WO2003027132A2 - METHOD OF PREPARING 17β-(N-TERT-BUTYLCARBAMOYL)-3-ONE STEROID DERIVATIVES - Google Patents
METHOD OF PREPARING 17β-(N-TERT-BUTYLCARBAMOYL)-3-ONE STEROID DERIVATIVES Download PDFInfo
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- WO2003027132A2 WO2003027132A2 PCT/KR2002/001776 KR0201776W WO03027132A2 WO 2003027132 A2 WO2003027132 A2 WO 2003027132A2 KR 0201776 W KR0201776 W KR 0201776W WO 03027132 A2 WO03027132 A2 WO 03027132A2
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- butylcarbamoyl
- tert
- butylamine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
Definitions
- the present invention relates to a method of preparing a 17 ⁇ -(N-tert- butylcarbamoyl)-3-one steroid derivative which is an useful intermediate of finasteride.
- Finasteride i.e., 17 ⁇ -(N-tert-butylcarbamoyl)-5 ⁇ -4-aza-androst-l-en-3- one of formula (II), is a useful medicament for treating benign prostatic hypertrophy and androgenic alopecia:
- Benign prostatic hypertrophy and androgenic alopecia are induced by binding of androgen receptor to excessive 5 ⁇ -dehydrotestosterone("DHT") which is formed from testosterone by the action of testosterone 5 ⁇ -reductase.
- DHT 5 ⁇ -dehydrotestosterone
- Finasteride a testosterone 5 ⁇ -reductase inhibitor, is known to lower the concentration of DHT by preventing testosterone from converting to 5 ⁇ - dehydrotestosterone in plasma and cells, thereby restoring the prostate gland and enhancing hair growth.
- Finasteride may be prepared by various known methods that involve the step of converting the 17 ⁇ carboxyl group of 3-oxo-4-androsten-17 ⁇ -carboxylic acid or 3-oxo-4-aza-5 ⁇ -androstan-17 ⁇ -carboxylic acid into a t-butylcarbamoyl group.
- US Patent No. 4,760,071 discloses a method of preparing a 17 ⁇ -t-butylcarbamoyl derivative by converting the 17 ⁇ -carboxyl group into a pyridylthio ester which is subsequently reacted with t-butylamine.
- this method requires the use of expensive 2,2'-pyridyl disulfide; and the multi- step procedure is not economically feasible.
- US Patent No. 5,670,643 offers a method of converting the 17 ⁇ - carboxyl group into an acid chloride and reacting the acid chloride with t- butylamine. However, this method necessitates the use of toxic thionyl chloride which is difficult to handle.
- US Patent Nos. 5,468,860 and 5,652,365 and EP Patent No. 599,376 teach a method of reacting an organomagnesium halide with t-butylamine to obtain a t-butylaminomagnesium halide, and then reacting the t- butylaminomagnesium halide with a 17 ⁇ -carboalkoxy compound. However, this method is not suitable for large-scale production due to moisture-sensitivity of the organomagnesium halide.
- a method of preparing a 17 ⁇ -N-tert-butylcarbonyl-3-one steroid compound of formula (I) which comprises reacting a 17 ⁇ -carboxy-3-one steroid compound of formula (III) with a pivaloyl halide of formula (IN) to obtain a pivaloyl acid anhydride of formula (N) and reacting the pivaloyl acid anhydride of formula (V) with t-butylamine in an organic solvent in the presence of a base:
- X is CH 2 , CH, NH or N; ⁇ is a single or double bond; and Y is Cl, Br or I.
- a 17 ⁇ -carboxy-3-one steroid compound of formula (III) may be prepared in accordance with the method disclosed in [J. Med. Chem., 29, p2298, (1986)] or US Patent No. 4,760,071.
- Pivaloyl halide of formula (IN) which is commercially available or prepared in accordance with the known methods in the art (See Beil, 2, 320), may be employed in an amount ranging from 1.0 to 2.0 equivalents, preferably from 1.1 to 1.3 equivalents, based on the amount of the 17 ⁇ -carboxy-3-one steroid compound of formula (III).
- the organic solvent employed in the present invention may be any one of the conventional organic solvents including methylene chloride, chloroform, tetrahydrofuran and dimethylformamide.
- the base employed in the present invention may be aniline, triethylamine, n-tributylamine, t-butylamine, ⁇ , ⁇ - dimethylaniline, pyridine, N,N-dimethylaminopyridine, benzylamine, cyclohexylamine dicyclohexylamine or a mixture thereof, preferably triethylamine.
- the base is employed in an amount ranging from 0.5 to 3.0 equivalents, preferably from 0.7 to 1.2 equivalents, based on the amount of the 17 ⁇ -carboxy-3-one steroid compound of formula (III).
- the pivaloyl acid anhydride of formula (V) which is formed by reacting the compound of formula (III) with the compound of formula (IN) may be reacted with t-butylamine without the isolation thereof from the reaction mixture. Since the pivaloyl acid anhydride is not sensitive to water, the reaction does not require an anhydrous condition.
- t-butylamine is employed in an amount ranging from 1.0 to 4.0 equivalents, preferably from 1.5 to 2.5 equivalents, based on the amount of the 17 ⁇ -carboxy-3-one steroid compound of formula (III).
- the inventive reaction may be performed at a temperature ranging from -10 to 30 °C , preferably from -5 to 20 ° C for a period sufficient to complete the reaction, e.g., about from 3 to 6 hours.
- a 17 ⁇ -(N-butylcarbamoyl)-3- one steroid compound of formula (I) can be easily obtained in a high purity of at least 98%, via a simple process conducted under a mild reaction condition.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
A highly pure 17β-N-tert-butylcarbamoyl-3-one steroid compound of formula (I) is prepared in a high yield under a mild condition, by reacting a 17β-carboxy-3-one steroid compound with a pivaloyl halide to obtain a pivaloyl acid anhydride and reacting the pivaloyl acid anhydride with t-butylamine in an organic solvent in the presence of a base formula (I) wherein X is CH2, CH, NH or N; is a single or double bond; and Y is Cl, Br or I.
Description
METHOD OF PREPARING
17β-(N-TERT-BUTYLCARBAMOYL)-3-ONE STEROID DERIVATIVES
Field of the Invention
The present invention relates to a method of preparing a 17β-(N-tert- butylcarbamoyl)-3-one steroid derivative which is an useful intermediate of finasteride.
Background of the Invention
Finasteride, i.e., 17β-(N-tert-butylcarbamoyl)-5α-4-aza-androst-l-en-3- one of formula (II), is a useful medicament for treating benign prostatic hypertrophy and androgenic alopecia:
Benign prostatic hypertrophy and androgenic alopecia are induced by binding of androgen receptor to excessive 5α-dehydrotestosterone("DHT") which is formed from testosterone by the action of testosterone 5α-reductase. Finasteride, a testosterone 5α-reductase inhibitor, is known to lower the concentration of DHT by preventing testosterone from converting to 5α- dehydrotestosterone in plasma and cells, thereby restoring the prostate gland and enhancing hair growth.
Finasteride may be prepared by various known methods that involve the step of converting the 17β carboxyl group of 3-oxo-4-androsten-17β-carboxylic acid or 3-oxo-4-aza-5α-androstan-17β-carboxylic acid into a t-butylcarbamoyl group.
For example, US Patent No. 4,760,071 discloses a method of preparing a 17β-t-butylcarbamoyl derivative by converting the 17β-carboxyl group into a pyridylthio ester which is subsequently reacted with t-butylamine. However, this method requires the use of expensive 2,2'-pyridyl disulfide; and the multi- step procedure is not economically feasible.
US Patent No. 5,670,643 offers a method of converting the 17β- carboxyl group into an acid chloride and reacting the acid chloride with t- butylamine. However, this method necessitates the use of toxic thionyl chloride which is difficult to handle. US Patent Nos. 5,468,860 and 5,652,365 and EP Patent No. 599,376 teach a method of reacting an organomagnesium halide with t-butylamine to obtain a t-butylaminomagnesium halide, and then reacting the t- butylaminomagnesium halide with a 17β-carboalkoxy compound. However, this method is not suitable for large-scale production due to moisture-sensitivity of the organomagnesium halide.
International patent application No. PCT/ES00/0239 provides a method of preparing a 17β-butylcarbamoyl compound by reacting lithium t-butylamide with a 17β-carboxyalkoxy compound. However, this method makes use of t- butylamide which is difficult to handle and very dangerous due to flammability. EP Patent No. 271,200 describes a method of converting the 17β- carboxyl group into a hydroxybenzothiazolyl ester or imidazolide which is subsequently reacted with butylamine. However, this method has problems in that the reaction yields a product of low purity or calls for an anhydrous condition. Accordingly, there has been a need to develop an improved method for preparing a 17β-(N-tert-butylcarbamoyl)-3-one steroid compound.
Summary of the Invention
Accordingly, it is a primary object of the present invention to provide an improved method of preparing a 17β-N-tert-butylcarbamoyl-3-one steroid derivative, an intermediate in the preparation of finasteride, under a mild condition in a high purity and yield.
In accordance with one aspect of the present invention, there is provided a method of preparing a 17β-N-tert-butylcarbonyl-3-one steroid compound of formula (I) which comprises reacting a 17β-carboxy-3-one steroid
compound of formula (III) with a pivaloyl halide of formula (IN) to obtain a pivaloyl acid anhydride of formula (N) and reacting the pivaloyl acid anhydride of formula (V) with t-butylamine in an organic solvent in the presence of a base:
O CH3
II I
Y-C-C— CH3 I
CH3 (IV)
wherein X is CH2, CH, NH or N; ^^^ is a single or double bond; and Y is Cl, Br or I.
Detailed Description of the Invention
A 17β-carboxy-3-one steroid compound of formula (III) may be prepared in accordance with the method disclosed in [J. Med. Chem., 29, p2298, (1986)] or US Patent No. 4,760,071.
Pivaloyl halide of formula (IN) which is commercially available or prepared in accordance with the known methods in the art (See Beil, 2, 320), may be employed in an amount ranging from 1.0 to 2.0 equivalents, preferably from 1.1 to 1.3 equivalents, based on the amount of the 17β-carboxy-3-one steroid compound of formula (III).
The organic solvent employed in the present invention may be any one of the conventional organic solvents including methylene chloride, chloroform, tetrahydrofuran and dimethylformamide. The base employed in the present invention may be aniline, triethylamine, n-tributylamine, t-butylamine, Ν,Ν- dimethylaniline, pyridine, N,N-dimethylaminopyridine, benzylamine, cyclohexylamine dicyclohexylamine or a mixture thereof, preferably triethylamine. The base is employed in an amount ranging from 0.5 to 3.0 equivalents, preferably from 0.7 to 1.2 equivalents, based on the amount of the 17β-carboxy-3-one steroid compound of formula (III).
The pivaloyl acid anhydride of formula (V) which is formed by reacting the compound of formula (III) with the compound of formula (IN) may be reacted with t-butylamine without the isolation thereof from the reaction mixture. Since the pivaloyl acid anhydride is not sensitive to water, the
reaction does not require an anhydrous condition. t-butylamine is employed in an amount ranging from 1.0 to 4.0 equivalents, preferably from 1.5 to 2.5 equivalents, based on the amount of the 17β-carboxy-3-one steroid compound of formula (III).
The inventive reaction may be performed at a temperature ranging from -10 to 30 °C , preferably from -5 to 20 °C for a period sufficient to complete the reaction, e.g., about from 3 to 6 hours.
In accordance with the present invention, a 17β-(N-butylcarbamoyl)-3- one steroid compound of formula (I) can be easily obtained in a high purity of at least 98%, via a simple process conducted under a mild reaction condition.
The present invention is further described in the following Examples which are given only for the purpose of illustration, and are not intended to limit the scope of the invention.
Example 1: Preparation of 17β-(N-tert-butylcarbamoyl)-andiOst-4-en-3-one
3.16 g (10 rnmol) of androst-4-en-3-one-17β-carboxylic acid (a compound of formula (III)) and 1 ml of triethylamine were dissolved in 50 ml of methylen chloride and 1.45 g (12 rnmol) of pivaloyl chloride was slowly added thereto at about 0°C . The mixture was stirred at a temperature ranging from 5 to 10°C for 1 hour and 1.46 g (20 rnmol) of t-butylamine was slowly added thereto. This mixture was then stirred at room temperature for 2 hours, cooled to 0°C , and, thereafter, 50 ml of IN HCl was added thereto. The organic layer was separated, dried over anhydrous MgS0 , filtered, concentrated under a reduced pressure, and then purified by column chromatography to obtain 3.45 g of the title compound as a pale white powder
(Yield: 93%). The product was analyzed to have the following characteristics: H-NMR(δ, CDC13): 0.62(3H,s,18-CH3), 0.91(3H,s,19-CH3), 1.20~
1.27(4H,m,cyclo-CH), 1.25(9H,3,t-Bu), 1.29 ~2.11(10H,m,cyclo-CH), 2.43 ~
2.48(2H,m,2-CH2), 5.13(lH,bs,-NH), 5.74(lH,s,4-CH)
Example 2: Preparation of 17β-(N-tert-butylcarbamoyl)-4-aza-androst-5-en-3- one
3.17 g (10 mmol) of 4-aza-androst-5-en-3-one-17β-carboxylic acid (a compound of formula (III)) and 1 ml of triethylamine were dissolved in 60 ml of tetrahydrofuran at room temperature. Then the mixture was cooled to about 0°C and 1.45 g (12 mmol) of pivaloyl chloride (a compound of formula (IN)) was slowly added thereto. The mixture was then stirred at 5 to 10 °C for 2 hours and 1.46 g (20 mmol) of t-butylamine was added thererto. The reaction mixture was stirred at room temperature for 2 hours, cooled to 0°C, and then 50 ml of IN HCl was added thereto. The organic layer was separated, dried over anhydrous MgS04, filtered, concentrated under a reduced pressure, and then purified by column chromatography, to obtain 3.38 g of the title compound as a pale white powder (Yield: 91%), having the following characteristics: H-ΝMR(δ, CDC13): 0.69(3H,s,18-CH3), 0.86(3H,s,19-CH3), 1.05 ~ 1.27(4H,m,cyclo-CH), 1.29(9H,3,t-Bu), 1.32~2.15(10H,m,cyclo-CH), 2.51 ~ 2.55(2H,m,2-CH2), 4.81(lH,s,6-CH), 5.19(lH,bs,-NH), 5.87(lH,bs,-NH)
Example 3: Preparation of 17β-(N-tert-butylcarbamoyl)-4-aza-5α-androstan-3- one
H-ΝMR(δ, CDC13): 0.71(3H,s,18-CH3), 0.92(3H,s,19-CH3), 1.05 ~ 1.27(4H,m,cyclo-CH), 1.25(9H,3,t-Bu), 1.30~2.10(10H,m,cyclo-CH), 2.47 ~ 2.51(2H,m,2-CH2), 3.35(lH,dd,5α-CH), 5.38(lH,bs,-NH), 5.89(lH,bs,-NH)
Reference Example: Preparation of 17β-(N-tert-butylcarbamoyl)-5α-4-aza- androst-l-en-3-one (finasteride)
3.74 g (10 mmol) of 17β-(N-tert-butylcarbamoyl)-4-aza-5α-androstan- 3 -one obtained in Example 3 and 5.04 g (14 mmol) of benzeneseleninic anhydride were suspended in 10 ml of chlorobenzene. The suspension was refluxed for 3 hours using a Dean-stark apparatus and then concentrated under a reduced pressure to obtain a dark brown residue. The residue was diluted with 100 ml of methylene chloride, washed with 50 ml of saturated sodium bicarbonate and 50 ml of saturated brine. Then the residue was dried over anhydrous MgS04, filtered, and the solvent was removed. The residue was subjected to column chromatography and the product was recrystallized in methylene chloride/ethyl acetate, to obtain 2.83 g of the title compound as a
white crystalline (Yield: 76%), having the following properties: Melting point (mp): 256~258 °C
H-NMR(δ, CDC13): 0.73(3H,s,18-CH3), 0.99(3H,s,19-CH3), 1.05 - 1.27(4H,m,cyclo-CH), 1.27(9H,3,t-Bu), 1.30~2.10(10H,m,cyclo-CH), 3.33(lH,dd, 5α-CH), 5.31(lH,bs,-NH), 5.82(lH,dd,2-CH), 5.93(lH,bs,-NH), 6.81 (1 H,dd,1 -CH)
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which may also fall within the scope of the invention as defined by the appended claims.
Claims
1. A method of preparing a 17β-N-tert-butylcarbamoyl-3-one steroid compound of formula (I), which comprises (i) reacting a compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (V) and (ii) then reacting the compound of formula (V) with t-butylamine in an organic solvent in the presence of a base:
O CH3
II I
Y-C— C— CH3 CH3 (IV) 
wherein X is CH2, CH, NH or N; zz::z represents a single or double bond; and Y is Cl, Br or I.
2. The method of claim 1, wherein steps (i) and (ii) are conducted continuously without isolating the compound of formula (V).
3. The method of claim 1, wherein the compound of formula (IN) is employed in an amount ranging from 1.0 to 2.0 equivalents based on the amount of the compound of formula (III).
4. The method of claim 1, wherein t-butylamine is employed in an amount ranging from 1.0 to 4.0 equivalents based on the amount of the compound of formula (III).
5. The method of claim 1, wherein the base is selected from the group consisting of aniline, triethylamine, n-tributylamine, t-butylamine, Ν,Ν- dimefhylaniline, pyridine, N,N-dimefhylaminopyridine, benzylamine, cyclohexylamine, dicyclohexylamine and a mixture thereof.
6. The method of claim 1 or 5, wherein the base is employed in an amount ranging from 0.5 to 3.0 equivalents based on the amount of the compound of formula (III).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2001-0058825A KR100415858B1 (en) | 2001-09-22 | 2001-09-22 | PROCESS FOR THE PREPARATION OF 17β-(N-TERT-BUTYLCARBAMOYL)-3-ONE STEROID COMPOUND |
| KR2001/58825 | 2001-09-22 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| WO2003027132A2 true WO2003027132A2 (en) | 2003-04-03 |
| WO2003027132A3 WO2003027132A3 (en) | 2003-11-06 |
| WO2003027132A8 WO2003027132A8 (en) | 2004-04-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2002/001776 Ceased WO2003027132A2 (en) | 2001-09-22 | 2002-09-19 | METHOD OF PREPARING 17β-(N-TERT-BUTYLCARBAMOYL)-3-ONE STEROID DERIVATIVES |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR100415858B1 (en) |
| WO (1) | WO2003027132A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010062506A3 (en) * | 2008-10-28 | 2010-10-07 | Lead Therapeutics, Inc. | Decahydro-1h-indenoquinolinone and decahydro-3h-cyclopentaphenanthridinone cyp17 inhibitors |
| WO2011004242A3 (en) * | 2009-07-09 | 2011-04-21 | Aurobindo Pharma Limited | An improved process for the preparation of dutasteride |
| CN102532236A (en) * | 2012-01-05 | 2012-07-04 | 中国药科大学 | Steroidal 5α-reductase inhibitor, its preparation method and its medical use |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100698400B1 (en) | 2004-04-14 | 2007-03-23 | 이은주 | Pharmaceutical composition for the treatment of alopecia and prostatic hyperplasia |
| MXPA06011870A (en) | 2004-04-14 | 2006-12-14 | Lee Eunjoo | Pharmaceutical composition for treating hair loss and benign prostatic hyperplasia. |
| KR101036688B1 (en) * | 2009-06-10 | 2011-05-23 | 이규휘 | Infant Teaching Tool |
| KR101103459B1 (en) * | 2010-08-18 | 2012-01-09 | 이규휘 | Infant Teaching Tool |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4760071A (en) * | 1984-02-27 | 1988-07-26 | Merck & Co., Inc. | 17β-N-monosubstituted carbamoyl-4-aza-5α-androst-1-en-3-ones which are active as testosterone 5α-reductase inhibitors |
| US5468860A (en) * | 1992-11-19 | 1995-11-21 | Merck & Co., Inc. | New finasteride processes |
| US5670643A (en) * | 1995-03-16 | 1997-09-23 | Glaxo Wellcome Inc. | Method for preparing finasteride |
| US5777134A (en) * | 1995-10-26 | 1998-07-07 | Merck & Co., Inc. | 4-oxa and 4-thia steriods |
| ES2153789B1 (en) * | 1999-07-05 | 2001-10-16 | Raga Consultores S L | PROCEDURE FOR OBTAINING 178- (N-TERC-BUTLCARBAMOIL) -3-ONA-4-AZA-STEROIDS |
-
2001
- 2001-09-22 KR KR10-2001-0058825A patent/KR100415858B1/en not_active Expired - Fee Related
-
2002
- 2002-09-19 WO PCT/KR2002/001776 patent/WO2003027132A2/en not_active Ceased
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010062506A3 (en) * | 2008-10-28 | 2010-10-07 | Lead Therapeutics, Inc. | Decahydro-1h-indenoquinolinone and decahydro-3h-cyclopentaphenanthridinone cyp17 inhibitors |
| WO2011004242A3 (en) * | 2009-07-09 | 2011-04-21 | Aurobindo Pharma Limited | An improved process for the preparation of dutasteride |
| CN102532236A (en) * | 2012-01-05 | 2012-07-04 | 中国药科大学 | Steroidal 5α-reductase inhibitor, its preparation method and its medical use |
| CN102532236B (en) * | 2012-01-05 | 2014-04-16 | 中国药科大学 | Steroidal 5α-reductase inhibitor, its preparation method and its medical use |
Also Published As
| Publication number | Publication date |
|---|---|
| KR100415858B1 (en) | 2004-01-24 |
| WO2003027132A3 (en) | 2003-11-06 |
| KR20030025669A (en) | 2003-03-29 |
| WO2003027132A8 (en) | 2004-04-29 |
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