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
Links
- 238000000034 method Methods 0.000 claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- 150000001875 compounds Chemical class 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 238000002441 X-ray diffraction Methods 0.000 claims description 5
- 238000002955 isolation Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 230000001376 precipitating effect Effects 0.000 claims description 4
- 238000001228 spectrum Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000009835 boiling Methods 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000002002 slurry Substances 0.000 description 4
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- XSOKHXFFCGXDJZ-UHFFFAOYSA-N telluride(2-) Chemical compound [Te-2] XSOKHXFFCGXDJZ-UHFFFAOYSA-N 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929206414A GB9206414D0 (en) | 1992-03-24 | 1992-03-24 | N-t-butyl-androst-3,5-diene-17b-carboxamide-3-carboxylic acid polymorph b |
| GB9206414 | 1992-03-24 | ||
| 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)
| 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)
| 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 |
-
1992
- 1992-03-24 GB GB929206414A patent/GB9206414D0/en active Pending
-
1993
- 1993-03-24 EP EP93908611A patent/EP0643722A4/fr not_active Ceased
- 1993-03-24 WO PCT/US1993/002862 patent/WO1993019080A1/fr not_active Ceased
- 1993-03-24 AU AU39373/93A patent/AU3937393A/en not_active Abandoned
- 1993-03-24 JP JP5516851A patent/JPH07505369A/ja active Pending
Patent Citations (1)
| 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)
| Title |
|---|
| See also references of WO9319080A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0643722A1 (fr) | 1995-03-22 |
| JPH07505369A (ja) | 1995-06-15 |
| WO1993019080A1 (fr) | 1993-09-30 |
| GB9206414D0 (en) | 1992-05-06 |
| AU3937393A (en) | 1993-10-21 |
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Legal Events
| Date | Code | Title | Description |
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| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
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| RTI1 | Title (correction) |
Free format text: N-T-BUTYL-ANDROST-3,5-DIENE-17-BETA-CARBOXAMIDE-3-CARBOXYLIC ACID POLYMORPH B |
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| STAA | Information on the status of an ep patent application or granted ep patent |
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| 18R | Application refused |
Effective date: 19991213 |