction Between Rat Prostatic Steroid 5x- Reductase and 3-Carboxy-17B-Substituted Steroids: Novel Mechanism of Enzyme Inhibition", pp. 571-575, see 572-3. *
Proceedings of the National Academy of Sciences, 1992, HARRIS et al., "Identification and Selective 5x-Reductase in Human Scalp", pp. 10787-10791, see p. 10789. *
See also references of EP0643722A4 *

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EP0643722A4 (en) 1995-05-17
GB9206414D0 (en) 1992-05-06
AU3937393A (en) 1993-10-21
JPH07505369A (en) 1995-06-15
EP0643722A1 (en) 1995-03-22

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